Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of <i>CDCP1</i> and Cardiac Fibrosis
Duan Liu, Min Wang, Vishakantha Murthy, Dennis M. McNamara, Thanh Thanh L. Nguyen, Trudy Janice Philips, Hridyanshu Vyas, Huanyao Gao, Jyotan Sahni, Randall C. Starling, Leslie T. Cooper, Michelle Skime, Anthony Batzler, Gregory D. Jenkins, Simona Barlera, Silvana Pileggi, Luisa Mestroni, Marco Merlo, Gianfranco Sinagra, F Pinet, Jan Krejčí, Anna Chaloupka, Jordan D. Miller, Pascal de Groote, Daniel J. Tschumperlin, Richard M. Weinshilboum, Naveen L. Pereira
Abstract
BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.