Development Of Cardiovascular Disease Research Articles

Racial Disparities in Fluid Intake and Plasma Copeptin in Young Adults

INTRO: Underhydration, or habitual low water intake, is associated with increased plasma copeptin, a surrogate marker of arginine vasopressin. Importantly, plasma copeptin is associated with development of cardiovascular disease (CVD) and chronic kidney disease (CKD). Compared with White individuals, Black individuals are more likely to be underhydrated, to develop CVD and end-stage CKD, and exhibit higher plasma copeptin in middle-age and older adulthood. However, there is limited information on potential racial differences in plasma copeptin in young apparently healthy adults, which may have implications for incident CVD and CKD. Therefore, we sought to determine whether young Black adults reported lower fluid intake and exhibited higher plasma copeptin concentration when compared with young White adults. Methods: We analyzed pre-existing data from two registered clinical trials (NCTs 04576338 and 05132556). Participants (n=86, sex; 40F/46M, race; White n=48, Black n=38, age; 21±2 years, BMI; 25±4 kg/m2) completed a three-day food and fluid log and underwent a venous blood draw to measure plasma copeptin concentration (BRAHMS Copeptin proAVP KRYPTOR). Food and fluid records were analyzed using the Nutrition Data System for Research for % fluid from food or water. Separately, records were used to operationalize beverage intake into 8 categories (water, sugar-sweetened beverages (SSB), milk/non-dairy alternatives, 100% juice, non-caloric beverages, plain coffee or tea, milk/sugar added coffee or tea, and alcohol). Statistical analyses included Mann-Whitney U tests for fluid intake data and ANCOVA for plasma copeptin concentration (controlled for site). Plasma copeptin was log transformed. Additionally, we assessed relations between fluid intakes and plasma copeptin concentration using Spearman’s (ρ) correlations. We set α at ≤ 0.05. Results: Compared with White adults, Black adults consumed less total fluid (Black; 1981 ±1035 vs. White; 2780±1242mL), water, alcohol, and coffee/tea (plain and milk/sugar-added), but more juice (all p’s<0.05). There were no differences in % fluid from food or water, milk/non-dairy alternatives, non-caloric beverages, or SSBs. Black individuals exhibited ~22% higher plasma copeptin concentration (Black; 5.5±2.8 vs. White; 4.5±2.8pmol/L, ANCOVA p=0.022). Irrespective of race, copeptin was negatively correlated with water intake (ρ=-0.230, p=0.034). CONCLUSION: Black young adults reported a significantly lower fluid intake and exhibited higher plasma copeptin concentration when compared with White young adults. Future studies should attempt to address racial disparities in hydration practices, which may attenuate racial differences in copeptin and corresponding health disparities. NIH-K01HL147998 (ATR), Auburn University Offce of Vice President for Research Support Program (ATR). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Elucidating the role of chemokines in inflammaging associated atherosclerotic cardiovascular diseases

Age-related inflammation or inflammaging is a critical deciding factor of physiological homeostasis during aging. Cardiovascular diseases (CVDs) are exquisitely associated with aging and inflammation and are one of the leading causes of high mortality in the elderly population. Inflammaging comprises dysregulation of crosstalk between the vascular and cardiac tissues that deteriorates the vasculature network leading to development of atherosclerosis and atherosclerotic-associated CVDs in elderly populations. Leukocyte differentiation, migration and recruitment holds a crucial position in both inflammaging and atherosclerotic CVDs through relaying the activity of an intricate network of inflammation-associated protein-protein interactions. Among these interactions, small immunoproteins such as chemokines play a major role in the progression of inflammaging and atherosclerosis. Chemokines are actively involved in lymphocyte migration and severe inflammatory response at the site of injury. They relay their functions via chemokine-G protein-coupled receptors-glycosaminoglycan signaling axis and is a principal part for the detection of age-related atherosclerosis and related CVDs. This review focuses on highlighting the detailed intricacies of the effects of chemokine-receptor interaction and chemokine oligomerization on lymphocyte recruitment and its evident role in clinical manifestations of atherosclerosis and related CVDs. Further, the role of chemokine mediated signaling for formulating next-generation therapeutics against atherosclerosis has also been discussed.

Abstract 3116: Elucidating The Molecular Progression Of Hereditary Vascular Dementia In A Novel Mouse Model

Aging is an immutable risk factor for the development of numerous cardiovascular diseases, including vascular dementia. Vascular dementia is the second most common cause of dementia with up to 20% of dementia cases in the elderly attributed to dysfunctional vasculature. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a mendelian vascular dementia characterized by progressive dysfunction of vascular smooth muscle cells (vSMCs) due to gene variants in NOTCH3 . With over 250 known disease - causing variants in NOTCH3 identified in the past 24 years, the allelic heterogeneity observed in CADASIL has long contributed to our impaired understanding of the molecular progression from NOTCH3 variation to clinical presentation. Recent work published by our group has shown that Notch3 is lost from in the cerebral vasculature of mouse ( Notch3 -/- ) and humans during aging. With time, the progressive loss of Notch3 in the aging mouse brain vasculature drives the formation of cerebral micro-aneurysms as well as impairs vascular reactivity and cerebral blood flow. These vascular consequences also hinder glymphatic flow which promotes an accelerated aggregation of glycosaminoglycans and the development of neuronal gene signature analogous to those observed in other neurodegenerative diseases such as Alzheimer’s disease. To assess if CADASIL represents a loss of NOTCH3 function and thus an accelerated cerebral aging or novel gain of function in NOTCH3, we used CRISPR-Cas9 genome editing to create a novel CADASIL mouse model: Notch3C175Y (N3Y). This alteration faithfully recapitulates the human variant within the same locus and shows the pathological hallmark of CADASIL: GOMs (granular osmiophilic material). Histopathological assessment of the N3Y mouse shows dysregulation of the vSMC organization as early as 8 weeks of age along with novel structural abnormalities as compared to the Notch3 -/- . Using single-cell RNA sequencing we also performed in-depth molecular characterization of the vascular changes in N3Y. Analysis at 2 months and at 24 months allowed us to identify temporal progression of the disease and provided novel molecular insights into the mechanisms of this mendelian form of vascular dementia.

Статеві та клініко-інструментальні паралелі рівнів ліпопротеїн(а) в пацієнтів з дуже високим серцево-судинним ризиком

In recent years it has been established that elevated levels of Lp(a) are an independent genetic risk factor for the development of atherosclerotic cardiovascular diseases and aortic stenosis, however, issues of gender and age characteristics remain controversial.The aim of study was to analyze the gender characteristics of the relationship between Lp(a) levels and atherogenic changes in the lipid spectrum of the blood, clinical and instrumental characteristics, taking into account damage to the aortic valve and the results of coronary angiography in patients with stable coronary heart disease. Materials and methods. The 106 patients with chronic coronary heart disease (CAD) were examined. The average age of the subjects was 55.00±1.0 years (95% CI 51.11-58.89), among them: 78 men and 28 women.The entire cohort of patients was divided depending on the Lp(a) levels: 1group (n=58) with a Lp(a) level less than 50 mg/dl; 2 group (n=20) with Lp(a) level 50-100 mg/dl; 3 group (n=8) with Lp(a) level 101-150 mg/dl and 4 group (n=20) with Lp(a) level more than 150 mg/dl.Research methods included: 1. General clinical examination; 2. Laboratory characteristics of lipid (with determination of Lp(a)) and carbohydrate metabolism, as well as standard biochemical parameters; 3. Instrumental examination (electrocardiography, echocardiography, ultrasound peripheral vessels examination, coronary angiography); 4. Mathematical and statistical processing of the results obtained.Results and conclusions. In patients with CAD verified by clinical-instrumental and coronary angiographic criteria, it is noted that Lp(a) levels in women are on average significantly higher (P< 0.05) than in men and increase with the onset of menopause.Close correlations have not been recorded between Lp(a) in mg/dL and total cholesterol, LDL cholesterol and non-HDL cholesterol, as well as the concentrations of glucose, glycosylated hemoglobin, serum creatinine, and the concentration of thyroid-stimulating hormone (TSH).Determined that in patients with documented atherosclerotic lesions of the coronary arteries against the Lp(a) levels above 100 mg/dl, there is a greater need for coronary revascularization. A close relationship is observed between the increase in Lp(a) levels and the percentage of detection of aortic stenosis, which confirms the pathogenetic role of this lipoprotein in the formation of this acquired aortic valve disease.

Excessive Hypercholesterolemia in Pregnancy Impairs Later-life Maternal Vascular Function in Rats

Background: Preeclampsia is a significant risk factor for the development of later-life cardiovascular disease; however, the underlying molecular mechanisms are not fully understood. Studies have shown that excessive hypercholesteremia occurring during pregnancy increases the risk of vascular pregnancy complications, such as preeclampsia. Bioavailability of nitric oxide (NO), a critical endothelium-derived vasodilator in pregnancy, is reduced in both hypercholesteremia and preeclampsia. However, the later-life vascular impact of excessive pregnancy-specific hypercholesteremia is not known. Hypothesis: Excessive hypercholesteremia in pregnancy impairs later-life maternal vascular function by reducing NO availability. Methods: Sprague-Dawley rats were fed a control diet (CD) or high cholesterol diet (HCD; 2% cholesterol + 0.5% cholic acid) from gestational day 6 to 20 (term=22 days; n=10-12). After pregnancy, all dams received a CD. Three months after pregnancy (equal to ~10 years in humans), mesenteric (systemic resistance arteries) and carotid (vascular bed that supplies blood to the cerebral vasculature) arteries were isolated, and endothelium-dependent (to methacholine, MCh) and -independent (to sodium nitroprusside, SNP) vasodilation, plus vasoconstriction responses (to phenylephrine, PE) were assessed using wire myography. NO contribution was assessed using a pan-NO synthase inhibitor (L-NAME; 100 μmol). Data were summarized as maximum responses (Emax), sensitivity (pEC50), or delta Emax (control vs. L-NAME). The statistical tests applied were a Student’s t-test or two-way ANOVA with Sidak’s post-hoc test (significance: p<0.05). Results: In mesenteric arteries, vasodilation to MCh or SNP was not different between the CD and HCD groups three months after the insult. However, L-NAME reduced maximum vasodilation to MCh in the HCD group (p=0.0433) but not in CD animals. Similarly, vasoconstriction to PE was not different between groups, but L-NAME increased the PE sensitivity in the HCD group (p=0.0423), without effects in the CD animals. In carotid arteries, a HCD during pregnancy reduced vasodilation to MCh (p=0.0345), and while L-NAME prevented vasodilation to MCh in both groups (p<0.0001), this effect was more pronounced in the HCD compared to CD group (delta Emax, p=0.0422). Vasodilation to SNP was similar between groups. Vasoconstriction responses to PE were increased in carotid arteries of HCD compared to CD animals (p=0.0357). L-NAME increased PE-mediated vasoconstriction in both groups (CD: 4.32-fold and HCD: 2.71-fold), but this NO modulation was significantly less in the HCD group compared to CD (delta Emax, p=0.0337). Conclusion: Exposure to a HCD, during pregnancy only, impaired later-life maternal vascular function in carotid, but not mesenteric arteries, suggesting vascular-bed specific effects in animals with a history of preeclampsia. Moreover, a HCD during pregnancy altered the NO pathway in both vascular beds, indicating that long-term alterations in NO were established during pregnancy. In summary, excessive pregnancy-specific hypercholesterolemia contributes to later-life maternal vascular dysfunction via modulation of the NO pathway, which may help explain the increased cardiovascular risk after preeclampsia. This work was supported by a foundation grant from the Canadian Institutes of Health Research (CIHR FS154313) and by the Women and Children’s Health Research Institute (WCHRI) through the generosity of the Stollery Children’s Hospital Foundation and the Alberta Women’s Health Foundation. A.A.O. is supported by a WCHRI postdoctoral fellowship through the generosity of the Stollery Children’s Hospital Foundation and the Alberta Women’s Health Foundation. E.E. was supported by a summer research studentship from Alberta Innovates. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Exercise Intensities on Changes in Pro-/Anti-inflammatory Cytokines following 8-weeks of Aerobic Exercise Training

Inflammatory cytokines are useful biomarkers in predicting the development of metabolic and cardiovascular diseases and may be positively affected by physical activity and weight loss. Despite much interest in chronic low-level inflammation in the obese population, effects of aerobic training intensity on inflammatory cytokines remain elusive. PURPOSE: The purpose of this study was to investigate effects of 8-week aerobic exercise training at high and low intensities on changes in pro-/anti-inflammatory cytokines. Methods: Fifty three inactive obese Hispanic females (mean BMI = 34.5 kg/m2, aged 34-46 years) were divided into one of three groups: low intensity training group (LT: walking at 55% VO2max, n=16), high intensity training group (HT: running at 70% VO2max, n=18), and control group (CON: no intervention, n=19). LT and HT performed aerobic exercises three times per week at the given intensities. Exercise volume for two exercise groups was equated relative to kilograms of body weight by adjusting duration of exercise session (approximately 60 minutes for LT and 40 minutes for HT per session). Blood samples were collected before and after 8 weeks of intervention to measure levels of adiponectin, C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α). Two-way repeated measures ANOVA and Tukey post hoc tests were used for data analysis. Results: Level of adiponectin showed no significant change in any groups after 8 weeks of aerobic exercise intervention. A significant decrease in CRP was observed in the HT group only (4.12 ±.26mg/L mean±SE → 3.89±.37, P=.041), but levels of TNF-a were significantly decreased in both LT (4.57±.24pg/mL → 4.14±.31, P=.019) and HT (4.54±.25 → 4.02±.41, P=.011). No changes were observed in CON. CONCLUSIONS: Significant decreases in CRP and TNF-a were found following high intensity aerobic exercise training while low intensity training reduced TNF-a only. The greater changes of pro-inflammatory cytokines in HT indicates high intensity aerobic exercise training may be more beneficial than low intensity training. Specifically, for controlling low-grade inflammation and immune function in obese Hispanic females. This study confirmed results of previous studies suggesting that longer period of exercise training with distinct fat loss may be required to induce significant changes in adiponectin in obese adults. TAMIU university research grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

SYSTEMIC DISEASES ARE A GROUP OF INFLAMMATORY ILLNESSES THAT CAN DAMAGE THE ARTERIAL WALL ASSESSED ACCORDING TO NON-INVASIVE ARTERIAL TONOMETRY

Objective: Objective: Hypertensive Cardiovascular Disease is a complex, multifactorial, and chronic illness, frequently beginning during childhood or adolescence, could develop functional and/or structural organ damage by the increase of arterial stiffness and the curve volume/pressure that in turn can raise the stress into the ventricular-arterial coupling and the appearance of arrhythmias. The aim of this study was to assess systemic inflammatory diseases according to non-invasive arterial tonometry and their possible complications. Design and method: Design & Method: This cross-sectional study registered 339 patients, women 77%, both sexes, presented various systemic inflammatory diseases such as Psoriasis (123), Rheumatoid Arthritis (26), Celiac disease (13), Sjögren's disease (9), Crohn's disease (7), Ulcerative colitis (10), Endometriosis (10), Polycystic Ovary Syndrome (141). Anthropological data, Systolic/Diastolic Blood Pressure, and Heart Rate were measured. Central Hemodynamic Parameters (Central Aortic Pressure, End-Systolic Pressure, Mean Arterial Pressure, Pulse Pressure, Augmentation Pressure) and the difference between the maximum normal level and the observed value of the Augmentation Index (Diff-AIx), the surrogated value of arterial stiffness, were assessed with the SphygmoCor System-PVX, according to established protocols by sex and age. Results: Results: The mean age of women and men was 45-51 years. The mean of Systolic/Diastolic Blood Pressure among women and men was 132.5/81.6-135.2/85.9 mmHg, respectively. The Diff-AIx among women was 4.8 and among men was 5.4. The most important finding of the assessment of the systemic inflammatory diseases was the presence of hypertensive cardiovascular disease, considering the measurements of high systolic and diastolic blood pressure, and the abnormal Central hemodynamic parameters. The most important complication observed was the brief phases of atrial fibrillation during the 24-hour Holter monitoring (7.4%), the mean age of patients was 64.2 years, range of 44-88 years, and the highest percentage of each group were Ulcerative colitis (20.0%), Rheumatoid Arthritis (15.4%), and Crohn's disease (14.3%), Psoriasis (10.6%), Endometriosis (10.0%). Conclusions: Conclusions: The systemic diseases can damage the arterial wall and contribute to the development of Hypertensive Cardiovascular Disease. Cardiologists and clinical physicians, in the anamnesis, should include the search for inflammatory systemic diseases for a more complete clinical evaluation and therapeutic guidance.

Evidence of Premature Vascular Dysfunction in Young Adults who Regularly Use E-cigarettes and the Impact of Usage Length

Background: Electronic (e-) cigarettes are increasingly popular novel tobacco products on the US market. Traditional tobacco products are well known to cause vascular dysfunction, one of the earliest indicators of cardiovascular disease (CVD) development. Despite the popularity of e-cigarettes, little is known about the effect of regular e-cigarette use on vascular function. The purpose of this study was to investigate the impact of regular e-cigarette use on vascular function and cardiovascular health in young, healthy adults. Methods: Twenty-one regular users of e-cigarettes (ECU, age: 23±3 y.) and twenty-one demographically matched non-users (NU, age: 25±5 y.) completed this study. Vascular health was assessed in the cutaneous microcirculation through different reactivity tests to evaluate overall functionality as well as endothelium-dependent vasodilation (EDD) and endothelium-independent vasodilation (EID). Macrovascular function was assessed using flow-mediated dilation (FMD). Results: Our results suggest that regular users of e-cigarettes present with premature microvascular impairment compared to non-users. Specifically, they exhibit lower hyperemic ( p=0.003), thermal ( p=0.010), and EDD ( p=0.004) responses. No differences in EID between the groups were identified. We also identified that individuals who use e-cigarettes for longer than three years also present with systemic manifestations, as observed by significantly reduced macrovascular ( p=0.002) and microvascular ( p≤0.044) function. Conclusions: Our novel data suggests that young, apparently healthy, regular users of e-cigarettes present with premature vascular dysfunction in the microcirculation compared to non-users. We have also identified systemic vascular dysfunction affecting both the micro and macrovasculature in those young individuals who used e-cigarettes for longer than three years. Taken together, these findings associate regular e-cigarette use with premature vascular dysfunctions and adverse cardiovascular outcomes. Supported in part by a Rapid Response Project NIDA/FDA (PRM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diminished insulin-induced vasodilation of the posterior cerebral artery in db/db mice is associated with reduced presence of endothelial insulin receptor alpha and inward remodeling

Type 2 diabetes (T2D) is a major risk factor for cardiovascular disease (CVD) development and associated mortality. In the cerebral circulation, T2D-related vascular disfunction also contributes to diverse cerebrovascular diseases including stroke, cognitive impairment, and dementia. Previous research has documented that endothelial dysfunction and inward remodeling are prevalent pathophysiological characteristics of the arterial circulation in T2D. We have further documented that reduced presence of endothelial insulin receptor alpha (IRα) contributes to impaired insulin-dependent vasodilation in omental arteries from T2D patients. Herein, we tested the hypothesis that, compared to wild-type (WT) mice, diabetic db/db mice have reduced insulin-induced vasodilation of the posterior cerebral artery (PCA) in association with reduced presence of endothelial IRα and inward remodeling. We used pressure myography in isolated PCAs to assess vascular reactivity and remodeling, and confocal microscopy to determine IRα content on the endothelial surface. All reported differences are significant at P<0.05. Our results indicate that, when compared with WT controls, PCAs from db/db mice have reduced insulin-induced vasodilatory responses in association with reduced presence of endothelial IRα, inward remodeling, and increased arterial stiffness. The amount of IRβ, elastin, or collagen present in the PCAs did not differ between groups. These findings provide evidence of cerebrovascular endothelial dysfunction in the form of impaired insulin-induced vasodilation in db/db mice, a defect likely attributed to the reduced presence of endothelial IRα and associated with vascular inward remodeling. These changes may contribute to cerebrovascular disease development and progression in T2D, including stroke, cognitive impairment, and associated dementias. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A novel antibody that neutralizes corticotropin-releasing factor attenuates the cardiovascular effects of chronic social defeat stress in mice

According to the World Health Organization, cardiovascular disease (CVD) continues to be the leading cause of death worldwide. While a myriad of genetic and environmental factors influence the development of CVD, there are several lines of evidence suggesting that psychological stress contributes to health disparities in CVD observed amongst different populations. Our lab seeks to understand the effects of psychosocial stress on cardiovascular health using a model of chronic social defeat stress (CSDS) in mice. In this paradigm, male C57BL/6 mice undergo brief daily defeat sessions and are housed in the same cage as the larger, more aggressive CD1 defeater mouse, separated by a polycarbonate divider that allows for continuous visual, auditory, and olfactory contact while preventing physical contact. We have previously demonstrated that this paradigm causes robust and persistent elevations in blood pressure, indices of chronic inflammation, elevations in plasma corticosterone and cardiac and adrenal hypertrophy. Social defeat also leads to robust activation of corticotropin releasing factor (CRF) neurons within the paraventricular nucleus of the hypothalamus (PVN). In the present studies, we investigate whether we can alleviate some of the adverse effects of CSDS through targeting the HPA axis using CTRND05, a novel anti-CRF antibody. Adult male C57BL/6 mice were assigned to either CSDS or control (paired) housing. Following 14 days of CSDS or control housing, mice were treated with one injection of CTRND05 (25 mg/kg, i.p.) or vehicle (IgG), followed by 14 more days of CSDS or control housing. A booster administration of CTRND05 (12.5 mg/kg, i.p.) was given 7 days after the initial dose. Adrenal weights were significantly reduced in pair housed mice treated with CTRND05 compared to pair housed mice treated with IgG, and there was a trend towards a reduction in adrenal weight of CSDS mice treated with CTRND05 in comparison with CSDS mice treated with IgG. There was also a trend for reduced basal corticosterone in CSDS mice treated with CTRND05. Importantly, while IgG treatment had no effect on the systolic blood pressure (SBP) of CSDS mice, treatment with CTRND05 significantly lowered the SBP of CSDS mice when compared with pre-treatment. These data suggest that targeting CRF may serve as a therapeutic tactic for treatment of stress-related hypertension. R35HL150750, R01HL136595. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Association between non-registration of chronic kidney disease and mortality and cardiovascular outcome: a time-to-event analysis of retrospective primary care data

ObjectivePatients with impaired kidney function and increased albuminuria are at risk of developing cardiovascular disease (CVD). Previous research has revealed that a substantial proportion of patients with chronic kidney disease...

Metabolic dysfunction in the myocardium three months after exertional heat stroke in mice

In humans, exposure to heat stroke has proven to be a risk factor for development of cardiovascular disease later in life. We hypothesized that exposure to exertional heat stroke (EHS) would result in the development of similar long-term cardiac disease in mice. In this study we followed mice for three months after EHS, using ultrasound imaging of the heart, metabolomics and histological analysis of ventricular tissue and biomarker analysis after 4 weeks of recovery. Methods: Mice were instrumented with temperature telemetry devices and were trained to run on forced running wheels using an incremental exercise protocol. EHS mice ran in an temperature elevated environmental chamber; females 37.5°C; males 34°C; whereas, matched exercise control mice (EXC) ran in 22-23°C. Running stopped when EHS mice reached symptom limitation (unconsciousness). The mice were followed for 12 wks post EHS, with two ultrasound measures at 2 and 10 wks of recovery. At the end of the study, mice were anesthetized, a blood sample drawn, and ventricular tissue collected for metabolomics. RESULTS: Male but not female EHS mice gained ~10% greater body mass compared to EXC over the course of recovery ( P<0.01). Hearts from male but not female EHS mice exhibited elevations in heart mass per tibia length ( P<0.01). At three months, metabolomics in male EHS hearts revealed significant elevations in glucose and glucose metabolites and significant decreases in acylcarnitines consistent with a metabolic shift toward glucose and away from lipid metabolism. In contrast, female hearts exhibited fewer abnormalities but with significant elevations in lipid and arachidonate metabolites. At two weeks post, there were no differences in male ultrasound measures between EHS and EXC mice but in females there was a reduced posterior wall velocity ( P=0.012) and a trend towards narrower posterior wall thickness ( P= 0.06) . Between 2 and 12 wks post EHS, there were significant elevations in fractional shortening in males ( P<0.05) and elevations in posterior wall velocity ( P<0.01). In contrast, females exhibited significant reductions posterior wall velocity. From blood samples, male EHS mice had increased HDL and females exhibited decreased HDL (p<0.01 in both). LDL increased only in males P<0.05. Vascular adhesion molecules sICAM ( P<0.01) and Pecam1 ( P<0.01) were significantly decreased in EHS males and females and e-Selectin was decreased in EHS males only ( P<0.001). Total serum protein was significantly reduced in both male and females ( P<0.01). Male EHS mice also exhibited significant elevations in white blood cell count and total lymphocytes ( P=0.01) suggesting ongoing activation of the immune system . CONCLUSIONS: In this controlled preclinical model of EHS, both male and female mice exhibited long-lasting cardiovascular and systemic disorders that could account for the lingering incidence of cardiovascular disease and poor overall health in heat stroke victims. Supported by US Army Med. Research and Devel. Command BA180078 and the BK and Betty Stevens Endowment. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

ASSOCIATION BETWEEN PERCEIVED STRESS AND VASCULAR ELASTICITY: AN OBSERVATIONAL STUDY FROM SOUTH-WESTERN SWEDEN

Objective: The association between perceived stress and arterial stiffness has yet to be fully explored. This study aims to determine the associations between perceived mental stress and arterial elasticity. Design and method: Our observational study was based on the Vara- Skövde Cohort. Between 2012 and 2014, a total of 1327 individuals were examined for risk factors for the development of cardiovascular disease. Known hypertension, missing information on mental stress and artery elasticity were exclusion criteria. In total, 785 individuals (men=379) were included. Body height, weight, heart rate, and blood pressure were measured, while data on medical history and lifestyle factors such as alcohol consumption, smoking, and physical activity were collected through validated questionnaires. Perceived stress was evaluated with the PSS-10 (Perceived Stress Scale), which contains ten questions with 0 - 4 points per item and focuses on the perceived stress in the last month. Small artery elasticity (C2) was estimated using an applanations tonometer (Pulsewave CR-2000, Hypertension Diagnostics Inc.) over the arteria radialis. Logistic regression was used in our analyses. In model 1, we adjusted for age, sex, systolic blood pressure and heart rate. In model 2, we adjusted for the variables in model 1 plus waist-hip ratio, LDL-cholesterol, and C-reactive protein. In model 3, we included model 2 plus lifestyle factors such as smoking, alcohol consumption, and physical activity. Results: The mean age was 54.5 (±10) years. There were no significant sex differences in the association between stress and vascular elasticity (interaction test p=0.371). In the fully adjusted model in logistic regression, a one-point rise in PSS-10 correlated with having an elasticity index in the lowest quartile of C2 by 5% in the entire study population (OR=1.05, CI: 1.009- 1.093, p= 0.015). Correspondingly, one quartile higher PSS-10 was associated with a 25% elevated risk of having a cardiovascular elasticity in the lowest quartile of C2 (OR=1.25, CI: 1.03- 1.52, p= 0.021). Conclusions: Increased perceived stress was associated with decreased vascular elasticity in this cohort.

The bottlenose dolphin (Tursiops truncatus): A novel model for studying healthy vascular aging

Aging is the primary non-modifiable risk factor for the development of cardiovascular diseases (CVD). CVD are often preceded by arterial dysfunction, including endothelial dysfunction and aortic stiffening. Our preliminary results suggest that the circulating milieu is associated with differences in arterial function in young and mid-life/older (ML/O) adults. Moreover, incubation of mouse arteries with serum from young and ML/O adult humans can directly transfer arterial aging phenotypes for endothelial function and aortic stiffness. These results suggest that age-related changes in the circulating milieu are an underlying mechanism of age-related arterial dysfunction. Dolphins are mammals that have evolutionary adapted to diving, with constant cycles of tissue hypoxia/reoxygenation and disturbed shear stress -- exposures which cause arterial dysfunction in humans. Dolphins also have long lifespans and are relatively free of CVD. Taken together, dolphins may be a unique model of healthy vascular aging, with possible applications to clinical medicine. PURPOSE: To determine if the serum of bottlenose dolphins ( Tursiops truncatus) induces the same arterial aging phenotypes as the serum of age-equivalent humans. Methods: Common carotid arteries and aorta rings from young (Y; 5 mo) and old (O; 25 mo) wildtype female (F) and male (M) C57BL/6N mice were exposed ex vivo for 24 and 48h, respectively, to 5% sex-matched adult dolphin serum. Dolphin serum of Y (17 ± 4 years; n = 16: 5F / 11 M) and ML/O (29 ± 2 years; n = 4: 1F/3M) adults was obtained from the National Marine Mammal Tissue Bank. Endothelial function was assessed as carotid artery endothelium-dependent dilation (EDD) in response to increasing doses of acetylcholine. Aortic stiffness was measured as elastic modulus, a measure of intrinsic mechanical wall stiffness. Dolphin serum-mediated responses in mouse arteries were compared with that of adult human serum data (Y, 24 ± 1 years, n=10: 5F/5M; ML/O, 67 ± 3 years, n=10: 5F/5M). Differences were assessed via 2-way ANOVAs; within species post hoc analyses conducted between age groups. Results: Endothelial Function. Peak EDD in Y mouse carotid arteries was lower following exposure to serum from ML/O adult humans (ML/O, 78 ± 2 v. Y, 92 ± 2%; P < 0.001) and higher in O mouse carotid arteries after exposure to Y adult serum (92 ± 2 vs. 73 ± 5%, P = 0.001). In contrast, EDD was similarly high across all groups following dolphin serum exposure (³ 93% peak EDD), independent of the age of the serum donor or the mouse arteries (Y v. ML/O serum donor in Y arteries, P = 0.773; in O mouse arteries, P = 0.942). Aortic Stiffness. Stiffness in Y aortic rings was ~60% higher following exposure to ML/O adult human serum (P = 0.001 v. Y adult serum). In O mouse aortic rings, stiffness was 25% lower after exposure to Y adult serum (P = 0.044 v. ML/O adult serum). In contrast, stiffness was similar across all groups following dolphin serum exposure, independent of age of the serum donor or the arteries (Y v. ML/O serum donor in Y aortic rings, P = 0.974; in O aortic rings P = 0.157). CONCLUSIONS: The circulating milieu of bottlenose dolphins may be geroprotective, which could serve as a model to investigate mechanisms and potential therapies for preventing adverse vascular aging and promoting CV health and longevity in humans. FUNDING: R21 AG078408 & MSCA-IF-2019:892267. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Obesity induces an increase in fatty acid uptake in endothelium of visceral adipose arteries without altering CD36 expression

Obesity is a prevalent metabolic condition and major contributor to the development of cardiovascular disease. Arteries of visceral adipose present with significant endothelial dysfunction whereas subcutaneous adipose arteries remain functional in obese humans and diet-induced obese mice. Obesity is also associated with elevated plasma long chain fatty acids (LCFAs), well-established contributors to endothelial dysfunction, which require a receptor to facilitate their uptake. CD36, a scavenger receptor, facilitates LCFA uptake, which when in excess would contribute to endothelial dysfunction. Therefore, we aimed to determine the role of CD36 in arteries ex vivo in both mouse and human subcutaneous and visceral adipose arteries as well as examine the difference in uptake of LCFAs in arteries from both depots. First, to determine if CD36 contributes to obesity-induced endothelial dysfunction in visceral adipose arteries, mesenteric (visceral) and subcutaneous adipose arteries isolated from lean and diet-induced obese WT and CD36 knockout were mounted for pressure myography. As expected, visceral adipose arteries of obese mice exhibited a blunted response to endothelium-dependent stimuli, whereas subcutaneous adipose arteries remained functional. CD36 ablation restored endothelium-dependent vasodilation in visceral arteries of obese mice, suggesting a critical role for CD36 in obesity-induced endothelial dysfunction. We next aimed to determine if obesity alters endothelial CD36 expression using two distinct approaches: flow cytometry and immunofluorescence staining of en face preparations in isolated mouse and/or human arteries. For flow cytometry, arteries were digested and sorted to identify the endothelial cell population (i.e., CD45-CD31+ cells). En face preparations were stained for VE-cadherin to locate the endothelial cell layer via confocal microscopy. In both experiments, an antibody that detects an extracellular epitope to CD36 was used to detect membrane expression. Obesity did not alter the expression of CD36 expression in visceral adipose arteries relative to lean counterpart controls or subcutaneous arteries from obese mice or humans. We next aimed to determine if LCFA uptake was altered by obesity. Arteries were exposed to a fluorescent fatty acid, and internalized endothelial LCFA uptake was assessed at different time points via confocal microscopy. Visceral arteries from obese mice and humans had elevated LCFA uptake relative to respective controls which may be an underlying mediator for the dichotomy in endothelial dysfunction observed in obesity. Ongoing work in our lab is focused on determining if this is indeed the case and, if so, if this process is mediated by endothelial CD36. National Institutes of Health (NIH) Grant P20GM113125-6564 (IF). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Androgenetic Alopecia in Men: An Update On Genetics.

Androgenetic alopecia (AGA) is defined as the alopecia induced by androgens in genetically predisposed individuals. AGA results in progressive miniaturization of the hair follicles leading to vellus transformation of terminal hair. The high prevalence and wide range of expressed phenotypes in AGA is a result of a polygenic inheritance mode. The androgen receptor (AR) gene located on the X chromosome at Xq11-12 is the first gene to show genetic association with AGA. Newer genetic associations with AGA are under study. In early-onset AGA, obesity, diabetes, hypertension, dyslipidaemia, insulin resistance, benign prostatic hyperplasia (BPH), prostate cancers and coronary artery disease (CAD) are associated with AGA. Screening of early-onset AGA patients and intervention for metabolic syndrome and insulin resistance can prevent the development of cardiovascular disease (CVD) at an early stage. As effective treatments continue to be topical minoxidil, systemic finasteride and hair transplantations, newer modalities are under investigation. Understanding the genetic factors involved in AGA and continued research into newer therapies, such as cell-based therapies, will lead to effective treatment and improve the quality of life in patients with AGA.

Exploring the Role of Visceral Fat as a Negative Regulator of Vascular Function In Obesity

Background and Objective. Obesity promotes endothelial dysfunction, a major contributor to the development of cardiovascular disease. Work from our lab and others previously showed robust impairment of arteries embedded within visceral adipose tissue as compared to those within subcutaneous adipose tissue. Here, our research is focused on obesity-induced changes in adipose tissue gene expression, and how it may negatively or positively impact the functioning of the vascular system within the tissue. Method. Visceral adipose tissue and subcutaneous adipose tissue were extracted from lean and diet-induced obese mice after 12-14 months on respective diets (normal chow and high fat, Western diet, respectively). RNA-seq was conducted to analyze the gene expression profiles, followed by quantitative polymerase chain reaction (qPCR) to validate specific gene expression changes. Finally, Western blots were performed to evaluate if changes were occurring at the protein level. Result. We identified obesity-induced changes in over two hundred eighty genes in visceral adipose tissue and more than two hundred twenty genes in subcutaneous adipose tissue when compared to visceral and subcutaneous adipose tissue from lean mice through RNA-seq analysis. We further identified genes that are over-expressed in subcutaneous adipose tissue but not in visceral adipose tissue, and vice versa, in response to diet-induced obesity. Changes in select genes were confirmed by polymerase chain reaction as well as Western blot. Discussion and Conclusions. These data may lead to important insights into the role of the identified adipose genes as they relate to the impact on arterial function. Future directions will involve approaches that delve deeper into the molecular and physiological understanding of the roles of specific adipose genes in influencing both adipose and endothelial function of the embedded arteries. We aim to ultimately determine if identified genes upregulated only in subcutaneous adipose tissue with obesity serve to spare the embedded vasculature from endothelial dysfunction and whether overexpressing such genes can restore visceral adipose artery endothelial function in obesity. This study was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under award number 2P20GM113125 (Ibra Fancher). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Predictors of Incident Stroke and Subsequent Mortality Among a Sample of Veterans with Experience of Housing Instability

Abstract: Homelessness is associated with poor health outcomes and early development of cardiovascular disease. This study investigated the correlates of incident stroke and its association with mortality among Veterans experiencing housing instability. Using a national sample of Veterans (n=565,608) with incident housing instability between 2014–2018, we compared characteristics of Veterans who did and did not experience incident stroke and conducted logistic regressions to assess two outcomes: incident stroke and mortality. Almost four percent experienced a first stroke and were more frequently male, older than 55 years, Black, and non-Hispanic. A higher rate of mortality was observed among those with a first stroke compared with those with no stroke (17.6% vs. 10.8%), although the difference was not statistically significant. Incident stroke was associated with triple the odds of death among unstably-housed Veterans compared with those who did not have an incident stroke. Implications include the need to screen and monitor for stroke risk among Veterans with experience of housing instability, particularly for those who are older.

Comparing Habituation of Cardiovascular Reactivity to Acute Mental Stress and the Cold Pressor Test

Exaggerated cardiovascular reactivity (CVR) to acute laboratory stress has been linked to the development of cardiovascular disease. However, recent evidence within the field of psychophysiology reveals that exaggerated CVR may actually be adaptive for long-term health if the response is relatively brief and decreases across subsequent stress exposures (i.e., habituation). Extensive research has validated the occurrence of CVR habituation, specifically to repeated mental stress. However, to our knowledge, no research to date has attempted to directly compare CVR habituation to mental stress with other types of stress tasks (i.e., the cold pressor test; CPT) within the same individuals. The present study aimed to compare CVR habituation to mental stress and CPT across repeated exposures. Based upon prior CVR profiles for repeated mental stress and CPT, we hypothesized that CVR habituation would be observable in response to repeated mental stress, but not repeated CPT. Sixteen healthy young adults (9M/7F, 21±1 yrs, 23±1kg/m2) participated in three experimental sessions. The initial two sessions were administered during a single laboratory visit and separated by a 45 min rest period. The third session occurred one month later at a follow-up visit. Each session included a mental stress trial (5 min baseline, 5 min mental arithmetic task) and a CPT trial (3 min baseline, 2 min CPT), with continuous recordings of heart rate (HR; electrocardiogram) and beat-by-beat arterial blood pressure (finger plethysmography). Reactivity (i.e., stress — baseline) was calculated separately for HR and mean arterial pressure (MAP). Repeated measures ANOVAs revealed a significant main effect of time for HR, F(2, 30) = 6.57, p = 0.004, η2 = 0.30, and MAP, F(2, 30) = 4.37, p = 0.02, η2 = 0.23 in response to the repeated mental stress, but not in response to the repeated CPT (all p-values ≥ 0.05). Post hoc analyses demonstrated HR reactivity to be significantly lower during session 3 of the mental stress (Δ20±9 beats/min, ps ≤ 0.015) compared to session 1 (Δ25±10 beats/min) and session 2 (Δ23±10 beats/min). No significant differences were observed between HR reactivity at sessions 1 and 2 of mental stress ( p = 0.151). MAP reactivity was significantly lower during session 2 (Δ13±5 mmHg) and session 3 (Δ12±6 mmHg) of the mental stress compared to session 1 (Δ15±5 mmHg, ps ≤ 0.030). No significant differences were observed between MAP reactivity at sessions 2 and 3 of mental stress ( p = 0.374). In summary, HR and MAP reactivity significantly habituated in response to repeated mental stress, but not in response to the repeated CPT. Findings suggest that the cardiovascular system adapts to repeated laboratory mental stress, but remains consistently engaged during repeated exposures to the CPT. National Heart, Lung, and Blood Institute (HL-122919). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Estimated pulse wave velocity predicts mortality in patients with heart failure with preserved ejection fraction

ObjectiveEstimated pulse wave velocity (ePWV), a newly established arterial stiffness (AS) parameter, predicts the development of cardiovascular disease (CVD) and death in the general population or in patients with CVD risk factors. However, whether ePWV is associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. Our study aimed to evaluate the prognostic value of ePWV on clinical outcomes in HFpEF. Methods and ResultsWe analyzed HFpEF participants from the Americas in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with available baseline data (n = 1764). Cox proportional hazard model was used to explore the prognostic value of ePWV on long-term clinical outcomes (all-cause mortality, cardiovascular mortality, all-cause hospitalization, and heart failure hospitalization). Each ePWV increase by 1 m/s increased the risk for all-cause death by 16% (HR:1.16; 95% CI:1.10–1.23; P < 0.001) and CVD mortality by 13% (HR:1.13; 95% CI:1.04–1.21; P = 0.002) after adjusting for confounders. Patients were then grouped into 4 quartiles of ePWV. Our study indicated that the highest ePWV quartile (ePWV ≥ 12.806 m/s) was associated with increased risk of all-cause mortality (HR: 1.96; 95% CI: 1.43–2.69; P < 0.001) and CVD mortality (HR: 1.72; 95% CI: 1.16–2.56; P = 0.008) after adjusting for potential confounders. ConclusionThese results suggested ePWV is independently associated with increased all-cause mortality and CVD mortality in HFpEF patients, indicating ePWV is an appropriate predictor of prognosis in patients with HFpEF.