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.

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.

Beyond symptoms: Unlocking the potential of coronary calcium scoring in the prevention and treatment of coronary artery disease.

Coronary Artery Disease (CAD) represents a persistent global health menace, particularly prevalent in Eastern European nations. Often asymptomatic until its advanced stages, CAD can precipitate life-threatening events like myocardial infarction or stroke. While conventional risk factors provide some insight into CAD risk, their predictive accuracy is suboptimal. Amidst this, Coronary Calcium Scoring (CCS), facilitated by non-invasive computed tomography (CT), emerges as a superior diagnostic modality. By quantifying calcium deposits in coronary arteries, CCS serves as a robust indicator of atherosclerotic burden, thus refining risk stratification and guiding therapeutic interventions. Despite certain limitations, CCS stands as an instrumental tool in CAD management and in thwarting adverse cardiovascular incidents. This review delves into the pivotal role of CCS in CAD diagnosis and treatment, elucidates the involvement of calcium in atherosclerotic plaque formation, and outlines the principles and indications of utilizing CCS for predicting major cardiovascular events.

Phytosterol intake and risk of coronary artery disease: Results from 3 prospective cohort studies.

BACKGROUND: Phytosterols are structurally similar to cholesterol and partially inhibit intestinal absorption of cholesterol, although their impact on coronary artery disease (CAD) risk remains to be elucidated. OBJECTIVES: This study aimed to prospectively assess the associations between total and individual phytosterol intake and CAD risk in United States health professionals. METHODS: The analysis included 213,992 participants from 3 prospective cohorts-the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study-without cardiovascular disease or cancer at baseline. Diet was assessed using a validated food frequency questionnaire every 2-4 y since baseline. Associations between phytosterol intake and the risk of CAD, such as nonfatal myocardial infarction and fatal CAD, were evaluated using Cox proportional hazards regression models. RESULTS: More than 5,517,993 person-years, 8725 cases with CAD were documented. Comparing extreme quintiles, pooled hazard ratios (95% CIs) of CAD were 0.93 (0.86, 1.01; P-trend = 0.16) for total phytosterols, 0.89 (0.82, 0.96; P-trend = 0.05) for campesterol, 0.95 (0.88, 1.02; P-trend = 0.10) for stigmasterol, and 0.92 (0.85, 1.00; P-trend = 0.09) for ß-sitosterol. Nonlinear associations were observed for total phytosterols, campesterol, and ß-sitosterol: the risk reduction plateaued at intakes above ∼180, 30, and 130 mg/d, respectively (P-nonlinearity < 0.001). In a subset of participants (N range between 11,983 and 22,039), phytosterol intake was inversely associated with plasma concentrations of total cholesterol, triglycerides, high-density lipoprotein cholesterol, and IL-6 and positively associated with adiponectin, whereas no significant associations were observed for low-density lipoprotein cholesterol or C-reactive protein concentrations. CONCLUSIONS: Higher long-term intake of total and major subtypes of phytosterols may be associated with a modest reduction in CAD risk, displaying a nonlinear relationship that plateau at moderate intake levels. The role of phytosterols in preventing CAD warrants further investigation.

'Super Rehab': can we achieve coronary artery disease regression? A feasibility study protocol.

INTRODUCTION: Patients diagnosed with coronary artery disease (CAD) are currently treated with medications and lifestyle advice to reduce the likelihood of disease progression and risk of future major adverse cardiovascular events (MACE). Where obstructive disease is diagnosed, revascularisation may be considered to treat refractory symptoms. However, many patients with coexistent cardiovascular risk factors, particularly those with metabolic syndrome (MetS), remain at heightened risk of future MACE despite current management.Cardiac rehabilitation is offered to patients post-revascularisation, however, there is no definitive evidence demonstrating its benefit in a primary prevention setting. We propose that an intensive lifestyle intervention (Super Rehab, SR) incorporating high-intensity exercise, diet and behavioural change techniques may improve symptoms, outcomes, and enable CAD regression.This study aims to examine the feasibility of delivering a multicentre randomised controlled trial (RCT) testing SR for patients with CAD, in a primary prevention setting. METHODS AND ANALYSIS: This is a multicentre randomised controlled feasibility study of SR versus usual care in patients with CAD. The study aims to recruit 50 participants aged 18-75 across two centres. Feasibility will be assessed against rates of recruitment, retention and, in the intervention arm, attendance and adherence to SR. Qualitative interviews will explore trial experiences of study participants and practitioners. Variance of change in CAD across both arms of the study (assessed with serial CT coronary angiography) will inform the design and power of a future, multi-centre RCT. ETHICS AND DISSEMINATION: Ethics approval was granted by South West-Frenchay Research Ethics Committee (reference: 21/SW/0153, 18 January 2022). Study findings will be disseminated via presentations to relevant stakeholders, national and international conferences and open-access peer-reviewed research publications. TRIAL REGISTRATION NUMBER: ISRCTN14603929.

Determination of Vascular Age in Men Using the Coronary Calcium Score and its Impact on Restratification of Cardiovascular Risk. / Determinação da Idade Vascular em Homens Através do Escore de Cálcio Coronariano e seu Impacto na Reestratificação do Risco Cardiovascular.

BACKGROUND: Identifying asymptomatic individuals at risk of developing cardiovascular disease is one of the main goals of preventive cardiology. The coronary calcium score (CCS) makes it possible to estimate vascular age, which has shown to be more reliable than chronological age for determining cardiovascular risk. OBJECTIVES: To reclassify cardiovascular risk based on arterial age and evaluate CCS progression during follow-up. METHODS: We included 150 asymptomatic men who underwent clinical and CCS evaluation in 2 evaluations with an interval of 7.6 years. We classified patients by traditional risk scores and arterial age. We evaluated which variables were associated with greater CCS progression during the period, considering a statistical significance level of 5% (p < 0.05). RESULTS: The use of arterial age in the stratification of cardiovascular risk in comparison with the Framingham risk score (FRS) reclassified 29% of individuals to a higher risk category and 37% to a lower risk category. Regarding the American Heart Association and American College of Cardiology score (ASCVD), 31% were reclassified as higher risk and 36% as lower risk. The initial classification by arterial age was directly related to the progression of CCS throughout follow-up (p < 0.001). This was not observed for the FRS (p = 0.862) or ASCVD (p = 0.153). The individual variables most associated with CCS progression were high systolic blood pressure and low HDL. CONCLUSION: Cardiovascular risk stratification using arterial age showed a better association than the FRS and ASCVD in identifying individuals with higher risk of atherosclerosis progression.

FUNDAMENTO: Identificar os indivíduos assintomáticos sob risco de desenvolver doenças cardiovasculares é um dos principais objetivos da cardiologia preventiva. O escore de cálcio coronariano (ECC) permite estimar a idade vascular, que se mostrou mais fidedigna que a idade cronológica na determinação do risco cardiovascular. OBJETIVOS: Reclassificar o risco cardiovascular com base na idade arterial e avaliar a progressão do escore de cálcio durante o seguimento. MÉTODOS: 150 homens assintomáticos foram submetidos a avaliação clínica e do ECC em 2 avaliações com intervalo de 7,6 anos. Classificamos os pacientes pelos escores de risco tradicionais e pela idade arterial. Avaliamos quais variáveis se associaram a maior progressão do ECC durante o período. O nível de significância estatística considerado foi de 5% (p < 0,05). RESULTADOS: A utilização da idade arterial na estratificação do risco cardiovascular em comparação ao escore de risco de Framingham (ERF) reclassificou 29% dos indivíduos para uma categoria de risco superior e 37% para uma categoria inferior. Em relação ao escore da AHA e ACC (ASCVD), 31% passaram para um risco maior e 36% para um risco menor. A classificação inicial pela idade arterial teve relação direta com a progressão do ECC ao longo do seguimento (p < 0,001), fato que não foi observado para o ERF (p = 0,862) e ASCVD (p = 0,153). As variáveis individuais que mais se associaram à progressão do ECC foram a pressão arterial sistólica e o HDL baixo. CONCLUSÃO: A estratificação de risco cardiovascular utilizando a idade arterial apresentou melhor associação que o ERF e ASCVD na identificação de indivíduos com maior risco de progressão da aterosclerose.

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.

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 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.

Statins Accelerate Coronary Calcification and Reduce the Risk of Cardiovascular Events.

Lipid-lowering therapy with statins is well recognized as an effective therapy in reducing adverse cardiovascular events. However, the relationship between statin therapy and progression of coronary artery calcification (CAC) is unclear. A few of studies suggested that statins fail to slow and even accelerate progression of CAC; meanwhile, some researchers demonstrate opposite results. With the purpose of seeking out the effect of statin therapy on CAC, we summarized the existing evidence on statins and undertook meta-analyses of clinical trials assessing the effect of statin therapy on CAC. Fourteen trials were identified suitable for inclusion in the analysis of the effect of statin treatment on CAC, of which 11 were randomized controlled trails, 1 was case-control study, 1 was cross-sectional study, and 1 was observational study. In the meta-analysis of CAC progression, statin therapy seemed to accelerate the progression of CAC. Meanwhile, the analysis revealed a significant correlation between statin treatment and lower risk of cardiovascular events. In conclusion, meta-analyses of the available trials have shown a significant reduction of risk of cardiovascular events. In contrast, statins accelerated CAC. This suggests that statin-mediated atheroma calcification may enhance plaque stability and reduce the risk of plaque rupture.

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.

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.

Low-Dose Colchicine for Secondary Prevention of Coronary Artery Disease: JACC Review Topic of the Week.

Among statin-treated patients, inflammation assessed by means of high-sensitivity C-reactive protein (hsCRP) is a more powerful determinant of cardiovascular death and all-cause mortality than low-density-lipoprotein cholesterol (LDL-C). Several therapies that target residual inflammatory risk significantly reduce vascular event rates. For coronary artery disease patients already taking guideline-directed medical care, including statins, low-dose colchicine (0.5 mg/d orally) has been shown to safely lower major adverse cardiovascular events by 31% among those with stable atherosclerosis and by 23% after recent myocardial infarction. These magnitudes of benefit are larger than those seen in contemporary secondary prevention trials of adjunctive lipid-lowering agents. Low-dose colchicine is contraindicated in patients with significant renal or liver dysfunction and should be temporarily discontinued when taking concomitant agents such as clarithromycin, ketoconazole, and cyclosporine that share metabolism pathways. Lipid lowering and inflammation inhibition are not in conflict but are synergistic. In the future, combined use of aggressive LDL-C-lowering and inflammation-inhibiting therapies may become standard of care for most atherosclerosis patients. In June 2023, the U.S. Food and Drug Administration approved the use of low-dose colchicine to reduce the risk of myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

Coronary Artery Calcium in Assessment of Atherosclerotic Cardiovascular Disease Risk and its Role in Primary Prevention.

Coronary artery calcium (CAC), which is detected using computed tomography scanning, is a well-established indicator of subclinical atherosclerosis. The CAC score is independently associated with atherosclerotic cardiovascular disease (ASCVD) outcomes and provides improved predictive values for estimating the risk of ASCVD beyond traditional risk factors. Thus, CAC is considered to have important implications for reclassification as a decision aid among individuals in the preclinical phase and as the primary prevention of ASCVD. This review is focused on epidemiological evidence on CAC in asymptomatic population-based samples from Western countries and Japan. We also discuss the usability of CAC as a tool for assessing ASCVD risk and its role in the primary prevention of ASCVD. A lack of evidence for the CAC score in ASCVD risk assessment beyond traditional risk factors in populations other than those in Western countries (including Japan) warrants further investigation. Clinical trials are also necessary to demonstrate the usefulness and safety of CAC screening in the primary prevention of ASCVD.