Unraveling the Mystery of Troponin Elevation in Heart Failure^∗Free Access

Introduction

The measurement of circulating troponin levels has become a central diagnostic tool in the assessment of a variety of cardiac disorders, most notably in patients presenting with suspected acute coronary syndromes. In this context, troponin is widely understood to be a highly sensitive marker of myocyte necrosis, and as such is now central to the universal definition of myocardial infarction. However, elevations in troponin are common in a variety of conditions other than acute coronary syndromes, including heart failure (HF), pulmonary embolism, myocarditis, hypertensive crisis, sepsis, tachycardia (2), and even in otherwise healthy adults after vigorous exercise or stress testing (3). In HF specifically, elevations in troponin (above the 99th upper reference limit for myocardial infarction) are common in chronic HF and nearly ubiquitous in patients with acute decompensated HF (4). Generally, regardless of the setting, elevations in troponin in patients with HF have been associated with worse outcomes (4,5). Current guidelines now recommend measurement of cardiac troponin for risk stratification in hospitalized HF patients as a Class I, Level of Evidence: A indication (6).

Although this information may be sufficient to inform routine clinical decision making, critical biological questions about the mechanism underlying these observations remain unanswered. What specific pathological processes drive troponin release in HF? Troponin elevation in the setting of HF is often posited to be the result of supply–demand mismatch due to increased transmural pressure with small vessel obstruction or subendocardial ischemia in the setting of hypoperfusion and hypotension (5). The main source of troponin is thought to be myocyte necrosis or the release of an intracellular stored pool of troponin following cell membrane disruption, independent of cell necrosis (7). Although the classical experiments indicate that ischemia of upward of 20 min is required to cause myocardial necrosis, a recent study demonstrated that brief ischemia (10 min) can elicit a delayed troponin release in a swine model (8). Notably, the observed troponin release was not due to myocyte necrosis or the release of stored troponin pools, but rather due to apoptosis (programmed cell death).

In this issue of the Journal, Weil et al. (9) explore the pathophysiological effects of transient left ventricular pressure elevation on cardiomyocytes and the associated mechanism of troponin release in an in vivo swine model. Increased left ventricular loading conditions (with mean systolic blood pressure increased from 137 to 192 mm Hg and mean left ventricular end diastolic pressure from 17 to 30 mm Hg) were induced via a 1-h long phenylephrine injection. The observed left ventricular chamber dilation and reduced left ventricular ejection fraction during phenylephrine injection persisted for at least 1 h post-infusion but recovered at 24 h. The temporary ventricular “stunning” was accompanied by a delayed release of troponin I. Two key findings from this innovative translational study are of particular importance. First, temporary myocardial strain was not accompanied by an impaired subendocardial blood flow or flow reserve as tested with a microsphere perfusion technique, suggesting that the observed troponin increase and myocardial stunning were independent of demonstrable myocardial ischemia. Second, transient cardiac dysfunction was accompanied by myocyte apoptosis without evidence of necrosis. This important observation suggests that in the setting of elevated loading conditions (such as occur in heart failure), troponin release may not be synonymous with myocyte necrosis as has commonly been assumed. These findings demonstrate for the first time in an in vivo model that acute hemodynamic pressure overload can induce transient left ventricular dysfunction causing myocyte injury in the absence of ischemia or necrosis, thus confirming earlier in vitro work by Feng et al. (10).

What are the implications of these findings for the clinical care of patients with HF? Conceptually, a variety of overlapping terms are invoked to explain the pathophysiology of troponin elevation in HF patients, including myocyte necrosis, type 2 myocardial infarction, myocyte injury, myocardial ischemia, and the more vague “troponin release.” HF is a syndrome associated with a number of pathological processes that can lead to myocardial injury, independently of myocardial stretch-related injury or true myocardial ischemia as a result of supply–demand mismatch. Potential contributing mechanisms include inflammatory cytokine release, neurohormonal stimulation, and altered myocyte calcium handling (11). Notably, a key characteristic of HF is hemodynamic congestion with elevations in intracardiac pressure elevations that persist for days, weeks, or years, in contrast to the hyperacute pressure elevation used in the study by Weil et al. (9). Thus, it remains to be determined to what extent the present animal model and the mechanism of cardiac decompensation is applicable to the human physiology of acute and chronic HF. It is plausible that the sequelae of elevated filling pressures in HF (i.e., myocyte necrosis or apoptosis) may depend on the relation of duration and severity of pressure/volume overload. Although population data suggest that troponin elevation in acute and chronic HF patients are associated with poor clinical outcomes, whether the prognostic significance of an elevated troponin level is similar when triggered by myocardial stretch or supply–demand mismatch is unknown, because we lack the ability to distinguish these mechanisms at the bedside. Regardless, greater recognition of the diverse potential mechanisms of troponin elevation in HF has the potential to facilitate greater precision in risk stratification and the development of new therapies for HF. Ongoing translational work like the current study by Weil and colleagues will continue to provide insights that may facilitate the ongoing translation of biomarker data into actionable intelligence at the bedside.

Footnotes