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Background The economic burden of nonvalvular atrial fibrillation (NVAF) is substantial. Many patients with NVAF are obese and manage other health conditions requiring multiple medications. This real‐world study compared health care resource use (HRU) and costs for rivaroxaban and warfarin in patients with NVAF who had polypharmacy and obesity. Methods and Results We used health care claims databases (Merative MarketScan commercial and Medicare supplemental claims) to identify patients initiating the direct oral anticoagulant rivaroxaban or warfarin with ≥1 diagnostic claim for atrial fibrillation, presence of polypharmacy (based on 3 categories for the number of concurrent medications: 1–4, 5–9, ≥10), and obesity. Cohorts were balanced for demographic and baseline characteristics using propensity score matching. All‐cause and NVAF‐related HRU rates and costs were compared between treatments using rate ratios and adjusted mean differences per patient per year. Eligible patients totaled 95 875, with 19 990 patients in each treatment cohort following propensity score matching. All‐cause HRU rates were significantly lower with rivaroxaban versus warfarin, and hospital stays were reduced by 3.1 days with rivaroxaban. Mean (95% CI) all‐cause total medical and total health care costs per patient per year were significantly reduced with rivaroxaban versus warfarin (−$4499 [−$5660 to −$3305] and –$1627 [−$2790 to −$438], respectively). NVAF‐related HRU was reduced with rivaroxaban versus warfarin, but total NVAF‐related medical costs were not significantly different between treatment groups ($144 [−$756 to $1079] per patient per year). Subgroup and sensitivity analysis results were generally consistent with the main analysis. Conclusions Among patients with NVAF, polypharmacy, and obesity, rivaroxaban was associated with a reduction in HRU and all‐cause costs compared with warfarin.

Background Valvular heart disease (VHD) is a major focus of cardiovascular medicine, but limited data are available for racial and ethnic minorities. The aim was to assess the burden and clinical correlates of VHD in a highly diverse area of the United States. Methods and Results Individuals with echocardiographic diagnosis of native VHD between January 2010 and December 2019 at a quaternary care health system of the Bronx (New York, USA) were included. Prevalence and correlates of VHD were assessed per each racial and ethnic group. From a total of 330 570 adult echocardiograms, 80 584 individuals were diagnosed with VHD and included in the final study population. Stratified by race and ethnicity, 38.0%, 23.2%, 2.1%, and 36.7% were non‐Hispanic Black, non‐Hispanic White, Asian, and Hispanic, respectively. The mean age was 67.7±16.3 years, with non‐Hispanic Black, non‐Hispanic Asian, and Hispanic individuals being younger and having a higher burden of comorbidities. The prevalence of VHD increased with age, irrespective of race or ethnicity. In people aged ≥75 years, tricuspid and mitral regurgitation were the most prevalent VHD (21.1% and 16.1%, respectively). Non‐Hispanic White individuals more frequently had tricuspid regurgitation, mitral regurgitation, and multiple VHDs, but among those aged

Background The effect of worsening renal function and baseline chronic kidney disease (CKD) on outcomes in patients with chronic coronary syndrome in the setting of optimal medical therapy remains unknown. Methods and Results The REAL‐CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy With Pitavastatin in Coronary Artery Disease) study is a prospective, multicenter, randomized trial of high‐dose (pitavastatin 4 mg/day) or low‐dose (pitavastatin 1 mg/day) statin therapy in 12 118 patients with chronic coronary syndrome. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, or unstable angina requiring hospitalization (major adverse cardiac and cerebral events [MACCE]). CKD was defined as an estimated glomerular filtration rate [eGFR]

Background Meta‐analyses have suggested that the risk of cardiovascular disease events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation, but the populations at highest risk have not been well characterized to date. Methods and Results The authors analyzed the risk of atherosclerotic cardiovascular disease (ASCVD) hospitalizations after COPD hospitalization compared with before COPD hospitalization and patient factors associated with ASCVD hospitalizations after COPD hospitalization among 2 high‐risk patient cohorts. The primary outcome was risk of an ASCVD hospitalization composite outcome (myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, stroke, transient ischemic accident) after COPD hospitalization relative to before COPD hospitalization. Additional analyses evaluated for risk factors associated with the composite ASCVD hospitalization outcome. In the high‐risk primary prevention cohort, the hazard ratio (HR) estimate following adjustment for the composite ASCVD hospitalization outcome after COPD hospitalization versus before COPD hospitalization for 30 days was 0.74 (95% CI, 0.66–0.82; P≤0.0001); for 90 days, 0.69 (95% CI, 0.64–0.75; P≤0.0001); and for 1 year, 0.78 (95% CI, 0.73–0.82; P≤0.0001). In the secondary prevention cohort, the HR for 30‐day hospitalization was 1.15 (95% CI, 1.05–1.26; P=0.0036); 90‐day hospitalization, 1.08 (95% CI, 1.01–1.15; P=0.0178); and 1‐year hospitalization, 1.07 (95% CI, 1.02–1.11; P=0.0026). Among the 19 characteristics evaluated, hyperlipidemia and history of acute ASCVD event were associated with the highest risk of ASCVD events 1 year after COPD hospitalization in the high‐risk primary and secondary prevention cohorts. Conclusions The risk of ASCVD hospitalization was higher in patients with established ASCVD and lower among high‐risk patients without established ASCVD after‐COPD hospitalization relative to before hospitalization. We identified multiple risk factors for ASCVD hospitalization after COPD hospitalization.

Background Transport by mobile stroke units (MSUs), which provide access to computed tomography scanning and intravenous blood pressure medications and thrombolytics, reduces time to treatment and may improve short‐term functional outcomes for patients with acute stroke. The longer‐term clinical and financial impacts remain incompletely understood. The aim of the study was to determine whether MSU care is associated with better health, utilization, and spending outcomes for patients with suspected acute stroke. Methods and Results This was a retrospective, observational study of Medicare patients transported by MSUs versus traditional ambulances in New York City, from October 2016 to December 2019. The study included 167 Medicare patients with suspected acute stroke transported by MSU and 2518 propensity score–matched controls. Primary outcomes included length of stay and discharge destination at the index hospitalization, as well as risk of repeat hospitalization, number of emergency department visits, total costs of care, and death at 1 year. Of 167 patients (mean age, 79.9 years; 56.3% women) transported by an MSU for suspected acute stroke, 61.1% had an ischemic stroke/transient ischemic attack, 7.8% had an intracerebral hemorrhage, and 31.1% had a stroke mimic or other diagnosis. Compared with propensity score–matched control patients, MSU patients were significantly more likely to receive tissue‐type plasminogen activator (49.9% versus 9.4%; difference, 37.5 percentage points [95% CI, 30.2–45.6]; P

Background The coexistence of transthyretin cardiac amyloidosis (ATTR‐CA) and aortic stenosis (AS) is increasingly recognized, but the clinical consequences are unclear. We aimed to characterize clinical outcomes in AS plus ATTR‐CA compared with only AS or ATTR‐CA. Methods and Results In a retrospective cohort study, patients with AS only, ATTR‐CA only, or AS plus ATTR‐CA were identified using all‐payer claims data (2015–2021). Eligible patients had ≥1 claim for AS or cardiac amyloidosis (excluding light‐chain cardiac amyloidosis); were aged ≥60 years; and were continuously enrolled in medical plans for ≥6 months after diagnosis. Ad hoc subanalyses were conducted in patients with aortic valve replacement at first diagnosis (surrogate for severe AS). Of 355 430 eligible patients, 345 771 (97.3%), 8453 (2.4%), and 1239 (0.3%) were included in the AS‐only, ATTR‐CA–only, and AS–plus–ATTR‐CA cohorts, respectively; 41 312 (11.9%), 14 (0.2%), and 212 (17.1%) had aortic valve replacement. Two‐year mortality rates were 16.1% (95% CI, 15.9–16.2), 14.8% (95% CI, 13.9–15.7), and 19.2% (95% CI, 16.9–21.8) in the AS‐only, ATTR‐CA–only, and AS–plus–ATTR‐CA cohorts; heart failure hospitalization rates were 29.4% (95% CI, 29.2–29.5), 22.8% (95% CI, 21.9–23.8), and 48.7% (95% CI, 45.7–51.7). AS plus ATTR‐CA was associated with increased risk of death (HR, 1.3 [95% CI, 1.1–1.4]; P

Background Prostaglandin E2 (PGE2) in the rostral ventrolateral medulla (RVLM) has been recognized as a pivotal pressor substance in hypertension, yet understanding of its effects and origins in the RVLM remains largely elusive. This study aimed to elucidate the pivotal enzymes and molecular mechanisms underlying PGE2 synthesis induced by central Ang II (angiotensin II) and its implications in the heightened oxidative stress and sympathetic outflow in hypertension. Methods and Results RVLM microinjections of PGE2 and Tempol were administered in Wistar‐Kyoto rats. Intracisternal drug delivery and adeno‐associated viral vectors microinjection were used in both Wistar‐Kyoto rats and spontaneous hypertensive rats to modulate the function of Ang II, PGE2 receptor 3, and expression of COX2 (cyclooxygenase 2). Microinjection of PGE2 into the RVLM significantly augmented sympathetic activity (25.380±1.566%) and oxidative stress level, whereas intracisternal infusion of a prostaglandin E receptor 3 antagonist attenuated sympathetic activity in both spontaneous hypertensive rats and Ang II‐induced hypertensive rats. Furthermore, Ang II treatment upregulated COX2 expression in RVLM neurons (1.000±0.112 versus 1.506±0.370 fold change), with no significant effect on other enzymes involved in PGE2 synthesis. Additionally, inhibition of the JAK2/STAT3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathway nullified Ang II‐mediated elevation of COX2 expression, as evidenced by phosphorylated STAT3 binding to the COX2 sequence in PC12 cells. Conclusions Central Ang II induces the accumulation of RVLM PGE2 through the neuronal AT1R (angiotensin type 1 receptor)/JAK2/STAT3/COX2 pathway, thereby promoting oxidative stress, augmenting sympathetic outflow, and contributing to essential hypertension.

Background A coronary function test (CFT) is the recommended diagnostic test to identify coronary vasomotor dysfunction as a cause of symptoms in patients with angina and nonobstructive coronary arteries (ANOCA). Acetylcholine is the commonly used pharmacological agent for spasm provocation. We aimed to investigate an association between severity of symptoms and provocative acetylcholine dose. Methods and Results We included ANOCA patients undergoing clinically indicated CFT from the Netherlands Registry of Invasive Coronary Vasomotor Function Testing: NL‐CFT. Patients with epicardial spasm (n=251) were divided according to acetylcholine spasm triggering dose: low (2–20 mcg, EpiLOW), middle (100 mcg, EpiMIDDLE) or high (200 mcg, EpiHIGH). Patients with microvascular spasm (n=157) were analyzed irrespective of triggering dose. The patient groups were compared to each other and to a control group with negative CFT results (n=101). We assessed mean Seattle Angina Questionnaire angina frequency and summary scores at baseline and follow‐up and the proportion of patients improving or deteriorating. An inverse relationship between provocation dosage and angina frequency at baseline was found in epicardial spasm: the lower the triggering dose, the more frequently patients experienced angina (EpiLOW 48±20, EpiMIDDLE 53±21, EpiHIGH 57±19, microvascular spasm 61±21, controls 64±21, overall P=0.003). A trend was seen toward most patients improving in the high triggering dose group, and most patients deteriorating in the low triggering dose group. Conclusions A significant dose‐dependent relationship between spasm provocation and anginal complaints exists. Acetylcholine provocation dose could be incorporated as a risk stratification factor or surrogate outcome in future clinical trials. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT06083155.

Background Intracranial atherosclerotic stenosis is a leading cause of ischemic stroke and recurrent events due to plaque instability. High‐resolution magnetic resonance imaging identifies plaque enhancement as a key marker of instability. This study evaluated the efficacy of combined high‐intensity statins and proprotein convertase subtilisin/kexin type 9 inhibitors in plaque stabilization. Methods In this prospective, single‐arm study, patients with acute stroke and intracranial atherosclerotic stroke in the M1 segment of the middle cerebral artery or basilar artery were enrolled. After 24 weeks of intensive statin and evolocumab therapy, high‐resolution magnetic resonance imaging assessments of intracranial vessels were conducted at baseline and follow‐up. The primary end point was the change in stenosis degree; secondary end points included changes in plaque enhancement (contrast ratio) and plaque burden. Results Thirty‐six patients (median age, 58 years) participated. After therapy, stenosis decreased from 75.9% (interquartile range, 69.5%–84.8%) to 65.3% (interquartile range, 53.8%–75.0%; P

Background Carotid endarterectomy (CEA) is widely used to treat carotid artery stenosis (CAS). However, the effects of CEA on unilateral CAS‐induced cognitive impairment and the underlying mechanism remain poorly understood. Methods and Results Thirteen patients diagnosed with unilateral severe CAS underwent pre‐ and post‐CEA assessments, including 18fluoro‐2‐deoxy‐d‐glucose positron emission tomography/magnetic resonance imaging, cognitive assessments, and routine blood tests before and after CEA. Unilateral carotid common artery occlusion and ligation release (reperfusion) surgeries were performed in mice to mimic CAS and CEA. Cognitive function, cerebral blood flow, and white matter damage were evaluated in mice using the Morris water maze test, Doppler flowmetry, laser‐speckle imaging, diffusion tensor imaging, Luxol fast blue staining, transmission electron microscopy, and western blot assays post unilateral carotid common artery occlusion and reperfusion. Genomic sequencing of the white matter was performed to explore the potential underlying mechanism. CEA significantly enhanced the Montreal Cognitive Assessment scores in patients with CAS and preoperative cognitive impairment. Moreover, CEA led to notable improvements in cerebral blood flow, energy metabolism, and white matter integrity, while concurrently reducing blood inflammation. In the mouse model, reperfusion surgery alleviated cognitive deficits, increased cerebral blood flow, and alleviated white matter damage following unilateral carotid common artery occlusion. Furthermore, transcriptional surveys have revealed substantial alterations in the upregulation of Nrf2 signaling and metabolic pathways, coupled with the inhibition of neuroinflammation, cellular communication, and immune cell population signaling following reperfusion. Conclusions CEA ameliorated CAS‐induced cognitive dysfunction by improving the cerebral functional structure. These beneficial effects may be attributed to their antioxidant and anti‐inflammatory properties.

Background Preprocedural fasting is widely used before percutaneous coronary intervention (PCI). However, the incidence of procedural intubation during PCI is unknown. This study aims to identify the incidence and predictors for procedural intubation during PCI. Methods and Results A retrospective cohort study was performed on patients undergoing PCI between 2014 and 2021 within the Victorian Cardiac Outcomes Registry. Patients were classified into urgent, semiurgent, or elective PCI on the basis of recorded PCI indication. Those undergoing semiurgent or elective PCI were presumed to be fasted preprocedurally. The incidence of procedural intubation was reported for each PCI group. Inverse probability treatment weighting was used to determine the association between 30‐day death and procedural intubation. Logistic regression was performed to determine clinical, procedural, and lesion characteristics associated with procedural intubation among fasted patients. Among 83 929 patients, the incidence of procedural intubation was 0.5%. Patients undergoing urgent PCI (odds ratio [OR], 19.68 [95% CI, 13.91–27.86]; P

Background Heart failure with preserved ejection fraction (HFpEF) is linked to prolonged endoplasmic reticulum (ER) stress. P21‐activated kinase 2 (Pak2) facilitates a protective ER stress response. This study explores the mechanism and role of Pak2 in HFpEF pathology. Methods and Results The HFpEF mouse model was established using a high‐fat diet combined with the nitric oxide synthase inhibitor Nω‐Nitro‐l‐arginine methyl ester (high‐fat diet+Nω‐Nitro‐l‐arginine methyl ester). The model exhibited the typical characteristics of HFpEF (cardiac hypertrophy, diastolic dysfunction with preserved systolic function, and lung edema) as determined by echocardiography and hemodynamic analysis. Terminal deoxynucleotidyl transferase dUTP nick end labeling and dihydroethidium staining results showed that cell death and reactive oxygen species generation were higher in the high‐fat diet+Nω‐Nitro‐l‐arginine methyl ester–treated group. Transmission electron microscopy revealed disruption of the ER subcellular structures in the HFpEF mouse model, while western blot analysis confirmed reduced Pak2 phosphorylation and impaired inositol‐requiring enzyme 1/X‐box binding protein 1 splicing ER stress response signaling. Furthermore, H9c2 cells subjected to the palmitic acid–mediated metabolic stress developed temporal changes in unfolded protein response proteins and Pak2 activity. The inositol requiring enzyme 1/X‐box binding protein 1 splicing branch of unfolded protein response was impaired earlier than other branches. Overexpression of Pak2 by adenovirus in H9c2 cells sustained the activation of inositol requiring enzyme 1/X‐box binding protein 1 splicing. Pak2 deficiency in the mouse heart accelerated the HFpEF progression, and this phenomenon occurred as early as 10 weeks in Pak2 cardiomyocyte‐specific knockout mice. Conversely, adeno‐associated virus serotype 9–mediated Pak2 overexpression mitigated HFpEF symptoms, underscoring its protective role against HFpEF progression. Conclusions Pak2 prevents HFpEF progression, exerting cardioprotective effects against ER stress. These insights underscore the therapeutic value of Pak2 in HFpEF.

Background Disopyramide is used to treat heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM) with known medium‐term efficacy and safety, while long‐term outcomes are unknown. Methods and Results A total of 92 consecutive patients with symptomatic obstructive HCM with peak left ventricular outflow tract gradients of ≥30 mm Hg at rest or with provocation who were maintained on disopyramide for ≥5 years at 2 dedicated HCM centers were included: 92 patients; mean age, 62.5 years; 54% women; treated with disopyramide for median 7.2 years (left ventricular wall thickness 18±4 mm; median peak outflow gradient 95 mm Hg). At last follow‐up, 62 (67%) patients continued disopyramide, including 57 with symptom improvement ≥1 New York Heart Association class. The other 30 (33%) patients discontinued disopyramide due primarily to incomplete symptom resolution and required surgical myectomy or alcohol septal ablation (n=23) at 7.4 years from initiation. With disopyramide, resting left ventricular outflow gradients were reduced by 37% (to median 19 mm Hg), and provoked gradients decreased by 57% (to median 41 mm Hg), with no residual outflow obstruction (5 years.

Background This study examined the longitudinal associations of psychosocial stress subgroups with cardiovascular disease (CVD) events and whether social support, neighborhood cohesion, and physical activity modified these associations in MESA (Multi‐Ethnic Study of Atherosclerosis). Methods and Results Data from 6349 adults (aged: 62.2 ± 10.2 years; 52.9% women) from the MESA study with no prior CVD in 2000 to 2002 (baseline) were used in this analysis. Latent class analysis was used to specify distinct psychosocial stress subgroups based on self‐reported stressors stemming from respondents' neighborhood and social environment. Adjudicated CVD events (fatal and nonfatal events) were ascertained annually through the year 2019. Cox proportional hazards models were used to examine the associations between subgroup membership and CVD events. Five distinct psychosocial stress subgroups were identified via latent class analysis and were labeled “moderate neighborhood noise” (12.1%), “excessive neighborhood noise” (6.4%), “multiple high stressors” (6.3%), “high discrimination” (21.4%), and “optimal” (53.8%). By 2019, 1121 participants had experienced a CVD event. Membership in the high discrimination (hazard ratio [HR], 1.29 [95% CI, 1.10–1.51]) subgroup was associated with higher risk of a CVD event when adjusted for sociodemographic characteristics and cardiovascular health metrics. Neither social support, neighborhood cohesion, nor physical activity modified this association (P>0.05). Conclusions Distinct subgroups of individuals with high self‐reported psychological distress—particularly related to discrimination and chronic stress are associated with high incident cardiovascular events.

Background Sex inequality in randomized controlled trials (RCTs) related to cardiovascular disease has been observed. This study examined the proportion of women enrolled in atrial fibrillation (AF) ablation RCTs and the potential risks of underrepresentation of women. Methods and Results We systematically searched PubMed and Embase for AF ablation RCTs published from 2015 to 2022. Participant characteristics were compared among trials with higher and lower proportions of women. Of 147 AF ablation RCTs (30,055 participants), only 10 trials had enrolled women ≥50% of the total participants. Additionally, 42 trials (28.57%) excluded pregnant/breastfeeding women; 6 (4.1%) excluded reproductive‐age women without reliable birth control. The proportion of women in AF RCTs ranged from 9% to 71% (median 31.5%), whereas the median proportion of men was 67.7%. The rate of women included in the trials was stable from 2015 to 2022 (P=0.49). Study characteristics, including funding source, showed no correlation with the rate of inclusion of women. RCTs with a higher proportion of female participants enrolled older patients with AF, had a higher prevalence of hypertension but less persistent AF, and smaller left atrium size (P

Background The study investigates the prognostic impact of sex and sex‐related differences in patients hospitalized with heart failure with mildly reduced ejection fraction (HFmrEF). More data regarding the characterization of patients and their outcomes in the presence of HFmrEF are needed. Methods and Results Consecutive patients hospitalized with HFmrEF (ie, left ventricular ejection fraction 41%–49% and signs or symptoms of HF) were retrospectively included at one institution from 2016 to 2022. Female patients were compared with male patients with regard to the primary end point of all‐cause mortality at 30 months (median follow‐up). Statistical analyses comprised Kaplan–Meier, multivariable Cox proportional regression analyses and propensity score matching. From a total of 2184 patients hospitalized with HFmrEF, 64.6% were male. Female patients with HFmrEF were older than male patients (median age 78 versus 73 years; P=0.001) and had lower rates of ischemic cardiomyopathy (46.6% versus 63.6%; P=0.001). Within the entire study cohort, sex was not associated with the risk of all‐cause mortality (hazard ratio [HR], 0.931 [95% CI, 0.797–1.088]; P=0.372). However, male sex was associated with a lower risk of HF‐related rehospitalization at 30 months (HR, 0.761 [95% CI, 0.600–0.966]; P=0.026), which was confirmed after multivariable adjustment (HR, 0.759 [95% CI, 0.592–0.973]; P=0.029) and propensity score matching (HR, 0.722 [95% CI, 0.539–0.967]; P=0.029). Conclusion Although almost two thirds of patients hospitalized with HFmrEF were male, sex was no predictor for the risk of all‐cause mortality at 30 months. However, female sex was associated with a higher risk of HF‐related rehospitalization. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT05603390.

Background Elevated low‐density lipoprotein cholesterol is a risk factor for atherosclerotic cardiovascular disease, including acute ischemic stroke (AIS), due to large‐ and small‐vessel disease. Cholesterol management guidelines recommend lipid‐lowering therapy (LLT) to prevent atherosclerotic cardiovascular disease events. This study assessed use of LLT at the time of AIS according to guideline recommendations and determined the association of prestroke LLT use with stroke severity. Methods and Results We conducted a retrospective study of patients hospitalized with AIS from 2015 to 2020 at a large academic comprehensive stroke center. Patients with AIS secondary to either small‐vessel disease or large‐artery atherosclerosis recorded in the institutional Get With The Guidelines‐Stroke registry and with a prestroke indication for LLT were included. Using propensity score subclassification, adjusted logistic regression models were built to explore the associations between LLT use before AIS when indicated and presenting National Institutes of Health Stroke Scale score >4. There were 384 patients with AIS who met guideline‐recommended criteria for prestroke LLT (median age 70 years, 57% men), of whom only 207 patients (54%) were prescribed LLT before AIS. Not being prescribed LLT when indicated was associated with a significantly higher likelihood of a presenting with National Institutes of Health Stroke Scale score >4, even when adjusted for specific stroke cause (odds ratio, 1.13 [95% CI, 1.03–1.20]; P=0.006). Conclusions LLT is underused in patients who present with atherosclerosis‐related AIS. Lack of prestroke LLT use was associated with more severe stroke symptoms upon presentation. These findings emphasize the need to prescribe LLT when indicated, because its use may mitigate poststroke disability.

Background Data on the predictive value of coronary computed tomography angiography–derived fractional flow reserve (CT‐FFR) for long‐term outcomes are limited. Methods and Results A retrospective pooled analysis of individual patient data was performed. Deep‐learning‐based CT‐FFR was calculated. All patients enrolled were followed‐up for at least 5 years. The primary outcome was major adverse cardiovascular events. The secondary outcome was death or nonfatal myocardial infarction. Predictive abilities for outcomes were compared among 3 models (model 1, constructed using clinical variables; model 2, model 1+coronary computed tomography angiography–derived anatomical parameters; and model 3, model 2+CT‐FFR). A total of 2566 patients (median age, 60 [53–65] years; 56.0% men) with coronary artery disease were included. During a median follow‐up time of 2197 (2127–2386) days, 237 patients (9.2%) experienced major adverse cardiovascular events. In multivariable‐adjusted Cox models, CT‐FFR≤0.80 (hazard ratio [HR], 5.05 [95% CI, 3.64–7.01]; P

Background Cardiovascular autonomic neuropathy (CAN) is a severe complication of type 2 diabetes. Significant sex‐related differences have been observed in type 2 diabetes consequences such as mortality. However, the effect of sex on the association between CAN and mortality in patients with type 2 diabetes is currently unknown. Methods and Results We assessed 7866 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, including 4730 men and 3136 women. CAN was diagnosed using a combination of heart rate variability and QT interval index, which has 3 different definitions. There were 1364 cases of all‐cause mortality and 452 cases of cardiovascular disease mortality during a median follow‐up of 9.7 years. We used multivariable Cox regression models to assess the association between different CAN definitions and mortality. In women, various CAN measures were statistically significant associated with an increased risk of all‐cause mortality (CAN1: hazard ratio [HR], 1.64 [95% CI, 1.28–2.09]; CAN2: HR, 1.58 [95% CI, 1.17–2.15]; CAN3: HR, 1.78 [95% CI, 1.20–2.65]) and mortality (CAN1: HR, 2.25 [95% CI, 1.44–3.52]; CAN 2: HR, 2.22 [95% CI, 1.28–3.87]; CAN3: HR, 3.31 [95% CI, 1.67–6.57]). CAN was not significantly associated with mortality in men. A significant multiplicative interaction of CAN and sex was observed on both mortality outcomes (P

Background Significant tricuspid regurgitation (TR) is associated with increased morbidity and mortality. The development of transcatheter valve repair therapies has opened a wide range of opportunities for treatment of patients with high surgical risk. Real‐world data might improve patient selection and outcome. The authors sought to investigate acute and short‐term cardiovascular outcomes of tricuspid transcatheter edge‐to‐edge repair (T‐TEER) with dedicated devices in a real‐world setting. Methods and Results This is a retrospective, single‐arm, multicenter registry conducted at 15 sites in Spain. The primary end point was a composite of all‐cause death, rehospitalization for heart failure, and tricuspid valve re‐intervention. Patients included (n=283) were older (76±9 years, 70% female), and showed significant comorbidities. Massive or torrential TR was present in 55% of subjects, with secondary cause being the main mechanism of regurgitation in ≈80% of individuals. Intraprocedural success was achieved in 79% of patients. At 1‐year follow‐up, significant improvements in TR grade (≥3+, 100% to 25%, P

Background Hypertension control and related cardiovascular outcomes among Americans remain suboptimal, and differ by race, ethnicity, and geography. Healthcare access is one of multiple critical factors in hypertension control. Understanding the degree to which healthcare access, versus other factors, produce these outcomes can inform policies and interventions to improve cardiovascular outcomes and reduce disparities. Department of Veterans Affairs Healthcare System data provide a unique opportunity to understand residual racial and ethnic differences in hypertension control after accounting for healthcare access. Our objective was to describe pre‐pandemic post‐Affordable Care Act implementation hypertension control by geographic sector and race and ethnicity, and assess spatial clustering of hypertension control. Methods and Results A secondary data analysis of hypertension control among US veterans (n=1 619 414) nationwide and in 4 US territories was conducted using electronic health record data. Age‐ and sex‐adjusted regression models estimated overall and race‐ and ethnicity‐specific rates by geographic sector. We created choropleth maps of hypertension control rates and assessed spatial autocorrelation. Hypertension control rates varied across sectors by race and ethnicity (range, 44.1%–97.5%); Black veterans, followed by American Indian or Alaska Native veterans, had the lowest mean control rates (72.5% and 75.4%, respectively). There was clustering of low hypertension control rates for Black veterans in the Pacific Northwest, Southwest, Missouri, Kansas, and Arkansas, and for American Indian or Alaska Native veterans in the West and Southwest. Conclusions Hypertension control rates varied geographically for veteran groups experiencing racial and ethnic disparities. Geographic areas with concentrations of low rates of hypertension control should be a focus for interventions to address racial and ethnic disparities.

Background The use of mechanical circulatory support devices for high‐risk percutaneous coronary intervention (PCI) has increased over the past decade despite limited data of benefit. We sought to examine the association between intravascular microaxial left ventricular assist device (LVAD) versus intra‐aortic balloon pump use in patients without cardiogenic shock (CS) undergoing PCI. Methods and Results This retrospective study analyzed claims data from a large, insured population who underwent PCI without CS from April 1, 2016 to July 31, 2022. Using inverse probability treatment weighting, we assessed for the association between device type and clinical outcomes. The primary outcome was all‐cause mortality. Secondary outcomes included stroke, bleeding, incident dialysis, repeat revascularization, and total health care costs during the index admission and at 30 days. We identified 2879 patients without CS who underwent PCI with either an intra‐aortic balloon pump or microaxial LVAD. The mean±SD age was 68.2±12.5 years, and 27% (n=764) were women. After propensity weighting, intravascular LVAD use was not associated with a significant difference in either in‐hospital (odds ratio [OR] 1.30 [95% CI, 0.88–1.91]; P=0.19) or 30‐day mortality (OR, 1.19 [95% CI, 0.84–1.69]; P=0.33) compared with intra‐aortic balloon pump use. Compared with those receiving an intra‐aortic balloon pump, the mean total costs for the index admission ($96 716 versus $71 892; P0.05). Conclusions In patients without CS undergoing PCI, intravascular LVAD use was associated with higher costs but not associated with lower mortality. Randomized data are needed to improve device selection for patients without CS undergoing PCI.

Background Use of pulmonary vein isolation (PVI) to treat atrial fibrillation continues to increase. Despite great interest in leveraging administrative data for real‐world analyses, contemporary procedural codes for identifying PVI have not been evaluated. Methods and Results In this observational retrospective cohort study, inpatient PVIs were identified among US Medicare fee‐for‐service beneficiaries using Current Procedural Terminology (CPT) code 93656 in Carrier Line Files. Each patient was matched with their claims from Medicare Provider Analysis and Review to compare CPT with International Classification of Diseases, Tenth Revision, Procedure Coding System (ICD‐10‐PCS) claims submitted by health care facilities to bill for PVIs. We performed the reverse for commonly matched ICD‐10‐PCS codes, to identify corresponding CPT‐billed procedures. Finally, we reviewed institutional cases for additional comparison of CPT and ICD‐10‐PCS assignation for PVI. We identified 25 617 inpatient PVIs from January 2017 to December 2021, of which 18 165 (71%) were linked to Medicare Provider Analysis and Review. Of these, 16 672 (92%) were billed as ICD‐10‐PCS 02583ZZ: “Destruction of Conduction Mechanism, Percutaneous Approach.” The reverse process yielded heterogeneous results: among 75 003 procedures billed as ICD‐10‐PCS 02583ZZ, only 15 691 (21%) matched with CPT 93656 (PVI), as several other unrelated procedures were billed under this ICD‐10‐PCS code. Institutional case review confirmed the greater specificity of CPT codes. Conclusions The ICD‐10‐PCS code associated with CPT‐billed PVI procedures actually referred to ablation of the atrioventricular junction. Yet this ICD‐10‐PCS code also matched with a wide range of other procedures distinct from PVI. We conclude that ICD‐10‐PCS codes alone are not sensitive nor specific for identifying PVI in claims and cannot be reliably used in isolation for health services research on this important procedure.

Background Our study aimed at evaluating the association between plasma human cartilage glycoprotein‐39 (YKL‐40) and cognitive impairment at 3 months among patients with acute ischemic stroke. Methods and Results Plasma YKL‐40 levels were measured in 604 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. Cognitive impairment outcomes were assessed at 3 months poststroke using the Mini‐Mental State Examination and the Montreal Cognitive Assessment. According to the Mini‐Mental State Examination score, patients in the highest quartile of YKL‐40 had a 2.01‐fold (95% CI, 1.23–3.29; P for trend=0.009) risk of poststroke cognitive impairment compared with those in the lowest quartile. Each 1 SD difference of logarithm‐transformed YKL‐40 was associated with a 28% (95% CI, 7–53) increased risk for the outcome. The multiple‐adjusted spline regression model confirmed dose–response relationships between YKL‐40 and poststroke cognitive impairment (P for linearity=0.01). Adding YKL‐40 to a model containing conventional risk factors significantly improved the discriminatory power (area under the receiver operating characteristic curve improved by 0.02, P=0.03). When cognitive impairment was defined using the Montreal Cognitive Assessment score, similar findings were observed. Conclusions Elevated YKL‐40 levels were associated with an increased risk of cognitive impairment at 3 months among patients with acute ischemic stroke. Registration URL: clinicaltrials.gov; Unique Identifier: NCT01840072.

Background Left ventricular (LV) geometric patterns are associated with cognitive impairment and cerebral small vessel disease. As a novel magnetic resonance imaging marker of cerebral small vessel disease and a risk factor for cognitive dysfunction, cortical cerebral microinfarcts (CMIs) have been associated with heart disease through mechanisms including cardioembolism and cerebral hypoperfusion. Further investigation is required to determine whether cortical CMIs could arise from hemodynamic changes related to LV geometry, thus elucidating the connection between LV geometry and cognitive function. This study aims to investigate the cross‐sectional relationship between LV geometric patterns, cortical CMIs, and cognition. Methods and Results A total of 261 patients, aged 75.3±6.8 years, were enrolled from a memory clinic study. LV dimensions were obtained using 2‐dimensional echocardiography. LV mass index and relative wall thickness were determined to categorize LV geometric patterns. Cortical CMIs were graded on 3T magnetic resonance imaging. Cognition was assessed using neuropsychological tests and clinical diagnosis. Linear, zero‐inflated Poisson, and logistic regression were employed for continuous, count, and binary outcomes, respectively. Mediation analysis was conducted to examine the mediation effect of cortical CMIs. A significant association was observed between concentric LV hypertrophy and cortical CMI counts (rate ratio, 3.85 [95% CI, 1.85–8.01]), as well as the odds of having dementia (odds ratio, 2.86 [95% CI, 1.07–7.89]), in the fully adjusted model. Cortical CMIs may partly explain the relationship between concentric LV hypertrophy and cognitive function. Conclusions Concentric LV hypertrophy was associated with cortical CMIs and dementia. Further verification is warranted to determine the role of cortical CMIs in the association between LV geometry and cognition.

Background Acute type A aortic dissection (AAD) and acute type A intramural hematoma (AIMH) are life‐threatening conditions with high mortality rates, and prognostic indicators are critical for guiding urgent treatment decisions. We assessed the prognostic significance of admission D‐dimer levels in patients with AAD and AIMH. Methods and Results The prospective, multicenter, observational study in China recruited participants from 2013 to 2019. Patients with AAD and AIMH were respectively categorized into quartiles based on admission D‐dimer levels. Cox regression analysis was used to assess the association between D‐dimer levels and mortality. A total of 3132 patients with AAD (mean age: 50.63 years [SD, 12.56]) and 353 patients with AIMH (mean age: 59.63 years [SD, 11.00]) were included. In patients with AAD, overall mortality rates increased across D‐dimer quartiles: 13.7% (Q1, ≤0.72 mg/L), 16.7% (Q2, 0.72–1.91 mg/L), 22.8% (Q3, 1.91–4.21 mg/L), and 28.5% (Q4, 4.21–20.00 mg/L). In patients with AIMH, mortality rates by quartile were 3.4% (Q1, ≤0.51 mg/L), 5.7% (Q2, 0.51–1.25 mg/L), 4.6% (Q3, 1.25–3.44 mg/L), and 10.2% (Q4, 3.44–20.00 mg/L). After adjusting for confounders, D‐dimer was an independent predictor of overall mortality (hazard ratio [HR], 1.42 [95% CI, 1.11–1.80]) and in‐hospital mortality (HR, 1.47 [95% CI, 1.13–1.92]) in patients with AAD. D‐dimer levels were not significantly associated with the overall (HR, 2.61 [95% CI, 0.70–9.73]) or in‐hospital mortality (HR, 1.78 [95% CI, 0.44–7.24]) of patients with AIMH by multivariable adjustment. Conclusions Elevated admission D‐dimer levels are independently associated with higher mortality in patients with AAD but are not significantly associated with prognosis in patients with AIMH. Our findings suggest that D‐dimer may serve as a useful prognostic marker in patients with AAD. Registration www.chictr.org.cn. Unique identifier: ChiCTR230006854.

Background Pulmonary vein stenosis in children is associated with a poor prognosis. However, the cause and risk factors for mortality remain uncertain. Methods This retrospective, single‐center study identified children with primary and secondary pulmonary vein stenosis through a cardiac catheterization database. Kaplan‐Meier analysis, log‐rank tests, and Cox regression analysis were performed to assess outcome and identify significant predictors of mortality. Results Among 56 children with pulmonary vein stenosis (33 male children, 59%), 20 (36%) died at a median age of 10 months (interquartile range, 4–24 months). All patients underwent cardiac catheterization, with 45 (80%) undergoing at least 1 interventional procedure. Causes of death included multiorgan failure (35%), progressive respiratory failure (20%), and sudden cardiac death (15%). Prematurity, chronic lung disease, a genetic syndrome, or the number of affected pulmonary veins did not significantly correlate with mortality. However, right ventricular (RV) systolic pressure greater than half systemic pressure was associated with mortality (hazard ratio [HR], 5.5 [95% CI, 2.2–14.1]; P

Background The impact of long‐term renal function change on stroke outcomes remains unclear. This study used the CNSR‐III (Third China National Stroke Registry) cohort to determine whether changes in estimated glomerular filtration rate based on creatinine and cystatin C (eGFRCr+CysC) during the first year post stroke were associated with 5‐year stroke outcomes. Methods and Results We included 4270 patients with centrally tested serum creatinine and cystatin C at admission and 1 year post admission and evaluated 5‐year follow‐up data. Patients were stratified into quintiles based on the 1‐year changes in eGFR. The primary outcomes included all‐cause mortality, stroke disability, and stroke recurrence. In patients with acute ischemic stroke, the mean baseline eGFRCr+CysC was 88.6±22.6 mL/min per 1.73 m2, which decreased by 5.6% to 83.6±20.7 mL/min per 1.73 m2 at 1 year. Compared with patients with relatively stable eGFRCr+CysC (Q3), those with decreased eGFRCr+CysC (Q1) exhibited significantly increased adjusted risk of death (hazard ratio [HR], 1.96 [95% CI, 1.27–3.04], P=0.003) and those with increased eGFRCr+CysC (Q5) exhibited borderline significance (HR, 1.51 [95% CI, 0.94–2.42], P=0.09), after adjusting for confounders, including baseline eGFRCr+CysC and albumin‐to‐creatinine ratio. Patients with a significant decrease (odds ratio [OR], 1.74 [95% CI, 1.25–2.42], P=0.001) or increase (OR, 1.51 [95% CI, 1.06–2.15], P=0.02) in eGFRCr+CysC also experienced a higher risk of disability. Conclusions Both the decline and increase in eGFRCr+CysC levels in the first year post stroke were independently associated with all‐cause mortality and stroke disability. These findings indicate that monitoring eGFRCr+CysC changes could be important for predicting long‐term outcomes and informing poststroke care strategies.

Background This study aimed to assess attack rates of ischemic cerebrovascular events (CVEs) in a population‐based registry and to estimate the current and projected burden of the disease in whole France. Methods and Results All cases of ischemic CVE (including ischemic stroke and transient ischemic attack) were prospectively identified through the population‐based Dijon Stroke Registry, France (2013–2020). Annual attack rates and temporal trends were assessed. The number of patients in whole France and projections by 2050 were estimated by standardization to age‐ and sex‐specific attack rates. A total of 2869 cases of ischemic CVE were recorded (mean age, 75.7±15.9 years, 54.4% women) including 1763 ischemic stroke and 1106 transient ischemic attack (crude attack rate, 230/100 000 per year). The age‐standardized rate was 237 (95% CI, 229–246), with rates of 144 (95% CI, 137–150) for ischemic stroke and 93 (95% CI, 88–98) for transient ischemic attack. The rates were 152 (95% CI, 145–159) and 85 (95% CI, 80–90), respectively, when considering the tissue‐based American Heart Association/American Stroke Association definition. The attack rate during the 2019 to 2020 period was slightly lower than that observed during 2013 to 2014 (age‐standardized attack rate ratio, 0.90[95% CI, 0.81–0.99]; P=0.035) but did not differ from that of other periods. The number of ischemic CVEs was estimated to be 164 126 annually in France during 2013 to 2020. An increase of 35% and 56% is expected by 2035 and 2050, respectively. Conclusions Our study highlighted a high burden of ischemic CVE that has been largely underestimated in France by administrative databases. Despite roughly stable attack rates over time, the absolute number of cases is expected to dramatically increase in coming years, thus questioning the sustainability of the health care system.

Background Patients with atrial fibrillation (AF) who suffered a previous stroke are at increased risk of recurrent thromboembolic events and other major outcomes. The impact of the number of stroke episodes on the natural history of patients with AF is still unclear. Methods and Results Using data from the international, multicenter, and prospective GLORIA‐AF (Global Registry on Long‐Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation) Registry Phase III, we categorized patients with a recent diagnosis of non‐valvular AF according to the number of previous strokes (either 0, 1, or ≥2 episodes). We analyzed use of oral anticoagulants through multiple logistic regression model, and risk of major outcomes using multiple Cox‐regression models; our primary outcome was all‐cause death. Among 21 223 patients (mean age: 70.2±10.3 years; 44.9% female) included, 2251 (10.6%) had a previous history of stroke, and 216 (1.0%) had ≥2 or more strokes. Oral anticoagulants were used in ≥80% of patients regardless of the numbers of previous stroke, although those with 1 (versus >1) prior stroke showed lower odds of receiving oral anticoagulants (odds ratio [95% CI]: 0.83 [0.73–0.94]). During 3‐years follow‐up, the risk of all‐cause mortality increased with the number of previous strokes (hazard ratio [95% CI]: 1.46 [1.28–1.67] and 2.43 [1.79–3.29] for 1 versus 0 and ≥2 versus 0 previous strokes, respectively). Similar results were observed for other secondary outcomes, including thromboembolism, but not for major bleeding. Conclusions History of stroke still represents a key risk factor in patients with AF. Patients who suffered more than 1 episodes of stroke had significantly worse prognosis and further efforts may be required to improve their clinical outcomes.

Background The purpose of this study was to investigate whether circulating pyruvate kinase M2 (PK‐M2) levels are elevated in the peripheral blood and to assess their association with diagnosis and prognosis in patients with heart failure (HF). Methods and Results We conducted a prospective investigation involving 222 patients with HF and 103 control subjects, measuring PK‐M2 concentrations using ELISA. The primary outcome, assessed over a median follow‐up of 2 years (interquartile range: 776 to 926 days), was the time to the first occurrence of either rehospitalization for worsening HF or cardiovascular death. Patients with HF had higher PK‐M2 levels than controls (17.4±4.1 versus 7.8±2.3 U/mL, P

Background Epistaxis is common with antithrombotic therapy and is often troublesome to patients, yet its frequency, severity, and outcomes are poorly characterized. Methods and Results Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF‐TIMI 48) randomized 21 105 patients with atrial fibrillation and CHADS2 risk score ≥2 to higher‐dose edoxaban regimen (60 mg daily, dose‐reduced to 30 mg), lower‐dose edoxaban regimen (30 mg, dose reduced to 15 mg, daily), or warfarin. Bleeds were adjudicated using International Society on Thrombosis and Haemostasis criteria. Patients with intracranial hemorrhage during follow‐up were excluded; those with >1 bleeding event were categorized according to their most severe event. The safety cohort with interval censoring during drug interruption was analyzed. Proportions were compared using Pearson's chi‐square test and treatment arms were compared using a Cox proportional hazards model. Among 5247 patients with a bleeding event, 1008 (19.2%) had epistaxis and 4239 (80.8%) had nonepistaxis bleeding. Epistaxis events were less severe than nonepistaxis bleeds (International Society on Thrombosis and Haemostasis major: 3.2% versus 20.7%; clinically relevant nonmajor: 64.7% versus 60.1%; minor: 32.1% versus 19.2%; P

Background Cardiac biomarkers improve risk prediction in patients with atrial fibrillation (AF). We recently demonstrated that the NFL (neuron‐specific protein neurofilament light chain) was associated with ischemic stroke in patients with AF not receiving oral anticoagulation. The association of other neuroglial biomarkers reflecting brain injury (ie, GFAP [glial fibrillary acidic protein], total tau [tau], and UCHL1 [ubiquitin carboxy‐terminal hydrolase L1]) with the risk of stroke and other cardiovascular outcomes in AF is unknown. Methods and Results Baseline plasma samples were available from 967 patients with AF not receiving oral anticoagulation treatment. Concentrations of NFL, GFAP, tau, and UCHL1 were determined with a Single Molecule Array kit (Simoa). Associations between baseline biomarker level, clinical characteristics, and outcomes (ischemic stroke, hospitalization for heart failure, and all‐cause death) were analyzed with multivariable Cox regression adjusted for clinical characteristics and other biomarkers. Higher levels of all 4 neuroglial biomarkers were correlated with increasing age and female sex. During a median follow‐up of 3.6 years, NFL was associated with increased risk of ischemic stroke (for a doubling in NFL, hazard ratio [HR], 1.27 [95% CI, 1.03–1.56]) and death (HR, 1.46 [95% CI, 1.25–1.70]). In adjusted analyses, GFAP, tau, and UCHL1were not associated with stroke or death. NFL, tau, and UCHL1 were significantly associated with hospitalization for heart failure. Conclusions In patients with AF not receiving oral anticoagulation, NFL was the only neuroglial biomarker significantly and independently associated with the risk of ischemic stroke and death. Further studies evaluating NFL for stroke risk assessment in patients with AF and the impact of contemporary oral anticoagulation treatment are warranted.

Background Excessive supraventricular ectopic activity (ESVEA) is regarded as a risk marker for later atrial fibrillation (AF) detection. Methods and Results The investigator‐initiated, prospective, open, multicenter MonDAFIS (Impact of Standardized Monitoring for Detection of Atrial Fibrillation in Ischemic Stroke) study randomized 3465 patients with acute ischemic stroke without known AF 1:1 to usual diagnostic procedures for AF detection or additive Holter monitoring in hospital for up to 7 days, analyzed in a core laboratory. Secondary study objectives include the comparison of recurrent stroke, myocardial infarction, major bleeding, and all‐cause death within 24 months in patients with ESVEA (defined as ectopic supraventricular beats ≥480/day or atrial runs of 10–29 seconds or both) versus patients with newly diagnosed AF versus patients without ESVEA or AF (non‐ESVEA/AF), randomized to the intervention group. Overall, 1435 (84.8%) of 1714 patients randomized to the intervention group had analyzable study ECG monitoring of at least 48 hours' duration within the first 72 hours of monitoring. ESVEA was detected in 363 (25.3%) patients, while AF was first detected in 48 (3.3%) patients. Within 24 months, AF was newly detected in 67 (18.5%) patients with ESVEA versus 60 (5.9%) patients without ESVEA/AF‐ (P

Background Coronary angiography (CAG) and targeted temperature management (TTM) may improve clinical outcomes after out‐of‐hospital cardiac arrest. This study aimed to assess whether the intervention effects differed according to timing and percutaneous coronary intervention (PCI) performance. Methods and Results Adult patients with presumed cardiac cause who underwent CAG and TTM within 24 hours following out‐of‐hospital cardiac arrest were included from the Korean nationwide out‐of‐hospital cardiac arrest registry. We investigated the associations between the timing of interventions and whether CAG was performed before TTM initiation (CAG‐first) and good neurological outcomes. Intervention times were divided into 4 quartiles, and odds ratios (ORs) were calculated with the fourth quartile as the reference. A total of 844 patients were enrolled. CAG and TTM were initiated a median of 2.4 hours (interquartile range [IQR], 1.8–3.2) and 4.3 hours (IQR, 3.2–6.0) after OHCA, respectively. Univariable analysis revealed associations between the earliest intervention groups and good neurological outcomes. However, after adjustment, neither the intervention time nor intervention prioritization was associated with good outcomes. The first quartile of CAG time (

Background Carotid intima‐media thickness (IMT) is a measure of atherosclerosis and a predictor of vascular diseases. Traditional vascular risk factors and genetic variants do not completely explain the variation in carotid IMT. We sought to identify epigenetic factors that may contribute to the remaining carotid IMT variability. Methods and Results An epigenome‐wide association study was performed in 61 Dominican families with 769 individuals. A cytosine nucleotide that precedes a guanine nucleotide methylation in blood‐derived DNA was measured using the Human MethylationEPIC BeadChip. Linear mixed model analyses were performed regressing bifurcation carotid IMT (bIMT) on beta values for cytosine nucleotide that precedes a guanine nucleotide sites, adjusting for covariates, followed by differentially methylated region (DMR) analysis. One‐sample Mendelian randomization analysis was conducted to investigate causal associations between DMRs and bIMT. Twenty‐five DMRs were associated with bIMT (Sidak P

Background Polyamines have been suggested to play pivotal roles in ischemic stroke and neurodegenerative disorders, but the associations of plasma polyamines with poststroke cognitive impairment (PSCI) remain unclear. We aimed to prospectively investigate the associations of plasma putrescine, spermidine, and spermine with PSCI among patients with ischemic stroke in a multicenter cohort study. Methods and Results We measured plasma polyamine levels at baseline among 619 patients with ischemic stroke from a preplanned ancillary study of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). We used the Mini‐Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3‐month follow‐up after ischemic stroke, and PSCI was defined as Mini‐Mental State Examination score

Background Chronic arterial hypertension restructures the vascular architecture of the brain, leading to a series of pathological responses that culminate in cerebral small‐vessel disease. Pericytes respond dynamically to vascular challenges; however, how they manifest under the continuous strain of hypertension has not been elucidated. Methods and Results In this study, we characterized pericyte behavior alongside hypertensive states in the spontaneously hypertensive stroke‐prone rat model, focusing on their phenotypic and metabolic transformation. Flow cytometry was used to characterize pericytes by their expression of platelet‐derived growth factor receptor β, neuroglial antigen 2, cluster of differentiation 13–alanyl aminopeptidase, and antigen Kiel 67. Microvessels were isolated for gene expression profiling and in vitro pericyte expansion. Immunofluorescence validated the cell culture model. Plasma‐derived extracellular vesicles from hypertensive rodents were applied as a treatment to assess their effects on pericyte function and detailed metabolic assessments on enriched pericytes measured oxidative phosphorylation and glycolysis. Our results reveal a shift in platelet‐derived growth factor receptor β+ pericytes toward increased neuroglial antigen 2 and cluster of differentiation 13–alanyl aminopeptidase coexpression, indicative of their critical role in vascular stabilization and inflammatory responses within the hypertensive milieu. Significant alterations were found within key pathways including angiogenesis, blood–brain barrier integrity, hypoxia, and inflammation. Circulating extracellular vesicles from hypertensive rodents distinctly influenced pericyte mitochondrial function, evidencing their dual role as carriers of disease pathology and potential therapeutic agents. Furthermore, a shift toward glycolytic metabolism in hypertensive pericytes was confirmed, coupled with ATP production dysregulation. Conclusions Our findings demonstrate that cerebral pericytes undergo phenotypic and metabolic reprogramming in response to hypertension, with hypertensive‐derived plasma‐derived extracellular vesicles impairing their mitochondrial function. Importantly, plasma‐derived extracellular vesicles from normotensive controls restore this function, suggesting their potential as both therapeutic agents and precision biomarkers for hypertensive vascular complications. Further investigation into plasma‐derived extracellular vesicle cargo is essential to further explore their therapeutic potential in vascular health.

Background The optimal definition and risk stratification approach to identify high‐risk patients with prediabetes and stable coronary heart disease has not been well studied to date. The objective of the current study is to compare the prognostic value of different definitions of prediabetes, and to explore the role of “very‐high‐risk” (VHR) criteria according to the 2018 American Heart Association/American College of Cardiology cholesterol guideline in the risk stratification of patients with prediabetes and stable coronary heart disease. Methods and Results This prospective large‐cohort study enrolled a total of 7930 patients with stable coronary heart disease. Prediabetes was defined according to various guidelines and further classified on the basis of the VHR criteria according to the 2018 American Heart Association/American College of Cardiology guideline. The primary end point was major adverse cardiovascular events (MACEs), which was defined as the composite end point of cardiac death, nonfatal acute myocardial infarction, and stroke. During a median of 3 years’ follow‐up, a total of 256 MACEs occurred. Prediabetes defined according to the World Health Organization/International Expert Committee criteria was associated with significant increased MACE risk compared with normoglycemia (adjusted hazard ratio [HR], 1.484 [95% CI, 1.139–1.935]; P=0.0035). The VHR group was associated with increased MACE risk compared with the non‐VHR group (adjusted HR, 1.783 [95% CI, 1.344–2.366], P

Background Current guidelines lack recommendations regarding the use of proton pump inhibitors (PPIs) for preventing upper gastrointestinal bleeding (UGIB) among patients at low risk for UGIB treated with dual antiplatelet therapy for ischemic stroke (IS). Our objective was to assess the effectiveness of PPIs in lowering the risk of significant UGIB in this patient group. Methods and Results A retrospective cohort study was conducted involving patients at low risk for UGIB admitted for IS between 2014 and 2018 and treated with dual antiplatelet therapy. The study used a nationwide claims database in Korea. The primary end point was significant UGIB during 12 months after IS. To evaluate the risk of significant UGIB based on PPI use, we performed a multivariable Cox regression analysis. Subgroup analyses and propensity score matching analysis were conducted for validation. Among 96 722 patients with IS at low risk for UGIB who were on dual antiplatelet therapy (mean age, 67.0 years; men: 63.0%), 16 084 (16.6%) were treated with PPIs. During 12 months of follow‐up, 325 patients experienced significant UGIB, and 479 experienced any UGIB. PPI use was associated with a reduced risk of significant UGIB (hazard ratio, 0.63 [95% CI, 0.45–0.89]; P=0.009). This association was consistent in the subgroup and propensity score matching analyses. Conclusions In patients with IS receiving dual antiplatelet therapy, PPI use reduced the risk of significant UGIB by 37% on average, even among low‐risk patients. However, the use of PPIs in this patient group was limited, highlighting the need for additional prospective studies.

Background Immune checkpoint inhibitors have improved the clinical outcomes of several cancers but have also been associated with a greater risk of immune‐related adverse effects, especially when combined. The objective of this study was to investigate the incidence of myocarditis in relation to the use of dual concurrent versus single immune checkpoint inhibitors therapies. Methods and Results A cohort study was conducted using medical and pharmacy claims data (2011–2022) from a large US commercial insurer. Cox regression quantified the comparative risks of myocarditis or heart failure in patients with cancer receiving treatment with combination therapy (nivolumab and ipilimumab) in comparison to taking a single immune checkpoint inhibitor only. Mean follow‐up time in 53 018 patients was 226 days (interquartile range, 93–495 days). There were 148 cases of myocarditis (0.3%), 33 (0.7%) in patients on combination therapy, and 115 (0.2%) in patients on monotherapy. The risk of myocarditis per 1000 patients was 7.40 in the combination therapy group and 2.37 in the monotherapy group (risk ratio, 3.12 [95% CI, 2.12–4.60]). Using multivariable regression analysis, the hazard ratio for myocarditis in the combination therapy group was 2.38 (1.57–3.63). No difference in the risk of heart failure was found between combination and single therapy. Conclusions Therapy with 2 immune checkpoint inhibitors was associated with an increased risk of myocarditis compared with monotherapy, with most cases occurring in the first 6 months of therapy.