Skip Navigation

European Journal of Heart Failure 2005 7(6):1040-1048; doi:10.1016/j.ejheart.2004.11.003
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Cioffi, G.
Right arrow Articles by Opasich, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cioffi, G.
Right arrow Articles by Opasich, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2005 European Society of Cardiology

Pharmacological left ventricular reverse remodeling in elderly patients receiving optimal therapy for chronic heart failure

Giovanni Cioffia,*, Luigi Tarantinib, Stefania De Feoc, Giovanni Pulignanod, Donatella Del Sindacoe, Carlo Stefenellia and Cristina Opasichc

a Department of Cardiology, "Villa Bianca" Hospital Trento, Italy
b Department of Cardiology, "S. Martino" Hospital Belluno, Italy
c "Salvatore Maugeri" Foundation, IRCCS, Pavia Medical Center Italy
d Department of Cardiology, "S. Camillo" Hospital Rome, Italy
e Department of Cardiology INRCA IRCCS Rome Italy

* Corresponding author. Division of Cardiology, Villa Bianca Hospital, Trento. via Piave 78, 38100, Trento, Italy. Tel.: +39 461 916 000; fax: +39 461 916874. E-mail address: gcioffi{at}albaclick.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background and aims: In recent years, reversal of established left ventricular (LV) dilatation has been increasingly recognized in middle-aged patients with dilated cardiomyopathy receiving angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers. We performed this prospective study to evaluate whether optimized therapy for heart failure also induces LV reverse remodeling in older patients.

Methods: One hundred and twenty-four patients aged >70 years with LV ejection fraction <40% underwent clinical and echocardiographic evaluation at baseline and after 1 year. During the early stage of follow-up, pharmacological therapy was optimized. LV reverse remodeling was defined as a reduction in LV end-diastolic volume >25% from baseline to final evaluation.

Results: LV reverse remodeling was recognized in 32 patients (26%). Compared to the subjects who did not improve LV geometry, those with reverse remodeling had, at baseline, higher arterial blood pressure, lower serum creatinine levels, shorter duration of symptoms of heart failure, more frequently received beta-blocker therapy and had predominantly nonischemic aetiology. The variables associated with the development of reverse remodeling in the multivariate analysis were shorter duration of symptoms of heart failure (Odds ratio: 7.7; CI: 2.5–23.3, p=0.0001) and beta-blocker therapy (Odds ratio: 6.0; CI: 1.6–23.3, p=0.01).

Conclusions: LV reverse remodeling takes place in elderly as well as in younger heart failure patients. A significant proportion of elderly patients undergoes this favourable process which occurs prevalently in patients receiving beta-blocker therapy with a short history of cardiac disease.

Key Words: Chronic heart failure • Left ventricular reverse remodeling • Elderly population • Dilated cardiomyopathy • Left ventricular systolic dysfunction

Received June 11, 2004; Revised October 12, 2004; Accepted November 11, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Reversal of established left ventricular (LV) dilatation was described several years ago as an uncommon phenomenon observed experimentally [1,2] and occasionally detected in human chronic heart failure (CHF) [3–5]. In recent years, it has been increasingly recognized in middle-aged patients with ischemic and nonischemic dilated cardiomyopathy receiving optimized pharmacological therapy for CHF, after cardiac resynchronisation by biventricular pacing or moderate exercise training [6–12]. In these subjects, the development of LV reverse remodeling was usually associated with improvement in clinical status, LV systolic function and good outcome. Few studies have analyzed this phenomenon in the elderly and the results are inconclusive [13,14].

Accordingly, this prospective investigation was designed to define the prevalence, the predictors and the changes in clinical and echocardiographic variables associated with LV reverse remodeling in elderly patients with CHF due to ischemic and nonischemic dilated cardiomyopathy.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patient population
Patients >70 years of age with CHF and LV dilatation associated with an ejection fraction <40% were selected for this investigation. The clinical diagnosis of CHF was made according to the modified Framingham criteria [15]. Subjects with hypertrophic or restrictive cardiomyopathy, those with acute myocarditis or with alcohol-induced myocardial injury were excluded from the study. Those subjects who experienced a myocardial infarction and/or who underwent percutaneous transluminal coronary angioplasty or coronary artery bypass graft within 3 months of the first evaluation or during the follow-up were also excluded. The study patients were consecutively enrolled between January 2000 and January 2001 and underwent a 12-month prospective evaluation.

2.2. Assessment and follow-up
A careful history was obtained from all patients and a clinical assessment was performed at baseline and after 12 months, which included New York Heart Association functional class evaluation, physical and echocardiographic examination, routine blood tests and standard electrocardiography. Charlson's index was computed in all patients, to evaluate the presence and the impact of prognostic comorbidities [16]. During follow-up, patients received diuretics (flexible regimen), fixed low dose of spironolactone (25 mg), digitalis and the highest tolerated dose of angiotensin-converting enzyme (ACE) inhibitors (or angiotensin II type 1 receptor blockers if not tolerated). All patients received carvedilol, if not contraindicated, and ACE inhibitors and were managed as previously reported [17]. Anticoagulant treatment was given to patients with a valvular prosthesis or atrial fibrillation. Patients were educated to the early recognition of symptoms, diet, flexible use of diuretics, and frequent controls of body weight and blood pressure. Hospitalizations for worsening CHF or for cardiovascular reasons occurring during the follow-up were considered as clinical outcomes. The protocol of the present study was approved by the local institutional review board and written informed consent was obtained from all recruited patients.

2.3. Reproducibility of echocardiographic measurements
To verify the statistical significance of the changes in LV size and ejection fraction observed during the time for the a priori definition of LV reverse remodeling, shortly before the beginning of the recruitment period, we tested the reproducibility of echocardiographic parameters using the videotape recordings of 50 elderly patients with CHF previously admitted to our center. These data have been reported previously [17]. The mean difference between two measurements was ±12 ml/m2 for the LV end-diastolic volume and ±5 units percentage (%) for LV ejection fraction. The standard deviations of these differences were ±12% and 16%, respectively. Based on these findings, we established that changes in LV end-diastolic volume and ejection fraction were significant for values >24 ml/m2 and >10 units percentage (%), respectively (>2 standard deviations of the mean). Similar to the SOLVD and SAVE echocardiography substudies [18,19], we used the change in the combined LV end-diastolic volume from baseline to 1 year as a measure of LV enlargement.

2.4. Definitions
The phenomenon of LV reverse remodeling was recognized if LV end-diastolic volume decreased >24 ml/m2 from baseline to the final evaluation. The improvement in LV systolic function was defined as an increase in LV ejection fraction >10 units percentage (%) from baseline. The diagnosis of coronary heart disease was based on a history of myocardial infarction or on the results of exercise/echo-stress test or coronary angiography. The cause of heart failure in the remaining patients who were not classified as coronary heart disease was defined as nonischemic heart disease.

2.5. Echocardiography
A standard transthoracic echocardiographic study was systematically performed in all patients at baseline and at the end of the follow-up. LV volumes and ejection fraction were computed from apical two- and four-chamber views by the area–length method [20]. Mitral regurgitation was diagnosed by color Doppler and quantified using a 1–4+ grading system [21].

2.6. Statistical analysis
The variables chosen for analysis were presented as mean value ±1 standard deviation (parametric variables) or median and quartiles (nonparametric variables). Unpaired Student's test and {chi}2 statistics were used to compare differences between patients with and without LV reverse remodeling of continuous and categorical variables, respectively. Paired Student's test was used to measure the variations of the parameters documented during the time in the study groups. For the comparison between the groups, the statistical significance of such variations was tested using the analysis of variance (ANOVA). Multiple logistic regression analysis by a stepwise forward-conditional procedure was carried out, using Systat 8.0 Release, to identify the independent factors associated with the development of the LV reverse remodeling and the improvement in LV systolic function. K-means clustering analysis was performed to split the study population into subgroups by maximizing between-cluster variation in baseline LV end-diastolic volume. Distinct clusters were identified and compared using Euclidean distance metric. The hospitalization for worsening CHF/cardiovascular cause-free survival in the two study groups was assessed with Kaplan Meier curves and the differences between the curves were tested for significance by the log-rank test. The null hypothesis was rejected at a two-tailed {alpha}<5%.

2.7. Control group
With the aim of assessing whether the change in LV geometry and systolic function (evaluated in terms of end-diastolic volume and ejection fraction) was due to optimal pharmacological treatment or to the particular characteristics of our patients, a statistically matched sample was retrospectively obtained from a group of patients who were referred to our heart failure unit before the initiation of beta-blockers, angiotensin type 1 receptor-blockers and spironolactone (the recruitment period lasted from March 1998 to December 1999) and who survived for 12 months. For this analysis, the following procedure was used: a Gower's generalized distance for each of the study patients and all of the patients selected as controls was computed and ranked in ascending order. The distance was calculated using the following variables: aetiology of heart failure, New York Heart Association functional class, diabetes mellitus, LV end-diastolic volume, LV ejection fraction, mitral regurgitation. The study patients were divided in subgroups formed by the three closest cases. The control group was then defined by taking for each subgroup of study patients the closest retrospective case.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
There were 176 patients who met the recruitment criteria established in the study protocol. Sixteen patients did not undergo the final echocardiographic evaluation and 36 patients (20%) who died during the follow-up were not included in the analysis, leaving a final study group of 124 subjects. The control group comprised 41 patients. Table 1 shows the general characteristics of the patients and controls. Beta-blocker therapy was given to 82 of 124 (66%) study patients. It was not started in 16 cases due to severe chronic obstructive pulmonary disease, in 5 cases for low systolic arterial blood pressure (<90 mmHg), and in 5 cases for low heart rate (<50 bpm). The remaining 16 patients had no absolute clinical contraindication to carvedilol.


View this table:
[in this window]
[in a new window]

  		Table 1 Mean baseline characteristics of the 124 patients recruited into the study and 41 patients selected as controls

 
3.1. Prevalence of LV reverse remodeling and features of study groups
LV reverse remodeling was detected in 32 of the 124 study patients (26%) and in 2 of 41 controls (5%; p=0.001). LV end-diastolic volume varied from 118 to 78 ml/m2 (p=0.00001) in patients who exhibited LV reverse remodeling, from 107 to 109 ml/m2 (p=ns) in those who did not, and from 103 to 96 ml/m2 (p=ns) in the controls.

After 12 months of optimized therapy, the patients who developed LV reverse remodeling had better New York Heart Association functional class (2.0±0.7 vs. 2.4±0.7, p=0.02), LV ejection fraction (49±12% vs. 34±9%, p=0.009), and renal function (serum creatinine 1.3±0.4 vs. 1.6±0.5 mg/dl, p=0.04), lower heart rate (64±8 vs. 70±11 bpm) and less-severe degree of mitral regurgitation (score 1.0±0.7 vs. 1.4±0.8, p=0.00001) than those who did not. Carvedilol was given more frequently to patients with LV reverse remodeling (91% vs. 52%, p=0.0001), who received a higher dose of angiotensin-converting enzyme inhibitor (equivalent of enalapril 15±7 vs. 11±8, p=0.02). During the follow-up, all patients with LV reverse remodelling tolerated carvedilol well, however, carvedilol therapy was withdrawn in 5 of 53 patients (9%, p=0.08) who received the beta-blocker and who did not improve LV geometry.

A significant improvement in New York Heart Association functional class, mitral regurgitation, and left ventricular ejection fraction was observed at the final evaluation both in patients who developed LV reverse remodeling and in those who did not. The magnitude of these improvements, however, was significantly greater in the LV reverse remodeling group, compared to patients without LV reverse remodeling and controls (Fig. 1), in whom a similar effect was observed.


Figure 1
View larger version (14K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Variations in clinical and echocardiographic variables measured at baseline and after 12 months in patients with and without LV reverse remodeling. BP=blood pressure; LVED=Left ventricular end-diastolic; LVEF=left ventricular ejection fraction; MR=mitral regurgitation; NYHA=New York Heart Association. All differences between the control group and the "no reverse remodeling" group were not significant (p>0.05). The statistical difference between patients who showed reverse remodeling and those who did not is shown in brackets. (*)=p<0.05; (**)=p<0.005; (***)=p<0.0005.

 
3.2. LV systolic function
An improvement in LV function was observed in 34 of 124 study patients (27%) and in 3 of 41 controls (7%, p=0.01). As expected, this improvement occurred more frequently in patients who showed LV reverse remodeling than those who did not (66% vs. 14%, p=0.00001). LV ejection fraction increased from 28±7% to 49±10% in the reverse remodeling patients (p=0.00001), from 30±8% to 34±10% (p=0.01) in the patients who did not show reverse remodeling and from 31±8% to 34±10% in the controls (p=0.03). Univariate analysis (data not shown) and multiple logistic regression analysis were performed to identify the factors associated with the improvement in LV systolic function diagnosed in patients with LV reverse remodeling. Logistic analysis revealed that the absence of diabetes mellitus (odds ratio: 3.5; 95% IC: 1.01–11.92, p=0.04) was the sole independent predictor of improvement in LV ejection fraction in these patients.

3.3. Predictors
There were several differences in baseline clinical variables between the patients who experienced LV reverse remodeling and those who did not (Table 2). Stepwise regression analysis combining clinical and echocardiographic variables showed that the phenomenon of LV reverse remodeling depended on the duration of CHF symptoms and beta-blocker therapy (Fig. 2).


View this table:
[in this window]
[in a new window]

  		Table 2 Baseline clinic characteristics of the 124 study patients classified in the "reverse remodeling" and the "no reverse remodeling" groups according to the changes in left ventricular end-diastolic volume during the follow up

 


Figure 2
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Variables emerging by multivariate analysis (stepwise logistic regression analysis) as independent predictors of left ventricular reverse remodeling at 12-month follow up.

 
To test whether baseline LV size could influence LV geometry and systolic function over time, the 124 study patients were clustered according to LV end-diastolic volume and classified as either mild (<94 ml/m2), moderate (94 to 135 ml/m2), or severe (>135 ml/m2) LV dilatation. After 12 months of follow-up, the prevalence of LV reverse remodeling and improvement in LV ejection fraction was similar in the three groups of patients (Table 3).


View this table:
[in this window]
[in a new window]

  		Table 3 Prevalence of left ventricular (LV) reverse remodeling and of improvement in LV ejection fraction in the three subgroups of patients classified as mild, moderate, severe LV dilation according to the baseline LV end-diastolic volume

 
3.4. Clinical outcomes
Hospitalization for cardiovascular causes and worsening CHF occurred in 5 (15%) and 4 (12%) patients, respectively, who developed LV remodeling and in 36 (39%) and 20 (21%) patients who did not (62% and 43% risk reduction in the former group, respectively). The probability of survival without hospitalization for worsening CHF or cardiovascular cause was similar between the two study groups and controls during the first 6 months of follow-up, while in the second 6-month period, it became gradually higher in the group of patients who showed LV remodeling (Fig. 3).


Figure 3
View larger version (18K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Kaplan–Meier analysis of cumulative risk of hospitalization for worsening heart failure (left panel) and for cardiovascular cause (right panel) in patients with and without LV reverse remodeling and controls.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
Myocardial remodeling is considered to be a relevant driving force behind the dramatic natural history of CHF and an independent contributor to adverse outcomes in patients with LV dysfunction [1,22]. In CHF patients, clinical events including death and hospitalisation for cardiovascular reason are classically related to progressive heart failure or sustained cardiac arrhythmias, two circumstances resulting from and enhanced by the LV remodelling process. Inhibition of this pathological phenomenon is regarded as one of the main targets of therapy for CHF and is currently a theme of intensive research interest. This is justified by the fact that all therapeutic interventions, which slow down or revert the process of LV remodeling, have resulted in a significant improvement in clinical status and reduction in morbidity and mortality [6,9,23,24]. The positive effect on clinical outcomes could be explained by the fact that the LV reverse remodeling process is associated with many structural and pathophysiological cardiac changes, such as recovery of diastolic reserve and systolic function, decrease in mitral regurgitation, and a reduction in LV mass and myocardial stress, which have been shown to be powerful prognostic predictors in such patients [6,23,24].

4.1. Technical considerations
Data on the reproducibility of echocardiography to calculate LV size and function in the CHF population are not available. In addition, its value for the assessment of serial LV volume and ejection fraction changes over time in these patients is also unknown [25]. For these reasons, we evaluated the reproducibility of echocardiographic parameters in our laboratory before the beginning of the study and identified the values by which LV end-diastolic volume (>24 ml/m2) and ejection fraction (>10 points %) had to vary in order to exceed the echocardiographic variability. Of note, large changes in these variables were required to properly diagnose LV reverse remodeling and improvement in systolic function. Using this methodological approach, we could measure the changes within and between the study groups, recognize LV reverse remodeling and the improvement in LV systolic function in the individual patients and define the prevalence and the predisposing factors for this behaviour in our study population.

4.2. Reverse LV remodeling with age
Until the last decade, drug therapies used in CHF provided favourable effects on symptoms and hospitalizations but failed to reverse the LV remodeling process. The subsequent introduction of angiotensin-converting enzyme inhibitors and the rediscovery of beta-blockers positively affected the modifications in LV geometry, giving rise to an antiremodeling process which usually paralleled the increase in LV ejection fraction and reduction in mitral regurgitation [9,11,26,27]. These positive structural changes have been frequently observed in middle-aged patients with CHF. In 1999, Kawai et al. [6], and more recently Metra et al. [28] reported that a meaningful proportion of subjects with dilated cardiomyopathy (22% and 26%, respectively) had a marked reduction in LV volume and increase in LV ejection fraction after long-term therapy with angiotensin-converting enzyme inhibitors and/or beta blockers. Finally, results of the CARMEN study [29] demonstrated the powerful effect of carvedilol plus enalapril in inducing antiremodeling effects on the left ventricle.

However, there is conflicting data, about the reversal of LV remodeling in elderly patients with CHF. Levine et al. [13] studied the effect of up-titrated CHF therapy in older vs. younger patients over 1 year, and noted that although the older patients significantly improved clinical status and reduced hospitalizations, the phenomenon of LV reverse remodeling could only be detected in the younger patients. In contrast, reversal of LV dilatation in the elderly was clearly documented by Palazzuoli et al. [14] who followed 48 patients with severe LV systolic dysfunction, aged >70 years, previously randomized to treatment with either carvedilol or placebo. Similarly, Konstam et al. [8] analyzing data from the ELITE ventricular function sub-study, found that at 48 weeks both captopril and losartan significantly reduced LV end-diastolic volume index in elderly patients with CHF. Our results accord with these clinical experiences and seem powerful enough to suggest that LV reverse remodeling can occur in older as well as in younger CHF patients, that it develops in a significant percentage of elderly patients receiving optimal CHF therapy, and that it is associated with an improvement in functional class and LV ejection fraction, decrease in mitral regurgitation and reduction in hospitalizations. As previously reported by several authors who analyzed younger CHF populations [14,26,28], our experience confirms that several months of treatment are required for these favourable effects to occur, even in the elderly.

4.3. Predictors of LV reverse remodeling
The factors related to LV reverse remodeling in the elderly have never been investigated. In younger individuals, higher baseline values of arterial blood pressure and nonischemic aetiology of CHF are the two variables which constantly emerged as the most important predictors [6,7,28]. The present study identified these clinical features as markers of LV reverse remodeling in the elderly in univariate analysis, but this was not confirmed in the final logistic model, including other parameters that powerfully influenced the response to the medical therapy and the natural evolution of the LV remodeling process. The most important predictor of LV reverse remodeling in our patients was the short duration of symptoms of heart failure, a condition that notoriously predisposes to the improvement in LV systolic function and is associated with an excellent long-term outcome [17,30,31]. On the basis of these findings, it seems reasonable to hypothesize that the documented pharmacological-induced changes in myocardial gene expression [32], the reset of neurohumoral drive [33] and the inhibitory effect on apoptosis [34] which intuitively should herald and hold up LV reverse remodeling, arise more frequently in the early phase of cardiac disease when the reversal of alterations of myocardial architecture is still possible.

The second associated marker for LV reverse remodeling emerging from our analysis was beta-blocker therapy with carvedilol, which markedly influenced the results of the present study. These results are consistent with previous investigations [9,10,14,17,26–28] and confirms that the positive effect of carvedilol on LV geometry in CHF patients is independent of age.

Our study also documented that both LV reverse remodeling and the improvement in LV systolic function, which usually parallels the reduction of LV volume, could develop in elders with severe as well as in those with mild or moderate LV dilatation. The observation that the presence of an high degree of LV dilatation does not preclude the possibility of a favourable change in LV geometry during this time seems encouraging if we consider that severe LV dilatation is one of the strongest predictors of poor outcome [1,22].

Another important finding from our study was that, among the patients with LV reverse remodelling, those with diabetes mellitus exhibited a reduced susceptibility of the myocardium to the effects of the medical treatment compared to the nondiabetic patients (the likelihood of improvement in LV ejection fraction was 3.5-fold lower in the diabetic than in the nondiabetic patients). This observation is in line with the results of the SAVE trial [19], which recently demonstrated that the increased incidence of heart failure and deaths in patients with ischemic cardiomyopathy and diabetes mellitus cannot be explained by an increased propensity for LV enlargement; there are many pathological mechanisms that may affect myocardial structure and metabolism, resulting in abnormal systolic and diastolic function [35]. For these patients, more aggressive care in the early stages of the disease is therefore mandatory.

4.4. Study limitations
The protocol of the present study did not permit evaluation of when changes in LV volume started or whether LV reverse remodeling could occur after 1 year of optimal pharmacological therapy for CHF. The duration of follow-up was also too short to quantify the expected effects of improved LV geometry on clinical outcomes. Furthermore, in our study, patients were monitored by echocardiography, which is not the gold standard method for measuring LV volumes [24]. The final consideration concerns the control group, who were recruited retrospectively and had clinical and echocardiographic characteristics similar to the study patients who were prospectively enrolled. Although both the number and type of examinations were the same for both the controls and the study patients, the different selection modalities (prospective vs. retrospective) and recruiting time could have amplified the positive effect of the optimized medical treatment observed in the study group.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
LV reverse remodeling takes place in elderly as well as in younger CHF patients. A significant proportion of elders optimally treated for CHF undergo this favourable process which occurs predominantly in patients receiving beta-blocker therapy with a short history of cardiac disease. These results emphasise the need to validate newer and simpler techniques for early diagnosis of LV dysfunction and to optimize pharmacological therapy for CHF in the early stages of disease.


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

  1. Francis G.S., Chu C. Post-infarction myocardial remodelling: why does it happen? Eur Heart J (1995) 16(Suppl. N):31–36.[Abstract/Free Full Text]
  2. Saavedra W.F., Tunin R.S., Paolocci N., Mishima T., Suzuki G., Emala C.W., et al. Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure. J Am Coll Cardiol (2002) 39:2069–2076.[Abstract/Free Full Text]
  3. Cioffi G., Stefenelli C. Reversibility of left ventricular dysfunction in elderly patients with dilated cardiomyopathy undergoing treatment with carvedilol. Report of a case. Ital Heart J (2001) 2:668–672.
  4. Arizon J.M., Anguita M., Torres F., Gimenez D., Bueno G., Concha M., et al. Spontaneous remission in a patient with long-term idiopathic dilated myocardiopathy. Rev Esp Cardiol (1992) 45:354–356.[Medline]
  5. Saini J., Rich M.W., Lyss A.P. Reversibility of severe left ventricular dysfunction due to doxorubicin cardiotoxicity. Report of three cases. Ann Intern Med (1987) 106:814–816.[Abstract/Free Full Text]
  6. Kawai K., Takaoka H., Hata K., Yokota Y., Yokoyama M. Prevalence, predictors, and prognosis of reversal of maladaptive remodeling with intensive medical therapy in idiopathic dilated cardiomyopathy. Am J Cardiol (1999) 84:671–676.[CrossRef][Web of Science][Medline]
  7. Levine T.B., Levine A.B., Keteyian S.J., Narins B., Lesch M. Reverse remodeling in heart failure with intensification of vasodilator therapy. Clin Cardiol (1997) 20:697–702.[Web of Science][Medline]
  8. Konstam M.A., Patten R.D., Thomas I., Ramahi T., La Bresh K., Goldman S., et al. Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function substudy. Am Heart J (2000) 139:1081–1087.[CrossRef][Web of Science][Medline]
  9. Doughty R.N., Whalley G.A., Gamble G., MacMahon S., Sharpe N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia–New Zealand Heart Failure Research Collaborative Group. J Am Coll Cardiol (1997) 29:1060–1066.[Abstract]
  10. Khattar R.S., Senior R., Soman P., van der Does R., Lahiri A. Regression of left ventricular remodeling in chronic heart failure: comparative and combined effects of captopril and carvedilol. Am Heart J (2001) 142:704–713.[CrossRef][Web of Science][Medline]
  11. Yu C.M., Chau E., Sanderson J.E., Fan K., Tang M.O., Fung W.H., et al. Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation (2002) 105:438–445.[Abstract/Free Full Text]
  12. Giannuzzi P., Temporelli P.L., Corrà U., Tavazzi L. for the ELVD-CHF Study Group. Antiremodeling effect of long-term exercise training in patients with stable chronic heart failure. Results of the exercise in left ventricular dysfunction and chronic heart failure (ELVD-CHF) trial. Circulation (2003) 108:554–559.[Abstract/Free Full Text]
  13. Levine T.B., Levine A.B., Bolenbaugh J., Green P.R. Reversal of heart failure remodeling with age. Am J Geriatr Cardiol (2002) 11:299–304.[CrossRef][Medline]
  14. Palazzuoli A., Bruni F., Puccetti L., Pastorelli M., Angori P., Pasqui A.L., et al. Effects of carvedilol on left ventricular remodeling and systolic function in elderly patients with heart failure. Eur J Heart Fail (2002) 4:765–770.[Abstract/Free Full Text]
  15. Senni M., Tribouilloy C.M., Rodeheffer R.J., Jacobsen S.J., Evans J.M., Bailey K.R., et al. Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation (1998) 98:2282–2289.[Abstract/Free Full Text]
  16. Charlson M.E., Pompei P., Ales K.L., MacKenzie C.R. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis (1987) 40:373–383.[CrossRef][Web of Science][Medline]
  17. Cioffi G., Stefenelli C., Tarantini L., Opasich C. Prevalence, predictors and prognostic implications of improvement in left ventricular systolic function and clinical status in patients >70 years of age with recently diagnosed systolic heart failure. Am J Cardiol (2003) 92:166–172.[Web of Science][Medline]
  18. Greenberg B., Quinones M.A., Koilpillai C., Limacher M., Shindler D., Benedict C., et al. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Circulation (1995) 91:2573–2581.[Abstract/Free Full Text]
  19. Solomon S.D., St John Sutton M., Lamas G.A., Plappert T., Rouleau J.L., Skali H., et alSurvival and Ventricular Enlargement (SAVE) Investigators. Ventricular remodeling does not accompany the development of heart failure in diabetic patients after myocardial infarction. Circulation (2002) 106:1251–1255.[Abstract/Free Full Text]
  20. Schiller N.B., Shah P.M., Crawford M., DeMaria A., Devereux R., Feigenbaum H., et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr (1989) 2:358–367.[Medline]
  21. Miyatake K., Izumi S., Okamoto M., Kinoshita N., Asonuma M., Nakagawa H., et al. Semiquantitative grading of severity of mitral regurgitation by real time two dimensional Doppler flow imaging technique. J Am Coll Cardiol (1986) 7:82–88.[Abstract]
  22. Lee T.H., Hamilton M.A., Stevenson L.W., Moriguchi J.D., Fonarow G.C., Child J.S., et al. Impact of left ventricular cavity size on survival in advanced heart failure. Am J Cardiol (1993) 72:672–676.[CrossRef][Web of Science][Medline]
  23. Konstam M.A., Kronenberg M.W., Rousseau M.F., Udelson J.E., Melin J., Stewart D., et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. SOLVD (Studies of Left Ventricular Dysfunction) Investigators. Circulation (1993) 88:277–283.
  24. Yu C.M., Fung W.H., Lin H., Zhang Q., Sanderson J.E., Lau C.P. Predictors of left ventricular reverse remodeling after cardiac resynchronization therapy for heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am J Cardiol (2003) 91:684–688.[CrossRef][Web of Science][Medline]
  25. Anand I.S., Florea V.G., Solomon S.D., Konstam M.A., Udelson J.E. Non invasive assessment of left ventricular remodeling: concepts, techniques, and implications for clinical trials. J Card Fail (2002) 8:S452–S464.[CrossRef][Web of Science][Medline]
  26. Lowes B.D., Gill E.A., Abraham W.T., Larrain J.R., Robertson A.D., Bristow M.R., et al. Effects of carvedilol on left ventricular mass, chamber geometry, and mitral regurgitation in chronic heart failure. Am J Cardiol (1999) 83:1201–1205.[CrossRef][Web of Science][Medline]
  27. Capomolla S., Febo O., Gnemmi M., Riccardi G., Opasich C., Caporotondi A., et al. Beta-blockade therapy in chronic heart failure: diastolic function and mitral regurgitation improvement by carvedilol. Am Heart J (2000) 139:596–608.[Web of Science][Medline]
  28. Metra M., Nodari S., Parrinello G., Giubbini R., Manca C., Dei Cas L. Marked improvement in left ventricular ejection fraction during long-term beta-blockade in patients with chronic heart failure: clinical correlates and prognostic significance. Am Heart J (2003) 145:292–299.[CrossRef][Web of Science][Medline]
  29. Coletta A.P., Louis A.A., Clark A.L., Nikitin N., Cleland J.G. European Society of Cardiology. Clinical trials update from the European Society of Cardiology: CARMEN, EARTH, OPTIMAAL, ACE, TEN-HMS, MAGIC, SOLVD-X and PATH-CHF II. Eur J Heart Fail (2002) 4:661–666.[Abstract/Free Full Text]
  30. Cicoira M., Zanolla L., Latina L., Rossi A., Golia G., Brighetti G., et al. Frequency, prognosis and predictors of improvement of systolic left ventricular function in patients with "classical" diagnosis of idiopathic dilated cardiomyopathy. Eur Heart Fail J (2001) 3:323–330.[CrossRef]
  31. Opasich C., Rapezzi C., Lucci D., Gorini M., Pozzar F., Zanelli E., et al. Italian network on congestive heart failure (IN-CHF) investigators. Precipitating factors and decision-making processes of short-term worsening heart failure despite "optimal" treatment (from the IN-CHF registry). Am J Cardiol (2001) 88:382–387.[CrossRef][Web of Science][Medline]
  32. Lowes B.D., Gilbet E.M., Abraham W.T., Minobe W.A., Larrabee P., Ferguson D., et al. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med (2002) 346:1357–1365.[Abstract/Free Full Text]
  33. Fujimura M., Yasumura Y., Ishida Y., Nakatani S., Komamura K., Yamagishi M., et al. Improvement in left ventricular function in response to carvedilol is accompanied by attenuation of neurohumoral activation in patients with dilated cardiomyopathy. J Card Fail (2000) 6:3–10.[CrossRef][Web of Science][Medline]
  34. Romeo F., Li D., Metha J.L. Carvedilol prevents epinephrine-induced apoptosis in human coronary artery endothelial cells: modulation of Fas/Fas ligand and caspase-3 pathway. Cardiovasc Res (2000) 45:788–794.[Abstract/Free Full Text]
  35. Depre C., Vanoverschelde J.L., Taegtmeyer H. Glucose for the heart. Circulation (1999) 99:578–588.[Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J CARDIOVASC PHARMACOL THERHome page
D. Chen, R. Chang, B. Umakanthan, L. N. Stoletniy, and J. T. Heywood
Improvement of Cardiac Function Persists Long Term With Medical Therapy for Left Ventricular Systolic Dysfunction
Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2007; 12(3): 220 - 226.
[Abstract] [PDF]

Home page
 J CARDIOVASC PHARMACOL THERHome page
J. Patel and J. T. Heywood
Mode of Death in Patients With Systolic Heart Failure
Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2007; 12(2): 127 - 136.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Cioffi, G.
Right arrow Articles by Opasich, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cioffi, G.
Right arrow Articles by Opasich, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?