Thoracic aortic aneurysms (TAA) consist of abnormal dilation or the widening of a portion of the ascending aorta, due to weakness or destructuring of the walls of the vessel and are potentially lethal. The congenital bicuspid aortic valve (BAV) is considered a risk factor for the development of TAA because asymmetric blood flow through the bicuspid aortic valve detrimentally influences the wall of the ascending aorta. NOTCH1 mutations have been associated with non-syndromic TAAs as a consequence of BAV, but little is known regarding its haploinsufficiency and its relationship with connective tissue abnormalities. We report two cases in which there is clear evidence that alterations in the NOTCH1 gene are the cause of TAA in the absence of BAV. On the one hand, we describe a 117 Kb deletion that includes a large part of the NOTCH1 gene and no other coding genes, suggesting that haploinsufficiency can be considered a pathogenic mechanism for this gene associated with TAA. In addition, we describe two brothers who carry two variants, one in the NOTCH1 gene and another in the MIB1 gene, corroborating the involvement of different genes of the Notch pathway in aortic pathology.

Dilated cardiomyopathy (DCM) has significant morbidity and mortality. Familial transmission is reported in 20–35% of cases, highlighting the role of genetics in this disorder. We present an interesting family in which the index case is a 64-year-old woman who survived a sudden cardiac arrest. She presented left ventricular dilatation and dysfunction, which indicated the presence of DCM, as well as a history of DCM and sudden arrest in her family (mother and sister). Genetic testing identified a heterozygous mutation c.74A > G missense change that causes an amino acid, p.Glu25Gly, change in the N-terminal domain of the SCN5A protein. After performing an exhaustive family medical history, we found that this previously not described mutation segregated within the family. All relatives with the DCM phenotype were carriers, whereas none of the noncarriers showed signs of heart disease, so this mutation is the most likely cause of the disease. This is the first time that a variant in the N-terminal domain of SCN5A has been associated with DCM.

Hypertrophic cardiomyopathy (HCM) is a genetic disease characterised by increased left ventricle (LV) wall thickness caused by mutations in sarcomeric genes. Finding a causal mutation can help to better assess the proband’s risk, as it allows the presence of the mutation to be evaluated in relatives and the follow-up to be focused on carriers. We performed an observational study of patients with HCM due to the novel p.Arg652Lys variant in the MYH7 gene. Eight families and 59 patients are described in the follow-up for a median of 63 months, among whom 39 (66%) carry the variant. Twenty-five (64%) of carriers developed HCM. A median maximum LV wall thickness of 16.5 mm was described. The LV hypertrophy was asymmetric septal in 75% of cases, with LV outflow tract obstruction in 28%. The incidence of a composite of serious adverse cardiovascular events (sudden death, aborted sudden death, appropriate implantable cardiac defibrillator discharge, an embolic event, or admission for heart failure) was observed in five (20%) patients. Given the finding of the p.Arg652Lys variant in patients with HCM, but not in controls, with evident segregation in patients with HCM from eight families and the location in an active site of the protein, we can define this variant as likely pathogenic and associated with the development of HCM.

The p.Arg301Gln variant in the α -galactosidase A gene (GLA) has been poorly described in the literature. The few reports show controversial information, with both classical and nonclassical Anderson–Fabry Disease (AFD) presentation patterns. The aim of this study was to analyze the penetrance, clinical phenotype, and biochemical profile of an international cohort of patients carrying the p.Arg301Gln genetic variant in the GLA gene. This was an observational, international, and retrospective cohort case series study of patients carrying the p.Arg301Gln variant in the GLA gene associated with AFD disease. Forty-nine p.Arg301Gln GLA carriers, 41% male, were analyzed. The penetrance was 63% in the entire cohort and 1.5 times higher in men. The mean age of symptoms onset was 41 years; compared to women, men presented symptoms earlier and with a shorter delay to diagnosis. The typical clinical triad—cornea verticillate, neuropathic pain, and angiokeratomas—affected only 20% of the cohort, with no differences between genders. During follow-up, almost 20% of the patients presented some type of nonfatal cardiovascular and renal event (stroke, need for dialysis, heart failure, and arrhythmias requiring intracardiac devices), predominantly affecting men. Residual levels were the most common finding of α-GAL A enzyme activity, only a few women had a normal level; a small proportion of men had undetectable levels. The incidence of combined outcomes including all causes of death was 33%, and the cumulative incidence of all-cause mortality was 9% at the follow-up. Patients carrying the p.Arg301Gln GLA variant have a high penetrance, with predominantly cardiorenal involvement and clinical onset of the disease in middle age. Only a small proportion showed the classic clinical presentation of AFD. As in other X-linked diseases, males were more affected by severe cardiovascular and renal events. This genotype–phenotype correlation could be useful from a practical clinical point of view and for future decision making.

Evidence supports associations of lifestyle (including diet and physical activity) and weight with cognitive functioning, but the pathways responsible for these associations have not been fully elucidated. Because healthier lifestyles have been associated with better left atrial structure and function, which in turn is associated with better cognitive functioning, we tested the hypothesis that left atrial structure and function is a potential mediator of the association between lifestyle and cognition. We included 476 participants classed as overweight or obese with metabolic syndrome from three centers in Spain. These participants underwent lifestyle assessments and transthoracic echocardiography at baseline and repeated measurements of the Trail Making A test, a measure of executive function, taken at baseline and at the two-year follow-up. We conducted mediation analyses to test if measures of left atrial structure and function mediated associations between adherence to the Mediterranean diet scores, physical activity, and weight at baseline, as well as a two-year change in Trail Making A scores. The analysis did not find an association between these factors and Trail Making A scores, and no indirect effects appeared to be mediated by echocardiographic measurements. The modest sample size in this analysis is a limitation, and larger studies should be conducted to determine potential cardiovascular factors mediating the association between lifestyle and cognition.

Background/Objectives: Respiratory syncytial virus (RSV) causes morbidity in older adults with cardiovascular disease, in whom infection may precipitate severe lower respiratory tract disease, hospitalization, functional decline, and cardiovascular destabilization. We evaluate the evidence for RSV vaccination in cardiovascular disease and propose a jurisdiction-adaptable framework for integrating vaccination into cardiovascular care. Methods: Observational studies, randomized trials, pragmatic and test-negative studies, prespecified cardiovascular analyses of DAN-RSV, and eligibility recommendations were narratively synthesized and translated into a pathway encompassing patient identification, eligibility and risk assessment, vaccine delivery and co-administration, documentation, and follow-up. Results: Acute cardiac events are frequent during RSV hospitalization, and cardiovascular risk may persist after infection. Randomized trials establish protection against RSV-associated lower respiratory tract disease and respiratory illness, while real-world studies support effectiveness against RSV-related hospitalization. DAN-RSV reduced all-cause cardiorespiratory hospitalization but did not demonstrate significant reductions in cardiovascular hospitalization, myocardial infarction, heart failure (HF) hospitalization, atrial fibrillation, stroke, cardiovascular death, or major adverse cardiovascular events; observational associations with lower post-vaccination cardiovascular-event rates remain hypothesis-generating. The framework prioritizes adults aged ≥75 years and those aged 50–74 years with high-risk cardiovascular conditions where consistent with national recommendations, embeds vaccination assessment across cardiology, HF, primary care, pharmacy, and long-term care, and incorporates co-administration, documentation, and outcome surveillance. Conclusions: The principal contribution is a pathway for moving RSV vaccination from recommendation to routine preventive care for adults with cardiovascular disease. It anchors implementation in established RSV and cardiorespiratory benefits while treating cardiovascular-event reduction as a research priority rather than a demonstrated indication.