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Left Bundle Branch Block (LBBB) is a frequently encountered electrical abnormality in patients with chronic (more than 3 months after myocardial infarction, or evidence of coronary artery disease with ischemia) coronary syndromes (CCS), but its prognostic significance remains unclear. We aimed to describe the prevalence, incidence and five-year outcomes of LBBB in outpatients with CCS using the CLARIFY registry. Main outcome was a composite of CV death, MI or stroke. Secondary outcomes included all cause death, hospitalization for heart failure (HF) and permanent pacemaker implantation. Among 23.544 patients with available information regarding LBBB status at baseline, 1.041 (4.4%) had LBBB at baseline and 1.015 (4.5%) patients developed a new LBBB during 5-year follow-up. In multivariate analysis, LBBB at baseline was not associated with the composite outcome of CV death, MI or stroke (HR 1.06, 95% CI [0.86 - 1.31], p = 0.67) or the risk of all-cause death (HR 1.07, 95% CI [0.87 - 1.32], p = 0.52) but was significantly associated with a higher risk of hospitalization for HF (HR 1.50, 95% CI [1.21 - 1.88], p < 0.001) and permanent pacemaker implantation (HR 2.11, 95% CI [1.45 - 3.07], p < 0.001). The main factors associated with new-onset LBBB were male sex (HR 0.8 [0.66-0.98], p = 0.028) history of atrial fibrillation (HR 1.29, 95% CI [1.01 - 1.64], p = 0.04), CABG (HR 1.27, [1.08 - 1.51], p = 0.004) and MI (HR 1.19, 95% CI [1.01 - 1.40], p = 0.034). In conclusion, in a contemporary registry of outpatients with CCS, the prevalence of LBBB was 4.4% and the additional 5-years incidence 6.2%. LBBB, in itself, was not associated with a higher risk of major adverse cardiovascular events or all cause mortality. It was however an independent predictor of risk of hospitalization for heart failure and permanent pacemaker implantation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome., Research Design and Methods: In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A 1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A 1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random)., Results: At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes., Conclusions: In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib., (© 2020 by the American Diabetes Association.)

Background: High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS)., Methods: The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment., Results: Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P = .81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment., Conclusions: Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS., (Published by Elsevier Inc.)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition by monoclonal antibodies has been shown to reduce low density lipoprotein (LDL-C) but its effects on cardiovascular (CV) outcomes have not been fully described. The aim of this study is to assess the impact of PCSK9 inhibition on mortality and CV outcomes by pooling data from all available randomized clinical trials (RCT) of PCSK9 inhibitors. We conducted a comprehensive search of electronic databases, up to December 1, 2018, for all RCTs comparing PCSK9 inhibition to placebo or ezetimibe in patients with hypercholesterolemia or coronary artery disease receiving maximally tolerated statin for primary or secondary prevention of mortality and cardiovascular outcomes. We used random-effects meta-analyses to summarize the studies. We retained 23 RCTs having included 88,041 patients in primary and secondary prevention. The follow-up ranged from 6 to 36 months. PCSK9 inhibition was not significantly associated with reductions in total mortality (odds ratio [OR] 0.91, 95% confidence interval [CI] 078 to 1.06; p = 0.22) and CV mortality (OR 0.95, 95% CI 0.84 to 1.07; p = 0.37). In contrast, PCSK9 inhibition was associated with reductions in myocardial infarction (OR 0.80, 95% CI 0.71 to 0.91; p <0.0001), stroke (OR 0.75, 95% CI 0.65 to 0.85; p <0.0001), and coronary revascularization (OR 0.82, 95% CI 0.77 to 0.88; p <0.0001). In conclusion, PCSK9 inhibition was associated with reductions in myocardial infarction, stroke, and coronary revascularization. Future analyses may identify high-risk patients who may benefit more from these agents and longer follow-up of current or new trials may show a mortality benefit., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD., Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events., Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints., Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Blood lipids are important modifiable risk factors for coronary heart disease and various drugs have been developed to target lipid fractions. Considerable efforts have been made to identify genetic variants that modulate responses to drugs in the hope of optimizing their use. Pharmacogenomics and new biotechnologies now allow for meaningful integration of human genetic findings and therapeutic development for increased efficiency and precision of lipid-lowering drugs. Polygenic predictors of disease risk are also changing how patient populations can be stratified, enabling targeted therapeutic interventions to patients more likely to derive the highest benefit, marking a shift from single variant to genomic approaches in pharmacogenomics.

Background: Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk., Methods and Results: To address this question, we examined data from the dal-OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF <40%), III, or IV HF were excluded. Aldosterone was measured at randomization in 4073 patients. The primary outcome was a composite of coronary heart disease death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. Hospitalization for HF was a secondary endpoint. Over a median follow-up of 37 months, the primary outcome occurred in 366 patients (9.0%), and hospitalization for HF occurred in 72 patients (1.8%). There was no association between aldosterone and either the time to first occurrence of a primary outcome (hazard ratio for doubling of aldosterone 0.92, 95% confidence interval 0.78-1.09, P=0.34) or hospitalization for HF (hazard ratio 1.38, 95% CI 0.96-1.99, P=0.08) in Cox regression models adjusted for covariates., Conclusions: In patients with recent acute coronary syndrome but without advanced HF, aldosterone does not predict major cardiovascular events., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00658515., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

We studied the relationship between cardiovascular status (CV) and risk factor numbers, macrovascular (flow mediated dilatation: FMD) and microvascular function using near-infrared spectroscopy (NIRS) in adults with different CV status. Seventy adults with different CV status (27 controls, 18 metabolic syndrome (MetS) and 25 coronary heart disease (CHD) patients) underwent a 5-min forearm arterial occlusion in supine position. High-resolution ultrasound examination of the brachial artery was performed during 1 minute at rest and 45 to 120 seconds after cuff release. Oxy, de-oxy and total hemoglobin signals (O2Hb, HHb and tHb) were measured continuously with NIRS on brachio-radialis muscle. FMD was reduced in CHD patients (P<0.05) compared to controls. Max. amplitude of O2Hb and Hmax of tHb were reduced (P<0.05) in MetS patients vs. controls. Post-deflation area under the curve (A.U.C) of O2Hb was lower in CHD (P<0.01) patients vs. controls and MetS patients. Independent predictors of microvascular function (A.U.C of O2Hb) were abdominal obesity and LDL-cholesterol whereas macrovascular function (FMD) was predicted by CV status. Only A.U.C of O2Hb related to CV risk numbers whereas FMD was not. Although macro and microvascular function were impaired in MetS and CHD patients, microvascular function was more strongly related to CV risk factors.

Clinical trials have not provided evidence for a role of statin therapy in reducing aortic valve stenosis (AVS) severity in patients with documented AVS. However, whether statin therapy could prevent the onset of AVS is unknown. Our objectives were (1) to compare the incidence rates of AVS among patients treated with high-dose versus usual-dose statin or placebo and (2) to identify clinical risk factors associated with the development of AVS. We conducted post hoc analyses in 23,508 participants from 3 large-scale multicenter atorvastatin randomized blinded clinical trials: Treating to New Targets, the Incremental Decrease in End Points Through Aggressive Lipid Lowering, and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels. The main outcome measure was the incidence of clinical AVS over a median follow-up of 4.9 years (82 cases). Among patients who developed AVS, 39 (47.6%) were treated with atorvastatin 80 mg and 43 (52.4%) were treated with lower dose statin (atorvastatin 10 mg in Treating to New Targets, simvastatin 20 to 40 mg in Incremental Decrease in End Points Through Aggressive Lipid Lowering, or placebo in Stroke Prevention by Aggressive Reduction in Cholesterol Levels; hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.59 to 1.41, p=0.67). In multivariate analyses forcing treatment, sex, and race into the model, factors that were significantly associated with AVS included age (HR 2.17, 95% CI 1.61 to 2.93, p<0.0001 per 1-SD increment), diabetes (HR 1.67, 95% CI 1.00 to 2.80, p=0.05), vitamin K antagonist use (HR 3.25, 95% CI 2.06 to 5.16, p<0.0001), and previous statin use (HR 2.65, 95% CI 1.54 to 4.60, p=0.0008). In conclusion, random allocation to high-dose versus usual-dose statin therapy or placebo did not impact the incidence of AVS among patients without known AVS. Age, diabetes, vitamin K antagonists, and previous statin use were significant predictors of incident AVS in these high-risk patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: High-intensity interval exercise (HIIE) is gaining in popularity in fitness centres, even among coronary heart disease (CHD) patients. However, whether HIIE can have deleterious acute effects on the vasculature in CHD has not been studied. We hypothesized that when compared with moderate-intensity continuous exercise (MICE), a single bout of HIIE could lead to vascular damage and increasing numbers of circulating endothelial and platelet microparticles (EMPs, PMPs) in stable, physically fit CHD patients., Methods: Nineteen male CHD patients (aged 62 ± 11 years) underwent, in random order, a single session of HIIE corresponding to 15-second intervals at 100% of peak power output and 15-second passive recovery intervals, and an isocaloric MICE session. EMPs (CD31+ and/or CD62E+ and CD42b-); PMPs (CD42b+); nitrates and nitrites; prostacycline; and troponin T, cardiac form (cTnT), were measured 10 minutes before exercise and 20 minutes, 24 hours, and 72 hours after both exercise sessions., Results: EMPs, PMPs, nitrates and nitrites, prostacycline, and cTnT remained unchanged after both HIIE and MICE exercise sessions. Initial EMP concentration correlated inversely with EMP concentration 20 minutes post exercise, irrespective of exercise modality (r = 0.78, P < 0.0001)., Conclusions: A single HIIE session with very short exercise and passive recovery periods appears safe and does not induce changes to markers of endothelial function. Future studies are required to determine the safety of a long-term HIIE training program., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Coronary computed tomography angiography has become the foremost noninvasive imaging modality of the coronary arteries and is used as an alternative to the reference standard, conventional coronary angiography, for direct visualization and detection of coronary artery stenoses in patients with suspected coronary artery disease. Nevertheless, there is considerable debate regarding the optimal target population to maximize clinical performance and patient benefit. The most obvious indication for noninvasive coronary computed tomography angiography in patients with suspected coronary artery disease would be to reliably exclude significant stenosis and, thus, avoid unnecessary invasive conventional coronary angiography. To do this, a test should have, at clinically appropriate pretest likelihoods, minimal false-negative outcomes resulting in a high negative predictive value. However, little is known about the influence of patient characteristics on the clinical predictive values of coronary computed tomography angiography. Previous regular systematic reviews and meta-analyses had to rely on limited summary patient cohort data offered by primary studies. Performing an individual patient data meta-analysis will enable a much more detailed and powerful analysis and thus increase representativeness and generalizability of the results. The individual patient data meta-analysis is registered with the PROSPERO database (CoMe-CCT, CRD42012002780)., Methods/design: The analysis will include individual patient data from published and unpublished prospective diagnostic accuracy studies comparing coronary computed tomography angiography with conventional coronary angiography. These studies will be identified performing a systematic search in several electronic databases. Corresponding authors will be contacted and asked to provide obligatory and additional data. Risk factors, previous test results and symptoms of individual patients will be used to estimate the pretest likelihood of coronary artery disease. A bivariate random-effects model will be used to calculate pooled mean negative and positive predictive values as well as sensitivity and specificity. The primary outcome of interest will be positive and negative predictive values of coronary computed tomography angiography for the presence of coronary artery disease as a function of pretest likelihood of coronary artery disease, analyzed by meta-regression. As a secondary endpoint, factors that may influence the diagnostic performance and clinical value of computed tomography, such as heart rate and body mass index of patients, number of detector rows, and administration of beta blockade and nitroglycerin, will be investigated by integrating them as further covariates into the bivariate random-effects model., Discussion: This collaborative individual patient data meta-analysis should provide answers to the pivotal question of which patients benefit most from noninvasive coronary computed tomography angiography and thus help to adequately select the right patients for this test.

Aims/hypothesis: We sought to understand the relationships between glycaemic status and both severity and progression of coronary artery disease (CAD), the leading cause of death in diabetes., Methods: Baseline fasting blood glucose (FBG) and HbA1c (%)were measured in 426 patients with known or suspected stable CAD, who underwent coronary artery intravascular ultrasound(IVUS) at baseline and after a mean follow-up period of 664 days (range 257 to 961). The patients were categorised as normoglycaemic (n=226, 53%), or as having impaired fasting glucose (n=118, 28%) or diabetes (n=82, 19%)., Results: The maximum percentage coronary atheroma area at baseline was greater in diabetic patients (73.33+/-8.86%) than in those with normoglycaemia (69.08+/-10.43%; p=0.001) and impaired fasting glucose (69.32+/-9.59%; p=0.0031). In averaged IVUS measurements of the 30-mm target segment(n=332 participants), change in percentage atheroma area during follow-up was also greater in the diabetes (1.86+/-3.90%) than in other groups (0.28+/-3.32% and 0.56+/-2.96%,p=0.0047 global). FBG correlated with maximum percentage atheroma area at baseline (r=0.17; p=0.0003). HbA1c also correlated with maximum percentage atheroma area at baseline (r=0.26; p=0.0001) and with change in maximum plaque area (r=0.16; p=0.016). A similar pattern of results occurred with plaque volume. The relationships between diabetes or HbA1c and both IVUS measurements of plaque burden and remodelling persisted after adjustment., Conclusions/interpretation: Fasting blood glucose, HbA1c and the presence of diabetes are associated with the severity and progression of coronary atherosclerosis. These observations support the hypothesis that better glycaemic control may favourably influence CAD in patients with abnormal glucose tolerance or diabetes.

Background: Although several epidemiological studies demonstrate the association between resting heart rate (HR) and cardiovascular morbidity and mortality, an elevated HR remains a neglected cardiovascular risk factor., Sources of Data: This review summarizes the results of published studies on the relationship between elevated HR and cardiovascular risk., Areas of Agreement: The role of HR in myocardial ischaemia in coronary patients is well known. Experimental data and clinical observations support the importance of HR in the pathophysiology of atherosclerosis and plaque rupture. A large body of evidence points to high resting HR as a risk factor for mortality in various populations, including coronary patients., Areas of Controversy: HR reduction is suggested to be a mechanism explaining the prognostic benefit of beta-blockers after myocardial infarction or in heart failure patients. However, it was unclear whether HR reduction per se directly affects cardiovascular prognosis. Treatment with ivabradine, a pure HR-reducing agent, provides an opportunity to assess the effects of selectively lowering HR without altering other aspects of cardiac function., Growing Points: The results of the recent Morbidity-Mortality Evaluation of the I(f) Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction study underline the importance of HR reduction in the management of stable coronary artery disease. The prospective analysis of data from the placebo arm demonstrated that elevated resting HR (>or=70 bpm) is a strong independent predictor of clinical outcomes. Consistent with these data, ivabradine significantly improved coronary outcomes in patients with a HR of 70 bpm or more. AREAS TIMELY FOR DEVELOPMENT: These data support the importance of HR in the management of stable coronary artery disease to assess prognosis and to guide optimal therapy.

Background: Coronary artery bypass graft (CABG) surgery is effective in relieving angina and improving survival and quality of life in patients with obstructive coronary artery disease; however, recurrent angina, myocardial infarction, neurological injury, and death can occur in the perioperative and postoperative period. MC-1 (pyridoxal 5'-phosphate) is a novel agent that has shown promise in reducing myocardial necrosis by reducing cellular calcium overload after percutaneous coronary intervention and CABG surgery in high-risk patients undergoing these procedures., Methods: MEND-CABG II is a phase III study evaluating the efficacy and safety of MC-1 in reducing cardiovascular morbidity and mortality after CABG. High-risk patients undergoing CABG surgery will be randomly assigned to receive either MC-1 (250 mg/d) or matching placebo immediately before and continuing for 30 days after the procedure. The primary end point is the occurrence of cardiovascular death or nonfatal myocardial infarction through postoperative day 30. A total of 3023 patients were enrolled at 130 sites in Canada, the United States, and Germany between October 2006 and September 2007, with results anticipated shortly after completion of 90-day follow-up in March 2008., Conclusions: The data from the MEND-CABG II trial will establish whether peri- and postoperative treatment with MC-1 can decrease the short- and intermediate-term morbidity and mortality of high-risk patients undergoing CABG surgery.

Background: We assessed racial differences in lipoprotein particle size, a marker of atherosclerosis risk, among women with coronary disease., Methods: We studied 378 women (33% non-White, predominantly African American) at the baseline visit of the Women's Angiographic Vitamin and Estrogen Trial (WAVE), a multicenter trial of hormone replacement and antioxidant vitamin therapy in postmenopausal women with established coronary artery disease. Average particle sizes for high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein were measured by nuclear magnetic resonance in these women, and angiography was performed at baseline and followup., Results: Adjusted for age, race, diabetes, smoking, blood pressure, and use of lipid-lowering and antihypertensive medications, non-White women had larger LDL particle size (difference .2 nm, 95% CI .1-.3 nm) and HDL particle size (difference.2 nm, 95% CI .1-.2 nm). Neither angiographic disease progression nor survival without myocardial infarction (median follow-up time of 2.8 years) was associated with lipoprotein particle size or race., Conclusions: Non-White women have a less atherogenic profile of lipoprotein particle sizes than do White women. However, this difference did not affect event-free survival or angiographic progression of coronary atherosclerosis.

Background: Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib., Methods: We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina., Results: At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P<0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change., Conclusions: Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, NCT00134264 [ClinicalTrials.gov].)., (Copyright 2007 Massachusetts Medical Society.)

Although diabetic patients represent approximately one-quarter of all those undergoing revascularization, their outcomes after revascularization are usually worse compared with non-diabetic patients. We examined the recent advances in percutaneous and surgical revascularization that are relevant to the treatment of diabetic patients. A systematic review of publications in the past 5 years (2000 to 2005) relating to coronary revascularization in diabetes was undertaken. Early and mid-term follow-up of diabetic patients after revascularization indicates that the incidence of myocardial infarction and repeat revascularization are reduced in surgically treated patients compared with those treated by balloon angioplasty alone. Percutaneous coronary intervention (PCI) with bare metal stents has reduced the surgical advantage (for reintervention) in the early-mid-term; however, repeat revascularization in diabetic patients continues to be substantially higher after PCI. Advances in PCI include the use of drug-eluting stents and adjunctive drug therapies, such as abciximab. Glycemic control is an important determinant of outcome after revascularization in diabetic patients, and the impact of tight glycemic control after PCI is currently being investigated in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 in Diabetes). Improvements in PCI and coronary artery bypass graft surgery are leading to better results in diabetic patients, and clinical trials are presently comparing contemporary PCI with surgery.

Diabetes mellitus (DM) is a worldwide epidemic. Its prevalence is rapidly increasing in both developing and developed countries. Coronary heart disease (CHD) is highly prevalent and is the major cause of morbidity and mortality in diabetic patients. The purpose of this review is to assess the clinical impact of recent advances in the epidemiology, prevention, and management of CHD in diabetic patients. A systematic review of publications in this area, referenced in MEDLINE in the past 5 years (2000 to 2005), was undertaken. Patients with CHD and prediabetic states should undergo lifestyle modifications aimed at preventing DM. Pharmacological prevention of DM is also promising but requires further study. In patients with CHD and DM, routine use of aspirin and an angiotensin-converting enzyme inhibitor (ACE-I)--unless contraindicated or not tolerated-and strict glycemic, blood pressure, and lipid control are strongly recommended. The targets for secondary prevention in these patients are relatively well defined, but the strategies to achieve them vary and must be individualized. Intense insulin therapy might be needed for glycemic control, and high-dose statin therapy might be needed for lipid control. For blood pressure control, ACE-Is and angiotensin receptor blockers are considered as first-line therapy. Noncompliance, particularly with lifestyle measures, and underprescription of evidence-based therapies remain important unsolved problems.

Heart rate reduction is a well accepted and effective approach for the prevention of angina pectoris. Ivabradine is the first selective and specific inhibitor of the I(f) current and provides pure heart rate reduction without altering myocardial contractility. Clinical evidence of the antianginal and anti-ischaemic efficacy and tolerability of ivabradine comes from the largest clinical development programme that has ever been performed in stable angina pectoris, involving more than 5000 patients. Ivabradine at the dosages of 5 or 7.5mg twice daily is as effective as reference antianginal approaches such as beta-adrenoceptor antagonists and calcium channel antagonists. The clinical efficacy and safety of ivabradine has also been confirmed in a 1-year follow-up study. Ivabradine is well tolerated and free from the most commonly observed adverse effects of currently prescribed antianginal drugs. Visual symptoms can occur in a minority of patients treated with ivabradine and are not associated with structural ocular changes. The ongoing clinical development programme with the two major morbidity-mortality studies, BEAUTIFUL and SHIfT, has the potential to greatly extend the use of ivabradine in patients with coronary artery disease as well as in those with heart failure.

Clinical trials indicate that hormone therapy (HT) does not decrease cardiovascular disease events or angiographic coronary disease progression. The effects of HT on SVG vessels are unknown. To determine whether postmenopausal hormone therapy started after coronary bypass surgery (CABG) decreases saphenous vein graft (SVG) disease, we conducted a multicenter randomized placebo-controlled angiographic study of estradiol+/-medroxyprogesterone started within 6 months of CABG in 83 postmenopausal women. Angiographic and intravascular ultrasound (IVUS) assessment at 6 and 42 months was planned to assess SVG disease progression. The study was stopped early following publication of the Women's Health Initiative Estrogen/Progestin study. Eighty-three subjects underwent a 6-month angiogram with 63 undergoing IVUS. Forty-five subjects completed the 42-month angiogram (20 underwent 42-month IVUS). In analysis of paired 6- and 42-month angiogram and IVUS studies, HT slowed angiographic progression of SVG disease assessed by mean percent stenosis (p<0.001), minimal lumen diameter (p=0.029), and total plaque volume (p=0.006). In contrast, HT accelerated disease progression in non-bypassed native coronary arteries (minimum lumen diameter, p=0.01). SVG disease and closure occurred in 38% subjects within 1-year post-CABG. The groups had similar frequency of cardiovascular events expect for angioplasty that occurred in eight HT compared to one placebo subject (p<0.05). In HT subjects angioplasty was indicated for native coronary arterial stenoses while in the placebo subject angioplasty was indicated for SVG stenosis. This study suggests that hormone treatment may slow SVG disease progression while accelerating atherosclerosis in non-bypassed native coronary arteries.

Background: The metabolic syndrome confers an increased risk of major cardiovascular events in individuals initially free from coronary heart disease (CHD). Presently, approximately 25% of the US population possesses the metabolic syndrome as defined using the National Cholesterol Education Program (NCEP) criteria. We sought to assess the impact of the metabolic syndrome and its individual components on intermediate-term and long-term outcomes in patients with CHD., Methods: The CASS registry represents a database of 24,958 patients with suspected or proven CHD who underwent cardiac catheterization between 1974 and 1979. Mean long-term follow-up was 12.6 +/- 5.1 years. Metabolic syndrome was defined using modified definitions of the NCEP and World Health Organization (WHO) because high-density lipoprotein cholesterol measures were not available., Results: We identified 3279 and 1080 patients with metabolic syndrome using our modified NCEP and WHO definitions, respectively. Adjusted long-term all-cause death was higher in patients with metabolic syndrome (hazard ratio [HR] 1.21, 95% CI 1.14-1.29; HR 1.56, 95% CI 1.43-1.70 for NCEP and WHO criteria, respectively). Similarly, long-term adjusted risk of cardiovascular death and intermediate-term risk of morbidity and mortality were higher in patients with the metabolic syndrome. Fasting blood glucose > or = 110 mg/dL was responsible for most of the increased risk associated with the metabolic syndrome (adjusted HR 1.47, 95% CI 1.39-1.56)., Conclusions: The metabolic syndrome confers a higher risk of long-term death in patients with preexisting CHD, and dysglycemia appears to be responsible for most of the associated risk.

The time course and differential effects of statin regimens on endothelial function after acute coronary syndromes (ACSs) are unknown and could contribute to the superiority of a more intense strategy. A subset of subjects who were enrolled in the PROVE IT-TIMI 22 trial (n = 50) underwent evaluation of vascular reactivity by high-resolution brachial ultrasound. Endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent sublingual nitroglycerin-mediated dilation (NMD) were measured at baseline and at 48 hours, 1 month, and 4 months after the initiation of 40 mg of pravastatin (n = 26) or 80 mg of atorvastatin (n = 24). After 4 months, low-density lipoprotein cholesterol was decreased by 32% in the atorvastatin group but was not different from baseline after ACS in the pravastatin group. C-reactive protein decreased similarly in the 2 groups. Brachial artery diameters at rest were similar in the 2 groups and at each time point of the trial. FMD and NMD increased significantly after 4 months by 27% and 24%, respectively (p <0.05), with no difference between groups. There was no correlation between the change in FMD and the change in lipids or C-reactive protein. In subjects who had received previous statin therapy (n = 15), there was no significant variation in FMD (p = 0.140) and NMD (p = 0.129). In conclusion, initiation of statin therapy soon after ACS is associated with improvements in endothelium-dependent and independent vascular reactivities after 4 months.

Endothelial dysfunction and large artery stiffness occur in patients with risk factors for coronary artery disease (CAD) and in those with established CAD. We evaluated the relation between endothelial function and conduit vessel distensibility in normal subjects, in patients with documented stable CAD, and in patients demonstrating only risk factors but no overt atherosclerosis. Endothelium-dependent dilatation was evaluated by way of flow-mediated dilatation of the brachial artery using high-resolution ultrasound. Large artery stiffness was assessed using tonometry. After adjusting for age and intergroup differences, percent flow-mediated dilatation showed statistically significant correlations with several measures of stiffness, including central pulse pressure (r = -0.457, p = 0.019), central systolic pressure (r = -0.442, p = 0.024), peripheral pulse pressure (r = -0.393, p = 0.039), peripheral systolic pressure (r = -0.398, p = 0.036), and proximal aortic compliance (r = 0.390, p = 0.049). Measures of arterial stiffness correlate significantly with those of endothelial function. An increase in large conduit vessel stiffness may represent either a cause or consequence of endothelial dysfunction and may explain why elevated pulse pressure is a new cardiovascular risk factor.

Background: The value of stress harmonic power Doppler imaging (HPDI) for the evaluation of myocardial perfusion has never been assessed in patients after acute coronary syndrome (ACS)., Objective: To evaluate the agreement between stress HPDI and single photon emission computed tomography (SPECT) imaging for the assessment of myocardial perfusion after unstable angina or myocardial infarction., Patients and Methods: Thirty patients with a recent ACS underwent HPDI and SPECT. Images were obtained at rest and during dipyridamole infusion (0.56 mg/kg over 4 min). Apical two- and four-chamber views were used for HPDI. Ten myocardial segments were scored for myocardial perfusion. Semiquantitative and quantitative video intensity analysis with background subtraction were performed., Results: Concordance by patients between quantitative HPDI and SPECT was 76% (kappa=0.40, Phi=0.46) for normal versus abnormal perfusion. When semiquantitative analysis was used, concordance was 72% (kappa=0.42, Phi=0.46). Agreement between methods was best in the left anterior descending artery territory for quantitative (80%) (kappa=0.60, Phi=0.60) and semiquantitative analysis (78%) (kappa=0.51, Phi=0.60) for normal versus abnormal perfusion. Discrepancies between HPDI and SPECT were most important in the circumflex territory, with a concordance of 59% (kappa=0.22) for identification of normal perfusion versus irreversible and reversible defects., Conclusions: These results suggest that HPDI can detect myocardial perfusion at rest and during pharmacological stress in patients after a recent ACS. Given the suboptimal agreement with SPECT, further advances are required before the routine use of contrast echocardiography is possible for the assessment of myocardial perfusion.

This review article focuses on the morphological and functional alterations that characterize patients with myocardial bridges (MB) as well as the currently available diagnostic and treatment strategies. Because of incomplete understanding of the pathophysiology of MB, their clinical significance has been the subject of debate for the last quarter century. Investigational tools now available in the cardiac catheterization laboratory have helped clarify why symptoms and signs of ischemia can occur in such patients, especially when the only angiographic finding appears to be systolic compression or milking effect of a coronary vessel. Quantitative coronary angiography and intravascular ultrasound (IVUS) clearly demonstrate that the phasic systolic vessel compression visualized on the angiogram is coupled with a persistent diastolic diameter reduction. Intracoronary Doppler reveals increased flow velocities, retrograde systolic flow, and reduced coronary flow reserve. The clinical diagnosis can be established by significant percent lumen diameter and area narrowing, increased flow velocity, and by characteristic patterns such as the "half moon" phenomenon on IVUS and the early diastolic "finger tip" phenomenon on intracoronary Doppler. Successful medical, interventional, or surgical therapy leads not only to marked improvement or normalization of these alterations but also relief of angina and ischemia.

The Women's Angiographic Vitamin and Estrogen trial was a randomized, double-blind, placebo-controlled study designed to test the efficacy of estrogen replacement and antioxidant vitamins for preventing angiographic progression of coronary artery disease. Postmenopausal women with one or more angiographically documented coronary stenoses of 15-75% at baseline were assigned in a 2 x 2 factorial randomization to active hormone replacement therapy (conjugated estrogens for women who had had a hysterectomy or conjugated estrogens with medroxyprogesterone for women with intact uteri) or placebo and to active vitamins E and C or their placebos. Seven clinical centers, five in the United States and two in Canada, randomized 423 women between July 1997 and July 1999. Quantitative coronary angiography was performed at baseline and repeated after projected mean follow-up of 3 years.

Background: It has been shown in the MultiVitamins and Probucol (MVP) trial that probucol reduces angiographic lumen loss by 68% after percutaneous transluminal coronary angioplasty (PTCA). Restenosis occurred in 40% of patients not treated with probucol and in 20% of those in the probucol alone group., Objective: To determine the morphological predictors of restenosis in patients treated with probucol., Patients and Methods: Beginning 30 days before angioplasty, 317 patients were randomly assigned to receive probucol, multivitamins, the combined treatment or placebo. Patients were then treated for six months after angioplasty. Intravascular ultrasound (IVUS) examination was performed immediately after angioplasty and at follow-up in 94 patients (108 segments). The angioplasty operator was blinded to the IVUS results. The cross-section selected for serial analysis was the one at the angioplasty site with the smallest lumen area at follow-up. Receiver operating characteristic curves were used to determine the performance of criteria to predict angiographic restenosis at follow-up., Results: In probucol-treated patients, the cross-sectional area (CSA) narrowing of 67.6% or less was the best IVUS predictor for the absence of restenosis (P=0.03). Diameter stenosis of 35% or less almost reached significance as a predictor in these patients (P=0.056). The restenosis rate when either of these predictors was met was less than 13%. Rates of repeat PTCA in patients treated with probucol were 9.7% when CSA narrowing was 67.6% or less on IVUS and 3.1% with a post-PTCA stenosis of 35% or less on quantitative coronary angiography (QCA). No predictor of the absence of restenosis in patients not treated with probucol was identified., Conclusions: The presence after balloon angioplasty of a CSA narrowing of 67.6% or less on IVUS or a diameter stenosis of 35% or less on QCA is associated, in patients treated with probucol, with extremely low rates of coronary restenosis and repeat angioplasty.

Background: The treatment of unstable angina targets the specific pathophysiological thrombotic process at the site of the active culprit lesion. In unstable angina due to a restenotic lesion, smooth muscle cell proliferation and increased vasoreactivity may play a more important role than thrombus formation. Therefore, the relative benefits of nitroglycerin and heparin might differ in unstable angina associated with restenosis compared with classic unstable angina., Methods and Results: We randomized 200 patients hospitalized for unstable angina within 6 months after angioplasty (excluding those with intracoronary stents) to double-blind administration of intravenous nitroglycerin, heparin, their combination, or placebo for 63+/-30 hours. Recurrent angina occurred in 75% of patients in the placebo and heparin-alone groups, compared with 42.6% of patients in the nitroglycerin-alone group and 41.7% of patients in the nitroglycerin-plus-heparin group (P<0.003). Refractory angina requiring angiography occurred in 22.9%, 29.2%, 4. 3%, and 4.2% of patients, respectively (P<0.002). The odds ratios for being event free were 0.24 (95% CI, -0.13 to 0.45, P=0.0001) for nitroglycerin versus no nitroglycerin and 0.98 (95% CI, -0.55 to 1. 73, P=NS) for heparin versus no heparin. No patient died or suffered myocardial infarction., Conclusions: Intravenous nitroglycerin is highly effective in preventing adverse ischemic events (recurrent or refractory angina) in patients with unstable angina secondary to restenosis, whereas heparin has no effect.

Background: Cholesterol lowering reduces coronary events. One mechanism could be improvement of endothelial function. In line with this hypothesis, this study investigates whether cholesterol reduction can result in rapid improvement of endothelial function after acute coronary syndromes., Methods and Results: Patients with acute myocardial infarction or unstable angina and total cholesterol levels at admission >/=5.2 mmol/L or LDL >/=3.4 mmol/L were randomized to placebo (n=30) or pravastatin 40 mg daily (n=30) for 6 weeks. Brachial ultrasound was used to measure endothelium-dependent flow-mediated dilatation (FMD) and response to endothelium-independent nitroglycerin. Changes in the levels of markers of platelet activation, coagulation factors, and plasma endothelin levels were also assessed. Total and LDL cholesterol levels were similar at admission and before randomization in both groups. With pravastatin, but not with placebo, they decreased by 23% (P<0.05) and 33% (P<0.01), respectively. FMD was unchanged with placebo, 5.43+/-0.74% (mean+/-SEM) to 5.84+/-0.81%, but increased with pravastatin, 4.93+/-0.81% to 7.0+/-0.79% (P=0.02), representing a 42% relative increase. Responses to nitroglycerin were similar during the time course of the study in the 2 groups. Markers of platelet activity, coagulation factors, and endothelin levels were not affected by pravastatin., Conclusions: Cholesterol reduction with pravastatin initiated early after acute coronary syndromes rapidly improves endothelial function after 6 weeks of therapy.

Recently, the use of ionizing radiations has received much interest as a new treatment tool to reduce restenosis after angioplasty or stent implantation. There are two main approaches for delivering endovascular radiation: one is based on gamma or beta sources with very high activities to deliver locally through a catheter the dose in a limited period of time. The other approach is based on a stent rendered radioactive for long exposure and continuous low-dose rate treatment. External radiation is also contemplated but indications seem more oriented towards the peripheral vascular system. After a brief introduction to fundamentals of radiobiology, radiation physics and radioprotection, we review the experimental data which have led to large ongoing multicenter trials. The results of these trials involving more than 2000 patients will be available in the next few years and will allow to better define the risk/benefit ratio of this potentially new indication for radiotherapy.

Background: Restenosis remains the major limitation of coronary angioplasty. Coronary stents have reduced the incidence of restenosis in selected patients with relatively large vessels. No strategies to date have demonstrated a beneficial effect in vessels < 3.0 mm in diameter. We have shown in the MultiVitamins and Probucol (MVP) Trial that probucol, a potent antioxidant, reduces restenosis after balloon angioplasty. The purpose of this study was to determine whether the benefit of probucol therapy is maintained in the subgroup of patients with smaller coronary vessels., Methods and Results: We studied a subgroup of 189 patients included in the MVP trial who underwent successful balloon angioplasty of at least one coronary segment with a reference diameter < 3.0 mm. One month before angioplasty, patients were randomly assigned to one of four treatments: placebo, probucol (500 mg), multivitamins (beta-carotene 30000 IU, vitamin C 500 mg, and vitamin E 700 IU), or probucol plus multivitamins twice daily. The treatment was maintained until follow-up angiography was performed at 6 months. The mean reference diameter of this study population was 2.49+/-0.34 mm. Lumen loss was 0.12+/-0.34 mm for probucol, 0.25+/-0.43 mm for the combined treatment, 0.35+/-0.56 mm for vitamins, and 0.38+/-0.51 mm for placebo (P=.005 for probucol). Restenosis rates per segment were 20.0% for probucol, 28.6% for the combined treatment, 45.1% for vitamins, and 37.3% for placebo (P=.006 for probucol)., Conclusions: Probucol reduces lumen loss and restenosis rate after balloon angioplasty in small coronary arteries.

Background: Oxidizing metabolites generated at the site of coronary angioplasty can induce chain reactions that may lead to restenosis. Antioxidants may counter oxidative stress and modify neointimal formation and vascular remodeling. Experimental data and small clinical studies have suggested that antioxidants may prevent restenosis after angioplasty. In a double-blind, randomized trial, we studied whether drugs with antioxidant properties decrease the incidence and severity of restenosis after angioplasty., Methods: One month before angioplasty, 317 patients were randomly assigned to receive one of four treatments: placebo, probucol (500 mg), multivitamins (30,000 IU of beta carotene, 500 mg of vitamin C, and 700 IU of vitamin E), or both probucol and multivitamins-all given twice daily. Patients were treated for four weeks before and six months after angioplasty. Patients received an extra 1000 mg of probucol, 2000 IU of vitamin E, both probucol and vitamin E, or placebo 12 hours before angioplasty, according to their treatment assignments. Base-line and follow-up angiograms were interpreted by blinded investigators using a quantitative approach., Results: The mean (+/-SD) reduction in luminal diameter six months after angioplasty was 0.12 +/- 0.41 mm in the probucol group, 0.22 +/- 0.46 mm in the combined-treatment group, 0.33 +/- 0.51 in the multivitamin group, and 0.38 +/- 0.50 mm in the placebo group (P = 0.006 for those receiving vs. those not receiving probucol, and P = 0.70 for those receiving vs. those not receiving vitamins. Restenosis rates per segment were 20.7 percent in the probucol group, 28.9 percent in the combined-treatment group, 40.3 percent in the multivitamin group, and 38.9 percent in the placebo group (P = 0.003 for probucol vs. no probucol). The rates of repeat angioplasty were 11.2 percent. 16.2 percent, 24.4 percent, and 26.6 percent, respectively (P = 0.009 for probucol vs. no probucol)., Conclusions: The antioxidant probucol is effective in reducing the rate of restenosis after balloon coronary angioplasty.

Resistant coronary lesions remain a challenge for modern angioplasty. Classical approaches include high-pressure inflations, prolonged inflations, or balloon oversizing. More recently, new technologies like rotablator, atherectomy, or laser have been proposed as adjunct to balloon angioplasty for the treatment of these specific lesions. However, all these technologies remain more difficult to handle, costly, and they do not offer long-term benefit over conventional methods. Therefore, a simple device such as the cutting balloon catheter which has been developed from a standard over the wire balloon catheter, may prove to be useful in resistant coronary lesions. We present our single center experience using the new cutting balloon catheter in six resistant lesions.

Coronary angiography has many limitations for the assessment of coronary artery disease. Intracoronary ultrasound imaging may overcome some of these limitations by providing direct visualization of the luminal area. This report describes a case where intracoronary ultrasound imaging was useful for correct assessment of left main coronary artery disease which enabled avoidance of coronary artery bypass grafting in this patient. Intravascular ultrasound may be a good complement to coronary angiography in selected cases of left main coronary artery lesion.

Objectives: The purpose of this study was to evaluate the utility of multiplane transesophageal echocardiography in assessing the coronary artery tree., Background: Evaluation of coronary disease with single-plane and biplane transesophageal echocardiography is limited to the very proximal vessels. The numerous views provided by multiplane imaging may enhance visualization of coronary arteries and detection of their abnormalities., Methods: Intraoperative multiplane transesophageal echocardiography was performed in 45 consecutive adults who had recently undergone angiography. Recordings were reviewed in blinded manner., Results: We describe the coronary segments visualized with the different imaging planes and define new views. The left main coronary artery with its bifurcation was visualized in all 45 patients. Sensitivity and specificity for detection of coronary narrowings were 100% when results were compared with angiographic data. Visualization of proximal, mid and distal segments of the left anterior descending coronary artery was possible in 69%, 31% and 16% of patients, respectively. Among patients in whom the proximal segment was visualized, sensitivity and specificity for detection of significant narrowings were 80% and 100%. Proximal, mid and distal portions of the left circumflex coronary artery were visualized in 80%, 51% and 20% of patients. Among patients in whom the proximal portion was well seen, sensitivity and specificity were 89% and 100%. The proximal, mid and distal portions of the right coronary artery were visualized in 84%, 16% and 11% of patients. Among patients in whom the proximal segment was visualized, sensitivity and specificity were 82% and 100%. Color Doppler examination was less useful because it detected only 52% of all patients with proximal stenosis., Conclusions: Multiplane transesophageal echocardiography allows enhanced visualization of extended lengths of coronary arteries and the reliable identification of coronary artery abnormalities.

Intravascular ultrasound is an emerging imaging modality that employs miniaturized transducers at the tips of catheters to provide detailed information about the morphology of small and large arteries. While there is ongoing development in technology, currently available intravascular ultrasound instrumentation already augments angiography in the assessment of structural and dynamic abnormalities of the peripheral and coronary arterial systems. Recent studies have consistently demonstrated significant underestimation of atherosclerotic disease by angiography. Demonstration by intravascular ultrasound of disease in the angiographically normal "reference" segment and of remodeling of the diseased segment may explain this angiographic underestimation. Intravascular ultrasound also has many applications during various catheter-based therapeutic procedures. In addition to contributing to our understanding of the mechanisms of interventions and restenosis, intravascular ultrasound may lead to better guidance and ultimately better outcome during various procedures such as balloon angioplasty, atherectomy, and stent placement.