Established Coronary Heart Disease Research Articles

Abstract MP23: Circulating Gut Microbiota-Related Metabolites and Risk of Coronary Heart Disease: A Prospective, Multiethnic, Metabolomic Study

Introduction: Despite the importance of gut microbiota in human cardiometabolic health, the associations between circulating levels of gut microbiota-related metabolites and incident coronary heart disease (CHD) remain largely unexplored. Hypothesis: Certain circulating microbial metabolites are associated with incident CHD. Methods: This is a multi-stage and multiethnic metabolomics study. We first conducted a global, semi-quantitative assay for discovery among 900 incident CHD cases and 900 age-/sex-/race-matched controls (300 pairs of Black Americans, White Americans, and Chinese adults, respectively) selected from the Southern Community Cohort Study and Shanghai Men’s and Women’s Health Studies. We focused on 226 metabolites that were potentially related to gut microbiota and applied conditional logistic regression to estimate odds ratios (ORs) of CHD associated with a 1-SD increase of log-transformed metabolites adjusting for traditional CHD risk factors. Then, an in-silico validation was conducted using existing metabolites data of 9,264 participants from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study. Results: In the discovery stage, we identified 73 named microbial metabolites related to incident CHD risk with a false discovery rate<0.10 or nominal p <0.05 and a large effect size (ORs >1.5 or <0.5). These metabolites were from super pathways of amino acids (n=28), lipids (n=24), nucleotides (n=6), carbohydrates (n=4), energy (n=4), xenobiotics (n=4), and cofactors/vitamins (n=3). Of them, 61 metabolites were available for the in-silico validation, and 30 showed a significant association ( p <0.05) with the same direction as the discovery results. After further adjustments for established CHD risk factors (e.g., glucose and LDL-cholesterol), 25 metabolites remained significant. A 14%-48% increased risk was observed for N-acetylglutamate (OR=1.48), sphingomyelin (1.42), imidazole propionate (1.37), hypoxanthine (1.29), guaiacol sulfate (1.28), glutamate (1.22), 2-hydroxyphenylacetate (1.20), 3-hydroxybutyrate (1.19), 3-hydroxy-2-ethylpropionate (1.17), 1-methyl-4-imidazoleacetate (1.16), urea (1.16), urate (1.16), 4-hydroxyphenylacetate (1.15), choline (1.15), isoleucine (1.14), and glycerol (1.14). Meanwhile, a significant inverse association was found for taurine (OR=0.64), asparagine (0.75), serotonin (0.78), histidine (0.79), threonine (0.81), glutamine (0.83), glycine (0.84), oxalate (0.85), and N-methylproline (0.89). Conclusions: Among ethnically and geographically diverse populations, we identified and validated some circulating gut microbiota-related metabolites as potential novel biomarkers for incident CHD. Targeted quantitative assays to confirm these results are ongoing, which are essential to inform potential clinical utility.

Apolipoprotein Proteomics for Residual Lipid-Related Risk in Coronary Heart Disease.

Recognition of the importance of conventional lipid measures and the advent of novel lipid-lowering medications have prompted the need for more comprehensive lipid panels to guide use of emerging treatments for the prevention of coronary heart disease (CHD). This report assessed the relevance of 13 apolipoproteins measured using a single mass-spectrometry assay for risk of CHD in the PROCARDIS case-control study of CHD (941 cases/975 controls). The associations of apolipoproteins with CHD were assessed after adjustment for established risk factors and correction for statin use. Apolipoproteins were grouped into 4 lipid-related classes [lipoprotein(a), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides] and their associations with CHD were adjusted for established CHD risk factors and conventional lipids. Analyses of these apolipoproteins in a subset of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) were used to assess their within-person variability and to estimate a correction for statin use. The findings in the PROCARDIS study were compared with those for incident cardiovascular disease in the Bruneck prospective study (n=688), including new measurements of Apo(a). Triglyceride-carrying apolipoproteins (ApoC1, ApoC3, and ApoE) were most strongly associated with the risk of CHD (2- to 3-fold higher odds ratios for top versus bottom quintile) independent of conventional lipid measures. Likewise, ApoB was independently associated with a 2-fold higher odds ratios of CHD. Lipoprotein(a) was measured using peptides from the Apo(a)-kringle repeat and Apo(a)-constant regions, but neither of these associations differed from the association with conventionally measured lipoprotein(a). Among HDL-related apolipoproteins, ApoA4 and ApoM were inversely related to CHD, independent of conventional lipid measures. The disease associations with all apolipoproteins were directionally consistent in the PROCARDIS and Bruneck studies, with the exception of ApoM. Apolipoproteins were associated with CHD independent of conventional risk factors and lipids, suggesting apolipoproteins could help to identify patients with residual lipid-related risk and guide personalized approaches to CHD risk reduction.

9p21 Locus Polymorphism Is A Strong Predictor of Metabolic Syndrome and Cardiometabolic Risk Phenotypes Regardless of Coronary Heart Disease.

The world population is genetically predisposed to metabolic syndrome (MetS) and its components, also known as cardiometabolic risk phenotypes, which can cause severe health complications including coronary heart disease (CHD). Genetic variants in the 9p21 locus have been associated with CHD in a number of populations including Pakistan. However, the role of the 9p21 locus in MetS and cardiometabolic risk phenotypes (such as obesity, hypertension, hyperglycemia, and dyslipidemia) in populations with CHD or no established CHD has not been explored. Therefore, the present study was designed to explore the association of the minor/risk allele (C) of 9p21 locus SNP rs1333049 with MetS or its risk phenotypes regardless of an established CHD, in Pakistani subjects. Genotyping of rs1333049 (G/C) was performed on subjects under a case-control study design; healthy controls and cases, MetS with CHD (MetS-CHD+) and MetS with no CHD (MetS-CHD-), respectively. Genotype and allele frequencies were calculated in all study groups. Anthropometric and clinical variables (Means ± SD) were compared among study groups (i.e., controls, MetS + CHD and MetS-CHD) and minor/risk C allele carriers (GC + CC) vs. non-carriers (Normal GG genotype). Associations of the risk allele of rs1333049 SNP with disease and individual metabolic risk components were explored using adjusted multivariate logistic regression models (OR at 95% CI) with a threshold p-value of ≤0.05. Our results have shown that the minor allele frequency (MAF) was significantly high in the MAF cases (combined = 0.63, MetS-CHD+ = 0.57 and MetS-CHD- = 0.57) compared with controls (MAF = 0.39). The rs1333049 SNP significantly increased the risk of MetS, irrespective of CHD (MetS-CHD+ OR = 2.36, p < 0.05 and MetS-CHD- OR = 4.04, p < 0.05), and cardiometabolic risk phenotypes; general obesity, central obesity, hypertension, and dyslipidemia (OR = 1.56-3.25, p < 0.05) except hyperglycemia, which lacked any significant association (OR = 0.19, p = 0.29) in the present study group. The 9p21 genetic locus/rs1333049 SNP is strongly associated with, and can be a genetic predictor of, MetS and cardiometabolic risks, irrespective of cardiovascular diseases in the Pakistani population.

Abstract P029: Non-high Density Lipoprotein Is A Residual Risk For The Progression Of Endothelial Dysfunction In Patients With Well Controlled Low-density Lipoprotein Cholesterol: Multicenter Prospective Study FMDJ Study

Introduction: Recently, several guidelines suggest the usefulness of non-high density lipoprotein cholesterol (non-HDLC) as a secondary treatment target for CVD prevention, next to low-density lipoprotein cholesterol (LDLC). However, its effect on endothelial dysfunction have not been fully clarified. The objective of this multicenter-prospective-observational study, FMD-J Study, is to evaluate whether non-HDLC is a residual risk for the progression of endothelial dysfunction in patients with hypertension. Hypothesis: Non-HDLC is a residual risk for the progression of endothelial dysfunction in patients with hypertension. Methods: 633 treated hypertensive patients (mean age 62±9 years) in the FMD-J study were followed for 3 years. Endothelial function was evaluated by the change of flow mediated vasodilation (FMD). Multivariate regression analysis adjusted for established coronary heart disease (CHD) risk factors (sex, age, BMI, systolic blood pressure, heart rate, fasting blood glucose, high density lipoprotein cholesterol, baseline FMD, current smoking, treatment of diabetes, and treatment of dyslipidemia) was performed to evaluate whether LDLC and non-HDLC were associated with the change of FMD. We also performed secondary analysis to evaluate whether non-HDLC is associated with progression of endothelial dysfunction in patients with well controlled LDLC level according to their CHD risk. CHD risk was evaluated by Suita score, which is established risk score to assess the 10-year risk of CHD for the Japanese population. (High-risk: 56≦Suita score, Mid-risk: 41≦Suita score≦55, Low-risk: Suita score≦40) Target controlled LDLC levels according to CHD risk were defined as follows; High-risk: LDLC<70 mg/dl, Mid-risk: LDLC<100 mg/dl, Low-risk: LDLC<70 mg/dl. Results: Mean change of FMD after 3 years was 0.07±2.97% and mean Suita score was 46.4±8.9. Overall, both higher LDLC and non-HDLC was significantly associated with impairment of FMD. (Adjusted 1SD increase of LDLC; β: -0.26±0.11, P=0.02, Adjusted 1SD increase of non-HDLC; β: -0.25±0.11, P=0.03 ). In secondary analysis, 97 patients’ LDLC reached target LDLC level according to CHD risk. Among LDLC controlled group, higher non-HDLC was significantly associated with impairment of FMD. (Adjusted 1SD increase of non-HDLC; β: -0.75±0.13, P=0.02). However, among 536 patients whose LDLC did not reach target LDLC value, non-HDLC was not associated with the change pf FMD. (Adjusted 1SD increase of non-HDLC; β: -0.15±0.12, P=0.20). Conclusions: Non-HDLC may be a residual risk for the progression of endothelial dysfunction in patients with hypertension, especially in hypertensive patients with well controlled LDLC.

Statin Use and Major Adverse Cardiac Events among High Cardiac Risk Patients with Lung Cancer Receiving Radiotherapy

Statin use is recommended in patients with high Framingham risk or established coronary heart disease (CHD). Patients with lung cancer have a high prevalence of pre-existing CHD and face excess cardiac risk following thoracic radiotherapy (RT). We sought to characterize statin use by cardiac risk in a large cohort of patients with locally advanced non-small cell lung cancer (NSCLC) treated with RT. Retrospective analysis of 748 locally advanced NSCLC patients treated with thoracic RT. Patients were stratified by 10-year Framingham risk. High cardiac risk was defined as either high (≥20%) Framingham risk or pre-existing CHD or CHD risk equivalent. The cumulative incidence of major adverse cardiac events (MACE; unstable angina, heart failure, myocardial infarction [MI], coronary revascularization, and cardiac death) was estimated and Fine and Gray regressions were performed (non-cardiac death as a competing risk). The median follow-up was 20 months overall and 48 months in patients alive. Among CHD-negative patients (64.2%), 27.9% were low Framingham risk, 25.0% moderate and 47.1% high risk. At the time of RT, statin use by Framingham risk group (low, moderate, or high) or known CHD was 15.7%, 25.8%, 37.2%, and 63.1%, respectively. Among all high cardiac risk patients (66%, n = 496), only 51.2% were on a statin at the time of RT. High cardiac risk patients on statins (compared to no statin) were more likely to have a history of hypertension (73.3% vs. 51.4%, P<.001), hyperlipidemia (83.4% vs. 29.2%, P<.001), diabetes (28.1% vs. 11.5%, P<.001), former smoking (62.1% vs. 49.4%, P = .017), peripheral vascular disease (17.1 vs. 7.4%, P = .001), stroke (4.4% vs. 1.2%, P = .032), coronary artery disease (52.2% vs. 32.5%, P<.001), MI (49.6% vs. 26.0%, P = .001), and congestive heart failure (17.8% vs. 6.6%, P<.001), with no significant difference in age, sex, performance status, cancer stage, chemotherapy use, RT prescription dose, or cardiac or coronary RT dose exposure (P>.05). Statin use was associated with increased risk of MACE in high cardiac risk patients on univariable analysis (hazard ratio [HR] 1.76; 95% CI: 1.06-2.90; P = .027) with 2-year MACE estimates of 10.9% vs. 4.5%, but not when adjusted for known cardiac prognostic factors (P = 0.4). Only half of statin-eligible high cardiac risk patients with locally advanced NSCLC are on a statin at the time of RT. Even among high cardiac risk patients, those on statins harbored significantly more cardiac risk factors than those not on statins, suggesting only those of highest cardiac risk are on anti-lipid therapy at the time of RT. These results highlight that NSCLC patients represent a distinctly high cardiac risk population due to elevated baseline risk factors and cardiac radiation exposure with an unmet need for improved cardiac risk reduction, including optimization of medical therapy.

Peripheral arterial disease and intermittent claudication in coronary heart disease patients

Background and aimPeripheral artery disease (PAD) is associated with an increased risk of fatal and non-fatal coronary heart disease (CHD). The aims of the this study were 1) to investigate the prevalence of PAD and suspected PAD in a large population of established CHD patients, and 2) to assess the prevalence and control of risk factors in these patients as well health-related quality of life. Material and methodsIn the EUROASPIRE V survey, 8243 patients with documented CHD were recruited from 27 ESC member countries and were invited to attend a study visit. Patients were investigated using questionnaires, in-depth interviews and a clinical examination. Intermittent claudication (IC) was assessed using the Edinburgh Claudication Questionnaire. Patients without previously diagnosed PAD were suspected of having PAD if they were found to have IC. ResultsOverall, 6.4% of the patients had already a confirmed diagnosis of PAD and another 6.3% were suspected of having PAD. Independent of age and gender, patients with previously diagnosed PAD were significantly more frequently current smokers, had the lowest smoking cessation rates, were less physically active, reported more often previously diagnosed diabetes and had significantly higher blood pressure levels, compared to patients without PAD. They had also significantly higher levels of serum triglycerides, lower HDL-C levels, and had more often renal insufficiency. In comparison with patients without PAD, those with suspected PAD demonstrated significantly higher smoking cessation rates but their obesity rates were significantly higher. In CHD patients with a history of PAD, the use of calcium channel blockers and diuretics was significantly higher than in patients without PAD. Compared to the latter group, the use of diuretics, anti-arrhythmics and anti-depressants in patients with suspected PAD was significantly higher. Moreover, patients with previously diagnosed PAD had significantly higher levels of anxiety and depression and reported a significantly worse health-related quality of life (HRQoL), in comparison with those without PAD. HRQoL levels were significantly reduced in patients with suspected PAD as well. ConclusionIn CHD patients without a previous diagnosis of PAD, IC is not infrequent. Diagnosed PAD was significantly associated with a worse CHD risk factor profile. Patients with known PAD as well as those with suspected PAD had a considerable loss of health-related quality of life. Therefore, physicians should consider to screen for IC in all their CHD patients.

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

P5507Growth differentiation factor-15 and mortality in suspected or known coronary heart disease patients with chronic kidney disease: a subanalysis of the ANOX study

Abstract Background Chronic kidney disease (CKD) is an independent risk factor for the development and progression of coronary heart disease (CHD). Growth differentiation factor-15 (GDF-15), a distant member of the transforming growth factor-β cytokine superfamily, plays a role in the initiation of inflammation in atherosclerotic lesions. Elevated GDF-15 was found in various diseases including CKD and stable CHD, and was reported to predict mortality and cardiovascular events in general or established CHD population. However, the prognostic value of GDF-15 in suspected or known CHD patients with CKD is unknown. Methods Serum GDF-15 levels were measured in 999 suspected or known CHD patients with CKD undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict cardiovascular events (ANOX) study, and followed up for 3 years. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Results During the follow-up, 154 patients died from any cause, 61 died from cardiovascular disease, and 96 developed MACE. After adjustment for established risk factors, GDF-15 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.78; 95% confidence interval [CI], 1.57–2.00), cardiovascular death (HR, 1.88; 95% CI, 1.58–2.25), and MACE (HR, 1.54; 95% CI, 1.32–1.79). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of GDF-15 levels further improved the prediction of all-cause death (continuous net reclassification improvement [NRI], 0.401; 95% CI, 0.231–0.571; P&lt;0.001; integrated discrimination improvement [IDI], 0.041; 95% CI, 0.021–0.062; P&lt;0.001) and cardiovascular death (NRI, 0.297; 95% CI, 0.039–0.555; P=0.024; IDI, 0.032; 95% CI, 0.010–0.055; P=0.005), but not that of MACE (NRI, 0.138; 95% CI, v0.070–0.347; P=0.194; IDI, 0.012; 95% CI, −0.000–0.024; P=0.053). Conclusions In suspected or known CHD patients with CKD undergoing elective coronary angiography, elevated GDF-15 levels may predict all-cause and cardiovascular mortality independent of established risk factors and cardiovascular biomarkers. Acknowledgement/Funding The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization.

5195Growth differentiation factor-15 and mortality in suspected or known coronary heart disease patients with diabetes: a subanalysis of the ANOX study

Abstract Background Diabetes is a risk factor for coronary heart disease (CHD), but further risk stratification in patients with diabetes is necessary to improve the prediction and prevention of cardiovascular events and deaths. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine, which plays an important role in the regulation of the inflammatory response, growth and cell differentiation. Elevated GDF-15 was found in various diseases including diabetes and stable CHD, and was reported to predict mortality and cardiovascular events in general or established CHD population. However, the prognostic value of GDF-15 in suspected or known CHD patients with diabetes is unknown. Methods Serum GDF-15 levels were measured in 1,087 suspected or known CHD patients with diabetes undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict cardiovascular events (ANOX) study, and followed up for 3 years. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Results During the follow-up, 147 patients died from any cause, 47 died from cardiovascular disease, and 94 developed MACE. After adjustment for established risk factors, GDF-15 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.66; 95% confidence interval [CI], 1.48–1.86), cardiovascular death (HR, 1.63; 95% CI, 1.34–1.99), and MACE (HR, 1.41; 95% CI, 1.20–1.65). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of GDF-15 levels further improved the prediction of all-cause death (continuous net reclassification improvement [NRI], 0.344; 95% CI, 0.172–0.517; P&lt;0.001; integrated discrimination improvement [IDI], 0.049; 95% CI, 0.026–0.072; P&lt;0.001), but not that of cardiovascular death (NRI, −0.013; 95% CI, −0.300–0.274; P=0.931; IDI, 0.023; 95% CI, 0.003–0.043; P=0.026) or MACE (NRI, 0.059; 95% CI, −0.151–0.268; P=0.583; IDI, 0.005; 95% CI, −0.004–0.015; P=0.244). Conclusions In suspected or known CHD patients with diabetes undergoing elective coronary angiography, elevated GDF-15 levels may predict all-cause mortality independent of established risk factors and cardiovascular biomarkers. Acknowledgement/Funding The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization.

Repeat Measurements of High Sensitivity Troponins for the Prediction of Recurrent Cardiovascular Events in Patients With Established Coronary Heart Disease: An Analysis From the KAROLA Study.

BackgroundHigh‐sensitivity cardiac troponins T and I (hs‐cTnT and hs‐cTnI) are established biomarkers for myocardial injury and used for diagnostic and prognostic purposes. However, whether repeat measurements improve prediction of recurrent cardiovascular disease (CVD) events in patients with stable coronary heart disease (CHD) after adjustment for several other novel biomarkers remains unclear.Methods and ResultsWe measured both troponins in 873 coronary heart disease patients from the KAROLA (Langzeiterfolge der Kardiologischen Anschlussheilbehandlung) study about 9 weeks after their initial acute event (baseline) and after 12 months, followed them for 12 years, assessed a combined CVD end point, and adjusted for several risk factors. As we found evidence for effect modification, results were stratified according to presence of myocardial infarction at baseline. During follow‐up, 186 fatal and non‐fatal CVD events occurred. Both baseline and 12‐months troponin concentrations were significantly associated with CVD events in patients without myocardial infarction at baseline; in tendency 12 months of troponin showed stronger hazard ratios (hs‐cTnT: hazard ratios 1.91 (95% CI 1.17–3.11) versus baseline values 1.71 (95% CI 1.08–2.70) and for hs‐cTnI: hazard ratio 1.55 (95% CI 1.05–2.30) versus baseline value 1.22 (95% CI 0.88–1.68) in the fully and simultaneously adjusted model.ConclusionsBoth troponins are consistently associated with recurrent cardiovascular events after adjustment for emerging risk factors during follow‐up in our study especially evident in patients without myocardial infarction at baseline. Troponin values at 12 months of follow‐up showed independent associations with future CVD events in addition to baseline assessments of troponins.

Elevated plasma cystathionine is associated with increased risk of mortality among patients with suspected or established coronary heart disease

Elevated circulating cystathionine levels are related to atherosclerotic cardiovascular disease, a leading cause of death globally. We investigated whether plasma cystathionine was associated with mortality in patients with suspected or established coronary heart disease (CHD). Data from 2 independent cohorts of patients with suspected stable angina pectoris (SAP) (3033 patients; median 10.7 y follow-up; 648 deaths) or acute myocardial infarction (AMI) (3670 patients; median 7.0 y follow-up; 758 deaths) were included. Hazard ratios with 95% CIs per SD increment of log-transformed cystathionine were calculated using Cox regression modeling. Endpoint data was obtained from a national health registry. Among patients with SAP, there was a positive association between plasma cystathionine and death (age- and sex-adjusted HRs [95% CI] per SD: 1.23 [1.14, 1.32], 1.29 [1.16, 1.44], and 1.17 [1.05, 1.29] for total, cardiovascular, and noncardiovascular mortality, respectively). Corresponding risk estimates were 1.28 (1.19, 1.37) for all-cause, 1.33 (1.22, 1.45) for cardiovascular, and 1.19 (1.06, 1.34) for noncardiovascular death among AMI patients. In both cohorts, estimates were slightly attenuated after multivariate adjustments for established CHD risk factors. Subgroup analyses showed that the relation between cystathionine and all-cause mortality in SAP patients was stronger among nonsmokers and those with lower plasma concentration of pyridoxal-5'-phosphate (P-interaction≤0.01 for both). Elevated plasma cystathionine is associated with both cardiovascular and noncardiovascular mortality among patients with suspected or established CHD. The joint risk associations of high plasma cystathionine with lifestyle factors and impaired vitamin B-6 status on mortality need further investigation. This trial was registered at clinicaltrials.gov as NCT00354081 and NCT00266487.

Subsequent Event Risk in Individuals With Established Coronary Heart Disease.

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. 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. 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. 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.

A11742 Continous improvement of treatable cardiovascular risk factors control in secondary prevention of established coronary heart disease.

Objectives: In established CHD the prevention guidelines recommend random hypolipidemic treatment and control of blood pressure. However, even stronger mortality risk may present diabetes and even prediabetes. We analysed, how standing reccommendations are followed. Methods: Analysis of five independent surveys of patiens with stabilized manifest CHD performed in 1995 - 2017 (Czech samples of EUROASPIRE I, II, III, IV and V surveys), pts interviewed at least 6 months after hospitalization for acute coronary syndrome and/or revascularization). Results: 2098 pts investigated. 1995–2017 systolic BP decreased from144.1 to 132.5 mmHg (p < 0.001), diastolic BP from 87.5 to 80.3 mmHg (p < 0.001). Control of hypertension improved from 45 to 86%. Use of betablockers increased from 65.2 to 88.1%, of ACEI /sartans from 28.0 to 85.6%. Total cholesterol decreased from 5.41 to 4. 33 mmol/l (p < 0.0001), LDL cholesterol from 3.4 to 2.34 mmol/l (p < 0.0001). Hypolipidaemic drugs were used in 28.7% in 1995 and in 95.1% in 2017, statins in7.3 and 94.6 % respectively. Prevalence of diabetes (fasting glycaemia > 7 mmol/L or use of antidiabetic treatment) increased from 26% to53%. Diabetes carries in these patients, according to our follow up data, considerably higher mortality risk than elevated blood pressure or hypercholesterolaemia. Conclusion: Despite progress in control of high blood pressure and hypercholesteroleemia in patients with established CHD, prevalence of diabetes is increasing and diabetes carries higher mortality risk than elevated blood pressure or hypercholesterolemia

Use of guideline-recommended management in established coronary heart disease in the observational DYSIS II study

BackgroundGuidelines recommend lifestyle modification and medications to control risk factors in coronary heart disease (CHD). Using data from the observational DYSIS II study, we sought to evaluate the use of guideline-recommended treatments at discharge for acute coronary syndromes (ACS) or in the chronic phase for CHD, and participation in rehabilitation/secondary prevention programs. Methods and resultsBetween 2013 and 2014, 10,661 patients (3867 with ACS, 6794 with stable CHD) were enrolled in 332 primary and secondary care centers in 18 countries (Asia, Europe, Middle East). Patients with incident ACS were younger and more likely to be smokers than patients with recurrent ACS or stable CHD (both p < 0.0001). Sedentary lifestyle was common (44.4% of ACS patients; 44.2% of stable CHD patients); 22.8% of ACS patients and 24.3% of stable CHD patients were obese. Prevalence of low high-density lipoprotein cholesterol (<40 mg/dL in men/50 mg/dL in women) was 46.9% in chronic CHD and 55.0% in ACS. Rates of secondary prevention medications were lower among CHD versus ACS (all p < 0.0001): antiplatelet 94.3% vs 98.0%, beta-blocker 72.0% vs 80.0%, lipid-lowering therapy 94.7 vs 97.5%, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers 69.4% vs 73.7%, respectively. Attendance at cardiac rehabilitation (16.8% of patients with a first ACS, 10.8% with recurrent ACS) or a secondary prevention program (3.7% of ACS and 11.7% of stable CHD patients) was infrequent. ConclusionsThe high prevalence of risk factors in all CHD patients and reduced rates of secondary prevention medications in stable CHD offer areas for improvement. Translational aspectsThe findings of DYSIS II may reinforce the importance of adopting a healthy lifestyle and prescribing (by clinicians) and adhering (by patients) to evidence-based medications in the management of CHD, not only during the short term but also over the longer term after a cardiac ischemic event. The results may help to increase the proportion of ACS patients who are referred to cardiac rehabilitation centres.

Association of Fibroblast Growth Factor 23 With Risk of Incident Coronary Heart Disease in Community-Living Adults

Higher circulating fibroblast growth factor 23 (FGF23) concentrations are associated with cardiovascular disease events linked to heart failure, but associations of FGF23 with coronary heart disease (CHD) have been less consistent. To determine the association of plasma FGF23 concentrations with incident CHD and whether this association differs by race, sex, or chronic kidney disease status. We examined the association of FGF23 concentrations with incident CHD risk within the Reasons for Geographic and Racial Differences in Stroke study, a prospective cohort of black and white adults 45 years and older enrolled between January 2003 and October 2007 with follow-up through December 31, 2011. Using a case-cohort design, we measured FGF23 concentrations in 829 participants who developed incident CHD and in 812 participants randomly selected from the Reasons for Geographic and Racial Differences in Stroke study cohort (cohort random sample). To account for the stratified sampling design, the cohort random sample was weighted back to the original cohort overall (n = 22 127). Cox proportional hazards models were used to examine the association of FGF23 concentration with incident CHD, adjusting for CHD risk factors and kidney function. In prespecified analyses, we examined whether race, sex, or chronic kidney disease modified the association of FGF23 concentration with incident CHD. Plasma C-terminal FGF23 concentrations. Investigator-adjudicated incident CHD events. Of the 22 127 participants in the weighted cohort random sample, 13 059 (58.9%) were female and 9435 (42.6%) were black, and the mean age was 64.3 (95% CI, 63.7-64.9) years. Greater age, lower estimated glomerular filtration rate, higher urine albumin to creatinine ratio, and female sex were associated with higher FGF23 concentration at baseline. In multivariable models adjusted for established CHD risk factors and kidney function, higher FGF23 concentrations were associated with greater risk of CHD (hazard ratio [HR] comparing fourth with first quartile, 2.15; 95% CI, 1.35-3.42). The magnitude and strength of these associations differed by sex. However, these differences were no longer observed when adjusting for hormone therapy in women (men: HR comparing fourth with first quartile, 2.40; 95% CI, 1.30-4.42; women: HR comparing fourth with first quartile, 2.34; 95% CI, 1.04-5.27) or when using sex-specific FGF23 quartiles (men: HR comparing fourth with first quartile, 2.65; 95% CI, 1.43-4.90; women: HR comparing fourth with first quartile, 2.26; 95% CI, 1.02-5.03). Higher FGF23 concentrations were associated with greater risk of CHD. Heterogeneity in the association by sex may be caused by differences in the distribution of plasma FGF23 concentrations or the use of hormone therapy in men vs women.

Depression and anxiety symptom trajectories in coronary heart disease: Associations with measures of disability and impact on 3-year health care costs

BackgroundAs mortality from coronary heart disease (CHD) falls, years lived with disability increase. Depression and anxiety are known indicators of poor outcomes in CHD, but most research has measured distress symptoms at one time point, often following acute events. Here we consider the long-term trajectories of these symptoms in established CHD, and examine their association to distinct measures of disability and impact on costs. Methods and results803 patients with diagnosis of CHD were recruited from primary care, and completed detailed assessments every 6months for 3years. Latent class growth analysis (LCGA) was used to identify 5 distinct symptom trajectories based on the Hospital Anxiety and Depression Questionnaire (HADS): ‘stable low’, ‘chronic high’, ‘improving’, ‘worsening’, and ‘fluctuating’. The ‘chronic high’ group had highest association with reporting of chest pain (RRR 5.8, CI 2.9 to 11.7), smoking (2.9, 1.1 to 6.3), and poorer physical (0.88, 0.83–0.93) and mental (0.78, 0.73–0.84) quality of life. The ‘chronic high’ and ‘worsening’ trajectories had significantly higher health-care costs over the ‘stable low’ trajectory (107.2% and 95.5% increase, respectively). In addition, our trajectories were the only significant variable associated with increased health-care costs across the 3years. ConclusionsSymptoms of depression and anxiety are highly prevalent in stable CHD patients, and their long-term trajectories are the single biggest driver of health care costs. Managing morbidity in these patients, in which depression and anxiety play a key role in, should become the primary focus of policy makers and future clinical trials.

Impact of Selection Bias on Estimation of Subsequent Event Risk.

Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown. We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was <10, bias was usually <10% (downward toward the null). Despite the low bias, the probability that a confidence interval included the true effect decreased (undercoverage) with increasing sample size because of increasing precision. Importantly, false-positive rates were not affected by selection bias. In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal.

Risk of incident myocardial infarction by gender: Interactions with serum lipids, blood pressure and smoking. The Tromsø Study 1979–2012

Background and aimsOverall, men have roughly twice the risk of myocardial infarction (MI) compared to women, but what causes this contrast is unclear. Identification of subgroups where the gender contrast in risk is particularly low or high, may provide new insight. In the search for such subgroups, we focus on gender-specific effects of established coronary heart disease (CHD) risk factors. Heterogeneity across age groups is also explored. MethodsPopulation-based prospective study from Tromsø, Norway, comprising 33,859 individuals (51% women); 2746 individuals (854 women) received a diagnosis of MI during follow-up at ages 35–94 years. Incidence rate ratios (IRR) were calculated as estimates of relative risk in Poisson regression analyses. ResultsThe association between total cholesterol and risk of MI was stronger for men than women, and IRR for men vs. women accordingly increased with increasing cholesterol, but the risk was higher for men in all subgroups (IRR in range 1.63–3.27), except among older people with low cholesterol levels. The adverse effect of increasing blood pressure (BP) was stronger for women, and IRR for gender diminished with increasing systolic (from 3.90 to 1.38) and diastolic BP (from 2.87 to 1.54). The gender contrast in risk was also substantially reduced in smokers ≥75 years. Associations with high-density lipoprotein cholesterol (HDL-C) did not differ between genders. ConclusionsGender heterogeneity in associations with total cholesterol but not HDL-C indicates gender differences in associations with non-HDL-C. The stronger association with BP in women may relate to more severe hypertension-induced left ventricular hypertrophy.

Equity in healthcare for coronary heart disease, Wales (UK) 2004-2010: A population-based electronic cohort study.

BackgroundDespite substantial falls in coronary heart disease (CHD) mortality in the United Kingdom (UK), marked socioeconomic inequalities in CHD risk factors and CHD mortality persist. We investigated whether inequity in CHD healthcare in Wales (UK) could contribute to the observed social gradient in CHD mortality.Methods and findingsLinking data from primary and secondary care we constructed an electronic cohort of individuals (n = 1199342) with six year follow-up, 2004–2010. We identified indications for recommended CHD interventions, measured time to their delivery, and estimated risk of receiving the interventions for each of five ordered deprivation groups using a time-to-event approach with Cox regression frailty models. Interventions in primary and secondary prevention included risk-factor measurement, smoking management, statins and antihypertensive therapy, and in established CHD included medication and revascularization. For primary prevention, five of the 11 models favoured the more deprived and one favoured the less deprived. For medication in secondary prevention and established CHD, one of the 15 models favoured the more deprived and one the less deprived. In relation to revascularization, six of the 12 models favoured the less deprived and none favoured the more deprived–this evidence of inequity exemplified by a hazard ratio for revascularization in stable angina of 0.79 (95% confidence interval 0.68, 0.92). The main study limitation is the possibility of under-ascertainment or misclassification of clinical indications and treatment from variability in coding.ConclusionsPrimary care components of CHD healthcare were equitably delivered. Evidence of inequity was found for revascularization procedures, although this inequity is likely to have only a modest effect on social gradients in CHD mortality. Policymakers should focus on reducing inequalities in CHD risk factors, particularly smoking, as these, rather than inequity in healthcare, are likely to be key drivers of inequalities in CHD mortality.

Effects of RG7652, a Monoclonal Antibody Against PCSK9, on LDL-C, LDL-C Subfractions, and Inflammatory Biomarkers in Patients at High Risk of or With Established Coronary Heart Disease (from the Phase 2 EQUATOR Study)

RG7652 (MPSK3169A), a fully human immunoglobulin G1 (IgG1) monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9), blocks the interaction between PCSK9 and low-density lipoprotein (LDL) receptor. EQUATOR (ClinicalTrials.govNCT01609140), a randomized, double-blind, and dose-ranging phase 2 study, evaluated RG7652 in patients (1) at high risk for or (2) with coronary heart disease (CHD). The primary end point was change in LDL cholesterol (LDL-C) from baseline to day 169. Patients (n= 248; median age, 64years; 57% men; 52% with established CHD; 82% on statins) with baseline LDL-C levels of 90 to 250mg/dl (mean, 126mg/dl) continuing on standard-of-care therapy were randomized to receive 1 of 5 RG7652 doses or placebo, subcutaneously every 4, 8, or 12weeks for 24weeks. Significant dose-dependent reductions in LDL-C levels from baseline to nadir (56 to 74mg/dl [48% to 60%]) were observed in all RG7652-dosed patients; effects persisted to day 169 with the highest doses (reduction vs placebo up to 62mg/dl [51%]) with no unexpected safety signals. RG7652 reduced apolipoprotein B and lipoprotein(a) levels. LDL-C subfraction analysis by nuclear magnetic resonance spectroscopy revealed a prominent decrease in large LDL-C and some decrease in small LDL particles. There was significant reduction in mean particle size of LDL-C on day 169 but no significant reductions in systemic markers of inflammation (high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha). RG7652 reduced LDL-C levels and was well tolerated in patients at high risk for or with CHD on standard-of-care therapy. In conclusion, RG7562 treatment affected large LDL-C and, to a lesser extent, small LDL-C particles; RG7562 did not affect systemic circulating pro-inflammatory cytokines or high-sensitivity C-reactive protein.