Cardiac Function

1. 18 Cardiac Function

2. Objectives • Explain the inflammatory response associated with atherosclerosis. • Define acute coronary syndrome (ACS). • List five factors that define an ideal cardiac biomarker. • Define hs-CRP relative to cardiac usefulness.

3. Objectives • Identify the clinical usefulness of cardiac biomarkers: • Lipoprotein (a) • Myeloperoxidase • Cardiac troponin I and T • Brain-type natriuretic peptide and NT-proBNP • Ischemia-modified albumin (IMA)

4. Objectives 6. Discuss the rise and fall, and concentration of each the following relevant to acute myocardial infarction (AMI): • Myoglobin • CK-MB • Cardiac troponin I

5. Objectives 7. Explain the differences between cTnT, cTnI, BNP and NT-ProBNP and include Function and Specificity 8. Identify potential sources of interferences both analytically and physiologically for the Troponins and CK-MB

6. Objectives 9. Identify the limitations of the following biomarkers relative to various disease states: • CK-MB • Myoglobin • Cardiac troponin I and T

7. Figure 18-1 The anterior view of a human heart.

8. Cardiac Tissue • Myocardium – heart muscle wall • Pericardium – double walled sac enclosing heart – provides cushioning and barrier • Endocardium – inner lining of myocardium, • Endothelium – continuous lining of arteries and veins, made up of endothelial cells

9. Figure 18-2 Electrocardiogram of the human heart. SA—sinoatrial node, AV—atrioventricular node, LV—left ventricle. P wave is caused by the depolarization of the atrial muscle tissues, QRS wave corresponds to depolarization of ventricular muscle, and T wave corresponds to ventricular repolarization.

10. Atherosclerosis • “Athero” is Greek for gruel and refers to the massive accumulation of lipids in these vascular lesions. • Caused by plaque formation in coronary arteries which supply the cardiac muscle with O2 and nutrients. • Occlusion (blockage) leads to loss of function (ischemia) and cell death (necrosis).

11. Atherosclerotic Vascular Disease (ASVD) • Past: ASVD was considered to be a bland lipid storage disease. • Now: ASVD is thought to evolve from the inflammatory process. • From that inflammatory process rose several new markers, some measured in the labs now and some undergoing development to become the next clinically significant cardiac biomarker

12. The Inflammatory Process of Atherosclerosis • The initial insult is endothelial injury and subsequent dysfunction via the deleterious effects of known cardiac risk factors such as oxidized LDL, infection, hyperglycemia, hypertension, or smoking. • The presence of a series of biomarkers can signal stages of the inflammatory process, and levels of damage.

13. The Inflammatory Process of Atherosclerosis • Damage to Endothelial cells triggers inflammatory activation which increases expression of cytokines, APR, and vascular adhesion molecules. • These induce adhesion of monocytes which modify LDL to form foam cells (lipid-laden macrophages). • Foam cells secrete cytokines that promote and maintain WBC adhesion.

14. The Inflammatory Process of Atherosclerosis • More cells arrive: mast cells, T-cells, and stick to the atheroma. • Risk factors continue process of growth to more complex plaque. • Leads to vessel obstruction and angina, MI • Or plaque can destabilize and rupture, sending plaque to new location where it can cause blockage, MI, stroke

15. Cardiovascular Diseases • Acute coronary syndrome (ACS) – continuous range of symptoms from angina, SOB, to AMI • Coronary Artery Disease (CAD) also Coronary Heart Disease (CHD) and Atherosclerotic Heart Disease (AHD) • Congestive Heart Failure (CHF) – low output & fluid build-up

16. Figure 18-3 Number of deaths associated with major cardiovascular diseases for males and females according to CDC data for 2005.

17. Cardiac Biomarkers • The release of cardiac biomarkers is influenced by several factors: • Cytosolic enzymes – chemical features • Subcellular location – where to find molec • Molecular mass – size of molec • Plasma clearance – time in bloodstream • Concentration gradients – conc. inc/dec

18. Figure 18-4 Progression of CVD to cell death or cardiac dysfunction and associated biomarkers.

21. Biomarker Release

22. Biomarker Release

23. Myoglobin • A complex protein similar to hemoglobin • Present in muscle & excreted in urine • Increased in: • Cardiac and skeletal muscle damage • Familial myoglobinuria • High fevers, • Stress • Vigorous exercise

24. Myoglobin • Advantages • High sensitivity and negative predictive value • Useful for early detection of MI and reperfusion • Disadvantages • Low specificity in presence of skeletal muscle injury and renal insufficiency • Rapid clearance after necrosis

25. Creatine Kinase Isoenzymes • Exists as a dimer, with two subunits • Cardiac and Skeletal Muscle (M) and brain (B) • Three isoenzymes: MM, MB, and BB • Diagnostic significance: • AMI - CKMB • Muscular dystrophy (Duchenne) • Elevated in numerous other diseases

27. Troponins • Troponins consist of three subunits: • Troponin I • Troponin T • Troponin C • The subunits form a complex with actin and tropomyosin to create a large series of interconnected molecules that are responsible for muscle contraction.

28. Troponin I (Tnl) and Troponin T (TnT) • Cardiac: • One isoform of TnI - cTnI • Several isoforms of TnT – cTnT • High diagnostic specificity and sensitivity • Early release after AMI • Remain elevated for long interval • Low to undetectable in patients with no CVD

29. Possible Causes of False Results for Cardiac Troponin Assays • Heterophile antibodies • Circulating cTnI autoantibodies • Rheumatoid factor • Immunocomplex formation • Bilirubin, hemoglobin, lipemia • Fibrin clots, Analyzer malfunction

31. WHO Criteria for Making the Diagnosis of Acute Myocardial Infarction (AMI) • History of characteristic chest pain • Diagnostic changes in the EKG • Changes in serum cardiac enzyme levels

32. ESC - European Society of CardiologyACC - American College of Cardiology • Proposed to modify the WHO definitions regarding AMI • Promote troponin to a pivotal role • Relegate CKMB to a secondary role • Eliminate the need for CK

33. Heart Failure • 50% of patients die within 5 years after diagnosis. • The cost of HF is $20 billion. • More than MI and all cancers combined • About 45 million Americans have HF-related conditions.

34. Congestive Heart Failure • Diagnosis is based on clinical symptoms, history, and physical finding which include: • Elevated jugular and venous pressure • Irregular heart or lung sounds • Signs of volume overload • Cardiomegaly • SOB • Fatigue • Heart palpitations • Limitation of physical activity

35. B (Brain) Type Natriuretic Peptide (BNP) • BNP is one of two naturally occurring natriuretic peptides* (32 amino acids) secreted by the ventricles, especially the left ventricle, of the heart as part of the body’s defense against volume overload and hypertension. *the other is atrial natriuretic peptide (ANP)

36. B (Brain) Type Natriuretic Peptide (BNP) • BNP release from atrial and ventricular cardiac cells is stimulated by a decline in cardiac function resulting in an increase in cardiac myocyte stretch or intracavitary pressure.

37. (B)-Type Natriuretic Peptide (BNP) • BNP is thought to: • Dilate blood vessels • Increase the excretion of sodium and fluids • Reduce concentrations of neurohormones that lead to: • Vessel constriction • Fluid retention • Elevated blood pressure

38. Figure 18-5 Overview of the biochemical formation of BNP and NT-proBNP.

39. NT-proBNP • N-terminal pro-B-type natriuretic peptide • Has a longer half-life (60-120) minutes than BNP-32 (~30 minutes) • Has a higher plasma concentration (approximately four times higher) in New York Hosptial Association class I, II, III and IV patients than BNP-32

40. NT-proBNP • Elevated plasma NT-proBNP indicates the presence of heart failure and provides information about its severity. • NT-proBNP has been demonstrated to be a diagnostic aid in identifying left ventricular dysfunction.

41. C-Reactive Protein (CRP) • CRP is an acute-phase reactant whose concentration in blood rises dramatically in response to nonspecific inflammatory stimuli. • It has been linked to cardiovascular disease: • In serum of patients after AMI • In the wall of human coronary arteries involved in atherosclerosis

42. CRP in Atherosclerosis • Its presence in the arterial wall predicts severity of atherosclerosis • able to bind to damaged membranes and lipids • Reflects inflammation related to: • Coronary vessel pathogens • Extent of atherosclerosis • Myocardial ischemia and necrosis • Activity of circulating pro-inflammatory cytokines

43. CRP in Atherosclerosis • Conventional CRP • Pt ref range = 1-90mg/L • High sensitivity CRP – hs-CRP • For non-cardiac patients • Risk assessment • Cardiac CRP – cCRP • Wide Range Assays (0.05-320mg/L)

44. Cardiac Ischemia • A condition in which an imbalance between oxygen supply and demand lead to insufficient oxygen reaching the heart • Loss of function in cells and tissues

45. Current Approach to Evaluating Myocardial Ischemia • Clinical judgment • Serial 12-lead electrocardiogram • Single-photon emission CT (SPECT) • Blood Test ???

46. Ischmia-Modified Albumin • IMA is produced when circulating albumin comes in contact with ischemic tissue in the heart or other organ. During ischemia, the N-terminus of albumin is altered, probably through a series of chemical reactions involving free radical damage.

47. Ischmia-Modified Albumin • This altered albumin, termed ischemia modified albumin, is produced continually during ischemia, which means its blood concentrations rise quickly and remain elevated during an ischemic event.

48. Albumin Cobalt Binding Test • The ability of the N-terminal region of human albumin to bind cobalt is diminished by myocardial ischemia. • Free radicals damage albumin during an ischemic attack leading to IMA.

49. Myeloperoxidase (MPO) • MPO is secreted by activated leukocytes and is enriched in unstable atherosclerotic lesions. • It may serve as both a marker and mediator of vascular inflammation. • Elevated results are seen in patients with AMI (>50 ng/mL).

50. Function of Lp(a) • Biological function is unclear! • Homology with LDL and plasminogen • Roles may be to: • Respond to tissue injury and vascular lesions • Prevent infectious pathogens from invading cells • Promote wound healing