Composite Cardiovascular Disease Endpoint Research Articles

Abstract 18968: Bromocriptine-QR: A Potential Novel Strategy for Cardiovascular Risk Reduction in Type 2 Diabetes

Type 2 diabetes (T2D) is associated with a substantially increased risk of cardiovascular disease (CVD). Of the available therapies for T2D, none have been conclusively shown to reduce CVD risk. Metformin has long been considered the only agent with some evidence, albeit limited, of a potential CVD benefit. Bromocriptine-QR (BQR), a quick release sympatholytic dopamine agonist, is a newer FDA-approved therapy for T2D. Based on preclinical and clinical study findings, it is postulated that BQR restores the normal circadian peak in central dopaminergic tone diminished in insulin resistant states, which in turn reduces hyperactive sympathetic tone and improves central fuel sensing thereby reducing postprandial hepatic glucose and lipid output as well as reduces vascular resistance, oxidative stress, and inflammation. In a one-year randomized trial of BQR vs. placebo added to standard therapy (diet and/or ≤ 2 diabetes medications including sulfonylureas, TZD, metformin, or insulin) in 3070 T2D subjects (average duration of T2D: 7.9 years), including individuals with pre-existing CVD, BQR therapy resulted in a 40% hazard rate reduction (HRR) in major CVD events, pre-specified as a composite of time to first myocardial infarction, stroke, coronary revascularization, hospitalization for angina or congestive heart failure. In the present study, this CVD effect of BQR was evaluated in a subset of this original study population on metformin +/- another anti-diabetes therapy at baseline (N = 1791). The composite CVD end point occurred in 16/1208 BQR-treated (1.3%) and 18/583 placebo-treated (3.1%) subjects resulting in a 53% CVD HRR (ITT group, Cox regression analysis; HR 0.47, 95% CI 0.24, 0.92, P = 0.028) adjusted by age (HR 1.08, 95% C.I. 1.04, 1.12, P = 0.0003) and pre-existing CVD (HR 2.27, 95% C.I. 1.02, 5.07, P = 0.041). Kaplan-Meier Curves of the cumulative incidence rate yielded a CVD HRR of 58% (HR 0.42, 95% C.I. 0.21, 0.85, Log-Rank = 0.017). These findings reaffirm prior observations of CVD risk reduction with BQR therapy and further demonstrate the potential for a marked additive effect of BQR above any derived from metformin, suggesting a potential novel strategy for CVD risk reduction in T2D.

The levels of MDA-LDL in circulating immune complexes predict myocardial infarction in the VADT study

ObjectiveCirculating immune complexes (IC) containing modified forms of LDL (mLDL) are strongly pro-inflammatory and strong predictors of cardiovascular disease (CVD) progression in type 1 diabetes. The present study was undertaken to determine whether the levels of oxidized LDL (oxLDL), malondialdehyde-LDL (MDA-LDL) and advanced glycation end products-LDL (AGE-LDL) in IC predict incident CVD events in type 2 diabetes (VADT cohort). Methods and resultsLevels of mLDL in IC were measured in 907 patients of the VADT cohort, a median of two years after entry into the study. Participants were followed for an average of 3.7 years for vascular outcomes. Hazard ratios (HRs) for CV endpoints in relation to mLDL-IC quartiles were calculated by Cox proportional hazard models. The primary composite CVD endpoint included documented myocardial infarction (MI); stroke; death from CVD; congestive heart failure; cardiac, cerebrovascular, or peripheral VD surgical intervention; inoperable CVD; and amputation for ischemic gangrene. During follow-up, 4.7% and 16.8% of participants had an MI or a composite endpoint, respectively. After adjustments by conventional risk factors, individuals in the highest quartile of MDA-LDL-IC were at higher risk of MI [HR = 2.44 (95% CI: 1.03, 5.77)] and composite endpoint [HR = 1.71 (95% CI: 1.04, 2.80)], relative to individuals in the lowest quartile. Similar comparisons for oxLDL and AGE-LDL levels yielded HR values of 1.08 and 1.31 for MI and 0.91 and 1.34 for composite endpoint. ConclusionsOur study indicates that high levels of MDA-LDL in isolated IC predict future MI and acute CV events in patients with type 2 diabetes.

Predictors of heart rate variability and its prognostic significance in chronic kidney disease

Heart rate variability (HRV), a noninvasive measure of autonomic dysfunction and a risk factor for cardiovascular disease (CVD), has not been systematically studied in nondialysis chronic kidney disease (CKD). HRV was assessed using 24-h Holter monitoring in 305 subjects from the Renal Research Institute-CKD Study, a four-center prospective cohort of CKD (Stages 3-5). Multiple linear regression was used to assess predictors of HRV (both time and frequency domain) and Cox regression used to predict outcomes of CVD, composite of CVD/death and end-stage renal disease (ESRD). A total of 47 CVD, 67 ESRD and 24 death events occurred over a median follow-up of 2.7 years. Lower HRV was significantly associated with older age, female gender, diabetes, higher heart rate, C-reactive protein and phosphorus, lower serum albumin and Stage 5 CKD. Lower HRV (mostly frequency domain) was significantly associated with higher risk of CVD and the composite end point of CVD or death. Significantly, lower HRV (frequency domain) was associated with higher risk of progression to ESRD, although this effect was relatively weaker. This study draws attention to the importance of HRV as a relatively under recognized predictor of adverse cardiovascular and renal outcomes in patients with nondialysis CKD. Whether interventions that improve HRV will improve these outcomes in this high-risk population deserves further study.

Genetic variants in eleven telomere-associated genes and the risk of incident cardio/cerebrovascular disease: The Women's Genome Health Study

Background Candidate genes associated with telomere length maintenance, an important molecular marker for biological aging, represent potential risk predictors for cardiovascular disease (CVD). To date, no prospective data are available. Methods The associations between 154 tag-single nucleotide polymorphisms (tSNPs) of 11 telomere-associated candidate genes ( TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP, and TERC) were investigated in 23,294 Caucasian participants of the Women's Genome Health Stud y. All were free of known CVD and cancer at baseline. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction (MI), or death due to ischemic CVD); other measures were incident MI and ischemic stroke. During follow-up, 1178 total incident CVD, 315 incident MI cases, and 323 incident ischemic stroke events were identified. Multivariable Cox regression analysis and a haplotype-based approach were performed to investigate the relationship between genotypes/haplotypes and CVD risk, assuming an additive model. Results In a marker-by-marker analysis, 7 ( TEP1, TNKS, and ACD), 11 ( TEP1, ACD, and TERT), and 24 ( TEP1, TNKS, TERT, TERF2IP, TNKS2, and UCP2) SNPs were associated—at the level of p < 0.05—with the total CVD, MI, and ischemic stroke risk, respectively. Further analysis using a haplotype-based approach showed similar findings. Although none remained significant after the correction of multiple testing, the false discovery rate analysis revealed 28% of the nominally significant SNPs with true associations in relation to ischemic stroke risk. Conclusions The present large prospective study encourages further investigation of the biological role of telomere-associated pathway genes in the pathogenesis and early assessment of vascular events.

Cellular Aging Reflected by Leukocyte Telomere Length Predicts Advanced Atherosclerosis and Cardiovascular Disease Risk

To determine the association between leukocyte telomere length (TL) and atherosclerosis and its clinical sequelae stroke and myocardial infarction. Within the scope of the prospective population-based Bruneck Study, leukocyte TL was measured by quantitative polymerase chain reaction in 800 women and men aged 45 to 84 years (in 1995). The manifestation of cardiovascular disease (CVD) (1995-2005) and the progression of atherosclerosis (1995-2000) were carefully assessed. The TL was shorter in men than in women (age-adjusted mean [95% CI], 1.41 [1.33 to 1.49] versus 1.55 [1.47 to 1.62]; P=0.02) and inversely correlated to age (r=-0.22, P<0.001) and family history of CVD (P=0.03). Participants with CVD events during follow-up (n=88) had significantly shorter telomeres (age- and sex-adjusted mean [95% CI], 1.25 [1.08 to 1.42] versus 1.51 [1.45 to 1.57]; P<0.001). In multivariable Cox models, baseline TL emerged as a significant and independent risk predictor for the composite CVD end point and its individual components (myocardial infarction and stroke); however, this was not the case for de novo stable angina and intermittent claudication. Subjects in the top and bottom TL tertile group differed in their CVD risk by a factor of 2.72 (95% CI, 1.41 to 5.28), which is the risk ratio attributable to a 13.9-year difference in chronological age. Remarkably, in our atherosclerosis progression model, TL was strongly associated with advanced, but not early, atherogenesis. All findings were consistent in women and men. Our findings indicate a differential role of telomere shortening in the various stages of atherosclerosis, with preferential involvement in advanced vessel pathology and acute vascular syndromes.

Gender Differences in Genetic Risk Profiles for Cardiovascular Disease

BackgroundCardiovascular disease (CVD) incidence, complications and burden differ markedly between women and men. Although there is variation in the distribution of lifestyle factors between the genders, they do not fully explain the differences in CVD incidence and suggest the existence of gender-specific genetic risk factors. We aimed to estimate whether the genetic risk profiles of coronary heart disease (CHD), ischemic stroke and the composite end-point of CVD differ between the genders.Methodology/Principal FindingsWe studied in two Finnish population cohorts, using the case-cohort design the association between common variation in 46 candidate genes and CHD, ischemic stroke, CVD, and CVD-related quantitative risk factors. We analyzed men and women jointly and also conducted genotype-gender interaction analysis. Several allelic variants conferred disease risk for men and women jointly, including rs1801020 in coagulation factor XII (HR = 1.31 (1.08–1.60) for CVD, uncorrected p = 0.006 multiplicative model). Variant rs11673407 in the fucosyltransferase 3 gene was strongly associated with waist/hip ratio (uncorrected p = 0.00005) in joint analysis. In interaction analysis we found statistical evidence of variant-gender interaction conferring risk of CHD and CVD: rs3742264 in the carboxypeptidase B2 gene, p(interaction) = 0.009 for CHD, and rs2774279 in the upstream stimulatory factor 1 gene, p(interaction) = 0.007 for CHD and CVD, showed strong association in women but not in men, while rs2069840 in interleukin 6 gene, p(interaction) = 0.004 for CVD, showed strong association in men but not in women (uncorrected p-values). Also, two variants in the selenoprotein S gene conferred risk for ischemic stroke in women, p(interaction) = 0.003 and 0.007. Importantly, we identified a larger number of gender-specific effects for women than for men.Conclusions/SignificanceA false discovery rate analysis suggests that we may expect half of the reported findings for combined gender analysis to be true positives, while at least third of the reported genotype-gender interaction results are true positives. The asymmetry in positive findings between the genders could imply that genetic risk loci for CVD are more readily detectable in women, while for men they are more confounded by environmental/lifestyle risk factors. The possible differences in genetic risk profiles between the genders should be addressed in more detail in genetic studies of CVD, and more focus on female CVD risk is also warranted in genome-wide association studies.

Intercellular Adhesion Molecule 1 (ICAM1) Lys56Met and Gly241Arg Gene Variants, Plasma-Soluble ICAM1 Concentrations, and Risk of Incident Cardiovascular Events in 23 014 Initially Healthy White Women

The objective of this study was to examine the association of 2 nonsynonymous intercellular adhesion molecule 1 (ICAM1) gene variants (Lys56Met and Gly241Arg) with baseline plasma soluble ICAM1 concentrations and with risk of total and selected cardiovascular disease (CVD) events in a prospective cohort of 23 014 apparently healthy white American women followed for 10 years. ICAM1 variations have been associated with plasma soluble ICAM1 concentrations and inflammatory conditions, including atherosclerosis. However, to date, no large prospective, genetic-epidemiological data set is available that would allow evaluation of the degree of association of these gene variants with risk of CVD. ICAM1 genotypes and baseline plasma soluble ICAM1 concentrations were determined. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction, or death due to ischemic CVD); other measures were incident ischemic stroke, myocardial infarction, and coronary revascularization. During follow-up, 751 total incident CVD events, 187 incident myocardial infarction cases, 203 incident ischemic stroke cases, and 433 coronary revascularization events occurred. All observed genotype frequencies were in Hardy-Weinberg equilibrium across the whole sample population. We found baseline plasma soluble ICAM1 concentrations to be significantly reduced among carriers of Met56 allele (P<0.0001) and Arg241 allele (P<0.0001) as compared with the respective noncarriers of these variants. However, the polymorphisms tested and the respective haplotypes were neither associated with overall risk nor with risk with risk for selected CVD events regardless of whether analyses were adjusted for traditional CVD risk factors/confounders (all P values >0.10). In this large prospective study, we found an association of the nonsynonymous gene variants tested with reduced baseline plasma soluble ICAM1 concentrations. However, no evidence was found for an association of the gene variants tested with the overall or selected CVD end points examined, suggesting that these variants may not add useful aids to current risk predictors for early assessment of cardiovascular events.

Lipoprotein(a) as a Predictor of Cardiovascular Disease in a Prospectively Followed Cohort of Patients With Type 1 Diabetes

Lipoprotein(a) [Lp(a)] concentrations are genetically determined (1,2), and numerous epidemiological studies in the general population have identified elevated Lp(a) levels as a risk factor for atherosclerotic disorders (3,4). However, this association is not as clearly defined in patients with type 1 diabetes (5), since large prospective studies are missing. We therefore analyzed the role of Lp(a) for the incidence of cardiovascular disease (CVD) complications. The 429 consecutive, unrelated type 1 diabetes patients included in this observational study were from the Hospital Lainz-Vienna. Inclusion criteria described recently (6) were regular attendance at the outpatient clinic in the last year and stable metabolic control. For patient characteristics, see Table 1. The recruitment period lasted from 1993 to 1999. Regular follow-ups were performed every 3–6 months. Yearly follow-ups included detailed history, laboratory parameters, measurement of peripheral and autonomic neuropathy, staging of retinopathy, and feet inspection. Previous CVD complications were obtained by self reports verified from hospital records. Patients’ blood was drawn after an overnight fast. Lp(a) quantification was carried out, as described in detail (7). Apolipoprotein(a) phenotyping was performed by SDS agarose gel electrophoresis (8). Glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease equation (9). A composite CVD end point during follow-up was defined as coronary artery disease, cerebrovascular disease, and …

Methods to evaluate risks for composite end points and their individual components

Objective Both randomized and observational studies commonly examine composite end points, but the literature on model development and criticism in this setting is limited. Study Design and Setting We examined approaches for evaluating heterogeneity in the effects of risk factors for different components of the end point, and determining the impact of heterogeneity on the ability to predict the composite end point. A specific example considered the composite cardiovascular disease end point in the Physicians' Health Study that occurred in 1,542 (myocardial infarction, n = 716; stroke, n = 557; cardiovascular death, n = 269) of 16,688 participants with complete information on baseline covariates. The strategy compared alternative polytomous logistic regression models assuming different effects of risk factors on components of the end point and a comparable logistic model assuming common effects. Results Likelihood ratio tests identified heterogeneity in the effects of age, alcohol consumption, and diabetes across components of the outcome, but comparability in the effects of other risk factors. However, a model assuming uniform effects explained over 90% of the log-likelihood change in the best polytomous model, and the two models also performed similarly based on a comparison of ROC curves. Conclusion The overall strategy may be helpful for evaluating the validity of a composite end point analysis and identifying heterogeneity in risk factors.