Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke.

BACKGROUND: Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied. METHODS: In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding - both assessed within 90 days. RESULTS: A total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel-aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel-aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P = 0.03). CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.).

Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke.

Clonal hematopoiesis (CH) is common among older people and is associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. Age and inflammation are major risk factors for ischemic stroke, yet the association of CH with risk of secondary vascular events and death is unknown. We investigated CH in peripheral blood DNA from 581 patients with first-ever ischemic stroke from the Prospective Cohort With Incident Stroke-Berlin study using error-corrected targeted sequencing. The primary composite end point (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. A total of 348 somatic mutations with a variant allele frequency ≥1% were identified in 236 of 581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = .01) and white matter lesion (P < .001). CH-positive patients showed increased levels of proinflammatory cytokines, such as interleukin-6 (IL-6), interferon gamma, high-sensitivity C-reactive protein, and vascular cell adhesion molecule 1. CH-positive patients had a higher risk for the primary CEP (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.04-2.31; P = .03), which was more pronounced in patients with larger clones. CH clone size remained an independent risk factor (HR, 1.30; 95% CI, 1.04-1.62; P = .022) in multivariable Cox regression. Although our data show that, in particular, larger and TET2- or PPM1D-mutated clones are associated with increased risk of recurrent vascular events and death, this risk is partially mitigated by a common germline variant of the IL-6 receptor (IL-6R p.D358A). The CH mutation profile is accompanied by a proinflammatory profile, opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

Socioeconomic Disparities and Mediators for Recurrent Atherosclerotic Cardiovascular Disease Events After a First Myocardial Infarction.

BACKGROUND: Low socioeconomic status is associated with worse secondary prevention use and prognosis after myocardial infarction (MI). Actions for health equity improvements warrant identification of risk mediators. Therefore, we assessed mediators of the association between socioeconomic status and first recurrent atherosclerotic cardiovascular disease event (rASCVD) after MI. METHODS: In this cohort study on 1-year survivors of first-ever MI with Swedish universal health coverage ages 18 to 76 years, individual-level data from SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) and linked national registries was collected from 2006 through 2020. Exposure was socioeconomic status by disposable income quintile (principal proxy), educational level, and marital status. The primary outcome was rASCVD and secondary outcomes were cardiovascular and all-cause mortality. We initially assessed the incremental attenuation of hazard ratios with 95% CIs in sequential multivariable models adding groups of potential mediators (ie, previous risk factors, acute presentation and infarct severity, initial therapies, and secondary prevention). Thereafter, the proportion of excess rASCVD associated with a low income mediated through nonparticipation in cardiac rehabilitation, suboptimal statin management, a cardiometabolic risk profile, persistent smoking, and blood pressure above target after MI were calculated using causal mediation analysis. RESULTS: Among 68 775 participants (73.8% men), 7064 rASCVD occurred during a mean 5.7-year follow-up. Income, adjusted for age, sex, and calendar year, was associated with rASCVD (hazard ratio, 1.63 [95% CI, 1.51-1.76] in the lowest versus highest income quintile). Risk attenuated most by adjustment for previous risk factors and by adding secondary prevention variables for a final model (hazard ratio, 1.38 [95% CI, 1.26-1.51]) in the lowest versus highest income quintile. The proportions of the excess 15-year rASCVD risk in the lowest income quintile mediated through nonparticipation in cardiac rehabilitation, cardiometabolic risk profile, persistent smoking, and poor blood pressure control were 3.3% (95% CI 2.1-4.8), 3.9% (95% CI, 2.9-5.5), 15.2% (95% 9.1-25.7), and 1.0% (95% CI 0.6-1.5), respectively. Risk mediation through optimal statin management was negligible. CONCLUSIONS: Nonparticipation in cardiac rehabilitation, a cardiometabolic risk profile, and persistent smoking mediate income-dependent prognosis after MI. In the absence of randomized trials, this causal inference approach may guide decisions to improve health equity.

Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Limited data exist on American College of Cardiology/American Heart Association valvular heart disease (VHD) stage prevalence, progression, and association with incident cardiovascular diseases in late life. METHODS: Participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective community-based cohort study, underwent protocol echocardiography at ARIC visits 5 (2011-2013) and 7 (2018-2019), and their aortic stenosis, aortic regurgitation, mitral stenosis, and mitral regurgitation stage were defined according to American College of Cardiology/American Heart Association guidelines. The overall VHD stage prevalence at visit 5 was measured. The associations between VHD stages and incident adjudicated death, heart failure, coronary heart disease, stroke, and atrial fibrillation were assessed with Cox proportional hazard models adjusted for age, sex, race, hypertension, diabetes, prior myocardial infarction, heart failure, body mass index, study center, systolic blood pressure, estimated glomerular filtration rate, and low-density lipoprotein at visit 5. Longitudinal changes in VHD stage prevalence over ≈6 years were estimated with inverse probability of attrition weights to account for participant attrition. RESULTS: Among 6118 ARIC participants, the mean±SD age was 76±5 years, 42% were male, and 22% reported Black race. Stage A VHD was present in 39%, stage B in 17%, and stage C/D in 1.1%;, 0.7% had previously undergone valve replacement or repair. A graded association was observed between stage A, B, and C/D VHD and risk of all-cause mortality, incident heart failure, incident atrial fibrillation, and incident coronary heart disease, but not incident stroke. Similar findings were observed for stages of each valvular lesion individually. During the 6.6 years (interquartile range, 6.1-7.0 years) between visits 5 and 7 (mean age, 81±4 years), the prevalence of freedom from VHD stage decreased from 43% to 24%, whereas the prevalence of stage C/D VHD increased from 1% to 7%. CONCLUSIONS: Subclinical VHD is common in older adults, with 39% at risk (stage A) and 17% with progressive VHD (stage B), and is independently associated with risk of incident cardiovascular events. VHD stages progress over 6 years in late life, with a several-fold increase in prevalence of severe VHD (stage C/D), highlighting the public health importance of interventions to mitigate VHD progression.

Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study.

BACKGROUND: The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects. METHODS: This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643 800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model. RESULTS: Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35-1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF. CONCLUSIONS: Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure.

Cardiovascular complications of rheumatoid arthritis.

PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients remain at higher cardiovascular (CV) risk compared to non-RA patients, driven by accelerated atherosclerosis, leading to plaque rupture and acute CV events (CVE), including heart failure (HF). It has been hypothesized that chronic inflammation is the main driving force behind such outcomes. We summarize the current evidence supporting this hypothesis, focusing on arterial disease and myocardial disease. RECENT FINDINGS: RA patients demonstrate higher prevalence of subclinical atherosclerosis (high risk plaque and arterial inflammation) compared to non-RA patients, with RA disease activity correlating independently with CVE and death. Nonischemic HF with preserved ejection fraction (HFpEF) is more common in RA compared to non-RA, with subclinical myocardial structural and functional alterations also more prevalent in RA. HFpEF and myocardial remodeling and dysfunction bear a strong and independent association with inflammatory correlates. SUMMARY: All of this suggests that inflammation contributes to enhanced risk of CVE in RA. A more accurate and specific CV risk stratification tool for RA, incorporating biomarkers or imaging, is needed. Likewise, more prospective studies outlining the trajectory from preclinical to clinical HF, incorporating biomarkers and imaging, are also needed.

High glucose levels accelerate atherosclerosis via NLRP3-IL/ MAPK/NF-κB-related inflammation pathways.

BACKGROUND: As a chronic inflammatory disease, diabetes mellitus (DM) contributes to the development of atherosclerosis (AS). However, how the NLRP3 inflammasome participates in diabetes-related AS remains unclear. Therefore, this study aimed to elucidate the mechanism through which NLRP3 uses high glucose (HG) levels to promote AS. METHODS: Serum and coronary artery tissues were collected from coronary artery disease (CAD) patients with and without DM, respectively. The expression of NLRP3 was detected, and the effects of this inflammasome on diabetes-associated AS were evaluated using streptozotocin (STZ)-induced diabetic apoE-/- mice injected with Adenovirus-mediated NLRP3 interference (Ad-NLRP3i). To elucidate the potential mechanism involved, ox-LDL-irritated human aortic smooth muscle cells were divided into the control, high-glucose, Si-NC, and Si-NLRP3 groups to observe the changes induced by downregulating NLRP3 expression. For up-regulating NLRP3, control and plasmid contained NLRP3 were used. TNF-α, IL-1ß, IL-6, IL-18, phosphorylated and total p38, JNK, p65, and IκBα expression levels were detected following the downregulation or upregulation of NLRP3 expression. RESULTS: Patients with comorbid CAD and DM showed higher serum levels and expression of NLRP3 in the coronary artery than those with only CAD. Moreover, mice in the Ad-NLRP3i group showed markedly smaller and more stable atherosclerotic lesions compared to those in other DM groups. These mice had decreased inflammatory cytokine production and improved glucose tolerance, which demonstrated the substantial effects of NLRP3 in the progression of diabetes-associated AS. Furthermore, using the siRNA or plasmid to downregulate or upregulate NLRP3 expression in vitro altered cytokines and the MAPK/NF-κB pathway. CONCLUSIONS: NLRP3 expression was significantly increased under hyperglycemia. Additionally, it accelerated AS by promoting inflammation via the IL/MAPK/NF-κB pathway.

Immune checkpoint inhibitors in cancer: the increased risk of atherosclerotic cardiovascular disease events and progression of coronary artery calcium.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have contributed to a significant advancement in the treatment of cancer, leading to improved clinical outcomes in many individuals with advanced disease. Both preclinical and clinical investigations have shown that ICIs are associated with atherosclerosis and other cardiovascular events; however, the exact mechanism underlying this relationship has not been clarified. METHODS: Patients diagnosed with stages III or IV non-small cell lung cancer (NSCLC) at the Wuhan Union Hospital from March 1, 2020, to April 30, 2022, were included in this retrospective study. Coronary artery calcium (CAC) volume and score were assessed in a subset of patients during non-ECG-gated chest CT scans at baseline and 3, 6, and 12 months after treatment. Propensity score matching (PSM) was performed in a 1:1 ratio to balance the baseline characteristics between the two groups. RESULTS: Overall, 1458 patients (487 with ICI therapy and 971 without ICI therapy) were enrolled in this cardiovascular cohort study. After PSM, 446 patients were included in each group. During the entire period of follow-up (median follow-up 23.1 months), 24 atherosclerotic cardiovascular disease (ASCVD) events (4.9%) occurred in the ICI group, and 14 ASCVD events (1.4%) in the non-ICI group, before PSM; 24 ASCVD events (5.4%) occurred in the ICI group and 5 ASCVD events (1.1%) in the non-ICI group after PSM. The CAC imaging study group comprised 113 patients with ICI therapy and 133 patients without ICI therapy. After PSM, each group consisted of 75 patients. In the ICI group, the CAC volume/score increased from 93.4 mm3/96.9 (baseline) to 125.1 mm3/132.8 (at 12 months). In the non-ICI group, the CAC volume/score was increased from 70.1 mm3/68.8 (baseline) to 84.4 mm3/87.9 (at 12 months). After PSM, the CAC volume/score was increased from 85.1 mm3/76.4 (baseline) to 111.8 mm3/121.1 (12 months) in the ICI group and was increased from 74.9 mm3/76.8 (baseline) to 109.3 mm3/98.7 (12 months) in the non-ICI group. Both cardiovascular events and CAC progression were increased after the initiation of ICIs. CONCLUSIONS: Treatment with ICIs was associated with a higher rate of ASCVD events and a noticeable increase in CAC progression.

Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics.

BACKGROUND: Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial. METHODS: Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m2 were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis). RESULTS: Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m2. Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing. CONCLUSION: SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit.

Vascular health years after a hypertensive disorder of pregnancy: The EPOCH study.

BACKGROUND: Preeclampsia is associated with a two-fold increase in a woman's lifetime risk of developing atherosclerotic cardiovascular disease (ASCVD), but the reasons for this association are uncertain. The objective of this study was to examine the associations between vascular health and a hypertensive disorder of pregnancy among women ≥ 2 years postpartum. METHODS: Pre-menopausal women with a history of either a hypertensive disorder of pregnancy (cases: preeclampsia or gestational hypertension) or a normotensive pregnancy (controls) were enrolled. Participants were assessed for standard ASCVD risk factors and underwent vascular testing, including measurements of blood pressure, endothelial function, and carotid artery ultrasound. The primary outcomes were blood pressure, ASCVD risk, reactive hyperemia index measured by EndoPAT and carotid intima-medial thickness. The secondary outcomes were augmentation index normalized to 75 beats per minute and pulse wave amplitude measured by EndoPAT, and carotid elastic modulus and carotid beta-stiffness measured by carotid ultrasound. RESULTS: Participants had a mean age of 40.7 years and were 5.7 years since their last pregnancy. In bivariate analyses, cases (N = 68) were more likely than controls (N = 71) to have hypertension (18% vs 4%, P = .034), higher calculated ASCVD risk (0.6 vs 0.4, P = .02), higher blood pressures (systolic: 118.5 vs 111.6 mm Hg, P = .0004; diastolic: 75.2 vs 69.8 mm Hg, P = .0004), and higher augmentation index values (7.7 vs 2.3, P = .03). They did not, however, differ significantly in carotid intima-media thickness (0.5 vs 0.5, P = .29) or reactive hyperemia index (2.1 vs 2.1, P = .93), nor in pulse wave amplitude (416 vs 326, P = .11), carotid elastic modulus (445 vs 426, P = .36), or carotid beta stiffness (2.8 vs 2.8, P = .86). CONCLUSION: Women with a prior hypertensive disorder of pregnancy had higher ASCVD risk and blood pressures several years postpartum, but did not have more endothelial dysfunction or subclinical atherosclerosis.

Atherosclerosis on CT coronary angiography and the risk of long-term cardiovascular events after liver transplantation.

Computed tomography coronary angiography (CTCA) is increasingly utilized for preoperative risk stratification before liver transplantation (LT). We sought to assess the predictors of advanced atherosclerosis on CTCA using the recently developed Coronary Artery Disease-Reporting and Data System (CAD-RADS) score and its impact on the prediction of long-term major adverse cardiovascular events (MACE) following LT. We conducted a retrospective cohort study of consecutive patients who underwent CTCA for LT work-up between 2011 and 2018. Advanced atherosclerosis was defined as coronary artery calcium scores > 400 or CAD-RADS score ≥ 3 (≥50% coronary artery stenosis). MACE was defined as myocardial infarction, heart failure, stroke, or resuscitated cardiac arrest. Overall, 229 patients underwent CTCA (mean age 66 ± 5 y, 82% male). Of these, 157 (68.5%) proceeded with LT. The leading etiology of cirrhosis was hepatitis (47%), and 53% of patients had diabetes before transplant. On adjusted analysis, male sex (OR 4.6, 95% CI 1.5-13.8, p = 0.006), diabetes (OR 2.2, 95% CI 1.2-4.2, p = 0.01) and dyslipidemia (OR 3.1, 95% CI 1.3-6.9, p = 0.005) were predictors of advanced atherosclerosis on CTCA. Thirty-two patients (20%) experienced MACE. At a median follow-up of 4 years, CAD-RADS ≥ 3, but not coronary artery calcium scores, was associated with a heightened risk of MACE (HR 5.8, 95% CI 1.6-20.6, p = 0.006). Based on CTCA results, 71 patients (31%) commenced statin therapy which was associated with a lower risk of all-cause mortality (HR 0.48, 95% CI 0.24-0.97, p = 0.04). The standardized CAD-RADS classification on CTCA predicted the occurrence of cardiovascular outcomes following LT, with a potential to increase the utilization of preventive cardiovascular therapies.

From Atherosclerosis to Spontaneous Coronary Artery Dissection: Defining a Clinical and Genetic Risk Spectrum for Myocardial Infarction.

PURPOSE OF REVIEW: Spontaneous coronary artery dissection (SCAD) has been increasingly recognized as a significant cause of acute myocardial infarction (AMI) in young and middle-aged women and arises through mechanisms independent of atherosclerosis. SCAD has a multifactorial etiology that includes environmental, individual, and genetic factors distinct from those typically associated with coronary artery disease. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD and highlight those factors which differentiate SCAD from atherosclerotic coronary artery disease. RECENT FINDINGS: Recent studies have revealed several associated variants with varying effect sizes for SCAD, giving rise to a complex genetic architecture. Associated genes highlight an important role for arterial cells and their extracellular matrix in the pathogenesis of SCAD, as well as notable genetic overlap between SCAD and other systemic arteriopathies such as fibromuscular dysplasia and vascular connective tissue diseases. Further investigation of individual variants (including in the associated gene PHACTR1) along with polygenic score analysis have demonstrated an inverse genetic relationship between SCAD and atherosclerosis as distinct causes of AMI. SCAD represents an increasingly recognized cause of AMI with opposing clinical and genetic risk factors from that of AMI due to atherosclerosis, and it is often associated with complex underlying genetic conditions. Genetic study of SCAD on a larger scale and with more diverse cohorts will not only further our evolving understanding of a newly defined genetic spectrum for AMI, but it will also inform the clinical utility of integrating genetic testing in AMI prevention and management moving forward.

Metabolic dysfunction-associated steatotic liver disease and atherosclerosis.

PURPOSE OF REVIEW: To update information about the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and atherosclerosis. This review emphasizes the potential mechanisms linking MASLD with atherosclerosis and the possible causal relationships between these conditions. RECENT FINDINGS: An increased risk of cardiovascular disease is related to MASLD. Several molecular, cellular, and metabolic mechanisms have been described to explain the development of atherothrombosis in MASLD patients. These include atherogenic dyslipidemia, low-grade vascular inflammation, endothelial dysfunction, foam cell formation, proliferation of vascular smooth muscle cells, insulin resistance, gut microbiota dysbiosis, activation of renin-angiotensin and sympathetic nervous systems, hypercoagulability, and decreased fibrinolysis. Also, there is recent evidence suggesting an association between genetically driven liver fat and coronary heart disease mediated by the causal effect of apoB-containing lipoproteins. Several meta-analyses and systematic reviews have reported a strong association between MASLD and cardiovascular outcomes. MASLD is an important and independent risk factor for atherosclerosis development. Multiple mechanisms may be involved in this association. Further research is required to establish a causal association between MASLD and atherosclerosis.

Targeting systemic inflammation in metabolic disorders. A therapeutic candidate for the prevention of cardiovascular diseases?

Cardiovascular disease (CVD) remains the leading cause of death and disability worldwide. While many factors can contribute to CVD, atherosclerosis is the cardinal underlying pathology, and its development is associated with several metabolic risk factors including dyslipidemia and obesity. Recent studies have definitively demonstrated a link between low-grade systemic inflammation and two relevant metabolic abnormalities: hypercholesterolemia and obesity. Interestingly, both metabolic disorders are also associated with endothelial dysfunction/activation, a proinflammatory and prothrombotic phenotype of the endothelium that involves leukocyte infiltration into the arterial wall, one of the earliest stages of atherogenesis. This article reviews the current literature on the intricate relationship between hypercholesterolemia and obesity and the associated systemic inflammation and endothelial dysfunction, and discusses the effectiveness of present, emerging and in-development pharmacological therapies used to treat these metabolic disorders with a focus on their effects on the associated systemic inflammatory state and cardiovascular risk.

Moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with metabolic syndrome and atherosclerotic cardiovascular disease: A post-hoc analysis of the RACING trial.

AIM: This study evaluated the safety and efficacy of a moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with metabolic syndrome (MetS) and atherosclerotic cardiovascular disease. MATERIALS AND METHODS: In this post-hoc subgroup analysis of the RACING trial, patients were analysed based on the presence of MetS. MetS was defined as meeting at least three of the five following criteria: (a) elevated waist circumference; (b) elevated triglycerides; (c) reduced high-density lipoprotein cholesterol; (d) elevated blood pressure; and (e) elevated fasting glucose. The primary outcome was a 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke. RESULTS: Of the 3780 patients enrolled in the RACING trial, 1703 (45.1%) had MetS at baseline. The primary outcome rate was 10.1% and 10.3% in patients with MetS receiving ezetimibe combination therapy versus high-intensity statin monotherapy (hazard ratio = 0.97; 95% confidence interval = 0.72-1.32; p = .868). Lower rates of intolerance-related drug discontinuation or dose reduction (3.9% vs. 8.0%; p < .001) and lower low-density lipoprotein cholesterol levels (57 vs. 65 mg/dl; p < .001) were observed with ezetimibe combination therapy versus high-intensity statin monotherapy. Furthermore, the rate of new-onset diabetes was 18.5% and 19.1% in each group (p = .822). There were no significant interactions between MetS and therapy regarding study outcomes in the total population. CONCLUSIONS: In patients with MetS and atherosclerotic cardiovascular disease, a moderate-intensity statin with ezetimibe combination therapy had comparable cardiovascular benefits with those of high-intensity statin monotherapy. Meanwhile, ezetimibe combination therapy was associated with lower drug intolerance and low-density lipoprotein cholesterol levels, but there was no apparent between-group difference in new-onset diabetes.

Angiography-based hemodynamic features predict recurrent ischemic events after angioplasty and stenting of intracranial vertebrobasilar atherosclerotic stenosis.

OBJECTIVES: To assess the predictive value of hemodynamic features for stroke relapse in patients with intracranial vertebrobasilar atherosclerotic stenosis treated with percutaneous transluminal angioplasty and stenting (PTAS) using quantitative digital subtraction angiography (q-DSA). METHODS: In this retrospective longitudinal study, patients with intracranial vertebrobasilar atherosclerotic stenosis and who underwent PTAS treatment between January 2012 and May 2020 were enrolled. The q-DSA assessment was performed before and after PTAS. ROIs 1-4 were placed along the vertebral artery, proximal and distal basilar artery, and posterior cerebral artery; ROIs 5-8 were in 5 mm and 10 mm proximal and distal to the lesion, respectively. Relative time to peak (rTTP) was defined as the difference in TTP between ROIs. Cox regression analyses were performed to determine risk factors for recurrent stroke. RESULTS: A total of 137 patients (mean age, 62 years ± 10 [standard deviation], 83.2% males) were included, and 26 (19.0%) patients had stroke relapse during follow-up (median time of 42.6 months [interquartile range, 19.7-60.7]). Preprocedural rTTP4-1 (adjusted hazard ratio (HR) = 2.270; 95% CI 1.371-3.758; p = 0.001) and preprocedural rTTP8-5 (adjusted HR = 0.240; 95% CI 0.088-0.658; p = 0.006) were independently associated with the recurrent stroke. These hemodynamic parameters provided an incremental prognostic value for stroke relapse (AUC, 0.817 [0.704-0.931]; the net reclassification index, 0.431 [0.057-0.625]; and the integrated discrimination index, 0.140 [0.035-0.292]). CONCLUSIONS: In patients with intracranial vertebrobasilar atherosclerosis treated with PTAS, preprocedural prolonged TTP of the target vessel and shortened trans-stenotic TTP difference were associated with stroke relapse. Q-DSA-defined hemodynamic parameters provided incremental predictive value over conventional parameters for stroke recurrence. CLINICAL RELEVANCE STATEMENT: Quantitative DSA analysis enables intuitive observation and semi-quantitative evaluation of peri-therapeutic cerebral blood flow. More importantly, quantitative DSA-defined hemodynamic parameters have the potential for risk stratification of patients with intracranial atherosclerotic stenosis. KEY POINTS: Semi-quantitative angiography-based parameters can reflect pre- and postprocedural subtle changes in blood flow in patients with intracranial atherosclerotic stenosis. Although angioplasty procedures can significantly improve blood flow status, patients with more restricted baseline blood flow still show a higher risk of stroke recurrence. Angiography-based hemodynamic features possess prognostic value and can serve as clinical markers to assess stroke risk of patients with intracranial atherosclerotic stenosis.

Association of Dental Infections with Intracranial Atherosclerotic Stenosis.

INTRODUCTION: Periodontal disease (PD) and dental caries are oral infections leading to tooth loss that are associated with atherosclerosis and cerebrovascular disease. We assessed the hypothesis that PD and caries are associated with asymptomatic intracranial atherosclerosis (ICAS) in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Full-mouth clinical periodontal measurements (7 indices) collected at 6 sites per tooth from 6,155 subjects from the Dental Atherosclerosis Risk in Communities Study (DARIC) without prior stroke were used to differentiate seven PD stages (Periodontal Profile Class [PPC]-I to -VII) and dental caries on coronal dental surface (DS) and dental root surface (DRS). A stratified subset underwent 3D time-of-flight MR angiogram and 3D high isotropic-resolution black blood MRI. ICAS was graded according to the criteria established by the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial. We evaluated the relationship between PD stage and dental caries with asymptomatic ICAS, graded as no ICAS, <50% ICAS, and ≥50% ICAS. RESULTS: Among dentate subjects who underwent vascular imaging, 801 (70%) had no ICAS, 232 (20%) had <50% ICAS, and 112 (10%) had ≥50% ICAS. Compared to participants without gum disease (PPC-I), participants with mild-moderate tooth loss (PPC-VI), severe tooth loss (PPC-VII), and severe PD (PPC-IV) had higher odds of having <50% ICAS. Participants with extensive gingivitis (PPC-V) had significantly higher odds of having ≥50% ICAS. This association remained significant after adjusting for confounding variables: age, gender, race, hypertension, diabetes, dyslipidemia, 3-level education, and smoking status. There was no association between dental caries (DS and DRS) and ICAS <50% and ≥50%. CONCLUSION: We report significant associations between mild-moderate tooth loss, severe tooth loss, and severe PD with <50% ICAS as well as an association between extensive gingivitis and ≥50% ICAS. We did not find an association between dental caries and ICAS.

Cardiovascular Disease and Thrombosis in HIV Infection.

HIV infection has transitioned from an acute, fatal disease to a chronic one managed by antiretroviral therapy. Thus, the aging population of people living with HIV (PLWH) continues to expand. HIV infection results in a dysregulated immune system, wherein CD4+ T cells are depleted, particularly in the gastrointestinal tract, disrupting the gut epithelial barrier. Long-term HIV infection is associated with chronic inflammation through potentially direct mechanisms caused by viral replication or exposure to viral proteins and indirect mechanisms resulting from increased translocation of microbial products from the intestine or exposure to antiretroviral therapy. Chronic inflammation (as marked by IL [interleukin]-6 and CRP [C-reactive protein]) in PLWH promotes endothelial cell dysfunction and atherosclerosis. PLWH show significantly increased rates of cardiovascular disease, such as myocardial infarction (risk ratio, 1.79 [95% CI, 1.54-2.08]) and stroke (risk ratio, 2.56 [95% CI, 1.43-4.61]). In addition, PLWH have increased levels of the coagulation biomarker D-dimer and have a two to ten-fold increased risk of venous thromboembolism compared with the general population. Several small clinical trials analyzed the effect of different antithrombotic agents on platelet activation, coagulation, inflammation, and immune cell activation. Although some markers for coagulation were reduced, most agents failed to reduce inflammatory markers in PLWH. More studies are needed to understand the underlying mechanisms driving inflammation in PLWH to create better therapies for lowering chronic inflammation in PLWH. Such therapies can potentially reduce atherosclerosis, cardiovascular disease, and thrombosis rates in PLWH and thus overall mortality in this population.

Maternal Inheritance of Familial Hypercholesterolemia Gene Mutation Predisposes to Coronary Atherosclerosis as Assessed by Calcium Score in Adulthood.

BACKGROUND: Animal studies have demonstrated that fetal exposure to high maternal cholesterol levels during pregnancy predisposes to aortic atheroma in the offspring. In humans, little is known about the consequences of this exposure on the development of atherosclerotic cardiovascular disease later in life. We wanted to assess whether maternal/paternal inheritance of familial hypercholesterolemia (FH) gene mutation could be associated with subclinical coronary atherosclerosis. METHODS: We retrospectively included 1350 patients, followed in the French registry of FH, with a documented genetic diagnosis. We selected 556 age- and sex-matched pair of patients based on the sex of the parents who transmitted the FH gene mutation, free of coronary cardiovascular event, and with a subclinical coronary atherosclerosis evaluation assessed using coronary artery calcium (CAC) score. We performed univariate and multivariate analysis to assess the individual effect of parental inheritance of the FH gene mutation on the CAC score. RESULTS: In the whole population, patients with maternal inheritance of FH gene mutation (n=639) less frequently had a family history of premature cardiovascular events (27.7% versus 45%, P<0.0001) and were 2 years older (46.9±16.8 versus 44.7±15.9 years old, P=0.02) than those with paternal inheritance (n=711). There was no difference in the prevalence of cardiovascular events between the two groups. In the matched subgroup, maternal inheritance was significantly associated with an increase in CAC score value by 86% (95% CI, 23%-170%; P=0.003), a 1.81-fold risk of having a CAC score ≥100 Agatston units (95% CI, 1.06-3.11; P=0.03), and a 2.72-fold risk of having a CAC score ≥400 Agatston units (95% CI, 1.39-5.51; P=0.004) when compared with paternal inheritance in multivariate analysis. CONCLUSIONS: Maternal inheritance of FH gene mutation was associated with more severe subclinical coronary atherosclerosis assessed by CAC score and may be considered as a potential cardiovascular risk factor.

Differential expression of Semaphorin-7A /CD163-positive macrophages in large artery and cardiogenic stroke.

BACKGROUND: Identification of the causes of stroke of undetermined etiology, specifically cardioembolism (CE) and non-CE causes, can inform treatment planning and prognosis prediction. The objective of this study was to analyze the disparities in thrombus composition, particularly Semaphorin-7A (Sema7A) and CD163, between patients diagnosed with large-artery atherosclerosis (LAA) and those with CE, and to investigate their potential association with prognosis. METHODS: Thrombi were collected from patients who underwent mechanical thrombectomy at two hospitals. The patients were categorized into two groups: LAA and CE. We compared the levels of Sema7A and CD163 between these groups and analyzed their relationships with stroke severity, hemorrhagic transformation and prognosis. RESULTS: The study involved a total of 67 patients. Sema7A expression was found to be significantly higher in the CE group compared to LAA (p < 0.001). Conversely, no statistically significant differences were observed for CD163 between the groups. The presence of Sema7A/CD163 did not show any associations with stroke severity or hemorrhagic transformation (all p > 0.05). However, both Sema7A (OR, 2.017; 95% CI, 1.301-3.518; p = 0.005) and CD163 (OR, 2.283; 95% CI, 1.252-5.724; p = 0.03) were associated with the poor prognosis for stroke, after adjusting for stroke severity. CONCLUSION: This study highlights that CE thrombi exhibited higher levels of Sema7A expression compared to LAA thrombi. Moreover, we found a positive correlation between Sema7A/CD163 levels and the poor prognosis of patients with acute ischemic stroke.