RESUMO
MYPBC3 and MYH7 are the most frequently mutated genes in patients with hereditary HCM. Homozygous and compound heterozygous genotypes generate the most severe phenotypes. A 35-year-old woman who was a homozygous carrier of the p.(Pro1066Arg) variant in the MYBPC3 gene, developed HCM phenocopy associated with left ventricular noncompaction and various degrees of conduction disease. Her father, a double heterozygote for this variant in MYBPC3 combined with the variant p.(Gly1931Cys) in the MYH7 gene, was affected by HCM. The variant in MYBPC3 in the heterozygosis-produced phenotype was neither in the mother nor in her only sister. Familial segregation analysis showed that the homozygous genotype p.(Pro1066Arg) was located in a region of 26 Mb loss of heterozygosity due to some consanguinity in the parents. These findings describe the pathogenicity of this variant, supporting the hypothesis of cumulative variants in cardiomyopathies, as well as the modulatory effect of the phenotype by other genes such as MYH7. Advancing HPO phenotyping promoted by the Human Phenotype Ontology, the gene-disease correlation, and vice versa, is evidence for the phenotypic heterogeneity of familial heart disease. The progressive establishment of phenotypic characteristics over time also complicates the clinical description.
RESUMO
BACKGROUND: Pulmonary hypertension (PH) conveys a worse prognosis in heart failure (HF), in particular when right ventricular (RV) dysfunction ensues. Cardiovascular magnetic resonance (CMR) non-invasively estimates pulmonary vascular resistance (PVR), which has shown prognostic value in HF. Importantly, RV to pulmonary artery (PA) coupling is altered early in HF, before significant rise in PV resistance occurs. The aim of this study was to assess the prognostic value of mean velocity at the pulmonary artery (mvPA), a novel non-invasive parameter determined by CMR, in HF with reduced ejection fraction (HFrEF) with and without associated PH. METHODS: Prospective inclusion of 238 patients admitted for new-onset HFrEF. MvPA was measured with CMR during index admission. The primary endpoint was defined as a composite of HF readmissions and all-cause mortality. RESULTS: During a median follow-up of 25 months, 91 patients presented with the primary endpoint. Optimal cut-off value of mvPA calculated by the receiver operator curve for the prediction of the primary endpoint was 9 cm/s. The primary endpoint occurred more frequently in patients with mvPA≤9 cm/s, as indicated by Kaplan-Meier survival curves; Log Rank 16.0, p < 0.001. Importantly, mvPA maintained its prognostic value regardless of RV function and also when considering mortality and HF readmissions separately. On Cox proportional hazard analysis, reduced mvPA≤9 cm/s emerged as an independent prognostic marker, together with NYHA III-IV/IV class, stage 3-4 renal failure and ischemic cardiomyopathy. CONCLUSIONS: In our HFrEF cohort, mvPA emerged as an independent prognostic indicator independent of RV function, allowing identification of a higher-risk population before structural damage onset. Moreover, mvPA emerged as a surrogate marker of the RV-PA unit coupling status.
