HIGH-SENSITIVITY cTn VERSUS H-FABP

H-FABP is a low-molecular-mass cytoplasmic protein that, along with myoglobin, is among the earliest markers released into circulation after acute myocardial injury. 

The H-FABP content of skeletal muscle is only 10-20 % of that of cardiac muscle, whereas the myoglobin content of skeletal muscle is approximately twice that of cardiac muscle. Along with other groups, we have shown that H-FABP is more useful than myoglobin and cTn for the early diagnosis of AMI [8-10].

Recently, we prospectively investigated the diagnostic and prognostic value of the serum level of high-sensitivity cardiac troponin T (cTnT) relative to H-FABP in 460 consecutive patients (median age 67.5 years) hospitalized in the cardiac emergency department for suspected ACS within 6 hours after onset of chest symptoms. 

Cardiac events, which were defined as cardiac death or rehospitalization for ACS or heart failure, were monitored for 12 months after admission. The final diagnosis was adjudicated by two independent cardiologists. A total of 224 (48.7 %) patients were diagnosed as having AMI (ST-segment elevation myocardial infarction, 154 patients; emergent coronary angiography within 24 hours after admission, 195 patients).

The area under the receiver operating characteristic curve (AUROC) was higher for high-sensitivity cTnT than for H-FABP.  

FIG. 1: Receiver operating characteristic (ROC) curves of high-sensitivity cTnT and H-FABP concentration between the AMI group and the non-AMI group. For the detection of AMI within 6 hours of onset of chest pain, the upward and leftward shift in the ROC curve between the AMI group and the non-AMI group was greater for high-sensitivity cTnT than for H-FABP. The area under the ROC curve of high-sensitivity cTnT (0.88, 95 % CI = 0.84-0.92) was significantly (P = 0.01) greater than the area under the H-FABP curve (0.82, 95 % CI = 0.78-0.88).

TABLE I: Clinical performance of high-sensitivity cTnT vs H-FABP

The sensitivity and negative predictive value (NPV) of increased high-sensitivity cTnT (>14 pg/mL of the 99th percentile of a healthy population) were higher than those of increased H-FABP (≥6.2 ng/mL of the upper reference limit). 

In addition, there was no significant difference in specificity between high-sensitivity cTnT and H-FABP. During a 12-month follow-up period, there were 38 (8.3 %) cardiac events, including 11 cardiac deaths. 

In a stepwise Cox regression analysis, increased high-sensitivity cTnT (relative risk, 14.5; P = 0.009), but not H-FABP, was independently associated with cardiac events. 

Patients with increased high-sensitivity cTnT had a higher risk of cardiac events within 12 months than those without (14.1 % vs 0.5 %, respectively; P < 0.0001). These findings indicate that a high-sensitivity cTnT assay may provide diagnostic and prognostic information superior compared with that of the H-FABP assay in the early phase of suspected ACS. 

Additional testing of other early makers, such as H-FABP, is no longer required.

DISCRIMINATING BETWEEN AMI AND CHRONIC CAUSES OF CTN ELEVATIONS 

Elevation of cTn indicates myocardial injury regardless of its etiology, and does not necessarily indicate the presence of AMI. Improvements in analytical sensitivity have increased detection of cTn elevations, particularly mild cTn elevation, because of AMI but also because of numerous acute or chronic diseases other than AMI [4].

TABLE II: Elevations of cardiac troponin values because of myocardial injury

Accordingly, the specificity and positive predictive value of an elevated high-sensitivity cTn level are reduced if the diagnosis of AMI alone is considered.

With high-sensitivity assays, mild elevation of cTn detected in several patients with stable angina [11] or chronic heart failure [12] as well as in the general population [13, 14] is used to identify patients with either silent or clinically underestimated disease and, therefore, with a high risk of death. 

Several studies have shown that high-sensitivity cTn elevation may be associated with adverse outcomes in patients with diabetes mellitus [15] or chronic kidney disease [16], suggesting that high-sensitivity cTn may be used as biomarkers in primary prevention of cardiovascular disease, leading to identification of high-risk populations or individuals with silent heart disease. 

Recently, we showed that quartiles of high-sensitivity cTnT values were associated with an increased cardiac event rate in 442 ambulatory patients with chronic kidney disease who were not undergoing dialysis (Fig. 2) [16].

FIG. 2: Kaplan-Meier curves for cardiac events according to quartiles of high-sensitivity cTnT values. During the follow-up period (median 22 months), 63 cardiac events occurred in 442 ambulatory chronic kidney disease patients not on dialysis whose estimated glomerular filtration rate was <60 mL/min/1.73 m². Kaplan-Meier incidence rates of cardiac events for 3 years were 0.88 %, 11.5 %, 19.0 %, and 41.4% among quartiles 1, 2, 3, and 4 according to high-sensitivity cTnT levels (P <0.0001) A clear difference among quartiles is evident. Modified from Hasegawa M, Ishii J, Kitagawa F et al [16].

Considering the high frequency of mildly elevated high-sensitivity cTn values in the community, particularly in patients with cardiovascular comorbidities, an increased high-sensitivity cTn concentration alone will be inadequate for clinical decision making. 

The exception may be extremely elevated values, which are most often caused by AMI or myocarditis [17]. In other circumstances, cTn has to be interpreted as a quantitative variable. 

It is important to distinguish AMI, which requires a rise and/or fall of cTn values, from chronic elevations that are associated with structural heart disease and tend not to acutely change.

Serial high-sensitivity cTn measurements and detection of early changes could improve specificity and overall diagnostic performance. 

Recently, Reichlin et al demonstrated that a simple algorithm incorporating high-sensitivity cTnT baseline values and absolute changes within the first hour could be used to safely rule out and accurately identify AMI if performed within 1 hour in 77 % patients with chest pain [18].

FIG. 3:  Algorithm for diagnosis of AMI using high-sensitivity cTnT in patients presenting with chest pain. Results are displayed for the validation cohort (n = 436). High-sensitivity cTnT values are presented in pg/mL. 0 hours indicates high-sensitivity cTnT at presentation to the emergency department; Delta 1 hour, absolute change of high-sensitivity cTnT within the first hour; NPV, negative predictive value; and PPV, positive predictive value. Modified from Reichlin T, Schindler C, Drexler B et al [18].

DISCRIMINATING BETWEEN TYPE 1 AND TYPE 2 MYOCARDIAL INFARCTION

It should be clear that a rise and/or fall of cTn values is not specific for AMI but is rather indicative of acute myocardial injury. 

The diagnosis of AMI is no longer restricted to those with a primary coronary event, usually atherosclerotic plaque rupture (MI type 1), but also in those with conditions caused by an imbalance between myocardial oxygen supply and/or demand in the coronary circulation (MI type 2; e.g., coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy/bradyarrhythmia, anemia, respiratory failure, hypotension, and hypertension). 

With high-sensitivity cTn assays, the frequency of MI type 2 appears to increase. A rise and/or fall of cTn values on serial testing may or may not be useful in differentiating MI type 1 from type 2 [19]. However, the etiology is entirely different. Thus, the clinical features should be considered to differentiate between MI type 1 from MI type 2.

CONCLUSIONS

High-sensitivity cTn assays improve the early diagnosis, particularly early rule-out AMI, and additional testing of other early makers, such as H-FABP, is no longer needed. 

Improvements in analytical sensitivity also have increased the number of cTn elevations in various acute and chronic conditions with cardiac involvement other than AMI. Thus, clinicians need to understand how to most effectively use high-sensitivity cTn assays in clinical practice.