Arrhythmia and impaired myocardial function in heritable thoracic aortic disease: An international retrospective cohort study

Arrhythmia; Heritable thoracic aortic diseaseArritmia; Enfermedad hereditaria de la aorta torácicaArrítmia; Malaltia hereditària de l'aorta toràcicaBackground Heritable thoracic aortic diseases (HTAD), typically entailing aortic complications, can be caused by pathogenic variants or likely pathogenic variants (PV/LPVs) in several genes, including fibrillin1 (FBN1), Actin Alpha2 (ACTA2) and genes encoding components of the transforming growth factor (TGF)-β signaling pathway. In addition to aortic complications, non-aortic cardiac disease such as impaired myocardial function and/or arrhythmia have been increasingly reported, mainly in Marfan syndrome with underlying FBN1 PV/LPVs and are acknowledged as additional causes of morbidity and mortality. The prevalence of these manifestations in the various HTAD entities is largely unknown. Methods This international multicentre retrospective study collected data on patients with HTAD presenting non-aortic cardiac disease. A total of 9 centers from 7 different countries participated. Patients 12 years or older carrying a PV/LPV in one of the following genes: FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3 and ACTA2 were screened. Non-aortic cardiac disease included impaired myocardial function and/or arrhythmia. Impaired myocardial function was defined as (a)symptomatic reduced ejection fraction (EF<50%). Arrhythmias included atrial fibrillation (AF), atrial flutter (AFL), ventricular tachycardia (VT), ventricular fibrillation (VF) and (aborted) sudden cardiac death (presumed arrhythmogenic) (SCD). Results Medical records of 3219 patients with HTAD were screened (2761, 385 and 73 carrying a PV/LPV in FBN1, in a TGF-β signaling gene and in ACTA2 respectively). Non-aortic cardiac disease was reported 142 times in 101 patients (3.1%) (age 37 [range 12–77] years, 39% female): 88 patients carrying an FBN1 PV/LPV and 13 carrying a PV/LPV in one of the TGF-β signaling genes. Neither impaired myocardial function nor arrhythmia was reported in screened patients carrying a PV/LPV in ACTA2. Among the 142 reported non-aortic cardiac diseases, 68 (48%) were impaired myocardial function, 47 (33%) were AF/AFL and 27 (19%) were VT/VF/SCD. Among the patients with non-aortic cardiac disease, prior cardiac surgery was noted in 80% and severe valvular disease (valvular surgery or severe valvular regurgitation) in 58%, while 18% of the patients developed non-aortic cardiac disease in the absence of any of the latter. Conclusions In patients with HTAD, arrhythmia and impaired myocardial function was reported in patients with PV/LPVs in FBN1 and in the TGF-β signaling genes and not in patients harboring PV/LPVs in ACTA2. Though infrequent, non-aortic cardiac disease should be acknowledged as potentially severe, also occurring in young patients with no underlying significant valvular or aortic disease

Predictors of Ascending Aorta Enlargement and Valvular Dysfunction Progression in Patients with Bicuspid Aortic Valve

Aneurisma; Estenosis aórtica; Válvula aórtica bicúspideAneurisma; Estenosi aòrtica: Vàlvula aòrtica bicúspideAneurysm; Aortic stenosis; Bicuspid aortic valveBicuspid aortic valve (BAV) patients are at high risk of developing progressive aortic valve dysfunction and ascending aorta dilation. However, the progression of the disease is not well defined. We aimed to assess mid-long-term aorta dilation and valve dysfunction progression and their predictors. Patients were referred from cardiac outpatient clinics to the echocardiographic laboratories of 10 tertiary hospitals and followed clinically and by echocardiography for >5 years. Seven hundred and eighteen patients with BAV (median age 47.8 years [IQR 33–62], 69.2% male) were recruited. BAV without raphe was observed in 11.3%. After a median follow-up of 7.2 years [IQR5–8], mean aortic root growth rate was 0.23 ± 0.15 mm/year. On multivariate analysis, rapid aortic root dilation (>0.35 mm/year) was associated with male sex, hypertension, presence of raphe and aortic regurgitation. Annual ascending aorta growth rate was 0.43 ± 0.32 mm/year. Rapid ascending aorta dilation was related only to hypertension. Variables associated with aortic stenosis and regurgitation progression, adjusted by follow-up time, were presence of raphe, hypertension and dyslipidemia and basal valvular dysfunction, respectively. Intrinsic BAV characteristics and cardiovascular risk factors were associated with aorta dilation and valvular dysfunction progression, taking into account the inherent limitations of our study-design. Strict and early control of cardiovascular risk factors is mandatory in BAV patients

Are Aortic Root and Ascending Aorta Diameters Measured by the Pediatric versus the Adult American Society of Echocardiography Guidelines Interchangeable?

Aortic dimensions; Echocardiography; Guideline’s recommendationsDimensions aòrtiques; Ecocardiografia; Recomanacions de les directriusDimensiones aórticas; Ecocardiografía; Recomendaciones de las directricesAscending aorta diameters have important clinical value in the diagnosis, follow-up, and surgical indication of many aortic diseases. However, there is no uniformity among experts regarding ascending aorta diameter quantification by echocardiography. The aim of this study was to compare maximum aortic root and ascending aorta diameters determined by the diastolic leading edge (DLE) and the systolic inner edge (SIE) conventions in adult and pediatric patients with inherited cardiovascular diseases. Transthoracic echocardiograms were performed in 328 consecutive patients (260 adults and 68 children). Aorta diameters were measured twice at the root and ascending aorta by the DLE convention following the 2015 American Society of Echocardiography (ASE) adult guidelines and the SIE convention following the 2010 ASE pediatric guidelines. Comparison of the diameters measured by the two conventions in the overall population showed a non-significant underestimation of the diameter measured by the SIE convention at root level of 0.28 mm (CI −1.36; 1.93) and at tubular ascending aorta level of 0.17 mm (CI −1.69; 2.03). Intraobserver and interobserver variability were excellent. Maximum aorta diameter measured by the leading edge convention in end-diastole and the inner edge convention in mid-systole had similar values to a mild non-significant underestimation of the inner-to-inner method that permits them to be interchangeable when used in clinical practice

Natural History of MYH7-Related Dilated Cardiomyopathy

BACKGROUND Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 +/- 19.2 years) recruited from 29 international centers. RESULTS At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% +/- 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of <= 35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality