Over-Expression of DSCAM and COL6A2 Cooperatively Generates Congenital Heart Defects

A significant current challenge in human genetics is the identification of interacting genetic loci mediating complex polygenic disorders. One of the best characterized polygenic diseases is Down syndrome (DS), which results from an extra copy of part or all of chromosome 21. A short interval near the distal tip of chromosome 21 contributes to congenital heart defects (CHD), and a variety of indirect genetic evidence suggests that multiple candidate genes in this region may contribute to this phenotype. We devised a tiered genetic approach to identify interacting CHD candidate genes. We first used the well vetted Drosophila heart as an assay to identify interacting CHD candidate genes by expressing them alone and in all possible pairwise combinations and testing for effects on rhythmicity or heart failure following stress. This comprehensive analysis identified DSCAM and COL6A2 as the most strongly interacting pair of genes. We then over-expressed these two genes alone or in combination in the mouse heart. While over-expression of either gene alone did not affect viability and had little or no effect on heart physiology or morphology, co-expression of the two genes resulted in ≈50% mortality and severe physiological and morphological defects, including atrial septal defects and cardiac hypertrophy. Cooperative interactions between DSCAM and COL6A2 were also observed in the H9C2 cardiac cell line and transcriptional analysis of this interaction points to genes involved in adhesion and cardiac hypertrophy. Our success in defining a cooperative interaction between DSCAM and COL6A2 suggests that the multi-tiered genetic approach we have taken involving human mapping data, comprehensive combinatorial screening in Drosophila, and validation in vivo in mice and in mammalian cells lines should be applicable to identifying specific loci mediating a broad variety of other polygenic disorders

Impact of Timing of Smoking Cessation on 30-Day Outcomes in Veterans Undergoing Lobectomy for Cancer

The adverse effects of tobacco use on postoperative outcomes are well documented. While smoking cessation is associated with overall improvement in long-term survival for lung cancer patients, the effects of cessation shortly before lung surgery are unclear. This study compares 30-day outcomes after lobectomy between active smokers, recent quitters, and nonsmokers. Patients who underwent lobectomy for cancer at national Veterans Affairs medical centers from 2012 to 2018 were retrospectively identified in the Veterans Affairs Surgical Quality Improvement Program database. The sample was stratified into 3 groups: smokers within 2 weeks of surgery (“active smokers”), those who quit between 2 weeks and 3 months prior to surgery (“recent quitters”), and “nonsmokers.” Propensity score matching was performed to compare groups. Of 5715 patients who met inclusion criteria, 2696 were nonsmokers, 774 were recent quitters, and 2245 were active smokers. After propensity matching, 572 patients comprised each group. Compared to recent quitters, active smokers had 48% higher odds of suffering a pulmonary complication (95% confidence interval [CI]: 1.03–2.14; P = 0.035) and 72% higher odds of suffering multiple complications (CI: 1.07–2.76; P = 0.026). Relative to nonsmokers, active smokers had 81% higher odds of pulmonary complications (CI: 1.34–2.65; P = 0.003). No differences were detected in outcomes comparing recent quitters to nonsmokers. Veterans undergoing lobectomy for cancer who quit 2 weeks before surgery had less pulmonary complications than active smokers. Recent quitters have similar outcomes to nonsmokers. Surgeons should therefore encourage patients to quit smoking, including just prior to lung surgery

Influence of age on cardiac surgery outcomes in United States veterans

© 2020 Forum Multimedia Publishing LLC. All rights reserved. Objective: Heart disease is still the leading cause of death for both men and women in the United States, and the rate of cardiovascular disease in veterans is even higher than in civilians. This study examines age-related outcomes for veterans undergoing cardiac surgeries at a single institution. Methods: We included all veterans undergoing coronary artery bypass grafting (CABG) and/or valve surgery between 1997 to 2017 at a single Veterans Affairs (VA) medical center. We stratified this cohort into 4 age groups: ≤59 years old, 60-69 years old, 70-79 years old, and ≥80 years old. Outcomes in age groups were compared using standard statistical methods with the ≤59 years old group as reference. Results: A total of 2,301 patients underwent open cardiac procedures at our institution. The frequency of simultaneous CABG and valve operations increased with age. Usage of cardiopulmonary bypass versus off-pump CABG and operative time was not associated with age. Increased pulmonary and renal complications as well as rates of postoperative arrhythmias all were associated with increasing age. There was no statistically significant difference in 30-day mortality. However, multivariable analysis adjusted for covariates showed all-cause mortality significantly was increased with older age groups (aHR ≥80 years old: 2.94 [2.07-4.17], P \u3c .01; aHR 70-79 years old: 2.15 [1.63-2.83], P \u3c 0.01, with ≤59 years old as reference). Conclusions: Older patients may have comparable perioperative mortality as their younger counterparts. However, age still is a significant predictor of all-cause mortality, pulmonary and renal complications, and postoperative arrhythmia, and should be considered as a major factor in preoperative risk assessment

Influence of Age on Cardiac Surgery Outcomes in United States Veterans

© 2020 Forum Multimedia Publishing LLC. All rights reserved. Objective: Heart disease is still the leading cause of death for both men and women in the United States, and the rate of cardiovascular disease in veterans is even higher than in civilians. This study examines age-related outcomes for veterans undergoing cardiac surgeries at a single institution. Methods: We included all veterans undergoing coronary artery bypass grafting (CABG) and/or valve surgery between 1997 to 2017 at a single Veterans Affairs (VA) medical center. We stratified this cohort into 4 age groups: ≤59 years old, 60-69 years old, 70-79 years old, and ≥80 years old. Outcomes in age groups were compared using standard statistical methods with the ≤59 years old group as reference. Results: A total of 2,301 patients underwent open cardiac procedures at our institution. The frequency of simultaneous CABG and valve operations increased with age. Usage of cardiopulmonary bypass versus off-pump CABG and operative time was not associated with age. Increased pulmonary and renal complications as well as rates of postoperative arrhythmias all were associated with increasing age. There was no statistically significant difference in 30-day mortality. However, multivariable analysis adjusted for covariates showed all-cause mortality significantly was increased with older age groups (aHR ≥80 years old: 2.94 [2.07-4.17], P \u3c .01; aHR 70-79 years old: 2.15 [1.63-2.83], P \u3c 0.01, with ≤59 years old as reference). Conclusions: Older patients may have comparable perioperative mortality as their younger counterparts. However, age still is a significant predictor of all-cause mortality, pulmonary and renal complications, and postoperative arrhythmia, and should be considered as a major factor in preoperative risk assessment

Long-Term Outcomes of Coronary Artery Bypass Grafting in Veterans with Ischemic Cardiomyopathy

© 2020 Forum Multimedia Publishing, LLC. Background: The Surgical Treatment for Ischemic Heart Failure (STICH) trial showed that surgical revascularization in ischemic cardiomyopathy (ICM) patients improves longterm mortality compared with medical treatment alone. This study examines how veterans with ICM undergoing revascularization fare against patients without ICM; it also examines the outcomes in the veteran population. Methods: This is a retrospective review of a singlecenter database. From 2000 to 2018, 1,461 patients underwent isolated coronary artery bypass grafting (CABG). Two-hundred-one patients with an ejection fraction less than 35% were classified as the ICM cohort. The primary outcome was mortality. Secondary outcomes included postoperative complications. Subgroup analysis was performed within the ICM cohort comparing off-pump CABG (OPCAB) versus on-pump CABG (ONCAB). Results: ICM patients had a higher incidence of myocardial infarction (MI), diabetes, chronic kidney disease (CKD), and preoperative intra-aortic balloon pump (IABP) use. The non-ICM cohort was more functionally independent. OPCAB was performed in 80.1% of ICM and 66.3% of non-ICM cohorts. There was no statistical difference between ICM and non-ICM cohorts in 30-day mortality (OR 1.94[0.79 - 4.75], P = .15). The ICM cohort had an increased 5-year mortality (OR 1.75[1.14 - 2.69], P = .01) and 10-year mortality (OR 1.71[1.09 - 2.67], P = .02). The ICM cohort showed improved, although not statistically significant, short-term mortality with OPCAB compared with ONCAB (3.1% versus 12.5%, OR 0.31[0.05 - 1.82], P = .20). Conclusion: Veterans with ICM undergoing CABG demonstrated similar short-term survival compared with non-ICM veterans. The long-term survival in the ICM cohort still is inferior to patients without ICM. There is a trend toward improved short-term survival in patients with ICM undergoing OPCAB

Dependent functional status rather than age is a better predictor of adverse outcomes after excision of an infected abdominal aortic graft

OBJECTIVE: The optimal management of infected abdominal aortic grafts is complete surgical excision plus in situ or extra-anatomic revascularization in patients who can tolerate this morbid operation. In addition to using age and the presence of comorbidities for risk assessment, physicians form a global clinical impression when deciding whether to offer excision or to manage conservatively. Functional status is a distinct objective measure that can inform this decision. This study examines the relative impact of age and functional status on outcomes of infected abdominal aortic graft excision to guide surgical decision-making. METHODS: Current Procedural Terminology code 35907 was used to identify patients undergoing excision of infected abdominal aortic graft in the 2005 to 2017 American College of Surgeons - National Surgical Quality Improvement Program (NSQIP) database. Patients were stratified by the upper age quartile (75 years old) as a cutoff, and then by functional status, independent vs dependent (as defined by NSIQIP). The patients were then stratified into four groups: Younger (\u3c75)/Independent, Younger (\u3c75)/Dependent, Older (≥75)/Independent, and Older (≥75)/Dependent. Outcomes measured included 30-day mortality and major organ-system dysfunction. RESULTS: There were 814 patients who underwent infected abdominal aortic graft excision: 508 patients (62%) were Younger/Independent, 89 patients (11%) were Younger/Dependent, 176 patients (22%) were Older/Independent, and 41 patients (5%) were Older/Dependent. There was no statistically significant difference in 30-day mortality for Younger/Dependent (odds ratio [OR], 1.66; 95% confidence interval [CI], 0.90-3.09; P = .536) or Older/Independent (OR, 1.31; 95% CI, 0.78-2.19; P = .311) patients when compared with Younger/Independent patients, which suggests that neither old age nor dependent functional status by itself adversely affects mortality. However, when both factors were present, Older/Dependent patients had three times higher mortality when compared with Younger/Independent patients (41.5% vs 13.4%, respectively; OR, 3.13; 95% CI, 1.46-6.71; P = .003). Furthermore, as long as patients presented with independent functional status, old age by itself did not adversely affect major organ-system dysfunction (ORs for Older/Independent vs Younger/Independent were 0.76 [P = .454], 1.04 [P = .874], and 0.90 [P = .692] for cardiac, pulmonary, and renal complications, respectively). On the contrary, even in younger patients, dependent functional status was significantly associated with higher pulmonary complications (Younger/Dependent vs Younger/Independent: OR, 2.22; 95% CI, 1.33-3.73; P = .002) and higher rates of unplanned reoperation (OR, 2.67; 95% CI, 1.62-4.41; P \u3c .0001). CONCLUSIONS: Dependent functional status has significant association with adverse outcomes after excision of infected abdominal aortic grafts, whereas old age alone does not. Therefore, this procedure could be considered in appropriately selected elderly patients with otherwise good functional status. However, caution should be applied in dependent patients regardless of age due to the risk of pulmonary complications

Long-term outcomes of coronary artery bypass grafting in veterans with ischemic cardiomyopathy

© 2020 Forum Multimedia Publishing, LLC. Background: The Surgical Treatment for Ischemic Heart Failure (STICH) trial showed that surgical revascularization in ischemic cardiomyopathy (ICM) patients improves longterm mortality compared with medical treatment alone. This study examines how veterans with ICM undergoing revascularization fare against patients without ICM; it also examines the outcomes in the veteran population. Methods: This is a retrospective review of a singlecenter database. From 2000 to 2018, 1,461 patients underwent isolated coronary artery bypass grafting (CABG). Two-hundred-one patients with an ejection fraction less than 35% were classified as the ICM cohort. The primary outcome was mortality. Secondary outcomes included postoperative complications. Subgroup analysis was performed within the ICM cohort comparing off-pump CABG (OPCAB) versus on-pump CABG (ONCAB). Results: ICM patients had a higher incidence of myocardial infarction (MI), diabetes, chronic kidney disease (CKD), and preoperative intra-aortic balloon pump (IABP) use. The non-ICM cohort was more functionally independent. OPCAB was performed in 80.1% of ICM and 66.3% of non-ICM cohorts. There was no statistical difference between ICM and non-ICM cohorts in 30-day mortality (OR 1.94[0.79 - 4.75], P = .15). The ICM cohort had an increased 5-year mortality (OR 1.75[1.14 - 2.69], P = .01) and 10-year mortality (OR 1.71[1.09 - 2.67], P = .02). The ICM cohort showed improved, although not statistically significant, short-term mortality with OPCAB compared with ONCAB (3.1% versus 12.5%, OR 0.31[0.05 - 1.82], P = .20). Conclusion: Veterans with ICM undergoing CABG demonstrated similar short-term survival compared with non-ICM veterans. The long-term survival in the ICM cohort still is inferior to patients without ICM. There is a trend toward improved short-term survival in patients with ICM undergoing OPCAB