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Biomarkers of Necrosis

Biomarkers of Myocardial Necrosis

Past, Present, and Future

Robert H. Christenson, PhD

and Hassan M. E. Azzazy, PhD, DABCC

Contents

Introduction

Background: Biomarkers of Cardiac Necrosis

Necrosis Biomarkers of the Past

Necrosis Biomarkers of the Present

Necrosis Biomarkers Still in Development

Future Markers of Myocardial Necrosis

Conclusion

References

Summary

Biochemical markers play a crucial role in accurate diagnosis of myocardial necrosis and, more importantly, for assessing risk and directing appropriate therapy that improves clinical outcome. Development and utilization of biomarkers has evolved substantially over the past three decades. The earliest biomarkers, such as alanine aminotransferase and lactate dehydrogenase, have fallen out of use with the development of moer sensitive and specific assays for creatine kinase isoenzyme MB and particularly cardiac troponin. Cardiac troponin T or I measurements are now considered surrogates for necrosis and myocardial infarction when elevated in the setting of acute cardiac ischemia. This chapter offers insight into evolution of cardiac biomarkers and offers thoughts regarding the future of necrosis biomarkers.

Key Words: Myocardial necrosis; lactate dehydrogenase; myosin light chains; aspartate aminotransferase; creatine kinase; CK-MB; cardiac troponin T; cardiac troponin I; myoglobin; heart-type fatty acid-binding protein; carbonic anhydrase III; acute coronary syndromes.

introduction

The homeostasis of healthy cells is disturbed when subjected to a supply-demand mismatch resulting in insufficient oxygen delivery, deprivation of nutrients, and decreased clearance of waste products. Acute cellular changes commonly include disruption of the

From: Contemporary Cardiology: Cardiovascular Biomarkers: Pathophysiology and Disease Management Edited by: David A. Morrow © Humana Press Inc., Totowa, NJ

sodium-potassium pump, leakage of excess calcium into the cell, depletion of energy reserves, and conversion from aerobic to anaerobic cellular metabolism (1). If the mismatch is prolonged, ultrastructural cellular damage becomes irreversible, resulting in cell death and necrosis. Cells of tissues differ in their susceptibility and response to a metabolic mismatch. Figure 1 shows the progression of cellular changes for myocardial cells during persistent ischemia, the transition from reversible to irreversible injury, and cell death after approx 30 min to 1 h (1). Release of necrosis biomarkers occurs thereafter in the general time frames indicated in Fig. 1.

Although a cellular mismatch in supply vs demand can be caused by a number of physiological events, the root cause of most acute coronary syndromes (ACSs), a continuum of cardiac ischemia from unstable angina through myocardial infarction (MI), is plaque instability, plaque rupture, and occlusive intracoronary thrombus formation. Coronary occlusions causing ischemia damage not only myocytes but also arterioles in a process that is thought to hinder microvascular flow by increasing distal vascular resistance, stimulating arteriolar spasm, and causing endothelial dysfunction (2). Downstream from the organized occlusion, platelet microemboli are believed to shower the microcirculation, causing microvascular obstruction that further limits tissue perfusion, particularly if the epicardial infarct-related artery is recanalized (3). Microvascular dysfunction also occurs in non-infarct-related vessels, suggesting that myocardial ischemia may stimulate global signaling of an inflammatory response through a complex process with several interrelating stimuli and factors including the release of cytokines (4). As such, thrombus formation and the resulting supply-demand mismatch are followed by a complicated cascade of events, the end point of which is myocardial ischemia and myocardial cell necrosis.

Biomarkers have provided important information for the clinical assessment of patients with suspected MI patients since the early 1950s. As displayed in Fig. 2, utilization of biomarkers has evolved substantially over the past 30-40 yr. Biomarkers were previously considered to be one of the three important variables, along with changes on the electrocardiogram (ECG) and clinical signs and symptoms, necessary for the diagnosis

Fig. 2. Evolution ofcardiac biomarkers. MI, myocardial infarction; AST, aspartate transaminase; LD, lactate dehydrogenase; CK, creatine kinase; RIA, radioimmunoassay.

of MI as defined by the World Health Organization (WHO) in 1979 (5). The biomarkers cardiac troponin T (cTnT) and I (cTnl) are now designated as surrogates for necrosis and MI when elevated in the setting of acute cardiac ischemia, according to the consensus document ofthe European Society of Cardiology (ESC) and the American College of Cardiology (ACC) (6).

Although the ACS continuum includes unstable angina and reversible myocardial injury, we focus here be on biomarkers of necrosis, offering insight into their evolution and, more important, conveying thoughts regarding the future of necrosis biomarkers.

background: biomarkers of cardiac necrosis

The Ideal Cardiac Biomarker

Table 1 summarizes the ideal characteristics for biomarkers ofcardiac necrosis. Although several biomarkers satisfy one or more of these criteria, no single marker has yet been identified that satisfies them all. cTnl and cTnT come closest to the ideal, their forte being exquisite myocardial specificity. No tissue other than heart has been documented as a source of cardiac troponin (7), and cTnT and cTnl are abundant in myocardial tissue and virtually absent in blood from healthy individuals (8,9). cTnT and cTnl are elevated for days to weeks after MI. On the other hand, cTnT and cTnl are structural proteins and, consequently, their release kinetics are relatively slow, requiring 4-6 h after the acute event for the detection of elevated levels with high diagnostic sensitivity (9). In addition, accuracy in predicting cardiac troponin release patterns is complicated and varies among patients. Although most experts agree that cardiac troponin is released only with cardiac necrosis and not with reversible ischemia, increases in cTnI and cTnT occur in conditions other than MI (7). Furthermore, methods for measuring cardiac troponin yield heterogeneous results (10). Thus, there are several issues that preclude cardiac troponin from being the "holy grail" of diagnostic tests for myocardial necrosis. Despite these caveats, cardiac troponin is currently the cornerstone for evaluating myocardial necrosis in patients with signs and symptoms of cardiac ischemia. Table 2 summarizes important characteristics of available and developing biomarkers of cardiac necrosis.

Table 1

Ideal Characteristics of Cardiac Necrosis Biomarkers

• Absolute cardiac specificity: Biomarkers should not be present in noncardiac tissues under any physiological or pathological conditions.

• Specific for irreversible injury: Biomarkers must differentiate reversible (ischemia) from irreversible (necrosis) injury.

• Early release: Biomarkers should be released shortly after necrosis. Lower molecular-weight biomarkers generally have faster release kinetics. Release kinetics of soluble cytoplasmic biomarkers is theoretically faster than that of structural biomarkers.

• High tissue sensitivity: Biomarkers should be abundant in cardiac tissue and absent in blood under all pathological conditions except necrosis. Biomarker release should be robust.

• Stable release: To allow suitable detection, biomarkers should persist in circulation for hours to days following the acute necrotic event.

• Predictable clearance: Clearance kinetics should be dynamic; predictable, to allow modeling; and unaffected by comorbidities such as renal insufficiency or hepatic injury. Predictable clearance also allows detection of recurrent events such as reocclusion and assessment timing of the necrosis event.

• Complete release: Myocyte release should be complete. Release should be in direct proportion to the extent of necrosis (infarct sizing).

• Measurable by conventional methods: The nature of the biomarker should allow quantitative measurement by reliable, rapid, precise, and cost-effective methodology that is readily available.

"Activity" vs "Mass" Measurements

The terms activity and mass are frequently used to describe biomarker assays. Activity measurement refers to biomarker quantification based on functionality, and results are usually reported in terms of international units per liter. In this context, activity assays often measure the ability of an enzyme cardiac biomarker to catalyze chemical conversion of a substrate reagent into a product under defined conditions such as temperature and pH. Quantitation is possible by monitoring formation of the product or depletion of substrate reagent. The fundamental principle is that the greater the concentration of bio-marker in a patient sample, the greater the proportionate change will be in the product or substrate.

Mass assays are direct measurements of the amount (or mass) of the biomarker. The term mass was coined because these assays are reported in terms of mass units such as nanograms per milliliter, milligrams per deciliter, grams per liter, or moles per liter. State-of-the-art immunoassays for cardiac biomarkers are all mass assays and, therefore, results are reported in mass units.

necrosis biomarkers of the past

Lactate Dehydrogenase Activity and Isoenzyme Fractionation

Lactate dehydrogenase (LD) is a cytoplasmic enzyme that has relatively high activity in myocytes and also in other tissues including skeletal muscle, liver, kidney, platelets, and erythrocytes (11). Measurement of LD as a cardiac biomarker was performed as early as 1960 (Fig. 2); fractionation of LD isoenzyme components, originally performed in the 1970s by electrophoresis or column chromatography, was applied to improve cardiac specificity by separating out the five major LD isoenzymes, LD1-LD5. The LD1 and

Table 2

Properties of Biomarkers of Myocardial Necrosisa

Molecular Biochemical mass Cardiac marker (Daltons) specific?b

Advantages

Disadvantages

Duration of elevation

Diagnostic performance/comments

Myoglobin 18,000

H-FABP 15,000

mass assays

High sensitivity and negative predictive value; useful for early detection of MI and reperfusion Early detection of MI

Ability to detect reinfarction; large clinical experience; previous "gold standard" for myocardial necrosis

Low specificity in presence of skeletal muscle injury and renal insufficiency; rapid clearance after necrosis Low specificity in presence of skeletal muscle injury and with renal insufficiency

Lowered specificity in skeletal muscle injury

12-24 h 2-6 h after presentation:

sensitivity: 90% (95% CI: 88-93%); specificity: 86% (95% CI: 85-87%); negative predictive value: 96% 18-30 h Biomarker for detection of cardiac injury in acute coronary syndromes within 6 h of symptoms onset. Although a relatively small number of clinical studies have been performed to date (12 studies comprising a total of 2130 patients), all indicate that H-FABP performance was either similar to or better than myoglobin for the early diagnosis of AMI 24-36 h Two serial values above 99th percentile of control reference population in setting of ischemia is benchmark for myocardial necrosis

(continued)

Table 2 (Continued)

Molecular

Biochemical mass Cardiac Duration Diagnostic marker (Daltons) specific?b Advantages Disadvantages of elevation performance/comments

Table 2 (Continued)

Molecular

Biochemical mass Cardiac Duration Diagnostic marker (Daltons) specific?b Advantages Disadvantages of elevation performance/comments

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