The cardiomyopathies: from epidemiology to clinical work-up

This editorial refers to ‘Epidemiology of cardiomyopathies: essential context knowledge for a tailored clinical work-up’, by D. Pasqualucci et al., pp. 1190–1199.

Interest in the study of cardiomyopathies has significantly increased in recent years as a result of more research work in this field and particularly thanks to advances in medical genetics and cardiovascular imaging.

Cardiomyopathies are a heterogeneous group of heart diseases characterized by a primary involvement of the myocardium.¹ However, we should not forget that in many cases exposure to other pathologies and/or risk factors may favour their clinical expression. These diseases are characterized by variable penetrance, i.e. phenotypic expression depends not only on the presence of a mutation but also on other epigenetic and environmental factors.²

At times, the phenotypes may be confused. In fact, mutations that affect the same gene may give rise to variable expressions such as hypertrophic, dilated, arrhythmogenic or restrictive cardiomyopathy even within a single family. This, in turn, influences cross-sectional studies making them less precise.

We currently know that the prevalence of cardiomyopathies is higher than estimated. The increase in their diagnosis is related with the development of imaging techniques (echocardiography and nuclear magnetic resonance imaging). However, it is probably the spread of genetic testing, thanks to the development of next-generation sequencing techniques and the real availability to clinicians of these tests, that has brought to light asymptomatic subjects and healthy carriers, thus resulting in a higher number of diagnoses.³

In any case, the prevalence of cardiomyopathies remains underestimated. In view of the fact that sudden death may be the first clinical presentation among these individuals, autopsy has become an essential element for knowledge about the exact prevalence of cardiomyopathies. Efforts should therefore be made to perform a post-mortem study, including a genetic study, of all episodes of sudden death, as family members would also benefit from the possibility of early diagnosis.⁴

Genetic testing offers not only the opportunity to determine the aetiology of cases with a hereditary origin but also the confirmation of sporadic cases and a differential diagnosis with phenotypes (similar phenotypic expression but with a different genetic or non-genetic origin). But above all, it provides a diagnosis of family members (incipient and/or asymptomatic cases) and healthy carriers of pathogenic genetic mutations who require periodic monitoring in order to make an early diagnosis. In addition, for non-carriers of the mutation, it allows us to rule out the possibility of them developing the disease.⁵

What constitutes the main preventive consideration of genetic testing probably rests in the possibility of eradicating the disease from a family. Cascade screening for the diagnosis of family members, which derives from genetic testing, offers the possibility of genetic and reproductive counselling for carriers and non-carriers of mutations. The former would be able to take decisions about whether to consider having biological children and/or opting for embryo selection techniques. The latter are ensured the impossibility of transmission to their descendants.

An early diagnosis of non-symptomatic diseases would allow therapies tailored to avoid a progression to more advanced phases, encourage lifestyles that promote cardiovascular health, and facilitate preventive decision-making (implantation of devices in the case of high-risk ventricular arrhythmia).

The diagnosis of healthy carriers would also permit close monitoring for early diagnosis of the onset of heart diseases and disorders. It would also allow adoption of preventive habits in the case of competitive physical activity (a possible factor in an earlier or more severe onset) or the avoidance of environmental exposure to factors that may give rise to phenotypic expression (consumption of alcohol, chemotherapy, myocarditis, etc.), since phenotypic expression is the result of an interaction between genetic and environmental factors.

During an evaluation before that start of therapies with cardiotoxic drugs (for instance, cytostatics), genetic testing should be performed to rule out an unfavourable genotype, and opt for substances that do not have a noxious effect on the myocardium. On the other hand, if no alternatives exist, testing would indicate the need for a closer follow-up and/or preventive treatment before and during therapy. We now know that the presence of mutations in titin is frequent among oncology patients undergoing chemotherapy.⁶

Likewise, alcoholic, peripartum, or post-myocarditis cardiomyopathy would make it necessary to perform genetic testing, since in a large number of cases there is an underlying genetic substrate that favours them.⁷ In the future, we will have to decide whether one of these agents is the cause of dilated cardiomyopathy or if a patient is the carrier of a genetic mutation for which exposure to this factor has triggered the onset of the cardiomyopathy.⁸ We currently know that dilated cardiomyopathy patients who have a presence of radical mutations in titin usually respond well to the standard treatment for heart failure, showing a tendency to myocardial recovery after appropriate treatment, which would allow postponement of a decision about implantation of a device.⁹

An important aspect is the timing of when to perform genetic testing on a first degree relative of a patient who has presented a genetic mutation that causes cardiomyopathy. Among adults, the general recommendation should be to carry out genetic testing as a first step, even before performing an electrocardiogram or imaging study. Only the carriers of a mutation should undergo a diagnostic study with imaging techniques to find evidence of the presence of phenotypic expression. Subjects who are not carriers will require no further study. This strategy has proved to be cost-effective as it reduces expenditure on non-carriers (who would otherwise have had to undergo periodic testing for the rest of their lives), and focuses diagnostic-therapeutic efforts on the carriers with and without phenotypic expression.^10,11

The review article by Pasqualucci et al.¹² that appears in the current issue of the European Journal of Preventive Cardiology synthesizes current epidemiological knowledge of the main cardiomyopathies, reviews the majority of studies undertaken to date and their corresponding limitations, and essentially focuses on the study of dilated and hypertrophic cardiomyopathy. Unfortunately, cross-sectional studies of restrictive and arrhythmogenic cardiomyopathy are subject to major limitations. In the case of the former, in addition to being infrequent diseases, a restrictive physiology may be present in particularly severe and advanced forms in the case of hypertrophic cardiomyopathy. In the latter, we must consider that diagnostic criteria have changed over the last 20 years, which means that cross-sectional data also vary because they depend on the criteria. Likewise, the studies published to date have found varying predominance, with frequency populations that are high in specific geographical areas for no apparent reason.

We have to trust that with advances in knowledge of the natural history of these diseases (above all with the diagnosis of new mutations and in monitoring healthy carriers) and of their genetic substrate (often confusing, particularly in the case of arrhythmogenic cardiomyopathy), cross-sectional studies will become more reliable, offering specific data about the frequency of presentation and allowing personalized management and prevention of clinical expression, which will permit an appropriate prognostic stratification.

Conflict of interest: none declared.

The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Preventive Cardiology or of the European Society of Cardiology.

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