Evangelista, Arturo

BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

Abstract Background Aortic valve calcification (AVC), as measured by gold-standard computed tomography (CT) Agatston score, provides an anatomic assessment of aortic stenosis (AS) severity and is a key predictor of AS progression and need for valve replacement. AVC detection and quantification from transthoracic echocardiography (TTE) could expand AS early diagnosis and risk stratification, currently limited by CT availability and radiation exposure. Methods A multi-view video-based deep learning framework was developed using 1166 TTE aortic valve videos from 187 TTE studies acquired in 110 patients with available AVC score by CT. EchoAVC architecture includes a feature extraction model followed by a quality-aware model that aggregates video-level information to obtain patient-level predictions for AVC detection and quantification (score). The framework was validated internally with 173 TTE studies from 86 patients across seven centres, and externally using 430 TTE studies from 280 patients across four different centres. The associations between EchoAVC estimations and AS severity, progression, and need for aortic valve replacement were examined. Results EchoAVC demonstrated excellent performance in AVC detection (AUROC 0.98, accuracy 94.4%), and quantification (R = 0.64) in the external multi-centre testing set. EchoAVC score was correlated with echocardiographic AS severity descriptors, including aortic valve mean pressure gradient (ρ = 0.749) and peak velocity (ρ = 0.757), and predicted future increase in mean pressure gradient (ρ = 0.382), peak velocity (ρ = 0.433) and calcium score by CT (ρ = 0.650). In 361 patients followed for a median of 3.8 years, 139 underwent aortic valve replacement. Baseline presence and extent of AVC as predicted by EchoAVC showed strong risk-stratification power for aortic valve replacement, remarkably in line with those obtained by CT, and incremental over TTE AS descriptors. EchoAVC was further tested in routine clinical practice images, confirming strong associations with AS severity and progression, including stratification for incident AS in previously unaffected individuals (p<0.001). Conclusions EchoAVC enables accurate and non-invasive detection and quantification of AVC, offering substantial diagnostic and prognostic value for aortic stenosis progression and need for valve replacement. This technique holds promise as a scalable tool for early detection and clinical management of aortic valve stenosis. Clinical Perspective What Is New? * Aortic valve calcification can be detected and quantified on standard, two-dimensional transthoracic echocardiography * EchoAVC score is associated with echocardiographic metrics of aortic stenosis severity * EchoAVC predicts progressive increase in aortic stenosis severity and need for aortic valve replacement What Are the Clinical Implications? * This openly available deep learning framework can be used to estimate aortic valve calcium in patients at risk of or presenting aortic stenosis to predict aortic stenosis progression * EchoAVC may help identify patients likely to have high aortic valve calcium and prioritize them for confirmatory CT assessment, thereby supporting earlier identification of calcific aortic valve disease in clinical pathways.

Background: Stroke is one of the most dreaded complications of type A acute aortic dissection (TA-AAD). However, few data exist on its incidence and association with prognosis. Methods: We evaluated 2202 TA-AAD patients [pts, mean age 61.9 ± 14.4, 1487 (67.5%) male] from the International Registry of Acute Aortic Dissection (IRAD) to determine the incidence and prognostic influence of stroke in TA-AAD. Results: Stroke was present at arrival in 132 (6.0%) TA-AAD pts. Stroke pts were older (65±12 vs. 62±15 yrs; p=.002) and more likely to have hypertension (86% vs. 71%; p=.001) or atherosclerosis (29% vs. 22%; p=.042). While chest pain at arrival was less common (70% vs. 82%; p<.001), stroke pts presented more often with syncope (44% vs. 15%; p<.001), shock (14% vs. 7%; p=.005) or pulse deficit (51% vs. 29%; p=<.001). Arch vessels involvement was more frequent among the stroke pts (68% vs. 37%; p<.001). Stroke pts were treated less frequently by surgery (74% vs. 85%; p<.001). Hospital stay was significantly longer in patients presenting with stroke (median 17.9 versus 13.3 days, p<0.001). Stroke patients demonstrated more frequent in-hospital complications (Table) and higher mortality (adjusted OR 1.62, 95% CI .99-2.65, p=.055) Among hospital survivors, mortality at follow-up was similar in pts with and without stroke (adjusted HR 1.15, 95% CI 0.46-2.89, p=.761). Conclusions: Stroke occurred in greater than 1 of 20 pts with TA-AAD and was associated with increased morbidity and in-hospital, but not long-term mortality. Whether aggressive early intervention will reduce morbidity and improve mortality remains to be evaluated in future studies.

Introduction/Purpose: To examine trends in patient presentation, diagnosis and outcomes of acute aortic dissection over 15 years since the original report from the International Registry of Acute Aortic Dissection (IRAD). Methods: Patient data were collected at 28 international referral centers from 1996 up to the present. Trends were analyzed among 3275 patients divided according to date of enrollment into 6 equal groups and by Type: A (n=2110) or B (n=1165). Results: There was no change over time in the presenting complaints of severe or worst ever pain for Type A and Type B (90% and 96%, respectively), or in the incidence of chest pain ( 80% in Type A and 70% in Type B, respectively), with considerable overlap in chest vs. back pain between types. The report of pulse deficits did not change over time, present in 30% of Type A patients. Normal chest X-ray on presentation increased in Type A acute aortic dissection (AoD) from 13.7% to 31.3% over time (p-value for trend <0.001). In Type B the report of normal chest X-ray increased from 19.9% to 40.9% (p-value for trend <0.001). There were significant trends in initial imaging modalities for Type A: increased use of CT (from 49.4% to 71.6%, p-value for trend <0.001) and decreased use of TEE (from 45.3% to 25.4%, p-value for trend <0.001). For Type B, use of CT increased from 77.2% to 88.4% (p-value for trend .013). A decrease in overall mortality over time was significant for both Type A and Type B patients (see graph). Surgical mortality in Type A patients fell from 25.3% to 16.5% (p-value for trend 0 .003). Conclusions: No significant difference was seen over time in pain severity, chest pain, and presence of pulse deficits. The incidences of a normal chest X-ray, originally thought to be uncommon in dissection cases, increased over time to 30% in Type A and 40% in Type B AoD. Use of CT as the initial imaging modality increased for both Type A and Type B. Lastly, a significant decrease in overall mortality was seen for both Type A and Type B patients.

Abstract This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.

Abstract This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.

AbstractBicuspid aortic valve is the most prevalent cardiac valvular malformation. It is associated with a high rate of long‐term morbidity including development of calcific aortic valve disease, aortic regurgitation and concomitant thoracic aortic aneurysm and dissection. Recently, basic and translational studies have identified some key processes involved in the development of bicuspid aortic valve and its morbidity. The development of aortic valve disease and thoracic aortic aneurysm and dissection is the result of complex interactions between genotypes, environmental risk factors and specific haemodynamic conditions created by bicuspid aortic valve anatomy. Herein, we review the pathobiology of bicuspid aortic valve with a special emphasis on translational aspects of these basic findings. Important but unresolved problems in the pathology of bicuspid aortic valve and thoracic aortic aneurysm and dissection are discussed, along with the molecular processes involved.