Background-Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of -amyloid impair cell function and lead to cell death. Methods and Results-We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca 2ϩ homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. Conclusions-On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca 2ϩ handling and a direct effect of PSEN1 sequence variants on excitationcontraction coupling protein function. (Circulation. 2010;121:1216-1226.) Key Words: calcium Ⅲ cardiomyopathy Ⅲ genetics Ⅲ heart failure Ⅲ myocytes I n 1906, Alois Alzheimer discovered, in the brain of a patient suffering from early-age onset of dementia, aggregates of a proteinaceous material, later identified to be composed of amyloid fibers. 1 Alzheimer disease (AD) is associated with several genetic defects and the abnormal accumulation of the amyloid- protein (A) and in the form of extracellular (senile plaques) and intracellular (neurofibrillar tangles) aggregates, respectively. 2 In the heart, amyloid degeneration leading to dilated cardiomyopathy (DCM) has been limited to 3 conditions: (1) light-chain amyloidosis secondary to multiple myeloma; (2) transthyretin cardiomyopathy 3 ; and (3) desmin cardiomyopathy. 4,5 In a smaller number of cases of nonischemic origin, the pathogenesis of heart failure (HF) is infective, toxic, or genetically determined. When 1 of these causative events cannot be recognized, the myocardial disease is classified as idiopathic DCM (iDCM).
Clinical Perspective on p 1226Genetically, DCM has been found in only 35% of HF cases, indicating that the cause of this disease remains largely unknown. 6 Mutations in genes encoding sarcomeric, cytoskeletal, and nuclear proteins as well as proteins involved in the regulation of Ca 2ϩ homeostasis have been described. 7,8 Allelic and locus heterogeneities occur in DCM, 9 and these alterations, together with environmental factors, can disclose an otherwise silent genetic background as occurs in neurodegenerative diseases. Recently, 2 mutations in the familial early-onset AD-associated presenilin genes (PSEN1 D333G and PSEN2 S130L), 2 have been found in 0.9% of tested DCM families (3/325). 10 The presenilins (PS1 and PS2) are highly conserved polytopic membrane proteins that are required for ␥-secretase activity, an enzyme responsible for proteolytic processing of the amyloid precursor protein to genera...
