Abstract Multiple sclerosis (MS) may impair ventricular‐vascular coupling (VVC), a measure of the interaction between the cardiac and vascular systems. We evaluated if VVC differed between individuals with and without MS with similar age‐predicted fitness. Individuals with MS ( n = 20) and without (CON, n = 18) underwent VVC measurement before and immediately after a maximal incremental cycle test with peak oxygen consumption (VO 2 peak) measurement. VVC was quantified as the ratio of arterial elastance (E A : end‐systolic pressure (ESP)/stroke volume) to ventricular elastance (E LV : ESP/end‐systolic volume). ESP was assessed with radial applanation tonometry, and cardiac volumes were obtained from apical four‐chamber echocardiography. Sex, BMI and VO 2 peak were not different between groups. Individuals with MS were older, had higher E A ( p < 0.01) and E LV ( p = 0.02), but VVC did not differ between groups. After adjustment for age, the group differences in E A and E LV remained significant. VVC was similar between individuals with and without MS, before and immediately after maximal exercise. However, individuals with MS had higher E A and E LV , suggesting higher arterial and ventricular loads. Our data suggest that individuals with MS with similar fitness to controls exhibit higher E A and E LV with preserved coupling.

Background: Hypertension and chronic low muscle strength—the primary indicator of sarcopenia—commonly co-occur in older adults and significantly contribute to CVD risk. While resistance training lowers blood pressure (BP) in younger hypertensive populations, its efficacy in older adults with low muscle strength remains unclear. In the INERTIA study, we evaluated the feasibility and preliminary effects of a 12-week progressive resistance training (PRT) intervention on changes in BP in older adults with low muscle strength. Methods: Older adults (≥60 years) without diagnosed CVD or conditions precluding PRT exercise were enrolled. Low muscle strength was defined using standardized criteria for grip strength (<30 kg men; <20 kg women). Participants were randomized (2:1 block allocation) to 12 weeks of biweekly supervised moderate-intensity PRT (60 to 80% 1RM, n=51) or an attention-control group (n=21) receiving home exercise mailings every 3 weeks. Paired t-tests assessed within-group BP changes from baseline to 12 weeks, and linear regression evaluated between-group differences in BP change. Linear mixed effect models estimated BP changes over time within the PRT group at baseline, 6 weeks, and 12 weeks (primary endpoint). Results: Seventy-one participants were randomized (average age 70.1±6.3 years) with 76% female, 44% non-white; and 42% on antihypertensive therapy. At baseline, resting BP was higher in the PRT group versus controls (131/82 mmHg vs 126/81mmHg, p =0.11). Within the PRT group, there was significant reduction in systolic (-7.0 mmHg, 95% CI 1.96, 12.0, p =0.0154) and diastolic BP (-4.8 mmHg, 95% CI 2.13, 7.52, p =0.0016) from baseline to week 12, while negligible changes were observed in controls ( Table ). Between-group differences in BP change were significant for diastolic BP only. Within the PRT group, significant BP reductions were evident by 6 weeks and remained significant at week 12 weeks for systolic (-6.2 mmHg; 95% CI –11.6, –0.79; p=0.025) and diastolic BP (–4.8 mmHg; 95% CI -7.56, -2.00; p=0.001; Figure ). Conclusion: PRT meaningfully reduced BP in older adults with hypertension and low muscle strength. Larger trials are warranted to confirm these findings and examine integrated strategies targeting both muscle health and BP to reduce CVD risk in aging populations.

Introduction: Drinking over the recommended limits, or at-risk drinking, is associated with aortic stiffening, which contributes to an increased risk of hypertension and cardiovascular disease. However, whether alcohol reduction/abstinence reduces aortic stiffness in mid-life adults remains unknown. Objective: This study aims to investigate the effects of 8-week alcohol abstinence on aortic stiffness in mid-life adults who drink over the recommended limit, or at-risk drinkers. Hypothesis: We hypothesized that an 8-week alcohol abstinence intervention would reduce aortic stiffness in mid-life at-risk drinkers. Methods: A total of 12 midlife men and 5 postmenopausal women (age 58.2±4.0 years and body mass index: 28.3±4.4 kg/m 2 ; mean±SD), who were at-risk drinkers and free of major clinical diseases and smoking, completed an 8-week alcohol abstinence intervention. Seven participants were on anti-hypertensive medications (≥2 months). Before and after the intervention, participants completed the in-laboratory assessment of arterial stiffness (measured as carotid-to-femoral pulse wave velocity, cfPWV) as well as supine peripheral and aortic blood pressure (BP). Alcohol use was monitored by using both an alcohol biomarker (dried blood spot phosphatidylethanol, PEth) and self-report questionnaires (14-day timeline followback calendar for calculating weekly alcohol consumption and U.S. Alcohol Use Disorders Identification Test for calculating the USAUDIT-C score). Results: Following the 8-week alcohol abstinence intervention, cfPWV decreased only in participants who were free of anti-hypertensive medications (n=11; 8.7±1.6 to 7.4±0.9 m/sec, P< 0.001), while it remained unchanged in participants taking anti-hypertensive medications (n=7; 8.5±0.9 to 8.5±1.0 m/sec, P=0.861; P=0.006 for the time × medication use interaction effect). No changes were found in supine peripheral and aortic BP following the intervention (P≥0.397 for time effect). Alcohol intake significantly decreased as evidenced by a reduction in PEth (65.1±59.9 to 14.2±41.5 ng/mL, P<0.001), weekly alcohol consumption (14.9±9.3 to 0.2±0.4 drinks/week, P<0.001), and the USAUDIT-C score 9.7±2.4 to 2.4±3.7, P ≤0.001;). Conclusions: Our preliminary findings indicate that the 8-week abstinence intervention reduced aortic stiffness in mid-life adult at-risk drinkers, free of anti-hypertensive medication use, without change in supine BP. These findings suggest that reducing or eliminating alcohol use can result in de-stiffening effect of the aorta in mid-life adults. Funding Resources: NIAAA AA028537 to CLH This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

We manipulated baseline peripheral arterial stiffness via changes in local arterial pressure with different limb positions to test the hypothesis that the magnitude of decrease in arterial stiffness post exercise/compression would be less when baseline stiffness is higher with the arm below the heart. Brachial-radial pulse wave velocity (PWV) was measured with tonometers in 19 healthy volunteers before and after 5 min of rhythmic handgrip exercise or passive forearm compressions with the arm positioned below or above the heart. Brachial-radial PWV was reduced 5 min after handgrip exercise below (10.4 ± 2.6 to 8.7 ± 2.2 m/s) and above (6.4 ± 1.3 to 5.3 ± 1.0 m/s) the heart, with no difference between positions (p > 0.05). PWV was also reduced 5 min after passive compressions with the arm below (10.8 ± 2.0 to 9.8 ± 2.1 m/s) and above (7.5 ± 1.4 to 5.7 ± 1.1 m/s), with no difference between positions (p > 0.05). Changes in local arterial pressure associated with arm position resulted in differences in baseline PWV but did not affect the magnitude of reduction in PWV with exercise or compressions. Reductions in peripheral arterial stiffness observed after rhythmic handgrip exercise and passive compressions were independent of baseline arterial stiffness.

Hypothesis: 8 weeks of supervised resistance exercise will reduce blood pressure and improve vascular function Methods: We prospectively recruited 59 adult men and women (BMI 30.8 ± 5.1, SBP 124 ± 12 mmHg, DBP 78 ± 10mmHg) who were randomized to either aerobic exercise (AE, 65-85% heart rate reserve, n = 27) or resistance exercise (RT, 8-12 repetitions at 65-85% 10RM, n = 32) for 30-45 minutes 3 times per week for 8 weeks. Peripheral blood pressure was assessed by oscillometry. Cardiorespiratory fitness was assessed via VO 2 peak. Arterial stiffness was assessed by carotid-to-femoral pulse wave velocity and analysis. Results: Systolic blood pressure and diastolic blood pressure decreased overall (∆4.1; ∆2.9 mmHg, respectively; p < 0.05) without significant interaction effects from age, ethnicity, or training type. Pulse wave analysis demonstrated significant improvements in augmentation index normalized for heart rate (AIx 75 ∆ -3.6%, p = 0.018). Pulse wave velocity was reduced but did not reach significance (∆ -0.2 m/s, p = 0.05). In an unadjusted model, Peak VO 2 did not significantly change although older age did significantly predict a negative change in VO 2 (β = -0.188, r 2 = 0.181, p <0.01). Conclusion: Eight weeks of supervised exercise improved blood pressure and vascular function. Arterial stiffness was reduced following exercise training with either intervention. This study suggests that adults can improve their cardiovascular health using either resistance or aerobic training programs. NIH 5R01HL130513 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

INTRODUCTION:Peripheral arterial stiffness measured with pulse wave velocity (PWV) is reduced 5-min after an acute bout of dynamic exercise. The mechanism for the reduction in peripheral arterial stiffness is unknown. We hypothesized that increased blood flow and compression of the vasculature are potential mechanisms involved in post-exercise reduction in peripheral arterial stiffness. METHODS:Brachial-radial PWV was measured with tonometers on the exercising arm of 20 healthy young volunteers (10 females, 30 ± 5 yrs, mean ± SD) before and after 5 min of rhythmic handgrip exercise at 30% of maximal voluntary contraction (MVC), 50% MVC, and a 5 min set of passive forearm compressions. Brachial blood flow was monitored with Doppler ultrasound during exercise/compression. RESULTS:Brachial-radial PWV was lower than baseline at 5 min post (p < 0.001) for 30% MVC, 50% MVC, and compression, with responses similar among all conditions (p > 0.05). PWV remained lower than baseline at 15 min and 30 min only for 50% MVC. Blood flow and changes in brachial diameter during exercise/compression were not factors in the PWV reduction (p > 0.05). CONCLUSION:These findings suggest that compression of the forearm vasculature contributes to the initial reduction in peripheral PWV after handgrip exercise, but the reductions in peripheral PWV are not associated with changes in blood flow.

Cardiotoxicity is a significant challenge associated with common first-line breast cancer (BC) anti-neoplastic (CTx) treatments including anthracyclines (AC) and targeted immunotherapies, such as anti-Her-2 therapy. Non-Hispanic black/African American (NHB) women are at higher risk for CTx induced cardiotoxicity compared to Non-Hispanic White (NHW) women. To date, most study efforts to mitigate cardiotoxicity target large vessels and cardiac damage. However, impaired microvascular function may also be implicated. Further, although exercise interventions reduce systemic inflammation and cardiovascular risk, few cardio-oncology studies examine the effect of exercise on CTx cardiotoxicity, and none have quantified microvascular endothelial function. An additional gap is the paucity of studies focused on racial disparities. The Discovery and Elimination of Cardio-Oncology Disparities for Equity in the Heartland (DECODE Heartland) Center addresses these gaps with three overarching goals to: (1) Test the feasibility and efficacy of the Take Charge during Treatment (TCT) exercise intervention designed to mitigate the adverse effects of CTx; (2) Quantify differences on exercise capacity and quality of life (QoL), endothelial function and molecular differences in inflammation in NHB versus NHW BC patients before and following CTx; and (3) Examine the influence of socio-ecological factors (individual, interpersonal, systemic, environmental) on inflammation, microvascular endothelial function, QoL in response to the exercise intervention. NHB and NHW women diagnosed with non-metastatic BC, scheduled to receive AC and/or anti-Her2 therapy, will be recruited and randomized to participate in the TCT intervention or usual care. TCT is a virtual exercise program with weekly coaching sessions, six of which include supervised exercise. Assessments include surveys, dual X-ray absorptiometry, flow-mediated dilation, pulse wave velocity and analysis, VO2 peak cycling test, fat biopsy, venous puncture blood draw, geocoding of patient addresses, and measurement of neighborhood characteristics. Assessments will be captured prior to treatment, post-intervention (16-20 weeks), and at follow-up/study completion (12-18 months post-diagnosis). This study reflects a first step in a research trajectory to identify upstream determinants of disparities and discern how behavioral strategies can assist diverse BC survivors to move through treatment toward better health, including reduced rates of cardiotoxicity following anti-cancer treatment.

As the innermost lining of blood vessels, endothelial cells (ECs) regulate blood flow, maintain vascular tone, and limit inflammation for vessel health. EC-derived nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), is a vasodilator essential for improving blood flow and vascular homeostasis. The RhoA/ROCK pathway regulates eNOS levels, where overactivation decreases eNOS expression and downstream NO production. As such, RhoA/ROCK hyperactivity and increased pMLC have been identified as major contributors to age-associated vasoconstriction and hypertension. Intriguingly, recent studies identify Sun1, a key component of the linker of nucleoskeleton and cytoskeleton (LINC) complex, as a major regulator of RhoA/ROCK activity. Moreover, endothelial aging deteriorates nuclear pore complexes (NPCs) (i.e. nucleoporin [Nup93]) and impairs nucleocytoplasmic transport, thereby insinuating a role for nuclear envelope components in vessel homeostasis. Here, we show that targeted loss of endothelial Nup93 in adult mice significantly reduces eNOS expression and NO bioavailability for consequent defects in NO-dependent vasodilatory responses. In vitro knockdown of Nup93 in primary human ECs also decreases both eNOS expression and NO production. Mechanistically, we find that loss of Nup93 significantly reduces endothelial Sun1 levels for a concomitant increase in RhoA activity. Indeed, restoring Sun1 protein levels in Nup93-deficient ECs mitigates RhoA activity to rescue both eNOS expression and NO production. Taken together, we demonstrate endothelial Nup93, through Sun1 stabilization, as a novel regulator of eNOS-NO signaling and vessel reactivity, contributing to the growing importance of nuclear membrane components in EC and vascular biology.

Background This exploratory study examined plasma levels of pro-inflammatory cytokines, chemokines and growth factors as well as intestinal fatty acid-binding protein (iFABP) and zonulin levels between young adult male and female low-risk and at-risk drinkers. Methods A total of 33 low-risk (phosphatidylethanol levels <20 ng/ml; 19 female) and 44 at-risk drinkers (phosphatidylethanol levels ≥20 ng/ml; 30 female) were included in this study. Fasting blood samples were obtained in all participants. A multiplex assay was used to measure 48 chemokines and growth factors. An enzyme-linked immunoassay was used to measure plasma levels of human iFABP and zonulin. Results We found that in young female, at-risk drinkers had a lower level of granulocyte-macrophage colony-stimulating factor (p = 0.04) and platelet-derived growth factor BB (P = 0.04) than low-risk drinkers, while in males, an elevated level of interferon-gamma was found in at-risk drinkers compared to low-risk drinkers (P = 0.04). Intestinal fatty acid-binding protein levels were significantly higher and zonulin levels were significantly lower in at-risk-risk drinkers compared to low-risk drinkers (P = 0.001 and P = 0.02, respectively). Conclusions These findings suggest that at-risk drinking in young adults is associated with alterations in specific cytokines and proteins involved in intestinal barrier function.

High-fat diet (HFD)-induced obesity remains a significant global health challenge. In this study, we show that a global knock-in CRISPR mouse with the Kir2.1 L222I single-point mutation exhibits remarkable resistance to HFD-induced obesity. We identify palmitic acid (PA), a prevalent long-chain fatty acid in obesity, as a novel negative regulator of Kir2.1. Kir2.1 L222I previously shown to protect against cholesterol-mediated inhibition of Kir2.1, also confers protection against PA-induced suppression. Moreover, PA-induced suppression of Kir2.1 results in a significant loss of flow-induced vasodilation (FIV), while the L222I mutation exerts a protective effect. Notably, Kir2.1 L222I mice display significant protection against HFD-induced weight gain and adiposity independent of caloric intake. Specifically, the mutant mice show increased lean mass and decreased fat mass, specifically in both visceral and subcutaneous white adipose tissue (WAT) and intrascapular brown adipose tissue (BAT). Importantly, visceral-to-subcutaneous white adipose ratios decrease while BAT/WAT tissue ratios increase, suggesting a metabolically favorable fat distribution. This protection correlates with enhanced physical activity and increased energy expenditure. Metabolomic analysis reveals elevated TCA cycle metabolites in adipose tissue of Kir2.1 L222I mice, consistent with their enhanced energy expenditure. These findings highlight Kir2.1 channels as potential therapeutic targets for obesity and related metabolic disorders.

BACKGROUND:The association between alcohol and hypertension has been predominantly based on office blood pressure (BP) measurements. However, little is known about the effect of alcohol use on nighttime BP and the underlying mechanisms. The purpose of this study was to investigate the effects of at-risk alcohol use on nighttime BP, urinary catecholamines, and sleep quality in midlife adults. METHODS:A total of 32 midlife men and 30 postmenopausal women, free of major clinical diseases and nonsmokers (age: 58 ± 4; mean ± SD), were included. Among all participants, 22 were currently taking antihypertensive medications. At-risk drinkers were defined as those who had a dried blood spot phosphatidylethanol level ≥20 ng/mL. All participants completed 24-h ambulatory BP monitoring and urine collection to determine nighttime (or asleep) BP and nighttime urinary catecholamine levels. Sleep quality was determined by using the Pittsburgh Sleep Quality Index. RESULTS:In midlife adults free of antihypertensive medications, at-risk drinkers had a higher nighttime systolic (118 ± 14 vs. 107 ± 14 mmHg, p = 0.02) and diastolic BP (70 ± 9 vs. 62 ± 9 mmHg, p = 0.003) than low-risk drinkers with no between-group differences in sleep quality component scores (p ≥ 0.14). In midlife adults taking antihypertensive medications, no difference in nighttime BP was found between at-risk drinkers and low-risk drinkers (p ≥ 0.68), with a higher score for the "use of sleeping medication" component in high-risk drinkers (p = 0.02). Regardless of antihypertensive medication use, no difference between at-risk drinkers and low-risk drinkers was found in nighttime urinary catecholamine levels (p ≥ 0.19). CONCLUSIONS:Our findings suggest that in midlife adults free of antihypertensive medication use, at-risk alcohol use is associated with an increase in nighttime BP, and the increase in nighttime BP may be mediated by mechanisms other than increased catecholamines and poor sleep quality.

Abstract Background The Duke Activity Status Index (DASI) questionnaire has been the focus of numerous investigations - its discriminative and prognostic capacity has been continuously explored, supporting its use in the clinical setting, specifically during rehabilitation in patients with chronic heart failure (CHF).However, studies exploring optimal DASI questionnaire threshold scores are limited. Objective To investigate optimal DASI questionnaire thresholds values in predicting mortality in a CHF cohort and assess mortality rates based on the DASI questionnaire using a thresholds values obtained. Methodology This is a prospective cohort study with a 36-month follow-up in patients with CHF. All patients completed a clinical assessment, followed by DASI questionnaire, pulmonary function, and echocardiography. The Receiver Operating Characteristic (ROC) curve analysis was used to discriminate the DASI questionnaire score in determining the risk of mortality. For survival analysis, the Kaplan-Meier model was used to explore the impact of ≤/>23 points on mortality occurring during the 36-month follow-up. Results One hundred and twenty-four patients were included, the majority being elderly men. Kaplan Meier analysis revealed that ≤/> 23 was a strong predictor of CHF mortality over a 36-month follow-up. Conclusion A score of ≤/>23 presents good discriminatory capacity to predict mortality risk in 36 months in patients with CHF, especially in those with reduced or mildly reduced ejection fraction. Age, ejection fraction, DASI questionnaire score and use of digoxin are risk factors that influence mortality in this population.

BACKGROUND:Regular exercise significantly reduces cardiovascular risk and helps prevent primary and secondary cardiac events. However, the mechanisms through which exercise affects cardiovascular health remain unclear. This study investigates the acute effects of high-intensity interval training (HIIT) versus moderate-intensity continuous exercise (MOD) on endothelial function and glycemic control in patients with type 2 diabetes (T2D). OBJECTIVES:The study aimed to compare the acute effects of a single session of HIIT and MOD on endothelial function, hemodynamic parameters, and blood glucose levels in T2D patients. DESIGN:This was a randomized controlled trial (RCT). SETTING:Conducted at the Laboratory of Cardiopulmonary Rehabilitation. PARTICIPANTS:Fifty-seven sedentary patients with type 2 diabetes (39 women and 18 men) participated in the study. METHODS:Participants were randomly assigned to either HIIT (10 sprints of 30 s at 85-100% of maximum heart rate, with 1-min active pauses) or MOD (continuous exercise at 60-70% of maximum heart rate for 30 min). Brachial artery flow-mediated dilation (%FMD) and blood glucose levels were measured before and immediately after the sessions. RESULTS:HIIT significantly increased %FMD (9.3 ± 5.3% vs 20.05 ± 9.3%, p < 0.01) and reduced glucose levels (189 [106-335] mg/dL vs 149 [70-448] mg/dL, p < 0.01). Although MOD also showed positive responses, HIIT yielded more pronounced improvements in endothelial function. CONCLUSION:HIIT is more effective for cardiovascular protection than MOD, although both exercises improve glycemic control in T2D patients. Higher %FMD is associated with better physical capacity and heart rate recovery, indicating a favorable prognosis.

Purpose/Aim: Cardiovascular function is controlled and regulated by a functional brain-heart axis. Although the exact mechanism is not fully understood, several studies suggest a hemispheric asymmetry in the neural control of cardiovascular function. Thus, the purpose of this study was to examine whether endothelial function and arterial compliance differ between individuals with left- and right-sided strokes.Materials and Methods: This was a cross-sectional exploratory study. Thirty individuals more than 6 months after stroke participated in the study. The endothelial function was assessed by ultrasound-measured flow-mediated dilation of the nonparetic arm brachial artery (baFMD). The arterial stiffness was assessed by measuring carotid-femoral pulse wave velocity (cfPWV) and central aortic pulse wave analysis [augmentation index (AIx), augmentation index normalized to a heart rate of 75 bpm (AIx@75) and reflection magnitude (RM)] using applanation tonometry. Results: Participants with right-sided stroke had worse endothelial function than those with left-sided stroke. This difference (baFMD = 2.51%) was significant (p = 0.037), and it represented a medium effect size (r = 0.38). Likewise, they had higher arterial stiffness than those with left-sided stroke. This difference (AIx = 10%; RM = 7%) was significant (p = 0.011; p = 0.012), and it represented a medium effect size (r = 0.48; r = 0.47).Conclusions: Our findings suggest that individuals with right-sided stroke have reduced endothelial function and arterial compliance compared to those with left-sided stroke. These data may indicate that those with right-sided strokes are more susceptible to cardiovascular events.

Dyslipidemia is a critical factor in endothelial dysfunction; however, the mechanisms are still not well understood. Our studies showed that cholesterol-induced suppression of endothelial flow-sensitive Kir2.1 channels contributes significantly to the impairment of flow-induced vasodilation (FIV) in hypercholesterolemic ApoE -/- mice. Notably, a CRISPR mouse generated to substitute Kir2.1 with its cholesterol-insensitive mutant via a single-point mutation results in a full rescue of FIV under hypercholesterolemia. To extend our observations to humans, 16 healthy subjects were recruited with LDL-cholesterol ranging from 51-153 mg/dl, and FIV was assessed in resistance arterioles isolated from gluteal adipose. Kir2.1-dependent FIV was assessed by transducing intact resistance arteries with the adenoviral construct expressing dominant-negative Kir2.1 (dn-Kir2.1) driven by an endothelial-specific ( Cdh5 ) promoter. Our results show that Kir2.1-dependent FIV of resistance arteries contributed ~50% of the vasodilatory response in participants with normal/low LDL levels (<100 mg/dL) and was sharply reduced in participants with LDL levels >100 mg/dL. A significant negative correlation was observed between FIV and LDL, which was accounted for by the loss of Kir2.1-dependent FIV component. Furthermore, impaired FIV in in arteries from participants with high-LDL was fully rescued by overexpressing WT-Kir2.1 in the endothelium. These data suggest that cholesterol-induced suppression of Kir2.1 is a major mechanism underlying endothelial dysfunction in hypercholesterolemia. Mechanistically, we showed previously that Kir2.1 is required for the flow-activation of Akt1/eNOS. Our new data show that Kir2.1 is also required for the upstream event of flow-induced activation of Piezo1, PECAM1, PI3K and that transducing the arteries with endothelial specific construct of Akt1 stably located at the membrane (myrAkt1) eliminates the dependence of FIV on Kir2.1. Based on our observation, we conclude that Kir2.1 is required for the translocation of Akt1 to the membrane, and the cholesterol suppression of Kir2.1 interferes Akt1-dependent flow-induced NO production.

Background: Vascular diseases, including atherosclerotic cardiovascular disease (ASCVD) and stroke, increase the risk of Alzheimer’s disease and cognitive impairment. Serum biomarkers, such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF-1), may be indicators of cognitive health. Objective: We examined whether vascular risk was associated with levels of cognition and serum biomarkers in older women with cardiovascular disease (CVD). Methods: Baseline data from a lifestyle trial in older women ( n = 253) with CVD (NCT04556305) were analyzed. Vascular risk scores were calculated for ASCVD (ASCVD risk estimator) and stroke (CHA2DS2-VASc) based on published criteria. Cognition-related serum biomarkers included BDNF, VEGF, and IGF-1. Cognition was based on a battery of neuropsychological tests that assessed episodic memory, semantic memory, working memory, and executive function. A series of separate linear regression models were used to evaluate associations of vascular risk scores with outcomes of cognition and serum biomarkers. All models were adjusted for age, education level, and racial and ethnic background. Results: In separate linear regression models, both ASCVD and CHA2DS2-VASc scores were inversely associated with semantic memory (β= –0.22, p = 0.007 and β= –0.15, p = 0.022, respectively), with no significant findings for the other cognitive domains. There were no significant associations between vascular risk scores and serum biomarkers. Conclusions: Future studies should prospectively examine associations between vascular risk and cognition in other populations and additionally consider other serum biomarkers that may be related to vascular risk and cognition.

Introduction: Endothelial dysfunction can trigger the development and progression of cardiovascular disease. We hypothesize that cardiovascular PASC is induced by persistent endothelial dysfunction mediated via asymmetric-dimethylarginine (ADMA, the endogenous inhibitor of endothelial nitric oxide synthase). ADMA levels rise in response to viral infections, but it is usually degraded by the enzyme DDAH1, which is inhibited by chronic inflammation and oxidative stress. This study aims to determine whether cardiovascular PASC is associated with endothelial dysfunction and to clarify the role of ADMA in this relationship. Methods: We recruited subjects who had been previously infected and developed cardiovascular symptoms (PASC+), those who had been infected but did not have PASC (PASC-), and those who had never been infected (controls) (n=20 each). Groups were matched for age, sex, and BMI and underwent blood draws and fat biopsies. Vascular function was assessed in-vivo via ultrasound imaging and ex-vivo in fat-isolated arterioles. Results: Compared to PASC- and controls, PASC+ subjects exhibited 80% higher serum levels of ADMA and 40% reduced nitric oxide levels. DDAH1 activity was elevated in the PASC+, suggesting a compensatory mechanism for the elevated ADMA levels. However, PASC+ obese subjects exhibited substantially lower DDAH1 activity than non-obese subjects, which was associated with lower insulin sensitivity and higher ADMA levels. Compared to the other two groups, the PASC+ group exhibited lower brachial artery vasoreactivity, while nitroglycerin-induced dilation did not differ statistically, suggesting impaired endothelial function. In the PASC+ group, microvascular recruitment in response to reactive hyperemia was diminished, as was the ex vivo measured flow-induced arteriolar dilation and NO generation. Left ventricle (LV) dysfunction was observed in 80% of the PASC+ group, as opposed to 5% of the PASC- and controls. The LV ejection fraction and global longitudinal strain (GLS) were substantially reduced in the PASC+ group, which was correlated with higher ADMA, C-reactive protein, and troponin-1, as well as lower NO and vascular function. Obese PASC+ subjects had the highest ADMA and the lowest endothelial-dependent vasodilation and insulin sensitivity. Conclusion: Cardiovascular PASC symptoms are related to persistent endothelial dysfunction and elevated ADMA levels, which may be further exacerbated by obesity and reduced DDAH1 activity.