Pilot Study to Assess the Influence of β-Blockade on Mitral Regurgitant Volume and Left Ventricular Work in Degenerative Mitral Valve Disease
Background— A medical treatment that decreases the likelihood of left ventricular (LV) dysfunction or symptoms would benefit patients with moderate to severe degenerative mitral regurgitation. The aim of this pilot study was to determine the short-term effects of a β-blocker on mitral regurgitant volume and LV work in these patients.
Methods and Results— Twenty-five patients with moderate or severe degenerative mitral regurgitation were randomized in a double-blind crossover study to the β1-selective adrenergic blocker metoprolol (mean daily dose, 119 mg; range 23.75 to 190 mg) and placebo for 14±3 days. At the end of each treatment period, ascending aortic flow and LV stroke volume were measured by cardiac magnetic resonance imaging, and mitral regurgitant volume was calculated. On β-blocker, heart rate decreased from 65±10 by 10±7 bpm (mean±SD) and systolic blood pressure decreased from 138±18 by 16±12 mm Hg (P<0.0001 for both). No significant change occurred in LV ejection fraction (from 65±5%; change, −0.6±2.7%; P=0.3) or mitral regurgitant volume (from 59±36 mL; change, 3±13 mL; P=0.3), but forward stroke volume increased from 89±21 by 5±11 mL (P=0.03). Because heart rate was lower on metoprolol, cardiac output decreased from 5.68±1.04 by 0.56±0.78 L/min (P=0.001), but a greater decrease occurred in LV output, from 9.51±2.22 by 1.30±1.08 L/min (P<0.0001). Mitral regurgitant volume per minute decreased from 3.83±2.41 by 0.74±1.00 L/min (P=0.001). The decrease in LV work on β-blocker (mean, 21%; 95% confidence interval, 15 to 27) was greater (P=0.001) than the decrease in cardiac output (mean, 9%; 95% confidence interval, 3 to 15).
Conclusions— In this pilot study, short-term treatment with a β-blocker did not change mitral regurgitant volume per beat but decreased LV work in patients with moderate to severe degenerative mitral regurgitation. Further research is needed to determine whether longer-term treatment with β-blockers will decrease progressive LV dysfunction and symptomatic deterioration.
Received February 1, 2008; accepted July 2, 2008.
In asymptomatic patients with moderate to severe mitral regurgitation, a major concern is gradual onset of left ventricular (LV) dysfunction,1 which may be difficult to detect by echocardiography or may be missed between clinic assessments.2,3 A medical treatment that decreases the likelihood of LV dysfunction would therefore be beneficial. In large clinical trials of patients with LV systolic dysfunction, β-blockers improve prognosis4,5 and reduce adverse LV remodeling.6 These favorable effects may be due in part to a long-term reduction in excessive myocyte work, which also occurs in the chronic LV volume overload of mitral regurgitation.7 To date, however, no published clinical trials have evaluated the potential benefits of β-blockers on LV function in patients with severe mitral regurgitation caused by degenerative mitral valve disease.
Clinical Perspective p 1046
In addition to the lack of evidence of long-term effects on LV function and prognosis, data on the effects of β-blockers on mitral regurgitant volume and LV stroke volume are limited in these patients. In degenerative mitral valve prolapse, the severity of regurgitation may vary during systole as the position of the mitral leaflets and the degree of prolapse change.8 The regurgitant volume also may be influenced by changes in LV loading conditions.9 It is therefore possible that changes in heart rate, blood pressure, and LV contractility with β-blockade could influence the mitral regurgitant volume. The aim of this study is to determine the short-term effects of treatment with a β1-adrenergic receptor blocker on the mitral regurgitant volume, LV output (or LV volume pumped per minute), and LV work in patients with moderate to severe mitral regurgitation caused by primary degenerative disease of the mitral valve.
Patients were eligible for the study if they had moderate or severe mitral regurgitation, defined as vena contracta width >3 mm, regurgitant volume >30 mL/beat, effective regurgitant orifice area >0.2 cm2 on Doppler echocardiography, or a combination of these findings.10 All patients had normal LV systolic function on 2-dimensional echocardiography (ejection fraction >55%) and were in sinus rhythm. Patients were excluded if they had New York Heart Association class III or IV symptoms, previous myocardial infarction, angina, significant renal disease (creatinine >0.16 mmol/L), respiratory disease, other significant valvular disease, or a contraindication to β-blocker treatment or cardiac magnetic resonance scanning. Consecutive patients who attended the Green Lane Cardiovascular Service for outpatient evaluation of mitral regurgitation and met study inclusion criteria were invited to participate. The study protocol was approved by the regional ethics committee, and all subjects gave written informed consent.
A double-blind, randomized, crossover design was used. The baseline assessment included a detailed history, clinical examination, 12-lead ECG, 2-dimensional echocardiogram, and Doppler study. Cardiac magnetic resonance imaging was not performed at the baseline assessment. Two treatment periods of 14±3 days were defined, with a washout of 2 to 14 days between treatments. Subjects were randomized double-blind to metoprolol in an extended-release formulation followed by placebo or vice versa. The initial dose was 1 continuous-release Betaloc tablet (47.5 mg) or placebo per day. The dose was increased every 3 to 4 days if the patient had no side effects, resting heart rate was ≥60 bpm, and systolic blood pressure was ≥110 mm Hg, with a maximum dose of 190 mg/d. The dose was reduced if clinically indicated. At the end of each treatment period, a clinical assessment, ECG, and cardiac magnetic resonance scan were performed at a single visit. Nonstudy medication was not changed during the study.
Cardiac Magnetic Resonance Imaging
Gated steady-state free precession anatomic cine images were acquired with a 1.5-T scanner with a phased-array surface coil and ECG R-wave triggering. LV images were acquired in 6 equally spaced short-axis locations from apex to base and 6 long-axis slices orthogonal to the LV short axis orientated at 30° increments while breath holding. Typical imaging parameters were repetition time of 30 ms, echo time of 1.6 ms, flip angle of 60°, field of view of 360 mm, slice thickness of 6 mm, and image matrix of 256×208 at ≈25 cine frames per slice. LV end-systolic and LV end-diastolic volumes were measured with the guide-point modeling method in which the complete beating curved endocardial and epicardial surfaces were accurately re-created using mathematical optimization as previously described.11 LV stroke volume was calculated from the difference between the maximum and minimum LV volumes. Forward stroke volume (or aortic flow volume) was calculated from velocity-encoded phase-contrast images and aortic cross-sectional area measured ≈2 cm above the aortic valve.12 In previous validation experiments in 15 asymptomatic volunteers with no mitral or aortic regurgitation, the difference between ventricular stroke volume and aortic flow volume measured by these methods was <1 mL.11
Mitral regurgitant volume was calculated from the difference between LV stroke volume and aortic flow volume. LV work (in mm Hg×L/min)13 was calculated as LV stroke volume times heart rate times arterial blood pressure (BP) at end systole (Pes), which was calculated as follows: Pes=2/3 systolic BP+1/3 diastolic BP measured by sphygmomanometer.14 LV pump efficiency was calculated from aortic stroke volume per minute divided by LV work.13
Paired comparison of cardiac magnetic resonance measurements on β-blocker and placebo in 25 patients was estimated to have >85% power at the 0.05 significance level for detecting a standardized effect size of 1 in mitral regurgitant volume between treatments. Paired-sample Student t tests or Wilcoxon signed-rank test for nonnormally distributed data was used to compare continuous variables by treatment. Pearson correlation coefficients were reported for linear associations. Two-sided tests were used in all analysis, and a value of P<0.05 was considered statistically significant. SAS 9.1 and R2.1.1 (SAS Institute, Inc, Cary, NC) were used.
The authors had full access to and take full responsibility for the integrity of data. All authors have read and agree to the manuscript as written.
Demographic and clinical data for study participants are presented in Table 1. The mean age was 61±10 years; 21 participants were male. Eighteen patients were asymptomatic, and 7 had mild dyspnea on exertion (New York Heart Association class IIa). Twelve subjects had a history of hypertension treated with an angiotensin-converting enzyme inhibitor (n=8), diuretic (n=1), or β-blocker (n=3). For these 3 patients, the β-blocker was withdrawn 2 weeks before randomization. No patients had diabetes, and no patients were taking antiarrhythmic drugs.
On metoprolol compared with placebo, heart rate decreased by an average of 10±7 bpm, systolic blood pressure decreased by 16±12 mm Hg, and diastolic blood pressure decreased by 6±10 mm Hg. Both LV end-diastolic volume and LV end-systolic volume were slightly greater on metoprolol, but no significant change was noted in LV ejection fraction or LV stroke volume. The decrease in mitral regurgitant volume was small and not statistically significant, but the average increase in forward stroke volume of 5 mL on metoprolol was statistically significant (P=0.03) (Table 2). A modest correlation was found between the decrease in mitral regurgitant volume and decrease in blood pressure on β-blocker (for arterial blood pressure at end systole, r=0.48, P=0.015). A trend was also found for a greater increase in forward stroke volume with a larger decrease in arterial blood pressure at end systole (r=−0.36, P=0.07). No significant association was observed between change in heart rate and change in either mitral regurgitant volume (r=−0.04, P=0.86) or forward stroke volume (r=−0.17, P=0.43) on β-blocker.
Changes in key outcome measures on metoprolol, expressed as a percentage change from the placebo measurement with 95% confidence intervals (CIs), are plotted in Figure 1. Cardiac output was 5.68±1.04 L/min on placebo and decreased by an average of 0.56 L/min or 9% (95% CI, 3 to 15) on metoprolol (P=0.001). LV output was on average 9.51±2.22 L/min on placebo and decreased by an average of 1.30 L/min or 13% (95% CI, 9 to 17; P<0.0001) on metoprolol (Table 3). Therefore, the average decrease in LV output per minute was greater than the decrease in forward cardiac output (1.30 versus 0.56 L/min; P=0.002). This is illustrated for individual subjects in Figure 2. Mitral regurgitant volume was 3.83±2.41 L/min on placebo and decreased by an average of 0.74 L/min or 15% (95% CI, 1 to 27) on metoprolol.
LV work is plotted against mitral regurgitant volume for individual patients in Figure 3. LV work increased with an increase in regurgitant volume on both placebo (r=0.47, P=0.02) and metoprolol (r=0.42, P=0.04). LV work decreased by 21% (95% CI, 16 to 27) on metoprolol compared with placebo. The decrease in LV work was on average greater than the decrease in forward cardiac output (21% versus 9%; P=0.001). LV pump efficiency increased by 18% (95% CI, 8 to 27) on metoprolol compared with placebo (Table 3).
In asymptomatic or mildly symptomatic patients with moderate to severe degenerative mitral regurgitation, short-term treatment with metoprolol decreased both LV output per minute and LV work. Previous research suggests that treatments that decrease LV work, including β-blockers, in general have a favorable effect on LV function in the long term.15 It is therefore possible that the observed effects of β-blockade will translate to a lower risk of LV dysfunction. A decrease in the mitral regurgitant volume per minute also may reduce the adverse consequences of the increased left atrial pressure and volume load, which include atrial fibrillation and pulmonary hypertension.
Several factors contributed to the reduction in LV work on β-blockers. First, the β-blocker decreased blood pressure and therefore LV afterload. Second, slowing of the heart rate resulted in a greater absolute decrease in LV output than cardiac output because LV output includes the regurgitant volume and is therefore larger. By comparison, in patients with no mitral regurgitation, LV and forward outputs decrease by the same amount with a decrease in heart rate. Third, on β-blocker, a small increase in forward stroke volume was found with no increase in mitral regurgitant volume per beat (or a nonsignificant decrease), resulting in a small increase in “effective” forward stroke volume. This finding explains why mitral regurgitant volume per minute decreased more than cardiac output with slowing of the heart rate on metoprolol. Improvement in LV pump efficiency on β-blocker was due predominantly to the reduction in blood pressure, with a small contribution from an increase in effective forward stroke volume. Changes in heart rate do not influence the calculation of LV pump efficiency.
Chronic volume overload is the major factor leading to LV dysfunction in chronic mitral regurgitation. Its pathophysiology is similar to that occurring after myocardial infarction in which progressive LV dilation and increased myocyte work are also present.7 LV function often improves after surgical correction of mitral regurgitation,16 as with chronic LV unloading in severe heart failure by a ventricular assist device.17 Clinical trials have demonstrated favorable effects of β-blockers on LV remodeling6 and on prognosis4,5 in patients with heart failure and after myocardial infarction. In addition, β-blockers reduce LV volumes and the severity of mitral regurgitation in patients with LV systolic dysfunction and mitral annular dilation.18 However, no previous clinical studies have reported the effects of β-blockers in primary mitral valve disease.
Several studies using canine models of mitral regurgitation and heart failure support conclusions from this study. In 1 study, 3-month treatment with atenolol reduced mitral regurgitant volume, improved LV end-systolic stiffness, and decreased left atrial and pulmonary artery pressures, but an angiotensin-converting enzyme inhibitor did not have these favorable effects.19 β-Blockers improve the contractile function of cardiomyocytes isolated from dogs with severe mitral regurgitation by restoring contractile elements.20 However, β-blockers had no favorable effect when pacing is added to increase heart rate, suggesting that slowing of heart rate is an important mechanism of benefit.21
Additional potential beneficial effects of β-blockers were not evaluated in the present study. In heart failure, β-blockers improve myocardial efficiency, defined as myocardial oxygen consumption per unit work.22,23 The present study did not include measurement of myocardial oxygen consumption, and this potential additional effect of β-blockers on myocyte efficiency was not evaluated. The sympathetic nervous system is activated in severe mitral regurgitation,24 and in a dog model of mitral regurgitation, β1-receptor blockade decreases the adverse effects of excess norepinephrine release on myocardial function.25 In large clinical trials, β-blockers decreased the risk of sudden death,4,5 an occasional catastrophic event that is known to occur in asymptomatic patients with mitral regurgitation.26
This study evaluated short-term effects of β-blocker treatment. At ≈14 days, potential favorable effects of the β-blocker on LV function and remodeling are not yet present, and the negative inotropic action of β-blocker is likely to contribute to the reduction in cardiac output.27 On the other hand, the effects of β-blocker on heart rate and blood pressure continue during long-term treatment. Although the present study suggests that β-blockers are likely to be beneficial, a large clinical trial with a parallel-group design is needed to confirm that long-term treatment with β-blockers decreases the risk of LV dysfunction and adverse clinical events in these patients.
A 14-day treatment period was chosen instead of a longer duration to decrease the potential for disease progression or dropouts from referral to surgery and the impact of LV remodeling in a crossover study. In this study, any carryover effects from the first to the second treatment period are likely to be small. A delay of >2 weeks from the last dose of metoprolol to the second study assessment would allow complete elimination of the drug and any post–β-blocker rebound effects to have resolved, and LV remodeling is likely to be minor. Statistical analysis found no difference in the effects of β-blocker compared with placebo by treatment order.
Cardiac magnetic resonance imaging and the crossover design allowed measurement of small changes in LV stroke volume and aortic flow, but estimation of mitral regurgitant volume, which was calculated from these 2 measurements, was less precise. Individual differences in the change in mitral regurgitant volume on metoprolol are likely to reflect both measurement error and differences in the response to treatment. The narrow CIs suggest that on average any effect of metoprolol on beat-by-beat mitral regurgitant volume is small. The impact of mitral regurgitation on LV afterload is uncertain, but the possible error in using arterial blood pressure at end systole to estimate LV work will be similar on β-blocker and placebo.
The study included some patients with early symptoms and with a partial or flail mitral leaflet. These patients were clinically stable during the study, but most were referred for mitral valve surgery within 6 months of study completion. The average age of study participants was similar to that of previous studies, but in this study, 80% of subjects were men. Although early studies of mitral valve prolapse reported a higher prevalence in women, studies of degenerative mitral regurgitation with severe mitral regurgitation or a flail leaflet have reported a male predominance.1 Patients with clinical evidence of coronary artery disease were not eligible for the study, but coronary angiography and stress imaging were undertaken only for a clinical indication. We therefore cannot exclude subclinical coronary artery disease in study participants.
The reduction in LV work on metoprolol was smaller than would be achieved by surgical correction of mitral regurgitation. Evidence for benefit from β-blockers is therefore unlikely to change current indications for surgical valve repair in patients with severe degenerative mitral regurgitation.2,3 However, surgery is not indicated in all patients with moderate to severe mitral regurgitation, including those in whom mitral regurgitation is less severe, in asymptomatic patients when successful valve repair is less likely, and in patients with contraindications to surgery. β-Blockers may have a role in these patients.
In this pilot study of patients with moderate to severe degenerative mitral regurgitation, treatment with a β-blocker did not change beat-by-beat mitral regurgitant volume but decreased mitral regurgitant volume per minute and LV work at the expense of a smaller decrease in cardiac output. These observations support the rationale for undertaking a large randomized clinical trial to determine whether the short-term favorable effects of β-blockers on LV work will translate to a lower risk of progressive LV dysfunction and symptomatic deterioration during long-term treatment.
Sources of Funding
This study was supported by grants from the Auckland Medical Research Foundation and the Green Lane Research and Education Trust, Auckland, New Zealand.
The authors would like to acknowledge Sandra Winsor, Anna-Maria Lydon, and Shelley Park at the Centre for Advanced MRI and Benjamin Wen, Celestina Chang, Augustin Okamura, Lane Jordan, John, John Baek, and Alison Zhang at the Auckland MRI Research Group.
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Mitral valve regurgitation increases left ventricular (LV) stroke volume. Over time, the resulting increase in LV work may cause progressive LV dysfunction, which may be difficult to detect clinically. A medical treatment that decreased this risk would be beneficial. This pilot study determined the short-term effects of a β1-adrenergic receptor blocker on mitral regurgitant volume and LV work in 25 patients with moderate to severe mitral regurgitation caused by primary degenerative disease of the mitral valve. Participants were randomized to both metoprolol and placebo for ≈14 days using a double-blind crossover study design. At the end of each treatment period, forward stroke volume and LV stroke volume were measured by cardiac magnetic resonance imaging, and mitral regurgitant volume and LV work were calculated. On β-blocker compared with placebo, no change was observed in mitral regurgitant volume but a small increase was found in forward stroke volume. Because the β-blocker decreased heart rate, cardiac output was lower. However, the decrease in LV volume pumped per minute was about twice as large as the decrease in forward cardiac output, and LV work was ≈20% lower on metoprolol. These observations suggest that in patients with degenerative mitral regurgitation, long-term treatment with a β-blocker may, by decreasing LV work, reduce the risk of progressive LV dysfunction. A large clinical trial is needed to confirm this hypothesis.