Dilated cardiomyopathy (DCM) is characterized by left ventricular (LV) systolic dysfunction and LV enlargement, in the absence of abnormal loading conditions such as hypertension, valvular disease, or coronary artery disease (CAD) that could explain the myocardial abnormality. The presence of the disorder is defined by an LV end-diastolic diameter (LVEDD) greater than 2 standard deviations (SD) of the predicted values and LV fractional shortening < 25% or an LV ejection fraction (EF) < 45%.
The prognosis of DCM patients has significantly improved over the last decades due to pharmacological and non-pharmacological advances, earlier diagnosis due to familial screening, and pre-participation cardiac evaluation and individualized long-term follow-up. In the past few decades the prognosis of DCM has significantly improved, and survival along with no need for heart transplantation has risen to > 80% at 8-year follow-up.
Classification concepts of dilated cardiomyopathy
Over the past few decades, the etiology and natural history of DCM have been further elucidated. It has been demonstrated that various etiologies, causing LV dysfunction may manifest with the same clinical phenotype as DCM. According to the ESC classification of cardiomyopathies, DCM can be further subdivided into two main groups, genetic or acquired. There are, however, several cases in which the phenotypic expression is strongly affected by the environmental stressors of the individual.
Inflammatory dilated cardiomyopathy
Myocardial injury caused by infectious agents (viral or bacterial myocarditis), autoimmune disorders (i.e., sarcoidosis), toxic agents (i.e., cocaine), or other factors may trigger an inflammatory response starting with the activation of a proinflammatory cascade of cytokines, followed by an immune response and eventually leading to LV dysfunction and dilatation. Myocarditis progresses to DCM in up to 30% of cases. Almost half of DMC cases show evidence of inflammation in the myocardium.
Genetic background and inheritance patterns
Various patterns of inheritance have been recognized, including autosomal dominant, X-linked, autosomal recessive and matrilinear transmission. The genetic yield of DCM is estimated to be about 20–37%. Until now, more than 50 DCM related genes have been reported. With the development and advances of sequencing technologies, the analysis and discovery of more genes involved in DCM has become feasible, decreasing the frequency of “idiopathic DCM”. Studies using next-generation sequencing have identified the presence of two or more variants in more than 38% of affected cases of DCM suggesting a pattern of oligogenic rather than monogenic inheritance in some patients. Of note, there is a considerable overlap of genes involved in the pathogenesis of DCM and other forms of cardiomyopathy, or channelopathies such as Brugada syndrome. The presence of more than one pathogenic or likely pathogenic variants in an individual, as well as variants that cause an overlapping cardiomyopathy phenotype, may explain the variable penetration and phenotypic expression, even within the same family.
DCM patients often show intermediate phenotypes not fulfilling the standard diagnostic criteria due to variable phenotypic expression and age-dependent penetrance. Advanced imaging techniques such as CMR are able to identify subtle or even extensive myocardial scar in patients with normal LV dimensions and function. Significant VAs and SCD may precede any evident structural or morphological changes. Pinto et al. attempted to overcome these limitations, by proposing a revised definition for DCM in 2016 and updating the diagnostic criteria for relatives of DCM patients. A preclinical phase with no or mild cardiac abnormalities such as the expression of anti-heart antibodies or mild LV dilatation was recognized in carriers of DCM-causing variants who were identified through family screening.
Diagnostic criteria for DCM relatives
In the absence of a definite pathogenic variant in a family, familial disease is defined as the presence of: (i) 2 or more individuals (first- or second-degree relatives) with definite DCM or HNDC or (ii) 1 patient fulfilling the diagnostic criteria for DCM or HNDC and a first-degree relative who suffered SCD < 50 years of age and autopsy-proven DCM.
Echocardiography is vital in the diagnosis, follow-up, and family screening of DCM. LVEF is a vital parameter and an independent predictor of outcome, since low LVEF values and NYHA functional classes III–IV at baseline have been associated with a higher incidence of death or heart transplantation, in both adults and children. LV dilatation has been described as a predictor of early VAs. Diffuse LV hypokinesia is usually seen but regional wall motion abnormalities may also be present. It is important to distinguish these from wall motion abnormalities due to CAD, especially if the abnormalities correspond to the anatomic perfusion of a coronary artery. Usually, LV eccentric hypertrophy is present in DCM, along with LV diastolic dysfunction.
According to the latest HRS expert consensus statement on arrhythmogenic cardiomyopathy, genetic testing should be performed in all individuals with a clinical diagnosis of cardiomyopathy or in decedents who were diagnosed with cardiomyopathy at necropsy. The initially selected gene panel and subsequent interpretation should both be based on the phenotype of the patient. Cascade genetic screening and genetic counseling should be offered to first degree relatives if a pathogenic or likely pathogenic variant has been detected in the family. Practice until today suggested that genotype and phenotype negative family members were assured that they carry no risk for developing DCM, and their follow-up was ceased.
However, non-monogenic DCM cases have been described, and numerous variants that may potentially affect the phenotypic expression are still classified as variants of unknown significance. At the same time, environmental factors play a vital role in the expression of DCM. It is therefore plausible to say that genotype-negative relatives have a lower risk of developing DCM rather than no risk at all. Continuous surveillance but at more sparse intervals, possibly excluding genes with high penetrance such as LMNA, is an alternative strategy for these individuals.
Dilated cardiomyopathy, an “umbrella” term describing the final common phenotype of various etiologies and gene–environment interactions, is now entering a new epoch. We are witnessing the end of the “one-size-fits-all” approach aiming to alleviate symptoms or possibly delay disease progression and the beginning of the precision medicine era.
We endorse the concept that we are no longer targeting symptomatic treatment, but instead, we are searching and targeting for the root of the disorder in each individual, with disease prevention or even disease reversal as a goal. We believe that the creation of multi-disciplinary teams in healthcare units may form the core of the individualized management of DCM patients bringing the best patient care possible.