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The association between thyroid stimulating hormone (TSH) and cardiovascular disease has mainly been determined using clinical categories of disease. We tested the hypothesis that TSH on a continuous scale is associated with risk of atrial fibrillation (AF), myocardial infarction (MI), stroke, heart failure (HF), aortic valve stenosis (AVS), and major adverse cardiovascular events (MACE) and whether these associations are likely to be causal. We first tested whether plasma TSH on a continuous scale was observationally associated with incident cardiovascular events in a prospective cohort study of 105,224 individuals from the Copenhagen General Population Study followed for a median 7 years. Next, we tested whether a genetic risk score weighted on TSH was associated with cardiovascular endpoints. Finally, using Mendelian randomization, we tested whether the observed associations were likely to be causal. Using restricted cubic splines, lower concentrations of TSH relative to the population median (=1.53 mIU/L) were associated with higher risk of AF, MI, stroke, HF, AVS, and MACE. Comparing individuals with TSH ≤5th percentile (≤0.54 mIU/L) versus >50th percentile (>1.53 mIU/L), hazard ratios (HRs) ranged from 1.12 (1.00–1.26) for stroke to 1.27 (1.11–1.46) for HF. Genetic risk estimates per standard deviation decrease in TSH were 1.28 (1.08–1.52) for AF, 1.35 (1.06–1.71) for MI, 1.06 (0.89–1.26) for stroke, 1.19 (0.94–1.52) for HF, 1.53 (1.03–2.26) for AVS, and 1.09 (0.97–1.23) for MACE. In 105,224 individuals from the general population low plasma TSH was observationally and genetically associated with increased risk of AF, MI, and AVS suggesting that these observations may reflect causal pathways. [Display omitted] • We tested the hypothesis that TSH was associated with cardiovascular disease (CVD). • 105,224 individuals from the general population were followed for a median of 7 years. • Observationally, TSH below the median was associated with increased risk of CVD. • Genetically, Mendelian randomization suggested possible causal associations. [ABSTRACT FROM AUTHOR]

Mendelian randomization confirmed multiple risk factors for primary events of coronary artery disease (CAD), but no such studies have been performed on recurrent major coronary events despite interesting insights derived from other designs. We examined the associations between genetically-influenced classical cardiovascular risk factors and the risk of recurrent major coronary events in a cohort of CAD patients. We included all first-time CAD cases (defined as angina pectoris, chronic ischemic heart disease or acute myocardial infarction) of European ancestry from the UK Biobank. Cases were followed till the end of follow-up, death or when they developed a recurrent major coronary event (chronic ischemic heart disease or acute myocardial infarction). Standardized weighted genetic risk scores were calculated for body mass index (BMI), systolic blood pressure, LDL cholesterol and triglycerides. From a total of 22,949 CAD patients (mean age at first diagnosis 59.8 (SD 7.3) years, 71.1% men), 12,539 (54.6%) reported a recurrent major coronary event within a period of maximum 17.8 years. One standard deviation higher genetically-determined LDL cholesterol was associated with a higher risk of a recurrent major coronary event (odds ratio: 1.08 [95% confidence interval: 1.05, 1.11]). No associations were observed for genetically-influenced BMI (1.00 [0.98, 1.03]), systolic blood pressure (1.01 [0.98, 1.03]) and triglycerides (1.02 [0.995, 1.05]). Despite the use risk-reducing medications following a first coronary event, this study provided genetic evidence that, of the classical risk factors, mainly high LDL cholesterol was associated with a higher risk of developing recurrent major coronary events. [Display omitted] • Most Mendelian randomization studies were performed on primary disease. • In atherosclerosis patients, LDL cholesterol associated with secondary disease. • Other classical cardiovascular disease did not associate with secondary disease. • LDL cholesterol should be mainly targeted to reduce secondary disease risk. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Outcome has improved during the last decades due to secondary prevention and widespread coronary interventions, but recent studies still show sex differences and insufficient drug adherence. We aimed to determine differences in the treatment strategies and outcomes between women and men with ST-elevation myocardial infarction (STEMI) in Germany. From the Federal Association of the Local Health Insurance Funds (Allgemeine Ortskrankenkasse), 175,187 patients were identified who were hospitalized due to STEMI in Germany between January 1, 2010 and December 31, 2017. Compared to men, women were older (median 76 vs. 64 years) and had more often diabetes, hypertension, chronic heart failure, and chronic kidney disease (all p < 0.001). Women suffered from higher rates of in-hospital complications such as bleeding (9.3 vs. 6.6%), longer hospitalizations (12.2 vs. 11.7 days) and were less likely to undergo percutaneous coronary intervention (75.5 vs. 85.2%). After adjustment for patient's risk profile, female sex was associated with decreased overall survival (HR 1.02, 95% confidence interval (CI) 1.00–1.04; p= 0.036). Notably, more men received all four guideline-recommended drugs after STEMI (women 65.7% vs. men 69.8% after 90 days; p < 0.001). With increasing number of prescribed drugs, patients benefit even more. This concerned both sexes, but was more pronounced in men (with 4 prescribed drugs: women HR 0.52, 95%CI 0.50–0.55; men HR 0.48, 95% CI 0.47–0.50, p int = 0.014). In a contemporary nationwide analysis, women with STEMI were older, had more comorbidities, underwent revascularization less often and had an increased risk for major complications as well as overall survival. Guideline-recommended drug therapy was applied less frequently in women although associated with an improved overall-survival. [Display omitted] • Compared to men, women with STEMI were older and had more comorbidities. • Women had higher rates of inpatient complications, received percutaneous coronary intervention less often, and when adjusted for the risk profile, the female sex was associated with reduced overall survival. • After STEMI, women received all four guideline-recommended drugs less often, although the prognosis improved with the increase in these drugs. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Outcome has improved during the last decades due to secondary prevention and widespread coronary interventions, but recent studies still show sex differences and insufficient drug adherence. We aimed to determine differences in the treatment strategies and outcomes between women and men with ST-elevation myocardial infarction (STEMI) in Germany. From the Federal Association of the Local Health Insurance Funds (Allgemeine Ortskrankenkasse), 175,187 patients were identified who were hospitalized due to STEMI in Germany between January 1, 2010 and December 31, 2017. Compared to men, women were older (median 76 vs. 64 years) and had more often diabetes, hypertension, chronic heart failure, and chronic kidney disease (all p < 0.001). Women suffered from higher rates of in-hospital complications such as bleeding (9.3 vs. 6.6%), longer hospitalizations (12.2 vs. 11.7 days) and were less likely to undergo percutaneous coronary intervention (75.5 vs. 85.2%). After adjustment for patient's risk profile, female sex was associated with decreased overall survival (HR 1.02, 95% confidence interval (CI) 1.00–1.04; p= 0.036). Notably, more men received all four guideline-recommended drugs after STEMI (women 65.7% vs. men 69.8% after 90 days; p < 0.001). With increasing number of prescribed drugs, patients benefit even more. This concerned both sexes, but was more pronounced in men (with 4 prescribed drugs: women HR 0.52, 95%CI 0.50–0.55; men HR 0.48, 95% CI 0.47–0.50, p int = 0.014). In a contemporary nationwide analysis, women with STEMI were older, had more comorbidities, underwent revascularization less often and had an increased risk for major complications as well as overall survival. Guideline-recommended drug therapy was applied less frequently in women although associated with an improved overall-survival. [Display omitted] • Compared to men, women with STEMI were older and had more comorbidities. • Women had higher rates of inpatient complications, received percutaneous coronary intervention less often, and when adjusted for the risk profile, the female sex was associated with reduced overall survival. • After STEMI, women received all four guideline-recommended drugs less often, although the prognosis improved with the increase in these drugs. [ABSTRACT FROM AUTHOR]

RNA transcripts are not finished products. Like proteins undergo posttranslational modifications, RNAs undergo posttranscriptional modifications. Some of these modifications affect processing, stability or turnover of RNAs, others can 'edit' nucleotides, change the RNA's function and rewrite the genetic code. The body of RNA modifications is collectively called the 'epitranscriptome'. The epitranscriptome is dynamically regulated. This is the most clear for N6-methyladenosine (m6A), where both m6A-'writers' and –'erasers' have been identified and are also already being employed in studies on the effects of broad-scale m6A modifications on human disease, including cardiovascular disease. Even though not all modifications are readily reversible like m6A, most, if not all, other modifications are actively regulated in response to stressors, such as ischemia, starvation, or incubation with for example cytokines or oxidized LDL, all important factors in vascular remodelling and cardiovascular disease. Epitranscriptome research in human disease in general and in cardiovascular research is still in its infancy and methods to reliably detect and/or manipulate most RNA modifications are still lacking. Nonetheless, the number of studies on RNA modification and on writer-, eraser-, and reader-protein in various forms of vascular remodelling has increased dramatically over the last three years. This review aimed to discuss the available literature on the most common RNA modifications in different forms of vascular remodelling. Both adaptive vascular remodelling, including postischemic angiogenesis, as well as maladaptive remodelling, like atherosclerosis and aneurysm formation, and their direct consequences, such as myocardial infarction, acute stroke, peripheral artery disease and abdominal aorta aneurysm, have been discussed. [Display omitted] • The epitranscriptome, the collective of posttranscriptional modifications of RNAs, adds a layer of regulation of gene expression and function. • Over the past three years, epitranscriptome research in the cardiovascular field has started to take flight. • m6A and A-to-I editing dominate the epitranscriptome field in CVD, but other modifications are gaining momentum too. [ABSTRACT FROM AUTHOR]

Elevated body weight in adolescence is associated with early cardiovascular disease, but whether this association is traceable to weight in early adulthood, weight in midlife or to weight gain is not known. The aim of this study is to assess the risk of midlife coronary atherosclerosis being associated with body weight at age 20, body weight in midlife and body weight change. We used data from 25,181 participants with no previous myocardial infarction or cardiac procedure in the Swedish CArdioPulmonary bioImage Study (SCAPIS, mean age 57 years, 51% women). Data on coronary atherosclerosis, self-reported body weight at age 20 and measured midlife weight were recorded together with potential confounders and mediators. Coronary atherosclerosis was assessed using coronary computed tomography angiography (CCTA) and expressed as segment involvement score (SIS). The probability of having coronary atherosclerosis was markedly higher with increasing weight at age 20 and with mid-life weight (p < 0.001 for both sexes). However, weight increase from age 20 until mid-life was only modestly associated with coronary atherosclerosis. The association between weight gain and coronary atherosclerosis was mainly seen in men. However, no significant sex difference could be detected when adjusting for the 10-year delay in disease development in women. Similar in men and women, weight at age 20 and weight in midlife are strongly related to coronary atherosclerosis while weight increase from age 20 until midlife is only modestly related to coronary atherosclerosis. [Display omitted] • Weight at age 20 and in midlife is strongly related to coronary atherosclerosis. • Weight gain from age 20 until midlife is modestly related to coronary atherosclerosis. • There is no sex difference in the relation between weight and coronary atherosclerosis. • Weight control programs in early adulthood may reduce cardiac disease later in life. [ABSTRACT FROM AUTHOR]

Systolic blood pressure interarm difference (IAD) predicts cardiovascular morbidity and mortality in primary prevention populations. We examined the predictive value of IAD and the effects of treatment with the combination of rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg once daily according to IAD in patients with chronic coronary artery disease or peripheral artery disease. COMPASS trial patients with IAD <15 mmHg and IAD >15 mmHg were compared with respect to thirty-month incidence risk of: 1) composite of stroke, myocardial infarction, or cardiovascular death (MACE), 2) composite of acute limb-ischemia or vascular amputation (MALE), 3) composite of MACE or MALE, and 4) effects of treatment with the combination versus aspirin alone on these outcomes. 24,539 patients had IAD<15 mmHg and 2,776 had IAD ≥15 mmHg. Relative to patients with IAD ≥15 mm Hg, those with IAD<15 mmHg had similar incidence rates for all measured outcomes including the composite of MACE or MALE (HR 1.12 [95% CI: 0.95 to 1.31], p = 0.19), with the exception of stroke (HR 1.38 [95% CI: 1.02 to 1.88], p = 0.04). Compared to aspirin alone, the combination consistently reduced the composite of MACE or MALE in both IAD <15 mmHg (HR 0.74 [95% CI: 0.65–0.85], p < 0.0001, ARR = −23.1) and IAD>15 mmHg (HR 0.65 [95% CI: 0.44–0.96], p = 0.03; ARR = −32.6, p interaction = 0.53) groups. Unlike primary prevention populations, measuring IAD for risk stratification purposes does not appear to be useful in patients with established vascular disease. [Display omitted] • No significant differences in cardiovascular outcomes were observed in patients with a systolic IAD>15 mmHg or IAD<15 mmHg. • Measuring IAD for risk stratification purposes does not appear to be useful in patients with established vascular disease. • Patients with IAD≥15 mmHg and IAD<15 mmHg were at a similar risk of cardiovascular outcomes – with the exception of stroke. [ABSTRACT FROM AUTHOR]

The prognostic impact of nonobstructive coronary artery disease (CAD), as opposed to normal coronary arteries, on long-term outcomes of patients with myocardial infarction with no obstructive coronary arteries (MINOCA) is unclear. We aimed to address the association between nonobstructive-CAD and major adverse events (MAE) following MINOCA. We conducted a retrospective cohort study of consecutive MINOCA patients admitted to a large referral medical center between 2005 and 2018. Patients were classified according to coronary angiography as having either normal-coronaries or nonobstructive-CAD. The primary outcome was MAE, defined as the composite of all-cause mortality and recurrent acute coronary syndrome (ACS). Of the 1544 MINOCA patients, 651 (42%) had normal coronaries, and 893 (58%) had CAD. The mean age was 61.2 ± 12.6 years, and 710 (46%) were females. Nonobstructive-CAD patients were older and less likely to be females, with higher rates of diabetes, hypertension, dyslipidemia, atrial fibrillation, and chronic renal-failure (p < 0.05). At a median follow-up of 7 years, MAE occurred in 203 (23%) patients and 67 (10%) patients in the nonobstructive-CAD and normal-coronaries groups, respectively (p < 0.01). In multivariable models, nonobstructive -CAD was significantly associated with long-term MAE [adjusted-hazard-ratio (aHR):1.67, 95% confidence-interval (95%CI):1.25–2.23; p < 0.001]. Other factors associated with a higher MAE-risk were older-age (aHR:1.05,95%CI:1.03–1.06; p < 0.001) and left ventricular ejection-fraction<40% (aHR:3.04,95%CI:2.03–4.57; p < 0.001), while female-sex (aHR:0.72, 95%CI: 0.56–0.94; p= 0.014) and sinus rhythm at presentation (aHR:0.66, 95%CI: 0.44–0.98; p= 0.041) were associated with lower MAE-risk. In MINOCA, nonobstructive-CAD is independently associated with a higher MAE-risk than normal-coronaries. This finding may promote risk-stratification of patients with nonobstructive-CAD-MINOCA who require tighter medical follow-up and treatment optimization. [Display omitted] • Myocardial infarction with no obstructive coronary arteries (MINOCA) carries a considerable long-term risk for death and recurrent acute coronary syndrome (re-ACS). • In MINOCA, the presence of nonobstructive CAD carries higher risk for death or re-ACS. • Reduced LVEF and older age are associated with increased risk for death and re-ACS. • Sinus rhythm and female sex are associated with lower risk for death and re-ACS. [ABSTRACT FROM AUTHOR]

The homeostatic chemokines CCL21 and CCL19 have been explored as biomarkers in cardiovascular disease prediction in patients with established cardiovascular disease, but associations between these chemokines and first-time coronary event incidence have not been investigated before. Here, we explored associations between CCL21 or CCL19 and first-time incident coronary events in the general population-based Malmö Diet and Cancer cohort with two decades of follow-up. CCL21 and CCL19 levels in plasma were analysed with ELISA and proximity extension assay and associations with disease incidence were explored with conditional logistic regression in a nested case-control cohort (CCL21; n = 676) and with Cox regression in a population-based cohort (CCL19; n = 4636). High CCL21 levels in plasma were associated with incident first-time coronary events independently of traditional risk factors (odds ratio of 2.64 with 95% confidence interval 1.62–4.31, p < 0.001, comparing the highest versus the lowest tertile of CCL21), whereas CCL19 was not. CCL19 was, however, associated with incident heart failure, as well as increased all-cause, cardiovascular and cancer mortality independently of age and sex. Even though CCL21 and CCL19 both signal through CCR7, these chemokines may not be interchangeable as disease predictors and CCL21 could be used for prediction of future coronary events in individuals without any previous coronary heart disease history. [Display omitted] • Higher CCL21 & CCL19 levels at baseline in patients who suffered a coronary event. • High levels of CCL21 are associated with increased risk of incident coronary events. • High levels of CCL19 are associated with increased risk of mortality & heart failure. [ABSTRACT FROM AUTHOR]

Myocardial ischemia with no obstructive coronary arteries (INOCA) is a chronic coronary syndrome condition that is increasingly being recognized as a substantial contributor to adverse cardiovascular mortality and outcomes, including myocardial infarction and heart failure with preserved ejection fraction (HFpEF). While INOCA occurs in both women and men, women are more likely to have the finding of INOCA and are more adversely impacted by angina, with recurrent hospitalizations and a lower quality of life with this condition. Abnormal epicardial coronary vascular function and coronary microvascular dysfunction (CMD) have been identified in a majority of INOCA patients on invasive coronary function testing. CMD can co-exist with obstructive epicardial coronary artery disease (CAD), diffuse non-obstructive epicardial CAD, and with coronary vasospasm. Epicardial vasospasm can also occur with normal coronary arteries that have no atherosclerotic plaque on intravascular imaging. While all predisposing factors are not clearly understood, cardiometabolic risk factors, and endothelium dependent and independent mechanisms that increase oxidative stress and inflammation are associated with microvascular injury, CMD and INOCA. Cardiac autonomic dysfunction has also been implicated in abnormal vasoreactivity and persistent symptoms. INOCA is under-recognized and under-diagnosed, partly due to the heterogenous patient populations and mechanisms. However, diagnostic testing methods are available to guide INOCA management. Treatment of INOCA is evolving, and focuses on cardiac risk factor control, improving ischemia, reducing atherosclerosis progression, and improving angina and quality of life. This review focuses on INOCA, relations to HFpEF, available diagnostics, current and investigational therapeutic strategies, and knowledge gaps in this condition. [Display omitted] • INOCA is associated with adverse cardiovascular mortality and outcomes, including myocardial infarction and heart failure. • INOCA portends an adverse prognosis in both sexes. Women are more impacted by angina, recurrent hospitalizations, and a lower quality of life. • In addition to diffuse atherosclerosis and endothelial dysfunction, CMD is implicated in INOCA. Vasospasm can also occur without visible plaque. • Invasive coronary function testing assesses abnormal epicardial and microcirculatory dysfunction as well as vasospasm. • Treatment includes anti-anginal/anti-ischemic and non-pharmacologic strategies, while outcomes-based trials are ongoing. [ABSTRACT FROM AUTHOR]

Pathological reports have shown that plaque erosion (PE), a common cause of acute coronary syndrome (ACS), can form in both fibrous plaque and lipid-rich plaque (LRP). In plaque rupture (PR), which is the main cause of ACS, the underlying plaque is LRP with a thin fibrous cap. In this study, we aimed to investigate the clinical features and lipid profiles of PE with or without LRP in comparison with those of PR. A total of 166 patients with ACS, who underwent percutaneous coronary intervention using optical coherence tomography (OCT) and met the criteria for PR or PE, were included. LRP was defined as plaque with a maximal lipid arc (>180°). Culprit lesions were categorized into PR and PE with/without LRP [PE (Lipid) or PE (Fibrous) ]. The prevalence of PR, PE (Lipid) , and PE (Fibrous) was 104 (62.7%), 43 (25.9%), and 19(11.4%), respectively. The patients with PR and PE (Lipid) had a significantly higher peak creatine kinase level (1338 and 1584U/L, respectively, p < 0.01) and prevalence of ST-elevation myocardial infarction (71.2% and 79.1%, respectively, p < 0.01) than those with PE (Fibrous) (214U/L and 21.1%, respectively). The various lipid profiles were mostly comparable between the patients with PE (Lipid) and PR, but different in those with PE (Fibrous). The levels of small dense low-density lipoprotein cholesterol were significantly higher in the patients with PR and PE (Lipid) than in those with PE (Fibrous) (39.0, 35.3, and 25.7 mg/dL, respectively, p = 0.02). The clinical features and lipid profiles are substantially different between PE (Lipid) and PE (Fibrous) , but are somewhat similar between PE (Lipid) and PR. [Display omitted] • Approximately 70% of plaque erosion (PE) presented as PE (Lipid). • The prevalence of STEMI was lower in the PE (Fibrous) than in the PE (Lipid). • The lipid profiles of PE (Lipid) were different from those of PE (Fibrous). [ABSTRACT FROM AUTHOR]

Individuals with or at high risk of cardiovascular disease (CVD) often receive long-term treatment with low-density lipoprotein cholesterol (LDL-C) lowering therapies, but whether the effects of LDL-C reduction remain stable over time is uncertain. This study aimed to establish the course of the effects of LDL-C reduction on cardiovascular risk over time. Randomized controlled trials (RCTs) of LDL-C lowering therapies were identified through a search in MEDLINE and EMBASE (1966–January 2023). The primary analyses were restricted to statins, ezetimibe, and proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, with other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the hazard ratio (HR) for major vascular events (cardiovascular death, myocardial infarction, unstable angina, coronary revascularization, or stroke) per 1 mmol/L LDL-C reduction. Course of the effects over time was assessed using random-effects meta-regression analyses for the association between follow-up duration, age, and the HR for major vascular events per 1 mmol/L LDL-C reduction. Additionally, treatment-by-time interactions were evaluated in an individual participant data meta-analysis of six atorvastatin trials. A total of 60 RCTs were identified (408,959 participants, 51,425 major vascular events). The HR for major vascular events per 1 mmol/L LDL-C reduction was 0.78 (95 % confidence interval [CI] 0.75–0.81). Follow-up duration was not associated with a change in the HR for major vascular events (HR for change per year 0.994; 95 % CI 0.970–1.020; p = 0.66). The HR attenuated with increasing age in primary prevention (HR for change per 5 years 1.097; 95 % CI 1.031–1.168; p = 0.003), but not secondary prevention (HR for change per 5 years 0.987; 95 % CI 0.936–1.040; p = 0.63). Consistent results were found for statin trials only, and all trials combined. In the individual participant data meta-analysis (31,310 participants, 6734 major vascular events), the HR for major vascular events did not significantly change over follow-up time (HR for change per year 0.983; 95 % CI 0.943–1.025; p = 0.42), or age (HR for change per 5 years 1.022; 95 % CI 0.990–1.055; p = 0.18). Based on available RCT data with limited follow-up duration, the relative treatment effects of LDL-C reduction are stable over time in secondary prevention, but may attenuate with higher age in primary prevention. [Display omitted] • Based on all relevant RCTs of lipid-lowering therapies the HR for major vascular events per 1 mmol/L LDL-C reduction is 0.78. • The HR per 1 mmol/L LDL-C reduction is slightly more favourable in primary (0.74) as compared to secondary prevention (0.80). • In secondary prevention, the HR per 1 mmol/L LDL-C reduction is stable over follow-up time and age. • In primary prevention, the HR per 1 mmol/L LDL-C reduction may significantly attenuate with higher age. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for advancements in risk assessment and management strategies. Although significant progress has been made recently, identifying and managing apparently healthy individuals at a higher risk of developing atherosclerosis and those with subclinical atherosclerosis still poses significant challenges. Traditional risk assessment tools have limitations in accurately predicting future events and fail to encompass the complexity of the atherosclerosis trajectory. In this review, we describe novel approaches in biomarkers, genetics, advanced imaging techniques, and artificial intelligence that have emerged to address this gap. Moreover, polygenic risk scores and imaging modalities such as coronary artery calcium scoring, and coronary computed tomography angiography offer promising avenues for enhancing primary cardiovascular risk stratification and personalised intervention strategies. On the other hand, interventions aiming against atherosclerosis development or promoting plaque regression have gained attention in primary ASCVD prevention. Therefore, the potential role of drugs like statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, omega-3 fatty acids, antihypertensive agents, as well as glucose-lowering and anti-inflammatory drugs are also discussed. Since findings regarding the efficacy of these interventions vary, further research is still required to elucidate their mechanisms of action, optimize treatment regimens, and determine their long-term effects on ASCVD outcomes. In conclusion, advancements in strategies addressing atherosclerosis prevention and plaque regression present promising avenues for enhancing primary ASCVD prevention through personalised approaches tailored to individual risk profiles. Nevertheless, ongoing research efforts are imperative to refine these strategies further and maximise their effectiveness in safeguarding cardiovascular health. [Display omitted] • Recent advancements in ASCVD management focus on identifying at-risk individuals and plaque regression strategies. • ASCVD can manifest without traditional risk factors, necessitating a paradigm shift in preventive approaches. • Targeting plaque progression rather than just traditional risk factors is crucial for preventing adverse events. • Personalised medicine, advanced imaging, and biomarker research offer new avenues for refining risk stratification. • Integrating genetic, imaging, and biomarker data, alongside AI tools, promises to optimize cardiovascular risk management. [ABSTRACT FROM AUTHOR]

There are a limited number of pharmacologic therapies for coronary artery disease, and few rodent models of occlusive coronary atherosclerosis and consequent myocardial infarction with which one can rapidly test new therapeutic approaches. Here, we characterize a novel, fertile, and easy-to-use HDL receptor (SR-B1)-based model of atherogenic diet-inducible, fatal coronary atherosclerosis, the SR-B1ΔCT/LDLR KO mouse. Additionally, we test intramyocardial injection of Stromal Cell-Derived Factor-1 alpha (SDF-1α), a potent angiogenic cytokine, as a possible therapy to rescue cardiac function in this mouse. SR-B1ΔCT/LDLR KO mice were fed the Paigen diet or standard chow diet, and we determined the effects of the diets on cardiac function, histology, and survival. After two weeks of feeding either the Paigen diet (n = 24) or standard chow diet (n = 20), the mice received an intramyocardial injection of either SDF-1α or phosphate buffered saline (PBS). Cardiac function and angiogenesis were assessed two weeks later. When six-week-old mice were fed the Paigen diet, they began to die as early as 19 days later and 50% had died by 38 days. None of the mice maintained on the standard chow diet died by day 72. Hearts from mice on the Paigen diet showed evidence of cardiomegaly, myocardial infarction, and occlusive coronary artery disease. For the five mice that survived until day 28 that underwent an intramyocardial injection of PBS on day 15, the average ejection fraction (EF) decreased significantly from day 14 (the day before injection, 52.1 ± 4.3%) to day 28 (13 days after the injection, 30.6 ± 6.8%) (paired t -test, n = 5, p = 0.0008). Of the 11 mice fed the Paigen diet and injected with SDF-1α on day 15, 8 (72.7%) survived to day 28. The average EF for these 8 mice increased significantly from 48.2 ± 7.2% on day 14 to63.6 ± 6.9% on day 28 (Paired t -test, n = 8, p = 0.003). This new mouse model and treatment with the promising angiogenic cytokine SDF-1α may lead to new therapeutic approaches for ischemic heart disease. [Display omitted] • The SR-B1ΔCT/LDLR KO mouse is a novel mouse model of diet-induced atherosclerosis, myocardial infarction, and cardiomegaly. • This new mouse model is fertile and easily maintained. • SR-B1ΔCT/LDLR KO mice can be used to explore the mechanisms underlying cardiovascular disease and test potential therapies. • Treatment with intramyocardial SDF-1α rescued cardiac function in SR-B1ΔCT/LDLR KO mice fed an atherogenic diet. [ABSTRACT FROM AUTHOR]

Secondary mitral regurgitation (sMR), a major valvular disease, is prevalent in patients with coronary artery disease (CAD), and is associated with higher incidence of heart failure (HF) and mortality when present in combination with abnormal glucose metabolism. We aimed to evaluate the relationship between stress hyperglycemia ratio (SHR) and worsening HF in CAD patients with significant (grade ≥2) sMR. We performed a multi-center observational study of 874 participants with significant sMR following percutaneous coronary intervention (PCI) in the Cardiorenal Improvement-II (CIN-II) cohort. Patients with glucose and glycated hemoglobin (HbA1c) data at admission were included in the analysis, and categorized according to the SHR, the ratio of mmol/L blood glucose to % HbA1c, as quartiles: Q1: <0.74; Q2: 0.74–0.91; Q3: 0.91–1.14; and Q4: ≥1.14. The primary clinical endpoint was worsening HF and the secondary endpoint was major adverse cardiac events (MACE). Of the 874 participants (64.1 ± 10.8 years, 80% male), 174 showed worsening HF and 226 developed MACE during a median follow-up of 3.7 years (interquartile range: 1.8–6.2 years). Compared to participants in the lowest quartile (Q1) of SHR, the highest quartile group (Q4) was at significantly higher risks of worsening HF (adjusted hazard ratio, 2.44; 95% confidence interval, 1.51–3.94; p< 0.001), while this was not associated with increased risk of MACE (p> 0.05) after adjustment for potential covariates. For worsening HF, the results obtained for the normal glucose regulation subgroup may be more meaningful than those for the diabetes mellitus (DM) and pre-DM groups (p -interaction<0.001). For MACE, the acute myocardial infarction (AMI) (Q4 vs. Q1; HR: 0.65, 95%CI: 0.26–1.59) and non-AMI (Q4 vs. Q1; HR: 2.20, 95%CI: 1.36–3.54) subgroups differed significantly on MACE (p -interaction = 0.006). Increasing SHR is associated with a higher risk of worsening of HF in patients with significant sMR, especially in those with normoglycemia. [Display omitted] • Secondary mitral regurgitation is prevalent in patients with coronary artery disease, and is associated with higher incidence of heart failure and mortality when combined with abnormal glucose metabolism. • We evaluated the clinical utility of stress hyperglycemia ratio and further assessed its predictive value in different glucose metabolic statuses. • Increasing stress hyperglycemia ratio was associated with higher risk of worsening of HF in patients with significant secondary mitral regurgitation (sMR), especially in those with normoglycemia. • Stress hyperglycemia ratio may be useful for cardiovascular risk stratification of patients with significant sMR. [ABSTRACT FROM AUTHOR]

Lipoprotein(a) is a well-known causal risk factor for cardiovascular morbidity and mortality. Little is known about the effect of age and sex on lipoprotein(a) levels, and it is largely unknown if the same elevation in lipoprotein(a) confers the same increase in risk in women and men. We investigated whether lipoprotein(a) levels and lipoprotein(a) associated risks of morbidity and mortality by age are similar in women and men. We included 37,545 women and 32,497 men from the Copenhagen General Population Study. Plasma lipoprotein(a) increased with age, and in women we found an additional increase around age 50 (age by sex interaction p = 8∙10−7). In women, levels were 27% higher after menopause (p = 4∙10−61) and 12% lower during hormone replacement therapy (p = 2∙10−19). Adjustment for estimated Glomerular Filtration Rate in both sexes and plasma estradiol in women resulted in attenuated sex differences in lipoprotein(a) levels. In sex and age stratified multivariable adjusted models, lipoprotein(a) >40 mg/dL(83 nmol/L) versus <10 mg/dL(18 nmol/L) was associated with increased risk of myocardial infarction, ischemic heart disease, aortic valve stenosis, and heart failure (men only), but not statistically significant with risk of ischemic stroke, cardiovascular mortality, or all-cause mortality. Lipoprotein(a) levels increased modestly around age 50 selectively in women; however, risk of morbidity and mortality for high lipoprotein(a) was similar in women and men above age 50. This implies that elevated lipoprotein(a) above age 50 is a relatively more common cardiovascular risk factor in women, pointing toward repeat measurements in women above age 50. [Display omitted] • Lipoprotein(a) levels increase with increasing age in women and men. • Lipoprotein(a) levels increase around age 50 selectively in women. • Risk of morbidity and mortality for high lipoprotein(a) levels was similar in women and men above age 50. • These results imply that elevated lipoprotein(a) above age 50 is a relatively more common cardiovascular risk factor in women than men. [ABSTRACT FROM AUTHOR]

A considerable number of patients who undergo percutaneous coronary intervention (PCI) also have peripheral arterial disease (PAD) – a signal of more advanced atherosclerosis. After bare metal and early-generation drug-eluting coronary stent implantation, PAD patients showed inferior outcome. As stents and medical treatment were further improved, we aimed to assess the impact of PAD on outcome of PCI with contemporary new-generation stents. We analyzed 3-year pooled patient-level data from 4 large-scale randomized new-generation stent trials to compare all-comer patients with and without (core lab-verified) history of symptomatic PAD, defined as obstructive lesions in peripheral locations including lower and upper extremities, carotid, vertebral, mesenteric and renal arteries. Main endpoint was target vessel failure: cardiac death, target vessel-related myocardial infarction, or clinically indicated target vessel revascularization. Of all 9204 patients, 695 (7.6%) had a history of symptomatic PAD. They were older and had more often diabetes, renal failure, hypertension, hypercholesterolemia, and prior stroke. PAD was an independent risk factor for target vessel failure (adjusted-HR:1.42, 95%-CI:1.12–1.73, p = 0.001). Target vessel revascularization (adjusted-HR:1.37, 95%-CI:1.04–1.80, p = 0.026), death (adjusted-HR:1.52, 95%-CI:1.17–1.99, p = 0.002), and major adverse cardiovascular event risks (adjusted-HR:1.36, 95%-CI:1.13–1.64, p = 0.001) were also substantially higher. A history of symptomatic PAD still allows to simply identify patients with increased risk of unfavorable clinical outcome after PCI, including a higher risk of repeated coronary revascularization, despite using contemporary stents. In clinical practice, this knowledge about higher event risks of PAD patients is helpful both during Heart Team discussions and when informing patients about the procedural risk. [Display omitted] • Patients with peripheral arterial disease have higher complication risks after percutaneous coronary intervention (PCI). • Peripheral arterial disease also increases the risk of repeated revascularization. • In addition, all-cause mortality and major adverse cardiac event risks are higher. • Yet, the adverse event rates are much lower as compared to historical controls. [ABSTRACT FROM AUTHOR]

Statin therapy is a cornerstone of secondary prevention after myocardial infarction (MI). However, many patients do not use statins. We studied the association of not using statin early after MI with adverse outcomes. Consecutive MI patients admitted to 20 Finnish hospitals (n = 64,401; median age 71) were retrospectively studied. Statin was not used by 17.1% within 90 days after MI discharge (exposure). Differences in baseline features, comorbidities, revascularization, and other evidence-based medications were balanced with propensity score matching, resulting in 10,051 pairs of patients with and without statin. Median follow-up was 5.9 years. Patients not using statin early after MI had higher all-cause mortality in 1-year (15.8% vs. 11.9%; HR 1.38; CI 1.30–1.46; p < 0.0001) and 10-year follow-up (71.1% vs. 65.2%; HR 1.34; CI 1.30–1.39; p < 0.0001) in the matched cohort. The number needed to harm by not using statin was 24.1 at 1-year and 9.5 at 10-years. The cumulative incidence of major adverse cardiovascular event was higher at 1- and 10-years in matched patients not using statins (sHR 1.15; p < 0.0001 for both). Cardiovascular death, new MI, and ischemic stroke were more frequent without early statin. A lack of statin was associated with outcomes regardless of sex, age, atrial fibrillation, dementia, diabetes, heart failure, revascularization, or usage of other evidence-based secondary preventive medications in subgroup analyses. Lack of statin therapy early after MI is associated with adverse outcomes across the spectrum of MI patients. Results underline the importance of timely statin use after MI. [Display omitted] • Association of not using early statin with outcomes after myocardial infarction was studied. • 10,051 propensity matched patient pairs with median follow-up of 5.9 years. • Higher all-cause mortality without early statin with NNH of 9.5 • More major adverse cardiovascular events without statin. • Results underline the importance of timely statin use after myocardial infarction. [ABSTRACT FROM AUTHOR]

High-dose eicosapentaenoic acid (EPA) therapy was beneficial in high-risk patients without clinical cardiovascular disease (CVD). Whether higher plasma levels of EPA and docosahexaenoic acid (DHA) have similar benefits in those without subclinical CVD is unclear. We aim to evaluate the interplay between plasma omega-3 fatty acids and coronary artery calcium (CAC) in relation to CVD events. We examined 6568 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with plasma EPA and DHA levels and CAC measured at baseline. The primary outcome was incident CVD events (myocardial infarction, angina, cardiac arrest, stroke, CVD death). Hazard ratios for the primary outcome were adjusted for potential confounder using Cox regression. Mean ± SD age was 62.1 ± 10.2 years and 52.9% were females. The median follow-up time was 15.6 years. Higher log e (EPA) (adjusted hazard ratio, aHR = 0.83; 95% CI, 0.74–0.94) and log e (DHA) (aHR = 0.79; 95% CI, 0.66–0.96) were independently associated with fewer CVD events. The difference in absolute CVD event rates between lowest vs. highest EPA tertile increased at higher CAC levels. The adjusted HR for highest vs. lowest EPA tertile within CAC = 0 was 1.02 (95% CI, 0.72–1.46), CAC = 1–99 was 0.71 (95% CI, 0.51–0.99), and CAC≥100 was 0.67 (95% CI, 0.52–0.84). A similar association was seen in tertiles of DHA by CAC category. In an ethnically diverse population free of clinical CVD, higher plasma omega-3 fatty acid levels were associated with fewer long-term CVD events. The absolute decrease in CVD events with higher omega-3 fatty acid levels was more apparent at higher CAC scores. [Display omitted] • Higher plasma omega-3 fatty acids significantly predict long-term vardiovascular disease (CVD) events independent of traditional CVD risk factors. • When coronary artery calcium (CAC) is present, higher plasma omega-3 fatty acids are associated with lower CVD events. • Significant residual CVD risk exists in patients with elevated CAC even when plasma omega-3 fatty acid levels are high. [ABSTRACT FROM AUTHOR]

Genetic risk scores for common diseases as myocardial infarction (MI) gain increasing attention for individual's risk prediction. One might wonder if assessing family history becomes redundant. It was the aim of this study to evaluate the amount of shared information between family history and genetic risk scores and to assess their independent and combined effects on prevalent and incident MI risk. A genome wide polygenic risk score (PGS) and one family risk score (FamRS) were calculated in a population-based study from Southern Germany (n = 3071) with up to 11 years of follow-up. Logistic and Cox Regression models were used adjusting for lifestyle and classical risk factors. A right shift in MI risk for increasing values of PGS was found, with. considerably increasing ORs along the top quantiles of PGS (OR = 3.03 for top 10%; OR = 5.55 for top 2.5%). The PGS was not associated with incident MI cases, though. The FamRS was significantly associated with both prevalent and incident MI cases with an OR of 2.9 for participants with a strong positive family history compared to average. ORs and HRs did hardly change in a combined model including both measures, indicating independent contribution to MI risk. The simultaneous addition of PGS and FamRS to a model including classical risk factors significantly enhanced prediction for prevalent cases and non-cases (p = 3.28 × 10−5). These findings emphasize that both genetic information and family history are relevant for the determination of MI risk and that neither of them can replace the other. [Display omitted] • A genome-wide polygenic risk score (PGS) was shown to be a strong risk predictor for especially "early" prevalent myocardial infarction (MI) cases. • A family risk score (FamRS) was a stronger predictor than simpler family history measures as "diseased parents". • The FamRS was highly informative for both prevalence and incidence. • Addition of PGS and FamRS to a model including classical risk factors enhanced prediction for prevalent cases and non-cases. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) confers a high risk for poor cardiovascular outcomes. We conducted a systematic review and meta-analysis to estimate the effects of revascularization as the initial management strategy compared with medical therapy among patients with CKD and coronary artery disease. A Medline/PubMed literature research was conducted to identify randomized studies comparing early coronary revascularization with optimal medical therapy or medical therapy alone in patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 or maintenance dialysis). The primary outcome was myocardial infarction. The secondary outcomes were all-cause mortality or progression to kidney failure. The risk ratio (RR) was estimated using a random-effects model. Eleven randomized trials were included (3422 patients). Revascularization was associated with lower incidence of myocardial infarction compared with medical therapy in patients with CKD: RR 0.71 (95% confidence interval [CI] 0.54–0.94; p= 0.02). This result was mainly driven from a significantly lower incidence of myocardial infarction with early revascularization among patients with stable coronary artery disease: RR 0.59; 95% CI 0.37–0.93. A similar incidence of all-cause mortality was observed with both treatment strategies: RR 0.88 (95% CI 0.72–1.08; p= 0.22). A trend towards lower incidence of all-cause mortality was observed with revascularization in the subgroup of patients presenting with NSTE-ACS: RR 0.73 (95% CI 0.51–1.04; p= 0.08) but not among patients with stable coronary disease. There was no difference in progression to kidney failure between the two strategies. Coronary revascularization may be superior to medical therapy among patients with CKD and coronary disease. [Display omitted] • In patients with coronary artery disease (CAD) and chronic kidney disease (CKD), coronary revascularization may be superior to medical therapy for myocardial infarction (MI) prevention. • A trend towards lower all-cause mortality was observed with early revascularization among patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) and CKD. • A patient-level data meta-analysis is needed to identify the optimal management strategy in patients with CAD and CKD. [ABSTRACT FROM AUTHOR]

Alcohol consumption has complex effects on myocardial infarction (MI) and ischemic stroke. We investigated the difference in associations according to drinking patterns (drinking frequency vs. amount per occasion) and sex. This population-based retrospective study included 11,595,191 subjects participating in national health examinations between 2009 and 2010. Using Cox regression analyses, we calculated MI and ischemic stroke risk according to weekly alcohol consumption, drinking frequency, and amount per occasion. For MI, all weekly alcohol consumption amounts showed lower risk compared to non-drinkers: mild (adjusted hazard ratio [aHR], 0.78; 95% confidence intervals [CI], 0.77–0.79), moderate (aHR, 0.71; 95% CI, 0.70–0.73), and heavy (aHR, 0.74; 95% CI, 0.72–0.76). Drinking frequency and amount per occasion did not differ in MI risk. However, women showed increased risk with heavy drinking and ≥8 drinks per occasion. For ischemic stroke, a J-shaped association was observed for weekly alcohol consumption: mild (aHR, 0.91; 95% CI, 0.90–0.92), moderate (aHR, 0.94; 95% CI, 0.93–0.96), and heavy (aHR, 1.04; 95% CI, 1.02–1.06). Among women, ischemic stroke risk began to increase with moderate drinking. Given similar weekly alcohol consumption levels, ischemic stroke risk increased with higher frequency of drinking, not with amount per occasion. Drinking frequency may be a more important risk factor for ischemic stroke than amount per occasion. Among women, the protective effect of alcohol against MI was not evident in heavy amounts, and the risk of ischemic stroke began to increase at lower levels compared to men. [Display omitted] • We investigated drinking patterns and risk of MI and ischemic stroke. • Drinking patterns were drinking frequency vs. amount per occasion, and weekly consumption. • Overall, drinking frequency and amount per occasion did not differ in myocardial infarction (MI) risk. • For women, heavy drinking and ≥8 drinks per occasion showed increased MI risk. • For ischemic stroke, risk increased with higher frequency of drinking, not with amount. [ABSTRACT FROM AUTHOR]

Polygenic risk scores (PRSs) can be used to quantify the effect of genetic contribution to LDL-cholesterol (LDL-C) and systolic blood pressure (SBP). Several PRSs for LDL-C and SBP have been shown to be associated with cardiovascular disease (CVD) in the general population. This study aimed to evaluate the effect of an LDL-C PRS and an SBP PRS on the risk of recurrent CVD in patients with CVD. Genotyping was performed in 4,416 patients included in the UCC-SMART study. Weighted LDL-C PRS (279 LDL-C-related SNPs) and SBP PRS (425 SBP-related SNPs) were calculated. Linear regression models were used to evaluate the relation between both PRSs and LDL-C and SBP. The effects of the LDL-C PRS and SBP PRS, and its combination on the risk of recurrent CVD (stroke, myocardial infarction, and vascular death) were analyzed with Cox proportional-hazard models. Per SD increase in LDL-C PRS, LDL-C increased by 0.18 mmol/L (95%CI 0.15–0.21). Per SD increase in SBP PRS, SBP increased by 3.19 mmHg (95%CI 2.60–3.78). During a follow-up of 11.7 years (IQR 9.2–15.0) 1,198 recurrent events occurred. Neither the LDL-C nor the SBP PRS were associated with recurrent CVD (HR 1.05 per SD increase in LDL-C PRS (95%CI 0.99–1.11) and HR 1.04 per SD increase in SBP PRS (95%CI 0.98–1.10)). The combination of both scores was neither associated with recurrent CVD (HR 1.09; 95%CI 0.93–1.28). In patients with vascular disease, LDL-C PRS and SBP PRS, both separately and in combination, were not significantly associated with recurrent CVD. [Display omitted] • Low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) are highly heritable traits • Few studies have reported on the association between polygenic risk scores (PRSs) for LDL-C and SBP and recurrent CVD • RS for LDL-C and PRS SBP were associated with LDL-C and SBP in patients with CVD • Both PRS were not significantly associated with the risk of recurrent CVD • Genetically determined LDL-C and SBP do not explain residual cardiovascular risk in patients with CVD [ABSTRACT FROM AUTHOR]

The role of Lp(a) in multi-ethnic Asian populations with coronary artery disease (CAD) has not been well established. The aims of this study were (i) to investigate whether Lp(a) is a predictor of CAD, and (ii) amongst patients with CAD, to ascertain whether Lp(a) is a predictor of acute myocardial infarction (AMI) and severity of CAD. We compared three cardiovascular phenotypes from patients recruited at coronary angiography. CAD was defined as ≥50% coronary artery stenosis and subdivided into a group with AMI history (CAD+AMI+) and a group without (CAD+AMI-). Minimal CAD group (CAD-) was defined as normal or <30% coronary artery stenosis and no AMI. The severity of CAD was defined using the modified Gensini score. We studied 2025 patients comprising 94.5% men and 61.4% of Chinese ethnicity. The median Lp(a) level was highest in CAD+AMI+, followed by CAD+AMI- and CAD- (26.2, 20.1, and 15.8 nmol/L respectively). Similarly, the frequency of patients with Lp(a) ≥120 nmol/L were in the same order (11.8%, 9.1% and 2.4%). Lp(a) levels were highest among Asian Indians, followed by Malays and Chinese patients (p < 0.001). Lp(a) levels and Lp(a) ≥120 nmol/L were significant predictors of CAD (Odds ratio (OR) = 1.12 per 10 nmol/L increment, p < 0.001, and OR = 5.41 p = 0.004 respectively). Among patients with CAD, higher Lp(a) levels were associated with increased AMI risk (OR = 1.02 per 10 nmol/L increment, p = 0.024). Lp(a) ≥120 nmol/L was positively associated with CAD severity (p = 0.020). Plasma Lp(a) concentration is a positive predictor of CAD and AMI in a mostly male South East Asian population. [Display omitted] • Higher Lp(a) levels were associated with increased coronary artery disease (CAD) risk in multi-ethnic Asians. • Lp(a) was associated with increased acute myocardial infarction (AMI) risk and severity of CAD. • Distribution of Lp(a) is a right skew pattern in Chinese, Malays and Asians Indians. [ABSTRACT FROM AUTHOR]

It is not known whether the presence of retinal atherosclerosis (RA) is associated with incident heart failure (HF) in the general population. We aimed to investigate the relationship between RA and the risk of HF development using a nationwide population-based database. We studied 319,501 adults without a history of cardiovascular disease (CVD) and with available data on retinoscopy at health check-up registered in the JMDC Claims Database between January 2005 and April 2020. We performed Cox regression analyses to assess the relationship of RA, defined as Keith-Wagener-Barker system grade ≥1, with incident HF and other CVD, including myocardial infarction (MI), angina pectoris (AP), and stroke. The median age (interquartile range) was 47 (41–54) years, and 159,710 participants (50.0%) were men. RA was observed in 26,168 participants (8.2%). During a median (interquartile range) follow-up of 2.9 (1.6–4.6) years, 6,821 (2.1%) HF, 692 (0.2%) MI, 7,016 (2.2%) AP and 3,584 (1.1%) stroke events occurred. After adjustment for potential confounders, multivariable Cox regression analyses showed that RA was associated with a greater incidence of HF (hazard ratio 1.13, 95% confidence interval [CI] 1.05–1.21) and other CVDs. Hazard ratios of RA for MI, AP, and stroke were 1.17 (95% CI, 0.95–1.44), 1.13 (95% CI, 1.05–1.21), and 1.25 (95% CI, 1.14–1.37), respectively. This association was present in all subgroups. The assessment of RA may be useful to identify people at high-risk for the development of HF and other atherosclerotic CVD events in a general population. [Display omitted] • Little is known about the relationship between retinal atherosclerosis (RA) and incident heart failure (HF). • We studied 319,501 adults without a history of cardiovascular disease and with available data on retinoscopy at health check-up. • RA was associated with a greater risk for developing HF. • RA was also associated with a higher incidence for other atherosclerotic cardiovascular events. • Assessment of RA may be useful to identify people at high-risk for developing HF and other atherosclerotic cardiovascular events in the general population. [ABSTRACT FROM AUTHOR]

Few studies have determined whether the declining incidence of myocardial infarction carries into the current decade, and how it is affected by age and sex. We aimed to determine age- and sex-specific changes in myocardial infarction incidence in Denmark from 2005 through 2021. First-time myocardial infarction admissions in adults aged ≥18 years were identified through Danish nationwide registries. Incidence rates per 100,000 persons with 95% confidence intervals (CI) were calculated across calendar year, sex, and age groups (≤49, 50–69, 70–84, ≥85 years). We also presented incidence rate ratios (IRR) with 95% CIs for 2019–2021 compared to 2005–2007. From January 1, 2005, through August 4, 2021, there were 116,481 incident acute myocardial infarctions in approximately 4.5 million Danes aged ≥18 years. Overall incidence rate of myocardial infarction per 100,000 persons decreased in both sexes from 2005 through 2021 (females: 143 to 80; males: 243 to 174) and across all age groups. The steepest declines in incidence were observed for ages ≥85 years (males: 55%, IRR: 0.45 [0.41–0.49]; females: 58%, IRR: 0.42 [0.39–0.45]) and 70–84 years (males: 46%, IRR: 0.54 [0.52–0.57]; females: 52%, IRR: 0.48 [0.46–0.51]). Rates also declined significantly for ages 50–69 (males: 19%, IRR: 0.81 [0.79–0.84]; females: 17%, IRR: 0.83 [0.78–0.88]) and ≥49 years (males: 30%, IRR: 0.70 [0.64–0.76]; females: 37%, IRR: 0.63 [0.54–0.74]). Declines in the incidence of myocardial infarction continued into the current decade across age groups and sex. However, significantly steeper absolute and relative declines were observed among the oldest age groups (≥70 years). • Myocardial infarction incidence continues to decline into the current decade. • Steeper absolute and relative declines were observed among the elderly. • Future studies should determine if more focus on prevention is needed in the young. [ABSTRACT FROM AUTHOR]

Tissue factor (TF) and activated factor XI (FXIa) have been associated with acute coronary syndrome, ischemic stroke and venous thromboembolism. Their predictive value in stable coronary artery disease (CAD) is unclear. We investigated whether active TF and FXIa were associated with clinical outcomes in CAD patients in long-term observation. In 124 stable patients with multivessel CAD, we assessed the presence of circulating, active TF and FXIa by measuring a response of thrombin generation to respective inhibitory antibodies. We recorded the composite endpoint of myocardial infarction (MI), stroke, systemic thromboembolism and cardiovascular death during follow-up (median 106 months, interquartile range 95–119). Circulating FXIa and active TF were detected in 40% and 20.8% of the 120 patients (aged 65.0 [57.0–70.3] years, men, 78.3%), who completed follow-up. The composite endpoint occurred more frequently in patients with detectable active TF and FXIa present at baseline (hazard ratio [HR] 4.02, 95% confidence interval [CI] 2.26–7.17, p < 0.001 and HR 6.21, 95% CI 3.40–11.40, p < 0.001, respectively). On multivariate analysis FXIa, but not active TF, was an independent predictor of the composite endpoint, as well as MI, stroke/systemic thromboembolism, and cardiovascular death, when analyzed separately. To our knowledge, this study is the first to show that circulating FXIa predicts arterial thromboembolic events in advanced CAD, supporting a growing interest in FXIa inhibitors as novel antithrombotic agents. [Display omitted] • The prognostic role of active tissue factor (TF) and activated FXI (FXIa) in coronary artery disease (CAD) is unclear. • We investigated the impact of active TF and FXIa on long-term outcomes in CAD patients. • FXIa and, to a lesser extent, active TF were associated with cardiovascular events in CAD. • Targeting FXIa might represent a promising preventive strategy in high-risk CAD patients. [ABSTRACT FROM AUTHOR]

We tested the association of polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD) with LDL-C and risk of ischemic heart disease (IHD) in the Danish general population. We included a total of 21,485 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study. For everyone, LDL-PRS and CAD-PRS were calculated, each based on >400,000 variants. We also genotyped four rare variants in LDLR or APOB known to cause familial hypercholesterolemia (FH). Heterozygous carriers of FH-causing variants in APOB or LDLR had a mean LDL-C of 5.40 and 6.09 mmol/L, respectively, and an odds ratio for IHD of 2.27 (95 % CI 1.43–3.51) when compared to non-carriers. The LDL-PRS explained 13.8 % of the total variation in LDL-C in the cohort. Individuals in the lowest and highest 1 % of LDL-PRS had a mean LDL-C of 2.49 and 4.75 mmol/L, respectively. Compared to those in the middle 20–80 %, those in the lowest and highest 1 % of LDL-PRS had odds ratios for IHD of 0.58 (95 % CI, 0.38–0.88) and 1.83 (95 % CI, 1.33–2.53). The corresponding odds ratios for CAD-PRS were 0.61 (95 % CI, 0.41–0.92) and 2.06 (95 % CI, 1.49–2.85). The top 1 % of LDL-PRS and CAD-PRS conferred effects on LDL-C and risk of IHD comparable to those seen for carriers of rare FH-causing variants in APOB or LDLR. These results highlight the potential value of implementing such PRS clinically. [Display omitted] • The top 1 % of an LDL-PRS conferred 1.18 mmol/L higher LDL-C and 1.8-fold higher IHD risk compared to percentiles 20-80 %. • Individuals with a PRS for CAD in the top 1 % had a 2.1-fold higher risk of IHD as compared to the population average. • Carriers of FH-causing variants in APOB or LDLR had 2.24 mmol/L higher LDL-C and 2.3-fold higher risk of IHD than non-carriers. • These results demonstrate the potential clinical value of an LDL-PRS or CAD-PRS. [ABSTRACT FROM AUTHOR]

Recurrent events after myocardial infarction (MI) are common and often originate from native non-culprit (NC) lesions that are non-flow limiting. These lesions consequently pose as targets to improve long-term outcome. It is, however, largely unknown whether these lesions differ between sexes. The aim of this study was to assess such potential differences. From the PECTUS-obs study, we assessed sex-related differences in plaque characteristics of fractional flow reserve (FFR)-negative intermediate NC lesions in 420 MI-patients. Among the included patients, 80 (19.1 %) were female and 340 (80.9 %) male. Women were older and more frequently had hypertension and diabetes. In total, 494 NC lesions were analyzed. After adjustment for clinical characteristics and accounting for within-patients clustering, lesion length was longer in female patients (20.8 ± 10.0 vs 18.3 ± 8.5 mm, p = 0.048) and minimum lumen area (2.30 ± 1.42 vs 2.78 ± 1.54 mm2, p < 0.001) and minimum lumen diameter (1.39 ± 0.45 vs 1.54 ± 0.44 mm, p < 0.001) were smaller. The minimum fibrous cap thickness was smaller among females (96 ± 53 vs 112 ± 72 μm, p = 0.025), with more lesions harboring a thin cap fibroatheroma (39.3 % vs 24.9 %, p < 0.001). Major adverse cardiovascular events at two years occurred in 6.3 % of female patients and 11.8 % of male patients (p = 0.15). FFR-negative NC lesions after MI harbored more high-risk plaque features in female patients. Although this did not translate into an excess of recurrent events in female patients in this modestly sized cohort, it remains to be investigated whether this difference affects clinical outcome. [Display omitted] • Non-culprit lesions pose as targets to improve patient outcome, but sex-related differences are largely unknown. • Non-culprit lesions in female patients demonstrated more high-risk plaque features, including thin-cap fibroatheromas. • Although this did not translate into worse clinical outcome among female patients, confirmation in future studies is warranted. [ABSTRACT FROM AUTHOR]

The PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial. Among 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT. In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (−0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94–0.99) for a -7 mg/dL (−0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01–1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01–1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96–1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91–1.15) in the PROMINENT trial. Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm. [Display omitted] • Absolute mass changes in remnant cholesterol, LDL cholesterol, and apo B can explain results of the PROMINENT trial. • To reduce ASCVD lipid lowering drugs, total atherogenic cholesterol and total number of atherogenic particles need to be reduced. • Understanding the potential for causing ASCVD, lipoproteins should be judged by their absolute mass of cholesterol content. [ABSTRACT FROM AUTHOR]

Patients with prior coronary artery bypass grafting (CABG) presenting with an acute coronary syndrome (ACS) have poor outcomes and the optimal treatment strategy for this population is unknown. Using linked administrative databases, we examined patients with an ACS between 2008 and 2019, identifying patients with prior CABG. Patients were categorized by ACS presentation type and treatment strategy. Our primary outcome was the composite of death and recurrent myocardial infarction at one year. Of 54,641 patients who presented with an ACS, 1670 (3.1%) had a history of prior CABG. Of those, 11.0% presented with an ST-elevation myocardial infarction (STEMI) of which, 15.3% were treated medically, 31.1% underwent angiography but were treated medically, 22.4% with fibrinolytic therapy and 31.1% with primary PCI. The primary outcome rate was the highest (36.8%) in patients who did not undergo angiography and was similar in the primary PCI (20.8%) and fibrinolytic group (21.9%). In patients presenting with a non-ST elevation acute coronary syndrome (NSTE-ACS) (89.0%), 33.2% were treated medically, 38.5% underwent angiography but were treated medically and 28.2% were treated with PCI. Compared to those who underwent PCI, patients treated conservatively demonstrated a higher risk of the composite outcome (14.8% vs 27.3%; adjusted hazard ratio 1.70, 95% confidence interval 1.22–2.37). Patients with prior CABG presenting with an ACS are often treated conservatively without PCI, which is associated with a higher risk of adverse events. [Display omitted] • Of 54,541 patients presenting with ACS from 2008 and 2019 in Alberta, Canada, 1670 (3.1%) had a prior history of coronary artery bypass graft surgery. • In STEMI (11%), medical management without angiography was associated with a higher rate of death/recurrent MI at one-year compared to invasive approaches (36.8% vs 17–22%). • In NSTE-ACS (89%), similarily, medical therapy alone demonstrated a higher risk of adverse outcomes compared to percutaneous coronary intervention (14.8% vs 27.3%). [ABSTRACT FROM AUTHOR]

The effects of protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on endothelial function as assessed by flow-mediated dilation (FMD) in patients with acute myocardial infarction (AMI) are unknown. Therefore, we aimed to investigate the effects of the PCSK9 inhibitor alirocumab added to high-intensity statin on FMD, and its association with coronary atherosclerosis in non-infarct related arteries using intracoronary intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT). This was a pre-specified substudy among patients recruited at Bern University Hospital, Switzerland, for the randomized-controlled, double-blind, PACMAN-AMI trial, which compared the effects of biweekly alirocumab 150 mg vs. placebo added to rosuvastatin. Brachial artery FMD was measured at 4 and 52 weeks, and intracoronary imaging at baseline and 52 weeks. 139/173 patients completed the substudy. There was no difference in FMD at 52 weeks in the alirocumab (n = 68, 5.44 ± 2.24%) versus placebo (n = 71, 5.45 ± 2.19%) group (difference = −0.21%, 95% CI −0.77 to 0.35, p = 0.47). FMD improved throughout 52 weeks in both groups similarly (p < 0.001). There was a significant association between 4 weeks FMD and baseline plaque burden (IVUS) (n = 139, slope = −1.00, p = 0.006), but not with lipid pool (NIRS) (n = 139, slope = −7.36, p = 0.32), or fibrous cap thickness (OCT) (n = 81, slope = −1.57, p = 0.62). Among patients with AMI, the addition of alirocumab did not result in further improvement of FMD as compared to 52 weeks secondary preventative medical therapy including high-intensity statin therapy. FMD was significantly associated with coronary plaque burden at baseline, but not with lipid pool or fibrous cap thickness. [Display omitted] • This randomized trial assessed the effect of alirocumab/statin vs. placebo/statin on flow mediated dilation (FMD) in acute myocardial infarction (AMI). • FMD improved throughout 1 year after AMI with medical therapy similarly in alirocumab/statin vs. placebo/statin treated patients. • FMD at baseline was significantly inversely associated with coronary plaque burden on intravascular ultrasound. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) provocation testing can detect vasomotor disorders in patients with ischemia and non-obstructed coronary arteries (INOCA) or myocardial infarction and non-obstructed coronary arteries (MINOCA). We aimed to derive and validate a simple risk score to predict a positive ACh test response. We prospectively enrolled consecutive INOCA and MINOCA patients undergoing ACh provocation testing. Patients were split in two cohorts (derivation and validation) according to time of enrolment. The score was derived in 386 patients (derivation cohort) and then validated in 165 patients (validation cohort). 551 patients were enrolled, 371 (67.3%) INOCA and 180 (32.7%) MINOCA. ACh test was positive in 288 (52.3%) patients. MINOCA, myocardial bridge (MB), C-reactive protein (CRP) and dyslipidaemia were independent predictors of a positive ACh test in the derivation cohort. The ABCD (Acute presentation, Bridge, CRP, Dyslipidaemia) score was derived: 2 points were assigned to MINOCA, 3 to MB, 1 to elevated CRP and 1 to dyslipidaemia. The ABCD score accurately identified patients with a positive ACh test response with an AUC of 0.703 (CI 95% 0.652–0.754, p < 0.001) in the derivation cohort, and 0.705 (CI 95% 0.626–0.784, p < 0.001) in the validation cohort. In the whole population, an ABCD score ≥4 portended 94.3% risk of a positive ACh test and all patients with an ABCD score ≥6 presented a positive test. The ABCD score could avoid the need of ACh provocation testing in patients with a high score, reducing procedural risks, time, and costs, and allowing the implementation of a tailored treatment strategy. These results are hypothesis generating and further research involving larger cohorts and multicentre trials is needed to validate and refine the ABCD score. [Display omitted] • Acetylcholine provocation testing is still largely underused, leading to inappropriate medical therapies and worse outcomes. • The ABCD score demonstrated high specificity in identifying patients likely to have a positive acetylcholine test response. • Performing the test could be avoided in patients with high scores (i.e., ≥4), reducing procedural risks, time, and costs. [ABSTRACT FROM AUTHOR]

Because of paucity of published data, we evaluated the 2-year major clinical outcomes between early invasive (EI) and delayed invasive (DI) strategies according to the stage of chronic kidney disease (CKD) in patients with non-ST-segment elevation myocardial infarction (NSTEMI), who underwent a successful newer-generation drug-eluting stent (DES) implantation. A total of 8241 NSTEMI patients were recruited from the Korea Acute Myocardial Infarction Registry (KAMIR). Based on baseline estimated glomerular filtration rate (eGFR; ≥90, 60–89, 30–59, and <30 mL/min/1.73 m2), the patients were classified into groups A (n = 3498), B (n = 3109), C (n = 1178), and D (n = 1178). Thereafter, these 4 groups were sub-classified into the EI and DI groups. Major adverse cardiac events (MACE), defined as all-cause death, recurrent MI (re-MI), and any repeat revascularization, were evaluated. After multivariable-adjusted and propensity score-adjusted analyses, the cumulative incidence of MACE (group A, p = 0.139 and p = 0.103, respectively; group B, p = 0.968 and p = 0.608, respectively; group C, p = 0.111 and p = 0.196, respectively; group D, p = 0.882 and p = 0.571, respectively), all-cause death, re-MI, and any repeat revascularization was similar between the EI and DI groups in the 4 different renal function groups. In the era of newer-generation DES, EI and DI strategies showed comparable major clinical outcomes in patients with NSTEMI and CKD during a 2-year follow-up period. However, to confirm these results, further randomized, large-scale, long-term follow-up studies are needed. [Display omitted] • Current guideline's preference for early invasive (EI) strategy is not based on contemporary drug-eluting stent (DES). • 2-year outcomes were evaluated in patients with non-ST-segment elevation myocardial infarction (NSTEMI) and chronic kidney disease (CKD). • EI and delayed invasive (DI) strategy showed similar results after newer-generation DES implantation. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) patients have a high burden of comorbidities that could predispose them to ischemic vascular event. The profile of ischemic risk among HFpEF patients is not fully understood. We aim to evaluate the risk, risk factors, and prognostic significance of ischemic events among HFpEF patients. A total of 1767 HFpEF patients from Americas in the TOPCAT trial were included in our analysis. Ischemic event was defined as myocardial infarction or ischemic stroke during follow-up. Multivariate competing risks regression model was used to identify risk factors of ischemic event. Time-dependent Cox models were constructed to evaluate the association of incident ischemic event and mortality risk. During a median follow-up period of 2.9 years, 164 (9.3%) patients had at least 1 ischemic event. The crude incidence rate was 3.3% per year. Body mass index, prior myocardial infarction, insulin use, peripheral artery disease, hypertension, and current smoking were independent risk factors of ischemic event in HFpEF patients. HF hospitalization turned out to be an important trigger of ischemic event. Risk of ischemic event increased 4.7-fold (hazard ratio 4.70, 95% confidence interval: 2.23–9.89, p < 0.001) within the first month after the first HF hospitalization, and dropped rapidly thereafter. Incident ischemic event was associated with significant higher short-term risks of all-cause mortality and cardiovascular mortality. HFpEF patients from Americas were at a high risk of ischemic events, which was associated with mortality risk. A subset of baseline characteristics and HF hospitalization during follow-up could predict ischemic event. [Display omitted] • HFpEF patients had a high risk of ischemic event, which was significantly associated with increased mortality risk. • BMI, prior MI, insulin usage, PAD, hypertension, and current smoking were risk factors of ischemic event in HFpEF patients. • HF hospitalization was an important trigger of ischemic event in HFpEF patients. [ABSTRACT FROM AUTHOR]

Patients with peripheral artery disease (PAD) represent a high risk group, and have an increased risk of cardiovascular events and worse cardiovascular outcomes. Our aim was to study the impact of PAD among patients undergoing percutaneous coronary intervention (PCI) with a newer-generation thin-strut DES. In this analysis of the e‐ULTIMASTER registry, patients with and without known PAD undergoing PCI were compared. A propensity-score was used to adjust for differences between the groups. The primary outcome was target lesion failure (TLF): a composite of cardiac death, target‐vessel related myocardial infarction, and/or clinically driven target lesion revascularization at 1‐year follow‐up. Of 33,880 patients included in the analysis, PAD was present in 2255 (6.7%). Patients with PAD were older (69.0 ± 10.0 vs. 63.8 ± 11.3 years) with a higher burden of comorbidities. Patients with PAD were less likely to present with STEMI (9.6% vs. 21%), and more likely to undergo complex PCI (left main 5.5% vs. 3.0% ostial lesions 10.4% vs. 7.0%, bifurcations 14.5% vs. 12.3% and calcification 26.8% vs. 17.8%). PAD was found to be independently associated with 41% increased risk for TLF. The risk for all cause death and for cardiac death was 75% and 103% higher, respectably. No difference was found in the rates of stent thrombosis, clinically driven target lesion revascularization, or myocardial infarction (MI). Patients with PAD are at higher risk for (cardiac) death post PCI, but not target vessel or lesion repeat revascularizations. The PAD cohort represents a population with a higher risk clinical profile. Further research combining medical and device therapies is needed to further improve the outcomes in this high-risk population. [Display omitted] • Using the e‐ULTIMASTER PCI registry [n = 33,880 patients], outcomes were compared according to peripheral artery disease (PAD) 2,255 (6.7%) or no PAD. • Patients with PAD were older with a higher burden of comorbidities, and underwent more complex interventions. • PAD was found to be independently associated with 41% increased risk for target lesion failure (TLF). • No difference was found in the rates of stent thrombosis, clinically driven target lesion revascularization, or myocardial infarction (MI). • Patients with PAD treated with contemporary DES are at higher risk for cardiac death post percutaneous coronary intervention (PCI), but similar repeat revascularization risk. [ABSTRACT FROM AUTHOR]

Wall shear stress (WSS) has been associated with atherogenesis and plaque progression. The present study assessed the value of WSS analysis derived from conventional coronary angiography to detect lesions culprit for future myocardial infarction (MI). Three-dimensional quantitative coronary angiography (3DQCA), was used to calculate WSS and pressure drop in 80 patients. WSS descriptors were compared between 80 lesions culprit of future MI and 108 non-culprit lesions (controls). Endothelium-blood flow interaction was assessed by computational fluid dynamics (10.8 ± 1.41 min per vessel). Median time between baseline angiography and MI was 25.9 (21.9–29.8) months. Mean patient age was 70.3 ± 12.7. Clinical presentation was STEMI in 35% and NSTEMI in 65%. Culprit lesions showed higher percent area stenosis (%AS), translesional vFFR difference (ΔvFFR), time-averaged WSS (TAWSS) and topological shear variation index (TSVI) compared to non-culprit lesions (p < 0.05 for all). TSVI was superior to TAWSS in predicting MI (AUC-TSVI = 0.77, 95%CI 0.71–0.84 vs. AUC-TAWSS = 0.61, 95%CI 0.53–0.69, p < 0.001). The addition of TSVI increased predictive and reclassification abilities compared to a model based on %AS and ΔvFFR (NRI = 1.04, p < 0.001, IDI = 0.22, p < 0.001). A 3DQCA-based WSS analysis was feasible and can identify lesions culprit for future MI. The combination of area stenoses, pressure gradients and WSS predicted the occurrence of MI. TSVI, a novel WSS descriptor, showed strong predictive capacity to detect lesions prone to cause MI. [Display omitted] • Lesions culprit of future myocardial infarction (MI) had higher area stenosis, pressure gradient, time-averaged wall shear stress (TAWSS) and topological shear variation index (TSVI). • A three-dimensional quantitative coronary angiography (3DQCA)-based software provided in few minutes reliable WSS simulations. • The WSS topological skeleton feature TSVI showed strong predictive capacity for MI. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether N -benzyl- N -methyl-2-[7,8-dihydro-7-(2-[18F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide (18F-FEDAC), a probe for translocator protein (TSPO), can visualize atherosclerotic lesions in rabbits and whether TSPO is localized in human coronary plaques. 18F-FEDAC-PET of a rabbit model of atherosclerosis induced by a 0.5% cholesterol diet and balloon injury of the left carotid artery (n = 7) was performed eight weeks after the injury. The autoradiography intensity of 18F-FEDAC in carotid artery tissue sections was measured, and TSPO expression was evaluated immunohistochemically. TSPO expression was examined in human coronary arteries obtained from autopsy cases (n = 16), and in human coronary plaques (n = 12) aspirated from patients with acute myocardial infarction (AMI). 18F-FEDAC-PET visualized the atherosclerotic lesions in rabbits as high-uptake areas, and the standard uptake value was higher in injured arteries (0.574 ± 0.24) than in uninjured arteries (0.277 ± 0.13, p < 0.05) or myocardium (0.189 ± 0.07, p < 0.05). Immunostaining showed more macrophages and more TSPO expression in atherosclerotic lesions than in uninjured arteries. TSPO was localized in macrophages, and arterial autoradiography intensity was positively correlated with macrophage concentration (r = 0.64) and TSPO (r = 0.67). TSPO expression in human coronary arteries was higher in AMI cases than in non-cardiac death, or in the vulnerable plaques than in early or stable lesions, respectively. TSPO was localized in macrophages in all aspirated coronary plaques with thrombi. 18F-FEDAC-PET can visualize atherosclerotic lesions, and TSPO-expression may be a marker of high-risk coronary plaques. [Display omitted] • 18F-FEDAC is a tracer of 18-kDa translocator protein. • 18F-FEDAC-positron emission tomography visualizes a rabbit atherosclerotic artery. • Higher 18F-FEDAC radioactivity in rabbit atherosclerotic artery than in myocardium. • Translocator protein expression in macrophages in rabbit and human atherosclerosis. • Translocator protein overexpression in coronary vulnerable and thrombotic plaques. [ABSTRACT FROM AUTHOR]

The association of plasma trimethylamine N -oxide (TMAO) with atherosclerotic cardiovascular disease (ASCVD), diabetes mellitus (DM) and its determinants, as well as the role of TMAO as a predictor for short and long-term mortality, is still under discussion. We investigated associations between four plasma metabolites of the TMAO pathway and different clinical manifestations of atherosclerosis, diabetes determinants, and risk of short and long-term mortality in patients with stable ASCVD, acute myocardial infarction (AMI), cardiogenic shock (CS), and DM in three independent cohorts. TMAO and its dietary precursors were simultaneously quantified by liquid chromatography-tandem mass spectrometry in a total of 2655 participants of the German Leipzig Research Center for Civilization Diseases (LIFE)-Heart study, LIFE-Adult study, and the European Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) multicenter trial. Associations with ASCVD manifestations, metabolic syndrome, 30-day mortality of patients with AMI and CS, and long-term mortality of subjects with suspected coronary artery disease (CAD) were analyzed. TMAO plasma levels were not independently associated with stable ASCVD. Elevated TMAO plasma concentrations were independently associated with obesity (odds ratio, 1.23; p < 0.01) and DM (odds ratio, 1.37; p < 0.001) in LIFE-Heart. The latter association was confirmed in LIFE-Adult. We found no association of TMAO plasma levels with short-term mortality in patients with AMI and CS. However, TMAO plasma levels were independent predictors of long-term mortality in patients with suspected CAD (hazard ratio, 1.24; p < 0.05). Potential proatherogenic mechanisms of TMAO seem to have no short-term effect in AMI. Presented associations with diabetes mellitus and obesity suggest that TMAO might have a functional role in metabolic syndrome. • No association of trimethylamine N -oxide (TMAO) with atherosclerotic cardiovascular disease in a large, deeply-characterized cohort. • TMAO is no independent predictor of short-term mortality in acute myocardial infarction with cardiogenic shock. • Association of TMAO with diabetes mellitus in a cohort of the general population. [ABSTRACT FROM AUTHOR]

CCN family member 1 (CCN1) has recently been proposed as a novel biomarker of myocardial injury, improving prediction of 30-day and one-year mortality following acute coronary syndromes. Among ST-elevation myocardial infarction (STEMI) patients, we evaluated the utility of CCN1 measured immediately before primary percutaneous coronary intervention (PPCI) as a predictor of two earlier endpoints: final myocardial infarct size and post-infarction left ventricular ejection fraction (LVEF). Furthermore, we evaluated the impact of CCN1 on the discriminatory power of the CADILLAC score. STEMI patients were obtained from the SPUM-ACS cohort. Serum CCN1 was measured prior to PPCI. Linear regression assessed the association between CCN1, peak creatinine kinase (CK), and post-infarction LVEF. Cox models assessed an association between CCN1 and 30-day all-cause mortality. CCN1 was measured in 989 patients with a median value of 706.2 ng/l (IQR 434.3–1319.6). A significant correlation between CCN1, myocardial infarct size (peak CK) and LVEF was observed in univariate and multivariate analysis (both p < 0.001). Even among patients with normal classical cardiac biomarker levels at the time of PPCI, CCN1 correlated significantly with final infarct size. CCN1 significantly improved prediction of 30-day all-cause mortality by the CADILLAC score (C-index 0.864, likelihood-ratio chi-square test statistic 6.331, p = 0.012; IDI 0.026, p= 0.050). Compared with classical cardiac biomarkers, CCN1 is potentially the earliest predictor of final myocardial infarct size and post-infarction LVEF. CCN1 improved the discriminatory capacity of the CADILLAC score suggesting a potential role in the very-early risk stratification of STEMI patients. [Display omitted] • CCN1 measured in STEMI patients prior to PPCI exhibits a significant correlation with final infarct size and LVEF. • Even when classical cardiac biomarker levels are normal at the time of PPCI, CCN1 correlates with final infarct size. • Addition of CCN1 to the CADILLAC score improves the prediction of 30-day all-cause mortality. [ABSTRACT FROM AUTHOR]