Prognostic Role of Cardiac Troponin in Heart Failure
Troponin is an intracellular protein essential in the regulation of muscular contraction. It is made up of three subunits, Troponin I, T, and C. Cardiac troponins I (cTnI) and T (cTnT) are unique to cardiomyocytes, and unlike Troponin C, they are not expressed in skeletal muscle.1 Therefore, increases in circulating cardiac troponins (cTn) are highly specific for ongoing myocardial damage, and have been utilized for the past two decades as markers for defining myocardial infarction.2 Less well understood is the fact that cardiac troponin levels may also be elevated in both acute and chronic heart failure,3-4 as well as in other settings with less clear mechanisms of myocardial injury such as septic shock, pulmonary embolism, myocarditis, drug-induced cardiotoxicities, and renal dysfunction.5
One possible explanation for elevated cardiac troponins in chronic heart failure may arise from reversible or irreversible myocardial supply and demand mismatch. 6 Here, cTn release may be caused by both acute and chronic myocardial stress, as well as chronic sub-clinical sub-endocardial ischemia or directly related to cardiomyocyte injury.7 This release of troponin may also signify increased cardiomyocyte turnover in the setting of progressing myocardial dysfunction.8 This may also explain how cardiac troponins can be detectable in non-cardiac situations where metabolic demand increases substantially relative to supply such as hypotension and shock.9 An alternative explanation for higher circulating cardiac troponin levels may be related to diminished renal clearance rather than heightened ongoing myocardial damage.
Detectable circulating cardiac troponin may extend beyond the heart failure setting, and some may even argue that it is more representative of subclinical myocardial dysfunction. In the general population, elevated cTnT marks subclinical cardiac injury10 and elevations of cTnT quantified via high sensitivity assays mark an increased risk for structural heart disease and all-cause mortality.11 Interestingly, circulating levels measured by newer-generation, highly-sensitive cTn assays are frequently detectable even in non-heart failure patients. Furthermore, detectable cTn using these assays is independently associated with all-cause mortality, cardiovascular mortality, and incident heart failure in the general population, despite controlling for renal function, amino terminus pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (CRP).11-14 Interestingly, a recent analysis of high sensitivity cTnI in the Framingham Offspring Study found an association with heart failure, but not with incident myocardial infarction.15 Meanwhile, changes in cTnT levels over time also correlate with heart failure risk. After adjusting for baseline high sensitivity cTnT and other risk factors, elderly subjects followed for 2-3 years in Cardiovascular Health Study with high sensitivity cTnT 50% or higher from baseline were found at increased risk for developing heart failure12
Higher levels of cTnT and cTnI occur in the acute heart failure setting when compared to chronic levels.16 A recent meta-analysis involving 16 studies of cTn levels in patients with chronic systolic or diastolic heart failure, revealed that cTn levels predict both all-cause and cardiovascular mortality and adverse cardiovascular outcomes.17 These trends persisted despite changes in medical therapy. High sensitivity cTnI and cTnT assays detect levels of cTn much lower than 10 ng/L, which is below the 99th percentile decision limit for assisting in the diagnosis of myocardial infarction. At these levels, although high sensitivity cTn levels may confer improved sensitivity compared to standard cTn assays, there is a decrement in the specificity for myocardial infarction.18 This questions the utility of these assays in an acute coronary syndrome, but also raises the possibility that high sensitivity cTn levels may be used to risk stratify chronic stable patients. Patients with chronic heart failure typically have elevated high sensitivity cTn when compared to standard cTn assays (63.9% versus 31.1%).17 In a study with a very high proportion (92%) of subjects with chronic heart failure and positive high-sensitivity cTn suggested a weaker association of high-sensitivity cTn assays with prognosis when compared to the standard assays.19 Although, this trend has not been replicated in other studies.17 To our knowledge, no studies currently exist determining the prognostic significance of a detectable high sensitivity cTn levels in patients with chronic heart failure and undetectable cTn via standard assay. This would, ideally, identify a population at higher risk that may benefit from intensifying therapy.
In conclusion, detectable cTn levels offer prognostic information for developing heart failure and in patients with chronic heart failure. Their presence predicts both mortality and other adverse cardiovascular outcomes. Both the high sensitivity and standard cTn assays yield important prognostic information. However, the prognostic utility of detectable high sensitivity cTn in the setting of a negative standard cTn has yet to be elucidated and would identify an otherwise undetected high-risk subgroup of patients with chronic heart failure. The biggest challenge remains to be the task of identifying specific actionable triggers that may triage patients with higher risks deemed by elevated cTn assays to be managed or followed by their healthcare providers in a different manner. Prospective studies will be needed to test this hypothesis in order to further extend the clinical application of cTn testing in the management of heart failure.
- Mohammed AA, Januzzi JL, Jr. Clinical applications of highly sensitive troponin assays. Cardiol Rev 2010;18:12-9.
- Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol 2007;50:2173-95.
- Peacock WF, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med 2008;358:2117-26.
- Kociol RD, et al. Troponin elevation in heart failure prevalence, mechanisms, and clinical implications. J Am Coll Cardiol 2010;56:1071-8.
- Roongsritong C, Warraich I, Bradley C. Common causes of troponin elevations in the absence of acute myocardial infarction: incidence and clinical significance. Chest 2004;125:1877-84.
- Wu AH. Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression? Intensive Care Med 2001;27:959-61.
- Feng J, et al., Preload induces troponin I degradation independently of myocardial ischemia. Circulation 2001;103:2035-7.
- Narula J., et al. Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci USA 1999;96:8144-9.
- Jeremias A, Gibson CM, Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med 2005;142:786-91.
- Wallace TW, et al. Prevalence and determinants of troponin T elevation in the general population. Circulation 2006;113:1958-65.
- de Lemos JA, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA 2010;304:2503-12.
- deFilippi CR, et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA 2010; 304:2494-502.
- Saunders JT, et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation 2011; 123:1367-76.
- Neeland IJ, et al. Biomarkers of chronic cardiac injury and hemodynamic stress identify a malignant phenotype of left ventricular hypertrophy in the general population. J Am Coll Cardiol 2013;61:187-95.
- Wang TJ, et al., Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation 2012;126:1596-604.
- Healey JS, et al. Prognostic use of cardiac troponin T and troponin I in patients with heart failure. Can J Cardiol 2003;19:383-6.
- Nagarajan V, Hernandez AV, Tang WH. Prognostic value of cardiac troponin in chronic stable heart failure: a systematic review. Heart 2012;98:1778-86.
- Keller T, et al. Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction. JAMA 2011;306:2684-93.
- Latini R, et al. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation 2007;116:1242-9.
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