High Risk Of Cardiovascular Events Research Articles

Hyperandrogenism after menopause: diagnostic evaluation

Excessive androgen levels in women after menopause often result from an imbalance in ovarian steroid secretion: a rapid decline in estrogen secretion associated with a slow decrease in androgen secretion, compounded by a physiological decrease in sex hormone-binding globulin. Hyperandrogenism is associated with a higher risk of cardiovascular events and gynecological neoplasms, also impacting the emotional well-being of affected women. Therefore, the aim of these guidelines is to guide the clinical physician in the appropriate clinical and biochemical evaluation of hyperandrogenism after menopause, thus optimizing therapeutic outcomes. The most frequent consultation in this stage of life is facial hirsutism associated with hair loss. If the onset of signs is abrupt, severe, associated with virilization and accompanied by serum testosterone levels in the male range, it is necessary to rule out a tumoral origin. A thorough medical history guides the diagnosis. Determination of total testosterone using reliable methods and imaging studies are valid tools to assist when doubts arise in the differential diagnosis.

Cardiovascular, Metabolic, and Safety Outcomes with Semaglutide by Baseline Age: Post Hoc Analysis of SUSTAIN6 and PIONEER6.

The high risk of cardiovascular events in people with type2 diabetes increases with age. The cardiovascular effects of once-weekly subcutaneous and once-daily oral semaglutide versus placebo in people with type2 diabetes at high cardiovascular risk were investigated in the SUSTAIN6 and PIONEER6 cardiovascular outcomes trials, respectively. It is unknown whether the effects of semaglutide are age dependent. This post hoc analysis evaluated cardiovascular, metabolic, and safety outcomes with semaglutide versus placebo in age subgroups (≤ 60; > 60 to ≤ 65; > 65 to ≤ 70; and > 70years) pooled from SUSTAIN6 and PIONEER6. Major adverse cardiovascular events (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), changes from baseline in glycated hemoglobinA1c (HbA1c) and body weight, and adverse events were analyzed. Semaglutide reduced major adverse cardiovascular events and its components versus placebo across age subgroups (most hazard ratios < 1.0; pinteraction > 0.05). The treatment difference in HbA1c reduction was greater in those aged ≤ 60years than in older subgroups (pinteraction = 0.01). Reductions in body weight with semaglutide versus placebo were consistent across agesubgroups (pinteraction = 0.124). Serious adverse events or severe hypoglycemic episodes did not differ between semaglutide and placebo across age subgroups. Semaglutide consistently reduced major adverse cardiovascular events and body weight versus placebo across age subgroups; its safety profile did not differ with age. These results suggest that relaxing HbA1c targets based solely on age may not always be required for people with type2 diabetes. SUSTAIN6 (NCT01720446) and PIONEER6 (NCT02692716) are registered at ClinicalTrials.gov.

Cardiovascular risk according to biological agent exposure in patients with ankylosing spondylitis: a nationwide population-based study.

Patients with ankylosing spondylitis (AS) have a higher risk of cardiovascular events than controls. Although biological disease-modifying anti-rheumatic drugs (bDMARDs) are efficacious in treating AS, their effect on cardiovascular risk remains unclear. This study evaluated the effect of tumour necrosis factor inhibitors (TNFis) and interleukin-17 inhibitors (IL-17is) on cardiovascular risk in patients with AS. Data of 43,502 patients diagnosed with AS from 2010 onwards and without prior history of cardiovascular events were extracted from the Korean nationwide database. Cardiovascular events were defined as incident myocardial infarctions or strokes. Patients were followed-up through 2021. The risk of cardiovascular events was compared between TNFis exposure (vs. bDMARDs non-exposure), IL-17is exposure (vs. bDMARDs non-exposure), and IL-17is exposure (vs. TNFis exposure), using time-dependent Cox models. The incidence rates of cardiovascular events during bDMARDs non-exposure, TNFis exposure, and IL-17is exposure were 18.66, 8.92, and 12.87 per 10,000 person-years, respectively. TNFis exposure (vs. bDMARDs non-exposure) was significantly associated with a lower risk of cardiovascular events (adjusted hazard ratio [aHR] = 0.697, 95% confidence interval [CI] = 0.499-0.973), whereas IL-17is exposure (vs. bDMARDs non-exposure) was not (aHR = 0.962, 95% CI = 0.134-6.920). The risk of cardiovascular events did not differ between IL-17is and TNFis exposures (aHR = 1.381, 95% CI = 0.189-10.087). TNFis exposure (vs. bDMARDs non-exposure) was associated with approximately 30% lower risk of cardiovascular events in patients with AS. IL-17is exposure had no significant association with the risk of cardiovascular events compared with bDMARDs non-exposure or TNFis exposure. Key Points • TNFis exposure was associated with a 30% lower cardiovascular risk in patients with AS. • IL-17is exposure had no significant association with cardiovascular risk in patients with AS. • TNFis could be the preferred bDMARD with regard to cardiovascular risk in patients with AS.

Systemic Immune Inflammatory Index as Predictor of Blood Pressure Variability in Newly Diagnosed Hypertensive Adults Aged 18–75

Background: Accumulating evidence from clinical trials, large registries, and meta-analyses of population studies shows that increased Blood Pressure Variability (BPV) is predictive of Cardiovascular (CV) outcomes, independently of the average Blood Pressure (BP) values. One of the mechanisms explaining the relationship between BPV and target organ damage is the inflammatory response. The Systemic Immune Inflammation Index (SII), which relies on peripheral blood cell counts, including platelets, neutrophils, and lymphocytes, has emerged as a predictor of prognosis and outcomes in various diseases. The aim of this study was to investigate the association of the SII with Ambulatory Blood Pressure Variability (ABPV) in newly diagnosed hypertensive patients. Methods: This study was designed as a cross-sectional observational study. A total of 1606 consecutive newly diagnosed Hypertension (HT) patients were included in the study. The population was evaluated across 3 different categories according to HT grades (5 groups), eligibility for antihypertensive therapy (2 groups) and ABPV levels (2 groups). Results: Significant differences were observed between ABPV groups in terms of Neutrophil to Lymphocyte ratio, Platelet to Lymphocyte ratio, glucose, SII, high-sensitive CRP, HT grade, Inter-Ventricular Septum, Posterior Wall thickness, and Left Ventricular Mass (p &lt; 0.005). There was a significant relationship between SII and ABPV (r: 0.619, p &lt; 0.05). At the cutoff value of 580.49, SII had 77% sensitivity and 71% specificity for ABPV &gt; 14 (AUC: 0.788). Conclusions: SII may assist in developing an early treatment approach to minimize complications in patients with high ABPV who are at a higher risk of CV events.

QRISK3 and SCORE2 are equally reliable predictors of carotid plaques in patients with systemic lupus erythematosus.

Cardiovascular (CV) disease is the leading cause of death among patients with systemic lupus erythematosus (SLE). This study aimed to compare the performance of QRESEARCH-risk estimator version 3 (QRISK3) and the Systematic Coronary Risk Evaluation-2 (SCORE2) scores to identify SLE patients at high risk of CV events, as indicated by the presence of carotid plaques. Subclinical atherosclerosis was evaluated using carotid ultrasound in 365 SLE patients. QRISK3 and SCORE2 were calculated. The relationship between these scores and the presence of carotid plaques was analyzed by treating the scores as continuous and categorical variables, and separately and in combination. Logistic regression and area under the receiver operating characteristic curve (AUC) analyses were used to assess their predictive accuracy. The discriminatory capacity of QRISK3, with an AUC of 0.770 (95%CI : 0.720, 0.821), and SCORE2, with an AUC of 0.800 (95%CI : 0.753, 0.843), for carotid plaque was similar, with no statistically significant difference (p= 0.070). However, when examining the association of both calculators considered continuously and together with their interaction, the discriminatory capacity of this combination was significantly greater than that of QRISK3 alone (p= 0.034) but did not differ from SCORE2 (p= 0.71). QRISK3 and SCORE2 are equally reliable predictors of carotid plaques in SLE patients. The combination of both calculators offers significantly better discrimination than QRISK3 alone but shows no significant difference when compared with SCORE2 alone. Therefore, SCORE2 alone, without the need for additional tools, can be used to identify patients with SLE who are at high risk of CV events.

Arterial calcification volume is associated with a higher risk of cardiovascular events in pseudoxanthoma elasticum

Background and aims– Pseudoxanthoma elasticum (PXE) patients have more arterial calcification due to lower levels of inorganic pyrophosphate, caused by mutations in the ABCC6 gene, but the relation with vascular complications is poorly understood. Because of the slow progressing nature of arterial disease in PXE patients, there is a need for a valid and reliable intermediate endpoint to be used in future clinical trials. Arterial calcification measured on computed tomography (CT) is a promising candidate, if associated with future cardiovascular events. We aimed to establish the relation between arterial calcification measured on CT and future cardiovascular events in patients with PXE. Methods– In this prospective cohort study, patients with PXE from the Dutch UMC Utrecht Expertise Center for PXE (UECP) were included. Arterial calcification volume was measured on low dose full body CT scans. Patient were followed for incident cardiovascular events. The relation between arterial calcification and the risk of cardiovascular events was analyzed using Cox proportional hazard models. Results– In 326 patients (median follow-up 6.0, IQR 3.8 – 8.2 years) 41 cardiovascular events were observed (21 events per 1000 person years). In patients with no cardiovascular history, there was a significant relation between the log arterial calcification volume at baseline and future cardiovascular events (adjusted HR: 1.87, 95% CI: 1.14 – 3.09, per 1 log unit increase in arterial calcification). There was no relation in patients with clinical manifest cardiovascular disease at baseline between arterial calcification volume and future cardiovascular events. Conclusions– Higher arterial calcification volumes on CT in PXE patients are associated with a higher risk of a first cardiovascular event. This cohort study suggests that arterial calcification can be used as an intermediate endpoint in studies evaluating interventions to lower the risk of cardiovascular events.

Evaluating the risk of cardiovascular events associated with different immunosuppression treatments for glomerular diseases.

Patients with glomerular disease are at high risk of cardiovascular disease but the contribution of immunosuppression to this risk is unclear. In this retrospective cohort study of 1912 patients (comprised of 759 with IgA nephropathy, 540 with focal segmental glomerulosclerosis, 387 with membranous nephropathy and 226 with minimal change disease) from British Columbia, Canada, we evaluated the association between exposure to specific immunosuppressive medications and a composite outcome including coronary artery, cerebrovascular and peripheral arterial events. Survival models were adjusted for baseline cardiovascular risk factors, type of glomerular disease, estimated glomerular filtration rate (eGFR) and proteinuria over time. During a median follow-up of 6.8 years, 212 patients (11.1%) experienced the primary outcome. Corticosteroid exposure was not significantly associated with the primary outcome after adjusting for cardiovascular risk factors. In fully adjusted models, cumulative calcineurin inhibitor exposure at modest (150-300 defined daily doses [DDD]) and higher (300 or more DDD) doses were associated with a 2-fold higher risk of cardiovascular events (hazard ratio 2.98, 95% confidence interval 1.27-6.95) and (2.78, 1.32-5.84), respectively. A peak daily dose of antimetabolite (azathioprine, mycophenolate mofetil and mycophenolate sodium) of 0.5 or more DDD was associated with higher risk of cardiovascular events after adjustment for baseline risk factors and type of glomerular disease, but not after adjusting for time-varying eGFR and proteinuria (1.70, 0.91-3.20). Each 10 grams of cumulative cyclophosphamide exposure was associated with a 1.5-fold higher risk of cardiovascular events in a fully adjusted model (1.46, 1.22-1.75) Thus, our findings suggest that immunosuppressive therapies used in the treatment of glomerular disease may have different cardiovascular risk profiles, which should be considered when deciding on immunosuppression for individual patients and as a safety endpoint in future clinical trials.

A Randomized Controlled Trial of Gamification to Increase Physical Activity Among Black and Hispanic Breast and Prostate Cancer Survivors: Rationale and Design of the ALLSTAR Clinical Trial

Survivors of breast and prostate cancer, especially those that are Black and/or Hispanic, are at high risk for cardiovascular events. Physical activity can reduce the risk of cardiovascular events in cancer survivors, but Black and Hispanic people are less likely to engage in routine physical activity. Concepts from behavioral economics have been used to design scalable, low-touch, gamification interventions that increase physical activity in individuals at high risk for cardiovascular events, but the effectiveness of these strategies in Black and Hispanic survivors of breast and prostate cancer is uncertain. ALLSTAR (NCT05176756) is a pragmatic, virtual, randomized controlled trial designed to evaluate the effectiveness of a gamification intervention informed by behavioral economic concepts to increase daily physical activity in Black and Hispanic breast and prostate cancer survivors who received cardiotoxic therapies and have additional risk factors for cardiovascular disease. Patients were either referred by their cancer care team or identified by electronic health record searches; contacted by letter, email, text message and/or phone; and complete enrollment and informed consent on the Penn Way to Health online platform. Patients are then provided with a wearable fitness tracker, establish a baseline daily step count, set a goal to increase daily step count by 1500-3000 steps from baseline, and are randomized 1:1 to control or gamification. Interventions continue for 6 months, with follow-up for an additional 3 months to evaluate the durability of behavior change. The trial has met its enrollment goal of 150 participants, with a primary endpoint of change from baseline in daily steps over the 6-month intervention period. Key secondary endpoints include change from baseline in daily steps over the 3-month post-intervention follow-up period, change in moderate to vigorous physical activity over the intervention and follow-up periods, and change in patient-reported measures of physical function, fatigue, and overall quality of life. ALLSTAR is a virtual, pragmatic randomized clinical trial powered to demonstrate whether gamification is superior to control in increasing physical activity in Black and Hispanic breast and prostate cancer survivors. Its results will have important implications for strategies to promote physical activity in survivors of breast and prostate cancer, specifically among minority populations. clinicaltrials.gov; https://clinicaltrials.gov/study/NCT05176756.

Excessive occupational sitting increases risk of cardiovascular events among working individuals with type 1 diabetes in the prospective Finnish Diabetic Nephropathy Study

BackgroundSedentary behavior, such as excessive sitting, increases risk of cardiovascular disease and premature mortality in the general population, but this has not been assessed in type 1 diabetes. Occupational sitting is increasingly ubiquitous and often constitutes the largest portion of daily sitting time. Our aim was to identify clinical factors associated with excessive occupational sitting in type 1 diabetes and, in a prospective setting, to explore its association with cardiovascular events and all-cause mortality, independent of leisure-time physical activity.MethodsAn observational follow-up study of 1,704 individuals (mean age 38.9 ± 10.1 years) from the Finnish Diabetic Nephropathy Study. Excessive occupational sitting, defined as ≥ 6 h of daily workplace sitting, was assessed using a validated self-report questionnaire. Data on cardiovascular events and mortality were retrieved from national registries. Multivariable logistic regression identified independently associated factors, while Kaplan-Meier curves and Cox proportional hazard models were used for prospective analyses.ResultsFactors independently and positively associated with excessive occupational sitting included a high occupational category [OR 6.53, 95% CI (4.09‒10.40)] and older age [1.02 (1.00‒1.03)], whereas negatively associated factors included current smoking [0.68 (0.50‒0.92)], moderate albuminuria [0.55 (0.38‒0.80)], and high leisure-time physical activity [0.52 (0.36‒0.74)]. During a median follow-up of 12.5 (6.5–16.4) years, 163 individuals (9.6%) suffered cardiovascular events, and during a median follow-up of 13.7 (9.4–16.6) years, 108 (6.3%) deaths occurred. Excessive occupational sitting increased cardiovascular event risk (hazard ratio [HR] 1.55 [95% CI 1.10‒2.18]) after adjustment for confounders and other covariates. Furthermore, in a stratified multivariable analysis among current smokers, excessive occupational sitting increased the risk of all-cause mortality (2.06 [1.02‒4.20]).ConclusionsExcessive occupational sitting is associated with a higher risk of cardiovascular events and all-cause mortality in individuals with type 1 diabetes. This association persists regardless of leisure-time physical activity, after adjusting for independently associated variables identified in our cross-sectional analyses. These findings underscore the need to update physical activity guidelines to better address sedentary behavior and improve outcomes for individuals with type 1 diabetes. Targeting occupational sitting should be considered a key focus for interventions aimed at reducing overall sedentary time.

Delirium and risk of incident cardiovascular events in elderly: data from a global health research network

Abstract Introduction Delirium is a common complication of acute medical disorders. A strong association between cardiovascular events and the occurrence of delirium has been recorded. Thus far, no data are available regarding the risk of incident cardiovascular events after delirium onset in older adults. Methods Using data from TriNetX, a global health federated research network, we performed a propensity score matched (PSM) analysis of older adults (age ≥65 years) admitted to the emergency department (ED) reporting delirium within two weeks, who were compared with those without delirium. We evaluated the occurrence of a composite outcome of cardiovascular events (myocardial infarction, ischemic stroke, heart failure, intracranial haemorrhage, ventricular arrhythmias, takotsubo syndrome, and atrial fibrillation) at 30 days and 1 and 3 years of follow-up. Results 4,480,229 patients were retrieved for the analysis, and 82,693 (1.8%) reported delirium. Before PSM, patients reporting delirium were older, with more prevalent comorbidities. After PSM, a total of 165,386 patients were included in the analysis (mean (SD) age 76.6 (9.0) years, 51.1% females). Throughout the entire follow-up period, the cumulative composite cardiovascular events outcome was significantly higher in patients which reported delirium [Red Line, Figure 1]. Delirium was associated with cardiovascular events at 30 days (HR 1.96, 95% CI 1.92-2.00) ,1 year (HR 1.75, 95% CI 1.72-1.78) and 3 years (HR 1.67, 95% CI 1.64-1.69) of follow-up, as well as for each of its components (Table 1). The presence of delirium was also associated with a higher risk of all-cause death and hospital access (Table 1), evaluated as secondary outcomes. In patients with delirium associated with the occurrence of incident cardiovascular events, there was a higher risk of recurrent cardiovascular events at 1 year (HR 3.11, 95% CI 2.92-3.31) and 3 years (HR 2.84, 95% CI 2.67-3.01) of follow-up. Conclusions In a large, unselected cohort of older adults admitted to ED, occurrence of delirium was associated with a higher risk of cardiovascular events, both in the short and long-term follow-up.Figure 1:Delirium and CV EventsTable 1:Cox Regression Analysis

Remnant cholesterol and mortality in 37.559 patients from LIPIDOGRAM 2004, 2006 and 2015 studies

Abstract Introduction Remnant cholesterol (remnant-C) is produced by metabolism of triglyceride rich proteins and contributes to residual cardiovascular (CVD) risk. Purpose To asses association between remnant cholesterol and all-cause mortality in a large cohort of patients under the care primary care physicians. Methods The LIPIDOGRAM studies were carried out in the primary care in Poland in 2004, 2006 and 2015. Patients (n=47,398) recruited in all 16 administrative regions in Poland and physicians were proportionally distributed to the number of inhabitants in each administrative region. Each patient was asked to fill the questionnaire on risk factors, chronic diseases, treatment, and lifestyle. In the present analysis we included consecutive patients with body mass index (BMI) &amp;gt;18.5 kg/m2 aged 18-70 years. Median follow up was (5.3 years (interquartile range 5.7-17.3). For this analysis we approved the cut-off point of fasting remnant cholesterol &amp;gt;30 mg/dL (&amp;gt;0.77 mmol/L) that differentiated subjects at high risk of cardiovascular events. We used univariate and multivariate Cox regression modelling to assess the association between remnant-C and all-cause mortality. Results Finally, 37,559 patients were included meeting the inclusion criteria and for which the follow-up data was available. Mean remnant-C concentration was: 27 mg/dl / 0.7 mmol/l (standard deviation 15 mg/dl/ 0.38 mmol/l). Remnant-C was associated with 5-year mortality and overall mortality during the study period, with hazard ratios (HR) of 1.21 (95% CI: 1.04-1.41, p&amp;lt;0.001) and 1.42 (95% CI: 1.32-1.53, p&amp;lt;0.001) for each 1 mmol/l increase, respectively. After adjusting for age, sex, BMI, education level, place of residence, hypertension, diabetes mellitus, smoking, previous myocardial infarction, metabolic syndrome presence, and statin and fibrate treatments, remnant-C was associated with long-term mortality—HR (per 1 mmol/l) of 1.08 (95% CI: 1.00-1.17, p=0.049)—but not with 5-year mortality—HR (per 1 mmol/l) of 0.97 (95% CI: 0.83-1.13, p=0.7). Predefined level of remnant-C &amp;gt; 30 mg/dl (0.77 mmol/l) was associated with higher 5 year (HR- 1.15, 95%CI (1.02-1.31, p=0.021) (Figure 1A) and long-term all-cause mortality (HR- 1.26, 95%CI (1.19-1.33, p&amp;lt;0.001) (Figure 1B). Conclusions Higher remnant-C cholesterol levels are associated with long term all-cause mortality in patients aged 18-70 years.

Neutrophil-to-lymphocyte ratio can predict the clinical prognosis of patients with primary adosteronism

Abstract Background Excess aldosterone-mediated inflammatory response is thought to be a factor in the high risk of cardiovascular events in patients with primary aldosteronism (PA). Leucocyte related inflammatory parameters, especially NLR, were significantly independent of aldosterone (PAC) in PA patients. However, the impact of NLR on the long-term prognosis of PA patients is unclear. Objective To explore the predictive value of neutrophil-to-lymphocyte ratio (NLR) on the long-term prognosis of patients with primary aldosteronism (PA). Methods The data for this study were derived from the Tianjin Health and Medical Big Data Super platform, comprising a retrospective cohort of patients discharged from 72 hospitals in our city from 2010 to 2023. According to the inclusion and exclusion criteria, 570 patients were ultimately included in the statistical analysis. Each patient had laboratory measurements, including blood cell counts, taken after admission and before interventional treatment. The primary endpoint was major cardiovascular events (MACEs), defined as cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke. Results During a mean follow-up period of 5 years, 125（21.9%）MACEs were recorded. ROC curve analysis displayed that the best cut-off value of NLR for predicting MACEs was 4.87. The MACEs of the high NLR group at 1 year, 3 years, and 5 years were higher than those of the low NLR group（25.0% vs 9.4%，40.3% vs17.1% 和 40.3% vs 19.3%；P＜0.05).Kaplan-Meier survival curve analysis showed that the survival rate of the low NLR group was higher than that of the high NLR group (P&amp;lt;0.001). The results of multivariate Cox proportional hazards regression analysis showed that NLR was an independent risk factor affecting the prognosis of PA patients, and the difference was statistically significant (P&amp;lt;0.05). Conclusions Elevated NLR is associated with adverse prognosis in patients with PA. NLR can serve as a simple and practical indicator to evaluate the long-term prognosis of PA patients. These findings warrant external validation, preferably in a prospective design.

Remnant cholesterol, clinical characteristics and mortality in 41.767 patients from LIPIDOGRAM 2004-2015 studies - the factor analysis for mixed data cluster analysis

Abstract Introduction Remnant cholesterol (remnant-C) contributes to residual cardiovascular risk and is produced by metabolism of triglyceride rich proteins. Aim To assess association between clinical characteristics of patients with elevated remnant-C in a large cohort of patients under the care of primary care physicians. Methods The LIPIDOGRAM studies were carried out in the primary care in Poland in 2004, 2006 and 2015. Patients (n=47,398) recruited in all 16 administrative regions in Poland and physicians were proportionally distributed to the number of inhabitants in each administrative region. Each patient was asked to fill the questionnaire on risk factors, chronic diseases, treatment and lifestyle. In the present analysis we included patients with body mass index (BMI )&amp;gt;18.5 kg/m2 aged 18-75 years. We set the cut-off point of fasting remnant cholesterol at &amp;gt;30 mg/dL (&amp;gt;0.77 mmol/L) that differentiated subjects at high risk of cardiovascular events. We carried out Factor Analysis for Mixed Data (FAMD) cluster analysis to discern groups of patients with similar clinical profiles. Results 41,767 patients, for which we had all relevant data, were included in the analysis. Follow-up rate was 97.8%. Three FAMD-derived clinical characteristics patterns accounted for 47.8% of the total variance and were retained for further analysis. The first pattern was associated with higher prevalence of metabolic syndrome (MetS), higher waist circumference, higher levels of non-HDL-C and remnant-C levels. The second pattern was distinguished by lipid parameters, particularly higher HDL-C levels, and was not significantly associated with comorbid conditions. The third pattern was linked to male sex, previous myocardial infarction, smoking, age, lower remnant-C levels, and reduced prevalence of obesity. All patterns were associated with 5-year mortality. The hazard ratio (HR) for mortality per 1 standard deviation (SD) increase in the first pattern score was 1.18 (95% CI: 1.16-1.22, p&amp;lt;0.001). Patients with clinical characteristics corresponding to second pattern had more favorable outcome HR (per 1SD score increase) – 0.75, 95%CI (0.73-0.78, p&amp;lt;0.001). Patients in third cluster, similarly to patients in cluster 1 had increased mortality HR (per 1SD score) – 1.10, (95%CI:1.06-1.15, p &amp;lt;0.001). Higher (&amp;gt;0.77 mmol/l / 30 mg/dl) remnant-C cholesterol significantly contributed to classification of patients into first and third clusters. It was positively associated with first pattern (r=0.64, p&amp;lt;0.001), but negatively with the third pattern (r=0.39, p&amp;lt;0.001). Conclusions Elevated Remnant-C was associated with clinical pattern typical for metabolic syndrome. Interestingly, lower remnant-C levels in patients with comorbidities and more advanced age may not automatically be indicative of a better prognosis – this requires further investigation.Figure 1.Figure 2.

Long-term cardiovascular events in individuals hospitalised with COVID-19: a retrospective cohort

Abstract Background The post-COVID condition involves a range of persistent or new symptoms affecting various organs, including an increased risk of cardiovascular issues. As there are limited data on cardiovascular events in post-acute COVID-19 patients, we aimed to estimate their incidence and assess its association with patient and infection characteristics in Portugal. Methods We conducted a registry-based retrospective cohort study from seven hospitals across Portugal, including individuals hospitalised due to COVID-19 between March 2020 and March 2021. Our outcome of interest was cardiovascular events in the post-acute phase of COVID-19, occurring at least 30 days after the positive SARS-CoV-2 test. The variables of interest considered were the severity of the episode, existing cardiovascular risk and vaccination status before the SARS-CoV-2 test. Person-years and incidence rates were estimated. A Cox proportional hazard regression model was employed to assess risk factors. Results We included 1,803 patients in the analysis, of which 143 (7.9%) experienced at least one cardiovascular event following COVID-19 hospitalisation. The overall incidence rate of having at least one cardiovascular event was 34.65 per 1,000 person-years (95% confidence interval (CI): 29.20; 40.82). We found a higher risk of cardiovascular events for individuals with pre-existing cardiovascular risk (adjusted hazard ratio (aHR): 3.76, 95% CI: 1.53; 9.24) and lower risk for individuals with at least one vaccine dose before the SARS-CoV-2 test (partial - aHR: 0.44, 95%CI: 0.30; 0.64, complete - aHR: 0.46, 95%CI: 0.2; 0.80). We did not find a significant difference between the severity of the COVID-19 episode and the risk of having cardiovascular events post-COVID-19. Conclusions Our results indicate the presence of cardiovascular complications post-COVID-19, emphasising the need for healthcare systems to initiate screening and preventive strategies for individuals deemed at elevated risk. Key messages • COVID-19 vaccination decreases the risk of cardiovascular events post-COVID-19. • Healthcare systems should start screening and preventive strategies for individuals with pre-existing risk of cardiovascular events.

Diabetes and the risk of cardiovascular events and all-cause mortality among older adults: an individual participant data analysis of five prospective studies.

Guidelines and studies provide conflicting information on whether type 2 diabetes (T2D) should be considered a coronary heart disease risk (CHD) equivalent in older adults. We synthesized participant-level data on 82,723 individuals aged ≥65 years from five prospective studies in two-stage meta-analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D (presence versus absence) on a primary composite outcome defined as cardiovascular events or all-cause mortality. Secondary outcomes were the components of the composite. We evaluated CHD risk equivalence by comparing outcomes between individuals with T2D but no CHD versus CHD but no T2D. The median age of participants was 71 years, 20% had T2D and 17% had CHD at baseline. A total of 29,474 participants (36%) experienced the composite outcome. Baseline T2D was associated with higher risk of cardiovascular events or all-cause mortality versus no T2D (HR 1.44, 95% CI [1.40-1.49]). The association was weaker in individuals aged ≥75 years versus 65-74 years (HR 1.32 [1.19-1.46] vs. 1.56 [1.50-1.62]; p-value for interaction = .032). Compared to individuals with CHD but no T2D, individuals with T2D but no CHD had a similar risk of the composite outcome (HR 0.95 [0.85-1.07]), but a lower risk of cardiovascular events (HR 0.76 [0.59-0.98]). T2D was associated with increased risk of cardiovascular events and all-cause mortality in older adults, but T2D without CHD conferred lower risk of cardiovascular events compared to CHD without T2D. Our results suggest that T2D should not be considered a CHD risk equivalent in older adults.

Sex related cardiovascular risk is non-dichotomous: artificial intelligence enhanced electrocardiography reveals continuum of risk in females

Abstract Background Females are typically underserved in cardiovascular medicine and often considered lower risk of cardiovascular disease. The use of sex as a dichotomous variable for risk stratification fails to capture the heterogeneity of risk within each sex. Purpose We aimed to develop an artificial intelligence-enhanced ECG (AI-ECG)-derived continuous sex score that can capture the continuum of risk and sex phenotypes within each sex, with the particular goal of addressing the female disadvantage. Methods We trained a convolution neural network to identify sex using the 12-lead ECG. The derivation cohort was 1,163,401 ECGs from 189,538 subjects from a USA secondary care hospital cohort and validated inthe UK Biobank (UKB). The model outputs a continuous value from 0 to 1 for sex prediction. The AI-ECG sex discordance score is the difference between predicted sex and biological sex. Results AI-ECG accurately identified sex in both the USA cohort (AUROC 0.943 (0.942-0.943)) and UKB datasets (n = 42,386, AUROC 0.971 (0.969-0.972)). In explainability analyses we found QRS duration, T wave morphology, QT interval, heart rate and QRS voltage as the most important factors in contributing to AI-ECG sex identification. In females only but not in males, sex discordance score was associated with a covariate-adjusted increased risk of cardiovascular death in outpatients with normal ECGs from the USA cohort, (Females hazard ratio (HR) 1.64 (1.18-2.29) p = 0.003, Males HR 1.04 (0.66-1.63), p = 0.86). This pattern persisted in the UKB: Females HR 1.39 (1.08-1.78) p = 0.01, Males HR 0.97 (0.77-1.22), p = 0.80, Fig 1). In phenome-wide association studies, we found females with a higher sex score discordance were more likely to have heart failure or myocardial infarction. Covariate-adjusted cox models confirmed the association of sex score discordance with increased future heart failure (HR 1.21 (1.07-1.37) p = 0.002 and future myocardial infarction (HR 1.32 (1.11-1.56) p = 0.001). In age- and body size-adjusted analyses, females with higher sex discordance score had increased left ventricular mass, and chamber volumes as well as increased muscle mass, reduced body fat percentage (Fig 2). In a genome-wide association study of sex discordance score we identified variants adjacent to IGF1R and NDRG4 in females, which have been previously associated with LV mass and sex hormone levels (Fig 2). Conclusion We describe sex discordance score as a novel AI-ECG biomarker capable of identifying females with disproportionately elevated cardiovascular risk. Sex discordance score may help uncover potential underlying mechanisms of cardiovascular disease among females, and future clinical studies are needed to determine its potential utility in identification of females at higher risk of cardiovascular events. Rather than exacerbating biases, AI-ECG has the potential to reduce female cardiovascular health inequalities.

Prediction of cardiovascular risk in patients type 2 diabetes using the SCORE2-Diabetes risk score

Abstract Background/Introduction The SCORE2-Diabetes risk score was developed to predict the risk of cardiovascular events (CV-death, non-fatal MI and non-fatal stroke) in patients with T2DM without known cardiovascular disease. Current ESC guidelines recommend the use of this risk score to tailor treatment strategies in this population. Purpose We sought to determine whether the SCORE2-Diabetes risk score was able to appropriately stratify an international cohort of patients from recent cardiovascular clinical outcomes trials. Furthermore, we sought to determine the accuracy and precision of the model including in patients with and without known cardiovascular disease. Methods Patients from 4 randomized cardiovascular outcome trials (DEVOTE, LEADER, PIONEER-6, SUSTAIN-6) were included (n=23,464). Mean follow-up was 2.6 years and outcomes were adjudicated. The SCORE2-Diabetes risk score was calculated using the uncalibrated version which does not account for risk-region. Patients were stratified into low (&amp;lt;5%), moderate (5-&amp;lt;10%), high (10-&amp;lt;20%), and very high risk (≥20%) groups. The SCORE2-Diabetes risk predication model was designed to predict 10-year risk; however, given the mean follow-up from the cohort, outcomes were reported at 36 months. The Brier score, which evaluates estimated risk, and c-index, which evaluates the ability to discriminate between participants, were used to evaluate the precision of the risk score. We further compared the risk score with an estimated risk of MACE calculated using a cause specific Cox model that accounts for competing risk. Results Most patients in the cohort did not have prior myocardial infarction or stroke (57.4%, n=13,467). The SCORE2-Diabetes risk score was able to stratify patients into low, moderate, high, and very high risk cohorts (Figure 1). Observed cardiovascular events at 36 months were higher than the SCORE2-Diabetes risk score predicted (Table 1). The risk score, when included in a regression model, independently predicted cardiovascular death, myocardial infarction, or stroke (HRadj 1.03, p&amp;lt;0.001) and non-cardiovascular death (HRadj 1.05, p&amp;lt;0.001). Including the score in models with only age and sex improved the discrimination and performance of the model. The c-index for the risk score in the overall cohort was 0.62 and was 0.66 in the cohort without known cardiovascular disease. When using the Brier score to evaluate the utility of the model, the Brier score of the SCORE2-D model was 0.08 which is no different than a null model which assumes a baseline risk of 10% in all patients. Conclusion In a cohort of patients that was older, more geographically diverse, and at higher risk of cardiovascular events, the SCORE2-D risk score appropriately stratified patients into categories of risk. However, the overall risk prediction underestimated the risk of cardiovascular events and the discrimination of the risk score was modest.Figure:CV events over timeTable:CV events by risk group

C-C motif chemokine ligand 3 is associated with atherosclerotic plaque vulnerability and increased risk of mortality

Abstract Background and Purpose Chemokines play a crucial role in the inflammatory process underlying atherosclerotic plaque formation, progression and subsequent cardiovascular events. However, the specific role of C-C motif chemokine ligand 3 (CCL3) in atherosclerosis remains largely unexplored. This study aims to explore associations between intra-plaque levels of CCL3 and plaque vulnerability as well as to investigate the prognostic role of circulating CCL3 levels in patients undergoing carotid endarterectomy. Methods The CCL3 protein expression was measured using a proximity extension assay in 207 human carotid plaques and 558 plasma samples from patients undergoing carotid endarterectomy, all enrolled in the Carotid Plaque Imaging Project (CPIP) cohort. Protein expression is quantified as normalized protein expression (NPX), an arbitrary unit on a log2-scale. Plaque components and extracellular matrix including smooth muscle cells, macrophages, neutral lipids, intraplaque hemorrhage, collagen (by histology), and matrix metalloproteinases (assessed biochemically), were quantified. Plaque vulnerability index was calculated as the sum percentage of plaque areas stained for lipids, macrophages and hemorrhage, divided by the sum percentage of smooth muscle cells and collagen. Patients were followed up to 10.2 years to record cardiovascular events and mortality. Results Plaque and circulating levels of CCL3 were higher in symptomatic patients compared to asymptomatic patients (plaque, median NPX (interquartile range, IQR): 18.2 (17.4–19.1) vs 17.2 (16.4–18.0), P&amp;lt;0.001; plasma, median NPX (IQR): 1.78 (1.42–2.21) vs 1.56 (1.28–1.97), P&amp;lt;0.001). Plaque levels of CCL3 showed positive correlations with neutral lipids, macrophages, intraplaque hemorrhage, plaque vulnerability index and matrix metalloproteinases including MMP1, MMP2, MMP9, MMP10 and TIMP1, but inversely with smooth muscle cells. Among 511 patients with complete follow-up and circulating CCL3 measures, 144 (28.2%) patients developed cardiovascular events and 123 (24.1%) patients died. Elevated circulating CCL3 levels were associated with increased risk of cardiovascular events (hazard ratio (HR) per standard deviation (SD) = 1.40, 95% CI 1.06–1.84) and mortality (HR per SD=1.77, 95% CI 1.34–2.33), respectively. Higher levels of circulating CCL3 remained independently associated with an increased risk of mortality (HR per SD=1.50, 95% CI 1.09–2.04) even after adjustment for potential confounders. Conclusions Plaque levels of CCL3 are associated with plaque vulnerability features. Circulating levels of CCL3 predict higher risk of cardiovascular events and mortality among carotid endarterectomy patients.

Race in heart failure: a pooled participant-level analysis of the global PARADIGM-HF and PARAGON-HF trials

Abstract Background Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF). Early experiences with neprilysin inhibition suggested possible increased risks of angioedema, especially among Black individuals. We aimed to examine the safety and efficacy profile of sacubitril/valsartan in a pooled participant-level dataset of 2 large cohorts of patients with HF by self-reported race. Methods PARADIGM-HF and PARAGON-HF were multicenter, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor (RASi, enalapril or valsartan, respectively) in patients with HF and LVEF ≤40% (PARADIGM-HF) or LVEF ≥45% (PARAGON-HF). We included all patients with available data on self-reported race and categorized patients as White, Asian, or Black. We assessed adjudicated outcomes including the composite of first HF hospitalization (HFH) or cardiovascular (CV) death, its components, and angioedema by racial group. Results Among 12,097 included participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Asian participants were from 19 countries, with highest enrollment from India, China, and the Philippines. Black participants were from 18 countries, with highest enrollment from the US, South Africa, and Brazil. Black patients had the worst baseline health status (adjusted KCCQ-OSS mean 70.3), while White (71.4) and Asian patients (76.4) had better health status; P&amp;lt;0.001. Over 2.4-years of median follow-up, Black (adjusted HR 1.67; 95% CI 1.37-1.89; P&amp;lt;0.001) and Asian patients (adjusted HR 1.32; 95% CI 1.16-1.50; P&amp;lt;0.001) experienced higher risks of the primary outcome compared with White patients (Figure 1). The treatment effects of sacubitril/valsartan vs. RASi on the primary endpoint were consistent among White (HR 0.84; 95% CI: 0.77-0.91), Asian (HR 0.92; 95% CI: 0.78-1.10), and Black patients (HR 0.79; 95% CI: 0.58-1.07; Pinteraction = 0.39). In light of higher baseline risks, Black patients accrued the greatest absolute risk reduction with sacubitril/valsartan (Figure 2). Consistent treatment benefits by race were also observed for the individual components (CV death alone and first HFH alone). Rates of any adjudicated angioedema were numerically higher with sacubitril/valsartan vs. RASi across race groups (White 0.4% vs. 0.2%; Asian 0.6% vs. 0.2%; Black 2.3% vs. 0.8%), however no patient in either trial experienced airway compromise or required mechanical airway protection. Conclusions In a pooled experience of over 12,000 participants enrolled in 2 trials conducted across 56 countries, Black and Asian patients exhibited a higher risk of CV events than White patients. Rates of non-serious angioedema were numerically higher with sacubitril/valsartan across race groups. The relative CV benefits of sacubitril/valsartan were consistent across races, with greatest absolute benefits observed in Black patients.

Prognostic significance of coronary flow velocity reserve in patients with peripheral arterial disease

Abstract Background Patients with lower extremity peripheral arterial disease (PAD) have a higher risk of cardiovascular events. Stress echocardiography (SE) based on regional wall motion abnormality (RWMA) is imperfect for risk stratification in PAD, but it can be complemented with an assessment of coronary flow velocity reserve (CFVR) in the mid-distal left anterior descending coronary artery. Purpose To assess the value of SE with RWMA and CFVR to predict survival in PAD. Methods In a retrospective analysis of prospectively acquired data in an observational, multicenter study, we recruited 359 patients (age 69±8 years, 240 [67%] males) with PAD referred for dipyridamole SE in 3 accredited laboratories. We assessed RWMA and CFVR (abnormal value &amp;lt;2.0). All patients were followed up for a median of 4.7 (interquartile range: 2.0 to 8.2 years). All-cause death was the outcome end-point. Results The positivity rate was 37/359 (10%) for RWMA and 159/359 (44%) for CFVR. During follow-up, 97 (27%) deaths were registered. At multivariable analysis, inducible RWMA and/or CFVR &amp;lt;2.0 (HR 2.58, 95% CI 1.65-4.04; p&amp;lt;0.0001), age ≥70 years, diabetes, dialysis treatment, and ejection fraction ≤50% were associated with decreased survival. The annual mortality was 7.4% in patients with RWMA and/or CFVR &amp;lt;2.0 and 2.7% in those with no RWMA and CFVR &amp;gt;2.0 (Figure, p&amp;lt;0.0001). Conclusion In patients with PAD, SE shows more than 4-fold higher prevalence of abnormal CFVR compared to RWMA. The prognostic value of CFVR outperforms RWMA, showing the importance of coronary microvascular dysfunction and diffuse, subcritical coronary atherosclerosis in determining the outcome.