NYMC Faculty Publications

Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study

Mark Hofmeyer, MedStar Health Research Institute, Medstar Washington Hospital Center, Washington, DC (M.H.).
Garrie J. Haas, The Davis Heart and Lung Research Institute (G.J.H., E.J., J.C., D.D.K., H.N., R.E.H.), Department of Internal Medicine, The Ohio State University, Columbus.
Elizabeth Jordan, The Davis Heart and Lung Research Institute (G.J.H., E.J., J.C., D.D.K., H.N., R.E.H.), Department of Internal Medicine, The Ohio State University, Columbus.
Jinwen Cao, The Davis Heart and Lung Research Institute (G.J.H., E.J., J.C., D.D.K., H.N., R.E.H.), Department of Internal Medicine, The Ohio State University, Columbus.
Evan Kransdorf, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (E.K.).
Gregory A. Ewald, Washington University, St Louis, MO (G.A.E.).
Alanna A. Morris, Emory University School of Medicine, Atlanta, GA (A.A.M.).
Anjali Owens, Center for Inherited Cardiovascular Disease, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (A.O.).
Brian Lowes, University of Nebraska Medical Center, Omaha (B.L., D.S.).
Douglas Stoller, University of Nebraska Medical Center, Omaha (B.L., D.S.).
W H. Wilson Tang, Heart Vascular and Thoracic Institute, Cleveland Clinic, OH (W.H.W.T.).
Sonia Garg, University of Texas Southwestern Medical Center, Dallas (S.G.).
Barry H. Trachtenberg, Houston Methodist DeBakey Heart and Vascular Center, J.C. Walter Jr Transplant Center, TX (B.H.T.).
Palak Shah, Inova Heart and Vascular Institute, Falls Church, VA (P.S.).
Salpy V. Pamboukian, University of Alabama, Birmingham, during study conduct; current affiliation, University of Washington, Seattle (S.V.P.).
Nancy K. Sweitzer, Sarver Heart Center, University of Arizona, Tucson, during study conduct; current affiliation, Washington University, St Louis, MO (N.K.S.).
Matthew T. Wheeler, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (M.T.W.).
Jane E. Wilcox, Northwestern University Feinberg School of Medicine, Chicago, IL (J.E.W.).
Stuart Katz, New York University Langone Medical Center, New York (S.K., S.P.).
Stephen Pan, New York University Langone Medical Center, New York (S.K., S.P.).Follow
Javier Jimenez, Miami Cardiac & Vascular Institute, Baptist Health South, FL (J.J.).
Frank Smart, Louisiana State University Health Sciences Center, New Orleans (F.S.).
Jessica Wang, University of California Los Angeles Medical Center (J.W.).
Stephen S. Gottlieb, University of Maryland School of Medicine, Baltimore (S.S.G.).
Daniel P. Judge, Medical University of South Carolina, Charleston (D.P.J.).
Charles K. Moore, University of Mississippi Medical Center, Jackson (C.K.M.).
Gordon S. Huggins
Daniel D. Kinnamon, The Davis Heart and Lung Research Institute (G.J.H., E.J., J.C., D.D.K., H.N., R.E.H.), Department of Internal Medicine, The Ohio State University, Columbus.
Hanyu Ni, The Davis Heart and Lung Research Institute (G.J.H., E.J., J.C., D.D.K., H.N., R.E.H.), Department of Internal Medicine, The Ohio State University, Columbus.
Ray E. Hershberger, The Davis Heart and Lung Research Institute (G.J.H., E.J., J.C., D.D.K., H.N., R.E.H.), Department of Internal Medicine, The Ohio State University, Columbus.

Author Type(s)

Faculty

DOI

10.1161/CIRCULATIONAHA.123.064847

Journal Title

Circulation

First Page

872

Last Page

881

Document Type

Article

Publication Date

9-12-2023

Department

Medicine

Abstract

BACKGROUND: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS: Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

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