Number 21, 2003
Hibernation preconditioning

Hypertrophic cardiomyopathies: role of genetic mutations in proteins involved in sarcomere function and energy metabolism in the pathogenesis of this disorder

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Gary Lopaschuk
Cardiovascular Research Group, University of Alberta, Edmonton, Canada
Correspondence: Professor Gary Lopaschuk, 423 Heritage Medical Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta Canada T6G 2S2.
Tel: +17804922170, fax: +17804929753, e-mail: gary.lopaschuk@ualberta.ca

Hypertrophic cardiomyopathy (HCM) is usually associated with hypertrophy of the left ventricle in the absence of dilatation of the ventricular chamber. Diastolic dysfunction is a common feature of HCM, due both to impaired relaxation and reduced compliance. A greater susceptibility to arrhythmias and sudden death is also associated with HCM. The hypertrophy associated with HCM does not occur due to other causes of hypertropy (such as hypertension or aortic stenosis), but rather due to genetically heterogenous causes. Mutations in a number of different genes have been associated with HCM, many of these occurring in the cardiac sarcomeric proteins. The genetics of hypertrophic cardiomyopathy is nicely reviewed in this issue by Drs Kok and Baars, who describe the major sarcomeric protein mutations that result in hypertrophic cardiomyopathy. These authors also discuss the metabolic counseling that should be provided to patients with HCM.
The goal of therapy in symptomatic patients with HCM is to improve functional capacity and to improve the outflow tract gradient. Medical therapy with negative inotropic drugs such as ß-blockers, verapamil, or disopyramide are a first-line approach to treating HCM. In this issue, Dr McKenna and colleagues outline the current clinical management of HCM. The need to treat arrhythmias that can lead to sudden death is also stressed in these patients. However, patients with marked outflow tract obstruction may be unresponsive to medical therapy. This is important, since a significant proportion of patients with HCM have intraventricular pressure gradients due to left ventricular outflow tract obstruction. In this issue, Drs Seggerwiss and Rigopoulos update the use of percutaneous transluminal septal myocardial ablation through alcohol-induced ablations of a septal branch as an approach to improve left ventricular outflow tract gradient.
Alterations in energy metabolism may also be an important contributor to contractile dysfunction in HCM patients. Impairment in oxidative metabolism is an early manifestation of HCM that may contribute to an energetic deficiency. The cardiac metabolic changes observed in HCM patients are nicely reviewed in this issue by Dr Tadamura. The concept that energetics is compromised in HCM is supported by a recent study by Javadpour et al [1], who show a decreased energetic driving force within the cardiomyocytes of mice containing a common sarcomeric mutation seen in HCM. This suggests that sarcomeric mutations in HCM can enhance the activation of myofibrillar ATPase activity, resulting in an excessive energy utilization by the contractile proteins. It also raises the intriguing possibility that a mismatch in energy use by the heart may be one of the pathogenic mechanisms of familial HCM.
In addition to sarcomeric mutations resulting in an energetically deficient heart, evidence is also emerging that mutations in proteins involved in energy metabolism can contribute to HCM. Considerable interest has recently been generated in the possible involvement of mutations in AMP-activated protein kinase (AMPK), as a cause of hypertrophic cardiomyoapthy [2,3,4]. AMPK is an important “fuel sensor” in the heart, that controls both fatty acid oxidation [5] and glucose uptake [6]. Mutations in the gamma subunit of AMPK are associated with HCM, glycogen accumulation in the heart, and electrophysiological abnormalities. In this issue, Dr Redwood discusses the potential involvement of AMPK mutations, as well as sarcomeric protein mutations, as contributing factors to energetic compromise in HCM. The key role that these mutations have in alterations in calcium homeostasis in HCM is also discussed.
Although the genetic mutations in HCM are diverse, understanding the cellular changes that occur in HCM should provide new and specific approaches to treating the clinical complications of HCM. While targeting the sarcomere is one potential approach, optimizing energy production in the heart may be another novel therapeutic approach to treating HCM.▪

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REFERENCES

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