Emel A. Ergul

De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot

Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. We then examined a second, independent TOF cohort (n = 398) for additional CNVs at these loci. We identified CNVs at chromosome 1q21.1 in 1% (5/512, P = 0.0002, OR = 22.3) of nonsyndromic sporadic TOF cases. We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes. Our findings predict that at least 10% (4.5–15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.

Management of diseases of the descending thoracic aorta in the endovascular era: a Medicare population study.

Objective:Prospective trials have shown improved perioperative outcomes with endovascular repair of thoracic aortic (TEVAR) pathologies compared with conventional surgery (OPEN). There are no long-term population data detailing the impact of TEVAR on practice patterns and results of treatment of descending thoracic aortic pathology (DTA), which are the goal of this study. Methods:All procedures performed on the DTA captured in the Medicare database from 2004 to 2007 were identified by ICD-9 codes and stratified into OPEN and TEVAR cohorts. Outcomes included perioperative mortality (&khgr;2) and 5-year actuarial survival. Results:There were 11,166 patients identified (4838 [43%] TEVAR vs. 6328 [57%] OPEN) with 7247 (65%) nonruptured, degenerative thoracic aortic aneurysms (TAA), 2701 (24%) descending aortic dissections, 1033 (9%) thoracic aortic ruptures, and 185 (2%) traumatic aortic tears. The distribution of cases changed significantly during the study period (P < 0.0001) with an increase in TEVAR, decrease in OPEN, and increase in total cases over time (Table 1). The perioperative mortality was lower in the TEVAR group for the entire population (360 [7.4%] TEVAR vs. 1175 [18.5%] OPEN, P < 0.0001), and for the individual pathologies: TAA (182/3529 [5%] TEVAR vs. 451/3718 [12%] OPEN, P < 0.001), dissections (76/833 [9%] TEVAR vs. 399/1868 [21%] OPEN, P < 0.001) and ruptures (87/368 [24%] TEVAR vs. 298/665 [45%] OPEN, P < 0.0001). The Kaplan–Meier curve significantly favored TEVAR for the entire cohort because of the early mortality of the OPEN cohort but the curves converged by 5 years. The 5-year survival by indication was: entire population (53.4% TEVAR vs. 53.3% OPEN, P < 0.0001), TAA (55.8% TEVAR vs. 59.7% OPEN, P = 0.84), dissection (58.2% TEVAR vs. 50.6% OPEN, P < 0.0001), ruptures (23.3% TEVAR vs. 25.3% OPEN, P = 0.001), and trauma (62.9% TEVAR vs. 50.9% OPEN, P = 0.12). Conclusion:There has been a significant increase in the use of TEVAR for management of diseases of the DTA. TEVAR offers a significant perioperative survival advantage when compared with OPEN regardless of the indication for repair. However, in the Medicare population, the 5-year survival is similar between the 2 cohorts.

Evolution of operative strategies in open thoracoabdominal aneurysm repair

OBJECTIVE During a 24-year interval, we managed >90% of thoracoabdominal aortic aneurysm (TAA) repairs with a clamp-and-sew (clamp/sew) approach supplemented with protective adjuncts, including renal hypothermia and epidural cooling with aggressive intercostal reconstruction for spinal cord protection. A finite paraplegia rate led to operative modifications using distal aortic perfusion (DAP) through atriofemoral bypass to support cord collateral circulation and selective intercostal reconstruction based on motor evoked potential (MEP) monitoring. This study evaluated the effect of DAP/MEP on perioperative outcomes. METHODS Consecutive patients undergoing repair of nonruptured Crawford extent I-III TAA using DAP/MEP were compared with propensity-matched patients treated with the clamp/sew technique. Outcomes included 30-day mortality and paraplegia. RESULTS There were 52 patients in the DAP cohort vs 127 undergoing clamp/sew. The DAP and clamp/sew cohorts differed in age (62.6 vs 69.5 years, P = .0003), presence of Marfan disease (10% vs 2%, P = .01), and chronic dissection (37% vs 8%, P = .001). Operative mortality was low (DAP, 2%; clamp/sew, 5%; P = .38). Postoperative renal insufficiency, although doubled in clamp/sew (17%) vs DAP (8%; P = .10), was not significant. DAP patients had a significantly lower incidence of intercostal reconstruction than the clamp/sew group (10% vs 34%, P < .0001), yet there was no paraplegia in the DAP cohort vs 5% in clamp/sew (P = .11). The composite death/paraplegia rate was decreased with DAP at 1 of 52 (2%) vs clamp/sew at 11 of 127 (9%; P = .01). Paraparesis with complete recovery occurred in 5 of 52 (10%) of the DAP group. CONCLUSIONS Elective TAA repair was accomplished with a low mortality in the DAP and clamp/sew cohorts. The use of MEP in the DAP cohort (despite a higher spinal cord ischemic risk due to the number of chronic dissection patients) decreased the need for intercostal reconstruction, with no paraplegia to date. DAP with MEP is the preferred operative strategy for extent I to III TAA repair.

The natural history of medically managed acute type B aortic dissection

OBJECTIVE Although medical management of acute uncomplicated type B aortic dissection remains the standard of care, contemporary data regarding the natural history of medically treated patients are sparse. The goal of this study was to evaluate the natural history of patients with acute type B aortic dissection who were initially managed with medical therapy alone. METHODS All patients with acute type B aortic dissection who were initially managed medically between March 1999 and March 2011 were included. Failure of medical therapy was defined as any death or aorta-related intervention. Early failure occurred within 15 days of presentation. Predictors of long-term outcomes were determined using backward stepwise regression. RESULTS A total of 298 patients with medically managed acute type B dissections were identified. The cohort had an average age of 65.9 years at presentation and was 61.7% male. There were 174 (58.4%) failures including 119 deaths and 87 interventions (24 endovascular, 63 open); 57 (66%) interventions were performed for aneurysmal degeneration. There were 37 (12%) early failures including 14 deaths and 25 interventions (10 endovascular, 15 open). Aneurysmal degeneration was the indication for intervention in six patients (24%). Mean follow-up was 4.2 years (range, 0.1-14.7 years). Kaplan-Meier estimate demonstrated that freedom from intervention was 77.3% ± 2.4% at 3 years and 74.2% ± 2.5% at 6 years. There were no predictors of freedom from intervention. Kaplan-Meier estimate demonstrated that the intervention-free survival was 55.0% ± 3.0% at 3 years and 41.0% ± 3.2% at 6 years. End-stage renal disease was predictive of failure of medical treatment (hazard ratio, 2.60; confidence interval, 1.19-5.66; P = .02), and age >70 years was protective against failure (hazard ratio, 0.97; confidence interval, 0.95-0.98; P < .01). Kaplan-Meier estimate demonstrated that survival after 6 years was higher in patients who underwent interventions (76% vs 58%; P = .018). CONCLUSIONS The majority of patients with acute type B dissection will fail medical therapy over time as evidenced by a 6-year intervention-free survival of 41%. Patients who underwent any aortic intervention had a significant survival advantage over those who were treated with medical management alone. Further study is necessary to determine who will benefit most from early intervention.

Continued favorable results with open surgical repair of type IV thoracoabdominal aortic aneurysms

OBJECTIVES Type IV thoracoabdominal aortic aneurysm (TAAA) repair, despite low risk of spinal cord ischemia (SCI), is reported to have significant morbidity and mortality. This has led some to apply adjuncts (eg, extracorporeal circulation) used in more extensive TAAA repair or to consider alternative approaches, such as hybrid operations. We have used a consistent, simplified surgical approach to type IV TAAA, and the goal of the present study is to review experience over 2 decades with such treatment and to identify correlates of surgical morbidity. METHODS All type IV repairs at Massachusetts General Hospital from January 1989 through September 2009 were evaluated for clinical features, technical operative details, and 30-day outcomes. Logistic regression identified predictors of morbidity. Survival was assessed using Kaplan-Meier analysis. RESULTS A total of 179 patients underwent type IV repair, with elective repair in 156 (87%) and urgent in 23 (13%). The clamp-and-sew technique was used for all operations, with routine hypothermic renal perfusion. Clinical features were age 73 ± 8 years, coronary artery disease in 89 (50%), and creatinine level >1.8 mg/dL defining chronic renal insufficiency (CRI) in 32 (18%). Operative reconstruction in 166 (93%) consisted of one beveled proximal anastomosis incorporating the descending thoracic aorta, celiac, superior mesenteric artery, and right renal arteries origins (mean visceral clamp time, 36 ± 12 minutes) and a side-arm graft to the left renal artery. Technical details included previous abdominal aortic aneurysm (AAA) repair in 52 (29%), operative time of 290 ± 90 min, estimated blood loss of 2.7 ± 1.4 L, and splenectomy in 57 (32%). The 30-day outcomes were death in 5 (2.8%), myocardial infarction in 6 (3.4%), hemodialysis in 5 (2.8%), and any degree of SCI in 4 (2.2%). Regression analysis identified a history of CRI as an independent predictor of postoperative complication or death (odds ratio, 3.4; 95% confidence interval, 1.4-8). Survival rates at 1, 5, and 10 years were 89% ± 2%, 62% ± 4%, and 36% ± 5%, respectively. CONCLUSIONS A simplified operative approach for type IV TAAA repair is associated with favorable perioperative results. These data refute the need for surgical adjuncts commonly applied in more extensive TAAA and indicate that the hybrid operation is an illogical posture. CRI should figure prominently in clinical decision making. Long-term survival equates that observed after routine AAA repair.

Impact of hospital volume and type on outcomes of open and endovascular repair of descending thoracic aneurysms in the United States Medicare population.

OBJECTIVE Favorable outcomes of thoracic endovascular aortic repair (TEVAR) compared with open repair for descending thoracic aortic aneurysms (DTAs) have led to increasing TEVAR use. We evaluated the effect of case volume and hospital teaching status on clinical outcomes of intact DTA repair. METHODS The Medicare Provider Analysis and Review (MEDPAR) data set (2004 to 2007) was queried to identify open repair or TEVAR for DTA. Hospitals were stratified by DTA volume into high volume (HV; ≥ 8 cases/y) or low volume (LV; <8 cases/y) and teaching or nonteaching. The effect of hospital variables on the primary study end point of 30-day mortality and secondary end points of 30-day complications and long-term survival after open repair and TEVAR DTA repair were studied using univariate testing, multivariable regression modeling, Kaplan-Meier survival analysis, and Cox proportional hazards regression modeling. RESULTS We identified 763 hospitals performing 3554 open repairs and 3517 TEVARs. Overall DTA repair increased (P < .01) from 1375 in 2004 to 1987 in 2007. The proportion of hospitals performing open repair significantly decreased from 95% in 2004 to 57% in 2007 (P < .01), whereas those performing TEVAR increased (P < .01) from 24% to 76%. Overall repair type shifted from open (74% in 2004, the year before initial commercial availability of TEVAR) to TEVAR (39% open in 2007; P < .01). The fraction of open repairs at LV hospitals decreased from 56% in 2004 to 44% in 2007 (P < .01), whereas TEVAR increased from 24% in 2004 to 51% in 2007 (P < .01). Overall mortality during the study interval for open repair was 15% at LV hospitals vs 11% at HV hospitals (P < .01), whereas TEVAR mortality was similar, at 3.9% in LV vs 5.5% in HV hospitals (P = .43). LV was independently associated with increased mortality after open repair (odds ratio, 1.4; 95% confidence interval, 1.1-1.8; P < .01) but not after TEVAR. There was no independent effect of hospital teaching status on mortality or complications after open repair or TEVAR repair. CONCLUSIONS The total number of DTA repairs has significantly increased. Operative mortality for TEVAR is independent of hospital volume and type, whereas mortality after open surgery is lower at HV hospitals, suggesting that TEVAR can be safely performed across a spectrum of hospitals, whereas open surgery should be performed only at HV hospitals.

Further experience with distal aortic perfusion and motor-evoked potential monitoring in the management of extent I-III thoracoabdominal aortic anuerysms

BACKGROUND Prior studies indicated improved early mortality and paraplegia rates in a small cohort of patients with type I-III thoracoabdominal aortic aneurysms (TAAs) treated with atriofemoral bypass (AFB) and motor-evoked potentials (MEVPs) when compared with a propensity-matched cohort of patients treated with the clamp and sew (CS) method, wherein epidural cooling was the principal spinal cord protective adjunct. The use of AFB/MEVP increases the complexity of TAA repair and in this study, we address whether the early benefits will be sustained when this is applied to a general population with type I-III TAAs. METHODS Consecutive patients undergoing repair of nonruptured Crawford extent I-III TAAs from 1/1987 to 12/2011 were identified. Patients were stratified according to operative approach (AFB/MEVP vs CS). Endpoints included long-term survival, and the composite outcome of perioperative death and paraplegia. A multivariate, risk-adjusted model was then created to determine if operative approach independently influenced outcome. RESULTS There were 485 patients (CS = 385 [79%]; AFB/MEVP = 100 [21%]). The cohorts differed in that the AFB/MEVP group was younger (65.8 ± 12.5 years vs 70.9 ± 9.7 years; P < .001), had more extent I/II aneurysms (66% vs 50.1%; P = .005), and had more chronic dissections (30.3% vs 18.9%; P = .018). Operative variables differed in that the AFB/MEVP cohort had longer operative times (434 ± 112 minutes vs 324 ± 98 minutes; P < .001) and higher blood turnover (6028 ± 3473 mL vs 3581 ± 3111 mL; P < .0001). There was no difference in the rate of intraoperative death (AFB/MEVP = 1.0% vs CS = 0.5%; P = .50), length of intensive care unit stay (AFB/MEVP = 9.6 ± 8.6 days vs CS = 9.5 ± 12.3 days; P = .95) or hospital length of stay (AFB/MEVP = 19.9 ± 12.6 days vs CS = 21.6 ± 23.5 days; P = .49). The composite perioperative death and paraplegia rate was lower in the AFB/MEVP cohort (7% vs 19%; P = .004). The multivariate model for predictors of the composite outcome showed that AFB/MEVP was protective (odds ratio, 0.39; 95% confidence interval, 0.17-0.9; P = .028). Long-term (4-year) survival was improved in the AFB/MEVP group as well (73 ± 6% vs 60 ± 3%; P = .004). CONCLUSIONS AFB/MEVP is an independent predictor of improved perioperative death and paraplegia rates as well as long-term survival in patients undergoing repair of type I-III TAAs and is the preferred operative strategy.

May-Thurner syndrome: can it be diagnosed by a single MR venography study?

PURPOSE We aimed to evaluate the longitudinal stability of left common iliac vein (LCIV) compression by the right common iliac artery on magnetic resonance venography (MRV). MATERIALS AND METHODS This retrospective study included 214 patients diagnosed with May-Thurner syndrome by MRV. We identified a subset of patients who underwent contrast-enhanced cross-sectional imaging of the pelvis six months before or anytime after the MRV and did not undergo any interventional venous procedures between the two studies; 36 patients met these criteria. The degree of venous compression was calculated in both the index and comparison study. RESULTS On the index MRV, the mean compression of the LCIV was 62%. However, on the comparison study in the same patients, the mean compression was 39%. The mean change in degree of compression between the two studies was 23% (P < 0.0001), ranging from a 12% increase to 69% decrease in degree of compression on the comparison study. CONCLUSION The compressed LCIV on a single MRV study was not stable over time and thus may be insufficient to diagnose May-Thurner syndrome.

Aneurysmal degeneration of the thoracoabdominal aorta after medical management of type B aortic dissections

BACKGROUND Patients with uncomplicated type B aortic dissections who are managed medically are at risk of aortic aneurysmal degeneration over time. However, the effect of improvement in antihypertensive medications and stricter blood pressure control is unknown. The goal of this study was to determine the rate of aneurysmal degeneration in a contemporary cohort of patients with medically treated type B dissection. METHODS Included were all patients with acute uncomplicated type B aortic dissection who were initially managed medically between March 1999 and March 2011 and had follow-up axial imaging studies. Maximum aortic growth was calculated by comparing the initial imaging study to the most current scan or imaging obtained just before any aortic-related intervention. An increase of ≥5 mm was the threshold considered as aortic growth. Predictors of aortic aneurysmal degeneration were determined using Cox proportional hazards models. RESULTS We identified 200 patients (61% men) with medically managed acute type B dissections receiving multiple imaging studies. Patients were an average age of 63.4 years, and 75.5% had a history of hypertension. Mean follow-up was 5.3 years (range, 0.1-14.7 years). Mean time between the initial and final imaging studies was 3.2 years (range, 0.1-12.9 years). At 5 years, only 51% were free from aortic growth. Fifty-six patients (28%) required operative intervention (50 open, 6 endovascular repair) for aneurysmal degeneration, and the actuarial 5-year freedom from intervention was 76%. After excluding five patients (2.5%) with early rapid degeneration requiring intervention within the first 2 weeks, the mean rate of aortic growth was 12.3 mm/y for the total aortic diameter, 3.8 mm/y for the true lumen diameter, and 8.6 mm/y for the false lumen diameter. Only aortic diameter at index presentation >3.5 cm was a risk factor for future growth (odds ratio, 2.54; 95% confidence interval, 1.34-4.81; P < .01). Complete thrombosis of the false lumen was protective against growth (odds ratio, 0.19; 95% confidence interval, 0.11-0.42; P < .01). CONCLUSIONS Although medical management of uncomplicated acute, type B aortic dissections has been the standard of care, at 5 years, a significant number of patients will require operative intervention for aneurysmal degeneration. Further studies of early intervention (eg, thoracic endovascular aortic repair) for type B aortic dissection to prevent late aneurysm formation are needed.

Late Aortic Remodeling Persists in the Stented Segment After Endovascular Repair of Acute Complicated Type B Aortic Dissection

OBJECTIVE Thoracic endovascular aortic repair (TEVAR) for acute complicated type B aortic dissection (AD) promotes early positive aortic remodeling. However, little is known about the long-term effect of TEVAR on the dissected aorta, which is the goal of this study. METHODS Between August 2005 and August 2009, 31 patients with complicated type B AD were treated with TEVAR and had >1-year follow-up imaging. Computed tomography angiograms obtained at 1 month, 1 year, and long term (average, 42 months) were compared with baseline scans. The largest diameters of the stented thoracic aorta, stented true lumen, and stented false lumen were recorded at each time point, as were the values in the unstented distal thoracic aorta and the abdominal aorta. Changes over time were evaluated by a mixed effect analysis of variance model of repeated measures. RESULTS The average age of the cohort was 56 years, and 74% were male. Indications for TEVAR were as follows: 61% malperfusion, 32% refractory hypertension, 45% impending rupture, and 32% persistent pain; 58% had more than one indication. All patients were treated in the acute phase within 7 days of the initial presentation. The average length of aorta covered was 19 cm. Observation of the stented segment over time showed that the maximum diameter of the stented thoracic aorta was stable (P = NS), the diameter of the stented true lumen increased (P < .001), and the diameter of the stented false lumen decreased (P < .001); 84% had complete false lumen obliteration across the stented aortic segment. Observation of the uncovered thoracic aorta over time showed that the maximum diameter increased (P = .014), as did the visceral segment of the aorta (P < .001). The average growth of the visceral segment was 31% in patients with a patent false lumen vs 3% in those with a thrombosed false lumen (P = .004). One patient had aneurysmal degeneration of the false lumen and required an additional endograft at 18 months. CONCLUSIONS TEVAR of acute AD promotes long-term remodeling across the stented segment, with false lumen obliteration in 84% of patients. However, false lumen obliteration beyond the stented segment appears necessary to prevent late aneurysmal degeneration of the distal aorta.