Search

OBJECTIVE: The potential for choline metabolism to influence the development of diabetes has received increased attention. Previous studies on circulating choline metabolites and incident diabetes have been conducted in samples of older adults, often with a high prevalence of risk factors. RESEARCH DESIGN AND METHODS: Participants were from year 15 of follow-up (2000-2001) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (n = 3,133, aged 33-45 years) with plasma choline metabolite (choline, betaine, and trimethylamine N-oxide [TMAO]) data. We quantified associations between choline metabolites and 15-year risk of incident diabetes (n = 387) among participants free of diabetes at baseline using Cox proportional hazards regression models adjusted for sociodemographics, health behaviors, and clinical variables. RESULTS: Betaine was inversely associated with 15-year risk of incident diabetes (hazard ratio 0.76 [95% CI 0.67, 0.88] per 1-SD unit betaine), and TMAO was positively associated with 15-year risk of incident diabetes (1.11 [1.01, 1.22] per 1-SD unit). Choline was not significantly associated with 15-year risk of incident diabetes (1.05 [0.94, 1.16] per 1-SD). CONCLUSIONS: Our findings are consistent with other published literature supporting a role for choline metabolism in diabetes. Our study extends the current literature by analyzing a racially diverse population-based cohort of early middle-aged individuals in whom preventive activities may be most relevant.

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

We aimed to compare the associations of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) with coronary artery calcification (CAC). Patients who simultaneously underwent ultrasonography to diagnose hepatic steatosis and cardiac computed tomography to detect CAC were included. The presence and severity of CAC were defined with CAC-score thresholds of > 0 and > 300, respectively, and patients were divided into the following groups: no MASLD or MAFLD (reference), MASLD-only, MAFLD-only, and overlapping groups. Overall, 1,060/2,773 (38.2%) patients had CAC, of which 196 (18.5%) had severe CAC. The MASLD and MAFLD prevalence rates were 32.6% and 45.2%, respectively, with an overlap of 30.7%. In an ASCVD risk score-adjusted model, both MASLD (adjusted odd ratios [aOR], 1.21; 95% confidence interval [CI], 1.02-1.44; p = 0.033) and MAFLD (aOR 1.20; 95% CI 1.01-1.42, p = 0.034) were associated with CAC, whereas only MASLD (aOR 1.38; 95% CI 1.01-1.89, p = 0.041) was associated with severe CAC. Compared to the reference group, the overlapping group showed an association with CAC (aOR 1.22; 95% CI 1.01-1.47; p = 0.038); however, the MASLD and MAFLD subgroups did not differ in their association with CAC. MASLD may predict a higher risk of ASCVD more effectively than MAFLD.

BACKGROUND: Oral anticoagulants (OACs) are routinely used for the management of atrial fibrillation (AF) while antiplatelet agents are used in coronary artery disease (CAD). However, data regarding the comparative clinical outcomes of OAC monotherapy versus dual antithrombotic therapy (anticoagulant plus antiplatelet agent) in patients with AF and stable CAD are limited. METHODS: A comprehensive search of major databases including PubMed/MEDLINE, Cochrane Library, and Embase was performed from inception to September 1, 2024 to identify randomized control trials (RCTs) that compared OAC monotherapy with dual antithrombotic therapy in patients with AF and stable CAD. The risk ratios (RRs) were estimated with corresponding 95% confidence intervals (CIs) for all outcomes. RESULTS: A total of three RCTs reported data for 3945 patients with AF and stable CAD. The mean age of patients was 73.8 (±11.85) years and the mean follow-up was 22 months. OAC monotherapy was associated with a significantly reduced relative risk of major bleeding (RR: 0.55, 95% CI: 0.32-0.95) compared to dual therapy. The risk of all-cause death (RR: 0.85, 95% CI: 0.49-1.48), cardiovascular death (RR: 0.84, 95% CI: 0.50-1.41), any stroke event (RR: 0.74, 95% CI: 0.46-1.18), and myocardial infarction (RR: 1.57, 95% CI: 0.79-3.12) remained comparable across the two groups. CONCLUSION: OAC monotherapy led to a significant relative risk reduction for major bleeding with similar rates of ischemic events and mortality compared to dual antithrombotic therapy in patients with AF and stable CAD.

Purpose To clarify the predominant causative plaque constituent for periprocedural myocardial injury (PMI) following percutaneous coronary intervention: (a) erythrocyte-derived materials, indicated by a high plaque-to-myocardium signal intensity ratio (PMR) at coronary atherosclerosis T1-weighted characterization (CATCH) MRI, or (b) lipids, represented by a high maximum 4-mm lipid core burden index (maxLCBI4 mm) at near-infrared spectroscopy intravascular US (NIRS-IVUS). Materials and Methods This retrospective study included consecutive patients who underwent CATCH MRI before elective NIRS-IVUS-guided percutaneous coronary intervention at two facilities. PMI was defined as post-percutaneous coronary intervention troponin T values greater than five times the upper reference limit. Multivariable analysis was performed to identify predictors of PMI. Finally, the predictive capabilities of MRI, NIRS-IVUS, and their combination were compared. Results A total of 103 lesions from 103 patients (median age, 72 years [IQR, 64-78]; 78 male patients) were included. PMI occurred in 36 lesions. In multivariable analysis, PMR emerged as the strongest predictor (P = .001), whereas maxLCBI4 mm was not a significant predictor (P = .07). When PMR was excluded from the analysis, maxLCBI4 mm emerged as the sole independent predictor (P = .02). The combination of MRI and NIRS-IVUS yielded the largest area under the receiver operating curve (0.86 [95% CI: 0.64, 0.83]), surpassing that of NIRS-IVUS alone (0.75 [95% CI: 0.64, 0.83]; P = .02) or MRI alone (0.80 [95% CI: 0.68, 0.88]; P = .30). Conclusion Erythrocyte-derived materials in plaques, represented by a high PMR at CATCH MRI, were strongly associated with PMI independent of lipids. MRI may play a crucial role in predicting PMI by offering unique pathologic insights into plaques, distinct from those provided by NIRS. Keywords: Coronary Plaque, Periprocedural Myocardial Injury, MRI, Near-Infrared Spectroscopy Intravascular US Supplemental material is available for this article. © RSNA, 2024.

Coronary artery calcification is a significant predictor of cardiovascular disease, with current detection methods like Agatston scoring having limitations in sensitivity. This study aimed to evaluate the effectiveness of a novel CAC quantification method using dual-energy material decomposition, particularly its ability to detect low-density calcium and microcalcifications. A simulation study was conducted comparing the dual-energy material decomposition technique against the established Agatston scoring method and the newer volume fraction calcium mass technique. Detection accuracy and calcium mass measurement were the primary evaluation metrics. The dual-energy material decomposition technique demonstrated fewer false negatives than both Agatston scoring and volume fraction calcium mass, indicating higher sensitivity. In low-density phantom measurements, material decomposition resulted in only 7.41% false-negative (CAC = 0) measurements compared to 83.95% for Agatston scoring. For high-density phantoms, false negatives were removed (0.0%) compared to 20.99% in Agatston scoring. The dual-energy material decomposition technique presents a more sensitive and reliable method for CAC quantification.

This study compared the prognostic value of quantified thoracic artery calcium (TAC) including aortic arch on chest CT and coronary artery calcium (CAC) score on ECG-gated cardiac CT.MethodsA total of 2412 participants who underwent both chest CT and ECG-gated cardiac CT at the same period were included in the Multi-Ethnic Study of Atherosclerosis Exam 5. All participants were monitored for incident atherosclerotic cardiovascular disease (ASCVD) events. TAC is defined as calcification in the ascending aorta, aortic arch and descending aorta on chest CT. The quantification of TAC was measured using the Agatston method. Time-dependent receiver-operating characteristic (ROC) curves were used to compare the prognostic value of TAC and CAC scores.ResultsParticipants were 69±9 years of age and 47% were male. The Spearman correlation between TAC and CAC scores was 0.46 (p

IntroductionCoronary artery calcium (CAC) scans contain useful information beyond the Agatston CAC score that is not currently reported. We recently reported that artificial intelligence (AI)-enabled cardiac chambers volumetry in CAC scans (AI-CAC™) predicted incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis (MESA). In this study, we investigated the performance of AI-CAC cardiac chambers for prediction of incident heart failure (HF).MethodsWe applied AI-CAC to 5750 CAC scans of asymptomatic individuals (52% female, White 40%, Black 26%, Hispanic 22% Chinese 12%) free of known cardiovascular disease at the MESA baseline examination (2000-2002). We used the 15-year outcomes data and compared the time-dependent area under the curve (AUC) of AI-CAC volumetry versus NT-proBNP, Agatston score, and 9 known clinical risk factors (age, gender, diabetes, current smoking, hypertension medication, systolic and diastolic blood pressure, LDL, HDL for predicting incident HF over 15 years.ResultsOver 15 years of follow-up, 256 HF events accrued. The time-dependent AUC [95% CI] at 15 years for predicting HF with AI-CAC all chambers volumetry (0.86 [0.82,0.91]) was significantly higher than NT-proBNP (0.74 [0.69, 0.77]) and Agatston score (0.71 [0.68, 0.78]) (p ​

BackgroundIschemic cardiomyopathy is the leading cause of heart failure (HF). Most patients do not undergo coronary assessment after HF diagnosis. There are no randomized clinical trials of coronary assessment after HF diagnosis.MethodsUsing an electronic health record cohort of all individuals with HF within the San Francisco Health Network from 2001 to 2019, we identified factors associated with coronary assessment. Then, we studied the association of coronary assessment within 30 days of HF diagnosis with all-cause mortality and a composite of mortality and emergent angiography using a target trial emulation observational comparative-effectiveness approach. Target trial emulation is an approach to causal inference based on creating a hypothetical randomized clinical trial protocol and using observational data to emulate the protocol. We used propensity scores for covariate adjustment. We used national death records to improve the ascertainment of mortality and included falsification end points for the cause of death.ResultsAmong 14 829 individuals with HF (median, 62 years old; 5855 [40%] women), 3987 (26.9%) ever completed coronary assessment, with 2467/13 301 (18.5%) with unknown coronary artery disease status at HF diagnosis assessed. Women, older individuals, and people without stable housing were less likely to complete coronary assessment. Among 5972 eligible persons of whom 627 underwent early elective coronary assessment, coronary assessment was associated with lower mortality (hazard ratio, 0.84 [95% CI, 0.72-0.97]; P=0.025), reduced risk of the composite outcome (hazard ratio, 0.86 [95% CI, 0.73-1.00]), higher rates of revascularization (odds ratio, 7.6 [95% CI, 5.4-10.6]), and higher use of medical therapy (odds ratio, 2.5 [95% CI, 1.7-3.6]), but not the falsification end points.ConclusionsIn a safety-net population, disparities in coronary assessment after HF diagnosis are not fully explained by coronary artery disease risk factors. Early coronary assessment is associated with improved HF outcomes possibly related to higher rates of revascularization and guideline-directed medical therapy but with low certainty that this finding is not attributable to unmeasured confounding.

AIMS: The incremental impact of atherosclerosis imaging-quantitative computed tomography (AI-QCT) on diagnostic certainty and downstream patient management is not yet known. The aim of this study was to compare the clinical utility of the routine implementation of AI-QCT versus conventional visual coronary CT angiography (CCTA) interpretation. METHODS AND RESULTS: In this multi-centre cross-over study in 5 expert CCTA sites, 750 consecutive adult patients referred for CCTA were prospectively recruited. Blinded to the AI-QCT analysis, site physicians established patient diagnoses and plans for downstream non-invasive testing, coronary intervention, and medication management based on the conventional site assessment. Next, physicians were asked to repeat their assessments based upon AI-QCT results. The included patients had an age of 63.8 ± 12.2 years; 433 (57.7%) were male. Compared with the conventional site CCTA evaluation, AI-QCT analysis improved physicians confidence two- to five-fold at every step of the care pathway and was associated with change in diagnosis or management in the majority of patients (428; 57.1%; P < 0.001), including for measures such as Coronary Artery Disease-Reporting and Data System (CAD-RADS) (295; 39.3%; P < 0.001) and plaque burden (197; 26.3%; P < 0.001). After AI-QCT including ischaemia assessment, the need for downstream non-invasive and invasive testing was reduced by 37.1% (P < 0.001), compared with the conventional site CCTA evaluation. Incremental to the site CCTA evaluation alone, AI-QCT resulted in statin initiation/increase an aspirin initiation in an additional 28.1% (P < 0.001) and 23.0% (P < 0.001) of patients, respectively. CONCLUSION: The use of AI-QCT improves diagnostic certainty and may result in reduced downstream need for non-invasive testing and increased rates of preventive medical therapy.

Clinical risk scores based on traditional risk factors of atherosclerosis correlate imprecisely to an individuals complex pathophysiological predisposition to atherosclerosis and provide limited accuracy for predicting major adverse cardiovascular events (MACE). Over the past two decades, computed tomography scanners and techniques for coronary computed tomography angiography (CCTA) analysis have substantially improved, enabling more precise atherosclerotic plaque quantification and characterization. The accuracy of CCTA for quantifying stenosis and atherosclerosis has been validated in numerous multicentre studies and has shown consistent incremental prognostic value for MACE over the clinical risk spectrum in different populations. Serial CCTA studies have advanced our understanding of vascular biology and atherosclerotic disease progression. The direct disease visualization of CCTA has the potential to be used synergistically with indirect markers of risk to significantly improve prevention of MACE, pending large-scale randomized evaluation.

Multiomics has shown promise in noninvasive risk profiling and early detection of various common diseases. In the present study, in a prospective population-based cohort with ~18 years of e-health record follow-up, we investigated the incremental and combined value of genomic and gut metagenomic risk assessment compared with conventional risk factors for predicting incident coronary artery disease (CAD), type 2 diabetes (T2D), Alzheimer disease and prostate cancer. We found that polygenic risk scores (PRSs) improved prediction over conventional risk factors for all diseases. Gut microbiome scores improved predictive capacity over baseline age for CAD, T2D and prostate cancer. Integrated risk models of PRSs, gut microbiome scores and conventional risk factors achieved the highest predictive performance for all diseases studied compared with models based on conventional risk factors alone. The present study demonstrates that integrated PRSs and gut metagenomic risk models improve the predictive value over conventional risk factors for common chronic diseases.

OBJECTIVES: Coronary computed tomography angiography (CCTA) has higher diagnostic accuracy than coronary artery calcium (CAC) score for detecting obstructive coronary artery disease (CAD) in patients with stable chest pain, while the added diagnostic value of combining CCTA with CAC is unknown. We investigated whether combining coronary CCTA with CAC score can improve the diagnosis of obstructive CAD compared with CCTA alone. METHODS: A total of 2315 patients (858 women, 37%) aged 61.1 ± 10.2 from 29 original studies were included to build two CAD prediction models based on either CCTA alone or CCTA combined with the CAC score. CAD was defined as at least 50% coronary diameter stenosis on invasive coronary angiography. Models were built by using generalized linear mixed-effects models with a random intercept set for the original study. The two CAD prediction models were compared by the likelihood ratio test, while their diagnostic performance was compared using the area under the receiver-operating-characteristic curve (AUC). Net benefit (benefit of true positive versus harm of false positive) was assessed by decision curve analysis. RESULTS: CAD prevalence was 43.5% (1007/2315). Combining CCTA with CAC improved CAD diagnosis compared with CCTA alone (AUC: 87% [95% CI: 86 to 89%] vs. 80% [95% CI: 78 to 82%]; p

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P

BACKGROUND: Despite the initial evidence supporting the utility of intravascular imaging to guide percutaneous coronary intervention (PCI), adoption remains low. Recent new trial data have become available. An updated study-level meta-analysis comparing intravascular imaging to angiography to guide PCI was performed. This study aimed to evaluate the clinical outcomes of intravascular imaging-guided PCI compared with angiography-guided PCI. METHODS AND RESULTS: A random-effects meta-analysis was performed on the basis of the intention-to-treat principle. The primary outcomes were major adverse cardiac events, cardiac death, and all-cause death. Mixed-effects meta-regression was performed to investigate the impact of complex PCI on the primary outcomes. A total of 16 trials with 7814 patients were included. The weighted mean follow-up duration was 28.8 months. Intravascular imaging led to a lower risk of major adverse cardiac events (relative risk [RR], 0.67 [95% CI, 0.55-0.82]; P

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

BACKGROUND: The value of physiological ischemia versus anatomic severity of disease for prognosis and management of patients with stable coronary artery disease (CAD) is widely debated. METHODS: A total of 1764 patients who had rest-stress cadmium-zinc-telluride single-photon emission computed tomography myocardial perfusion imaging and angiography (invasive or computed tomography) were prospectively enrolled and followed for cardiac death/nonfatal myocardial infarction. The CAD prognostic index (CADPI) was used to quantify the extent and severity of angiographic disease. Prognostic value was assessed using Cox models, adjusted for pretest risk, known CAD, stressor, left ventricular ejection fraction, %ischemia and infarct, CADPI, and early (90-day) revascularization. Incremental prognostic value was evaluated using net reclassification index. RESULTS: The mean age was 69.7±9.5 years, 24.4% were women, and 29.3% had known CAD. Significant ischemia (>10%) was present in 28.4%. Nonobstructive, single, and multivessel disease was present in 256 (14.5%), 772 (43.8%), and 736 (41.7%), respectively. Early revascularization occurred in 579 (32.8%). Cardiac death/myocardial infarction occurred in 148 (8.4%) over a 4.6-year median follow-up. Both %ischemia and CADPI provided independent and incremental prognostic value over pretest clinical risk (P<0.001). In a model containing both ischemia and anatomy, ischemia was prognostic (hazard ratio per 5% ↑, 1.35 [95% CI, 1.11--1.63]; P=0.002) but CADPI was not (hazard ratio per 10-unit ↑, 1.09 [95% CI, 0.99--1.20]; P=0.07). Early revascularization modified the risk associated with %ischemia (interaction P=0.003) but not with CADPI (interaction P=0.6). %Ischemia and single-photon emission computed tomography variables added incremental prognostic value over clinical risk and CADPI (net reclassification index, 20.3% [95% CI, 9%--32%]; P<0.05); however, CADPI was not incrementally prognostic beyond pretest risk, %ischemia, and single-photon emission computed tomography variables (net reclassification index, 3.1% [95% CI, -5% to 15%]; P=0.21). CONCLUSIONS: Ischemic burden provides independent and incremental prognostic value beyond CAD anatomy and identifies patients who benefit from early revascularization. The anatomic extent of disease has independent prognostic value over clinical risk factors but offers limited incremental benefit for prognosis and guiding revascularization beyond physiological severity (ischemia). [ABSTRACT FROM AUTHOR]

BackgroundPericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population.MethodsIn this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates.ResultsAmong 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001).ConclusionsAmong PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH.

Management of intracoronary calcium (ICC) continues to be a challenge for interventional cardiologists. There have been significant advances in calcium treatment devices. However, there still exists a knowledge gap regarding which devices to choose for the treatment of ICC. The purpose of this manuscript is to review the principles of intravascular lithotripsy (IVL) and clinical data. The technique of IVL will then be compared to alternative calcium treatment devices. Clinical data will be reviewed concerning the treatment of coronary, peripheral artery and valvular calcifications. Controversies to be discussed include how to incorporate IVL into your practice, what is the best approach for treating calcium subtypes, how to approach under-expanded stents, what is the ideal technique for performing IVL, how safe is IVL, whether imaging adds value when performing IVL, and how IVL fits into a treatment program for peripheral arteries and calcified valves.

Purpose of reviewCoronary artery disease is a complex disorder and the leading cause of mortality worldwide. As technologies for the generation of high-throughput multiomics data have advanced, gene regulatory network modeling has become an increasingly powerful tool in understanding coronary artery disease. This review summarizes recent and novel gene regulatory network tools for bulk tissue and single cell data, existing databases for network construction, and applications of gene regulatory networks in coronary artery disease.Recent findingsNew gene regulatory network tools can integrate multiomics data to elucidate complex disease mechanisms at unprecedented cellular and spatial resolutions. At the same time, updates to coronary artery disease expression data in existing databases have enabled researchers to build gene regulatory networks to study novel disease mechanisms. Gene regulatory networks have proven extremely useful in understanding CAD heritability beyond what is explained by GWAS loci and in identifying mechanisms and key driver genes underlying disease onset and progression. Gene regulatory networks can holistically and comprehensively address the complex nature of coronary artery disease. In this review, we discuss key algorithmic approaches to construct gene regulatory networks and highlight state-of-the-art methods that model specific modes of gene regulation. We also explore recent applications of these tools in coronary artery disease patient data repositories to understand disease heritability and shared and distinct disease mechanisms and key driver genes across tissues, between sexes, and between species.

AimsStudies have indicated inconsistent results regarding the association between plasma levels of Lipoprotein(a) [Lp(a)] and coronary artery calcification (CAC). We performed a systematic review and meta-analysis to investigate the association between elevated levels of Lp(a) and risk of CAC in populations free of cardiovascular disease (CVD) symptoms.Data synthesisPubMed, Web of Science, Embase, and Scopus were searched up to July 2022 and the methodological quality was assessed using Newcastle-Ottawa Scale (NOS) scale. Random-effects meta-analysis was used to estimate pooled odds ratio (OR) and 95% confidence interval. Out of 298 studies, data from 8 cross-sectional (n = 18,668) and 4 cohort (n = 15,355) studies were used in meta-analysis. Cohort studies demonstrated a positive significant association between Lp(a) and CAC, so that individuals with Lp(a)≥30-50 exposed to about 60% risk of CAC incidence compared to those with lower Lp(a) concentrations in asymptomatic CVD subjects (OR, 1.58; 95% CI, 1.38-1.80; l2, 0.0%; P, 0.483); Subgroup analysis showed that a cut-off level for Lp(a) measurement could not statistically affect the association, but race significantly affected the relationship between Lp(a) and CAC (OR,1.60; 95% CI, 1.41-1.81). Analyses also revealed that both men and women with higher Lp(a) concentrations are at the same risk for increased CAC.ConclusionsBlood Lp(a) level was significantly associated with CAC incidence in asymptomatic populations with CVD, indicating that measuring Lp(a) may be a useful biomarker for diagnosing subclinical atherosclerosis in individuals at higher risk of CAC score.Prospero registration numberCRD42022350297.

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

Translation of small-diameter tissue-engineered vascular grafts (TEVGs) for the treatment of coronary artery disease (CAD) remains an unfulfilled promise. This is largely due to the limited integration of TEVGs into the native vascular wall-a process hampered by the insufficient smooth muscle cell (SMC) infiltration and extracellular matrix deposition, and low vasoactivity. These processes can be promoted through the judicious modulation of the SMC toward a synthetic phenotype to promote remodeling and vascular integration; however, the expression of synthetic markers is often accompanied by a decrease in the expression of contractile proteins. Therefore, techniques that can precisely modulate the SMC phenotypical behavior could have the potential to advance the translation of TEVGs. In this review, we describe the phenotypic diversity of SMCs and the different environmental cues that allow the modulation of SMC gene expression. Furthermore, we describe the emerging biomaterial approaches to modulate the SMC phenotype in TEVG design and discuss the limitations of current techniques. In addition, we found that current studies in tissue engineering limit the analysis of the SMC phenotype to a few markers, which are often the characteristic of early differentiation only. This limited scope has reduced the potential of tissue engineering to modulate the SMC toward specific behaviors and applications. Therefore, we recommend using the techniques presented in this review, in addition to modern single-cell proteomics analysis techniques to comprehensively characterize the phenotypic modulation of SMCs. Expanding the holistic potential of SMC modulation presents a great opportunity to advance the translation of living conduits for CAD therapeutics.

BACKGROUND: Adipocytes are crucial regulators of cardiovascular health. However, not much is known about gene expression profiles of adipocytes residing in nonfat cardiovascular tissues, their genetic regulation, and contribution to coronary artery disease. Here, we investigated whether and how the gene expression profiles of adipocytes in the subcutaneous adipose tissue differ from adipocytes residing in the heart. METHODS: We used single-nucleus RNA-sequencing data sets of subcutaneous adipose tissue and heart and performed in-depth analysis of tissue-resident adipocytes and their cell-cell interactions. RESULTS: We first discovered tissue-specific features of tissue-resident adipocytes, identified functional pathways involved in their tissue specificity, and found genes with cell type-specific expression enrichment in tissue-resident adipocytes. By following up these results, we discovered the propanoate metabolism pathway as a novel distinct characteristic of the heart-resident adipocytes and found a significant enrichment of coronary artery disease genome-wide association study risk variants among the right atrium-specific adipocyte marker genes. Our cell-cell communication analysis identified 22 specific heart adipocyte-associated ligand-receptor pairs and signaling pathways, including THBS (thrombospondin) and EPHA (ephrin type-A), further supporting the distinct tissue-resident role of heart adipocytes. Our results also suggest chamber-level coordination of heart adipocyte expression profiles as we observed a consistently larger number of adipocyte-associated ligand-receptor interactions and functional pathways in the atriums than ventricles. CONCLUSIONS: Overall, we introduce a new function and genetic link to coronary artery disease for the previously unexplored heart-resident adipocytes.

BACKGROUND: The contemporary burden and characteristics of coronary atherosclerosis, assessed using coronary computed tomography angiography (CCTA), is unknown among asymptomatic adults with diabetes and prediabetes in the United States. The pooled cohort equations and coronary artery calcium (CAC) score stratify atherosclerotic cardiovascular disease risk, but their association with CCTA findings across glycemic categories is not well established. METHODS: Asymptomatic adults without atherosclerotic cardiovascular disease enrolled in the Miami Heart Study were included. Participants underwent CAC and CCTA testing and were classified into glycemic categories. Prevalence of coronary atherosclerosis (any plaque, noncalcified plaque, plaque with ≥1 high-risk feature, maximal stenosis ≥50%) assessed by CCTA was described across glycemic categories and further stratified by pooled cohort equations-estimated atherosclerotic cardiovascular disease risk and CAC score. Adjusted logistic regression was used to evaluate the associations between glycemic categories and coronary outcomes. RESULTS: Among 2352 participants (49.5% women), the prevalence of euglycemia, prediabetes, and diabetes was 63%, 30%, and 7%, respectively. Coronary plaque was more commonly present across worsening glycemic categories (euglycemia, 43%; prediabetes, 58%; diabetes, 69%), and similar pattern was observed for other coronary outcomes. In adjusted analyses, compared with euglycemia, prediabetes and diabetes were each associated with higher odds of any coronary plaque (OR, 1.30 [95% CI, 1.05-1.60] and 1.75 [1.17-2.61], respectively), noncalcified plaque (OR, 1.47 [1.19-1.81] and 1.99 [1.38-2.87], respectively), and plaque with ≥1 high-risk feature (OR, 1.65 [1.14-2.39] and 2.53 [1.48-4.33], respectively). Diabetes was associated with stenosis ≥50% (OR, 3.01 [1.79-5.08]; reference=euglycemia). Among participants with diabetes and estimated atherosclerotic cardiovascular disease risk

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

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

ObjectiveChildren with Kawasaki disease (KD) and an initial echocardiogram that demonstrates coronary artery aneurysms (CAAs, Z score ≥2.5) are at high risk for severe cardiovascular complications. We sought to determine if primary adjunctive infliximab treatment at a dose of either 5 or 10 mg/kg, compared with intravenous immunoglobulin (IVIG) alone, is associated with a greater likelihood of CAA regression in patients with KD with CAA at the time of diagnosis.Design and settingSingle-centre observational study.PatientsChildren with acute KD and Z score ≥2.5 at baseline.InterventionsPrimary adjunctive infliximab (5 or 10 mg/kg) within 48 hours of initiating IVIG 2 g/kg.Main outcome measuresIncidence of CAA regression to Zmax

Background Residual risk of cardiovascular events and plaque progression remains despite reduction in low-density lipoprotein cholesterol. Factors contributing to residual risk remain unclear. The authors examined the role of eicosapentaenoic acid and docosahexaenoic acid in coronary plaque regression and its predictors. Methods and Results A total of 240 patients with stable coronary artery disease were randomized to eicosapentaenoic acid plus docosahexaenoic acid (3.36 g/d) or none for 30 months. Patients were stratified by regression or progression of coronary fatty plaque measured by coronary computed tomographic angiography. Cardiac events were ascertained. The mean±SD age was 63.0±7.7 years, mean low-density lipoprotein cholesterol level was

OBJECTIVE: The effectiveness of coronary artery calcification (CAC) for risk stratification in obesity, in which imaging is often limited because of a reduced signal to noise ratio, has not been well studied. METHODS: Data from 9334 participants (mean age: 53.3 ± 9.7 years; 67.9% men) with BMI ≥ 30 kg/m2 from the CAC Consortium, a retrospectively assembled cohort of individuals with no prior cardiovascular diseases (CVD), were used. The predictive value of CAC for all-cause and cause-specific mortality was evaluated using multivariable-adjusted Cox proportional hazards and competing-risks regression. RESULTS: Mean BMI was 34.5 (SD 4.4) kg/m2 (22.7% Class II and 10.8% Class III obesity), and 5461 (58.5%) had CAC. Compared with CAC = 0, those with CAC = 1-99, 100-299, and ≥300 Agatston units had higher rates (per 1000 person-years) of all-cause (1.97 vs. 3.5 vs. 5.2 vs. 11.3), CVD (0.4 vs. 1.1 vs. 1.5 vs. 4.2), and coronary heart disease (CHD) mortality (0.2 vs. 0.6 vs. 0.6 vs. 2.5), respectively, after mean follow-up of 10.8 ± 3.0 years. After adjusting for traditional cardiovascular risk factors, CAC ≥ 300 was associated with significantly higher risk of all-cause (hazard ratio [HR]: 2.05; 95% CI: 1.49-2.82), CVD (subdistribution HR: 3.48; 95% CI: 1.81-6.70), and CHD mortality (subdistribution HR: 5.44; 95% CI: 2.02-14.66), compared with CAC = 0. When restricting the sample to individuals with BMI ≥ 35 kg/m2 , CAC ≥ 300 remained significantly associated with the highest risk. CONCLUSIONS: Among individuals with obesity, including moderate-severe obesity, CAC strongly predicts all-cause, CVD, and CHD mortality and may serve as an effective cardiovascular risk stratification tool to prioritize the allocation of therapies for weight management.

Background and aimsHigher truncated-to-native proteoform ratios of apolipoproteins (apo) C-I (C-I'/C-I) and C-II (C-II'/C-II) are associated with less atherogenic lipid profiles. We examined prospective relationships of C-I'/C-II and C-II'/C-II with coronary heart disease (CHD) and coronary artery calcium (CAC).MethodsApoC-I and apoC-II proteoforms were measured by mass spectrometry immunoassay in 5790 MESA baseline plasma samples. CHD events (myocardial infarction, resuscitated cardiac arrest, fatal CHD, n = 434) were evaluated for up to 17 years. CAC was measured 1-4 times over 10 years for incident CAC (if baseline CAC = 0), and changes (follow-up adjusted for baseline) in CAC score and density (if baseline CAC>0).ResultsC-II'/C-II was inversely associated with CHD (n = 434 events) after adjusting for non-lipid cardiovascular risk factors (Hazard ratio: 0.89 [95% CI: 0.81-0.98] per SD), however, the association was attenuated after further adjustment for HDL levels (0.93 [0.83-1.03]). There was no association between C-I'/C-I and CHD (0.98 [0.88-1.08]). C-II'/C-II was positively associated with changes in CAC score (3.4% [95%CI: 0.6, 6.3]) and density (6.3% [0.3, 4.2]), while C-I'/C-I was inversely associated with incident CAC (Risk ratio: 0.89 [95% CI: 0.81, 0.98]) in fully adjusted models that included plasma lipids. Total apoC-I and apoC-II concentrations were not associated with CHD, incident CAC or change in CAC score.ConclusionsIncreased apoC-II truncation was associated with reduced CHD, possibly explained by differences in lipid metabolism. Increased apoC-I and apoC-II truncations were also associated with less CAC progression and/or development of denser coronary plaques.

PurposeSouth Asian (SA) persons have increased risks for diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD). We examined whether the association of DM with subclinical atherosclerosis assessed by coronary artery calcium (CAC) differs in SA versus other ethnic groups.MethodsWe studied adults from the Multi-Ethnic Study of Atherosclerosis and the Mediators of Atherosclerosis in South Asians Living in America studies without ASCVD. CAC was examined among those normoglycemic, pre-DM and DM. Logistic regression examined pre-DM and DM with the odds of any CAC > 0 and CAC ≥ 100.ResultsAmong 7562 participants, CAC > 0 and CAC ≥ 100 in those with DM was highest in non-Hispanic White (NHW) (80% and 48%) and SA (72% and 41%) persons. Adjusted Ln (CAC + 1) was highest in NHW (3.68 ± 0.21) and SA (3.60 ± 0.23) (p < .01) DM patients. SA and NHW adults with DM (vs normoglycemic) had highest odds of CAC > 0 (2.13 and 2.27, respectively, p < .01). For CAC ≥ 100, SA and Chinese adults had the highest odds (2.28 and 2.27, respectively, p < .01). Fasting glucose and glycated hemoglobin were most strongly associated with CAC among SA.ConclusionsDiabetes mellitus most strongly relates to any CAC in SA and NHW adults and CAC ≥ 100 in SA and Chinese adults, helping to explain the relation of DM with ASCVD in these populations.

AIMS: The totality of atherosclerotic plaque derived from coronary computed tomography angiography (CCTA) emerges as a comprehensive measure to assess the intensity of medical treatment that patients need. This study examines the differences in age onset and prognostic significance of atherosclerotic plaque burden between sexes. METHODS AND RESULTS: From a large multi-center CCTA registry the Leiden CCTA score was calculated in 24 950 individuals. A total of 11 678 women (58.5 ± 12.4 years) and 13 272 men (55.6 ± 12.5 years) were followed for 3.7 years for major adverse cardiovascular events (MACE) (death or myocardial infarction). The age where the median risk score was above zero was 12 years higher in women vs. men (64-68 years vs. 52-56 years, respectively, P < 0.001). The Leiden CCTA risk score was independently associated with MACE: score 6-20: HR 2.29 (1.69-3.10); score > 20: HR 6.71 (4.36-10.32) in women, and score 6-20: HR 1.64 (1.29-2.08); score > 20: HR 2.38 (1.73-3.29) in men. The risk was significantly higher for women within the highest score group (adjusted P-interaction = 0.003). In pre-menopausal women, the risk score was equally predictive and comparable with men. In post-menopausal women, the prognostic value was higher for women [score 6-20: HR 2.21 (1.57-3.11); score > 20: HR 6.11 (3.84-9.70) in women; score 6-20: HR 1.57 (1.19-2.09); score > 20: HR 2.25 (1.58-3.22) in men], with a significant interaction for the highest risk group (adjusted P-interaction = 0.004). CONCLUSION: Women developed coronary atherosclerosis approximately 12 years later than men. Post-menopausal women within the highest atherosclerotic burden group were at significantly higher risk for MACE than their male counterparts, which may have implications for the medical treatment intensity.

BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease. METHODS: Participants from the UK Biobank and Womens Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease. RESULTS: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Womens Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2×10-12). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P

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

Recent studies have found an association between high volumes of physical activity and increased levels of coronary artery calcification (CAC) among older male endurance athletes, yet the underlying mechanisms have remained largely elusive. Potential mechanisms include greater exposure to inflammatory cytokines, reactive oxygen species and oxidised low-density lipoproteins, as acute strenuous physical activity has been found to enhance their systemic release. Other possibilities include post-exercise elevations in circulating parathyroid hormone, which can modify the amount and morphology of calcific plaque, and long-term exposure to non-laminar blood flow within the coronary arteries during vigorous physical activity, particularly in individuals with pre-existing atherosclerosis. Further, although the association has only been identified in men, the role of testosterone in this process remains unclear. This brief review discusses the association between high-volume endurance exercise and CAC in older men, elaborates on the potential mechanisms underlying the increased calcification, and provides clinical implications and recommendations for those at risk.

AimsIcosapent ethyl (IPE) significantly reduced ischaemic events in statin-treated patients with atherosclerosis or diabetes and elevated triglycerides in REDUCE-IT, including large reductions in myocardial infarction and elective, urgent, and emergent coronary revascularization. However, the mechanisms driving this clinical benefit are not fully known. The EVAPORATE trial demonstrated that IPE significantly reduced plaque burden. No study to date has assessed the impact of IPE on coronary physiology. Fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) data sets (FFRCT) applies computational fluid dynamics to calculate FFR values in epicardial coronary arteries. Our objective was to assess the impact of IPE on coronary physiology assessed by FFRCT using imaging data from EVAPORATE.Methods and resultsA total of 47 patients and of 507 coronary lesions at baseline, 9 months, and 18 months with coronary CTA and FFRCT were studied in a blinded core lab. The pre-specified primary endpoint was the FFRCT value in the distal coronary segment from baseline to follow-up in the most diseased vessel per patient using IPE compared with placebo. The pre-specified secondary endpoint was the change in translesional FFRCT (ΔFFRCT) across the most severe (minimum 30% diameter stenosis) coronary lesion per vessel. Baseline FFRCT was similar for IPE compared with placebo (0.83 ± 0.08 vs. 0.84 ± 0.08, P = 0.55). There was significant improvement in the primary endpoint, as IPE improved mean distal segment FFRCT at 9- and 18-month follow-up compared with placebo (0.01 ± 0.05 vs. -0.05 ± 0.09, P = 0.02, and -0.01 ± 0.09 vs. -0.09 ± 0.12, P = 0.03, respectively). ΔFFRCT in 140 coronary lesions was improved, although not statistically significant, with IPE compared with placebo (-0.06 ± 0.08 vs. -0.09 ± 0.1, P = 0.054).ConclusionIcosapent ethyl demonstrated significant benefits in coronary physiology compared with placebo. This early and sustained improvement in FFRCT at 9- and 18-month follow-up provides mechanistic insight into the clinical benefit observed in the REDUCE-IT trial. Furthermore, this is the first assessment of FFRCT to determine drug effect.

9p21.3 locus polymorphisms have the strongest correlation with coronary artery disease, but as a noncoding locus, disease connection is enigmatic. The lncRNA ANRIL found in 9p21.3 may regulate vascular smooth muscle cell (VSMC) phenotype to contribute to disease risk. We observed significant heterogeneity in induced pluripotent stem cell-derived VSMCs from patients homozygous for risk versus isogenic knockout or nonrisk haplotypes. Subpopulations of risk haplotype cells exhibited variable morphology, proliferation, contraction, and adhesion. When sorted by adhesion, risk VSMCs parsed into synthetic and contractile subpopulations, i.e., weakly adherent and strongly adherent, respectively. Of note, >90% of differentially expressed genes coregulated by haplotype and adhesion and were associated with Rho GTPases, i.e., contractility. Weakly adherent subpopulations expressed more short isoforms of ANRIL, and when overexpressed in knockout cells, ANRIL suppressed adhesion, contractility, and αSMA expression. These data suggest that variable lncRNA penetrance may drive mixed functional outcomes that confound pathology.

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

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

BackgroundCoronary artery calcification (CAC), often assessed by computed tomography (CT), is a powerful marker of coronary artery disease that can guide preventive therapies. Computed tomographies, however, are not always accessible or serially obtainable. It remains unclear whether other widespread tests such as transthoracic echocardiograms (TTEs) can be used to predict CAC.MethodsUsing a data set of 2,881 TTE videos paired with coronary calcium CTs, we trained a video-based artificial intelligence convolutional neural network to predict CAC scores from parasternal long-axis views. We evaluated the model's ability to classify patients from a held-out sample as well as an external site sample into zero CAC and high CAC (CAC ≥ 400 Agatston units) groups by receiver operating characteristic and precision-recall curves. We also investigated whether such classifications prognosticated significant differences in 1-year mortality rates by the log-rank test of Kaplan-Meier curves.ResultsTransthoracic echocardiogram artificial intelligence models had high discriminatory abilities in predicting zero CAC (receiver operating characteristic area under the curve [AUC] = 0.81 [95% CI, 0.74-0.88], F1 score = 0.95) and high CAC (AUC = 0.74 [0.68-0.8], F1 score = 0.74). This performance was confirmed in an external test data set of 92 TTEs (AUC = 0.75 [0.65-0.85], F1 score = 0.77; and AUC = 0.85 [0.76-0.93], F1 score = 0.59, respectively). Risk stratification by TTE-predicted CAC performed similarly to CT CAC scores in prognosticating significant differences in 1-year survival in high-CAC patients (CT CAC ≥ 400 vs CT CAC < 400, P = .03; TTE-predicted CAC ≥ 400 vs TTE-predicted CAC < 400, P = .02).ConclusionsA video-based deep learning model successfully used TTE videos to predict zero CAC and high CAC with high accuracy. Transthoracic echocardiography-predicted CAC prognosticated differences in 1-year survival similar to CT CAC. Deep learning of TTEs holds promise for future adjunctive coronary artery disease risk stratification to guide preventive therapies.

Coronary computed tomographic angiography (CCTA) is becoming the first-line investigation for establishing the presence of coronary artery disease and, with fractional flow reserve (FFRCT), its haemodynamic significance. In patients without significant epicardial obstruction, its role is either to rule out atherosclerosis or to detect subclinical plaque that should be monitored for plaque progression/regression following prevention therapy and provide risk classification. Ischaemic non-obstructive coronary arteries are also expected to be assessed by non-invasive imaging, including CCTA. In patients with significant epicardial obstruction, CCTA can assist in planning revascularisation by determining the disease complexity, vessel size, lesion length and tissue composition of the atherosclerotic plaque, as well as the best fluoroscopic viewing angle; it may also help in selecting adjunctive percutaneous devices (e.g., rotational atherectomy) and in determining the best landing zone for stents or bypass grafts.

Individuals of South Asian (SA) ancestry are predisposed to a higher risk of atherosclerotic cardiovascular disease (ASCVD). Coronary artery calcium (CAC) volume and density can identify coronary plaque characteristics unique to SA that may provide important prognostic information to identify high risk individuals beyond traditional CAC scores. We used data from the Mediators of Atherosclerosis in South Asians Living in America (MASALA). CAC density and volume were assessed according to established protocols. ASCVD risk was estimated using the pooled cohort equations (PCE). Multivariable-adjusted linear regression models were used to study the association between the PCE and advanced CAC measures, and between cardiovascular risk factors and CAC density and volume. Our analyses included 1,155 participants (mean age 57 (SD 9) years, 52% men) with information on advanced CAC measures. After multivariable-adjustment, the PCE was associated with both CAC density (β 0.24, 95% CI 0.12,0.35) and CAC volume (β 0.43, 95% CI 0.38,0.48). High-density lipoprotein cholesterol was directly associated with CAC density while waist circumference was inversely associated with it. Body mass index, hypertension status, statin use, diabetes, and HOMA-IR were all directly associated with CAC volume. Estimated ASCVD risk was associated with both CAC volume and density. Different cardiometabolic risk factors are associated with CAC density and volume. Future longitudinal studies are required to demonstrate the interrelationship of advanced CAC measures and cardiovascular risk factors with incident ASCVD outcomes.

Background and aimsPreviously, osteoporosis and coronary artery disease were considered unrelated. However, beyond age, these two conditions appear to share common etiologies that are not yet fully understood. We examined the relationship between thoracic spine bone mineral density (BMD) and severity of coronary artery calcium (CAC) score.Methods and resultsMESA is a prospective cohort study of 6814 men and women between the ages of 45 and 84 years, without clinical cardiovascular disease. This study included participants who underwent non-contrast chest CT scans to determine CAC score and thoracic spine BMD. The thoracic spine BMD was categorized into osteoporosis (defined as T score: ≤ -2.5), osteopenia (T-score between: -2.5 and -1) and normal BMD (T-score ≥ -1). There were 3392 subjects who had CAC >0 at baseline. The prevalence of CAC >0 was 36% in normal BMD group, 49% in the osteopenia and 68% in osteoporosis group. After adjusting for risk factors of atherosclerosis, in multivariate regression models we found a significant association between CAC and osteoporosis (OR: 1.40, 95% CI 1.16-1.69, p value

BackgroundLipoprotein(a) (Lp[a]) and oxidized phospholipids (OxPLs) are each independent risk factors for atherosclerotic cardiovascular disease. The extent to which Lp(a) and OxPLs predict coronary artery disease (CAD) severity and outcomes in a contemporary, statin-treated cohort is not well established.ObjectivesThis study sought to evaluate the relationships between Lp(a) particle concentration and OxPLs associated with apolipoprotein B (OxPL-apoB) or apolipoprotein(a) (OxPL-apo[a]) with angiographic CAD and cardiovascular outcomes.MethodsAmong 1,098 participants referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study, Lp(a), OxPL-apoB, and OxPL-apo(a) were measured. Logistic regression estimated the risk of multivessel coronary stenoses by Lp(a)-related biomarker level. Cox proportional hazards regression estimated the risk of major adverse cardiovascular events (MACEs) (coronary revascularization, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) in follow-up.ResultsMedian Lp(a) was 26.45 nmol/L (IQR: 11.39-89.49 nmol/L). Lp(a), OxPL-apoB, and OxPL-apo(a) were highly correlated (Spearman R ≥0.91 for all pairwise combinations). Lp(a) and OxPL-apoB were associated with multivessel CAD. Odds of multivessel CAD per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.10 (95% CI: 1.03-1.18; P = 0.006), 1.18 (95% CI: 1.03-1.34; P = 0.01), and 1.07 (95% CI: 0.99-1.16; P = 0.07), respectively. All biomarkers were associated with cardiovascular events. HRs for MACE per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.08 (95% CI: 1.03-1.14; P = 0.001), 1.15 (95% CI: 1.05-1.26; P = 0.004), and 1.07 (95% CI: 1.01-1.14; P = 0.02), respectively.ConclusionsIn patients undergoing coronary angiography, Lp(a) and OxPL-apoB are associated with multivessel CAD. Lp(a), OxPL-apoB, and OxPL-apo(a) are associated with incident cardiovascular events. (Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868).

Background and hypothesisThe recently introduced Bayesian quantile regression (BQR) machine-learning method enables comprehensive analyzing the relationship among complex clinical variables. We analyzed the relationship between multiple cardiovascular (CV) risk factors and different stages of coronary artery disease (CAD) using the BQR model in a vessel-specific manner.MethodsFrom the data of 1,463 patients obtained from the PARADIGM (NCT02803411) registry, we analyzed the lumen diameter stenosis (DS) of the three vessels: left anterior descending (LAD), left circumflex (LCx), and right coronary artery (RCA). Two models for predicting DS and DS changes were developed. Baseline CV risk factors, symptoms, and laboratory test results were used as the inputs. The conditional 10%, 25%, 50%, 75%, and 90% quantile functions of the maximum DS and DS change of the three vessels were estimated using the BQR model.ResultsThe 90th percentiles of the DS of the three vessels and their maximum DS change were 41%-50% and 5.6%-7.3%, respectively. Typical anginal symptoms were associated with the highest quantile (90%) of DS in the LAD; diabetes with higher quantiles (75% and 90%) of DS in the LCx; dyslipidemia with the highest quantile (90%) of DS in the RCA; and shortness of breath showed some association with the LCx and RCA. Interestingly, High-density lipoprotein cholesterol showed a dynamic association along DS change in the per-patient analysis.ConclusionsThis study demonstrates the clinical utility of the BQR model for evaluating the comprehensive relationship between risk factors and baseline-grade CAD and its progression.

Background Obesity, as measured by body mass index, is widely recognized as a risk factor for the development of cardiovascular disease. However, the role of body composition components such as fat and lean mass is not well studied. Methods and Results A total of 3129 patients who underwent computed tomography scans for quantification of coronary artery calcification and had bioelectrical impedance analysis of body composition (fat mass and fat-free mass) during exam 5 of MESA (Multi-Ethnic Study of Atherosclerosis) were included in this cross-sectional analysis. Multivariable adjusted linear regression analysis was performed to assess the relationship between both fat mass and fat-free mass to prevalent coronary artery calcification, a marker of subclinical coronary artery disease quantified by both the coronary artery calcification (CAC) Agatston score and the spatially weighted calcium score. CAC and spatially weighted calcium score were natural log-transformed for analysis as continuous variables. Fat-free mass, but not fat mass, was independently associated with CAC. There was a 7.6% prevalence risk difference for CAC>0 per 10 kg. Fat-free mass was also significantly associated with natural log of CAC (coefficient=0.272, P

BackgroundCytomegalovirus (CMV) infection is thought to result in increased immune activation in people with human immunodeficiency virus (HIV, PWH). Although some data have linked asymptomatic CMV infection to cardiovascular disease among PWH, it remains unknown whether CMV is associated with increased or high-risk coronary plaque.MethodsThe Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) enrolled PWH aged 40-75 years on stable antiretroviral therapy (ART) with low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk. Among a subset of US REPRIEVE participants, coronary plaque was assessed by coronary computed tomography angiography. Here, we assessed the relationship between CMV immunoglobulin G (IgG) titer and (1) levels of immune activation, (2) inflammatory biomarkers, and (3) coronary plaque phenotypes at study entry.ResultsOf 672 participants, mean age was 51 years, 83% were men, median ASCVD risk score was 4.5%, and 66% had current CD4+ T-cell count ≥500 cells/mm3. Higher CMV IgG quartile group was associated with older age and lower current and nadir CD4+ T-cell counts. CMV IgG titer was associated with specific inflammatory biomarkers (sCD163, MCP-1, interleukin [IL]-6, hsCRP) in univariate analysis, but not after controlling for HIV-specific factors. In contrast, CMV IgG titer was not associated with coronary artery disease indexes, including presence of plaque, coronary artery calcium (CAC) score >0, vulnerable plaque presence, or Leaman score >5.ConclusionsNo meaningful association was seen between CMV IgG titer and coronary artery disease indexes among ART-treated PWH at study enrollment. Longitudinal assessments in REPRIEVE will determine the relationship of CMV IgG titer to plaque progression and cardiovascular events.Clinical trials registrationNCT02344290.

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

BACKGROUND: Absence of a dicrotic notch on finger photoplethysmography is an easily ascertainable and inexpensive trait that has been associated with age and prevalent cardiovascular disease. However, the trait exists along a continuum, and little is known about its genetic underpinnings or prognostic value for incident cardiovascular disease. METHODS: In 169 787 participants in the UK Biobank, we identified absent dicrotic notch on photoplethysmography and created a novel continuous trait reflecting notch smoothness using machine learning. Next, we determined the heritability, genetic basis, polygenic risk, and clinical relations for the binary absent notch trait and the newly derived continuous notch smoothness trait. RESULTS: Heritability of the continuous notch smoothness trait was 7.5%, compared with 5.6% for the binary absent notch trait. A genome-wide association study of notch smoothness identified 15 significant loci, implicating genes including NT5C2 (P=1.2×10-26), IGFBP3 (P=4.8×10-18), and PHACTR1 (P=1.4×10-13), compared with 6 loci for the binary absent notch trait. Notch smoothness stratified risk of incident myocardial infarction or coronary artery disease, stroke, heart failure, and aortic stenosis. A polygenic risk score for notch smoothness was associated with incident cardiovascular disease and all-cause death in UK Biobank participants without available photoplethysmography data. CONCLUSIONS: We found that a machine learning derived continuous trait reflecting dicrotic notch smoothness on photoplethysmography was heritable and associated with genes involved in vascular stiffness. Greater notch smoothness was associated with greater risk of incident cardiovascular disease. Raw digital phenotyping may identify individuals at risk for disease via specific genetic pathways.