Miocardiopatía dilatada familiar: genética, características clínicas y respuesta al tratamiento en función del genotipo

Idiopathic dilated cardiomyopathy (DCM) is a primary disease of the heart muscle characterized by left ventricular dilatation and systolic dysfunction, in the absence of abnormal loading conditions. It is genetically determined in 20-50% of patients. Given its genetic heterogeneity, it is essential to carry out studies to establish genotype-phenotype correlations. Furthermore, the relationship between specific genotypes and the response to optimal medical treatment (OMT) assessed in terms of left ventricular reverse remodeling (LVRR) and the analysis of events at follow-up, remains quite unknown. Objectives: 1) To describe the genotype and phenotype of patients with DCM in our environment. 2) To study the response to OMT depending on the genotype based on the appearance of LVRR and clinical events in the follow-up. 3) To characterize two new genes involved in the development of cardiomyopathies: JPH2 and FHL1. Material and Methods: Retrospective single-center study that included 145 consecutive genotyped patients with DCM seen at the Virgen de la Arrixaca Hospital. They were classified into clusters of genes belonging to the same cellular subcompartment or with differential shared characteristics (cytoskeleton, desmosomal, sarcomeric, titin truncations, lamin, other mutations and negative study). The patients were under maximum tolerated medical treatment and had at least two separate echocardiographic studies in 6 months. The appearance of LVRR and clinical events were analyzed at follow-up. On the other hand, members of the 2 families with new mutations identified in JPH2 and FHL1 genes were included in order to characterize the specific phenotype associated with them. Conclusions: 1. The genetic spectrum of DCM in our environment is heterogeneous and involves multiple genes, the most common being motor sarcomeric. 2. NGS technology coupled with a detailed family assessment allows identification of the causal mutation in 68% of DCM cases. 3. The clinical characteristics of patients with genetically determined DCM include: higher prevalence of males, age around 45 years, low comorbidity, low prevalence of atrial fibrillation, low prevalence of ventricular arrhythmias, low prevalence of conduction disturbances, and low percentage of neuromuscular involvement. 4. 37.9% of patients with genetically determined DCM have RRVI under OMT. 5. The genotype was not significantly associated with the appearance of LVRR. 6. Titin mutations were associated with a phenotype with more severe baseline involvement but with a high proportion of patients with LVRR and greater survival free of death, transplantation, and admissions for heart failure than the rest of the genetic groups. 7. Clustering of desmosomal genes, lamin, and phospholamban was significantly associated with decreased survival free of sudden cardiac death, recovered cardiac arrest, sustained ventricular tachycardia, and appropriate ICD shock, with an almost 6-fold increased risk of the combined event. 8. The mutation p. Glu85Lys in JPH2 represents the first description of a mutation in this gene related to DCM. The phenotype is characterized by DCM associated with hypertrabeculation, conduction disturbances, and low prevalence of atrial and ventricular arrhythmias. 9. The p.Cys255Ser mutation in the FHL1 gene causes an unclassifiable cardiomyopathy characterized by mild non-obstructive left ventricular hypertrophy and left ventricular non-compaction that coexists with musculoskeletal involvement. FHL1 cardiomyopathy also shows histopathological characteristics of biventricular arrhythmogenic cardiomyopathy. The prognosis is poor, with systolic dysfunction and arrhythmias that often require ICD implantation and transplantation at an early age. The presence of thrombopenia and CK elevation associated with X-linked inherited cardiomyopathy should raise the suspicion of a FHL1 mutation.