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OBJECTIVE: To reanalyze the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial using a new composite cardiovascular disease (CVD) outcome to determine how best to treat patients with type 2 diabetes mellitus (T2DM) and stable coronary artery disease (CAD). METHODS: From January 1, 2001 to November 30, 2008, 2,368 T2DM patients with angiographically defined CAD were randomly assigned to insulin sensitizing (IS) or insulin providing (IP) therapy and simultaneously to coronary revascularization (REV) versus no or delayed revascularization (MED) with all patients receiving intensive medical treatment. The outcome for this analysis was a composite of eight CVD events. RESULTS: Four-year composite CVD outcome Kaplan-Meier rates were 35.8% (95% CI: 33.1–38.5%) with IS versus 41.6% (38.7–44.5%) with IP (P=.004). Most of this difference was associated with lower in-trial levels of fibrinogen, c-reactive protein, and hemoglobin A1c (HbA1c) with IS. Four-year composite CVD rates were 32.7% (30.0–35.4%) with REV versus 44.7% (41.8–47.6%) with MED (P

Background The optimal coronary revascularization strategy in patients with stable ischemic heart disease (SIHD) who have type 2 diabetes (T2DM) and chronic kidney disease (CKD) remains unclear. Objectives This patient-level pooled analysis sought to compare outcomes of 3 large, federally-funded randomized trials in SIHD patients with T2DM and CKD (COURAGE [Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation], BARI 2D [Bypass Angioplasty Revascularization Investigation 2 Diabetes], and FREEDOM [Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-vessel Disease]). Methods The primary endpoint was the composite of major adverse cardiovascular or cerebrovascular events (MACCE) including all-cause death, myocardial infarction (MI), or stroke adjusted for trial and randomization strategy. Results Of the 4,953 patients with available estimated glomerular filtration rate (eGFR) at baseline, 1,058 had CKD (21.4%). CKD patients were more likely to be older, be female, and have a history of heart failure. CKD subjects were more likely to experience a MACCE (adjusted hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.28 to 1.71; p = 0.0001) during a median 4.5-year follow-up. Both mild (eGFR 45 to 60 ml/min/1.73 m2) and moderate to severe (eGFR Conclusions Among SIHD patients with T2DM and no CKD, CABG + OMT significantly reduced MACCE compared with PCI + OMT. In subjects with CKD, there was a nonsignificant trend toward a better MACCE outcome with CABG and a significant reduction in subsequent revascularization.

Background and aims The impact of treatment strategies on outcomes in patients with stable coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) according to presenting angina has not been rigorously assessed. Methods We performed a patient-level pooled-analysis (n = 5027) of patients with stable CAD and T2DM randomized to optimal medical therapy [OMT], percutaneous coronary intervention [PCI] + OMT, or coronary artery bypass grafting [CABG] + OMT. Endpoints were death/myocardial infarction (MI)/stroke, post-randomization revascularization (both over 5 years), and angina control at 1 year. Results Increasing severity of baseline angina was associated with higher rates of death/MI/stroke (p = 0.009) and increased need for post-randomization revascularization (p = 0.001); after multivariable adjustment, only association with post-randomization revascularization remained significant. Baseline angina severity did not influence the superiority of CABG + OMT to reduce the rate of death/MI/stroke and post-randomization revascularization compared to other strategies. CABG + OMT was superior for angina control at 1 year compared to both PCI + OMT and OMT alone but only in patients with ≥ Class II severity at baseline. Comparisons between PCI + OMT and OMT were neutral except that PCI + OMT was superior to OMT for reducing the rate of post-randomization revascularization irrespective of presenting angina severity. Conclusions Presenting angina severity did not influence the superiority of CABG + OMT with respect to 5-year rates of death/MI/stroke and need for post-randomization revascularization. Presenting angina severity minimally influenced relative benefits for angina control at 1 year.

Introduction: There are limited data on the impact of isolated tricuspid valve (TV) surgery on recovery of right ventricular (RV) function and RV reverse remodeling. Methods: Among 223 patients who had isolated TV procedures between 2001 and 2017, 60 (27%) underwent TV repair and 163 (73%) received TV replacement. RV reverse remodeling was assessed by echocardiography at a median of 11.3 months (IQR 5.9-13.5) post dismissal. Kaplan-Meier analysis and the log-rank test were used to estimate and create survival curves. Cox proportional hazards analysis was performed to study the association of clinical and echocardiographic parameters with mortality. Results: Mean age was 67.3 ± 13.7 years, and 57% were female. Indication for surgery was functional TR in 64% (n=143) patients. Overall 30-day mortality was 2.7%. After a median follow-up period of 9.5 years (IQR 3.6-12.9) there were a total of 122 (54.7%) deaths. Adjusted Cox regression analysis revealed comparable survival for TV repair and replacement and identified older age, and presence of RV dysfunction (HR 1.84, 95% CI 1.14-2.98; P=0.01) as independent predictors of poor survival. Impact of early RV reverse remodeling on survival after TV surgery was evaluated in 90 patients; In 39 RV function and/or RV size recovered, but in 51 RV dysfunction and/or RV enlargement persisted or worsened. Patients who exhibited RV reverse remodeling had significantly improved survival compared to those who did not (Log-Rank P=0.005) and reverse remodeling was independently associated with improved survival (HR 0.42, 95% CI 0.24-0.74; P=0.003). In a multivariable analysis lower preoperative right atrial pressure (OR 0.83, 95% CI 0.73-0.94; P=0.004) was an independent predictor of early right heart reverse remodeling. Conclusions: Isolated TV surgery can be performed with acceptable outcomes, and overall survival is best in patients who receive the operation before developing severe RV systolic dysfunction. Adjusted survival was similar for patients undergoing TV repair or replacement. Reverse remodeling of RV during the first 18 months after surgery appears to provide survival benefit. Preoperative RA pressure is an independent determinant of postoperative RV remodeling.

Background There are limited data on the impact of isolated tricuspid valve (TV) surgery on recovery of right ventricular (RV) function and RV reverse remodeling. Methods Among 223 patients who had isolated TV procedures between 2001 and 2017, 60 (27%) underwent TV repair and 163 (73%) received TV replacement. Indication for surgery was functional tricuspid valve regurgitation in 64%, lead induced in 18%, and primary leaflet dysfunction in 18%. RV reverse remodeling was assessed by echocardiography at a median of 11.3 months (interquartile range [IQR] 5.9-13.5) post-dismissal. Results Mean age was 67.3 ± 13.7 years, and 57% were female. Overall 30-day mortality was 2.7%. After a median follow-up period of 9.5 years (IQR 3.6-12.9), adjusted Cox regression analysis revealed comparable survival for TV repair and replacement and identified older age, and presence of RV dysfunction (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.14-2.98; P = .01), as independent predictors of poor survival. Patients who exhibited RV reverse remodeling within 18 months postoperatively had significantly improved survival compared with those who did not (log-rank P = .005), and reverse remodeling was independently associated with improved survival (HR 0.42, 95% CI 0.24-0.74; P = .003). Lower preoperative right atrial pressure (odds ratio 0.83, 95% CI 0.73-0.94; P = .004) was predictive of early RV reverse remodeling. Conclusions Isolated TV surgery can be performed with acceptable outcomes (early mortality 2.7%), and overall survival is best in patients who receive the operation before developing RV systolic dysfunction. Adjusted survival was similar for patients undergoing TV repair or replacement. Early reverse remodeling of RV after surgery is associated with survival benefit.

Elevated low-density lipoprotein cholesterol (LDL-C) is associated with increased cardiovascular events, especially in high-risk populations.This study sought to evaluate the influence of LDL-C on the incidence of cardiovascular events either following a coronary revascularization procedure (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or optimal medical therapy alone in patients with established coronary heart disease and type 2 diabetes (T2DM).Patient-level pooled analysis of 3 randomized clinical trials was undertaken. Patients with T2DM were categorized according to the levels of LDL-C at 1 year following randomization. The primary endpoint was major adverse cardiac or cerebrovascular events ([MACCE] the composite of all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke).A total of 4,050 patients were followed for a median of 3.9 years after the index 1-year assessment. Patients whose 1-year LDL-C remained ≥100 mg/dl experienced higher 4-year cumulative risk of MACCE (17.2% vs. 13.3% vs. 13.1% for LDL-C between 70 and 100 mg/dl and LDL-C 70 mg/dl, respectively; p = 0.016). When compared with optimal medical therapy alone, patients with PCI experienced a MACCE reduction only if 1-year LDL-C was 70 mg/dl (hazard ratio: 0.61; 95% confidence interval: 0.40 to 0.91; p = 0.016), whereas CABG was associated with improved outcomes across all 1-year LDL-C strata. In patients with 1-year LDL-C ≥70 mg/dl, patients undergoing CABG had significantly lower MACCE rates as compared with PCI.In patients with coronary heart disease with T2DM, lower LDL-C at 1 year is associated with improved long-term MACCE outcome in those eligible for either PCI or CABG. When compared with optimal medical therapy alone, PCI was associated with MACCE reductions only in those who achieved an LDL-C 70 mg/dl.

Background Temporal declines in cardiac stress tests results, coronary revascularization, and cardiovascular mortality have suggested a decline in the population burden of coronary disease until the 2000s. However, recent data indicate these favorable trends could be ending. We aimed to assess the evolution of the population burden of coronary disease in the community by examining trends in angiography and revascularization. Methods and Results We analyzed age‐ and sex‐adjusted trends from all coronary angiographic diagnostic procedures and revascularizations performed in Olmsted County, MN from 2000 to 2018. A total of 12 981 invasive angiograms were performed among 9049 individuals (64% men; 55% aged ≥65 years). Adjusted angiography rates decreased by 30% (95% CI , 25%–34%) between 2000 and 2009 and leveled off thereafter. Including computed tomography, angiography uncovered an increase in angiography use in recent years (risk ratio=1.15 [95% CI , 1.07–1.23] for 2018 versus 2014) and a decline in the prevalence of anatomic CAD from 2000 to 2018. CAD severity declined substantially from 2000 to 2009, followed by a plateau. Among 6570 revascularizations (72% men; 57% aged ≥65 years), 77% were percutaneous coronary interventions and 23% coronary artery bypass graft surgeries. The adjusted revascularization rates declined by 34% (95% CI , 27%–39%) from 2000 to 2009, followed by a plateau (risk ratio=1.10 [95% CI , 1.00–1.22]). Conclusions Between 2000 and 2018 in the community, coronary angiography use declined initially, leveled off, and then increased. Trends in CAD severity and revascularization use decreased then plateaued. The most recent trends are concerning as they suggest the burden of coronary disease is no longer declining. This warrants reinvigorated primary prevention and population surveillance.

[Figure][1] Robert L. Frye, MD Dr. Shahbudin H. Rahimtoola died December 9, 2018. We mourn with his family, but we celebrate a life lived with enthusiasm, dedication, high achievement in academic medicine, as well as the devotion with which he served his patients. Born in Bombay, India (

OBJECTIVES Our goal was to compare the rates of in-hospital and 30-day major adverse cardiac and cerebrovascular events (MACCE) including death, stroke, myocardial infarction and repeat revascularization in patients with multivessel disease undergoing multiarterial (MultArt) coronary artery bypass grafting (CABG) with the left internal mammary artery/saphenous vein (LIMA/SV) CABG or percutaneous coronary intervention (PCI). METHODS From 1 January 1993 to 31 December 2009, 12 615 consecutive patients underwent isolated primary CABG (n = 6667) with LIMA/SV (n = 5712) or MultArt (n = 955) or were treated by PCI (n = 5948) with balloon angioplasty (n = 1020), bare metal stent (n = 3242), and drug-eluting stent (n = 1686). We excluded patients with acute myocardial infarction. We matched the CABG group with the 3 PCI subgroups, and the PCI group with the 2 CABG subgroups. Multivariable analyses were used to evaluate the impact of CABG versus PCI and their subgroups on early MACCE. RESULTS Unadjusted early MACCE were lower for MultArt (1.5%) than for LIMA/SV (4.5%, P

Background The extent of coronary disease affects clinical outcomes and may predict the effectiveness of coronary revascularization with either coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score quantifies the extent of coronary disease. Objectives This study sought to determine whether SYNTAX scores predicted outcomes and the effectiveness of coronary revascularization compared with medical therapy in the BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. Methods Baseline SYNTAX scores were retrospectively calculated for BARI-2D patients without prior revascularization (N = 1,550) by angiographic laboratory investigators masked to patient characteristics and outcomes. The primary outcome was major cardiovascular events (a composite of death, myocardial infarction, and stroke) over 5 years. Results A mid/high SYNTAX score (≥23) was associated with a higher risk of major cardiovascular events (hazard ratio: 1.36, confidence interval: 1.07 to 1.75, p = 0.01). Patients in the CABG stratum had significantly higher SYNTAX scores: 36% had mid/high SYNTAX scores compared with 13% in the PCI stratum (p Conclusions Among patients with diabetes and stable ischemic heart disease, higher SYNTAX scores predict higher rates of major cardiovascular events and were associated with more favorable outcomes of revascularization compared with medical therapy among patients suitable for CABG. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes; NCT00006305)

Objective There has been debate on the importance and pathophysiologic effects of the dynamic subaortic pressure gradient in hypertrophic obstructive cardiomyopathy. The study was conducted to elucidate the hemodynamic abnormalities associated with the dynamic pressure gradient in hypertrophic obstructive cardiomyopathy. Methods Eight patients with hypertrophic obstructive cardiomyopathy and 7 patients with valvular aortic stenosis underwent a detailed hemodynamic study of pressure flow relationships before and after myectomy or aortic valve replacement during operation. Results In aortic stenosis, the increased gradient after premature ventricular contraction was associated with an increase in peak flow (325 ± 122 mL/s to 428 ± 147 mL/s, P = .002) and stroke volume (75.0 ± 27.3 mL to 88.0 ± 24.0 mL, P = .004), but in hypertrophic obstructive cardiomyopathy peak flow remained unchanged (289 ± 79 mL/s to 299 ± 85 mL/s, P = .334) and stroke volume decreased (45.9 ± 18.7 mL to 38.4 ± 14.4 mL, P = .04) on the postpremature ventricular contraction beat. After myectomy, the capacity to augment stroke volume on the postpremature ventricular contraction beats was restored in patients with hypertrophic obstructive cardiomyopathy (45.6 ± 14.4 mL to 54.4 ± 11.8 mL, P = .002). Conclusions The pressure flow relationship in hypertrophic obstructive cardiomyopathy supports the concept of true obstruction to outflow, with a low but continued flow during late systole, when the ventricular-aortic pressure gradient is the highest. Septal myectomy can abolish obstruction and restore the ability to augment stroke volume, which may explain the mechanism of symptomatic improvement after operation.

To assess long-term survival with repeat coronary artery bypass grafting (RCABG) or percutaneous coronary intervention (PCI) in patients with previous CABG.From January 1, 2000, through December 31, 2013, 1612 Mayo Clinic patients underwent RCABG (n=215) or PCI (n=1397) after previous CABG. The RCABG cohort was grouped by use of saphenous vein grafts only (n=75), or with additional arterial grafts (n=140); the PCI cohort by, bare metal stents (BMS; n=628), or drug-eluting stents (DES; n=769), and by the treated target into native coronary artery (n=943), bypass grafts only (n=338), or both (n=116). Multivariable regression and propensity score analysis (n=280 matched patients) were used.In multivariable analysis, the 30-day mortality was increased in RCABG versus PCI patients (hazard ratio [HR], 5.32; 95%CI, 2.34-12.08; P.001), but overall survival after 30 days improved with RCABG (HR, 0.72; 95% CI, 0.55-0.94; P=.01). Internal mammary arteries were used in 61% (129 of 215) of previous CABG patients and improved survival (HR, 0.82; 95% CI, 0.69-0.98; P=.03). Patients treated with drug-eluting stent had better 10-year survival (HR, 0.74; 95% CI, 0.59-0.91; P=.001) than those with bare metal stent alone. In matched patients, RCABG had improved late survival over PCI: 48% vs 33% (HR, 0.57; 95% CI, 0.35-0.91; P=.02). Compared with RCABG, patients with PCI involving bypass grafts (n=60) had increased late mortality (HR, 1.62; 95% CI, 1.10-2.37; P=.01), whereas those having PCI of native coronary arteries (n=80) did not (HR, 1.09; 95% CI, 0.75-1.59; P=.65).RCABG is associated with improved long-term survival after previous CABG, especially compared with PCI involving bypass grafts.

Diabetic medications can cause hypoglycemia, which may lead to myocardial damage.This study sought to determine whether hypoglycemia is associated with higher levels of high-sensitivity cardiac troponin T (hsTnT).The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial randomized patients with type 2 diabetes mellitus and stable coronary artery disease, and closely followed them for hypoglycemia over the first year. Hypoglycemia was classified by maximum severity and frequency. hsTnT was measured at baseline and 1 year, and analyzed using multivariable regression.Of 1,984 patients, follow-up hypoglycemia was absent in 1,026 (52%) patients, mild in 875 (44%), and severe in 83 (4%), and occurred less than weekly in 561 (28%) and greater than or equal to weekly in 397 (20%). hsTnT levels were associated with hypoglycemia: a median of 11.4 ng/l (interquartile range [IQR]: 8.1 to 17.3 ng/l) for none, 12.5 ng/l (IQR: 8.3 to 19.3 ng/l) for mild, and 13.7 ng/l (IQR: 9.9 to 24.9 ng/l) for severe hypoglycemia (p = 0.0001); and 12.5 ng/l (IQR: 8.3 to 18.1 ng/l) for less than weekly and 13.0 ng/l (IQR: 8.8 to 21.1 ng/l) for greater than or equal to weekly hypoglycemia (p = 0.0013). Severe hypoglycemia was associated with 34% higher 1-year hsTnT levels (p 0.0001) in unadjusted analysis, 17% higher (p = 0.006) after adjustment for baseline factors unrelated to diabetes, and 6% higher (p = 0.23) after further adjustment for the duration and severity of diabetes. Hypoglycemia greater than or equal to weekly was associated with 14% higher hsTnT (p = 0.0003) in unadjusted analysis, 12% higher (p = 0.0002) after adjustment for baseline factors unrelated to diabetes, and 4% higher (p = 0.16) after adjustment for diabetes related factors.Hypoglycemia was associated with elevated hsTnT levels, but this may be due to more severe diabetes in patients who developed hypoglycemia, rather than the direct result of hypoglycemia. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI2D]; NCT00006305).

Cardiac troponin concentrations are used to identify patients who would benefit from urgent revascularization for acute coronary syndromes. We hypothesized that they might be used in patients with stable ischemic heart disease to identify those at high risk for cardiovascular events who might also benefit from prompt coronary revascularization.We measured the cardiac troponin T concentration at baseline with a high-sensitivity assay in 2285 patients who had both type 2 diabetes and stable ischemic heart disease and were enrolled in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes trial. We tested for an association between the troponin T concentration and a composite end point of death from cardiovascular causes, myocardial infarction, or stroke; we then evaluated whether random assignment to prompt revascularization reduced the rate of the composite end point in patients with an abnormal troponin T concentration (≥14 ng per liter) as compared with those with a normal troponin T concentration (14 ng per liter).Of the 2285 patients, 2277 (99.6%) had detectable (≥3 ng per liter) troponin T concentrations and 897 (39.3%) had abnormal troponin T concentrations at baseline. The 5-year rate of the composite end point was 27.1% among the patients who had had abnormal troponin T concentrations at baseline, as compared with 12.9% among those who had had normal baseline troponin T concentrations. In models that were adjusted for cardiovascular risk factors, severity of diabetes, electrocardiographic abnormalities, and coronary anatomy, the hazard ratio for the composite end point among patients with abnormal troponin T concentrations was 1.85 (95% confidence interval [CI], 1.48 to 2.32; P0.001). Among patients with abnormal troponin T concentrations, random assignment to prompt revascularization, as compared with medical therapy alone, did not result in a significant reduction in the rate of the composite end point (hazard ratio, 0.96; 95% CI, 0.74 to 1.25).The cardiac troponin T concentration was an independent predictor of death from cardiovascular causes, myocardial infarction, or stroke in patients who had both type 2 diabetes and stable ischemic heart disease. An abnormal troponin T value of 14 ng per liter or higher did not identify a subgroup of patients who benefited from random assignment to prompt coronary revascularization. (Funded by the National Institutes of Health and Roche Diagnostics; BARI 2D ClinicalTrials.gov number, NCT00006305.).

Objectives Conclusive evidence is lacking regarding the benefits and risks of performing off-pump versus on-pump coronary artery bypass graft (CABG) for patients with diabetes. This study aims to compare clinical outcomes after off-pump and on-pump procedures for patients with diabetes. Methods The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial enrolled patients with type 2 diabetes and documented coronary artery disease, 615 of whom underwent CABG during the trial. The procedural complications, 30-day outcomes, long-term clinical and functional outcomes were compared between the off-pump and on-pump groups overall and within a subset of patients matched on propensity score. Results On-pump CABG was performed in 444 (72%) patients, and off-pump CABG in 171 (28%). The unadjusted 30-day rate of death/myocardial infarction (MI)/stroke was significantly higher after off-pump CABG (7.0 vs 2.9%, P = 0.02) despite fewer complications (10.3 vs 20.7%, P = 0.003). The long-term risk of death [adjusted hazard ratio (aHR): 1.41, P = 0.2197] and major cardiovascular events (death, MI or stroke) (aHR: 1.47, P = 0.1061) did not differ statistically between the off-pump and on-pump patients. Within the propensity-matched sample (153 pairs), patients who underwent off-pump CABG had a higher risk of the composite outcome of death, MI or stroke (aHR: 1.83, P = 0.046); the rates of procedural complications and death did not differ significantly, and there were no significant differences in the functional outcomes. Conclusions Patients with diabetes had greater risk of major cardiovascular events long-term after off-pump CABG than after on-pump CABG.

Cardiac troponin is the preferred marker of myocardial necrosis in patients with suspected myocardial infarction (MI). Increasingly sensitive assays have allowed the detection of very low circulating troponin concentrations in ambulatory patients, and these low troponin levels are strong

Little is known about the cellular biology of fat surrounding the human heart. In this study, we obtained paired samples of epicardial fat, the visceral fat depot attached to the heart, and subcutaneous skin fat from patients undergoing open heart surgery to test the hypothesis that human epicardial fat cells differentially express bioactive molecules that have the potential to affect cardiac function. First, we characterized the free fatty acids (FFAs), adipocytokines, and growth factors secreted by isolated adipocytes and preadipocytes in cell culture. There was little to distinguish the fat cell secretory products in terms of FFAs and adipocytokines. The most striking finding was that preadipocytes from epicardial adipose tissue expressed high levels of pregnancy‐associated plasma protein‐A (PAPP‐A), a novel metalloproteinase that enhances local insulin‐like growth factor (IGF) action through cleavage of inhibitory IGF binding protein‐4 (IGFBP‐4). PAPP‐A levels were 15‐fold higher in conditioned medium from epicardial preadipocytes than from subcutaneous preadipocytes (P

Background— Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown. Methods and Results— To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan–Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58–1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55–0.93) and stroke (HR, 0.36; 95% CI, 0.16–0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05–2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54–1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84–1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different. Conclusions— Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00006305.

ObjectivesThis study evaluated data from 3 federally funded trials that focused on optimal medical therapy to determine if formalized attempts at risk factor control within clinical trials are effective in achieving guideline-driven treatment goals for diabetic patients with coronary artery disease (CAD).BackgroundDespite clear evidence of benefit for CAD secondary prevention, the level of risk factor control in clinical practice has been disappointing.MethodsWe obtained data from the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) diabetes subgroup, (n = 766 of 2,287), the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial (n = 2,368), and the FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial (n = 1,900) to evaluate the proportion of patients achieving guideline-based, protocol-driven treatment targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking cessation, and hemoglobin A1c. The primary outcome measure was the proportion of diabetic CAD patients meeting all 4 pre-specified targets at 1 year after enrollment.ResultsThe pooled data include 5,034 diabetic patients. The percentages of patients achieving the 1-year low-density lipoprotein cholesterol targets compared with baseline increased from 55% to 77% in COURAGE, from 59% to 75% in BARI 2D, and from 34% to 42% in FREEDOM. Although similar improved trends were seen for systolic blood pressure, glycemic control, and smoking cessation, only 18% of the COURAGE diabetes subgroup, 23% of BARI 2D patients, and 8% of FREEDOM patients met all 4 pre-specified treatment targets at 1 year of follow-up.ConclusionsA significant proportion of diabetic CAD patients fail to achieve pre-specified targets for 4 major modifiable cardiovascular risk factors in clinical trials. We conclude that fundamentally new thinking is needed to explore approaches to achieve optimal secondary prevention treatment goals. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657) (Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]; NCT00006305) (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450)

Objectives The purpose of this analysis was to assess in patients with type 2 diabetes and stable coronary artery disease (CAD) whether the risk of all-cause mortality and cardiovascular events varied according to the presence or absence of angina and angina equivalent symptoms. Background Data on the prognostic value of symptoms in these patients are limited. Methods Post-hoc analysis was performed in 2,364 patients with type 2 diabetes and documented CAD enrolled in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial to determine the occurrence of death and composite of death, myocardial infarction, and stroke during a 5-year follow-up according to cardiac symptoms at baseline. Results There were 1,434 patients with angina (A), 506 with angina equivalents (E), and 424 with neither of these (N). The cumulative death rates (total 316) were 12% in A, 14% in E, and 10% in N (p = 0.3), and cardiovascular composite rates (total 548) were 24% in A, 24% in E, and 21% in N (p = 0.5). Compared with N, the hazard ratios adjusted for confounders were not different for death in A (1.11; 99% CI: 0.81 to 1.53) and E (1.17; 99% CI: 0.81 to 1.68) or for cardiovascular events in A (1.17; 99% CI: 0.92 to 1.50) and E (1.11; 99% CI: 0.84 to 1.48). Conclusions Whatever their symptom status, patients with type 2 diabetes and stable CAD were at similar risk of cardiovascular events and death. These findings suggest that these patients may be similarly managed in terms of risk stratification and preventive therapies. (Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]; NCT00006305)

Background— The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial assigned patients with type 2 diabetes mellitus to prompt coronary revascularization plus intensive medical therapy versus intensive medical therapy alone and reported no significant difference in mortality. Among patients selected for coronary artery bypass graft surgery, prompt coronary revascularization was associated with a significant reduction in death/myocardial infarction/stroke compared with intensive medical therapy. We hypothesized that clinical and angiographic risk stratification would affect the effectiveness of the treatments overall and within revascularization strata. Methods and Results— An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham Risk Score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups. Overall, no outcome differences between the intensive medical therapy and prompt coronary revascularization groups were seen in any risk stratum. The 5-year risk of death/myocardial infarction/stroke was 36.8% for intensive medical therapy compared with 24.8% for prompt coronary revascularization among the 381 coronary artery bypass graft surgery–selected patients in the highest angiographic risk tertile ( P =0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% intensive medical therapy versus 27.1% prompt coronary revascularization; P =0.010; hazard ratio=2.10; P =0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the coronary artery bypass graft surgery stratum, or in any subgroups within the percutaneous coronary intervention stratum. Conclusion— Among patients with diabetes mellitus and stable ischemic heart disease, a strategy of prompt coronary artery bypass graft surgery significantly reduces the rate of death/myocardial infarction MI/stroke in those with extensive coronary artery disease or impaired left ventricular function. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00006305.

The extent of coronary disease affects clinical outcomes and may predict the effectiveness of coronary revascularization with either coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score quantifies the extent of coronary disease.This study sought to determine whether SYNTAX scores predicted outcomes and the effectiveness of coronary revascularization compared with medical therapy in the BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial.Baseline SYNTAX scores were retrospectively calculated for BARI-2D patients without prior revascularization (N = 1,550) by angiographic laboratory investigators masked to patient characteristics and outcomes. The primary outcome was major cardiovascular events (a composite of death, myocardial infarction, and stroke) over 5 years.A mid/high SYNTAX score (≥23) was associated with a higher risk of major cardiovascular events (hazard ratio: 1.36, confidence interval: 1.07 to 1.75, p = 0.01). Patients in the CABG stratum had significantly higher SYNTAX scores: 36% had mid/high SYNTAX scores compared with 13% in the PCI stratum (p 0.001). Among patients with low SYNTAX scores (≤22), major cardiovascular events did not differ significantly between revascularization and medical therapy, either in the CABG stratum (26.1% vs. 29.9%, p = 0.41) or in the PCI stratum (17.8% vs. 19.2%, p = 0.84). Among patients with mid/high SYNTAX scores, however, major cardiovascular events were lower after revascularization than with medical therapy in the CABG stratum (15.3% vs. 30.3%, p = 0.02), but not in the PCI stratum (35.6% vs. 26.5%, p = 0.12).Among patients with diabetes and stable ischemic heart disease, higher SYNTAX scores predict higher rates of major cardiovascular events and were associated with more favorable outcomes of revascularization compared with medical therapy among patients suitable for CABG. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes; NCT00006305).

Introduction: The benefits of optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery have been evaluated in patients with Type 2 Diabetes Mellitus (T2DM) and stable coronary artery disease (CAD) but analyses have not been stratified by detailed angiographic CAD burden or left ventricular ejection fraction (LVEF). Methods: A patient-level meta-analysis was undertaken among T2DM patients enrolled in COURAGE, BARI 2D and FREEDOM to assess the impact of randomization to OMT, PCI + OMT, or CABG + OMT on a composite end-point of Death/MI/Stroke and stratified by LVEF (≥ 50%, < 50%), 1, 2 or 3 vessel disease (VD) (% diameter stenosis ≥ 50%) and presence or absence of proximal left anterior descending (pLAD) disease. Hazard ratios (HR) for treatment groups were calculated from Cox regression models including all patients adjusting for trial and revascularization stratum in BARI 2D. Multivariable adjustment for risk factors was performed as a sensitivity analysis. Results: There were 5,034 patients included in the analysis (BARI 2D: n=2,368, COURAGE: n=766, FREEDOM: n=1,900) of whom 17% had LVEF < 50%, 29% had pLAD, and 77% had 2 or 3 VD. A total of 1,591 patients were randomized to OMT alone, 2,118 to PCI + OMT, and 1,325 to CABG + OMT. There were 1,116 events during a median 4.5 year follow-up. There was no significant effect on outcomes with OMT vs PCI + OMT irrespective of LVEF, presence/absence of pLAD and number of VD. By contrast, CABG + OMT significantly reduced the risk of Death/MI/Stroke in patients with 2 or 3 VD, irrespective of LVEF and presence/absence of pLAD (see Table). Results were similar with multivariable adjustment. Conclusions: In patients with T2DM and stable CAD, OMT alone appears to be as effective as PCI + OMT while CABG + OMT significantly reduces cardiovascular events in those with multivessel CAD, irrespective of LVEF or presence of pLAD.

Previous studies have observed high rates of perioperative cardiovascular events in patients with coronary stents undergoing noncardiac surgery (NCS). It is uncertain whether this finding reflects an independent association.The goal of this study was to assess the independent relationship between prior coronary stent implantation and the occurrence of perioperative major adverse cardiac and cerebrovascular events (MACCE) and bleeding and its relation with time from stenting to NCS.A total of 24,313 NCS cases at the Mayo Clinic (Rochester, Minnesota) from 2006 through 2011 were included in the study; 1,120 (4.6%) cases involved patients with coronary stents. MACCE was defined as death, myocardial infarction, cardiac arrest, or stroke. Age-adjusted odds ratios (aORs) were calculated after propensity adjustment for Revised Cardiac Risk Index factors and other conventional risk factors.The 30-day MACCE rates were 3.7% and 1.5% in stented and unstented patients, respectively (p0.001). The risk of MACCE was largely related to the time from stent implantation to NCS, indicating substantially elevated risk in the first year after stenting (aOR: 2.59; 95% confidence interval [CI]: 1.36 to 4.94) but not thereafter (aOR: 0.89; 95% CI: 0.59 to 1.36). Bleeding displayed a similar pattern, indicating elevated risk in the first year after stenting (aOR: 2.23; 95% CI: 1.55 to 3.21) but not thereafter (aOR: 1.07; 95% CI: 0.89 to 1.28). Subgroup analysis in patients with known stent type found that the increased risk of both MACCE and bleeding1 month after stent implantation was not limited to only those with drug-eluting stents.This study found that prior coronary stent implantation is an independent risk factor for MACCE and bleeding when time from stenting to NCS is1 year, both in patients with bare-metal and drug-eluting stents.

Objective To evaluate the cardiovascular (CV) prognostic value of adipokines in a large prospective cohort of patients participating in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. Patients and Methods The effects of the adipokine levels at baseline and change from baseline on the composite outcome (CV death, myocardial infarction, and stroke) were analyzed using unadjusted and fully adjusted Cox models in 2330 patients with type 2 diabetes and coronary artery disease who had participated in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (from January 1, 2001, through December 1, 2008). Results In a fully adjusted model, baseline leptin and change from baseline leptin were protective for CV events, whereas baseline adiponectin, baseline tumor necrosis factor α (TNF-α), change from baseline TNF-α, baseline C-reactive protein (CRP), and change from baseline CRP were harmful. The effect of baseline leptin on CV events depended on the body mass index (BMI), such that the hazard ratios (HRs) varied between 0.6 and 1.4 across the BMI quintiles (interaction P =.03). The same was true for baseline adiponectin (HR varied from 0.7 to 1.7; interaction P =.01), change from baseline monocyte chemoattractant protein-1 (HR varied from 0.8 to 1.8; interaction P =.03), change from baseline TNF-α (HR varied from 0.9 to 1.4; interaction P =.02), and change from baseline IL-6 (HR varied from 0.7 to 1.8; interaction P =.005). Conclusion Adipokines are independent predictors of CV events in patients with type 2 diabetes and coronary artery disease. The association between the specific adipokines and CV outcome varies depending on BMI. This reflects the complex pathophysiology of CV disease in obesity and may help explain the "obesity paradox." Trial Registration clinicaltrials.gov Identifier: NCT00006305.

There are scant outcomes data in patients with type 2 diabetes and stable coronary artery disease (CAD) stratified by detailed angiographic burden of CAD or left ventricular ejection fraction (LVEF).This study determined the effect of optimal medical therapy (OMT), with or without percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), on long-term outcomes with respect to LVEF and number of diseased vessels, including proximal left anterior descending artery involvement.A patient-level pooled analysis was undertaken in 3 federally-funded trials. The primary endpoint was the composite of death, myocardial infarction (MI), or stroke, adjusted for trial and randomization strategy.Among 5,034 subjects, 15% had LVEF 50%, 77% had multivessel CAD, and 28% had proximal left anterior descending artery involvement. During a median 4.5-year follow-up, CABG + OMT was superior to PCI + OMT for the primary endpoint (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.59 to 0.85; p = 0.0002), death (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.024), and MI (HR: 0.50; 95% CI: 0.38 to 0.67; p = 0.0001), but not stroke (HR: 1.54; 95% CI: 0.96 to 2.48; p = 0.074). CABG + OMT was also superior to OMT alone for prevention of the primary endpoint (HR: 0.79; 95% CI: 0.64 to 0.97; p = 0.022) and MI (HR: 0.55; 95% CI: 0.41 to 0.74; p = 0.0001), and was superior to PCI + OMT for the primary endpoint in patients with 3-vessel CAD (HR: 0.72; 95% CI: 0.58 to 0.89; p = 0.002) and normal LVEF (HR: 0.71; 95% CI: 0.58 to 0.87; p = 0.0012). There were no significant differences in OMT versus PCI + OMT.CABG + OMT reduced the primary endpoint during long-term follow-up in patients with type 2 diabetes and stable CAD, supporting this as the preferred management strategy.

Background— Coronary artery disease (CAD) is the major cause of death in patients with type 2 diabetes mellitus. Although demographic and clinical factors associated with extent of CAD in patients with diabetes mellitus have been described, genetic factors have not. We hypothesized that genetic variation in peroxisome proliferator-activated receptor (PPAR) pathway genes, important in diabetes mellitus and atherosclerosis, would be associated with extent of CAD in patients with diabetes mellitus. Methods and Results— We genotyped 1043 patients (702 white, 175 blacks) from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) genetic cohort for 3351 variants in 223 PPAR pathway genes using a custom targeted-genotyping array. Angiographic end points were determined by a core laboratory. In whites, a single variant (rs1503298) in TLL1 was significantly ( P =5.5×10 −6 ) associated with extent of CAD, defined as number of lesions with percent diameter stenosis ≥20%, after stringent Bonferroni correction for all 3351 single nucleotide polymorphisms. This association was validated in the diabetic subgroups of 2 independent cohorts, the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) post–myocardial infarction registry and the prospective Family Heart Study (FHS) of individuals at risk for CAD. TLL1 rs1503298 was also significantly associated with extent of severe CAD (≥70% diameter stenosis; P =3.7×10 −2 ) and myocardial jeopardy index ( P =8.7×10 −4 ). In general linear regression modeling, TLL1 rs1503298 explained more variance of extent of CAD than the previously determined clinical factors. Conclusions— We identified a variant in a single PPAR pathway gene, TLL1 , that is associated with the extent of CAD independently of clinical predictors, specifically in patients with type 2 diabetes mellitus and CAD. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00006305.

Diabetes mellitus is a risk factor for late death in patients undergoing coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). Whether extending multiple arterial grafts (MA) to diabetic patients improves survival compared with conventional left internal mammary artery

This component of the series “Careers in Cardiovascular Research: A Primer for New Investigators” will address ethical conduct of research involving humans. The dramatic decline in cardiovascular mortality (Figure) provides testimony to the societal benefits of research leading to new therapies and systems of care.1 In concert with these rapid developments, changing expectations have resulted in the emergence of ethical issues with highly publicized examples of concern over conduct of research in humans.2–5 Whereas professional ethics should, and for most physicians do, “regulate” conduct of biomedical research, “self-regulation” does not always meet societal expectations. Dr Barry Coller6 has pointed out that science lacks intrinsic morality. Thus, the laudable goals of improving patient care, understanding mechanisms of disease, or protecting society from perceived external threats do not justify ignoring fundamental human rights that guide (and regulate) the conduct of research. Figure. Death rates for cardiovascular disease in the United States, 1900 to 2005 (not adjusted for age). At the same time it is important to reflect on the importance of physicians participating in research and providing the opportunity for their patients to do so. Although some have argued this compromises the basic physician responsibility to a patient,7 we believe the best interest of the patient can and must be protected in the research setting. Two brief examples demonstrate the fundamental changes in understanding that may arise from direct involvement of physicians in research. As late as the 1970s, the prevailing wisdom to explain the presence of intracoronary thrombus on postmortem examination of patients after myocardial infarction was simply wrong; pathologists studying hearts in this setting found evidence to “suggest that coronary thrombi are consequences rather than causes of acute myocardial infarction”8 and “consideration is given to the possibility that some thrombi may follow rather than precede …

Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established.We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention.At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003).Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.)

Background.Research has shown less aggressive treatment and poorer control of cardiovascular disease (CVD) risk factors in women than men.Methods.We analyzed sex differences in pharmacotherapy strategies and attainment of goals for hemoglobin A1c (HbA1c), blood pressure (BP), and low density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and established coronary artery disease enrolled into the BARI 2D trial.Results.Similar numbers of drugs were prescribed in both women and men. Women were less frequent on metformin or sulfonylurea and more likely to take insulin and to be on higher doses of hydroxymethylglutaryl-CoA reductase inhibitors (statins) than men. After adjusting for baseline differences and treatment prescribed, women were less likely to achieve goals for HbA1c (OR = 0.71, 95% CI 0.57, 0.88) and LDL-C (OR = 0.64, 95% CI 0.53, 0.78). More antihypertensives were prescribed to women, and yet BP ≤ 130/80 mmHg did not differ by sex.Conclusions.Women entering the BARI 2D trial were as aggressively treated with drugs as men. Despite equivalent treatment, women less frequently met targets for HbA1c and LDL-C. Our findings suggest that there may be sex differences in response to drug therapies used to treat diabetes, hypertension, and hyperlipidemia.

CD4 T cells, through the release of cytokines as well as direct effector functions, have been implicated in promoting inflammation of the atherosclerotic plaque. Plaque-infiltrating CD4 T cells include a specialized subset of CD4+CD28−T cells that express a unique profile of regulatory receptors and are responsive to novel microenvironmental cues. Here we report that CD4+CD28−T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation. CD4+CD28−IL-12R+cells responded to IL-12 stimulation with the upregulation of the chemokine receptor CCR5 and the C-type lectin receptor CD161, both implicated in regulating tissue homing of effector T cells. IL-12 treatment of CD4+CD28−T cells enhanced their chemotaxis and transendothelial migration toward the chemokine CCL5. In vivo relevance for the role of IL-12 in regulating the recruitment of CD4+CD28−T cells into the atheroma was examined in human atheroma-SCID mouse chimeras. Exposure of nonstimulated CD4+CD28−T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, CD4+CD28−T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12–inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions.

The rapid development of new drugs, therapies, and devices has created a dramatic increase in the number of trials needed to properly evaluate them. The majority of patients treated today, many of whom could be eligible for participation in these studies, are seen in community hospitals and medical practices that are not affiliated with an academic medical center. Thus, there is a demonstrable need for physicians in private practice to enlist as investigators in these trials. This article is intended to encourage those physicians by describing the need and providing the rationale for their participation. It covers basic requirements for participating in clinical trials and outlines ethical, regulatory, financial, and other logistical issues of importance for the potential investigator and provides an algorithm for selecting a study for participation. Finally, the appendices review basic elements of study design and statistical principles, which may be of interest to a potential investigator.

Mitral regurgitation (MR) has become the predominant mitral valve disease as a result of the regression of rheumatic diseases and the aging of the population. The high prevalence in the elderly of degenerative and ischemic MR implies that MR is currently a public health problem. Recent data suggest that MR has severe outcome implications that are dependent on the degree of regurgitation, both for MR due to organic disease of the mitral valve and MR due to ischemic heart disease. This combination of high prevalence and relatively high risk requires careful examination of therapies applicable to MR. Unfortunately for patients with MR, therapeutic approaches for both medical and surgical treatment have not been evaluated by the state-of-the-art method—ie, by randomized clinical trials. Therefore, observational studies form the basis of our clinical decision-making process, and the quality of evidence is less than optimal. Our assessment of the improvement of outcome provided by various strategies (eg, medical treatment versus untreated observation, surgical treatment versus medical treatment of asymptomatic patients, valve repair versus valve replacement in patients who require surgery) is based on observational studies that have intrinsic limitations. The first implication of this situation is that we need (for a lack of a stronger word) appropriately designed randomized clinical trials comparing various strategies of treatment. The second implication is that it is not surprising that various observational studies, such as that presented by Thourani and colleagues in the present issue of Circulation ,1 may have findings different from each other in accordance with the population examined. Consequently, it is essential to examine the current status of our knowledge and determine how to interpret data that may seem to contradict existing information. See p 298 What does the current literature say about the potential outcome benefit of mitral valve repair for patients …

OBJECTIVES The study was conducted to test the hypothesis that the prevalence of coronary atherosclerosis is greater among diabetic than among nondiabetic individuals and is similar for diabetic individuals without clinical coronary artery disease (CAD) and nondiabetics with clinical CAD. BACKGROUND Persons with diabetes but without clinical CAD encounter cardiovascular mortality similar to nondiabetic individuals with clinical CAD. This excess mortality is not fully explained. We examined the association between diabetes and coronary atherosclerosis in a geographically defined autopsied population, while capitalizing on the autopsy rate and medical record linkage system available via the Rochester Epidemiology Project, which allows rigorous ascertainment of coronary atherosclerosis, clinical CAD, and diabetes. METHODS Using two measures, namely a global coronary score and high-grade stenoses, the prevalence of atherosclerosis was analyzed in a cohort of autopsied residents of Rochester, Minnesota, age 30 years or older at death, while stratifying on diabetes, clinical CAD diagnosis, age, and gender. RESULTS In this cohort, diabetes was associated with a higher prevalence of atherosclerosis. Among diabetic decedents without clinical CAD, almost three-fourths had high-grade coronary atherosclerosis and more than half had multivessel disease. Without diabetes, women had less atherosclerosis than men, but this female advantage was lost with diabetes. Among those without clinical CAD, diabetes was associated with a global coronary disease burden and a prevalence of high-grade atherosclerosis similar to that observed among nondiabetic subjects with clinical CAD. CONCLUSIONS These findings provide mechanistic insights into the excess risk of clinical CAD among diabetic individuals, thereby supporting the need for aggressive prevention of atherosclerosis in all diabetic individuals, irrespective of clinical CAD symptoms.

Objectives The study was done to define the incidence, determinants and prognostic implications of onset of atrial fibrillation (AF) during follow-up of mitral regurgitation (MR) initially in sinus rhythm. Background The rates and clinical implications of AF in MR are undefined. Methods We analyzed the occurrence of AF under conservative management in two populations of patients with degenerative MR in sinus rhythm at diagnosis: 1) 360 patients (65 ± 13 years, 74% men) with MR due to flail leaflets; and 2) 89 residents of Olmsted County, Minnesota (67 ± 17 years, 56% men) with grade 3 or 4 MR due to simple mitral valve prolapse (MVP) diagnosed echocardiographically. Results In patients with MR due to flail leaflets, AF rates at 5 and 10 years were 18 ± 3% and 48 ± 6%, respectively, and the linearized rate was 5.0 ± 0.7% per year. Development of AF during follow-up was independently associated with high risk of cardiac death or heart failure (adjusted risk ratio 2.23, p = 0.025). The AF rate at 10 years was higher in patients ≥65 years (75 ± 10% vs. 24 ± 6%, p 0.50) and predictors of AF (age and LA dimension, both p Conclusions In patients with degenerative MR in sinus rhythm at diagnosis, the incidence of AF occurring under conservative management is high and similar whether the cause of MR is flail leaflet or simple MVP. After onset of AF, an increased cardiac mortality and morbidity are both observed under conservative management. The risk of AF increases with advancing age and larger LA dimension. These data suggest that the clinical management of MR should take into account the high incidence, excess risk, and predictors of AF.

To determine the effects of insulin sensitization (IS) and insulin provision (IP) treatment strategies on adipokines associated with cardiovascular disease in patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (BARI 2D).Changes in adipokine levels were compared in patients with type 2 diabetes mellitus and coronary artery disease randomized to IS (n = 1037) versus IP (n = 1019) treatment strategies in BARI 2D. Circulating concentrations of leptin, adiponectin, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, interleukin 6 and C-reactive protein were evaluated at baseline and one year. IS and IP treatment strategies exerted significant (p 0.0001) differential effects on: leptin (IS: 0.02% decrease, p = 0.01; IP: 13% increase, p 0.0001); adiponectin (IS: 73% increase, p 0.0001; IP: no change, p = 0.52); interleukin 6 (IS: 14% decrease, p 0.0001; IP: no change, p = 0.68). Changes in monocyte chemoattractant protein-1 and tumor necrosis factor-alpha were not statistically different between groups. C-reactive protein decreased, but the effect was significantly greater in the IS group (-32%, p 0.0001) than in the IP group (-5%, p = 0.0005).The IS and IP treatment strategies exerted divergent effects on adipokine and inflammatory profile in patients with type 2 diabetes mellitus and coronary artery disease. The IS treatment strategy-induced changes may be more favorable than the IP treatment strategy regarding cardiovascular pathophysiology.

They point out that, in contrast to our results, previous pooled analyses of randomized trials of rosiglitazone showed a higher incidence of myocardial infarction, and that our observed differences (or rather lack of differences) in cardiovascular outcomes associated with rosiglitazone were potentially attributable to residual confounding. They also raise the point that we did not report a falsification end point that could have assessed the likelihood that observed results were more likely attributable to confounding than true effects. Our study reported prospectively collected longitudinal results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial cohort based on the diabetes mellitus treatment received, and was not a cross-sectional analysis. We agree that there is no substitute for randomization and no observational study, ours included, can fully exclude residual confounding. We should then also note the potential weaknesses of the meta-analysis that first implicated rosiglitazone as a cause of myocardial infarction, and reemphasize the unique aspects of the BARI 2D design and analysis that would be expected to minimize the impact of confounding. Even a well-conducted meta-analysis of limited studies will remain limited, because it is unable to compensate for the weaknesses of the original studies and may even unintentionally conceal those weaknesses. A carefully performed, independent examination of the meta-analysis regarding cardiovascular hazard from rosiglitazone concluded that the risk for myocardial infarction and death for diabetic patients taking rosiglitazone remained uncertain. 2 It is within this context that the BARI 2D design and results merit further consideration. In the BARI 2D trial, 3 patients were randomly assigned to a glycemic strategy of insulin sensitization or insulin provision. Therefore, initiation of rosiglitazone was generally determined by treatment assignment rather than patient indication, and the biases seen when the initiation of drug treatment is influenced by severity of illness were minimized. We used propensity-matching to further reduce any baseline differences when comparing treatment groups. Despite this, we did not detect a signal of ischemic cardiovascular harm from rosiglitazone. Similar conclusions were recently confirmed by a thorough FDA review of the independent readjudication of the 1 completed randomized trial designed to test the cardiovascular safety of rosiglitazone. 4

Atrial fibrillation (AF), the most common sustained cardiac rhythm disturbance, is increasing in prevalence as the population ages. Although it is often associated with heart disease, AF occurs in many patients with no detectable disease. Hemodynamic impairment and thromboembolic events result in significant morbidity, mortality, and cost. Accordingly, the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) created a committee of experts to establish guidelines for management of this arrhythmia. The committee was composed of 8 members representing the ACC and AHA, 4 representing the ESC, 1 from the North American Society of Pacing and Electrophysiology (NASPE), and a representative of the Johns Hopkins University Evidence-Based Practice Center representing the Agency for Healthcare Research and Quality’s report on Atrial Fibrillation in the Elderly. This document was reviewed by 3 official reviewers nominated by the ACC, 3 nominated by the AHA, and 3 nominated by the ESC, as well as by the ACC Clinical Electrophysiology Committee, the AHA ECG and Arrhythmia Committee, NASPE, and 25 reviewers nominated by the writing committee. The document was approved for publication by the governing bodies of the ACC, AHA, and ESC and officially endorsed by NASPE. These guidelines will be reviewed annually by the task force and will be considered current unless the task force revises or withdraws them from distribution. The committee conducted a comprehensive review of the literature from 1980 to June 2000 relevant to AF using the following databases: PubMed/Medline, EMBASE, the Cochrane Library (including the Cochrane Database of Systematic Reviews and the Cochrane Controlled Trials Registry), and Best Evidence. Searches were limited to English language sources and to human subjects. ### A. Atrial Fibrillation AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function. On the electrocardiogram (ECG), AF …

Acute coronary syndromes (ACS) are complications of atherosclerotic vascular disease that are triggered by the sudden rupture of an atheroma. Atherosclerotic plaque stability is determined by multiple factors, of which immune and inflammatory pathways are critical. Unstable plaque is characterized by an infiltrate of T cells and macrophages, thereby resembling a delayed hypersensitivity reaction. On activation, T cells secrete cytokines that regulate the activity of macrophages, or the T cells may differentiate into effector cells with tissue-damaging potential. Constitutive stimulation of T cells and macro-phages in ACS is not limited to the vascular lesion but also involves peripheral immune cells, suggesting fundamental abnormalities in homeostatic mechanisms that control the assembly, turnover, and diversity of the immune system as a whole. This review gives particular attention to the emergence of a specialized T-cell subset, natural killer T cells, in patients with ACS. Natural killer T cells have proinflammatory properties and the capability of directly contributing to vascular injury.

Objective Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) was a study of management strategies for diabetic patients with myocardial ischemia and coronary artery disease. In a 2 × 2 design, early revascularization versus medical management with or without late revascularization and insulin sensitization versus insulin provision were examined. No advantage for either strategy was seen, except in the group undergoing early coronary artery bypass grafting (CABG). In that group, a reduction in subsequent myocardial infarction was noted. The purpose of our report was to characterize the conduct and short-term outcomes for CABG that led to this result. Methods Data from the BARI 2D CABG stratum were collected, including the baseline demographic and cardiovascular characteristics, technical details of the operation, and perioperative morbidity and mortality, and analyzed. Results A total of 347 patients were studied. The average cardiac function was normal, and most had multivessel disease. Almost all had undergone CABG by way of a median sternotomy using an internal mammary artery, and one third were off pump. The perioperative morbidity and mortality were low and compared well with larger outcomes databases. Conclusions BARI 2D showed that early CABG in patients with type 2 diabetes and myocardial ischemia and multivessel disease reduced the subsequent myocardial infarction rates. The present results have demonstrated that this was achieved using off-pump surgery in certain cases, standard myocardial protection, and routine use of the internal mammary artery or other arterial grafts.