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Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis

Duan Liu1, Min Wang2, Vishakantha Murthy1,2,3

  • 1Departments of Molecular Pharmacology and Experimental Therapeutics (D.L., V.M., T.T.L.N., T.J.P., H.G., R.M.W., N.L.P.), Mayo Clinic, Rochester, MN.

Circulation Research
|October 6, 2023
PubMed

Insights

Genome-wide association study identified CDCP1 as a key gene in myocardial recovery for dilated cardiomyopathy (DCM) patients. This finding offers new insights into heart failure treatment and biomarker discovery.

Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Dilated cardiomyopathy (DCM) is a primary cause of heart failure with high mortality.
  • Patient response to standard drug therapy for DCM-related heart failure is highly variable.
  • Identifying biomarkers for myocardial recovery is crucial for improving patient outcomes.

Purpose of the Study:

  • To identify novel biomarkers for myocardial recovery in DCM using a genome-wide association study (GWAS).
  • To gain insight into the biological mechanisms underlying myocardial recovery in DCM.
  • To investigate the role of identified genetic loci in cardiac function and fibrosis.

Main Methods:

  • Performed a GWAS for changes in left ventricular ejection fraction in 686 White subjects with recent-onset DCM on standard pharmacotherapy.
  • Functionally validated GWAS signals in cellular models to understand molecular mechanisms.
  • Utilized transcriptomic profiling to assess gene function in human cardiac fibroblasts.

Main Results:

  • A significant GWAS signal (rs6773435) mapped to the 5'-flanking region of the CDCP1 gene.
  • The variant allele was associated with improved cardiac function and decreased CDCP1 transcription.
  • CDCP1 knockdown in human cardiac fibroblasts repressed proliferation, decreased AKT phosphorylation, and reduced soluble ST2 expression, indicating a role in attenuating cardiac fibrosis.

Conclusions:

  • CDCP1 plays a significant role in myocardial recovery in recent-onset DCM.
  • CDCP1 mediates its effects primarily by attenuating cardiac fibrosis.
  • The study highlights CDCP1 as a potential therapeutic target and biomarker for DCM.
Abstract

Keywords:
cardiomyopathy, dilatedfibrosisgeneticsgenome-wide association studyheart failurehumansventricular remodeling

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