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European Journal of Heart Failure 2007 9(12):1196-1204; doi:10.1016/j.ejheart.2007.10.001
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© 2007 European Society of Cardiology

Improvement but no cure of left ventricular systolic dysfunction in treated heart failure patients

Niamh F. Murphy, Christina O'Loughlin, Mark Ledwidge, Dermot McCaffrey and Kenneth McDonald*

Heart Failure Unit, Department of Cardiology, St Vincent's University Hospital, and University College Dublin Dublin 4, Ireland

* Corresponding author. Department of Cardiology, St Vincent's University Hospital Elm Park, Dublin 4, Ireland. Tel.: +353 1 2845735; fax: +353 1 2304639. kenneth.mcdonald{at}ucd.ie (K. McDonald).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Recent advances in pharmacological and pacemaker-based treatments for heart failure (HF) have brought about significant improvements in left ventricular function.

Aims: To identify the proportion of treated systolic HF patients in whom left ventricular systolic function improves and/or returns to normal.

Methods: This was a retrospective analysis of 221 HF patients. Improvement in left ventricular function was defined as an improvement in ejection fraction (LVEF) of ≥10% on echocardiography. Return to normal was defined as an improvement of LVEF to ≥50% and a reduction in left ventricular end diastolic diameter to ≤55 mm. Changes in BNP were also recorded.

Results: Improvement in LVEF was observed in 44.3% of patients and return to normal systolic function in 10.9%, only 2.3% had both a return to normal echocardiographic parameters and a BNP<100 pg/ml. A higher percentage of the improved group were on target doses of β-blockers (p=0.004). Baseline BNP was not a predictor of improvement. There was a trend towards a reduction in HF readmissions in the improved group (p=0.07) but no difference in the risk of death or all-cause readmission.

Conclusion: While a substantial proportion of treated HF patients have an improvement in left ventricular function over time, only a small proportion return to normal dimensions and LVEF, underlining the permanent nature of ventricular damage in the vast majority of patients.

Key Words: Heart failure • Left ventricular function • Echocardiography • B-type natriuretic peptide • Improvement • Return to normal

Received August 30, 2007; Accepted October 3, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Many recent treatments for heart failure, both pharmacological and pacemaker-based, have brought about significant improvements in left ventricular systolic function [1-4]. Specifically, disease modifying treatments such as β-blockers [1-3,5-13], aldosterone receptor blockers [14,15], ACE inhibitors [16], angiotensin receptor blockers [17] as well as cardiac resynchronisation therapy [18] and revascularization [19] have been shown to lead to an improvement in left ventricular systolic function. Previously, the only expectation of a return to normal left ventricular function was in patients with alcohol related cardiomyopathy [20-22], viral myocarditis [23] and post-partum cardiomyopathy [24]. Now with the advent of new therapies for heart failure it is reasonable to anticipate significant improvement in left ventricular systolic dysfunction and return to normal ventricular dimensions. As a result, terms such as "remission" or even "cure" may become increasingly used in the context of heart failure. However, the frequency of such structural and functional improvements in a community population remains unknown. A clear understanding of this would allow more accurate discussion of prognosis with heart failure patients, as well as planning of possible therapy withdrawal strategies in patients that demonstrate return to normal function. Therefore, to address this issue we looked at the proportion of treated heart failure patients with left ventricular systolic dysfunction in whom significant improvements in left ventricular structure and function were observed during follow-up in a disease management programme.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study design
This is a retrospective report looking at improvement in left ventricular size and systolic function in survivors of a heart failure admission, who were followed in a disease management programme between November 1999 and August 2005. Details of the disease management programme have been described previously [25,26]. In short, all emergency class IV heart failure admissions were invited to enrol in the disease management programme following stabilisation of their condition. Heart failure was defined by history and examination compatible with heart failure, pulmonary oedema on CXR, elevated BNP and echocardiographic evidence of systolic and/or diastolic dysfunction. Patients with a previous heart failure admission as well as those presenting with heart failure for the first time were included. Patients were excluded if heart failure was not thought to be the primary diagnosis, if resident in a nursing home or where prognosis was compromised. Only those patients with left ventricular systolic dysfunction at baseline, defined as a left ventricular ejection fraction (LVEF)<45%, were included in this study.

Heart failure was categorised as ischaemic if there was history of prior myocardial infarction or angina with documented evidence of ischaemia or significant coronary artery disease on angiography. Hypertensive heart failure was defined when there was a longstanding history of hypertension or if there was sustained hypertension during the hospital admission with no evidence of coronary artery disease or other cardiac pathology. A valvular aetiology was defined in the presence of at least moderate aortic and/or mitral valve disease observed at echocardiography. An alcohol-related aetiology was assumed in patients with a longstanding history of heavy alcohol consumption with no other evident aetiology. Patients with no obvious precipitating factors were categorised as idiopathic and those with a preceding prodromal viral illness were categorised as viral myocarditis with subsequent viral cardiomyopathy. Health Related Quality of Life was assessed using the Minnesota Living with Heart Failure questionnaire in a subgroup of 106 patients [27,28]. B-Type Natriuretic Peptide was measured using the Biosite Triage test.

2.2. Echocardiography
Patients had echocardiograms performed during their index hospital stay, at 3 months, following β-blocker uptitration and at yearly intervals. The first available (baseline) which was usually during index hospital stay and last available echocardiograms were compared. LVEF was calculated using the Simpson's method. In a small number of cases (n=4) with poor views or image quality LVEF was visually estimated. Left ventricular end-diastolic (LVEDd), end-systolic (LVESd) internal dimension and left atrial size were measured using standard techniques. Mitral regurgitation was quantified as mild, moderate or severe by Doppler analysis. Patients with less than 30 days between their first and last echocardiogram were excluded. For the purpose of the analysis the patients were divided into two groups; those with an improvement of ≥10% in LVEF and those without a ≥10% improvement. Patients who improved were further divided into 2 groups; those with and those without a ‘full’ return to normal left ventricular systolic function and size. Return to normal was defined as an improvement in LVEF to ≥50% and a reduction in LVEDd to ≤55 mm.

2.3. Clinical outcomes
We compared clinical outcomes in those patients with and without an improvement in left ventricular ejection fraction. The following clinical outcomes were examined: death from any cause, heart failure readmission, all-cause readmission and unscheduled outpatient visit. Heart failure emergency admissions were defined as requiring at least one night in-hospital stay and were confirmed or refuted by a cardiologist based on the presence of the following four criteria: history and examination compatible with heart failure, chest X-ray appearance of congestion, echocardiography evidenced left ventricular systolic and/or diastolic dysfunction and response to initial therapy. All-cause admissions are defined as any non-elective emergency hospital admission including heart failure admissions. The requirement for revascularisation procedures, cardiac resynchronisation therapy and cardiac defibrillators during the follow-up period was also noted.

2.4. Statistical analysis
Data are presented as the mean±the standard deviation (SD) for continuous variables and frequencies with percentages in parentheses for categorical variables. Continuous variables were compared using paired sampled t-tests and categorical variables were compared using Chi square tests (two-sided, {alpha}=0.05). BNP, sodium, urea and creatinine were not normally distributed and therefore were log transformed. BNP was only available for 171 patients at follow-up. NYHA at baseline was dichotomised into NYHA functional class III and NYHA functional classes II and I. Univariable and multivariable analyses were conducted using binary logistic regression using improvement of EF ≥10% versus no improvement as the outcome measures. The multivariable model included theoretically reasonable baseline variables and those with univariable p-values of ≤0.25 [29]. Proportional hazards statistical models were computed to identify whether those patients with an improvement versus no improvement had similar morbidity (time to heart failure readmission, all-cause readmission) and mortality (all-cause death); covariate adjusted survival curves were also estimated. Time to event was calculated from the date of discharge from index heart failure admission. Patients were censored at the last known contact with the clinic or at the last recorded event. All analyses were carried out using SPSS Version 11 statistical software (Statistical Package for the Social Sciences: SPSS Inc., Chicago, Illinois, 2001).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Demographics on complete population
Five hundred and thirty six patients admitted with class IV heart failure were subsequently followed in a heart failure disease management programme. Two hundred and twenty-one patients with left ventricular systolic dysfunction on baseline echocardiogram, and with serial follow-up echocardiograms, were included in the current analysis. The mean follow-up time was 29.7±19.9 months. Baseline characteristics and baseline medications at discharge are shown in Table 1. Sixty-two percent of patients had ischaemic aetiology and in 76% this was the first heart failure admission. The mean LVEF of the baseline echocardiogram was 30±8% (range 11-44%). LVEF increased to an average of 39±14% (range 10-79%) at last follow-up (p<0.001). Although there was no significant decrease in the LVEDd (63.6±11.0 mm to 62.2±10.6 mm; p=0.132) there was a significant reduction in the LVESd from 54.6±9.8 mm at baseline to 49.2±13.2 mm (p<0.001) at follow up. The mean time between the two echocardiograms was 20.9±18.3 months.


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  		Table 1 Baseline characteristics of 221 patients with heart failure and left ventricular dysfunction

 
3.2. Improvement in LVEF group
Ninety eight patients (44.3%) had an improvement in LVEF of ≥10% and 10 patients (4.5%) had a >10% deterioration in LVEF. In the group with an improvement in LVEF there was a mean increase in LVEF of 22±10%, a mean reduction in LVESd of 9.5±9.1 mm and a mean reduction in LVEDd of 3.7±10.6 mm (Table 2). There was no difference between the improvement and no improvement groups in left atrial size (42.1±1.9 mm versus 44.4±1.3 mm respectively; p=0.29) or the proportion of patients with moderate or severe mitral regurgitation (29.6% versus 19.5% reduction respectively; p=0.11). 56.1% of those patients with a ≥10% improvement in LVEF had an echocardiogram performed an average of 3.7±1.2 months post-discharge. Of these patients 67.3% had an improvement in EF of >10% on this early post-discharge echocardiogram.


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  		Table 2 Change in echo parameters between baseline and last echocardiogram

 
Patients with an improvement in left ventricular function were less likely to have an ischaemic aetiology (p<0.001) and more likely to have an alcohol-related aetiology (p=0.04) (Table 1). They were also less likely to have other co-morbidities such as COPD or asthma (p=0.04). Patients with an improvement in left ventricular function had a lower baseline creatinine (p=0.01). There was no difference in baseline BNP between the groups. There was no difference in revascularisation procedures between the groups (17.1% in improvement group versus 15.3% in no improvement group; p=0.72). As anticipated there were less cardiac defibrillators in those with an improvement in LVEF (3.1% versus 13.0%; p=0.02) and more cardiac resynchronisation therapy in the group with persistent impaired left ventricular function (1.0% versus 4.9%; p=0.059).

In multivariable analysis after controlling for age and sex, patients with an ischaemic aetiology (OR: 0.378, 95% CI: 0.205, 0.694) and higher creatinine (OR: 0.990, 95% CI: 0.982, 0.999) were less likely to have an improvement in left ventricular function. Patients with worse NYHA class (OR 7.632, 95%CI: 2.657, 21.927) were more likely to have an improvement. We also noted the presence of cancer (OR: 3.446, 95%CI: 1.212, 9.797) was associated with an improvement. Baseline BNP was not a significant predictor of an improvement in left ventricular function.

Patients with an improvement in left ventricular function were more likely to be on the clinical target dose of β-blockers (p=0.004) at their last visit compared to those with no improvement in LVEF (Table 3). Patients whose left ventricular function improved were less likely to be on an aldosterone receptor blocker (p=0.057). There was no difference between the groups in the proportion of patients on triple therapy (β-blockers and ACE inhibitors or angiotensin receptor blocker and aldosterone receptor blocker) and there was no difference in aspirin or statin prescribing between the groups.


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  		Table 3 Number and proportion of individuals in the improvement group and no improvement group prescribed ACE inhibitors, angiotensin receptor blockers and β-blockers at last visit and percent of individuals achieving clinical trial dose

 
3.3. Return to normal left ventricular size and function
In the improved group, 24 patients (10.9% of total group) demonstrated return to normal left ventricular dimensions and function. This subgroup showed significant improvement in LVEF (p<0.001), LVESd (p<0.001) and LVEDd (p=0.007) compared to those that improved but did not normalise (Table 2). Four patients (16.7%) had normalised their parameters on their early post-discharge echocardiogram. Those patients with a return to normal LV dimensions and function had significantly better renal function (p=0.04) (Table 4). Furthermore, there was a trend towards more female patients in those who normalised.


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  		Table 4 Baseline characteristics of all patients with an improvement in LVEF, according to whether or not they had return to normal left ventricular size and systolic function

 
3.4. Change in BNP
The mean BNP at the time of follow-up was significantly lower in patients with an improvement in left ventricular function (268.1±320.3 pg/ml; p<0.001) and in patients with a return to normal left ventricular size and function (211.3±142.2 pg/ml; p<0.001) compared to those with no improvement (580.8±775.3 pg/ml) (Table 5). The median BNP was 129 pg/ml in patients who were asymptomatic, 341 pg/ml in those who were NYHA II and 409 pg/ml in those who were NYHA III. BNP fell to less than 100 pg/ml in 32.4% of the improved group compared to 13.4% of the no improvement group (p=0.003). In the return to normal group only 22.7% (n=5) reduced their BNP to <100 pg/ml. Therefore only five patients or 2.3% of the total population had a return to normal left ventricular size and systolic function and a normalisation of BNP.


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  		Table 5 B-type natriuretic peptide (BNP) levels at baseline and at follow-up in improved and no improvement groups

 
3.5. Change in symptoms
In the return to normal group, 33.3% were asymptomatic or NYHA I, 62.5% were NYHA II and 4.2% NYHA III. Quality of life as measured by the Minnesota Living with Heart Failure questionnaire at follow-up was not significantly different between the groups (no improvement group 25.0±21.3; improvement group 23.2±22.2 (p=0.67); return to normal group 26.7±28.3 (p=0.63).

3.6. Outcome in patients with an improvement in LVEF
In patients with an improvement in LVEF there was a trend towards in a reduction in the risk of heart failure readmission (Fig. 1) compared to those with no improvement in LVEF (p=0.07). There was no difference in all-cause readmission (HR 1.32 (95% CI 0.91, 1.93) for the improved versus no improvement group; p=0.15) or death (1.27 (0.67, 2.40); p=0.46).


Figure 01
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  		Fig. 1 Age and sex adjusted Cox survival curve for heart failure readmission in patients with and without an improvement in left ventricular systolic function.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This report provides unique data on the natural history of ventricular function in patients with proven systolic dysfunction managed in a disease management programme. The data demonstrate that 44.3% of the population have a substantial improvement in left ventricular systolic function and 10.9% have a return to normal ejection fraction and left ventricular dimensions. However, only 2.3% of the total population demonstrated a return to normal left ventricular size and systolic function with normalisation of BNP. As anticipated, the group that improved had less ischaemic heart disease and better renal function at baseline. BNP at discharge from hospital was not a predictor of improvement. However, BNP at follow up was significantly lower in patients in whom left ventricular systolic function improved. Finally, this group demonstrated a trend towards a better outcome, as manifest by a reduction in heart failure readmissions.

Little is known about the proportion of heart failure patients in the general population in whom left ventricular ejection fraction returns to normal, an important observation which may influence ongoing therapy. An improvement in left ventricular function has been previously demonstrated in certain aetiologies of heart failure, all related to modifiable insults. For example, in patients with an alcohol-related cardiomyopathy, abstinence has been shown to result in a significant improvement in left ventricular ejection fraction [20-22]. In a study of 123 women with peripartum cardiomyopathy, normalisation of left ventricular ejection fraction occurred in 54% [24]. An improvement in left ventricular function has also been demonstrated in patients with idiopathic dilated cardiomyopathy who have enterovirus on endomyocardial biopsy [23].

Whilst the primary goal of neurohumoral modulating drugs in heart failure is to reduce morbidity and mortality some of the newer therapies for heart failure have been shown to improve left ventricular systolic function. β-blockers result in a significant improvement in ejection fraction in patients with systolic heart failure [1-3,5-13]. ACE inhibitors [16], angiotensin receptor blockers [17] and aldosterone receptor blockers [14,15] have also been shown to improve left ventricular function and reverse remodelling. Cardiac resynchronization therapy in patients with moderate to severe systolic heart failure and ventricular dyssynchrony increases ejection fraction and reduces ventricular size [18]. Revascularisation of viable myocardium is also associated with an improvement in ejection fraction in patients with left ventricular dysfunction after myocardial infarction [19]. Therefore, in modern day treatment of systolic heart failure, we can anticipate an improvement in left ventricular ejection fraction to an extent that terms used more commonly in other medical areas, such as remission or cure, may become accepted goals in the management of ventricular dysfunction.

However, few data are available on the subject of improvement or normalisation of left ventricular function, which is of importance to issues such as the need for ongoing therapy and counselling patients who develop heart failure. An improvement in left ventricular ejection fraction may result from a reversal of remodelling and/or an improvement in left ventricular systolic function as a result of ventricular unloading [30]. Reverse remodelling is potentially more likely in non-ischaemic aetiologies where myocyte necrosis may not be as dominant a feature compared with patients with ischaemic cardiomyopathies. However, more work is required on the ability to reverse interstitial structural changes which may be the dominant feature explaining remodelling in non-ischaemic cardiomyopathies. The observation within this study that improvement in ejection fraction is less likely to be seen in the ischaemic population is consistent with the fact that less function may return or remodelling be reversed when permanent damage has occurred. Nonetheless, substantial improvement can occur in this population as evidenced by the fact that 35.5% of the ischaemic group demonstrated an increase in LVEF of ≥10%. It is of interest that those patients with an improvement in left ventricular systolic function were more likely to be on a clinical target dose of β-blockers. Up-titration in patients who failed to improve may have been limited by hypotension or bradycardia.

There were some differences in BNP values in our population compared with a group of 558 ambulatory patients with stable chronic heart failure reported by Tang et al. [31]. The main difference was in NYHA class II patients and is likely explained by differences in patient selection. BNP at baseline in our study was not a predictor of those patients who returned to normal. BNP at follow-up was significantly lower in the group of patients whose left ventricular function improved. Nonetheless, it is of interest that the majority of patients who demonstrated a return to normal function and dimensions did not demonstrate a reduction in BNP to <100 pg/ml. Therefore, these data would indicate that while there has been substantial improvement in structural parameters there is still biochemical evidence of ongoing ventricular strain. Furthermore, few of these patients became asymptomatic. These observations may suggest ongoing subtle cardiomyopathy despite the reassuring echocardiographic data.

Similar to large multicenter trials, we have shown that the "real life" application of guideline therapy results in improved ventricular function in a substantial number of patients. These encouraging results are tempered by the observation that only a small proportion of treated heart failure patients in a real life clinical setting are potentially ‘cured’. This is in keeping with heart failure being a condition that can be put into remission but can be rarely cured. Finally, these data would indicate that withdrawal of disease modifying therapy may not be appropriate in the majority of patients with a return to normal dimensions and systolic function.

In considering these data, it must be kept in mind that this is a retrospective report from a clinical unit where patients had routine echocardiograms performed as part of their ongoing heart failure management. Secondly, echocardiogram measurements were not standardised for body surface area and we did not have available other systolic and diastolic parameters including left ventricular volumes, tissue Doppler or dyssynchrony indices. Our findings may not be applicable to other populations with different race and ethnicity structures and different post-discharge structures of care for heart failure patients [32]. All patients in this study were followed in a heart failure disease management programme, in which application of disease modifying therapy was optimized. The clinical outcomes in our study were for the whole follow-up period and therefore are not necessarily linked to the timing of the echocardiograms. Therefore, it is likely that we have probably overestimated events in the improved group which may explain why we did not observe significant differences in outcome between the groups.

In conclusion, a substantial proportion of optimally treated heart failure patients demonstrate evidence of improvement, but not normalisation, of left ventricular function and size during long term follow up. Despite effective therapy, this underlines the natural history of heart failure as being a chronic disease requiring ongoing observation and management. Remission is therefore possible but cure remains elusive.


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

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