Are we ready for pharmacogenomics in heart failure?

Heart failure is a major health problem and is associated with a high morta lity and morbidity. Recently, the role of the genetic background in the ons et and development of the disease has been evidenced in both heart failure with and without systolic dysfunction, and in familial and non-familial for ms of this condition. Familial forms of dilated cardiomyopathy are more fre quent than previously thought. Various modes of inheritance and phenotypes have been reported and this condition appears genetically highly heterogeno us. Five genes (dystrophin, cardiac actin, desmin, lamin A/C and delta-sarc oglycan), and additional loci, have been identified in families in which di lated cardiomyopathy is isolated or associated with other cardiac or non-ca rdiac symptoms. It has been postulated that the molecular defect involved c ould lead to abnormal interactions between cytoskeletal proteins, responsib le either for defect in force transmission or for membrane disruption. More recently, the identification of mutations in genes encoding sarcomeric pro teins has led to a second hypothesis in which the disease might also result from a force generation defect. In non-monogenic dilated cardiomyopathy, s usceptibility genes (role in the development of the disease) and modifier g enes (role in the evolution/prognosis of the disease) have so far been iden tified. Some data suggest that the efficacy of angiotensin converting enzym e inhibitors, and side-effects, might be related to some genetic polymorphi sms, such as the I/D polymorphism of the angiotensin converting enzyme gene . Although preliminary, these data are promising and might be the first ste p towards application of pharmacogenetics in heart failure. This is of para mount importance as the medical treatment of heart failure is characterized by the need for polypharmacy. One of the major challenges of the next mill enium, therefore, will he to identify genetic factors which might help defi ne responders to major treatment classes, including angiotensin converting enzyme inhibitors, beta -adrenoreceptor antagonists, angiotensin AT(1) rece ptor antagonists, spironolactone, vasopeptidase inhibitors and endothelin r eceptor antagonists. (C) 2001 Elsevier Science B.V. All rights reserved.