Composite Cardiovascular Disease Events Research Articles

Abstract 4137914: Eligibility for Semaglutide in US Adults with Diabetes and Potentially Preventable Cardiovascular Events Projected from the SUSTAIN-6 Trial

Background: The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial showed cardiovascular disease (CVD) benefits of semaglutide therapy in patients with type 2 diabetes mellitus (T2DM). Purpose: To estimate the number of US adults with T2DM that may be eligible for semaglutide based on SUSTAIN-6 eligibility criteria and the number of preventable CVD events from semaglutide treatment based on observed CVD event reductions in SUSTAIN-6. Methods: We included US adults with T2DM from the National Health and Nutrition Examination Survey (NHANES) 2011– 2020 who had eligibility criteria from SUSTAIN-6. This included an HbA1c>7.0%, age > 50 with established CVD, heart failure, or chronic kidney disease or an age > 60 with at least one CVD risk factor. We estimated the number of primary composite and secondary CVD endpoints that would occur based on SUSTAIN-6 treated and placebo published event rates, with the difference indicating the number of preventable events (and annualized based on median 2.1 year follow-up time). Results: Among 5002 (projected to 34.0 million [M]) adults we identified with T2DM, we estimated 1,132 (6.9 million) (20.3%) to fit SUSTAIN-6 eligibility criteria. Compared to SUSTAIN-6 trial participants, our sample was slightly older, had a higher proportion of Black participants, shorter duration of diabetes, lower HbA1c and diastolic blood pressure, but similar body mass index and systolic blood pressure. Prior history of ischemic heart disease, myocardial infarction, and stroke were also less common in our NHANES sample. From SUSTAIN-6 semaglutide and placebo primary composite CVD event rates of 6.6% and 8.9%, respectively, we estimated 456,060 and 614,990 events would occur, respectively, for a total of 159,930 preventable CVD events, or 75,681 on an annualized basis. We similarly estimated annualized preventable events for secondary outcomes as shown in the Figure. Conclusion: Semaglutide may prevent many fatal and non-fatal CVD events if provided to US adults meeting SUSTAIN-6 eligibility criteria. More efforts are needed to educate the healthcare providers on the CVD benefits from newer diabetes therapies, including semaglutide.

Abstract 4137917: Eligibility and Preventable CVD Events in US Adults with Cardiovascular Disease and Overweight or Obesity: Projections from the SELECT Trial

Background: The Trial to Evaluate Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT) showed cardiovascular disease (CVD) benefits of semaglutide therapy in patients with preexisting CVD and overweight or obesity. Purpose: To estimate the number of US adults with CVD and overweight or obesity that may be eligible for semaglutide based on SELECT eligibility criteria and the number of preventable CVD events from semaglutide treatment based on observed CVD event reductions in SELECT. Methods: We included US adults from the National Health and Nutrition Examination Survey (NHANES) 2011-2020 who had eligibility criteria from SELECT. This included patients aged > 45 years who had preexisting CVD and a BMI of > 27kg/m 2 but no history of diabetes. Using NHANES sample weighting, we estimated the number of SELECT-eligible US adults and primary composite and secondary CVD endpoints that would occur based on SELECT treated and placebo published event rates, with the difference indicating the number of preventable events (and annualized based on mean 3.3-year follow-up). Results: Among 8783 (projected to 77.9 million [M]) adults with overweight or obesity, we estimated 493 (4.1 million) (5.61%) to fit SELECT eligibility criteria. Compared to SELECT trial participants, our sample had a higher proportion of Black participants and was older with higher levels of diastolic blood pressure, total, LDL and HDL-cholesterol, and lower BMI, HbA1c, eGFR and triglycerides. Prior myocardial infarction was less common, but stroke was more common in our sample. From SELECT semaglutide and placebo primary composite CVD event rates of 6.5% and 8.0%, respectively, we estimated 79949 and 98399 CVD events would occur annually, the difference being 18450 potentially preventable CVD events. Moreover, we similarly estimated 104,549 and 357,928 annual preventable cases of diabetes and pre-diabetes, respectively. The Figure shows the estimated number of primary and secondary CVD outcomes that could be prevented annually. Conclusion: Semaglutide may prevent many fatal and non-fatal CVD events, as well as incident cases of diabetes and pre-diabetes if provided to US adults meeting SELECT eligibility criteria. More efforts are needed to educate clinicians and patients on the benefits of semaglutide 2.4mg in those with preexisting CVD and overweight or obesity.

Cardiovascular Risks With SGLT2 Inhibitors in Clinical Practice Among Patients With Type 2 Diabetes

Cardiovascular disease (CVD) can be recurrent during type 2 diabetes (T2D) progression in this aging population. The effectiveness of sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy on total (ie, first and subsequent) CVD among patients with T2D in clinical practice remains uncertain. To analyze the comparative association of SGLT2i vs dipeptidyl peptidase 4 inhibitor (DPP4i) therapy with total CVD among patients with T2D in clinical practice. This retrospective cohort study used electronic medical records at the National Cheng Kung University Hospital, a leading medical center in Taiwan, from 2015 through 2021. Adult patients with T2D who initiated first use of the study drugs from 2016 through 2019, with up to 6 years of follow-up, were identified. The primary outcomes included total composite CVD events and individual CVD subtypes (ie, atrial fibrillation, coronary heart disease, heart failure, stroke, myocardial infarction, and transient ischemic attack). A shared frailty model analysis was used to assess the association of treatment with repeat CVD events. Data from patients at high risk for CVD recurrence were further analyzed. Data were analyzed from September 1, 2022, to December 31, 2023. Overall, 8384 patients with T2D were identified (mean [SD] age, 63.7 [12.4] years; 4645 [55.4%] male). A total of 1632 propensity score-matched pairs of SGLT2i (mean [SD] age, 57.8 [12.0] years; 673 [41.2%] female and 959 [58.8%] male) and DPP4i (mean [SD] age, 58.2 [12.9] years; 655 [40.1%] female and 977 [59.9%] male) users were included. SGLT2i was associated with reduced total CVD risk vs DPP4i therapy (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98]) but not the first CVD event (with the use of SGLT2i therapy were more prominent for patients at high risk of CVD (ie, HR, 0.70 [95% CI, 0.62-0.80] for individuals with estimated glomerular filtration rate lower than 60 mL/min/1.73 m2; HR, 0.70 [95% CI, 0.64-0.78]; for individuals having any diabetes-related complications; and HR, 0.72 [95% CI, 0.65-0.80] for individuals with a history of CVD) compared with the overall cohort. Among patients at high risk of CVD, greater reduced total CVD burden associated with SGLT2i therapy was observed for women vs men (eg, HR, 0.59 [95% CI, 0.49-0.72] in the subgroup with CVD history). In this cohort study of patients with T2D, the use of SGLT2is vs DPP4is was associated with reduced total cardiovascular burden, suggesting that long-term use of this therapy may optimize treatment benefit among patients with chronic CVD. The SGLT2i-associated benefit among patients with high risk of CVD encourages the prioritization of SGLT2i use for these vulnerable individuals.

Impact of mental disorders on the all-cause mortality and cardiovascular disease outcomes in adults with new-onset type 1 diabetes: A nationwide cohort study

AimsThis population-based study aimed to investigate the impact of mental disorders on the risk of mortality and cardiovascular disease (CVD) outcomes in adults with new-onset type 1 diabetes. Materials and methodsWe included 17,429 patients with new-onset type 1 diabetes without CVD from the Korean National Health Insurance Service database. Mental disorders include depression, bipolar, persistent affective and other affective disorders, anxiety, eating disorders, personality and behavioral disorders, and substance abuse. Individuals with or without mental disorders were matched 1:1 by age, sex, and year of the index date. The primary outcomes were all-cause mortality and composite CVD events. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using multivariate Cox proportional hazards regression models. ResultsDuring a median follow-up of 7.99 years, all-cause mortality (composite CVD outcomes) occurred in 1,562 patients (1,993 patients with CVD outcomes) with mental disorders and 1,211 patients (1,611 patients with CVD outcomes) without mental disorders. The adjusted HR for all-cause mortality and composite CVD outcomes in patients with mental disorders was 1.35 and 1.32, respectively, compared to those without mental disorders. The aHR for the all-cause mortality and composite CVD events was 1.27 and 1.28 in the subgroup with one mental disorder and 1.57 and 1.43 in the subgroup with multiple mental disorders, compared to those without mental disorders. ConclusionsMental disorders are associated with an elevated risk of all-cause mortality and CVD in adults with newly diagnosed type 1 diabetes. Early detection and greater attention to premature death and CVD development are required in patients with new-onset type 1 diabetes and mental disorders.

Biological aging mediates the association between periodontitis and cardiovascular disease: results from a national population study and Mendelian randomization analysis

BackgroundThe relationship between periodontitis and cardiovascular disease (CVD) has been extensively studied, but the role of biological aging in this relationship remains poorly understood. This study is dedicated to investigating the effect of periodontitis on the incidence of CVD and to elucidating the potential mediating role of biological aging. Furthermore, this study will seek to elucidate the causal association between periodontitis, CVD, and biological aging.MethodsWe included 3269 participants from the National Health and Nutrition Examination Survey (2009–2014) with diagnostic information on periodontitis and composite CVD events. Biological aging was evaluated by utilizing both the Klemera–Doubal method’s calculated biological age (KDMAge) and phenotypic age (PhenoAge). Logistic regression, restricted cubic spline (RCS) analysis, and subgroup analysis were used for data analysis. Mediation analysis was employed to explore the mediating role of biological aging. Subsequently, Mendelian randomization (MR) analyses were performed using genome-wide association study databases to explore potential causal relationships between periodontitis, CVD, and biological aging.ResultsPeriodontitis was associated with a higher risk of CVD. Participants with periodontitis were found to have increased levels of biological aging, and elevated levels of biological aging were associated with increased CVD risk. Mediation analyses showed a partial mediating effect of biological aging (PhenoAge: 44.6%; KDMAge: 22.9%) between periodontitis and CVD risk. MR analysis showed that periodontitis played a causal role in increasing the risk of small vessel stroke, while myocardial infarction was found to increase the risk of periodontitis. In addition, reverse MR analysis showed that phenotypic aging can increase the risk of periodontitis, and there is a two-way causal relationship between CVD and biological aging.ConclusionsPeriodontitis is associated with an increased CVD risk, partially mediated by biological aging, with a complex causal interrelationship. Targeted interventions for periodontal health may slow the biological aging processes and reduce CVD risk.

Life’s Essential 8 and Incident Cardiovascular Disease in U.S. Women With Breast Cancer

BackgroundRelationships between lifestyle risk factors and cardiovascular disease (CVD) risk in women with breast cancer (BC) are underexplored. ObjectivesTo evaluate the incidence of CVD in relation to the Life’s Essential 8 (LE8) score among women with BC. MethodsData from the Women’s Health Initiative were utilized. The primary exposure was the LE8 score assessed prior to BC diagnosis. The LE8 score was stratified into low (0-59), moderate (60-79), and high (80-100) cardiovascular health (CVH). The primary endpoint was a composite of incident CVD events, which included coronary heart disease, defined as myocardial infarction along with coronary revascularization, CVD death, and stroke. We calculated the cumulative incidence of CVD and estimated hazard ratios. ResultsAmong 7,165 participants, the median age was 70.1 years at BC diagnosis. The mean LE8 score was 62.0 ± 12.2. Over a median follow-up period of 6 years, 490 composite CVD events occurred. The risk of CVD events was highest for low CVH compared with moderate and high CVH. Compared with low CVH, the hazard ratio for incident CVD was 0.57 (95% CI: 0.46-0.69) for moderate CVH and 0.34 (95% CI: 0.20-0.59) for high CVH. LE8, in conjunction with age, provided a C-statistic of 0.74 for the composite risk of CVD. ConclusionsHigher LE8 scores were associated with a lower risk of incident CVD among women with BC in the United States.

BP classification using the 2017 ACC/AHA BP guidelines with risk of cardiovascular events in older individuals

BackgroundThe association between stage 1 hypertension and the risk of cardiovascular disease (CVD) has not been established in older adults. Furthermore, little is known about whether lowering blood pressure (BP) is beneficial in older adults with stage 1 hypertension. MethodsThis cohort study analyzed nationwide data collected from the Japanese DeSC database, including 476,654 individuals aged ≥60 years. Individuals were categorized into four groups according to the 2017 ACC/AHA BP guidelines: normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension. The primary outcome was a composite CVD event, including myocardial infarction, angina pectoris, stroke, and heart failure. ResultsDuring a mean follow-up of 3.1 years, 53,946 composite CVD events were recorded. Hazard ratios of stage 1 hypertension for composite CVD events, myocardial infarction, angina pectoris, stroke, and heart failure were 1.10 (95 % CI, 1.07–1.13), 1.16 (95 % CI, 1.03–1.31), 1.06 (95 % CI, 1.01–1.10), 1.13 (95 % CI, 1.08–1.18), and 1.13 (95 % CI, 1.09–1.16), respectively. Individuals with a ≥5 mmHg decrease in systolic BP over one year had a lower risk of stroke among individuals with stage 1 hypertension. The positive association between stage 1 hypertension and composite CVD events was attenuated in individuals aged ≥75 years. ConclusionsStage 1 hypertension is associated with a higher risk of developing CVD events among older adults. The 2017 ACC/AHA BP guidelines could be applied to older populations; however, the applicability of these guidelines to older adults aged ≥75 years requires further investigations.

Cardiovascular and Kidney Outcomes of Non-Diabetic CKD by Albuminuria Severity: Findings From the CRIC Study

The clinical trajectory of normoalbuminuric chronic kidney disease (CKD), particularly in the absence of diabetes, has not yet been well-studied. This study evaluated the association of kidney and cardiovascular outcomes with levels of albuminuria in a cohort of patients with nondiabetic CKD. Prospective cohort study. 1,463 adults with nondiabetic CKD without known glomerulonephritis and diagnosed with hypertensive nephrosclerosis or unknown cause of CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. Albuminuria stage at study entry. Primary outcome: Composite kidney (halving of estimated glomerular filtration rate [eGFR], kidney transplantation, or dialysis), Secondary outcomes: (1) eGFR slope, (2) composite cardiovascular disease events (hospitalization for heart failure, myocardial infarction, stroke, or all-cause death), (3) all-cause death. Linear mixed effects and Cox proportional hazards regression analyses. Lower levels of albuminuria were associated with female sex and older age. For the primary outcome, compared with normoalbuminuria, those with moderate and severe albuminuria had higher rates of kidney outcomes (adjusted hazard ratio [AHR], 3.3 [95% CI, 2.4-4.6], and AHR, 8.6 [95% CI, 6.0-12.0], respectively) and cardiovascular outcomes (AHR, 1.5 [95% CI, 1.2-1.9], and AHR, 1.5 [95% CI, 1.1-2.0], respectively). Those with normoalbuminuria (<30μg/mg; n=863) had a slower decline in eGFR (-0.46mL/min/1.73m2 per year) compared with those with moderate (30-300μg/mg, n=372; 1.41mL/min/1.73m2 per year) or severe albuminuria (>300μg/mg, n=274; 2.63mL/min/1.73m2 per year). In adjusted analyses, kidney outcomes occurred, on average, sooner among those with moderate (8.6 years) and severe (7.3 years) albuminuria compared with those with normoalbuminuria (9.3 years) whereas the average times to cardiovascular outcomes were similar across albuminuria groups (8.2, 8.1, and 8.6 years, respectively). Self-report of CKD etiology without confirmatory kidney biopsies; residual confounding. Participants with normoalbuminuric nondiabetic CKD experienced substantially slower CKD progression but only modestly lower cardiovascular risk than those with high levels of albuminuria. These findings inform the design of future studies investigating interventions among individuals with lower levels of albuminuria. Diabetes and hypertension are the leading causes of chronic kidney disease (CKD). Urine albumin levels are associated with cardiovascular and kidney disease outcomes among individuals with CKD. However, previous studies of long-term clinical outcomes in CKD largely included patients with diabetes. As well, few studies have evaluated long-term outcomes across different levels of urine albumin among people without diabetes. In this study, we found individuals with nondiabetic CKD and low urine albumin had much slower decline of kidney function but only a modestly lower risk of a cardiovascular events compared with those with high levels of urine albumin. Individuals with low urine albumin were much more likely to have a cardiovascular event than progression of their kidney disease. These findings inform the design of future studies investigating treatments among individuals with lower levels of albuminuria.

Association between depressive symptoms and cardiovascular diseases in the Korean geriatric population: A nationwide retrospective cohort study

IntroductionDepression has emerged as a modifiable risk factor for cardiovascular disease (CVD). However, evidence on whether depressive symptoms measured using a self-report questionnaire are associated with CVD incidence is scarce. Therefore, we aimed to investigate the association between depressive symptoms and CVD risk using data from national health examinations and insurance claim records. MethodsThis retrospective cohort study included participants who underwent the Korean National Screening Program for Transitional Ages at age 66 years between 2007 and 2017. The presence of depressive symptoms was defined as affirmative responses to any of three questions (loss of activities and interests, worthlessness, and hopelessness) selected from the Geriatric Depression Scale. Incident composite CVD event included myocardial infarction, stroke, heart failure, and CVD death. The association between depressive symptoms and CVD risk was evaluated using hazard ratios (HRs) and 95 % confidence intervals (CIs) estimated with Cox proportional hazards models. ResultsAmong 88,765 participants (48.5 % women) aged 66 years, 4036 incident CVD events occurred during a mean follow-up of 6.8 years. Participants with depressive symptoms had a significantly higher risk of CVD than those without depressive symptoms (adjusted HR = 1.16 [95 % CI: 1.07–1.24]). The three individual depressive symptoms showed similar associations with CVD risk (loss of activities and interests, adjusted HR = 1.17 [95 % CI: 1.08–1.26]; worthlessness, 1.15 [1.03–1.29]; hopelessness, 1.13 [1.01–1.26]). LimitationsThe study was limited to participants aged 66 years. Despite extensive adjustment for potential confounders and multiple sensitivity analyses, residual confounding and reverse causality could not be ruled out. ConclusionThe presence of depressive symptoms was associated with an increased risk of CVD. Screening for depressive symptoms in the general population may effectively mitigate the burden of CVD.

Age-Dependent Relationship of Physical Inactivity With Incident Cardiovascular Disease: Analysis of a Large Japanese Cohort

BackgroundThere have been limited studies examining age-dependent associations between physical inactivity and cardiovascular disease (CVD). We aimed to clarify the age-dependent relationship of physical inactivity with incident CVD. MethodsWe analyzed 1,097,424 participants, aged 18 to 105 years, without histories of CVD, enrolled in the DeSC database (median age, 63 years; 46.4% men). We categorized participants into the following 4 groups based on age: ≤ 44 years (n = 203,835); 45 to 64 years (n = 403,619); 65 to 79 years (n = 437,236); and ≥ 80 years (n = 52,734). We used 3 physical inactivity components gained from the self-reported questionnaire during a health checkup. The outcomes were composite CVD events including myocardial infarction, stroke, heart failure, and each CVD event. ResultsDuring a mean follow-up of 3.2 ± 1.9 years, 81,649 CVD events were observed. The hazard ratios of 3 physical inactivity components for CVD events increased with age category (P for interaction < 0.001). For example, the hazard ratio (95% confidence interval) of physical inactivity defined as not doing light sweaty exercise for 30 minutes at least twice a week for incident CVD in the groups aged ≤ 44 years, 45 to 64 years, 65 to 79 years, and ≥ 80 years were 0.97 (0.88-1.05), 1.08 (1.05-1.12), 1.12 (1.10-1.15), and 1.17 (1.12-1.21), respectively (P for interaction < 0.001). This association was consistent across subtypes of CVD including heart failure, myocardial infarction, and stroke. ConclusionsThe association of physical inactivity with a higher risk of developing CVD increased with age. Preventive efforts for physical activity optimization may be more valuable in older people.

Machine learning model for cardiovascular disease prediction in patients with chronic kidney disease.

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). This study aimed to develop CVD risk prediction models using machine learning to support clinical decision making and improve patient prognosis. Electronic medical records from patients with CKD at a single center from 2015 to 2020 were used to develop machine learning models for the prediction of CVD. Least absolute shrinkage and selection operator (LASSO) regression was used to select important features predicting the risk of developing CVD. Seven machine learning classification algorithms were used to build models, which were evaluated by receiver operating characteristic curves, accuracy, sensitivity, specificity, and F1-score, and Shapley Additive explanations was used to interpret the model results. CVD was defined as composite cardiovascular events including coronary heart disease (coronary artery disease, myocardial infarction, angina pectoris, and coronary artery revascularization), cerebrovascular disease (hemorrhagic stroke and ischemic stroke), deaths from all causes (cardiovascular deaths, non-cardiovascular deaths, unknown cause of death), congestive heart failure, and peripheral artery disease (aortic aneurysm, aortic or other peripheral arterial revascularization). A cardiovascular event was a composite outcome of multiple cardiovascular events, as determined by reviewing medical records. This study included 8,894 patients with CKD, with a composite CVD event incidence of 25.9%; a total of 2,304 patients reached this outcome. LASSO regression identified eight important features for predicting the risk of CKD developing into CVD: age, history of hypertension, sex, antiplatelet drugs, high-density lipoprotein, sodium ions, 24-h urinary protein, and estimated glomerular filtration rate. The model developed using Extreme Gradient Boosting in the test set had an area under the curve of 0.89, outperforming the other models, indicating that it had the best CVD predictive performance. This study established a CVD risk prediction model for patients with CKD, based on routine clinical diagnostic and treatment data, with good predictive accuracy. This model is expected to provide a scientific basis for the management and treatment of patients with CKD.

Risk of cancer history in cardiovascular disease among individuals with hypertension

Hypertension is the leading risk factor for cardiovascular disease (CVD). Although cancer has recently been increasingly recognized as a novel risk factor for CVD events, little is known about whether co-morbid cancer in individuals with hypertension could further increase the risk of CVD events. We sought to determine the association between the cancer history and the risk of CVD in individuals with hypertension. We retrospectively analyzed a large cohort of 747,620 individuals diagnosed with hypertension from January 2005 through May 2022 using the JMDC Claims Database. Composite CVD events, including myocardial infarction (MI), angina pectoris (AP), stroke, heart failure (HF), and atrial fibrillation (AF), were recorded, and a Cox proportional hazard regression was done to estimate hazard ratios (HR) based on the history of cancer and chemotherapy. 26,531 individuals had a history of cancer. During the mean follow-up period of 1269 ± 962 days, 67,154 composite CVD events were recorded. Compared with individuals without a cancer history, cancer survivors had a higher risk of developing composite CVD events (HR: 1.21, 95% confidence interval [CI]: 1.17–1.26). The HRs (95% CIs) associated with cancer history for MI, AP, stroke, HF, and AF were 1.07 (0.90–1.27), 1.13 (1.06–1.20), 1.14 (1.06–1.24), 1.31 (1.25–1.38), and 1.22 (1.10–1.35), respectively. Lastly, individuals who had received chemotherapy for cancer had a particularly higher risk of developing CVD compared to those who did not undergo chemotherapy. A history of cancer was associated with a greater risk of developing CVD among individuals with hypertension.

Long-Term Body Mass Index Variability and Adverse Cardiovascular Outcomes

Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is a commonly used estimate of obesity, which is a complex trait affected by genetic and lifestyle factors. Marked weight gain and loss could be associated with adverse biological processes. To evaluate the association between BMI variability and incident cardiovascular disease (CVD) events in 2 distinct cohorts. This cohort study used data from the Million Veteran Program (MVP) between 2011 and 2018 and participants in the UK Biobank (UKB) enrolled between 2006 and 2010. Participants were followed up for a median of 3.8 (5th-95th percentile, 3.5) years. Participants with baseline CVD or cancer were excluded. Data were analyzed from September 2022 and September 2023. BMI variability was calculated by the retrospective SD and coefficient of variation (CV) using multiple clinical BMI measurements up to the baseline. The main outcome was incident composite CVD events (incident nonfatal myocardial infarction, acute ischemic stroke, and cardiovascular death), assessed using Cox proportional hazards modeling after adjustment for CVD risk factors, including age, sex, mean BMI, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes status, and statin use. Secondary analysis assessed whether associations were dependent on the polygenic score of BMI. Among 92 363 US veterans in the MVP cohort (81 675 [88%] male; mean [SD] age, 56.7 [14.1] years), there were 9695 Hispanic participants, 22 488 non-Hispanic Black participants, and 60 180 non-Hispanic White participants. A total of 4811 composite CVD events were observed from 2011 to 2018. The CV of BMI was associated with 16% higher risk for composite CVD across all groups (hazard ratio [HR], 1.16; 95% CI, 1.13-1.19). These associations were unchanged among subgroups and after adjustment for the polygenic score of BMI. The UKB cohort included 65 047 individuals (mean [SD] age, 57.30 (7.77) years; 38 065 [59%] female) and had 6934 composite CVD events. Each 1-SD increase in BMI variability in the UKB cohort was associated with 8% increased risk of cardiovascular death (HR, 1.08; 95% CI, 1.04-1.11). This cohort study found that among US veterans, higher BMI variability was a significant risk marker associated with adverse cardiovascular events independent of mean BMI across major racial and ethnic groups. Results were consistent in the UKB for the cardiovascular death end point. Further studies should investigate the phenotype of high BMI variability.

Sex Differences in the Association Between Depression and Incident Cardiovascular Disease

BackgroundDepression is a known risk factor for cardiovascular disease (CVD), but the potential sex differences in this association remain unclear. ObjectivesThe aim of this study was to investigate the association between depression and subsequent CVD events, and to explore potential sex differences. MethodsThe authors conducted a retrospective analysis using the JMDC Claims Database between 2005 and 2022. The study population included 4,125,720 individuals aged 18 to 75 years without a history of cardiovascular disease or renal failure and missing data at baseline. Participants were followed up for a mean of 1,288 days to assess the association between depression and subsequent CVD events, such as myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. ResultsOur analysis revealed a significant association between depression and subsequent composite CVD events in both men and women, with a stronger association observed in women. The HR for the composite endpoint was 1.64 (95% CI: 1.59-1.70) in women and 1.39 (95% CI: 1.35-1.42) in men after multivariable adjustment (P for interaction <0.001). Furthermore, the individual components of the composite endpoint were also associated with depression in both men and women, each of which was also observed to be more strongly associated in women. ConclusionsOur study provides evidence of a significant association between depression and subsequent CVD events in both men and women, with a more pronounced association observed in women. These findings highlight the importance of addressing depression and tailoring prevention and management strategies according to sex-specific factors.

Sex Differences in the Relationship Between Schizophrenia and the Development of Cardiovascular Disease.

There are few data on sex differences in the association between schizophrenia and the development of cardiovascular disease (CVD). We sought to clarify the relationship of schizophrenia with the risk of developing CVDs and to explore the potential modification effect of sex differences. We conducted a retrospective analysis using the JMDC Claims Database between 2005 and 2022. The study population included 4 124 508 individuals aged 18 to 75 years without a history of CVD or renal replacement therapy. The primary end point is defined as a composite end point that includes myocardial infarction, angina pectoris, stroke, heart failure, atrial fibrillation, and pulmonary thromboembolism. During a mean follow-up of 1288±1001 days, we observed 182 158 composite end points. We found a significant relationship of schizophrenia with a greater risk of developing composite CVD events in both men and women, with a stronger association observed in women. The hazard ratio for the composite end point was 1.63 (95% CI, 1.52-1.74) in women and 1.42 (95% CI, 1.33-1.52) in men after multivariable adjustment (P for interaction=0.0049). This sex-specific difference in the association between schizophrenia and incident CVD was consistent for angina pectoris, heart failure, and atrial fibrillation. Our analysis using a large-scale epidemiologic cohort demonstrated that the association between schizophrenia and subsequent CVD events was more pronounced in women than in men, suggesting the clinical importance of addressing schizophrenia and tailoring the CVD prevention strategy based on sex-specific factors.

Associations of trajectories in body roundness index with incident cardiovascular disease: a prospective cohort study in rural China.

The body roundness index (BRI) has good predictive ability for both body fat and visceral adipose tissue. Longitudinal BRI trajectories can reveal the potential dynamic patterns of change over time. This prospective study assessed potential associations between BRI trajectories and incident cardiovascular disease (CVD) in rural regions of Northeast China. In total, 13,209 participants (mean age: 49.0 ± 10.3 years, 6,856 [51.9%] male) were enrolled with three repeated times of BRI measurements at baseline (2004-2006), 2008, and 2010, and followed up until 2017 in this prospective study. Using latent mixture model, the BRI trajectories were determined based on the data from baseline, 2008 and 2010. Composite CVD events (myocardial infarction, stroke, and CVD death combined) was the primary endpoint. Cox proportional-hazards models were used to analyze the longitudinal associations between BRI trajectories and incident CVD. Three distinct BRI trajectories were identified: high-stable (n = 538), moderate-stable (n = 1,542), and low-stable (n = 11,129). In total, 1,382 CVD events were recorded during follow-up. After adjustment for confounders, the moderate-stable and high-stable BRI groups had a higher CVD risk than did the low-stable BRI group, and the HR (95%CI) were 1.346 (1.154, 1.571) and 1.751 (1.398, 2.194), respectively. Similar associations were observed between the trajectories of BRI and the risk of stroke and CVD death. The high-stable group was also significantly and independently associated with CVD, myocardial infarction, stroke, and CVD death in participants aged <50 years. BRI trajectory was positively associated with incident CVD, providing a novel possibility for the primary prevention of CVD in rural regions of China.

Impact of Hypomethylating Agents on Cardiovascular Disease Risk Among Patients with Myelodysplastic Syndromes

Introduction: The association between clonal hematopoiesis (CH) and cardiovascular disease (CVD) risk has drawn attention to cardiovascular outcomes in myelodysplastic syndromes (MDS). CVD accounts for 25% of deaths in MDS, potentially via CH-mediated accelerated atherosclerosis from inflammatory vascular responses. We previously demonstrated that MDS was independently associated with increased risk of CVD in older adults from SEER-Medicare. We subsequently hypothesized that treatment with hypomethylating agents (HMA) could reduce CVD risk by ameliorating CH clones and reducing the inflammation. In this study, we aimed to define the impact of HMA on incident cardiovascular events among older adults with MDS. Methods: We identified subjects ≥66 years diagnosed with MDS from 2007 to 2017 in SEER-Medicare. Exclusion criteria including lacking continuous Medicare parts A, B, and D, enrolled in HMO, or incomplete follow-up. Demographics included age, sex, race, rurality, socioeconomic quintile, marital status, and geographic region. Baseline CVD risk factors, defined from ICD-9/10 codes, included hypertension, hyperlipidemia, diabetes, atrial fibrillation, pre-existing cardiac disease, obesity, and smoking. MDS factors, defined using HCPCS codes, ICD-O-3 codes and prescription records, included MDS subtype and histologic risk stratification, transfusion dependence and treatment with hypomethylating agents (HMA), lenalidomide, or erythropoietin-stimulating agents (ESA) as time-varying variables. Incident CVD was defined as new myocardial infarction (MI) and/or ischemic stroke occurring after MDS diagnosis, using published ICD-9/10 algorithms. We controlled for confounding using 2 complementary analytic approaches. First, we assessed the association between HMA use and CVD using propensity score adjusted cause-specific competing risk Cox hazard models with death as competing risk, Second, we used a case-crossover design with conditional logistic regression, in which subjects with CVD served as their own controls, using a 3-month HMA treatment window and a control period 6 months prior to the incident event. Results: We identified a cohort of 15,227 eligible patients with MDS. Of these, 1,125 patients had an MI and/or ischemic stroke within 1 year before MDS diagnoses and were excluded. We analyzed 14,102 MDS patients, with median age 82 years (IQR 77 - 86), who were predominantly male (53.8%), non-Hispanic white (88.6%), and from urban/suburban areas (86.2%). MDS was of low, intermediate, and high histologic risk in 14.7%, 72.8%, and 12.5%, respectively, and 28.6% were transfusion dependent. Pre-existing CVD risk factors at time of MDS diagnosis were present in 12,538 patients, with baseline cardiovascular risk defined as low, intermediate, and high in 11.1%, 32.3%, and 56.6% of the cohort. The cumulative incidences of MI, ischemic stroke and composite CVD events were 11.3%, 10.6% and 20.4%, respectively. The propensity score (PS) conditional probability for being treated with HMA included demographic variables, CVD risk factors, MDS histology and transfusion dependence. Our PS model adequately predicted HMA treatment propensity (AUC 0.76). Cause-specific regression with death as competing risk, adjusted for PS and other MDS-specific treatments (ESA and lenalidomide), showed no significant effect of HMA on the risk of composite CVD events, MI, or ischemic stroke (Table 1). Conditional logistic regression in the case-crossover analysis of 1,907 patients with composite CVD events showed no significant effect of HMA. Results were similar for analysis of patients with MI and ischemic stroke (Table 2). Conclusions: No study has previously investigated the effect of HMA therapy on cardiovascular outcomes in patients with MDS. We demonstrate that HMA therapy is not associated with a significant risk reduction in cardiovascular events among patients with MDS patients from the SEER-Medicare database. These results show that HMA therapy is unlikely to reduce cardiovascular mortality and underscore the need for alternative therapeutic strategies targeting cardiovascular health patients with MDS.

Vitamin D Metabolites and Risk of Cardiovascular Disease in Chronic Kidney Disease: The CRIC Study.

Background The ratio of 24,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95-1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0-1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

Subtypes of Type 2 Diabetes and Incident Cardiovascular Disease Risk: UK Biobank and All of Us Cohorts

ObjectiveTo characterize and validate the subtypes of type 2 diabetes (T2D) using a novel clustering algorithm and to further assess their associations with the risk of incident cardiovascular disease (CVD) events. MethodsUnsupervised k-means clustering based on glycated hemoglobin level, age at onset of T2D, body mass index, and estimated glomerular filtration rate was conducted among participants with T2D from the UK Biobank (March 13, 2006, to October 1, 2010) and replicated in the All of Us cohort (May 30, 2017, to April 1, 2021). ResultsFive distinct T2D clusters were identified in the UK Biobank and validated in the All of Us cohort, characterizing the phenotypically heterogeneous subtypes. With a median follow-up of 11.69 years for patients with T2D in the UK Biobank, risks of incident CVD events varied considerably between the clusters after adjustment for potential confounders and multiple testing (all P<.001). With cluster 1 characterized by early onset of T2D and mild abnormalities of other variables as the reference, patients in cluster 5 characterized by poor renal function had the highest risk of CVD events (hazard ratio [95% CI], 1.72 [1.45 to 2.03], 2.41 [1.93 to 3.02], and 1.62 [1.35 to 1.94] for composite CVD event, CVD mortality, and CVD incidence, respectively; all P<.001), followed by cluster 4 characterized by poor glycemic control and cluster 3 characterized by severe obesity. No consistently significant difference was found between cluster 2 characterized by late onset of T2D and cluster 1. ConclusionOur study, using a novel clustering algorithm to identify robust subtypes of T2D, found heterogeneous associations with incident CVD risk among patients with diabetes.

Does inclusion of cognitive measures improve the predictive performance of SCORE2 for future cardiovascular events in older adults?

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104) - Funded by the European Union – Next Generation EU. Introduction The cardiovascular disease (CVD) risk prediction model SCORE2 uses several biomedical and behavioural factors. It is likely that other factors also contribute to CVD risk prediction. Cognitive impairment and CVD are associated and share several risk factors. While the causality of this relationship remains unclear, adding cognitive measures to risk prediction may improve the prediction of future CVD events. Objective We tested the hypothesis that including simple measures of cognitive functions improve the prediction of SCORE2 for future CVD events among middle aged and older subjects. Methods We used data on 13,391 Polish, Lithuanian and Czech adults without CVD at baseline (45–69 years) from the Health, Alcohol and Psychosocial factors In Eastern Europe cohort. Incident cases of myocardial infarction (MI), stroke, CVD mortality and composite (fatal and non-fatal) CVD events were identified over a 10-year follow-up. Baseline cognitive measures included immediate and delayed word recall (verbal memory and learning), animal naming (verbal fluency) and letter cancellation (attention, mental speed and concentration). Using competing-risks regression, relationships between cognitive functions and CVD outcomes were examined. Improvement in Area Under Curve Receiver Operator Characteristic (AUC-ROC) was used to compare predictive performance for CVD events of models including SCORE2 variables combined with cognitive tests vs SCORE2 alone. Results The incidence rates of MI, stroke, CVD mortality and composite CVD events were 5%, 4%, 4% and 11%, respectively. In multivariable analyses, all four cognitive measures were inversely associated with CVD outcomes; e.g. one standard deviation increase in immediate word recall score was associated with a 28% and 17% reduction in risk of CVD mortality and composite CVD events, respectively (all p-values &amp;lt;0.001). Adding cognitive measures to SCORE2 variables slightly improved the AUC-ROC for prediction of MI, CVD mortality and composite CVD events. For example, for the composite CVD measure, inclusion of all four cognitive measures increased the AUC-ROC from 0.6948 to 0.7030 (p&amp;lt;0.001) and similar improvement was seen for word recall. The results were consistent across countries. Conclusion Inclusion of a simple cognitive test in the assessment of cardiovascular health is feasible and it may improve prediction of future CVD risk, although in our data the improvement was not clinically important (despite being statistically significant). Further studies are needed to assess this proposition in larger prospective datasets.