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European Journal of Heart Failure 1999 1(2):121-126; doi:10.1016/S1388-9842(99)00026-4
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© 1999 European Society of Cardiology

Genetic aspects of heart failure

Michel Komajda*, Philippe Charron and Frédérique Tesson

Association Claude Bernard, Université Paris VI, Hôpital Pitié, Salpêtrière, Service de Cardiologie 47–83 Boulevard de l'Hôpital, 75013 Paris, France

* Corresponding author. Tel.: +33-142-176-814; fax: +33-142-176-800


   Abstract
Top
 Abstract
1. Introduction
 2. Genetic aspects of...
 3. Genetic aspects of...
 4. Conclusion and perspectives
 References
 
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 the 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. Preliminary studies suggest that the I/D polymorphism of the Angiotensin Converting Enzyme gene influence the development of left ventricular hypertrophy, a major determinant of heart failure. Familial hypertrophic cardiomyopathy (FHC) is a highly heterogenous autosomal dominant disease. Seven genes have been identified which all encode proteins of the sarcomere or proteins involved in the regulation of contraction. More than one hundred mutations have been evidenced. Modifier genes such as the I/D polymorphism seem to play a role in the expression of the disease. Susceptibility genes have been searched for in sporadic forms of dilated cardiomyopathy and conflicting results have been published with regard to the I/D polymorphism. Finally, familial forms of dilated cardiomyopathy (FDC) are frequent. Various modes of inheritance and phenotypes have been reported and this condition appears genetically highly heterogenous. It has been postulated that the molecular defect involved in FDC is an abnormality in the transmission of contractile force. The analysis of genetic factors that predispose to heart failure looks promising: it should allow better understanding of the underlying mechanisms that promote the progression of the disease, to identify subjects at risk of the disease who would benefit from early medical management and promote the development of pharmacogenetics.

Key Words: Genetics • Heart failure • Hypertrophic cardiomyopathy • Dilated cardiomyopathy • Left ventricular hypertrophy

Accepted November 18, 1998


   1. Introduction
Top
 Abstract
 1. Introduction
2. Genetic aspects of...
 3. Genetic aspects of...
 4. Conclusion and perspectives
 References
 
Heart failure is a condition associated with a high morbidity and mortality and is the final pathway of many cardiovascular problems. Thus, the socio-economic impact of this syndrome is important. The understanding of factors associated with the development and the progression of heart failure has considerably evolved during the past decades and the pivotal role of factors such as neurohormonal stimulation has been emphasised. However, only recently has the potential role of genetic factors been identified. This article will briefly review the current knowledge of familial and non-familial heart failure.


   2. Genetic aspects of heart failure with normal systolic function
Top
 Abstract
 1. Introduction
 2. Genetic aspects of...
3. Genetic aspects of...
 4. Conclusion and perspectives
 References
 
Left ventricular hypertrophy (LVH) is a major and independent risk factor for morbidity and mortality in cardiovascular diseases [1], even among normotensive subjects. In addition, the degree of hypertrophy in response to pressure overload may vary to a great extent. The reason why some individuals but not others develop LVH in the presence of a similar pressure overload remains largely unknown and it has been suggested that the genetic background may play a role.

2.1. Non-familial hypertrophic cardiomyopathy
Even in non-familial forms of HCM, some studies indicate that the genetic background contributes to the regulation of cardiac hypertrophy, in addition to other factors including blood pressure, age, gender, body surface area, exercise, etc. Indeed, the analysis of monozygotic and dizygotic twins indicates that LV mass is partly determined by familial influence [2] and it was suggested that over 60% of the variability in LV mass can be explained by heritable factors [3,4].

Since clinical and experimental data point out the role of the local renin–angiotensin system in myocardial growth, it has been suggested that polymorphisms of the genes involved in this pathway play a role in the genetic predisposition to LVH. Rigat et al. described in 1990 a genetic polymorphism in intron 16 of the ACE gene, characterised by an insertion (I) or a deletion (D) of a 287-bp sequence [5]. This ACE I/D polymorphism is strongly related to ACE plasma level and myocardial concentration. The fact that the ACE I/D polymorphism has a functional role by itself or is only a marker in linkage disequilibrium with a functional variant remains debated.

So far, the ACE gene has been therefore the most studied polymorphism in relation to LVH. Results of studies are conflicting, some studies find an association between the ACE I/D polymorphism and LVH whereas others do not. Shunkert et al. studied 717 men and 711 women selected from the population covered by the Monica register of Augsburg (Germany) [4]. In this population, the D allele was associated with LVH defined by electrocardiography (odds ratio, 1.76; 95% CI, 1.50–2.53) and the association was stronger in men and in normotensive subjects. In contrast, a lack of association was found between the polymorphism and LVH (determined by echocardiography) in the study by Lindpainter et al., which examined 2439 subjects from the Framingham Heart Study [6]. The exact role of the ACE I/D polymorphism remains therefore to be determined. However, the impact of this polymorphism may be more pronounced when the heart is under stress or when the renin–angiotensin system is also activated for other reasons. Montgomery et al. recently examined 140 male recruits form the British Army who were submitted to a 10-week intensive stress exercise training. Subjects with the DD genotype displayed the most important increase of left ventricular mass as estimated by echocardiography, electrocardiography or BNP measurements [7]. Further investigations in British Army recruits and in elite mountaineers confirmed the role of the ACE I/D polymorphism in physical performance [8]. The ACE polymorphism may therefore act only under specific conditions suggesting an interaction between ACE polymorphism and pressure overload, or other factors, in the modulation of LV mass. The hypothesis is strengthened by other observations. In subjects with aortic stenosis, LV wall thickness was higher in patients with the DD genotype [9]; and after renal transplantation, the increase of LV mass was significantly higher in subjects with the DD genotype [10].

2.2. Familial HCM
The prevalence of idiopathic forms of LVH was recently reported to be as high as 0.2% in young adults [11]. More than 50% of such cases are familial forms of the disease and the mode of inheritance of familial hypertrophic cardiomyopathy (FHC) is usually autosomal dominant [12]. The results of molecular genetic studies have shown that the disease is genetically heterogeneous since seven different responsible genes have been identified as responsible for the disease (Table 1). All these genes encode proteins of the myofilaments in the sarcomere: the β-myosin heavy chain, ventricular myosin essential and regulatory light chains, cardiac troponin T and I, cardiac myosin binding protein C and {alpha}-tropomyosin [13]. Numerous mutations have been identified within each of these genes (more than 100 mutations in all genes), and none of them predominates in spite of some hot spots for codon mutations.


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  		Table 1
 
Due to the great clinical and genetic heterogeneity, studies were performed to determine whether the genetic heterogeneity could account for the phenotypic heterogeneity. Results should be considered as preliminary but several concepts begin to emerge. In families related to the β-MHC gene, the phenotype varies considerably according to the mutation. Some mutations were associated with a malignant or a benign prognosis. For example, the Arg403Gly mutation appears associated with a complete penetrance in adults, a high degree of hypertrophy and a markedly reduced survival [14]. In contrast, the Val606Met was associated with a low penetrance and a very good prognosis [14]. In families related to the cardiac troponin T gene, the phenotype appears similar for the different mutations, and characterised by an incomplete penetrance (75%), a relatively mild and sometimes subclinical hypertrophy (mean 17±5 mm) but a high incidence of sudden death before 30 years of age [15]. In families related to the cardiac myosin binding protein C gene, the phenotype appears also similar for the different mutations and characterised by a low penetrance and degree of hypertrophy before 30 years of age (respectively 41% and 12±4 mm), a delayed age at onset of symptoms and a favourable prognosis before 30 years of age [16,17]. All these results could be particularly useful in the risk stratification of patients with FHC and allow a better clinical management and genetic counselling. However, caution is required and further studies are needed to confirm these data since some exceptions to these general phenotype–genotype correlations have been reported [18–20].

Because of the great variability of the phenotype among subjects, even in a given family, genetic and/or environmental factors are certainly implied in the expression of the disease. The ACE I/D polymorphism was studied in FHC, and the DD genotype was associated with a greater LVH mass [21] and a higher incidence of sudden deaths [22]. In genotyped families, however, the effect of the DD genotype differed according to the gene and mutation involved. There was a strong association only in subjects with a mutation in codon 403 of the beta MHC gene [23]. Finally, a polymorphism in the endothelin 1 gene was recently found to be associated with the degree of LVH [24].


   3. Genetic aspects of heart failure associated with systolic dysfunction
Top
 Abstract
 1. Introduction
 2. Genetic aspects of...
 3. Genetic aspects of...
4. Conclusion and perspectives
 References
 
3.1. Non-familial forms of systolic dysfunction
Data available are scarce in this particular subgroup of patients. The search for genetic factors associated with non-familial heart failure has been mainly performed in non-ischaemic heart failure using case control studies. In this situation, the usual strategy is to look for an association between the disease and genetic markers of potential candidate genes. This approach allows identification of gene defects either directly involved in the pathophysiology of the disease or modifying the expression of the disease. All available studies have focused on the search for an association between the I/D ACE gene polymorphism and dilated cardiomyopathy. One study demonstrated an association with the DD genotype (112 patients/79 controls) whereas no association was found in another study (99 patients/364 controls) [25,26]. In another study including idiopathic heart failure patients, homozygous subjects for the D allele exhibited a significant increase in ventricular mass and mortality [27].

These conflicting results may be the consequence of an insufficient sample size and/or of a bias in recruitment of patients or controls. To avoid these limitations, a national collaboration was established in France which studied 433 patients with idiopathic dilated cardiomyopathy matched with control subjects from the MONICA registry and genetic analyses are currently under way (the Cardigene network).

In ischaemic heart disease, the influence of the I/D polymorphism on the remodelling process, a key issue for the development of heart failure, was demonstrated in the CATS study: left ventricular dilatation following an anterior myocardial infarction was significantly greater after 1 year of follow-up in DD subjects as compared to the other patients [28].

These findings, although preliminary, suggest that the genetic background may influence the development and the progression of both ischaemic and non-ischaemic heart failure and the identification of new genetic factors predisposing to heart failure should improve our understanding of this process in the future.

3.2. Familial dilated cardiomyopathy
Familial forms of dilated cardiomyopathy have been underestimated in the past and might represent 20–30% of the total number of this disease [29,30]. Various modes of inheritance have been reported in association with different phenotypes (Table 2) but the autosomal dominant forms are the most common ones [31,32].


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  		Table 2
 
Various subtypes have been reported:
  1. In "pure" dilated cardiomyopathy, one gene, the cardiac actin, and two chromosomal loci have been identified (9q 13–22 and 1q32) [33–35].
  2. Dilated cardiomyopathy with conduction defects and arrhythmias with an autosomal dominant pattern has been associated with two loci (1p1–q1 and 3p22) [36,37].
  3. An autosomal dominant form of dilated cardiomyopathy with mitral valve prolapse has been associated with a locus on chromosome 10 q21–q23 [38].
  4. An autosomal dominant variety of dilated cardiomyopathy associated with conduction disorders and myopathy has been linked to chromosome 6q23 [39].
  5. Autosomal recessive forms of the disease have occasionally been reported. No location has been published.
  6. Dilated cardiomyopathy linked to chromosome X is related to deletions, duplications or point mutations in the dystrophin gene [40–47].
  7. Large deletions of mitochondrial DNA have been associated with matrilineal transmitted dilated cardiomyopathy; however the alterations of the mitochondrial DNA have been reported in many other diseases, thus the causal role of these genetic alterations is not definitely established.

These findings underline the fact that familial dilated cardiomyopathy is highly heterogenous. So far, genetic abnormalities have been identified in single families, except for the cardiac actin gene (two families) and the chromosome 9 locus (three families) and many families are not linked to any of the published loci.

In the cardiac actin gene, two missense mutations (Arg312His and Glu361Gly) have been identified in exons 5 and 6 [33]. These exons encode a binding domain of the protein to Z bands or intercalated disks.

DNA alterations involved in the dystrophin gene are located (i) in the muscular promotor — first muscular exon — first intron regions. These alterations consist of deletions or of a point mutation in the splice consensus site of the first intron [40,41,43]. They result in the absence of the protein in the cardiac muscle whereas dystrophin expression is preserved or slightly reduced in skeletal muscle; (ii) in exons 2–7, 9, 45–49, 48–49, 49–51 [42,44–47] where other genetic alterations have been identified. The genetically affected individuals usually develop a severe form of dilated cardiomyopathy at adolescence or in young adults. Although no skeletal muscle involvement is evident, serum creatine kinase levels are usually high.

The fact that [1] the genetic alterations identified in the actin and the dystrophin genes are related to the cytoskeleton; [2] experimental forms of dilated cardiomyopathy suggest that two cytoskeletal proteins are involved ({delta} sarcoglycan in Syrian hamsters and muscle LIM protein in deficient transgenic mice) has raised the hypothesis that dilated cardiomyopathy results from alterations in genes coding structural proteins of the cytoskeleton or the sarcomere. According to this hypothesis, the disease would be the result of abnormalities of the transmission of contraction from one sarcomere to the other or from one myocyte to the neighbour ones.


   4. Conclusion and perspectives
Top
 Abstract
 1. Introduction
 2. Genetic aspects of...
 3. Genetic aspects of...
 4. Conclusion and perspectives
References
 
Obviously, the genetic approach of heart failure is just starting and published results are preliminary, particularly in the setting of non-familial heart failure. However, the analysis of the genetic aspects of heart failure appears promising and various DNA banks are currently set up at national or international levels. Identification of the genetic alterations involved either in familial or in non-familial heart failure should unravel the molecular mechanisms that lead from left ventricular dysfunction to overt heart failure, and allow to identify patients at risk of developing heart failure. Other potential promising perspectives are the early management of subjects at risk in order to prevent the progression of the disease and targeting therapy based on individual molecular defects. The identification of potential subgroups of patients responders to the various pharmacological interventions available to date is a major issue for the third millennium and should lead to the development of cardiovascular pharmacogenetics.


   References
Top
 Abstract
 1. Introduction
 2. Genetic aspects of...
 3. Genetic aspects of...
 4. Conclusion and perspectives
 References
 

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