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European Journal of Heart Failure 2003 5(6):811-819; doi:10.1016/S1388-9842(03)00159-4
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© 2003 European Society of Cardiology

Congestive heart failure with preserved left ventricular systolic function after acute myocardial infarction: clinical and prognostic implications

Jacob Eifer Møllera,*, Bente Brendorpb, Michael Ottesenb, Lars Køberc, Kenneth Egstrupd, Steen Hvitfelt Poulsene and Christian Torp-Pedersenb

a Department of Cardiology, Odense University Hospital Odense, Denmark
b Department of Cardiology, Gentofte Univerity Hospital Denmark
c Department of Cardiology Rigshospitalet, Copenhagen, Denmark
d Department of Medicine, Svendborg Hospital Denmark
e Department of Cardiology, Skejby University Hospital Denmark

* Corresponding author. Tel.: +45-6611-3333 E-mail address: jem{at}dadlnet.dk


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Aims: To characterise the prevalence, in-hospital complications, management, and long-term outcome of patients with congestive heart failure but preserved left ventricular systolic function after acute myocardial infarction.

Methods: 3166 consecutive patients screened for entry in the Bucindolol Evaluation in Acute Myocardial Infarction Trial with definite acute myocardial infarction and echocardiographic assessment of left ventricular systolic function were included between 1998 and 1999 in this prospective observational study. Main outcome measures were occurrences of in-hospital complications and all cause mortality.

Results: Congestive heart failure was seen during hospitalisation in 1464 patients (46%), 717 patients had preserved left ventricular systolic function (wall motion index ≥1.3 corresponding to ejection fraction ≥0.40), and 732 patients had systolic dysfunction (wall motion index <1.3). One year mortality in patients with no heart failure, heart failure with preserved systolic function, and heart failure with systolic dysfunction were 6, 22 and 35%, P<0.0001. Unadjusted risk of death from all causes associated with heart failure and preserved systolic function was 3.3 (95% CI 2.8–4.0), and after adjustment for baseline characteristics and left ventricular systolic function in multivariate Cox proportional hazards analysis the risk was 2.1 (95% CI 1.7–2.6), P<0.0001.

Conclusions: Congestive heart failure is frequently present in patients with preserved left ventricular systolic function, and is associated with increased risk of in-hospital complications and death following acute myocardial infarction.

Key Words: Left ventricular systolic function • Acute myocardial infarction • Congestive heart failure

Received March 5, 2003; Revised April 24, 2003; Accepted July 17, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Patients with congestive heart failure due to left ventricular systolic dysfunction following acute myocardial infarction are at increased risk of progressive left ventricular failure, arrhythmic complications and death, even if the symptoms of heart failure resolves rapidly [1]. Although the development of chronic heart failure often is a result of loss of contractile function and ventricular dilation, heart failure may frequently be seen among patients with preserved or only mildly impaired systolic function [2,3]. The mechanisms involved in the development of heart failure in these patients is not well characterised although activation of cardiac peptides [4] and the renin angiotensin system [5] has been suggested to contribute to the pathogenesis. In 40–50% of patients acute myocardial infarction is complicated by transient or persistent congestive heart failure [1,6]. Some of these patients would be expected to have preserved systolic function [1]. The prevalence, clinical characteristics and long-term outcome of these patients with congestive heart failure and preserved left ventricular systolic function are not well characterised. This understanding is, however, of great importance for proper management of these patients and for design of future interventional trials to improve their outcome.

The present study, therefore, assesses the prevalence, clinical characteristic, in-hospital complications, treatment and long-term prognosis of patients with evidence of congestive heart failure despite preserved left ventricular systolic function among a large consecutive population suffering an acute myocardial infarction between 1998 and 1999.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
During May 1998 to June 1999, 3326 consecutive patients admitted alive with acute myocardial infarction to 33 Danish hospitals were screened for entry in the Bucindolol Evaluation in Acute Myocardial Infarction Trial [7]. Assessment of left ventricular function was available in 3166 patients (95%). These patients were enrolled in the present study.

The diagnosis of AMI was based on presence of typical clinical symptoms and/or electrocardiographic signs of AMI, and a documented elevation of cardiac enzymes (creatine kinase and creatine kinase MB) to at least twice the upper limit of the laboratory of the participating hospital. On each patient demographic data, medical history, in-hospital complications and electrocardiographic interpretation were recorded. Killip class, and in-hospital complications were recorded for different time periods (from hospital admission to reperfusion therapy or during the initial 24 h in hospital/day 2–4/day 5 to discharge). Killip class I was considered in patients with no signs of heart failure. Killip class II in patients with basilary rales. Killip class III in patients with pulmonary oedema and class IV in patients with cardiogenic shock. For this study congestive heart failure was considered in any patient with Killip class ≥II transient or persistent during hospitalisation or a history of congestive heart failure treated with a diuretic agent on admission.

Left ventricular systolic function was assessed by two-dimensional echocardiography within 6 days of infarction. All examinations were videotaped and sent by courier to the central office for blinded analysis. From the parasternal long axis view, multiple short axis views, and apical 2-, 4-, and long axis views wall motion index was assessed. The left ventricle was divided in to 16 segments, and each segment was assigned a score based on myocardial thickening and endocardial excursion (3=hyperkinesis, 2=normokinesis, 1=hypokinesis, 0=akinesis and –1=paradoxical motion). Wall motion index was calculated by dividing the sum of scores by the number of segments analysed. Using this reverse scoring system, a simple transformation from wall motion index to left ventricular ejection fraction may be done by multiplying the wall motion index by 0.30 as described by Berning et al. [8].

We considered patients with wall motion index ≥1.3 corresponding to ejection fraction ≥0.40 to have preserved left ventricular systolic function.

The study was approved by the regional scientific ethical committee of all participating hospitals and by the Danish Data Protection Agency.

2.1. Mortality
Survival information of the population was obtained through the Danish Central Personnel Register where all deaths in the country are recorded within 2 weeks. No patient was lost to follow-up.

2.2. Statistical analysis
Continuous data are expressed as medians with interquartile ranges, and rank sum test were used for comparisons. Categorical variables were compared with the chi-square test.

Mortality was calculated as the product limit method, and was plotted according to the Kaplan–Meier method. Comparisons of death rates between subgroups were tested with the log–rank test. To assess the effect of congestive heart failure on mortality after adjustment of various covariates multivariate Cox proportional Hazards analysis was performed. This was also done for patients with no heart failure, heart failure and preserved systolic function, and heart failure and systolic dysfunction separately. The assumptions of the proportional hazard model (proportional hazards, linearity of continuous parameters and lack of interactions) were tested and were valid unless otherwise specified. A P value of less than 0.05 was considered significant. SPSS version 10.0 (SPSS Inc. Chicago, Illinois) was used for calculations.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
Clinical and demographic characteristics of 3166 patients enrolled in this study are shown in Table 1. In total 1464 patients (46%) met the criteria of congestive heart failure. During the initial 24 h of hospitalisation, 1136 patients (36%) showed signs and symptoms of heart failure (Killip class≥II) or were in treatment for heart failure, and furthermore, 313 patients (10%) developed clinical heart failure during the remaining hospitalisation. Among 2133 patients with preserved left ventricular systolic function (wall motion index ≥1.3 corresponding to ejection fraction ≥0.40) heart failure was seen in 717 patients (34%) (Fig. 1). Among 1033 patients with left ventricular systolic dysfunction 732 patients (71%) had symptomatic heart failure (Fig. 1). Heart failure was seen despite normal regional systolic function (wall motion score index ≥2.0) in 167 patients (Fig. 1). Compared to patients with systolic dysfunction, patients with heart failure and preserved systolic function were characterised by higher prevalence of hypertension, lover prevalence of previous myocardial infarction, lower peak creatine kinase MB, lower prevalence of anterior myocardial infarction and bundle branch block, but higher prevalence of inferior myocardial infarction, Table 1.


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  		Table 1 Clinical characteristics according to evidence of heart failure and left ventricular systolic function

 


Figure 1
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  		Fig. 1 Occurrence of congestive heart failure according to degree of left ventricular systolic dysfunction.

 
During hospitalisation, patients with heart failure and preserved systolic function has significantly increased occurrence of ischemic complications, atrial fibrillation and ventricular tachycardia compared to patients free of heart failure (Table 2).


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  		Table 2 In hospital complications at discharge according to presence of heart failure and left ventricular systolic function

 
3.1. Management of acute myocardial infarction
Thrombolytic therapy was used in 1130 patients (36%), and 99 patients (3%) were treated with primary angioplasty. Patients with no heart failure were more often treated with thrombolytic therapy than patients with heart failure (Table 1). Low molecular or unfractionated heparin was used in 1445 patients (46%), aspirin in 2873 (91%), and nitrates in 2610 patients (82%), all were evenly distributed between patients with and without heart failure. During hospitalisation, angioplasty was performed in 135 patients (4%) and coronary bypass surgery in 52 patients (2%). Medication on hospital discharge is shown in Table 3.


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  		Table 3 Medical treatment on discharge in 3014 hospital survivors

 
3.2. All cause mortality
During follow-up of median 34 months, range 0–49 months, 853 patients died. In the whole population 1- and 3-year mortality rates (95% confidence interval) were 17% (15–18%)/28% (26–30%). The unadjusted 1- and 3-year mortality rates were significantly increased in patients with heart failure without left ventricular systolic dysfunction (22/37%) and with systolic dysfunction (35/53%) compared with patients without heart failure (6/13%), P<0.00001 (Figs. 2 and 3). Unadjusted risk ratio associated with heart failure and preserved systolic function was 3.3 (95% CI 2.8–4.0), P<0.0001. After adjustment for co-morbidity and well known risk factors in a multivariate Cox regression analysis congestive heart failure and preserved left ventricular systolic function was associated with a risk ratio of 2.10 (95% CI 1.74–2.55), P<0.0001 compared with patients with no heart failure. The importance of management, wall motion index, and co-morbidity on survival in the three groups are presented in Table 4. Wall motion index and use of an angiotensin converting enzyme (ACE) inhibitor on discharge was less important in patients with congestive heart failure and preserved systolic function than the other groups (Table 4).


Figure 2
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  		Fig. 2 Kaplan–Meier analysis of the probability of survival among 3166 patients with a recent acute myocardial infarction divided according to no in-hospital heart failure (No CHF), heart failure and preserved left ventricular systolic function (CHF+WMI>1.3) and heart failure and left ventricular systolic dysfunction (CHF+WMI<1.3). *P<0.00001 by log rank test for comparison of No CHF with CHF+WMI>1.3. {dagger}P<0.00001 by log rank test for comparison of CHF+WMI>1.3 and CHF+WMI<1.3.

 


Figure 3
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  		Fig. 3 Kaplan–Meier analysis of the probability of survival among 3166 patients with a recent acute myocardial infarction divided according to no in-hospital heart failure (No CHF), heart failure and preserved left ventricular systolic function (CHF+WMI>1.3), and heart failure and left ventricular systolic dysfunction (CHF+WMI<1.3), and stratified according to age. *P<0.00001 by log rank test for comparison of No CHF with CHF+WMI>1.3. {dagger}P<0.00001 by log rank test for comparison of CHF+WMI>1.3 and CHF+WMI<1.3.

 


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  		Table 4 Multivariate Cox proportional hazards analysis for predictors of all cause mortality

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The present study demonstrates in a large population with definite myocardial infarction that the overall mortality remains high. Heart failure is frequently complicating myocardial infarction and approximately half of patients with clinical heart failure have preserved left ventricular systolic function. Even though systolic function is preserved, these patients are at increased risk of in-hospital complications and death during follow-up.

4.1. Heart failure with preserved systolic function after myocardial infarction
The progression of cardiovascular disease can be regarded as a continuum of events [9]. According to this concept the presence of risk factors such as hypertension, diabetes and dyslipidemeia predisposes to the development of atherosclerosis and left ventricular hypertrophy. This eventually leads to overt coronary artery disease and cardiac failure. In the present study we found patients with preserved systolic function and heart failure were more likely to have a history of hypertension and diabetes as well as many atherosclerotic manifestation compared to patients that did not develop heart failure. One could speculate that these patients, due to increased risk burden, poorly tolerate an acute loss of even relatively small amounts of cardiac muscle. Recent studies have suggested that elevated left ventricular end-diastolic pressure [10] increased release of cardiac peptides [4] and activation of the renin angiotensin system [5] is involved in the pathogenesis of diastolic heart failure. After myocardial infarction less is known of the pathogenesis of heart failure when occurring in patients with preserved systolic function. However, Doppler echocardiographic signs of elevated filling pressures are frequently present in these patients and are of prognostic importance [11,12]. Also, in a recent study Otterstad et al. [13] demonstrated in a large population with myocardial infarction and preserved systolic function (ejection fraction >0.40) that an increased release of cardiac peptides was a powerful predictor of cardiac death. Thus, it appears that diastolic left ventricular dysfunction with elevation of filling pressures and compensatory neurohormonal activation also is involved in the development of heart failure in these patients. As elevated filling pressures and increased release of cardiac peptides are important predictors of outcome after myocardial infarction [14,15], this could help explain the increased mortality in these patients.

The acute phase medical management of acute myocardial infarction was not different in patients with heart failure and either preserved or depressed systolic function. This was not the case at hospital discharge. In theory the activation of the renin angiotensin system, as well as the high prevalence of hypertension and diabetes in these patients suggest that this population could benefit from treatment with an angiotensin converting enzyme (ACE) inhibitor. This is also supported by the Acute Infarction Ramipril Efficacy (AIRE) study [16], where the ACE inhibitor ramipril proved to reduce all cause mortality by 27% in patients with heart failure after acute myocardial infarction. Assessment of left ventricular function was not mandatory in the AIRE study, but subgroup analysis of more than 500 patients showed a high prevalence of preserved systolic function [17]. Although it also seems likely that also patients with preserved systolic function did benefit from ramipril in the AIRE study, the study was not designed to assess the importance of treatment in these subgroups. The present study did not demonstrate any effect on survival of an ACE inhibitor in patients with preserved systolic function and heart failure, which was in contrast to patients with systolic dysfunction. As the study was observational and not randomised this could possibly reflect ACE inhibitors were more likely used in patients with highest risk profiles. However, the data emphasise the importance of randomised trials in this large patient population to determine the optimal management.

The present study demonstrates a high prevalence of angina pectoris and ischemic in-hospital complications in patients with heart failure and preserved systolic function. Aggressive treatment of ongoing myocardial ischemia would seem important in these patients. Given this, it would seem likely that a medical approach including beta adrenergic blockade would be beneficial, which also was suggested by the multivariate analyses.

4.2. All cause mortality
The present results show that the mortality after acute myocardial infarction remains very high. This is important when introducing results from large scale randomised trials to daily clinical practice. Recent large-scale randomised trials aiming on recruiting high-risk patients after myocardial infarction have enrolled populations with 1-year mortality rates of approximately 10% [18,19]. We found in this unselected population that the 1-year mortality rate of similar high-risk patients was at least three times higher (approx. 30%), indicating that even in clinical trials aiming to enrol high-risk patients the true high-risk patients are excluded. Even though in many cases it seems likely that these true high-risk patients will have the same or even greater benefit as patients enrolled in clinical trials it remains speculative in many cases. This emphasises the importance of enrolling true high-risk patients in clinical trials.

4.3. Limitations
The diagnosis of heart failure based on any criteria is prone to misclassification. Indeed, previous studies of patients suspected of diastolic heart failure have shown in many cases that dyspnea could be explained by other factors such as obesity and chronic obstructive pulmonary disease [20]. This may also have been the case for some patients in the present study. Obstructive pulmonary disease was seen more often among patients with heart failure than patients without heart failure. However, 85% of patients with heart failure and preserved systolic function did not have any history of pulmonary diseases, suggesting misclassification was not a major problem. Another possible explanation for the occurrence of heart failure in these patients could be transient ischemic left ventricular systolic dysfunction that may have resolved at the time of echocardiography. This is, however, contradicted by a recent study of patients presenting with pulmonary oedema and preserved systolic function where transient systolic dysfunction could not be identified [21].


   5. Conclusion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In summary, the present large observational study shows that the overall mortality after myocardial infarction remains high. Furthermore, evidence of heart failure is also frequently present in patients with preserved left ventricular systolic function. In these patients, it is associated with considerably increased risk of in-hospital complications and death. As no large randomised controlled trials specifically have been completed in these patients the optimal management of this large population is not known.


   Acknowledgements
 
This work was supported by a grant from Knoll A/G.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
{star} This article is for the Bucindolol Evaluation in Acute Myocardial Infarction Trial Group.


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

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