Prior Coronary Heart Disease Research Articles

Unraveling the paradox: the impact of one or more traditional risk factors on short-term mortality following acute coronary syndromes.

Abstract Background It has been recently suggested that individuals without exposure to any standardized modifiable risk factors may have an increased risk of all-cause mortality from acute coronary syndromes (ACS) compared with their counterparts with one or more risk factors, including diabetes. Purpose To estimate the individual contribution of the four traditional risk factors to the risk of adverse outcomes from first ACS. Methods We analyzed data from 70,953 Caucasian patients presenting with first ACS, but without prior coronary heart disease in the International Survey of Acute Coronary Syndromes (ISACS) Archives registry network from October 2005 to January 2021. The primary outcome was all-cause mortality within 30 days after hospital admission. We calculated sex-specific risk ratios (RRs) stratifying traditional risk factors, current smoking, diabetes, hypercholesterolemia and hypertension into mutually exclusive categories using a balancing strategy by inverse probability weighting. Results Compared with patients presenting without risk factors, those with diabetes had significantly higher 30-day mortality in both women (RR, 1.29; 95% CI, 1.06-1.57) and men (RR, 1.40; 95% CI, 1.16-1.69). By contrast, patients who were current smokers or presented with a history of hypercholesterolemia or hypertension had significantly lower 30-day mortality than patients with no risk factors with RRs ranging from 0.53; 95% CI 0.42–0.67 in women who were smokers to 0.46; 95% CI 0.37–0.59 in men with hypercholesterolemia. The impact of diabetes on mortality was obscured in patients who concomitantly presented with diabetes and one more traditional risk factor. The RRs in combination with current smoking were 1.39; 95% CI 0.92 -2.09 in women and 0.89; 95% CI 0.68 -1.17 in men; with hypercholesterolemia: 0.91; 95% CI 0.66 -1.25 in women and 0.75; 95% CI 0.53–1.06 in men; with hypertension: 1.14; 95% CI 0.99–1.32 in women and 1.12; 95% CI 0.96–1.31 in men. Conclusions Diabetes confers a significant independent excess mortality risk at 30 days following ACS. Dilution bias in this setting refers to the weakening of the observed effect of diabetes because of the inclusion of "one more" risk factor with lower risk profile. Potential misinterpretation of the relationship between diabetes and death from ACS may negatively affect healthcare organization

Polygenic risk and incident coronary heart disease in a large multiethnic cohort

ObjectiveMany studies support the notion that polygenic risk scores (PRS) improve risk prediction for coronary heart disease (CHD) beyond conventional risk factors. However, PRS are not yet considered risk-enhancing factor in guidelines. Our objective was to determine the predictive performance of a commercially available PRS (CARDIO inCode-Score®) compared with the Pooled Cohorts Equations (PCE) in a contemporary, multi-ethnic cohort. MethodsParticipants (n = 63,070; 67 % female; 18 % non-European) without prior CHD were followed from 2007 through 12/31/2022. The association between the PRS and incident CHD was assessed using Cox regression adjusting for genetic ancestry and risk factors. Event rates were estimated by categories of PCE and by low/intermediate/high genetic risk within PCE categories; risk discrimination and net reclassification improvement (NRI) were also assessed. ResultsThere were 3,289 incident CHD events during 14 years of follow-up. Adjusted hazard ratio (aHR) for incident CHD per 1 SD increase in PRS was 1.18 (95 % CI:1.14–1.22), and the aHR for the upper vs lower quintile of the PRS was 1.66 (95 % CI:1.49–1.86). The association was consistent in both sexes, in European participants compared with all minority groups combined and was strongest in the first 5 years of follow-up. The increase in the C-statistic was 0.004 (0.747 vs. 0.751; p < 0.0001); the NRI was 2.4 (0.9–3.8) for the entire cohort and 9.7 (7.5–12.0) for intermediate PCE risk individuals. After incorporating high genetic risk, a further 10 percent of participants at borderline/intermediate PCE risk would be candidates for statin therapy. ConclusionInclusion of polygenic risk improved identification of primary prevention individuals who may benefit from more intensive risk factor modification.

Abstract P277: Adherence to Time-Restricted Eating, Plasma Metabolomic Signatures, and Risk of Coronary Heart Disease

Introduction: Early time-restricted eating (TRE) has been recently suggested as an effective dietary intervention strategy to improve risk factors of coronary heart disease (CHD), whereas late TRE may be related to poor cardiometabolic health. Metabolomic pathways linking the adherence to habitual TREs depending on the time of the day and CHD risk are unknown. Hypothesis: We tested whether adherence to early or late TRE was related to distinct metabolomic signatures (including those in pathways of energy/purine pyrimidine metabolism, lipids, carbohydrates, and acylcarnitines). We then tested whether TRE-related plasma metabolites were associated with the risk of incident CHD among women without prior CHD. Methods: This study included 674 women without cardiovascular disease who completed 7-day food records and measurements of untargeted plasma metabolomics in a sub-study of the Nurses’ Health Studies (NHS/NHSII). TRE was indicated by 4-12 hours of daily eating window. The adherence to TRE was assessed by summing up the TRE days in a week (0-7 days). We analyzed two TRE habits: early TRE (starting before 9 a.m./ending no later than 9 p.m.) and late TRE (beginning after 9 a.m.). Separately, plasma metabolites were measured in a prospective nested case-control of 762 incident cases of CHD and 762 matched controls identified over 10-14 years of follow-up in the NHS. A metabolomic risk score for predicting adherence to late TRE (MRS-TRE late ) was created based on metabolites selected through the elastic net procedure with a 10-fold cross-validation. Results: Adherence to late TRE was positively associated with greater adiposity, insulin/proinsulin, uric acid, and medium-chain fatty acids/acylcarnitines; the late TRE habit was inversely related to metabolites in the TCA cycle/pyruvate metabolism and specific PC species ( P FDR &lt;0.05). On the other hand, metabolites in lipid pathways (including diglyceride DG 38:5) and glucose were inversely related to the adherence to early TRE. Individual levels of late-TRE-related metabolites in energy/phosphatidylcholine /acylcarnitine pathways were significantly associated with an increased risk of CHD. Every 1 SD increment of MRS-TRE late , based on 21 metabolites in various metabolic pathways, was associated with a relative risk (RR) of 1.24 (95% CI: 1.11, 1.38) for CHD in a model adjusted for matching factors, and a RR of 1.15 (1.02, 1.29) after adjusting for covariates, such as demographic factors, diet quality, alcohol, lifestyle factors, and BMI. Women in the top tertile of MRS-TRE late had a 1.44-fold (1.10, 1.89) increased risk of CHD as compared to those in the lowest tertile after adjusting for the covariates. Conclusions: TRE habit, depending on the timing, was related to distinct metabolomic pathways, and adherence to late TRE may be associated with metabolic reliance linked to the risk of incident CHD among women.

Association between Urine Albumin-to-creatinine Ratio and Intracranial Atherosclerotic Plaque in Chinese Adults - Results from the PRECISE Study.

Intracranial plaque may cause stroke in the absence of luminal stenosis. Although urine albumin-to-creatinine ratio (ACR) has been proved an established risk factor for cardiovascular disease, stroke and carotid atherosclerosis, little is known on the relationship between urine ACR and intracranial plaque. Subjects with history of stroke or coronary heart disease (CHD) were excluded in the PRECISE study. The intracranial plaque was assessed by vessel wall magnetic resonance imaging (MRI). Subjects were stratified according to ACR tertiles. Logistic regression and ordinal regression were performed to analyze the association between ACR and the presence of intracranial plaque or sum of the stenosis score for each artery. 2962 individuals were included with the mean age of 61.0±6.6 years. The median ACR was 11.7mg/g (interquartile range 7.0-22.0 mg/g), and the mean estimated glomerular filtration rate (eGFR) based on combination of creatinine and cystatin C was 88.5±14.8 ml/min·1.73m2. 495 (16.7%) participants had intracranial plaque. The highest ACR tertile with ACR ＞16.00mg/g was independently associated with the presence of intracranial plaque (OR 1.38, 95% CI: 1.05-1.82, p=0.02) and the odds of higher intracranial plaque burden (common OR 1.39, 95% CI: 1.05-1.83, p=0.02) after adjustment of confounding factors. No significant association was observed between eGFR and intracranial plaque presence or intracranial plaque burden. Among a low-risk community-dwelling population without prior stroke or CHD in China, ACR was independently associated with intracranial plaque presence and plaque burden measured by vessel wall MRI.

Sex-specific associations of the difference between 2-hour post-load and fasting plasma glucose with cardiovascular risk in a normoglycemic population

Abstract Background Elevated levels of fasting plasma glucose (FPG) and 2-hour post-load glucose (2hPG) have been established as individual risk factors for cardiovascular disease (CVD), coronary heart disease (CHD), and stroke. However, it is unclear whether the difference between 2hPG and FPG (2hPG-FPG) within normoglycemic influences the cardiovascular risk in women and men. Purpose To investigate the association between 2hPG-FPG and the incidence of CVD, CHD, and stroke among normoglycemic women and men in a large population-based cohort. Methods In this prospective cohort study, a total of 7224 participants with the normoglycemic state (mean age 37±11; women, 57.4%) that had baseline measurements of both FPG and 2hPG values and did not have prior CVD, CHD, or stroke were included and were followed for incidence of outcomes annually until March 2018. The normoglycemic range was defined as FPG&amp;lt; 5.55 and 2 h-PG&amp;lt; 7.77 mmol/L and not taking anti-diabetic medications. CHD was defined as either positive ECG findings and biomarkers, cardiac symptoms accompanied by either positive ECG or biomarker, or angiographic-proven CHD. Stroke was defined based on the WHO criteria. Also, CVD was defined as a composite of CHD and stroke. A Multivariable Cox­-regression model adjusted for age, body mass index, hypertension, hyperlipidemia, FPG, education level, and smoking status was used to assess the association between 2hPG-FPG and incident CVD, CHD, and stroke in women and men. We also used a cumulative incidence curve to illustrate the cumulative sex-specific incidence of CVD, CHD, and stroke during the follow-up time (Figure 1). Results During a median follow-up of 17.9 years (IQR: 13.75-18.46), 487 CVD (174 women), 427 CHD (140 women), and 76 stroke (37 women) events occurred. Among men, 2hPG-FPG was associated with an increased risk of CVD (hazard ratio [HR]:1.11, 95% confidence interval [CI]:1.01-1.22, p=0.03) and CHD (HR:1.11, 95% CI:1.00-1.22, p=0.04 ), but not stroke (HR:1.14, 95% CI:0.88-1.50, p= 0.33). No significant associations among women were found between 2hPG-FPG and the incidence of outcomes, with adjusted HRs of 1.02 (95% CI, 0.88-1.18, p=0.82), 1.00 (0.85-1.17, p=0.99), and 1.10 (0.80-1.52, p=0.54) for incident CVD, CHD, and stroke, respectively (Table 1). Conclusion A greater difference between 2hPG and FPG (2hPG-FPG) within the normoglycemic range was associated with an increased risk for incidence of CVD and CHD in men but not women. Further studies are warranted to explore the potential use of 2hPG-FPG for cardiovascular risk stratification, particularly among those with normal glucose parameters.Association of 2hPG-FPG with CV riskCumulative incidence of CVD, CHD, stroke

Abstract 16665: Traditional Risk Factors and Acute Coronary Syndrome Free Survival

Introduction: Recent studies claim that the discriminatory power of traditional risk factors (RF) in predicting acute events and mortality from coronary heart disease (CHD) is low. This claim implies a potential misinterpretation, which may negatively affect healthcare organizations Aim: To investigate the association between the four traditional RF, hypertension, current smoking, hypercholesterolemia and diabetes, and the lifetime occurrence of first acute coronary syndrome (ACS) and consequent mortality Methods: We analysed data of 70953 Caucasian patients presenting with first ACS, but without prior CHD enrolled in the ISACS Archives. RF were used to stratify patients into mutually exclusive categories using a balancing strategy by inverse probability weighting. Trends were evaluated by the Pearson's correlation coefficient (r). Primary endpoints were patient’ age at hospital presentation for ACS and rates of all-cause mortality within 30 days after hospital admission Results: For fatal ACS (n=6097), exposure to at least one RF ranged from 77.6% in women to 74.5% in men. The presence of all four RF significantly (P trend&lt;0.001) decreased the age at time of ACS event by nearly half a decade compared with the absence of any RF in both women (from 67.1 to 61.9 years) and men (from 62.8 to 58.9 years). Similar trends were observed for fatal ACS among women (from 73.3 to 67.6 years) and men (from 69.3 to 63.2 years). Current smoking (ORs 4.17 in women; 3.00 in men) and hypercholesterolemia (ORs 1.34 in women; 1.44 in men) were the predominant RFs for premature ACS presentation, with diabetes being the largest for death from premature ACS (ORs 1.50 in women; 1.65 in men). In contrast, there was an inverse association between the presence of RFs and the risk of 30-day mortality. The risk ratios (RR) among individuals with at least one RF vs those with no RFs were 0.72 (95%CI 0.65-0.79) in women and 0.64 (95%CI 0.59-0.70) in men. This association was consistent among patient subgroups Conclusions: In contrast with recent thinking, the presence of traditional RFs is associated with very high lifetime risk of developing ACS and markedly shorter survival. Public health policies should still place significant emphasis on traditional RFs and the lifestyle behaviors causing them

Independent relevance of adiposity measures to coronary heart disease risk among 0.5 million adults in UK Biobank.

Evidence on body fat distribution shows opposing effects of waist circumference (WC) and hip circumference (HC) for coronary heart disease (CHD). We aimed to investigate the causality and the shape of such associations. UK Biobank is a prospective cohort study of 0.5million adults aged 40-69years recruited between 2006 and 2010. Adjusted hazard ratios (HRs) for the associations of measured and genetically predicted body mass index (BMI), WC, HC and waist-to-hip ratio with incident CHD were obtained from Cox models. Mendelian randomization (MR) was used to assess causality. The analysis included 456 495 participants (26 225 first-ever CHD events) without prior CHD. All measures of adiposity demonstrated strong, positive and approximately log-linear associations with CHD risk over a median follow-up of 12.7 years. For HC, however, the association became inverse given the BMI and WC (HR per usual SD 0.95, 95% CI 0.93-0.97). Associations for BMI and WC remained independently positive after adjustment for other adiposity measures and were similar (1.14, 1.13-1.16 and 1.18, 1.15-1.20, respectively), with WC displaying stronger associations among women. Blood pressure, plasma lipids and dysglycaemia accounted for much of the observed excess risk. MR results were generally consistent with the observational, implying causality. Body fat distribution measures displayed similar associations with CHD risk as BMI except for HC, which was inversely associated with CHD risk (given WC and BMI). These findings suggest that different measures of body fat distribution likely influence CHD risk through both overlapping and independent mechanisms.

Physical Activity and Cause-Specific Cardiovascular Mortality Among People With and Without Cardiovascular Disease: A Cohort Study of 0.6 Million US Adults

ObjectiveTo assess the association of physical activity (PA) with cause-specific cardiovascular disease (CVD) mortality among people with preexisting CVD and to analyze the relationship of PA with CVD-related mortality in people without CVD as well as the association of PA with nonspecific CVD mortality in both populations. Participants and MethodsOf the total participants in the 1997 through 2018 US National Health Interview Survey waves, 87,959 adults with CVD and 527,185 without CVD were included. Leisure-time PA was self-reported; based on frequency and duration, minutes per week in PA were calculated and subsequently classified into: (1) none: 0 min/wk, (2) insufficient: 1 to 149.9 min/wk, (3) recommended: 150 to 300 min/wk, and (4) additional: more than 300 min/wk. Mortality data were obtained through link to records from the National Death Index. Statistical analyses were performed with Cox regression adjusted for potential confounders. ResultsDuring a mean follow-up of 8.5 years, 12,893 participants with CVD, 9943 with coronary heart disease (CHD), and 843 with stroke died of CVD mortality, diseases of heart mortality, and cerebrovascular mortality, respectively. In fully adjusted models, compared with no PA, insufficient, recommended, and additional PA were associated with 25.9%, 37.1%, and 42.0% lower risk of diseases of heart mortality among people with prior CHD, respectively. Among people with stroke, recommended and additional PA was related to 30.7% and 59.3% lower risk of cerebrovascular mortality, respectively. The protective effect of PA on cause-specific CVD mortality was greater in people with CVD than in those without prior CVD. Moreover, PA was more markedly inversely associated with cause-specific CVD mortality than with nonspecific CVD mortality in people with CVD. ConclusionPhysical activity was strongly associated with lower risk of CVD-, CHD-, and stroke-related mortality among people with a history of these specific diseases. Health care professionals should emphasize the importance of a physically active lifestyle in patients with CVD.

Suboptimal self-care trajectories of patients with coronary heart disease call for multiple levels of interventions: results from a longitudinal survey study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): University of Akureyri Research Fund Landspitali University Hospital Science Fund. Background Self-care is an important part of secondary prevention for patients with coronary heart disease (CHD). But, we have limited knowledge about how self-care of CHD changes over time. The purpose of this prospective, longitudinal survey study was to determine if distinct trajectories of change in self-care behaviors could be identified following a hospitalization for CHD, and identify which characteristics are helpful in predicting trajectory membership. Methods Patients hospitalized acutely or electively for CHD were included in the study and completed questionnaires at hospital discharge and 6 months later. Self-care was measured with the Self-Care of Coronary Heart Disease Inventory, version 2.2 which consisted of 2 behavioral subscales (i.e., maintenance and management) that were standardized to range from 0-100 with higher scores indicating better self-care. Symptoms of anxiety and depression were assessed with the Hospital Anxiety and Depression Scale and health literacy with the Health Literacy Survey Questionnaire. Latent growth mixture modeling was used to identify distinct trajectories of CHD self-care behaviors over time. Results A total of 430 patients with CHD completed the study (mean age 64.3 ±8.9, 79% male). Overall, self-care was poor at enrollment (maintenance 61.6±15.4, management 53.5±18.5). Two trajectories of self-care behaviours were identified. The first "worse CHD self-care" trajectory (57.2% of the sample) had comparatively worse self-care maintenance and management at both enrollment and 6-month follow-up; self-care maintenance improved slightly (4.0±14.5-point improvement, p&amp;lt;0.001) but self-care management got worse (6.3±24.4-point worsening, p = 0.005) over time in this trajectory. The second "better CHD self-care" trajectory (42.8% of the sample) had comparatively better self-care maintenance and management at both enrollment and 6-month follow-up; self-care maintenance improved slightly (5.0±16.2-point improvement, p&amp;lt;0.001), and self-care management remained unchanged (0.8±21.9-point worsening, p = 0.713) in this trajectory (Figure 1). Predictors of fitting in the "worse CHD self-care" trajectory were older age, lower education, not having prior CHD hospitalizations, worse depression and anxiety symptoms, lower health literacy, and not participating in rehabilitation after hospitalization. Conclusion The determinants of change in CHD self-care overtime are complex and include multiple levels of potential intervention including health systems (e.g. rehabilitation) and individual care (e.g. red flags of poor literacy and affective symptoms). As such, care models which provide sufficient patient education, address mental health and focus on self-care management might help patients improve their self-care behaviour.Trajectories of self-care

Associations of circulating fatty acids with incident coronary heart disease: a prospective study of 89,242 individuals in UK Biobank

BackgroundThe role of fatty acids in coronary heart disease (CHD) remains uncertain. There is little evidence from large-scale epidemiological studies on the relevance of circulating fatty acids levels to CHD risk. This study aims to examine the independent associations of the major circulating types of fatty acids with CHD risk.MethodsUK Biobank is a prospective study of adults aged 40–69 in 2006–2010; in 2012–2013, a subset of the participants were resurveyed. Analyses were restricted to 89,242 participants with baseline plasma fatty acids (measured using nuclear magnetic resonance spectroscopy) and without prior CHD. Cox proportional hazards models were used to estimate hazard ratios (HRs) for the associations with incidence CHD, defined as the first-ever myocardial infarction, unstable angina pectoris, coronary-related death, or relevant procedure. And the major types of fatty acids were mutually adjusted to examine the independent associations. Hazard ratios were corrected for regression dilution using the correlation of baseline and resurvey fatty acids measures.ResultsDuring a median follow-up of 11.8 years, 3,815 incident cases of CHD occurred. Independently of other fatty acids, CHD risk was positively associated with saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA), inversely associated with omega-3 polyunsaturated fatty acids (PUFA), but there was no strong evidence of an association with omega-6 PUFA: HR per standard deviation higher were 1.14 (95% CI, 1.09–1.20), 1.15 (1.10–1.21), 0.91 (0.87–0.94), and 1.04 (0.99–1.09) respectively. Independently of triglycerides and cholesterol, the inverse association with omega-3 PUFA was not materially changed, but the positive associations with SFA and MUFA attenuated to null after adjusting for triglycerides levels.ConclusionsThis large-scale study has quantitated the independent associations of circulating fatty acids with CHD risk. Omega-3 PUFA was inversely related to CHD risk, independently of other fatty acids and major lipid fractions. By contrast, independently of other fatty acids, the positive associations of circulating SFA and MUFA with CHD risk were mostly attributed to their relationship with triglycerides.

Association between control of cardiovascular risk factors and acute myocardial infarction among re-hospitalized young patients with prior coronary heart disease.

Association between control of cardiovascular risk factors and acute myocardial infarction among re-hospitalized young patients with prior coronary heart disease.

Abstract MP24: Atherogenic Gut Microbial Metabolite Scores and Risk of Coronary Heart Disease Among Women in the Nurses’ Health Study

Introduction: Recent evidence suggests that dietary proteins modulate the microbial composition and metabolite production to influence host physiology. Gut-microbiota-related metabolites, such as trimethylamine N-oxide (TMAO) and its precursors, phenylacetylglutamine (PAGln) and p-tolyl (cresol) sulfate, have been recently implicated as atherogenic metabolites derived from the microbial metabolism of protein foods (such as red meat) and amino acids. Hypothesis: We tested a hypothesis that combined effects of atherogenic gut microbiota-related metabolites may be strongly related to the risk of incident coronary heart disease (CHD) among women. Methods: We conducted a prospective nested case-control study of 762 incident cases of CHD (fatal CHD and nonfatal myocardial infarction) and 762 matched controls identified over 10-14 years of follow-up. Plasma metabolites (TMAO, N,N,N-trimethyllysine, PAGln, and p-tolyl (cresol) sulfate) were measured at baseline. We regressed the CHD outcome against metabolites using conditional logistic regression and then calculated an atherogenic microbial metabolite score (AMMS) of CHD by summing the β effects of metabolites. Results: Every 1 SD increment of AMMS was associated with a matching factor-adjusted RR of 1.28 (95% CI: 1.15, 1.44) and a multivariable-adjusted RR of 1.26 (1.12, 1.42) for CHD controlling for demographic, dietary, and lifestyle factors, postmenopausal hormone use, and body mass index. Dose-response analysis showed a linear relation between AMMS and the risk of CHD ( P &lt;0.001). In addition, there was a 1.20 (1.06, 1.36) times increased risk of CHD per 1 SD of AMMS after adjusting for common metabolic comorbidities (diabetes, hypertension, and dyslipidemia). The highest quintile (Q5) group had an adjusted RR of 1.60 (1.08, 2.37) for CHD, as compared to the lowest quintile (Q1) ( Fig ). Conclusions: Atherogenic gut microbiota-related metabolite scores were significantly associated with risk of incident CHD among women without prior CHD.

Abstract 41: Comprehensive Plasma Metabolomic Risk Scores to Predict Incident Coronary Heart Disease Events

Introduction: Integrating multiple metabolomics signatures related to coronary heart disease (CHD) into a metabolomic risk score (MRS) may contribute to improving the risk prediction beyond traditional risk factors, although applications of the MRS remain underdetermined, especially in people at usual risk. Hypothesis: We analyzed associations of plasma metabolites with the risk of CHD to develop MRS for predicting risk of incident CHD by incorporating comprehensive metabolic pathways among women at usual risk from the Nurses’ Health Study (NHS). We also tested whether changes in CHD-related plasma metabolites were associated with significant reductions in atherosclerotic cardiovascular disease (ASCVD) risk scores among participants in the POUNDS Lost trial. Methods: Untargeted metabolomics profiling was performed to measure plasma metabolites at baseline in a prospective nested case-control of 762 incident cases of CHD (fatal CHD and nonfatal myocardial infarction) and 762 matched controls identified over 10-14 years of follow-up time in NHS. An MRS of CHD risk was created based on metabolites that were selected through conditional logistic regression with the elastic net procedure. The POUNDS Lost trial included adults with overweight/obesity who consumed weight-loss diets with different macronutrient intakes. We measured untargeted plasma metabolomics signatures at baseline, 6 months, and 2 years to calculate changes in response to the dietary interventions. The primary outcome in the POUNDS Lost trial was the reduction of 10-year ASCVD risk scores calculated by the validated pooled cohort equations. Results: Various plasma metabolites (such as gut-microbiota-related and others in the pathways of ceramides, phospholipids, and polyamine metabolism) were associated with the risk of incident CHD ( P FDR &lt;0.05). We developed MRS for CHD combining 122 metabolites and found that the highest quartile (Q4) was associated with 11.3 times (95% CI: 6.88, 18.6) higher risk of CHD, as compared to the lowest quartile (Q1), even after adjusting for covariates including common CHD risk factors (such as a family history of MI, lifestyle factors, obesity, diabetes, hypertension, and dyslipidemia). Every 1 SD increment of MRS was associated with an adjusted RR of 3.23 (95% CI 2.62, 3.97) for CHD events. In the POUNDS Lost, diet-intervention-induced changes in CHD-related metabolites, particularly those in ceramide pathways, were significantly associated with reductions in the ASCVD risk score at 6 months and 2 years. Conclusions: Comprehensive metabolomic scores were strongly related to the risk of incident CHD among women without prior CHD. Dietary interventions may modify the unfavorable relations between CHD-risk-related metabolites and ASCVD risk. Further studies in other populations are warranted to validate the performance of MRS in predicting ASCVD events.

Herpes Zoster and Long-Term Risk of Cardiovascular Disease.

Background We investigated the longitudinal association of herpes zoster (HZ), commonly known as "shingles," and long-term risk of stroke or coronary heart disease (CHD) among participants in 3 large US cohorts, the NHS (Nurses' Health Study), NHS II (Nurses' Health Study II), and HPFS (Health Professionals Follow-Up Study). Methods and Results Participants were 79 658 women in the NHS (2000-2016), 93 932 women in the NHS II (2001-2017), and 31 440 men in the HPFS (2004-2016), without prior stroke or CHD. Information on HZ, stroke, and CHD was collected on biennial questionnaires and confirmed by medical record review. Cox proportional hazards regression models were used to estimate multivariable-adjusted hazard ratios for stroke and for CHD according to years since HZ compared with never HZ. During >2million person-years of follow-up, 3603 incident stroke and 8620 incident CHD cases were documented. History of HZ was significantly and independently associated with higher long-term risk of stroke and CHD. In pooled analyses, compared with individuals with no history of HZ, the multivariable-adjusted hazard ratios (95% CIs) for stroke were 1.05 (0.88-1.25) among those with 1 to 4 years since HZ, 1.38 (1.10-1.74) for among those with 5 to 8 years since HZ, 1.28 (1.03-1.59) among those with for 9 to 12 years since HZ, and 1.19 (0.90-1.56) among those with ≥13 years since HZ. For CHD, the corresponding multivariable-adjusted hazard ratios (95% CIs) were 1.13 (1.01-1.27) for 1 to 4 years, 1.16 (1.02-1.32) for 5 to 8 years, 1.25 (1.07-1.46) for 9 to 12 years, and 1.00 (0.83-1.21) for ≥13 years. Conclusions HZ is associated with higher long-term risk of a major cardiovascular event. These findings suggest there are long-term implications of HZ and underscore the importance of prevention.

Assessing the quality of cardiac rehabilitation programs by measuring adherence to the Australian quality indicators

BackgroundEvery year, over 65,000 Australians experience an acute coronary syndrome (ACS) and around one-third occur in people with prior coronary heart disease. Cardiac rehabilitation (CR) aims to prevent a repeat ACS by supporting patients’ return to an active and fulfilling lifestyle. CR programs are efficacious, but audits of clinical practice show variability of program delivery, which may compromise patient outcomes. Core components, quality indicators and accreditation of programs have been introduced internationally to increase program standardisation. With Australian quality indicators (QIs) for cardiac rehabilitation recently introduced, we aimed to conduct a survey in one state of Australia to assess the extent to which programs adhere to the measurement of QIs comparing country, metropolitan, telephone and face to face programs.MethodsA cross- sectional survey design with face validity testing was used to formulate questions to evaluate cardiac rehabilitation program and personnel characteristics and QI adherence. Between October 2020- December 2021, 23 cardiac rehabilitation programs across country and metropolitan areas were invited to participate. Quality improvement was defined as adherence to the Australian Quality Indicators, and we developed an objective score to calculate program performance categorised by quartiles. Significance of CR completion and time to enrolment between program type (telephone versus face to face) and location (country versus metropolitan were compared using Pearson’s Chi-square and Mann–Whitney U tests.ResultsAmong the 23 CR programs, 15 were country and 8 metropolitan-based and 22 were face to face and 1 telephone-based. Median wait time from discharge was 27.0 days, (interquartile range 19.3–46.0) across all programs and country completions of enrolled were 76.9% versus metropolitan 56.5%, p < 0.001 and telephone versus face to face 92.9% versus 59.6% p < 0.001. Pre-program QI adherence was higher than post program for depression, medication adherence, health-related quality of life and comprehensive re-assessment. Seventy four percent of programs were ranked at a medium level of performance (mean score: 11.4/16, SD ± 0.79).ConclusionsA survey of 23 cardiac rehabilitation programs, showed variability in adherence to measurement of the Australian Cardiovascular and Rehabilitation Association and Australian Heart Foundation Cardiac Rehabilitation Quality Indicators.Trial registrationAustralia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12621000222842, registered 03/03/2021.

Abstract 11401: The Association of Carotid-Femoral Pulse Wave Velocity with Coronary and Extra-Coronary Calcification: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Increased carotid-femoral pulse wave velocity (cfPWV) is considered the standard non-invasive measurement of central arterial stiffness and is associated positively with cardiovascular disease. However, its relationship with coronary artery calcium (CAC) and extra-coronary calcification (ECC) in older adults is unclear. Hypothesis: cfPWV has a stronger relationship with aortic calcification as it is a large conduit artery, compared to small end-organ coronary arteries. Methods: In 1,409 ARIC participants aged 74-91 without prior coronary heart disease at visit 7 (2018-19), we quantified associations of cfPWV and high CAC or ECC using multivariable logistic regression models. PWV test was conducted at either visit 6 (2016-2017) or 7, and 725 participants completed PWV test at visit 6. cfPWV was measured using VP-1000plus (Omron Healthcare) and was categorized into tertiles. High CAC and ECC (aortic valve, aortic valve ring, mitral valve, ascending aorta, and descending aorta calcification) &gt;75th percentile of Agatston score were analyzed separately as dependent variables. Results: Those in the highest (vs. lowest) tertile of cfPWV were significantly more likely to have high CAC (adjusted OR 1.66 [1.19, 2.33]) (Table). The strongest association was seen for high descending aorta calcification, with adjusted ORs of 3.53 (2.47, 5.03) for the highest tertile of cfPWV and 1.90 (1.33, 2.71) for the middle tertile, compared with the lowest tertile. High mitral valve calcification but not aortic valve calcification was significantly associated with cfPWV. Conclusions: Higher cfPWV was robustly associated with high calcification of some, but not all, vascular beds examined, especially descending aorta calcification. Our findings further support unique pathophysiological processes across different vascular beds. The robust association between cfPWV and mitral valve calcification warrants future investigation.

Abstract 12334: Concerns About the Use of Digoxin in Acute Coronary Syndromes

Introduction: The use of digitalis has been plagued by controversy since its initial use. Previous observations have shown that digoxin can be safely used in patients with chronic heart failure (HF), but concern remains about the effects of digoxin on mortality in patients with incident HF in the acute setting, especially in those with myocardial infarction. Hypothesis: We aimed to determine the relationship between digoxin use and outcomes in hospitalized patients with acute coronary syndromes (ACS) complicated by HF accounting for sex difference and prior heart diseases. Methods: We analyzed information on 88,774 patients presenting with acute HF (Killip class ≥2) in the International Survey of Acute Coronary Syndromes (ISACS)-Archives (NCT04008173) registry, 4,722 (18.7%) who received digoxin on hospital admission. Patients with pre-existing nonischemic congestive cardiomyopathy and without HF were excluded, leaving a final study population of 25,187 patients. The main outcome measure was all-cause 30-day mortality. Estimates were evaluated by inverse probability of treatment weighting models. Results: Women who received digoxin had a higher rate of death than women who did not receive it (33.8% vs. 29.2 %; relative risk [RR] ratio:1.24;95 % confidence interval [CI]: 1.12-1.37). Similar odds for mortality with digoxin were observed in men (28.5 % vs. 24.9 %; RR ratio 1.20; 95% CI:1.10-1.32). Comparable results were obtained in patients with no prior coronary heart disease (RR ratios:1.26; 95 % CI: 1.10 to 1.45 in women and RR:1.21; 95 % CI: 1.06 to 1.39 in men) and those in sinus rhythm at admission (RR ratios:1.34; 95% CI 1.15 to 1.54 in women and 1.26; 95% CI 1.10 to 1.45 in men). Conclusions: Digoxin therapy is associated with an increased risk of early death among women and men with ACS complicated by HF. This finding highlights the need for re-examination of digoxin use in the clinical setting of ACS.

Concerns about the use of digoxin in acute coronary syndromes.

The use of digitalis has been plagued by controversy since its initial use. We aimed to determine the relationship between digoxin use and outcomes in hospitalized patients with acute coronary syndromes (ACSs) complicated by heart failure (HF) accounting for sex difference and prior heart diseases. Of the 25 187 patients presenting with acute HF (Killip class ≥2) in the International Survey of Acute Coronary Syndromes Archives (NCT04008173) registry, 4722 (18.7%) received digoxin on hospital admission. The main outcome measure was all-cause 30-day mortality. Estimates were evaluated by inverse probability of treatment weighting models. Women who received digoxin had a higher rate of death than women who did not receive it [33.8%vs. 29.2%; relative risk (RR) ratio: 1.24; 95% confidence interval (CI): 1.12-1.37]. Similar odds for mortality with digoxin were observed in men (28.5%vs. 24.9%; RR ratio: 1.20; 95% CI: 1.10-1.32). Comparable results were obtained in patients with no prior coronary heart disease (RR ratio: 1.26; 95% CI: 1.10-1.45 in women and RR ratio: 1.21; 95% CI: 1.06-1.39 in men) and those in sinus rhythm at admission (RR ratio: 1.34; 95% CI: 1.15-1.54 in women and RR ratio: 1.26; 95% CI: 1.10-1.45 in men). Digoxin therapy is associated with an increased risk of early death among women and men with ACS complicated by HF. This finding highlights the need for re-examination of digoxin use in the clinical setting of ACS.

Association of Clonal Hematopoiesis With Incident Heart Failure

BackgroundAge-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). ObjectivesThis study sought to evaluate whether CHIP is associated with incident HF. MethodsCHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. ResultsOf 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. ConclusionsCHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

1129-P: The Genetic Architecture of Cardiovascular Disease in Individuals with Type 2 Diabetes

Background: Type 2 diabetes mellitus (T2DM) is a known risk factor for cardiovascular disease including coronary heart disease (CHD), stroke, and peripheral vascular disease (PVD). However, the genetic underpinnings of cardiovascular disease in those with T2DM is not well understood. Methods: Using 15 studies from dbGaP and the UK Biobank, we conducted the largest to date genome-wide association studies (GWAS) for CHD, stroke and PVD in up to 61,880 individuals with T2DM including 47,140 of European, 8,891 of African, 2,622 of Hispanic, 2,120 of South Asian and 1,107 of East Asian ancestry. GWAS were combined via ancestry-specific and transethnic meta-analyses with fixed-effects. Additional transethnic analysis with MR-MEGA was conducted to account for heterogeneity in allelic effects correlated with ancestry. Results: We replicated previously reported CHD associated loci at genome-wide significance (GW, p≤5×10-8) including 9p21, LPA, and PSRC1. Combining our results with those of prior CHD GWAS in T2DM revealed additional GW significant signals in known CHD loci: PHACTR1, ADAMTS7, HHIPL1, and LPL. European ancestry specific analysis confirmed prior GW significant associations between LPA and PHACTR1 loci and PVD. MR-MEGA analysis of PVD identified novel GW significant loci in CNST and AVPI1. We found a significant genetic correlation of 0.74 (SE= .27) between CHD and PVD. Transethnic analysis of stroke GWAS yielded no GW significant loci. However, African ancestry specific analysis yielded two novel GW signals in the NKAIN2 and BRF1 loci. A significant association between interleukin-6 signaling and stroke was identified using pathway analysis. Conclusions: Ancestry-specific and transethnic analysis of cardiovascular disease in T2DM confirmed prior CHD GWAS findings and revealed novel associations with PVD and stroke that warrant further investigation. Disclosure E. L. Richard: None. S. Cao: None. A. Shadyab: None. R. Salem: None. Funding National Institutes of Health