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.

Aims Mitral valve prolapse (MVP) is a common valvular disorder associated with significant morbidity and mortality, with a strong genetic basis. This study aimed to identify a mutation in a family with MVP and to characterize the valve phenotype in LTBP2 knockout (KO) mice.Methods and results Exome sequencing and segregation analysis were performed on a large family with MVP. Two mouse strains were generated: a complete KO of the LTBP2 gene and a knockin (KI) of the human mutation. At 6 months, phenotyping was conducted using echocardiography, histology, eye optical coherence tomography, and quantitative polymerase chain reaction analysis for TGF-beta signalling targets (periostin/POSTN, RUNX2, and CTGF) in valve tissues. LTBP2 rs117800773 V1506M mutation exhibited segregation with MVP. LTBP2 KO mice had a higher incidence of myxomatous changes by histology (7 of 9 of KO vs. 0 of 7 control animals, P = 0.00186) and echocardiography (7 of 9 vs. 0 of 8, P = 0.0011). LTBP2 KI mice for the human mutation showed a significantly elevated myxomatous histological phenotype (8 of 8 vs. 0 of 9, P = 0.00004) as well as by echocardiography (6 of 8 vs. 0 of 9, P = 0.00123). Knockout mice demonstrated an increase in the depth of the anterior chamber as well as reduced visual acuity. LTBP2 KO mice demonstrated overexpression of both TGF-beta signalling targets RUNX2 and periostin (P = 0.0144 and P = 0.001826, respectively).Conclusion We report a KO mouse strain with an LTBP2 mutation, demonstrating a valve phenotype, alongside a family with a novel mutation linked to MVP.

BACKGROUND Cardiac tamponade (TMP) is a catastrophic complication of type A acute aortic dissection (TAAAD), increasing the risk of morbidity and mortality. OBJECTIVES The present study aimed to assess the characteristics, management, and outcomes of TAAAD patients with preoperative TMP enrolled in the International Registry of Acute Aortic Dissection database from 1996 to 2022. METHODS Data from 63 aortic centers were analyzed and TAAAD patients with and without preoperative TMP were compared. Multivariable modeling to assess factors associated with the presence of preoperative cardiac TMP and survival curves were performed. Overall median follow-up was 35.8 months (Q1-Q3: 11.6-59.4 months). RESULTS Of the 6,014 patients with TAAAD in the International Registry of Acute Aortic Dissection during the 25-year study period, 865 individuals (14.4%) developed TMP. Patients with TMP were older (age 64.9 vs 60.8 years; < 0.0001) and less often male (61.8% vs 66.8%; P = 0.005). No differences were seen in time to presentation or diagnosis. Prior cardiac surgery was less common in patients with TMP (7.6% vs 12.8%; P < 0.0001). Syncope (37.4% vs 13.4%; P < 0.0001) and coma or altered consciousness (28% vs 8%; P < 0.0001) on presentation were more frequent in the TMP group. The majority of the cohort were managed surgically, rates of which were similar between groups (87.5% vs 87.7%; P = 0.911). In-hospital mortality was higher in patients with TMP (38.4% vs 15.4%; P < 0.001) but 4-year survival was similar (log-rank P = 0.767). CONCLUSIONS TMP is an important prognosticator of in-hospital mortality. It is associated with increased mortality of TAAAD and prompt surgery is required. Those who survive the hospital course, go on to share the same postdischarge course as those who did not have TMP. (JACC Adv. 2025;4:101632) (c) 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

AbstractBackgroundMitral Valve Prolapse (MVP) is a prevalent valvular disorder linked to considerable morbidity and mortality, affecting approximately 2.4% of the general population. A prior genome association study linked LTBP2 to this trait. We report a knockout mouse with LTBP2 mutation demonstrating valve phenotype as well as a family with a novel mutation causing MVPMethodsExome sequencing and segregation analysis were conducted on a large pedigree to identify mutations associated with MVP. Using CRISPR-Cas9 technology, two strains of mice were generated: one with a complete knockout (KO) of the LTBP2 gene and another with a knock-in (KI) mutation corresponding to the putative causative mutation. Echocardiography and histological examinations of valves were performed in the KO and the KI at the age of 6 months. Optical coherence tomography (OCT) and histological examination of the eyes was done at the same time. mRNA qPCR analysis for TGFβ signaling targets (periostin/POSTN, RUNX2, and CTGF) in valve tissues was analysed.ResultsThe LTBP2 rs117800773 V1506M mutation exhibited segregation with the MVP trait. LTBP2 KO mice had higher incidence of myxomatous changes by histology (7 of 9 of KO vs. 0 of 7 control animals, p=0.00186) and echocardiography (7 of 9 vs. 0 of 8, p=0.0011). LTBP2 Knock-in mice for the human mutation showed a significantly elevated myxomatous histological phenotype (8 of 8 vs. 0 of 9, p=0.00004) as well as by echocardiography (6 of 8 vs. 0 of 9, p=0.00123). KO mice demonstrated a significant increase in the depth of the anterior chamber as well as reduced visual acuity. LTBP2 KO mice demonstrated overexpression of both TGFβ signaling targets RUNX2 and periostin (P=0.0144 and P=0.001826, respectively).ConclusionAnimal models of LTBP2 KO and KI recapitulate MVP phenotype indicating that LTBP2 mutations are indeed causing myxomatous degeneration. Further, LTBP2 rs117800773 V1506M segregated with MVP in a large pedigree. Our data indicate the importance of LTBP2 in normal mitral valve function and that mutations in the gene care causing myxomatous valve.

Background: Racial disparities are known to exist in cardiovascular disease such as acute coronary syndrome and heart failure. However, data are limited in examining possible racial disparities related to aortic dissection due to the rare nature of this disease. Hypothesis: We hypothesize that, among patients presenting with acute type B aortic dissection, racial differences exist in disease severity at time of presentation as well as initial management, in-hospital and long-term outcomes. Methods: Our analysis included white (n = 2517, 80%) and black (n = 629, 20%) patients with acute Type B aortic dissection in the International Registry of Acute Aortic Dissection collected from 62 sites between 1996 and 2024. Other races were excluded given small sample size and limited follow up data. Results: When compared with white patients, black patients were younger (mean age 58 ± 12 years vs 65 ± 14 years, P < .0001), and more likely to have a history of hypertension (94% vs 83%, P < .0001), diabetes (19% vs 11%, P < .0001), chronic kidney disease (18% vs 9.5%, P < .0001), and cocaine use (14% vs 1.6%, P < .0001). Black patients were also more likely to present with abdominal pain (51% vs 43%, P = .003), lower extremity pain (16% vs 11%, P = .018), hypertension (72% vs 61%, P < .0001), renal malperfusion (24% vs 12%, P < .0001), abdominal vessel involvement (58% vs 47%, P < .0001) and pericardial effusion (12% vs 6%, P = .001). Black patients were more likely to undergo endovascular management (40% vs 28%, P < .0001) and less likely to be medically managed alone (49% vs 61%, P < .0001). Prior to any intervention, black patients were more likely to experience stroke (3.3% vs 1.1%, P = .001) and extension of dissection (10% vs 7.2%, P = .028). In-hospital mortality was similar (black 6.5% vs white 8.4%, P = .139). Overall survival was also similar at 4 years post-discharge (black 86% vs white 83%, P = .172). Among patients with endovascular management, black patients had better 4-year survival (93% vs 81%, P = .028). Conclusions: Our analysis shows differences in baseline characteristics, presentation, management, and in-hospital adverse events for black patients presenting with acute type B dissection compared to white patients; however, without any significant difference in in-hospital or 4 year mortality. Future studies may aim to evaluate modifiable risk factors and optimal treatment strategies to reduce the incidence of aortic dissection in black patients.

BACKGROUND: Over the past 25 years, diagnosis and therapy for acute aortic dissection (AAD) have evolved. We aimed to study the effects of these iterative changes in care. METHODS: Patients with nontraumatic AAD enrolled in the International Registry of Acute Aortic Dissection (61 centers; 15 countries) were divided into time-based tertiles (groups) from 1996 to 2022. The impact of changes in diagnostics, therapeutic care, and in-hospital and 3-year mortality was assessed. Cochran-Armitage trend and Jonckheere-Terpstra tests were conducted to test for any temporal trend. RESULTS: Each group consisted of 3785 patients (mean age, ≈62 years old; ≈65.5% males); nearly two-thirds had type A AAD. Over time, the rates of hypertension increased from 77.8% to 80.4% ( P =0.002), while smoking (34.1% to 30.6%, P =0.033) and atherosclerosis decreased (25.6%–16.6%; P <0.001). Across groups, the percentage of surgical repair of type A AAD increased from 89.1% to 92.5% ( P <0.001) and was associated with decreased hospital mortality (from 24.1% in group 1 to 16.7% in group 3; P <0.001). There was no difference in 3-year survival ( P =0.296). For type B AAD, stent graft therapy (thoracic endovascular aortic repair) was used more frequently (22.3%–35.9%; P <0.001), with a corresponding decrease in open surgery. Endovascular in-hospital mortality decreased from 9.9% to 6.2% ( P =0.003). As seen with the type A AAD cohort, overall 3-year mortality for patients with type B AAD was consistent over time ( P =0.084). CONCLUSIONS: Over 25 years, substantial improvements in-hospital survival were associated with a more aggressive surgical approach for patients with type A AAD. Open surgery has been partially supplanted by thoracic endovascular aortic repair for complicated type B AAD, and in-hospital mortality has decreased over the time period studied. Postdischarge survival for up to 3 years was similar over time.

OBJECTIVE:The International Registry of Acute Aortic Dissection (IRAD) celebrated its 25th anniversary in January 2021. This study evaluated IRAD's role in promoting the understanding and management of acute aortic dissection (AD) over these years. METHODS:IRAD studies were identified, analyzed, and ranked according to their citations per year (c/y) to determine the most-cited IRAD studies and topics. A systematic search of the literature identified cardiovascular guidelines on the diagnosis and management of acute AD. Consequently, IRAD's presence and impact were quantified using these documents. RESULTS:Ninety-seven IRAD studies were identified, of which 82 obtained more than 10 cumulative citations. The median c/y index was 7.33 (25th-75th percentile, 4.01-16.65). Forty-two studies had a greater than median c/y index and were considered most impactful. Of these studies, most investigated both type A and type B AD (n = 17, 40.5%) and short-term outcomes (n = 26, 61.9%). Nineteen guideline documents were identified from 26 cardiovascular societies located in Northern America, Europe, and Japan. Sixty-nine IRAD studies were cited by these guidelines, including 38 of the 42 most-impactful IRAD studies. Among them, partial thrombosis of the false lumen as a predictor of postdischarge mortality and aortic diameters as a predictor of type A occurrence were determined as most-impactful specific IRAD topics by their c/y index. CONCLUSIONS:IRAD has had and continues to have an important role in providing observations, credible knowledge, and research questions to improve the outcomes of patients with acute AD.

Objectives: This article aims to evaluate the accuracy of the color-Doppler-based technique to evaluate residual mitral regurgitation post TEER. Background: The evaluation of residual mitral regurgitation (MR) post-mitral transcutaneous edge-to-edge repair (mitral TEER) is a critical determinant in patients' outcomes. The common methods used today, based on the integration of color flow Doppler parameters, may be misleading because of the multiple jets and high velocities created by the TEER devices. Methods: Patients undergoing TEER at Hadassah hospital were recruited between 2015 and 2019. Post-procedural MR was evaluated using the integrated qualitative approach as recommended by the guidelines. In addition, the MR volume for each patient was calculated by subtracting the forward stroke volume (calculated by multiplying the LVOT area with the velocity time integral of the LVOT systolic flow) from the total stroke volume (calculated by the biplane Simpson method of discs). We compared the two methods for concordance. Results: Overall, 112 cases were enrolled. In 55.4% of cases, the volumetric residual MR was milder than the MR severity assessed by the guidelines' recommended method. In 25.1%, the MR severity was similar in both methods. In 16.2%, the MR severity was worse when calculated using the volumetric method (pValue < 0.001, Kappameasure of agreement = 0.053). The lower residual MR degree using the volumetric approach was mostly observed in patients classified as "moderate" by the integrated approach. Conclusions: MR severity after TEER is often overestimated by the guideline-recommended integrative method when compared with a volumetric method. Alternative methods should be considered to assess the MR severity after mitral TEER.

Introduction: Mitral Valve Prolapse (MVP) is a cardiac valvular disorder often associated with significant morbidity and mortality with a prevalence of 2.4% in the general population. Familial studies of MVP suggest an autosomal dominant model of inheritance with incomplete penetrance. Hypothesis: The aim of the current study was to identify a genetic etiology for MVP through trait segregation in a progeny with MVP. Methods: We used exome sequencing and segregation analysis to identify mutations linked to MVP in a progeny which includes members. We then generated two strains of mice using Crisper-Cas9 technology, a complete knockout and a knock-in mouse of the top candidate mutation. At 6 months of age echocardiography was done, the mice were sacrificed and the valves were examined pathologically as well as histologically by Movat pentachrome staining. The readers of both the echo and histology were blinded to the genotype. Results: Of 11 genes with rare deleterious mutations only LTBP2 Val1506Met variant (minor allele frequency of 0.0001) segregated with the trait with a LOD score of 1.5[-DR1] . Knockout mice were more likely to demonstrate myxomatous changes by histology (7 of 9 vs 2 of 6 animals, p=0.03) and echocardiography (14 of 22 vs 1 of 8, p=0.01). Knock-in mice demonstrated significantly higher phenotype rate by histology (8 of 8 vs 0 of 7, p<0.0005) and higher nominal phenotype by echo (4 of10 vs 1 of 9, p=0.2). Conclusions: LTBP2 Val1506Met variant segregated with MVP in a large pedigree. Animal models that recapitulate the phenotype suggest that the mutation is indeed pathogenic and leads to myxomatous valvular change.

Importance Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. Objective To identify a new gene for nsBAV. Design, Setting, and Participants This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. Main Outcomes and Measures To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. Results A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue ( MIB1 ) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. Conclusions and Relevance This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.

Aims:There are no comprehensive machine learning (ML) tools used by oncologists to assist with risk identification and referrals to cardio-oncology. This study applies ML algorithms to identify oncology patients at risk for cardiovascular disease for referrals to cardio-oncology and to generate risk scores to support quality of care. Methods and results:De-identified patient data were obtained from Vanderbilt University Medical Center. Patients with breast, kidney, and B-cell lymphoma cancers were targeted. Additionally, the study included patients who received immunotherapy drugs for treatment of melanoma, lung cancer, or kidney cancer. Random forest (RF) and artificial neural network (ANN) ML models were applied to analyse each cohort: A total of 20 023 records were analysed (breast cancer, 6299; B-cell lymphoma, 9227; kidney cancer, 2047; and immunotherapy for three covered cancers, 2450). Data were divided randomly into training (80%) and test (20%) data sets. Random forest and ANN performed over 90% for accuracy and area under the curve (AUC). All ANN models performed better than RF models and produced accurate referrals. Conclusion:Predictive models are ready for translation into oncology practice to identify and care for patients who are at risk of cardiovascular disease. The models are being integrated with electronic health record application as a report of patients who should be referred to cardio-oncology for monitoring and/or tailored treatments. Models operationally support cardio-oncology practice. Limited validation identified 86% of the lymphoma and 58% of the kidney cancer patients with major risk for cardiotoxicity who were not referred to cardio-oncology.

Background: Cancer patients with heart failure (HF) and se- vere mitral regurgitation (MR) are often considered to be at risk for surgical mitral valve repair/replacement. Severe MR inducing symptomatic HF may prevent delivery of potentially cardiotoxic chemotherapy and complicate fluid management with other cancer treatments. Objectives: To evaluate the outcome of percutaneous mitral valve repair (PMVR) in oncology patients with HF and significant MR. Methods: Our study comprised 145 patients who underwent PMVR, MitraClip, at Hadassah Medical Center between August 2015 and September 2019, including 28 patients who had active or history of cancer. Data from 28 cancer patients were compared to 117 no-cancer patients from the cohort. Results: There was no significant difference in the mean age of cancer patients and no-cancer patients (76 vs. 80 years, P = 0.16); 67% of the patients had secondary (functional) MR. Among cancer patients, 21 had solid tumor and 7 had hematologic malignancies. Nine patients (32%) had active malignancy at the time of PMVR. The mean short-term risk score of the patients was similar in the two groups, as were both 30-day and 1-year mortality rates (7% vs. 4%, P = 0.52) and (29% vs. 16%, P = 0.13), respectively. Conclusion: PMVR in cancer patients is associated with similar 30-day and 1-year survival rate compared with patients without cancer. PMVR should be considered for cancer patients presenting with HF and severe MR and despite their malignancy. This approach may allow cancer patients to safely receive planned oncological treatment.

Background: People over the age of 85 are the world's most rapidly growing age group and have a high incidence of cardiovascular mortality. Ejection fraction (EF), the most commonly used index of systolic function, may be limited prognostically in this population given the high incidence of left ventricular hypertrophy and myocardial contraction fraction (MCF) may be more accurate. The objective of this longitudinal study was to assess the prognosis of MCF in an age-homogenous, community-dwelling population of subjects. Methods: Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed with a portable echocardiograph at the subjects place of residence. Standard echocardiographic assessment of cardiac structure and function including MCF was performed. 5-year mortality was assessed via a centralized government database. Results: 418 subjects (197 males, 218 females) were enrolled in the study of whom 113 (27%) died at the time of 5-year follow-up. Subjects who died had significantly lower MCF (32 ± 14% vs. 36 ± 12%; p < 0.004) and EF (51.6 ± 11.6% vs 56.3 ± 9.4%; p< 0.0001) than survivors. On Kaplan-Meier analysis MCF was more significantly associated with mortality than EF (p< 0.0005 vs p < 0.04). The association between MCF and mortality remained significant on multivariate analysis as both a categorical and continuous variable while EF was only significant as a continous variable. Conclusions: MCF assessed by home echocardiography provides additional prognostic information to EF and may be a superior predictor of 5-year mortality in a community-dwelling population of the oldest old.

Bicuspid aortic valve (BAV) is a common congenital heart disease, with a 10-fold higher prevalence in first-degree relatives. BAV has different phenotypes based on the morphology of cusp fusion. These phenotypes are associated with different clinical courses and prognoses. Currently, the determinants of the valve phenotype are unknown. In this study we evaluated the role of genetics using familial cohorts. Patients with BAV and their first-degree relatives were evaluated by echocardiography. The concordance in BAV phenotype between pairs of family members was calculated and compared with the concordance expected by chance. We then performed a systematic literature review to identify additional reports and calculated the overall concordance rate. During the study period, 70 cases from 31 families and 327 sporadic cases were identified. BAV was diagnosed in 14% of the screened relatives. The proportions of the morphologies identified was: 12.3% for type 0, 66.2% for type 1-LR, 15.4% for type 1-RN, 4.6% for type 1-NL, and 1.5% for type 2. For the assessment of morphologic concordance, we included 120 pairs of first-degree relatives with BAV from our original cohort and the literature review. Concordance was found only in 62% of the pairs which was not significantly higher than expected by chance. In conclusion, our finding demonstrates intrafamilial variability in BAV morphology, suggesting that morphology is determined by factors other than Mendelian genetics. As prognosis differs by morphology, our findings may suggest that clinical outcomes may vary even between first-degree relatives.