Can a β-adrenergic receptor blocker reverse or at least attenuate left ventricular remodelling due to chronic non-ischaemic(primary) mitral regurgitation?

Abstract

Rheumatic Heart Disease (RHD) is one of the main causes of heart failure in Africa. One of the major manifestations of RHD is chronic primary mitral regurgitation (CPMR), which causes an abnormal volume overload on the left ventricle (LV) resulting in adverse LV remodelling. Currently, no medical therapy has been proven to attenuate this adverse remodelling or to improve outcomes in patients with CPMR. Beta-adrenergic receptor blockers have been found to attenuate LV adverse remodelling in animal models of CPMR and in humans with heart failure due to systolic dysfunction, but no prior study has prospectively examined the LV response to carvedilol in patients with CPMR. The current study was divided in to three components. Firstly, clinical, echocardiographic and serum markers of LV remodelling were measured in CPMR patients in response to carvedilol therapy. Secondly, the expression of genes, important in LV remodelling, was compared between patients with CPMR and tissue from normal hearts in order to establish baseline abnormalities in gene expression levels in CPMR. Lastly, changes in LV remodelling gene expression were measured in response to carvedilol therapy in the patients with CPMR. Twenty consecutive patients with isolated CPMR, who met pre-specified inclusion and exclusion criteria, were recruited to the study over a five-year period. Seven patients did not complete the study. Following baseline investigations including clinical evaluation, transthoracic echocardiography (TTE), serum analysis and LV endomyocardial biopsy (EMB), thirteen patients with severe CPMR awaiting mitral valve surgery were randomized to carvedilol therapy (n=7) or standard of care (n=6). At the time of surgery (at a median of 10 and 7 months after baseline in the two groups, respectively), noninvasive investigations and EMB were repeated. Baseline expression levels of 109 genes important in volume-overload LV remodelling were compared with levels in normal hearts (n=5). To account for the small sample size, patients were used as their own controls in order to counter heterogeneity within the two groups. Carvedilol failed to improve serum or echocardiographic measures of LV remodelling. In particular, in patients treated with carvedilol TTE measures of LV function did not improve while measures of right ventricular function deteriorated. Furthermore, serum markers of adverse cardiac function, including MMP-2, Fas and NT-pro-BNP increased in patients treated with carvedilol. At baseline, compared with normal hearts, patients with severe CPMR displayed abnormal expression of a number of genes important in β-adrenergic signalling, calcium handling, cell survival, apoptosis and extra-cellular matrix regulation. This is the first study to demonstrate significant down-regulation the β-adrenergic receptor-1 and the angiotensin- II-receptor-1 genes in patients with severe CPMR. Subsequently, after treatment with carvedilol, there was significant down-regulation of cardio-protective β-arrestin2, PDE1A, and PDGFα and a trend towards significant down-regulation of cardio-protective PDE4D. Significant up-regulation of PLN, which has previously been found to be associated with abnormal calcium regulation, contractile dysfunction and premature cardiac death, was noted in patients treated with carvedilol. Taken together, these findings suggest that carvedilol fails to attenuate adverse remodelling in patients with severe chronic primary mitral regurgitation.