In this report, we describe the case of a young athletic male with hyperlipidemia and family history of early cardiac death, who presented with atypical chest pain and an elevated serum troponin. The initial differential diagnosis was broad and reflected the common causes of troponinemia.
In addition to acute coronary syndromes (ACS), cardiac troponin elevations above a 99th percentile cutoff occur in many conditions (Table 1). In most cases, myocyte necrosis occurs from either mismatch between oxygen supply and demand within the heart or direct injury from trauma or toxins [6,7,8,9,10,11]. Impaired renal clearance also contributes to troponin elevation despite the lack of detectability in urine . Lastly, analytical errors in the assay and interfering substances such as heterophile antibodies from a patient’s serum can lead to elevated measured troponins that do not reflect myocardial injury (i.e., “false positives”) .
In this patient’s workup, ACS was deemed as an unlikely cause for this patient’s troponinemia given the atypical nature of his symptoms, the lack of any ischemic changes on ECG, and the lack of a significant change in the serum troponin level on serial measurements during his hospital stay . In addition, obstructive coronary disease was excluded with CCTA. Acute pulmonary embolism was briefly entertained but was not formally evaluated with CT angiography due to extremely low pre-test probability (WELLS score of 0). Echocardiography did show evidence of mild LVH, but his normal cMRI likely excluded hypertrophic cardiomyopathy and additionally excluded myocarditis and infiltrative disease. Importantly, however, with the history of his father’s early sudden cardiac death, combined with his premature non-obstructive coronary disease and elevated serum LDL, the patient meets criteria for possible familial hypercholesterolemia by the Dutch Lipid Clinic Network .
After the work-up, two diagnoses seemed plausible: heterophile antibody mediated false-positive troponinemia and/or exercise-mediated troponinemia. The presence of heterophile antibody in his serum suggested that his troponin assay might have been falsely positive. On the other hand, his serum troponin seemed to be elevated only in the context of rigorous aerobic exercise, and normalized when he refrained from activity.
Heterophile antibodies are among the many substances that can potentially interfere with a troponin assay (Table 1). These antibodies are produced against poorly defined antigens, weakly bind with immunoglobulins from two or more non-human animal species, and can act like a rheumatoid factor (bind to the Fc portion of human immunoglobulin) . Their multi-specific binding potential can crosslink assay antibodies in the absence of the antigen of interest, causing inconsistent false-positive results. Test manufacturers typically add blocking antibodies to reduce the chance of interference, but a high serum concentration of heterophile antibody may overcome this protection (which was the case in our patient) . While a dynamic rise and/or fall in troponin levels in the appropriate clinical setting suggests true myocardial damage, a sustained, relatively fixed increase in troponin levels in the absence of other evidence of cardiac injury raises the likelihood of assay false-positivity .
In contrast to the benign implication of heterophile antibody-mediated troponinemia, the prognosis of exercise-mediated troponinemia remains unclear. Many studies report rises in cardiac troponin levels after exercise [17, 18], while others have published a lack of this relationship [19, 20]. A meta-analysis examining 26 studies on exercise and troponin levels found that post-exercise levels rose above the lower limit of detection in approximately 50% of subjects, with higher likelihoods of positivity after running events (as opposed to cycling or a triathlon) and with shorter events (rather than longer events), suggesting a correlation with higher intensity exercise . In marathon runners, troponin can be detected as early as 60 min into exercise and as late as 24 h from the event . Imaging studies suggest against a correlation between post-exercise troponin elevation and radiographic evidence of permanent myocardial damage, but long-term data examining this question are sparse . Moreover, recent data published by Roos et al. suggest that patients with chest pain and elevated troponin not due to myocardial infarction or other causes are at increased risk of all-cause and cardiovascular mortality . In light of this evidence, and in conjunction with a family history of sudden cardiac death and possible familial hyperlipidemia, this patient’s troponinemia should not be prematurely dismissed as benign, regardless of the presence of a serum heterophile antibody.