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European Journal of Heart Failure 2008 10(8):772-779; doi:10.1016/j.ejheart.2008.06.009
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© 2008 European Society of Cardiology

Clinical significance of cardiac troponins I and T in acute heart failure

Tuomo Ilvaa,*, Johan Lassusb, Krista Siirilä-Warisb, John Melinc, Keijo Peuhkurinend, Kari Pulkkie, Markku S. Nieminenb, Harri Mustonenf, Pekka Porelag and Veli-Pekka Harjolab

a Department of Internal Medicine, Kanta-Hame Central Hospital Finland
b Divisions of Cardiology and Emergency Care, Helsinki University Central Hospital Finland
c Department of Medicine, Central Finland Central Hospital Finland
d Department of Cardiology, Kuopio University Hospital Finland
e Department of Clinical Chemistry, Helsinki University Finland
f Department of Surgery, Helsinki University Central Hospital Finland
g Department of Medicine, Turku University Central Hospital Finland

* Tel.: +358 50 5826979. E-mail address: tuomo.ilva{at}pp.inet.fi


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Elevated cardiac troponin (cTn) levels are relatively common in acute heart failure (AHF).

Aims: To evaluate the prevalence and prognostic significance of elevated cTnI and cTnT in AHF.

Methods: FINN-AKVA is a prospective, multicenter study in AHF. In this analysis, 364 non-ACS patients with measurements of cTnI and cTnT taken on admission and 48 h thereafter were analyzed.

Results: Of the 364 AHF patients, 51.1% had cTnI and 29.7% cTnT levels above the cut-off value. Six-month all-cause mortality was 18.7%. Both cTnI (OR 2.0, 95% CI 1.2–3.5, p=0.01) and cTnT (OR 2.6, 95% CI 1.5–4.4, p=0.0006) were associated with adverse outcome. The mortality risk was proportional to the magnitude of cTn release. On multivariable analysis, Cystatin C (OR 6.3, 95% CI 3.2–13, p<0.0001), logNT-proBNP (OR 1.4, 95% CI 1.0–1.8, p=0.03) and systolic blood pressure on admission (/10 mm Hg increase, OR 0.9, 95% CI 0.8–0.9, p=0.0004) were independent risk markers, whereas the troponins were not significantly associated with increased mortality.

Conclusions: cTn elevations are frequent in AHF patients without ACS. cTnI is more often elevated than cTnT. Both cTnI and cTnT elevations are associated with increased mortality proportional to the degree elevation but they do not act as independent risk markers.

Key Words: Acute heart failure • Troponin I • Troponin T • Prognosis

Received December 27, 2007; Revised April 27, 2008; Accepted June 9, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Acute heart failure (AHF) is a highly prevalent condition, being the single most costly medical syndrome in cardiology [1,2]. Patients are characterized by a poor prognosis, with 12-month mortality of up to 37.3% and 5-year mortality as high as 78.5% [3]. There is an urgent need for simple measurements to allow better risk stratification of these patients. Elevations of both cardiac troponin I (cTnI) and T (cTnT) have been previously reported in chronic heart failure (CHF) even in the absence of acute coronary syndromes (non-ACS) and in these studies they were associated with more severe forms of heart failure and adverse outcome [4-7]. The influence of these prognostic risk factors and especially cTn elevations in the setting of unselected patients with AHF due to reasons other than ACS is relatively poorly established. Some previous studies have shown that cTnT has independent prognostic significance among non-ACS AHF patients [8,9]). We have previously shown [10] that in AHF, older age, male gender, lower systolic blood pressure (SBP) and renal failure (RF) were independently associated with poor prognosis. Cystatin C (CysC) was the single most powerful predictor of adverse outcome. However, cTns were not included in that analysis.

The progression of CHF is characterized by ongoing left ventricular remodelling and myocyte death, making it logical that the release of cTn is associated with adverse outcome. In the setting of AHF, cardiac troponin elevations have also been shown to relate to the excessive myocardial wall tension related to acute volume and pressure overload. Increased wall strain leads to subendocardial ischaemia thus offering a potential explanation for cTn elevation in AHF. Furthermore, there are also many other factors (arrhythmias, infections, pulmonary oedema/congestion etc.) which lead to an imbalance between oxygen demand and supply, thus exposing patients to myocardial ischaemia and cTn elevations in AHF.

There are numerous assays for cTnI but only a single assay for cTnT. Compared to cTnT, the cTnI assay used in the present study has previously demonstrated superior clinical performance in the setting of ACS patients [11]. There are no previous studies comparing cTnT and cTnI in AHF. Furthermore, there is high prevalence of renal failure (RF) among AHF patients and it is widely accepted that cTnT elevations are more frequently compared to cTnI elevations in the setting of end stage renal disease [12]. A very recent study among haemodialysis patients without ACS, reported that the prevalence of elevated cTnI was 2-3% whereas the prevalence of elevated cTnT was as high as 27% [13]. Thus, the aim of the present study was to identify the possible differences in prevalence and prognostic significance between cTnI and cTnT assays among patients with AHF. Special attention was paid to the clinically significant patient subgroups, like patients with or without a history of coronary artery disease (CAD), CHF or RF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population and laboratory procedures
The original study population consisted of 620 consecutive patients hospitalised with AHF [14]. Patients were enrolled at 14 hospitals in Finland between February and May 2004, as previously described [14]. For the purposes of this study, ACS patients (N=198) were excluded. The exclusive diagnosis of ACS was made by the treating clinicians based on all available data including symptoms, ECGs, possible coronary angiograms and locally analyzed cTns. The clinicians were unaware of the results of cTnI and cTnT measurements used in the present study.

Furthermore, patients with missing investigational blood samples for cTnI and cTnT analyses (N=58) were excluded. Thus, the final study population consisted of 364 patients.

Blood samples were taken on admission and approximately 48 h thereafter. Analyses of cTnT, cTnI, CysC and NT-proBNP were performed in a central laboratory, and maximal test values of the two samples taken were used in the statistical analysis.

cTnT levels were measured with the Roche Elecsys 2010 assay. According to the manufacturer, the assay has a minimum detectable concentration (MDC) of 0.01 {varepsilon}g/L and the lowest concentration at which the CV is ≤10% is 0.03 {varepsilon}g/L. In our precision study, CVs were 5.6% at 0.134 {varepsilon}g/L and 4.7% at 2.99 {varepsilon}g/L.

cTnI levels were measured with the Architect STAT Troponin I assay (Abbott Diagnostics Division, Abbott Park, IL). According to the manufacturer, the assay has a minimum detectable concentration (MDC) of ≤0.01 {varepsilon}g/L and the lowest concentration at which the CV is ≤10% is 0.032 {varepsilon}g/L. CVs of the assay used in our central laboratory were 5.0% at 0.1 {varepsilon}g/L, 3.7% at 0.6 {varepsilon}g/L and 2.7% at 16.0 {varepsilon}g/L.

CysC was measured using Dako Cytomation assay, as previously described [10]. RF was defined as CysC above 1.2 mg/L for individuals aged less than 50 years and 1.4 mg/L for subjects aged over 50 years. NT-ProBNP was analyzed using the commercial Roche Diagnostics Elecsys assay.

2.2. Statistical analysis
Results are presented as mean±SD for continuous variables and percentage of subjects for categorical variables. Comparisons of baseline characteristics were made with Student's t test for continuous variables and Fisher's or McNemar's tests for categorical variables. Odds ratios (OR) were calculated to evaluate the predictors of 6-month overall mortality. Mortality data were obtained from the national Population Register Centre. The following variables were tested: age, sex, CHF, history of CAD, hypertension and diabetes. Biochemical markers included were CysC, anaemia (WHO definition: blood haemoglobin <130 g/L for men and <120 g/L for women), hyponatraemia (plasma sodium<135 mmol/L), cTnI (≥0.032 {varepsilon}g/L), cTnT (≥0.03 {varepsilon}g/L) and NT-proBNP (logarithmic value). We also included systolic blood pressure (SBP) on admission as well as left ventricular ejection fraction (LVEF) ≤45%. To evaluate the prognostic significance of the magnitude of cTn release, the Cox proportional-hazard analysis was performed (Hazard ratio, HR) and survival curves were constructed by the Kaplan-Meier method and were analyzed with the log-rank test. To evaluate the independent prognostic utility of cardiac troponins, a multivariable logistic regression analysis was performed with stepwise selection of variables including all variables with p<0.10 in univariate analysis. p-values <0.05 were considered statistically significant. The statistical analyses were performed using SAS statistical software (Version 8.1; SAS Institute, Cary, NC, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Baseline data of all patients according to cTn positivity
Baseline characteristics of the patient population categorized according to cTn positivity are shown in Table 1A. Patients were on average 74.8 (SD 10.9) years old. Half of the patients were male. Approximately half of the patients had previously diagnosed CAD, hypertension and CHF and 29% had diabetes. 12% of the patients had dilated cardiomyopathy (DCM) and 14% had significant valvular disease. AHF was precipitated by atrial fibrillation in 40% of patients. Ejection fraction was reported in two thirds (N=229) of the patients, of which 54% had preserved LVEF ≥45%.


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  		Table 1A Baseline characteristics of the patient population (N=364)

 
186/364 (51.1%) had cTnI and 108/364 (29.7%) cTnT release during the index hospitalisation indicating a higher proportion of cTnI positive compared to cTnT positive subjects (p<0.001). CHF patients were likely to have cTn elevation (cTnI positive in 56% and cTnT in 37% of cases). NT-proBNP and CysC levels were significantly higher among cTn positive patients compared with cTn negative patients. Arrhythmias, mainly atrial fibrillation as a cause of AHF were more common among cTn negative patients. Older age, previously documented CAD, significant valvular disease, chronic renal failure, and cardiogenic shock on admission were associated only with cTnT positivity but not with cTnI positivity. Interestingly, cTnI positivity alone was linked to DCM and systolic heart failure (LVEF<45%).

89 patients had cTnI elevation but normal cTnT values (cTnI+/cTnT–). Compared to patients positive with respect to both cTnI and cTnT (cTnI+/cTnT+), cTnI+/cTnT– patients had significantly lower absolute levels of NT-proBNP, CysC and cTnI (Table 1B). The prevalence of significant valvular disease as the cause of AHF was also statistically lower than in cTnI+/cTnT+ patients.


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  		Table 1B Baseline characteristics of the patient population (N=186)

 
Only 11 patients were cTnT positive and cTnI negative. According to CysC measurements all of these patients had RF, which probably explains these cTnT elevations.

3.2. The percentages of cTn positive patients
Fig. 1 shows the percentages of cTnI and cTnT positive patients in different patient groups based on maximal cTn values. In each patient subgroup the proportion of cTnI positive patients was statistically higher compared to cTnT. In the subgroup of RF patients the amount of cTnT positive patients was relatively high, and probably part of these cTnT elevations were due to the renal dysfunction. Corresponding percentages based on only the 48-hour cTn samples were remarkably similar (data not shown).


Figure 01
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  		Fig. 1 Percentage of cTn positivity in different patient subgroups. p-values for difference between cTnI and cTnT positivities are <0.001 in all subgroups except in RF patients (p=0.001) and in LVEF>45% subgroup (p=0.002).

 
3.3. The prognostic impact of cTn positivity
Six-month all-cause mortality was 18.7% (68/364). Both cTnT (OR 2.6, 95% CI 1.5-4.4, p=0.0006) and cTnI (OR 2.0, 95% CI 1.2-3.4, p=0.01) were associated with worsened prognosis (Fig. 2). Among patients with previous HF both cTnT (OR 2.7, 95% CI 1.4-5.3, p=0.003) and cTnI (OR 2.5, 95% CI 1.2-5.1, p=0.01) were predictors of outcome, whereas in de novo AHF patients neither cTns were associated with adverse outcome. ?tlsb-.09pt?>Among patients without RF the mortality was only 7.0%. In those patients, neither cTnT (OR 3.0, 95% CI 0.9-9.7, p=0.06) nor cTnI (OR 2.4, 95% CI 0.8-7.3, p=0.14) was statistically a significant predictor of mortality. In the RF subgroup, the 6-month mortality was as high as 33.1%, but neither cTnI nor cTnT was a predictor of outcome. In the subgroups of patients with CAD (OR 2.5, 95% CI 1.2-5.2, p=0.01), LVEF>45% (N=123, OR 3.4, 95% CI 1.1-10, p=0.03) and LVEF<45% (N=106, OR 3.5, 95% CI 1.2-11, p=0.02) only cTnT was associated with adverse outcome. The corresponding ORs and confidence intervals are shown in Fig. 2. The corresponding OR based on only 48-hour cTn values demonstrated values similar to those based on maximal cTn values (data not shown).


Figure 02
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  		Fig. 2 Odds ratios for 6-month mortality in cTn positive vs. cTn negative patients in different subgroups of AHF patients.

 
The 89 cTnI+cTnT– patients (see Table 1B) had similar prognosis compared to cTn– patients (OR 1.2, 95% CI 0.6-2.5, p=0.58) demonstrating prognostic insignificance of these minor cTnI elevations.

In multivariable analysis of the whole study population CysC (OR 6.3, 95% CI 3.2-13, p<0.0001), NT-proBNP (logarithmic value, OR 1.4, 95% CI 1.0-1.8, p=0.03) and SBP on admission (/10 mm Hg increase, OR 0.9, 95% CI 0.8-0.9, p=0.0004) remained significant prognostic factors, whereas cTns did not.

3.4. The prognostic value of the magnitude of cTn release
We divided the patients into 3 groups with respect to maximal cTn value; cTn negative patients constituted the lowest group and cTn positive patients were divided into two groups with equal number of patients. The mortality was proportional to the magnitude of cTn release. In cTnI-based classification (Fig. 3A), the difference between the 1st (N=178) and 3rd (N=93) groups was highly significant (HR 2.2, 95% CI 1.3-3.9, p=0.005), whereas the difference between the 1st and 2nd (N=93) groups did not reach statistical significance (HR 1.6, 95% CI 0.9-2.9, p=0.13) indicating again the limited prognostic significance of minor cTnI releases. In the cTnT based classification (Fig. 3B) the comparisons between the 1st (N=256) and 2nd (N=54, HR 2.3, 95% CI 1.3-4.2, p=0.007) and 1st and 3rd (N=54, HR 2.5, 95% CI 1.4-4.5, p=0.002) groups were both statistically significant.


Figure 03
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  		Fig. 3 A. Prognostic significance of the magnitude of cTnI release. All-cause mortality at 6 months: 13.5% for 1st group (upper line, cTnI<0.032 {varepsilon}g/L, n=178), 20.4% for 2nd group (middle line, cTnI 0.032-0.088 {varepsilon}g/L, n=93) and 26.9% for 3rd group (lower line, cTnI>0.088 {varepsilon}g/L, n=93). p-values (log rank) for difference between patient groups: 1st vs. 2nd p=0.13, 1st and 3rd p=0.005. B. Prognostic significance of the magnitude of cTnT release. All-cause mortality at 6 months: 14.1% for 1st group (upper line, cTnT<0.03 {varepsilon}g/L, n=256), 27.8% for 2nd group (middle line, cTnT 0.03-0.07 {varepsilon}g/L, n=54) and 31.5% for 3rd group (lower line, cTnT>0.07 {varepsilon}g/L, n=54). p-values (log rank) for difference between patient groups: 1st vs. 2nd p=0.007, 1st and 3rd p=0.002.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this study we evaluated for the first time the prevalence and prognostic significance of cTnI and cTnT positivities in the setting of non-ACS AHF patients. We found that cTn positivity was highly prevalent, cTnI positivity being more common than cTnT positivity. We also found that the characteristics of cTnI and cTnT positive patients were remarkably different. Both cTns were markers of increased mortality. Furthermore, the mortality risk was proportional to the magnitude of cTn release. However, cTns did not have independent prognostic significance.

4.1. The prevalence of cTn positivity
Both cTnI (23 kD) and cTnT (35 kD) are structural proteins of cardiomyocytes, however, a small portion of cTns (6-8% for cTnT and 3.5% for cTnI) is found free in the cytosolic pool [15]. Low-grade elevation of cTns has been documented in multiple cardiac and non-cardiac diseases, including AHF and also in other clinical conditions, such as acute atrial fibrillation, myocarditis, etc. which are often present among AHF patients [16]. The pathophysiological mechanisms behind cTn elevations in AHF are not fully understood but are undoubtedly multifactorial, including ongoing myocyte death through necrosis and apoptosis which is a prominent pathophysiological mechanism in the progression of CHF. It has also been suggested that reversible cell injury could cause troponin release from the cytosolic pool alone [4].

We found that cTnI was elevated in half of the patients, whereas the proportion of cTnT positive patients was significantly lower. The higher sensitivity of the cTnI assay probably explains these results [11]. In accordance with this, most cTnI+/cTnT– patients had cTnI values near the detection limit whereas most of the cTnT positive patients were also cTnI positive. Whether the differences in the structural properties of cTns, including molecular size and possible reversible myocyte injury caused by cTn release from the cytosolic pool has a role in these results, remains beyond the scope of our study.

Previously documented HF and higher levels of NT-proBNP and CysC as a marker of renal dysfunction are factors that were associated with both cTnI and cTnT positivities and are commonly observed with more progressed and severe HF. Otherwise cTnT and cTnI positive patients were somewhat different. cTnT positivity was associated with older age, CAD, CVD and known valvular disease. cTnI positivity alone was linked to DCM as a cause of AHF. Furthermore, cTnI positivity was associated with reduced LVEF.

The differences between cTnT and cTnI-based classifications were driven by the 89 cTnI+/cTnT– patients, a subgroup characterized by low absolute levels of cTnI release, high prevalence of DCM and reduced LVEF.

Goser et al. [17] have recently shown that immunizing mice with murine cTnI (mc-TnI) causes cardiomegaly, fibrosis, depressed fractional shortening on echocardiography and increased mortality. However, immunization with mc-TnT did not cause similar effects. It has been suggested that the discordant results between the two different cTn subunits may be explained by the fact that the cTnI subunit is found both in the intracellular compartment of the cardiomyocytes and on the surface of ventricular cardiomyocytes, whereas cTnT is not found on the myocyte surface [18]. Furthermore, Shmilovich et al. [19] have demonstrated that 15.6% of DCM and 18.2% of ischaemic cardiomyopathy (ICM) patients, but none of the healthy controls, had measurable cTnI autoantibodies (cTnIAbs). Recently, Miettinen et al. [20] have demonstrated that in a cohort of 95 DCM patients, 16% had measurable cTnIAbs and the existence of cTnIAbs and cTnI elevation was highly correlated. However, both these trials failed to demonstrate that cTnIAbs had clinical or prognostic significance. However, the association between DCM and cTnI immunization in the aforementioned studies [17,19,20] and our findings is interesting and identifies an area in which future studies are required.

4.2. The prognostic impact of cTn positivity
Some previous studies have shown that cTnT has independent prognostic significance among AHF patients [8,9]. In our study both cTnI and cTnT were predictors of adverse outcome in univariate analysis. In the subgroup analysis, cTns were poor predictors of outcome in the subgroups of patients with RF and de novo HF. Among patients with previous HF, both cTnI and cTnT performed relatively well. Among patients with CAD, only cTnT was a predictor of adverse events.

The magnitude of cTn elevation was directly proportional to patient prognosis as can be seen from Fig. 3. The low-positive cTnI cohort was not statistically associated with adverse outcome. Parallel results were noticed among cTnI+/cTnT– patients that were characterized by low-level cTnI elevations and prognosis similar to cTnI– patients.

Finally, in the multivariable analysis, cTns did not have independent prognostic value. CysC was the single most powerful predictor of adverse outcome. It is worth mentioning that even if variables measuring renal function were excluded from the multivariable analysis, cTns would have remained prognostically insignificant. The difference in our results compared to some previous studies [8,9], where cTns were independently associated with adverse outcome, probably has several explanations. These include different patient selection and different cut-off values for cTnT. Metra et al. [9] excluded patients with acute arrhythmias, myocarditis, valve stenosis, cardiac tamponade, aortic dissection, high output syndrome and patients with evidence of non-cardiovascular factors as the main cause of symptoms. In contrast, our study cohort included all non-ACS AHF patients. Metra et al. also used cTnT cut-off values which were derived from ROC analysis which differ from the clinically accepted cut-off values for myocardial infarction in our study. Perna et al. [8] had neither NT-proBNP/BNP nor any marker of renal function in their multivariable model. In another article by Perna et al. [21], in which NT-proBNP was included in a multivariable model, cTnT was not an independent risk marker. Similarly, in the article by Sakhuja et al. [22] cTnT was not an independent predictor of increased mortality. It should also be noted that the patient cohorts (which ranged in size from 76 to 209 patients) in these studies [8,9,21,22] were considerably smaller compared to our study. Overall we think that cTns are probably better risk stratifiers in the follow-up of chronic heart failure patients, in which cTn positivity better reflects the ongoing pathophysiology of HF. In AHF, the reason for cTn elevation is multifactorial, and includes many reversible components like infections or acute arrhythmias leading to an imbalance between oxygen demand and supply.

4.3. Study limitations
In our study, the exclusive diagnosis of ACS was based on the judgement of the clinician in charge of the patient and it was not possible to check the consistency of the clinical diagnosis. Therefore it is possible that some patients in our study actually had ACS as the cause of AHF.

Since this was a prospective patient cohort, the cut-off values of cTns were based on the European Society of Cardiology/American College of Cardiology Joint Committee guidelines [23] followed at the time when the study was conducted. The most recent guidelines [24,25] prefer the use of even lower cut-offs corresponding to only 99% URL. The use of these lower cut-offs would probably have some influence on the results and undoubtedly increased the proportion of cTn positive patients in our patient cohort. The manufacturers are currently developing more and more sensitive cTn assays. Implementation of such assays would inevitably lead to higher percentage of cTn positive patients in AHF, as already demonstrated in a cohort of CHF patients by Latini et al. [26]. In clinical practice, it is important to understand that cTn elevations in AHF are highly prevalent, and it is often very difficult to differentiate whether an AHF patient has ACS or not.

4.4. Conclusions
cTn elevations are highly frequent in AHF patients without ACS. cTnI is more often elevated than cTnT. The characteristics of cTnI and cTnT positive patients are different. Interestingly, cTnI identifies patients with high a prevalence of DCM and low LVEF. The degree of cTn elevation is associated with adverse outcome. However, even though both cTnI and cTnT elevations are associated with increased mortality, they do not appear to be independent risk markers in AHF.


   Acknowledgements
 
The study was supported by grants from the Finnish Foundation for Cardiovascular Research, Paulo Foundation, and an unrestricted grant from Orion Pharma. Roche Diagnostics kindly provided kits for the analysis of NT-proBNP and Abbott Diagnostics kits for the analysis of cTnI, and both companies financially supported the study sample logistics. Tuomo Ilva was supported financially by Kanta-Häme Central Hospital Research fund.

We are thankful to Mervi Pietilä for technical assistance and Pirjo Tanner and Aija Helin for laboratory analysis. The participants of the FINN-AKVA study have been listed in our previous publication [14].


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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