Evaluation of Cardiac Injury and Function

Introduction

• CHD,– The most important disease affecting the heart is

coronary heart disease• ACS,– CHD, can lead to an acute blockage of coronary

blood flow known as an acute coronary syndrome • MI,– ACS with frank necrosis of any amount of

myocardium is known as myocardial infarction

Background

• Ischemia – the lack of an adequate blood supply

• Atherosclerosis– a chronic process involving damage to

endothelium and the build-up of vessel occluding lesions called plaque.

• angina pectoris (exertional angina)– Once the diameter of a coronary artery is reduced

to less than 10-20% of its original size

Background

• Myocardial infarction (MI)– Complete blockage of blood flow• Irreversible ischemic damage

• Unstable angina (UA)– When the blockage is not complete– irreversible muscle damage may be avoided– experience severe angina, even at rest

Diagnosis of Cardiac diseases(Outline)

• Cardiac diseases discussed in this session – Coronary heart disease (CHD)– Heart failure (HF)

• Diagnosis of Cardiac diseases– Clinical (non laboratory) examination

• e.g, Clinical history, ECG, angiography, echocardiography

– Biochemical markers• Markers of Myocardial Damage• Risk factors associated with the development and

progression of CHD.

ECG;ElectroCardioGraphy

Heart Disease Statistics for the US

Markers of Myocardial Damage

• Cardiac enzymes– Transaminases (SGOT,SGPT)– Lactate dehydrogenase (LD) – Creatine kinase (CK)

• Improved cardiac specificity– with separation of isoenzymes.• LD1 is relatively abundant in cardiac muscle

– Flipped LD, where the normal finding LD2> LD1] is reversed.

• In normal heart, 15-20% of the CK is CK-MB• Changes in LD observable for a much longer

time than changes in CK.• The isoenzyme analyses were relatively

lengthy & tedious– Could only be performed about once per day

• CK-MB Mass Assay– Can be performed rapidly

Kinetics of several cardiac markers following an MI

Cardiac Troponin

• The most important laboratory test for cardiac diagnosis.

• TnT (tropomyosin-binding subunit, 37 kDa)• Tnl (inhibitory subunit, 24 kDa), • TnC (calcium-binding subunit, 18 kDa).

Cardiac Troponin

• Tnl has a cardiospecific form (cTnl)• TnT also has distinct forms in myocardium

(cTnT)– Also, Fetal skeletal muscle and diseased skeletal

muscle.• post-translational modifications cause detectable

differences

Cardiac Troponin

• Bound form– released slowly over the course of 1-2 weeks following

myocardial infarction.• Free form– time frame similar to that of CK-MB, with cTn reaching a

peak at about 24 h following MI• cTnT and cTnl are nearly absent from normal serum• Small elevations– pericarditis, myocarditis, pulmonary embolism, renal

failure, sepsis, and other critical illness

• The high sensitivity and specificity of cTn• Patients with ischemic symptoms who also

have elevations in cTn receive greater benefit from therapies with various antiplatelet and anti thrombotic agents

Myoglobin

• Lacking cardiac specificity,• more rapidly than other proteins • Within 2-3 h following onset of MI, earlier

than with troponin or other markers• myoglobin peaks about 6 h after MI and

returns to baseline after 24• half-life,approximately 4 hours, but is longer if

renal function is impaired.

Myoglobin

• Muscle mass and muscle activity – Higher in men

• increases with increasing age• Day-to-day variation is about 10-15%• offers fairly high clinical specificity (> 95%)

when patients with renal failure or suspected injury to skeletal muscle are excluded.

• Sensitivity can be enhanced– δ Mb

Other Markers

• Carbonic Anhydrase III(CA III)– present in skeletal but not cardiac muscle,• Negative cardiac marker.

• Creatine Kinase Isoforms– a high ratio of MB2/MB1 suggests that a recent

release of enzyme has occurred.– in the first 3-4 hours following symptom onset,

improved sensitivity for MI detection

Limitations

• cTn– is a highly heterogeneous analyte.– Reference ranges and decision points have been a

matter of some confusion

Diagnosis of ACS

• Biochemical markers play a secondary role in the initial management of patients with suspected ACS.

• The earliest decision-making, which should ideally take place within 10 min of the patient's arrival in the ED, is based on history, physical examination, and 12-lead ECG

• Likely to be negative at this early time.

ACS: acute coronary syndrome. ED: emergency department

• Choice of markers and time points– cTn (either I or T) is the preferred marker for

definitive diagnosis• Also for early diagnosis,– Myoglobin but possibly CK isoforms, at the 0 and

1- to 4-h time points.

• noninvasive indicator that reperfusion has occurred,– Myoglobin was found to perform better than CK-

MB or cTn• early reinfarction – CK-MB appears to be superior to cTn because of

its more rapid decline following MI– myoglobin is also useful.

• Diagnosis of MI following surgical procedures– cTn is clearly the marker of choice in this situation,

Markers of Coronary Risk

• Laboratory tests– Serum cholesterol• LDL• HDL, a negative risk factor • Triglyceride

• C-Reactive Protein (CRP)– In acute illness, cytokines, chiefly interleukin-6,

stimulate hepatic production of CRP

Clinical (non laboratory) risk factors for CHD

Markers of Coronary Risk

• the usefulness of the hsCRP test in individual patients has been controversial.– the variations in quantitative risk estimates,– the unclear role of CRP in pathogenesis of vascular

disease,– the lack of specific treatment for high CRP,

Markers of Coronary Risk

• epidemiology studies – confirm a correlation between moderate Hey levels and CHD.

• Homocysteine (Hey)– total homocysteine (tHcy):

• free sulfhydryl group, • as a disulfide (homocystine), • as a mixed disulfide,

– linked to a plasma protein via one of its cysteine residues.

• Excessive levels of circulating Hcy– Enzyme defect

• Cystathionine-β-synthase

Chemical structure of homocysteine and related compounds.

Markers of Coronary Risk

• Clinical manifestations– thromboembolic disease, including CHD

• The basis of the damaging effects of Hcy is uncertain.– Oxidant stress and inhibition of transmethylation

reactions are likely• Measurment – Chromatographic – Enzymatic

Clinical algorithm for treating patients presenting to an emergency department with symptoms suggesting ACS.

Markers of Congestive Heart Failure

• Cardiac Natriuretic Peptides– brain natriuretic peptide (BNP) produced mainly in

the cardiac ventricle– Secretion enhanced by ventricular wall stretch and

volume overload, as occurs in HF– Circulating half-life is approximately 22 minutes.– (N-terminal fragment)N-BNP is considerably

longer (60-120 min)

Markers of Congestive Heart Failure

• Applications of BNP testing– The best-established application

• For diagnosing acutely ill patients presenting to emergency service with shortness of breath.

• At a decision point of 100 pg/mL, the BNP test had the following characteristics for diagnosis of HF:– Sensitivity 90%,– Specificity 76%, – Positive predictive value 79%,– Negative predictive value 89%

Markers of Congestive Heart Failure

• Other applications of BNP testing– Monitoring the course and treatment of patients

with HF– Risk stratification of patients with ACS– Monitoring disease severity in patients with

stable CHD– Screening for ventricular dysfunction– Testing for drug cardiotoxicity

Markers of Congestive Heart Failure

• The major limitation of BNP – Decision point • a wide range of values is observed in patients with and

without HF

– Patients with symptomatic HF especially when it is chronic and stable, can have 'normal' levels

• So,– the most appropriate use of the BNP test is as an

adjunctive test to rule out HF in the acute setting.

Markers of Congestive Heart Failure

• BNP has natriuretic, vasodilatory, and other effects that are ameliorative for the syndrome, and is in fact available as the drug nesiritide (Natrecor) for treatment of HF