cTnT in the PROTECT Study
Editor's Note: This article is in response to O'Connor C.M., Fiuzat M., Lombardi C., et al. Impact of Serial Troponin Release on Outcomes in Patients With Acute Heart Failure: Analysis From the PROTECT Pilot Study. Circ Heart Fail 2011; 4:724-32.
Cardiac troponin (cTn) elevations are common and predict adverse outcomes in patients with acute heart failure (AHF). Prior studies have been limited to sampling cTn at the time of admission; whether subsequent release occurs during hospitalization, and the frequency this occurs has not been well described. To address this, patients enrolled in the PROTECT pilot study (designed to assess the effects of the A1 receptor antagonist rolofylline in patients with AHF) underwent serial sampling of cTnT during their AHF hospitalization, which were subsequently correlated with outcomes.
In this study, cTnT was measured with the third generation cTnT Roche assay, and was collected at randomization and days 2, 3, 4, and 7. Patients were classified based of their baseline cTnT levels: positive (>0.03 ng/mL), detectable (>0.01 ng/mL), and negative (≤0.01 ng/mL). Patients who had a detectable cTnT level that occurred after the first sample were classified as cTnT conversion. End-points for this sub-study included death, worsening heart failure or heart failure readmission, or persistently worsened renal function.
The mean age of the 288 patients was 71, and 59% were male. The clinical profile of the patients was similar to large acute HF registries, and included a high proportion of patients with prior MI (55%), diabetes (52%), and elevated BNP. A total of 172 (60%) patients had detectable cTnT levels (>0.01 ng/ml) at baseline, with 97 (34%) having positive values (>0.03 ng/mL). Of the 116 patients with (-) cTnT at baseline, 24 (21%) had detectable cTnT levels by day 7. All patients with detectable cTnT at baseline had detectable TnT on subsequent samples.
Clinical characteristics were similar between patients with detectable cTnT, those who converted to detectable levels cTnT by day 7, and those who were persistently cTnT (-), except for a higher prevalence of diabetes (p<0.05) in (+) cTnT patients. Important variables that were not different between the 2 groups included a history of coronary disease, renal function, or worsening of creatinine clearance during the study. Patients who converted from (-) to (+) cTnT had intermediate BNP levels (729 pg/ml) compared to those with (-) cTnT (491 pg/ml) or those who were cTnT (+) at baseline (1393 pg/ml), although NT-proBNP levels were similar among the 3 groups (2770, 2680 and 3000 pg/ml).
On multivariable analysis, detectable cTnT at baseline was an independent predictor of the composite end point of cardiovascular/renal rehospitalization or death at 60 days, which occurred in 33% of these patients (hazard ratio, 1.8; 95% CI, 1.04–3.26; p<0.04). Patients who developed (+) cTnT during hospitalization had a similar rate outcomes (33%) to those who were TnT (+) at baseline, and was significantly higher than those who were persistently cTnT (-)(13%).
The authors concluded that patients with AHF had a high prevalence of baseline cTnT elevation, which predicted adverse outcomes. In addition, conversion to (+) cTnT was associated with adverse outcomes at a rate similar to that of patients who were (+) cTn at baseline.
Despite significant advances in medical treatment of CHF, acute heart failure (AHF) is common, with a high morbidity and mortality. Therefore, the ability to better identify patients who are more likely to experience adverse events, either during hospitalization or shortly after discharge, is important. Measurement of markers that predict events could potentially provide a simple way to better identify high risk patients. Prior studies have found that cTn is detectable in a significant proportion of CHF patients. In the current study,(1) the authors expand on prior studies, presenting a number of interesting findings. First, detectable cTnT was common in patients admitted for AHF, with most patients having persistently detectable cTnT. Second, detectable cTnT was associated with worse outcomes, and third, a significant minority of patients (21% in this study) who were initially cTnT (-) developed dectable cTnT on serial follow-up over the next week.
Multiple studies have reported that cTn can be detected in patients with CHF, in populations ranging from stable outpatients to AHF.(2) The frequency that cTn is detected has varied considerably across studies, and is dependent on the patient population studied, the specific assay and the cut-off value used.(2) Initial studies used relatively insensitive assays, and in some cases, elevations thought to be from AHF may have resulted from ischemia/MI.(3) Differentiating CHF and MI can be difficult in older patients, as chest discomfort is less frequent and atypical presentations are more common. In contrast, current generation assays are more sensitive, so that cTn, particularly at low levels, are unlikely to represent an ACS event in HF patients.
There are a variety of potential mechanisms for cTn release in patients with HF, and include increased left ventricular end-diastolic pressure, and low systemic and coronary perfusion pressure resulting in subendocardial and microvascular ischemia/infarction. AHF is also associated with adrenergic stimulation, increased inflammatory cytokines, tachycardia and pulmonary edema, all of which can all further contribute to ischemia. Ischemia/infarction from vessel occlusion, as seen in patients with ACS, is unlikely, as detectable cTn occurs in patients with non-ischemic cardiomyopathy.(4) The lack of association of detectable cTn and coronary disease in most studies also makes epicardial coronary disease less likely as a significant contributor.
Detectable cTn in HF patients or asymptomatic coronary disease patients appears to predict HF events and death but not MI.(5) This would appear to indicate that myocardial stretch from increased left ventricular stretch may be an important mechanism. However, the continued release of cTnT, as seen in this study that occurred despite treatment and symptomatic improvement, indicates other processes, such as continued myocyte necrosis, apoptosis, or cTn degradation or release are likely involved.
An interesting aspect of the study is the significant minority of patients who were initially cTnT (-) who became (+), which likely reflects cell injury after admission. Development of cTn (+) over time has been previously reported in a out-patient HF population,(6) and is associated with worse outcomes, such as seen in the current study, with higher frequencies of HF exacerbations and death.(6, 7) There did not appear to be significant differences among the groups to explain why this occurred. Further information on in-hospital treatments and events would hopefully help to clarify this. It is also possible that some, if not all of these patients would have had dectectable cTnT if the newest high sensitivity cTnT assay had been used (one that is significantly more sensitive and more accurate at lower ranges).(8)
This study has limitations. As noted above, the cTnT assay used was relatively insensitive; using a the high sensitivity assay could allow quantitative rather than just qualitative measurement of cTn changes.(7,8) Another limitation is that although cTn can predict patients who are going to do worse, it is unclear what potential therapies could modify this outcome. Only outcomes based on cTnT values were reported; combining cTn with other markers such as BNP and markers of collagen synthesis and extracellular matrix remodeling would be informative.(9) Finally, the relatively small cohort size (only 8 events in the patients who converted to cTnT (+)) can result in overfitting when performing multivariate analysis.
Future studies, using high sensitivity cTn assays, will be important to determine whether changes in cTn, either increased or decreased, are associated with changes in outcomes. Additionally, determining if treatments that are associated with improved outcomes also reduce cTn will be important. Combining cTn with other markers, such as BNP, may provide a biomarker profile that could potentially allow targeted treatment to high risk patients.
- O'Connor C.M., Fiuzat M., Lombardi C., et al. Impact of Serial Troponin Release on Outcomes in Patients With Acute Heart Failure: Analysis From the PROTECT Pilot Study. Circ Heart Fail 2011; 4:724-32.
- Kociol R.D., Pang P.S., Gheorghiade M., et al. Troponin Elevation in Heart Failure Prevalence, Mechanisms, and Clinical Implications. J Am Coll Cardiol 2010; 56:1071-8.
- Peacock W.F., De Marco T., Fonarow G.C., et al. Cardiac Troponin and Outcome in Acute Heart Failure. N Engl J Med 2008; 358: 2117–2126.
- Sato Y., Yamada T., Taniguchi R., et al. Persistently Increased Serum Concentrations of Cardiac Troponin T in Patients with Idiopathic Dilated Cardiomyopathy are Predictive of Adverse Outcomes. Circulation 2001; 103:369-74.
- Sundström J., Ingelsson E., Berglund L., et al. Cardiac Troponin-I and Risk of Heart Failure: A Community-Based Cohort Study. Eur Heart J 2009; 30:773-81.
- Miller W.L., Hartman K.A., Burritt M.F., et al. Serial Biomarker Measurements in Ambulatory Patients with Chronic Heart Failure: The Importance of Change Over Time. Circulation 2007; 116:249–257.
- deFilippi C.R., de Lemos J.A., Christenson R.H., 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.
- Latini R., Masson S., Anand I.S., et al. Prognostic Value of Very Low Plasma Concentrations of Troponin T in Patients with Stable Chronic Heart Failure. Circulation 2007; 116:1242–1249.
- Biolo A., Fisch M., Balog J., et al. Episodes of Acute Heart Failure Syndrome are Associated with Increased Levels of Troponin and Extracellular Matrix Markers. Circ Heart Fail 2010; 3:44–50
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