Single-Centre Registry Analysis of Patients Who Underwent Percutaneous Coronary Intervention on Their Coronary Bypass Grafts.

Background: The study assessed the outcomes of patients undergoing percutaneous coronary intervention (PCI) to bypass grafts, focusing on all-cause mortality and target vessel failure (TVF) rates. Methods: A single-centre registry analysis included 364 patients who underwent PCI on coronary bypass grafts between 2008 and 2019. The study analyzed all-cause mortality and TVF, which encompassed target lesion revascularization, target vessel revascularization, and medically treated occluded target graft post-PCI. Results: The median age of the patients was 71 years (interquartile range: [IQR] 65-78), with 82.1% being male. Most patients (94.8%) received PCI on saphenous vein grafts, and the median graft age was 13.0 years (IQR: 8.4-17.6). Drug-eluting stents were used more frequently (54.4%) than bare-metal stents (45.6%), with a median stent diameter of 3.5 mm (IQR: 3-4) and length of 19 mm (IQR: 18-28). Outcome differences were not significant for PCI sites (aorto-ostial, graft body, anastomosis), use of drug-eluting stents, or use of protection devices. The 1-year mortality rate was 3.3%, whereas the combined rate of TVF or death was 20.3%. After 5 years, the mortality rate increased to 14.9%, and the combined TVF or death rate rose to 40.3%. Multivariable analyses revealed that chronic kidney disease was independently associated with mortality (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.16-2.61, P = 0.007), whereas hypertension (HR 2.42, 95% CI 1.32-4.42, P = 0.004) and increased stent length (HR 1.01, 95% CI 1.00-1.02, P = 0.007) were independently associated with the TVF-or-mortality outcome. Conclusions: Patients undergoing PCI to bypass grafts experience considerable adverse outcomes over a 5-year period, highlighting the need for further strategies in managing this high-risk population.

Contexte: L'étude visait à évaluer l'issue des patients ayant subi une intervention coronarienne percutanée (ICP) sur un greffon coronarien, en mettant l'accent sur le taux de mortalité toutes causes confondues et le taux d'échecs de revascularisation du vaisseau cible (EVC). Méthodologie: Une analyse du registre d'un seul établissement a porté sur 364 patients ayant subi une ICP sur un greffon coronarien de 2008 à 2019. L'étude a analysé la mortalité toutes causes confondues et les EVC, qui comprenaient la revascularisation de la lésion cible, la revascularisation du vaisseau cible et le traitement médical de l'occlusion du greffon coronarien cible après l'ICP. Résultats: L'âge médian des patients était de 71 ans (intervalle interquartile [IIQ] de 65 à 78) et 82,1 % d'entre eux étaient de sexe masculin. La plupart des patients (94,8 %) avaient subi une ICP sur un greffon de veine saphène; l'âge médian des greffons était de 13,0 ans (IIQ de 8,4 à 17,6). Les endoprothèses médicamentées avaient été utilisées plus fréquemment (54,4 %) que les endoprothèses non médicamentées (45,6 %), le diamètre médian de l'endoprothèse étant de 3,5 mm (IIQ de 3 à 4) et sa longueur, de 19 mm (IIQ de 18 à 28). Les différences pour ce qui est de l'issue clinique n'étaient pas significatives à l'égard des sites d'ICP (aorto-ostial, corps du greffon, anastomose), de l'utilisation d'une endoprothèse médicamentée, ou encore de l'utilisation de dispositifs de protection. Le taux de mortalité à 1 an était de 3,3 %, alors que le taux combiné d'EVC ou de décès était de 20,3 %. Après 5 ans, le taux de mortalité avait augmenté à 14,9 %, alors que le taux combiné d'EVC ou de décès s'élevait à 40,3 %. Les analyses multivariables ont révélé que la néphropathie chronique était indépendamment associée au décès (rapport des risques instantanés [RRI] de 1,74, intervalle de confiance [IC] à 95 % de 1,16 à 2,61, p = 0,007), alors que l'hypertension (RRI de 2,42, IC à 95 % de 1,32 à 4,42, p = 0,004) et une longueur accrue de l'endoprothèse (RRI de 1,01, IC à 95 % de 1,00 à 1,02, p = 0,007) étaient indépendamment associées à une issue d'EVC ou de décès. Conclusions: Les patients qui ont subi une ICP sur un greffon coronarien présentent des complications considérables sur une période de 5 ans, ce qui souligne le besoin de mettre en place davantage de stratégies de prise en charge pour cette population à risque élevé.

Incidence and Predictors of Outcome in the Treatment of In-Stent Restenosis with Drug-Eluting Balloons, a Real-Life Single-Centre Study.

Objectives: To determine the one-year and five-year occurrence and prognosticators of major adverse cardiac events (MACE: composition of all-cause death, myocardial infarction, target vessel revascularization, and vessel thrombosis), mortality, and target lesion revascularization (TLR) in patients with in-stent restenosis (ISR) treated with drug-eluting balloons (DEBs). Background: DEBs have become an emerging therapeutic option for ISR. We report the results of a single-center retrospective study on the treatment of ISR with DEB. Methods: 94 consecutive patients with ISR treated with the paclitaxel-eluting balloon were retrospectively studied between August 2011 and December 2019. Results: The one-year MACE rate was 11.8%, and the five-year MACE rate was 39.8%. The one-year mortality was 5.3%, and the five-year mortality rate was 21.5%. The one-year TLR rate was 4.3%, and the five-year rate was 18.7%. The univariable-Cox proportional hazard models for TLR showed lesion length, and the number of DEBs per vessel is associated with adverse outcomes with H.R. of 1.038 (1.007-1.069) and 4.7 (1.6-13.8), respectively. Conclusion: Our data indicate that at one year, DEBs provide an effective alternative to stenting for in-stent restenosis. Our five-year data, representing one of the longest-term follow-ups of DEB use, demonstrate high rates of MACE. The high five-year MACE reflects all-cause mortality in a high-risk population. This is offset by a reasonable five-year rate of TLR, indicating that DEB provides both short-term and long-term benefits in ISR.

Long-term outcomes following ostial left anterior descending artery intervention with or without crossover to left-main.

BACKGROUND: Ostial left anterior descending (LAD) artery lesions are a critical area for coronary stenting, given that the location subtends a large area of the myocardium and can also be more technically challenging. It remains controversial whether crossover stenting of ostial LAD back into the left-main (LM) is advantageous over stenting the ostium alone. METHODS: To evaluate the long-term clinical outcomes of stenting ostial LAD lesions, we retrospectively reviewed all ostial LAD lesions cases at QEII Health Science Centre between 2008 and 2018. Specifically, we compared the outcomes in those patients that had left main stent crossover vs. ostial stenting (OS) alone. RESULTS: The total number of patients included in the study was 175, with 25 patients (14%) having a crossover to the LM and 150 (86%) having OS. There were more patients with previous CABG (24%) in the crossover group compared to the OS group (9.2%) (P = 0.042). The one-year MACE was not significantly different between CO vs. OS (13.3% (10.5-16.1) vs. 12% (5.5-18.5)). The five-year MACE was numerically higher, although statistically not significant, in CO vs. OS (19.3 (15.9-22.7) vs. 25.9 (16.6-35.2)). CONCLUSION: This study shows that percutaneous intervention provides reasonable long-term outcomes and low rates of repeat revascularization for isolated ostial LAD lesions, with no noticeable difference in outcomes with crossover stenting into the LM vs. OS alone. A larger, prospective study may be required to determine the optimal strategy for treating ostial LAD lesions.

Elevated level of lecithin:cholesterol acyltransferase (LCAT) is associated with reduced coronary atheroma burden.

BACKGROUND AND AIMS: Lecithin:cholesterol acyltransferase (LCAT), a key enzyme in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT), has been associated with atheroprotection. However, its relation to plaque characteristics has not been confirmed to date. We aimed to determine the relationship between plasma LCAT mass concentration and plaque burden in a multi-center imaging study. METHODS: Two hundred sixty-seven patients with angiographically proven coronary artery disease (CAD) underwent intravascular ultrasonography (IVUS) imaging. Ninety-six patients without CAD served as controls for biochemistry assessments. RESULTS: Plasma LCAT mass concentration was higher in CAD patients as compared to controls (8.94 ±â€¯2.51 µg/mL vs. 7.89 ±â€¯2.99 µg/mL, p = 0.003), while cholesterol esterification rate (CER) was downregulated (253.6 ±â€¯83.9 µM/2 h vs. 315.3 ±â€¯115.0 µM/2 h, p<0.0001). Both parameters correlated inversely with total atheroma volume (r = -0.14, p = 0.027 and r = -0.14, p = 0.024, respectively), while only LCAT mass was found to be a significant predictor of atheroma volume (ß-coefficient -0.18, p = 0.0047) when tested in a stepwise linear regression model against known CAD risk factors as predictor variables. Accordingly, patients with LCAT mass in the highest quartile had significantly less atheroma burden than those in the lower quartiles (39.7 ±â€¯10.7% vs. 45.4 ±â€¯10.4%, p = 0.0014 for highest vs. lowest quartile of LCAT mass). CONCLUSIONS: Plasma LCAT mass concentration is upregulated in CAD patients and inversely related to plaque volume, suggesting atheroprotective effects. LCAT mass concentration outperformed LCAT activity in risk prediction models for atheroma burden, suggesting that LCAT mass is a key variable in atheroprotection. Further studies assessing LCAT as a therapeutic target in cardiovascular disease are warranted.

Initial experience with pre-activation of the cardiac catheterization lab and emergency room bypass for patients with ST-elevation myocardial infarction in Halifax, Nova Scotia.

BACKGROUND: To determine whether pre-activation of the cardiac catheterization lab by Emergency Health Services (EHS) with a single call system in the field was associated with reduced time to reperfusion in patients with ST-Elevation Myocardial Infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). METHODS: Consecutive STEMI patients identified by EHS and subsequently taken to the Queen Elizabeth II Health Sciences Center (QEIIHSC) for PPCI between February 1, 2011 and January 30, 2013 were examined. Patients who had pre-activation of the catheterization lab from the field (pre-act group) after the acquisition of the LifeNet® system (Physio Control, Redmond Washington) were compared to those who had usual activation (routine group) prior to the acquisition of the LifeNet® system, for outcomes including treatment timeline data and mortality. RESULTS: 271 patients were included in the analysis, 149 patients in the pre-act group and 122 patients in the routine group. Door-to-device (DTD) times of less than 90min were achieved more frequently in the Pre-act group (91.9% vs. 62.2%; P<0.001). DTD time was shorter in the Pre-act group (48min IQR: 38 to 63min vs. 78min IQR: 64-101min; p=0.001) as was first medical contact-to-device (FMCTD) time (91min IQR: 78 to 106min vs. 115min IQR: 90 to 139min; P<0.001). False activation of the catheterization lab was infrequent (1.3%). CONCLUSIONS: Implementation of catheterization lab pre-activation using the LifeNet® system was associated with more efficient reperfusion times as measured by reduced FMCTD and DTD times without excess false activation rates.

Validation of improved vessel-specific leads (VSLs) for detecting acute myocardial ischemia.

BACKGROUND: Existing criteria recommended by ACC/ESC for identifying patients with ST elevation myocardial infarction (STEMI) from the 12-lead ECG perform with high specificity (SP), but low sensitivity (SE). In our previous studies, we found that the SE of ischemia detection can be markedly improved without any loss of SP by calculating, from the 12-lead ECG, ST deviation in 3 "optimal" vessel-specific leads (VSLs). Our original VSLs, based on ΔST body-surface potential maps (BSPMs), have been modified by using the more appropriate J-point BSPMs at peak ischemia (without subtraction of pre-occlusion distributions). The aim of the present study was to compare the performance of these new VSLs with that achieved by the STEMI criteria used in current practice. METHODS: Two independent datasets of 12-lead ECGs were used: the STAFF III dataset acquired during ischemic episodes caused by balloon inflation in LAD (n=35), RCA (n=47), and LCx (n=17) coronary arteries, and the Glasgow dataset comprising admission 12-lead ECGs of 116 patients who were hospitalized for chest pain and underwent contrast-enhanced cardiac MRI that confirmed AMI in 58 patients (50%). RESULTS: We found that, in the STAFF III dataset, the detection of ischemic state by the STEMI criteria attained SE/SP of 60/97%, whereas SE/SP values of VSLs were 72/98%. In the Glasgow dataset, STEMI criteria yielded SE/SP of 43/98%, whereas the VSLs improved SE/SP to 60/98%. The most significant increase in diagnostic performance appeared in patients with LCx coronary artery occlusion: in STAFF III data (n=17) SE achieved by STEMI criteria was improved by the VSLs from 35% to 71%; in Glasgow data (n=12) SE of 31% achieved by STEMI criteria was improved by the VSLs to 69%. CONCLUSION: In our study population, existing ACC/ESC STEMI criteria complemented by the new VSLs yielded much improved sensitivity of ischemia detection without any detrimental effect on specificity. This finding needs to be corroborated on a larger chest-pain patient population with typical prevalence of acute ischemia presented to the emergency rooms.

The relationship between anthropometric indexes of adiposity and vascular function in the FATE cohort.

OBJECTIVE: Numerous indexes of adiposity have been proposed and are currently in use in clinical practice and research. However, the correlation of these indexes with measures of vascular health remain poorly defined. This study investigated which measure of adiposity is most strongly associated with endothelial function. DESIGN AND METHODS: Data from the Firefighters And Their Endothelium (FATE) study was used. The relationships between three measures of vascular function: flow-mediated dilation (FMD), hyperemic velocity time integral (VTI), and hyperemic shear stress (HSS), and five measures of adiposity: BMI, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and body adiposity index (BAI) were tested. Univariate comparisons were made, and subsequently models adjusted for traditional risk factors were constructed. RESULTS: A total of 1,462 male firefighters (mean age 49 ± 9) without cardiovascular disease comprised the study population. No measure of adiposity correlated with FMD; all five measures of adiposity were negatively correlated with VTI and HSS (P values <0.0001), with WHtR most strongly correlated with VTI, and WC most strongly correlated with HSS (both P < 0.05). In models including all five measures of obesity simultaneously, BMI, WC, and WHtR were all predictive of HSS (all P values <0.05), and BMI and WHR were both predictive of VTI (P values <0.05). CONCLUSIONS: Anthropometric measures of adiposity may help refine estimations of atherosclerotic burden. BMI was most consistently associated with endothelial dysfunction, but measures of adiposity that reflect distribution of mass were additive.

Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study.

BACKGROUND: Biomarkers of atherosclerosis may refine clinical decision making in individuals at risk of cardiovascular disease. The purpose of the study was to determine the prognostic significance of endothelial function and other vascular markers in apparently healthy men. METHODS AND RESULTS: The cohort consisted of 1574 men (age, 49.4 years) free of vascular disease. Measurements included flow-mediated dilation and its microvascular stimulus, hyperemic velocity, carotid intima-media thickness, and C-reactive protein. Cox proportional hazard models evaluated the relationship between vascular markers, Framingham risk score, and time to a first composite cardiovascular end point of vascular death, revascularization, myocardial infarction, angina, and stroke. Subjects had low median Framingham risk score (7.9%). Cardiovascular events occurred in 71 subjects (111 events) over a mean follow-up of 7.2±1.7 years. Flow-mediated dilation was not associated with subsequent cardiovascular events (hazard ratio, 0.92; P=0.54). Both hyperemic velocity (hazard ratio, 0.70; 95% confidence interval, 0.54 to 0.90; P=0.006) and carotid intima-media thickness (hazard ratio, 1.45; confidence interval, 1.15 to 1.83; P=0.002) but not C-reactive protein (P=0.35) were related to events in a multivariable analysis that included Framingham risk score (per unit SD). Furthermore, the addition of hyperemic velocity to Framingham risk score resulted in a net clinical reclassification improvement of 28.7% (P<0.001) after 5 years of follow-up in the intermediate-risk group. Overall net reclassification improvement for hyperemic velocity was 6.9% (P=0.24). CONCLUSIONS: In men, hyperemic velocity, the stimulus for flow-mediated dilation, but not flow-mediated dilation itself was a significant risk marker for adverse cardiovascular outcomes. The prognostic value was additive to traditional risk factors and carotid intima-media thickness. Hyperemic velocity, a newly described marker of microvascular function, is a novel tool that may improve risk stratification of lower-risk healthy men.

Cardiometabolic effects of rosiglitazone in patients with type 2 diabetes and coronary artery bypass grafts: A randomized placebo-controlled clinical trial.

OBJECTIVES: To assess the efficacy and safety of rosiglitazone on saphenous vein graft (SVG) atherosclerosis prevention and on modification of the global cardiometabolic risk profile. METHODS AND RESULTS: This was a double-blind, randomized, placebo-controlled, multicenter trial which enrolled 193 post-CABG patients with type 2 diabetes. Atherosclerosis changes in one SVG were assessed with intravascular ultrasound at baseline and at 12 months. Serial cardiometabolic assessments were performed. At baseline, both groups had mean HbA(1C)<7%, LDL-cholesterol (LDL-C)<2.3 mmol/l, HDL-cholesterol (HDL-C)>1.0 mmol/l and blood pressure<130/75 mmHg. After 12 months, plaque volume in SVG had increased (median [interquartile range]) by 7.7 mm(3) (-17.2 to 37.9) in the placebo group and decreased by 0.3mm(3) (-19.1 to 22.3) in the rosiglitazone group (P=0.22). Compared to placebo, rosiglitazone treated patients had a higher (mean + or - SD) body weight (89 + or - 15 kg vs. 84 + or - 15 kg, P=0.02) at the end of the study, mostly related to an increment in subcutaneous adipose tissue. Rosiglitazone treated patients also displayed further improvements in glycemic control compared to placebo (HbA(1C): 6.4 + or - 0.7% vs. 7.0 + or - 0.9%, P<0.001) as well as in several cardiometabolic parameters such as lipids (HDL-C: 1.16 + or - 0.28 mmol/l vs. 1.06 + or - 0.23 mmol/l, P=0.003), inflammatory profile (C-reactive protein: 0.92 mg/l [0.51-1.56] vs. 1.37 mg/l [0.79-3.08], P=0.02), and adiponectin levels (11.1 microg/ml [8.19-17.9] vs. 4.65 microg/ml [3.27-7.15], P<0.001). There was no significant difference in the incidence of serious adverse cardiovascular events. However, more patients in the rosiglitazone group had peripheral oedema (33% vs. 18%, P=0.0019). CONCLUSION: After a 12-month follow-up, we found no evidence for a statistically significant effect of rosiglitazone on SVG atherosclerosis whereas significant effects on glycemic control and on the cardiometabolic risk profile appeared to be modulated in part by changes in subcutaneous adiposity.

Intensive multifactorial intervention for stable coronary artery disease: optimal medical therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial.

OBJECTIVES: This paper describes the medical therapy used in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial and its effect on risk factors. BACKGROUND: Most cardiovascular clinical trials test a single intervention. The COURAGE trial tested multiple lifestyle and pharmacologic interventions (optimal medical therapy) with or without percutaneous coronary intervention in patients with stable coronary disease. METHODS: All patients, regardless of treatment assignment, received equivalent lifestyle and pharmacologic interventions for secondary prevention. Most medications were provided at no cost. Therapy was administered by nurse case managers according to protocols designed to achieve predefined lifestyle and risk factor goals. RESULTS: The patients (n = 2,287) were followed for 4.6 years. There were no significant differences between treatment groups in proportion of patients achieving therapeutic goals. The proportion of smokers decreased from 23% to 19% (p = 0.025), those who reported <7% of calories from saturated fat increased from 46% to 80% (p < 0.001), and those who walked >or=150 min/week increased from 58% to 66% (p < 0.001). Body mass index increased from 28.8 +/- 0.13 kg/m(2) to 29.3 +/- 0.23 kg/m(2) (p < 0.001). Appropriate medication use increased from pre-randomization to 5 years as follows: antiplatelets 87% to 96%; beta-blockers 69% to 85%; renin-angiotensin-aldosterone system inhibitors 46% to 72%; and statins 64% to 93%. Systolic blood pressure decreased from a median of 131 +/- 0.49 mm Hg to 123 +/- 0.88 mm Hg. Low-density lipoprotein cholesterol decreased from a median of 101 +/- 0.83 mg/dl to 72 +/- 0.88 mg/dl. CONCLUSIONS: Secondary prevention was applied equally and intensively to both treatment groups in the COURAGE trial by nurse case managers with treatment protocols and resulted in significant improvement in risk factors. Optimal medical therapy in the COURAGE trial provides an effective model for secondary prevention among patients with chronic coronary disease. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657).

A multicentre, randomized, double-blind placebo-controlled trial evaluating rosiglitazone for the prevention of atherosclerosis progression after coronary artery bypass graft surgery in patients with type 2 diabetes. Design and rationale of the VeIn-Coronary aTherOsclerosis and Rosiglitazone after bypass surgerY (VICTORY) trial.

BACKGROUND: The number of patients with coronary artery disease and type 2 diabetes will increase dramatically over the next decade. Diabetes has been related to accelerated atherosclerosis and many patients with diabetes will require coronary artery bypass graft (CABG) surgery utilizing saphenous vein grafts. After CABG, accelerated atherosclerosis in saphenous vein grafts leads to graft failure in approximately 50% of cases over a 10-year period. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been shown to improve multiple metabolic parameters in patients with type 2 diabetes. However, its role in the prevention of atherosclerosis progression is uncertain. STUDY DESIGN: VeIn-Coronary aTherOsclerosis and Rosiglitazone after bypass surgerY (VICTORY) is a cardiometabolic trial in which patients with type 2 diabetes, one to 10 years after CABG, will be randomly assigned to receive rosiglitazone (up to 8 mg/day) or a placebo after qualifying angiography and intravascular ultrasound of a segment of one vein graft with or without a native anastomosed coronary artery. A comprehensive set of athero-thrombo-inflammatory markers will be serially assessed during the 12-month follow-up period. Body fat distribution and body composition will be assessed by computed tomography and dual energy x-ray absorptiometry, respectively, at baseline, six months and 12 months follow-up. For atherosclerosis progression evaluation, repeat angiography and intravascular ultrasound will be performed after 12 months follow-up. The primary end point of the study will be the change in atherosclerotic plaque volume in a 40 mm or longer segment of one vein graft. CONCLUSIONS: The VICTORY trial is the first cardiometabolic study to evaluate the antiatherosclerotic and metabolic effects of rosiglitazone in post-CABG patients with type 2 diabetes.

Comparison of new measures of vascular function to flow mediated dilatation as a measure of cardiovascular risk factors.

Although flow-mediated dilatation (FMD) is widely used, the ideal vascular parameter for the measurement of cardiovascular risk is not clear. Recently, it has been proposed that shear stress and blood velocity during hyperemia (VRH) may provide stronger correlations with cardiovascular risk factors than FMD. The aim of this study was to evaluate the relations of VRH and shear stress during reactive hyperemia (SSRH) to FMD and the association of these measures to cardiovascular risk factors in 1,477 men without cardiovascular disease. SSRH and VRH showed weak correlations with FMD in bivariate analysis (r = 0.239, p <0.001, and r = 0.108, p <0.001, respectively). The only cardiovascular risk factor independently associated with FMD was systolic blood pressure (beta = -0.073, p <0.01). In contrast, as the dependent variable, SSRH (R2 for model = 0.107) was independently associated with age, systolic blood pressure, low-density lipoprotein cholesterol, and body mass index. As the dependent variable, VRH was associated with the same risk factors with a slightly weaker R2 value of 0.095. In conclusion, SSRH and simply calculated VRH have stronger associations with cardiovascular risk factors than FMD. This may reflect greater sensitivity of these measures to detect early abnormalities associated with risk factors in a relatively young and healthy population.

The differential association between various anthropometric indices of obesity and subclinical atherosclerosis.

BACKGROUND: Recent observational studies have reported differential quantitative relationships between the different anthropometric indices of obesity and risk for cardiovascular (CV) events. Specifically, waist circumference and waist-to-hip ratio (WHR) as crude measures of abdominal obesity were shown to be more predictive of CV events than body mass index (BMI). However, it remains undetermined whether indices of abdominal obesity are also more strongly associated with early subclinical atherosclerosis in asymptomatic individuals. METHODS: The associations between carotid intimal-medial thickness (cIMT) as a validated marker of subclinical atherosclerosis and each of BMI, waist circumference and WHR were compared among 1578 middle-aged men free of clinical CV disease enrolled in the Fire Fighter and Their Endothelium (FATE) study. RESULTS: In univariate analyses, the correlation with cIMT as well as the ability to predict substantially increased atherosclerotic burden (cIMT>75% percentile of the cohort) was strongest for WHR, intermediate for waist circumference, and weakest for BMI (Pearson's coefficient of 0.21, 0.18 and 0.12, respectively; area under the receiver operating characteristics curve [AUC] of 0.65, 0.62 and 0.58, respectively, P<0.01 for differences). Within each traditional BMI category, WHR uniformly outperformed waist circumference in further refining discrimination for increased atherosclerotic burden. In multivariable analyses, WHR consistently demonstrated the strongest graded independent relationship with cIMT, beyond most of the established risk factors of atherosclerosis, and superseded both waist circumference and BMI. CONCLUSION: Our findings support the use of WHR for estimating adiposity-related atherosclerotic burden in clinical practice and in obesity research. Moreover, our study suggests that the increased CV risk associated with abdominal obesity may be mediated in part by the increased anatomic extent of atherosclerotic vascular disease.

Relationship between brachial artery flow-mediated dilatation, hyperemic shear stress, and the metabolic syndrome.

Metabolic syndrome (MetSyn) may predispose to cardiovascular disease (CVD) by causing vascular dysfunction. This study aimed to determine the association of MetSyn with vascular function, as assessed by brachial artery flow-mediated dilatation (FMD) and hyperemic shear stress (HSS). A total of 1,417 male firefighters without established diabetes and CVD were classified for MetSyn, according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP) definition. MetSyn was present in 267 individuals (19%). Although FMD was lower in those with versus without MetSyn (8.1 +/- 4.1 vs 8.7 +/- 4.0%; p = 0.02), this was not significant after adjusting for baseline differences (age, smoking, and brachial artery diameter) (p = 0.2). However, HSS was significantly lower in those with versus without MetSyn (72.0 +/- 27.8 vs 80.9 +/- 24.8 dyne/cm(2); p < 0.001), and there was a significant inverse graded relationship with the number of NCEP criteria present (mean HSS for those with 0, 1, 2, 3, 4, and 5 criteria: 83.2 +/- 22.5, 82.2 +/- 24.7, 76.5 +/- 27.2, 74.3 +/- 27.4, 66.5 +/- 28.4, 67.1 +/- 27.6 dyne/cm(2); p < 0.001 for trend). The individual NCEP criteria of abdominal obesity, systolic hypertension, and impaired fasting glucose were independent predictors for HSS. In conclusion, MetSyn was not associated with impaired FMD. Alternatively, HSS, a measure of microvascular function, was significantly lower in those with MetSyn. Thus, MetSyn may contribute to CVD by causing microvascular dysfunction.

Modulation of arterial reactivity using amlodipine and atorvastatin measured by ultrasound examination (MARGAUX).

OBJECTIVE: To evaluate the effect of the calcium channel blocker amlodipine on endothelial function in normotensive patients with coronary disease taking concomitant atorvastatin therapy. METHODS AND RESULTS: Atorvastatin was titrated (10-80 mg/day) to maintain LDL-C<2.5 mmol/L and patients were randomized to receive amlodipine (5-10mg/day, n=64) or placebo (n=70) for 12 months. Brachial artery flow-mediated vasodilation (FMD) was assessed using vascular ultrasound. Inflammatory markers were also measured. At 12 months there was a significant decrease in mean low-density lipoprotein cholesterol (LDL-C) (4.4-2.1 mmol/L, P<0.0001), high-sensitivity C-reactive protein (hsCRP) (3.8-2.3mg/L, P<0.0001) and soluble vascular cell adhesion molecule-1 (sVCAM-1) (710-665 ng/mL, P<0.0001) for all patients, compared with baseline. Amlodipine was associated with a mean blood pressure reduction of 8/3 mm Hg (P<0.0001) whereas patients on placebo had no significant change. In the atorvastatin-placebo group, mean FMD increased (7.3-9.5%, P<0.05) with no change in nitroglycerin-mediated dilation. No further benefit on FMD or inflammatory markers was observed with the addition of amlodipine. CONCLUSIONS: Intensive reduction of LDL-C with atorvastatin improves endothelium-dependent vasodilation and reduces markers of inflammation in patients with coronary disease. Amlodipine was not associated with a significant additional benefit on these variables.

Effects of the antioxidant succinobucol (AGI-1067) on human atherosclerosis in a randomized clinical trial.

BACKGROUND: The antioxidant AGI-1067 was shown to reduce experimental atherosclerosis. The present study originally intended to study restenosis as a primary endpoint but was subsequently modified to primarily investigate the effects of AGI-1067 on coronary atherosclerosis. METHODS AND RESULTS: This placebo-controlled randomized trial assessed the effects of AGI-1067 280 mg qd started before percutaneous coronary intervention (PCI) and administered for 12 months after PCI on atherosclerosis progression as assessed by coronary intravascular ultrasound (IVUS). Among patients with IVUS examinations considered technically adequate both at baseline and follow-up upon central laboratory assessments (n=232), plaque volume was not significantly modified with placebo (least squares mean change: -0.4mm(3), P=0.85 versus baseline), but was significantly reduced by -4.0mm(3) at end of treatment in the AGI-1067 group (P=0.001 versus baseline, P=0.12 versus placebo). LDL-cholesterol varied by -9% and +4% in the placebo and AGI-1067 groups, respectively (P<0.05 between groups), and HDL-cholesterol was reduced by 1% with placebo and 14% with AGI-1067 (P<0.05 between groups). Plasma myeloperoxidase was reduced by 6% with AGI-1067 (P<0.05) but hs-CRP was not significantly different between groups. CONCLUSIONS: Atherosclerosis regression (-4.0mm(3)) was observed in patients treated with AGI-1067, although this was not significantly different from placebo. The anti-inflammatory effect of AGI-1067 is supported by reduced levels of myeloperoxidase.

Optimal medical therapy with or without PCI for stable coronary disease.

BACKGROUND: In patients with stable coronary artery disease, it remains unclear whether an initial management strategy of percutaneous coronary intervention (PCI) with intensive pharmacologic therapy and lifestyle intervention (optimal medical therapy) is superior to optimal medical therapy alone in reducing the risk of cardiovascular events. METHODS: We conducted a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease at 50 U.S. and Canadian centers. Between 1999 and 2004, we assigned 1149 patients to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal myocardial infarction during a follow-up period of 2.5 to 7.0 years (median, 4.6). RESULTS: There were 211 primary events in the PCI group and 202 events in the medical-therapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P=0.62). There were no significant differences between the PCI group and the medical-therapy group in the composite of death, myocardial infarction, and stroke (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P=0.62); hospitalization for acute coronary syndrome (12.4% vs. 11.8%; hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P=0.56); or myocardial infarction (13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P=0.33). CONCLUSIONS: As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. (ClinicalTrials.gov number, NCT00007657 [ClinicalTrials.gov].).

The effect of iron status on vascular health.

The effect of increased iron stores on the progression of atherosclerosis and endothelial health remains inconclusive. This study was designed to evaluate the relationship between hemochromatosis genotypes, serum ferritin levels and presymptomatic vascular abnormalities in a cohort of healthy subjects. Carotid intima-media thickness (CIMT) and brachial flow-mediated vasodilation (FMD) were assessed by high-resolution ultrasound in 907 male (47 +/- 10 years) participants enrolled in the Firefighters and their Endothelium (FATE) study. Analyses of the hemochromatosis C282Y, H63D and S65C alleles were simultaneously determined by a single nucleotide polymorphism (SNP) primer extension method. It was found that brachial FMD was not related to serum ferritin or hemochromatosis genotype status. The presence of a hemochromatosis-associated genotype (n = 18) or heterozygosity for the C282Y genotype (n = 98) was not associated with an increased mean CIMT. After adjustment for conventional risk factors, serum ferritin was also not associated with mean CIMT. In conclusion, neither ferritin nor a hemochromatosis genotype was related to brachial endothelial function or carotid atherosclerosis. The present study does not support the hypothesis that mild to moderately increased iron stores are associated with enhanced atherosclerosis risk.

Folic acid improves endothelial dysfunction in type 2 diabetes--an effect independent of homocysteine-lowering.

Diabetes is associated with endothelial dysfunction, which in part may be related to uncoupling of the endothelial nitric oxide (NO) synthase enzyme, thus reducing the availability of NO. As folates may potentially reverse the uncoupling of NO synthase, we wanted to determine whether folic acid supplementation could modulate endothelial function and markers of inflammation in patients with type 2 diabetes without vascular disease. Nineteen patients with type 2 diabetes were treated with folic acid (10mg/day for 2 weeks) versus placebo in a randomized, placebo-controlled, cross-over study with an 8-week washout period between treatments. Fasting endothelium-dependent flow-mediated dilatation (FMD) of the brachial artery, endothelium-independent nitroglycerin-mediated dilatation (NMD), plasma homocysteine, serum lipids, folate, and inflammatory markers (high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, interleukin-18, tumor necrosis factor-alpha) were assessed after each 2-week treatment period. Folic acid supplementation significantly increased folate levels and lowered plasma homocysteine levels. Folic acid significantly improved FMD compared to placebo (5.8 +/- 4.8% vs 3.2 +/- 2.7%, p = 0.02). There were no significant effects of folic acid supplementation on lipids, NMD, or the inflammatory markers. There was no relationship between the change in homocysteine and the improvement in FMD. Thus, 2 weeks of folic acid supplementation can improve endothelial dysfunction in type 2 diabetics independent of homocysteine-lowering, but does not modulate markers of inflammation.

Improved prediction of early-onset coronary artery disease using APOE epsilon4, BChE-K, PPARgamma2 Pro12 and ENOS T-786C in a polygenic model.

OBJECTIVES: Coronary artery disease (CAD) is often polygenic due to multiple mutations that contribute small effects to susceptibility. Since most prior studies only evaluated the contribution of single candidate genes, we therefore looked at a combination of genes in predicting early-onset CAD [apolipoprotein E (APOE) epsilon4, butyrylcholinesterase (BChE) K, peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala and endothelial nitric oxide synthase (ENOS) T-786C]. DESIGN AND METHODS: We examined the frequencies, individually and in combination, of all four alleles among patients with early-onset CAD (n = 150; <50 years), late-onset CAD (n = 150; >65 years) and healthy controls (n = 150, age range 47-93 years). Differences in the proportion of subjects in each group with the given gene combination were assessed and likelihood ratios (LR) were calculated using logistic regression to combine the results of multiple genes. RESULTS: Early-onset CAD patients had increased, but non-significant, frequencies of PPARgamma2 Pro12/Pro12 (P = 0.39) and ENOS T-786C (P = 0.72), while BChE-K was only significantly higher in early-onset CAD patients compared to controls (P = 0.03). There were significantly more APOE epsilon4 alleles alone (P = 0.02) or in combination with BChE-K (P = 0.02) among early-onset CAD patients compared to late-onset CAD ones or controls. When combined, there was a higher prevalence of all four alleles in early-onset CAD (early-onset CAD patients: 10.7%, late-onset CAD patients: 3.3% and controls: 2.7%, P = 0.01). LR for early-onset CAD for a single allele was relatively small (1.08 for PPARgamma2 to 1.70 for APOE epsilon4). This increased to 2.78 (1.44-5.37) when combining all four alleles, therefore increasing the pre-test probability of CAD from 5% to a post-test probability of 12.7%. CONCLUSIONS: While any single mutation causes only a mildly increased LR (none > 1.7), in combination, the likelihood of early-onset CAD increased to 2.78 with four mutations. The genetics of early-onset CAD appear to be multifactorial, requiring polygenic models to elucidate risk.