Large Artery Stiffness Research Articles

Proteome-wide associations of pulse pressure in the UK Biobank

Abstract Introduction Large artery stiffness (LAS) significantly contributes to the burden of cardiovascular morbidity and mortality, and is marked by an increased pulse pressure (PP)(1). Therapeutically targeting LAS may help in mitigating cardiovascular disease and other comorbidities. Purpose We aimed to investigate the proteomic associations of PP, and their putative causal role using Mendelian randomization (MR). Methods We first investigated associations between baseline circulating protein levels for 2,941 protein analytes measured using Olink technology, and PP in the UK Biobank (N=54,219). Regression analyses were adjusted for age, sex, mean arterial pressure, body mass index and stroke volume. Next, we conducted two-sample MR analyses to evaluate associations between genetically-predicted plasma protein levels and PP, for 1,820 proteins with available genetic instruments. We conducted inverse-variance weighted MR as our main analysis, and genetic colocalization analyses as sensitivity. We used a 5% false discovery rate (FDR) threshold to account for multiple comparisons. Results After correction for multiple comparisons, measured levels of 61 out of 2,923 proteins were significantly associated with PP (Figure 1). Genetically-predicted levels for 58 proteins were significantly associated with PP after FDR correction (Figure 2). At nominal significance, 31 proteins were concordantly associated with PP in both analyses, and 19 had consistent directions of effect, including natriuretic peptide B (NPPB, βobservational=0.04, Standard Error (SE)=0.009, PFDR<0.001), thrombospondin-2 (THBS2, βobservational=0.05, SE=0.009, PFDR<0.001), paraoxonase-2 (PON2, βobservational=-0.03, SE=0.008, PFDR<0.001), and sclerostin (SOST, βobservational=-0.03, SE=0.009, PFDR<0.001). NPPB was concordant in direction of effect and met an FDR-corrected significance threshold. Conclusions Our study identifies multiple novel proteins with a putative causal effect on PP. Our findings identify NPPB with a high level of statistical confidence, which could have important implications given the current availability of FDA-approved medications to boost NPPB effects. Our findings will lead to further investigations regarding the biology and clinical role of the identified candidate therapeutic targets.

Prediction of central Augmentation Index in healthy adults.

Central Augmentation Index (AIx) is a surrogate marker of large artery stiffness that may provide valuable insight to cardiovascular health. The aim of this study was to evaluate the relationship between AIx and components of physical fitness. One hundred eighty-five healthy men and women (aged 20-79 years) underwent non-invasive assessment of arterial wave reflection to determine AIx, which was corrected to a heart rate of 75 beats per minute (AI×75). Body composition was evaluated using dual energy X-ray absorptiometry (DXA) and aerobic capacity (VO<inf>2max</inf>) was derived from expired gas analysis during a symptom limited exercise test on a treadmill. A multiple linear regression revealed age and VO<inf>2max</inf> as significant predictors of AI×75 [AI×75=32.055 + (0.252×age) - (0.722×VO<inf>2max</inf>)]. Upon removal of VO<inf>2max</inf> from regression analysis, resting heart rate (RHR) and % body fat (BF%) were revealed to be significant predictors of AI×75: AI×75=-61.316 + (0.481×age) + (0.565×BF%) + (0.56×RHR). Our findings demonstrate that central Augmentation Index can be reliably predicted in healthy adults who undergo a maximal exercise or body composition assessment. These prediction equations may be applied in non-medical settings to assist in creating comprehensive health and fitness profiles for healthy clientele.

Estimating pulmonary arterial remodeling via an animal-specific computational model of pulmonary artery stenosis.

Pulmonary artery stenosis (PAS) often presents in children with congenital heart disease, altering blood flow and pressure during critical periods of growth and development. Variability in stenosis onset, duration, and severity result in variable growth and remodeling of the pulmonary vasculature. Computational fluid dynamics (CFD) models enable investigation into the hemodynamic impact and altered mechanics associated with PAS. In this study, a one-dimensional (1D) fluid dynamics model was used to simulate hemodynamics throughout the pulmonary arteries of individual animals. The geometry of the large pulmonary arteries was prescribed by animal-specific imaging, whereas the distal vasculature was simulated by a three-element Windkessel model at each terminal vessel outlet. Remodeling of the pulmonary vasculature, which cannot be measured in vivo, was estimated via model-fitted parameters. The large artery stiffness was significantly higher on the left side of the vasculature in the left pulmonary artery (LPA) stenosis group, but neither side differed from the sham group. The sham group exhibited a balanced distribution of total distal vascular resistance, whereas the left side was generally larger in the LPA stenosis group, with no significant differences between groups. In contrast, the peripheral compliance on the right side of the LPA stenosis group was significantly greater than the corresponding side of the sham group. Further analysis indicated the underperfused distal vasculature likely moderately decreased in radius with little change in stiffness given the increase in thickness observed with histology. Ultimately, our model enables greater understanding of pulmonary arterial adaptation due to LPA stenosis and has potential for use as a tool to noninvasively estimate remodeling of the pulmonary vasculature.

Association between leisure-time physical activity and arterial stiffness in adults of the ELSA-Brasil study: a mediation analysis.

We aimed at defining the direct and the mediated pathways for the association between leisure-time physical activity (LTPA) and carotid-to-femoral pulse wave velocity (cf-PWV), and also to identify whether these effects are influenced by sex and age. Cross-sectional data from 13 718 adults (35-74 years) were obtained at the baseline of the ELSA-Brasil study. The cf-PWV was obtained by measuring the pulse transit time and the distance traveled by the pulse between the carotid and the femoral, as well as clinical and anthropometric parameters were measured. The levels of LTPA were determined by applying the long form of the International Physical Activity Questionnaire (IPAQ). Classical cardiovascular risk factors were independently associated with cf-PWV. Path analysis showed that increased levels of LTPA were directly associated with lower cf-PWV in both men and women ( β : -0.123 ± 0.03 vs. 0.065 ± 0.029, P for sex = 0.165), except for diabetes. Also, the mediated effect of LTPA on SBP and DBPs, heart rate, BMI, and fasting glucose, was associated with lower cf-PWV in men and women ( β : -0.113 ± 0.016 vs. -0.104 ± 0.016, P for sex = 0.692), except for diabetes. When age was tested as a moderator, the direct effect did not change significantly according to participants' age, regardless of sex. However, the mediated effect increases in both men and women over 50 years. Our findings support that LTPA in adults reduces cf-PWV by acting in different ways according to age. Physical activity in older individuals improves cardiometabolic risk factors and thus mitigates the stiffening of large arteries.

P229 INFLUENCE OF ASTHMA ON BLOOD PRESSURE OF CHILDREN AND ADOLESCENTS: THE ASMAVIX PROJECT

Background and Objectives: Asthma is a prevalent disease in children and the chronic inflammatory may affect blood vessel stiffness and blood pressure (BP). Systolic BP increases progressively along the childhood tending to reach stable values at the beginning of adulthood. Higher BP levels in infancy predispose to hypertension development hypertension in adulthood. Our aim was to investigate the influence of asthma on the age-dependent BP increase in children and adolescents. Methods Asthmatic (Asth, n = 166), 7-15 years (67% boys) attending to Public Health Units of Vitória (an industrialized city of the coastal plain of southeastern Brazil) were included. Non-asthmatic children (N-Asth, n =50; 33% boys) living in the neighborhood of Asth were used as controls. Clinic and laboratory exams were performed in an outpatient clinic at the University Hospital. BP was measured with an oscillometric device (Onrom HBP 1100) and large artery stiffness was estimated by carotid-to-femoral pulse wave velocity (cf-PWV; Complior SP-2). The 90th percentile of systolic or diastolic BP was used to identify high BP considering gender, age, and height. Age-dependent BP increase was determined by linear regression with and without adjustment for covariates (gender and body mass index). Statistical significance was set at p&lt;0.05. Results Asth and N-Asth groups were similar (p&gt;0.05) considering age (11.7 ± 2.3 vs 11.1 ± 2.1 years), body mass index (20.2 ± 4.2 vs 20.3 ± 5.7 kg/m2), systolic (102 ± 11 vs 104 ± 10 mmHg) and diastolic (62 ± 7 vs 63 ±8 mmHg) BP. However, cf-PWV was higher in Asth (48.9 ± 9.0 vs 44.0 ± 9.1 cm/s; p&lt;0.01). The crude age-dependent systolic BP increase was 34% higher in the Asth group (1.74 mmHg/year; 95%CL 1.06;2.43 vs 1.37 mmHg/year; 95% CL 0.02;2.72). This difference remained similar after adjusting for gender and body mass index (1.47 mmHg/year; 95%CL 0.80; 2.14 vs 1.10; -0.47;2.67). The percentage of children with elevated BP was higher in the Asth group (10.2% vs 4.0%). Conclusion: The higher stiffness of large arteries seems to accelerate the systolic BP increase along childhood and adolescence and may predispose to an earlier onset of hypertension in adulthood. Acknowledgment: This study was supported with grants from ArcelorMittal, CNPq and Fapes.

P197 PULSE WAVE ANALYSIS IN POST COVID PATIENTS WITH AND WITHOUT DE NOVO ARTERIAL HYPERTENSION. HOSPITAL UNIVERSITARIO DE LOS ANDES (HULA) VENEZUELA. 2021-2023

Background and Objective: COVID 19 infection is characterized by an acute respiratory process that can range from mild to severe and has been related to short- and long-term complications. Post COVID 19 syndrome has been described among these long-term complications, where alterations in pulse wave velocity define vascular alteration, increasing risk of systemic arterial hypertension. The objective is analyze pulse wave velocity and arterial stiffness in post-COVID 19 patients with and without de novo arterial hypertension at the HULA, Venezuela between 2021-2023. Methods: Observational case-control study on pulse wave velocity in post-COVID-19 patients with and without de novo arterial hypertension in the HULA post-COVID-19 consultation, 2021-2023. Results: The sample consisted of 90 patients: 30 cases and 60 controls, there was no statistically significant difference in variables such as sex, body mass index (BMI) and abdominal circumference between both cohorts, with a predominance of the age group between 35 to 49 years with 33.3%, and less frequency at the extremes of life, where the group of 18-34 years and over 65 corresponded to 20%, there was a statistically significant association between syndrome post COVID 19 and arterial stiffness, the risk of de novo arterial hypertension was found to be 4.9 times and 7.9 times higher in the small and large vessel arterial stiffness group compared to the group without arterial stiffness, respectively. Conclusions: It is impressive that the age group between 35 and 49 years has a higher risk of developing arterial hypertension associated with COVID 19, the alteration of pulse wave analysis in the patients in the consultation post COVID 19 was associated with a higher risk of developing de novo arterial hypertension compared to those who did not present alterations.

Gonadal status modulates large elastic artery stiffness in healthy middle-aged and older men.

Hypogonadism is a risk factor for cardiovascular disease (CVD) in men related, in part, to increased oxidative stress. Elevated large artery stiffness and central pulsatile hemodynamics (e.g., pulse pressure and wave reflection magnitude) are independent risk factors for CVD. However, whether large artery stiffness and central pulsatile hemodynamics are (1) elevated in hypogonadal men independent of traditional CVD risk factors and (2) related to increased oxidative stress is unknown. Young men (N = 23; 30 ± 4years) and middle-aged/older (MA/O) men with normal (> 400-1000ng/dL; n = 57; 59 ± 7years) or low testosterone (< 300ng/dL; n = 21; 59 ± 7years) underwent assessments of large artery stiffness (carotid ß-stiffness via ultrasonography) and central pulsatile hemodynamics (pulse wave analysis; SphygmoCor XCEL) following an infusion of saline or vitamin C to test the tonic suppression of vascular function by oxidative stress. Carotid stiffness differed by age (p < 0.001) and gonadal status within MA/O men (low testosterone vs. normal testosterone: 9.3 ± 0.7 vs. 8.0 ± 0.3U, p = 0.036). Central pulsatile hemodynamics did not differ by age or gonadal status (p > 0.119). Vitamin C did not alter carotid stiffness in any group (p > 0.171). There was a significant group × infusion interaction on aortic reflection magnitude (p = 0.015). Vitamin C treatment reduced aortic reflection magnitude in young and MA/O men with normal testosterone (both p < 0.001) but not MA/O men with low testosterone (p = 0.891). Collectively, hypogonadism may accelerate age-related large artery stiffening in MA/O men with low testosterone, independent of CVD risk factors; however, this is not related to increased reactive oxygen species sensitive to an acute vitamin C infusion.

Proteome-Wide Genetic Investigation of Large Artery Stiffness

Proteome-Wide Genetic Investigation of Large Artery Stiffness

Socioeconomic status as a potential mediator of arterial aging in marginalized ethnic and racial groups: current understandings and future directions.

Cardiovascular diseases (CVDs) are the leading cause of death in the United States. However, disparities in CVD-related morbidity and mortality exist as marginalized racial and ethnic groups are generally at higher risk for CVDs (Black Americans, Indigenous People, South and Southeast Asians, Native Hawaiians, and Pacific Islanders) and/or development of traditional CVD risk factors (groups above plus Hispanics/Latinos) relative to non-Hispanic Whites (NHW). In this comprehensive review, we outline emerging evidence suggesting these groups experience accelerated arterial dysfunction, including vascular endothelial dysfunction and large elastic artery stiffening, a nontraditional CVD risk factor that may predict risk of CVDs in these groups with advancing age. Adverse exposures to social determinants of health (SDOH), specifically lower socioeconomic status (SES), are exacerbated in most of these groups (except South Asians-higher SES) and may be a potential mediator of accelerated arterial aging. SES negatively influences the ability of marginalized racial and ethnic groups to meet aerobic exercise guidelines, the first-line strategy to improve arterial function, due to increased barriers, such as time and financial constraints, lack of motivation, facility access, and health education, to performing conventional aerobic exercise. Thus, identifying alternative interventions to conventional aerobic exercise that 1) overcome these common barriers and 2) target the biological mechanisms of aging to improve arterial function may be an effective, alternative method to aerobic exercise to ameliorate accelerated arterial aging and reduce CVD risk. Importantly, dedicated efforts are needed to assess these strategies in randomized-controlled clinical trials in these marginalized racial and ethnic groups.

The association of structural versus load-dependent large artery stiffness mechanisms with cerebrovascular damage and cortical atrophy in humans.

Large central arterial stiffness is a risk factor for cerebrovascular damage and subsequent progression of neurodegenerative diseases, including Alzheimer's disease and dementia. However, arterial stiffness is determined by both the intrinsic components of the arterial wall (structural stiffness) and the load (i.e., arterial blood pressure) exerted upon it by the blood (load-dependent stiffness). This study aimed to determine the degree to which structural and/or load-dependent mechanisms of central arterial stiffness are associated with cerebrovascular damage. Among 128 healthy individuals (aged 63±6, age range: 50-80 years, 42% men), aortic and carotid artery stiffness was measured via carotid-femoral pulse wave velocity and B-mode ultrasonography, respectively. Using participant-specific exponential models, both aortic and carotid artery stiffness were standardized to a reference blood pressure to separate their structural and load-dependent stiffness mechanisms. Magnetic resonance imaging was used to derive total, periventricular, and deep cerebral white matter lesion volume (WMLV) and global cortical thickness. After adjusting for common cardiovascular disease risk factors, a 1 m/s increase in structural aortic stiffness was associated with 15% greater total WMLV (95% confidence interval [CI] = 0.01, 0.27, P = 0.036), 14% greater periventricular WMLV (95%CI = 0.004, 0.25, P = 0.044) and 0.011mm lower cortical thickness (95%CI = -0.022, -1.18, P = 0.028). No association was observed between structural carotid stiffness and WMLVs (total, periventricular, and deep), and neither aortic nor carotid load-dependent stiffness was associated with WMLVs or cortical thickness. Structural, not load-dependent, mechanisms of aortic stiffness are related to cerebrovascular-related white matter damage.

Arterial stiffness in non-alcoholic fatty liver disease

Background. The presence of metabolic-associated pathology, namely obesity, diabetes mellitus, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD), significantly accelerates the development of the cardiovascular continuum. This is associated with an increased risk of major cardiovascular events (myocardial infarction, stroke). An important organ damage in hypertension (HTN) is the remodeling of small arteries and an increase in stiffness of large arteries. The relationship between NAFLD, dyslipidemia, hypertriglyceridemia, obesity (especially abdominal), diabetes, and HTN is well studied, but there is a lack of clinical studies examining changes in arterial stiffness in NAFLD. Aim of the research was to study the parameters of arterial stiffness in patients with NAFLD. Materials and methods. Eighty-two Caucasian patients with NAFLD (mean age (56.8 ± 1.1) years, 59.8 % men) were enrolled. Participants were divided into two groups: group 1 (n = 44) — NAFLD and concomitant HTN, group 2 (n = 38) — HTN without NAFLD. All patients underwent a standard general clinical examination, laboratory and instrumental work-up. In addition, all patients were assessed for the parameters of arterial stiffness via non-invasive arteriography. Results. Patients with NAFLD had significantly higher office systolic and diastolic blood pressure (by 15.2 and 10.4 %, respectively, p &lt; 0.01) despite comparable drug therapy. The same trends were observed in relation to the central aortic pressure, which was 19.3 % higher in patients with NAFLD (p &lt; 0.01), and central pulse pressure that was 35.9 % higher than in patients without NAFLD (p &lt; 0.01). Brachial artery augmentation index in NAFLD turned to be elevated compared to patients without NAFLD (p &lt; 0.01), but aortic augmentation index was comparable between groups. The return time interval in group 1 was 50.3 % higher than in group 2 (p &lt; 0.01). Finally, patients with NAFLD had a significant increase in pulse wave velocity by 52.3 % compared to those without NAFLD with average value exceeding 12 m/sec (p &lt; 0.01). Conclusions. There is an association between NAFLD and worse indices of arterial stiffness in patients with concomitant HTN.

Stiffening of the human proximal pulmonary artery with increasing age.

Adverse effects of large artery stiffening are well established in the systemic circulation; stiffening of the proximal pulmonary artery (PPA) and its sequelae are poorly understood. We combined invivo (n = 6) with exvivo data from cadavers (n = 8) and organ donors (n = 13), ages 18 to 89, to assess whether aging of the PPA associates with changes in distensibility, biaxial wall strain, wall thickness, vessel diameter, and wall composition. Aging exhibited significant negative associations with distensibility and cyclic biaxial strain of the PPA (p ≤ 0.05), with decreasing circumferential and axial strains of 20% and 7%, respectively, for every 10 years after 50. Distensibility associated directly with diffusion capacity of the lung (R2 = 0.71, p = 0.03). Axial strain associated with right ventricular ejection fraction (R2 = 0.76, p = 0.02). Aging positively associated with length of the PPA (p = 0.004) and increased luminal caliber (p = 0.05) but showed no significant association with mean wall thickness (1.19 mm, p = 0.61) and no significant differences in the proportions of mural elastin and collagen (p = 0.19) between younger (<50 years) and older (>50) exvivo samples. We conclude that age-related stiffening of the PPA differs from that of the aorta; microstructural remodeling, rather than changes in overall geometry, may explain age-related stiffening.

Antihypertensive therapy with indapamide in comorbid patients: safety, effectiveness, neutrality

The article highlights the problem of hypertension, which requires a comprehensive approach that includes prevention, diagnosis and treatment. The risk factors for hypertension published in the guidelines of the European Society of Hypertension are listed. Indapamide, to which the study is devoted, has not only high antihypertensive efficiency, but also a neutral metabolic effect and organoprotective properties. It affects endothelial dysfunction, reduces stiffness of large arteries, left ventricular hypertrophy, microalbuminuria, and is metabolically neutral. This makes its use effective and economically beneficial.

Load-Dependent Arterial Stiffness Mechanisms are Responsible for Increased Large Artery Stiffness Observed among Women with a History of Preeclampsia

Introduction: Preeclampsia is a pregnancy complication characterized by hypertension and multi-organ dysfunction and is a leading cause of maternal morbidity and mortality. Preeclampsia results in a two-four fold increased risk of developing hypertension and cardiovascular disease later in life. Large artery stiffness (LAS), a robust risk factor for hypertension and cardiovascular disease, and blood pressure (BP) are elevated after pregnancy in women with a history of preeclampsia (hxPE) and is associated with reduced cardiovagal baroreflex sensitivity (BRS). Whether elevated LAS in women with a hxPE is a consequence of structural remodeling of the arterial wall or the load applied to the arterial wall by the blood (i.e., BP) is unclear. Furthermore, it is unknown whether one or both LAS mechanisms are associated with differences in BRS. Therefore, we hypothesized that 1) structural- and load- dependent LAS would be elevated in women with a hxPE versus no hxPE postpartum controls, and 2) structural- and load- dependent LAS would be associated with BRS in women with hxPE.Methods: LAS was measured via carotid-femoral pulse wave velocity (aortic LAS), and carotid ultrasonography/tonometry (carotid LAS) among 115 women 1-5 years postpartum (age 34 ±4yrs; hxPE n=51; controls n=64). Participant-specific exponential models were used to standardize LAS measurements to a ‘reference’ BP (aortic: 90mmHg mean arterial pressure; carotid: BP 120/80mmHg) and used to calculate structural LAS. Load-dependent LAS was calculated as total minus structural LAS. Spontaneous cardiovagal BRS was measured using the sequence technique. Results: Systolic and diastolic BP were higher in women with hxPE compared with controls (all p&lt;0.001). Aortic, but not carotid, LAS was 0.57 m/s higher in women with hxPE compared with controls (p=0.025). Load-dependent LAS was 0.39 m/s (aortic) and 0.5 m/s (carotid) higher in women with hxPE (p&lt;0.001 for aortic and carotid), but no difference was observed for structural LAS measures (p&gt;0.14 for both). Women with hxPE had 4.13 ms/mmHg lower BRS compared to controls (p=0.042). In women with hxPE, BRS was negatively associated with both aortic and carotid LAS (r=-0.37, p=0.042 and r=-0.38, p=0.025, respectively), and aortic load-dependent LAS (r=-0.39, p=0.033), after adjusting for age and body mass index. Conclusion: Load-dependent LAS mechanisms explained the higher aortic and carotid LAS observed among women with a hxPE and was associated with lower BRS. Our findings suggest that changes in BP and cardiovagal BRS may underpin in part the higher LAS observed in women with a hxPE. Grant funding: American Heart Association 22TPA969732 (to GLP) and 18SCG34350001 (to MKS). 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.

AMYLOID-BETA 40 ADVERSELY INFLUENCES LARGE ARTERY STIFFNESS AND CUTANEOUS MICROVASCULAR FUNCTION IN OLDER ADULTS WITH DIVERSE CARDIOVASCULAR RISK

Objective: Amyloid-beta (Aβ) peptides are considered to play a prominent role in Alzheimer's disease, but emerging experimental and clinical observations link Aβ40 with adverse extracerebral vascular manifestations and cardiovascular disease events. However, it is unclear if Aβ40 adversely influences both large artery stiffness and cutaneous microvascular function in humans. We sought to determine whether Aβ40 was associated with large artery stiffness and cutaneous microvascular function in older adults with diverse cardiovascular risk. Design and method: This cross-sectional study analysed data from 610 older adults (65.7±8.7 yrs, 242F). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (CFPWV) using a SphygmoCor device, and cutaneous microvascular function was assessed by measuring acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) responses following iontophoresis. Plasma Aβ40 concentration was measured using a human Aβ40 assay kit (Simoa Human A β40). Results: One standard deviation increase in Aβ40 was significantly associated with 0.74 (0.52, 0.96) m/s greater CFPWV in an age- and sex-adjusted model (Model-1, p&lt;0.001), which remained significant after further adjustments for conventional cardiovascular disease risk factors [Model-2, 0.46 (0.26, 0.66) m/s, p&lt;0.001]. Additionally, one standard deviation increase in Aβ40 was significantly associated with lower cutaneous acetylcholine [-27.3 (-38.9, -15.7) au] and sodium nitroprusside [-27.0 (-38.1, -15.9) au] responses in Model-1 (both p&lt;0.001). Further adjustments for conventional cardiovascular disease risk factors did not modify the inverse association [Model-2, acetylcholine response, -20.7 (-32.5, -8.8) au: sodium nitroprusside response, -21.1 (-32.3, -9.9) au: both p&lt;0.001]. Subgroup analyses found an indication of interaction effect whereby female sex influenced more on the association between Aβ40 and CFPWV, and type 2 diabetes influenced more on the association between Aβ40 and cutaneous acetylcholine responses (both p&lt;0.05). Conclusions: Aβ40 was associated with increased large artery stiffness and decreased cutaneous microvascular function in older adults with diverse cardiovascular risk. These findings suggest a potential mechanistic link between Aβ40 deposition in the systemic circulation and previously observed adverse cardiovascular disease outcomes.

T cell specific Eomes Deletion Does Not Protect Against High Fat Diet Induced Large Artery Stiffening

We have found that T cells contribute to age-related large artery stiffness. The T-box transcription factor, Eomes is an important regulator of CD8+ (Cytotoxic) T cell differentiation from a naïve to a memory phenotype. We previously reported that these effector memory CD8+ T cells accumulate in the aorta of old mice. We aimed to investigate whether inhibiting CD8+ T cell memory differentiation in mice, specifically through T cell-specific Eomes deletion, would protect these animals from high-fat diet (HFD)-induced large artery stiffness. Mice with a CD8 driven Cre Recombinase were bred with mice with loxp sites surrounding the Eomes gene resulting in wild type (CD8 Eomes+/+) and T cell specific Eomes deleted (CD8 Eomesf/f) mice. Mice were randomly divided into a normal chow (NC) and HFD. Resulting in 8 mice of each genotype and diet. The NC group was given a normal diet containing 4% fat and the HFD group was given a high-fat diet containing 60% fat. At 4-8 months of age, doppler pulse wave velocity was used to assess large artery stiffness. Following euthanasia, aortic T cell phenotype was assessed using flow-cytometry. Group differences were assessed by two-way ANOVA and Tukey’s post-hoc test. Data shown as mean ± SD. Regardless of genotype, HFD had a significant impact on pulse wave velocity (PWV), indicating elevated aortic stiffness. In the HFD group, both CD8 Eomesf/f and CD8 Eomes+/+ mice exhibited higher PWV values (330.08±72.33 cm/s;312.5±53.74 cm/s) compared to their counterparts in the NC group (256.4±63.67 cm/s;259.2±66.36 cm/s, p=0.0172). To determine whether HFD-induced increases in aortic stiffness are accompanied by changes in aortic T cell phenotype, flow cytometric analysis was performed on the aorta. First, we observed, regardless of mouse genotype, HFD had a significant impact on CD4+ (Helper T) naïve cells, resulting in a blunted percentage of these cells. This dietary effect was observed in both CD8 Eomesf/f and CD8 Eomes+/+ mice (NCD CD8 Eomesf/f: 70.92±5.912%; NCD CD8 Eomes+/+ mice: 56.46±20.62%; HFD CD8 Eomesf/f: 47.5±7.865%; HFD CD8 Eomes+/+ mice: 50.58±13.907%; p=0.0206). In contrast, the percentages of CD8+ naïve cells did not display a significant change in response to the high-fat diet (p=0.6303). HFD significantly influenced CD4+ memory cells, resulting in an increase in percentages, regardless of mouse genotype (NCD CD8 Eomesf/f: 29.09± 5.909%; NCD CD8 Eomes+/+ mice: 44.27±19.17%; HFD CD8 Eomesf/f: 52.47±7.875%; HFD CD8 Eomes+/+ mice: 49.44±13.9%; p=0.02). However, HFD did not produce any significant alterations in CD8+ memory cell percentages (p=0.6). These results suggest that contrary to our hypothesis, T cell specific Eomes deletion is not suffcient to protect against diet induced large artery stiffness. However, this may be due to greater proportions of CD4+ memory cells in the aorta with high fat feeding. Funding: AHA 940023, NIH R01AG060395, K01AG061271. 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.

High altitude sojourn elicits divergent effects in aortic and carotid stiffness in healthy-young adults

High altitude exposure challenges the cardiovascular system to compensate for barometric pressure-mediated reductions in arterial oxygen content. Reductions in oxygen content elicit simultaneous increases in sympathetic nervous system activity and vasodilation that may have competing effects on changes in large artery stiffness. The objective of this study was to examine changes in aortic and carotid stiffness during high altitude sojourn in healthy, young adults. We hypothesized that short-term high-altitude sojourn would increase both aortic and carotid stiffness. 17 Generally healthy adults (23±4 yrs, 25.0±3.0 BMI, n=9 females) underwent vascular assessments in the supine position at 1400 m and after an 8-day incremental ascent to 4300 m. Aortic stiffness and carotid β-stiffness were derived from carotid-femoral pulse wave velocity (cfPWV) via applanation tonometry and right common carotid artery ultrasonography, with blood pressure assessed via oscillometry. Ascent from 1400 m to 4300 m resulted in decreased arterial oxygen saturation (-11±4 %, p&lt;0.001) and carotid β-stiffness (-4.48±2.73 au, p&lt;0.001), and increased cfPWV, (+54.98±78.10 cm/s, p=0.01) and mean arterial pressure (+4±7 mmHg, p=0.02). Changes in cfPWV, arterial oxygen saturation, and blood pressure were moderately to strongly correlated (r=-0.425-0.503, p=0.09-0.04). Our data suggest that short term exposure to high altitude has differential effects on carotid versus aortic stiffness despite increases in mean blood pressure. Increases in aortic stiffness appear related to hypoxia-induced reductions in arterial oxygen saturation and concomitant increases in blood pressure, while reductions in carotid stiffness may stem, in-part, from compensatory carotid artery dilation necessary to increase cerebral blood flow at high altitude. Additional research is necessary to further understand mechanisms underlying differential changes in large artery stiffness during high altitude sojourn. 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.

ASSOCIATIONS BETWEEN GENETICALLY PREDICTED PULSE PRESSURE AND TARGET ORGAN DAMAGE: A MENDELIAN RANDOMIZATION STUDY

Objective: Large-artery stiffness (LAS) leads to an increased pulse pressure (PP) and is thought to induce target organ damage (TOD). However, causal associations of PP have not been unequivocally assessed in humans. We aimed to investigate the bi-directional associations between genetically predicted increased PP and phenotypes of TOD using Mendelian randomization (MR). Design and method: Bi-directional MR analyses were performed to investigate associations between genetically predicted PP and: left ventricular mass (LVM), myocardial interstitial fibrosis, heart failure (HF), chronic kidney disease (CKD), cognitive performance, brain white matter hyperintensities (WMH), type 2 diabetes (T2D) and preeclampsia (PrE). Multivariable MR was conducted to investigate the effect of PP on significant outcomes, independently of mean arterial pressure (MAP). Results: For a 10-mmHg increase in genetically-predicted PP, the odds ratios (ORs) were 1.113 (95%CI=1.085-1.137, P&lt;0.001) for HF, 1.075 (95%CI=1.048-1.103, P&lt;0.001) for CKD, 1.137 (95%CI=1.102-1.173, P&lt;0.001) for T2D, and 1.435 (95%CI=1.256-1.638, P&lt;0.001) for PrE. Similarly, a 10-mmHg increase in genetically-predicted PP was associated with a greater LVM (beta estimate=3.527 g/m2, 95%CI=3.026-4.028, P&lt;0.001). The association of genetically predicted PP on risk of HF, CKD and T2D was independent of genetically-predicted MAP. Bidirectional MR also supported a causal effect of genetically predicted log-odds of T2D on PP (beta estimate=0.527 mmHg, 0.396-0.658, P&lt;0.001), and PrE on PP (beta estimate=2.365 mmHg, 0.783-3.947, P=0.003) indicating a potential bidirectional relationship. Conclusions: We provide evidence supporting causal associations between PP and T2D, CKD, HF and increased risk of LV hypertrophy in humans, consistent with the deleterious effects of LAS on LV afterload and on microvascular integrity in low-resistance target organs. Early interventions aimed at lowering LAS may lead to lowering the risk of adverse outcomes.

Effect of miR-181b Treatment on Senescent Human Aortic Smooth Muscle Cells

Large Artery Stiffness (LAS) is independently associated with increased cardiovascular morbidity and mortality and its development is multifactorial and has been associated with the onset of cellular senescence (CS). CS is defined as a stable cell cycle arrest, characterized by an altered cell phenotype with impaired function and detrimental secretory profile. Vascular smooth muscle cells (VSMCs) are present in two main phenotypes: the contractile phenotype seen in young populations, and the synthetic phenotype related to aging and senescent VSMCs. Micro-RNAs (miR) are non-coding RNAs that can alter protein expression. miR-181b has been demonstrated to undergo downregulation with aging with a close to 80% decrease, this correlates with an upregulation of markers of senescence. To test the hypothesis that miR-181b could modulate the senescent phenotype in VSMCs and promote a more contractile phenotype, a cellular model comprising young and old human aortic smooth muscle cells (HASMCs) was employed. These cells were transfected with either a miR-181b mimic or a scrambled miR control (SCR), resulting in an 11-fold increase in the young and a 3.3-fold increase in the old. Cell proliferation was measured using electric cell-substrate impedance sensing (ECIS) technology, where it was found to be lower in older HASMCs (1.05±0.001) compared to the young (1.1±0.001, p&lt;0.05). When miR-181b was introduced, there was a significant increase in proliferation for both age groups by 0.03-fold compared to SCR (p&lt;0.05). Old HASMCs demonstrated a decreased average ionomycin-induced contractile response (3.65%±0.46) when compared to the young (7.17%±0.60, p&lt;0.05). Lipofectamine-mediated transfection of HASMCs with miR-181b resulted in an increased contractility response in the old HASMCs (5.46%±0.91) compared to scrambled control (1.41%±0.39, p&lt;0.05), while there was no significant difference for the young cells. The percentage of Senescence-Associated-β-galactosidase (Saβ-gal) positive cells, a marker of senescence, was higher in old (39.74%±3.04) vs young (4.35%±0.72, p&lt;0.05). The percentage of Saβ-gal positive cells tended to decrease in old VSMCs after miR-181b transfection (SCR 79.65%±4.38 vs Old181b 70.39±4.03, p=0.2.02), with no effect on young cells. Immunofluorescence in situ hybridization (IF-FISH) staining for the double-stranded DNA break marker (53BP1) was lower in the young (4.65%) compared to old HASMCs (32.69%). Likewise, the percentage of cells with one or more 53BP1 foci colocalization in telomeres, referred to as Telomere dysfunction-induced foci (TIF), was higher in old (11.54%) compared to young (2.33%) VSMCs (p=0.002). However, miR-181b transfection did not impact these markers regardless of age (p=0.94). Transfection of HASMCs with miR-181b did not impact senescent cell abundance, but improved contractility and cellular proliferation. Combined with our prior data demonstrating a senomorphic effect of miR-181b transfection to improve cellular stiffness and favorably modulate of senescence-associated secretory factors, our results demonstrate an enhancement in the phenotypic characteristics of the old HASMCs group, suggesting that miR-181b participates in the modulation of the senescent VSMCs phenotype. This translates to a potential improvement in HASMC health that could reduce the development of LAS. National Institutes of Health Awards: K08 AG070281 (ET), T32 HL139451 (DM), R01 AG048366 (LAL), R01 AG060395 (AJD), and Western Institute for Veterans Research (ET). 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.

Fibulin-5 Is Required for Small Artery Development and Function

Introduction: Fibulins are a family of eight extracellular matrix proteins with diverse functions. Fibulin-4 and -5 (FBLN-4 and -5), in particular, have been shown to be important for elastic fiber assembly. Mutations in each of the genes lead to cutis laxa, a syndrome characterized by loose skin with variable organ involvement, particularly in the vasculature, lungs and skeleton. We recently characterized a mouse model carrying a disease-causing mutation in Fbln4 (E57K) and, contrary to conduit arteries that had elastic fiber fragmentation and stiffness, Fbln4E57K resistance arteries were structurally intact. Functionally however, Fbln4E57K mesenteric arteries exhibited endothelial dysfunction secondary to increased shear stress from large artery stiffness. Loss of FBLN5 has been shown to lead to elastic fiber fragmentation in conduit arteries, but the consequences of its loss on resistance arteries are unknown. Therefore, the objectives of this study were to determine the structural and functional consequences of FBLN5 loss on resistance arteries. Methods: We utilized adult Fbln5 knock-out (KO) mice and examined the ultrastructure of renal and mesenteric arteries via transmission electron microscopy. Functionally, using pressure myography, we characterized the myogenic tone and reactivity of Fbln5 KO and littermate control third-order mesenteric arteries to various vasoactive substances including acetylcholine, papaverine, angiotensin II, phenylephrine and potassium chloride. Results: While the internal elastic lamina (IEL) of Fbln5KO mice resistance arteries was largely intact, the external elastic lamina (EEL) was nearly absent. Similar to Fbln4E57K mice, Fbln5KO mesenteric arteries exhibited impaired endothelial-dependent vasorelaxation, likely secondary to proximal large artery stiffness. Unlike Fbln4E57K mesenteric arteries however, Fbln5 KO mesenteric arteries exhibited increased myogenic tone as well as a hypercontractile response to angiotensin II and potassium chloride, but not to phenylephrine. Conclusions: In addition to highlighting differences in the requirements for elastic fiber assembly along the arterial tree, these data emphasize the differential contribution of FBLN4 and FBLN5 to IEL vs. EEL in resistance arteries and suggest pathway-specific changes in smooth muscle cell contractility secondary to FBLN5 deficiency. This work was supported by the Washington University Pediatric Nephrology Research Core Pilot Grant Program to CMH. Funds were also provided by The Department of Pediatrics at Washington University in St. Louis School of Medicine to CMH. 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.