Nuevos parámetros diagnósticos y pronósticos de imagen multimodalidad en miocardiopatía arritmogénica

Abstract

Arrhythmogenic cardiomyopathy is a genetically determined disease of the heart muscle characterised by the progressive replacement of healthy myocardium with fibroadipose tissue, predisposing to the development of malignant ventricular arrhythmias and heart failure. Although it was initially described as a pathology exclusively affecting the right ventricle (arrhythmogenic right ventricular dysplasia), today it encompasses a broader spectrum, also affecting the left ventricle and both ventricles, being the most widespread current term arrhythmogenic cardiomyopathy. Throughout advances in genetic diagnosis, around 16 genes are currently known to be involved in the pathogenesis of the disease, 5 of which are responsible for proteins that constitute the desmosome (desmosomal genes), a structure whose main function is to maintain intercellular junctions. The remaining genes (nondesmosomal genes) encode proteins of different cellular structures (cytoskeleton, nuclear envelope, channels, ...) that are directly or indirectly involved in cellular mechanotransduction, so that mutations that condition impaired proteins at this level can lead to the loss of this microarchitecture, resulting in cellular death and accumulation of fibrosis. It is one of the leading causes of sudden cardiac death in people under 35 years of age and elite athletes, and is often the first manifestation of the disease in early stages of its natural history. Therefore, early diagnosis is crucial not only to identify and stratify the risk of the patient under assessment, but also for the detecting family members affected by the disease. The combination of variables obtained by cardiac imaging techniques (transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR), electrocardiographic depolarisation and repolarization disorders, identification of ventricular arrhythmias, genetic and histopathological analysis are essential for correct diagnosis. In order to better characterise this disease, combining genetics and diagnostic imaging, the hypothesis of this PhD Programme is to study the capacity of new multimodality cardiac imaging techniques in the diagnosis and prognosis of patients with arrhythmogenic cardiomyopathy. The objectives are to study the genotype-phenotype correlation by CMR, the prognostic value of myocardial deformation techniques by TTE, as well as a histopathological description of cases with biventricular phenotype in carriers of mutations in non-desmosomal genes. For genotype-phenotype correlation, patients were characterised by clinical variables, family history, arrhythmic events, histopathological analysis, as well as genetic study (classified as carriers of desmosomal, non-desmosomal and negative gene mutations). All patients underwent morpho-functional analysis of the cardiac chambers by CMR and tissue characterisation by late gadolinium enhancement technique (LGE), assessing its presence, pattern, location and extension. Myocardial deformation analysis was performed by global longitudinal strain (GLS) specific for each myocardial layer of the left ventricle in TTE, so that its predictive capacity to identify patients with arrhythmic risk markers (ventricular arrhythmias, LGE, genetics) was analysed. At the end of the study, the following conclusions could be drawn: - Patients with arrhythmogenic cardiomyopathy frequently presented late enhancement in CMR of the inferolateral wall of the left ventricle, although with different morpho-functional expression depending on the underlying genetics, observing a characteristic extensive annular enhancement pattern in the left ventricle mainly in those carriers of mutation in the DES gene, as well as a greater tendency of LGE in the right ventricle in carriers of mutations in desmosomal genes. - The layer-specific GLS assessment identified subjects with high-risk arrhythmic markers, being epicardial GLS the best predictor for detecting arrhythmic risk factors. - A marked increase in interstitial connective tissue and intercellular space has been observed in histological samples of left ventricle from carriers of mutations in non-desmosomal genes.