Eagle, Kim A.

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.

Background: Shock is a highly dreaded complication of type A acute aortic dissection (TAAAD). However, few data exist on its incidence and association with prognosis. Methods: We evaluated 2704 TAAAD patients [mean age 61.4 ± 14.5, (67.6%) male] from the International Registry of Acute Aortic Dissection. Results: Shock was present at arrival in 407 (15.1%) TAAAD patients. These patients demonstrated no difference in age (61.5 ± 15.2 with shock vs. 61.4 ± 14.4 years without; p=0.873), but were more likely to have history of hypertension (83.1% vs. 73.0%; p<0.001), atherosclerosis (36.5% vs. 21.7%, p<0.001) and diabetes (12.3% vs. 7.0%, p=0.001) than patients without shock. They had more surgical management (90.9% vs. 86.0%; p=0.007). In-hospital complications such as hypotension (49.8% vs. 28.6%; p<0.001), coma (11.4% vs. 5.8%; p<0.001), tamponade (33.6% vs. 18.2%; p<0.001) and myocardial ischemia/infarction (19.7% vs. 13.7%; p=0.006) were more common among shock patients. Overall in-hospital mortality (30.2% vs. 23.9%; p=0.007) and mortality by management (surgical: 24.6% vs. 19.1%; p=0.015; medical: 88.9% vs. 53.3%, p<0.001) were higher among shock patients. Independent predictors of in-hospital mortality in shock patients are displayed in Table 1. Among hospital survivors, Kaplan-Meier estimates of follow-up mortality were similar between groups (p=0.609). Conclusions: Shock occurred in 15.1% of patients with TAAAD and was associated with increased in-hospital morbidity and mortality, but not long-term mortality.

Introduction: Prior cardiac surgery can complicate the clinical presentation, diagnosis, and management of patients with type A aortic dissection (TAAAD). This report from the International Registry of Acute Aortic Dissection (IRAD) examines this hypothesis. Methods: 352 of 2289 TAAAD patients (15.4%) enrolled in IRAD had cardiac surgery prior to dissection, including coronary artery bypass grafting (CABG, 34.6%), aortic or mitral valve surgery (38.4%), aortic surgery (44.7%), and other cardiac surgery (18.1%). Results: Comparative differences in baseline demographics, clinical presentation, and management time are shown in Table 1. Patients with prior cardiac surgery were more likely to undergo CABG (p=0.006) or mitral valve replacement (p=0.001) at the time of dissection repair. Total cardiopulmonary bypass time was higher in patients with prior cardiac surgery (p<0.001); no difference was seen in cardiac arrest time (p=0.113) or cerebral ischemia time (p=0.286). In-hospital mortality was significantly higher for patients with prior cardiac surgery (33.5% vs. 24.0%, p70 (RR1.58, 95% CI 1.25-1.99), and medical management of acute dissection (RR 4.79, 95% CI 3.62-6.34). Kaplan-Meier analysis is shown in Figure 1. Conclusion: Prior cardiac surgery not only delays presentation and diagnosis of acute type A dissections, but is also an important adverse risk factor for early and late mortality.

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.

Background: Little is known about the relationship between Type A Acute Aortic Dissection (TAAAD) and pulse pressure (PP), defined as the difference between systolic and diastolic blood pressure. This study explores the association between PP and presentation, complications and outcomes of TAAAD patients. Methods: PP at hospital presentation was used to divide 1,960 non-iatrogenic TAAAD patients into quartiles: narrowed (≤39 mmHg; n=430), normal (40-56 mmHg; n=554), mildly elevated (57-75 mmHg; n=490) and markedly elevated (≥76 mmHg; n=486). Variables relating to index presentation and in-hospital outcomes were analyzed. Results: TAAAD patients (patients) in the narrowed PP quartiles were more frequently older and Caucasian while patients with markedly elevated PPs tended to be male and have a history of hypertension. Patients who demonstrated abdominal vessel involvement more commonly demonstrated elevated PPs whereas patients with narrowed PPs were more likely to have periaortic hematoma and/or pericardial effusion. Narrowed PPs were also correlated with higher incidences of hypotension, cardiac tamponade and mortality. TAAAD patients who were managed with endovascular and hybrid procedures and those with renal failure tended to have elevated PPs. No difference in aortic regurgitation at presentation was noted between groups. Conclusions: TAAAD patients in the middle two PP quartiles had better in-hospital outcomes than patients in the outer quartiles. Patients with narrowed PPs experienced more cardiac complications, particularly cardiac tamponade, while those with elevated PPs were more likely to have abdominal aortic involvement. Presenting PP offers a clue to different manifestations of AAD that may facilitate initial triage and care.

Background: The debate for the optimal treatment of complicated Type B Acute Aortic Dissection (TBAAD) is primarily focused upon open surgical intervention versus thoracic endovascular aortic repair (TEVAR). The technique of fenestration with stenting has been proposed to resolve malperfusion. This study evaluated post-procedural outcomes of all three approaches for TBAAD. Methods: TBAAD patients enrolled in the International Registry of Acute Aortic Dissection were stratified by management type: TEVAR, fenestration and stenting, and surgery. Results: Of the 552 patients with TBAAD, 231 (41.8%) underwent TEVAR, 214 (38.8%) standard open surgery, and 107 (19.4%) fenestration and stenting. TEVAR or fenestration and stenting were more likely to be performed in classic double barrel aortic dissection when compared to open surgery (73.2%, 76.6%, 52.8% respectively; p<0.001). Patients treated with open repair were less likely to have distal extension into the abdominal aorta than those with TEVAR or fenestration and stenting (47.7%, 62.7%, 86.4%, respectively; p<0.001). In-hospital mortality was similar between groups (11.7% TEVAR, 14.0% fenestration and stenting, 15.9% surgery). At five years, Kaplan-Meier post-discharge all-cause survival estimates were highest for TEVAR, followed by endovascular fenestration and finally open surgical intervention (85.2%, 78.3%, 67.2%, respectively; p=0.039). Conclusion: Patients treated by endovascular approaches, whether with flap fenestration or thoracic endovascular aortic repair, had lower five year mortality when compared to patients who required open repair in the setting of TBAAD. Either endovascular approach may be helpful in the treatment of TBAAD. Further research is needed to determine how much of the observed difference represents patient selection versus differential effects of treatment.

Background Among patients with combined coronary artery and peripheral vascular disease, long-term benefits of surgical therapy compared with medical therapy for coronary artery disease are unknown. Methods and Results Using prospectively collected data from the Coronary Artery Surgery Study registry, we performed a retrospective cohort analysis of 1834 patients (mean age, 56 years; 20% women) with both coronary artery and peripheral vascular disease and evaluated their long-term outcomes. Of these patients, 986 received (nonrandomly) coronary artery bypass graft surgery, and 848 were treated medically. Perioperative mortality was 4.2% (2.9% in the absence of peripheral vascular disease; P =.02). In a mean follow-up period of 10.4 years, 1100 deaths occurred (80% due to cardiovascular causes). For the surgical group, 4-, 8-, 12-, and 16-year estimated probabilities of survival were 88%, 72%, 55%, and 41%, respectively, and 73%, 57%, 44%, and 34%, respectively, for the medical group ( P <.0001). Multivariate analysis demonstrated that type of therapy was independently associated with survival ( P =.0001; χ 2 =15.34). Subgroup analysis suggested that benefits of surgical treatment on survival were limited to patients with three-vessel coronary artery disease and were inversely related to ejection fraction. Survival free of death or myocardial infarction was also significantly better among the surgical group. Type of therapy was significantly associated with occurrence of late events ( P =.01; χ 2 =6.55). Subgroup analysis again demonstrated that beneficial effects of surgery were limited to patients with three-vessel coronary artery disease and were inversely related to ejection fraction. Conclusions Surgical treatment provides long-term benefit for certain subgroups of patients with combined coronary artery and peripheral arterial vascular disease.

Background— Fibromuscular dysplasia (FMD), a noninflammatory disease of medium-size arteries, may lead to stenosis, occlusion, dissection, and/or aneurysm. There has been little progress in understanding the epidemiology, pathogenesis, and outcomes since its first description in 1938. Methods and Results— Clinical features, presenting symptoms, and vascular events are reviewed for the first 447 patients enrolled in a national FMD registry from 9 US sites. Vascular beds were imaged selectively based on clinical presentation and local practice. The majority of patients were female (91%) with a mean age at diagnosis of 51.9 (SD 13.4 years; range, 5–83 years). Hypertension, headache, and pulsatile tinnitus were the most common presenting symptoms of the disease. Self-reported family history of stroke (53.5%), aneurysm (23.5%), and sudden death (19.8%) were common, but FMD in first- or second-degree relatives was reported only in 7.3%. FMD was identified in the renal artery in 294 patients, extracranial carotid arteries in 251 patients, and vertebral arteries in 82 patients. A past or presenting history of vascular events were common: 19.2% of patients had a transient ischemic attack or stroke, 19.7% had experienced arterial dissection(s), and 17% of patients had an aneurysm(s). The most frequent indications for therapy were hypertension, aneurysm, and dissection. Conclusions— In this registry, FMD occurred primarily in middle-aged women, although it presents across the lifespan. Cerebrovascular FMD occurred as frequently as renal FMD. Although a significant proportion of FMD patients may present with a serious vascular event, many present with nonspecific symptoms and a subsequent delay in diagnosis.