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GNAS gene variants affect ?-blocker-related survival after coronary artery bypass grafting.

ABSTRACT: Cardiac overexpression of the ?-adrenoreceptor (?AR)-coupled stimulatory G-protein subunit G?s enhances inotropic responses to adrenergic stimulation and improves survival in mice under ?AR blockade. The authors recently identified three common haplotypes in the GNAS gene encoding G?s, with the greatest G?s protein expression and signal transduction in haplotype *3 carriers and less in haplotype *2 and *1 carriers. The authors tested the hypothesis that these GNAS variants result in altered mortality in patients after coronary artery bypass graft surgery, particularly in those receiving ?AR blockade.This prospective analysis included 1,627 European ancestry patients undergoing primary coronary artery bypass graft surgery. Patients were genotyped for two GNAS haplotype tagging single-nucleotide polymorphisms defining three major haplotypes. Up to 5-yr all-cause mortality was estimated using a Cox proportional hazard model; hazard ratios and 95% CIs were calculated while adjusting for demographics, clinical covariates, and the new EuroSCORE II.Univariate analysis revealed haplotype-dependent 5-yr mortality rates (*1/*1: 18.9%, *2/*1: 13.7%, *2/*2: 9.3%, *3/*1: 10.6%, *3/*2: 9.1%, and *3/*3: 9.6%; P = 0.0006). After adjustment for other predictors of death, homozygote haplotype *1 carriers showed a doubled risk for death (hazard ratio, 2.2; 95% CI, 1.2 to 3.8; P = 0.006). Considering only patients receiving ?AR blockers (n = 1,267), the adjusted risk of death even tripled (hazard ratio, 3.0; 95% CI, 1.5 to 6.1; P = 0.002).GNAS haplotypes independently associate with an increased risk of death after primary coronary artery bypass graft surgery. These results are most pronounced in patients receiving ?AR blockers, strengthening the rationale for personalized treatment, to decrease medication side effects and improve outcomes.

SUBMITTER: Frey UH

PROVIDER: S-EPMC4070180 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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GNAS gene variants affect β-blocker-related survival after coronary artery bypass grafting.

Frey Ulrich H UH Muehlschlegel Jochen D JD Ochterbeck Christoph C Fox Amanda A AA Shernan Stanton K SK Collard Charles D CD Lichtner Peter P Peters Jürgen J Body Simon S

Anesthesiology 20140501 5

<h4>Background</h4>Cardiac overexpression of the β-adrenoreceptor (βAR)-coupled stimulatory G-protein subunit Gαs enhances inotropic responses to adrenergic stimulation and improves survival in mice under βAR blockade. The authors recently identified three common haplotypes in the GNAS gene encoding Gαs, with the greatest Gαs protein expression and signal transduction in haplotype *3 carriers and less in haplotype *2 and *1 carriers. The authors tested the hypothesis that these GNAS variants res ...[more]

PMID: 24755784

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Project description:BackgroundSeveral of the most extensively used risk prediction tools for coronary artery bypass grafting outcomes include female sex as an independent risk factor for postoperative outcomes. It is not clear whether this putative increased surgical risk impacts long-term survival. This study aimed to assess sex differences in 10-year all-cause mortality.MethodsRetrospective analysis of 5340 consecutive patients undergoing primary isolated coronary artery bypass surgery, performed from 2000 to 2015, in a Portuguese level III Hospital. The primary endpoint was all-cause mortality at ten years. We employed an overlap weighting algorithm to minimize confounding. Its target population highlights patients with the most overlap in their observed characteristics, and its corresponding estimand is the average treatment effect in the overlap population.ResultsWe identified that 5340 patients underwent isolated CABG: 1104 (20.7%) were female, and 4236 (79.3%) were male. Sixteen patients were lost to follow-up (0.3%). The median follow-up time was 12.79 (IQR, 9.52-16.66) years: 12.68 (IQR, 9.48-16.54) years for the male patient group and 13.13 (IQR, 9.75-16.98) years for the female patient group. The primary endpoint of all-cause mortality at ten years occurred in 1106 patients (26.1%) in the male patient group, compared with 315 (28.5%) in the female patient group. The unweighted survival analysis for both groups reveals the worst long-term prognosis for the female cohort (hazard ratio, 1.22; 95% CI, 1.10 to 1.35; p < 0.001), while in the overlap weighted survival analysis, such long-term difference in prognosis disappears (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; p = 0.693).ConclusionIn this longitudinal, population-level analysis of patients undergoing primary, isolated CABG, we demonstrated that the female sex is not associated with increased long-term all-cause mortality compared to their male counterparts. Thus, sex should not influence the undertaking of an adequate revascularization strategy.

Project description:Background Over 180 000 coronary artery bypass grafting (CABG) procedures are performed annually, accounting for $7 to $10 billion in episode expenditures. Assessing tradeoffs between spending and quality contributing to value during 90-day episodes has not been conducted but is essential for success in bundled reimbursement models. We, therefore, identified determinants of variability in hospital 90-day episode value for CABG. Methods Medicare and private payor admissions for isolated CABG from 2014 to 2016 were retrospectively linked to clinical registry data for 33 nonfederal hospitals in Michigan. Hospital composite risk-adjusted complication rates (≥1 National Quality Forum-endorsed, Society of Thoracic Surgeons measure: deep sternal wound infection, renal failure, prolonged ventilation >24 hours, stroke, re-exploration, and operative mortality) and 90-day risk-adjusted, price-standardized episode payments were used to categorize hospitals by value by defining the intersection between complications and spending. Results Among 2573 total patients, those at low- versus high-value hospitals had a higher percentage of prolonged length of stay >14 days (9.3% versus 2.4%, P=0.006), prolonged ventilation (17.6% versus 4.8%, P<0.001), and operative mortality (4.8% versus 0.6%, P=0.001). Mean total episode payments were $51 509 at low-compared with $45 526 at high-value hospitals (P<0.001), driven by higher readmission ($3675 versus $2177, P=0.005), professional ($7462 versus $6090, P<0.001), postacute care ($7315 versus $5947, P=0.031), and index hospitalization payments ($33 474 versus $30 800, P<0.001). Among patients not experiencing a complication or 30-day readmission (1923/2573, 74.7%), low-value hospitals had higher inpatient evaluation and management payments ($1405 versus $752, P<0.001) and higher utilization of inpatient rehabilitation (7% versus 2%, P<0.001), but lower utilization of home health (66% versus 73%, P=0.016) and emergency department services (13% versus 17%, P=0.034). Conclusions To succeed in emerging bundled reimbursement programs for CABG, hospitals and physicians should identify strategies to minimize complications while optimizing inpatient evaluation and management spending and use of inpatient rehabilitation, home health, and emergency department services.

Project description:ObjectivesThe aim of this study was to describe the potential of 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) to identify graft vasculopathy and to investigate the influence of coronary artery bypass graft (CABG) surgery on native coronary artery disease activity and progression.BackgroundAs well as developing graft vasculopathy, CABGs have been proposed to accelerate native coronary atherosclerosis.MethodsPatients with established coronary artery disease underwent baseline 18F-NaF PET, coronary artery calcium scoring, coronary computed tomographic angiography, and 1-year repeat coronary artery calcium scoring. Whole-vessel coronary microcalcification activity (CMA) on 18F-NaF PET and change in calcium scores were quantified in patients with and without CABG surgery.ResultsAmong 293 participants (mean age 65 ± 9 years, 84% men), 48 (16%) underwent CABG surgery 2.7 years [IQR: 1.4-10.4 years] previously. Although all arterial and the majority (120 of 128 [94%]) of vein grafts showed no 18F-NaF uptake, 8 saphenous vein grafts in 7 subjects had detectable CMA. Bypassed native coronary arteries had 3 times higher CMA values (2.1 [IQR: 0.4-7.5] vs 0.6 [IQR: 0-2.7]; P < 0.001) and greater progression of 1-year calcium scores (118 Agatston unit [IQR: 48-194 Agatston unit] vs 69 [IQR: 21-142 Agatston unit]; P = 0.01) compared with patients who had not undergone CABG, an effect confined largely to native coronary plaques proximal to the graft anastomosis. In sensitivity analysis, bypassed native coronary arteries had higher CMA (2.0 [IQR: 0.4-7.5] vs 0.8 [IQR: 0.3-3.2]; P < 0.001) and faster disease progression (24% [IQR: 16%-43%] vs 8% [IQR: 0%-24%]; P = 0.002) than matched patients (n = 48) with comparable burdens of coronary artery disease and cardiovascular comorbidities in the absence of bypass grafting.ConclusionsNative coronary arteries that have been bypassed demonstrate increased disease activity and more rapid disease progression than nonbypassed arteries, an observation that appears independent of baseline atherosclerotic plaque burden. Microcalcification activity is not a dominant feature of graft vasculopathy.

Project description:ObjectiveThe Cardiothoracic Surgical Trials Network reported that left ventricular reverse remodeling at 2 years did not differ between patients with moderate ischemic mitral regurgitation randomized to coronary artery bypass grafting plus mitral valve repair (n = 150) or coronary artery bypass grafting alone (n = 151). To address health resource use implications, we compared costs and quality-adjusted survival.MethodsWe used individual patient data from the Cardiothoracic Surgical Trials Network trial on survival, hospitalizations, quality of life, and US hospitalization costs to estimate cumulative costs and quality-adjusted life years. A microsimulation model was developed to extrapolate to 10 years. Bootstrap and deterministic sensitivity analyses were performed to address uncertainty.ResultsIn-hospital costs were $59,745 for coronary artery bypass grafting plus mitral valve repair versus $51,326 for coronary artery bypass grafting alone (difference $8419; 95% uncertainty interval, 2259-18,757). Two-year costs were $81,263 versus $67,341 (difference 13,922 [2370 to 28,888]), and quality-adjusted life years were 1.35 versus 1.30 (difference 0.05; -0.04 to 0.14), resulting in an incremental cost-effectiveness ratio of $308,343/quality-adjusted life year for coronary artery bypass grafting plus mitral valve repair. At 10 years, its costs remained higher ($107,733 vs $88,583, difference 19,150 [-3866 to 56,826]) and quality-adjusted life years showed no difference (-0.92 to 0.87), with 5.08 versus 5.08. The likelihood that coronary artery bypass grafting plus mitral valve repair would be considered cost-effective at 10 years based on a cost-effectiveness threshold of $100K/quality-adjusted life year did not exceed 37%. Only when this procedure reduces the death rate by a relative 5% will the incremental cost-effectiveness ratio fall below $100K/quality-adjusted life year.ConclusionsThe addition of mitral valve repair to coronary artery bypass grafting for patients with moderate ischemic mitral regurgitation is unlikely to be cost-effective. Only if late mortality benefits can be demonstrated will it meet commonly used cost-effectiveness criteria.

Dataset Information

GNAS gene variants affect ?-blocker-related survival after coronary artery bypass grafting.

Publications

GNAS gene variants affect β-blocker-related survival after coronary artery bypass grafting.

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