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(Circulation. 2003;108:833.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Cardiac Troponin I Is Associated With Impaired Hemodynamics, Progressive Left Ventricular Dysfunction, and Increased Mortality Rates in Advanced Heart Failure

Tamara B. Horwich, MD; Jignesh Patel, MD; W. Robb MacLellan, MD; Gregg C. Fonarow, MD

From Ahmanson-UCLA Cardiomyopathy Center, University of California–Los Angeles Division of Cardiology, Los Angeles, Calif.

Correspondence to Gregg C. Fonarow, MD, Ahmanson-UCLA Cardiomyopathy Center, UCLA Division of Cardiology, 47-123 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095-1679. E-mail gfonarow{at}mednet.ucla.edu

Received November 19, 2002; de novo received March 13, 2003; revision received May 12, 2003; accepted May 12, 2003.

	Abstract

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Background— Cardiac troponin I (cTnI), a sensitive and specific marker of myocardial cell injury, is useful in diagnosing and assessing prognosis in acute coronary syndromes. Small studies report that cTnI is elevated in severe heart failure (HF) and may predict adverse outcomes.

Methods and Results— The present study evaluated 238 patients with advanced HF referred for cardiac transplantation evaluation who had cTnI assay drawn at the time of initial presentation. Patients with acute myocardial infarction or myocarditis were excluded from analysis. cTnI was detectable (cTnI 0.04 ng/mL) in serum of 117 patients (49.1%). Patients with detectable cTnI levels had significantly higher B-type natriuretic peptide (BNP) levels (P<0.001) and more impaired hemodynamic profiles, including higher pulmonary wedge pressures (P=0.002) and lower cardiac indexes (P<0.0001). A significant correlation was found between detectable cTnI and progressive decline in ejection fraction over time. Furthermore, detectable cTnI was associated with increased mortality risk (RR, 2.05; 95% CI, 1.22 to 3.43). After adjustment for other factors associated with adverse prognosis including age, sex, ejection fraction, and coronary artery disease, cTnI remained a significant predictor of death. cTnI used in conjunction with BNP further improved prognostic value.

Conclusions— cTnI is associated with impaired hemodynamics, elevated BNP levels, and progressive left ventricular dysfunction in patients with HF. cTnI may be a novel, useful tool in identifying patients with HF who are at increased risk for progressive ventricular dysfunction and death.

Key Words: hemodynamics • natriuretic peptides • mortality • heart failure • tests

	Introduction

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Heart failure (HF) is a significant cause of morbidity and mortality, with a current US prevalence of 5 million and 5-year survival near 50%.¹ As medical and surgical therapies advance, it becomes important to identify high-risk patients who may derive increased benefit from transplantation referral or other aggressive treatment. Although some patients have significant improvement in left ventricular function over time in response to HF medical therapy, other patients do not respond or have progressive left ventricular dysfunction. A reliable marker to predict which patients are likely to have improvement in left ventricular systolic function would be particularly helpful in managing HF.

Troponins are proteins involved in the regulation of cardiac and skeletal muscle contraction. The presence of cardiac troponins in the serum indicates myocardial injury or loss of cell membrane integrity. Several small studies have reported elevated cardiac troponin levels in patients with decompensated HF, in the absence of acute coronary syndromes, and furthermore have correlated troponin elevation with poor prognosis.^2–6 Although the cardiac troponins, troponin I (cTnI) and troponin T, are well-established diagnostic and prognostic markers in acute coronary syndromes,^7,8 the role of troponins in the evaluation and risk stratification of patients with HF is less certain. Our study aimed to confirm and further explore the prognostic implications of cTnI levels in HF.

	Methods

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Patient Population
The study population consisted of 251 consecutive patients referred to a single university medical center for heart transplantation evaluation between June 2000 and March 2002 who had cTnI samples obtained at the time of initial evaluation. All subjects were followed in a comprehensive HF treatment program. Medical record review was approved by the Medical Institutional Review Board of the University of California–Los Angeles. Patients clinically diagnosed with acute myocardial infarction, acute coronary syndrome, or myocarditis at time of initial evaluation were excluded from analysis (n=13). No patients were receiving chronic inotropic therapy. The final study population consisted of 238 subjects (68 women, 170 men).

Baseline Patient Data
cTnI was analyzed in all patients at time of initial referral, and B-type natriuretic peptide (BNP) was analyzed in 98 patients at the time of initial referral. Both markers were analyzed through the use of industry-standard analytical platforms (Stratus CS STAT from Dade Behring for cTnI and Triage, Biosite, for BNP). For cTnI, whole blood was collected in a 4-mL sodium heparinized plastic tube; for BNP, blood samples were collected in 5-mL EDTA (K3 salt) glass tubes. Both cTnI and BNP blood samples were sent to the UCLA laboratory immediately after phlebotomy and subsequently were analyzed within 1 hour. The lower limit of detection of the cTnI assay is 0.04 ng/mL; the assay is linear up to 50 ng/mL. The measurable range of BNP was 20 to 1300 pg/mL.

Medications reported are those implemented after pulmonary artery catheter–guided hemodynamic optimization. Laboratory testing, echocardiography, and right heart catheterization occurred within 6 weeks of initial referral date. Prior left heart catheterization reports and films were reviewed or, if not done previously, left heart catheterization was performed. Significant coronary artery disease (CAD) was defined as any single stenosis >70% of the cross-sectional luminal diameter of the involved artery on angiography. Patients were classified as having HF of nonischemic cardiomyopathy if they had no prior history of myocardial infarction and cardiac catheterization was without significant CAD.

Definition of End Points
All-cause death or need for urgent transplantation was the primary end point in the study. Deaths were classified as sudden death, HF death, death secondary to myocardial infarction, noncardiovascular death, or unknown. Death was considered sudden if it was unexpected, based on the patient’s clinical status, and if it occurred out of the hospital within 15 minutes of the onset of unexpected symptoms or during sleep. Death during hospitalization for worsening congestive symptoms was considered an HF death. Urgent heart transplantation (status IA) was analyzed as progressive heart failure death. Status 1A patients are expected to live <1 week without transplantation and are dependent on intravenous medication, ventricular assist device, or mechanical ventilation.⁹ Nonurgent transplantation (status IB and II) was coded as a nonfatal end of follow-up at the time of transplantation. Patients lost to follow-up were also censored at time of last known alive-and-well date.

Statistical Analysis
Results are presented as mean±SD for continuous variables and percent total for categoric variables. Patients were divided into 2 groups, based on cTnI in serum (detectable, cTnI 0.04 ng/mL; undetectable, cTnI <0.04 ng/mL). Comparisons of baseline characteristics were made with an independent-samples t test for continuous variables and ² for categoric variables. Comparison of baseline patient variables with follow-up values instituted a paired-samples t test. Receiver operator curves (ROC) for death were constructed for cTnI and BNP levels in this patient cohort. Survival curves were calculated by the Kaplan-Meier method. The value of cTnI and other important baseline parameters in death prognosis were analyzed through the use of univariate and multivariate Cox regression models; these results are presented as estimated relative risks (RR) and 95% CI. All statistics were calculated with the use of the Statistical Package for Social Sciences (SPSS) for Windows, version 11.0.

	Results

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cTnI and Baseline Patient Characteristics
Detectable levels of serum cTnI (0.04 ng/mL) were found in 117 patients (49.1%); cTnI was undetectable in 121 patients (50.8%). Among patients with detectable cTnI, mean levels were 0.24±1.08 ng/mL, and the range was 0.04 ng/mL through 13.97 ng/mL.

The cohort was 29% women, and mean left ventricular ejection fraction (LVEF) was 0.25±0.09. Mean duration of HF symptoms before evaluation was 33±39 months, and 50% of patients were in New York Heart Association class IV at time of initial evaluation. The underlying cause was ischemic in 50% of patients and idiopathic in 33%; other causes included alcohol or drug-related, peripartum, and hypertrophic cardiomyopathy. Table 1 outlines baseline clinical and laboratory variables of the entire cohort and of cTnI-detectable and cTnI-undetectable patient groups. Demographic variables, medical history, baseline LVEF, underlying cause of HF, and renal function were similar in patients with and without detectable levels of cTnI. BNP was significantly higher (738±422 versus 461±407 pg/mL), and albumin and HDL levels were significantly lower in patients with HF with detectable cTnI levels ( 0.04 ng/mL).

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics of the Cohort: Detectable Versus Undetectable cTnI

cTnI and Cardiovascular Hemodynamics
The initial hemodynamic profile was markedly impaired in the cTnI-detectable group compared with the cTnI-undetectable group (Table 2). After optimization of medical therapy, patients with detectable cTnI still had significantly higher pulmonary artery and pulmonary capillary wedge pressures and lower cardiac indexes.

View this table: [in this window] [in a new window]   TABLE 2. Baseline and Optimal Hemodynamics in Patients With Detectable and Undetectable cTnI

cTnI and Drug Regimens
Although rates of ß-blocker therapy at time of evaluation were similar between the two groups, ACE inhibitor or angiotensin receptor blocker therapy was more common in the group with undetectable cTnI levels. Conversely, amiodarone was more common in the group with detectable cTnI (Table 3).

View this table: [in this window] [in a new window]   TABLE 3. Medication Regimens According to cTnI

cTnI and Ischemic Versus Nonischemic HF
cTnI was detectable in 48% of patients with ischemic and 52% of patients with nonischemic cause of HF. Patients with ischemic and nonischemic causes of HF were similar in terms of cTnI level and other laboratory values, NYHA class, LVEF, medications, and hemodynamics (Table 4).

View this table: [in this window] [in a new window]   TABLE 4. Patient Characteristics in Ischemic and Nonischemic Cardiomyopathy

Progression of Left Ventricular Dysfunction: Correlation With cTnI Levels
At the time of referral, mean LVEF was 0.25±0.09. In the 58 patients with 6-month follow-up echocardiography, mean LVEF increased to 0.29±0.11 (P=0.008). However, patients with detectable levels of cTnI were more likely to have progression of left ventricular systolic dysfunction (Table 5). In patients with detectable levels of cTnI, 44% had a decrease in LVEF on follow-up echocardiography, compared with only 18% of patients with undetectable cTnI levels (P<0.01).

View this table: [in this window] [in a new window]   TABLE 5. Change in Left Ventricular Ejection Fraction According to Baseline Cardiac Troponin I Level

cTnI and Survival
There were 29 deaths during the study period. Progressive HF death accounted for 14 (48%) of deaths, whereas 10 deaths were sudden and 5 were from other or unknown causes. At the end of the study period, 44 of the 238 patients had received heart transplantation (35 urgent, status IA; 9 nonurgent, status IB or II). Thus, 64 (26.9%) had end points counted as fatal (death or urgent transplantation).

Detectable levels of cTnI were significantly associated with death in this cohort of patients with advanced HF. cTnI level was significantly higher in patients who died or underwent urgent transplantation compared with those who survived (0.5±1.9 versus 0.1±0.5 ng/mL, P<0.01). On univariate analysis, detectable cTnI conferred a doubling of mortality risk (RR, 2.1; 95% CI, 1.3 to 3.5, P<0.0001). The survival curves of the 2 groups are shown in Figure 1.

View larger version (13K): [in this window] [in a new window]   Figure 1. Cumulative survival of patients with detectable and undetectable cTnI levels.

There was no stepwise increase in risk as cTnI level increased above 0.04 ng/mL. Among patients with detectable cTnI levels, the 3 tertiles of troponin level (0.04 to 0.06, 0.07 to 0.21, and 0.22 ng/mL) had similar survival (48%, 52%, and 45% respectively; P=0.7). ROC analysis identified a cTnI level of 0.04 ng/mL as the optimal inflection point for risk of death (data not shown). Any detectable level of cTnI was associated with an increased risk of mortality.

The association between cTnI and increased mortality rate was preserved in subgroups of patients with and without CAD, men and women, and in a cohort excluding patients with transplantation (Figure 2). After adjustment for additional risk factors on multivariate analysis, cTnI remained a predictor of death (Table 6). Furthermore, in the group of patients with cTnI values >0.04 ng/mL, ß-blocker therapy was associated with significantly lower mortality rates compared with patients not receiving ß-blocker therapy (34% versus 74%, P<0.003).

View larger version (12K): [in this window] [in a new window]   Figure 2. Risk of death associated with detectable levels of cTnI (0.04 ng/mL) for total cohort compared with subgroups of men and women, those with and without CAD, and excluding patients who underwent elective or urgent transplantation.

View this table: [in this window] [in a new window]   TABLE 6. cTnI as Determinant of Death in Advanced Heart Failure

cTnI used in conjunction with BNP further improved prognostic value; patients with detectable cTnI and BNP >485 pg/mL (optimal cutoff for this cohort based on ROC analysis) had a 12-fold increased risk of death compared with those with both undetectable cTnI and BNP <485 pg/mL (Figure 3).

View larger version (15K): [in this window] [in a new window]   Figure 3. Mortality rates stratified by cTnI and BNP: cTnI-, cTnI <0.04 ng/mL; cTnI+, cTnI 0.04 ng/mL; BNP-, BNP <485 pg/mL; BNP+, BNP 485 pg/mL.

	Discussion

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cTnI is a cardiac-specific structural protein that is part of the troponin-tropomyosin complex, although a small pool of cTnI exists in the cytosol. Low-level elevation of serum cTnI elevation has been documented in a number of cardiovascular diseases, including HF. Although elevation of serum cTnI is a well-validated marker of necrotic myocyte injury during myocardial infarction, the pathophysiology behind serum cTnI elevation in HF probably is distinct from that seen during myocardial infarction. The lesser elevations of serum cTnI in chronic HF, including those identified in the present study, could signify the presence of limited, irreversible myocyte injury and death, or alternatively could represent leakage of the cytosolic pool of cTnI during reversible injury as a result of loss of cell membrane integrity.¹⁰ Progressive myocyte loss through necrotic and apoptotic cell death is increasingly recognized as a prominent pathophysiological mechanism in the evolution of cardiac dysfunction in HF.^11–14 The mechanisms believed to be responsible for ongoing myocyte injury and/or cell death in HF include activation of adrenergic, renin-angiotensin-aldosterone, or endothelin signaling pathways, calcium-handling abnormalities, inflammatory cytokines, nitric oxide, oxidative stress, and mechanical stress.¹¹

In our study, release of cTnI into the serum was strongly correlated with elevation of cardiac filling pressures and BNP. In vitro experiments with cardiac muscle cells have identified a link between myocardial wall stretch and myocyte functional injury and cell death,¹⁵ and increased troponin proteolysis has been identified in volume-overloaded rat hearts.¹⁶ At the cellular level, multiple intracellular signaling cascades are activated in the heart in response to changes in mechanical loading. Of note, these include mitogen-activated protein kinases (MAPKs), including p44/42 extracellularly regulated kinases, c-Jun N-terminal kinase (JNK1/2), and p38 kinase, all of which have been to shown to be involved in the regulation of myocyte apoptosis.¹⁷ These signaling pathways are upregulated in the ventricles of patients with ischemic and dilated cardiomyopathy.¹⁷

Several reports propose a relation between cTnI and death in clinical scenarios other than HF in which ventricular wall stress increases, such as massive pulmonary embolism, acute medical illness requiring intensive care, and infusion of cardiotoxic chemotherapy.^18–21 The association between increased wall stress and myocyte death may be explained by multiple mechanisms. Increased wall stress may directly activate intracellular signaling cascades. It has also been hypothesized that increased myocardial wall stress leads to decreased subendocardial perfusion, even in the absence of CAD, resulting in a decline in systolic function.^10,22,23

Additional factors, including activation of the renin-angiotensin system, sympathetic nervous system, and inflammatory cytokine system, have been implicated in provoking myocyte injury and cell death in HF.^10,24 A study of patients with acute cardiogenic pulmonary edema found a correlation between serum cTnI levels and markers of sympathetic nervous system activation.²⁵ In our cohort of patients with advanced HF, elevation of cTnI was associated with significantly decreased albumin and HDL, findings associated with systemic cytokine activation and catabolic state.²⁶

Troponins and Risk Stratification
cTnI elevation in this cohort of patients with advanced HF signaled a significant, independent risk of death. Our findings are consistent with previous smaller studies. Sato et al³ studied 60 patients with dilated cardiomyopathy and found that cTnT was increased in 27 patients. Persistently elevated levels were associated with decline in LVEF and higher mortality rates.³ In another study, elevated cTnI was found in 10 of 34 patients (29%) hospitalized with HF and was a predictor of death at 3 months.² A study of 98 patients hospitalized with class III and IV HF found that a cTnT level >0.033 µg/L on admission was associated with an increased risk of cardiac death.²⁷

In our cohort, the prognostic power of cTnI appeared to be additive to other predictors of death in HF. The combination of elevated cTnI and elevated BNP identified patients with HF with a markedly increased risk of death (12-fold increase); this multimarker approach to risk stratification is similar to recent observations in patients with acute coronary syndromes in which cTnI, BNP, and C-reactive protein provided additive prognostic information.²⁸ Patients with abnormalities of both cTnI and BNP biomarkers may derive particular benefit from more aggressive treatment strategies such as heart transplantation or HF device therapy. Prospective studies of cTnI and BNP as predictors of therapeutic response to HF drug and device therapies are warranted.

Limitations
We acknowledge potential limitations of our study. Our study examines a selected population of patients with HF with advanced disease who were referred for transplantation evaluation. We did not collect information on race and ethnicity. cTnI levels were assessed at a single point in time. Neither neurohormones nor cytokines were measured in our patients, and BNP was available in only a subset of patients. We performed only a limited multivariate analysis, and since cTnI is associated with multiple predictors of HF death, we cannot claim that the prognostic value of cTnI is independent of all other predictors of death. Because this study was retrospective, we could not perform additional testing to determine the nature of the relation between cTnI, progressive ventricular dysfunction, and survival in HF.

Conclusions
In this cohort of patients with advanced HF, detection of serum cTnI was associated with impaired hemodynamics, elevated BNP levels, and progressive left ventricular dysfunction. cTnI was a significant predictor of increased mortality rates in patients with ischemic and nonischemic HF. Patients with detectable cTnI and elevated BNP were at particularly high risk of death or need for urgent transplantation, whereas patients without detectable cTnI and lower BNP levels had a substantially lower risk of adverse outcome. cTnI may be a novel, useful tool in identifying patients with HF who are at increased risk of progressive ventricular dysfunction and death, who probably will benefit from aggressive treatment strategies.

	References

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