Fatty acid utilization in the hypertrophied and failing heart: Molecular regulatory mechanisms

During the development of cardiac hypertrophy and in the failing heart, the chief myocardial energy source switches from Fatty acid P-oxidation to gly colysis: a reversion to the fetal energy substrate preference pattern. This review describes recent molecular studies aimed at delineating the gene re gulatory pathway involved in the energy metabolic switch in the hypertrophi ed heart and the potential role of the attendant metabolic consequences in the pathogenesis of heart failure. Studies have been performed with the 'sp ontaneous hypertensive and heart failure' rat strain and with human cardiom yopathic tissue. These studies have demonstrated that expression of the gen e that encodes medium-chain acyl-coenzyme A dehydrogenase (MCAD), a key fat ty acid P-oxidation enzyme, is downregulated during the progression from ca rdiac hypertrophy to ventricular dysfunction. A series of studies performed in mice transgenic for the human MCAD gene promoter have identified a tran scriptional regulatory pathway involved in the repression of MCAD gene expr ession in the hypertrophied mouse heart. Two categories of transcription fa ctors, nuclear hormone receptors and Sp factors, bind MCAD gene promoter re gulatory elements in response to pressure overload to reactivate a fetal me tabolic gene program. Studies are under way to manipulate this transcriptio nal regulatory pathway in mice using genetic engineering strategies to dete rmine whether this energy metabolic derangement plays a primary role in the development of cardiac hypertrophy and heart failure.