Effects of Early, Late, and Long-term Nonselective β-Blockade on Left Ventricular Remodeling, Function, and Survival in Chronic Organic Mitral Regurgitation

Abstract

Background-Mitral regurgitation (MR) produces sympathetic nervous system activation which is detrimental in other causes of heart failure. However, whether β-blockade is beneficial in MR has not been determined. Methods and Results-Eighty-seven rats with significant organic MR were randomized to the β-blockade group (n=43) or the control group (n=44). Carvedilol was started in week 2 post MR induction and given for 23 to 35 weeks in the β-blockade group. Echocardiography was performed at baseline and at weeks 2, 6, 12, 24, 30, and 36 after MR induction. After 23 weeks of β-blockade, heart rates were significantly reduced by carvedilol (308±25 versus 351±31 beats per minute; P<0.001). Left ventricular end-diastolic (2.2±0.7 versus 1.59±0.6 mL; P<0.001), end-systolic volumes (0.72±0.42 versus 0.40±0.19 mL; P<0.001), and mass index (2.40±0.55 versus 2.06±0.62 g/kg; P<0.001) were significantly higher, and left ventricular fraction shortening (33±7% versus 38±7%; P<0.001) and ejection fraction (69±11% versus 75±7%; P<0.001) were significantly lower in the β-blockade group than in the control group. Systolic blood pressure was lower in the β-blockade group than in the control group (114±10 versus 93±12 mm Hg; P<0.005). Survival probability was significantly lower in the early β-blockade group than in the control group (88% versus 96%; P=0.03). 14 This dissociation creates a possible pathophysiological contradiction because adverse LV remolding is often associated with LV dysfunction and poor long-term outcome in all forms of congestive heart failure. Therefore, it is important to determine whether beneficial effects of β-blockade could be demonstrated if chronic organic MR was treated in the early stages before the development of LV dysfunction and if treatment is long-term. It is also imperative to determine whether LV remodeling associated with β-blocker therapy could ultimately have a negative impact on LV function in chronic organic MR or if the early improvement in LV function and myocardial contractility observed in prior studies could lead to improvement in LV remodeling if treatment was initiated early and long-term. To clarify this important issue, we performed a prospective study to determine the effects of early, late, and long-term β-blockade on LV remodeling, systolic function, and survival in experimental chronic MR. The study design had the following unique characteristics: (1) the study used a unique rat model of chronic MR developed in our laboratory, 15 allowing us to use a large numbers of animals to test the hypothesis; (2) carvedilol (a nonselective β-adrenergic blocking agent with α 1 -blocking activity) was administered early before the development of LV systolic dysfunction; and (3) a long-term treatment strategy was applied. Conclusions-Early Methods Rat Model of MRThe study protocol was approved by the Institution's Animal Care and Use Committee of the Pennsylvania State University College of Medicine (assurance number A3045-01). The study was performed according to the guidelines of the Amer...

Impact of Beta-Blockade on Cardiac Events in Patients with Chronic Severe Nonischemic Mitral Regurgitation

“…The acuity and severity of surgically created MR in animal models versus the physiological response to chronic and gradually worsening MR in humans, along with differences in heart rate response and the use of different beta-blockers in different studies, had precluded firm conclusions on the utility of beta-blockers in this clinical setting [20]. In this context, our study provides insight into the effects of beta-blockers among initially asymptomatic patients with chronic severe nonischemic MR. Our data are consistent with previous studies which suggested an increase in LV dimension with use of beta-blockers [12,17,19], which could accelerate the development of commonly accepted indications for mitral valve surgery.…”

“…Moreover, subsequent studies failed to support a reduction in LV volumes with beta-blockade [15,17]. On the contrary, in an animal model of surgically induced MR, a reduction in heart rate associated with the use of nonselective beta-blockade with carvedilol resulted in significantly decreased LVEF and increased LV volumes and mortality [12,13]. …”

“…Beta-blockade in patients with primary (“organic”) MR has never produced beneficial effects on LV remodeling [11,19]. In contrast, in rats, Pu et al [12] reported that beta-blockers accelerate the progression of LV remodeling with worsening of LV function. The acuity and severity of surgically created MR in animal models versus the physiological response to chronic and gradually worsening MR in humans, along with differences in heart rate response and the use of different beta-blockers in different studies, had precluded firm conclusions on the utility of beta-blockers in this clinical setting [20].…”

“…Though definitive randomized controlled trials of beta-blockade in humans with MR have not been performed, pathophysiological studies in animals and humans [6,7,8,9] and observational data in humans [10], as well as a small randomized trial with inconclusive results [11], have suggested a benefit of beta-blockade. However, a recent randomized trial of beta-blockade in rats with surgically induced MR showed a significant reduction in survival with beta-blockade [12,13]. In the absence of definitive data, this observational study aims to determine the relationship between chronic beta-blockade and clinical outcomes among initially asymptomatic patients with chronic severe nonischemic (i.e., organic) MR. …”

Drug Therapy for Heart Valve Diseases

“…In animal models of chronic MR, beta blockade improves intrinsic contractile function of isolated cardiomyocytes and increases contractile elements 88, 89 . However, disturbingly, in a recent study of rodents with surgically-induced MR, carvedilol-mediated reduction in heart rate resulted in significant decrease in LVEF, increase in LV volumes and, most importantly, increase in mortality compared with no therapy 90, 91 .…”