Cardiac Function

A. Terminologies
Coronary Heart Disease (CHD) - most important disease affecting the heart Acute Coronary Syndrome (ACS) - acute blockage of coronary blood flow Ischemic Heart Disease or myocardial ischaemia, is a disease characterized by inadequate or reduced blood supply to the heart muscles Myocardial Infarction (MI) - commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die. o Myocardial Infarction is defined as an ACS that causes release of cardiac markers specifically troponins. Atherosclerosis (also known as arteriosclerotic vascular disease or ASVD) is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol.

B. Risk Factors
Age (men > 45 years; women > 55 years) Gender: men are more at risk than women Diabetes mellitus (type 1 or 2) High blood pressure Dyslipidemia/hypercholesterolemia (high LDL, low HDL & high triglycerides) Tobacco smoking, including secondhand smoke Short term exposure to air pollution including: carbon monoxide, nitrogen dioxide, and sulfur dioxide. Family history of ischaemic heart disease or myocardial infarction Obesity (defined by a body mass index of more than 30 kg/m) Lack of physical activity Psychosocial factors including, low socio-economic status, social isolation, negative emotions and stress Alcoholism Oral contraceptive pills Hyperhomocysteinemia/Homocysteinuria The primary tests for diagnosing ACS are electrocardiography (ECG) and laboratory measurement of cardiac markers. Cardiac markers are proteins released into the circulation from the damaged heart muscle.

Key Points
Clinically, MI is now essentially defined as an ACS that causes release of troponin. The most important cardiac marker today is cardiac troponin (cTn), which derives only from heart muscle. Troponin is a complex of three proteins, two of which are suitable as specific cardiac marker tests: cTnI and cTnT. There is a delay of a few hours following MI before cTn is detected in the circulation; it peaks in about 24hrs and then declines over several days. Myoglobin is a marker that appears in the circulation faster than cTn, but it is also present in skeletal muscle. The clinical laboratory measures risk factors associated with the development and progression of CHD. Rapid measurements of cTn, and possibly other laboratory markers, play a critical role. Significant laboratory markers of risk include lipids (cholesterol, triglycerides, and specific lipoprotein fractions), homocysteine (Hcy), and C-reactive protein (CRP). Homocysteine is an amino acid that exacerbates thrombosis. CRP is an inflammatory marker that appears to reflect the severity of CHD and may contribute to its pathogenesis.

Recommendations of a Joint Committee of the American Heart Association and the Centers for Disease Control and Prevention on CRP Testing to Assess CHD Risk (Pearson, 2003) Disease Control and Prevention on CRP Testing to Assess CHD Risk (Pearson, 2003) If inflammatory markers are to be used in assessment of CHD risk, hsCRP is the current analyte of choice Optimally, hsCRP results should be averaged from two specimens drawn about 2 weeks apart. If a level > 10 mg/L is identified, there should be a search for an obvious cause of infection or inflammation; that result should then be discarded, and another test done 2 weeks later Decision intervals are: o < 1 mg/L, low risk; o 13 mg/L, intermediate risk; o 3mg/L, high risk 3. Homocysteine (Hcy) This risk marker parallels that of cholesterol with regular occurrence of atherosclerosis in persons with massive elevation, due to an inborn error of metabolism Homocystinuria homozygous defect in the enzyme cystathionine-13synthase due to deficiency in vitamins B6 and B12. Clinical manifestations of Homocystenuria: dislocation of the optic lens osteoporosis with associated skeletal abnormalities mental retardation psychiatric disturbance thromboembolic disease => CHD

I. Markers of Coronary Risk

1. Lipids Serum Cholesterol o Low-density lipoprotein (LDL) fraction ( 70% of the total circulating cholesterol) o High-density lipoprotein (HDL) fraction (negative risk) o Triglycerides - major lipid class commonly measured in plasma Lipid profile or lipid panel is the collective term given to the estimation of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. An extended lipid profile may include very low-density lipoprotein. This is used to identify hyperlipidemia a risk factor for cardiovascular disease 2. C-Reactive Protein (CRP) First isolated in 1930 from the plasma of patients with pneumococcal pneumonia, CRP was so named because it binds to the C-polysaccharide of the pneumococcus. The protein appeared in plasma during many infectious or inflammatory conditions CRP was the original acute phase reactant. MI is among the acute illnesses associated with elevation of plasma CRP

II. Markers of Congestive Heart Failure

*The heart could be an endocrine organ Members of the natriuretic peptide family: 1. Atrial natriuretic peptide (ANP) isolated from human 2. Brain natriuretic peptide (BNP) isolated from porcine brain o In humans BNP is produced mainly in the cardiac ventricle, so the hormone is now commonly referred to as B-type natriuretic peptide. 3. C-type natriuretic peptide (CNP) not produced in the heart but in endothelial cells 4. D-type natriuretic peptide (DNP) isolated from green mamba snake, Dendroaspis angusticeps 5. Urodilatin is a form of ANP produced in the kidneys

BNP and the other natriuretic peptides downregulate the renin angiotensinaldosterone system, decrease sympathetic nerve activity in the heart and kidney, increase renal blood flow, and increase sodium excretion via a direct effect on the renal collecting duct Plasma levels of BNP are less than 100 pg/mL in most healthy individuals The best application of BNP is to distinguish Heart Failure from lung disease, such as emphysema BNP test for diagnosis of HF: sensitivity 90%, specificity 76%

III. Cardiac Markers for Myocardial Damage

1. Aspartate transaminase (AST) It is then known as GOT (glutamate-oxaloacetate transaminase) Transaminases have not endured as cardiac markers because of their abundance in liver, skeletal muscle, and other tissues. They were superseded for cardiac diagnosis by two other enzymes, lactate dehydrogenase (LD) and creatine kinase (CK). 2. Troponin (cTn) The most sensitive and specific test for myocardial damage. Because it has increased specificity compared with CK-MB, troponin is a superior marker for myocardial injury. Peak: 12 hours Troponin is released during MI from the cytosolic pool of the myocytes. Its subsequent release is prolonged with degradation of actin and myosin filaments. Troponins can also calculate infarct size but the peak must be measured in rd the 3 day. After myocyte injury, troponin is released in 24 hours and persists for up to 7 days. 3. Creatine Kinase (CK-MB) It is relatively specific when skeletal muscle damage is not present. Peak: 1024 hours CK-MB resides in the cytosol and facilitates movement of high energy phosphates into and out of mitochondria. It is distributed in a large number of tissues even in the skeletal muscle. It has a short duration, it CANNOT be used for late diagnosis of acute MI but can be used to suggest infarct extension if levels rise again. This is back to normal within 23 days. Creatine Kinase is a dimer of catalytic subunits (MW 40kDA) Has 2 subunits M (muscles) and B (brain) 3 isoenzymes: o CK-BB : brain and smooth muscles o CK-MB: increase in the right heart o CK-MM: skeletal muscles

4. Lactate dehydrogenase(LDH) Is not as specific as troponin. Peak: 72 hours Lactate dehydrogenase catalyses the conversion of pyruvate to lactate. A high LDH-1 level to LDH-2 suggests MI. LDH levels are also high in tissue breakdown or hemolysis. It can mean cancer, meningitis, encephalitis or HIV. This usually back to normal 1014 days. Functional lactate dehydrogenase (MW 134kDA) is homo or hetero tetramers composed of M and H protein. The major isoenzymes of skeletal muscle and liver, M 4, has four muscle (M) subunits, while H4 is the main isoenzymes for heart muscle in most species, containing four heart (H) subunits. The other variants contain both types of subunits. o LDH-1 (HHHH)in the heart o LDH-2 (HHHM)in the reticuloendothelial system o LDH-3 (HHMM)in the lungs o LDH-4 (HMMM)in the kidneys, placenta, and pancreas o LDH-5 (MMMM)in the liver and striated muscle Usually LDH-2 is the predominant form in the serum. LDH-1 level higher than the LDH-2 level (a "flipped pattern") suggests myocardial infarction (damage to heart tissues releases heart LDH, which is rich in LDH-1, into the bloodstream). The use of this phenomenon to diagnose infarction has been largely superseded by the use of Troponin I or T measurement. 5. Myoglobin (Mb) low specificity for myocardial infarction Peak: 2-6 hours Myoglobin is the primary oxygen-carrying pigment of muscle tissue. It is high when muscle tissue is damaged but it lacks specificity. It has the advantage of responding very rapidly, rising and falling earlier than CK-MB or troponin. It also has been used in assessing reperfusion after thrombolysis. 6. Ischemia-modified Albumin (IMA) Ischemia-modified albumin (IMA) Low specificity IMA measures ischemia in the blood vessels and thus returns results in minutes rather than traditional markers of necrosis that take hours. IMA can be detected via the albumin cobalt binding (ACB) test. ACB test has low specificity therefore generating high number of false positives and must be used in conjunction with ECG and physical exam.

7. Pro-brain Natriuretic peptide This is increased in patients with heart failure. A marker for acute congestive heart failure. Patients with < 80 have a much higher rate of symptom free survival within a year. Generally, patients with CHF will have > 100. 8. Glycogen phosphorylase isoenzyme BB High sensitivity and specificity early after chest pain Peak: 7 hours Glycogen phosphorylase isoenzyme BB (abbreviation: GPBB) is an isoenzyme of glycogen phosphorylase. This isoform exists in heart and brain tissue. Because of the bloodbrain barrier GP-BB can be seen as heart muscle specific. During the process of ischemia, GP-BB is converted into a soluble form and is released into the blood. GP-BB is one of the "new cardiac markers" which are discussed to improve early diagnosis in acute coronary syndrome. A rapid rise in blood levels can be seen in myocardial infarction and unstable angina. GP-BB elevated 13 hours after process of ischemia.

Summary
1. Coronary Risk 2. Congestive Heart Failure 3. Myocardial Damage Lipids C-Reactive Protein Homocysteine BNP Peak 12 hours 10-24 hours 72 hours 2-6 hours

Marker AST cTn CK-MB LDH (1>2) Mb IMA Pro-brain Natriuretic Peptide GP-BB

7 hours