Molecular etiologies of heart failure, an emerging cardiovascular epidemic 
affecting 4.7 million Americans and costing 17.8 billion health-care dollars 
annually, remain poorly understood. Here we report that an inherited human 
dilated cardiomyopathy with refractory congestive heart failure is caused by a 
dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban 
(PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic 
reticular Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice 
recapitulated human heart failure with premature death. Cellular and biochemical 
studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit 
SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked 
PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of 
calcium transients in myocytes. These results indicate that myocellular calcium 
dysregulation can initiate human heart failure-a finding that may lead to 
therapeutic opportunities.