Quality of Life in Patients With Chronic Limb-Threatening Ischemia Treated With Revascularization.

BACKGROUND: In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of revascularization strategy on health-related quality of life (HRQoL). METHODS: Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein. HRQoL was assessed over the trial duration using Vascular Quality-of-Life (VascuQoL), European Quality-of-Life-5D (EQ-5D), the Short Form-12 (SF-12) Physical Component Summary (SF-12 PCS), SF-12 Mental Component Summary (SF-12 MCS), Utility Index Score (SF-6D R2), and numeric rating scales of pain. HRQoL was summarized by cohort and compared within and between groups using mixed-model linear regression. RESULTS: A total of 1193 and 335 patients in cohorts 1 and 2 with a mean follow-up of 2.9 and 2.0 years, respectively, were analyzed. In cohort 1, HRQoL significantly improved from baseline to follow-up for both groups across all measures. For example, mean (SD) VascuQoL scores were 3.0 (1.3) and 3.0 (1.2) for Bypass and Endo at baseline and 4.7 (1.4) and 4.8 (1.5) over follow-up. There were significant group differences favoring Endo when assessed with VascuQoL (difference, -0.14 [95% CI, -0.25 to -0.02]; P=0.02), SF-12 MCS (difference, -1.03 [95% CI, -1.89 to -0.18]; P=0.02), SF-6D R2 (difference, -0.01 [95% CI, -0.02 to -0.001]; P=0.03), numeric rating scale pain at present (difference, 0.26 [95% CI, 0.03 to 0.49]; P=0.03), usual level during previous week (difference, 0.26 [95% CI, 0.04 to 0.48]; P=0.02), and worst level during previous week (difference, 0.29 [95% CI, 0.02 to 0.56]; P=0.04). There was no difference between treatment arms on the basis of EQ-5D (difference, -0.01 [95% CI, -0.03 to 0.004]; P=0.12) or SF-12 PCS (difference, -0.41 [95% CI, -1.2 to 0.37]; P=0.31). In cohort 2, HRQoL also significantly improved from baseline to the end of follow-up for both groups based on all measures, but there were no differences between Bypass and Endo on any measure. CONCLUSIONS: Among patients with chronic limb-threatening ischemia deemed eligible for either Bypass or Endo, revascularization resulted in significant and clinically meaningful improvements in HRQoL. In patients with an available single-segment great saphenous vein for bypass, but not among those without one, Endo was statistically superior on some HRQoL measures; however, these differences were below the threshold of clinically meaningful difference.

Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

NT-proBNP for Predicting All-Cause Death and Heart Transplant in Children and Adults with Heart Failure.

Plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) concentration is a heart failure (HF) biomarker in adults and children. Its prognostic value for HF-related events has been established only in adults. Therefore, we aimed to test the hypothesis that plasma NT-proBNP concentrations predicted the risk of heart transplantation or death in children with HF. We studied the medical records of 109 children with HF enrolled in the IBM Watson Explorys database and from 150 children enrolled in the Pediatric Cardiomyopathy Registry (PCMR). Nonlinear regression was used to assess the relationship between plasma NT-proBNP concentrations and the risk of events in the two cohorts. All children in the PCMR cohort had dilated cardiomyopathy. The Explorys cohort also included children with congenital cardiovascular malformations. Median plasma NT-proBNP concentrations were 1250 pg/mL and 184 pg/mL in the Explorys and PCMR cohorts, respectively. The percentage of deaths/heart transplantations was 7%/22%, over 2 years in the Explorys cohort and 3%/16% over 5 years in the PCMR cohort. Mean estimates of plasma NT-proBNP concentration indicative of half-maximum relative risk for events (EC50 values) at 2 and 5 years were 3730 pg/mL and 4199 pg/mL, respectively, values both close to the mean of 3880 pg/mL established for adults with HF. The plasma NT-proBNP concentration is suitable for estimating relative risk of mortality and heart transplantation in children with HF, independent of etiology and shows similar relations to clinical outcomes as in adults, indicating its likely value as a surrogate marker both for adult and pediatric HF.ClinicalTrials.gov Identifiers: NCT00005391 (May 26, 2000), NCT01873976 (June 10, 2013).

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy.

BACKGROUND: Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. METHODS: A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. RESULTS: In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. CONCLUSIONS: Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.

Relationship between WIfI stage and quality of life at revascularization in the BEST-CLI trial.

OBJECTIVE: The WIfI (Wound, Ischemia, foot Infection) stage measures the extent of wounds, ischemia, and foot infection in patients with chronic limb threatening ischemia (CLTI) and has been associated with the risk of major amputation. Patients with CLTI have impaired health-related quality of life (HRQoL), which can be multifactorial. We hypothesized that the severity of the limb threat (WIfI stage) would be associated with poor HRQoL among patients with CLTI presenting for revascularization. METHODS: The dataset of the BEST-CLI (best endovascular versus best surgical therapy in patients with CLTI) trial, a prospective, randomized trial comparing open and endovascular revascularization strategies, was queried for HRQoL assessments at patient enrollment. The HRQoL assessments included (1) Vascular Quality of Life; (2) 12-item short form survey (SF-12), containing the utility index score (short-form six-dimension R2 utility index, incorporating physical, emotional, and mental well-being) and mental and physical components; and (3) the EQ-5D. Multivariable regression analysis was used to identify the independent associations with the baseline HRQoL assessments. RESULTS: A total of 1568 patients with complete WIfI data were analyzed, of whom 71.5% were men. The WIfI distribution was 35.5% with stage 4, 29.6% with stage 3, 28.6% with stage 2, and 6.3% with stage 1. Patients presenting with WIfI stage 4, compared with stage 1 to 3, were more often men (74.9% vs 69.6%) and current smokers (25.4% vs. 17.6%), had had end-stage renal disease (13.3% vs 8.5%) and diabetes (83.6% vs 60.2%), were not independently ambulatory (56.8% vs 38.5%), and had had higher median morbidity scores (4 vs 3; P < .05 for all). On multivariable analysis, WIfI stage 4, compared with stage 1 to 3, was associated with lower SF-12 mental component scale scores (estimate, -2.43; 95% confidence interval, -3.73 to -1.13; P < .001) and short-form six-dimension R2 utility index scores (estimate, -0.02; 95% confidence interval, -0.03 to 0.001; P = .04). The WIfI stage was not independently associated with the baseline Vascular Quality of Life, SF-12 physical component scale, or EQ-5D assessments. CONCLUSIONS: WIfI stage was independently associated with poorer quality of life because of mental, rather than physical, health for patients with CLTI. Clinicians should be aware of the burden of mental stress borne by those with the greatest limb impairment.

Baseline modern medical management in the BEST-CLI trial.

OBJECTIVES: The use of optimal medical therapy (OMT) in patients with chronic limb-threatening ischemia (CLTI) has not been well-studied. The Best Endovascular vs Best Surgical Therapy in Patients with CLTI study (BEST-CLI) is a multicenter, randomized, controlled trial sponsored by the National Institutes of Health comparing revascularization strategies in patients with CLTI. We evaluated the use of guideline-based OMT among patients with CLTI at the time of their enrollment into the trial. METHODS: A multidisciplinary committee defined OMT criteria related to blood pressure and diabetic management, lipid-lowering and antiplatelet medication use, and smoking status for patients enrolled in BEST-CLI. Status reports indicating adherence to OMT were provided to participating sites at regular intervals. Baseline demographic characteristics, comorbid medical conditions, and use of OMT at trial entry were evaluated for all randomized patients. A linear regression model was used to identify the relationship of predictors to the use of OMT. RESULTS: At the time of randomization (n = 1830 total enrolled), 87% of patients in BEST-CLI had hypertension, 69% had diabetes, 73% had hyperlipidemia, and 35% were currently smoking. Adherence to four OMT components (controlled blood pressure, not currently smoking, use of one lipid-lowering medication, and use of an antiplatelet agent) was modest. Only 25% of patients met all four OMT criteria; 38% met three, 24% met two, 11% met only one, and 2% met none. Age ≥80 years, coronary artery disease, diabetes, and Hispanic ethnicity were positively associated, whereas Black race was negatively associated, with the use of OMT. CONCLUSIONS: A significant proportion of patients in BEST-CLI did not meet OMT guideline-based recommendations at time of entry. These data suggest a persistent major gap in the medical management of patients with advanced peripheral atherosclerosis and CLTI. Changes in OMT adherence over the course of the trial and their impact on clinical outcomes and quality of life will be assessed in future analyses.

Perioperative complications following open or endovascular revascularization for chronic limb-threatening ischemia in the BEST-CLI Trial.

OBJECTIVE: Anticipated perioperative morbidity is an important factor for choosing a revascularization method for chronic limb-threatening ischemia (CLTI). Our goal was to assess systemic perioperative complications of patients treated with surgical and endovascular revascularization in the Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial. METHODS: BEST-CLI was a prospective randomized trial comparing open (OPEN) and endovascular (ENDO) revascularization strategies for patients with CLTI. Two parallel cohorts were studied: Cohort 1 included patients with adequate single-segment great saphenous vein (SSGSV), whereas Cohort 2 included those without SSGSV. Data were queried for major adverse cardiovascular events (MACE-composite myocardial infarction, stroke, death), non-serious (non-SAEs) and serious adverse events (SAEs) (criteria-death/life-threatening/requiring hospitalization or prolongation of hospitalization/significant disability/incapacitation/affecting subject safety in trial) 30 days after the procedure. Per protocol analysis was used (intervention received without crossover), and risk-adjusted analysis was performed. RESULTS: There were 1367 patients (662 OPEN, 705 ENDO) in Cohort 1 and 379 patients (188 OPEN, 191 ENDO) in Cohort 2. Thirty-day mortality in Cohort 1 was 1.5% (OPEN 1.8%; ENDO 1.3%) and in Cohort 2 was 1.3% (2.7% OPEN; 0% ENDO). MACE in Cohort 1 was 4.7% for OPEN vs 3.13% for ENDO (P = .14), and in Cohort 2, was 4.28% for OPEN and 1.05% for ENDO (P = .15). On risk-adjusted analysis, there was no difference in 30-day MACE for OPEN vs ENDO for Cohort 1 (hazard ratio [HR] 1.5; 95% confidence interval [CI], 0.85-2.64; P = .16) or Cohort 2 (HR, 2.17; 95% CI, 0.48-9.88; P = .31). The incidence of acute renal failure was similar across interventions; in Cohort 1 it was 3.6% for OPEN vs 2.1% for ENDO (HR, 1.6; 95% CI, 0.85-3.12; P = .14), and in Cohort 2, it was 4.2% OPEN vs 1.6% ENDO (HR, 2.86; 95% CI, 0.75-10.8; P = .12). The occurrence of venous thromboembolism was low overall and was similar between groups in Cohort 1 (OPEN 0.9%; ENDO 0.4%) and Cohort 2 (OPEN 0.5%; ENDO 0%). Rates of any non-SAEs in Cohort 1 were 23.4% in OPEN and 17.9% in ENDO (P = .013); in Cohort 2, they were 21.8% for OPEN and 19.9% for ENDO (P = .7). Rates for any SAEs in Cohort 1 were 35.3% for OPEN and 31.6% for ENDO (P = .15); in Cohort 2, they were 25.5% for OPEN and 23.6% for ENDO (P = .72). The most common types of non-SAEs and SAEs were infection, procedural complications, and cardiovascular events. CONCLUSIONS: In BEST-CLI, patients with CLTI who were deemed suitable candidates for open lower extremity bypass surgery had similar peri-procedural complications following either OPEN or ENDO revascularization: In such patients, concern about risk of peri-procedure complications should not be a deterrent in deciding revascularization strategy. Rather, other factors, including effectiveness in restoring perfusion and patient preference, are more relevant.

Participation in a Chronic Limb Threatening Ischemia Randomized Trial Is Inversely Correlated With Regional Amputation Rate in Limb Threatening Ischemia Patients.

OBJECTIVE: The National Health Service demonstrated that regions of the United Kingdom with the highest number of patients enrolled in research studies had the lowest risk-adjusted mortality when patients were admitted to the hospital. Our goal was to investigate if this correlation was evident for patients with chronic limb threatening ischemia (CLI) treated in the United States (US). Accordingly, we examined correlations among sites participating in the Best Endovascular versus best Surgical Therapy in patients with Critical (BEST-CLI) trial, a multicenter, National Institute of Health-sponsored, international randomized controlled trial (RCT) comparing revascularization strategies in patients with CLI, and regional rates of major amputation from CLI. METHODS: We measured regional participation in the BEST-CLI trial by evaluating trial participation and enrollment rosters. To determine regional rates of lower limb amputation, we queried the Medicare database (2007-2016) for patients with concurrent peripheral arterial disease (PAD) and diabetes, then assessed how many had lower extremity amputations. Correlation of regional amputation rates with distribution of BEST-CLI sites in four US geographical regions was calculated using Pearson's correlation coefficients. Simple regression equations were used to calculate the significance of these correlation coefficients. RESULTS: Of 9,231,909 CLI patients, 342,406 underwent amputation in the Medicare dataset. Amputation rates per 1000 CLI patients differed by region (South 40.42, Midwest 40.12, West 34.81, Northeast 31.14). There were 116 US vascular centers, selected by volume and expertise that participated in BEST-CLI with the following distribution: South (n = 30, 26%), Midwest (n = 26, 22%), West (n = 29, 25%), and Northeast (n = 31, 27%). There was a negative correlation between the number of amputations per 1000 for Medicare CLI patients with diabetes and PAD and the number of BEST-CLI sites in the region which trended toward significance (Pearson R= -0.61, P = 0.39). CONCLUSIONS: Amputation rate among Medicare CLI patients is inversely correlated with US BEST-CLI site distribution. Higher participation in clinical research, especially within large RCTs, may be a marker of optimal PAD management.

Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial.

Bleeding remains a significant problem for many thrombocytopenic hematology/oncology patients in spite of platelet transfusions. Factors that might contribute to bleeding were analyzed for 16 320 patient-days on or after their first platelet transfusion in 1077 adult patients enrolled in the Platelet Dose (PLADO) trial. All patients had a greatly increased risk of bleeding at platelet counts of ≤5 × 109/L (odds ratio [OR], 3.1; 95% confidence interval [CI], 2.0-4.8) compared with platelet counts ≥81 × 109/L. Platelet counts between 6 × 109/L and 80 × 109/L were also associated with a somewhat elevated bleeding risk in patients receiving allogeneic stem cell transplants (SCTs) or chemotherapy but not in those undergoing autologous SCTs. Other significant laboratory predictors of bleeding were hematocrit ≤25% (OR, 1.29; 95% CI, 1.11-1.49), activated partial thromboplastin time (aPTT) 30 to ≤50 seconds (OR, 1.40; 95% CI, 1.08-1.81; P = .01), aPTT >50 seconds (OR, 2.34; 95% CI, 1.54-3.56), international normalized ratio (INR) 1.2 to 1.5 (OR, 1.46; 95% CI, 1.17-1.83), and INR >1.5 (OR, 2.05; 95% CI, 1.43-2.95). Transfusion of either platelets or red blood cells (RBCs) on days with bleeding was often not sufficient to change bleeding outcomes on the following day. Because bleeding occurred over a wide range of platelet counts among patients undergoing allogeneic SCT or chemotherapy and because platelet transfusions may not prevent bleeding, other risk factors may be involved. These may include low hematocrit and coagulation abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT00128713.

WBC alloimmunization: effects on the laboratory and clinical endpoints of therapeutic granulocyte transfusions.

BACKGROUND: Although the subject of many previous studies, the importance of white blood cell (WBC) alloimmunization in granulocyte transfusion therapy has not been settled. In this study, we report the results of the effects of WBC antibodies in the RING (Resolving Infection in Neutropenia with Granulocytes) study, a randomized controlled trial comparing the efficacy of daily granulocyte transfusion therapy plus antimicrobials versus antimicrobials alone; the primary outcome results have been published previously. STUDY DESIGN AND METHODS: One hundred fourteen subjects were enrolled in the study. Serum samples for WBC antibody determination were obtained from each subject at baseline and at 2 and 6 weeks. One hundred subjects had at least one antibody test result. Samples were tested for human leukocyte antigen (HLA) Class I and Class II antibodies as well as for granulocyte-specific antibodies using granulocyte agglutination and immunofluorescence techniques. All testing was performed at a central laboratory. RESULTS: Baseline WBC alloimmunization was modest, depending somewhat on the assay. Seroconversion during the study was slightly higher in the granulocyte transfusion arm, but the differences were not statistically significant. There was no demonstrable effect of the presence of alloimmunization on the primary outcome (survival and microbial response at 42 days), the occurrence of transfusion reactions (either overall or pulmonary), or posttransfusion neutrophil increments. CONCLUSION: The presence or development of WBC antibodies had no demonstrable effect on any clinical aspect of granulocyte transfusion therapy. It appears that, at least in the patient population studied, there is no evidence suggesting need for concern about recipient WBC alloimmunization when prescribing granulocyte transfusions.

Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection.

High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/µL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 10(9) granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 10(9) granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.

Clinical outcomes in a cohort of patients with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder usually prompting treatment with non-heparin anticoagulants. The benefits and risks of such treatments have not been fully assessed. METHODS: We analyzed data for 442 patients having a positive heparin-platelet factor 4 antibody test and recent heparin exposure. The primary outcome was a composite endpoint (death, limb amputation/gangrene, or new thrombosis). Secondary outcomes included bleeding and the effect of anticoagulation. FINDINGS: Seventy-one patients (16%) had HIT with thrombosis (HIT-T); 284 (64%) had HIT without thrombosis (isolated HIT); 87 (20%) did not have HIT. An intermediate or high "4T" score was found in 85%, 58%, and 8% of the three respective groups. Non-heparin anticoagulation was begun in 80%, 56%, and 45%. The composite endpoint occurred in 48%, 36%, and 17% (P = .01) of which 61%, 38%, and 40% were receiving non-heparin anticoagulation. Compared with the no HIT group, the composite endpoint was significantly more likely in HIT-T [HR 2.48 (1.35-4.55), P = .003)] and marginally more likely in isolated HIT [HR 1.66 (0.96-2.85), P = .071]. Importantly, risk increased (HR 1.77, P = .02) after platelet transfusion. Major bleeding occurred in 48%, 36%, and 16% of the three groups (P = .005). Non-heparin anticoagulation was not associated with a reduction in composite endpoint events in either HIT group. INTERPRETATION: HIT patients have high risks of death, limb amputation/gangrene, thrombosis, and bleeding. Non-heparin anticoagulant treatment may not benefit all patients and should be considered only after careful assessment of the relative risks of thrombosis and bleeding in individual patients.

Comparative efficacy of coronary artery bypass surgery vs. percutaneous coronary intervention in patients with diabetes and multivessel coronary artery disease with or without chronic kidney disease.

BACKGROUND: The optimal method of coronary revascularization among patients with diabetes mellitus (DM) and multivessel coronary artery disease (CAD) complicated by chronic kidney disease (CKD) remains unknown. PURPOSE: To examine the impact of coronary artery bypass surgery (CABG) vs. percutaneous coronary intervention (PCI) on cardiovascular outcomes in patients with diabetes with and without CKD. METHODS: We conducted an 'as-treated' subgroup analysis of the FREEDOM trial to examine the therapeutic efficacy of CABG vs. PCI among patients with DM stratified by the presence (n = 451) or absence (n = 1392) of CKD. We defined CKD as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. Baseline characteristics and clinical outcomes were compared between PCI and CABG groups within each CKD stratum. The primary endpoint was the composite occurrence of all-cause death, stroke or myocardial infarction [major adverse cardiovascular and cerebrovascular events (MACCE)]. Event rates were estimated at 5 years using the Kaplan-Meier approach and hazard ratios (HRs) for CABG (vs. PCI) were generated using Cox regression. RESULTS: Patients with CKD (mean eGFR 47 mL/min/1.73m2) were older and more often female compared to those without renal impairment. Over a median follow-up of 3.8 years, the effect of CABG on MACCE was consistent among those with CKD (26.0% vs. 35.6%; HR [95% CI]: 0.73 [0.50-1.05]) and without CKD (16.2% vs. 23.6%; HR [95% CI)]: 0.76 [0.58-1.00]) with no evidence of interaction (pint = 0.83). Stroke rates were non-significantly higher with CABG whereas rates of MI and repeat revascularization were significantly reduced with CABG in both groups. CONCLUSIONS: Compared to PCI, the effects of CABG on long-term risks for MACCE observed in the FREEDOM trial are preserved among patients with mild to moderate CKD.

Identification of a novel Parkinson's disease locus via stratified genome-wide association study.

BACKGROUND: Parkinson's disease (PD) is complex and heterogeneous. The numerous susceptibility loci that have been identified reaffirm the complexity of PD but do not fully explain it; e.g., it is not known if any given PD susceptibility gene is associated with all PD or a disease subtype. We also suspect that important disease genes may have escaped detection because of this heterogeneity. We used presence/absence of family history to subdivide the cases and performed genome-wide association studies (GWAS) in Sporadic-PD and Familial-PD separately. The aim was to uncover new genes and gain insight into the genetic architecture of PD. RESULTS: Employing GWAS on the NeuroGenetics Research Consortium (NGRC) dataset stratified by family history (1565 Sporadic-PD, 435 Familial-PD, 1986 controls), we identified a novel locus on chromosome 1p21 in Sporadic-PD (PNGRC = 4 × 10(-8)) and replicated the finding (P(Replication) = 6 × 10(-3); P(Pooled) = 4 × 10(-10)) in 1528 Sporadic-PD and 796 controls from the National Institutes of Neurologic Disease and Stroke (NINDS) Repository. This is the fifth PD locus to be mapped to the short arm of chromosome 1. It is flanked by S1PR1 and OLFM3 genes, and is 200 kb from a multiple sclerosis susceptibility gene. The second aim of the study was to extend the stratified GWAS to the well-established PD genes. SNCA_ rs356220 was associated with both Sporadic-PD (OR = 1.37, P = 1 × 10(-9)) and Familial-PD (OR = 1.40, P = 2 × 10(-5)). HLA_rs3129882 was more strongly associated with Sporadic-PD (OR = 1.38, P = 5 × 10(-10)) than Familial-PD (OR = 1.12, P = 0.15). In the MAPT region, virtually every single nucleotide polymorphism (SNP) had a stronger effect-size and lower P-value in Familial-PD (peak P = 8 × 10(-7)) than in Sporadic-PD (peak P = 2 × 10(-5)). CONCLUSIONS: We discovered and replicated a new locus for Sporadic-PD which had escaped detection in un-stratified GWAS. This demonstrates that by stratifying on a key variable the power gained due to diminished heterogeneity can sometimes outweigh the power lost to reduced sample size. We also detected distinct patterns of disease associations for previously established PD susceptibility genes, which gives an insight to the genetic architecture of the disease and could aid in the selection of appropriate study population for future studies.

Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee.

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P(2df) = 10(-6), GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10(-7)) but not in light coffee-drinkers. The a priori Replication hypothesis that "Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers" was confirmed: OR(Replication) = 0.59, P(Replication) = 10(-3); OR(Pooled) = 0.51, P(Pooled) = 7×10(-8). Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10(-3)), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10(-13)). Imputation revealed a block of SNPs that achieved P(2df)<5×10(-8) in GWAIS, and OR = 0.41, P = 3×10(-8) in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

Progressive Left Ventricular Remodeling for Predicting Mortality in Children With Dilated Cardiomyopathy: The Pediatric Cardiomyopathy Registry.

BACKGROUND: Pediatric dilated cardiomyopathy often leads to death or cardiac transplantation. We sought to determine whether changes in left ventricular (LV) end-diastolic dimension (LVEDD), LV end-diastolic posterior wall thickness, and LV fractional shortening (LVFS) over time may help predict adverse outcomes. METHODS AND RESULTS: We studied children up to 18 years old with dilated cardiomyopathy, enrolled between 1990 and 2009 in the Pediatric Cardiomyopathy Registry. Changes in LVFS, LVEDD, LV end-diastolic posterior wall thickness, and the LV end-diastolic posterior wall thickness:LVEDD ratio between baseline and follow-up echocardiograms acquired ≈1 year after diagnosis were determined for children who, at the 1-year follow-up had died, received a heart transplant, or were alive and transplant-free. Within 1 year after diagnosis, 40 (5.0%) of the 794 eligible children had died, 117 (14.7%) had undergone cardiac transplantation, and 585 (73.7%) had survived without transplantation. At diagnosis, survivors had higher median LVFS and lower median LVEDD Z scores. Median LVFS and LVEDD Z scores improved among survivors (Z score changes of +2.6 and -1.1, respectively) but remained stable or worsened in the other 2 groups. The LV end-diastolic posterior wall thickness:LVEDD ratio increased in survivors only, suggesting beneficial reverse LV remodeling. The risk for death or cardiac transplantation up to 7 years later was lower when LVFS was improved at 1 year (hazard ratio [HR], 0.83; P=0.004) but was higher in those with progressive LV dilation (HR, 1.45; P<0.001). CONCLUSIONS: Progressive deterioration in LV contractile function and increasing LV dilation are associated with both early and continuing mortality in children with dilated cardiomyopathy. Serial echocardiographic monitoring of these children is therefore indicated. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005391.

Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2.

OBJECTIVE: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility. METHODS: A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls). RESULTS: Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3×10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5×10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2×10(-9)/rs11248060; T: OR=1.35; p=2.0×10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2×10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5×10(-8) Combined Sample) (N370; OR=3.08; p=7×10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5×10(-5) Discovery Sample; p=1.52×10(-7) Replication sample; p=2×10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes. INTERPRETATION: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.

The heritability of risk and age at onset of Parkinson's disease after accounting for known genetic risk factors.

We questioned whether the evidence for the genetic component in Parkinson's disease (PD) in Caucasians could be explained by the causative and susceptibility genes that have already been identified. We estimated heritability of risk and age at onset of PD in a well-characterized sample of 504 nuclear families (2828 individuals). After excluding families with known pathogenic mutations and accounting for the major susceptibility genes, the heritability of risk of developing PD was 0.41 (P=0.01). These data suggest that approximately 40% of the variation in susceptibility to PD is due to as-yet unidentified genes, the remainder is likely environmental.