Infarction Death Research Articles

Abstract 4119535: Aspirin Use and Cardiovascular Disease Incidence in Adults with High Lipoprotein(a): A Multi-Cohort Study

Introduction: There is an active debate about who may benefit from taking aspirin to reduce their incidence of cardiovascular disease (CVD). Some prior cohort studies with small sample size suggest that aspirin use may be associated with a lower incidence of CVD or coronary heart disease (CHD) in adults with Lp(a) ≥50 mg/dL but not in those with Lp(a) <50 mg/dL, a hypothesis that needs confirmation. Research question: Does the association of aspirin use with incident CVD or CHD vary by Lp(a) among US adults? Methods: We analyzed publicly available data from adults without CVD at baseline in the ARIC (n=13,085, mean age 54 years), CHS (n=3,956, mean age 72 years), and MESA (n=6,324, mean age 62 years) studies. Lp(a) ≥50 mg/dL was defined as high. Participants were followed for incident CVD (myocardial infarction, stroke, or CVD death) and CHD (myocardial infarction or CHD death; median follow-up: ARIC 26 years, CHS 12 years, MESA 14 years). Hazard ratios associated with aspirin use were calculated after propensity score matching (primary analysis) and in all participants using multivariable adjustment (secondary analysis). Mixed-effects models were used to obtain pooled hazard ratios. Results: Aspirin use was 25.1% in ARIC, 29.6% in CHS, and 19.9% in MESA. In MESA, adults taking aspirin were older, had higher blood pressure, and were more likely to have diabetes and a low estimated glomerular filtration rate and to be taking antihypertensive medication and a statin versus those not taking aspirin. These differences were attenuated or not present in ARIC and CHS. The CVD incidence rate per 1,000 person-years (95%CI) was higher in adults with versus without high Lp(a): 16.3 (15.3-17.4) and 12.5 (12.1-13.0), respectively, in ARIC, 35.8 (31.5-40.1) and 32.3 (30.6-34.0) in CHS, and 10.8 (9.1-12.4) and 8.2 (7.5-8.9) in MESA. Aspirin use was not associated with CVD or CHD incidence in adults with or without high Lp(a) in the primary analysis ( Figure ). No association between aspirin use and CVD or CHD incidence was present in the secondary analysis using multivariable adjustment (data not shown). Conclusion: The association of aspirin use with CVD and CHD incidence did not differ by Lp(a) in this multi-cohort study.

Abstract 4137306: Percutaneous Coronary Intervention Versus Optimal Medical Therapy for Vulnerable Atherosclerotic Coronary Plaques: A Pilot Meta-Analysis of Randomized Controlled Trials

Background: Vulnerable coronary plaques are identified as thin-capped fibroatheromas with substantial plaque and a lipid-enriched necrotic core. These plaques are often non-flow-limiting on assessment; however, they have been associated with future adverse clinical outcomes, such as unstable angina, myocardial infarction, and sudden cardiac death. Current guidelines do not recommend revascularization of such coronary plaques; however, percutaneous coronary intervention (PCI) can theoretically slow atherosclerotic progression and potentially reduce future adverse events. Methods: Major electronic databases were searched for randomized controlled trials (RCTs) that compared PCI to optimal medical therapy (OMT) for vulnerable coronary plaques. The outcomes were pooled using a random-effects model, and the results were expressed as risk ratios (RR) with corresponding 95% confidence intervals (CI). Results: 3 RCTs with 1811 patients (909: PCI and 902: OMT) were included. PCI demonstrated a statistically insignificant trend towards a decreased risk of all-cause mortality [RR: 0.40; 95% CI: 0.13, 1.27; p=0.12], cardiovascular mortality [RR: 0.17; 95% CI: 0.02, 1.38; p=0.10], myocardial infarction [RR: 0.78; 95% CI: 0.35, 1.72; p=0.53], target vessel-related myocardial infarction [RR: 0.68; 95% CI: 0.04, 11.27; p=0.79], ischemia-driven target vessel revascularization [RR: 0.22; 95% CI: 0.04, 1.22; p=0.08], and major adverse cardiovascular events [RR: 0.41; 95% CI: 0.14, 1.18; p=0.10] compared to OMT. Conclusion: This study concluded that PCI was comparable to OMT in patients with vulnerable atherosclerotic coronary plaques. Further large-scale RCTs with longer follow-up durations are required to confirm these findings.

Abstract 4136202: Incident Hypertension and Survival Outcomes After Immune Checkpoint Inhibitor Initiation

Introduction: Immune checkpoint inhibitors (ICIs) are commonly used as anticancer agents linked with dramatic antitumor response but are associated with cardiotoxicity. Recent isolated reports have suggested ICIs may link with hypertension (HTN) after years of treatment. Yet, the timing and long-term ramifications of this HTN are unknown. Methods: From a large cohort of well-phenotyped cancer patients treated with ICIs from 2011-2022, we assessed the incidence of new or worsened HTN [systolic blood pressure (SBP) ≥130 mmHg (or in a higher HTN stage) on two occasions within a three-month period or addition of an antihypertensive medication] after ICI initiation. Secondary endpoints included major cardiovascular events (MACE), defined as symptomatic arrhythmia, myocardial infarction, stroke, heart failure, or cardiac death. Observed incident HTN rates were compared to Framingham-predicted rates, using JNC 8 cutoffs of 140/90 mmHg. Landmark analysis, excluding patients who were observed to have new HTN but had SBPs ≥130 mmHg on two occasions within six-months prior to ICI initiation, identified patients with possible undiagnosed HTN. Multivariable regression and survival analysis were used to define factors associated with new worsened HTN and MACE and the relationship between SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of ICI-related HTN will be assessed. Results: Overall, from 312 patients treated with ICIs (mean age 63.5 years, 67.4% baseline HTN, 11.0% on dual ICI-therapy), 50.0% (156/312) developed new or worsened HTN over a mean of 27 months follow-up. Cumulative incidence of new HTN by 1-year was 50.0% wherein the mean peak increase in SBP was 12 mmHg. In landmark analysis, excluding those with undiagnosed HTN and applying the JNC 8 cutoff of ≥140/90 mmHg, the observed new HTN rate was 21.4% at 1 year, >2-fold higher than the Framingham-predicted rate of 9.3% (RR 2.3, P <0.0001). In those with preexisting HTN, 49% developed worsened HTN. In multivariate analysis, only time on ICI treatment, ECOG status, and autoimmune disease history were associated with new or worsened HTN after ICI-initiation ( P <0.05 for all). Further, only prior autoimmune disease and ECOG status associated with MACE; while beyond traditional cancer factors, only new or worsening HTN associated with lower mortality. Conclusions: Collectively, these data suggest that HTN may be common with ICIs, and prognosticates survival.

Abstract 4114597: Spontaneous coronary artery dissection: Case series and review of associated cardiovascular risks

Background: Spontaneous coronary artery dissection (SCAD) has emerged as an important cause of ACS, myocardial infarction, and sudden death particularly among young women and individuals with few conventional atherosclerotic risk factors. We reveiwed possible risk factors that could predispose to SCAD. Methods: We reviewed 13 consecutive patients presenting with SCAD across three different institutions over a period of 5 yrs and determined risk fatcors associated with this disase entity. Results: 13 patients presented with SCAD represented % 0.5 of the total number of patients who underwent cardiac cathaterizations for chest pain requiring admissions. 11/13 (84%) were female. 5/13 (38%) were Caucasian or Hispanic, and 3/13 (23%) were African-American. Mean age age was 49.3 + years. 8/13 (61%) had associated hyperlipidemia with LDL levels > than 110 mg/dL, 9/13 (64%) had an A1c < 5.6% and only 1/13 (0.07%) had A1c of 6.4%. HTN was present in 6/13 (46%) of patients, and family history of SCD or heart disease were only seen in 2/13 (15%). None of the patients had features suggestive of associated fibromuscular dysplasia or connecive tissue disease. D-dimer was elevated in 5/13 (38%) with average value of 1578 ng/dL. Inflammatory markers were reviewed, only 3 patient has had ESR and CRP ordered, and only 1/3 had a mildly elevated CRP 3.9 mg/dL. Only 1/13 (0.07%) required intervention which was due to further drop in her ejection fraction requiring PCI, with improvement in her symptoms. All patients were treated with dual anti-platelet therapy for 1 year, 1 was discontinued due to persitent chest pain and decision was made to treat with only aspirin. Traditionally, risks for SCAD were thought to be due to non-atheresclerotic factors, however our case series shows that more then 60% of patients had elevated LDL's and 46% with hypertension, implying that traditional atheresclerotic risk factors should not be ignored and may play a crucial role. Autoimmune diseases were not found in any of our patients. Conclusion and implications: In this series patients who had SCAD had conventional risk factors of CAD including HLD and hypertension. The variability of co morbidities makes the identification of specific risk factors very difficult and none of the patients had Fibromuscular dysplasia or any signs of inflammation. Elevated D Dimer was also seen in a majority of patients, and all but one was managed medically with a favorable outcome

Abstract 4119517: Association of Systemic Inflammatory Response Syndrome with Cardiovascular Events after Mitral Transcatheter Edge-to-edge Repair

Background: Systemic inflammatory response syndrome (SIRS) following cardiovascular interventions is associated with adverse events during hospitalization and follow-up. Mitral transcatheter edge-to-edge repair (M-TEER) is increasingly utilized for treatment of mitral regurgitation (MR). Hypothesis: It is unknown whether SIRS following M-TEER may occur and be associated with adverse clinical outcomes. Goals: to investigate the frequency and impact of SIRS following M-TEER on major cardiovascular events (MACE) and MR recurrence. Methods: A total of 158 consecutive patients with severe MR undergoing M-TEER were studied. SIRS was defined by leukocytosis (≥12×10 9 /L) and fever (T≥38 °C) within 48 hours after intervention. Baseline inflammation was measured by absolute neutrophil and lymphocyte counts and neutrophil: lymphocyte ratio (NLR). The primary endpoint of MACE was the composite of non-fatal myocardial infarction (MI), non-fatal stroke, and all-cause death. Recurrent MR at follow-up was also recorded. Results: The mean patient age was 80.8±8.8 years. 44 (27.9%) developed SIRS. NLR correlated with onset of leukocytosis and fever (p=0.04). During a median follow-up of 12.5±8.2 months, the primary endpoint occurred in 27 (17.1%) patients (6 MI, 5 strokes and 16 deaths). Patients with SIRS more often had severe MR (79.5% vs. 62.7%, p=0.02) and adverse left ventricular (LV) remodeling indicated by lack of reduction in end-diastolic diameter (LVEDD) at follow-up (p=0.12 for SIRS-patients vs. p=0.0012 for non-SIRS patients). After adjustment for pertinent variables, SIRS (HR 3.24, CI 1.13-9.31, p=0.03) was independently associated with MACE. Conclusion: SIRS after M-TEER is a strong independent predictor of MACE. Closer follow-up is warranted as patients with SIRS have more severe MR and unfavorable LV remodeling at follow-up.

Abstract 4129195: Mechanisms of Healthy Aging in the Prevention of Atrial Fibrillation

Introduction: Atrial Fibrillation (AF) is the most frequent cardiac arrhythmia. AF can lead to severe complications such as myocardial infarction, strokes, and sudden death. With 70% of AF patients aged 65 and older, aging stands as the major risk factor for AF. Our group have recently contributed to reveal that old Wistar rats (20 months) are more susceptible to AF than younger rats (5 months). Interestingly, Lou/c/jall (LOU) rats, a model of healthy aging derived from Wistar rats, can live up to ~35 months old (equivalent to 100 human years). LOU rats have been identified as resistant to age-related diseases such as obesity, hypertension, and neurodegenerative disorders, which are major risk factors for AF. However, the susceptibility of LOU rats to AF have never been reported. Hypothesis: LOU rats may carry specific molecular adaptations conferring resistance to age-related cardiac remodeling and low AF vulnerability. Objectives: Characterize the vulnerability of very old LOU rats (32 months) to AF compared to old Wistar rats (22 months). Determine the atrial inflammatory profile of LOU rats and identify the molecular adaptations that may explain their resistance to AF Methods: Male and Female rats were divided into five groups: LOU and Wistar rats of 5 months (young), 20 months (old), and 32 months (very old: LOU/c rats only). AF inducibility was assessed in vivo using transesophageal electrophysiological study and cardiac structure and function were analyzed by in vivo echocardiography. Atrial electrical conduction was examined using ex vivo optical mapping. Histological analyses were performed to assess atrial fibrosis. Additionally, immunoblot analysis, qPCR, and RNA sequencing were employed to investigate the levels of biomarkers involved in atrial inflammation and fibrosis. Result: Old Wistar rats were more vulnerable to AF than young rats. Old and very old LOU were significantly more resistant to AF than old Wistar animals. LOU rats’ low susceptibility to AF was accompanied with absence of cardiac structural and functional remodeling and low levels of atrial fibrosis compared to old Wistar. Additionally, advanced age did not affect LOU rats’ atrial electrical conduction properties as compared to old Wistar rats. Conclusion: Promotion of healthy aging conditions mimicking LOU rats’ resistance to cardiac remodeling and reduction of atrial fibrosis may contribute to prevent AF in subjects with pathological aging.

Abstract 4124226: Long-term exposure to air pollutants and incidence of cardiovascular disease events and mortality in The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air)

Introduction: Exposure to ambient air pollution may increase the risk of cardiovascular disease events and mortality, but prior publications have primarily included administrative cohorts with outcomes that have not been individually reviewed and with air pollution estimates created without cohort-specific exposure monitoring. Multi-Ethnic Study of Atherosclerosis (MESA) is a multi-site cohort study designed specifically to prospectively collect and adjudicate cardiovascular disease (CVD) events. MESA Air recruited additional participants into sub-cohorts for enhanced air pollution variation and sample size. Research Question: The aim of this analysis was to characterize the relationship between long-term exposure to nitrogen dioxide (NO 2 ) and fine particulate matter (PM 2.5 ) and all-cause mortality and CVD events. Methods: Air pollution exposure was assessed using address history with a purpose-built exposure model incorporating cohort-specific monitoring including measurement and validation at participant homes. We used Cox models to assess the risk of rolling 2-year average exposures on all cause-mortality and on a composite CVD endpoint (definite angina, probable angina with revascularization, myocardial infarction, atherosclerosis or other CVD death, resuscitated cardiac arrest, and stroke). Models were stratified for baseline hazard by age, sub-cohort, and recruitment year and were additionally adjusted for age, sex, race/ethnicity, field center, smoking/second-hand smoke, pack-years, physical activity, education, income, neighborhood socioeconomic status, and statin use. Results: MESA Air participants were aged 44-87 years at enrollment between 2000 and 2007; follow-up averaged 14 years. 6,915 participants had follow-up for events, NO 2 exposure, and covariate information. We observed 1,442 deaths and 985 CVD events. The interquartile range over all 2-year averages was 10.5-23.1 ppb for NO 2 and 10.1-14.9 µ/m 3 for PM 2.5 . The adjusted hazard ratio (aHR) for a 10 ppb increment in NO 2 was 1.38 (95% CI: 1.17, 1.64) for all-cause mortality and 1.16 (95% CI: 0.95, 1.42) for incident CVD events. The aHR for a 5 µg/m 3 increment in PM 2.5 was 1.20 (95% CI: 0.99, 1.46) for all-cause mortality and 1.15 (95% CI: 0.95, 1.39) for incident CVD events Conclusions: These results add to growing literature demonstrating an association between air pollution exposure, mortality, and CVD in a cohort with well-characterized clinical endpoints and cohort-specific exposure assessment.

Abstract 4119941: Identification of individuals who benefit from omega-3 fatty acid supplementation to prevent coronary heart disease: A machine-learning analysis of the VITAL

Backgrounds: Randomized controlled trials (RCTs) have demonstrated benefits of marine omega-3 polyunsaturated fatty acids (omega-3 FA) supplementation for the prevention of coronary heart disease (CHD). However, it has not been clear which individuals would benefit the most from the supplementation. We sought to predict the individual treatment effect of omega-3 FA supplementation on CHD prevention and to develop an omega-3 effect score to stratify individuals according to their expected benefit from the supplementation. Methods: Among the 25,871 randomized participants without history of CVD in the VITamin D and OmegA-3 TriaL (VITAL), we applied machine-learning (ML) approaches to predict individual treatment effect of omega-3 FA supplementation on 5-year CHD risk (a composite of myocardial infarction, coronary revascularization, and CHD death) using 11 covariates pre-specified in the VITAL trial protocol. A 10-fold cross-validation was used and held-out test dataset was used for the evaluation. An omega-3 effect score was developed such that each covariate contributed linearly, and utility of the score was further evaluated by transportability analysis using the National Health and Nutrition Examination Survey (NHANES) data as the target population. Results: Omega-3 FA intervention led to absolute 0.48% [SE: 0.20] reduction in CHD in the total population. ML algorithms effectively stratified participants by their expected benefit according to individual factors; decreased CHD risk was observed in those with quintile 1 and 2 of the expected benefit (absolute CHD risk reduction %: 1.30 % [0.55] and 1.32 % [0.51] in quintile 1 and 2, respectively). Race, diabetes, and fish intake most contributed to the omega-3 effect score. CHD incidence rates per 1000 person-year were 5.5 [0.44] if treated and 8.5 [0.55] if not treated (35.3% reduction) in individuals with the score ≥11 (upper 40th percentile), and 3.9% [0.31] if treated and 3.4% [0.55] if not treated (14.7% increase) in those with the score <11, respectively. The transportability of the utility of the score to baseline NHANES data was confirmed. Conclusion: In VITAL, ML approaches identified individuals who experienced greater CHD reduction from the omega-3 FA intervention, and an omega-3 effect score stratified the expected benefit. Although it warrants testing in a new RCT, the omega-3 effect score holds promise for guiding the indication of omega-3 FA supplementation in US primary prevention population.

Association of Systemic Inflammatory Response Syndrome With Cardiovascular Events After Mitral Transcatheter Edge-to-Edge Repair.

Systemic inflammatory response syndrome (SIRS) following cardiovascular interventions is associated with adverse events during hospitalization and follow-up. Mitral transcatheter edge-to-edge repair is increasingly utilized for treatment of mitral regurgitation (MR). We investigated whether SIRS following mitral transcatheter edge-to-edge repair may occur and be associated with adverse clinical outcomes. A total of 158 consecutive patients with severe MR undergoing mitral transcatheter edge-to-edge repair were studied. SIRS was defined by leukocytosis (≥12 × 109/L) and fever (≥38 °C) within 48 hours after intervention. Baseline inflammation was measured by absolute neutrophil and lymphocyte counts and neutrophil-lymphocyte ratio. The primary end point of major cardiovascular events was the composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause death. Recurrent MR at follow-up was also recorded. The mean patient age was 80.8±8.8 years. Forty-four (27.9%) developed SIRS. Neutrophil-lymphocyte ratio correlated with onset of leukocytosis and fever (P=0.04). During a median follow-up of 12.5 (5.4-17.4) months, the primary end point occurred in 27 (17.1%) patients (6 myocardial infarction, 5 strokes, and 16 deaths). Patients with SIRS more often had severe MR (79.5% versus 62.7%, P=0.02) at follow-up. After adjustment for pertinent variables, SIRS (HR 2.73 [95% CI, 1.08-6.86]; P=0.03) was independently associated with major cardiovascular events. SIRS after mitral transcatheter edge-to-edge repair is a strong independent predictor of major cardiovascular events. Closer follow-up is warranted because patients with SIRS have more severe MR at follow-up.

Prognostic Value of Coronary Flow Capacity by 82Rb PET in Patients With Suspected Coronary Artery Disease and Normal Myocardial Perfusion at Semiquantitative Imaging Analysis.

Coronary flow capacity (CFC) is a measure that integrates hyperemic myocardial blood flow and myocardial flow reserve to quantify the pathophysiological impact of coronary artery disease on vasodilator capacity. We assessed the prognostic value of CFC derived from 82Rb positron emission tomography/computed tomography in patients with suspected coronary artery disease and normal myocardial perfusion imaging. We studied 1967 patients with suspected coronary artery disease and normal myocardial perfusion at the semiquantitative analysis of stress/rest cardiac 82Rb positron emission tomography/computed tomography imaging. Coronary artery calcium scores were calculated and categorized into 3 groups: 0, 0.1 to 99.9, and ≥100. Patients were classified as having myocardial steal, severely reduced CFC, moderately reduced CFC, mildly reduced CFC, minimally reduced CFC, or normal flow using previously defined thresholds. The outcome end points were myocardial infarction and cardiac death, whichever occurred first. During a mean time of 41±27 months, 49 events occurred (2.5% cumulative event rate, with an annualized event rate of 0.5% person-years). At multivariable Cox analysis, coronary artery calcium score categories and impaired CFC resulted as independent predictors of events (both P<0.001). The annualized event rate was higher in patients with impaired CFC compared with those with normal CFC (P<0.05). Kaplan-Meier analysis showed that patients with impaired CFC were at the highest risk of events. In patients with suspected coronary artery disease and normal myocardial perfusion, impaired CFC is associated with a higher risk of cardiac events. Evaluating CFC can help identify patients' candidates for additional therapies to prevent future events.

Risk of Major Adverse Cardiovascular Outcomes in Families With MASLD: A Population-Based Multigenerational Cohort Study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a risk factor for cardiovascular disease. However, whether family members of individuals with MASLD also share an increased cardiovascular risk is unknown. We created a nationwide multigenerational cohort study identifying all family members of Swedish adults diagnosed with biopsy-proven MASLD (1969-2017) and of matched general population comparators (by age, sex, calendar year, and county of residence). We calculated incidence rates and used Cox models to calculate adjusted hazard ratios (aHRs) and 95% CIs for incident major adverse cardiovascular events (MACE), including acute myocardial infarction, stroke, hospitalization for heart failure, or cardiovascular death. Cox models were adjusted for education, country of birth, diabetes, hypertension, obesity, dyslipidemia, chronic kidney disease, chronic obstructive pulmonary disease, and the Charlson comorbidity index. We identified 22 267 MASLD first-degree relatives (FDRs; parents, siblings, and offspring) and 5687 MASLD spouses, as well as 118 056 comparator FDRs and 29 389 comparator spouses without earlier cardiovascular disease. Overall, the mean age was 41.8 years (SD, 18.0), and 51.5% were females. Over a median of 24.6 years, the incidence rate for MACE was higher in MASLD FDRs than in comparator FDRs (65.0 versus 62.5/10 000 person-years; aHR, 1.06 [95% CI, 1.01-1.11]). MASLD FDRs had higher rates of acute myocardial infarction (23.0 versus 20.9/10 000 person-years; aHR, 1.09 [95% CI, 1.01-1.18]) and cardiovascular death (aHR, 1.09 [95% CI, 1.01-1.18]). Across generations of FDRs, the risk of MACE was uniformly increased with no differences by relationship (ie, parents, siblings, and offspring; Pinteraction>0.05). MASLD spouses were also at an increased risk of MACE (117.6 versus 103.5/10 000 person-years; aHR, 1.09 [95% CI, 1.01-1.18]). First-degree relatives of individuals with biopsy-proven MASLD are at slightly higher risk of incident MACE, but absolute risks do not support early screening for cardiovascular disease. Shared lifestyle factors may be the main contributors, as spouses of MASLD patients also had higher risks of MACE.

Novel factors affecting fibrin clot formation and their clinical implications.

Fibrin formation is pivotal in hemostasis, serving as a temporary barrier to blood loss following vascular injury, while in thrombosis this process is involved in thrombus progression, stability, and recurrence. Growing evidence shows an exceptional complexity of processes that determine fibrin clot structure and function, especially lysability, both in health and disease, which might be relevant in the pathogenesis of arterial and venous thromboembolic diseases. In this overview we summarized available data on novel factors that in recent years have been suggested to contribute to prothrombotic fibrin clot properties, involving formation of compact fibrin networks (reduced clot permeability) displaying impaired susceptibility to lysis (prolonged clot lysis time). The factors discussed in this review encompass elevated levels of factor (F)XI, and its activated form (FXIa), protein carbonylation as the most common type of post-translational modification, neutrophil extracellular traps (NETs) formation, increased levels of circulating lipopolysaccharide (LPS) and zonulin, a marker of gut permeability, along with antithrombin deficiency. These factors have been shown to be not only associated with ischemic stroke, myocardial infarction, pulmonary embolism, and cardiovascular death, but also with unfavorably altered fibrin clot characteristics, which underscores clinical relevance of fibrin clot properties. Given preclinical or ongoing studies aimed at modifying some of these factors, in particular FXI / FXIa inhibitors, recent findings might expand our knowledge on fibrin-related mechanisms of emerging therapeutic agents tested and stimulate further research into new targets for future therapeutic interventions to prevent thromboembolic events.

Effects of a coal to clean heating policy on acute myocardial infarction in Beijing: a difference-in-differences analysis

In 2015, the Chinese Government launched the coal to clean heating policy (CHP), designed to improve air quality and health in China. The CHP banned household coal burning and provided subsidies for clean electric or gas-powered heating for millions of peri-urban and rural households. We aimed to investigate whether the CHP affected the incidence of acute myocardial infarction in Beijing townships. In this quasi-experimental study, we obtained township data on acute myocardial infarction hospital admissions and deaths, exposure to the CHP (yes vs no), and a range of covariates for periods before (Jan 1, 2013, to Dec 31, 2014) and after the CHP began (Jan 1, 2016, to Dec 31, 2017; and Jan 1, 2018, to Dec 31, 2019). The policy was gradually rolled out across villages, and townships in our study were considered exposed to the policy in periods when more than 50% of their villages were assigned into the CHP. We estimated the effect of the CHP on township incidence of acute myocardial infarction for all adults (aged ≥35 years) and separately for sex and older adults (aged ≥65 years) using a difference-in-differences approach that accommodates the progressive roll-out of the policy. Of 307 townships in Beijing, we excluded 156 (51%) urban townships where most villages had central heating and were thus ineligible for the CHP. Of the 151 peri-urban and rural Beijing townships considered eligible for the CHP, 75 (50%) townships were exposed to the CHP by the end of 2017 and 92 (61%) by the end of 2019. We estimated an overall reduction of 6·6% (95% CI -12·3 to -0·8) in the incidence of acute myocardial infarction from before to after roll-out of the CHP in exposed townships relative to those not exposed to the policy, with some evidence of larger effects in women (-11·7% [-19·0 to -4·1%]), older adults (-10·7% [-17·4 to -3·6%]), and in townships exposed for longer (-3·5% [-9·5 to 2·8%] after <2 years and -9·7% [-18·3 to -0·5%] after 2-4 years). Our results provide among the first empirical evidence of possible cardiovascular benefits from a household clean energy policy, and support efforts to implement and assess such policies in China and globally. Wellcome Trust, the Canadian Institutes for Health Research, and the National Natural Science Foundation of China.

Effectiveness and Safety of the ESC-TROP (European Society of Cardiology 0h/1h Troponin Rule-Out Protocol) Trial.

European guidelines recommend the use of a 0h/1h hs-cTn (high-sensitivity cardiac troponin) protocol in patients with acute chest pain. We aimed to determine the performance of this protocol in routine care when supplemented with patient history and ECG and a recommendation to refrain from noninvasive testing in low-risk patients. This was a pre- and postimplementation study with concurrent controls. Patients with chest pain were enrolled at 5 Swedish emergency departments (EDs) during a 10-month period in both 2017 and 2018. All hospitals used a 0h/3h hs-cTnT protocol in 2017 and 3 EDs implemented a 0h/1h hs-cTnT protocol during 10 months in 2018. The 2 coprimary outcomes were the incidence of acute myocardial infarction and all-cause death within 30 days and ED length of stay. The study included 26 040 consecutive patients. In the intervention hospitals, 21 (0.40%) of the discharged patients had an acute myocardial infarction/death event during the control period (0h/3h testing) and 22 (0.45%) in the intervention period (0h/1h testing), which met the criteria for noninferiority. There was no significant difference in ED length of stay (ratio 0.99, P=0.48) or ED discharge rate between the periods in the intervention versus the control hospitals. A total of 3142 patients met low-risk 0h/1h hs-cTnT criteria and were discharged, of whom 2 had an acute myocardial infarction/death event. A 0h/1h hs-cTnT protocol incorporating patient history and ECG was as safe as using a 0h/3h protocol but did not reduce ED length of stay or increase the discharge rate. Refraining from noninvasive testing in patients identified as low risk was safe. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03421873.

Composition of non-HDL cholesterol and residual cardiovascular risk in secondary prevention

Abstract Background Non-high-density lipoprotein cholesterol (non-HDL-C) is associated with atherosclerotic cardiovascular disease (ASCVD) and is a recommended secondary prevention treatment target. However, the composition of non-HDL-C, that is, the relative contribution of remnant cholesterol (remnant-C) and low-density-lipoprotein cholesterol (LDL-C), is not considered for cardiovascular risk prediction. Purpose To examine ASCVD risk by composition of non-HDL-C. Methods Based on the Western Denmark Heart Registry, we established a cohort of patients with ischemic heart disease, including patients with acute coronary syndrome or stable angina pectoris, undergoing coronary angiography for evaluation of coronary artery disease between 2011 and 2020. A complete lipid panel within 1 year after coronary angiography on statin treatment was required. Patients with triglycerides &amp;gt;4.5 mmol/L were excluded. Exposures were remnant-C, LDL-C, non-HDL-C, and composition of non-HDL-C. The latter was defined as remnant-C of non-HDL-C, and LDL-C of non-HDL-C, in percentages. Cox regression analyses obtained adjusted hazard ratios (aHR) for myocardial infarction, ASCVD (myocardial infarction, ischemic stroke, and cardiovascular death), and all-cause death occurring from 1 year after coronary angiography to end of follow-up November 1, 2022. Results The secondary prevention cohort included 42,341 statin-treated patients (67.7% were men; median [IQR] age 66 [58-73] years). During median 4.1 years of follow-up, 3,846 patients developed ASCVD. Per 1 mmol/L increase in remnant-C, LDL-C, and non-HDL-C, the aHR for ASCVD was 1.41 (95% CI 1.28-1.55), 1.12 (95% CI 1.08-1.17), and 1.17 (95% CI 1.13-1.21), respectively (Figure 1). The relative contribution of remnant-C and LDL-C was median (IQR) 24.6% (18.5-33.1) and 75.4% (66.9-81.5) of non-HDL-C, respectively. When remnant-C constituted a larger percentage of non-HDL-C (and LDL-C a lower percentage), the aHR for ASCVD showed a linear increase in risk whereas the opposite trend was observed for LDL-C (Figure 2). Thus, per 10% increase in remnant-C of non-HDL-C, the aHR of ASCVD was 1.06 (95% CI 1.03-1.09) compared to 0.94 (95% CI 0.91-0.97) per 10% increase in LDL-C of non-HDL-C. Results were comparable for myocardial infarction and all-cause death, and by age, sex, and other clinically relevant subgroups. Conclusions The composition of non-HDL-C is strongly associated with ASCVD risk, with the risk escalating as remnant-C constitutes a larger percentage, and LDL-C a smaller percentage, of non-HDL-C. These findings challenge current guidelines and demonstrate the value of considering composition of non-HDL-C in clinical practice for more accurate risk assessment.Figure 1Figure 2

Unleashing the potential: early evaluation of blood pressure control with novel measurements in patients with hypertension

Abstract Objective To assess the prognostic value of two novel blood pressure measurements——short-term cumulative systolic blood pressure (SBP) load and Time in Target Rang (TTR) in major adverse cardiovascular outcomes and all-cause mortality. Method This is a post-hoc analysis of the SPIRNT (Systolic Blood Pressure Intervention Trial). Participants with complete record of BP values and no adverse events occurred in the initial 90-days follow-up were enrolled. Short-term cumulative SBP load and TTR were calculated by the 3-month SBP values in the follow-up period (Fig 1). The primary outcome was major adverse cardiovascular events (MACEs), defined as the composite of myocardial infarction, stroke, heart failure and cardiovascular death. Secondary outcomes were the components of the primary outcomes and all-cause mortality. Results The study population included 8639 adults (median [IQR]or mean (%) baseline age, 67 [61,76] years; 2940 women (35.1%); Median follow-up time 3.8[3.3-4.4] years). 559 MACEs were occurred. Participants categorized by tertiles of cumulative SBP Load (T1: [0,0.1572]; T2: (0.1572 ,3.5946]; T3: (3.5946 ,30.2949]) showed a significant increase hierarchical trend (P for trend &amp;lt;0.05) in the incidence of MACEs and stroke. For Participants grouped by SBP TTR (T1: [0,21.2657]; T2: (21.2657 ,71.1462]; T3: (71.1462 ,100]), it indicated a decrease hierarchical trend (P for trend &amp;lt;0.05) in the incidence of MACEs and MI (Fig2 and Fig3). Both short-term cumulative SBP Load (HR: 1.117(1.033-1.208)) and TTR (HR: 0.861(0.785-0.945)) were correlated with MACEs independently(tabal1). According to C-statistics and Net Reclassification Indexes (NRI), short-term cumulative SBP Load and TTR both outperformed mean SBP and SBP standard derivation (SD) on the prognosis value of MACEs. Moreover, our results showed that the coefficient of cumulative SBP Load under penalty decreased to 0 with the largest log(lambda),which indicted a major role across 4 different measures in models. (Fig 4). Conclusions Both short-term cumulative SBP load and TTR had an independent prognosis value for MACEs superior to mean SBP and SBP SD in hypertension patients without diabetes. This study provided the evidence of novel BP measurements for early assessment of BP levels after antihypertensive treatment.

Effects of deferment of clinic visit on cardiovascular outcomes during COVID-19 outbreak: a prospective cohort study

Abstract Background Current guidelines recommend 3-6 months interval outpatient follow-up for patients with cardiovascular (CV) diseases and risk factors such as hypertension, diabetes mellitus (DM) and dyslipidemia. The impact of longer follow-up intervals is unclear. From 2020 to 2022, due to the infection control measures for COVID-19 pandemic, many patients voluntarily deferred their scheduled clinic visits. This provided us with an opportunity to study the impact of prolonged visit intervals on management CV risk factors. Purpose We aimed to investigate the impact of prolonged clinic visit intervals on CV outcomes and CV risk factor management among patients with CV diseases. Methods Patients with at least 1 CV risk factor (DM, hypertension, dyslipidemia, or a history of CV disease) were recruited from cardiology outpatient clinics from a tertiary teaching hospital from 2020-2022. Patients who opted to defer their appointment (Deferred group) were compared to those who attended their scheduled appointment (Normal group). The primary outcomes were composite major adverse cardiovascular events (MACE) of myocardial infarction, stroke, or CV-related death. The secondary outcomes were any unscheduled hospitalizations, suboptimal DM control (haemoglobin A1C &amp;gt;7%) or hyperlipidemia (LDL &amp;gt; 1.4 mmol/L). Results Out of the 455 patients recruited from outpatient clinics, 162 patients (35.6%) opted to defer their scheduled clinic visit (mean age 64.7 ± 12, 37.7% female), and 293 patients (mean age 64.5 ± 10, 36.2% female) continued to attend their appointments. The mean appointment interval was 226 days for the normal group and 582 days for the deferred group (p&amp;lt; 0.001). There was no significant difference in the primary outcome of MACE between the ‘Normal’ group and the ‘Deferred’ group (2.5% vs 0.6%, p=NS). The number of patients with suboptimal DM control (11.4% vs 21.9%, p = 0.029) was higher in the deferred group, whereas suboptimal hyperlipidemia (73.1% vs 77.1%, p=NS) was not statistically different. There were a total of 27 of unscheduled hospitalizations, among which the majority was for CV-related events (63.0%). Patients in the ‘Deferred’ group had higher rates of unscheduled hospitalization (12.3% vs 2.4%, p &amp;lt; 0.001) and higher rate of CV-related hospitalization compared to the ‘Normal’ group (6.2% vs 2.4%, p=0.041). Conclusion Our prospective data demonstrates that a prolonged clinic visit interval of more than 365 days was not associated with significant increase in adverse CV event or worsening of lipid control. However, prolonged clinic visit interval was associated with worse DM control and more frequent unscheduled hospitalization. More frequent medical contact might allow timely management of medical emergency at the outpatient setting and contribute to the lower rate of hospitalization in the routine follow-up group.

Obesity paradox, weight-free anthropometric measures, and major adverse cardiovascular events in the elderly: Insight from the Northern Shanghai Study

Abstract Aims Many studies have investigated the obesity paradox in the elderly. However, besides body mass index (BMI), many other anthropometric measures, such as the waist-to-hip ratio (WHR), provide a better indication of body fat distribution and may be more useful in a geriatric population. Methods 3285 participants aged over 65 years old from the Northern Shanghai Study were included in this analysis. Eight anthropometric measures, including weight-related measures (BMI, weight-adjusted-waist index, body shape index and body surface area) and weight-free measures (WHR, waist-to-height ratio, body roundness index, relative fat mass) were measured and calculated with standard methods. Major adverse cardiovascular events (MACEs) included the non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Results Participants had an average age of 71.4 years and 1428 (43.47%) were men. The median follow-up was 5.4 years (IQR, 4.4-7.3 years) and 218 events occurred. Participants with obesity (BMI ≥ 28 kg/m2) were associated with a higher risk of MACEs compared with the normal (adjusted Hazard ratio = 1.54, 95% confidence interval (CI): 1.07-2.22, P=0.020). Restricted cubic splines also highlighted the robust correlation between high BMI and high MACEs risk (Pfor overall=0.025, Pfor nonlinear=0.339). Similarly, the aHR for the incidence of MACEs in WHR quartile 4 versus quartile 1 was 1.96 (95% CI: 1.26-3.05, P=0.003). When WHR was examined as a continuous variable, the result remained unaltered (Pfor overall=0.020, Pfor nonlinear=0.353). In adjusted model, all four weight-free measures were significantly associated with increased risk of MACEs (all P&amp;lt;0.05), while only two weight-related measures were related to the risk of MACEs. Conclusion In the elderly, BMI and alternative anthropometric measures showed no evidence of an "obesity paradox". Weight-free measures were more relevant to a risk of MACEs.Take home message

Prognostic significance of coexistent coronary artery disease in patients undergoing transcatheter aortic valve implantation for aortic stenosis

Abstract Background The optimal management of coronary artery disease (CAD) in patients undergoing transcatheter aortic valve implantation (TAVI) for aortic stenosis (AS) is uncertain. As TAVI expands into lower risk cohorts with longer life expectancies there is increasing need to determine the prognostic significance of coexistent CAD and identify which lesions may benefit from revascularisation. Purpose To evaluate the prognostic significance of coexistent CAD in patients with AS undergoing TAVI stratified according to myocardial territories at risk. Methods Using a retrospective, single-centre, observational registry, patients undergoing TAVI for severe AS between 2015 and 2020 were included. CAD was angiographically determined using computed tomography or invasive coronary angiography. CAD was stratified into 1) low-risk: &amp;lt;70% stenosis in all major epicardial coronary arteries or &amp;lt;50% in the left main (LM); 2) intermediate-risk: ≥70% stenosis in one or two arteries, except the proximal left anterior descending (LAD) and LM; 3) high-risk: ≥70% stenosis in the proximal LAD, ≥70% stenosis in 3 arteries or LM stenosis ≥50%. Patients with previous CABG were categorised as high-risk if: ≥70% stenosis of 3 coronary grafts or graft supplying a proximally stenosed LAD; and intermediate-risk if: ≥70% stenosis of 1 or 2 non-LAD grafts. Baseline characteristics and procedural outcomes were compared between the 3 cohorts, with the impact of CAD on outcomes evaluated after adjustment for demographics and comorbidities. Results 1805 patients were included; median age 84 (79-88), 51% male sex, median logistic Euroscore 13 (8-21). 1281 (71%), 384 (21%) and 140 (8%) patients were characterised as low-, intermediate- and high-risk coronary anatomy respectively. High risk patients were older than the other groups, however, did not have the highest prevalence of comorbidities (Table 1). Other than pacemaker implantation (9% vs 12% vs 6%, p=0.04), there were no differences in procedural complications or in-hospital mortality between groups (Table 1). At a median follow-up of 3.5 (2.3-4.8) years, 920 patients (51%) died, 292 (16%) had hospitalisation for heart failure (HHF) and 565 patients (31%) had a major adverse coronary event (MACE); defined as either myocardial infarction, HHF or cardiovascular death. Coronary anatomical stratification was associated with MACE (Log rank p&amp;lt;0.001) (Figure 1). After multivariate adjustment, high-risk anatomy was associated with all-cause mortality (hazard ratio (HR): 1.34, 95% confidence interval (CI): 1.06-1.68, p=0.013), HHF (HR: 1.49, 95% CI: 1.01-2.21, p=0.046) and MACE (HR: 1.68, 95% CI: 1.27-2.21, p&amp;lt;0.001). Conclusions Whilst the presence of CAD does not impact TAVI procedural safety, untreated high-risk coronary anatomy is associated with future adverse events and may warrant intensive medical therapy and/or revascularisation.

Red cell distribution width as a predictor of cardiovascular events in high-risk patients with statin intolerance: post-hoc analysis of the CLEAR Outcomes trial

Abstract Background Despite optimal lipid-lowering therapy there is up to 70% residual risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events, motivating further testing of alternative risk factors and disease pathways. Red cell distribution width (RDW) is a simple and reproducible marker of heterogeneity of cell size in the peripheral blood. High RDW is associated with an increased risk of ASCVD and death, independent of established risk factors. Recent data suggest no significant impact of PCSK9 inhibitors on hsCRP or RDW. In CLEAR Outcomes, baseline hsCRP predicted risk for future cardiovascular (CV) events and death more strongly than elevated LDL-C. It has been shown that bempedoic acid (BA) reduces hsCRP, but its effects on RDW are unknown. Purpose To analyze the effect of BA on a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death (MACE-4) and for CV death by baseline RDW, and to confirm the association of increased RDW with elevated risk of MACE. Methods A total of 13,970 individuals with statin intolerance, with or at high risk for ASCVD, were randomized in the multinational CLEAR Outcomes trial with a median follow up of 3.4 years. Compared to placebo, BA reduced mean LDL-C by 21% and median hsCRP by 22% at 6 months. Quartiles of increasing baseline RDW were assessed as predictors of future adverse events after adjustment for traditional risk factors, hsCRP, and randomized treatment assignment. Results Compared to placebo, BA reduced mean RDW by 0.28% at 6 months and 0.13% at 36 months (p&amp;lt;0.0001). There was a weak positive correlation between hsCRP and RDW at baseline (Figure 1). In the placebo group, higher baseline RDW was associated with an increase in the likelihood of MACE-4 and CV death, and the hazard ratios (HR) associated with a 1% increase in RDW after adjusting for covariates and hsCRP were 1.06 (95% CI 1.02-1.11) and 1.22 (1.15-1.29), respectively. When grouped by quartiles of baseline RDW, compared with a reference group with lowest RDW (&amp;lt;13.7%), there was a notable increase in the risk of MACE-4 and CV death among the higher quartiles in the placebo group (Table 1). Those in the 4th quartile demonstrated a 3-fold increase in the risk of CV death (HR, 3.03, 2.00-4.60). The adjusted HRs (95% CI) for BA vs placebo for MACE-4 were generally lower in individuals with elevated baseline RDW than in those in the first quartile [Q1: RDW≤13.7%; 0.96 (0.79-1.17), Q2: RDW 13.7%-14.4%; 0.81 (0.67-0.97), Q3: RDW 14.4%-15.2%; 0.90 (0.75-1.09), and Q4: RDW&amp;gt;15.2%; 0.84 (0.7-1.01)]. Conclusions In a large randomized controlled clinical trial setting, we confirmed an association between elevated RDW and MACE-4. Compared with placebo, BA demonstrated efficacy in reducing CV risk in patients with moderately increased RDW.Figure 1.Correlation of hsCRP and RDWTable 1.Risk of Outcome by RDW Quartile