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European Journal of Heart Failure 2005 7(7):1112-1117; doi:10.1016/j.ejheart.2005.01.016
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© 2005 European Society of Cardiology

Functional mitral regurgitation predicts 1-year mortality in elderly patients with systolic chronic heart failure

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

a Department of Cardiology, "Villa Bianca" Hospital via Piave 78, 38100, Trento, Italy
b Department of Cardiology, "S. Martino" Hospital Belluno, Italy
c Department of Cardiology, "Salvatore Maugeri" Foundation IRCCS, Pavia Medical Center, Italy
d Department of Cardiology, "S. Camillo" Hospital Italy
e Department of Cardiology INRCA IRCCS Roma Italy
f Department of Cardiology, "Riuniti" Hospital Trieste, Italy

* Corresponding auhtor. Tel.: +39 461 916000; fax: +39 461 916874. E-mail address: gcioffi{at}villabiancatrento.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background and aim: Mitral regurgitation (MR) has been demonstrated to be a powerful predictor of adverse outcome in middle-aged patients with chronic heart failure (CHF). In this study, we sought to define the prognostic impact of functional mitral regurgitation in a population of elderly patients with systolic CHF.

Methods: One hundred seventy-five outpatients aged >70 years with validated CHF and left ventricular ejection fraction <40% underwent clinical and echocardiographic evaluations at baseline. Mitral regurgitation was diagnosed by Color Doppler and quantified in 5 categorical values using a 0–4+ grading system. Outcome measures included 1-year mortality and hospitalization for worsening CHF.

Results: The distribution of patients according to the 5 different degrees of MR detected at baseline was: absent=11%, 1+=31%, 2+=38%, 3+=16%, 4+=4%. The relationship between MR and mortality was direct and approximately linear (r=0.39, p=0.00001). The prevalence of death in the 5 subgroups was 0%, 7%, 15%, 45%, 57%, respectively. Multivariate logistic regression analysis showed that MR was the strongest predictor of death (OR 4.47, 95% CI 1.50–13.0), independently of the presence of diabetes mellitus, older age and larger left ventricular end-diastolic volume. No association was found between MR and hospitalization for worsening CHF (r=0.08, p=0.41).

Conclusions: This study establishes the direct and independent relationship between MR severity and one-year mortality among elders with systolic CHF. Conversely, MR does not provide useful information regarding the risk of subsequent hospitalization for worsening CHF.

Key Words: Mitral regurgitation • Heart failure • Elderly population • Left ventricular systolic dysfunction

Received September 30, 2004; Revised December 8, 2004; Accepted January 27, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Functional mitral regurgitation (MR) is common in patients with chronic heart failure (CHF) and represents a significant complication of end-stage cardiomyopathy. In the middle-aged populations with left ventricular (LV) dilatation and CHF who are enrolled in controlled clinical trials, MR unfavorably influences the therapeutic response and clinical progression of the cardiac syndrome, which remains a leading cause of mortality [1–5]). Conversely, the prognostic value of functional MR in elders suffering from CHF has never been systematically studied and is still unknown.

Accordingly, in the present study, we tried to assess whether functional MR, measured with Color Doppler echocardiography, in a population of elderly patients with systolic CHF is a predictor of adverse outcomes, including 1-year mortality and 1-year hospitalization for worsening CHF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Population
Inclusion criteria for this study were age>70 years, LV ejection fraction<40%, and a diagnosis of CHF according to the modified Framingham criteria [6]. Patients were consecutively recruited and prospectively followed up for 12 months. Patients with MR related to primary valve disease, those with a diagnosis of acute myocarditis or with alcohol-induced myocardial injury or with poor short-term prognosis due to systemic diseases were excluded.

2.2. Study protocol
A careful history was obtained from all patients who underwent clinical assessment, routine blood tests and standard electrocardiography at baseline. Charlson's index was systematically computed to weight the value of prognostic comorbidities [7]. At entry, pharmacological therapy was standardized according to the current statements on quality of care [8,9]. Educational issues such as the early recognition of symptoms, physical activity, diet, flexible use of diuretics and the need for frequent monitoring of body weight and blood pressure were discussed with patients and their caregivers. Hospitalization for worsening CHF and death for all causes were the clinical events recorded during the follow up. The study was approved by the Institutional Review Board of Villa Bianca Hospital. Informed consent was obtained from each eligible subject.

2.3. Echocardiography
Standard transthoracic echocardiographic studies were systematically performed at baseline and at the end of the follow up, using a Megas Esaote Biomedica machine (Florence, Italy) equipped with a 2.5–3.5 Mhz annular-array transducer. LV volumes and ejection fraction were computed from apical two- and four-chamber views by the area–length method [10]. MR was diagnosed by Color Doppler and quantified in 5 degrees using a 0–4+ grading system based on the value of maximal regurgitant jet area detected in the left atrium [11]. Mitral flow velocities were assessed by pulsed-wave Doppler from the apical 4-chamber view by positioning the sample volume between the mitral leaflets at the level of their tips. The following measurements were averaged from 5 consecutive cycles: maximal velocity of early (E) and late (A) diastolic wave, the E/A ratio, the deceleration time of E. Details of the reproducibility of echocardiographic measurements from our laboratory have been recently reported [12,13].

2.4. Definitions
In the present study, MR was considered both as a semi-quantitative (5 degrees from 0 to 4+) and dichotomous variable (absence/mild MR=maximal regurgitant jet area measured in the left atrium <4.5 cm2 vs moderate/severe MR=maximal regurgitant jet area ≥4.5 cm2). On the basis of Doppler measurements the "restrictive" transmitral flow pattern was identified by a E/A ratio >1 and deceleration time of E wave≤130 ms. When only a single peak with a filling time ≤130 ms was present, the pattern was considered to be restrictive as well [13]. Chronic renal failure was defined as creatinine blood levels >1.4 mg/dl at entry in patients with a documented history of renal dysfunction, and a history of arterial hypertension as pharmacologically treated high blood pressure.

2.5. Statistical analysis
The variables selected prospectively for analysis are presented in the tables as mean value±1 standard deviation (parametric variables) or median (non-parametric variables). Unpaired Student's test and {chi}2 statistics were used to compare differences between the study groups (absent/mild MR and moderate/severe MR). In order to assess whether a possible relationship with outcomes existed, linear regression and breakdown analysis were performed to test MR severity examined as semi-quantitative and dichotomous variable, respectively. Multiple logistic regression analysis by a stepwise forward-conditional procedure was carried out, using Systat 8.0 Release, to test MR as independent predictor of adverse outcomes. Only variables with a univariate relationship of "p<0.05" were entered as candidate variables in the multivariate logistic regression analysis. The survival and the hospitalization for worsening CHF-free survival of the two study groups were 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%.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
The study population included 175 consecutive patients who were enrolled from January 2000 to January 2002. Fig. 1 (left panel) shows the distribution of patients divided in the 5 study subgroups according to the different degrees of MR detected at entry. Among the whole study population, 140 subjects (80%) had absent/mild MR, and 35 patients (20%) had moderate/severe MR. At baseline evaluation, the properties and the dosage of medications given to the 2 study groups of patients were similar. However, there were significant differences in renal function (worse in the moderate/severe MR group) and many echocardiographic variables (Table 1). Multivariate logistic regression analysis revealed that high LV end-diastolic volume was the only variable independently related to the presence of moderate/severe MR (OR 1.02, 95% IC 1.01–1.04, p=0.001).


Figure 1
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  		Fig. 1 Distribution of patients enrolled into the study divided into 5 subgroups according to the degree of mitral regurgitation detected at entry (left panel). One-year mortality rates (%) exhibited by the 5 study subgroups according to the degree of mitral regurgitation detected at baseline evaluation (right panel).

 


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  		Table 1 Baseline clinical characteristics of the 175 study patients classified in "absent–mild mitral regurgitation group" and "moderate–severe mitral regurgitation group" according to the degree of mitral regurgitation detected by echocardiography at entry

 
3.1. Relation between mitral regurgitation and mortality
At the 1-year evaluation 144 patients were alive (82%), and 31 patients had died during the follow up period (20=pump failure, 7=sudden death and 4=non-cardiac reason). The distribution of deaths in the 5 study subgroups according to the degree of MR is shown in Fig. 1 (right panel). Regression analysis confirmed the direct, linear relationship between MR and 1-year mortality in our population (r=0.39, p=0.00001). Considering MR as a dichotomous variable, the survival was 90% in the absence/mild MR group and 51% in the moderate/severe MR group (log rank=0.00001). The independent relation of MR and mortality was subsequently tested in a multivariate logistic model which identified MR as the strongest independent predictor of 1-year mortality (Table 2).


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  		Table 2 Multivariate analysis (stepwise logistic regression analysis)

 
3.2. Relation between mitral regurgitation and hospitalization for worsening CHF
Sixty-nine patients (39%) were hospitalized for worsening CHF during the follow up. The prevalence of hospitalization for worsening CHF was similar in the 5 study subgroups defined according to the degree of MR (absent MR 33%, MR + 33%, MR ++ 37%, MR +++ 61%, MR ++++ 43%). There was no association between MR and hospitalization for worsening CHF (r=0.08, p=0.41) which depended, instead, on impaired renal function and low systolic blood pressure (Table 2). Worsening CHF-free survival did not differ between patients with absent/mild MR (65%) and moderate/severe MR (43%, log rank 0.48).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
Functional MR has been demonstrated to be a powerful predictor of adverse outcome in middle-aged patients with left ventricular systolic dysfunction and CHF [2,4,5,14,15]. In the past, many authors tried to explain the physiopathological mechanisms by which functional MR influences myocardial function leading to the clinical manifestations of CHF. Some of these mechanisms have been elegantly identified by Corin et al. who showed that, whereas MR is associated with reduced LV ejection fraction, the constant of myocardial stiffness is increased [16] and LV end-systolic stress is higher than in controls without MR [17]. Similarly, Popovic et al. [18] demonstrated significant changes in LV elastance as a result of MR variations. Furthermore, Sakagoshi et al. [19] and Brodde et al. [20] clearly documented that MR induces per se a decrease in cardiac beta-adrenoceptor density and function involving both beta-1 and beta-2 type adrenoceptors independent of congestive cardiomyopathy.

In the present study we defined the prognostic impact of functional MR in a community population of elders with CHF and LV systolic dysfunction. Our results showed a direct, linear relationship between one-year mortality and MR in our population. The risk of death in our elders with moderate/severe MR was more than 4-fold higher than that of counterparts with absent/mild MR. In comparison with the latter, patients with moderate/severe MR had a worse renal and LV systolic function, higher prevalence of restrictive transmitral flow pattern and larger LV end-diastolic volume. The presence of moderate/severe MR likely represents the common expression of these impaired clinical, functional, structural and hemodynamic conditions in our patients. The role that MR may theoretically play on prognosis quoad vitam is crucial in elderly patients who often die from worsening CHF (65% in our experience) while it is probably less decisive in younger populations of CHF patients for whom sudden death occurs more frequently. As expected, in our elderly patients, the prevalence of left bundle branch block was particularly high, as a result this variable did not emerge as marker of adverse outcome in this population.

An additional meaningful finding in our study was that no association exists between MR and hospitalization for worsening CHF. This finding is in line with the results of other similar investigations [21–25]. This should not be considered a surprising result if we keep in mind that elders have a number of comorbidities (particularly renal failure) which are well-known predictors of clinical decompensation and hospital readmission, as well as socioenvironmental conditions (such as no occupation, living alone, low compliance with therapy) which, however, were not considered in the present investigation [23–25]. Correspondingly, we found in our study that chronic renal failure was the strongest predictor of hospital readmission for worsening CHF, the risk for this event being more than 3-fold higher in patients with levels of serum creatinine exceeding 1.4 mg/dl than in those with lower values.

Interestingly, our results confirmed that in the elderly as well as in the younger populations of patients with CHF [26,27] the high degree of LV dilatation is the condition that has the major role in inducing significant MR. Accordingly, Rosario et al. [28] showed in middle-aged patients with severe CHF undergoing hemodynamic monitoring for the optimization of medical therapy, that reduction of the regurgitant orifice area was related to decreased LV volumes and decreased annular distention but not through a change in the gradient across the mitral valve. This and many other investigations clearly show that aggressive unloading pharmacological therapy, tailored to hemodynamic goals, may lead to a reduction in the dynamic mitral regurgitation of CHF, and that this positive effect is sustained at long-term follow up with tailored vasodilator and beta-blocker oral therapy [28–32]. In a recent study of elders hospitalized for worsening CHF undergoing hemodynamic monitoring by echocardiographic techniques, we demonstrated that intensive unloading therapy significantly reduced both LV filling pressure and MR in about 2/3 of patients, who subsequently showed a relatively good prognosis after long-term follow up [33]. Non-invasive hemodynamic evaluation in elderly patients (for whom such pharmacological approach is generally denied) may be particularly useful for appropriate clinical management and a precise recognition of those subjects who have to be considered at high risk for developing cardiovascular events and carefully followed up. Elders with moderate/severe MR, which does not improve in spite of optimized medical therapy, should be certainly included in this group of CHF patients. For these subjects, mitral valve surgery could be a possible therapeutic choice, on condition that surgery is performed early and repair is preferred to replacement whenever feasible [34–36]. In the elderly, late mitral valve surgery, performed in the presence of severe LV systolic dysfunction and worsening functional class, contributes far more than age itself to poor outcome. New pacing/resynchronization strategies have recently been shown to be effective in helping to attenuate the magnitude of functional MR in selected populations of patients with LV dysfunction and CHF [37,38] but they have not been tested in the elderly.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
This study establishes the direct and linear relationship between MR severity and one-year mortality among elderly patients with systolic CHF. In these patients, the presence of moderate/severe MR is the strongest independent predictor of death, and it alone represents an impairment in LV structural, functional, and hemodynamic status. LV dilatation is the main cause of significant MR and requires an aggressive pharmacological approach.


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

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