Keywords
INTRODUCTION
Functional mitral regurgitation (MR) can occur even in a structurally normal valve as a consequence of left ventricular systolic dysfunction.1 In non-ischemic dilated cardiomyopathy, severe functional MR is associated with deterioration of the patient's clinical and hemodynamic status, and a poorer prognosis.2 Despite the high prevalence of this condition on echocardiography,3 functional MR is often clinically silent,4 a fact that makes its detection and clinical management difficult. The pathogenesis of functional MR is multifactorial and still uncertain. Several factors are involved in the loss of valve coaptation, including ring dilation, imbalance of the traction forces, local papillary remodeling, and a reduced transvalvular pressure gradient resulting from contractile dysfunction.5-7
In recent years the interest on this type of valve disease has increased, with the main therapeutic options being surgical techniques8 and biventricular resynchronization therapy.9 Apart from these approaches, the current role of medical treatment for the management of functional MR has not been established or assessed.
PATIENTS AND METHODS
Population and Design
The study included 112 consecutive patients referred for advanced heart failure between January 2002 and January 2003. All had non-ischemic, dilated myocardial disease consisting of left ventricular dilation with diffuse hypokinesia and no segmental abnormalitis or history of artery disease, confirmed by coronary angiography in 76 patients (68%). We selected the patients with severe functional mitral regurgitation (MR) and no organic valvular involvement on echocardiography, who were stable and had no changes in therapy or decompensation of the disease over the previous month. The patients' medical treatment was optimized to reach the maximum tolerated dose (maximum recommended or associated with adverse effects). Therapy consisted of an angiotensin-converting enzyme inhibitor (ACEI) or, in cases of intolerance, an angiotensin II type 2 receptor antagonist (ARA-II) plus a beta-blocker (BB). Patients were followed-up and at 6 months a new echocardiography study was performed. this was assessed on a blind basis with respect to the baseline study.
Echocardiography
Echocardiographic studies were performed by one blinded technician, using a Sonos 5500 instrument (Hewlett-Packard) and acquiring standardized views and measurements. The grade of MR was established as mild (1), moderate (2), or severe (3) according to the following parameters:10 1) maximum area of the jet: mild <4 cm², moderate 4-10 cm², severe >10 cm²; 2) proximal isovelocity surface area (PISA) with calculation of the effective regurgitant orifice area (EROA): mild <20 mm², moderate 20-40 mm², severe >40 mm²; 3) pulmonary venous flow pattern: inversion of the systolic wave in severe grade; and 4) mitral filling pattern: dominant E wave in severe grade.
Statistics
Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as a number (%). Between-group comparisons were performed with the χ² test (categorical variables) and Student's t test (quantitative variables). Student's t test for related samples was used for comparing the variables before and after medical treatment. Correlations between the observed changes were determined by Pearson's (r) and Spearman's (rs) bivariate correlations.
RESULTS
Among 112 consecutive patients, 15 (13.4%) presented severe MR. Coronary arteriography had been performed in 13 of these patients (87%) and none of the studies showed coronary disease. Baseline characteristics are shown in Table 1; patients with severe MR presented a poorer NYHA functional class. Drug therapy optimization consisted of a significant increase in the doses of ACEI (or ARA-II) and BB administered, with no changes in the dose of diuretics (Table 2).
At 6 months, MR grade had decreased in 13 (87%) patients, as did the area of the jet and the EROA (Table 3). This reduction was associated with an improvement in NYHA functional class and a reduction in the end-systolic volume. The end-diastolic volume and left atrial diameter showed no differences.
The decrease in MR grade correlated weakly with the rise in LVEF (P=.03; rs=0.56) and the reduction in end-systolic volume (P=.03; rs=0.55), but not with the end-diastolic volume or atrial diameter. The reduction in EROA correlated with the decrease in LVEF and the end-diastolic volume (P=.01 and r=0.62 for both), whereas the area of the jet additionally correlated with the left atrial diameter (P=.03; r=0.56). The changes recorded in blood pressure and heart rate showed no significant correlations.
DISCUSSION
Functional MR is sometimes silent and in severe cases is associated with greater clinical deterioration.2-4 In our population of patients with non-ischemic left ventricular systolic dysfunction, the prevalence of MR was 13.4%, and the condition was associated with a poorer NYHA functional class.
The first related studies, published more than a decade ago in patients with heart failure, showed that the reduction in functional MR was associated with a more favorable response to vasodilator and diuretic treatment.11,12 The decrease in postload obtained with nitroprusside or hydralazine achieved an acute reduction in MR and an increase in cardiac output, that was more apparent in patients with severe MR.12 In 1991, Hamilton et al13 found that the acute improvement persisted at 6 months of oral vasodilator treatment. Few studies have been performed on the response of MR to medical treatment since that time. One study conducted in 1998 by Rosario et al14 investigating 14 patients with severe MR (6 ischemic and 8 non-ischemic) found that intravenous therapy with vasodilators and diuretics was associated with a reduction in both the regurgitant volume and EROA.
In recent years there has been increasing interest in this condition, mainly from the perspective of surgery and biventricular resynchronization.8,9 In contrast to the earlier research with hydralazine and captopril, our study considers this subject in the light of more extensive current pharmacological options, including BB and ARA-II. The present study is the first to show that maximum optimization of ACEI/ARA-II and BB doses is associated with a significant improvement in the MR grade at middle term.
Correction of MR is based on its functional character, but little is known about the mechanism implicated in the reduction of MR with medical treatment. Rosario et al14 reported a correlation between the decrease in MR and reductions in the diastolic ventricular volume, mitral ring diameter, and right atrial diameter, suggesting a mechanism related to changes in the valvular geometry. Nevertheless, Otsuji et al5 have shown that dilation of the ring alone does not suffice to cause severe MR. Schwammenthal et al15 demonstrated that the EROA presents a dynamic pattern that responds to changes in the loading conditions. In addition, Hung et al6 found that the dynamic changes in the EROA are mainly determined by the transmitral gradient and not by changes in the valvular geometry. These findings are in keeping with the results of our study, in which the improvement in contractile function and the reduction in systolic volume, determinants of an increase in transmitral pressure, correlated with the reduction in MR grade and EROA. Although the present study does not measure the direct effect on ventricular preload and postload, it does suggest, together with the studies cited, that beyond interventions to reduce the mitral ring, severe functional MR can respond to therapies that reduce the loading conditions and improve cardiac function. Assessment of severe functional MR can be useful as a guide to the therapeutic and prognostic guide.
Limitations
The small number of patients included and the lack of a control group are the two main limitations of the study. Consequently, we cannot rule out that there may have been some influence of uncontrolled factors on the evolution of MR. In addition, it was not possible to establish causal relationships between the pharmacological optimization carried out and the changes observed in the parameters studied.
CONCLUSION
In this small series of patients with non-ischemic dilated cardiomyopathy and severe functional MR, optimization of ACEI, and BB therapy at the maximum tolerated doses resulted in an improvement of MR and echocardiographic parameters of left ventricular systolic function.
Correspondence: Dr. D.A. Pascual.
Corbalán, 11, 3.o B. 30002 Murcia. España.
E-mail: dapascual@servicam.com
Received October 14, 2004.
Accepted for publication April 21, 2005.