Review
Are we ready for pharmacogenomics in heart failure?

https://doi.org/10.1016/S0014-2999(01)00878-0Get rights and content

Abstract

Heart failure is a major health problem and is associated with a high mortality and morbidity. Recently, the role of the genetic background in the onset and development of the disease has been evidenced in both heart failure with and without systolic dysfunction, and in familial and non-familial forms of this condition. Familial forms of dilated cardiomyopathy are more frequent than previously thought. Various modes of inheritance and phenotypes have been reported and this condition appears genetically highly heterogenous. Five genes (dystrophin, cardiac actin, desmin, lamin A/C and delta-sarcoglycan), and additional loci, have been identified in families in which dilated cardiomyopathy is isolated or associated with other cardiac or non-cardiac symptoms. It has been postulated that the molecular defect involved could lead to abnormal interactions between cytoskeletal proteins, responsible either for defect in force transmission or for membrane disruption. More recently, the identification of mutations in genes encoding sarcomeric proteins has led to a second hypothesis in which the disease might also result from a force generation defect. In non-monogenic dilated cardiomyopathy, susceptibility genes (role in the development of the disease) and modifier genes (role in the evolution/prognosis of the disease) have so far been identified. Some data suggest that the efficacy of angiotensin converting enzyme inhibitors, and side-effects, might be related to some genetic polymorphisms, such as the I/D polymorphism of the angiotensin converting enzyme gene. Although preliminary, these data are promising and might be the first step towards application of phamacogenetics in heart failure. This is of paramount importance as the medical treatment of heart failure is characterized by the need for polypharmacy. One of the major challenges of the next millenium, therefore, will be to identify genetic factors which might help define responders to major treatment classes, including angiotensin converting enzyme inhibitors, β-adrenoreceptor antagonists, angiotensin AT1 receptor antagonists, spironolactone, vasopeptidase inhibitors and endothelin receptor antagonists.

Section snippets

Familial and monogenic forms of dilated cardiomyopathy

Familial forms of dilated cardiomyopathy had long been underestimated until prospective studies were performed. With such an approach, Michels et al. (1992) found that dilated cardiomyopathy was familial in at least 20% of cases (12 of 59 index patients). This was confirmed subsequently for other populations (familial forms, 20–56% of cases, depending on the studies) Keeling et al., 1995, Grünig et al., 1998, Mestroni et al., 1999a, Mestroni et al., 1999b. In addition, while the diagnosis of

Genetic factors for left ventricular dimensions and function in the general population

In the general population, studies performed in monozygotic and dizygotic twins do not suggest a significant genetic component for left ventricular dimensions (except for left ventricular mass), or for systolic function at rest (Bielen et al., 1991). However, some data indicate that during exercise tests, there is a significant genetic component for the increase of end-diastolic left ventricular dimensions, or of fractional shortening and for the maximal oxygen uptake Bielen et al., 1991,

Genetic factors for non-monogenic forms of systolic dysfunction

In idiopathic heart failure, most cases are sporadic and the disease is considered to be multifactorial with a possible genetic component. Some studies were therefore conducted to identify genetic factors involved in such cases. These factors are either susceptibility genes, factors involved in the pathophysiology of the disease and which influence the emergence of the disease, either modifier genes, factors modifying the expressivity of the disease, and which influence the degree or the

Genetic polymorphisms of the metabolism of drugs used in heart failure

The genetic determinants of the metabolism of certain drugs used in cardiology is one predictable cause of variability in their pharmacokinetics and effects. The main genetic polymorphisms of these drugs are polymorphisms of N angiotensin converting enzyme tylation and the cytochrome P-450 isozymes. Genetic polymorphisms are usually characterized by several metabolic phenotypes, two in most cases, which allow a distinction between fast and slow metabolisers (Funck-Brentano, 1991). For a given

Conclusion

Obviously, the genetic approach to heart failure is only starting and published results are preliminary. However, the analysis of the genetic aspects of heart failure appears promising and various DNA banks are currently being set up on national or international bases. Identification of the genetic alterations involved in either familial or non-familial heart failure should unravel the molecular mechanisms that lead from left ventricular dysfunction to overt heart failure, and allow the

References (67)

  • M.V. Raynolds et al.

    Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy

    Lancet

    (1993)
  • A.M. Remes et al.

    Mitochondrial DNA deletions in dilated cardiomyopathy: a clinical study employing endomyocardial sampling

    J. Am. Coll. Cardiol.

    (1994)
  • N. Sylvius et al.

    A new locus for autosomal dominant dilated cardiomyopathy identified on chromosome 6q12–q16

    Am. J. Hum. Genet.

    (2001)
  • F. Tesson et al.

    Characterization of a unique genetic variant in the beta 1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy

    J. Mol. Cell. Cardiol.

    (1999)
  • L. Tiret et al.

    Lack of association between polymorphisms of eight candidate genes in idiopathic dilated cardiomyopathy

    J. Am. Coll. Cardiol.

    (2000)
  • J.A. Towbin

    Role of cytoskeletal proteins in cardiomyopathies

    Curr. Opin. Cardiol.

    (1998)
  • A.H. Beggs

    Dystrophinopathy, the expanding phenotype. Dystrophin abnormalities in X-linked dilated cardiomyopathy

    Circulation

    (1997)
  • E.C. Bielen et al.

    Inheritance of acute cardiac changes during bicycle exercise: an echocardiographic study in twins

    Med. Sci. Sports Exercise

    (1991)
  • G. Bonne et al.

    Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy

    Nat. Genet.

    (1999)
  • M. Börjesson et al.

    A novel polymorphism in the gene coding for the beta1-adrenergic receptor associated with survival in patients with heart failure

    Eur. Heart J.

    (2000)
  • K.R. Bowles et al.

    Gene mapping of familial autosomal dominant dilated cardiomyopathy to chromosome 10q21–23

    J. Clin. Invest.

    (1996)
  • G.L. Brodsky et al.

    Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement

    Circulation

    (2000)
  • P. Charron et al.

    Identification of a genetic risk factor for idiopathic dilated cardiomyopathy: involvement of a polymorphism in the endothelin receptor type A gene

    Eur. Heart J.

    (1999)
  • M.B. Codd et al.

    Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy

    Circulation

    (1989)
  • M.C. Dalakas et al.

    Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene

    N. Engl. J. Med.

    (2000)
  • S. DiMauro et al.

    Mitochondria and heart disease

    Curr. Opin. Cardiol.

    (1998)
  • J.B. Durand et al.

    Localization of a gene responsible for familial dilated cardiomyopathy to chromosome 1q32

    Circulation

    (1995)
  • D. Fatkin et al.

    Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease

    N. Engl. J. Med.

    (1999)
  • C. Funck-Brentano

    Genetic polymorphism of the metabolism of drugs used in cardiac diseases

    Arch. Mal. Coeur Vaiss.

    (1991)
  • H.H. Goebel

    Desmin-related myopathies

    Curr. Opin. Neurol.

    (1997)
  • R.M. Graham et al.

    Pathogenesis of inherited forms of dilated cardiomyopathy

    N. Engl. J. Med.

    (1999)
  • M. Kamran Baig et al.

    Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease

    J. Am. Coll. Cardiol.

    (1998)
  • S. Ichihara et al.

    Association of a G994T missense mutation in the plasma platelet-activating factor angiotensin converting enzyme thylhydrolase gene with genetic susceptibility to non-familial dilated cardiomyopathy in Japanese

    Circulation

    (1998)
  • Cited by (17)

    View all citing articles on Scopus
    View full text