Rewiring Endothelial Sphingolipid Metabolism to Favor S1P Over Ceramide Protects From Coronary Atherosclerosis.

BACKGROUND: Growing evidence correlated changes in bioactive sphingolipids, particularly S1P (sphingosine-1-phosphate) and ceramides, with coronary artery diseases. Furthermore, specific plasma ceramide species can predict major cardiovascular events. Dysfunction of the endothelium lining lesion-prone areas plays a pivotal role in atherosclerosis. Yet, how sphingolipid metabolism and signaling change and contribute to endothelial dysfunction and atherosclerosis remain poorly understood. METHODS: We used an established model of coronary atherosclerosis in mice, combined with sphingolipidomics, RNA-sequencing, flow cytometry, and immunostaining to investigate the contribution of sphingolipid metabolism and signaling to endothelial cell (EC) activation and dysfunction. RESULTS: We demonstrated that hemodynamic stress induced an early metabolic rewiring towards endothelial sphingolipid de novo biosynthesis, favoring S1P signaling over ceramides as a protective response. This finding is a paradigm shift from the current belief that ceramide accrual contributes to endothelial dysfunction. The enzyme SPT (serine palmitoyltransferase) commences de novo biosynthesis of sphingolipids and is inhibited by NOGO-B (reticulon-4B), an ER membrane protein. Here, we showed that NOGO-B is upregulated by hemodynamic stress in myocardial EC of ApoE-/- mice and is expressed in the endothelium lining coronary lesions in mice and humans. We demonstrated that mice lacking NOGO-B specifically in EC (Nogo-A/BECKOApoE-/-) were resistant to coronary atherosclerosis development and progression, and mortality. Fibrous cap thickness was significantly increased in Nogo-A/BECKOApoE-/- mice and correlated with reduced necrotic core and macrophage infiltration. Mechanistically, the deletion of NOGO-B in EC sustained the rewiring of sphingolipid metabolism towards S1P, imparting an atheroprotective endothelial transcriptional signature. CONCLUSIONS: These data demonstrated that hemodynamic stress induced a protective rewiring of sphingolipid metabolism, favoring S1P over ceramide. NOGO-B deletion sustained the rewiring of sphingolipid metabolism toward S1P protecting EC from activation under hemodynamic stress and refraining coronary atherosclerosis. These findings also set forth the foundation for sphingolipid-based therapeutics to limit atheroprogression.

Associations Between Flavonoid Intake and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Flavonoids may play a role in mitigating atherosclerotic cardiovascular diseases, with evidence suggesting effects may differ between vascular beds. Studies examining associations with subclinical markers of atherosclerosis between subpopulations with different underlying risks of atherosclerosis are lacking. METHODS: Among 5599 participants from the MESA (Multi-Ethnic Study of Atherosclerosis), associations between dietary flavonoid intakes (estimated from a food frequency questionnaire) and subclinical measures of atherosclerosis (ankle-brachial index, carotid plaques and intima-media thickness, and coronary artery calcification) were examined using repeated measures models. Exposures and outcomes were measured at exam 1 (2000-2002) and exam 5 (2010-2011). Stratified analyses and interaction terms were used to explore effect modification by time, sex, race/ethnicity, and smoking status. RESULTS: In the analytic population, at baseline, ≈46% were men with a median age of 62 (interquartile range, 53-70) years and total flavonoid intakes of 182 (interquartile range, 98-308) mg/d. After multivariable adjustments, participants with the highest (quartile 4) versus lowest (quartile 1) total flavonoid intakes had 26% lower odds of having an ankle-brachial index <1 (odds ratio, 0.74 [95% CI, 0.60-0.92]) and 18% lower odds of having a carotid plaque (odds ratio, 0.82 [95% CI, 0.69-0.99]), averaged over exams 1 and 5. Moderate (quartile 3) to high (quartile 4) intakes of flavonols, flavanol monomers, and anthocyanins were associated with 19% to 34% lower odds of having an ankle-brachial index <1 and 18% to 20% lower odds of having carotid plaque. Participants with the highest intakes of anthocyanins (quartile 4) at baseline had a marginally slower rate of carotid plaque progression than those with moderate intakes (quartiles 2 and 3). There were no significant associations with intima-media thickness or coronary artery calcification. Observed associations did not differ by sex, race/ethnicity, or smoking status. CONCLUSIONS: In this multi-ethnic population, higher dietary flavonoid intakes were associated with lower odds of peripheral and carotid artery atherosclerosis. Increasing intakes of healthy, flavonoid-rich foods may protect against atherosclerosis in the peripheral and carotid arteries.

Incidental Coronary Artery Calcium: Opportunistic Screening of Previous Nongated Chest Computed Tomography Scans to Improve Statin Rates (NOTIFY-1 Project).

BACKGROUND: Coronary artery calcium (CAC) can be identified on nongated chest computed tomography (CT) scans, but this finding is not consistently incorporated into care. A deep learning algorithm enables opportunistic CAC screening of nongated chest CT scans. Our objective was to evaluate the effect of notifying clinicians and patients of incidental CAC on statin initiation. METHODS: NOTIFY-1 (Incidental Coronary Calcification Quality Improvement Project) was a randomized quality improvement project in the Stanford Health Care System. Patients without known atherosclerotic cardiovascular disease or a previous statin prescription were screened for CAC on a previous nongated chest CT scan from 2014 to 2019 using a validated deep learning algorithm with radiologist confirmation. Patients with incidental CAC were randomly assigned to notification of the primary care clinician and patient versus usual care. Notification included a patient-specific image of CAC and guideline recommendations regarding statin use. The primary outcome was statin prescription within 6 months. RESULTS: Among 2113 patients who met initial clinical inclusion criteria, CAC was identified by the algorithm in 424 patients. After chart review and additional exclusions were made, a radiologist confirmed CAC among 173 of 194 patients (89.2%) who were randomly assigned to notification or usual care. At 6 months, the statin prescription rate was 51.2% (44/86) in the notification arm versus 6.9% (6/87) with usual care (P<0.001). There was also more coronary artery disease testing in the notification arm (15.1% [13/86] versus 2.3% [2/87]; P=0.008). CONCLUSIONS: Opportunistic CAC screening of previous nongated chest CT scans followed by clinician and patient notification led to a significant increase in statin prescriptions. Further research is needed to determine whether this approach can reduce atherosclerotic cardiovascular disease events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04789278.

Different dose aspirin plus immunoglobulin (DAPI) for prevention of coronary artery abnormalities in Kawasaki disease: Study protocol for a multi-center, prospective, randomized, open-label, blinded end-point, non-inferiority trial.

BACKGROUND: Kawasaki disease is a pediatric acute systemic vasculitis that specifically involves the coronary arteries. Timely initiation of immunoglobulin plus aspirin is necessary for diminishing the incidence of coronary artery abnormalities (CAAs). The optimal dose of aspirin, however, remains controversial. The trial aims to evaluate if low-dose aspirin is noninferior to moderate-dose in reducing the risk of CAAs during the initial treatment of Kawasaki disease. METHODS: This is a multi-center, prospective, randomized, open-label, blinded endpoint, noninferiority trial to be conducted in China. The planned study duration is from 2023 to 2026. Data will be analyzed according to intention-to-treat principles. Participants are children and adolescents under the age of 18 with Kawasaki disease, recruited from the inpatient units. A sample size of 1,346 participants will provide 80% power with a one-sided significance level of 0.025. Qualifying children will be randomized (1:1) to receive either intravenous immunoglobulin (2 g/kg) plus oral moderate-dose aspirin (30-50 mg·kg-1·d-1) until the patient is afebrile for at least 48 hours, or immunoglobulin plus low-dose aspirin (3-5 mg·kg-1·d-1) as initial treatment. The primary outcome will be the occurrence of CAAs at 8 weeks after immunoglobulin infusion. Independent blinded pediatric cardiologists will assess the primary endpoint using echocardiography. CONCLUSIONS: There is a shortage of consensus on the dose of aspirin therapy for Kawasaki disease due to the lack of evidence. The results of our randomized trial will provide more concrete evidence for the efficacy and adverse events of low- or moderate-dose aspirin in the acute phase of Kawasaki disease. TRIAL REGISTRATION: www.chictr.org.cn: ChiCTR2300072686.

Intensive lifestyle intervention in type 2 diabetes and risk of incident coronary artery disease for the common haptoglobin phenotypes: the Look AHEAD study.

BACKGROUND: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) participants with the haptoglobin (Hp) 2-2 phenotype only. It remains unknown whether Hp phenotype modifies the effect of an intensive lifestyle intervention (ILI) on CAD in type 2 diabetes. METHODS: Haptoglobin phenotype was measured in 4542 samples from the Action for Health in Diabetes (Look AHEAD) study. Cox regression models assessed the effect of ILI (focused on weight loss from caloric restriction and physical activity) versus diabetes support and education (DSE) on CAD events in each phenotype group, and within pre-specified subgroups including race/ethnicity, sex, history of cardiovascular disease, diabetes medication use, and diabetes duration. RESULTS: 1590 (35%) participants had the Hp2-2 phenotype. The ILI did not lower glycated hemoglobin (%HbA1c) to < 6.5% in either phenotype, with a peak significant difference between treatment arms of 0.5% [non-Hp2-2] and 0.6% [Hp2-2]. The cumulative CAD incidence was 13.4% and 13.8% in the DSE arm and 12.2% and 13.6% in the ILI arm for non-Hp2-2 and Hp2-2 groups, respectively. Compared to DSE, the ILI was not associated with CAD among participants without (HR = 0.95, 95% CI 0.78-1.17) or with (0.89, 0.68-1.19) the Hp2-2 phenotype (p-interaction between Hp phenotype and ILI = 0.58). After Bonferroni correction, there were no significant results among any subgroups. CONCLUSIONS: Hp phenotype did not modify the effect of the weight loss ILI on risk of CAD in Look AHEAD, potentially because it did not substantially impact glycemic control among participants with or without the Hp2-2 phenotype. Further research is needed to determine if these results are conclusive.

Managing hypertriglyceridemia for cardiovascular disease prevention: Lessons from the PROMINENT trial.

BACKGROUND: Numerous epidemiological studies have shown that hypertriglyceridemia is a significant risk factor for cardiovascular diseases (CVD). However, large clinical studies on triglyceride-lowering therapy have yielded inconsistent results. In the current review, we reassess the importance of triglyceride-lowering therapy in preventing CVD based on previous literature and the recently published findings of the PROMINENT trial. METHODS: This narrative review is based on literature and public documents published up to November 2023. RESULTS: Meta-analyses of trials on peroxisome proliferator-activated receptor α agonists and triglyceride-lowering therapy, including the PROMINENT trial, have indicated that triglyceride-lowering therapy can reduce CVD events. Mendelian randomization studies have also indicated that triglyceride is indeed a true risk factor for coronary artery disease, leaving no doubt about its relationship to CVD. Meanwhile, the negative results from the PROMINENT trial were likely due to the insufficient triglyceride-lowering effect, slight increases in low-density lipoprotein cholesterol and apolipoprotein B, and the inclusion of mostly high-intensity statin users as target patients. It is unlikely that adverse events counteracted the effectiveness of pemafibrate on outcomes. Additionally, pemafibrate has shown positive effects on non-alcoholic fatty liver disease and peripheral artery disease. CONCLUSION: Although the PROMINENT trial did not demonstrate the significance of pemafibrate as a triglyceride-lowering therapy in a specific population, it does not necessarily negate the potential benefits of treating hypertriglyceridemia in reducing CVD events. It is necessary to explore appropriate populations that could benefit from this therapy, utilize data from the PROMINENT trial and other databases, and validate findings in real-world settings.

When Does Primary Prevention Encroach on Secondary Prevention?

PURPOSE OF REVIEW: The risk of incident atherosclerotic cardiovascular disease (ASCVD) in primary prevention is typically lower than in secondary prevention. However, there is a spectrum of risk among individuals undergoing primary prevention with the risk in some individuals approaching those of secondary prevention. We review the clinical conditions wherein the risk in primary prevention is similar to that observed in secondary prevention. RECENT FINDINGS: Among individuals without established ASCVD, coronary artery calcium (CAC) scores ≥ 300 AU are associated with ASCVD event rates similar to secondary prevention populations. CAC score ≥ 1,000 AU are associated with an ASCVD risk seen in very high-risk secondary prevention populations. Interpretation of these observations must however consider differences in the risk reduction strategies. Current guidelines dichotomize ASCVD prevention into primary and secondary prevention, but certain primary prevention patients have an ASCVD risk equivalent to that of secondary prevention populations. Identifying higher risk primary prevention populations will allow for better risk mitigation strategies.

PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice.

BACKGROUND: SR-B1 (scavenger receptor class B type 1)/LDLR (low-density lipoprotein receptor) double knockout mice fed a high-fat, high-cholesterol diet containing cholate exhibit coronary artery disease characterized by occlusive coronary artery atherosclerosis, platelet accumulation in coronary arteries, and myocardial fibrosis. Platelets are involved in atherosclerosis development, and PAR (protease-activated receptor) 4 has a prominent role in platelet function in mice. However, the role of PAR4 on coronary artery disease in mice has not been tested. METHODS: We tested the effects of a PAR4 inhibitory pepducin (RAG8) on diet-induced aortic sinus and coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis in SR-B1/LDLR double knockout mice. SR-B1/LDLR double knockout mice were fed a high-fat, high-cholesterol diet containing cholate and injected daily with 20 mg/kg of either the RAG8 pepducin or a control reverse-sequence pepducin (SRQ8) for 20 days. RESULTS: Platelets from the RAG8-treated mice exhibited reduced thrombin and PAR4 agonist peptide-mediated activation compared with those from control SRQ8-treated mice when tested ex vivo. Although aortic sinus atherosclerosis levels did not differ, RAG8-treated mice exhibited reduced coronary artery atherosclerosis, reduced platelet accumulation in atherosclerotic coronary arteries, and reduced myocardial fibrosis. These protective effects were not accompanied by changes in circulating lipids, inflammatory cytokines, or immune cells. However, RAG8-treated mice exhibited reduced VCAM-1 (vascular cell adhesion molecule 1) protein levels in nonatherosclerotic coronary artery cross sections and reduced leukocyte accumulation in atherosclerotic coronary artery cross sections compared with those from SRQ8-treated mice. CONCLUSIONS: The PAR4 inhibitory RAG8 pepducin reduced coronary artery atherosclerosis and myocardial fibrosis in SR-B1/LDLR double knockout mice fed a high-fat, high-cholesterol diet containing cholate. Furthermore, RAG8 reduced VCAM-1 in nonatherosclerotic coronary arteries and reduced leukocyte and platelet accumulation in atherosclerotic coronary arteries. These findings identify PAR4 as an attractive target in reducing coronary artery disease development, and the use of RAG8 may potentially be beneficial in cardiovascular disease.

Evaluation of a digital patient education programme in patients with coronary artery disease, a survey-based study.

INTRODUCTION: Patient education programmes focusing on risk factor modification and lifestyle changes are well established as part of cardiac rehabilitation in patients with coronary artery disease (CAD). As participation rates are low, digital patient education programmes (DPE) are interesting alternatives to increase access. Understanding patients' perceptions of DPE are important in terms of successful implementation in clinical practice but are not well known. Therefore, the aim of this study was to assess patients' perceptions of using a DPE in terms of end-user acceptance and usability, perceived significance for lifestyle changes and secondary preventive goal fulfilment in patients with CAD. METHODS: This was a cross-sectional survey-based study. The survey was distributed to all 1625 patients with acute coronary syndrome or chronic CAD with revascularisation, who were registered users of the DPE between 2020 and 2022 as part of cardiac rehabilitation. The survey contained 64 questions about e.g., acceptance and usability, perceived significance for making lifestyle changes and secondary preventive goal fulfilment. Patients who had never logged in to the DPE received questions about their reasons for not logging in. Data were analysed descriptively. RESULTS: A total of 366 patients (mean age: 69.1 ± 11.3 years, 20% female) completed the survey and among those 207 patients (57%) had used the DPE. Patients reported that the DPE was simple to use (80%) and improved access to healthcare (67-75%). A total of 69% of the patients were generally satisfied with the DPE, > 60% reported that the DPE increased their knowledge about secondary preventive treatment goals and approximately 60% reported having a healthy lifestyle today. On the other hand, 35% of the patients would have preferred a hospital-based education programme. Among the 159 patients (43%) who had never used the DPE, the most reported reason was a perceived need for more information about how to use the DPE (52%). CONCLUSIONS: This study shows an overall high level of patient acceptance and usability of the DPE, which supports its continued development and long-term role in cardiac rehabilitation in patients with CAD. Future studies should assess associations between participation in the DPE and clinical outcomes, such as secondary preventive goal fulfilment and hospitalisation.

Colchicine for the Prevention of Cardiovascular Disease: Potential Global Implementation.

PURPOSE OF REVIEW: Targeting traditional cardiovascular risk factors is effective in reducing recurrent cardiovascular events, yet the presence of residual cardiovascular risk due to underlying systemic inflammation is a largely unaddressed opportunity. This review aims to comprehensively assess the evolving role of colchicine as a therapeutic approach targeting residual inflammatory risk in the context of those with coronary artery disease (CAD). RECENT FINDINGS: Inflammation plays a significant role in promoting atherosclerosis, and targeting anti-inflammatory pathways has the potential to decrease cardiovascular events. Low-dose colchicine (0.5 mg/day orally), when added to guideline-directed medical care for CAD, safely decreases major adverse cardiovascular events (MACE) by 31% in stable atherosclerosis patients and 23% in those after recent myocardial infarctions. Meta-analyses of recent randomized control trials further support both the efficacy and safety of colchicine, particularly when added to other standard cardiovascular therapies, including statin therapy. The European Society of Cardiology and other national guidelines endorse the use of low-dose colchicine in patients across the spectrum of CAD. Recently, colchicine was FDA-approved in the United States as the first anti-inflammatory therapy for the reduction of cardiovascular events. In a period of a rising incidence of CAD across the globe, colchicine represents a unique opportunity to decrease MACE due to its large magnitude of benefits and general affordability. However, challenges with drug interactions must be addressed, especially in those regions where HIV, hepatitis, and tuberculosis are prevalent. Colchicine is safe and effective at reducing cardiovascular events across a broad spectrum of coronary syndromes. The ability to simultaneously target traditional risk factors and mitigate residual inflammatory risk marks a substantial advancement in cardiovascular prevention strategies, heralding a new era in the global battle against CAD.

Current and Emerging Approaches for Primary Prevention of Coronary Artery Disease Using Cardiac Computed Tomography.

PURPOSE OF REVIEW: To summarize the current use of cardiac computed tomography (CT) technologies as well as their pertinent evidence in regards to prevention of coronary artery disease (CAD). RECENT FINDINGS: Cardiac CTA has now become a main non-invasive method for the evaluation of symptomatic CAD. In addition to coronary calcium score, other CT technologies such as atherosclerotic plaque analysis, fractional flow reserve estimation by CT, pericoronary fat attenuation, and endothelial wall shear stress have emerged. Whether the use of CT modalities can enhance risk prediction and prevention in CAD has not been fully answered. We discuss the evidence for coronary artery calcium scoring and coronary CT angiography in primary prevention and the current barriers to their use. We attempt to delineate what can be done to expand use and what studies are needed to broaden adoption in the future. We also examine the potential roles of emerging CT technologies. Finally, we describe potential clinical approaches to prevention that would incorporate cardiac CT technologies.

The Effect of Magnesium Supplementation on Vascular Calcification in CKD: A Randomized Clinical Trial (MAGiCAL-CKD).

SIGNIFICANCE STATEMENT: Magnesium prevents vascular calcification in animals with CKD. In addition, lower serum magnesium is associated with higher risk of cardiovascular events in CKD. In a randomized, double-blinded, placebo-controlled trial, the authors investigated the effects of magnesium supplementation versus placebo on vascular calcification in patients with predialysis CKD. Despite significant increases in plasma magnesium among study participants who received magnesium compared with those who received placebo, magnesium supplementation did not slow the progression of vascular calcification in study participants. In addition, the findings showed a higher incidence of serious adverse events in the group treated with magnesium. Magnesium supplementation alone was not sufficient to delay progression of vascular calcification, and other therapeutic strategies might be necessary to reduce the risk of cardiovascular disease in CKD. BACKGROUND: Elevated levels of serum magnesium are associated with lower risk of cardiovascular events in patients with CKD. Magnesium also prevents vascular calcification in animal models of CKD. METHODS: To investigate whether oral magnesium supplementation would slow the progression of vascular calcification in CKD, we conducted a randomized, double-blinded, placebo-controlled, parallel-group, clinical trial. We enrolled 148 subjects with an eGFR between 15 and 45 ml/min and randomly assigned them to receive oral magnesium hydroxide 15 mmol twice daily or matching placebo for 12 months. The primary end point was the between-groups difference in coronary artery calcification (CAC) score after 12 months adjusted for baseline CAC score, age, and diabetes mellitus. RESULTS: A total of 75 subjects received magnesium and 73 received placebo. Median eGFR was 25 ml/min at baseline, and median baseline CAC scores were 413 and 274 in the magnesium and placebo groups, respectively. Despite plasma magnesium increasing significantly during the trial in the magnesium group, the baseline-adjusted CAC scores did not differ significantly between the two groups after 12 months. Prespecified subgroup analyses according to CAC>0 at baseline, diabetes mellitus, or tertiles of serum calcification propensity did not significantly alter the main results. Among subjects who experienced gastrointestinal adverse effects, 35 were in the group receiving magnesium treatment versus nine in the placebo group. Five deaths and six cardiovascular events occurred in the magnesium group compared with two deaths and no cardiovascular events in the placebo group. CONCLUSIONS: Magnesium supplementation for 12 months did not slow the progression of vascular calcification in CKD, despite a significant increase in plasma magnesium. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov ( NCT02542319 ).

[Research progress of lipid-derived parameters in atherosclerotic cardiovascular disease].

Dyslipidemia stands as an autonomous peril in the realm of atherosclerotic cardiovascular maladies. Prompt identification and timely intervention in the case of dyslipidemia hold promise for substantially curbing the onset and fatality rates associated with coronary heart disease. Traditional lipid surveillance metrics employed in clinical settings, such as low-density lipoprotein cholesterol, exhibit notable limitations. Conversely, lipid-derived parameters emerge as formidable contenders, demonstrating a capacity to amalgamate and quantify disparate risk factors and multifactorial etiologies inherent in a given disease. By encompassing a broader spectrum of information than singular indices, these parameters offer a more profound insight into disease progression by virtue of their grounding in the physiological intricacies of lipid metabolism. Drawing upon extant domestic and international guidelines and research, this discourse delineates and synthesizes four lipid-derived parameters with promising clinical applications: atherogenic index of plasma, non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, apolipoprotein B/A1 ratio, and lipoprotein combine index, and forwards a perspective grounded in current strides in clinical research.

Pleiotropy-Based Decomposition of Genetic Risk Scores: Association and Interaction Analysis for Type 2 Diabetes and CAD.

Genetic risk for a disease in the population may be represented as a genetic risk score (GRS) constructed as the sum of inherited risk alleles, weighted by allelic effects established in an independent population. While this formulation captures overall genetic risk, it typically does not address risk due to specific biological mechanisms or pathways that may nevertheless be important for interpretation or treatment response. Here, a GRS for disease is resolved into independent or nearly independent components pertaining to biological mechanisms inferred from pleiotropic relationships. The component GRSs' weights are derived from the singular value decomposition (SVD) of the matrix of appropriately scaled genetic effects, i.e., beta coefficients, of the disease variants across a panel of the disease-related phenotypes. The SVD-based formalism also associates combinations of disease-related phenotypes with inferred disease pathways. Applied to incident type 2 diabetes (T2D) in the Women's Genome Health Study (N = 23,294), component GRSs discriminate glycemic control and lipid-based genetic risk, while revealing significant interactions between specific components and BMI or physical activity, the latter not observed with a GRS for overall T2D genetic liability. Applied to coronary artery disease (CAD) in both the WGHS and in JUPITER (N = 8,749), a randomized trial of rosuvastatin for primary prevention of CVD, component GRSs discriminate genetic risk associated with LDL-C from risk associated with reciprocal genetic effects on triglycerides and HDL-C. They also inform the pharmacogenetics of statin treatment by demonstrating that benefit from rosuvastatin is as strongly related to genetic risk from triglycerides and HDL-C as from LDL-C.

Early computed tomography coronary angiography and preventative treatment in patients with suspected acute coronary syndrome: A secondary analysis of the RAPID-CTCA trial.

BACKGROUND: Computed tomography coronary angiography (CTCA) offers detailed assessment of the presence of coronary atherosclerosis and helps guide patient management. We investigated influences of early CTCA on the subsequent use of preventative treatment in patients with suspected acute coronary syndrome. METHODS: In this secondary analysis of a multicenter randomized controlled trial of early CTCA in intermediate-risk patients with suspected acute coronary syndrome, prescription of aspirin, P2Y12 receptor antagonist, statin, renin-angiotensin system blocker, and beta-blocker therapies from randomization to discharge were compared within then between those randomized to early CTCA or to standard of care only. Effects of CTCA findings on adjustment of these therapies were further examined. RESULTS: In 1,743 patients (874 randomized to early CTCA and 869 to standard of care only), prescription of P2Y12 receptor antagonist, dual antiplatelet, and statin therapies increased more in the early CTCA group (between-group difference: 4.6% [95% confidence interval, 0.3-8.9], 4.5% [95% confidence interval, 0.2-8.7], and 4.3% [95% confidence interval, 0.2-8.5], respectively), whereas prescription of other preventative therapies increased by similar extent in both study groups. Among patients randomized to early CTCA, there were additional increments of preventative treatment in those with obstructive coronary artery disease and higher rates of reductions in antiplatelet and beta-blocker therapies in those with normal coronary arteries. CONCLUSIONS: Prescription patterns of preventative treatment varied during index hospitalization in patients with suspected acute coronary syndrome. Early CTCA facilitated targeted individualization of these therapies based on the extent of coronary artery disease.

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2023 American College of Cardiology Conference.

PURPOSE OF REVIEW: To summarize selected late-breaking science on cardiovascular (CV) disease prevention presented at the 2023 American College of Cardiology (ACC) conference. RECENT FINDINGS: The CLEAR outcomes randomized control trial (RCT) compared bempedoic acid to placebo in patients at high-risk of cardiovascular disease (CVD) or prevalent CVD and statin intolerance for CV outcomes. The YELLOW III was a single-arm study that evaluated the effect of Evolocumab on coronary plaque characteristics in patients with stable coronary artery disease (CAD). A cohort evaluated the association between a self-reported low-carbohydrate high-fat (ketogenic) diet and serum lipid levels as compared to a standard diet. The LOADSTAR trial compared CV outcomes with targeted low-density lipoprotein cholesterol (LDL-C) approach vs. high-intensity statin in patients with CAD. The PCDS statin cluster randomized trial compared the effectiveness of an electronic reminder to the clinician on a high-intensity statin use among patients with a history of ASCVD as compared to no reminder. A prospective cohort study compared the extent of coronary atherosclerosis among lifelong endurance athletes and healthy non-athletes. A causal artificial intelligence study combined polygenic risk scores with data from large CV prevention RCTs to guide systolic blood pressure and LDL-C reduction targets to reach average CV risk. The ACCESS trial evaluated the impact of eliminating copayment for low-income older adults in Canada with chronic CV diseases on composite CV outcomes. A pooled analysis of 3 large RCTs evaluated the association between residual inflammatory risk and CV outcomes, as compared to residual elevated cholesterol risk in patients receiving statin therapy. A Phase 2B RCT compared the efficacy of an oral PCSK9i, MK-0616, in reducing LDL-C as compared to a placebo. The late-breaking clinical science presented at the 2023 conference of the ACC paves the way for an evidence-based alternative to statin therapy and provides data on several common clinical scenarios encountered in daily practice.

Machine Learning in Cardiovascular Risk Prediction and Precision Preventive Approaches.

PURPOSE OF REVIEW: In this review, we sought to provide an overview of ML and focus on the contemporary applications of ML in cardiovascular risk prediction and precision preventive approaches. We end the review by highlighting the limitations of ML while projecting on the potential of ML in assimilating these multifaceted aspects of CAD in order to improve patient-level outcomes and further population health. RECENT FINDINGS: Coronary artery disease (CAD) is estimated to affect 20.5 million adults across the USA, while also impacting a significant burden at the socio-economic level. While the knowledge of the mechanistic pathways that govern the onset and progression of clinical CAD has improved over the past decade, contemporary patient-level risk models lag in accuracy and utility. Recently, there has been renewed interest in combining advanced analytic techniques that utilize artificial intelligence (AI) with a big data approach in order to improve risk prediction within the realm of CAD. By virtue of being able to combine diverse amounts of multidimensional horizontal data, machine learning has been employed to build models for improved risk prediction and personalized patient care approaches. The use of ML-based algorithms has been used to leverage individualized patient-specific data and the associated metabolic/genomic profile to improve CAD risk assessment. While the tool can be visualized to shift the paradigm toward a patient-specific care, it is crucial to acknowledge and address several challenges inherent to ML and its integration into healthcare before it can be significantly incorporated in the daily clinical practice.

The relationship between nut consumption and premature coronary artery disease in a representative sample of Iranians: Iran-premature coronary artery disease (IPAD) study.

OBJECTIVE: The cardioprotective effects of nuts are well established. However, the positive impacts of nuts in preventing CVD at a younger age, a condition known as premature coronary artery disease (PCAD), is still debated. Therefore, we aim to determine the association between nuts and PCAD occurrence and its severity in different Iranian ethnicities. DESIGN: This case-control study was conducted within the framework of the Iran-premature coronary artery disease (I-PAD) study, an ongoing multi-centric study on Iranian patients of different ethnicities. SETTING: This multi-centric case-control study was conducted in among 3253 persons under the age of 70 years in women and 60 years in men from different ethnicities in Iran. PARTICIPANTS: Information on nut consumption was collected using a validated FFQ. Subjects were selected from among the candidates for angiography. Cases were those whose coronary angiography showed stenosis of more than 75 % in at least one vessel or more than 50 % of the left main artery, while the control group participants had normal angiography results. RESULTS: In the crude model, compared to the first quartile, the highest quartile of nut consumption was significantly associated with a lower risk of PCAD (OR = 0·26, 95 % CI (0·21, 0·32); Pfor trend = 0·001). In the top quartile of nut intake, a substantial decrease in PCAD was observed after controlling for putative confounders (OR = 0·32; 95 % CI (0·24, 0·43); Pfor trend = 0·001). Additionally, a 75 % decrease in the risk of severe PCAD was observed in the participants in the highest quartile of nut intake. CONCLUSION: A significant inverse association was observed between nut intake and the risk and severity of PCAD in the Iranian population. Large-scale clinical trials are required to confirm these findings.

The Role of Imaging in Preventive Cardiology in Women.

PURPOSE OF REVIEW: The prevalence of CVD in women is increasing and is due to the increased prevalence of CV risk factors. Traditional CV risk assessment tools for prevention have failed to accurately determine CVD risk in women. CAC has shown to more precisely determine CV risk and is a better predictor of CV outcomes. Coronary CTA provides an opportunity to determine the presence of CAD and initiate prevention in women presenting with angina. Identifying women with INOCA due to CMD with use of cPET or cMRI with MBFR is vital in managing these patients. This review article outlines the role of imaging in preventive cardiology for women and will include the latest evidence supporting the use of these imaging tests for this purpose. RECENT FINDINGS: CV mortality is higher in women who have more extensive CAC burden. Women have a greater prevalence of INOCA which is associated with higher MACE. INOCA is due to CMD in most cases which is associated with traditional CVD risk factors. Over half of these women are untreated or undertreated. Recent study showed that stratified medical therapy, tailored to the specific INOCA endotype, is feasible and improves angina in women. Coronary CTA is useful in the setting of women presenting with acute chest pain to identify CAD and initiate preventive therapy. CAC confers greater relative risk for CV mortality in women versus (vs.) men. cMRI or cPET is useful to assess MBFR to diagnose CMD and is another useful imaging tool in women for CV prevention.

The Protective Effect of Polymorphisms rs2681472 and rs17249754 of the ATP2B1 Gene Against Coronary Artery Disease and Hypertension is Abolished by Tobacco Smoking.

Aim    To study the relationship of single nucleotide polymorphisms rs2681472 and rs17249754 in the ATP2B1 gene with risk of ischemic heart disease (IHD) and arterial hypertension (AH) among residents of Central Russia and to evaluate the trigger role of smoking as a risk factor for development of IHD and AH in carriers of ATP2B1 gene polymorphic variants.Material and methods    The study included DNA samples from 1960 residents of Central Russia of Slavic origin. Among them, there were 1261 patients with cardiovascular diseases and 699 healthy persons. The vast majority of patients had both IHD and AH. Genotyping was performed using the iPLEX technique on a MassARRAY-4 genomic mass-spectrometer. The relationship of ATP2B1 alleles, genotypes, and haplotypes with the risk of diseases was calculated by logistic regression analysis with adjustments for sex and age.Results    Carriage of AG and GG (rs2681472) genotypes and GA (rs17249754) genotype was associated with a reduced risk of both IHD (p=0.0057 and p=0.022 for rs2681472 and rs17249754, respectively) and AH (p=0.016 and p=0.036, respectively). Rare rs2681472G-rs17249754G and rs2681472A-rs17249754A haplotypes were associated with a reduced risk of IHD (odds ratio, OR, 0.22; 95 % CI: 0.11-0.46, p=0.0001) and AH (OR, 0.22; 95 % CI: 0.10-0.47, p=0.0001). Analysis of the groups stratified by the smoking status showed that in smokers, the studied polymorphic variants did not have a protective action with respect of either IHD or AH. However, in non-smokers, the genotypes AG and GG rs2681472 (OR, 0.62; 95 % CI: 0.47-0.80, p=0.0004) and GA rs17249754 (OR, 0.61; 95 % CI: 0.47-0.81, p=0.0004) were associated with a reduced risk of IHD and AH (OR, 0.63; 95 % CI: 0.48-0.83, p=0.0004 for rs2681472; OR, 0.63; 95 % CI: 0.48-0.83, p=0.001 for rs17249754), as well as the carriage of the minor alleles rs2681472­G and rs17249754­A.Conclusion    It was shown for the first time that the polymorphic variants rs17249754 and rs2681472 of the ATP2B1 gene are associated with a reduced risk for IHD and AH only in non-smokers.