Keir McCutcheon1,2, Caroline Dickens3, Jos van Pelt4, Therese Dix-Peek3, Sacha Grinter1, Lindsay McCutcheon1, Atulkumar Patel5, Martin Hale6, Nqoba Tsabedze1, Ahmed Vachiat1, Don Zachariah1, Raquel Duarte3, Stefan Janssens2,7, Pravin Manga1. 1. Division of Cardiology, Department of Internal Medicine (K.M., S.G., L.M., N.T., A.V., D.Z., P.M.), Charlotte Maxeke Johannesburg Academic Hospital & University of the Witwatersrand, Johannesburg, South Africa. 2. Department of Cardiovascular Diseases, University Hospitals Leuven, Belgium (K.M., S.J.). 3. Molecular Biology Laboratory, Department of Internal Medicine (C.D., T.D.-P., R.D.), University of the Witwatersrand, Johannesburg, South Africa. 4. Department of Clinical Digestive Oncology, Faculty of Medicine, Katholieke Universiteit, Leuven and Leuven Cancer Institute, Leuven, Belgium (J.v.P.). 5. Department of Cardiothoracic Surgery (A.P.), Charlotte Maxeke Johannesburg Academic Hospital & University of the Witwatersrand, Johannesburg, South Africa. 6. Department of Anatomical Pathology (M.H.), University of the Witwatersrand, Johannesburg, South Africa. 7. Department of Cardiovascular Sciences, Katholieke Universiteit, Leuven, Belgium (S.J.).
Abstract
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.
RCT Entities:
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.
Authors: Thanh Thanh L Nguyen; Min Wang; Duan Liu; Seethalakshmi Iyer; Hilda Mariana Gonzalez Bonilla; Nancy Acker; Vishakantha Murthy; Sanskriti Shrivastava; Viral Desai; John C Burnett; Margaret Redfield; Kent R Bailey; Richard M Weinshilboum; Naveen L Pereira Journal: Circ Heart Fail Date: 2022-06-03 Impact factor: 10.447