Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.

Objective: The study objective was to evaluate the perioperative and long-term outcomes of aortic root repair and aortic root replacement and provide evidence for root management in acute type A aortic dissection.Methods: From 1996 to 2017, 491 patients underwent aortic root repair (n ¼ 307) or aortic root replacement (n ¼ 184) (62% bioprosthesis) for acute type A aortic dissection. Indications for aortic root replacement were intimal tear at the aortic root, root measuring 4.5 cm or more, connective tissue disease, or unrepairable aortic valvulopathy. Primary outcomes were in-hospital mortality, long-term survival, and reoperation rate for root pathology.Results: Patients' median age was 61 years and 56 years in the aortic root repair group and aortic root replacement group, respectively. The aortic root replacement group had more renal failure requiring dialysis, previous cardiac intervention or surgery, heart failure, coronary malperfusion syndrome, acute myocardial infarction, and severe aortic insufficiency, as well as concomitant coronary artery bypass grafting, tricuspid valve repair, and longer cardiopulmonary bypass and aortic crossclamp times but similar arch procedures. Perioperative outcomes were similar in the aortic root repair and aortic root replacement groups, including in-hospital mortality (8.5% and 8.2%), new-onset renal failure requiring permanent dialysis, stroke, myocardial infarction, and sepsis. Kaplan-Meier 10-year survival was 62% and 65%, and the 15-year cumulative incidence of reoperation was 11% and 7% in the aortic root repair and aortic root replacement groups, respectively. The primary indication for root reoperation was aortic root aneurysm in the aortic root repair group and bioprosthetic valve deterioration in the aortic root replacement group.Conclusions: Aortic root repair and aortic root replacement are appropriate surgical options for acute type A aortic dissection repair with favorable short-and long-term outcomes. Aortic root replacement should be performed for patients with acute type A aortic dissection presenting with an intimal tear at the aortic root, root aneurysm 4.5 cm or greater, connective tissue disease, or unrepairable aortic valvulopathy.

Objective: To compare perioperative and long-term outcomes in patients undergoing hemiarch and aggressive arch replacement for acute type A aortic dissection (ATAAD). Methods: From 1996-2017, we compared outcomes of hemiarch (n=322) versus aggressive arch replacements (zones 2 and 3 arch replacement with implantation of 2-4 arch branches, n=150) in ATAAD. Indications for aggressive arch were arch aneurysm >4 cm or intimal tear in the aortic arch that was not resectable by hemiarch replacement, or dissection of arch branches with malperfusion. Results: Patients in the aggressive arch group were significantly younger (mean age: 57 vs. 61 years old) and had significantly longer hypothermic circulatory arrest, cardiopulmonary bypass, and aortic cross-clamp times. There were no significant differences in perioperative outcomes between hemiarch and aggressive arch groups, including 30-day mortality (5.3% vs. 7.3%, p=0.38) and postoperative stroke rate (7% vs. 7%, p=0.96). Over 15 year Kaplan-Meier survival was similar between hemiarch and aggressive arch groups (log-rank p=0.55, 10-year survival 70% vs. 72%). Given death as a competing factor, incidence rates of reoperation over 15 years (2.1% vs. 2.0% per year, p=1) and 10-year cumulative incidence of reoperation (14% vs. 12%, p=0.89) for arch and distal aorta pathology were similar between the two groups. Conclusion: Both hemiarch and aggressive arch replacement are appropriate approaches for select patients with ATAAD. Aggressive arch replacement should be considered for an arch aneurysm >4 cm or an intimal tear at the arch unable to be resected by hemiarch replacement, or dissection of the arch branches with malperfusion.

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6–19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4–22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4–22.3, siblings: OR, 5.1; 95% CI, 1.1–23.9, children: OR, 6.0; 95% CI, 1.4–26.7). Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.