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Cardiac diseases

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Cardiac diseases

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Cardiac diseases

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Cardiac diseases

2.1 Atherosclerosis

2.1.1 Development of atherosclerosis

Atherosclerosis is a leading cause of morbidity and mortality in industrialized countries. It is an illness that remains asymptomatic for decades. Clinical symptoms do not appear until an advanced stage, by which time it is too late for preventive measures. Atherosclerosis is a multifactorial disease whose development depends on hereditary and acquired risk factors. The main clinical manifestations of atherosclerosis are coronary heart disease, cerebrovascular disease, and peripheral arterial occlusive disease. The pathogenesis of atherosclerosis is most commonly explained using the “response to injury” model, which combines components of the once controversial lipid and inflammation theories.

Atherosclerosis risk /1/

Important risk factors include genetic factors, age, gender, dyslipidemia, hypertension, smoking, chronic inflammation, diabetes mellitus, and chronic renal disease. These risk factors lead to vascular endothelial dysfunction. An individual’s risk of disease depends on the interplay between genetic factors, preexisting medical conditions, and lifestyle. This is one reason why the negative impact of an unhealthy lifestyle differs between individuals.

Biomarkers: cholesterol (LDL), triglycerides, Lp(a), HbA1c or oral glucose tolerance test, homocysteine, C-reactive protein, and creatinine.

Mechanisms of atherosclerosis /12/

Atherosclerotic plaques develop over the course of decades. In contrast the thrombotic complications of atherosclerotic disease occur suddenly, often without warning. Atheroscerotic plaques destabilize without resulting in a clinical syndrome The occurence of an acute coronary syndrome probably depends on the disruption of a balance between instability and healing of an atherosclerotic plaque.The two most frequent causes of thrombosis are plaque rupture and superficial erosion. Plaque rupture occurs when the fibrous cap covering the necrotic core fissures, exposing the highly thrombogenic core to the blood. Plaque erosion is caused by endothelial damage or denudation and overlying thrombosis in the absence of frank cap rupture.

Low-density lipoproteins (LDL) pass into the intima of arteries from where they are removed by the high-density lipoprotein (HDL) reverse transport process and macrophages if blood cholesterol levels are normal. According to the “response to retention” hypothesis, atherosclerosis develops as a result of LDL retention in the intima of arteries. The exudation of LDL into the intima is facilitated by vascular endothelial dysfunction caused by risk factors such as hypercholesterolemia, smoking, hypertension, and hyperglycemia. The cholesterol removal system is also overloaded.

LDL that has accumulated in the intima is oxidized (oxLDL) or enzymatically modified (eLDL). The oxLDL or eLDL activates the innate immune system. A local inflammatory response occurs and an atherosclerotic lesion (atherosclerotic plaque) develops. As a result of the migration of inflammatory cells, the continuous accumulation of LDL, and the multiplication of local cells and connective tissue elements, the intima expands and the vessel wall thickens, first eccentrically and later concentrically. This latter process leads to local stenosis. Atherosclerotic plaques, characterized by marked intimal lipid accumulation and cell debris and a thin fibrous cap, are particularly prone to rupture.

Contact between the blood and the macrophages and activated endothelial cells releases tissue factors and contact with lipids and collagen of the exposed intima triggers platelet aggregation and activates clotting. The resulting acute partial vascular occlusion can cause acute cerebrovascular syndrome, unstable angina pectoris, myocardial infarction, sudden unexplained cardiac death, or stroke.

LDL starts to accumulate in the intima in the form of fatty streaks as early as the first years of life and continues to do so as shown by the FELIC study, faster in children of mothers with hypercholesterolemia than in children of mothers with normal cholesterol levels /3/. Atherosclerotic plaques do not develop until the age of 12–16 years.

2.1.2 Diseases caused by atherosclerosis

Acute coronary syndrome (ACS)

In the setting of a clinical presentation with ACS on the basis of the history, electrocardiogram and biochemical markers a case is classified as ST-segment elevation (STEMI), non-STEMI or non ischemic chest pain. The usual initiating mechanism for acute myocardial infarction (AMI) is rupture or erosion of a vulnerable, lipid-laden atherosclerotic coronary plaque, resulting in exposure of circulating blood to highly thrombogenic core and matrix materials in the plaque. The inflammatory reaction in the plaque that leads to the rupture of its fibrous cap plays an important role. The inflammation activates the prothrombotic potential and inhibits the antifibrinolytic capacity of the hemostatic system and triggers thrombus formation on the plaque /4/.

Cerebrovascular atherosclerosis: ischemia is present in around 85% of strokes, mainly triggered by embolizing thrombi from the heart or carotid arteries.

2.1.2.1 Primary prevention of coronary heart disease

The goal of primary prevention is to prevent the occurrence of cardiovascular diseases. Independent, classic risk factors include age, male gender, smoking, family history of atherosclerotic vessel disease, diabetes mellitus, hypertension, hypercholesterolemia, high LDL cholesterol, and hypertriglyceridemia. A distinction is made between global risk (clinical significance of multiple risk factors in a risk profile) and the risk associated with a single, extremely elevated risk factor. Important isolated risk factors include the following:

  • Cholesterol: individuals whose total cholesterol is ≥ 320 mg/dL (8.0 mmol/L) or LDL cholesterol is ≥ 240 mg/dL (6.22 mmol/L) are considered high-risk patients /5/. With respect to global risk assessment, an LDL cholesterol concentration of 100 mg/dL (2.6 mmol/L), 130 mg/dL (3.4 mmol/L), or 160 mg/dL (4.1 mmol/L), depending on the estimated risk or score value, requires treatment.
  • Hypertension: patients whose blood pressure is higher than 180/110 mmHg are considered high-risk patients /5/. When global risk is assessed, a blood pressure ≥ 140/80 mmHg is considered pathological.

2.1.2.2 Risk stratification using algorithms and scores

With a view to preventing cardiovascular diseases, an individual’s global risk is determined and different risk factors are combined using algorithms or scores (Tab. 2.1-1 – Assessment of cardiovascular risk using algorithms and scores). The most widely recognized algorithms and scores have been derived from the German PROCAM study /6/ and the US Framingham study /7/. The ESC (European Society of Cardiology) score, the latest version of which was published in 2011, is widely used in Europe. The ESC score takes gender, age, smoking, blood cholesterol, blood pressure, and diabetes into account; the Framingham score considers gender, smoking, HDL cholesterol, blood pressure and family history; the PROCAM score also takes triglycerides and LDL cholesterol (rather than total cholesterol) into account.

Based on the severity of the risk factors, algorithms and scores are used to calculate a percentage 10-year risk of fatal or non-fatal myocardial infarction (PROCAM, Framingham) or death due to cardiovascular disease (European Society of Cardiology; ESC). The clinical significance of this risk is assessed as follows:

  • Scores above 20% (PROCAM, Framingham) or 5% (ESC) identify high-risk patients
  • Scores of 10–20% (PROCAM, Framingham) or 1–5% (ESC) indicate moderate risk
  • Scores below 10% (PROCAM, Framingham) or 1% (ESC) indicate low risk.

High-risk patients also include individuals with diabetes mellitus and manifest atherosclerosis and those with a history of the following preexisting conditions:

  • Stable or unstable angina pectoris
  • Myocardial infarction
  • Coronary artery bypass grafting or angioplasty
  • Abdominal aortic aneurysm
  • Ischemic stroke and transient ischemic attacks as well as carotid stenosis.

Strategies for prevention and treatment can be derived from the scores. Patients in the low-risk group should be encouraged to make lifestyle changes, patients at moderate risk should be strongly encouraged to make such changes and may also require medication, and intensive measures should be taken to reduce all risk factors in the high-risk group. The significance of the different scores varies. For example, the Framingham risk algorithm overestimates the risk of coronary heart disease by more than double for German men, whereas it is more reliable for the American population.

Overall, the algorithms and scores have a relatively good negative predictive value of over 90% for identifying low-risk patients. However, there is a significant false positive rate among individuals with moderate and high risk. A score for the assessment of the 10 years mortality risk is shown in Fig. 2.1-1 – European Society of Cardiology cardiovascular risk score.

2.1.2.3 New biomarkers

New markers for the primary prevention of coronary heart disease are being discussed (Tab. 2.1-2 – New risk markers for the primary prevention of cardiovascular disease (CVD)/8/. These are known as “emerging markers.” Although some of these markers are statistically associated with cardiovascular risk (independently of the classic risk markers), they do not improve the prognostic efficiency of the algorithms derived from the classic risk factors, or they improve them marginally at most. In the current recommendations for primary prevention, therefore, their use is restricted to the sub stratification of medium-risk patients.

2.1.3 Pathophysiology of atherosclerosis

One popular hypothesis is that risk factors such as hypertension, cigarette smoking, insulin resistance, and type 2 diabetes lead to vascular endothelial damage and that LDL then accumulates in the vessel wall, where it is modified enzymatically or oxidatively. The modified LDL initiates and maintains an inflammatory response that leads to progression of the atherosclerosis and rupture of atherosclerotic plaques. There are three phases in the development of atherosclerosis /115/:

  • Initiation of atherosclerosis
  • Progression to atherosclerotic plaque
  • Plaque rupture and acute coronary syndrome.

Initiation of atherosclerosis

LDL accumulates in the arterial intima to form fatty streaks. These are asymptomatic and can disappear again or develop into atherosclerotic plaques. The LDL in the fatty streaks is sequestered from antioxidants in the blood, which promotes oxidation or chemical modification of the LDL. The modified LDL induces a local inflammatory response.

Leukocyte adhesion is another factor that contributes to the initiation of atherosclerosis. Leukocytes do not normally adhere to endothelial cells. However, pro inflammatory stimuli such as the risk factors for atherosclerosis or modified LDL trigger the expression of P-selectin and vascular cell adhesion molecules such as VCAM-1, which mediate reversible rolling or irreversible adhesion of lymphocytes and monocytes to the endothelium. Leukocyte binding to VCAM-1 and ICAM-1 activates signal transduction, which ultimately triggers the opening of intercellular junctions and diapedesis of the leukocytes through the endothelium.

The differentiation of intimal monocytes increases under the influence of inflammatory mediators and monocytes mature into macrophages under the influence of macrophage colony-stimulating factors. Oxidative enzymes (e.g., myeloperoxidase, NADPH peroxidase, inducible nitric oxide synthase, or lipoxygenases) as well as macrophage lipases and proteases intensify LDL modification. The modified LDL is taken up in an uncontrolled manner by scavenger receptors on macrophages. The cholesterol of the modified LDL is stored in cytosolic vacuoles in the form of cholesterol esters. The cholesterol-laden cells are known as “foam cells” due to their appearance on electron microscopy. These exacerbate inflammation by producing growth factors and inflammatory cytokines and chemokines, which in turn stimulate the further migration of monocytes and lymphocytes into the intima as well as the proliferation and migration of smooth muscle cells in the media. The migrating cells also include CD4+T-cells , which mediate a helper T-cell adaptive immune response.

The presence of foam cells and the development of atheromas mark the first phase of atherosclerosis (Fig. 2.1-2 – Initiation of atherosclerotic plaques).

Progression to a complex atherosclerotic lesion

While fatty streaks contain mainly foam cells, atheromatous plaques, which represent an advanced stage of atherosclerosis, are characterized by the presence of fibrous material (Fig. 2.1-3 – Progression to atherosclerotic plaque). The extracellular matrix of the plaque consists predominantly of smooth muscle cells. Activated by the platelet-derived growth factor (PDGF) produced by macrophages and endothelial cells and other mediators, the smooth muscle cells proliferate and migrate from the media to the intima, which results in the degradation of the extracellular matrix. The degradation is mediated by MMP-9 and other proteases. In the intima, the smooth muscle cells produce extracellular matrix proteins such as collagen. Atheromas produce increased amounts of interleukin-18, which in turn stimulates the production of interferon gamma by macrophages, T-cells, and smooth muscle cells, thereby maintaining the inflammatory response.

In the next step, the plaque, which is hypoxic due to its thickness, is vascularized by the vasa vasorum. Local bleeding occurs with the release of thrombin. This stimulates endothelial cells, smooth muscle cells, macrophage, and platelets to produce inflammatory markers such as CD40 ligand and RANTES (regulated on activation, normal T-cell expressed and secreted) and macrophage migration inhibitor factor (MIF). The effects of CD40 ligand, RANTES, and MIF promote plaque progression and possibly rupture of the fibrous cap with subsequent thrombus formation. Platelets are also involved in the synergistic interaction between inflammation and thrombosis by producing CD40 ligand and PDGF.

Plaque rupture and acute coronary syndrome /4/

The lipid-rich center of an atheromatous plaque (also known as the necrotic core) is covered by a fibrous cap. This prevents contact between the blood with its latently activated clotting potential and the lipid-rich center that contains some thrombogenic material. The fibrous cap is often only μm thick. Ruptured plaques usually have a large, lipid-rich core and contain many inflammatory cells and spotty or patchy calcification.

The fibrous cap, which protects the atheromatous plaque from rupture, consists of fibrillar collagen produced by smooth muscle cells in the artery wall. The stability of the fibrous cap depends on the balance between collagen synthesis and breakdown.

Inflammatory cells such as activated CD4+T-helper cells have a significant influence on the integrity of the fibrous cap:

  • By synthesizing IFN-γ, CD4+T-helper cells inhibit the production of fibrillar collagen by smooth muscle cells
  • By synthesizing CD40-ligand (CD154), which activates the corresponding CD40 receptor on macrophages, they stimulate the macrophages to increase the production of matrix metalloproteinases (MMP). The interstitial collagenases MMP-1, MMP-8, and MMP-13 in particular degrade fibrillary collagen and, by doing so, destroy the integrity of the fibrous cap.
  • In summary, inflammation in the atheromatous plaque causes progressive thinning of the fibrous cap, which can lead to plaque rupture, thrombosis, and acute coronary syndrome.

2.1.3.1 Important new markers of atherosclerosis

New biomarkers have been recommended for the primary prevention of atherosclerosis and coronary heart disease. They are referred to as emerging markers because, although they are associated with increased risk, their causative, independent, and quantitative contributions are not as well documented as those of established criteria such as dyslipidemia, hypertension, and smoking. In addition, it has become evident that these markers and other mediators do not provide an advantage either for the early diagnosis of myocardial infarction (when compared to the necrosis marker troponin) or for risk management /15/. The pathophysiology of new biomarkers is described in Tab. 2.1-2 – New risk markers for the primary prevention of cardiovascular disease (CVD).

2.1.3.2 Clinical consequences of atherosclerosis

The sclerosis of coronary vessels is not a continuous process, but a disease that is characterized by alternating clinical phases of stability and instability. Acute coronary syndromes such as unstable angina pectoris and myocardial infarction are due to an acute or subacute reduction in myocardial oxygen supply caused by the rupture of an atherosclerotic plaque in combination with vasoconstriction, coronary thrombus formation, and distal coronary micro-embolization /10/.

Whether myocardial necrosis develops in the area depends on the extent and duration of the reduced oxygen supply. Although the vessel is initially occluded as a result of platelet aggregation, fibrin must also be produced to stabilize the aggregation and form a thrombus. By secreting serotonin and thromboxane A2, platelet-rich thrombi induce vasoconstriction at the site of the plaque rupture or more distally.

If embolization to distal arterioles and capillaries occurs as a result of an epicardial coronary artery thrombosis, focal micro necroses occur that can be demonstrated histologically and by means of a high sensitivity troponin assay. Small embolisms can cause micro necroses in the absence of epicardial coronary artery occlusion. As a result of blood stasis, fibrin-rich apposition thrombi can develop and occupy large areas of a vessel proximal and distal to a platelet-rich occlusive thrombus that was formed as the result of a plaque rupture.

2.1.3.3 Diabetes mellitus and atherosclerosis

Atherosclerotic vascular complications are the main causes of disability and mortality in patients with type 2 diabetes. The prevalence of coronary heart disease, stroke, and peripheral arterial occlusive disease is 2–4 times higher in these patients than in the general population. Traditional risk factors are:

  • Hypertonia (test: blood pressure measurement)
  • Hyperglycemia (tests: fasting glucose, HbA1c, glucose tolerance)
  • Dyslipidemia (cholesterin, LDL, triglycerides).

Pathophysiology of dysfunctions in patients with atherosclerosis:

  • Insulin resistance (tests: HOMA, leptin, adiponectin)
  • Destruction of islet cells (tests: insulin, proinsulin, glucagon)
  • Inflammation of adipose cells (tests: CRP, TNF-alpha, etc.).

Vascular complications in type 2 diabetics can be quantified as follows:

  • One in four patients shows signs of reduced cardiac perfusion, one in three has silent myocardial ischemia, and one in nine shows angiographic evidence of coronary stenosis /12/.
  • One-third of strokes in women and one-sixth of strokes in men can be linked to diabetes.
  • The prevalence of peripheral arterial occlusive disease is twice as high in diabetics as in the general population /16/.

References

1. Napoli C, Lilach O, Lerman FN, Gossl M, Balestrier ML, Lerman A. Rethinking primary prevention of atherosclerosis-related diseases. Circulation 2006; 114: 2517–27.

2. Vergalo R, Crea F. Atherosclerotic plaque healing. N Engl J Med 2020; 383: 846–57.

3. Napoli C, Glass CK, Witztum JL, Deutsch R, D’Armiento FP, Palinski W. Influence of maternal hypercholesterinemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 1999; 354: 1234–41.

4. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013; 368: 2004–12.

5. Pearson TA, Bazzarre TL, Daniels SR, Fair JM, Fortmann SP, Franklin BA, et al. American Heart Association guide for improving cardiovascular health at the community level: a statement for practice health practitioners, healthcare providers, and health policy makers from the American Heart Association Expert Panel on Population and Prevention Science. Circulation 2003; 107: 645–51.

6. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculation of the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Münster (PROCAM) study. Circulation 2002; 105: 310–5.

7. Wilson PW, D’Agostino RB, Belanger AM, Silberschatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837–47.

8. Apple FS, Smith SW, Pearce LA, Murakami MM. Assessment of the multiple-biomarker approach for diagnosis of myocardial infarction in patients presenting with symptoms suggestive of acute coronary syndrome. Clin Chem 2009; 55: 93–100.

9. Reiner Z, et al. ESC/EAC guidelines. Eur Heart J 2011; 32: 1769–1818.

10. Myers GL, Christenson RHM, Cushman M, Ballantyne CM, Cooper GR, Pfeiffer CM, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines: Emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem 2009; 55: 378–84.

11. US Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: US preventive services task force recommendation statement. Ann Intern Med 2009; 151: 474–82.

12. Murphy MJ, Hosking J, Metcalf BS, Voss LD, Jeffery AN, Sattar N, et al. Distribution of adinopectin, leptin, and metabolic correlates of insulin resistance: a longitudinal study in British children; 1. prepuberty (early bird 15). Clin Chem 2008; 54: 1298–1306.

13. Scirica BM, Sabatine MS, Jarolim P, Murphy SA, de Lemos JL, Braunwald E, Morrow DA. Assessment of multiple cardiac biomarkers in non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 trial. Eur Heart J 2011; 32: 697–705.

14. De Winther MPJ, Lutgens E. The link between hematopoiesis and atherosclerosis. N Engl J Med 2019; 380, 19: 1869–701.

15. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med 2000; 343: 16–22.

16. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, et al. Peripheral arterial disease detection, awareness and treatment in primary care. JAMA 2001; 286: 1317–24.

2.2 Metabolic vascular syndrome

The metabolic vascular syndrome (MVS) was first described as the coexistence of obesity, hyper-, and dyslipidemia, type 2 diabetes, gout and hypertension, associated with an increased incidence of atherosclerotic vascular diseases, fatty liver disease, and cholelithiasis due to a "common soil" of super nutrition and physical inactivity, and a genetic predisposition /12/.

The pathophysiological features of the MVS are:

  • Abdominal (central) obesity
  • Atherogenic dyslipidemia
  • Hypertension
  • Impaired glucose tolerance or type 2 diabetes.

Metabolic syndrome is diagnosed if three or more of the following findings are present:

  • Hyperglycemia
  • Elevated triglycerides
  • Low HDL cholesterol
  • Arterial hypertension
  • Visceral obesity.

Taken together, the features of the metabolic syndrome form an atherogenic network that increases the risk of non-alcoholic fatty liver disease, of diabetes mellitus and cardiovascular morbidity and mortality. In a study of 12,659 children with a mean age of 11.3 years, mortality rates up to the 55th year of life were 78% higher among children in the highest quartile of the cohort than those among children in the lowest quartile /3/. The assessment criteria were body mass index, hypertension, glucose intolerance, and serum cholesterol. In another study of overweight schoolchildren between the ages of 8 and 14 years, 6.5% had three or more features of the metabolic syndrome /4/.

The prevalence of the MVS is age-dependent and shows regional variation. In the USA /5/, it has a prevalence of 7%, 44%, and 42% in the age groups 20–29 years, 60–69 years, and over 70 years respectively, while in Hong Kong, the prevalence is only 6%. The prevalence of the metabolic syndrome in Germany is 22.7% among men and 18% among women /6/.

The MVS is not a single disease entity, but rather a constellation of interconnected clinical and laboratory findings that are associated with diabetes mellitus and coronary heart disease.

The definitions of the metabolic vascular syndrome are different (Tab. 2.2-1 – Definition of the metabolic vascular syndrome). The criteria have different cutoff values and different perspectives. The different perspectives are as follows /7/:

  • The NCEP defines the metabolic syndrome as a true syndrome, that is, a group of cardiovascular risk factors related to atherosclerosis that probably have more than one cause
  • According to the IDF definition, the metabolic syndrome has a specific cause and obesity is an earlier step in the etiological cascade
  • Many authors are of the opinion that a cluster of factors independent of obesity is responsible for cardiovascular risk in the metabolic syndrome and that insulin resistance plays an important etiological role.

The criteria for the diagnosis of the MVS are listed in Tab. 2.2-1 – Definition of the metabolic vascular syndrome. In the population, however, the specific predictive models recommended for coronary heart disease and type 2 diabetes are better criteria to identify persons at increased risk of these diseases than the criteria for metabolic syndrome. This has been demonstrated by the San Antonio Heart Study and the Mexico City Diabetes Study /8/. In these studies, the Framingham Risk Score was better than the criteria for metabolic syndrome for predicting the risk of cardiovascular disease /9/ and the Diabetes Predicting Model /10/ was better for predicting the risk of type 2 diabetes. Furthermore, after adjustment for diabetes, the metabolic syndrome does not improve the prediction of mortality in preexisting cardiovascular disease /11/. In individuals who have the metabolic syndrome according the NECP-ATP III definition, most studies show an increased cardiovascular risk with a mean hazard ratio of 1.6 /12/. Depending on the definition of the metabolic syndrome, the risk of cardiovascular mortality is 2.09–1.51 for men and 1.53–1.09 for women /12/.

In addition to dyslipidemia, diabetes, and hypertension, chronic inflammation of adipose tissue also acts as a link between the MVS and cardiovascular disease /13/

Refer to:

2.2.1 Adipokines

The term adipokines (adipose tissue cytokines) describes a group of polypeptides that are mainly, though not exclusively, secreted by adipose tissue /141516/. While adipokines are secreted into the circulation specifically by adipocytes, cytokines are also secreted by other cells in the adipose tissue such as macrophages, fibroblasts, and infiltrated monocytes. The adipocytes in adipose tissue make up around one-third of the cells in the body and have the following important functions:

  • Energy storage
  • Hydrolysis of triglycerides and production of free fatty acids to supply energy to tissues
  • Adipokine release. The main adipokines are leptin, resistin, and adiponectin.

Adipokines are involved in important physiological functions such as carbohydrate and fat metabolism, insulin sensitivity, appetite regulation, inflammatory processes, and cardiac function.

Ectopic adipose tissue, which in obese individuals is found mainly in the visceral fat of the omentum as well as the epicardial and mediastinal fat, plays an important role in adipokine production. Ectopic adipose tissue is responsible for the pathogenesis of many obesity-related diseases.

2.2.1.1 Adiponectin

Adiponectin is a peptide with a molecular weight of 30 kDa that circulates in the plasma in complexes of various sizes. Complexes with high molecular weight are the most active. Plasma adiponectin concentration is inversely related to obesity, insulin resistance, type 2 diabetes, and cardiovascular disease /1718/.

Pathophysiology: adiponectin exerts its effect via two receptors. The ADIPOR1 receptor is expressed by skeletal muscle and other tissues while the ADIPOR2 receptor is expressed by hepatocytes. Adiponectin inhibits hepatic glucose production and lipogenesis, stimulates insulin secretion, glucose uptake in the muscles, and fatty acid oxidation in the liver and muscles, modulates food intake and energy consumption, and inhibits the production of proinflammatory cytokines. Its secretion is stimulated by insulin sensitizers such as roglitazone. Adiponectin inhibits inflammation by stimulating the secretion of IL-10, blocks the activation of nuclear factor κB (see also Fig. 19.1-1), and inhibits the release of IL-6 and TNF-α. Conversely, adiponectin secretion is inhibited by inflammation, and the low-grade adipose inflammation in obese individuals in particular reduces its plasma concentration. In this way, adiponectin can be seen as a negative modulator of the systemic inflammation that characterizes the metabolic syndrome.

Indication: possible marker for assessing the risk of insulin resistance and coronary heart disease in obese individuals.

Specimen: serum: 1 mL

Reference interval: 7–12 mg/L, depending on the assay used /19/.

Clinical significance: adiponectin is an important marker for cardiovascular risk because it disrupts the dangerous cycle of inflammatory vascular damage that is associated with atherosclerosis and type 2 diabetes. Values below 4 mg/L are associated with a significant risk of atherosclerosis. Treating diabetics with insulin sensitizers increases adiponectin concentrations, reduces blood glucose and HbA1C values, and reduces insulin resistance, thereby also reducing cardiovascular risk. Weight loss leads to increased adiponectin concentrations.

The adiponectin/leptin ratio can be used to distinguish between type 1 and type 2 diabetes in young people. Mean adiponectin values of 18 mg/L and an adiponectin/leptin ratio of 3.8 have been demonstrated in young people with type 1 diabetes while values of 9 mg/L and a ratio of 0.46 have been demonstrated in those with type 2 diabetes /20/.

Note: over the course of 30 days, adiponectin concentrations demonstrate intraindividual variation of /21/:

  • 12.2% in overweight individuals with metabolic syndrome (equivalent to a change of 1.7 mg/L in the reference interval)
  • 18.8% in normal individuals (equivalent to a change of 3.6 mg/L in the reference interval). In non-obese individuals, minor fluctuations only in adiponectin concentrations were observed within a period of 15 months (initial value 8.3 ± 2.9 mg/L compared to 8.2 ± 3.0 after 15 months). Diurnal and 3-hour postprandial fluctuations are small.

2.2.1.2 Leptin

Leptin is an adipocyte secretory product whose plasma concentration increases with the amount of adipose tissue in the body /1518/. It circulates as a peptide with 164 amino acids and has a molecular weight of 16 kDa.

Pathophysiology: leptin inhibits food intake, stimulates energy consumption, inhibits hepatic glucose production and fatty acid synthesis, activates fatty acid oxidation in liver and muscle, stimulates insulin secretion and glucose uptake by liver and muscle, stimulates the secretion of inflammatory cytokines, and inhibits the expression of resistin. Leptin has an overall anti-obesity effect that is mediated by hypothalamic pathways. Obese individuals have elevated leptin concentrations, which suggests that they are resistant to adipokine.

Indication: assessment of the amount of adipose tissue in relation to food intake.

Specimen: serum: 1 mL

Reference interval: 2–15 μg/L, depending on the assay used.

Clinical significance: the serum leptin concentration depends on the amount of body fat. Increases in leptin levels are governed by food intake, insulin concentration, and serum cortisol concentration. Eating causes leptin levels to rise.

The leptin concentration increases exponentially as the amount of body fat increases.

During fasting, leptin levels are low. In a study /22/, cardiometabolic biomarkers were measured in schoolchildren. Being overweight was associated with increased concentrations of leptin, CRP, and fibrinogen and reduced concentrations of ApoA1. The respective odds ratios were 59.8 (leptin), 6.3 (CRP), 2.8 (fibrinogen), and 2.6 (ApoA1).

The adiponectin/leptin ratio is being evaluated as a means of distinguishing between type 1 and type 2 diabetes in young people. Refer to Tab. 2.2-2 – Individual components of the metabolic syndrome (MetS).

Note: stable in serum at 4 °C for two months.

2.2.1.3 Resistin

Resistin received its name from the observation that it induced insulin resistance in mice. It is a 12.5 kDa peptide that belongs to the family of cysteine-rich proteins also known as resistin-like molecules (RELMs). Resistin circulates in plasma primarily in high molecular weight (hexamer) form /1518/.

Pathophysiology: resistin is produced by adipose tissue and placenta. It reduces tissue insulin sensitivity and increases glucose production in the liver. It also stimulates the synthesis of pro inflammatory cytokines such as IL-6 and TNF-α. In summary, resistin provides a link between obesity and insulin resistance. It is thought that resistin plays a role in the development of obesity and insulin resistance.

Indication: research at present.

Specimen: serum: 1 mL

Reference interval: 5–15 μg/L, depending on the assay used.

Clinical significance: in theory, the resistin concentration should rise with increasing obesity and with the development of insulin resistance and type 2 diabetes. Treatment with the insulin sensitizer roglitazone down regulates resistin. In contrast to earlier studies, however, there is growing evidence that obesity and resistin concentrations are not related.

During pregnancy, insulin sensitivity falls continuously as the fetoplacental unit develops. In one study /23/, resistin concentrations in pregnant women with and without gestational diabetes (GDM) were compared. The women with normal glucose tolerance had resistin values of 9.3 ± 1.3 μg/L and those with GDM had values of 4.3 ± 1.6 μg/L. However, no relationship was found between insulin sensitivity and resistin concentration. Other investigators have found increased resistin levels in GDM.

References

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2. Kwasny C, Manuwald U, Kugler J, Rothe U. Systematic review of the epidemiology and natural history of the metabolic vascular syndrome and its coincidence with type 2 diabetes mellitus and cardiovascular diseases in different European countries. Horm Metab Res 2017; Nov 28. https://doi.org/10.1055/s-0043-122395.

3. Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, Looker HC. Childhood obesity, other cardiovascular risk factors, and premature death. N Engl J Med 2010; 362: 485–93.

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5. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356–9.

6. Moebus S, Hanisch J, Bramlage P, Lösch C, Hauner H, Wasem J, Jöckel KH. Regional unterschiedliche Prävalenz des metabolischen Syndroms. Dtsch Ärztebl 2008; 105: 207–19.

7. Reaven G. Why a cluster is truely a cluster: insulin resistance and cardiovascular disease. Clin Chem 2008; 54: 785–7.

8. Haffner SM. Hypertension in the San Antonio Heart Study and the Mexiko City Diabetes Study: clinical and metabolic correlates. Public Health Rep 1996; 111 (suppl2) 11–14.

9. Wilson PWF, D’Àgostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837–47.

10. Stern MP, Williams K, Haffner SM. Identification of individuals at high risk of type 2 diabetes: do we need the glucose tolerance test? Ann Intern Med 2002; 136: 575–81.

11. Stern MP, Williams K, Hunt KJ. Impact of diabetes/metabolic syndrome in patients with established cardiovascular disease. Atherosclerosis Supplements 2005; 6: 3–6.

12. Qiao Q, Gao W, Zhang L, Nyamdorj R, Tuomilehto. Metabolic syndrome and cardiovascular disease. Ann Clin Biochem 2007; 44: 232–63.

13. Tuan C-Y, Abbasi F, Lamendola C, McLaughlin T, Reaven G. Usefulness of plasma glucose and insulin concentration in identifying patients with insulin resistance. Am J Cardiol 2003; 92: 606–10.

14. Schöndorf T, Maiworm A, Emmison N, Forst T, Pfützner A. Biological background and role of adinopectin as marker for insulin resistance and cardiovascular risk. Clin Lab 2005; 51: 489–94.

15. Marra F, Bertolani C. Adipokines in liver disease. Hepatology 2009; 50: 957–69.

16. Hill MJ, Kumar S, McTernan PG. Adipokines and the clinical laboratory: what to measure, when and how? J Clin Pathol 2009; 62: 206–11.

17. Pischon T, Rimm EB. Adiponectin: a promising marker for cardiovaskular disease. Clin Chem 2006; 52: 797–9.

18. Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 2004; 50: 1511–25.

19. Pfützner A, Weber MM, Forst T. A biomarker concept for assessment of insulin resistance, β-cell function and chronic systemic inflammation in type 2 diabetes mellitus. Clin Lab 2008; 54: 485–90.

20. Maahs DM, Hamman RF, D’Àgostino Jr R, Dolan LM, Imperatore G, Lawrence JM, et al. The association between adinopectin/leptin ratio and diabetes type: the SEARCH for diabetes in youth. J Pediatr 2009; 155: 133–5.

21. Shand B, Elder P, Scott R, Frampton C, Willis J. Biovariability of plasma adinopectin. Clin Chem Lab Med 2006; 44: 1264–8.

22. Nagel G, Rapp K, Wabitsch M, Büchele G, Kroke A, Zöllner I, et al. Prevalence and cluster of cardiometabolic biomarkers in overweight and obese schoolchildren: results from a large survey in Southwest Germany. Clin Chem 2008; 54: 317–25.

23. Megia A, Vendrell J, Gutierrez C, Sabate M, Broch M, Fernandez-Real JM, et al. Insulin sensitivity and resistin levels in gestational diabetes mellitus and after parturition. Eur J Endocrinol 2008; 158: 173–8.

24. De Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 2008; 54: 945–55.

25. Sowers JR, Whalley-Conell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med 2009; 150: 776–83.

26. Krauss RM, Siri PW. Metabolic abnormalities: triglyceride and low-density lipoprotein. Endocrinol Metab Cli N Am 2004; 33: 405–15.

27. Arner P. Human fat cell lipolysis: Biochemistry, regulation and clinical role. Best Practice & Research Clinical Endocrinology& Metabolism 2005; 19: 471–82.

28. Jialal I. The role of the laboratory in the diagnosis of the metabolic syndrome. Am J Clin Pathol 2009; 132: 161–2.

29. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008; 359: 1811–21.

30. Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med 2007; 120: 442–7.

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2.3 Cardiovascular disease

Cardiovascular disease (CVD) is the first cause of premature mortality in the world and represented 46% of the deaths attributed to noncommunicable diseases in 2012. Because CVD has a multifactorial origin and most cardiovascular events occur in asymptomatic individuals, health authorities recommend global approaches to evaluate a patient risk profile. Decisions about whether to take preventive measures are based on the risk of experiencing acute myocardial infarction (AMI) or sudden unexplained cardiac death in the coming years. The risk profile involves estimating major risk factors such as age, sex, smoking, hypertension and predisposing risk factors such as familial background /1/.

Laboratory investigations play an important role in the CVD risk assessment and diagnosis of AMI:

  • The diagnosis of myocardial necrosis by determining necrosis markers in the serum, in particular cardiac troponin
  • Primary and secondary prevention of cardiovascular disease by determining blood markers, e.g., total cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting plasma glucose and HbA1c.
  • Assessment of cardiac function by determining the level of natriuretic peptide or NT-proBNP.

The causes of myocardial necrosis are listed in Tab. 2.3-1 – Myocardial necrosis due to myocardial damage.

2.3.1 Clinical aspects of cardiovascular disease

Definition of cardiovascular disease (CVD)

CVD refers to a group of ischemic disease entities that includes stable angina pectoris and acute coronary syndrome (ACS) /2/. Acute coronary syndrome can be divided into:

  • Unstable angina pectoris
  • Myocardial infarction
  • Sudden unexplained cardiac death.

Risk factors for cardiovascular disease

A cluster of risk factors exist for CVD that together make up the total risk. Various risk calculators are available for estimating this overall risk, such as the Framingham Risk Score, PROCAM score or ESC score (Tab. 2.1-1 – Assessment of cardiovascular risk using algorithms and scores). Based on these scores, individuals without cardiovascular disease and without diabetes mellitus are classified into categories with a low (under 10%), intermediate (10–20%), or high (over 20%) probability of experiencing a cardiovascular event. The traditional criteria used are age, gender, blood pressure, cholesterol concentration, and smoking (Section 2.1.2 – Diseases caused by atherosclerosis). In the USA, 31% of asymptomatic men and 7% of women fall into the intermediate risk group. “Non-traditional” markers can be used to further clarify the correct risk group for these patients (Tab. 2.3-2 – Cardiovascular disease, risk factors, and their frequency in the USA). According to the U.S. Preventive Services Task Force /3/, CRP is the only useful marker. 11% of men in the intermediate group were reclassified into the high-risk group based on a CRP value of over 3 mg/L (Tab. 2.1-2 – New risk markers for the primary prevention of cardiovascular disease) High-sensitivity troponin and B-natriuretic peptide are of similar importance.

2.3.1.1 Genetic predisposition to cardiovascular disease

Various gene mutations are associated with cardiovascular disease. The following are recognized /1/:

  • Genes associated with familial cardiomyopathies and arrhythmias
  • Diseases (familial hypercholesterolemia, autosomal recessive hypercholesterolemia, familial defective apolipoprotein B-100, apolipoprotein A-1 deficiency, sitosterolemia, Tangier disease, homocystinuria) and their gene variants that are associated with an increased risk of cardiovascular disease
  • Gene variants associated with an increased risk of cardiovascular disease.

2.3.1.2 Epidemiology of cardiovascular disease

In Germany, nearly one in two adults dies as a result of a cardiovascular disease (in decreasing order of frequency: CVD, stroke, heart failure, hypertension, peripheral arterial disease). The annual mortality rate from myocardial infarction is 107 per 100,000 of the population.

According to one study /4/, the average age for myocardial infarction was 76.1 years for women and 66.7 years for men. Frequent comorbid diseases were:

  • Diabetes mellitus; women 38.8%, men 29.5%
  • Hypertension; women 68.1%, men 66%
  • Heart failure; women 45%, men 35.2%
  • Renal insufficiency; women 22.1%, men 19.4%.

The following mortality rates were observed following myocardial infarction:

  • Hospital mortality 13.9%
  • 30-day mortality 16.7%
  • 90-day mortality 20.8%
  • 1-year mortality 28.1%.

After adjustment for age, mortality rates are the same for men and women.

Globally, acute myocardial infarction has a mortality rate of 30–50% within the first month, with half of all fatalities occurring during the first two hours.

According to a systematic review /5/, the outcome of acute myocardial infarction in patients who are not adequately treated and followed up is as follows:

  • 23% die before they reach hospital
  • 13% die following admission to hospital
  • After discharge from hospital, 10% die within the first year and a further 5% die during each subsequent year
  • After 15 years, the cumulative mortality rate is 70%
  • Following a second myocardial infarction, 33% die before reaching hospital, 20% die in hospital, and a further 20% die within one year of discharge. The annual mortality rate is 10% in each subsequent year.

2.3.2 Acute coronary syndrome (ACS)

Acute chest pain is the clinical cardinal symptom of the ACS and a common emergency. Acute myocardial infarction with its increased risk of cardiac mortality must be ruled out. If an ACS is suspected, the patient should referred immediately to an emergency department for evaluation. A 12-lead ECG is obtained and evaluated for ischemic changes. On the basis of the history and the ECG, rapid diagnostic triage is performed, with the case classified as

  • ST-segment elevation infarction (STEMI)
  • Possible or probable ACS without ST-segment elevation (NSTEMI)
  • Non-ischemic chest pain.

ACS is a constellation of symptoms triggered by ischemia. A diagnosis of ACS requires the presence of corresponding ischemic symptoms (chest pain radiating to the arm, acute dyspnea, nausea, vomiting, sweating) and/or characteristic ECG findings (Fig. 2.3-1 – Initial assessment of patients with suspected ACS). Up to half of patients do not have this combination of ischemic symptoms and ischemic ECG changes. These patients are treated as suspected cases of ACS and admitted to a chest pain unit for monitoring with a repeat ECG and cardiac troponin (cTn) assay. If the ECG and cTn assay are negative, patients can be reassured that they are experiencing angina pectoris rather than ACS (Tab. 2.3-3 – Definition and classification of angina pectoris). The clinical findings of ACS can be present in non-ischemic conditions (also known as non-coronary chest pain) can lead to differential diagnostic uncertainty.

Based on the electrocardiogram (ECG), different groups of patients are differentiated /678/:

  • Patients with acute chest pain and persistent (≥ 20 min) ST-segment elevation myocardial infarction (STEMI) generally reflects myocardial infarction type 1 (T1MI). A totally occluding thrombus typically leads to STEMI. The mainstay of treatment in these patients is immediate reperfusion by primary angioplasty or fibrinolytic therapy.
  • Patients with acute chest and non ST-segment elevation myocardial infarction (NSTEMI) reflects myocardial infarction type 2 (T2MI). The Third Universal Definition of MI task force document /6/ defines T2MI in instances of myocardial injury with necrosis where a condition without an acute atherothrombotic event contributes to an imbalance between myocardial oxygen supply and/or demand such as coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachyarrhythmias, bradyarrhytmias, anemia, respiratory failure, hypotension, and hypertension with or with out left ventricular hypertrophy.

2.3.3 Myocardial infarction (MI)

MI is an event of cardiomyocyte necrosis caused by an unstable ischemic syndrome /678/. Following the onset of myocardial ischemia, histological cell death is not immediate but takes at least 20 minutes. Post mortem examinations have shown that myocardial necrosis cannot be determined macroscopically and microscopically until a number of hours (> 2–4 hours) have passed. The disorder is diagnosed on the basis of clinical evaluation, the electrocardiogram (ECG), invasive and noninvasive imaging, pathological evaluation, and laboratory testing. Laboratory testing includes the detection of increase and/or decrease of cardiac biomarkers, preferably high-sensitivity cardiac troponin, with at least one value above the 99th percentile of the upper reference interval and at least one of the following /2/:

  • Symptoms of ischemia
  • New or presumed new significant ST-wave and T-wave changes or left bundle branch block on 12-lead ECG
  • Development of pathological Q-waves on ECG
  • Imaging evidence of new or presumed new loss of viable myocardium or regional wall motion abnormality
  • Intracoronary thrombus detected on angiography or autopsy.

Indicators of ischemia:

  • Clinical symptoms such as chest pain
  • ECG changes (e.g., ST elevation)
  • Imaging procedures such as myocardial perfusion scintigraphy (MPS), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). These procedures are used to determine localized reductions in heart wall thickness and motility. The same applies for echo cardiography.

Indicators of myocardial necrosis:

  • Rise in structural proteins and enzymes of myocardial cells (myoglobin, CK-MB, cTn) (Fig. 2.3-2 – Time profile of enzymes and cardiac troponin in myocardial infarction). The most sensitive and most specific necrosis marker is cTn.
  • Elevation of cTn > 99th percentile upper reference limit (URL) in healthy individuals. Although cTn is a highly specific indicator of myocyte damage, it provides no information about the etiology of the necrosis and so an increased cTn concentration alone is not sufficient to diagnose AMI.
  • Depending on the detection limit and the variation coefficient of the cTn assay, there can be a delay of 1–8 hours between the onset of ischemic symptoms and an increase in the concentration of the marker.

The recovery following an AMI lasts 5–6 weeks. An AMI can be small and involve only 1 g of myocardium or it can affect a significant part of the whole left ventricle. Although necrosis is ultimately triggered by ischemia, there are many different causes of AMI. For this reason, AMI are classified into different types according to the Third Universal Definition of Myocardial Infarction by the ESC/ACCF/AHA/WHF Task Force (Tab. 2.3-4 – Universal classification of myocardial infarction). Criteria for defining myocardial infarction are listed in Tab. 2.3-5 – Criteria of acute myocardial infarction.

2.3.3.1 Types of acute myocardial infarction

Myocardial infarction is formally divided into 5 types, classified by spontaneous (types 1–3) and conditions other than AMI associated with cTn elevation (Tab. 2.4-3 – Cardiac troponin in acute myocardial syndrome and other types of myocardial injury).

Type 1 myocardial infarction (T1MI)

T1MI is characterized by rupture or erosion of a vulnerable, lipid-laden, atherosclerotic plaque. The circulating blood is exposed to a highly thrombotic core material resulting in atherothrombosis in one or more coronary arteries. A totally occluding thrombus typically leads to STEMI (T1MI) and subsequent myocardial necrosis. Patients have acute coronary syndrome and positive cTn assays. Although patients may have severe preexisting cardiovascular disease, angiography fails to show an occlusive cause in 5–20% of cases, particularly in women /7/. Treatment is immediate, with aggressive anticoagulation and revascularisation (percutaneous coronary intervention or coronary bypass).

Type 2 myocardial infarction (T2MI)

The Third Universal Definition of MI task force document defines T2MI in instances of myocardial injury with necrosis where a condition without an acute atherothrombotic event contributes to an imbalance between myocardial oxygen supply and/or demand such as coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachyarrhythmias, bradyarrhytmias, anemia, respiratory failure, hypotension, and hypertension with or with out left ventricular hypertrophy /8/. Among women, T2MI is more frequent than T1MI, whereas in men, T1MI is more frequent than T2MI.

T2MI also occurs in critically ill patients, in major non-cardiac surgery, and as a toxic effect of high levels of circulating endogenous or exogenous catecholamines. T2MI is more frequent in women than men since endothelial dysfunction is more common in women. T2MI is associated with ischemic cTn elevation in which symptoms of ACS are often absent. T2MI is treated by treating the underlying causes.

Type 3 myocardial infarction (T3MI)

T3MI occurs in patients with classic MI (T1MI) and postmortem evidence of thrombosis. However, the patients die before elevated biomarkers can be identified.

Type 4 myocardial infarction (T4MI)

T4MI can occur during percutaneous coronary intervention or be associated with a confirmed subsequent stent thrombosis.

Type 5 myocardial infarction

T5MI occurs as a consequence of coronary artery bypass surgery.

2.3.3.2 Diagnosis of myocardial infarction

Acute myocardial infarction is diagnosed by the following /6/:

  • Clinical symptoms and ECG
  • Biomarkers of myocardial necrosis, in particular cardiac troponin (cTn); refer to rule in mechanism in Section 2.4.5.2
  • Imaging and laboratory findings.

2.3.3.3 Exclusion of myocardial infarction

An acute myocardial infarction can be ruled out as mentioned in Section 2.4.5.3.

2.3.3.4 Course of myocardial infarction

Progression over time

From a temporal perspective, acute myocardial infarction can be divided into the following phases:

  • Acute phase (6 hours to 7 days)
  • Recovery phase (7–28 days). ST elevation can persist during the recovery phase and biochemical markers of myocardial necrosis may still be abnormal.
  • Healed (from day 29).

Classification of infarct size and location

Acute myocardial infarctions are classified by size as follows /9/:

  • Microscopic (focal necrosis)
  • Small (less than 10% of the left ventricle)
  • Medium (10–30% of the left ventricle)
  • Large (involving more than 30% of the left ventricle)
  • Location: anterior, lateral, inferior, posterior, septal, or a combination of locations.

2.3.3.5 Risk assessment in patients with acute coronary syndrome

Scores are used to assess the future cardiac risk in patients with acute coronary syndrome.

TIMI risk score /10/

The Thrombolysis in Myocardial Infarction (TIMI) risk score assesses the risk of recurrent ischemia, acute myocardial infarction, or death of inpatients with acute coronary syndrome during the next 14 days using the following parameters: age over 65 years, three or more risk factors for cardiovascular disease (family history of cardiovascular disease, hypertension, diabetes, smoking), known cardiovascular disease, two or more episodes of chest pain in the previous 24 hours, use of aspirin in the 7 days before admission to hospital, ST segment deviation of more than 0.05 mV, a rise in a myocardial necrosis marker. One point is awarded for each criterion and the total number of points is calculated. The algorithm and its rating are available on the Internet.

GRACE risk model /11/

The Global Registry of Acute Coronary Events (GRACE) risk model assesses the risk of recurrent ischemia, acute myocardial infarction, or death of inpatients with acute coronary syndrome and the 6 months following the acute event using the following parameters: increased age, history of acute myocardial infarction, cardiac failure, increased pulse rate, low systolic blood pressure, elevated serum creatinine, an elevated myocardial necrosis marker, ST segment depression on the ECG. The eight criteria are added to give an overall score, which is then compared with a reference nomogram.

ASCVD (Atherosclerotic cardiovascular Disease) risk factor from AHA (American Heart Association) and ACC (American College Cardiology)

The calculator determines the 10-year risk of heart disease or stroke. The prerequisites are age of 40–75 years and LDL-cholesterol below 190 mg/dL (4.9 mmol/L) Diabetes, sex, race, smoking, total cholesterol, HDL-cholesterol, and systolic and diastolic blood pressure are considered. At a risk threshold of 10% in 10 years, the ASCVD equation has a sensitivity to identify future CVD events of approximately 80%, with the highest specificity (69%) and positive predictive value (17%) among 9 calculations tested /12/.

Important prognostic factors

Along with age, the following factors are important prognostic indicators for the outcome of myocardial infarction:

  • Medical history: first infarction, second infarction, diabetes mellitus, renal insufficiency
  • Infarct size and location (anterior or posterior wall infarction)
  • Low initial blood pressure
  • Extent of ischemia; represented by biochemical markers and ST segment elevation
  • Diabetes mellitus. Diabetics with acute coronary syndrome have a one-year mortality hazard ratio of 1.65 compared to non-diabetics with acute coronary syndrome /13/.

ECG and acute myocardial infarction

Acute ST segment elevation on the ECG in conjunction with continuing clinical symptoms has a high predictive value for acute myocardial infarction and coronary reperfusion measures should be introduced immediately. This is because patients who present within 6 hours of the acute event may not yet show elevated biochemical necrosis markers unless sensitive or high-sensitivity cardiac troponin assays are used.

Persistent ST segment elevation indicates persistent occlusive thrombosis. It is a sensitive marker of myocardial ischemia and can be detected within minutes of the onset of clinical symptoms. It has a diagnostic sensitivity of 80–90% for type 1 acute myocardial infarction. However, only 30–40% of patients with acute chest pain have ST segment elevation on admission. ST segment elevation in acute myocardial infarction is more obvious and occurs more frequently in men than in women. In the presence of clinical symptoms, a normal ECG does not exclude AMI and a rise or fall in biochemical cardiac markers is also sufficient to make a diagnosis /7/.

Assessment of infarct size

Comparative magnetic resonance imaging investigations in acute myocardial infarction have shown that the extent and temporal course of increases in CK-MB mass and cTn correlate with the infarct size and reperfusion.

Diagnosis of early re-infarction /6/

The term “re-infarction” applies to an acute myocardial infarction that occurs within 28 days of an incident or recurrent myocardial infarction /6/. A re-infarction should be considered if ST segment elevation ≥ 0.1 mV or new pathological Q-waves recur in at least two leads. A cTn assay should be performed immediately and repeated 3–6 hours later. A rise in cTn of ≥ 20% in the second sample points to re-infarction /14/.

2.3.4 Biomarkers of myocardial necrosis

During myocyte necrosis, structural proteins, cytoplasmic proteins, and other proteins are released into the cardiac interstitium /15/. These proteins, which include cTn, CK-MB, CK, myoglobin, AST, and LD can be measured in the serum. cTn has proven to be the most reliable marker. Myoglobin and the enzymes are less specific than cTn. A typical course of the necrosis markers in acute myocardial infarction is shown in Fig. 2.3-2 – Time profile of enzymes, cardiac troponin, and CK-MB mass in acute myocardial infarction.

2.3.5 Secondary prevention of coronary heart disease (CHD)

Patients with preexisting coronary heart disease present a significant problem. It is important to correctly stratify risk in individual patients and tailor treatment accordingly. Important predictive markers include BNP/NT-proBNP, CRP, cystatin C, and cTn. In one study /12/ 12 markers were determined to evaluate the risk of a coronary event occurring over 3.6 years in stable cardiovascular disease. The hazard ratios for each standard deviation increase were as follows:

  • NT-proBNP 1.71; median without event 89 ng/L, with event 501 ng/L
  • Cystatin C 1.43; median without event 0.81 mg/L, with event 0.86 mg/L
  • CRP 1.33; median without event 2.09 mg/L, with event 3.86 mg/L.

In another study /16/, the prognostic value of a high-sensitive cTn assay was evaluated. Patients had acute coronary syndrome without ST segment elevation. Patients whose baseline cTnI value was ≥ 0.04 μg/L were at significantly higher risk of myocardial infarction/cardiac death at day 30 than patients with a lower value. After adjusting for the TIMI risk score, a baseline cTnI value ≥ 0.04 μg/L was associated with a 3-fold (2.2–4) increase in the risk of myocardial infarction/cardiac death at 30 days. These preliminary findings demonstrate the high predictive value of sensitive cTn assays.

Inflammation is one of the central pathomechanisms of atherosclerosis. Elevation of high sensitivity CRP and interleukin-1β are associated with increased risk of cardiovascular events. Statin therapy relates to both a reduction in cholesterol level and inflammation inhibition. Reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Reducing vascular inflammation in the absence of concomitant lipid lowering reduces the rates of cardiovascular events. In a study /17/ patients with a history of myocardial infarction and a high sensitivity CRP concentration of more than 2 mg/L were treated with canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β. Treatment with canakinumab led to a significantly lower rate of recurrent cardiovascular events than placebo.

2.3.6 Primary prevention of coronary heart disease (CHD)

Individual risk assessment is currently based on scoring systems such as the ESC, Framingham, or PROCAM scores. However, biomarkers can also demonstrate an association with the occurrence of cardiovascular events in the longer term in population groups.

This was investigated in the MONICA, risk, genetics, archiving, and monograph (MORGAM) biomarker project /18/. Thirty biomarkers were evaluated and integrated into one score and the risk of cardiovascular events was followed up for 10 years. The score was based on the markers with the highest prognostic significance: NT-proBNP (hazard ratio 1.23), CRP (hazard ratio 1.23), and sensitive troponin (hazard ratio 1.18).

References

1. Vittorini S, Clerico A. Cardiovascular biomarkers: increasing impact of laboratory medicine in cardiology practice. Clin Chem Lab Med 2008; 46: 748–63.

2. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2015; https://doi.org/10.1093/eurheartj/ehv320.

3. US Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: US preventive services task force recommendation statement. Ann Intern Med 2009; 151: 474–82.

4. Heller G, Babitsch B, Günster C, Möckel M. Sterblichkeitsrisiko von Frauen und Männern nach Myokardinfarkt. Dtsch Ärztebl 2008; 105: 279–91.

5. Law, MR, Watt HC, Wald NJ. The underlying risk of death after myocardial infarction in the absence of treatment. Arch Intern Med 2002; 162: 2405–10.

6. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, WHite HD;, the writing group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Eur Heat J 2012; 33: 2551–67.

7. Anderson JL, Morrow DA. Acute myocardial infarction. N Engl J Med 2017; 376: 2053–64.

8. Sandoval Y, Thygesen K. Myocardial infarction type 2 and myocardial injury. Clin Chem 2017; 63: 101–7.

9. Newby LK, Jesse RL. ACCF 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations. J Am Coll Cardiol 2012; 60: 2427–63.

10. Antman E, Cohen M, Bernink PJLM, McCabe CH, Horacek T, Papuchis G, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000; 284: 835–42.

11. Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, van de Werf F, et al. A validated prediction model for all forms of acute coronary syndrome. JAMA 2004; 291: 2727–33.

12. Grammer TB, Dressel A, Gergei I, Kleber ME, Laufs U,Scharnagl H, et al. Cardiovascular risk algorithms in primary care: results from the DETECT study. Nature Scientific Reports 2019; https://doi.org/10.1038/s41598-018-37092-7.

13. Battler A. European Heart Survey of acute coronary syndromes. Eur Heart J 2002; 23: 1109–201.

14. Morrow DA, Cannon CP, Jesse RL, Newby LK, Ravkilde J, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guideline: Clinical characteristics and utilization of biochemical markers in acute coronary syndromes. Clin Chem 2007; 53: 552–74.

15. Jaffe AS. Third universal definition of myocardial infarction. Clin Biochem 2013; 46: 1–4.

16. Bonaca M, Scirica B, Sabatine M, Dalby A, Spinar J, Murphy SA, et al. Prospective evaluation of the prognostic implications of improved assay performance with a sensitive assay for cardiac troponin I. J Am Coll Cardiol 2010; 55: 2118–24.

17. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377: 1119–30.

18. Blankenberg S, Zeller T, Saarela O, Havulinna AS, Knee F, Tunstall-Pedoe H, et al. Contribution of 30 biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts. The MONICA, risk, genetics, archiving, and monograph (MORGAM) biomarker project. Circulation 2010; 121: 2388–97.

2.4 Cardiac troponins (cTn)

The preferred biomarker for myocardial injury and myocardial infarction is cardiac troponin (cTn), which has both high myocardial tissue specificity and clinical sensitivity, although not decisive for a disease /1/. Two isoforms cTn are differentiated troponin T (TnT) and troponin I (TnI). Both troponins are muscle proteins that form part of the complex that regulates muscular contractility. Troponin and tropomyosin make up the thin filament of the contractile structure of striated muscle (Fig. 2.4-1 – Structure of a thin filament of troponin complex). The cTn can be detected in low concentrations in the blood using highly sensitive assays, even in some healthy individuals. The high sensitivity has presented the practitioner with both advantages and disadvantages. A marked proportion of patients with elevated cTn concentrations receive a diagnosis for a cause of myocardial injury other than acute myocardial infarction (AMI) /2/.

For patent-related reasons, only cTnT assays of one manufacturer are commercially available, whereas cTnI assays are produced by a number of diagnostics manufacturers.

A distinction is made between sensitive and high-sensitivity (hs-cTn) immunoassays for cTnT and cTnI. Both sensitive and high-sensitivity assays are used in the diagnosis of myocardial cell necrosis.

2.4.1 Indication

Investigation of acute myocardial necrosis:

  • Diagnosis and course of acute myocardial infarction
  • Detection of focal necrosis following invasive cardiologic interventions
  • Detection of subclinical myocardial necrosis
  • Detection of stress-induced myocardial ischemia
  • Detection of toxic myocardial necrosis
  • Suspected myocarditis
  • Evaluation of the success of thrombolytic therapy
  • Primary and secondary prevention of cardiovascular disease (CVD).

2.4.2 Method of determination

On basis of the lower detection limit sensitive and high sensitivity cTn immunoassays are differentiated. The term high sensitivity reflects the assay’s characteristics and does not refer to a difference in the form of cTn being measured. The concentrations of sensitive cTn immunoassays are reported usually in μg/L, the concentrations of high-sensitivity immunoassays in ng/L.

Immunoassays for the diagnosis of AMI have to meet two basic criteria /3/.

  • The total imprecision at the 99th percentile value for healthy individuals should be ≤ 10%
  • Measurable concentrations below the 99th percentile should be attainable with an assay at a concentration value above the assay’s limit of detection for at least 50% (and ideally > 95%) of healthy individuals to attain the highest level of scorecard designation.

Important features of the hs-cTn assays are:

  • The significant higher precision at the upper reference limit (URL) for healthy individuals (99th percentile of the upper reference limit; URL) /3/
  • The higher predictive value for AMI
  • The 4% absolute and 20% relative increase in the detection of type 1 AMI and a corresponding decrease in the diagnosis of unstable angina
  • The 2-fold increase in the detection of type 2 AMI.

Sensitive immunoassays (Tab. 2.4-1– Analytical characteristics of sensitive cTn assays) and high-sensitivity cTn immunoassays (Tab. 2.4-2 – Analytical characteristics of high-sensitivity cTn assays) are used in the laboratory and as point of care tests at the bedside and in the doctor’s office.

Point of care TnT tests in whole blood

Principle: whole blood applied to the test pad releases cTnT antibodies a biotinylated labeled and a gold-labeled monoclonal antibody. Cellular blood components are retained by a filter. In the presence of cTnT, immune complexes are formed when the biotin-labeled cTnT antibody complexes bind to immobilized streptavidin. The gold-labeled indicator antibody binds to the immobilized cTnT antibody complex and makes the reaction visible in the results window. Another test pad is used as a positive control on which the gold-labeled TnT antibody binds directly to immobilized cTnT /4/. Accurate results are measured when the hematocrit is 14–55%.

Sensitive cTnT assay in serum /5/

Principle: the quantitative cTnT assay is performed as a one-step sandwich assay using streptavidin technology. The antibodies recognize two adjacent epitopes in the central part of the cTnT molecule. Therefore, the assay is not susceptible to proteolytic degradation of cTnT. The assay detects free and complex-bound cTnT. The point of care test and automated assay are compatible with each other.

Point of care cTnI tests in whole blood

Principle: for point of care tests, immunoassays are available on individual test pads or cartridges with two monoclonal or polyclonal antibodies against different cTnI epitopes. The indicator antibody that indicates a positive reaction is labeled using different enzymes.

Sensitive cTnI assay in serum

Principle: the cTnI assay is performed as a one or two-step immunoassay using two monoclonal or polyclonal antibodies against different epitopes of the cTnI molecule. Because the cTnI molecule is degraded in the blood, antibodies that recognize the central part of the molecule should be used. Because cTnI is present in the blood as part of a binary cTnI-TnC complex, the antibodies used should also recognize this complex.

High-sensitivity cTnT assay /6/

The hs-cTnT assay uses the Fab fragments of two monoclonal mouse antibodies. They are directed against epitopes in the central region of the TnT molecule. The capture antibody is biotinylated and directed against epitopes of amino acids 125–131 and the detection antibody is directed against an epitope of amino acids 136–147.

High-sensitivity cTnI assay

An evaluated hs-cTnI assay uses three different monoclonal antibodies to detect cTn epitopes: one against amino acids (AA) 30–35, one against AA 41–56, and one against AA 171–190. The lower detection limit is 0.8 ng/L and the upper reference interval value is 48 ng/L. Detectable hs-cTnI concentrations are present in 93% of healthy individuals /5/.

2.4.3 Specimen

Laboratory tests: serum, plasma (heparin, citrate): 1 mL

Point of care test (POCT): whole blood: 0.05–1 mL

2.4.4 Concepts of troponin testing

The cTn testing is used as absolute change strategy or relative change strategy for rule-in and rule-out criteria of AMI.

Sensitive cTn assays: absolute change strategy

The European Society Guidelines defined a criterion for the management of acute coronary syndroms in patients without persistent ST-segment elevation /7/. With the use of sensitive cTn assays and a diagnostic cutoff for AMI at the 99th percentile upper reference limit (URL), a strategy of measurement at presentation and 3 to 6 hours later was implemented. For patients with values exceeding the 99th percentile URL cases should be categorized as myocardial injury or myocardial infarction. In 2012, a rise or fall of cTn was added as a criterion but this rise or fall was not defined explicitly. Relative and absolute change strategies are used to demonstrate a rise or fall.

Absolute change: if, for example, the cTn concentration is 5 μg/L on admission and 12 μg/L 3 or 6 hours later, the absolute change is 7 μg/L.

Sensitive cTn assays: relative change strategy

The relative percentage change is assessed. For example, if the cTn value is 0.4 μg/L on admission and 0.8 μg/L three hours later, the relative change Δ is:

Δ = [(0.8–0.4)/0.4] × 100 = 100%

According to the guidelines /8/, a change of 15–20% is postulated as a diagnostic criterion for acute myocardial necrosis.

High-sensitivity cTn assays

With the use of hscTn assays the following strategies are used:

  • The interval between serial sampling is reduced to 1 hour (1-hour algorithm) or two hours (2-hour algorithm) for rule-out or rule-in.
  • A one-size single cutoff criterion for simultaneous rule-in and rule-out (cTn measurement at presentation).

2.4.5 Clinical assessment

Myocardial injury with necrosis may occur either in the presence of overt ischemia from myocardial infarction (MI), or in the absence of overt ischemia from myocardial injury accompanying other conditions /9/. Working groups of the WHO established a primarily electrocardiographic (ECG) based definition of MI /10/. If an acute coronary symptom is suspected myocardial infarction is classified on the basis of the presence or absence of ST-segment elevation. Type 1 is due to coronary atherothrombosis and is based on ST-segment elevation /11/. MI Type 2 is a condition without ST-segment elevation and occurs in the clinical setting without overt myocardial ischemia where a condition other than an acute atherothrombotic event is the major contributor to a significant imbalance between myocardial oxygen supply and/or demand /9/.

Sensitive and high-sensitivity cTn assays enable the diagnosis of myocardial necrosis and allow on the basis of history and ECG a rapid diagnostic triage. The cases are classified as ST-segment elevation infarction (STEMI), possible or probable acute coronary syndrome without ST-segment elevation (non-STEMI) or nonischemic chest pain /11/.

2.4.5.1 Serial measurement of cTn

Serial measurement of sensitive cTn is the preferred method for differentiating non-STEMI from unstable angina pectoris and other than acute coronary syndromes. With the use of sensitive cTn assays and a diagnostic cutoff for Mi at the 99th percentile upper reference limit, a strategy of measurement at presentation and 3 and 6 hours later provides a negative predictive value of greater than 99% in low-risk patients without ischemic ECG abnormalities /7/. High-sensitivity immunoassays of cTn increase diagnostic sensitivity. However this was not the case in the following study /12/. Blood was drawn for the determination of high-sensitivity cTnI (level of detection, 3.4 pg/mL) and sensitive cTnI (level of detection, 10 pg/mL) ad admission and 3 and 6 hours later. Using levels ad 3 hours after admission, the negative predictive value was 99.4% for both high-sensitivity cTnI and sensitive cTnI. The positive predictive value (for ruling in myocardial infarction) for high-sensitivity cTnI increased from 75.1% at admission to 95.8% after 3 hours and for sensitive cTnI from 80.9% to ad admission to 96.1% after 3 hours.

2.4.5.2 Two-hour algorithm and one-hour algorithm for rule-out and rule-in of myocardial infarction

High-sensitivity assays for cTn increase diagnostic sensitivity and make it possible to reduce the interval between serial sampling to 1 to 2 hours while maintaining an negative predictive value of about 99% among otherwise low risk patients /2/. The European Society of Cardiology practice guidelines for management of non-ST-segment elevation acute coronary syndrome recommended that, if an high-sensitivity cTn assays with a validated 0-hour and 1-hour algorithm is available, testing at presentation and 1 hour is an alternative to testing at 0 and 3 hours /8/.

Two-hour algorithm

In a multicentre study using high-sensitivity cTnI a two-hour algorithm for triage toward rule-out and rule-in of myocardial infarction was investigated /13/. Baseline values as well as absolute changes after 2 hours were incorporated. The 2-h algorithm classified 56% of patients as rule-out, 17% as rule-in and 27% as observation. Resulting diagnostic sensitivity and negative predictive value were 99.2% and 99.8% for rule-out; specificity and positive predictive value were 95.2% and 75.8% for rule-in. Refer to Fig. 2.4-2 – The use of the 0h/3h rule.

One-hour algorithm

In a multicentre study using high-sensitivity cTnT a one-hour algorithm for triage toward rule-out and rule-in of AMI was investigated /14/. Baseline values as well as absolute changes after 1 hour were incorporated. The 1-h algorithm classified 59.5% of patients as rule-out, 16.4% as rule-in and 24,1% as observation. Resulting diagnostic sensitivity and negative predictive value were 99.6% and 99.9% for rule-out; specificity and positive predictive value were 95.7% and 78.2% for rule-in. Refer to Fig. 2.4-3 – The use of the 0h/1h assessment.

2.4.5.3 A one single criterion at presentation

High-sensitivity cTn may rule-out acute myocardial infarction after a single sample has been obtained /2/.

A review of high-sensitivity cTnI at presentation in patients with suspected acute coronary syndrome showed the following results /15/: in patients without myocardial infarction at presentation cTnI concentrations were less than 5 ng/L in 61% with a negative predictive value of 99.6% for the primary outcome. At 1 year, these patients had a lower risk of myocardial infarction and cardiac death than did those with a cTnI concentration of 5 ng/L and more.

In a second study a pooled analysis of five international prospective, observational cohort studies with blinded outcome assessment and 30-day follow-up was reported /16/. Eligible patients had non-ischemic ECG determined and high-sensitivity cTnI measured at presentation. The lower limit of detection of cTnI was 1.2 ng/L. Acute myocardial infarction developed in 9.2% of patients. The 1.2 ng/L limit of detection gave a sensitivity of 99.0% and a negative predictive value of 99.5%. This cutoff level would allow for early discharge of 18.8% of patients. All higher cutoff values had a negative predictive values less than 98.0%.

Testing with one single criterion has decreased diagnostic specificity for myocardial infarction, since high-sensitivity assays detect the presence of cTn in most normal persons. In a number of disorders, other than myocardial infarction high-sensitivity cTn concentrations are measured. Refer to Tab. 2.4-3– cTn in acute coronary syndrome and other types of myocardial injury.

2.4.5.4 Extracardiac elevation of cTn

Patients with T2MI can have elevated cTn concentrations without cardiovascular disease /9/, e.g., infection, sepsis, congestive heart failure, chronic kidney disease (Tab. 2.4-4 – Conditions other than acute myocardial infarction associated with cTn elevation).

2.4.5.5 cTn as a prognostic marker

Adults without cardiovascular disease

High-sensitivity cTn assays are positive in many adults without recognized cardiovascular disease. In the Dallas Heart Study /12/, 27% of individuals aged 30–65 years were positive for hs-cTnT and 3.4% of those had values above the 99th percentile URL. In the Atherosclerosis Risk in Communities (ARIC) study /13/ and the Cardiovascular Health Study /14/, 66% of middle-aged and older individuals had detectable hs-cTnT levels. In the ARIC study, 7.4% had values > 99th percentile URL and in the Cardiovascular Health Study, 16.6% had hs-cTnT values of over 12.9 ng/L. These studies and others have shown that advanced age, male gender, previous ischemic or non-ischemic cardiovascular disease, chronic kidney disease, and cardiovascular risk factors are associated with detectable or elevated cTn values.

Patients with stable cardiovascular disease

High-sensitivity cTn assays can also be used to identify patients with cardiovascular disease who are at increased risk of myocardial infarction in the future. For example, patients with hs-cTnT concentrations of 8–14 ng/L (normal range) have a hazard ratio of 1.47 for future myocardial infarction /15/. In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial /16/, hs-cTnT values above 6.3 ng/L were associated with an increased cumulative incidence of cardiovascular death in individuals with stable cardiovascular disease. In the ARIC study, hs-cTnT values above 3 ng/L were associated with increased mortality and hospitalization and values above 6 ng/L with the risk of ischemic heart disease. For risk stratification of CVD. Refer to Tab. 2.4-5 – Risk stratification of patients/individuals with/without ACS.

Patients with suspected acute coronary syndrome (ACS)

Early risk stratification in patients with suspected ACS is carried out by means of a cTn assay and evaluation of the results with respect to the 99th percentile URL and the clinical symptoms /17/. cTn assays in patients whose clinical history is consistent with ACS have shown that patients with values in the lower range have a higher risk of recurrent cardiac events than those with undetectable cTn levels. In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI 18) study, patients whose cTnI was just above the 99th percentile URL (0.1 μg/L, CV 20%) had a > 3-fold increased risk of recurrent cardiac events or cardiac mortality compared to patients with lower cTn levels /18/.

In a further study /19/, patients with ACS associated with T2MI and hs-cTnI values ≥ 40 ng/L on admission had a 3-fold increased risk of further myocardial infarction or cardiac death within 30 days.

2.4.5.6 Cardiac troponins and the treatment of acute coronary syndrome

The choice of cTn value as of which treatment takes place is a decisive factor in therapeutic success. For example, in the TACTICS-TIMI 18 study, 25% more patients had a positive outcome when percutaneous revascularization was carried out at a cTnT value of just 0.01 μg/L instead of 0.1 μg/L /18/. Treatment guidelines have been defined by the American Heart Association /20/.

2.4.6 Comments and problems

Specimen

Since heparin can interfere with cTn assays, in particular due to the formation of micro fibrin clots, serum samples are recommended for some commercial assays. Because EDTA splits the troponin complex, EDTA blood samples are not recommended for cTnI assays.

Method of determination /19/

cTnI: many commercial assays are available for automated analyzers and point-of-care testing with antibodies against various cTnI epitopes. However, because the amino and carboxy terminal parts of cTnI are susceptible to proteolysis, which, in turn, depends on the degree of ischemia, the assays behave differently during acute myocardial infarction. Because they are not standardized, cTnI assays cannot be compared.

cTnT: because cTnT assays are produced by one manufacturer only, the quantitative assays performed automated analyzers and point-of-care testing show the same results since they are calibrated using the same reference material. Since the assays use two monoclonal antibodies that are directed against central cTn antigens, there is little cross-reactivity with skeletal muscle TnT. The assay is robust in the face of molecular changes and TnT degradation products.

Point of care test: POCT should be implemented in a hospital if the in-house laboratory cannot determine cTn within 30 minutes.

Stability

Depending on the assay, storing the sample at room temperature for several hours can lead to an increase or decrease in the concentration due to cTn degradation.

Hemolysis

Hemolysis can interfere with cTnI and cTnT assays. Follow the manufacturer’s instructions.

Standardization of cTnI

The National Institute of Standards and Technology (NIST) together with the American Association of Clinical Chemistry (AACC) and International Federation of Clinical Chemistry (IFCC) has created certified reference material for cTnI (SRM 2921) for standardization purposes /22/. The cTnI concentration is 31.2 mg/L.

False positive cTn results /23/

The prevalence of false positive cTn results is 0.2–3%. False positives result from analytical interferences due to fibrin clots and micro particles in the sample, heterophile antibodies, human anti-animal (mouse) antibodies, rheumatoid factors, hyperbilirubinemia, hemolysis, lipemia, alkaline phosphatase, and the formation of macro immune complexes. These interferences are manufacturer-specific and do not apply to all cTn assays.

Autoantibodies against cTn

Autoantibodies against cTnI and cTnT are present in the serum of approximately 10% of individuals, mostly directed against cTnI or cTnT, but also to both cTn in around 1%. They can interfere with cTn assays and cause falsely low or even false negative cTn measurements in patients with acute coronary syndrome /24/. Persistent autoantibodies can still be detected in patients with acute coronary syndrome 3–12 months after admission.

Criterion for the diagnosis of acute myocardial infarction

To support the diagnosis of acute myocardial infarction the 99th percentile URL remains the best-established approach given the absence of cTn assays standardization /21/.

2.4.7 Pathophysiology

The troponin complex consists of three different structural proteins that are located in the thin filament of the contractile apparatus (Fig. 2.4-1 – Structure of a thin filament of troponin complex). Both in cardiac muscle and skeletal muscle, each of the proteins is coded by a specific gene. The three proteins are cTnT, cTnI, and cTnC, with molecular weights of 39 kDa, 26 kDa, and 19 kDa respectively. Specific isoforms of TnT and TnI are present in cardiac and skeletal muscle. TnC is identical in cardiac and skeletal muscle and is therefore not suitable for diagnosing myocardial injury. A significant proportion of cTnT and cTnI is structure-bound in the thin muscle filament.

Following myocardial damage, cTn is rapidly broken down and released into the circulation. Only 6–8% of cTnT and 3–4% of cTnI is present in a soluble form in the cytoplasm. The different compartmentalization of cTnT and cTnI is one reason for the biphasic release of cTnT and the monophasic release of cTnI. The majority of the cTn is not released from the myofibrils until around 12 hours later, as binary cTnI/C or ternary cTnI/C/T complexes following proteolytic degradation. The ternary complex clearly predominates (Fig. 2.4-4 – Compartmentalization and release of cTnT and cTnI following myocardial injury). Binary and ternary cTn are responsible for the protracted cTn elevation in acute myocardial infarction. Some of the cTnI released from the cytosol combines with soluble cTnC (sTnC) to form the binary complex cTnI/sTnC in the circulation, which is detected to different degrees by the commercially available immunoassays /21/.

cTn is released from cardiac muscle in various ways. In acute ischemia with myocyte necrosis, it is released following irreversible damage to the cell membrane. Transient ischemia can cause cTn release due to temporary cell membrane leakage. This mechanism is possibly also present in multi-organ failure e.g., in sepsis. hs-cTn values < 99th percentile URL are a sign of ongoing myocardial damage due to reduced blood flow in atherosclerosis.

Autoantibodies against cTnI are directed against the central fragment of cTnI, in particular the C-terminal part.

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2.5 CK-MB mass

CK-MB is an isoenzyme of CK that is present mainly in cardiac muscle. CK-MB is released during myocardial necrosis (for CK and CK-MB, see also Tab. 1.8-4 – CK and CK-MB activities in acute myocardial injury).

The CK-MB mass is analyzed by determining the protein concentration of the CK-MB isoenzyme. Compared with the measurement of CK-MB enzyme activity, this offers improved sensitivity and specificity for diagnosing acute myocardial infarction (AMI) /12/.

2.5.1 Indication

If cardiac troponin determination is not possible:

  • Early diagnosis of acute myocardial infarction
  • Monitoring of acute myocardial infarction for early identification of re infarction
  • Monitoring of thrombolytic therapy
  • Infarct diagnosis following coronary artery bypass surgery
  • Prognosis in unstable angina pectoris.

2.5.2 Method of determination

Point of care test in whole blood

Principle: whole blood applied to the test pad releases both a monoclonal, immobilized, CK-MB-specific antibody and an indicator antibody labeled with gold, for example. Cellular blood components are retained by a filter. If CK-MB is present, it binds to the immobilized antibody to form immune complexes. The second, gold-labeled antibody binds to the immobilized CK-MB-antibody complex and makes the reaction visible in the results window.

Quantitative assay in serum/plasma

Principle: in a one-step sandwich assay, CK-MB in the specimen reacts with both a biotinylated monoclonal CK-MB-specific antibody and a CK-MB antibody labeled with a ruthenium complex to form a sandwich complex. The immune complex is bound to streptavidin coated paramagnetic micro particles using biotin. The electrochemiluminescence of the sandwich complexes is measured. However, other procedures also exist.

CK-MB isoforms

To improve the diagnostic sensitivity of CK-MB in the early stage of myocardial infarction, it is separated into its two isoforms, CK-MB 2 and CK-MB 1, using high voltage electrophoresis. These isoforms result from post synthetic modification of the primary CK-MB structure. CK-MB is transformed into the two isoforms by the enzymatic action of the enzyme carboxypeptidase. The electrophoresis gel is scanned with ultraviolet light to establish the CK-MB 2/CK-MB 1 ratio. This procedure is used in the differential diagnosis of increased CK activity that cannot be explained clinically.

2.5.3 Specimen

  • Serum, plasma: 1 mL
  • Whole blood (EDTA or heparin): 0.1 mL

2.5.4 Reference interval

CK-MB mass: Below 5–8 μg/L /34/ (depending on the manufacturer)

CK-MB-2/CK-MB-1 ratio: Below 1.7

2.5.5 Clinical significance

According to the guidelines of the European Society of Cardiology and the American Heart Association/American College of Cardiology (ESC/ACC), CK-MB mass assay has an important role in acute coronary syndrome in cases where cTn assay is not available /5/. This applies to diagnosis, risk stratification, and the choice of treatment methods for acute coronary syndrome with or without ST segment elevation on the ECG /6/. Although the CK-MB mass is less specific for the myocardium than cTn, it has higher diagnostic specificity for ruling out acute myocardial infarction /5/. As with cTn, an increased CK-MB mass concentration is defined as a value above the 99th percentile of upper reference limit (URL) for a healthy control group. In the acute coronary syndrome, the CK-MB mass should be determined on admission, after 2–4 h, after 6–9 h, and after 12 h. The behavior of the CK-MB mass in acute coronary syndrome is shown in Tab. 2.5-1 – CK-MB mass in acute coronary syndrome and other muscular damage.

A CK-MB 2/CK-MB 1 ratio above 1.7 is an early indicator of myocardial necrosis.

2.5.6 Comments and problems

Point of care test in whole blood

CK-MB concentrations above 5 μg/L produce a positive test result. Assays are available that can determine the CK-MB mass, myoglobin, and cTnI simultaneously in a serum sample.

Quantitative assay in serum/plasma

Because of the high analytical specificity of enzyme immunoassays, CKMM, CKBB, macro CK type 1 and type 2, and adenylate kinase only interfere at very high concentrations.

Interference factors

Hemoglobin ≤ 10 g/L (0.63 mmol/L), bilirubin ≤ 500 mg/L (850 μmol/L), triglycerides ≤ 1,350 mg/dL (15.4 mmol/L), rheumatoid factors ≤ 500 U/mL, and commonly used pharmaceuticals do not interfere with the assays. Samples that contain precipitates must be centrifuged before the assay. Fibrin clots interfere with the assay.

Stability

At room temperature for at least 12 hours, at 2–8 °C for at least 3 days. For longer-term storage, must be frozen (at –20 °C is stable for at least 12 months, freeze and thaw once only).

2.5.7 Pathophysiology

The CK-MB mass constitutes 3–5% of skeletal muscle and 5% of cardiac muscle. However, in pathologically altered cardiac muscle, the CK-MB mass proportion is 20–30% /3/. This explains why individuals without a history of heart disease can show only slight increases in CK-MB following myocardial infarction. Causes of an increased CK-MB proportion include chronic cardiac stress due to ventricular hypertrophy and coronary heart disease /3/.

Chronic stress also induces an increase in the CK-MB proportion of skeletal muscle. This is the case, for example, in marathon runners and other endurance athletes as well as in individuals who carry out a lot of physical work in everyday life. The CK-MB proportion can also be as high as 20–30% in myopathies such as Duchenne muscular dystrophy and polymyositis /47/. These examples explain why increased CK-MB mass concentrations can be detected not only in myocardial necrosis but also in skeletal muscle damage.

References

1. Mair J, Artner-Dworzak E, Dienstl A, et al. Early detection of acute myocardial infarction by measurement of mass concentration of creatine kinase-MB. Am J Cardiol 1991; 68: 1545–50.

2. Ravkilde J, Nissen H, Horder M, Thygesen K. Independent prognostic value of serum creatine kinase isoenzyme MB mass, cardiac troponin T and myosin light chain levels in suspected myocardial infarction. J Am Coll Cardiol 1995; 25: 574–81.

3. Ingwall JS, Kramer MF, Fifer MA, et al. The creatine kinase system in normal and diseased human myocardium. N Engl J Med 1985; 313: 1050–4.

4. Somer H, Duboeitz V, Donner M. Creatine kinase isoenzymes in neuromuscular diseases. J Neurol Sci 1976; 29: 129–36.

5. Bertrand ME, Simoons ML, Fox KAA, Wallentin LC, Hamm CW, McFadden E, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Task Force Report. European Heart J 2002; 23: 1809–40.

6. Myocardial Infarction redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; 36: 959–69.

7. Neumeier D, Jockers-Wretou E. Tissue specific and subcellular distribution of creatine kinase isoenzymes. In: Lang H, ed. Creatine kinase isoenzymes – pathophysiology and clinical application. Berlin; Springer 1981: 85–129.

8. Gibler WB, Young GP, Hedges JR, et al. Acute myocardial infarction in chest pain patients with non-diagnostic ECGs: Serial CK-MB sampling in the emergency department. Ann Emerg Med 1992; 21: 504–12.

9. Mair J, Morandell D, Genser N, Lechleitner P, Dienstl F, Puschendorf B. Equivalent early sensitivities of myoglobin, creatine kinase MB mass, creatine kinase isoform ratios, cardiac troponin I and T for acute myocardial infarction. Clin Chem 1995; 41: 1266–72.

10. Stewart J, French JK, Theroux P, et al. Early noninvasive identification of failed reperfusion after intravenous thrombolytic therapy in acute myocardial infarction. J Am Coll Cardiol 1998; 31: 1499–1505.

11. Brener SJ, Lytle BW, Schneider JP, Ellis GE, Topol EJ. Association between CK-MB elevation after percutaneous or surgical revascularisation and three-year mortality. J Am Coll Cardiol 2002; 40: 1961–7.

12. Thygesen K, Alpert JS, White HD, Joint ESC/ACCF/AHA/WHF Task Force for the Redifinition of Myocardial Infarction. Third universal definition of myocardial infarction. Circulation 2012; 126: 2020–35.

2.6 Myoglobin

Myoglobin is a protein found in cardiac and skeletal muscle that functions as a reservoir for oxygen.

2.6.1 Indication

Myoglobin has an important role in addition to the cardiac troponin in multi marker diagnostics for:

  • Early diagnosis or exclusion of myocardial necrosis in acute coronary syndrome (ACS)
  • Detection of re-infarction
  • Monitoring thrombolytic therapy for myocardial infarction
  • Risk stratification in acute coronary syndrome in combination with cardiac troponin and/or CK-MB mass.

2.6.2 Method of determination

Qualitative and quantitative point of care test in whole blood

Principle: see cardiac troponin. Myoglobin assay is also available in combination with cardiac troponin (cTn) and CK-MB mass on one test pad.

Immunoturbidimetric assay

Principle: polystyrene particles coated with antibodies to myoglobin form an immune complex with myoglobin in the serum by forming agglutinates. The increased turbidity caused by the agglutinates is measured photometrically and evaluated using a calibration curve.

Immunonephelometric assay

Principle: agglutination reaction between myoglobin and myoglobin antibodies that are bound covalently to plastic particles. Following incubation, light scattering measurement is used to calculate the extent of the agglutination using a logit-log function.

Enzyme immunoassay

Principle: myoglobin is determined using homogeneous or heterogeneous assays. One-step sandwich assays are commonly used.

2.6.3 Specimen

  • Serum or plasma: 1 mL
  • Whole blood: 0.1 mL
  • Urine if myoglobinuria due to skeletal muscle damage is suspected: 10 mL

2.6.4 Reference interval

Serum, plasma < 70–110 μg/L /1/

2.6.5 Clinical significance

Serial myoglobin measurements have no advantage over cTn in patients with acute coronary syndrome.

Behavior of myoglobin in myocardial infarction:

  • Myocardial necrosis within 6 hours can be reliably excluded if myoglobin assays performed on admission and at 2, 4, and 6 hours after the acute onset of pain are all normal
  • Unstable angina pectoris is suggested if no significant elevation is evident after 2–4 hours.

The behavior of myoglobin in acute coronary syndrome and other conditions is shown in Tab. 2.6-1 – Myoglobin in acute coronary syndrome and other muscular damage.

The disadvantages of myoglobin determination in patients with acute coronary syndrome are as follows:

  • The release kinetics of myoglobin are fast and its release into the blood is characterized by a “staccato phenomenon” with peaks that are often short-lived, lasting only 1–2 hours. Consequently, blood must be collected at short time intervals of 2 hours at most.
  • An increase in myoglobin that occurs for the first time 6–10 hours after the onset of chest pain is of limited significance since it could also be due to skeletal muscle damage.
  • A normal myoglobin concentration is of no value if it is measured for the first time 10 hours after the acute onset of pain.
  • It can be difficult to diagnose a re-infarction since the potential increase in myoglobin can show a high degree of variability.
  • Myoglobin has low diagnostic specificity since it is also increased following skeletal muscle trauma.

2.6.6 Comments and problems

Interference factors: hemoglobin > 3 g/L (0.18 mmol/L), bilirubin > 32.2 mg/dL (550 μmol/L), and high rheumatoid factor concentrations interfere with immunonephelometric and immunoturbidimetric assays and enzyme immunoassays. Lipemic serum must be centrifuged (for 10 min at 15,000 g).

Stability: in serum and plasma at room temperature, at least 2 days; at 4 °C, at least 1 month; and at –20 °C, for longer.

2.6.7 Pathophysiology

Myoglobin is an oxygen-binding heme protein found in striated muscle (skeletal and cardiac muscle). It has a molecular weight of 17.8 kDa and accounts for 2% of the total muscle protein /2/. Myoglobin is located in the cytoplasm of muscle cells and rapidly permeates the extracellular space in the event of damage to the cell membrane. Therefore, myoglobinemia occurs relatively quickly following injury to striated muscle.

Myoglobin reaches pathological values before the muscle enzymes and the cardiac proteins such as troponin that are bound to cell structures are activated. Myoglobin levels also return to the reference interval sooner than those of the enzymes and structural proteins mentioned since it is filtered rapidly by the kidneys due to its low molecular weight. Therefore, myoglobin levels can increase significantly in end-stage renal disease.

The physiological importance of myoglobin is based on its ability to bind molecular oxygen reversibly with greater affinity than hemoglobin. Myoglobin therefore plays an important role in transporting and storing oxygen in striated muscle.

In coronary artery surgery, myoglobin assays can diagnose perioperative myocardial infarction earlier and determine the time of infarction more effectively than assays of other biochemical cardiac markers /3/.

Myoglobin’s short biological half-life of 10–20 minutes compared to that of the CK-MB mass (approx. 12 hours) has diagnostic advantages. During percutaneous coronary intervention, changes in micro perfusion can be detected with minimal delay in the serum by means of a rapid succession of myoglobin peaks (staccato phenomenon) caused by variable perfusion of the infarct vessel. Therefore, the course of myocardial necrosis and its response to treatment over time can be monitored more effectively than with the cardiac troponin and CK-MB mass /4/.

References

1. Laperche T, Steg PG, Dehoux M, et al. A study of biochemical markers of reperfusion early after thrombolysis for acute myocardial infarction. Circulation 1995; 92: 2079–86.

2. Sylven C, Jansson E, Book K. Myoglobin content in human skeletal muscle and myocardium: relation to fibre and size and oxidative capacity. Cardiovasc Res 1984; 18: 443–6.

3. Mair P, Mair J, Seibt I, Balogh D, Puschendorf B. Early and rapid diagnosis of perioperative myocardial infarction in aortocoronary bypass surgery by immunoturbidimetric myoglobin measurements. Chest 1993; 103: 1508–11.

4. Drexel H, Dworzak E, Kirchmair M, et al. Myoglobinemia in the very early phase of acute myocardial infarction. Am Heart J 1983; 105: 642–51.

5. Ng, SM, Krishnaswamy P, Morissey R, et al. Ninety-minute accelerated critical pathway for chest pain evaluation. Am J Cardiol 2001; 88: 611–7.

6. McCord J, Nowak R, McCullough P, et al. Ninety-minute exclusion of acute myocardial infarction by use of quantitative point-of-care testing of myoglobin and troponin I. Circulation 2001; 104: 1483–8.

7. Zabel M, Hohnloser SH, Röster W, Prinz M, Kasper W, Just H. Analysis of creatine kinase, CK-MB, myoglobin, and troponin T time-activity curves for early assessment of coronary artery reperfusion after intravenous thrombolysis. Circulation 1993; 87: 1542–50.

2.7 Chronic heart failure (CHF)

2.7.1 Definition

Chronic heart failure is a clinical syndrome, arising from diverse causes. Primary decease in cardiac output or arterial under filling leads to activation of cardiac and systemic mechanisms such as the Frank-Starling mechanism, myocardial hypertrophy, and activation of neurohumoral and inflammatory mechanisms. The systemic response manifests as inadequate peripheral vasoconstriction, volume retention, and inefficient inotropic stimulation. This results in increased myocardial dysfunction and ischemic organ dysfunction of the kidneys, liver, brain, lungs, and skeletal muscle as well as pulmonary congestion, Na+ retention and fluid overload /1/.

2.7.2 Clinical symptoms

The typical symptoms of chronic heart failure are dyspnea or fatigue, either at rest or on exertion, and signs of fluid retention such as leg edema. However, because the diagnostic specificity of these symptoms is low, the clinical findings can only suggest, but not confirm, heart failure. Although dyspnea on exertion and orthopnea are useful indicators of left ventricular dysfunction, more than 30 causes exist for dyspnea and its prevalence in the population is 3–25%. However, once chronic heart failure has been diagnosed, the clinical symptoms can be used to classify the severity and monitor the response to therapy /2/.

2.7.3 Epidemiology

In the Framingham Study, the annual incidence rate of chronic heart failure was 2.3/1,000 in men and 1.8/1,000 in women /3/. In general, the expected annual incidence rate in Europe and North America is 1–4 new cases per 1,000 of the population. The prevalence depends on age. In Germany, the prevalence was 0.127% in individuals aged 45–65 years and 1.55% in those over 65 years of age, based on hospitalizations in 2006 /4/. According to the Glasgow study /5/, the overall prevalence of left ventricular systolic dysfunction determined by echo cardiography was 2.9%. The left ventricular systolic dysfunction was symptomatic in 1.5% of patients and asymptomatic in 1.4%.

2.7.4 Etiology

The etiologies of chronic heart failure are listed in Tab. 2.7-1 – Etiology of chronic cardiac failure. For most patients, more than one of the etiological factors are relevant. The main cause is coronary heart disease. Not all patients have left ventricular contractile dysfunction and a reduced ejection fraction. Many also have cardiac valvular disease, aortic stenosis or mitral regurgitation resulting in diastolic heart failure. Around 30% of heart failure patients have a conduction defect that leads to delayed left or right ventricular systole.

Some 20–50% of patients have preserved left ventricular function or a normal left ventricular ejection fraction. Although their hearts contract normally, cardiac relaxation (diastole) is abnormal. The American College of Cardiology/American Heart Association Guidelines for the Diagnosis and Management of Heart Failure recommend using the term “heart failure with preserved ejection fraction” instead of “diastolic heart failure” for this form of chronic heart failure /6/.

Many patients with chronic heart failure are over 60 years of age and 75% have hypertension. In the Glasgow study /5/, 50% of cases had a history of myocardial infarction and 62% had a history of angina pectoris. Of the 280,000 individuals who suffer a myocardial infarction each year in Germany, 56,000 of those who survive are left with significantly reduced left ventricular function and an ejection fraction below 40%; 5–7% have a severely reduced ejection fraction of below 30%.

2.7.5 Classification and prognosis

Chronic heart failure in adults is classified using the New York Heart Association (NYHA) classification /7/ or the American College of Cardiology/American Heart Association classification /8/.

The NYHA classification differentiates symptoms of chronic heart failure into four stages of severity that correspond to the degree of exercise intolerance (Tab. 2.7-2 – New York Heart Association (NYHA) classification of heart failure). This in turn correlates with the patient’s prognosis. The 1-year mortality for severe heart failure is 50% and the 4-year mortality is 40–50% for moderate heart failure and 20–30% for mild heart failure.

The American College of Cardiology/American Heart Association classification divides heart failure into four stages and identifies factors that can be used to identify high-risk patients (Tab. 2.7-3 – Classification of chronic heart failure according to the new criteria of the American College of Cardiology/American Heart Association). According to this classification, patients with chronic heart failure can progress from stage A to stage D but cannot return to a previous stage. According to the NYHA classification, however, patients with class 4 symptoms can improve quickly in response to diuretic therapy alone and return to class 3.

Patients who receive treatment when they are asymptomatic or when their ventricular function is only moderately reduced have a better prognosis and quality of life. This is why it is so important to detect chronic heart failure in the early stages of ventricular dysfunction.

2.7.6 Pathophysiology

Various models are combined to explain the pathophysiology of chronic heart failure /8/:

  • The hemodynamic model, which is based on an altered volume load on the failing ventricle and the remodeling that results from this
  • The neurohormonal model, in which activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system plays an important etiological role
  • Finally, the failure of autocrine and paracrine vasoactive substances that are synthesized by the myocardium in response to the stretching of cardiac muscle plays a role. Among these substances is B-type natriuretic peptide.

2.7.6.1 Cardiac muscle remodeling

When the heart muscle is injured by myocardial necrosis or as a result of pressure and volume overload, blood supply to perfuse organs adequately is not possible. This condition induces left ventricular remodeling, a process in which the size, structure, and function of the ventricle are altered by mechanical, neurohormonal, and possibly genetic factors. The aim of this process is to preserve the cardiac output. This type of process continues for months after myocardial infarction and the associated ventricular alterations can adversely affect the heart’s ability to pump blood /9/. Mitral valve insufficiency or conduction defects, for example, can occur as a result of remodeling.

During remodeling, myocytes respond with eccentric rather than physiological hypertrophy at cellular level. Physiological hypertrophy is characterized by a proportional increase in the length and width of cardiac myocytes. The assembly of contractile-protein units in series characterizes the eccentric hypertrophy. The length of myocytes is increased more than the width. When the ventricle is subject to pressure overload, new contractile proteins are added to myocytes in parallel so that there is a relative increase in the width of myocytes resulting in concentric hypertrophy of the ventricle /10/.

In hypertrophic cardiomyopathy, mutated contractile proteins are produced. This disturbs the arrangement of myofibrils, which leads to secondary hypertrophy of myocytes. This type of cardiac hypertrophy features increased expression of embryonic genes in the myocytes (e.g., for natriuretic peptide or fetal contractile proteins). The induction of genes for producing natriuretic peptides and thus the production of these peptides is a prognostic indicator of the clinical severity of dilated cardiomyopathy /10/.

2.7.6.2 Hemodynamic and hormonal mechanisms in chronic heart failure

Diminished cardiac output in low-output heart failure or reduced peripheral vascular resistance in high-output heart failure is associated with atrial under filling /11/. Baroreceptor-mediated neurohumeral events are initiated, particularly the activation of the sympathetic nervous system, the activation of the renin-angiotensin-aldosterone system, and the non osmotic release of vasopressin. All the systems maintain arterial perfusion of vital organs. These neurohumeral reflexes may have deleterious affects. In the acute phase arterial blood pressure is increased and ensures that vital organs are adequately perfused. However, chronic stimulation of these systems leads to persistent inadequate peripheral vasoconstriction, volume retention, and inefficient inotropic stimulation. The consequences include pulmonary edema, hyponatremia, increased cardiac after load, and cardiac remodeling. This altered hemodynamic, functional, and metabolic status gives rise to the cardinal symptoms of chronic heart failure such as exercise intolerance, easy fatigability, and dyspnea /12/.

2.7.6.2.1 Blood volume in chronic heart failure

Congestive heart failure is characterized by increased total body-fluid in combination with ventricular insufficiency. In patients with chronic heart failure, Na+ and water are paradoxically retained despite increased intravascular volume /11/. This is because the integrity of the arterial circulation, in which the left ventricular ejection fraction and peripheral arterial resistance play a crucial role, is the main determinant of renal water and Na+ excretion (Fig. 2.7-1 – Causes and consequences of reduced arterial blood volume in chronic heart failure).

2.7.6.2.2 Renin-angiotensin-aldosterone system (RAAS) and chronic heart failure

Patients with mild heart failure may have little or no increase in plasma renin and aldosterone /11/. Unlike primary hyperaldosteronism, the hyperaldosteronism associated with chronic heart failure and Na+ and water retention is persistent (see also Chapter 31 – Mineralocorticoid excess).

In primary hyperaldosteronism, Na+ retention initially leads to an increase of 1.5–2 liters in the extracellular fluid volume. However, Na+ retention than ceases Na+ balance is reestablished and there is no edema (escape phenomenon).

In chronic heart failure, this “escape” from the action of aldosterone does not occur and therefore patients continue to retain Na+ in response to aldosterone /11/. This failure of the escape phenomenon in chronic heart failure is caused by increased Na+ reabsorption in the proximal tubule, which means that less Na+ reaches the collecting ducts.

The increased reabsorption of Na+ in the proximal tubule is due to increased α-adrenergic and angiotensin II stimulation in chronic heart failure (Fig. 2.7-2 – Mechanisms by which arterial hypovolemia leads to reduced delivery of sodium and water at the distal tubule of the kidney). In patients with chronic heart failure, angiotensin II causes constriction of the afferent and efferent arterioles. It stimulates contraction of glomerular mesangial cells, which leads to a reduced glomerular filtration surface.

2.7.6.2.3 Arginine vasopressin release in chronic heart failure

Non-osmotic release of arginine vasopressin in chronic heart failure may lead to increased water retention and hyponatremia. Hyponatremia may be caused by increased water intake in response to increased thirst /11/. In normal individuals, arginine vasopressin secretion should be inhibited in the case of plasma hypo osmolality. This is not the case in chronic heart failure. On the contrary, persistently elevated concentrations of arginine vasopressin are recorded.

2.7.6.2.4 Natriuretic peptides and chronic heart failure

Type A and type B natriuretic peptides (e.g., ANP, BNP) are released by cardiomyocyte stretching in the atria and ventricles and their concentration in the blood increases when intraatrial pressure is increased. The natriuretic peptides exert an effect on the kidneys /11/. They dilate the afferent arterioles and constrict the efferent arterioles in the glomeruli, which increases the glomerular filtration rate. ANP and BNP lead to reduced reabsorption of Na+ in the collecting ducts and, thereby, increasing Na+ excretion. Because even in the early phase of chronic heart failure, concentrations of natriuretic peptides are increased in the blood, ANP and BNP are sensitive markers of chronic heart failure. See also Tab. 2.8-2 – Behavior of BNP and NT-proBNP in disease states.

2.7.6.2.5 Endothelial hormones and chronic heart failure

Prostaglandin E and prostacyclin are produced from arachidonic acid in many cells. Both hormones have a vasodilatory effect and therefore counteract the neurohumoral renal vasoconstriction effects that are present in chronic heart failure /11/. Nitric oxide (NO) synthesized by endothelial cells is also a vasodilator. It works together with the natriuretic peptides to antagonize the neurohormonal compensation mechanisms in chronic heart failure.

Endothelin, on the other hand, is a potent vasoconstrictor that is found in high concentrations in the blood of patients in NYHA classes III and IV. High endothelin levels are associated with a poor prognosis.

2.7.6.2.6 Effect of regulatory and counter-regulatory mechanisms in chronic heart failure

As long as the neurohormonal systems that cause vasoconstriction and fluid retention are completely antagonized by the natriuretic peptides, chronic heart failure remains asymptomatic and cardiac remodeling is slowed down.

If the natriuretic peptides can no longer completely counteract these neurohormonal systems, patients develop the typical heart failure symptoms described in NYHA II. In advanced heart failure, concentrations of catecholamines, renin and aldosterone, and endothelin are elevated.

As heart failure progresses (from NYHA III on), renal perfusion is compromised. This results in even greater stimulation of the renin-angiotensin-aldosterone and sympathetic nervous systems as well as increased peripheral vascular resistance.

Even though the natriuretic peptides are produced in large amounts, they begin to lose their effect on the kidneys, which leads to increased retention of sodium and water. This increases the intravascular volume and promotes cardiac dilatation, which leads to a further deterioration in cardiac function.

2.7.6.2.7 Severity of chronic heart failure

With respect to the severity of chronic heart failure, there is a clear relationship between clinical symptoms, the extent of the dysfunction, and the patient’s prognosis. The best predictor of the severity and prognosis of chronic heart failure is left ventricular function, which is assessed by determining the ejection fraction (EF).

2.7.6.2.8 Biomarkers in chronic heart failure

Biomarkers can be used to:

  • Estimate the extent of the disturbances in water and Na+ balance caused by chronic heart failure
  • Ascertain the supply of O2 to cardiac muscle
  • Assess the severity of chronic heart failure
  • Monitor therapy.

The assessment of specific biomarkers in chronic heart failure is the shown in:

References

1. Von Scheidt W. Diagnostik der Herzinsuffizienz. Internist 2000; 41: 115–26.

2. Khunti K, Baker R, Grimshaw G. Diagnosis of patients with chronic heart failure in primary care: usefulness of history, examination, and investigations. Br J General Practice 2000; 50: 50–4.

3. McKee PA, Kastelli WP, Mc Namara PM, Kannel WB. The natural history of congestive heart failure: the Framingham Study. N Engl J Med 1971; 285: 1441–6.

4. Neumann T, Biermann J, Neumann A, Wasem J, Ertl G, Dietz R, Erbel R. Herzinsuffizienz: Häufigster Grund für Krankenhausaufenthalte. Dtsch Ärztebl 2009; 106: 269–75.

5. McDonagh TA, Morrison CE, Lawrence A, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet 1997; 350: 829–33.

6. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganists TG, et al. ACC/AHA guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology and the American Heart Association Task Force on Practise Guidelines (Writing Committee to update the 2001 Guidelines for the Evaluation and Management of Heart Failure). Circulation 2005; 112, 12: e154-e235.

7. Criteria Committee, New York Heart Association Inc. Diseases of the heart and blood vessels. Nomenclature and criteria for diagnosis. 6th edn. Boston, Little Brown; 1973: 286.

8. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology and the American Heart Association Task Force on Practise Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001; 38: 2101–13.

9. Jessup M, Brozena S. Heart failure. N Engl J Med 2003; 348: 2007–18.

10. Hunter JJ, Chien KR. Signalling pathways for cardiac hypertrophy and failure. N Engl J Med 1999; 341: 1276–83.

11. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med 1999; 341: 577–85.

12. Mair J, Puschendorf B. Kardiale Diagnostik. In: Thomas L, ed. Labor und Diagnose, S 121–58. Frankfurt 2005; TH-Books.

2.8 B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP)

BNP is a 32 amino acid cardiac peptide is produced in the ventricular myocardium and is stored in modest quantities. BNP reduces blood pressure and increases Na+ excretion. In response to hemodynamic load in the ventricles, the pre-proBNP is converted into proBNP, which is rapidly cleaved to form BNP and NT-proBNP. BNP is hormonally active, whereas NT-proBNP is inactive. BNP functions physiologically as a natriuretic peptide (NP). The natriuretic peptides are natural antagonists of the renin-angiotensin-aldosterone system and sympathetic nervous system. They act in a coordinated manner centrally and peripherally to control fluid and electrolyte balance.

BNP and NT-proBNP are released from cardiac myocytes in response to ventricular wall stress. Wall stress is directly related to the ventricular diameter and transmural pressure and inversely correlated with ventricular thickness. Increased left ventricular diameter and pressure increase the production of BNP and NT-proBNP, which leads to higher concentrations in the blood.

BNP and NT-proBNP levels are increased in heart failure (HF) and their concentration in the blood rises with the extent and duration of ventricular dysfunction.

2.8.1 Indication

Conditions of the heart accompanied by volume and pressure overload /1234/:

  • Aid in the diagnosis of individuals suspected of having heart failure (e.g., in acute onset of dyspnea)
  • Detection of mild forms of cardiac dysfunction
  • Aid in the assessment of heart failure severity
  • Risk stratification of patients with acute coronary syndrome and congestive heart failure
  • Monitoring of treatment in patients with left ventricular dysfunction.

2.8.2 Method of determination

BNP assays use different antibodies and materials for peptide detection /5/. There is a paucity of standardization and differences up to 50% across various BNP assays are reported.

Laboratory BNP assay

Principle: BNP in the sample reacts with a BNP-specific antibody bound to a solid phase and a second, labeled indicator antibody to form a sandwich complex. The most frequent methods use antibodies specific for two distantly located epitopes of the peptide. One of these antibodies is specific for the intact cysteine ring, while the other antibody recognizes the C-terminus of BNP /5/. The indicator antibody is labeled using an enzyme, a luminescence label, or radioactivity /6/.

Point of care BNP assay /8/

Principle: sandwich immunoassay with two monoclonal antibodies that are directed against different epitopes of the BNP ring structure. The indicator antibody is labeled with a fluorescence label. The fluorescence emitted is measured using a detector. Whole blood is used as the sample material.

Laboratory NT-proBNP assay /9/

Principle: NT-proBNP in the sample reacts with a biotinylated polyclonal NT-proBNP-specific antibody and a ruthenium-labeled antibody to form a sandwich complex. Streptavidin-coated micro particles are then added and the sandwich complex binds to the micro particles by means of an interaction between streptavidin and biotin. The micro particles attach magnetically to the surface of an electrode in the measuring cell of the analyzer. Once the unbound components have been removed, chemiluminescence is induced by applying a voltage and the chemiluminescence emission is measured using a photomultiplier. The antibodies are of monoclonal origin and recognize the amino acids 22–28 and 42–46 of the central region of NT-proBNP.

Point of care NT-proBNP assay /10/

The assay is performed as an immunoassay with reagents on multi layer film slides. A gold-labeled monoclonal antibody recognizes amino acid sequence 27–31 on NT-proBNP and the biotinylated polyclonal antibody recognizes the sequence 42–46.

2.8.3 Specimen

Point of care test (POCT)

  • BNP: EDTA blood: 0.1–1 mL
  • NT-proBNP: EDTA or heparinized blood: 0.1–1 mL

Automated analyzer assays

  • BNP: EDTA plasma: 1 mL
  • NT-proBNP: EDTA or heparinized blood: 1 mL

2.8.4 Reference interval

The reference intervals depend on the assay used; refer to the instructions provided by the assay manufacturer (Tab. 2.8-1 – Age and manufacturer-specific upper reference limits for BNP and NT-proBNP).

2.8.5 Clinical significance

The results of the BNP and NT-proBNP assays are diagnostically and prognostically important in cardiology.

2.8.5.1 Diagnostic significance of BNP and NT-proBNP

Physiological and pathological conditions associated with volume expansion and/or stretching of the left ventricular myocardium lead to the release of BNP and NT-proBNP. Age and gender are the main factors that determine the concentration of BNP and NT-proBNP in healthy individuals. Since the assays for these cardiac markers are not standardized, the manufacturer’s specifications regarding the upper reference limits must be observed when evaluating the results. The concentrations of BNP and NT-proBNP increase with increasing age and are higher in women than in men. Because of these factors and differences between assays, standardized upper reference limits for BNP and NT-proBNP for diagnosing heart failure do not exist. However, diagnostic algorithms are available.

The incidence of heart failure increases with age. Around 10% of individuals over 65 years of age and more than 50% of individuals aged over 85 years have heart failure. Measured BNP or NT-proBNP concentrations must always be assessed in conjunction with the history, clinical picture, and other investigations (e.g., echo-cardiography and ECG.)

A flow diagram for diagnosing untreated patients with suspected heart failure and the differential diagnostic significance of BNP and NT-proBNP are shown in Fig. 2.8-1 – Interpretation of BNP and NT-proBNP concentrations in patients with acute dyspnea /4/. In patients who present with dyspnea and reduced exercise tolerance, NT-proBNP has a diagnostic sensitivity of 88%, a specificity of 92%, a positive predictive value of 96.7%, and a negative predictive value of 80.6% /13/. The negative predictive value of a NT-proBNP concentration below 300 ng/L is 98%. If values are greatly increased, systolic heart failure is often present.

Many patients with heart failure have normal systolic function but abnormal diastolic function. Diastolic heart failure has a similar mortality to systolic heart failure. Echo cardiography reveals a ventricular filling defect. BNP concentrations above 100 ng/L and NT-proBNP concentrations above 220 ng/L point to this type of heart failure, but echo cardiography is required to confirm it.

Patients with acute dyspnea and congestive heart failure generally have higher BNP and NT-proBNP concentrations than those with non-acute heart failure. When BNP and NT-proBNP assays with age and gender-specific cutoff values are used as a screening test for heart failure in the population (aged ≥ 45 years), they have a diagnostic sensitivity and specificity of 75–100% for detecting individuals with a left ventricular ejection fraction of ≤ 40%. Both parameters have approximately the same significance /14/.

When patients with acute dyspnea are admitted to hospital, a BNP or NT-proBNP determination can be used to distinguish between those with and without cardiac dysfunction (Fig. 2.8-1 – Interpretation of BNP and NT-proBNP concentrations in patients with acute dyspnea).

An important factor to consider when evaluating the BNP and NT-proBNP concentration is whether renal insufficiency is present. The concentrations of both biomarkers rise as the glomerular filtration rate decreases, which influences the cutoff value for patients with renal disease /16/.

Obese patients have lower BNP and NT-proBNP values /17/. A possible reason for this is that BNP is cleared more quickly from adipose tissue.

The behavior of BNP and NT-proBNP in cardiac dysfunction is shown in Tab. 2.8-2 – Behavior of BNP and NT-proBNP in disease states. The behavior of BNP and NT-proBNP in dyspnea is shown in Tab. 2.8-3 – NT-proBNP in patients with acute dyspnea with and without heart failure (HF).

The in-hospital mortality of acute coronary syndrome as a function of the BNP value is shown in:

Both BNP and NT-proBNP perform well to rule-out, but less to rule-in, in the diagnosis of heart failure among persons presenting to emergency departments or urgent care centers. For BNP, 100 ng/L appears to be a consensus point. No clear consensus has emerged for NT-proBNP, but the age-adjusted cutoffs of 450 ng/L for < 50 years, 900 ng/L for 50–75 years, and 1,800 ng/L for > 75 years appear promising /2/. In patients with septic shock and gold standard therapy NT-proBNP levels > 1,000 ng/L at 72 hours were associated with adverse outcome (mortality at 28 days) /7/.

2.8.5.2 Prognostic significance of BNP and NT-proBNP

BNP and NT-proBNP are better prognostic indicators than the NYHA classification in patients with chronic heart failure. In patients with stable angina pectoris, BNP and NT-proBNP concentrations provide information about cardiovascular events in the longer term and about mortality. In patients with a recent history of myocardial infarction, both markers provide information about left ventricular function, infarct size, and survival. BNP and NT-proBNP are also useful prognostic markers in volume overload associated with acute coronary syndrome, atrial fibrillation, and pulmonary embolism.

2.8.6 Comments and problems

Specimen

For BNP assays, EDTA plasma is the recommended specimen and for NT-proBNP the recommended specimen is serum.

Method of determination

The BNP and NT-proBNP values depend on the type of assay used, the antibody specificity, and the calibration sample. To use these markers correctly in everyday clinical practice, it is important to observe the manufacturer’s specifications regarding reference intervals /1246/. Overall, according to a systematic review /47/, BNP and NT-proBNP demonstrate a high degree of diagnostic accuracy without significant difference in the odds ratio (OR) for diagnosing chronic heart failure (ORBNP 8.4; ORNT-proBNP 23.4) and acute heart failure (ORBNP 16.5; ORNT-proBNP 18,6).

BNP or NT-proBNP results are not transferable among the current existing immunoassays owing to their differences in cross-reactivity and ability to detect various glycosylated forms of proBNP-derived fragments /48/. NT-proBNP assays are generally considered harmonized because all utilize one manufacturers antibodies and calibrators which are then configured to other manufacturers’immunoassay platforms.

BNP sampling

If an immunoassay with a combination of antibodies against epitopes of the amino acids 90–97 and 103–107 is used, the blood should be drawn in a plastic tube that contains EDTA /49/.

NT-proBNP sampling: serum tube or tube that contains lithium or NH4+ heparin. Separator gel does not interfere with the assay. Values can be up to 10% lower in EDTA plasma than in serum.

Stability

Stability of BNP /49/: measurements should be performed within 4 hours if blood is stored at room temperature. If this is not possible, the plasma should be separated from the corpuscular components and can be stored in a tube containing a kallikrein or serine protease inhibitor at 4 °C for up to 72 hours. Storage at –80 °C up to 1 year.

NT-proBNP stability /50/: stable in whole blood and plasma at room temperature or 4 °C for up to 72 hours –80 °C.

Influence factors

Blood sampling: should not take place following stressful investigations such as ergometry or stress echo cardiography. Under such conditions, BNP or NT-proBNP levels can also be increased in healthy individuals /51/.

Medications: diuretics, ACE inhibitors, and beta-blockers can reduce the plasma BNP concentration. A baseline value should be determined before treatment is started. The administration of synthetic BNP (natrecor, nesiritide) can lead to elevated BNP values. Administration of neutral endopeptidase inhibitors (e.g., omapatrilat) can influence the plasma concentration of BNP by inhibiting its breakdown. Treatment with these medications does not affect NT-proBNP values.

Dietary sodium loading: increased dietary sodium intake from 10 g (171 mmol)/day to 30 g (513 mmol)/day over a period of 5 days leads to a 53% increase in the BNP concentration. Although NT-proBNP is released in equimolar amounts, it has a longer half-life than BNP, so its concentration increases more steeply than that of BNP in response to chronic dietary sodium loading /52/.

Age and gender /53/: every 10 years from the age of 45, BNP increases by up to 50% and NT-pro-BNP increases by up to 74% on average. Women have higher BNP and NT-proBNP values than men of the same age.

Physical exertion: a rise in BNP concentration of 143% compared to baseline can be measured in subjects 1 minute after completing a standard treadmill ergometry protocol /54/. BNP values measured 15 minutes after a marathon are up to 211% higher than baseline values /51/. The heart rate also influences the concentration of BNP and NT-proBNP. For every increase in heart rate of 10 beats per minute, the concentration of BNP falls by 9% and the concentration of NT-proBNP falls by 15% /53/.

Body mass index: obesity is associated with glomerular hyper filtration and lower age-related NT-proBNP values. The estimated glomerular filtration rate (eGFR) should therefore be taken into account when evaluating NT-proBNP values. However, the Cockcroft-Gault formula should be used since it takes age and weight into account. A fall in the eGFRC-G of 10% is associated with a 9% increase in the NT-proBNP concentration /55/.

Intraindividual variation: in healthy individuals and patients with stable heart failure, the coefficient of variation (%) from week to week was 40% for BNP /56/ and 35% for NT-proBNP /5/.

Hospitalization days and costs of patients with elevated NT-proBNP: patients with heart failure (HF) are reportedly at high risk for all-cause re-hospitalization. Compared to HF-negative patients, the HF-positive patients had longer total hospitalization days (median 18 versus median 30). Medical costs for hospitalization were 0.76 million yen versus 2.38 million yen /57/.

2.8.7 Pathophysiology

The natriuretic peptides ANP, BNP, and C-CNP are characterized by a 17 amino acid ring structure with a disulfide bond between 2 cysteine residues (Fig. 2.8-5 – Cleavage of B-type natriuretic pro hormone (proBNP 1–108)). The ring structure is crucial for receptor binding and biological functions. The pro hormones are coded by separate genes. ANP and BNP are synthesized by ventricular myocytes during periods of increased vascular stretch and wall tension. In left ventricular dysfunction, ventricular hypertrophy, and other cardiac dysfunctions with chronically increased hemodynamic pressure or volume overload, ventricular myocytes undergo modification and start to re express fetal genes that code for increased synthesis of ANP and BNP /2/.

ANP is stored in secretory granules in the cardiac myocytes and is released rapidly in response to volume overload in the extracellular space. BNP, however, is not secreted from storage granules, but is released in bursts that are regulated by gene expression. Left ventricular myocardial stretching acts as a stimulus for this.

The natriuretic peptides exert their effects via three cell membrane receptors that transmit their signals to the inside of the cell by means of the guanylate cyclase pathway. Natriuretic peptide receptor A is activated preferentially by BNP and ANP and receptor B is activated with higher affinity by CNP and lower affinity by ANP and BNP. Natriuretic peptide receptor C is located in the liver, lungs, renal tubules, and vascular endothelium and removes natriuretic peptides from the circulation.

ANP and BNP act as antagonists of the renin-angiotensin-aldosterone system and sympathetic nervous system. Guanylate cyclase type A receptors are distributed throughout the body but the highest receptor density is found in the zona glomerulosa of the adrenal cortex and in the collecting ducts of the inner renal medulla. Atrial natriuretic peptides exerts its effects at the levels /58/:

  • Of the glomerulus, it causes efferent arteriolar constriction and afferent arteriolar dilation, thereby causing a temporary increase of the glomerular filtration. The excretion of is Na+ increased.
  • In the collecting duct, it causes a long-term decrease of Na+ reabsorption, thereby increasing Na+ excretion.

The physiological effects of ANP and BNP are listed in Tab. 2.8-5 – Effects of ANP and BNP.

The BNP gene encodes a 134 amino acid pre-proBNP precursor, which is converted to a 108-amino acid proBNP by the cleavage of a 26-amino acid signal peptide. The proBNP is cleaved by the serine protease corin in the cardiomyocytes to form BNP (amino acids 77–108) and the biologically inactive NT-proBNP (amino acids 1–76). BNP has a molecular weight of 3.5 kDa and NT-proBNP has a molecular weight of 8.5 kDa. Both peptides are released in equimolar amounts into the circulation. The half-life of BNP is around 20 minutes and the half-life of NT-proBNP is 1–2 hours /2/.

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Table 2.1-1 Assessment of cardiovascular risk using algorithms and scores

Assessment of cardiovascular risk

Framingham /7/

The Framingham score study estimates the individual risk of mortality from myocardial infarction or other coronary heart disease within the next 10 years. The risk estimate is based on a score developed in the Framingham Heart Study (USA). The score is calculated from the points awarded for individual risk factors. Risk factors include gender, age, cholesterol, systolic blood pressure, use of antihypertensive medication, and smoking. The risk is specified as a percentage. Along with patients whose risk of myocardial infarction in the next 10 years is greater than 20%, patients with existing coronary heart disease, other forms of atherosclerosis, and diabetes mellitus are also considered high-risk patients. The Framingham algorithm can be accessed at www.chd-taskforce.de. Not all patients who experience a first coronary event fit this traditional risk profile. Furthermore, risk is also reduced by factors that are not included in the score. The Nurses’ Health Study, for example, has shown that individuals can reduce their coronary risk by 84% by modifying their daily behavior (e.g., by engaging in physical activity and consuming moderate amounts of alcohol) /11/. Around 31% of asymptomatic men and 7% of women in the USA aged between 40 and 79 years and who do not suffer from diabetes are considered to be at medium risk. There is a lack of consensus about whether, and how, these individuals should be treated. If hsCRP is also assayed, around 11% of men in the medium-risk group are reassigned to the high-risk group and 12% are assigned to the low-risk group /12/.

PROCAM /6/

The PROCAM risk calculator estimates an individual’s risk of suffering myocardial infarction in the next 10 years. The risk assessment is based on data from the Prospective Cardiovascular Münster (PROCAM) study. The score is calculated from the points awarded for individual risk factors. Risk factors include gender, age, LDL cholesterol, HDL cholesterol, triglycerides, systolic blood pressure, smoking, diabetes mellitus, and positive family history (father, mother, brother, sister, son, or daughter suffered myocardial infarction before the age of 60 years). Risk can be estimated using an algorithm (www.chd-taskforce.de) or a points system (score). Individuals in the low-risk group (< 10% risk of myocardial infarction in the next 10 years) have a PROCAM score ≤ 41 points, those in the medium-risk group (10–20%) have a score of 42–50, and those in the high-risk group (> 20%) have a score of over 50 points. Along with individuals who are at risk of myocardial infarction in the next 10 years, patients who currently suffer from angina pectoris or those who have suffered myocardial infarction or stroke in the past are also classified as high-risk patients. The PROCAM risk calculator can be accessed at www.chd-taskforce.de.

ESC score /9/

The European Society of Cardiology (ESC) has developed a score to estimate the 10-year risk of a fatal cardiovascular event based on the blood pressure, cholesterol concentration, age, gender, and smoking for high and low risk regions (Fig. 2.1-1 – European Society of Cardiology cardiovascular risk score). Regardless of the score, risk is increased if the following criteria are present:

  • Atherosclerosis
  • or diabetes mellitus
  • or chronic renal insufficiency
  • or cholesterol above 300 mg/dL (8 mmol/L)
  • or LDL cholesterol above 232 mg/dL (6 mmol/L)
  • or blood pressure above 180/110 mmHg
  • or multiple risk factors that contribute to an estimated risk of fatal cardiovascular event of above 5% in the next 10 years.

Table 2.1-2 New risk markers for the primary prevention of cardiovascular disease (CVD)

Clinical and laboratory significance

New risk markers – Generalized

The National Academy of Clinical Biochemistry has proposed a list of biomarkers as “emerging risk factors” /10/.

Inflammation markers – Generalized

Fibrinogen and hsCRP levels and leukocyte count were included in the selection. Increased fibrinogen and hsCRP concentrations and increased leukocyte counts are all independently associated with an increased risk of cardiovascular disease.

Fibrinogen assay is not recommended due to analytical difficulties and a lack of standardization. Clear criteria for classifying cardiovascular risk based on the leukocyte count do not yet exist.

– hsCRP

A high-sensitivity C-reactive protein (hsCRP) assay classifies patients as follows: a) low risk < 1 mg/L; b) medium risk 1–3 mg/L; c) high risk > 3 mg/L; d) values ≥ 10 mg/L are not classified, repeat assay when any existing inflammation has resolved. If the value is below 3 mg/L, the test does not have to be repeated. A CRP concentration above 10 mg/L suggests acute inflammation and cannot be used to evaluate cardiovascular risk. The test must be repeated once the acute phase has passed. If the CRP concentration is between 3 and 10 mg/L, the test should be repeated. The lower value is then taken as the true value. Concentrations above 3 mg/L are probably associated with cardiovascular risk. hs-CRP should not be measured if the Framingham score is below 10%. If the Framingham score is 10–20%, hsCRP measurement can help clinicians to decide whether to initiate preventive therapy (statins, aspirin). Preventive therapy should be initiated if the hsCRP concentration is > 3mg/L. When hsCRP is measured as a single parameter, concentrations above 3mg/L are associated with a 1.58-fold increase in the relative risk of coronary heart disease (confidence interval 1.37–1.83) compared to concentrations below 1mg/L /11/.

Lipoprotein subclasses – Generalized

Although the concentration of small LDL particles is increased in incipient cardiovascular disease, LDL assay is not recommended due to analytical difficulties. Furthermore, the LDL size or the presence of small dense LDL no longer represent independent risk factors if triglycerides, HDL cholesterol, and glucose are taken into account.

– Lipoprotein(a)

Lipoprotein(a) concentrations are elevated if they are above a cut-off value of ≥ 300 mg/L. More recently, the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) have even recommended a cutoff value of 600 mg/L as an indicator of increased cardiovascular risk. Assays of Lp (a) should not be used to assess coronary risk for the purposes of primary prevention. However, there are some exceptions to this:

  • If risk scores indicate intermediate risk (10–20%) and preventive therapy is being considered
  • In individuals with a family history of CVD, to establish whether a predisposition exists

The coronary risk in individuals with a Lp(a) value above 300 mg/L is increased by a factor of 1.59 (confidence interval 1.29–1.79) compared to those with a value below 300 mg/L /11/. As yet, there is not enough data to support using Lp (a) determination to monitor therapy.

Apolipoproteins

The first step in evaluating a lipid-lowering therapy is to measure the LDL cholesterol. ApoB is at least as reliable as LDL cholesterol as a biomarker for assessing coronary risk. However, there are no practical advantages to measuring ApoB since preventive therapeutic targets have been defined for LDL cholesterol. The ApoB/ApoA1 ratio can also be used instead of the total cholesterol/HDL cholesterol ratio to evaluate cardiovascular risk.

Renal function

The following biomarkers should be determined for all patients with hypertension, diabetes mellitus, a family history of cardiovascular disease, and those with an intermediate cardiovascular risk: glomerular filtration rate (estimated GFR) and urinary albumin excretion.

Cardiac troponin

See Section 2.4 – Cardiac troponins (cTn).

Homocysteine

Its clinical application as a risk factor for cardiovascular disease is controversial. The risk is estimated based on the values (μmol/L): ≤ 10 desirable; > 10 to < 15 intermediate; ≥ 15 to < 30 high; ≥ 30 very high. Treating patients with elevated homocysteine values does not reduce the coronary risk /11/.

Natriuretic peptide

Elevated BNP and NT-BNP values are associated with increased cardiovascular morbidity and mortality in the following 2–7 years. It has also been shown for BNP and NT-ProBNP as well as sensitive troponin I and T that, unlike all other new risk factors (including hsCRP), risk prediction can be improved by using classic risk prediction models such as the Framingham model. BNP and NT-proBNP are not yet recommended as screening tests for the primary prevention of cardiovascular disease, however.

Adiponectin /12/

Adiponectin increases insulin sensitivity and plays an important role in regulating glucose and lipid metabolism. The adiponectin concentration falls as the amount of adipose tissue increases. Therefore, obese patients with type 2 diabetes, essential hypertension, dyslipidemia, and cardiovascular disease have lower blood concentrations of adiponectin than individuals of normal weight. Weight loss leads to increased adiponectin levels. A protective effect against the development of insulin resistance and type 2 diabetes has been attributed to adiponectin. Low adiponectin concentrations lead to increased release of pro inflammatory cytokines from adipose tissue and therefore promote the development of atherosclerosis.

Myeloperoxidase (MPO)

MPO is released from activated granulocytes and monocytes during inflammation. MPO increases the oxidative potential of H2O2 to form HOCL through the per oxidation of chloride. MPO promotes atherosclerosis through the oxidation of LDL, which leads to the formation of foam cells, which in turn leads to the formation of fatty streaks and atheromas. Several studies have found an independent association between MPO and cardiovascular risk, in particular the occurrence of heart failure. It has also been shown in patients with acute coronary syndrome that risk stratification is improved by using MPO in addition to clinical criteria (e.g., TIMI score). Therefore, MPO predicts cardiovascular events within 30 days and after 6 months in patients with acute coronary syndrome and negative troponin results. EDTA plasma specimens are used and the upper reference limit is 633 pmol/L (95th percentile) /13/.

Table 2.2-1 Definitions of the metabolic vascular syndrome. With friendly permission as per Lit. /2/

Criteria

WHO

EGIR

NCEP-ATP III

AHA/NHLBI

IDF

JIS

Abdominal adiposity

BMI > 30 kg/m2 and/or WHR > 0.9 for men and > 0.85 for women

WC ≥ 94 cm for men and ≥ 80 cm for women

WC > 102 cm for men and > 88 cm for women

WC > 102 cm for men and > 88 cm for women

WC ≥ 94 cm for men and ≥ 80 cm for women

WC ≥ 94 cm for men and ≥ 80 cm for women

Arterial pressure

≥ 140/90 mmHg

≥ 140/90 mmHg

≥ 130/85 mmHg

≥ 130/85 mmHg

≥ 130/85 mmHg

≥ 130/85 mmHg

HDL cholesterol

< 35 mg/dL for men or < 39 mg/dL for women

< 39 mg/dL for men and women

< 40 mg/dL for men and < 50 mg/dL for women

< 40 mg/dL for men and < 50 mg/dL for women

< 40 mg/dL for men and < 50 mg/dL for women

< 40 mg/dL for men and < 50 mg/dL for women

Triglycerides

> 150 mg/dL

> 150 mg/dL

> 150 mg/dL

> 150 mg/dL

> 150 mg/dL

> 150 mg/dL

Fasting glucose

> 110 mg/dL or IFG

> 110 mg/dL

> 100 mg/dL

> 100 mg/dL

> 100 mg/dL

Mikro-Albuminuria

Excretion rate ≥ 20 μg/min or albumin/ creatinine ratio ≥ 30 mg/g

Present MS when:

IGT, IFG, IR and/or T2DM and at least two more criteria

IR and at least two more criteria, but no T2DM

At least three criteria

At least three criteria

Abdominal adiposity and at least two more criteria

At least three criteria

AHA/NHLBI, American Heart Association/National Heart, Lung and Blood Institute; BMI, body mass index; EGIR, European Group for Study of Insulin Resistance; IDF, International Diabetes Federation; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IR, insulin resistance; JIS, Joint Interim Statement; MS, metabolic syndrome; T2DM diabetes mellitus type 2; WC, waist circumference; WHR, waist/hip ratio.

NECP ATP III, National Cholesterol Education Program Adult Treatment Panel III; IDF, International Diabetes Federation (IDF); FPG, fasting plasma glucose. The IDF defines central obesity as a waist circumference ≥ 90 cm for men and ≥ 80 cm for women in the Chinese and South Asian population (Malay and Asian Indian) and ≥ 90 cm for men and ≥ 85 cm for women in the North Japanese population. The European values also apply to Sub-Saharan Africans and the eastern Mediterranean and Middle East populations.

Table 2.2-2 Individual components of the metabolic vascular syndrome (MVS)

Clinical and laboratory findings

Overweight/obesity

Overweight and obesity are defined by the WHO as a body mass index (BMI) ≥ 25 kg/m2 (overweight) and ≥ 30 kg/m2 (obesity). In children, a BMI above the 85th percentile is classified as overweight and above the 95th percentile is classified as obesity. The BMI is calculated from the weight (kg)/(height [m])2. Since the metabolic syndrome is associated with central obesity, the waist circumference rather than the weight is specified as a diagnostic criterion. According to NECP ATP III, central obesity is defined as a waist circumference greater than 88 cm in women and greater than 102 cm in men. The IDF defines this criterion more narrowly (Tab. 2.2-1 – Definitions for metabolic vascular syndrome). Although obesity has a multifactorial etiology, the main cause is energy imbalance. Energy imbalance occurs when calorie intake is higher than energy expenditure. It leads to increased energy storage in the adipocytes, which increase both in size as a result of fat accumulation (hypertrophy) and in number (hyperplasia). When the storage capacity is exceeded, this produces stress and dysfunction in the mitochondria and endoplasmic reticulum /24/. This involves the production of adipokines, free fatty acids, and pro inflammatory cytokines. The adipokines, which include adiponectin, leptin, resistin, and ghrelin, circulate in the blood and exert a central influence over energy consumption and requirements. They induce systemic low-grade inflammation, insulin resistance, atherosclerosis, nonalcoholic steatohepatitis, and type 2 diabetes. In summary, obesity is a metabolic and cardiovascular risk factor.

In 2016 the WHO estimated that, globally, the prevalence of pediatric overweight and obesity was 18%. The prevalence of metabolic syndrome among adolescents with obesity has been reported to be as high as 60%, and is associated with the development of prediabetes, type 2 diabetes, and a twofold increase in the risk of coronary artery disease and stroke, and a 1.5-fold increase in the risk of all-cause mortality even in early adulthood. In a study /37/ in post-pubertal aged 14–18 years with BMI ≥ 30 kg/m2 the following thresholds for abnormal results indicating comorbitidies among adolescents with obesity were used: waist circumference (males > 96 cm, females > 80 cm), prediabetes (fasting glucose ≥ 5.6 mmol/L) (HbA1c ≥ 39 mmol/mol), insulin resistance (HOMA-IR increased), blood pressure ≥ 95. percentile, lipid profile (LDL males ≥ 1.03 mmol/L, females ≥ 1.29 mmol/L), cholesterol > 5.2 mmol/L, CRP > 5.0 mg/L, uric acid (males > 417 umol/L, females > 340 umol/L), liver function (aminotransferases elevated).

Insulin resistance /19/

The term “insulin sensitivity” refers to the ability of insulin to lower plasma glucose concentration by reducing hepatic glucose production and stimulating the uptake of glucose by skeletal muscle and adipose tissue. Insulin resistance describes reduced tissue sensitivity to insulin. When an individual develops insulin resistance due to hereditary factors or obesity, the increased insulin requirement is initially compensated by means of increased insulin production. However, insulin is the hormone that physiologically triggers the differentiation of mesenchymal stem cells into preadipocytes, which then develop into adipocytes. If sufficient calories are ingested, hyperinsulism can lead to obesity. If, due to overloading of the β cells, the capacity of the pancreas to split insulin from synthesized proinsulin is reduced, increased amounts of proinsulin reach the circulation. Although proinsulin does not have a significant glucose-lowering effect, it has the same effect as insulin on the mesenchymal stem cells. This leads to increased adipocyte formation, in the visceral adipose tissue in particular. This adipose tissue produces increased amounts of hormones known as adipokines, some of which can reduce insulin resistance.

One such hormone is adiponectin. Adiponectin enhances insulin sensitivity and also has an anti atherogenic effect. When fat cells have accumulated large amounts of fat, they produce less adiponectin. This leads to increased insulin resistance, which in turn leads to chronic progressive deterioration of the metabolic situation.

Laboratory findings: investigations used to diagnose insulin resistance or type 2 diabetes include fasting glucose, oral glucose tolerance test, HOMA, QUICKI, and proinsulin.

Hypertension /25/

Data from the NHANES III study shows that the prevalence of hypertension increases progressively with increasing BMI. Only 15% of individuals with a BMI below 25 kg/m2, but 40% of those with a BMI above 30 kg/m2, had hypertension. Hyperaldosteronism is thought to be an important factor in the MVS. Aldosterone reduces the metabolic effect of insulin, weakens vascular endothelial function, lowers β-cell function, lowers the insulin sensitivity of muscle cells, and promotes the production of pro inflammatory cytokines in adipose tissue.

Some of the effects of aldosterone are mediated by mineralocorticoid receptors. Overall, hyperaldosteronism has an adverse effect on metabolism that contributes to the development of the metabolic syndrome and endothelial dysfunction. The consequences are resistant hypertension, cardiovascular symptoms, and chronic renal disease.

Dyslipidemia /2627/

Increased triglycerides and reduced HDL cholesterol are characteristic findings in the MVS. Although the LDL cholesterol concentration is not a diagnostic criterion for the metabolic syndrome, many patients have increased numbers of small dense LDL particles, which are particularly atherogenic. Fat cells consist of over 95% triglycerides, which are hydrolyzed to free fatty acids (FFA) and glycerol. Fat cell lipolysis is carried out by triglyceride lipases in adipose tissue. It is influenced by insulin, catecholamines, and atrial natriuretic peptides. Lipolysis is activated by catecholamines and atrial natriuretic peptides. Lipolysis is activated more strongly in abdominal fat than in subcutaneous fat. Since the lipolysis of visceral fat only is connected directly to the liver (via the portal vein), increased amounts of visceral fat have a direct effect on lipid metabolism in the liver. The liver produces very-low-density-lipoprotein (VLDL) particles from the increased volume of free fatty acids, which increases the triglyceride concentration in the blood.

Laboratory findings /28/: the criteria for dyslipidemia in the MVS are triglyceride values greater than 150 mg/dL (1.7 mmol/L) and HDL cholesterol below 40 mg/dL (1.0 mmol/L) in men and 50 mg/dL (1.3 mmol/L) in women. A laboratory assay of non-HDL cholesterol, which includes all atherogenic apolipoprotein B-containing lipoproteins, should also be carried out. Non-HDL cholesterol is determined by subtracting the HDL cholesterol from the total cholesterol. It is particularly important in individuals whose triglyceride levels are above 200 mg/dL (2.3 mmol/L). The target value for non-HDL cholesterol should not exceed the LDL cholesterol concentration by more than 30 mg/dL (0.78 mmol/L). For a diabetic patient, the cut-off values are 100 mg/dL (2.6 mmol/L) for LDL cholesterol and 130 mg/dL (3.4 mmol/L) for non-HDL cholesterol. Non-HDL cholesterol levels greater than 130 mg/dL (3.4 mmol/L) are also a criterion for metabolic syndrome. Patients with MVS also have elevated concentrations of apolipoprotein B. Apolipoprotein B reflects the number of lipid particles and is a better indicator of the therapeutic success of statin therapy than LDL cholesterol. If the goal of therapy is an LDL cholesterol concentration of less than 100 mg/dL (2.6 mmol/L), the corresponding target value for apolipoprotein B is less than 90 mg/dL.

Albuminuria

While albuminuria is not a criterion for metabolic syndrome, it occurs with hyperglycemia, dyslipidemia, and hypertension. The albumin excretion in a spot urine sample can be used to determine whether kidney damage is reversible or progressive. A value of 30–299 mg/g creatinine points to reversible albuminuria while higher concentrations indicate clinical albuminuria (progressive renal damage). CRP values of 3–10 mg/L indicate that the treating physician should pay particular attention to the inflammatory and prothrombotic status of the patient and react accordingly. Possible approaches to treatment include lifestyle modification or appropriate pharmacotherapy.

Adiponectin

Although hypertension, dyslipidemia, and insulin resistance or type 2 diabetes are the main components of the metabolic syndrome and the causal relationship between obesity and atherosclerosis and coronary heart disease, the underlying pathological mechanism is not yet clear. Adiponectin is a possible link, since its concentration is inversely related to obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. In addition, treatment of type 2 diabetes with insulin sensitizers (thiazolidindione) increases the adiponectin concentration. Adiponectin is seen as an additional marker for evaluating the risk of insulin resistance, diabetes mellitus, atherosclerosis, and coronary heart disease. The relationship between the serum concentration of adiponectin and the risk of insulin resistance and atherosclerosis is interpreted as follows /19/:

  • Above 10 mg/L; low risk
  • 7–10 mg/L; medium risk
  • 4–7 mg/L; high risk
  • Below 4 mg/L; very high risk.

Uric acid /29/

Uric acid probably plays a role in the MVS. According to one hypothesis, hyperuricemia is caused by hyperinsulinism since the latter inhibits renal excretion of uric acid. Frequently, however, hyperuricemia precedes hyperinsulinism. Hyperuricemia also occurs in individuals with the metabolic syndrome who are not overweight. Only 5.9% of individuals with a normal BMI and a uric acid level below 6 mg/dL (357 μmol/L) had metabolic syndrome, compared to 59% of those who had a uric acid level above 10 mg/dL (595 μmol/L) /30/.

Table 2.2-3 Diseases associated with the metabolic vascular syndrome

Clinical and laboratory findings

Metabolic vascular syndrome (MVS) and cardiovascular disease

The MVS is a highly prevalent condition. Certain trajectories and combinations of components confer higher risks of incident cardiovascular disease (CVD). In the Framingham Heart Study /31/ MetS was defined according to the Adult Treatment Panel III criteria. The predictive ability of the presence of each component of the MVS on the subsequent development of MetS was examined. Additionally the probability of developing CVD or mortality by having specific combinations of three that diagnose MVS was examined. High blood pressure was most frequently present 77.3% when a diagnosis of MVS occured, and the presence of central obesity conferred the highest risk of developing MVS (odds ratio 4.75). Participants who entered the MVS having a combination of central obesity, high blood pressure, and hyperglycemia had a 2.36-fold increase of incident CVD events and a 3-fold increased risk of mortality.

Diabetes type 2

In individuals with MVS the risk for development diabetes type 2 is 5-fold increased /32/.

Non-alcoholic fatty liver disease (NAFLD)

Fatty liver (FL) is associated with insulin resistance, risk of cardiovascular disease (CVD), and early atherosclerosis. In Western countries 10–15% of normal individuals and 70–80% of obese individuals have NAFLD. The results of the RISC study /33/ showed that a fatty liver index > 60 was associated with elevated CVD risk and increase in low-density lipoprotein cholesterol, aminotransferases, systolic blood pressure and intima media thickness. The insulin sensitivity was reduced. The control group had fatty liver index ≤ 20.

Chronic hepatitis C (CHC)

CHC has been associated with type 2 diabetes and insulin resistance. According to a study hepatitis C infection per se was associated with peripheral and hepatic insulin resistance /34/.

Congenital adrenal hyperplasia (CAH)

Patients with classic CAH due to 21-hydroxylase deficiency exhibit several disease specific conditions. They show androgen excess with or without salt wasting. About half of the patients are overweight and up to 16% are obese. Adiponectin is a key insulin-sensitizing adipokine and improves peripheral insulin sensitivity. Adiponectin is inversely related to insulin resistance, showing lower levels in obesity and MVS. According to one study /35/ adiponectin concentrations were significantly higher in CAH patients (median 11 μg/L) compared to matched controls (6.7 μg/L). One could speculate whether adiponectin might protect from MVS.

The PCOS is one of the most common hormonal disorders in women, with a prevalence estimated 5–10%. Women with the disorder are at risk for the development of metabolic and cardiovascular abnormalities similar to those that make up the MVS. Thirty to 40% of women with PCOS have impaired glucose tolerance and about 10% have type 2 diabetes by their fourth decade.

Table 2.3-1 Myocardial necrosis due to myocardial damage /6/

Injury related to primary myocardial ischemia

  • Plaque rupture
  • Intraluminal coronary thrombosis formation

Injury related to supply/demand imbalance of myocardial ischemia

  • Tachy/bradyarrhythmias
  • Aortic dissection or severe aortic valve disease
  • Hypertrophic cardiomyopathy
  • Cardiogenic hypovolemia or septic shock
  • Severe respiratory failure
  • Severe anemia
  • Hypertension
  • Coronary artery spasm
  • Coronary embolism or vasculitis
  • Coronary endothelial dysfunction without significant cardiovascular disease

Injury not related to myocardial ischemia

  • Myocardial contusion, major surgery, ablation, pacing, defibrillator shock
  • Rhabdomyolysis with cardiac involvement
  • Myocarditis
  • Cardiotoxic substances such as anthracyclines and herceptin

Multifactorial or indeterminate myocardial injury

  • Cardiac defect
  • Stress cardiomyopathy
  • Severe pulmonary embolism or pulmonary hypertension
  • Sepsis and critical illness
  • Renal failure
  • Severe acute neurological illnesses (stroke, subarachnoid hemorrhage)
  • Infiltrative processes (sarcoidosis, amyloidosis)
  • Severe physical exertion

Table 2.3-2 Cardiovascular disease: the risk factors and their frequency in the USA

Disease

Frequency (%)

Cardiovascular disease

36.3

Arterial hypertension

33.3

Smoking

20.8

LDL cholesterol ≥ 130 mg/dL

23.8

HDL cholesterol < 40 (50) mg/dL

15.5

Diabetes mellitus

10.6

Lack of physical activity in leisure time

30.8

Obesity (BMI > 30 kg/m2)

33.9

Heart Disease and Stroke Statistics 2009 for the USA

Table 2.3-3 Definition and classification of angina pectoris

Angina pectoris occurs as a result of regional myocardial ischemia caused by reduced cardiac perfusion of the myocardium and is usually due to an inadequate myocardial O2 supply. Using highly sensitive assays, cardiac troponin can be detected in the blood of many patients (see Section 2.4 – Cardiac troponins (cTn)).

Stable angina pectoris: clinical symptoms are triggered by exertion or stress, are completely reversible, and usually recur at intervals of months or years. Chest pain that lasts from 3 to 15 minutes is the classic symptom. Symptoms are relieved by administration of nitroglycerin.

Unstable angina pectoris: typical characteristics include anginal pain at rest, recent onset, prolonged symptoms, and variable response to nitroglycerin. Ischemia can be demonstrated by a positive ergometric stress test and coronary artery disease by the discovery of vascular lesions at coronary angiography.

Table 2.3-4 Universal classification of myocardial infarction /6/

Type 1: Spontaneous myocardial infarction

Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or more coronary arteries leading to decreased myocardial blood flow or distal emboli with ensuing myocyte necrosis. The patient may have underlying severe coronary artery disease but, on occasion non-obstructive or no coronary artery disease.

Type 2: Myocardial infarction secondary to an ischemic imbalance

In instances of myocardial injury with necrosis where a condition other than coronary artery disease contributes to an imbalance between myocardial oxygen supply and/or demand (e.g., coronary endothelial dysfunction, coronary artery spasm, coronary embolism, coronary artery disease tachy-/brady-arrhythmias, anemia, respiratory failure, hypotension, and hypertension with or without left ventricular hypertrophy).

Type 3: Myocardial infarction resulting in death but biomarkers not available

Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ECG changes or new left bundle branch block, but death occurring before blood samples could be obtained, before cardiac biomarker could rise, or in rare cases cardiac biomarkers were not collected.

Type 4a: Myocardial infarction related to percutaneous coronary intervention (PCI)

Myocardial infarction associated with PCI is arbitrarily defined by elevation of cardiac troponin (cTn) > 5 × 99th percentile upper reference value (URL) in patients with normal baseline values (< 99th percentile URL) or a rise of cTn values > 20% if the baseline values are elevated and are stable or falling. In addition either (i) symptoms suggestive of myocardial ischemia, or (ii) new ischemic ECG changes or new left bundle branch block, or (iii) angiographic loss of patency of a major coronary artery or a side branch or persistent slow- or no-flow or embolization, or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required.

Type 4b: Myocardial infarction related to stent thrombosis

Myocardial infarction associated with stent thrombosis is detected by coronary angiography in the setting of myocardial ischemia and with a rise or fall of cardiac biomarker values with at least one value above the 99th percentile URL.

Type 5: Myocardial infarction related to coronary artery bypass grafting (CABG)

Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac biomarker values > 10 × 99th percentile URL in patients with normal baseline values ≤ 99. percentile URL. In addition, either (i) new pathological Q waves or new left bundle branch block, or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Table 2.3-5 Criteria for acute myocardial infarction (AMI) and prior myocardial infarction /7/

Criteria for acute myocardial infarction

The term “acute myocardial infarction” (AMI) should be used when there is evidence of myocardial necrosis and the clinical symptoms are consistent with acute myocardial ischemia. Under these conditions, any one of the following criteria meets the diagnosis for MI:

1. Evidence of a rise or fall in a cardiac biomarker (preferably cardiac troponin) with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following:

  • Symptoms of ischemia
  • New or presumed new ST segment elevation or new left bundle branch block
  • Development of pathological Q-waves in the ECG
  • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
  • Angiographic or autopsy evidence of an intracoronary thrombus

2. Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ECG changes or new left bundle branch block, but death occurred before cardiac biomarkers could be assayed or a change could be identified.

3. Myocardial infarction related to percutaneous coronary intervention (PCI) is defined arbitrarily on the basis of elevation of cardiac troponin (cTn) values > 5 × 99th percentile URL for patients with normal baseline values (≤ 99. percentile URL) or a rise in cTn values > 20% if baseline values are elevated and are stable or falling. In addition, at least one of the following is required:

  • Symptoms of ischemia
  • New or presumed new ST segment elevation or new left bundle branch block
  • Development of new Q-waves on the ECG
  • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
  • Angiographic or autopsy evidence of an intracoronary thrombus

4. Stent thrombosis associated with an MI, diagnosed with coronary angiography or at autopsy, with myocardial ischemia and in conjunction with a rise or fall in a cardiac biomarker with at least one value above the 99th percentile URL.

5. Myocardial infarction related to coronary artery bypass grafting (CABG) is arbitrarily defined by elevation of at least one value above 10 × 99th percentile URL for patients with normal baseline values (≤ 99. percentile URL) in addition to at least one of the following:

  • New or presumed new pathological Q-waves or new left bundle branch block
  • Angiographic evidence of graft or native coronary artery occlusion
  • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

Criteria for prior myocardial infarction

Any one of the following criteria meets the diagnosis for a prior MI:

1. Pathological Q-waves with or without symptoms, in the absence of non-ischemic causes

2. Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of non-ischemic causes

3. Pathological findings of a prior MI

Table 2.4-1 Analytical characteristics of sensitive cTn assays /3/

Assay

LoD
(ng/L)

99. pctl.
(ng/L)

10% CV
(ng/L)

cTnI* assays

  • Axym ADV

20

40

160

  • Abbott Architect

9

28

32

  • Abbott i-STAT

20

80

100

  • Alere Triage

50

< 50

ND

  • Alere Triage Cardio3

10

20

ND

  • Beckman Access Accu

10

40

60

  • Biomerieux Vidas Ultra

10

10

110

  • Mitsubishi Pathfast

8

29

14

  • Ortho Vitros ECi

12

34

34

  • Radiometer AQT90

9

23

39

  • Response RAMP

30

< 10

210

  • Roche Elecsys

160

160

300

  • Siemens Centaur Ultra

6

40

30

  • Siemens Dim. RxL

40

70

140

  • Siemens Immulite 2500

100

200

420

  • Siemens Stratus C

30

70

60

  • Siemens Vista

15

45

40

  • Tosoh AIA 21

60

< 60

90

cTnT* assays

  • Roche cobas h232

50

ND

ND

  • Roche Elecsys Gen 4

10

< 10

30

  • Roche Cardiac Reader

30

ND

ND

LoD, limit of detection; pctl., percentile; CV, coefficient of variation; ND, not defined

Table 2.4-2 Analytical characteristics of hs-cTn assays /3/

 

LoD
(ng/L)

99th pctl.
(ng/L)

10% CV
(ng/L)

hs-cTnI* assays

  • Abbott

Architect

1.2

16

3.0

  • Beckman

Access

2–3

8.6

8.6

  • Nanosphere

MTP

0.2

2.8

0.5

  • Singulex

Erenna

0.09

10.1

0.88

  • Siemens

Vista

0.5

9

3

hs-cTnT* assays

  • Roche Elecsys

5.0

14

13

LoD, limit of detection; perc., percentile; CV, coefficient of variation

Table 2.4-3 Cardiac troponin in acute coronary syndrome and other types of myocardial injury

Clinical and laboratory findings

Acute coronary syndrome (ACS) – Generalized

The term “acute coronary syndrome” (ACS) refers to a constellation of clinical symptoms that are caused by myocardial ischemia. It includes type 1 myocardial infarction (STEMI), type 2 NSTEMI and unstable angina pectoris (Tab. 2.3-4 – Universal classification of myocardial infarction).

– Myocardial infarction /25/

T1MI is characterized by acute myocardial injury due to plaque rupture and intraluminal thrombus formation in the coronary arteries, T2MI results from an imbalance between myocardial oxygen supply and/or demand and is a condition other than acute atherothrombotic event. See also Section 2.3.3 – Myocardial infarction. Patients have symptoms of ACS and cTn elevation. In addition to the other criteria for an AMI, the cTn value must be > 99th percentile URL and serial measurement must show a rise or fall in cTn concentration. To establish a difference between two cTn values, the difference must be > 3 standard deviations of the variance of the assay. Since the variance for the high-sensitivity cardiac troponin (hs-cTn) assay is 5–7%, a rise or fall ≥ 20% is considered significant.

– Unstable angina pectoris

Unstable angina can be distinguished from T2MI by means of a cTn assay. Positive values of sensitive cTn are not generally found in unstable angina. However, if there are measurable levels, this is associated with an increased risk of sudden unexpected cardiac death within the following twelve months. Furthermore, a rising cTn concentration during the hospital stay is associated with an increased 30-day mortality rate.

Studies using four sensitive cTn assays have shown that, with few exceptions, myocardial infarction is associated with cTn levels that are above 2 × 99th percentile URL whereas values in unstable angina pectoris are below this /27/.

– Procedure-related myocardial infarctions types 4 and 5 /17/

Procedure-related myocardial cell injury with necrosis can be diagnosed by determining sensitive cTn before the procedure, 3–6 hours after the procedure, and, optionally, 12 hours after the procedure. Elevated concentrations indicate procedure-related myocardial injury only if pre-procedural cTn levels were normal ( ≤ 99. percentile URL) for the assay used.

– Percutaneous coronary intervention (PCI) related myocardial infarction (T4aMI) /17/

In patients undergoing PCI with normal baseline cTn values (≤ 99. percentile URL), an elevation of cTn > 5 × 99th percentile URL occurring within 48 h of the procedure is defined as a type 4 AMI if one of the following criteria is also present:

  • Evidence of prolonged ischemia (20 min.) as demonstrated by prolonged chest pain
  • Ischemic ST changes or new Q waves
  • Angiographic evidence of reduced coronary blood flow
  • Evidence of reduced myocardial mobility or regional wall motion abnormality

If the cTn value following PCI ≤ 5 × 99th percentile URL and the value was normal before PCI, the term “myocardial damage” should be used instead of the term “myocardial infarction.” This is also the case if the value after PCI is > 5 × 99th percentile URL in the absence of ischemia and angiographic and imaging findings are normal.

According to one study /28/, the long-term prognosis for PCI patients depends mainly on the cTn value before the PCI; post-procedural values do not predict further myocardial infarction or death.

– Coronary artery bypass grafting (T5MI) /17/

During coronary artery bypass grafting (CABG), a number of factors can lead to myocardial injury with necrosis. These include manipulation of the heart, coronary dissection, global or regional ischemia, microvascular events related to re perfusion or insufficient re perfusion, and myocardial damage due to the generation of oxygen free radicals. An increase in cTn concentration of > 10 × 99th percentile URL in the 48 h following CABG points to a CABG-related myocardial infarction. Additional criteria:

  • New pathological Q-waves or left bundle branch block
  • Angiographic evidence of occlusion of a coronary artery or graft
  • Evidence of reduced mobility or regional myocardial wall motion abnormality.

– General cardiac surgical procedures

Major perioperative myocardial infarction can occur during and after cardiac surgical procedures and are usually accompanied by the development of new pathological Q-waves on the ECG. More common, however, is T2MI – in particular, small perioperative non-Q-wave infarctions. Measurable myocardial injury with cTn elevation always occurs, in spite of cardioprotective measures. The extent of the myocardial injury depends on the type of operation (bypass surgery, valve replacement, combined procedure), surgical technique (with or without cardiopulmonary bypass using heart-lung machine), and cardioplegia technique. There is a smooth transition between myocardial injury and small perioperative non Q-wave infarctions. For example, larger increases in cTn are expected for mitral valve surgery than aortic valve replacement since cardiotomy is required; the increases associated with aortic valve replacement are lower than those associated with conventional coronary artery bypass grafting. Increases following uncomplicated “minimally invasive” bypass operations without cardiopulmonary bypass are lower or marginal.

Myocardial infarction (MI) associated with non-cardiac procedures /17/

Perioperative myocardial infarction is a common vascular complication of non-cardiac surgery and is associated with a poor prognosis. Most patients do not have any ischemic symptoms. Asymptomatic perioperative MI has the same 30-day mortality as symptomatic MI. For this reason, a cTn assay is recommended in high-risk patients before and within 48–72 hours of surgery. When hs-cTn is assayed, 45% of patients have postoperative values > 99th percentile URL and 22% have rising values that indicate a developing MI /29/.

Critically ill patients: elevations in sensitive cTn are often associated with intensive care units and a poor prognosis, regardless of the disease or stage of illness. Some cTn elevations reflect T1MI and some reflect T2MI.

Myocardial injury (cardiac or non-cardiac)

Non-ischemic cardiac causes of myocardial injury often present with chest pain or other symptoms and create diagnostic uncertainty. The sensitive cTn assay is useful for assessing this type of situation /26/.

– Heart failure

Elevated cTn values are common in acute and chronic heart failure. cTn levels, using a sensitive assay, were measured for 81% of patients in the multicenter ADHERE (Acute Decompensated Heart Failure Registry) national database /30/. Of these, 6.2% had cTnI values ≥ 1,0 μg/L and cTnT values ≥ 0,1 μg/L. With cTnI cut-off values of 0.4 μg/L and cTnT cut-off values of 0.01 μg/L, 75% of patients had detectable cTn values. The universal definition of MI  states that the cTn assay alone is not sufficient to diagnose acute MI in patients with cardiac failure. Levels of BNP and NT-proBNP are increased depending on the extent of the heart failure.

– Tachycardia, valve defects

These conditions usually lead to a rise in cTn. Chronic tachycardias with hemodynamic effects can lead to secondary myocardial ischemia with cTn elevation.

– Myocarditis

From a clinical and pathophysiological perspective, myocarditis refers to active inflammatory destruction of myocardial tissue as a result of myocardial infection or an autoimmune reaction. The main causes include viral, bacterial, fungal, protozoal, and parasitic infections, as well as toxins, hypersensitivity reactions and immunological syndromes. Clinical manifestations range from asymptomatic ECG changes to cardiogenic shock. If myocarditis is suspected, a cTn assay is included in the routine investigations. In the Myocarditis Treatment Trial, 34% of patients with inflammation confirmed by biopsy had sensitive cTn values above 3.1 μg/L. This was the case in only 11% of patients with systolic cardiac symptoms but negative biopsy findings for myocarditis /31/.

– Myopericarditis

The myocardium is also involved in 22–71% of cases of pericarditis. The cTnI values were 0.5–50 μg/L /26/.

– History of cardioversion and defibrillation

Elevated sensitive cTn levels are not usually detected. Following administration of multiple (> 5–10) high-energy shocks, however, increases in hs-cTn can be detected. Transient rises in cTn above the cutoff value have been reported in individual patients following surgical implantation and intraoperative testing of intracardiac defibrillators.

– Coronary angiography, myocardial biopsy

Uncomplicated coronary angiography and cardiac catheterization do not lead to a rise in cTn. Myocardial biopsies can lead to increased hs-cTn values.

Sepsis

Elevated cTnI and cTnT levels were detected in 62% of cases on average using sensitive cTn assays /26/.

End-stage renal disease (ESRD) /21/

The prevalence of ischemic heart disease is 10–20 times higher in dialysis patients than in the general population. According to the United States Renal Data System, approximately 40% of patients in the end stage of chronic renal disease experience myocardial infarction or a percutaneous coronary intervention. The probability of surviving a myocardial infarction is also significantly reduced. Furthermore, these patients have an increased prevalence of other risk factors such as diabetes mellitus, hypertension, hyperlipidemia, and left ventricular hypertrophy.

ESRD patients on dialysis frequently have elevated cTn levels. Studies have reported elevated sensitive cTnT in 18–75% of patients and elevated cTnI in 4–17%. Detection of cTn is a prognostic marker and persistently elevated values indicate a negative cardiovascular prognosis. One study /32/ has shown that increases in cTnT and cTnI values in patients with ESRD were associated with a 2–5 fold increase in mortality, with cTnT indicating these patients more sensitively than cTnI. Another study /33/, however, in which the predictive value of increased cTnT was investigated for a longer period, did not show increased cTnT values in dialysis patients with stable coronary heart disease. An increase must always be interpreted as a sign of myocardial necrosis.

The National Kidney Foundation Disease Outcomes Quality Initiative Work Group recommends using cTnT assays for risk stratification in chronic dialysis patients.

Pulmonary embolism /18/

The main clinical symptom of acute pulmonary embolism is dyspnea. Since this is also a symptom of ACS and spontaneous pneumothorax, it must be possible to distinguish between pulmonary embolism and these differential diagnoses. In pulmonary embolism with hemodynamic effects and acute right heart failure, sensitive cTn can be elevated even in the absence of cardiovascular disease due to acute overburdening of the right heart. According to a meta-analysis /34/, cTn values are increased in 10–77% (median 39%) of patients. These patients have an increased 30-day mortality rate (odds ratio 5.24). Very large increases in D-dimers are often detected. D-dimers are increased only slightly in ACS and are normal in spontaneous pneumothorax. See also Section 2.8 – B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide.

Chemotherapy /26/

High-dose chemotherapy for malignant tumors with (e.g., anthracyclines, cyclophosphamide), and probably also platinum-based substances can lead not only to bone marrow toxicity but also to cardiotoxicity. A distinction is made between the following forms:

  • The acute/subacute form is more common and can occur at any time up to two weeks after the end of treatment. The ECG shows prominent re polarization abnormalities and QT-segment interval changes as well as supraventricular and ventricular arrhythmias.
  • The chronic form can be subdivided into a form that occurs within one year of the end of chemotherapy and a form that occurs after one year has passed. It is characterized clinically by asymptomatic systolic or diastolic left ventricular dysfunction that leads to congestive heart failure.

Levels of sensitive cTn are increased in cardiotoxicity and increased cTn can be detected in 30–38% of patients who are currently undergoing or have undergone high-dose chemotherapy. If cTn is still elevated one month after the end of treatment, this is associated with a 85% probability of severe cardiac events within the first year. Persistently non-elevated cTn has a negative predictive value for cardiotoxicity of 99%. It should be measured for the first time after the end of chemotherapy. Studies have shown the following /26/:

  • A positive sensitive cTn value at any concentration or at any time during multicyclic chemotherapy identifies patients at significant risk of a permanent and severe reduction in systolic function
  • The magnitude and frequency of rises in cTn increase as the cumulative dose increases
  • Patients who experience an early chemotherapy-related reduction in left ventricular ejection fraction demonstrate a complete return to normal functioning if cTn is not elevated
  • Minor increases in cTn are more likely to be associated with reduced diastolic function
  • A cTn level that remains normal has a very significant negative predictive value
  • Elevated sensitive cTn values 72 hours after high-dose chemotherapy are associated with reduced left ventricular function in the following year. Treatment with enalapril has been shown to prevent this. Treatment with enalapril was started one month after the last chemotherapy dose and was continued for one year.

Table 2.4-4 Conditions other than myocardial infarction associated with cTn elevation /17/

cTn elevation in myocardial ischemia without significant CVD

Myocardial ischemia due to other causes

  • Coronary artery spasm (Tsakotsubo syndrome)
  • Intoxication with sympathomimetics (e.g. cocaine) or sympathetic storm (e.g. in apical ballooning syndrome, subarachnoid hemorrhage, ischemic insult, intracerebral hemorrhage)
  • Vasculitis (systemic lupus erythematosus, kawasaki syndrome)

Secondary ischemia

  • Shock (e.g. hemorrhage)
  • Sustained tachycardia
  • Aortic dissection with coronary ostial involvement
  • Carbon monoxide intoxication
  • Hypertensive crisis (left ventricular hypertrophy)

Other causes without ACS

Increased myocardial wall tension and myocardial distension

  • Acute heart failure
  • Pulmonary embolism with hemodynamic effects
  • Severe chronic heart failure
  • Congenital heart disease (e.g. aortic valve stenosis)
  • Hypertrophic obstructive cardiomyopathy

Unknown cause

  • End-stage chronic renal insufficiency
  • Extreme endurance sport
  • Hypothyroidism

Direct myocardial damage without ACS

  • Trauma (myocardial contusion, repeated defibrillation, cardiac procedures)
  • Compression in infiltrative diseases (amyloidosis, sarcoidosis, hemochromatosis)
  • Inflammatory, immune-related (myocarditis, rejection after heart transplant)
  • Toxic (Adriamycin, 5-FU, Herceptin)
  • Sepsis, snake venom, burns, renal insufficiency

Table 2.4-5 Risk stratification of patients/individuals with/without acute coronary syndrome

Clinical and laboratory findings

Acute coronary syndrome (ACS)

Following a diagnosis of ACS without myocardial infarction, cTn values are an important risk indicator for recurrent ischemic events and mortality. More than 26 studies have shown a 4-fold increase in the risk of recurrent ischemic events and mortality in patients with ACS if hs-cTn assays demonstrate elevated concentrations. Patients with ACS had a hazard ratio > 3.7 for MI and death in the following six months if the hs-cTnI concentration was ≥ 10 ng/L instead of < 5 ng/L /35/.

Patients with MI and a hs-cTnI concentration > 99th percentile URL have an increased risk of negative outcome (recurrent ischemic events and mortality) in the 30 days following hospital admission (hazard ratio 1.96; 95% confidence interval 1.27–3.05) /36/.

Stable cardiovascular disease

Approximately 81% of patients with stable cardiovascular disease had detectable hs-cTnT concentrations. At the start of the study /37/, patients with higher concentrations had more severe anemia, a worse left ventricular ejection fraction, and lower ventricular mass and performed more poorly on the bicycle ergometer. Patients were followed up for 8.2 years, within which time each doubling of hs-cTnT levels led to a 37% higher rate of cardiovascular events.

Stable angina pectoris

In stable angina, sensitive cTn assays do not show an increase in cTn. This is not the case if hs-cTn assays are used. In a study using a hs-cTnT assay, 11.1% of patients with stable angina had a value above the 99th percentile URL (0.133 μg/L). During the study period of 5.2 years, the incidence of cardiovascular mortality correlated with the cTnT value /38/.

Marathon runners

Extreme endurance sport causes an inflammatory reaction and, depending on the assay used, a rise in cTn. In one study /39/, a cTnT value determined before the marathon did not identify values above the 99th percentile URL in any participants whereas the hs-cTnT assay detected values above the 99th percentile URL in 28% of participants. The IL-6 concentration was 2.1 ng/L (1.0–5.8). After the marathon, the sensitive cTnT assay showed a rise > 99th percentile URL in 43% of participants and the hs-cTnT assay detected a rise in 100% of participants. The IL-6 concentration increased to 27.6 ng/L (range 9.2–89.7). Transitory inflammation is assumed to be responsible for the release of cTn.

Healthy

When a hs-cTnI assay with a positive result in 93% of healthy individuals was used in the general population, higher values were associated with increasing age, male gender, higher systolic blood pressure, and increased ventricular mass /5/. In another study /40/, the sensitive cTnI concentration in healthy individuals with values < 99th percentile URL was 51% higher in 75 year old than in 70 year old individuals. This shows that age must be taken into account when determining the 99th percentile URL.

Table 2.5-1 CK-MB mass in acute coronary syndrome and other muscular damage

Clinical and laboratory findings

Acute coronary syndrome (ACS)

ACS includes myocardial infarction and unstable angina pectoris. Refer to Section 2.3 – Cardiovascular diseases and Section 2.4 – Cardiac troponins (cTn). In 12–39% of cases of myocardial infarction with elevated cardiac troponin (cTn), CK-MB is negative.

In patients with ACS, the CK-MB mass should be assayed as described for sensitive cTn assays. The serum CK-MB mass rises from 3–10 hours after the onset of acute chest pain. Peak values are detected at 24 hours and return to the reference interval 36–72 hours after the onset of pain. If there is early reperfusion of the occluded vessel, peak values are reached 10 hours earlier /18/. Because the concentration decreases quickly, the CK-MB mass cannot be used for late diagnosis of myocardial infarction.

Within the first 6–7 hours of the onset of acute chest pain, the diagnostic sensitivity of the CK-MB mass is comparable to that of myoglobin but its diagnostic specificity is higher /9/. Compared to cTn, the CK-MB mass has the advantage that it drops sooner. If the patient suffers an early re-infarction, this can be detected more easily using the CK-MB mass.

Thrombolytic therapy

An increase in the CK-MB mass of more than 24 μg/L/h, a greater than 4-fold relative increase in 90 minutes, or a greater than 5-fold increase in 60 minutes after the start of thrombolytic therapy indicates successful reperfusion of the occluded vessel /10/.

Percutaneous coronary intervention (PCI)

Following elective PCI, a rise > 3 × 99th percentile URL indicates myocardial infarction and a rise of 5–10 × 99th percentile URL is associated with increased mortality /11/. According to the Third Universal Definition of Myocardial Infarction (2012), > 5 × 99th percentile URL is recommended /12/.

Thrombosis

Thrombosis in the pelvic area can be associated with a rise in CK-MB.

Coronary artery bypass grafting

Values above 60 μg/L point to perioperative infarction; increases of more than 10 times the upper reference limit are associated with increased mortality /11/.

Skeletal muscle damage

CK-MB can be released into the circulation following injury to skeletal muscle. This can be due to transient severe myopathies (injuries, operations, burns, electrical accidents, necrosis following injections, physical exertion, cramps, myositis) or chronic myopathies (muscular dystrophy, polymyositis). When CK-MB concentrations are above the cut-off value, muscle damage should be considered as part of the differential diagnosis in the light of the history and clinical symptoms.

Table 2.6-1 Myoglobin in acute coronary syndrome and other muscular damage

Clinical and laboratory findings

Acute coronary syndrome (ACS)

ACS includes the myocardial infarction and unstable angina pectoris (see also Section 2.3 – Cardiovascular diseases and Section 2.4 – Cardiac troponins (cTn)).

Along with the ECG findings, serum myoglobin is a sensitive, rapidly measurable biomarker in the early phase of myocardial infarction. Serum myoglobin is elevated from 2–3 hours after the onset of chest pain. Myoglobin should not be assayed in patients who first present 10 hours or more after the onset of chest pain since levels may already have returned to within the reference interval.

The predictive values for myoglobin (pVneg 98% and pVpos 64%) indicate that acute myocardial infarction can be more confidently excluded than confirmed. Since most patients (85–95%) who are admitted to an emergency unit with suspected ACS do not develop a myocardial infarction, it is particularly important to be able to identify those who do not have an infarction.

Patients with elevated myoglobin levels require further close monitoring with measurement of cTnT or cTnI concentrations. Studies /56/ of patients with acute chest pain have shown that a decision could be made about the existence of an myocardial infarction just 90 minutes after admission by means of a myoglobin rapid assay. Peak myoglobin values in myocardial infarction are around 600–1,000 μg/L. Patients with myocardial infarction and elevated myoglobin, like those with cTn levels above the cut-off value, have a worse prognosis than ACS patients without cardiac marker elevation.

Percutaneous coronary intervention (PCI)

Patients who undergo elective PCI and reperfusion of the infarct vessel show a steep and significant rise in serum myoglobin, with values falling back to within the reference interval after 10–20 hours.

Thrombolytic therapy

During thrombolytic therapy, a rapid rise in myoglobin of ≥ 150 μg/L/h or a more than 4-fold relative increase within 90 minutes after the start of therapy indicates successful reperfusion /17/. A lower than 5-fold increase within the hour following the start of therapy rules out complete reperfusion (TIMI-3 flow) in the infarct vessel /7/.

Coronary artery bypass grafting

There are two causes of myocardial infarction in patients who undergo coronary artery bypass grafting:

  • Global ischemic myocardial damage during aortic cross-clamping and subsequent reperfusion
  • Postoperative myocardial infarction.

In one study /3/, it was shown that myocardial infarction could be early identified by the determination of myoglobin. In patients without infarction, myoglobin levels peaked 1 hour after aortic unclamping and returned to the reference interval within 4 hours. In patients who developed myocardial infarction, the myoglobin level continued to rise after 1 hour and after 3 hours was still higher than in patients who did not develop a perioperative myocardial infarction. Within the first 4 hours, all patients with perioperative myocardial infarction had a myoglobin concentration above 400 μg/L.

Skeletal muscle damage

Myoglobin is released into the circulation following skeletal muscle damage. This can be due to transient severe myopathies (injuries, operations, burns, electrical accidents, necrosis following injections, physical exertion, cramps, myositis) or severe chronic myopathies (muscular dystrophy, polymyositis). When myoglobin concentrations are above the reference interval, muscle damage should be considered as part of the differential diagnosis in the light of the history and clinical symptoms.

Renal insufficiency

Patients with a severely reduced glomerular filtration rate (serum creatinine > 2 mg/dL; 177 μmol/L) can have elevated serum myoglobin.

Table 2.7-1 Etiology of chronic cardiac failure /3/

Ischemic heart disease

82–95%

Hypertension

64–80%

Cardiac valve disease

25–32%

Cor pulmonale

3–7%

Cardiomyopathy

1–2%

Congenital cardiac disease

1–2%

Table 2.7-2 New York Heart Association (NYHA) classification of heart failure /7/

Class

Characteristics

1-year mortality

Class 1

(asymptomatic)

No limitation; indicators of heart disease but no symptoms of heart failure, even on exertion

< 5%

Class II

(mild)

Mild limitation; symptoms of heart failure only on severe physical exertion

10%

Class III

(moderate)

Marked limitation; symptoms of heart failure on minor exertion such as walking

20–30%

Class IV

(severe)

Severe limitation of physical activity, symptoms even at rest

50%

Table 2.7-3 Criteria of the American College of Cardiology/American Heart Association classification of chronic heart failure /7/

Stage

Explanation

A

High risk of developing chronic heart failure but no structural changes to the heart

B

Structural changes to the heart but no cardiac symptoms

C

Heart failure with underlying structural changes to the heart and frequent or recent clinical symptoms

D

Heart failure with symptoms of terminal disease that are refractory to standard treatment

Table 2.7-4 Common nonspecific findings in chronic heart failure /12/

Finding

Cause

Hyperglycemia

Diabetes mellitus, stress-related, diuretic therapy

Hypoglycemia, Ammonia , Cholesterol 

Marked and persistent venous congestion with liver failure

Urea , Creatinine , Uric acid 

Pre renal failure due to renal hypo perfusion; urea-creatinine ratio typically > 15 : 1

Proteinuria

Severe heart failure

Hyponatremia

Severe heart failure, diuretic therapy

Hypokalemia

Diuretic therapy

Hypomagnesemia

Diuretic therapy

Hyperkalemia

Potassium-sparing diuretics, angiotensin-converting-enzyme (ACE) inhibitors, renal insufficiency

AST , ALT , GGT , ALP , bilirubin 

Liver damage due to venous congestion in right heart failure

PT , albumin 

Disturbance of albumin and clotting factor synthesis in congestive hepatopathy

Blood gases (pO2 , pCO2 )

Impaired gas exchange in severe failure of the right ventricle with pulmonary edema

Lactate , pH 

Severe failure of the left ventricle with impaired tissue perfusion

cTn , CK , CKMB 

Acute myocardial infarction with heart failure; minor elevations in cTn possible following acute heart failure

Table 2.7-5 Biomarkers and their clinical significance in chronic heart failure (CHF)

Clinical and laboratory findings

Complete blood count

This is used to rule out anemia, or, if anemia is present, to estimate the degree to which the oxygen supply to the cardiac muscle is reduced. Moderate anemia with hemoglobin (Hb) values of 80–100 g/L is not tolerable in chronic heart failure since it exacerbates the symptoms. Therefore, appropriate measures should be taken to correct a moderate anemia to a mild anemia (Hb value > 100 g/L).

Sodium

The serum concentration can be used to assess neurohormonal activation since it is inversely proportional to the concentration of renin and aldosterone. In patients with chronic heart failure, Na+ and water are paradoxically retained despite an increase in intravascular fluid volume. Renal water and Na+ retention in these patients may not be regulated by the total blood volume but by the degree of filling of another compartment, the so-called effective blood volume /11/. More water than Na+ may be retained in patients with chronic heart failure. Hyponatremia of < 137 mmol/L that develops in this way has a poor prognosis. Patients with chronic heart failure, hyponatremia, and hypo osmolality have high levels of arginine-vasopressin /11/.

Potassium

In patients with chronic heart failure, serum K+ values should lie between 4–5 mmol/L. K+ values lower than this range indicate a poor prognosis.

Creatinine

The neurohumoral effect of high renin and aldosterone concentrations leads to vasoconstriction of the afferent and efferent arterioles in the kidneys. Mesangial contraction is also increased in the glomeruli. These mechanisms reduce the glomerular filtration rate and can lead to increased serum creatinine concentrations /11/.

Urinary albumin

As ventricular function deteriorates, the concentration of albumin in the urine increases.

Blood gas analysis

This can be used to assess the supply of oxygen to the heart in severe chronic heart failure.

BNP, NT-proBNP

Determination of B-type natriuretic peptide (BNP) and the N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) in the blood contribute significantly to the diagnostic workup of patients with a clinical picture suggestive of chronic heart failure. Because these peptides are elevated even in the early clinical stages of chronic heart failure, they are a sensitive marker for the disease. Because of its high negative predictive value for excluding a heart failure, a negative result is highly significant. See also Section 2.8 – B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP).

Catecholamines

The consequences of the baroreceptor-induced increase in sympathetic vascular tone that takes place in ventricular dysfunction include increased myocardial contraction, tachycardia, and other mechanisms (see Section 2.7.6 – Pathophysiology). Therefore, a plasma norepinephrine concentration of > 400 ng/L indicates a poor prognosis.

Renin, aldosterone

As with the catecholamines, the magnitude of the increase in renin and aldosterone is a prognostic marker for chronic heart failure. In patients with mild heart failure, renin and aldosterone concentrations are not increased or are increased only slightly; in patients with severe heart failure, renin and aldosterone concentrations are high /11/.

Table 2.8-1 Age dependend upper reference intervals for BNP and NT-proBNP (ng/L)

Manufacturer

Age

BNP /111/

< 45

45–54

55–64

65–74

≥ 75

Biosite

M

23.8

39.0

72.4

62.7

77.9

F

47.4

71.7

80.5

95.4

179.5

Siemens

M

29.4

32.8

38.8

67.6

121

F

35.9

56.7

75.5

72.9

167

Abbott

M

73

40

80

150

121

F

89

111

155

159

266

NT-proBNP*

18–44

45–54

55–64

65–74

 75

Roche /15/

M

86

121

210

376

486

F

130

249

287

301

738

Conversion

– BNP: 1 pmol/L = 3.5 ng/L

– NT-proBNP: 1 pmol/L = 8.57 ng/L, 1 pg /mL = 0.118 pmol/L

* 97.5th percentile (information in package insert)

Table 2.8-2 BNP and NT-proBNP in disease states /12/

Clinical and laboratory findings

Acute dyspnea

Around 10–15% of patients who attend an emergency department have dyspnea due to heart failure (HF) or pulmonary disease. Around 80% of patients with acute heart failure present with dyspnea /18/. A diagnosis can be made in the majority of cases based on a careful history, physical examination, ECG, chest X-ray, and oxygen saturation. When patients present with acute dyspnea, it is important to differentiate heart failure from other causes such as exacerbation of COPD/asthma, pulmonary embolism, pneumonia, pneumothorax, or hyperventilation. A BNP or NT-proBNP assay can be used to distinguish between cardiac and non-cardiac dyspnea. For example, heart failure is unlikely in patients with dyspnea and BNP values < 100 ng/L (diagnostic sensitivity 90%, specificity 76%, diagnostic accuracy 83%) /19/.

In further studies /152022/, NT-proBNP was determined. The decision point for rule-out for acute heart failure was confirmed at 300 ng/L (35 pmol/L). In 2/3 of cases with a tentative diagnosis of dyspnea due to heart failure, the dyspnea was non-cardiac; in 10% of cases in which a non-cardiac cause was suspected, heart failure was present. According to the authors, the use of NT-proBNP could reduce the number of intensive care admissions by 10% and shorten the length of stay. Other investigators do not support the routine use of natriuretic peptide assays in patients with dyspnea /21/.

Heart failure – Generalized

Overall, around 2% of the European population has symptomatic heart failure. It has an incidence of 10% in individuals above the age of 65 years and over 50% in individuals above the age of 85 years. This is why early diagnosis is so important. However, the clinical symptoms of heart failure are non-specific. Diagnostic strategies include ECG and doppler echo cardiography. The latter is considered the gold standard. However, it is not very precise and often fails to distinguish patients with normal cardiac function from those with heart failure. BNP and NT-proBNP have equally high diagnostic accuracy and clinical relevance for acute and chronic heart failure /22/.

– Diagnosis of chronic heart failure

Determination of BNP or NT-proBNP is an important primary investigation in suspected cases of chronic heart failure. Both correlate well with a left ventricular systolic fraction below 40 mL, with the diastolic fraction, and with the clinical severity of heart failure.

When BNP concentration was correlated with the severity of ventricular dysfunction as classified by the New York Heart Association (NYHA), the following concentrations corresponded to the NYHA classes (Biosite assay, Fig. 2.8-2 – Median concentrations, highest values, and lowest values of BNP (Biosite assay) in patients with chronic heart failure in each of the four New York Heart Association classes (NYHA I–IV)) /1/: 244 ± 286 ng/L for class I; 398 ± 374 ng/L for class II; 640 ± 447 ng/L for class III; 817 ± 435 for class IV. A BNP concentration of less than 50 ng/L ruled out a diagnosis of heart failure (negative predictive value 96%). Heart failure was improbable with a BNP concentration < 100 ng/L but highly probable with concentrations > 500 ng/L. The correlation of NT-proBNP measurements with the severity of heart failure according to the NYHA criteria produced the following values for the NYHA classes (Roche assay; median, 5th percentile, and 95th percentile): 342 ng/L (33–3410) for class I; 951 (103–6567) for class II; 1,571 (126–10,449) for class III; 1,707 (148–12,181) for class IV. An NT-proBNP value > 125 ng/L suggests chronic heart failure.

BNP and NT-proBNP have a lower diagnostic sensitivity and specificity for diagnosing diastolic dysfunction. Patients with diastolic dysfunction have significantly lower BNP and NT-proBNP concentrations /17/. Furthermore, levels are lower in patients in whom the ejection fraction is reduced by up to 50% but systolic function is preserved. This was shown by a study /23/ in which patients who had acute heart failure but preserved left ventricular systolic function had NT-proBNP concentrations (Roche assay) of 3070 ng/L (1344–7974) while patients with reduced systolic function had values of 6536 ng/L (2,777–13,407).

– Prognosis of chronic heart failure

BNP and NT-proBNP can be used to determine the short and long-term prognosis of chronic heart failure. BNP concentrations in patients with a predicted survival time of only 2–4 years are 3.5 to 5.6 times higher than BNP concentrations in patients who survive longer /23/. An NT-proBNP concentration greater than the group median predicted risk of death within a year /24/.

– Diagnosis of acute heart failure

The BNP decision point for rule-out for acute heart failure was confirmed at 100 ng/L /19/ the decision point of NT-proBNP for rule-out is 300 ng/L /152023/. The rule-in NT-proBNP thresholds for acute heart failure depend on the age of patients and are confirmed at 450, 900, and 1,800 ng/l for persons aged < 50, 50–75 or > 75, respectively. Elevated NT-proBNP values were superior to clinical judgment alone for diagnosing heart failure in the PRIDE study /25/. Patients with acute heart failure have significantly higher BNP and NT-proBNP values than patients with chronic heart failure /26/.

There is a significant difference between NT-proBNP values in patients with acute dyspnea in the absence of acute heart failure and patients with acute dyspnea and acute heart failure (Tab. 2.8-3 – NT-proBNP in patients with acute dyspnea with and without heart failure (HF)/15/.

– Prognosis of acute heart failure

In patients with dyspnea and acute heart failure, rising concentrations of BNP and NT-proBNP are a sign of progressive disease and indicate a poor prognosis. Concentrations > 480 ng/L were associated with a mortality of 51% and an increased rate of hospital admission in 6 months, while concentrations < 230 ng/L were associated with a mortality of only 2.5% /15/. In a study of 1,256 patients with acute heart failure, 8.6% died within 76 days. Their NT-proBNP concentrations were higher than those of the patients who survived. An NT-proBNP concentration > 5,180 ng/L had a higher predictive value for dying in the next 76 days (odds ratio = 5.2) (Fig. 2.8-3 – Median concentrations, highest and lowest values of NT-proBNP in patients without chronic heart failure and in patients with heart failure of NYHA II–IV/23/. The optimum cut-off values for predicting mortality within 60 days and 1 year were 428 ng/L and 352 ng/L for BNP and 5,562 ng/L and 3,174 ng/L for NT-proBNP /28/.

– Treatment of heart failure

Intensive treatment of acute decompensated heart failure should lead to a drop in NT-proBNP of at least 30%. Treatment of acute heart failure with complete resolution of symptoms led to a reduction of 55% in NT-proBNP compared with pre-treatment values and clinical stabilization led to a 37% reduction /29/.

In patients with chronic heart failure whose NYHA class improves, the BNP concentration falls by an average of 45% while in patients whose NYHA class is stable, the BNP concentration remains unchanged /30/. Four months of spironolactone therapy for chronic congestive heart failure leads to an average drop in BNP concentration from 200 ng/L to 80 ng/L.

Acute coronary syndrome – Generalized

Acute coronary syndrome (ACS) comprises unstable angina pectoris, non-ST elevation myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI). In patients with acute coronary syndrome, BNP or NT-proBNP should be determined on admission and 2–5 days after the onset of acute chest pain /4/. In patients with STEMI, there is a rapid increase in BNP and a sharper increase in NT-proBNP. Peak values are reached within 12–24 hours and the peak concentration is proportional to the size of the infarct. Although the BNP and NT-proBNP concentrations then fall continuously, they remain elevated for up to 12 weeks. Some patients, in particular those with extensive infarction, show a second peak on the 5th day, which may indicate an unfavorable outcome of myocardial remodeling. Patients with smaller infarctions have a monophasic peak only. BNP values remain persistently elevated for up to 90 days during the remodeling phase /12/.

– Risk stratification

In acute coronary syndrome, natriuretic peptide assays play an important role in identifying patients who are at increased risk of mortality or heart failure. This allows additional diagnostic and therapeutic measures to be taken during the first few hours of admission in addition to the routine measures. The Action Registry – GWTG /31/ registered 19,528 patients with STEMI and 9220 patients with NSTEMI in whom natriuretic peptide assays were performed within 24 hours of admission to hospital. The patients with NSTEMI and STEMI were grouped into quartiles based on the BNP value. There was a stepwise increase in the risk of in-hospital mortality with increasing BNP quartiles for both NSTEMI and STEMI. Patients with NSTEMI had higher BNP values than patients with STEMI. The presence of comorbid conditions in the NSTEMI patients was assumed to be the reason for this. The mortality rates are shown as a function of the BNP quartiles in Tab. 2.8-4 – In-hospital mortality of patients with acute coronary syndrome as a function of the BNP value.

In another study /32/, baseline NT-proBNP concentrations in patients with stable angina pectoris referred for coronary angiography were correlated with subsequent coronary events in the following 9 years. The NT-proBNP concentration was lower among patients who survived than among those who died from a cardiac cause [120 ng/L (50–318) compared to 386 ng/L (146–897)].

Atrial fibrillation (AF) /33/

Atrial fibrillation is the most common cardiac arrhythmia. It is associated with increased mortality and is a major risk factor for cardiovascular morbidity, heart failure, and stroke. Clinical symptoms are heterogeneous and often associated with structural heart disease. To determine the NT-proBNP cut-off value for predicting a diagnosis of atrial fibrillation, the relationship between atrial fibrillation and NT-proBNP was investigated in 5445 participants over a period of at least 10 years in the Cardiovascular Health Study. Manifest atrial fibrillation was diagnosed based on the ECG and prevalent atrial fibrillation was diagnosed based on the NT-proBP concentration in participants who later went on to develop manifest atrial fibrillation. When participants were divided into quintiles with NT-proBNP values of 5–50, 51–91, 92–156, 156–290 and > 290 ng/L, the hazard ratios for developing atrial fibrillation were 1.0, 1.4, 1.8, 2.4, and 4.0 respectively.

Pulmonary embolism /34/

In acute pulmonary embolism, BNP and NT-proBNP determination can be used in addition to echo cardiography to help diagnose right ventricular heart failure. Specifically, BNP values above 200 ng/L (cut-off value ≤ 100 ng/L) were shown to indicate right heart failure. All patients with right ventricular heart failure had NT-proBNP values > 500 ng/L. Because the in-hospital mortality of massive pulmonary embolism can be 40–50%, BNP and NT-proBNP have important prognostic value. A number of studies have shown that values of above 50–487 ng/L for BNP and above 500–1,000 ng/L for NT-proBNP are strong predictors of mortality.

Peripheral arterial disease

Peripheral arterial disease (PAD) indicates significant systemic atherosclerosis and can cause vascular occlusion. Patients with peripheral arterial disease have increased cardiovascular morbidity and mortality. In one study /35/, patients with peripheral arterial disease and NT-proBNP concentrations above 213 ng/L (1.27–4.03) had an increased mortality risk.

Cardiorenal syndrome

Compared to individuals with healthy kidneys, patients with chronic renal disease have a higher rate of cardiovascular disease and heart failure with increased mortality resulting from atherosclerosis and left ventricular hypertrophy. The relationship between renal insufficiency and heart failure is also known as the cardiorenal syndrome. Patients with this syndrome have elevated concentrations of BNP and NT-proBNP. However, that patients both with and without cardiac symptoms and with renal insufficiency have elevated values (NT-proBNP rises more than BNP) aggravate the interpretation of BNP and NT-proBNP values. Both peptides are cleared by glomerular filtration; BNP is cleared by the BNP receptor in addition. This explains why NT-proBNP rises more than BNP in patients with renal insufficiency. In patients undergoing hemofiltration, the BNP concentration decreases by 39% and the NT-proBNP concentration declines by 59% /36/. The increased concentrations of both peptides in the cardiorenal syndrome, however, are due more to the cardiac than the renal component /37/. Patients with end-stage chronic renal insufficiency and NT-proBNP values > 2,387 ng/L before starting hemodialysis had a 2.4-fold higher mortality risk after 3 months than patients whose NT-proBNP concentration was below 429 ng/L /38/. An attempt is made to counteract renal dysfunction in the cardiorenal syndrome by calculation of the BNP/NT-proBNP ratio /39/. In a prospective study /40/ of more than 200 patients with nondiabetic mild or moderate renal insufficiency, (eGFR 30–90 [mL × min–1 × (1.73 m2)–1]), BNP and NT-proBNP were also found to predict the progression of mild or moderate chronic renal insufficiency (end points: end-stage renal disease or doubling of baseline creatinine concentration).

Anti-inflammatory medication

Anti-inflammatory medications such as cyclooxygenase inhibitors (coxibs) and non-steroidal anti-inflammatory drugs (NSAIDs) increase the incidence of myocardial infarction and stroke. It is assumed that these pharmaceuticals inhibit the production of cardiovascular protective eicosanoids (prostacyclin), but not of thromboxane A2 /41/. This results in increased blood pressure and a higher rate of cardiovascular events and accelerates the development of atherosclerosis. In patients receiving treatment with NSAIDs, coxibs, or glucocorticoid medication, the risk of cardiovascular events within 200 days of starting treatment if NT-proBNP values are ≥ 100 ng/L is 1.95 times higher than in patients with NT-proBNP values < 100 ng/L. The risk is even higher for coxib therapy (7.41 times higher) /42/.

Cardiac surgery /43/

Information about developing cardiac dysfunction can be obtained by the determination of BNP and cardiac troponin I (cTnI) before and 20 hours after cardiac surgery. Patients with a postoperative rise in these biomarkers had a 12-fold increased risk of heart failure. Using a Siemens assay for cTnI and a Biosite assay for BNP, it was established that the optimum cut-off values for predicting the development of heart failure were a combination of cTnI > 5.4 μg/L and BNP > 450 ng/L.

Cardiovascular risk

Prospective studies show that BNP and NT-proBNP are associated with cardiovascular risk. A meta-analysis /44/ of 40 studies involving a total of 87,474 patients and 10,625 cardiovascular events demonstrated the following results: Probands with BNP values in the range 9–142 ng/L or NT-proBNP values in the range 30–750 ng/L were grouped into tertiles. The risk of future cardiovascular events was 2.9 times higher (95% CI 1.9–4.4) in subjects in the top tertile than those in the bottom tertile.

Serum CRP and albumin/creatinine ratio was measured in 658 residents of Copenhagen between the ages of 50 and 89 years to establish the prognostic value of NT-proBNP compared to the traditional risk markers for cardiovascular disease /45/. The occurrence of cardiovascular disease and cardiac death in the 5 years after blood was taken for the NT-proBNP assay was recorded. In individuals who died during this time period, the average NT-proBNP concentration at the start of the study was 505.5 (281.8–1138.3) ng/L, while in those who survived, it was 234.9 ng/L (134.9–461.5); the average albumin/creatinine ratios were 14.0 (7.0–30.0) mg/g creatinine vs. 6.0 (4.0–11.0) mg/g creatinine, respectively. No significant differences were noted between CRP levels in the two groups. The data regarding the occurrence of a first coronary event yielded similar results. The results indicate that NT-proBNP is a better risk marker for future cardiac events and mortality than the traditional risk factors.

Table 2.8-3 NT-proBNP in patients with acute dyspnea with and without heart failure (HF) /26/

 

Dyspnea without HF

 

Dyspnea with HF

Age

< 50

50–75

> 75

< 50

50–75

> 75

Mean

163

500

1,209

 

7947

7964

10,519

Median

42

121

327

 

5044

3512

5495

5th pctl.

5

10

25

 

393

416

658

97.5th pctl.

778

2101

7916

 

36,201

29,089

35,183

Data expressed in ng/L; pctl., percentile

Table 2.8-4 In-hospital mortality of patients with acute coronary syndrome as a function of the BNP level /31/

 

NSTEMI

STEMI

Quartile

BNP

Mortality

BNP

Mortality

Q1

≤ 95

1.3%

≤ 35

1.9%

Q2

> 95–≤ 316

3.2%

> 35–≤ 132

3.9%

Q3

> 316– ≤ 855

5.8%

> 132– ≤ 435

8.2%

Q4

> 855

11.2%

> 435

17.9%

BNP expressed in μg/L

Table 2.8-5 Effects of ANP and BNP

  • Sympathomimetic activity in the central and peripheral nervous system
  • Inhibition of drinking
  • Natriuresis and diuresis
  • Inhibition of the renin-angiotensin-aldosterone system
  • Smooth muscle relaxation and vasodilation
  • Increased permeability of vascular endothelium
  • Relaxation of smooth muscle in the lower respiratory tract
  • Increased lipolysis in adipose tissue
  • Inhibition of cardiac and vascular remodeling

Figure 2.1-1 European Society of Cardiology cardiovascular risk score /9/. Score chart: 10-year risk of a fatal cardiovascular disease (CVD) in populations at high CVD risk based in the following risk factors: age, gender, smoking, systolic blood pressure and total cholesterol. The numerical values in the chart express the risk in %.

Women Age Men Non-smokers Smokers Non-smokers Smokers Systolic blood pressure (mmHg) 180 7 8 9 10 12 13 15 17 19 22 65 14 16 19 22 26 26 30 35 41 47 10 years-mortality risk in % 160 5 5 6 7 8 9 10 12 13 16 9 11 13 15 16 18 21 25 29 34 140 3 3 4 5 6 6 7 8 9 11 6 8 9 11 13 13 15 17 20 24 120 2 2 3 3 4 4 5 5 6 7 4 5 6 7 9 9 10 12 14 17 180 4 4 5 6 7 8 9 10 11 13 60 9 11 13 15 18 18 21 24 28 33 160 3 3 3 4 5 5 6 7 8 9 6 7 9 10 12 12 14 17 20 24 140 2 2 2 3 3 3 4 5 5 6 4 5 6 7 9 8 10 12 14 17 120 1 1 2 2 2 2 3 3 4 4 3 3 4 5 6 6 7 8 10 12 180 2 2 3 3 4 4 5 5 6 7 55 6 7 8 10 12 12 13 16 19 22 160 1 2 2 2 3 3 3 4 4 5 4 5 6 7 8 8 9 11 13 16 140 1 1 1 1 2 2 2 2 3 3 3 3 4 5 6 5 6 8 9 11 120 1 1 1 1 1 1 1 2 2 2 2 2 3 3 4 4 4 5 6 8 180 1 1 1 2 2 2 2 3 3 4 50 4 4 5 6 7 7 8 10 12 14 160 1 1 1 1 1 1 2 2 2 3 2 3 3 4 5 5 6 7 8 10 140 0 1 1 1 1 1 1 1 1 2 2 2 2 3 3 3 4 5 6 7 120 0 0 1 1 1 1 1 1 1 1 1 1 2 2 2 2 3 3 4 5 180 0 0 0 0 0 0 0 0 1 1 40 1 1 1 2 2 2 2 3 3 4 160 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 3 140 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 2 2 120 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 Cholesterol (mmol/l)

Figure 2.1-2 Initiation of atherosclerotic plaques; modified from Ref. /14/. Plaque development starts with vascular endothelial dysfunction. This alters the endothelial permeability to lipoproteins, which penetrate into the intima. In the intima, pro inflammatory cytokines (e.g., tumor necrosis factors (TNFs)) are released by local inflammatory cells. The endothelial cells release adhesion molecules (selectin, VCAM, ICAM), which involve thrombocytes and immune cells in the reaction. LDL that reaches the intima is modified and then taken up by macrophages. The activated macrophages produce inflammatory cytokines such as interferon-γ, IL-1, TNF α, and reactive oxygen species (ROS) and oxidize the LDL to oxLDL. These activate and maintain the inflammation. Smooth muscle cells (SMC) become involved in the inflammatory reaction and start to proliferate. Macrophages become loaded with lipids and are converted into foam cells.

Endothelium Endothelium Internal elastic lamina Monocyte Blood vessel lumen LDL HDL LDL Mast cell LDL Mf SMC SMC LDL CCR2 LDL HDL Platelet aggregation LDL LDL LDL LDL LDL LDL VCAM-1 /ICAM-1 P-selectin E-selectin MCP-1Chemoattractant MCSF IFNg IL-1 ROS/TNF/IL-1/Ox LDL HDL Intima Foam cell Lymphocyte T

Figure 2.1-3 Progression to atherosclerotic plaque with fibrous collagen cap; modified from Ref. /14/. The pro inflammatory cytokines released by activated monocytes and T-lymphocytes cause smooth muscle cells (SMC) to migrate from the media to the intima, where they produce fibrous collagen. A fibrous collagen cap covers the expanding fibrous lipid core (lipid-rich gruel). If the fibrous collagen is degraded as a result of inflammation-induced synthesis of metalloproteases, the cap gets progressively thinner and eventually ruptures. Plaque rupture, which is initiated by the interaction of hemodynamic, cellular, and inflammatory mechanisms, induces thrombus formation through the contact activation of flowing blood by collagen and clotting factors.

T T T Mf Blood vessel lumen Monocytes degrade matrix and inhibit synthesis T-lymphocyte inhibits proliferation of SMC by TGFβ and IFNγ Tissue factor Thin shoulder FAS/FASL SMC apoptosis Lipid-rich gruel Mast cell Platelet aggregation Collagen Micro- vessel rupture SMC Lipid-rich gruel SMC

Figure 2.3-1 Initial assessment of patients with suspected acute coronary syndromes, modified according to Ref. /2/

The initial assessment is based on the following features:

– The clinical presentation (e.g. vital signs, symptoms)

– The result of the 12-lead ECG

– The absolute value and the course of cardiac troponin.

The respective boxes show the final diagnosis which is derived from the integration of the clinical and laboratory findings. Non-cardiac refers to thoracic diseases; UA, unstable angina; other cardiac refers to other cardiac diseases (e.g. myocarditis, tachyarrhythmia); NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction.

*/ ECGTroponinDiagnosis + ++ Other cardiac UA NSTEMI STEMI Non-cardiac Low likelihood High likelihood

Figure 2.3-2 Time profile of enzymes, cardiac troponin, and CK-MB mass in acute myocardial infarction.

Multiple of the upper reference interval501510 5 Troponin I Troponin T LD Myo-globin CK-MB (CK) 1 2 3 4 Days after myocardial infarction 5 6 7 10 Referenceinterval

Figure 2.4-1 Structure of a thin filament of troponin complex consisting of TnC, TnI, and TnT.

TnC Overlap with tropomyosin Tropo-myosin Actin Tnl TnT

Figure 2.4-2 The use of the 0 h/3 h rule-in and rule-out algorithm in suspected non-ST-elevation acute coronary syndromes using high-sensitivity cardiac troponin (hs-cTn) assays. Modification according to Reference /7/.

ULN: upper limit of normal (also called upper reference limit, URL) defined as 99th percentile of healthy controls.

GRACE: Global Registry of Acute Coronary Events (for further information refer to Section 2.3.3.5).

Δ change: the absolute changes of the hs-cTn level within 1 h can be used as surrogate for absolute changes over 3 h or 6 h (dependent on assay, see Fig. 2.4-3).

Highly abnormal hs-cTn: defines values beyond 5-fold the upper limit of normal (99th percentile).

Acute chest pain Re-test hs-cTn: 3 h hs-cTn < ULN Pain > 6 h hs-cTn no change Painfree, GRACE < 140,differential diagnoses excluded Δ change(hs-cTn value > ULN) Highly abnormal hs-cTN + clinical presentation hs-cTn no change Work-up differential diagnoses Pain < 6 h Discharge/Stress testing Invasive management hs-cTn > ULN

Figure 2.4-3 The 0 h/1 h assessments are recommended when high-sensitivity cardiac troponin (hs-cTn) assays with a validated algorithm are available. This rule-in and rule-out algorithms in patients presenting with suspected non-ST elevation myocardial infarction (NSTEMI) are an alternative to the 0 h/3 h algorithm. Modification according to reference /7/.

Myocardial infarction type 2 can be ruled out:

– At presentation of the patient if the hs-cTn level is very low (0 h level below assay specific value in column A)

– By the combination of a low baseline level and the lack of a relevant increase within 1 h (0 h level below assay specific value in column B and 0–1 h increase below assay specific value in column C).

Patients have a high likelihood for myocardial infarction:

– If the hs-cTn concentration at presentation is at least moderately elevated (0 h level ≥ assay specific value in column D)

– If the hs-cTn concentration shows a clear rise within the first hour (0–1 h increase ≥ assay specific value in column E).

Other 0 h ≥ D ng/lorΔ0-lh ≥ E ng/l 0 h < B ng/landΔ0-lh < C ng/l 0 h < A ng/l or Suspected NSTEMI Observe Rule-in Rule-out A B C D Ehs-cTnT (Elecsys) 5 12 3 52 5hs-cTnl (Architect) 2 5 2 52 6hs-cTnl (Dimension Vista) 0.5 5 2 107 19

Figure 2.4-4 Compartmentalization and release of cTnT and cTnI following myocardial injury. In the blood, cTnI exists mainly in the form of a binary complex cTnI/sTnC. sTnC, soluble TnC; cTnIC, binary complex of TNT; cTnTIC, ternary complex of TnT, modified from Ref. /21/.

Bound cTnTIC Cytoplasm cTnTIC sTnC cTnI/sTnC Free cTnT cTnI cTnIC cTnT cTnT Free cTnl

Figure 2.7-1 Causes and consequences of reduced arterial blood volume in chronic heart failure. Correction mechanisms are also shown. Modified with kind permission from Ref. /11/.

*/ ↓ Cardiac output Arterial underfilling ↓ Peripheral vascularresistance ↑ Cardiacoutput ↑ Peripheral vascular resistance Renal sodium andwater retention Restoration of arterial circulatory integrity

Figure 2.7-2 Mechanisms by which arterial hypovolemia leads to reduced delivery of sodium and water at the distal tubule of the kidney. This results in aldosterone escape as well as natriuretic peptide resistance. Modified with kind permission from Ref. /10/.

↓ Renal perfusion pressure ↓ Glomerular filtration rate Renal vaso-constriction α - Adrenergic activity ↑ Proximal tubular sodium and water reabsorption ↑ Angio-tensin II activity Decreased cardiac output or primary peripheral arterial vasodilatation Impaired escape from actions of aldosterone and resistance to natriuretic peptides ↓ Distal sodium and water delivery

Figure 2.8-1 Interpretation of BNP and NT-proBNP concentrations in patients with acute dyspnea and a GFR above 60 [mL × min–1 × (1.73 m2)–1/4/.

BNP < 100 ng/LorNT-proBNP < 300 ng/L BNP 100–400 ng/LorNT-proBNP< 450 ng/L (< 50 years)< 900 ng/L (50–75 years)< 1800 ng/L (> 75 years) BNP > 400 ng/LorNT-proBNP> 450 ng/L (< 50 years)> 900 ng/L (50–75 years)> 1800 ng/L (> 75 years) Further examinations Cardiac failureexcluded Cardiac failure likely

Figure 2.8-2 Median concentrations, highest values, and lowest values of BNP (Biosite assay) in patients with chronic heart failure in each of the four New York Heart Association classes (NYHA I–IV). With kind permission from Ref. /1/.

0 1,400 200 1,200 1,000 800 600 400 I II III IV NYHA BNP concentration (ng/l)

Figure 2.8-3 Median concentrations, highest values, and lowest values of NT-proBNP (Roche assay) in patients without chronic heart failure* and in patients with heart failure in New York Heart Association classes II to IV (NYHA II–IV). With kind permission from Ref. /15/.

* II III IV 0 20,000  10,000  2,000   1,500   1,000   500 NT-proBNP concentration (ng/L) NYHA

Figure 2.8-4 Kaplan-Meier curves showing the 76-day survival rate in patients with acute heart failure as a function of the NT-proBNP concentration. The cumulative survival rate is significantly higher for patients with NT-proBNP concentrations of ≤ 5,180 ng/L at the time of clinical presentation with acute destabilized heart failure. With kind permission from Ref. /15/.

0.70 0.75 0.80 0.85 0.90 0.95  1.00 0 10 20 30 40 50 60 70 80 NT-pro BNP > 5180 ng/l Days after acute chest pain Accumulated survival rate NT-pro BNP < 5180 ng/l

Figure 2.8-5 Cleavage of B-type natriuretic pro hormone (proBNP 1–108). ProBNP 1–108 is cleaved at position 76 by the peptidases corin or furin to produce the hormonally inactive 1–76 amino acid fragment NT-proBNP and the active 32-amino acid hormone BNP 77–108. Modified with kind permission from Ref. /3/.

proBNP (1–108) 1 1 10 70 76 10 70 76 80 90 100 Corin H 2 N COOH H 2 N NT-proBNP (1–76) BNP (77–108) Split COOH H P L G S P G S A S Y T Q G S G C K V L R R H L C C F C R K M S S S G D S R I L V R M A K P P R S 80 90 100 COOH Q G S G C K V L R R H L C C F C R K M S S S G D S R I V M K P S H P L G S P G S A S Y T L R A P E
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