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Background Studies have demonstrated an association between endothelial dysfunction and major depressive disorder (MDD). However, the link between coronary endothelial dysfunction (CED) and an incident diagnosis of MDD across sexes is unclear. Methods Patients with nonobstructive coronary artery disease (stenosis <40%) underwent an invasive assessment of CED. Macrovascular CED was defined as a percentage change in coronary diameter in response to acetylcholine of ≤−10% compared with baseline. Microvascular CED was defined as a percentage change in coronary blood flow in response to acetylcholine of ≤−50% compared with baseline. In the period after the index procedure, patients were followed up for developing a diagnosis of MDD, and logistic regression was performed to assess the association between baseline CED and incident MDD. Results In total, 2280 patients underwent invasive testing for CED. A total of 516 patients (23%) underwent an evaluation for MDD at a date after the index procedure (mean±SD age, 53±12 years; 72% women). A total of 160 (31%) were diagnosed with MDD. The percentage change in coronary diameter in response to acetylcholine was lower in those diagnosed with MDD in all patients (−10.8% versus −5.3%; P =0.008), and in men (−19.0% versus −4.8%; P =0.001). In men, a higher proportion of those with macrovascular CED were diagnosed with MDD compared with those not diagnosed with MDD (59% versus 38%; P =0.035). In multivariable analyses, macrovascular CED was associated with MDD in men (odds ratio: 2.99 [95% CI, 1.26–7.45]; P =0.015). Conclusions Macrovascular CED is significantly associated with incident MDD in men with nonobstructive coronary artery disease. Endothelial dysfunction in the coronary arteries could thus be a helpful biomarker to identify patients at risk of MDD.

Background Inadequate preventive dental care may contribute to inflammatory conditions such as periodontitis, increasing cardiovascular disease risk. Artificial intelligence–enabled electrocardiography (AI‐ECG) algorithms accurately estimate cardiovascular disease risk. We investigated the association between inadequate preventive dental care and the AI‐ECG–estimated risk of atrial fibrillation, aortic stenosis, low ejection fraction, cardiac amyloid, cardiovascular aging, and all‐cause mortality. Methods We retrospectively analyzed 266 637 Mayo Clinic patients (2018–2024) who completed a Social Determinants of Health Survey and had an ECG performed within 1 year of survey completion. AI‐ECG algorithms generated continuous risk scores (0 or 1) for atrial fibrillation, aortic stenosis, low ejection fraction, and amyloid. Cardiac aging was assessed by delta age, calculated as AI‐ECG–estimated physiological age minus the chronological age. Associations with preventive dental care were analyzed using logistic regression. Cox regression evaluated dental care predictiveness on all‐cause mortality. Results Among 266 637 individuals (mean age, 59.5±16.4 years; 51.1% women), 49 918 (18.7%) reported inadequate preventive dental care. These individuals had higher delta age and increased AI‐ECG–predicted risks of atrial fibrillation, aortic stenosis, amyloid, and reduced ejection fraction (all P <0.001). In multivariable logistic regression models including all AI‐ECG scores, inadequate preventive dental care was associated with higher probabilities of low ejection fraction (odds ratio [OR], 1.80 [95% CI, 1.69–1.91]), atrial fibrillation (OR, 1.10 [95% CI, 1.04–1.17]), aortic stenosis (OR, 1.90 [95% CI, 1.64–2.20]), amyloid (OR, 1.18 [95% CI, 1.12–1.25]), and higher delta age (OR, 1.03 [95% CI, 1.02–1.03]) (all P <0.001). Inadequate preventive dental care predicted all‐cause mortality after adjusting for demographics, risk factors, and AI‐ECG algorithms (HR, 1.45 [95% CI, 1.38–1.53], P <0.001). Conclusions Inadequate preventive dental care is associated with subclinical cardiovascular disease. AI‐ECG algorithms may facilitate cardiovascular risk stratification among individuals with limited preventive dental care access.

Abstract Endothelial dysfunction can be regarded as the earliest feature of vascular aging and may occur in individuals without traditional risk factors for cardiovascular disease. Once present, endothelial dysfunction is known to increase the risk for atherosclerosis, cardiovascular diseases and complications such as stroke or death. Identification of individuals with early features of vascular aging remains challenging and has fuelled investigative efforts to associated biologic, imaging, and digital markers with endothelial dysfunction. This review highlights emerging and traditional methods to identify patients with early endothelial dysfunction and summarizes available and experimental therapies aimed at mitigating the vascular aging process.

Methods: From a sample cohort of 274,539 consecutive adults who sought care at Mayo Clinic between 2018-2022, we ascertained demographic and clinical information, including clinically indicated TTE within 15 days and up to a year after the index clinical visit. The Area Deprivation Index (ADI), a tool that captures neighborhood-level disadvantages that are linked to cardiovascular morbidity and outcomes, was extracted from the Neighborhood Atlas and ranked accordingly as state percentiles stratified in quintiles, with the highest values representing “most disadvantaged” areas. We performed non-parametric multivariate regression models that adjusted for cardiovascular risk factors expressed in odds ratio (OR) and 95% confidence interval (CI). Results: A total of 45,823 (16.9%) subjects had a TTE performed, with a mean age of 63±16 years, 48% were women, and 86% were non-Hispanic white. According to the TTE, 4% of subjects had LVSD, while 11% had a high probability of LVSD by AI-ECG. Median state ADI was 4 IQR (2-7). In the whole cohort, subjects residing in the most disadvantaged areas were less likely to have a TTE [OR 0.94 CI (0.91- 0.97)] see Fig. 1-A ; conversely, they were more likely to have LVSD by TTE [OR 1.80 CI (1.52-2.13)] see Fig. 1-B , and higher probability of LVSD by AI-ECG [OR 1.43 CI (1.36-1.51)] when compared to those with the least disadvantage see Fig. 1-C , independent of age, sex, and cardiovascular risk factors, p for trend<0.001. Conclusion: Individuals living in socially disadvantaged areas were slightly less likely to have an echocardiogram despite a significantly higher likelihood of having an LVSD (suspected by AI-ECG and confirmed by TTE), independent of cardiovascular risk factors. Highlighting an important disparity in the diagnosis of LVSD.

Background A subset of individuals with major depressive disorder (MDD) have a high burden of cardiovascular risk factors and cerebral small‐vessel disease, implicating vascular disease in the development of depression. Cross‐sectional studies demonstrate a link between endothelial dysfunction and MDD, but the prospective association between peripheral endothelial dysfunction (PED) and an incident diagnosis of MDD is unknown. Methods and Results Patients undergoing a baseline assessment of cardiovascular risk were evaluated for PED using reactive hyperemia–peripheral arterial tonometry (≤1.8 consistent with PED). Patient medical records were reviewed to identify those who underwent a formal clinical evaluation of MDD after the index PED evaluation. The frequency of PED was compared in those with and without MDD. Logistic regression analyses were performed to assess the association between baseline PED and incident MDD. Between January 2006 and December 2020, 1614 patients underwent testing for PED. Four hundred eighty‐four (30.1%) patients underwent a formal evaluation for MDD after (0–15 years) the index procedure (mean±SD age, 52.8±13.8 years; 65.2% women). Of these, 157 (32.4%) had PED and 108 (31.0%) were diagnosed with MDD. Individuals with MDD had a higher frequency of PED (40.2% versus 30.2%; P =0.034) compared with those without MDD. In multivariable analyses, PED was significantly associated with MDD (odds ratio, 2.3 [95% CI, 1.4–3.8]; P <0.001). Conclusions PED is significantly associated with incident MDD. Thus, PED may be a useful marker to identify individuals at increased risk of depression who may benefit from more frequent and earlier management strategies.

Abstract Background Cardiovascular disease remains the leading cause of death and burden globally, warranting the need to explore novel predictors of major adverse cardiovascular events (MACE) using new technologies. Artificial Intelligence (AI)-enhanced ECG (AI-ECG) algorithms can provide information on cardiovascular health of individuals, independent of conventional risk factors. Purpose The current study aimed to understand whether a previously described AI-ECG sex estimation algorithm could be applied for risk stratification of major adverse cardiovascular events (MACE), with a focus on a population without previous history of MACE. Methods Patients having 12-lead ECGs between 2018-2019 were included and followed up until August 2023. Exclusion criterion was a prior history of MACE. AI-ECG sex estimation was determined using a previously described algorithm predicting sex based on 12-lead ECGs. The algorithm generates outputs ranging from 0 to 1, representing the estimated probability of being male. Outputs above 0.5 were considered as AI-ECG-estimated male, and below as AI-ECG-estimated female. This was compared with biological sex to determine whether the two matched. Inconsistency between AI-ECG estimated sex and biological sex was defined as discordance. MACE was defined as myocardial infarction, coronary revascularization, non-fatal stroke, and all-cause death. Results Among 80,578 subjects (mean age 59.1 ± 16.1 years, 52.4% female), 9.7% exhibited sex discordance in AI-ECG estimation. Discordance was associated with a 56% higher risk of MACE (HR, 1.56, 95% CI 1.46-1.65, p &lt;0.001), and remained significant in multivariable analysis with traditional risk factors (HR 1.35, 95% CI 1.27-1.43, p &lt;0.001) (Figure 1). Sex-specific analysis showed increased MACE risk in both discordant males and females (Figure 2). Conclusion In patients with no history of MACE, discordance in AI-ECG sex estimation is associated with increased risk of MACE. These findings suggest the potential of AI-ECG sex estimation algorithm for risk assessment, especially in patients with no history of MACE.Figure 1.Cox proportional hazard modelFigure 2.Kaplan-Meier of MACE by sex

Abstract Background Patients with carotid artery disease undergoing carotid endarterectomy (CEA) appear to be at high risk of all-cause mortality during their follow-up. However, the possible predictors of this adverse outcome are not elucidated yet. Purpose We aimed to test cardiovascular (CV) risk factors as possible predictors of all-cause mortality in patients undergoing CEA and to determine whether there is a difference between the mortality rate of our study cohort and the general population. We hypothesize that CEA-treated patients have a higher mortality rate during follow-up after surgery than the general population, which is not related to the presence of CV risk factors. Methods We prospectively enrolled and followed up patients undergoing CEA. Univariate and multivariable Cox regression were performed to test whether common CV risk factors (demographics, laboratory values, comorbidities, and events before CEA) were predictive of all-cause mortality. We then compared the standardized mortality ratio (SMR) of our population and the age-sex-matched Minnesota (MN) general population at 5,10, and 21 years of follow-up after CEA. Results A total of 710 patients were followed for a median of 7.1 [2.9-11.9] years after CEA. Mortality occurred in 198 (27.0%) patients during the follow-up. The median time to event was 11.0 [10.0-12.0] years. Age was the only predictor of all-cause mortality in CEA-treated patients in multivariable models adjusted for known CV risk factors (Model 1: HR 1.03 [95%CI 1.01-1.06]; p=0.004; Model 2: HR 1.02 [95%CI 1.00-1.04]; p=0.023) (Table 1). However, the CEA-treated group had a higher mortality rate than would have been expected in the MN population (log-rank p&lt;0.001) (Fig.1A). Compared to the MN population, at 5 years of follow-up only patients &lt;60 years old had a higher SMR (4.53 [1.95-8.92]; p=0.001), whereas, at 10 years and 21 years of follow-up, our study population had a higher mortality rate at any age (Fig.1B). Conclusions The elevated mortality risk post-CEA in our cohort cannot be solely attributed to chronological aging. The underlying process of atherosclerosis likely contributes to all-cause mortality, and plaque characteristics may offer additional insight into the risk stratification of this patient group.All cause mortality predictors after CEAStudy population vs. MN population SMR

Abstract Background Patients with carotid artery disease undergoing carotid endarterectomy (CEA) have a high risk of experiencing Major Adverse Cardiovascular Events (MACE) after surgery. The occurrence of MACE in CEA-treated patients is not predicted by common cardiovascular (CV) risk factors. Purpose We aimed to identify the association between plasma and plaque inflammatory cytokines and the incidence of MACE in the follow-up after CEA. We hypothesized that MACE is related to a higher level of circulating inflammatory cytokines at the time of surgery. Methods We prospectively enrolled patients with carotid artery disease undergoing CEA. Plasma and carotid plaques were collected during the surgery. Inflammatory cytokines (MCP-1/CCL2, IL-8/CXCL8, IFN-gamma, IL-10, IL-1beta/IL-1F2, IL-6, PDGF-AA, PDGF-AB/BB, TNF-alpha, VEGF) were measured in plasma and tissue homogenates using a customized 10-plex Luminex assay. Baseline demographics and clinical data for all the patients were extracted from electronic health records. MACE after CEA was defined as a composite measure of nonfatal cardiac events such as myocardial infarction with or without revascularization, cerebrovascular events (ischemic stroke, TIA, and amaurosis fugax), and all-cause mortality. Results Of 107 patients who underwent CEA with a median age of 73 (67-78) years, 57 (53.2%) experienced MACE during a median follow-up of 5.2 [2.2-9.3] years: 23 (40.3%) cardiac events, 9 (15.7%) CVA, and 25 (43.8%) all-cause mortality. Plaque cytokines levels did not differ between the groups with and without MACE in the follow-up after CEA. Instead, plasma cytokines were associated with MACE in the follow-up after CEA, as summarized in Figure 1. In the logistic regression analysis, plasma levels of MCP-1/CCL2, IFN-gamma, and TNF-alpha were independent predictors of MACE in follow-up post-CEA in univariate and multivariable models adjusted for CV risk factors such as age, BMI, systolic and diastolic blood pressure, low-density lipoprotein, high-density lipoprotein, and glucose level: MCP1/CCL2 (HR 1.009 [1.002-1.015]; p=0.007), IFN-gamma (HR 1.368 [1.014-1.845]; p=0.040), and TNF-alpha (HR 1.121 [1.022-1.228]; p=0.015) (Table 1). Conclusions Plasma levels of CCL2, IFN-gamma, and TNF-alpha are associated with the high incidence of MACE in the follow-up after CEA, indicating that these are potential biomarkers of MACE in this patient population and potential therapeutic targets in patients' progression of systemic atherosclerosis.Plasma cytokines and MACE after CEACytokines logistic regression analysis

Abstract Background One of the main features of vulnerability in atherosclerotic carotid plaques is intraplaque hemorrhage (IPH), which is related to a higher incidence of cerebrovascular events in patients with carotid artery disease. Additionally, inflammation plays a pivotal role in the progression of atherosclerotic disease. Purpose We aimed to determine plasma and tissue levels of inflammatory cytokines in patients with carotid artery disease hypothesizing that plaques with IPH are characterized by the presence of a more inflamed environment. Methods We retrospectively enrolled 104 consecutive patients undergoing carotid endarterectomy (CEA) with symptomatic (ischemic stroke, TIA, amaurosis fugax) or asymptomatic ipsilateral carotid artery disease. Plasma and carotid plaque specimens were collected at CEA. The tissue samples were stained with H&E to identify IPH and classified as specimens with and without IPH. Frozen homogenates of both plasma and tissue were analyzed using a customized 10-plex Luminex assay to determine the levels of inflammatory cytokines such as MCP-1/CCL2, IL-8/CXCL8, IFN-gamma, IL-10, IL-1beta/IL-1F2, IL-6, PDGF-AA, PDGF-AB/BB, TNF-alpha, and VEGF. Results IPH was identified in 53 patients (51.0 %). Cytokine levels in plasma and tissue from patients with and without IPH are reported in Table 1. In the univariate logistic regression MCP-1/CCL2, IL-8/CXCL8, IFN-gamma, IL-10, IL6, PDGF-AA, and PDGF-AB/BB were associated with IPH (Table 2). In the multivariate logistic regression, IL-6 was an independent predictor of IPH (HR 1.026 [95% CI 1.005-1.047]; p=0.014) after adjusting for cardiovascular risk factors such as age, BMI, sex, hypertension, diabetes mellitus, hyperlipidemia, ipsilateral carotid stenosis %. Conclusions Carotid plaques with IPH have an elevated inflammatory burden, potentially impacting adverse outcomes in this patient cohort. The local inflammatory cytokines in carotid plaques with IPH might serve as biomarkers and therapeutic targets in patients with carotid artery disease.

Introduction: Coronary microvascular dysfunction (CMD) is associated with increased morbidity and mortality. Anemia is an important predictor of outcomes in several cardiovascular diseases, such as heart failure and coronary artery disease (CAD), however its significance in patients with non-obstructive CAD is not fully elucidated. Hypothesis: We hypothesized that anemia would be associated with CMD and future adverse outcomes. Methods: We enrolled 1334 patients with signs and/or symptoms of ischemia and with non-obstructive CAD (<50% angiographic stenosis) who underwent invasive CMD evaluation and had follow-up data. CMD was defined as coronary flow reserve (CFR) (hyperemic flow/baseline flow as measured by the doppler wire) of ≤2 in response to intracoronary adenosine injection. Anemia was defined as a Hgb < 13.0 g/L in males and <12.0 g/L in females. MACE was defined as any incidence of myocardial infarction, cardiac revascularization (PCI, CABG) and all-cause mortality. Results: Overall mean age was 51.3±12.4 years, 66% were female. Patients with anemia were more likely to be female and have diabetes mellitus. Anemics were more likely to be diagnosed with CMD (Odds Ratio 2.01, 95% Confidence Interval [1.14-3.54]; P = 0.02). This relationship remained significant even after adjusting for cardiovascular risk factors like age, sex, hypertension, diabetes mellitus and dyslipidemia (OR 1.84, 95% CI [1.03-3.29], P = 0.04). Furthermore, patients with anemia were more likely to experience MACE (OR 1.86, 95% CI [1.30-2.66], P = 0.001), independent of possible confounders (OR 1.84, 95% CI [1.27-2.69], P = 0.002). Conclusions: Anemia is an independent predictor of CMD and future adverse cardiovascular events in patients with NOCAD. Moreover, it was associated with an increased risk of future adverse events. Further studies are needed to elucidate whether treatment of anemia in this population translates into outcomes.