High-sensitivity cardiac troponin in stable atherosclerotic vascular disease

High-sensitivity assays for cardiac-specific troponin (hs-cTn) have enabled detection of low concentrations of circulating cardiac troponin I and T in patients across the spectrum of cardiovascular diseases. Serial measurement of hs-cTn in patients presenting with suspected acute coronary syndromes accelerates the diagnostic evaluation and improves overall accuracy compared with prior generations of diagnostic biomarkers and is recommended by contemporary professional society guidelines.1,2 In parallel, a growing base of epidemiological evidence has begun to reveal potential clinical implications of measurable hs-cTn in chronic cardiovascular conditions, including atherosclerotic vascular disease, atrial fibrillation, valvular disease, and chronic heart failure. Over a decade and half ago, Eggers et al.3 reported that circulating cardiac troponin was measurable in more than one-third of patients 6 months after a myocardial infarction, with a significant minority exhibiting concentrations above the upper reference limit for myocardial infarction. Moreover, individuals with persistent elevation across multiple measurements from 6 weeks to 6 months were at more than double the risk of death over the ensuing 5 years. Since that time, subsequent studies have demonstrated a strong association between circulating concentration of hs-cTn and adverse cardiovascular outcomes in patients with stable coronary heart disease,4 as well as patients with other atherosclerotic vascular disease (ASCVD),5 and individuals with risk factors for but no established ASCVD.5 Across these and multiple other studies, the data consistently demonstrate that the relationship between hs-cTn and outcome is graded with increasing concentration, emerges continuously over years rather than over a short interval such as 30–90 days, and is present for a variety of outcomes important to patients with ASCVD, including future heart failure, myocardial infarction, stroke, and cardiovascular death.5 Notably, the vast majority of patients with established ASCVD will have detectable circulating cardiac troponin using high-sensitivity assays and as many as half of such patients may have concentrations that exceed the 99th percentile upper reference limit.5 Pathobiological constructs that identify causes of myocardial injury other than ischaemia help to explain this epidemiology.6 Moreover, we have continued to advance our understanding of clinical determinants of circulating cardiac troponin, revealing associations with male sex, older age, diabetes, kidney dysfunction, and left ventricular mass as among strongest clinical correlates.7 Given the prevalence of detectable circulating cardiac troponin, it is essential for clinicians to recognize and discriminate chronic myocardial injury from acute myocardial injury,8 both of which are associated with adverse prognosis,9 but have very different implications for therapy, depending on the aetiology. Importantly, prospective observational studies, including those nested in randomized clinical trials, have begun to reveal clinical interventions that appear to modify the risk associated with elevated hs-cTn in patients with stable ASCVD. Ford et al.10 observed that among patients at risk for coronary heart disease, compared with individuals administered placebo, those treated with pravastatin had lower concentrations of hs-cTn over time and that compared with placebo-treated individuals with no change in hs-cTn, those with the greatest decline in hs-cTn had a 70–80% lower relative risk of coronary heart disease death or myocardial infarction. Considering how such observations might be actionable in clinical practice, Marston et al.11 demonstrated that hs-cTn that was in the detectable range above the limit of quantification but below the 99th percentile URL conferred incremental discrimination of future risk of recurrent major ASCVD events compared with the clinical risk model used by the American Heart Association guidelines for the management of blood cholesterol. Application of this approach among patients with established ASCVD enrolled in a randomized trial of evolocumab revealed that patients reclassified by a higher hs-cTn (e.g. ≥ 6 ng/L with the particular assay studied) appeared to derive a magnitude of benefit from evolocumab similar to the clinically identified very high-risk group with a relative risk reduction of 20% and an absolute risk reduction for major cardiovascular events of 2.0%.12 With epidemiological observations of a consistent strong association with cardiovascular risk that is potentially modifiable with established preventive therapies, these and other data are mounting an emerging case for possible applications of hs-cTn in stable outpatients with ASCVD. At a minimum, enhanced risk stratification has the potential to stimulate intensified modification of known risk factors. However, there remains much to be learned about the natural history of hs-cTn concentrations over time, the impact of biological variability, and interactions with therapy. N.L.M. is supported by a Research Excellence Award (RE/18/5/34216) and a Chair Award (CH/F/21/90010) from the British Heart Foundation. None declared. No new data were generated in support of the article. Other members of the Study Group on Biomarkers of the ESC Association for Acute Cardiovascular Care include: Allan Jaffe, MD0, Evangelos Giannitsis, MD1, Lori Daniels, MD2, Kurt Huber, MD3, Johannes Mair, MD4, Louise Cullen, MD, PhD5, Ola Hammarsten, MD, PhD6, Martin Möckel, MD7, Konstantin Krychtiuk, MD8, Kristian Thygesen, MD9, and Matthias Thielmann, MD10 0Departments of Cardiology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester Minnesota, USA 1Department of Cardiology, University Heidelberg, Germany; 2Department of Medicine, Sulpizio Cardiovascular Center, University of California, San Diego; La Jolla, CA, USA; 3Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminenhospital, and Sigmund Freud University, Medical School, Vienna, Austria; 4Department of Internal Medicine III—Cardiology and Angiology, Medical University Innsbruck, Austria; 5Emergency and Trauma Centre, Royal Brisbane and Women’s Hospital, University of Queensland, Australia; 6Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, Sweden; 7Division of Emergency Medicine, Charité-Universitätsmedizin Berlin, Germany; 8Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria; 9Department of Cardiology, Aarhus University Hospital, Denmark; and 10Klinik für Thorax- und Kardiovaskuläre Chirurgie, Westdeutsches Herz- und Gefäßzentrum Essen, University of Duisburg-Essen, Germany