Cardiac Function

1. Cardiac Function Lecture 3

2. Introduction • Although the heart is an efficient and durable pump, a variety of pathologic processes are known to diminish cardiac function, possibly leading to a variety of dysfunctional clinical states, Cardiovascular Diseases. • A general term used to describe disorders that can affect the heart (cardio) and/or the body's system of blood vessels (vascular). • Coronary Artery Disease (CAD), Acute ischemic heart disease are the most common cardiac diseases. • Heart failure (HF), cases of which are increasing as we improve the treatment of acute ischemic heart disease.

3. CARDIAC DISEASEAcute Coronary Syndrome Total loss of coronary blood flow results in a clinical syndrome associated with what is known as (STEAMI or STEMI). Partial loss of coronary perfusion, if severe, can lead to necrosis as well, which is generally less severe and is known as (NSTEMI).

4. CARDIAC DISEASEAcute Coronary Syndrome • Occur in response to an acute event in the coronary artery, when circulation to a region of the heart is obstructed for some reason. • If the obstruction is high grade and persists, necrosis usually follows. • Because necrosis is known to take some time to develop, it is apparent that opening the blocked coronary artery in a timely fashion can often prevent some of the death of myocardial tissue. • This is clearly the case with STEMI. • With non-STEMI, early but not immediate intervention is advocated, because most often the infarct-related coronary artery is not totally occluded, and thus immediate intervention is less necessary.

5. CARDIAC DISEASEAcute Coronary Syndrome • The major cause of ACS is atherosclerosis, which contributes to significant narrowing of the artery lumen and a tendency for plaque disruption and thrombus formation.

7. CARDIAC DISEASEAcute Coronary Syndrome • The resulting impaired contractile performance of the segment occurs within seconds and is initially restricted to the affected segment(s). • Myocardial ischemia and subsequent infarction usually begin in the endocardium and spread toward the epicardium.

8. CARDIAC DISEASEAcute Coronary Syndrome • The extent of myocardial injury reflects: • the extent of occlusion, • the needs of the area deprived of perfusion, and • the duration of the imbalance in coronary supply. • Irreversible cardiac injury consistently occurs in animals when the occlusion is complete forat least 15 to 20 minutes. • Most damage occurs within the first 2 to 3 hours. • Restoration of flow within the first 60 to 90 minutes evokes maximal rescue of tissue, but benefits of increased survival are possible up to 4 to 6 hours. In some situations, the restoration of coronary perfusion even later is of benefit.

9. CARDIAC DISEASEAcute Coronary Syndrome • In almost all instances, the left ventricle is affected by AMI. • However, with right coronary and/or circumflex occlusion, the right ventricle also can be involved, • There is a clinical syndrome in which damage to the right ventricle predominates and is the major determinant of hemodynamics.

10. CARDIAC DISEASEAcute Coronary Syndrome • Coronary thrombi will undergo spontaneous lysis, even if untreated, in approximately 50% of cases within 10 days. • However, for patients with STEMI, opening the vessel earlier with clot-dissolving agents (thrombolysis) and/or percutaneous intervention (PCI) can often save myocardium and lives.

11. CARDIAC DISEASEAcute Coronary Syndrome • Initially, it was thought that the population of myocytes was fixed; however, it is now believed that the migration of a variety of precursor stem cells has the potential at least to replace some of the damaged myocytes. • It is now thought that the process of plaque rupture or erosion and thrombosis is one of the ways in which coronary atherosclerosis progresses, and that we recognize only more severe events.

12. CARDIAC DISEASEAcute Coronary Syndrome • Historically, most deaths caused by ischemic heart disease were acute, but as our therapeutic abilities have increased, the disease is becoming more chronic. • Deaths that occur acutely result from ventricular arrhythmias or pump dysfunction and congestive heart failure (CHF) with or without cardiogenic shock. • Death rates are sharply age dependent, both during hospitalization and in the year after infarction.

13. CARDIAC DISEASE/ Acute Coronary Syndrome Development and Progression of Atherosclerosis • Atherosclerosis is a chronic inflammatory disease. • The process of atherosclerosis progresses slowly, with involvement of lymphocytes, monocytes, macrophages, and smooth muscle cells. • The dynamic within a given plaque may vary, but there clearly is an inflammatory situation, in part mediated by substances such as CD40 ligand, which can be measured directly or indirectly as C-reactive protein (CRP). • Interleukins (IL)-1, IL-6, IL-8, and IL-18 also participate to various extents as part of this chronic inflammatory process.

14. CARDIAC DISEASE/ Acute Coronary Syndrome Development and Progression of Atherosclerosis

15. CARDIAC DISEASE/ Acute Coronary Syndrome Development and Progression of Atherosclerosis • The process involves adherence of white blood cells to the damaged endothelial surface, with subsequent degranulation and elaboration of myeloperoxidase. • Intermittent instability is noted because of inflammatory products within the plaque that release chemicals, such as metalloproteinases. • A categorization of plaques has been proposed to facilitate identification of those at risk for rupture that could lead to an acute event. • It is acknowledged that the tendency for a plaque to rupture probably reflects a systemic predilection rather than a local one.

16. CARDIAC DISEASE/ Acute Coronary Syndrome Development and Progression of Atherosclerosis • High-risk plaques have the following: • An active inflammatory environment that not only may be intrinsic but may be stimulated additionally by systemic infection; • A thin fibrous cap on the endothelial surface with a large lipid core that is filled with procoagulant substances, predominantly tissue factor; • Endothelial denudation and fissuring caused by the elaboration of metalloproteinases; • Local high shear stress, usually because they are severe, at branch points in the vessel.

17. CARDIAC DISEASE/ Acute Coronary Syndrome Diagnosis of Acute Myocardial Infarction • The diagnosis of AMI established by the WHO in 1986 included biomarkers as an integral part of the disorder and required that at least two of the following criteria be met: • A history of chest pain, • Evolutionary changes on the ECG, and/or • Elevations of serial cardiac markers to a level two times the normal value. • However, over time, it became rare for a diagnosis of AMI to be made in the absence of biochemical evidence of myocardial injury.

18. CARDIAC DISEASE/ Acute Coronary Syndrome Diagnosis of Acute Myocardial Infarction • A 2000 European Society of Cardiology/ American College of Cardiology (ESC/ACC) consensus conference updated in 2007 and 2012 (Global Task Force) codified the role ofmarkers by advocating that the diagnosis should be regarded as evidence of myocardial injury based on markers of cardiac damage in the appropriate clinical situation.

19. BIOMARKERS IN ACUTE CORONARY SYNDROMEHistory Timeline of the development of cardiac biomarkers for the diagnosis of acute myocardial infarction.

20. BIOMARKERS IN ACUTE CORONARY SYNDROMEHistory • Aspartate Transaminase (AST) became the first biomarker used in the diagnosis of AMI. • AST was widely used in the 1960s and was incorporated into the WHO definition of AMI. • However, AST is not specific for cardiac muscle, and its detection is, therefore, not specific for cardiac damage. • By 1970s, two further cardiac biomarkers were in use: lactate dehydrogenase (LDH) and creatine kinase (CK). • Although neither is absolutely specific for cardiac muscle, CK is more specific than LDH in the context of AMI, especially in patients having other co-morbidities such as muscle or hepatic disease.

21. BIOMARKERS IN ACUTE CORONARY SYNDROMEHistory • Myoglobin is a small globular oxygen carrying protein found in heart and striated skeletal muscle. • The first method to detect myoglobin in the serum was developed in 1978. • Myoglobin rises after acute myocardial injury, and it became a useful cardiac biomarker in the differential diagnosis of suspected AMI.

23. BIOMARKERS IN ACUTE CORONARY SYNDROMEHistory • Eventually, advancements in electrophoresis allowed the detection of cardiac-specific iso-enzymes of CK and LDH, • i.e., CK-MB and LDH 1 + 2. • Cardiac muscle has higher CK-MB levels (25–30%) compared to skeletal muscle (1%), which is mostly composed of CK-MM. • These assays played an important role in the diagnosis of AMI for two decades, and were included as one of the diagnostic criteria to rule out AMI by the WHO in 1979. • However, the lack of specificity and the high rate of false positive results limited their usefulness. • A more cardiac specific biomarker was needed.

24. BIOMARKERS IN ACUTE CORONARY SYNDROMEHistory • In 1965, a new protein constituent of the cardiac myofibrillar apparatus was discovered, which subsequently came to be known as troponin. • In the late 1990s, a sensitive and reliable RIA was developed to detect serum troponin. • Numerous studies demonstrate that troponins appear in the serum 4–10 h after the onset of AMI. • Troponin levels peak at 12–48 h, but remain elevated for 4–10 days. • The sensitivity for detecting troponin T and I approaches 100% when sampled 6–12 h after acute chest pain onset. • Therefore, in the context of acute chest pain, to reliably rule out AMI, patients need to have a repeat troponin sample 6–12 h after the initial assessment. • Consequently, patients were increasingly admitted to observational chest pain units.

25. BIOMARKERS IN ACUTE CORONARY SYNDROMETroponin • Myocardial damage detected by increases of cardiac troponin (cTn) is almost invariably associated with adverse clinical outcomes. • This statement summarizes more than 25 years of analytical and clinical investigations relating to the clinical utility of cTnI and cTnT.

26. BIOMARKERS IN ACUTE CORONARY SYNDROMETroponin • The myocardium contains bundles of striated muscle fibers, each of which is typically 10 to 15 mm in diameter and 30 to 60 mm in length. • The work of the heart is generated by the alternating contraction and relaxation of these fibers. • The fibers are composed of the cardiac-specific contractile proteins actin and myosin and regulatory proteins called troponins. • They also contain a variety of enzymes and proteinsthat are vital for energy use, such as myoglobin, creatine kinase (CK), and lactate dehydrogenase (LD), some of which can be used as markers of cardiac injury.

27. Structure of cardiac troponin (cTn) complex and troponin forms released after myofibril necrosis. cTn1, Cardiac troponin I; cTnT, cardiac troponin T

29. BIOMARKERS IN ACUTE CORONARY SYNDROMETroponin • The contractile proteins of the myofibril include the three troponin regulatory proteins. • The troponins are a complex of three protein subunits: • Troponin C (the calcium-binding component), • Troponin I (the inhibitory component), and • Troponin T (the tropomyosin-binding component). • The subunits exist in a number of isoforms. • The distribution of these isoforms varies between cardiac muscles and low- and fast-twitch skeletal muscle.

30. BIOMARKERS IN ACUTE CORONARY SYNDROMETroponin • Only two major isoforms of troponin C are found in human heart and skeletal muscle. • These are characteristic of slow- and fast-twitchskeletal muscle. • The heart isoform is identical to the slow twitch skeletal muscle isoform, thus the reason why cTnC was never developed as a cardiac-specific biomarker. • Isoforms of cardiac-specific troponin T (cTnT) and cardiac-specific troponin I (cTnI) also have been identified and are the products of unique genes. • Troponin is localized primarily in the myofibrils (94% to 97%), with a smaller cytoplasmic fraction (3% to 6%).

31. BIOMARKERS IN ACUTE CORONARY SYNDROMETroponin • cTnI and cTnT have different amino acid sequences from the skeletal isoforms and are encoded by unique genes. • Only one isoform of cTnI has been identified. cTnI is not expressed in normal, regenerating, or diseased human or animal skeletal muscle. • cTnT is encoded for by a different gene than the one that encodes for skeletal muscle isoforms. • An 11 amino acid amino-terminal residue gives this marker unique cardiac specificity. • In humans, cTnT isoform expression has been demonstrated in skeletal muscle specimens obtained from patients with muscular dystrophy, polymyositis, dermatomyositis, and end-stage renal disease.

32. BIOMARKERS IN ACUTE CORONARY SYNDROMEHigh-Sensitivity Cardiac Troponin (hs-cTn) • Most hospitals now have replaced conventional cTn tests with the new 5th generation hs-cTn T and I assays which can detect troponin at concentrations 10- to 100-fold lower than conventional assays.

33. BIOMARKERS IN ACUTE CORONARY SYNDROMEHigh-Sensitivity Cardiac Troponin (hs-cTn) • Between 2 and 6 h, a steep increase in levels of cardiac troponin can be seen that represents extensive myocardial necrosis (red-bars). • Only this major increase of cardiac troponin can be detected by first to fourth generation troponin assays. • hs-cTn (5th generation troponin assay) can also detect lower levels of troponin including ischemia/micronecrosis and even the normalturnover.

34. BIOMARKERS IN ACUTE CORONARY SYNDROMEBiomarkers No Longer of Clinical Use • Because of the lack of clinical utility the following biomarkers will not be discussed: • CK isoenzymes, • CK muscle type (CK-MM) (CK-1), and • CK brain type (CK-BB) (CK-3); • myoglobin; and • LD isoenzymes LD1, LD2, LD3, LD4, and LD5 • As discussed in numerous international guidelines, including the Third Universal Definition of Myocardial Infarction, • the only clinical utility of using CK-MB would be in the absence of cTn testing. • Further, the only clinical utility of using CK would be in the absence of both cTn and CK-MB.

35. BIOMARKERS IN ACUTE CORONARY SYNDROMEBiomarker That May Be Helpful: Copeptin • Copeptin is the preform of arginine vasopressin (AVP). • It is cleaved from vasopressin and has a longer half-life, making measurement much easier. • It correlates well with AVP, which is cleared very rapidly from the blood. • Because AVP is a stress hormone, copeptin has been used to define hemodynamic stress in two clinical situations: possible AMI and patients with HF.

36. BIOMARKERS IN ACUTE CORONARY SYNDROMEBiomarker That May Be Helpful: Copeptin • Copeptin rises very rapidly in response to hemodynamic stress and falls rapidly as well. • Its clinical use to rule out AMI has been predicated on its rapid increase. • Thus elevations may precede those of cTn even in patients who present very early after the onset of AMI. • Thus a normal copeptin value has been touted to provide accurate exclusion of AMI. • However, there have been several concerns about the use of copeptin. • One has been that many studies have not been as rigorous as would be ideal in making the diagnosis of AMI. • In addition, many studies have not included large numbers of patients presenting early after the onset of AMI.

37. BIOMARKERS IN ACUTE CORONARY SYNDROMEBiomarker That May Be Helpful: Copeptin • In HF patients, AVP is thought to be an important neurohormonal compensation that becomes dysregulated. • However, trials of AVP inhibitors have thus far been null. • Increasing values of copeptin are prognostic both at baseline and during follow-up, especially in patients with hyponatremia. • This raises the possibility that the marker may allow for the identification of patients who are in need or AVP inhibition and allow for more focused use of this therapy.

38. CARDIAC DISEASECongestive Heart Failure • CHF is a syndrome characterized by ineffective pumping of the heart, often leading to an accumulation of fluid in the lungs. • At least half comes as a result of the loss of the function of the cardiac tissue and is called: • heart failure with reduced ejection fraction(HFrEF). • The other half is due to increased stiffness of the cardiac muscle. This type of HF is referred to as: • heart failure with preserved ejection fraction or HFpEF. • Other forms include those related to valvular heart disease and so-called high-output HF. • The condition is one in which there is an abnormality of cardiac function such that the heart cannot pump sufficient blood to satisfy the requirements of metabolizing tissues, which are abnormally high.

39. CARDIAC DISEASECongestive Heart Failure

40. CARDIAC DISEASE/ Congestive Heart Failure Epidemiology • In the United States, CHF is the only cardiovascular disease (CVD) with an increasing incidence. • The National Heart, Lung, and Blood Institute estimates current prevalence at 4.8 million Americans and 23 millionworldwide with CHF. • There are approximately 580,000 new cases /year, with ~ 1 million admissions to hospitals for CHF /year. • CHF is the leading cause of hospitalization in individuals 65 years of age and older. • Therapeutic options for patients with HFpEF are morelimited than for those who have systolic abnormalities. • Current prognosis depends on disease severity, but overall it is poor. • Mortality at 5 years is approximately 50%, and 10-year mortality is 90%.

41. CARDIAC DISEASE/ Congestive Heart Failure Epidemiology • Currently, CHF patients are staged with the New York Heart Association (NYHA) functional classifications I to IV. • Class I patients are generally considered asymptomatic, with no restrictions on physical activity; • class IV patients are often symptomatic at rest, with severe limitations on physical activity. • The problem with this classification system is that much of it is based on subjective criteria. • Thus patients with comorbidities that reduce their activities are hard to classify. • In addition, dyspnea, which is the primary symptomin many of these individuals, has many causes.

42. CARDIAC DISEASE/ Congestive Heart Failure Epidemiology

43. CARDIAC DISEASE/ Congestive Heart Failure Epidemiology • Patients with CHF often go undiagnosed and untreated early in their disease or are misdiagnosed because of conditions such as pulmonary disease. • Initiating treatment in the more advanced disease state (higher degree of irreversible cardiac function) is challenging and more expensive • often requiring extended inpatient stay and leaves patients with considerable morbidity on a daily basis. • Obviously, misdiagnoses often lead to patient morbidity. • That is the reason why natriuretic peptides have been such an important advance in facilitating the diagnosis of HF.

44. Biomarkers in ACS and HF

45. BIOMARKERS IN HEART FAILURENatriuretic Peptides • In the 1960s, electron microscopy revealed granules in the cytoplasm of atrial myocytes, which structurally resemble secretory granules in known peptide hormone–producing cells. • The granules were purified and identified as a peptide comprising 28 amino acid residues and renamed atrial natriuretic peptide (ANP). • Then it was reported that infusion of atrial tissue extracts elicits renal excretion of sodium and water. • Moreover, a rapid decrease in blood pressure and increase in blood hematocrit was observed and the substance was named atrial natriuretic factor.

46. BIOMARKERS IN HEART FAILURENatriuretic Peptides • This discovery paved the way for identification of two structurally related peptides: • in the porcine brain: brain natriuretic peptide (BNP) • BNP is mainly expressed in the heart and the name “brain” natriuretic peptide is now replaced with B-type natriuretic peptide • C-type natriuretic peptide (CNP). • CNP is expressed in the invertebrate heart • The CNP gene is not expressed to the same extent in mammalian hearts and should not be considered a cardiac-derived hormone in humans, in which the gene dominantly is expressed in other tissues (vasculature and the male reproductive glands) • Other members of the natriuretic peptide family include Dendroaspis natriuretic peptide (DNP) and urodilatin.

47. BIOMARKERS IN HEART FAILURENatriuretic Peptides • The endocrine heart gained clinical interest when it was reported that patients with cardiac disease display increased concentrations of ANP in plasma. • In parallel, BNP circulates in highly increased concentrations in patients with CHF. • In addition to the bioactive end products, N-terminal fragments from the precursor peptides (proANP and proBNP) were also shown to circulate in HF plasma and provided new molecular targets for biochemical detection.

48. BIOMARKERS IN HEART FAILURENatriuretic Peptides

49. BIOMARKERS IN HEART FAILUREClinical Use of Natriuretic Peptides • BNP, NT-proBNP, and novel NP assays that are being developed have proved of assistance to clinicians in the evaluation of patients with impaired left ventricular function, with orwithout CHF and those with coronary heart disease. • On the other hand, the more we have learned about natriuretic peptides, the more complicated the biology of these biomarkers has become.

50. BIOMARKERS IN HEART FAILUREClinical Use of Natriuretic Peptides