Relationship between glomerular filtration rate and the adipokines adiponectin, resistin and leptin in coronary patients with predominantly normal or mildly impaired renal function

BACKGROUND: Due to their molecular weight, it is possible that the adipokines adiponectin, resistin and leptin accumulate when glomerular filtration rate (GFR) is decreased. In reduced renal clearance, altered serum concentrations of these proteins might affect cardiovascular risk. The objective of the study was to investigate the relationship between adipokine concentrations and GFR. METHODS: The association between GFR, as determined by the abbreviated MDRD equation, and the concentrations of the adipokines adiponectin, resistin and leptin was assessed in a cohort of coronary patients (n=538; 363 male, 165 female). After calculation of correlations between GFR and adipokine concentrations, the association was further assessed by analysis of covariance following adjustment for age, gender, BMI, presence of type 2 diabetes, presence of hypertension, history of smoking as well as for serum lipid concentrations. RESULTS: Mean GFR in our study population was 68.74+/-15.27 ml/min/1.73 m(2). 74.3% of the patients had a GFR >60 ml/min/1.73 m(2), 24% of the patients had a GFR between 30 and 60 ml/min/1.73 m(2), and 1.7% of the patients had a GFR <30 ml/min/1.73 m(2). There were significant inverse correlations between adiponectin (r=-0.372; p<0.001), resistin (r=-0.227; p<0.001) and leptin (r=-0.151; p=0.009) concentrations and GFR. After multivariate adjustment, the associations remained significant for adiponectin and resistin. Subgroup analysis in patients with GFR >60 ml/min/1.73 m(2) showed a significant correlation between GFR and adiponectin as well as leptin concentrations. However, after adjustment, these associations no longer were significant. CONCLUSIONS: There is an independent association between GFR and the serum concentrations of adiponectin and resistin. However, this association is not present at GFR >60 ml/min/1.73 m(2). This finding suggests that adipokine concentrations in mildly impaired and normal renal function are influenced by factors other than GFR.

A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men

BACKGROUND: Many HIV-infected patients on highly active antiretroviral therapy (HAART) experience metabolic complications including dyslipidaemia and insulin resistance, which may increase their coronary heart disease (CHD) risk. We developed a prognostic model for CHD tailored to the changes in risk factors observed in patients starting HAART. METHODS: Data from five cohort studies (British Regional Heart Study, Caerphilly and Speedwell Studies, Framingham Offspring Study, Whitehall II) on 13,100 men aged 40-70 and 114,443 years of follow up were used. CHD was defined as myocardial infarction or death from CHD. Model fit was assessed using the Akaike Information Criterion; generalizability across cohorts was examined using internal-external cross-validation. RESULTS: A parametric model based on the Gompertz distribution generalized best. Variables included in the model were systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, diabetes mellitus, body mass index and smoking status. Compared with patients not on HAART, the estimated CHD hazard ratio (HR) for patients on HAART was 1.46 (95% CI 1.15-1.86) for moderate and 2.48 (95% CI 1.76-3.51) for severe metabolic complications. CONCLUSIONS: The change in the risk of CHD in HIV-infected men starting HAART can be estimated based on typical changes in risk factors, assuming that HRs estimated using data from non-infected men are applicable to HIV-infected men. Based on this model the risk of CHD is likely to increase, but increases may often be modest, and could be offset by lifestyle changes.

HAART and the heart: changes in coronary risk factors and implications for coronary risk in men starting antiretroviral therapy

OBJECTIVES: To estimate changes in coronary risk factors and their implications for coronary heart disease (CHD) rates in men starting highly active antiretroviral therapy (HAART). METHODS: Men participating in the Swiss HIV Cohort Study with measurements of coronary risk factors both before and up to 3 years after starting HAART were identified. Fractional polynomial regression was used to graph associations between risk factors and time on HAART. Mean risk factor changes associated with starting HAART were estimated using multilevel models. A prognostic model was used to predict corresponding CHD rate ratios. RESULTS: Of 556 eligible men, 259 (47%) started a nonnucleoside reverse transcriptase inhibitor (NNRTI) and 297 a protease inhibitor (PI) based regimen. Levels of most risk factors increased sharply during the first 3 months on HAART, then more slowly. Increases were greater with PI- than NNRTI-based HAART for total cholesterol (1.18 vs. 0.98 mmol L(-1)), systolic blood pressure (3.6 vs. 0 mmHg) and BMI (1.04 vs. 0.55 kg m(2)) but not HDL cholesterol (0.24 vs. 0.32 mmol L(-1)) or glucose (1.02 vs. 1.03 mmol L(-1)). Predicted CHD rate ratios were 1.40 (95% CI 1.13-1.75) and 1.17 (0.95-1.47) for PI- and NNRTI-based HAART respectively. CONCLUSIONS: Coronary heart disease rates will increase in a majority of patients starting HAART: however the increases corresponding to typical changes in risk factors are relatively modest and could be offset by lifestyle changes.

Prediction of first coronary events with the Framingham score: a systematic review

BACKGROUND: Uncertainty exists about the performance of the Framingham risk score when applied in different populations. OBJECTIVE: We assessed calibration of the Framingham risk score (ie, relationship between predicted and observed coronary event rates) in US and non-US populations free of cardiovascular disease. METHODS: We reviewed studies that evaluated the performance of the Framingham risk score to predict first coronary events in a validation cohort, as identified by Medline, EMBASE, BIOSIS, and Cochrane library searches (through August 2005). Two reviewers independently assessed 1496 studies for eligibility, extracted data, and performed quality assessment using predefined forms. RESULTS: We included 25 validation cohorts of different population groups (n = 128,000) in our main analysis. Calibration varied over a wide range from under- to overprediction of absolute risk by factors of 0.57 to 2.7. Risk prediction for 7 cohorts (n = 18658) from the United States, Australia, and New Zealand was well calibrated (corresponding figures: 0.87-1.08; for the 5 biggest cohorts). The estimated population risks for first coronary events were strongly associated (goodness of fit: R2 = 0.84) and in good agreement with observed risks (coefficient for predicted risk: beta = 0.84; 95% CI 0.41-1.26). In 18 European cohorts (n = 109499), the corresponding figures indicated close association (R2 = 0.72) but substantial overprediction (beta = 0.58, 95% CI 0.39-0.77). The risk score was well calibrated on the intercept for both population clusters. CONCLUSION: The Framingham score is well calibrated to predict first coronary events in populations from the United States, Australia, and New Zealand. Overestimation of absolute risk in European cohorts requires recalibration procedures.

A meta-analysis of 16 randomized trials of sirolimus-eluting stents versus paclitaxel-eluting stents in patients with coronary artery disease

OBJECTIVES: Our purpose was to make a synthesis of the available evidence on the relative efficacy and safety of 2 drug-eluting stents (DES)--sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES)--in patients with coronary artery disease. BACKGROUND: It is not known whether there are differences in late outcomes between the 2 most commonly used DES: SES and PES. METHODS: Sixteen randomized trials of SES versus PES with a total number of 8,695 patients were included in this meta-analysis. A full set of individual outcome data from 5,562 patients was also available. Mean follow-up period ranged from 9 to 37 months. The primary efficacy end point was the need for reintervention (target lesion revascularization). The primary safety end point was stent thrombosis. Secondary end points were death and recurrent myocardial infarction (MI). RESULTS: No significant heterogeneity was found across trials. Compared with PES, SES significantly reduced the risk of reintervention (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.63 to 0.87, p < 0.001) and stent thrombosis (HR 0.66; 95% CI 0.46 to 0.94, p = 0.02) without significantly impacting on the risk of death (HR 0.92; 95% CI 0.74 to 1.13, p = 0.43) or MI (HR 0.84; 95% CI 0.69 to 1.03, p = 0.10). CONCLUSIONS: Sirolimus-eluting stents are superior to PES in terms of a significant reduction of the risk of reintervention and stent thrombosis. The risk of death was not significantly different between the 2 DES, but there was a trend toward a higher risk of MI with PES, especially after the first year from the procedure.

Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study

BACKGROUND: Stent thrombosis is a safety concern associated with use of drug-eluting stents. Little is known about occurrence of stent thrombosis more than 1 year after implantation of such stents. METHODS: Between April, 2002, and Dec, 2005, 8146 patients underwent percutaneous coronary intervention with sirolimus-eluting stents (SES; n=3823) or paclitaxel-eluting stents (PES; n=4323) at two academic hospitals. We assessed data from this group to ascertain the incidence, time course, and correlates of stent thrombosis, and the differences between early (0-30 days) and late (>30 days) stent thrombosis and between SES and PES. FINDINGS: Angiographically documented stent thrombosis occurred in 152 patients (incidence density 1.3 per 100 person-years; cumulative incidence at 3 years 2.9%). Early stent thrombosis was noted in 91 (60%) patients, and late stent thrombosis in 61 (40%) patients. Late stent thrombosis occurred steadily at a constant rate of 0.6% per year up to 3 years after stent implantation. Incidence of early stent thrombosis was similar for SES (1.1%) and PES (1.3%), but late stent thrombosis was more frequent with PES (1.8%) than with SES (1.4%; p=0.031). At the time of stent thrombosis, dual antiplatelet therapy was being taken by 87% (early) and 23% (late) of patients (p<0.0001). Independent predictors of overall stent thrombosis were acute coronary syndrome at presentation (hazard ratio 2.28, 95% CI 1.29-4.03) and diabetes (2.03, 1.07-3.83). INTERPRETATION: Late stent thrombosis was encountered steadily with no evidence of diminution up to 3 years of follow-up. Early and late stent thrombosis were observed with SES and with PES. Acute coronary syndrome at presentation and diabetes were independent predictors of stent thrombosis.

Functional polymorphism in ABCA1 influences age of symptom onset in coronary artery disease patients

ATP-binding-cassette-transporter-A1 (ABCA1) plays a pivotal role in intracellular cholesterol removal, exerting a protective effect against atherosclerosis. ABCA1 gene severe mutations underlie Tangier disease, a rare Mendelian disorder that can lead to premature coronary artery disease (CAD), with age of CAD onset being two decades earlier in mutant homozygotes and one decade earlier in heterozygotes than in mutation non-carriers. It is unknown whether common polymorphisms in ABCA1 could influence age of symptom onset of CAD in the general population. We examined common promoter and non-synonymous coding polymorphisms in relation to age of symptom onset in a group of CAD patients (n = 1164), and also carried out in vitro assays to test effects of the promoter variations on ABCA1 promoter transcriptional activity and effects of the coding variations on ABCA1 function in mediating cellular cholesterol efflux. Age of symptom onset was found to be associated with the promoter - 407G > C polymorphism, being 2.82 years higher in C allele homozygotes than in G allele homozygotes and intermediate in heterozygotes (61.54, 59.79 and 58.72 years, respectively; P = 0.002). In agreement, patients carrying ABCA1 haplotypes containing the -407C allele had higher age of symptom onset. Patients of the G/G or G/C genotype of the -407G > C polymorphism had significant coronary artery stenosis (>75%) at a younger age than those of the C/C genotype (P = 0.003). Reporter gene assays showed that ABCA1 haplotypes bearing the -407C allele had higher promoter activity than haplotypes with the -407G allele. Functional analyses of the coding polymorphisms showed an effect of the V825I substitution on ABCA1 function, with the 825I variant having higher activity in mediating cholesterol efflux than the wild-type (825V). A trend towards higher symptom onset age in 825I allele carriers was observed. The data indicate an influence of common ABCA1 functional polymorphisms on age of symptom onset in CAD patients.

Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: the SWISSI II randomized controlled trial

CONTEXT: The effect of a percutaneous coronary intervention (PCI) on the long-term prognosis of patients with silent ischemia after a myocardial infarction (MI) is not known. OBJECTIVE: To determine whether PCI compared with drug therapy improves long-term outcome of asymptomatic patients with silent ischemia after an MI. DESIGN, SETTING, AND PARTICIPANTS: Randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]) conducted from May 2, 1991, to February 25, 1997, at 3 public hospitals in Switzerland of 201 patients with a recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease. Follow-up ended on May 23, 2006. INTERVENTIONS: Percutaneous coronary intervention aimed at full revascularization (n = 96) or intensive anti-ischemic drug therapy (n = 105). All patients received 100 mg/d of aspirin and a statin. MAIN OUTCOME MEASURES: Survival free of major adverse cardiac events defined as cardiac death, nonfatal MI, and/or symptom-driven revascularization. Secondary measures included exercise-induced ischemia and resting left ventricular ejection fraction during follow-up. RESULTS: During a mean (SD) follow-up of 10.2 (2.6) years, 27 major adverse cardiac events occurred in the PCI group and 67 events occurred in the anti-ischemic drug therapy group (adjusted hazard ratio, 0.33; 95% confidence interval, 0.20-0.55; P<.001), which corresponds to an absolute event reduction of 6.3% per year (95% confidence interval, 3.7%-8.9%; P<.001). Patients in the PCI group had lower rates of ischemia (11.6% vs 28.9% in patients in the drug therapy group at final follow-up; P = .03) despite fewer drugs. Left ventricular ejection fraction remained preserved in PCI patients (mean [SD] of 53.9% [9.9%] at baseline to 55.6% [8.1%] at final follow-up) and decreased significantly (P<.001) in drug therapy patients (mean [SD] of 59.7% [11.8%] at baseline to 48.8% [7.9%] at final follow-up). CONCLUSION: Among patients with recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00387231.

Coronary collateral flow in response to endurance exercise training

BACKGROUND: In humans, it is not known whether physical endurance exercise training promotes coronary collateral growth. The following hypotheses were tested: the expected collateral flow reduction after percutaneous coronary intervention of a stenotic lesion is prevented by endurance exercise training; collateral flow supplied to an angiographically normal coronary artery improves in response to exercise training; there is a direct relationship between the change of fitness after training and the coronary collateral flow change. METHODS AND RESULTS: Forty patients (age 61+/-8 years) underwent a 3-month endurance exercise training program with baseline and follow-up assessments of coronary collateral flow. Patients were divided into an exercise training group (n=24) and a sedentary group (n=16) according to the fact whether they adhered or not to the prescribed exercise program, and whether or not they showed increased endurance (VO2max in ml/min per kg) and performance (W/kg) during follow-up versus baseline bicycle spiroergometry. Collateral flow index (no unit) was obtained using pressure sensor guidewires positioned in the coronary artery undergoing percutaneous coronary intervention and in a normal vessel. In the vessel initially undergoing percutaneous coronary intervention, there was an increase in collateral flow index among exercising but not sedentary patients from 0.155+/-0.081 to 0.204+/-0.056 (P=0.03) and from 0.189+/-0.084 to 0.212+/-0.077 (NS), respectively. In the normal vessel, collateral flow index changes were from 0.176+/-0.075 to 0.227+/-0.070 in the exercise group (P=0.0002), and from 0.219+/-0.103 to 0.238+/-0.086 in the sedentary group (NS). A direct correlation existed between the change in collateral flow index from baseline to follow-up and the respective alteration of VO2max (P=0.007) and Watt (P=0.03). CONCLUSION: A 3-month endurance exercise training program augments coronary collateral supply to normal vessels, and even to previously stenotic arteries having undergone percutaneous coronary intervention before initiating the program. There appears to be a dose-response relation between coronary collateral flow augmentation and exercise capacity gained.

Does the beta-blocker nebivolol increase coronary flow reserve?

INTRODUCTION: Nebivolol, a highly selective beta1-adrenergic receptor-blocker, increases basal and stimulated endothelial nitric oxide (NO)-release. It is unknown, whether coronary perfusion is improved by the increase in NO availability. Therefore, we sought to evaluate the effect of nebivolol on coronary flow reserve (CFR) and collateral flow. METHODS: Doppler-flow wire derived coronary flow velocity measurements were obtained in ten controls and eight patients with coronary artery disease (CAD) at rest and after intracoronary nebivolol. CFR was defined as maximal flow during adenosine-induced hyperemia divided by resting flow. In the CAD group, collateral flow was determined after dilatation of a flow-limiting coronary stenosis. Collateral flow index (CFI) was defined as the ratio of flow velocity during balloon inflation divided by resting flow. RESULTS: CFR at rest was 3.0+/-0.6 in controls and 2.1+/-0.4 in CAD patients. After intracoronary doses of 0.1, 0.25, and 0.5 mg nebivolol, CFR increased to 3.4+/-0.7, 3.9+/-0.9, and 4.0+/-0.1 (p<0.01) in controls, and to 2.3+/-0.7, 2.6+/-0.9, and 2.6+/-0.5 (p<0.05) in CAD patients. CFI decreased significantly with intracoronary nebivolol and correlated to changes in heart rate (r=0.75, p<0.001) and rate-pressure product (r=0.59, p=0.001). DISCUSSION: Intracoronary nebivolol is associated with a significant increase in CFR due to reduction in resting flow (controls), or due to an increase in maximal coronary flow (CAD patients). CFI decreased with nebivolol parallel to the reduction in myocardial oxygen consumption.

Beneficial effect of recruitable collaterals: a 10-year follow-up study in patients with stable coronary artery disease undergoing quantitative collateral measurements

BACKGROUND: The prognostic relevance of the collateral circulation is still controversial. The goal of this study was to assess the impact on survival of quantitatively obtained, recruitable coronary collateral flow in patients with stable coronary artery disease during 10 years of follow-up. METHODS AND RESULTS: Eight-hundred forty-five individuals (age, 62+/-11 years), 106 patients without coronary artery disease and 739 patients with chronic stable coronary artery disease, underwent a total of 1053 quantitative, coronary pressure-derived collateral measurements between March 1996 and April 2006. All patients were prospectively included in a collateral flow index (CFI) database containing information on recruitable collateral flow parameters obtained during a 1-minute coronary balloon occlusion. CFI was calculated as follows: CFI = (P(occl) - CVP)/(P(ao) - CVP) where P(occl) is mean coronary occlusive pressure, P(ao) is mean aortic pressure, and CVP is central venous pressure. Patients were divided into groups with poorly developed (CFI < 0.25) or well-grown collateral vessels (CFI > or = 0.25). Follow-up information on the occurrence of all-cause mortality and major adverse cardiac events after study inclusion was collected. Cumulative 10-year survival rates in relation to all-cause deaths and cardiac deaths were 71% and 88%, respectively, in patients with low CFI and 89% and 97% in the group with high CFI (P=0.0395, P=0.0109). Through the use of Cox proportional hazards analysis, the following variables independently predicted elevated cardiac mortality: age, low CFI (as a continuous variable), and current smoking. CONCLUSIONS: A well-functioning coronary collateral circulation saves lives in patients with chronic stable coronary artery disease. Depending on the exact amount of collateral flow recruitable during a brief coronary occlusion, long-term cardiac mortality is reduced to one fourth compared with the situation without collateral supply.