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Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling.

This article focuses on screening the major secreted proteins by the ischemia-challenged cardiac stromal fibroblasts (CF), the assessment of their expression status and functional role in the post-ischemic left ventricle (LV) and in the ischemia-challenged CF culture and to phenotype CF at single cell resolution based on the positivity of the identified mediators. The expression level of CRSP2, HSP27, IL-8, Cofilin-1, and HSP90 in the LV tissues following coronary artery bypass graft (CABG) and myocardial infarction (MI) and CF cells followed the screening profile derived from the MS/MS findings. The histology data unveiled ECM disorganization, inflammation and fibrosis reflecting the ischemic pathology. CRSP2, HSP27, and HSP90 were significantly upregulated in the LV-CABG tissues with a concomitant reduction ion LV-MI whereas Cofilin-1, IL8, Nrf2, and Troponin I were downregulated in LV-CABG and increased in LV-MI. Similar trends were exhibited by ischemic CF. Single cell transcriptomics revealed multiple sub-phenotypes of CF based on their respective upregulation of CRSP2, HSP27, IL-8, Cofilin-1, HSP90, Troponin I and Nrf2 unveiling pathological and pro-healing phenotypes. Further investigations regarding the underlying signaling mechanisms and validation of sub-populations would offer novel translational avenues for the management of cardiac diseases.

Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.

BACKGROUND AND AIMS: Extracellular vesicles (EVs) secreted by cardiosphere-derived cells exert immunomodulatory effects through the transmission of small non-coding RNAs. METHODS: The mechanism and role of yREX3, a small Y RNA abundant in EVs in myocardial injury, was investigated. RESULTS: yREX3 attenuates cardiac ischaemic injury by selective DNA methylation. Synthetic yREX3 encapsulated in lipid nanoparticles triggers broad transcriptomic changes in macrophages, localizes to the nucleus, and mediates epigenetic silencing of protein interacting with C kinase-1 (Pick1) through methylation of upstream CpG sites. Moreover, yREX3 interacts with polypyrimidine tract binding protein 3 (PTBP3) to methylate the Pick1 gene locus in a DNA methyltransferase-dependent manner. Suppression of Pick1 in macrophages potentiates Smad3 signalling and enhances efferocytosis, minimizing heart necrosis in rats with myocardial infarction. Adoptive transfer of Pick1-deficient macrophages recapitulates the cardioprotective effects of yREX3 in vivo. CONCLUSIONS: These findings highlight the role of a small Y RNA mined from EVs with a novel gene-methylating mechanism.

BACKGROUND: Evidence on the comparative outcomes following percutaneous microaxial ventricular assist devices (pVAD) versus intra-aortic balloon pump for nonacute myocardial infarction cardiogenic shock is limited. METHODS AND RESULTS: We included 704 and 2140 Medicare fee-for-service beneficiaries aged 65 to 99 years treated with pVAD and intra-aortic balloon pump, respectively, for nonacute myocardial infarction cardiogenic shock from 2016 to 2020. Patients treated using pVAD compared with those treated using intra-aortic balloon pump were more likely to be concurrently treated with mechanical ventilation, renal replacement therapy, and blood transfusions. We computed propensity scores for undergoing pVAD using patient- and hospital-level factors and performed a matching weight analysis. The use of pVAD was associated with higher 30-day mortality (adjusted odds ratio, 1.92 [95% CI, 1.59-2.33]) but not associated with in-hospital bleeding (adjusted odds ratio, 1.00 [95% CI, 0.81-1.24]), stroke (adjusted odds ratio, 0.91 [95% CI, 0.56-1.47]), sepsis (OR, 0.91 [95% CI, 0.64-1.28]), and length of hospital stay (adjusted mean difference, +0.4 days [95% CI, -1.4 to +2.3]). A quasi-experimental instrumental variable analysis using the cross-sectional institutional practice preferences showed similar patterns, though not statistically significant (adjusted odds ratio, 1.38; 95% CI, 0.28-6.89). CONCLUSIONS: Our investigation using the national sample of Medicare beneficiaries showed that the use of pVAD compared with intra-aortic balloon pump was associated with higher mortality in patients with nonacute myocardial infarction cardiogenic shock. Providers should be cautious about the use of pVAD for nonacute myocardial infarction cardiogenic shock, while adequately powered high-quality randomized controlled trials are warranted to determine the clinical effects of pVAD.

Background and Objectives: Coronavirus disease 2019 (COVID-19) caused several cardiovascular complications, including acute myocardial infarction (AMI), in infected patients. This study aims to understand the overall trends of AMI among COVID-19 patients during the first two years of the pandemic and the disparities and outcomes between the first and second years. Materials and Methods: The retrospective analysis was conducted via the 2020 and 2021 National Inpatient Sample (NIS) database for hospitalizations between April 2020 and December 2021 being analyzed for adults with a primary diagnosis of COVID-19 who experienced events of AMI. A comparison of month-to-month events of AMI and mortality of AMI patients with concomitant COVID-19 was made alongside their respective patient characteristics. Results: Out of 2,541,992 COVID-19 hospitalized patients, 3.55% experienced AMI. The highest rate of AMI was in December 2021 (4.35%). No statistical differences in trends of AMI mortality were noted over the 21 months. AMI cases in 2021 had higher odds of undergoing PCI (aOR 1.627, p < 0.01). They experienced higher risks of acute kidney injury (aOR 1.078, p < 0.01), acute ischemic stroke (aOR 1.215, p < 0.01), cardiac arrest (aOR 1.106, p < 0.01), need for mechanical ventilation (aOR 1.133, p < 0.01), and all-cause mortality (aOR 1.032, 95% CI 1.001-1.064, p = 0.043). Conclusions: The incidence of AMI among COVID-19 patients fluctuated over the 21 months of this study, with a peak in December 2021. COVID-19 patients reporting AMI in 2021 experienced higher overall odds of multiple complications, which could relate to the exhaustive burden of the pandemic in 2021 on healthcare, the changing impact of the virus variants, and the hesitancy of infected patients to seek care.

BackgroundWe examined the association between cannabis use and cardiovascular outcomes among the general population, among never-tobacco smokers, and among younger individuals.Methods and resultsThis is a population-based, cross-sectional study of 2016 to 2020 data from the Behavioral Risk Factor Surveillance Survey from 27 American states and 2 territories. We assessed the association of cannabis use (number of days of cannabis use in the past 30 days) with self-reported cardiovascular outcomes (coronary heart disease, myocardial infarction, stroke, and a composite measure of all 3) in multivariable regression models, adjusting for tobacco use and other characteristics in adults 18 to 74 years old. We repeated this analysis among nontobacco smokers, and among men

BACKGROUND: Muscle density is inversely associated with all-cause mortality, but associations with cardiovascular disease (CVD) risk are not well understood. This study evaluated the association between muscle density and muscle area and incident total CVD, coronary heart disease (CHD), and stroke in diverse men and women. METHODS AND RESULTS: Adult participants (N=1869) in the Multi-Ethnic Study of Atherosclerosis Ancillary Body Composition Study underwent computer tomography scans of the L2-L4 region of the abdomen. Muscle was quantified by density (Hounsfield units) and area in cm2. Sex-stratified Cox proportional hazard models assessed associations between incident total CVD, incident CHD, and incident stroke across sex-specific percentiles of muscle area and density, which were entered simultaneously into the model. Mean age for men and women at baseline were 64.1 and 65.1 years, respectively, and median follow-up time was 10.3 years. For men, associations between muscle density and incident CVD were inverse but not significant in fully adjusted models (P trend=0.15). However, there was an inverse association between density and CHD (P trend=0.02; HR, 0.26 for 95th versus 10th percentile), and no association with stroke (P trend=0.78). Conversely, for men, there was a strong positive association between muscle area and incident CVD (HR, 4.19 for 95th versus 10th percentile; P trend

It is still debated whether arterial elasticity provides prognostic information for cardiovascular risk beyond blood pressure measurements in a healthy population. To investigate the association between arterial elasticity obtained by radial artery pulse wave analysis and risk for cardiovascular diseases (CVD) in men and women. In 2002-2005, 2362 individuals (men=1186, 50.2%) not taking antihypertensive medication were included. C2 (small artery elasticity) was measured using the HDI/Pulse Wave CR2000. Data on acute myocardial infarction or stroke, fatal or non-fatal, was obtained between 2002-2019. Cox- regression was used to investigate associations between C2 and future CVD, adjusting for confounding factors such as age, sex, systolic blood pressure, heart rate, HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LDL- cholesterol, CRP (C-Reactive Protein), alcohol consumption, smoking and physical activity. At baseline, the mean age of 46 ± 10.6 years and over the follow-up period, we observed 108 events 70 events in men [event rate: 5.9%], 38 in women [event rate: 3.2%]. In the fully adjusted model, and for each quartile decrease in C2, there was a significant increase in the risk for incident CVD by 36%. (HR = 1.36, 95% CI: 1.01-1.82, p = 0.041). The results were accentuated for all men (HR = 1.74, 95% CI: 1.21-2.50, p = 0.003) and women over the age of 50 years (HR = 1.70, 95% CI: 0.69-4.20). We showed a strong and independent association between C2 and CVD in men. In women after menopause, similar tendencies and effect sizes were observed.

The diagnostic performance of the high-sensitivity troponin T (hs-cTnT) European Society of Cardiology (ESC) 0/1-h algorithm in sex and race subgroups of US Emergency Department (ED) patients is unclear. A pre-planned subgroup analysis of the STOP-CP cohort study was conducted. Participants with 0- and 1-h hs-cTnT measures from eight US EDs (1/2017 to 9/2018) were stratified into rule-out, observation, and rule-in zones using the hs-cTnT ESC 0/1 algorithm. The primary outcome was adjudicated 30-day cardiac death or MI. The proportion with the primary outcome in each zone was compared between subgroups with Fisher's exact tests. The negative predictive value (NPV) of the ESC 0/1 rule-out zone for 30-day CDMI was calculated and compared between subgroups using Fisher's exact tests. Of the 1422 patients enrolled, 54.2% (770/1422) were male and 58.1% (826/1422) white with a mean age of 57.6 ± 12.8 years. At 30 days, cardiac death or myocardial infarction (MI) occurred in 12.9% (183/1422) of participants. Among patients stratified to the rule-out zone, 30-day cardiac death or MI occurred in 1.1% (5/436) of women versus 2.1% (8/436) of men (p = .40) and 1.2% (4/331) of non-white patients versus 1.8% (9/490) of white patients (p = .58). The NPV for 30-day cardiac death or MI was similar among women versus men (98.9% [95% confidence interval, CI: 97.3-99.6] vs. 97.9% [95% CI: 95.9-99.1]; p = .40) and among white versus non-white patients (98.8% [95% CI: 96.9-99.7] vs. 98.2% [95% CI: 96.5-99.2]; p = .39). NPVs

AIM: The 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation and the 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

BackgroundThere is little robust data about the cardiovascular safety of hydroxychloroquine in patients with rheumatoid arthritis (RA), who often have cardiovascular comorbidities. We examined the association between use of hydroxychloroquine (HCQ) in patients with RA and major adverse cardiovascular events (MACE).MethodsIn a retrospective cohort of Medicare beneficiaries aged ≥ 65 years with RA, we identified patients who initiated HCQ (users) and who did not initiate HCQ (non-users) between January 2015-June 2017. Each HCQ user was matched to 2 non-users of HCQ using propensity score derived from patient baseline characteristics. The primary outcome was the occurrence of MACE, defined as acute admissions for stroke, myocardial infarction, or heart failure. Secondary outcomes included all-cause mortality and the composite of MACE and all-cause mortality. Cox proportional hazards model was used to compare outcomes between HCQ users to non-users.ResultsThe study included 2380 RA patients with incident HCQ use and matched 4633 HCQ non-users over the study period. The mean follow-up duration was 1.67 and 1.63 years in HCQ non-users and users, respectively. In multivariable models, use of HCQ was not associated with the risk of MACE (hazard ratio 1.1; 95% CI: 0.832-1.33). However, use of HCQ was associated with a lower risk of all-cause mortality (HR: 0.54; 95% CI: 0.45-0.64) and the composite of all-cause mortality and MACE (HR 0.67; 95% CI: 0.58-0.78).ConclusionHCQ use was independently associated with a lower risk of mortality in older adults with RA but not with incidence of MACE events. Key Points • Using an incident user design (to avoid the biases of a prevalent user design) and a population-based approach, we examined the effect of hydroxychloroquine (HCQ) on the risk of major cardiovascular events (MACE) in older patients with RA. • We did not find an association between HCQ use and incident MACE. We did, however, find a significant association with the composite outcome (MACE and all-cause mortality) driven by a significant reduction in all-cause mortality with HCQ use.

BACKGROUND: Long-term noise exposure is associated with cardiovascular disease (CVD), including acute cardiovascular events such as myocardial infarction and stroke. However, longitudinal cohort studies in the U.S. of long-term noise and CVD are almost exclusively from Europe and few modeled nighttime noise, when an individual is likely at home or asleep, separately from daytime noise. We aimed to examine the prospective association of outdoor long-term nighttime and daytime noise from anthropogenic sources with incident CVD using a U.S.-based, nationwide cohort of women. METHODS: We linked L50 nighttime and L50 daytime anthropogenic modeled noise estimates from a U.S. National Parks Service model (L50: sound pressure levels exceeded 50 percent of the time) to geocoded residential addresses of 114,116 participants in the Nurses Health Study. We used time-varying Cox proportional hazards models to estimate risk of incident CVD, coronary heart disease (CHD), and stroke associated with long-term average (14-y measurement period) noise exposure, adjusted for potential individual- and area-level confounders and CVD risk factors (1988-2018; biennial residential address updates; monthly CVD updates). We assessed effect modification by population density, region, air pollution, vegetation cover, and neighborhood socioeconomic status, and explored mediation by self-reported average nightly sleep duration. RESULTS: Over 2,548,927 person-years, there were 10,331 incident CVD events. In fully adjusted models, the hazard ratios for each interquartile range increase in L50 nighttime noise (3.67 dBA) and L50 daytime noise (4.35 dBA), respectively, were 1.04 (95% CI: 1.02, 1.06) and 1.04 (95% CI: 1.02, 1.07). Associations for total energy-equivalent noise level (Leq) measures were stronger than for the anthropogenic statistical L50 noise measures. Similar associations were observed for CHD and stroke. Interaction analyses suggested that associations of L50 nighttime and L50 daytime noise with CVD did not differ by prespecified effect modifiers. We found no evidence that inadequate sleep (

Troponin is the American College of Cardiology and American Heart Association preferred biomarker for diagnosing acute myocardial infarction (MI). We provide a modeling framework for high sensitivity cardiac Troponin I (hs-cTnI) detection in chromatographic immunoassays (flow displacement mode) with an analytical limit of detection, i.e., LOD

Background There is a paucity of large-scale epidemiological studies on the link between cardiac autonomic neuropathy (CAN) and the risk of silent myocardial infarction (SMI) in type 2 diabetes. We evaluated the association between CAN and the risk of SMI in a large sample of adults with type 2 diabetes. Methods and Results Participants with type 2 diabetes from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study without atherosclerotic cardiovascular disease at baseline were included. CAN was ascertained using heart rate variability indices calculated from 10-s resting electrocardiograms. The heart rate variability indices included standard deviation of all normal-to-normal R-R intervals and root mean square of successive differences between normal-to-normal R-R intervals. CAN was defined as both the standard deviation of all normal-to-normal R-R intervals and root mean square of successive differences between normal-to-normal R-R intervals less than the fifth percentile of the general population. We used Cox proportional hazards regression to generate hazard ratios (HRs) for incident SMI in relation to CAN measures. Among 4842 participants (mean age, 62.5 years; 46.6% women; 60.2% White), there were 73 incident SMI cases over a median follow-up of 4.9 years (incidence rate 3.1 out of 1000 person-years [95% CI, 2.5-3.9]). After adjusting for confounders, low heart rate variability was associated with a higher risk of SMI (HR, 1.67 [95% CI, 1.02-2.72] and HR, 1.56 [95% CI, 0.94-2.58] for low standard deviation of all normal-to-normal R-R intervals and root mean square of successive differences between normal-to-normal R-R intervals, respectively). Participants with CAN had a 1.9-fold greater risk of SMI (HR, 1.91 [95% CI, 1.14-3.20]). Conclusions In a large cohort of adults with type 2 diabetes, CAN was significantly associated with an increased risk of incident SMI.

Background Complex percutaneous coronary intervention (PCI) is increasingly performed in older adults (age ≥75 years) with stable ischemic heart disease. However, little is known about clinical outcomes. Methods and Results We derived a cohort of older adults undergoing elective PCI for stable ischemic heart disease across a large health system. We compared 12-month event-free survival (freedom from all-cause death, nonfatal myocardial infarction, stroke, and major bleeding), all-cause death, target lesion revascularization, and bleeding events for patients receiving complex versus noncomplex PCI and derived risk estimates with Cox regression models. We included 513 patients (mean age, 81±5 years). Patients receiving complex PCI versus noncomplex PCI did not significantly differ across a host of clinical characteristics including cardiovascular disease features, noncardiac comorbidities, guideline-directed medical therapy use, and frailty. Patients receiving complex PCI versus noncomplex PCI experienced worse event-free survival (80.4% versus 86.8%), which was not significant in adjusted analyses (hazard ratio [HR], 1.38 [95% CI, 0.88-2.16]). All-cause death at 1 year for patients undergoing complex PCI was nearly double that seen for patients receiving noncomplex PCI (10.2% versus 5.9%), and the risk was significant in models adjusted for clinical characteristics (HR, 1.97 [95% CI, 1.02-3.79]). Target lesion revascularization risk was lower for patients receiving complex PCI (2.2% versus 3.5%, adjusted HR), but bleeding events were not statistically different between groups (25.3% versus 20.5%; P=0.19). Conclusions Complex PCI in older adults with stable ischemic heart disease was associated with lower risk of target lesion revascularization but higher all-cause death compared with noncomplex PCI.

Mechanistic research suggests using Cannabis sativa L. (cannabis or marijuana) may increase the risk of cardiometabolic disease, but observational studies investigating associations between cannabis use and myocardial infarction (MI) have reported inconsistent results. Cross-sectional National Health and Nutrition Examination Survey data from five 2-year cycles between 2009 and 2018 and representing 9,769 middle-aged adults (35 to 59 years old) were analyzed. Multivariable logistic regression models accounting for sampling weights and adjusting for cardiovascular risk factors were used to assess associations between a history of monthly cannabis use before MI and a subsequent MI. A quarter of respondents (n = 2,220) reported a history of monthly use >1 year before an MI. A history of MI was reported by 2.1% of all respondents and 3.2.% of those who reported a history of monthly use. In fully adjusted multivariable models, and compared with never use, a history of monthly cannabis use preceding an MI was not associated with an MI (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.35 to 1.71). However, when stratified by recent use, the odds of MI were threefold greater (OR 2.98, 95% CI 1.08 to 8.60) when no use was reported within the past month than when use was reported within the past month. Duration of monthly use was also not significantly associated with MI, including monthly use >10 years (OR 0.78, 95% CI 0.30 to 2.01). In conclusion, in a representative sample of middle-aged US adults, a history of monthly cannabis use >1 year before an MI was not associated with a subsequent physician-diagnosed MI, except for threefold greater odds when cannabis was not used within the past month.

Purpose of reviewLipoprotein(a) is an independent risk factor for cardiovascular disease. We review the ongoing shifts in consensus guidelines for the testing and management of Lp(a) and provide insight into whether current evidence suggests that awareness and testing of Lp(a) is clinically actionable.Recent findingsGWAS and Mendelian randomization studies have established causal links between elevated Lp(a) and forms of CVD, including CAD and calcific aortic valve disease. Testing of Lp(a) identifies patients with similar risk to that of heterozygous FH, enhances risk stratification in patients with borderline/intermediate risk as determined through traditional factors, and facilitates the assessment of inherited CVD risk through cascade screening in patients with known family history of elevated Lp(a). Reductions in Lp(a) through non-targeted therapies including PCSK9 inhibition and lipoprotein apheresis have demonstrated reductions in ASCVD risk that are likely attributable to lowering Lp(a). Targeted therapies to potently lower Lp(a) are in clinical development. Lp(a) is actionable, and can be used to identify high risk patients for primary prevention and their family members through cascade screening, and to guide intensification of therapy in primary and secondary prevention of ASCVD.

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1-/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.

Background Racially and ethnically minoritized groups, people with lower income, and rural communities have worse access to percutaneous coronary intervention (PCI) than their counterparts, but PCI hospitals have preferentially opened in wealthier areas. Our study analyzed disparities in PCI access, treatment, and outcomes for patients with acute myocardial infarction based on the census-derived Area Deprivation Index. Methods and Results We obtained patient-level data on 629 419 patients with acute myocardial infarction in California between January 1, 2006 and December 31, 2020. We linked patient data with population characteristics and geographic coordinates, and categorized communities into 5 groups based on the share of the population in low or high Area Deprivation Index neighborhoods to identify differences in PCI access, treatment, and outcomes based on community status. Risk-adjusted models showed that patients in the most advantaged communities had 20% and 15% greater likelihoods of receiving same-day PCI and PCI during the hospitalization, respectively, compared with patients in the most disadvantaged communities. Patients in the most advantaged communities also had 19% and 16% lower 30-day and 1-year mortality rates, respectively, compared with the most disadvantaged, and a 15% lower 30-day readmission rate. No statistically significant differences in admission to a PCI hospital were observed between communities. Conclusions Patients in disadvantaged communities had lower chances of receiving timely PCI and a greater risk of mortality and readmission compared with those in more advantaged communities. These findings suggest a need for targeted interventions to influence where cardiac services exist and who has access to them.

IntroductionCurrent efforts to reduce dementia focus on prevention and risk reduction by targeting modifiable risk factors. As dementia and cardiometabolic non-communicable diseases (NCDs) share risk factors, a single risk-estimating tool for dementia and multiple NCDs could be cost-effective and facilitate concurrent assessments as compared with a conventional single approach. The aim of this study is to develop and validate a new risk tool that estimates an individual's risk of developing dementia and other NCDs including diabetes mellitus, stroke and myocardial infarction. Once validated, it could be used by the public and general practitioners.Methods and analysisTen high-quality cohort studies from multiple countries were identified, which met eligibility criteria, including large representative samples, long-term follow-up, data on clinical diagnoses of dementia and NCDs, recognised modifiable risk factors for the four NCDs and mortality data. Pooled harmonised data from the cohorts will be used, with 65% randomly allocated for development of the predictive model and 35% for testing. Predictors include sociodemographic characteristics, general health risk factors and lifestyle/behavioural risk factors. A subdistribution hazard model will assess the risk factors' contribution to the outcome, adjusting for competing mortality risks. Point-based scoring algorithms will be built using predictor weights, internally validated and the discriminative ability and calibration of the model will be assessed for the outcomes. Sensitivity analyses will include recalculating risk scores using logistic regression.Ethics and disseminationEthics approval is provided by the University of New South Wales Human Research Ethics Committee (UNSW HREC; protocol numbers HC200515, HC3413). All data are deidentified and securely stored on servers at Neuroscience Research Australia. Study findings will be presented at conferences and published in peer-reviewed journals. The tool will be accessible as a public health resource. Knowledge translation and implementation work will explore strategies to apply the tool in clinical practice.

BACKGROUND: In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hs-cTn)-based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays. METHODS: In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs-cTn assays were derived to estimate the individual MI probability (ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients. RESULTS: Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92 to 0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline-recommended strategy. CONCLUSION: We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care. TRIAL REGISTRATION NUMBERS: Data of following cohorts were used for this project: BACC ( www. CLINICALTRIALS: gov ; NCT02355457), stenoCardia ( www. CLINICALTRIALS: gov ; NCT03227159), ADAPT-BSN ( www.australianclinicaltrials.gov.au ; ACTRN12611001069943), IMPACT ( www.australianclinicaltrials.gov.au , ACTRN12611000206921), ADAPT-RCT ( www.anzctr.org.au ; ANZCTR12610000766011), EDACS-RCT ( www.anzctr.org.au ; ANZCTR12613000745741); DROP-ACS ( https://www.umin.ac.jp , UMIN000030668); High-STEACS ( www. CLINICALTRIALS: gov ; NCT01852123), LUND ( www. CLINICALTRIALS: gov ; NCT05484544), RAPID-CPU ( www. CLINICALTRIALS: gov ; NCT03111862), ROMI ( www. CLINICALTRIALS: gov ; NCT01994577), SAMIE ( https://anzctr.org.au ; ACTRN12621000053820), SEIGE and SAFETY ( www. CLINICALTRIALS: gov ; NCT04772157), STOP-CP ( www. CLINICALTRIALS: gov ; NCT02984436), UTROPIA ( www. CLINICALTRIALS: gov ; NCT02060760).

Cardiovascular diseases are a leading global cause of death. Coronary heart disease stands as the most prevalent, posing a significant global health challenge. The proper functioning of organs hinges on well-defined anatomical structures, making it imperative to comprehend the fundamental histological characteristics of the heart. In this manuscript, we explore microscopic features of acute myocardial infarction, post-myocardial infarction (post-MI), left ventricular hypertrophy, and fatty heart. The research, conducted ethically, utilized microscopic images captured at Uzhhorod National University, Ukraine. Specimen analyses revealed distinct histological changes associated with conditions such as intracellular lipid accumulation, myocardial hypertrophy, and acute myocardial infarction. This exploration serves as a valuable resource for students, researchers, and healthcare professionals seeking a deeper understanding of cardiac microanatomy, offering insights crucial for accurate diagnosis and management in cardiovascular healthcare. [ABSTRACT FROM AUTHOR]

OBJECTIVES: COMMANDER-HF was a randomised trial comparing rivaroxaban 2.5 mg two times a day to placebo, in addition to antiplatelet therapy, in patients hospitalised for worsening heart failure with coronary artery disease and sinus rhythm. Patients with diabetes are at increased risk of cardiovascular events and therefore have more to gain. METHODS AND RESULTS: In this post-hoc analysis, we evaluated the efficacy and safety of rivaroxaban in patients with (n=2052) and without diabetes (n=2970). The primary outcome was the composite of cardiovascular death, myocardial infarction (MI) or ischaemic stroke. HRs and 95% CIs with interaction analyses were used to describe event-rates and treatment effects. Patients with diabetes had a higher prevalence of cardiovascular comorbidities (eg, hypertension, obesity) and increased incidence of cardiovascular events. Adjusted HRs for events in people with versus without diabetes were 1.34 (95% CI 1.19 to 1.50) for the primary outcome, 1.21 (95% CI 0.84 to 1.75) for stroke, 1.51 (95% CI 1.14 to 1.99) for MI, 1.17 (95% CI 1.05 to 1.31) for heart failure hospitalisation and 1.06 (95% CI 0.56 to 2.01) for major bleeding. Rivaroxaban had no significant effect on event-rates in patients with and without diabetes (all interaction p values >0.05). Low-dose rivaroxaban was associated with an overall reduction in ischaemic stroke (HR 0.66; 95% CI 0.47 to 0.95), with no apparent subgroup interaction according to diabetes status (p-int=0.93). CONCLUSIONS: In COMMANDER-HF a diagnosis of diabetes conferred higher rates of cardiovascular events that, with exception of ischaemic stroke, was not substantially reduced by rivaroxaban. Rivaroxaban was associated with reduced risk of ischaemic stroke for patients with and without diabetes. TRIAL REGISTRATION NUMBER: NCT01877915; Post-results.

BackgroundHIV infection leads to endothelial activation, promoting platelet adhesion, and accelerating atherosclerosis. Our goal was to determine whether biomarkers of endothelial activation and hemostasis/thrombosis were elevated in people with treated HIV (PWH) before myocardial infarction (MI).MethodsIn a case-control study nested within the CFAR Network of Integrated Clinical Systems (CNICS) cohort, we compared 69 adjudicated cases with type 1 MI with 138 controls matched for antiretroviral therapy regimen. We measured angiopoietin-1, angiopoietin-2 (ANG-2), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), von Willebrand factor, C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, and apolipoprotein A1 in stored plasma. Conditional logistic regression identified associations with subsequent MI, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores.ResultsHigher IL-6 was associated with MI after adjustment for ASCVD score (adjusted odds ratio [AOR] 1.51, 95% confidence interval [95% CI]: 1.05 to 2.17 per standard-deviation-scaled log 2 increment). In a separate model adjusting for VACS score, higher ANG-2 (AOR 1.49, 95% CI: 1.04 to 2.14), higher CRP (AOR 1.45, 95% CI: 1.06 to 2.00), and higher IL-6 (AOR 1.68, 95% CI: 1.17 to 2.41) were associated with MI. In a sensitivity analysis excluding PWH with viral load ≥400 copies/mL, higher IL-6 remained associated with MI after adjustment for ASCVD score and after adjustment for VACS score.ConclusionsAmong PWH, higher levels of plasma IL-6, CRP, and ANG-2 predict subsequent type 1 MI, independent of conventional risk scores. IL-6 had the most consistent associations with type 1 MI, regardless of viral load suppression.

INTRODUCTION: Traffic-related air pollution can trigger myocardial infarction (MI). However, the hourly hazard period of exposure to nitrogen dioxide (NO2), a common traffic tracer, for incident MI has not been fully evaluated. Thus, the current hourly US national air quality standard (100 ppb) is based on limited hourly-level effect estimates, which may not adequately protect cardiovascular health. OBJECTIVES: We characterized the hourly hazard period of NO2 exposure for MI in New York state (NYS), USA, from 2000 to 2015. METHODS: For nine cities in NYS, we obtained data on MI hospitalizations from the NYS Department of Health Statewide Planning and Research Cooperative System and hourly NO2 concentrations from the US Environmental Protection Agencys Air Quality System database. We used city-wide exposures and a case-crossover study design with distributed lag non-linear terms to assess the relationship between hourly NO2 concentrations over 24 h and MI, adjusting for hourly temperature and relative humidity. RESULTS: The mean NO2 concentration was 23.2 ppb (standard deviation: 12.6 ppb). In the six hours preceding MI, we found linearly increased risk with increasing NO2 concentrations. At lag hour 0, a 10 ppb increase in NO2 was associated with 0.2 % increased risk of MI (Rate Ratio [RR]: 1.002; 95 % Confidence Interval [CI]: 1.000, 1.004). We estimated a cumulative RR of 1.015 (95 % CI: 1.008, 1.021) for all 24 lag hours per 10 ppb increase in NO2. Lag hours 2-3 had consistently elevated risk ratios in sensitivity analyses. CONCLUSIONS: We found robust associations between hourly NO2 exposure and MI risk at concentrations far lower than current hourly NO2 national standards. Risk of MI was most elevated in the six hours after exposure, consistent with prior studies and experimental work evaluating physiologic responses after acute traffic exposure. Our findings suggest that current hourly standards may be insufficient to protect cardiovascular health.

ObjectiveBlood pressure fluctuations are a common hemodynamic alteration following carotid artery stenting either with transfemoral (TFCAS) or transcarotid (TCAR) approach and are thought to be related to alteration in baroreceptor function due to angioplasty and stent expansion. These fluctuations are particularly worrisome in the high-risk patient population referred for CAS. This study aims to evaluate the outcomes of patients who required the administration of intravenous blood pressure medication (IVBPmed) for hypotension or hypertension after CAS.MethodsAll patients undergoing carotid revascularization in the Vascular Quality Initiative (VQI) database between 2016 and 2021 were included. We compared outcomes of patients who required postoperative IVBPmed to treat hyper- or hypotension with normotensive patients. In-hospital outcomes were compared using multivariable logistic regression. One-year outcomes were assessed using Kaplan-Meier survival and multivariable Cox proportional hazard regression analyses.ResultsWe identified 38,510 patients undergoing CAS (57.7% TCAR and 42.3% TFCAS), of which, 30% received IVBPmed for treatment of either postoperative hypertension (12.6%) or hypotension (16.4%). In multivariable analysis, postoperative hypotension was associated with a higher risk of stroke, death, or myocardial infarction (MI) (odds ratio [OR], 3.1; 95% confidence interval [CI], 2.6-3.6; P < .001), stroke or death (OR, 2.9; 95% CI, 2.4-3.5; P < .001), stroke (OR, 2.6; 95% CI, 2.1-3.2; P < .001), death (OR, 3.5; 95% CI, 2.6-4.8; P < .001), MI (OR, 4.7; 95% CI, 3.3-6.7; P < .001), and bleeding (OR, 1.96; 95% CI, 1.4-2.7; P < .001) compared with normotensive patients. Postoperative hypertension was associated with a higher risk of stroke, death, or MI (OR, 3.6; 95% CI, 3-4.4; P < .001), stroke or death (OR, 3.3; 95% CI, 2.7-4.1; P < .001), stroke (OR, 3.7; 95% CI, 3-4.7; P < .001), death (OR, 2.7; 95% CI, 1.9-3.9; P < .001), MI (OR, 5.7; 95% CI, 3.9-8.3; P < .001), and bleeding (OR, 1.9; 95% CI, 1.4-2.7; P < .001) compared with normotensive patients.ConclusionsPostoperative hypertension or hypotension requiring IVBPmed after CAS is associated with an increased risk of in-hospital stroke, death, MI, and bleeding. Postoperative hypertension is associated with worse survival at 1 year. This study indicates that the need for IVBPmed after CAS is not benign; therefore, these patients necessitate aggressive perioperative medical management and safe techniques to avoid hypo and hypertension. Close follow-up and continue medical management are needed to maximize these patients' survival.

BACKGROUND: People with human immunodeficiency virus (HIV) infection (PWH) are at higher risk of myocardial infarction (MI) than those without HIV. About half of MIs in PWH are type 2 (T2MI), resulting from mismatch between myocardial oxygen supply and demand, in contrast to type 1 MI (T1MI), which is due to primary plaque rupture or coronary thrombosis. Despite worse survival and rising incidence in the general population, evidence-based treatment recommendations for T2MI are lacking. We used polygenic risk scores (PRS) to explore genetic mechanisms of T2MI compared to T1MI in PWH. METHODS: We derived 115 PRS for MI-related traits in 9541 PWH enrolled in the Centers for AIDS Research Network of Integrated Clinical Systems cohort with adjudicated T1MI and T2MI. We applied multivariate logistic regression analyses to determine the association with T1MI and T2MI. Based on initial findings, we performed gene set enrichment analysis of the top variants composing PRS associated with T2MI. RESULTS: We found that T1MI was strongly associated with PRS for cardiovascular disease, lipid profiles, and metabolic traits. In contrast, PRS for alcohol dependence and cholecystitis, significantly enriched in energy metabolism pathways, were predictive of T2MI risk. The association remained after the adjustment for actual alcohol consumption. CONCLUSIONS: We demonstrate distinct genetic traits associated with T1MI and T2MI among PWH further highlighting their etiological differences and supporting the role of energy regulation in T2MI pathogenesis.

OBJECTIVES: People with HIV have a higher risk of myocardial infarction (MI) than the general population, with a greater proportion of type 2 MI (T2MI) due to oxygen demand-supply mismatch compared with type 1 (T1MI) resulting from atherothrombotic plaque disruption. People living with HIV report a greater prevalence of cigarette and alcohol use than do the general population. Alcohol use and smoking as risk factors for MI by type are not well studied among people living with HIV. We examined longitudinal associations between smoking and alcohol use patterns and MI by type among people living with HIV. DESIGN AND METHODS: Using longitudinal data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort, we conducted time-updated Cox proportional hazards models to determine the impact of smoking and alcohol consumption on adjudicated T1MI and T2MI. RESULTS: Among 13 506 people living with HIV, with a median 4 years of follow-up, we observed 177 T1MI and 141 T2MI. Current smoking was associated with a 60% increase in risk of both T1MI and T2MI. In addition, every cigarette smoked per day was associated with a 4% increase in risk of T1MI, with a suggestive, but not significant, 2% increase for T2MI. Cigarette use had a greater impact on T1MI for men than for women and on T2MI for women than for men. Increasing alcohol use was associated with a lower risk of T1MI but not T2MI. Frequency of heavy episodic alcohol use was not associated with MI. CONCLUSIONS: Our findings reinforce the prioritization of smoking reduction, even without cessation, and cessation among people living with HIV for MI prevention and highlight the different impacts on MI type by gender.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Immunoglobulin M (IgM) autoantibodies to oxidation-specific epitopes (OSEs) can be present at birth and protect against atherosclerosis in experimental models. This study sought to determine whether high titers of IgM titers to OSE (IgM OSE) are associated with a lower risk of acute myocardial infarction (AMI) in humans. IgM to malondialdehyde (MDA)-LDL, phosphocholine-modified BSA, IgM apolipoprotein B100-immune complexes, and a peptide mimotope of MDA were measured within 24 h of first AMI in 4,559 patients and 4,617 age- and sex-matched controls in the Pakistan Risk of Myocardial Infarction Study. Multivariate-adjusted logistic regression was used to estimate odds ratio (OR) and 95% confidence interval for AMI. All four IgM OSEs were lower in AMI versus controls (P < 0.001 for all). Males, smokers and individuals with hypertension and diabetes had lower levels of all four IgM OSE than unaffected individuals (P < 0.001 for all). Compared to the lowest quintile, the highest quintiles of IgM MDA-LDL, phosphocholine-modified BSA, IgM apolipoprotein B100-immune complexes, and MDA mimotope P1 had a lower OR of AMI: OR (95% confidence interval) of 0.67 (0.58-0.77), 0.64 (0.56-0.73), 0.70 (0.61-0.80) and 0.72 (0.62-0.82) (P < 0.001 for all), respectively. Upon the addition of IgM OSE to conventional risk factors, the C-statistic improved by 0.0062 (0.0028-0.0095) and net reclassification by 15.5% (11.4-19.6). These findings demonstrate that IgM OSE provides clinically meaningful information and supports the hypothesis that higher levels of IgM OSE may be protective against AMI.

This article discusses the relationship between microplastics and cardiovascular diseases, emphasizing the importance of considering coexisting environmental pollutants. While human studies have shown a link between microplastics and cardiovascular issues, it is crucial to recognize that microplastics do not exist alone in the real world and often serve as carriers for other contaminants. The composition of these coexisting contaminants can vary geographically, making it challenging to achieve consistent findings in human studies. The article suggests that assessing the adverse effects of microplastics on humans requires information from both experimental studies and epidemiological data, and alternative approaches to protection may be necessary. [Extracted from the article]

OBJECTIVE: Optimal temporal surgical management of significant carotid stenosis and coronary artery disease remains unknown. Carotid endarterectomy (CEA) and coronary artery bypass (CABG) are performed concurrently (CCAB) or in a staged (CEA-CABG or CABG-CEA) approach. Using the Vascular Quality Initiative-Vascular Implant Surveillance and Interventional Outcomes Coordinated Registry Network-Medicare-linked dataset, this study compared operative and long-term outcomes after CCAB and staged approaches. METHODS: The Vascular Quality Initiative-Vascular Implant Surveillance and Interventional Outcomes Coordinated Registry Network dataset was used to identify CEAs from 2011 to 2018 with combined CABG or CABG within 45 days preceding or after CEA. Patients were stratified based on concurrent or staged approach. Primary outcomes were stroke, myocardial infarction (MI), all-cause mortality, stroke and death as composite (SD) and all as composite within 30 days from the last procedure as well as in the long term. Univariate analysis and risk-adjusted analysis using inverse propensity weighting were performed. Kaplan-Meier curves of stroke, MI, and death were created and compared. RESULTS: There were 1058 patients included: 643 CCAB and 415 staged (309 CEA-CABG and 106 CABG-CEA). Compared with staged patients, those undergoing CCAB had a higher preoperative rate of congestive heart failure (24.8% vs 18.4%; P = .01) and decreased renal function (14.9% vs 8.5%; P < .01), as well as fewer prior neurological events (23.5% vs 31.4%; P

BACKGROUND: Randomized trials are the gold standard for generating clinical practice evidence, but follow-up and outcome ascertainment are resource-intensive. Electronic health record (EHR) data from routine care can be a cost-effective means of follow-up, but concordance with trial-ascertained outcomes is less well-studied. METHODS: We linked EHR and trial data for participants of the Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial comparing intensive and standard blood pressure targets. Among participants with available EHR data concurrent to trial-ascertained outcomes, we calculated sensitivity, specificity, positive predictive value, and negative predictive value for EHR-recorded cardiovascular disease (CVD) events, using the gold standard of SPRINT-adjudicated outcomes (myocardial infarction (MI)/acute coronary syndrome (ACS), heart failure, stroke, and composite CVD events). We additionally compared the incidence of non-CVD adverse events (hyponatremia, hypernatremia, hypokalemia, hyperkalemia, bradycardia, and hypotension) in trial versus EHR data. RESULTS: 2468 SPRINT participants were included (mean age 68 (SD 9) years; 26% female). EHR data demonstrated ≥80% sensitivity and specificity, and ≥ 99% negative predictive value for MI/ACS, heart failure, stroke, and composite CVD events. Positive predictive value ranged from 26% (95% CI; 16%, 38%) for heart failure to 52% (95% CI; 37%, 67%) for MI/ACS. EHR data uniformly identified more non-CVD adverse events and higher incidence rates compared with trial ascertainment. CONCLUSIONS: These results support a role for EHR data collection in clinical trials, particularly for capturing laboratory-based adverse events. EHR data may be an efficient source for CVD outcome ascertainment, though there is clear benefit from adjudication to avoid false positives.

While biomarkers have been proposed to identify individuals at risk for radiation-induced cardiovascular disease (RICVD), little is known about long-term associations with cardiac events. We examined associations of biomarkers of oxidative stress (myeloperoxidase, growth differentiation factor-15, 8-hydroxy-2-deoxyguanosine [8-OH-dG], placental growth factor), cardiac injury (troponin I, cystatin-C), inflammation (interleukin-6, C-reactive protein), and myocardial fibrosis (transforming growth factor-ß) with long-term RICVD in breast cancer (BC) survivors. We conducted a nested case-control study within the Womens Health Initiative of postmenopausal women with incident BC stages I-III, who received radiation and had pre- and post-BC diagnosis serum samples. Cases (n = 55) were defined as developing incident, physician-adjudicated myocardial infarction, coronary heart disease death, other CVD death, heart failure, or stroke after BC. Cases were matched to three controls (n = 158). After adjustment, a higher 8-OH-dG ratio was significantly associated with an elevated long-term risk of RICVD, suggesting oxidative DNA damage may be a putative pathway for RICVD.

OBJECTIVES: The relationship between chronic obstructive pulmonary disease (COPD) and cardiovascular disease in people with HIV (PWH) is incompletely understood. We determined whether COPD is associated with risk of myocardial infarction (MI) among PWH, and if this differs for type 1 (T1MI) and type 2 (T2MI). DESIGN: We utilized data from five sites in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort, a multisite observational study. METHODS: Our primary outcome was an adjudicated MI, classified as T1MI or T2MI. We defined COPD based on a validated algorithm requiring COPD diagnosis codes and at least 90-day continuous supply of inhalers. We conducted time-to-event analyses to first MI and used multivariable Cox proportional hazards models to measure associations between COPD and MI. RESULTS: Among 12 046 PWH, 945 had COPD. Overall, 309 PWH had an MI: 58% had T1MI ( N  = 178) and 42% T2MI ( N  = 131). In adjusted models, COPD was associated with a significantly increased risk of all MI [adjusted hazard ratio (aHR) 2.68 (95% confidence interval (CI) 1.99-3.60)] even after including self-reported smoking [aHR 2.40 (95% CI 1.76-3.26)]. COPD was also associated with significantly increased risk of T1MI and T2MI individually, and with sepsis and non-sepsis causes of T2MI. Associations were generally minimally changed adjusting for substance use. CONCLUSION: COPD is associated with a substantially increased risk for MI, including both T1MI and T2MI, among PWH. Given the association with both T1MI and T2MI, diverse mechanistic pathways are involved. Future strategies to decrease risk of T1MI and T2MI in PWH who have COPD are needed.

Artificial sweeteners are widely used sugar substitutes, but little is known about their long-term effects on cardiometabolic disease risks. Here we examined the commonly used sugar substitute erythritol and atherothrombotic disease risk. In initial untargeted metabolomics studies in patients undergoing cardiac risk assessment (n = 1,157; discovery cohort, NCT00590200 ), circulating levels of multiple polyol sweeteners, especially erythritol, were associated with incident (3 year) risk for major adverse cardiovascular events (MACE; includes death or nonfatal myocardial infarction or stroke). Subsequent targeted metabolomics analyses in independent US (n = 2,149, NCT00590200 ) and European (n = 833, DRKS00020915 ) validation cohorts of stable patients undergoing elective cardiac evaluation confirmed this association (fourth versus first quartile adjusted hazard ratio (95% confidence interval), 1.80 (1.18-2.77) and 2.21 (1.20-4.07), respectively). At physiological levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo. Finally, in a prospective pilot intervention study ( NCT04731363 ), erythritol ingestion in healthy volunteers (n = 8) induced marked and sustained (>2 d) increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies. Our findings reveal that erythritol is both associated with incident MACE risk and fosters enhanced thrombosis. Studies assessing the long-term safety of erythritol are warranted.

AimsCigarette smoking is among the most well-established risk factors for adverse cardiovascular outcomes. We sought to determine whether icosapent ethyl (IPE), a highly purified form of eicosapentaenoic acid with antiatherothrombotic properties, may reduce the excessive risk of cardiovascular disease (CVD) attributable to smoking.Methods and resultsReduction of Cardiovascular Events with Icosapent Ethyl Trial (REDUCE-IT) was a multinational, double-blind trial that randomized 8179 statin-treated patients with elevated triglycerides and CV risk to IPE or placebo, with a median follow-up period of 4.9 years. Icosapent ethyl reduced the primary composite endpoint [CV death, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, or hospitalization for unstable angina] by 25% (P

BackgroundThe Agatston coronary artery calcium (CAC) score provides robust cardiovascular disease risk prediction but upweights plaque area by a density factor. Density, however, has been shown to be inversely associated with events. Using CAC volume and density separately improves risk prediction, but it is unclear how to apply this method clinically. We aimed to evaluate the association between CAC density and cardiovascular disease across the spectrum of CAC volume to better understand how to incorporate these metrics into a single score.MethodsWe performed an analysis of MESA (Multi-Ethnic Study of Atherosclerosis) participants with detectable CAC to evaluate the association between CAC density and events by level of CAC volume using multivariable Cox regression models.ResultsIn a cohort of 3316 participants, there was a significant interaction (P130 mm3 was not significant (hazard ratio, 0.82 per unit of density [95% CI, 0.55-1.22]).ConclusionsThe lower risk for CHD associated with higher CAC density varied by level of volume, and volume ≤130 mm3 is a potentially clinically useful cut point. Further study is needed to integrate these findings into a unified CAC scoring method.

OBJECTIVES: To assess associations between SARS-CoV-2 infection and the incidence of hospitalisation with selected respiratory and non-respiratory conditions in a largely SARS-CoV-2 vaccine-naïve population . DESIGN, SETTING, PARTICIPANTS: Self-control case series; analysis of population-wide surveillance and administrative data for all laboratory-confirmed COVID-19 cases notified to the Victorian Department of Health (onset, 23 January 2020 - 31 May 2021; ie, prior to widespread vaccination rollout) and linked hospital admissions data (admission dates to 30 September 2021). MAIN OUTCOME MEASURES: Hospitalisation of people with acute COVID-19; incidence rate ratios (IRRs) comparing incidence of hospitalisations with defined conditions (including cardiac, cerebrovascular, venous thrombo-embolic, coagulative, and renal disorders) from three days before to within 89 days of onset of COVID-19 with incidence during baseline period (60-365 days prior to COVID-19 onset). RESULTS: A total of 20 594 COVID-19 cases were notified; 2992 people (14.5%) were hospitalised with COVID-19. The incidence of hospitalisation within 89 days of onset of COVID-19 was higher than during the baseline period for several conditions, including myocarditis and pericarditis (IRR, 14.8; 95% CI, 3.2-68.3), thrombocytopenia (IRR, 7.4; 95% CI, 4.4-12.5), pulmonary embolism (IRR, 6.4; 95% CI, 3.6-11.4), acute myocardial infarction (IRR, 3.9; 95% CI, 2.6-5.8), and cerebral infarction (IRR, 2.3; 95% CI, 1.4-3.9). CONCLUSION: SARS-CoV-2 infection is associated with higher incidence of hospitalisation with several respiratory and non-respiratory conditions. Our findings reinforce the value of COVID-19 mitigation measures such as vaccination, and awareness of these associations should assist the clinical management of people with histories of SARS-CoV-2 infection.

BACKGROUND: During the 2010 Deepwater Horizon (DWH) disaster, in-situ burning and flaring were conducted to remove oil from the water. Workers near combustion sites were potentially exposed to burning-related fine particulate matter (PM2.5). Exposure to PM2.5 has been linked to increased risk of coronary heart disease (CHD), but no study has examined the relationship among oil spill workers. OBJECTIVES: To investigate the association between estimated PM2.5 from burning/flaring of oil/gas and CHD risk among the DWH oil spill workers. METHODS: We included workers who participated in response and cleanup activities on the water during the DWH disaster (N = 9091). PM2.5 exposures were estimated using a job-exposure matrix that linked modelled PM2.5 concentrations to detailed DWH spill work histories provided by participants. We ascertained CHD events as the first self-reported physician-diagnosed CHD or a fatal CHD event that occurred after each workers last day of burning exposure. We estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for the associations between categories of average or cumulative daily maximum PM2.5 exposure (versus a referent category of water workers not near controlled burning) and subsequent CHD. We assessed exposure-response trends by examining continuous exposure parameters in models. RESULTS: We observed increased CHD hazard among workers with higher levels of average daily maximum exposure (low vs. referent: HR = 1.26, 95% CI: 0.93, 1.70; high vs. referent: HR = 2.11, 95% CI: 1.08, 4.12; per 10 μg/m3 increase: HR = 1.10, 95% CI: 1.02, 1.19). We also observed suggestively elevated HRs among workers with higher cumulative daily maximum exposure (low vs. referent: HR = 1.19, 95% CI: 0.68, 2.08; medium vs. referent: HR = 1.38, 95% CI: 0.88, 2.16; high vs. referent: HR = 1.44, 95% CI: 0.96, 2.14; per 100 μg/m3-d increase: HR = 1.03, 95% CI: 1.00, 1.05). CONCLUSIONS: Among oil spill workers, exposure to PM2.5 from flaring/burning of oil/gas was associated with increased risk of CHD.

OBJECTIVE: While Opioid Use Disorder (OUD) has been linked to inferior clinical outcomes, studies examining the clinical outcomes and readmission of OUD patients experiencing Acute Myocardial Infarction (AMI) remain lacking. The authors analyze the clinical and financial outcomes of OUD in a contemporary cohort of AMI hospitalizations. METHODS: All non-elective adult (≥ 18 years) hospitalizations for AMI were tabulated from the 2016‒2019 Nationwide Readmissions Database using relevant International Classification of Disease codes. Patients were grouped into OUD and non-OUD cohorts. Bivariate and regression analyses were performed to identify the independent association of OUD with outcomes after non-elective admission for AMI, as well as subsequent readmission. RESULTS: Of an estimated 3,318,257 hospitalizations for AMI meeting study criteria, 36,057 (1.1%) had a concomitant diagnosis of OUD. While OUD was not significantly associated with mortality, OUD patients experienced superior cardiovascular outcomes compared to non-OUD. However, OUD was linked to increased odds of non-cardiovascular complications, length of stay, costs, non-home discharge, and 30-day non-elective readmission. CONCLUSIONS: Patients with OUD presented with AMI at a significantly younger age than non-OUD. While OUD appears to have a cardioprotective effect, it is associated with several markers of increased resource use, including readmission. The present findings underscore the need for a multifaceted approach to increasing social services and treatment for OUD at index hospitalization.

Background Long-term exposure to outdoor fine particulate matter (PM2.5) is the leading environmental risk factor for premature mortality worldwide. Characterizing important pathways through which PM2.5 increases individuals' mortality risk can clarify the PM2.5-mortality relationship and identify possible points of interventions. Recent evidence has linked PM2.5 to the onset of diabetes and cardiovascular disease, but to what extent these associations contribute to the effect of PM2.5 on mortality remains poorly understood. Methods and Results We conducted a population-based cohort study to investigate how the effect of PM2.5 on nonaccidental mortality is mediated by its impacts on incident diabetes, acute myocardial infarction, and stroke. Our study population comprised ≈200 000 individuals aged 20 to 90 years who participated in population-based health surveys in Ontario, Canada, from 1996 to 2014. Follow-up extended until December 2017. Using causal mediation analyses with Aalen additive hazards models, we decomposed the total effect of PM2.5 on mortality into a direct effect and several path-specific indirect effects mediated by diabetes, each cardiovascular event, or both combined. A series of sensitivity analyses were also conducted. After adjusting for various individual- and neighborhood-level covariates, we estimated that for every 1000 adults, each 10 μg/m3 increase in PM2.5 was associated with ≈2 incident cases of diabetes, ≈1 major cardiovascular event (acute myocardial infarction and stroke combined), and ≈2 deaths annually. Among PM2.5-related deaths, 31.7% (95% CI, 17.2%-53.2%) were attributable to diabetes and major cardiovascular events in relation to PM2.5. Specifically, 4.5% were explained by PM2.5-induced diabetes, 22.8% by PM2.5-induced major cardiovascular events, and 4.5% through their interaction. Conclusions This study suggests that a significant portion of the estimated effect of long-term exposure to PM2.5 on deaths can be attributed to its effect on diabetes and cardiovascular diseases, highlighting the significance of PM2.5 on deteriorating cardiovascular health. Our findings should raise awareness among professionals that improving metabolic and cardiovascular health may reduce mortality burden in areas with higher exposure to air pollution.

Genetic substudies of randomized controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction; it is unknown if the association extends to statin users undergoing routine care. We sought to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of participants without previous myocardial infarction. We determined CHD polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Covariate-adjusted Cox regression models were used to compare the risk of cardiovascular outcomes between statin users and matched nonusers. Statin effectiveness on incident myocardial infarction showed no gradient with increasing 10-year Pooled Cohort Equations atherosclerotic cardiovascular disease (ASCVD) risk across low, borderline, intermediate, and high ASCVD risk score groups. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (hazard ratio (HR) 0.41, 95% confidence interval (CI), 0.31-0.53; P = 1.5E-11), intermediate in the intermediate polygenic risk score group (HR 0.56, 95% CI, 0.47-0.66; P = 8.4E-12), and smallest in the low polygenic risk score group (HR 0.67, 95% CI, 0.47-0.97; P = 0.03; P for high vs. low = 0.01). ASCVD risk and statin low-density lipoprotein cholesterol (LDL-C) lowering did not differ across polygenic risk score groups. In patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of LDL-C lowering. Our findings extend prior work by identifying a subset (i.e., self-identified White individuals with low CHD polygenic risk scores) with attenuated clinical benefit from statins.

BackgroundIndividuals with a greater perceived risk of heart attack or type 2 diabetes tend to adopt recommended lifestyle changes to minimize their risks. Despite the rapidly growing Hispanic population in the United States, data regarding their perceived risks are lacking.ObjectiveThis study aimed to examine the perceived risk of suffering a heart attack and/or developing type 2 diabetes and to explore the factors associated with these risk perceptions in Hispanic adults with overweight/obesity.MethodsWe analyzed 69 Hispanic adults with overweight/obesity who participated in the screening/baseline visit for the Adelgaza study, a weight loss and diabetes prevention trial, using descriptive statistics and logistic regressions. Heart attack or type 2 diabetes risk perception was assessed using a single-item questionnaire.ResultsThe mean (SD) values for age and body mass index (BMI) were 43.8 (11.2) years and 31.7 (4.5) kg/m 2 , respectively. Of all participants, 46.4% perceived a low risk for heart attack and 29.0% perceived a low risk for developing type 2 diabetes in their lifetime, whereas only 11.6% reported both risk perceptions. Older age, lower BMI, and longer walking duration (minutes) per day were significantly associated with a lower perceived risk of heart attack ( P < .05). Having no family history of heart attack, lower BMI, and lower fat intake were significant predictors of a lower diabetes-risk perception ( P < .05).ConclusionsHispanic adults with overweight/obesity seem to underestimate their risks of heart attack and type 2 diabetes.

Background Persistence to P2Y12 inhibitors after myocardial infarction (MI) remains low. Out-of-pocket cost is cited as a factor affecting medication compliance. We examined whether a copayment intervention affected 1-year persistence to P2Y12 inhibitors and clinical outcomes. Methods and Results In an analysis of ARTEMIS (Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study), patients with MI discharged on a P2Y12 inhibitor were stratified by baseline out-of-pocket medication burden: low ($0-$49 per month), intermediate ($50-$149 per month), and high (≥$150 per month). The impact of the voucher intervention on 1-year P2Y12 inhibitor persistence was examined using a logistic regression model with generalized estimating equations. We assessed the rates of major adverse cardiovascular events among the groups using a Kaplan-Meier estimator. Among 7351 MI-treated patients at 282 hospitals, 54.2% patients were in the low copay group, 32.0% in the middle copay group, and 13.8% in the high copay group. Patients in higher copay groups were more likely to have a history of prior MI, heart failure, and diabetes compared with the low copay group (all P

AimsIn a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis.Methods and resultsdal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98).ConclusionDalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype.Clinical trial registrationTrial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.

ObjectivesTo evaluate characteristics and outcomes of patients presenting with acute myocardial infarction and cardiogenic shock (AMICS) during the coronavirus disease 2019 (COVID-19) pandemic.BackgroundThe COVID-19 pandemic has created challenges in delivering acute cardiovascular care. Quality measures and outcomes of patients presenting with AMICS during COVID-19 in the United States have not been well described.MethodsWe identified 406 patients from the National Cardiogenic Shock Initiative (NCSI) with AMICS and divided them into those presenting before (N = 346, 5/9/2016-2/29/2020) and those presenting during the COVID-19 pandemic (N = 60, 3/1/2020-11/10/2020). We compared baseline clinical data, admission characteristics, and outcomes.ResultsThe median age of the cohort was 64 years, and 23.7% of the group was female. There were no significant differences in age, sex, and medical comorbidities between the two groups. Patients presenting during the pandemic were less likely to be Black compared to those presenting prior. Median door to balloon (90 vs. 88 min, p = 0.38), door to support (88 vs. 78 min, p = 0.13), and the onset of shock to support (74 vs. 62 min, p = 0.15) times were not significantly different between the two groups. Patients presented with ST-elevation myocardial infarction more often during the COVID-19 period (95.0% vs. 80.0%, p = 0.005). In adjusted logistic regression models, COVID-19 period did not significantly associate with survival to discharge (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.54-2.19, p = 0.81) or with 1-month survival (OR 0.82, 95% CI 0.42-1.61, p = 0.56).ConclusionsCare of patients presenting with AMICS has remained robust among hospitals participating in the NCSI during the COVID-19 pandemic.

BACKGROUND: Effects of animal source foods (ASF) on atherosclerotic cardiovascular disease (ASCVD) and underlying mechanisms remain controversial. We investigated prospective associations of different ASF with incident ASCVD and potential mediation by gut microbiota-generated trimethylamine N-oxide, its L-carnitine-derived intermediates γ-butyrobetaine and crotonobetaine, and traditional ASCVD risk pathways. METHODS: Among 3931 participants from a community-based US cohort aged 65+ years, ASF intakes and trimethylamine N-oxide-related metabolites were measured serially over time. Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, other atherosclerotic death) was adjudicated over 12.5 years median follow-up. Cox proportional hazards models with time-varying exposures and covariates examined ASF-ASCVD associations; and additive hazard models, mediation proportions by different risk pathways. RESULTS: After multivariable-adjustment, higher intakes of unprocessed red meat, total meat, and total ASF associated with higher ASCVD risk, with hazard ratios (95% CI) per interquintile range of 1.15 (1.01-1.30), 1.22 (1.07-1.39), and 1.18 (1.03-1.34), respectively. Trimethylamine N-oxide-related metabolites together significantly mediated these associations, with mediation proportions (95% CI) of 10.6% (1.0-114.5), 7.8% (1.0-32.7), and 9.2% (2.2-44.5), respectively. Processed meat intake associated with a nonsignificant trend toward higher ASCVD (1.11 [0.98-1.25]); intakes of fish, poultry, and eggs were not significantly associated. Among other risk pathways, blood glucose, insulin, and C-reactive protein, but not blood pressure or blood cholesterol, each significantly mediated the total meat-ASCVD association. CONCLUSIONS: In this large, community-based cohort, higher meat intake associated with incident ASCVD, partly mediated by microbiota-derived metabolites of L-carnitine, abundant in red meat. These novel findings support biochemical links between dietary meat, gut microbiome pathways, and ASCVD.

Common drugs of misuse, including cannabis, opioids, stimulants, alcohol, and anabolic steroids, have strikingly disparate acute and chronic vascular effects, leading to a wide range of clinical cardiovascular presentations. Acute cannabis smoking has been associated with increased risk for myocardial infarction and ischemic stroke in otherwise healthy young people. However, it remains uncertain if people who exclusively smoke cannabis have increased risk for accelerated atherosclerosis similar to that found in people who exclusively smoke tobacco cigarettes. Cocaine and methamphetamines, both stimulants, increase risk for stroke, myocardial infarction, aortic dissection, and accelerated atherosclerosis, but only methamphetamine use is strongly linked to pulmonary hypertension. Chronic alcohol use is strongly associated with chronic hypertension and hemorrhagic stroke, but perhaps confers a lower risk for myocardial infarction. Finally, anabolic steroid use, presumably through adverse effects on circulating lipids and the hematopoietic system, is associated with increased risk for accelerated atherosclerosis and myocardial infarction. Physicians, especially cardiologists, emergency medicine, and internal medicine physicians, should be familiar with the short- and long-term vascular consequences of use of these substances, thereby ensuring appropriate, specific, and informed counselling and treatment.