Troponin: an important prognostic biomarker in patients with heart failure and reduced ejection fraction?

This article refers to ‘Concentration-dependent clinical and prognostic importance of high-sensitivity cardiac troponin T in heart failure and a reduced ejection fraction and the influence of empagliflozin: the EMPEROR-Reduced trial’ by M. Packer et al., published in this issue on pages 1529–1538.. Measurements of troponin, in its cardiac-specific isoforms, was initially introduced to diagnose myocardial infarction in patients with suspected acute coronary syndrome. With the use of high-sensitivity assays, circulating troponin can be measured in most patients with heart failure and reduced ejection fraction (HFrEF), and it is now clear that the level of troponin is also predictive of outcomes in these patients.1-3 Despite this, troponin is currently not routinely measured in patients with heart failure. Many previous studies have included troponin in a dichotomous manner (i.e. normal vs. elevated – a division based on its use in myocardial infarction that makes little sense in the context of heart failure),4 and large-scale data on adverse outcomes across the spectrum of troponin concentrations are lacking. Furthermore, it is of great interest to investigate how the effect of heart failure therapies relate to troponin concentration. A recent meta-analysis has raised the possibility of an attenuated effect of sodium–glucose co-transporter 2 (SGLT2) inhibitors in patients with New York Heart Association (NYHA) class III–IV symptoms,5 which is arguably a more subjective measure of heart failure severity compared to the level of a biomarker such as troponin. Thus, it is of clinical relevance to examine the prognostic importance of troponin, across the spectrum of serum concentrations, and also whether SGLT2 inhibitors interact with the prognostic significance of troponin. In this issue of the Journal, Packer et al.6 present data on the clinical and prognostic significance of troponin concentrations and the influence of troponin on the effect of empagliflozin in 3636 patients with HFrEF enrolled in the EMPEROR-Reduced trial. In EMPEROR-Reduced, patients with NYHA class II–IV heart failure and a reduced ejection fraction (≤40%) were randomised to either placebo or 10 mg empagliflozin, and the primary endpoint was the composite of cardiovascular death or hospitalization for heart failure. Cardiac troponin T (hs-cTnT) was measured in more than 97% of the patients at baseline by use of high-sensitivity analyses. The authors reported a stepwise relationship between increasing hs-cTnT and measures of heart failure severity, including NYHA class III–IV symptoms, lower Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline, worsening of NYHA class within 3 months, likelihood of hospitalization for heart failure within the previous year, and increasing levels of N-terminal prohormone B-type natriuretic peptide (NT-proBNP). Interestingly, the troponin groups did not differ with respect to left ventricular ejection fraction. Among patients treated with placebo, there was a linear relationship between the logarithm of hs-cTnT and the risk of cardiovascular death or hospitalization for heart failure. Further, patients with high levels of hs-cTnT were more likely to experience a decline in estimated glomerular filtration rate and serious adverse renal events and less likely to have an improvement in the KCCQ at 52 weeks. Finally, the authors found that empagliflozin, compared to placebo, reduced the risk of cardiovascular death or hospitalization for heart failure (and the individual components) and improved the KCCQ clinical summary score, regardless of baseline hs-cTnT. There are several notable strengths of this study including the size of the cohort and the evaluation of stepwise relationships between hs-cTnT and risks of outcomes. This study is the first to examine the influence of baseline hs-cTnT on the response to SGLT2 inhibitor treatment in heart failure. However, there are also some limitations which deserve attention. In EMPEROR-Reduced, 22% of patients had troponin values in the normal range for a healthy population (i.e. ≤14 ng/L), which is lower than what was found by others.1, 7 Thus, caution should be taken when translating the findings to lower-risk heart failure populations. Changes in hs-cTnT during drug treatment were not included in this study, but the authors reported that these assessments are currently planned. Finally, the authors did not investigate whether hs-cTnT adds meaningful additional prognostic information to measurement of NT-proBNP in HFrEF, though the authors reported that there was a parallel stepwise increase in NT-proBNP as hs-cTnT progressively increased. It has previously been suggested that troponin conveys independent prognostic information from NT-proBNP.1, 7, 8 In PARADIGM-HF, NT-proBNP and troponin concentrations were additive in predicting risk.3 This deserves further exploration in future studies. Though the authors do not discuss heart failure aetiology, they report similar proportions of patients with prior myocardial infarction across the spectrum of troponin levels. In PARADIGM-HF, there was no difference in troponin levels between ischaemic and non-ischaemic HFrEF patients.3 An explanation for this could be microvascular disease leading to myocardial ischaemia and cardiomyocyte injury in the absence of or in addition to macrovascular coronary disease as seen in patients with diabetes.9 It is likely that the prognostic value of hs-cTnT is related to its ability to not only reflect the severity of heart failure, but also is influenced by the presence of several comorbidities such as diabetes, chronic kidney disease and atrial fibrillation, as noted by the authors. In summary, Packer et al.6 present important data on the significance of hs-cTnT and the influence of hs-cTnT on the effect of empagliflozin in HFrEF. There are several important take-away messages from this elegant study, including the ability of the level of hs-cTnT to reflect the severity and prognosis of HFrEF and the ability of empagliflozin to reduce the risk of adverse cardiovascular and renal endpoints regardless of baseline hs-cTnT. These findings may support a potential role for troponin measurements in ambulatory patients with heart failure in order to assess severity and prognosis. However, further studies are needed on whether measurements of hs-cTnT add clinical, meaningful additional information to measurement of NT-proBNP. Conflict of interest: none declared.