👤 Adriana Belo

Sudden cardiac death (SCD) risk stratification in dilated cardiomyopathy (DCM) has been based on left ventricular ejection fraction (LVEF), even though SCD may occur with LVEF > 35%. Family history of unexplained SCD, especially in the young, raises concern about potential inheritable risk factors. It remains largely unknown how genetic tests can be integrated into clinical practice, particularly in the selection of implantable cardioverter defibrillator (ICD) candidates. We aimed to assess the diagnostic yield of genetic testing in DCM patients with a class I recommendation for ICD implantation, based on current guidelines. We included ambulatory stable adult patients with idiopathic or familial DCM with previously implanted ICD. Molecular analysis included 15 genes ( We evaluated 21 patients, 12 (57%) males and 9 (43%) with familial DCM, including 3 (14%) with a family history of premature unexplained SCD. Mean age at DCM diagnosis was 40 ± 2 years, and mean age at ICD implantation was 50 ± 12 years. LVEF was 27 ± 9%, and LV end-diastolic diameter was 65 ± 7 mm. Genetic variants were found in six (29%) patients, occurring in 5 genes: In patients with DCM and ICD, genetic variants could be identified in a significant proportion of patients in several genes, highlighting the potential role of genetics in DCM SCD risk stratification. Show less

We present an ancillary study of the Portuguese Registry of Hypertrophic Cardiomyopathy (PRo-HCM). This is one of the largest HCM genetic studies based on a registry. Collected genetic variants were re-analysed for pathogenicity. Demographic, clinical, imaging and outcome data were analysed for associations with genotype, focusing on comparisons between patients with (G+) vs without (G-) a pathogenic/likely pathogenic (P/LP) variant in one the 9 main causal sarcomeric genes. From the 1042 patients in the registry, 528 (51%) had genetic testing. 152 (28%) were G+ and 98 pts. (19%) had variants of unknown significance. From the patients with the 9 mentioned genes sequenced (424 pts), 14.6% had P/LP variants in MYBPC3, 8.7% MYH7, 4.5% TNNT2, 1.7% TNNI3. Patients were 51 ± 16 years-old, 59% males. Genotype was associated with the following: birthplace (p = 0.005); age (p < 0.001); family history of HCM (p < 0.0005); hypertension (p < 0.0005); chest pain (p = 0.015); pattern of hypertrophy (p = 0.006); left ventricular hypertrophy on the ECG (p < 0.0005); family history of sudden cardiac death (SCD) (p = 0.002). G+ patients more frequently had more than one risk factor for SCD (p = 0.002) and a higher ESC-SCD risk score (p = 0.003). In survival analysis, G+ was associated with SCD (p = 0.017) and MYH7+ with LV systolic dysfunction (p = 0.038). Half of the registry patients had genetic testing. Sarcomere-positive patients had distinct demographics, ECG, imaging characteristics and family history and are at increased risk of SCD. The presence of a MYH7 mutation was associated with evolution towards LV systolic dysfunction. Show less

The pivotal mechanisms that govern the correct patterning and regionalization of the distinct areas of the mammalian CNS are driven by key molecules that emanate from the so-called secondary organizers at neural plate and tube stages. FGF8 is the candidate morphogenetic molecule to pattern the mesencephalon and rhombencephalon in the isthmic organizer (IsO). Recognizable relevance has been given to the intracellular pathways by which Fgf8 is regulated and modulated. In chick limb bud development, a dual mitogen-activated protein kinase phosphatase-3 (Mkp3) plays a role as a negative feedback modulator of Fgf8 signaling. We have investigated the role of Mkp3 and its functional relationship with the Fgf8 signaling pathway in the mouse IsO using gene transfer microelectroporation assays and protein-soaked bead experiments. Here, we demonstrate that MKP3 has a negative feedback action on the MAPK/ERK-mediated FGF8 pathway in the mouse neuroepithelium. Show less