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Quantifying Cardiac Hemodynamic Stress and Cardiomyocyte Damage in Ischemic and Nonischemic Acute Heart Failure

Originally publishedhttps://doi.org/10.1161/CIRCHEARTFAILURE.111.961243Circulation: Heart Failure. 2012;5:17–24

Abstract

Background—

The early and noninvasive differentiation of ischemic and nonischemic acute heart failure (AHF) in the emergency department (ED) is an unmet clinical need.

Methods and Results—

We quantified cardiac hemodynamic stress using B-type natriuretic peptide (BNP) and cardiomyocyte damage using 2 different cardiac troponin assays in 718 consecutive patients presenting to the ED with AHF (derivation cohort). The diagnosis of ischemic AHF was adjudicated using all information, including coronary angiography. Findings were validated in a second independent multicenter cohort (326 AHF patients). Among the 718 patients, 400 (56%) were adjudicated to have ischemic AHF. BNP levels were significantly higher in ischemic compared with nonischemic AHF (1097 [604–1525] pg/mL versus 800 [427–1317] pg/mL; P<0.001). Cardiac troponin T (cTnT) and sensitive cardiac troponin I (s-cTnI) were also significantly higher in ischemic compared with nonischemic AHF patients (0.040 [0.010–0.306] μg/L versus 0.018 [0.010–0.060] μg/L [P<0.001]; 0.024 [0.008–0.106] μg/L versus 0.016 [0.004–0.044 ] μg/L [P=0.002]). The diagnostic accuracy of BNP, cTnT, and s-cTnI for the diagnosis of ischemic AHF, as quantified by the area under the receiver-operating characteristic curve, was low (0.58 [95% CI, 0.54–0.63], 0.61 [95% CI, 0.57–0.66], and 0.59 [95% CI,0.54–0.65], respectively). These findings were confirmed in the validation cohort.

Conclusions—

At presentation to the ED, patients with ischemic AHF exhibit more extensive hemodynamic cardiac stress and cardiomyocyte damage than patients with nonischemic AHF. However, the overlap is substantial, resulting in poor diagnostic accuracy.

Introduction

Acute heart failure (AHF) remains a leading health problem worldwide. Despite substantial progress in diagnostic and therapeutic management in recent years, morbidity and mortality remain extremely high and largely unchanged in decades.1 In particular, patients with ischemic AHF, most AHF patients in industrialized countries, have a poor prognosis2 and also seem to respond differently to therapy (eg, phosphodiesterase inhibitors seem to increase mortality exclusively in patients with ischemic AHF).3 As a consequence, early identification of patients in terms of their etiology is of exigent clinical importance for targeting “individualized” diagnostic and therapeutic strategies. The treatment benefit of some therapies seems to depend on AHF etiology; pharmacological and invasive treatment for acute and chronic coronary artery disease (CAD), the underlying cause of ischemic AHF, has markedly improved throughout the past decades. In contrast, we have not made the same progress in the management and treatment of AHF in the acute-care setting. In this respect, the National Heart, Lung, and Blood Institute recently emphasized the need for advantages in the management of AHF4 and identified the important need to better characterize AHF already in the emergency department (ED).

Editorial see p 2

Clinical Perspective on p 24

In this respect, we hypothesized that 2 distinctly different pathophysiological mechanisms might allow us to differentiate ischemic from nonischemic AHF: hemodynamic cardiac stress, quantified using B-type natriuretic peptide (BNP),5,6 and cardiomyocyte damage, quantified using cardiac troponin (cTn). Recent data suggest that cardiac stress and myocardial ischemia may be triggers of BNP release.79 CTns, biomarkers used predominately to diagnose acute myocardial infarction (AMI), also have been described to be elevated in AHF.10

We hypothesized that patients with ischemic AHF exhibit more extensive hemodynamic cardiac stress and cardiomyocyte damage than patients with nonischemic AHF. Therefore, a multimarker strategy with BNP and cTns might allow for a rapid and accurate diagnosis of ischemic AHF already at presentation in the ED.

Methods

Study Design and Population

A total of 718 patients admitted to the ED of the University Hospital Basel (Switzerland) from May 2001 to April 2010 were prospectively enrolled in this study (derivation cohort). Patients presenting with acute dyspnea as the main symptom and diagnosed as having AHF were recruited. Exclusion criteria included aged <18 years and terminal renal failure requiring hemodialysis. Acute coronary syndrome was not an exclusion criterion. However, patients additionally diagnosed as having acute coronary syndrome were rarely included in the study because only patients with acute dyspnea, not chest pain, as the main symptom were recruited. For further demonstration of our study population, we constructed Figure 1. Details of the clinical assessment of patients are reported in the Online Only Data Supplement. The study was conducted according to the principles of the Declaration of Helsinki and approved by the local ethics committee. Written informed consent was obtained from all participating patients.

Figure 1.

Figure 1. Study population. Patients with acute dyspnea as the main symptom and diagnosis of acute heart failure (AHF) were included in the study, whereas patients with acute chest pain and noncardiac dyspnea were not recruited. AHF patients further were diagnosed as having acute coronary syndrome (ACS), comprising unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI), and STEMI, or as not having ACS at presentation.

Adjudicated Final Diagnosis

The final discharge diagnosis of AHF was adjudicated using all medical records pertaining to the patient (including results of standard investigations, the response to therapy, and autopsy data in those patients dying in the hospital). In all cases, guidelines of the European Society of Cardiology were applied for the diagnosis of acute decompensated heart failure.11

Classification as ischemic versus nonischemic AHF was based on medical history of CAD (defined by percutaneous coronary intervention and/or coronary bypass graft) or AMI, as well as objective evidence, such as coronary angiography or nuclear imaging findings performed in the past or during hospitalization, performed in most patients (>90%). The presence of a stenosis >75% in 2 vessels on angiography, as previously suggested by Felker et al,12 or myocardial scars during myocardial perfusion imaging (MPI) was regarded as ischemic AHF. MPI can provide additional and sometimes superior information regarding the presence or absence of myocardial ischemia, particularly in patients with moderate lesion severity (eg, diameter stenosis of 50–75%).13 In addition, we also classified patients with non–ST-elevation myocardial infarction (NSTEMI) and STEMI during hospitalization as having ischemic heart failure. NSTEMI and STEMI were defined and cTn measurements were used as recommended in current guidelines.14 In brief, AMI (NSTEMI, STEMI) was diagnosed when there was evidence of acute myocardial damage in a clinical setting, consistent with myocardial ischemia. Acute myocardial damage was defined as at least 1 cTn value >99th percentile of a normal reference population (with an imprecision of <10% for the standard cTn assays), accompanied by a significant change, as documented by an increasing and/or decreasing pattern of the cTn test.15

Biochemical Analysis

At the patient's presentation to the ED, venous blood samples were collected in tubes containing potassium EDTA. BNP and cardiac troponin T (cTnT) levels were measured immediately; otherwise, samples were centrifuged and frozen at -80°C until later analysis in a dedicated core laboratory. A detailed description of the biomarker assays (BNP, cTnT fourth generation, and sensitive cardiac troponin I [s-cTnI]) is presented in the Online Only Data Supplement.

Validation Cohort

Hemodynamic cardiac stress and cardiomyocyte damage in ischemic versus nonischemic AHF patients were subsequently analyzed in a cohort of 326 consecutive patients of the FINN-AKVA [Finnish Acute Heart Failure] study.16,17 In this prospective, multicenter study, patients were hospitalized with AHF and enrolled at 14 hospitals in Finland between February and May 2004. Hemodynamic cardiac stress was quantified using N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP) on admission. Regarding comparability with BNP, which was measured in the derivation cohort, multiple studies have confirmed that BNP and NT-pro-BNP have a high correlation (r>0.9) in patients with AHF.18 Cardiomyocyte damage was quantified using the same cTnT and s-cTnI assays as in the derivation cohort. A detailed description of the biomarker assays is presented in the Online Only Data Supplement.

Statistical Analysis

Categorical variables are expressed as numbers and percentages, and continuous variables are expressed as medians and interquartile range. Categorical variables were compared using the Pearson χ2 test, and continuous variables were compared using the Mann-Whitney U test. All hypothesis testing was 2 tailed, and P<0.05 indicated statistical significance. Receiver-operating characteristic (ROC) (curves) for diagnosis were calculated for BNP, cTnT, cTnI, and their combination to diagnose ischemic AHF. Multivariable logistic regression was then performed, including all variables that emerged significant from univariate analysis, to test the possible independent information for the diagnosis of ischemic AHF. To see whether there was any secular trend, we included a dummy variable for time of enrollment after 2004 into a logistic regression model for the likelihood of a diagnosis of ischemic AHF as a function of a specific blood marker. The blood marker values were logarithmized for this purpose for a better fit of the data. All calculations were made using SPSS/PC version 18.0 (SPSS Inc; Chicago, Ill).

Results

Characteristics of Patients

The baseline characteristics of the study population are presented in Table 1. Among the 718 patients with AHF, 400 (56%) were classified as having ischemic AHF and 318 (44%) were classified as having nonischemic AHF. Their mean age was 78 years, and 45% were women. Several baseline characteristics differed significantly between the ischemic and nonischemic patients, with ischemic patients more likely to be male and to have diabetes, dyslipidemia, and chronic kidney disease. In this respect, creatinine levels were significantly higher and the estimated glomerular filtration rate was lower in patients with ischemic AHF. In addition, ischemic AHF patients significantly more often experienced a history of heart failure. Regarding medication, aspirin, β-blockers, diuretics, and nitrates were more frequently prescribed in patients with ischemic AHF.

Table 1. Baseline Characteristics of the Derivation and Validation Cohort

CharacteristicsBASEL Cohort
FINN-AKVA Cohort
All (n = 718)Ischemic Acute Heart Failure (n = 400)Nonischemic Acute Heart Failure (n = 318)P ValueAll (n = 326)P Value*
Age, y78 (70–84)78 (71–84)78 (69–84)0.38277 (69–83)0.083
Male sex397 (55)245 (61)152 (48)<0.001162 (50)0.135
Risk factors
    Hypertension512 (72)313 (79)199 (63)<0.001192 (59)<0.001
    Diabetes mellitus215 (30)149 (38)66 (21)<0.001113 (35)0.190
    Dyslipidemia174 (34)134 (51)40 (16)<0.001
    Smoking92 (13)58 (15)34 (11)0.22639 (12)0.689
Medical history
    Previous heart failure238 (46)153 (57)85 (34)<0.001193 (59)0.001
    Chronic obstructive pulmonary disease174 (24)115 (29)59 (19)0.00449 (15)<0.001
    Chronic kidney disease290 (41)193 (49)97 (31)<0.00133 (10)<0.001
    Neoplastic disease118 (17)59 (15)59 (19)0.121
Medication at admission
    Diuretics482 (68)293 (74)189 (60)<0.001192 (59)0.012
    β-blockers373 (52)238 (60)135 (43)<0.001208 (64)0.002
    ACE inhibitor§/angiotensin receptor blocker100 (50)64 (48)36 (52)0.585172 (53)0.467
    Nitrates140 (20)106 (27)34 (11)<0.001117 (36)<0.001
    Aspirin291 (41)207 (52)84 (27)<0.001119 (37)0.002
Symptoms
    Dyspnea0.681<0.001
        NYHA II61 (9)33 (8)28 (9)69 (23)
        NYHA III347 (48)191 (48)156 (49)135 (45)
        NYHA IV296 (41)170 (43)126 (43)82 (27)
    Weight gain204 (29)118 (30)86 (27)0.534
    Chest pain246 (34)156 (39)90 (28)0.010
    Coughing359 (50)197 (50)162 (51)0.909
Signs
    Elevated jugular venous pressure270 (38)156 (39)114 (36)0.440
    Hepatojugular reflux165 (23)87 (22)78 (25)0.517
    Rales453 (64)263 (66)190 (60)0.143
    Lower extremity edema407 (57)229 (57)178 (56)0.509
Vital status
    Systolic blood pressure, mm Hg138 (122–160)138 (122–162)138 (121–158)0.744148 (127–169)<0.001
    Diastolic blood pressure, mm Hg84 (71–97)82 (69–95)85 (73–99)0.04883 (70–99)0.729
    Heart rate, beats/min90 (74–110)86 (72–104)95 (76–119)0.00185 (71–105)0.117
    Oxygen saturation, %96 (92–98)96 (93–98)96 (92–98)0.127
Laboratory tests
    Hemoglobin, g/L129 (114–143)125 (113–143)131 (115–144)0.031127 (115–140)0.073
    Sodium, mmol/L138 (136–140)138 (136–140)138 (135–140)0.760139 (136–141)0.965
    Creatinine, μmol/L105 (80–147)118 (85–162)96 (75–129)<0.00198 (81–125)<0.001
    Glomerular filtration rate, mL/min per 1.73 m252 (37–73)46 (32–68)57 (43–76)<0.001
Echocardiographic findings
    LV ejection fraction40 (30–60)39 (25–50)54 (35–60)<0.00145 (32–56)<0.001

Data are presented as median (interquartile range) or number (%) of patients. ACE indicates angiotensin-converting enzyme; NYHA, New York Heart Association.

*P value for comparison of the BASEL with the FINN-AKVA cohort regarding baseline characteristics.

Dyslipidemia available in 480 patients of the BASEL cohort.

Previous heart failure available in 513 patients of the BASEL cohort.

§ACE inhibitor/angiotensin receptor blocker available in 202 patients.

LV ejection fraction available in 464 patients of the BASEL cohort.

Diagnosis of Ischemic AHF

Of the 400 patients diagnosed as having ischemic AHF, 237 (59%) had a history of CAD (without past AMI) and 140 (35%) had a history of AMI, as shown in Table 2. During hospitalization, coronary angiography revealed stenosis >75% in 2 vessels in 50 (13%) of the patients and MPI demonstrated myocardial scars in 19 (5%) of the patients. In addition, 43 (11%) patients had NSTEMI and 4 (1%) had STEMI during hospitalization.

Table 2. Diagnosis of Ischemic AHF in the BASEL Cohort

VariableIschemic AHF (n = 400)*
History
    Coronary artery disease (defined by percutaneous coronary intervention and/or coronary artery bypass graft)237 (59)
    Past myocardial infarction140 (35)
Coronary angiography findings
    >75% Stenosis in 2 vessels50 (13)
Myocardial perfusion imaging
    Myocardial scars19 (5)
Event during hospitalization
    NSTEMI43 (11)
    STEMI4 (1)

Data are presented as number (%) of patients.

*Several patients fulfilled >1 criterion.

Performed during hospitalization.

Levels of BNP and cTn in the Ischemic and Nonischemic Groups

Levels of BNP and cTn in the different groups are displayed in Figure 2 (and in Online Only Data Supplement Table 1). Of the 718 consecutively enrolled patients, measurement of BNP was obtained at presentation from all 718 (100%), cTnT from 625 (87%), and s-cTnI from 373 (52%).

Figure 2.

Figure 2. Levels of B-type natriuretic peptide (BNP), fourth- generation cardiac troponin T (cTnT), and sensitive troponin I (s-cTnI), according to etiology of acute heart failure (AHF). BNP (P<0.001), cTnT (P<0.001), and s-cTnI (P=0.002) levels at presentation to the emergency department, according to the etiology of AHF. Boxes represent interquartile ranges; whiskers, ranges (without outliers further than 1.5 interquartile ranges from the end of the box).

Patients with ischemic AHF had significantly higher levels of BNP, cTnT, and s-cTnI compared with patients with nonischemic AHF. After adjustment for renal function and left ventricular (LV) ejection fraction, the significant difference between the groups regarding BNP and cTns levels remained.

BNP and cTns for the Diagnosis of Ischemic AHF

As displayed in Table 3 and Figure 3, the diagnostic accuracy at presentation for the diagnosis of ischemic AHF, as quantified by the area under the ROC curve, was 0.58 (95% CI, 0.54–0.63; n=718) for BNP, 0.61 (95% CI, 0.57–0.66; n=625) for cTnT, and 0.59 (95% CI, 0.54–0.65; n=373) for s-cTnI. The combination of BNP, cTnT, and s-cTnI in 373 patients did not increase the diagnostic accuracy provided by BNP, cTnT, or s-cTnI alone (area under the ROC curve of combination, 0.58; 95% CI, 0.52–0.65). In a subgroup analysis with 315 patients, in which all 3 biomarker measurements were available, the diagnostic accuracy was not significantly different than previously described (see the Online Only Data Supplement). For more information, we also report specificities, sensitivities, positive and negative predictive values, and the correctly classified rates (see the Online Only Data Supplement).

Table 3. Diagnostic Performance of Natriuretic Peptides and Troponin Assays at Presentation

Biomarker*BASEL Cohort
FINN-AKVA Cohort
AUC95% CIAUC95% CI
BNP, pg/mL (for BASEL cohort)0.580.54–0.630.610.55–0.67
NT-pro-BNP, pg/mL (for FINN-AKVA)
Fourth-generation cTnT, μg/L0.610.57–0.660.570.51–0.63
s-cTnI, μg/L0.590.54–0.650.570.51–0.64
Combination of BNP (BASEL-V)/NT-pro-BNP (FINN-AKVA), cTnT, and s-cTnI0.580.52–0.650.600.54–0.66

AUC indicates area under the ROC (curve).

*BNP was available in 718, cTnT in 625, and s-cTnI in 373 patients in the BASEL cohort; for combination of BNP, cTnT, and s-cTnI, values were available in 315 patients of the BASEL cohort; and in the FINN-AKVA cohort, all biomarkers were available in 326 patients.

Figure 3.

Figure 3. Diagnostic performance of B-type natriuretic peptide (BNP) and cardiac troponin assays at presentation (BASEL cohort). The area under the receiver-operating characteristic curves describes the diagnostic performance of the following at presentation in the diagnosis of ischemic acute heart failure: A, BNP (0.58; 95% CI, 0.54–0.63; n=718); B, troponin T (0.61; 95% CI, 0.57–0.66; n=625); and C, sensitive troponin I (0.59; 95% CI, 0.54–0.65; n=373).

Multivariable Regression Analysis

In multivariable analysis, only male sex, hypertension, and LV ejection fraction remained significantly associated with the diagnosis of ischemic AHF (Table 4). BNP and cTns were not significantly associated with the diagnosis of ischemic AHF.

Table 4. Possible Independent Factors for the Diagnosis of Ischemic AHF According to Multivariable Regression Analysis

VariableOR (95% CI)P Value*
Male sex3.7 (1.8–7.7)<0.001
Hypertension5.3 (2.1–13.3)<0.001
LV ejection fraction0.96 (0.94–0.99)0.007

OR indicates odds ratio.

*Only variables with P<0.05 are shown.

Secular Trend

In a logistic regression model for the likelihood of a diagnosis of ischemic AHF as a function of a specific blood marker, the time trend itself was negative, because the relative frequency of the diagnosis of ischemic AHF had decreased from the first to the second period of measurements (ie, from 66%–52%). However, there was no significant time trend concerning the diagnostic performance of the biomarkers (see the Online Only Data Supplement).

Validation Cohort

The validation cohort consisted of 326 consecutive AHF patients, of whom 192 (59%) experienced ischemic AHF and 134 (41%) experienced nonischemic AHF (Table 1). Analysis regarding the quantification of hemodynamic cardiac stress and myocardial damage in ischemic and nonischemic AHF showed similar results: NT-pro-BNP, cTnT, and s-cTnI were significantly higher in patients with ischemic AHF than in patients with nonischemic AHF (see Online Only Data Supplement Table 2). However, as for the derivation cohort, the diagnostic accuracy of NT-pro-BNP, cTnT, and s-cTnI at presentation for the diagnosis of ischemic AHF, as quantified by area under the ROC curve, was low (Table 3). In multivariable analysis, BNP and cTns were also not significantly associated with the diagnosis of ischemic AHF. These findings confirm the results in the derivation cohort.

Discussion

This prospective study quantified hemodynamic cardiac stress and cardiomyocyte damage in patients with ischemic versus nonischemic AHF. The major findings derived from 718 patients and validated in an independent cohort of 326 patients will be described.

First, BNP and NT-pro-BNP, as markers of hemodynamic cardiac stress, were significantly higher in patients with ischemic AHF compared with nonischemic AHF. Second, cTns, as markers of cardiomyocyte damage, were significantly higher in patients with ischemic AHF compared with nonischemic AHF. Third, natriuretic peptides, cTns, and the combination of BNP and cTns had only a low accuracy in the diagnosis of ischemic compared with nonischemic AHF at presentation. Fourth, the lack of early diagnostic usefulness of the biomarker approach was confirmed in multivariable analysis. Fifth, these findings were confirmed in the validation cohort from the FINN-AKVA study.16,17

Our results are of major clinical importance and extend previous observations. The rapid and accurate identification of AHF etiology in patients presenting to the ED is of major importance, considering that >80% of those treated for AHF are ultimately admitted to the hospital and that the ED serves as the principal portal of entry for hospitalized AHF patients.19 In particular, early differentiation of ischemic from nonischemic AHF could optimize targeting specific diagnostic and therapeutic strategies already in the ED. Individualized treatment could include early revascularization in patients identified as having ischemic AHF and possibly the avoidance of specific medical therapies with deleterious effects (eg, inotropic agents).3 However, diagnosis and treatment of AHF in the ED remains a clinical challenge and, in particular, the assessment of etiology of AHF via medical history, clinical examination, and even echocardiography alone is often insufficient. In fact, it requires complex decision-making skills to achieve rapid diagnosis and treatment and decrease mortality, length of stay, and costs.20 Although specific guidelines exist for patients with AMI complicated by AHF,21 assessment of CAD in the setting of AHF is particularly not well defined.22 One possible way to manage patients with underlying CAD admitted for AHF with cTn release is according to AMI guidelines; this important topic has not been adequately addressed by prospective studies. We hypothesized that a multimarker strategy with natriuretic peptides and cTns to differentiate ischemic from nonischemic AHF patients at presentation to the ED could be an easy and rapid approach considering that natriuretic peptides (BNP or NT-pro-BNP) and cTns already belong to the initial diagnostic evaluation of AHF patients in many centers and that both biomarkers seem to be released by myocardial ischemia. The independent pathophysiological pathways involved in the release of natriuretic peptides and cTns suggested that the combination of these 2 markers may perform better than either marker alone.

Natriuretic peptides are quantitative markers of hemodynamic cardiac stress because they are released by the cardiac ventricles in response to increased pressure and volume.5 In addition, recent data suggest that LV end-diastolic wall stress and wall stiffness may be the predominate triggers of BNP release.23,24 Ischemia can cause transient LV systolic and diastolic dysfunction. Therefore, we speculated that individuals who develop ischemia also could develop increased LV end-diastolic wall tension, thereby triggering the release of BNP. In addition, several studies demonstrated that inducible myocardial ischemia per se (ie, independent of a deterioration of LV function and cardiac stress) is a stimulus for the release of natriuretic peptides.79 However, there is also evidence that patients with nonischemic HF experience small asymptomatic ischemic events during disease progression,25 suggesting that natriuretic peptide levels also could be elevated in this group of patients and are at least as important in the nonischemic as in the ischemic group.

CTns are the most sensitive and specific biomarker of cardiomyocyte damage and, by guideline, the marker of choice for the diagnosis of AMI.14 Furthermore, elevated concentrations of cTns are frequently seen in patients with AHF.10,17 Multiple factors seem to activate mechanisms that result in myocardial cell death or damage in AHF. Ventricular remodeling,26 increased interstitial fibrosis,27 impaired coronary flow reserve,28 and increased wall stress contribute to myocyte degeneration and death. Thus, elevated cTns may be related to ongoing myocardial damage, which has been implicated as 1 of the mechanisms responsible for progression of cardiac failure.25 Consequently, previous studies showed that cTns are also elevated in nonischemic AHF,29 suggesting an essential role in this patient group. Elevated cTn concentrations may be the result of small asymptomatic ischemic events, possibly also occurring in nonischemic AHF.

Despite these sound pathophysiological considerations, our findings did not suggest clinical utility for either natriuretic peptides or cTns in the early detection of ischemic versus nonischemic AHF. Consequently, other strategies for the early identification of ischemic AHF patients in the ED are warranted. Different biomarkers could possibly succeed in identifying ischemic AHF patients, but no other marker, in particular no ideal “ischemia marker,” has been introduced. Furthermore, cardiac imaging has been substantially advancing and becoming indispensable for various cardiovascular diseases in recent years. It could become a promising tool, especially in the first 24 to 48 hours, for differentiation of AHF etiology. Cardiac magnetic resonance and MPI have been extensively assessed for detecting myocardial tissue abnormalities, such as ischemia, infarction, or scars, especially in patients with CAD or acute coronary syndrome.30,31 However, in AHF, these imaging techniques are mainly performed in stable patients later during their hospitalization and are often restricted in use because of higher costs and limited reimbursement. In addition, the utility of these imaging tools has only sparely been validated in AHF patients in the acute-care setting. Consequently, prospective studies for early cardiac imaging in the setting of AHF are urgently needed.

Study Limitations

Several limitations of the study merit consideration. First, we cannot comment on the role of BNPs and cTns among patients with terminal renal failure because these patients were excluded from our study. Second, despite our extensive efforts to adjudicate the presence or absence of myocardial ischemia in these AHF patients, we might have misclassified some of them. We acknowledge that the classification of ischemic AHF can be difficult because patients with stable CAD could experience AHF not due to ischemic events and related, for example, to hypertensive crisis or tachyarrhythmia. On the other hand, MPI, the imaging modality also used in several patients in this cohort, has a high sensitivity for the detection of high-grade coronary lesions.13 Still, the sensitivity of MPI is not 100%. Coronary angiography, although the gold standard for assessing the severity of CAD and diameter stenosis, does not directly assess the presence or absence of myocardial ischemia. Furthermore, we regarded patients with a documented history of CAD as ischemic AHF, although coronary angiography or MPI was not performed or results were not accessible in all patients with CAD. However, because the prevalence of ischemic AHF was similar to those observed in large registry studies (eg, ADHERE, Euro-HF, and OPTIMIZE-HF),32 we consider our results representative.

Conclusion

At presentation to the ED, patients with ischemic AHF exhibit more extensive hemodynamic cardiac stress and cardiomyocyte damage than patients with nonischemic AHF. However, the overlap is substantial, resulting in poor diagnostic accuracy.

Acknowledgments

We are indebted to the patients who participated in the study, the ED staff, and the laboratory technicians for their most valuable efforts; and Dr Kris Denhaerynck for expert statistical advice.

This article is dedicated to the memory of my father, Dr Helmut Drexler.

Sources of Funding

This study was supported by research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, Abbott, Brahms, and the Department of Internal Medicine, University Hospital Basel.

Disclosures

C.M. has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, Abbott, Biosite, Brahms, Nanosphere, Roche, Siemens, and the Department of Internal Medicine, University Hospital Basel; and speaker honoraria from Abbott, Biosite, Brahms, Roche, and Siemens. T.B. has received research grants from the University of Basel and the Department of Internal Medicine, University Hospital Basel, and the Swiss National Science Foundation. T.R. has received research grants from the University of Basel and the Department of Internal Medicine, University Hospital Basel; and speaker honoraria from Abbott, Brahms, and Roche. C.M. was supported by a grant from the Freie Akademische Gesellschaft Basel. All other authors declare that they have no conflict of interest.

Footnotes

The online-only Data Supplement is available with this article at http://circheartfailure.ahajournals.org/lookup/suppl/doi:10.1161/CIRCHEARTFAILURE.111.961243/-/DC1.

Correspondence to Christian Mueller, MD, FESC,
Department of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
. E-mail

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Clinical Perspective

The early and noninvasive differentiation of ischemic and nonischemic acute heart failure (AHF) in the emergency department (ED) is an unmet clinical need. In fact, it is particularly of exigent clinical importance to identify patients with ischemic AHF because treatment benefit seems to depend on AHF etiology and patients with ischemic AHF seem to respond differently to therapies. Because pharmacological and invasive treatment for acute and chronic coronary artery disease, the underlying cause of ischemic AHF, has markedly improved throughout the past decades, but we have not made the same progress in the management and treatment of AHF in the acute-care setting; new strategies are warranted to better characterize AHF already in the ED. In this respect, we hypothesized that 2 distinctly different pathophysiological mechanisms might allow the differentiation of ischemic from nonischemic AHF: hemodynamic cardiac stress was quantified using B-type natriuretic peptide (BNP), and cardiomyocyte damage was quantified using cardiac troponin (cTn). In 718 patients presenting to the ED with AHF and in a second independent multicenter cohort (326 AHF patients), we prospectively tested for BNP and 2 different cTn assays (troponin T and sensitive troponin I). The diagnosis of ischemic AHF was adjudicated using all information, including coronary angiography and myocardial perfusion imaging. Despite significantly higher BNP and cTn levels in patients with ischemic AHF versus nonischemic AHF, suggesting that patients with ischemic AHF exhibit more hemodynamic cardiac stress and cardiomyocyte damage, the diagnostic accuracy of these markers was low and failed to demonstrate early diagnostic usefulness.