Cardiac Troponin I

The VeriSens Cardiac Troponin I Test is a gold nanoparticle-based immunoassay with silver signal enhancement for the quantitative determination of cardiac troponin I (cTnI) levels in human serum and heparinized plasma using the Verigene System. 

BACKGROUND

Cardiac troponin (cTnI or cTnT) has been labeled the “biomarker of choice” for detecting cardiac damage. Measurement of cardiac troponin is a central tool in the diagnosis of myocardial infarction (MI).

Troponin (Tn) is the central regulatory protein of striated muscle contraction.  The cardiac Tn complex (cTn) consists of three proteins: cTnI (unprocessed: 24,008 Da) which is the inhibitor of actomyosin ATPase, cTnT (35,924 Da) which contains the binding site for tropomyosin, and cTnC (the “slow” non-skeletal form, 18,403 Da). The binding of calcium to cTnC abolishes the inhibitory action of cTn on actin filaments. Together, in the heart, they play a fundamental role in the transmission of intracellular calcium signals and the actin-myosin interaction (Opie 2008).

cTnI has additional amino acid residues on its N-terminal that do not exist on the skeletal forms of troponin thus making cTnI a specific marker of myocardial necrosis.  cTnI is released rapidly into the blood with the onset of acute myocardial infarction (AMI), and therefore, has become the biomarker of choice in the diagnosis and risk stratification of acute coronary syndromes (ACS). Levels of cTnI can remain elevated for up to 6 - 10 days (Antman and Braunwald 2008).

MI is caused by rupture of an atherosclerotic plaque in a coronary artery, leading to platelet aggregation and thrombus formation to an extent that oxygenation of the myocardial tissue is completely interrupted (i.e., total occlusion). This causes some degree of myocardial necrosis (Cannon and Lee 2008). High concentrations of cardiac enzymes and proteins (e.g., cardiac troponin I or T [cTnI or cTnT], CK-MB, myoglobin) are observed in blood as the result of significant irreversible injury to cardiac tissue distal to the site of rupture and secondary to arterial occlusion. Current assays can detect ST-segment elevated myocardial infarctions (STEMIs) and non-ST-segment elevated myocardial infarctions (NSTEMIs). By definition of the 2007 AHA/ACC updated guidelines for NSTEMI and unstable angina (UA), the NSTEMI threshold is defined as the 99^th percentile upper reference limit [URL] of a cardiac troponin (cTn) assay’s reference range in a healthy subject population (Thygesen, et al 2007).

Cardiovascular disease is the most frequent cause of morbidity and mortality among industrialized nations.  In the U.S., there are nearly 100 million adults who suffer from cardiovascular disease.  Over 8 million patients present to emergency departments (EDs) annually with a chief complaint consistent with ACS. A majority of these patients are found to be experiencing non-cardiac chest pain (i.e., about 70-82% of patients). Myocardial infarction (NSTEMIs = 6-10% of patients and STEMIs = 2-5% of patients) occurs in about 8-15% of these patients.  UA, which is often a precursor condition to MI, accounts for 10-15% of patients. Together, MI plus UA combine to define ACS (= about 18-30% patients) [American Heart Association website: www.americanheart.org].

As many as 2-4% of patients with MI (about 24,000-48,000 patients annually) are discharged from the ED with an associated short-term mortality of 10% to 26% (Duseja and Feldman 2004). These patients are perhaps best classified as “false negatives” (i.e., FNs).

Missed acute cardiac ischemia is one of the major causes of malpractice litigation against emergency physicians (Duseja and Feldman 2004). Even though chest pain patients (and other patients with symptoms consistent with ACS) represent only 6% of the ED patient volume, it has been estimated that 20% of ED-related malpractice dollars are expended for ischemic heart disease complications (Rusnak, et al 1989; Jesse and Kontos 1997). Therefore, the misdiagnosis of ischemic cardiac injury is of great importance from a human life and economic perspective.

In the typical hospital ED today, cardiac biomarkers are drawn and the results are back to the ED physician within about 90 minutes (i.e., therapeutic turnaround time [TTAT]; “vein to brain” time). Some hospitals have implemented point-of-care devices that can provide results within 10-15 minutes, although their relatively lower sensitivity (URL – ≥ 0.080 ng/mL) can significantly delay diagnosis and treatment compared to other methods.  At the other end of the spectrum, some EDs that are still dependent on the central laboratory that have a therapeutic turnaround time of 2-4 hours.

In the absence of definitive diagnostic information (e.g., cTnI biomarker elevation, diagnostic ECG, and/or other data), many chest pain patients that continue to have discomfort and other symptoms consistent with ACS are held in the ED or chest pain (observation) unit for >6 to <24 hours, before discharge, allowing for serial cardiac markers and continued observation. Therefore, subsequent generations of cTnI assay development have sought to increase sensitivity without compromising specificity (e.g., URL ~ 0.040 ng/mL down from 0.100 ng/mL) to positively impact this cardiac care timeline in the ED.  

The universal definition of myocardial infarction as updated and published in the November 27, 2007, issue of Circulation (Thygesen et al 2007) states that any rise or fall of cardiac troponin above an assay’s 99^th percentile of a reference range population, with concurrent clinical symptoms of ACS, is considered to be a myocardial infarction. This means that a single cTn value above the 99^th percentile threshold, after an earlier value below the threshold, should be labelled a myocardial infarction. Other co-morbid disease processes (e.g., hypertension, CHF, diabetes, cardiotoxicity, myocarditis, etc.) may lead to cTnI elevation. Therefore, it is important to evaluate these co-morbidities that, in themselves, carry an increased risk of cardiac mortality and morbidity.