Background:There is no proven medical therapy that attenuates adverse left ventricular remodeling in patients with chronic primary mitral regurgitation (CPMR). Identification of molecular pathways important in the progression of left ventricular remodeling in patients with CPMR may lead to development of new therapeutic strategies.Methods and Results:We performed baseline echocardiographic, cardiac catheterization, and serum NT-pro-BNP analysis in patients with severe CPMR awaiting mitral valve surgery and stratified the study population into compensated or decompensated CPMR. We obtained left ventricular endomyocardial biopsies (n=12) for mRNA expression analysis, and compared baseline transcript levels of 109 genes important in volume-overload left ventricular remodeling with levels in normal hearts (n=5) and between patients with compensated (n=6) versus decompensated (n=6) CPMR. Patients were then randomized to treatment with and without carvedilol and followed until the time of surgery (mean follow-up 8.3 months) when repeat endomyocardial biopsies were obtained to correlate transcriptional dynamics with indices of adverse remodeling. CPMR was associated with increased NPPA expression levels (21.6-fold, P=0.004), decreased transcripts of genes important in cell survival, and enrichment of extracellular matrix genes. Decompensated CPMR was associated with downregulation of SERCA2 (0.77-fold, P=0.009) and mitochondrial gene expression levels and upregulation of genes related to inflammation, the extracellular matrix, and apoptosis, which were refractory to carvedilol therapy.Conclusions:Transition to decompensated CPMR is associated with calcium dysregulation, increased expression of inflammatory, extracellular matrix and apoptotic genes, and downregulation of genes important in bioenergetics. These changes are not attenuated by carvedilol therapy and highlight the need for development of specific combinatorial therapies, targeting myocardial inflammation and apoptosis, together with urgent surgical or percutaneous valve interventions.

中文翻译：

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代偿性和代偿性慢性原发性二尖瓣关闭不全患者左心室重构不良分子特征的动态变化。

背景：目前尚无有效的药物疗法可减轻慢性原发性二尖瓣关闭不全（CPMR）患者的不良左心室重塑。识别对CPMR患者左心室重构有重要意义的分子途径可能会导致新的治疗策略的发展。方法和结果：我们对严重CPMR患者进行了基线超声心动图，心脏导管检查和血清NT-pro-BNP分析等待二尖瓣手术，并将研究人群分为补偿后或补偿后的CPMR。我们获得了左室心肌内膜活检标本（n = 12）用于mRNA表达分析，并比较了正常心脏（n = 5）以及补偿（n = 6）与失代偿（n = 6）CPMR患者之间的109个在超负荷左心室重塑中重要的基因的基线转录水平。然后将患者随机分为接受卡维地洛和不接受卡维地洛的治疗，直到手术时间（平均随访8.3个月），之后再次进行心内膜活检，以将转录动力学与不良重塑指数相关联。CPMR与增加NPPA表达水平（21.6倍，P = 0.004），对细胞存活重要的基因转录物减少以及细胞外基质基因的富集。失代偿的CPMR与SERCA2的下调相关（0.77倍，P= 0.009）和线粒体基因表达水平以及与炎症，细胞外基质和细胞凋亡相关的基因的上调，这对卡维地洛治疗是难治的。凋亡基因，以及在生物能学中重要的基因的下调。卡维地洛治疗并不能减轻这些变化，并强调需要开发针对心肌炎症和细胞凋亡的特定组合疗法，以及紧急的外科手术或经皮瓣膜干预。