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A randomized controlled phase IIb trial of beta(1)-receptor blockade for chronic degenerative mitral regurgitation.

ABSTRACT: The purpose of the study was to evaluate the effect of long-term ?(1)-aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR).Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function.Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or ?(1)-AR blockade (Toprol-XL, AstraZeneca, London, United Kingdom) for 2 years. Magnetic resonance imaging with tissue tagging and 3-dimensional analysis was performed at baseline and at 6-month intervals for 2 years. Rate of progression analysis was performed for endpoint variables for primary outcomes: LV end-diastolic volume/body surface area, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV ED 3-dimensional radius/wall thickness; LV end-systolic volume/body surface area, LV longitudinal strain rate, and LV early diastolic filling rate.Baseline LV magnetic resonance imaging or demographic variables did not differ between the 2 groups. Significant treatment effects were found on LV ejection fraction (p = 0.006) and LV early diastolic filling rate (p = 0.001), which decreased over time in untreated patients on an intention-to-treat analysis and remained significant after sensitivity analysis. There were no significant treatment effects found on LV ED or LV end-systolic volumes, LV ED mass/LV ED volume or LV ED 3-dimensional radius/wall thickness, or LV longitudinal strain rate. Over 2 years, 6 patients treated in the placebo group and 2 patients in the ?(1)-AR blockade group required mitral valve surgery (p = 0.23).?(1)-AR blockade improves LV function over a 2-year follow-up in isolated MR and provides the impetus for a large-scale clinical trial with clinical outcomes. (Molecular Mechanisms of Volume Overload-Aim 1 [SCCOR in Cardiac Dysfunction and Disease]; NCT01052428).

SUBMITTER: Ahmed MI

PROVIDER: S-EPMC3914413 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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A randomized controlled phase IIb trial of beta(1)-receptor blockade for chronic degenerative mitral regurgitation.

Ahmed Mustafa I MI Aban Inmaculada I Lloyd Steven G SG Gupta Himanshu H Howard George G Inusah Seidu S Peri Kalyani K Robinson Jessica J Smith Patty P McGiffin David C DC Schiros Chun G CG Denney Thomas T Dell'Italia Louis J LJ

Journal of the American College of Cardiology 20120718 9

<h4>Objectives</h4>The purpose of the study was to evaluate the effect of long-term β(1)-aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR).<h4>Background</h4>Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function.<h4>Methods</h4>Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or β(1)- ...[more]

PMID: 22818065

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Project description:ObjectivesDespite coherent guidelines, management of functional tricuspid regurgitation (FTR) consequences on outcome in the context of degenerative mitral regurgitation (DMR) remains controversial due to lacking series of large magnitude with rigorous application of tricuspid guidelines and strict long-term echocardiographic follow-up. Thus, we aimed at gathering such a cohort to examine outcomes of patients undergoing DMR surgery following tricuspid surgery guidelines.MethodsAll consecutive patients with isolated DMR 2005-2015 operated on with baseline FTR assessment and tricuspid annulus diameter measurement were identified. Operative complications, postoperative tricuspid regurgitation incidence, and survival were assessed overall and stratified by guideline-based tricuspid annuloplasty (TA) indication (severe FTR or tricuspid annulus diameter ≥40 mm).ResultsAmong 441 patients with DMR undergoing mitral repair (66 ± 13 years, 30% female, ejection fraction 66 ± 10%, systolic pulmonary artery pressures 39 ± 12 mm Hg) followed 6 [3-9] years, patients with TA (n = 234, 53%) had generally similar presentation versus without TA (n = 207, 47%; all P ≥ .2) except for more atrial fibrillation and larger left ventricle (both P ≥ .0003). Patients with TA showed longer bypass time, more maze procedures (all P ≤ .001), but hospital stay, renal-failure, pacemaker implantation, and operative mortality (overall 0.9%) were comparable (all P ≥ .2). Postoperative incidence of moderate/severe FTR (0% at 1 year) became over time greater among patients without TA (5-year 8% [4%-13%] vs 3% [1%-11%] and 10-year 10% [6%-16%] vs 4% [1%-16%], P = .01). Survival (95% confidence interval) throughout follow-up was 85% (77%-89%) at 10 years, with hazard ratio 0.57 (0.29-1.10), P = .09. for patients with TA versus without.ConclusionsIn this large surgical DMR cohort, guideline-based FTR management was safe and effective. While long-term mortality did not reach significance, postoperative incidence of moderate/severe FTR, overall low, was nevertheless greater in patients who did not appear to require TA at surgery and linked to tricuspid annular dimension. Thus, future multicenter prospective cohorts with long-term follow-up are warranted to re-examine thresholds for TA performance and impact on survival.

Project description:Introduction: Mitral regurgitation (MR) imposes volume overload on the left ventricle (LV) and elevates wall stress, triggering its adverse remodeling. Pronounced LV dilation, minimal wall thinning, and a gradual decline in cardiac ejection fraction (EF) are observed. The structural changes in the myocardium that define these gross, organ level remodeling are not known. Cardiomyocyte elongation and slippage have both been hypothesized, but neither are confirmed, nor are the changes to the cardiomyocyte structure known. Using a rodent model of MR, we used immunohistochemistry and transmission electron microscopy (TEM) to describe the ultrastructural remodeling of the cardiomyocyte. Methods: Twenty-four male Sprague-Dawley rats (350-400 g) were assigned to two groups: group (1) rats induced with severe MR (n = 18) and group (2) control rats that were healthy and age and weight matched (n = 6). MR was induced in the beating heart using a 23-G ultrasound-guided, transapical needle to perforate the anterior mitral leaflet, and the rats were followed to 2, 10, and 20 weeks (n = 6/time-point). Echocardiography was performed to quantify MR severity and to measure LV volume and function at each time-point. Explanted myocardial tissue were examined with TEM and immunohistochemistry to investigate the ultrastructural changes. Results: MR induced rapid and significant increase in end-diastolic volume (EDV), with a 50% increase by 2 weeks, compared with control. Rise in end-systolic volume (ESV) was more gradual; however, by 20 weeks, both EDV and ESV in MR rats were increased by 126% compared with control. A significant decline in EF was measured at 10 weeks of MR. At the ultrastructural level, as early as 2 weeks after MR, cardiomyocyte elongation and increase in cross-sectional area were observed. TEM depicted sarcomere shortening, with loss of Z-line and I-band. Desmin, a cytoskeletal protein that is uniformly distributed along the length of the cardiomyocyte, was disorganized and localized to the intercalated disc, in the rats induced with MR and not in the controls. In the rats with MR, the linear registry of the mitochondrial arrangement along the sarcomeres was lost, with mitochondrial fragmentation, aggregation around the nucleus, and irregularities in the cristae. Discussion: In the setting of chronic mitral regurgitation, LV dilatation occured by cardiomyocyte elongation, which manifests at the subcellular level as distinct ultrastructural alterations of the sarcomere, cytoskeleton, and mitochondria. Since the cytoskeleton not only provides tensegrity but has functional consequences on myocyte function, further investigation into the impact of cytoskeletal remodeling on progressive heart failure or recovery of function upon correcting the valve lesion are needed.

Project description:OBJECTIVES:The Cardiothoracic Surgical Trials Network recently reported no difference in the primary end point of left ventricular end-systolic volume index at 1 year postsurgery in patients randomized to repair (n = 126) or replacement (n = 125) for severe ischemic mitral regurgitation. However, patients undergoing repair experienced significantly more recurrent mitral regurgitation than patients undergoing replacement (32.6% vs 2.3%). We examined whether baseline echocardiographic and clinical characteristics could identify those who will develop moderate/severe recurrent mitral regurgitation or die. METHODS:Our analysis includes 116 patients who were randomized to and received mitral valve repair. Logistic regression was used to estimate a model-based probability of recurrence or death from baseline factors. Receiver operating characteristic curves were constructed from these estimated probabilities to determine classification cut-points maximizing accuracy of prediction based on sensitivity and specificity. RESULTS:Of the 116 patients, 6 received a replacement before leaving the operating room; all other patients had mild or less mitral regurgitation on intraoperative echocardiogram after repair. During the 2-year follow-up period, 76 patients developed moderate/severe mitral regurgitation or died (53 mitral regurgitation recurrences, 13 mitral regurgitation recurrences and death, and 10 deaths). The mechanism for recurrent mitral regurgitation was largely mitral valve leaflet tethering. Our model (including age, body mass index, sex, race, effective regurgitant orifice area, basal aneurysm/dyskinesis, New York Heart Association class, history of coronary artery bypass grafting, percutaneous coronary intervention, or ventricular arrhythmias) yielded an area under the receiver operating characteristic curve of 0.82. CONCLUSIONS:The model demonstrated good discrimination in identifying patients who will survive 2 years without recurrent mitral regurgitation after mitral valve repair. Although our results require validation, they offer a clinically relevant risk score for selection of surgical candidates for this procedure.

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A randomized controlled phase IIb trial of beta(1)-receptor blockade for chronic degenerative mitral regurgitation.

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A randomized controlled phase IIb trial of beta(1)-receptor blockade for chronic degenerative mitral regurgitation.

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