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Background: We reported 3 novel nonsynonymous single nucleotide variants of Bcl2-associated athanogene 3 (BAG3) in African Americans with heart failure (HF) that are associated with a 2-fold increase in cardiac events (HF hospitalization, heart transplantation, or death)., Methods and Results: We expressed BAG3 variants (P63A, P380S, and A479V) via adenovirus-mediated gene transfer in adult left ventricular myocytes isolated from either wild-type (WT) or cardiac-specific BAG3 haploinsufficient (cBAG3 +/- ) mice: the latter to simulate the clinical situation in which BAG3 variants are only found on 1 allele. Compared with WT myocytes, cBAG3 +/- myocytes expressed approximately 50% of endogenous BAG3 levels and exhibited decreased [Ca 2+ ] i and contraction amplitudes after isoproterenol owing to decreased L-type Ca 2+ current. BAG3 repletion with WT BAG3 but not P380S, A479V, or P63A/P380S variants restored contraction amplitudes in cBAG3 +/- myocytes to those measured in WT myocytes, suggesting excitation-contraction abnormalities partly account for HF in patients harboring these mutants. Because P63A is near the WW domain (residues 21-55) and A479V is in the BAG domain (residues 420-499), we expressed BAG3 deletion mutants (Δ1-61 and Δ421-575) in WT myocytes and demonstrated that the BAG but not the WW domain was involved in enhancement of excitation-contraction by isoproterenol., Conclusions: The BAG3 variants contribute to HF in African American patients partly by decreasing myocyte excitation-contraction under stress, and that both the BAG and PXXP domains are involved in mediating β-adrenergic responsiveness in myocytes., Competing Interests: Declaration of competing interest K.K. is a board member, scientific advisor, and holds equity in Excision Biotherapeutics, a biotech start-up that has licensed the viral gene editing technology from Temple University for commercial development and clinical trials. A.M.F. and K.K. have a pending US patent #611934,483 for BAG3 as a target for heart failure therapy. A.M.F. and J.Y.C. have a pending US patent #621205,990 for BAG3 composition and methods. Exclusive rights to the patents have been optioned by Temple University to Renovacor, Inc. A.M.F. and J.Y.C. hold equity in Renovacor, Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)