Arterial Stiffness Research Articles

VASCULAR AGE AS A KEY FOR A TEAM-BASED APPROACH TO MANAGE BLOOD PRESSURE AND CARDIOVASCULAR RISK BETWEEN COMMUNITY PHARMACISTS AND PRIMARY HEALTH CARE CENTERS (TOGETHER)

Objective: Hypertension (HTN) is the main cause of premature death worldide. Previous studies in Portugal, Austria and Spain have shown that estimating arterial stiffness in Community Farmacies (CPh) improves its management. The main objective is to evaluate whether empowering hypertensive subjects by determining arterial stiffness in CPh increases the rate of HTN control. Secondary objective is to establish paths of lasting cooperation between Primary Care (PC) doctors and CPh. Design and method: TOGETHER is a randomized study in Portugal, Austria and Spain. All consecutive expected 1260 subjects entering CPh will be offered blood pressure measurement and ambulatory blood pressure monitoring (ABPM) for those cases with high values. 140 CPh will be randomly grouped into a usual care arm (health education associated with HTN and communication of the results to PC). In the experimental care group, early vascular aging (EVA) will additionally be assessed estimating oscillometric pulse wave velocity. The concept and therapeutic options of EVA will be explained to patients and PC. HTN will be treated by PC according to usual clinical practice. After 6 months a second evaluation with ABPM will be performed and HTN control will be compared between the two arms. The degree of patient-doctor interaction and economic implications will be determined through validated surveys. Results: TOGETHER will address five fundamental unmet needs: 1) lack of HTN screening programs; 2) the concept of cardiovascular risk is difficult to understand. The EVA concept (“Your arteries are 10 years older than you”) is simple and more informative; 3) understanding CV risk on an individual basis (individual EVA) should improve patient adherence and reduce physician inertia; 4) TOGETHER will implement health educational programs, combined with the concept of EVA; 5) there is an objective need to improve collaboration and develop a team-based approach to HTN care between CPh and PC. Conclusions: The complementary strengths and organizational settings of CPh and PC will allow TOGETHER to create new strategies for early identification and intervention in HTN, ranging from lifestyle to medical treatment, taking social, economic, and behavioral aspects into account.

Influence of Commonly-Encountered Participant Behavior on Cardiovascular Measures during Physiological Testing

Objective: When conducting laboratory testing, it is essential for participants to rest quietly in the supine posture without much movement. This is to establish a stable baseline to minimize external interference and distractions that could affect physiological measures. However, it is rather common that some participants start talking to investigators, fall asleep, or use cell phones for texting during the resting period. It is also common to observe some participants change their posture to side laying to make themselves more comfortable. The extent to which these common laboratory encounters influence cardiovascular outcome measures such as blood pressure and arterial stiffness has not yet been studied. Methods: A total of 55 adults (16 men and 39 women, 36±15 years) were studied under the following seven conditions: 1) quiet supine rest, 2) pretending to sleep, 3) while and 4) after talking to investigators, 5) during and 6) after cell phone use for texting, and 7) lying on the side. Each condition was separated by 5 minutes. The order of the conditions was randomized. Systolic and diastolic blood pressure (BP), heart rate, brachial-ankle pulse wave velocity (baPWV), and carotid-femoral PWV (cfPWV) were measured during these conditions. Results: Compared with quiet rest (61±10 bpm), heart rate was elevated (p<0.05) when the participants were talking to the investigators (65±10 bpm) and texting on cell phones (69±15 bpm). Both systolic and diastolic BP were 3-4 mmHg greater when they were talking to the investigators but 4-5 mmHg lower in the ‘side lying’ position compared with quiet rest. In the ‘side lying’ condition, baPWV was not affected but cfPWV was not able to be measured in 16 participants resulting in a 38% failure rate. baPWV was greater (p<0.01) while and after the participants were talking to investigators. cfPWV was not able to be measured during talking but was not affected when it was assessed after talking. Pretending to sleep and texting on a cell phone did not significantly influence any of the BP and PWV measures. Conclusions: Talking during the testing period significantly increases all the cardiovascular measures assessed in the present study. However, pretending to sleep and cell phone texting do not appear to influence them. There was no funding source for this study. 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.

The Protective Role of Resilience on Cardiovascular Health in Young Adults Exposed to Adverse Childhood Experiences

Background: Adverse childhood experiences (ACEs) are strong emotional or physical stressors that occur during sensitive developmental periods and are associated with reduced cardiovascular health (CVH). Resilience, or the psychological capacity of individuals to cope with adversity, has been recently shown to have a positive influence on CVH. Despite the dose-dependent detrimental impact of ACEs on CVH, it is unknown whether resilience exerts a protective cardiovascular effect against early stress. Thus, the purpose of this study was to investigate the impact that resilience may have on CVH in young adults who experienced ACEs. Methods: Eighteen young and apparently healthy adults (22±3 yo) with a history of severe ACE exposure (≥4) participated in this study and provided self-reported data about resilience. CVH was assessed non-invasively through transcutaneous arterial tonometry to evaluate arterial stiffness (pulse-wave velocity, PWV), myocardial oxygen demand (Systolic Pressure Time Index, SPTI), myocardial oxygen supply (Diastolic Pressure Time Index, DPTI) and myocardial perfusion (Subendocardial Viability Ratio, SEVR). Circulating biomarkers related to CVH were also evaluated (high-sensitive C-reactive protein, hsCRP). Results: Eleven participants reported high resilience (HR: resilience score≥95), while seven reported low resilience (LR: resilience score<95). Young adults with high resilience presented with a significantly lower myocardial oxygen demand (SPTI; HR: 1866±111 vs. LR: 2227±117mmHg·s/min, p=0.047) and higher myocardial perfusion (SEVR; HR: 168±13 vs.LR: 127 ±9% , p=0.034) than those with low resilience and a positive association between SEVR and resilience was identified ( r=0.492; p=0.045). No differences in myocardial oxygen supply ( p=0.225) or arterial stiffness ( p=0.614) were observed between groups. However, circulating hsCRP was also significantly lower in the HR group than the LR (0.89±0.3 vs. 2.96±1 mg/dL, p=0.041) and negatively associated with resilience ( r=-0.511; p=0.051). Conclusions: Our data suggests that, among young and apparently healthy adults exposed to childhood adversity, those who are psychologically more resilient exhibit higher myocardial perfusion and overall better CVH than those less resilient despite a history of severe ACEs. These findings suggest that resilience may protect, at least partially, against the early impact of ACEs on CVH. Future studies are thus warranted to further explore the relationship between resilience and CVH. Supported in part by the Child Health Research Institute at VCU. 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.

Streptococcus pneumoniae infection promotes the long-term development of an atherosclerotic phenotype in atheroprone ApoE-deficient mice

Background: Epidemiological studies have identified pneumonia to be closely linked to an increased risk for cardiovascular events. Potential causality of this association, however, remains to be established, and underlying mechanisms are yet to be resolved. Here, we tested the hypothesis that prior pulmonary infection with Streptococcus pneumoniae accelerates the development of an atherosclerotic phenotype in mice. Such a phenotype would explain the increased cardiovascular risk in the epidemiological data. Methods: Atheroprone ApoE−/− mice were fed a high fat diet, and after 6 weeks nasally infected with either 2.5 x 107 S. pneumoniae or vehicle control. Antibiotic therapy was initiated 60h post infection (p.i.) by s.c. injections of ampicillin on 5 consecutive days followed by oral administration of amoxicillin for 10 days. At days 35 or 90 post-infection, aortas were harvested and assessed for vasoreactivity and arterial stiffness by wire myography. Morphological changes of the aortic vessel wall and eNOS expression levels were quantified by western blot and histological stainings. Results: Unexpectedly, 35 days p.i. aortas of infected mice presented with decreased aortic stiffness, increased endothelial-independent vasorelaxation and decreased wall thickness due to lower collagen-1 expression and reduced elastin fragmentation when compared to sham animals. After 90 days, however, these effects had reversed and animals with prior pneumonia showed increased aortic stiffness, attenuated endothelial dependent vasorelaxation that was associated with reduced eNOS protein expression and phosphorylation, and increased atherosclerotic plaque burden relative to vehicle control. Conclusion: Single episodes of pneumonia promote a delayed pro-atherogenic phenotype that manifests as endothelial dysfunction, aortic stiffening and enhanced plaque burden. Underlying mechanisms are currently under investigation to identify risk predictors for patient stratification and clinical targets for prevention of cardiovascular disease following pneumonia. Funding: German Ministry of Education and Research (BMBF) in the framework of SYMPATH (01ZX1906A). 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.

Identification and Characterization of Potential Anti-Hypertensive Therapeutic Candidates in Rho-related BTB Domain Containing 1 (RhoBTB1)-Cullin 3 (CUL3) Axis

Blood pressure (BP) is regulated by a variety of cellular mechanisms. We previously reported the regulation of endothelial nitric oxide (NO)-dependent vessel tone and BP through RhoBTB1-CUL3 mediated proteasomal turnover of Phosphodiesterase 5 (PDE5). We determined that the C-terminal half of RhoBTB1 consisting of two BTB-domains (B1 & B2) and the C-terminal (C) domain of RhoBTB1 can deliver PDE5 to proteasomal pathway. The cellular expression of RhoBTB1 and CUL3 is ubiquitous whereas expression of PDE5 is cell specific. Moreover, vessel tone is regulated through NO-independent mechanisms. Therefore, we hypothesized that RhoBTB1 may have other interacting partners, potentially functioning as regulators of vessel tone and BP in vascular smooth muscle (VSM) cells, through a similar mode of binding as PDE5. Therefore, we utilized ascorbate peroxidase (APEX2) proximity labelling system comprising APEX2 tagged B1B2C domain (B1B2C-APEX2) to identify unknown potential regulators of vasomotor tone in RhoBTB1-CUL3 axis in A7R5 VSM cells. The background of the proteomic screen was minimized by utilizing APEX2-B1B2 which lacks the final C-terminal region of the protein and cannot bind PDE5. We validated the interaction of several identified proteins with RhoBTB1 and the B1B2C domains using co-immunoprecipitation (Co-IP). Our Co-IP data corroborated the proteomic screen as several proteins demonstrated differential interaction with B1B2C and B1B2. Among them, we examined RbFox2, a regulator of mRNA splicing for further investigation. Further data established that RbFox2 is upregulated under the following conditions: 1) pharmacological inhibition of the proteasomal pathway, 2) in CRISPR edited CUL3KO HEK293 cells, 3) in aorta of VSM cell-specific CUL3 deleted mice, 4) by siRNA mediated knock-down of RhoBTB1 in SMCs, and 5) in Ang-II treated SMCs and aorta of Ang-II treated animals. We hypothesized that RbFox2 could modulate actin and actinin-dependent cytoskeletal dynamics, an important regulator of arterial stiffness. First, Co-IP data suggest an interaction between RbFox2 and SMC-specific alpha actinin. Next, siRNA-mediated knock down of RbFox2 altered the actin and actinin-dependent cytoskeletal dynamics in SMCs. Collectively, this establishes the potential regulation of RbFox2 through the RhoBTB1-CUL3 proteasomal pathway and that RbFox2 may play a mechanistic role in arterial stiffness in hypertension. Funding: NIH R35 HL144807 (to Dr. Curt D. Sigmund). 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.

Dietary Effect on Peripheral and Cerebral Vascular Function in Adults with Non-Alcoholic Fatty Liver Disease

Objective: Non-alcoholic fatty liver disease (NAFLD) is a recognized independent risk factor for cardiovascular and cerebrovascular dysfunction. The present study evaluated the effect of dietary interventions on peripheral and cerebral vascular function in individuals with NAFLD. Methods: We studied 30 middle-aged adults (55±9 years) with NAFLD or with elevated NAFLD risk (with prediabetes symptoms). Liver fat content was assessed via 1H magnetic resonance spectroscopy. NAFLD was defined as liver fat proton density fat fraction (PDFF) exceeding 5%. Participants were randomly assigned to a low-carbohydrate diet (carbohydrate intake <30 g/d) or a low-calorie diet (30% calorie intake reduction). Arterial stiffness (via brachial-ankle pulse wave velocity-baPWV), carotid artery intima-media thickness (IMT), endothelium-dependent vasodilation (via flow-mediated dilation-FMD), cerebrovascular reactivity (CVR) in the middle cerebral artery (MCA), and blood concentrations of cardiovascular risk factors were measured before and after a two-week dietary intervention. Results: Participants with NAFLD represented 70% of the current cohort. Following the dietary interventions, participants had significant reductions in body weight (95%CI [-3.22, -1.41 kg]) and fat mass (95%CI [-1.64, -0.56 kg]), accompanied by decreased liver fat content (95%CI [-2.62, -0.79%]). These changes were only evident in the NAFLD group with no significant differences between the two dietary interventions. Systolic and diastolic blood pressure as well as pulse pressure significantly decreased in both NAFLD and non-NAFLD groups. Total cholesterol (95%CI [-22.2, -1.5 mg/dL]) and triglyceride (95%CI [-30.4, -0.9 mg/dL]) concentrations decreased in those with NAFLD assigned to the low-carbohydrate diet. baPWV decreased (95%CI [-78.6, -12.4 cm/s]) only in individuals with NAFLD assigned to the low-calorie diet. FMD significantly increased (95%CI [0.5, 5.1%]) only in individuals with NAFLD assigned to the low-carbohydrate diet. Lower baseline liver fat content was associated with greater improvement in FMD (r=-0.60, p=0.008) in the NAFLD group. Carotid IMT and cerebrovascular parameters (e.g., pulsatility index, CVR, MCA blood flow velocity) remained unchanged in any groups. Changes in vascular function were not associated with the corresponding changes in liver fat content. Conclusion: The two-week dietary intervention involving either a low-carbohydrate or low-calorie diet elicited significant reductions in liver fat content and improvements in peripheral arterial stiffness and endothelium-dependent vasodilation in adults with NAFLD. UT Aging Initiatives. 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.

PRECLINICAL VASCULAR ORGAN DAMAGE AND VASCULAR AGEING ASSESMENT IN NON-ALCOHOLIC FATTY LIVER DISEASE AND METABOLIC ASSOCIATED FATTY LIVER DISEASE PATIENTS

Objective: Non-alcoholic fatty liver disease (NAFLD) and metabolic associated fatty liver disease (MAFLD) are a growing health problem, with a growing prevalence due to its association with metabolic syndrome and diabetes. It is known to be a risk factor for the development of cirrhosis and hepatocarcinoma, but it is also known to be an important cardiovascular risk factor. The aim of this study is to assess the burden of preclinical vascular organ damage. Design and method: The study enrolled 80 consecutive patients (mean age 63.3±15.0) who underwent hepatological evaluation in our department, with evaluation of liver fibrosis score (APRI score, FIB-4) and liver stiffness, and quantification of cardiovascular risk according to Guidelines (2021 ESC Guidelines on cardiovascular disease prevention in clinical practice). Carotid atherosclerotic burden was evaluated by B-mode ultrasound in each segment (common, bulb, internal), bilaterally, and expressed as mean of maximum IMT (M-MAX), right common carotid artery distensibility and stiffness (CardioVascular Suite 4, Quipu, Italy). Aortic stiffness was evaluated as carotid-femoral pulse wave velocity (PWV), measured by applanation tonometry (PulsePen DiaTecne, Italy), with calculation of vascular ageing. Results: We found no significant correlation between ultrasound or tonometry parameters and liver stiffness and fibrosis scores. VPWV was significantly above upper limit of normal of 10 m/s (11.6±6.0 m/s, p=0.02), and the percentiles for age were significantly higher than 50th (61.7±25.1, p<0.001), with 52,5% of patients showing increased PWV. Similarly, M-MAX was higher than the upper normality level of 0.9 mm (1.09±0.30 mm, p<0.001). 70% of patients had an increased M-MAX. Vascular age based on arterial stiffness resulted significantly higher than biological age (mean difference 4.6 years, p<0.001). 76.2% (71/80) of the overall cohort and 45,2% (14/31) of patients classified as low risk showed at least one type of vascular organ damage. Conclusions: Patients with NAFLD or MAFLD showed a large prevalence of arterial stiffening and increased IMT and an enhanced vascular ageing, even among those classified at low cardiovascular risk according to Guidelines. Vascular organ damage evaluation could be useful to identify preclinical organ damage in these patients

Daunorubicin Treatment Impairs Cardiac Function in The Ts65Dn Mouse Model Of Down Syndrome

Anthracycline treatment for leukemia is effective but has toxic side effects on the cardiovascular system. Few studies regarding the impact of anthracyclines on the heart in individuals with Down syndrome have been addressed although they are at a higher risk of developing leukemia. It is unknown if established mechanisms apply to individuals with Down syndrome. We hypothesize that anthracycline cardiotoxicity will lead to the enhanced impairment of cardiac function and initiate pronounced vascular dysfunction in a mouse model of Down syndrome. We used the Ts65Dn mouse model of Down syndrome to investigate the impact of daunorubicin chemotherapy on survival, arterial stiffness and left ventricular function. Four-month-old Ts65Dn (n=12) and wild-type control Ts65Dn (WT, n=8) mice were treated with 2mg/kg of daunorubicin or saline. Following treatment, left ventricular catheterization was performed to assess cardiac function. Serum cardiac troponin levels were evaluated using ELISA. Histological analysis was conducted on the heart and aorta of mice to assess the accumulation of elastin and collagen. We found decreased end-diastolic pressure (p=0.016) and ejection fraction (p=0.029) in Ts65Dn daunorubicin-treated mice compared to WT control. However, contractility (end-systolic pressure-volume relationship, p=0.221) and diastolic stiffness coeffcient (end-diastolic pressure-volume relationship, p=0.418) remained unchanged. Ts65Dn mice had a higher cardiac troponin concentration (p=0.02). Histological assessment showed no significant difference in collagen (p=0.841) and elastin (p=0.768) content. Daunorubicin negatively impacted end-diastolic pressure and ejection fraction of the Ts65Dn mouse model of Down syndrome. We demonstrated that we could recapitulate the findings of anthracycline cardiotoxicity in Ts65Dn mice indicating this is a good model to investigate toxicity. Continued work with this model will better elucidate the mechanisms underlying anthracycline cardiotoxicity in Down syndrome. This shows the need for constant screening after anthracycline treatment which will improve the survival of this population. NIH R21 HD099573. 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.

PHENOTYPIC CHARACTERISTICS OF PATIENTS WITH INCREASED ARTERIAL STIFFNESS IN A HYPERTENSION UNIT

Objective: Arterial stiffness is related to the increase in morbidity and mortality of patients with arterial hypertension (HTN). The characteristics of a sample of patients where PWV was performed. Our goal was to look for differential characteristics among those with increased PVW. Design and method: Retrospective study of patients assessed in the hypertension unit of a tertiary hospital during 2019. Patients were assessed through ABPM by Space labs(R), Ankle brachial index by ABI Huntleigh (R) and PWV measured by Sphygmocor®. Characteristics of patients with High PWV are presented. Results: A total of 22 patients were included, mean age was 60 (± 18.1), average abdominal circumference was 99.3 cm (± 18) and average BMI was 28.55 kg/m2 (± 6.4). Office Blood pressure (BP): Mean systolic BP of 156mmHg (± 22), a mean diastolic BP of 76.58mmHg (± 10.89), a mean heart rate (HR) of 69bpm (± 10), mean central systolic BP of 135.66mmHg (± 10.76) and mean central diastolic BP of 81mmHg (± 12.4). An ankle-brachial index (ABI) was performed on 9 patients, with a mean right ABI of 120 (± 11.87) with a mean intima media thickness (IMG) of 626 (± 206.1) and a mean left ABI of 118 (± 14.61) with an IMT of 631.7 (± 143.83). Ambulatory blood pressure monitoring (ABPM) was performed in 11 of the patients, which showed a mean systolic BP of 138mmHg (± 17.57), mean diastolic BP of 75mmHg (± 11.65), and mean HR of 68bpm (± 11.94). Regarding the correlation with the laboratory findings, a mean glucose value of 108 g/dL (± 29.9), mean triglycerides of 146.9mg/dL (± 54), mean cholesterol of 191.27mg/dL (± 40.94), mean LDL of 114mg/dL (± 36.57) and mean HDL of 48.7mg/dL (± 11.37), and a mean glomerular filtration rate of 64ml/min (± 14.25). This sample was compared with patients with non-pathological PWV, with no significant differences between the groups. Conclusions: We did not find statistically significant associations, in our data, that would allow us to differentiate patients who had pathological OPV during the first visit. More studies are needed

Abstract 3004: Intermittent Hypoxia Decreases Aortic Stiffness And Facilitates Abdominal Aortic Aneurysm

Introduction: Intermittent hypoxia (IH) is a phenomenon observed with obstructive sleep apnea (OSA), which is highly prevalent in patients with abdominal aortic aneurysm (AAA). However, it remains unknown if IH is a risk factor for the development of AAA. The goal of this study was to determine the effects of IH exposure on arterial stiffness, and to assess whether IH increases the susceptibility to angiotensin (Ang) II-induced AAA in mice. Methods: Male C57BL/6 mice (8-week-old) were subjected to IH (6.5%-21% O 2 , 90 s/cycle, 12 h/day) or room air (RA, 21% O 2 , 24 h/day) for short-term (6 weeks) or long-term (6 months) (n = 10/group). Short-term mice were examined for arterial stiffness by pulse wave velocity (PWV) and atomic force microscopy, while long-term mice were used for AAA studies. To induce AAA, mice were infused with Ang II (1 μg/kg/min) using osmotic minipumps during final 14 days of IH or RA exposure. Sham surgery was performed in control mice. Outcomes were assessed via transabdominal ultrasound imaging and histology. Results: Short-term IH exposure decreased the stiffness of the abdominal (0.88 vs. 2.32 m/s in RA; p=0.0006 ) and thoracic (2.0 vs. 3.5 kPa in RA; p=0.01 ) aorta. Ang II increased abdominal aortic diameter in RA mice compared to sham and long-term IH with Ang II further augmented the aortic diameter (1.56 vs. 1.34 mm in RA Ang II; p=0.03 ) and incidence of AAA (50 vs. 10% in RA Ang II; p=0.05 ). Histologically, long-term IH plus Ang II augmented medial elastin fragmentation (7.7 vs. 5.3 in RA Ang II; p=0.04 ) and aortic collagen content (3.1 vs. 1.3 in RA Ang II; p=0.06 ). Ang II tended to non-significantly increase PWV in both groups (RA sham 1.9 vs. RA Ang II 2.5 and IH Ang II 2.3 m/s). Notably, a negative correlation between maximum aortic diameter and PWV was observed in AAA-induced mice (R 2 =0.48, p=0.0009 ). Conclusions: IH favors AAA development in association with changes in aortic stiffness. These findings support a potential causal link between OSA and AAA pathogenesis. Clarification of the molecular mechanisms may reveal novel therapeutic targets for the management of AAA.

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<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<0.001 for aortic and carotid), but no difference was observed for structural LAS measures (p>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.

Increases in Central Arterial Stiffness and Reductions in Diastolic Velocity in the Large Cerebral Arteries are Associated with Age-Related Decline in Cerebral Blood Flow

Background: Advanced aging is characterized by a reduction in cerebral blood flow (CBF) and an increase in central arterial stiffness. Increased central arterial stiffness results in reduced Windkessel effects and augmented pulsatile arterial blood pressure and CBF. These changes are detrimental to small cerebral blood vessels because of increases in biomechanical stresses associated with the augmented pulsatile arterial blood pressure and CBF. Purpose: To examine the associations of central arterial stiffness with cerebral hemodynamics and age-related reductions in CBF. Methods: 171 healthy subjects (20-81 yrs, 63% F) underwent color-coded duplex ultrasonography of the left and right internal carotid (ICA) and vertebral artery (VA) to characterize individual artery blood flow (BF), velocity, pulsatility, and CBF. Structural Magnetic Resonance Imaging (MRI) was used to measure total brain tissue volume (TBV). Carotid β-stiffness and carotid-femoral pulse wave velocity (cfPWV) were measured via applanation tonometry to assess central artery stiffness. Data: Age was negatively associated with global CBF (r = -0.425, p < 0.001), and positively with cfPWV (r = 0.701, p < 0.001), and carotid β-stiffness (r = 0.660, p < 0.001). Arterial stiffness was negative associated with ICA diastolic velocity (r = -0.280, p < 0.001; r = -0.259, p < 0.001) and VA diastolic velocity (r = -0.280, p < 0.001; r = -0.248, p = 0.001) controlling for sex, body mass index (BMI), education, and TBV. Carotid β-stiffness moderated indirect effect between age and CBF through ICA diastolic velocity (index of moderated-mediation -0.47 ± 0.13, [-0.74,-0.23]. cfPWV did not moderate the indirect effect between age and CBF through ICA diastolic velocity (index of moderated-mediation -0.36 ± 0.18, [-0.69, 0.03]. The indirect effect of age on CBF through VA diastolic velocity was not moderated by cfPWV (0.03 ± 0.09, [-0.13, 0.23]) or carotid β-stiffness (-0.17 ± 0.09, [-0.33, 0.01]). Conclusions: Age-related decline in CBF is mediated by the decreases in ICA blood flow diastolic velocity, and this relationship was moderated by carotid β-stiffness. This data suggests that increases in central arterial stiffness and reductions in CBF diastolic velocity in the large cerebral arteries likely plays an important role in age-related decline in CBF. This study was supported by NIH R01HL102457-01 and NIH R01AG033106-01. 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.

ASSESSMENT OF CARDIOVASCULAR RISK IN PATIENTS WITH RHEUMATOID ARTHRITIS ACCORDING TO CURRENT HYPERTENSION GUIDELINES

Objective: Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease (CVD) by as much as 50% compared to the general population. Considering that disease-specific calculators have failed to provide more accurate CVD risk stratification in RA, CVD risk calculation in RA patients is challenging, especially for those who are not by definition at high risk based on concomitant established CVD or its equivalents. The presence of an immune-mediated inflammatory disease (e.g., RA) has been considered as a CVD risk modifier by the previous 2018 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines. Nevertheless, current 2023 ESH/ESC guidelines recommend assessment in RA using general CVD risk calculators. Design and method: We aimed to calculate CVD risk in RA patients using the most frequently applied CVD risk calculators in the general population. We only stratified patients free from established CVD (heart disease, stroke) or its equivalents (diabetes mellitus, chronic kidney disease) aged 40-74 years. The following algorithms were applied: (i) SCORE2 (Systemic Coronary Risk Estimation-2), (ii) Framingham Risk Score-Adult Treatment Panel (FRS-ATP) CVD risk calculator, and (iii) the American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equation. We further correlated the estimated CVD risk by each algorithm with surrogate CVD markers, i.e. arterial stiffness and carotid atherosclerosis. For this purpose, carotid-femoral pulse wave velocity (cfPWV) was measured using applanation tonometry (Sphygmocor ®), and carotid intima-media thickness (cIMT) was estimated using carotid ultrasound. Results: A total of 91 patients aged 60.3±8.1 years were included (78% females). Using the FRS-ATP algorithm, more patients were classified as high risk and fewer as low risk compared to the other calculators (Table 1). Moreover, CVD risk calculated with FRS-ATP correlated stronger with both cfPWV and cIMT, compared to CVD risk calculated with the other algorithms (Table 2). Conclusions: In RA patients without established CVD, diabetes, or chronic kidney disease, the FRS-ATP algorithm may be applied as a useful tool for CVD risk stratification. Prospective, large-scale studies are warranted to determine the most reliable CVD risk prediction model for patients with RA.

EXPLORING THE EFFECTS OF VIGOROUS INTERVAL TRAINING, MODERATE RESISTANCE TRAINING AND PILATES ON ARTERIAL STIFFNESS AND BLOOD PRESSURE DURING PREGNANCY: A RANDOMISED CROSS-OVER TRIAL

INTRODUCTION Regular moderate intensity exercise throughout pregnancy provides significant benefits to both maternal and foetal cardiovascular health outcomes. Current exercise guidelines recommend a combination of moderate intensity aerobic and resistance training (RT). However, there is limited research exploring the cardiovascular effects of higher intensities (vigorous/high) in comparison to common pregnancy exercise modalities such as RT and Pilates (PIL). AIM: To investigate the acute effects of three modes of exercise (resistance, vigorous aerobic intervals and Pilates) during trimester two (T2) and three (T3) of pregnancy on measures of arterial stiffness (pulse wave velocity [PWV]) and blood pressure (BP). METHODS Eleven women with uncomplicated pregnancies (age 32 ± 3 years, pre-pregnancy BMI 23.9 ± 3.5 kg/m2) completed testing in T2 (average 20 ± 1.6 weeks gestation) and T3 (average 29 ± 2.5 weeks gestation). Participants performed one each of vigorous intensity interval training (VIIT) (∼33 min), resistance training (RT) (∼35 min) and Pilates (PIL) (∼35 min) in T2 and T3 in randomised order approximately 1 week apart each trimester. Resting outcome measures of PWV, BP and foetal heart rate (FHR) were obtained following 5 minutes of rest and again immediately and 10 minutes post exercise session. BP, maternal heart rate (MHR), and rating of perceived exertion (RPE) were monitored throughout. RESULTS There was no difference in the acute PWV response to each type of exercise across the trimesters (1 min VIIT: T2 = 5.53 ± 0.85m/s, T3 = 5.26 ± 0.67m/s, 95%CI[-1.36-0.67]; RT: T2 = 5.4 ± 0.80m/s, T3 = 5.48 ± 0.56m/s, 95%CI[-0.88-1.10]; PIL: T2 = 5.44 ± 0.68m/s, T3 = 5.44 ± 0.68m/s, 95%CI[-0.93-1.01]). There was no significant difference in the acute response in SBP to VIIT (T2 = 116 ± 12.1mmHg, T3 = 122 ± 7.2mmHg, 95%CI[-0.42 - 1.65]. SBP was significantly higher in T3 than T2 1 minute following PIL (T2 = 110 ± 5.8mmHg, T3 = 121 ± 11.7mmHg, 95%CI[0.04-2.1]) and 10 minutes following RT (T2 = 105 ± 10.1mmHg, T3 = 116 ± 5.0mmHg, 95%CI[0.27 - 2.46]. CONCLUSION VIIT, RT and PIL appear to elicit similar post-exercise haemodynamic and arterial stiffness responses in both the mother and foetus. As such, VIIT may be a suitable addition to standard moderate intensity and RT prescription during an uncomplicated pregnancy.

CLUSTER ANALYSIS OF PULSE WAVE VELOCITY LONGITUDINAL TRENDS IN HYPERTENSIVE PATIENTS

Objective: Arterial stiffness (AS) is an important predictor of cardiovascular disease and mortality. Its trend over time, assessed through multiple measurements, is still largely unexplored. The aim of this study was to assess the determinants of trajectories of carotid-femoral pulse wave velocity (PWV) in a cohort of Italian hypertensive adults. Design and method: From a population of 2581 hypertensive patients referred to Hypertension Unit of Internal Medicine Division at University Hospital Città della Salute e della Scienza of Turin (Italy) from 2005 to 2023, those who had at least 3 PWV recordings over time were included in this study. Those with rare vascular diseases were excluded. Cluster analysis of PWV trajectories was performed using K-means method. Results: A total of 271 patients were included. Median follow-up time was 4.5 [0.6-8.4] years). Three clusters of PWV trends were identified: low-stable (A, n=126), high-increasing (B, n=107), and high-stable (C, n= 38) clusters. Patients in the clusters B and C were progressively older than those in cluster A (60.4±8.9 and 65.8±10.3 vs. 51.9±13.3 years, respectively). Mean BP (MBP) and PWV at baseline were progressively higher in the high-increasing and high-stable clusters compared to the low-stable one (MBP was 103±15 and 111±22 mmHg in clusters B, and C vs. 97±11mmHg in cluster A; PWV was 10.1±0.7 and 13.6±1.4 m/s in clusters B, and C vs. 7.8±0.9 m/s in cluster A; all p<0.001). There were no significant differences in sex distribution or anti-hypertensive treatment among the clusters. On multinomial regression analysis, older age and higher MBP at baseline were independently associated to increased probability of belonging to either B or C clusters when compared to the low-stable one. Conclusions: Through multiple PWV assessment in hypertensive patients during a large time span, this study shows that patients with less favorable arterial stiffness behavior present higher PWV values at baseline. Older age and higher MBP at baseline are associated with worse evolution of PWV over time.

ASSOCIATION OF ARTERIAL STIFFNESS WITH CARDIORENAL INJURY IN CHINESE PATIENTS WITH NEWLY-CONFIRMED PRIMARY ALDOSTERONISM: A CROSS-SECTION STUDY

Objective: Although the significant associations between arterial stiffness and target organ damage (TOD) have been established in essential hypertension, the evidence on the relationship in newly diagnosed primary aldosteronism (PA) are still limited. The present study aimed to investigate the association of arterial stiffness and TOD in Chinese newly confirmed PA patients. Design and method: Included were 823 newly diagnosed PA patients receiving the extremity blood pressure monitoring from January 2016 to December 2021 at the Fuwai Hospital. Spearman correlation analysis was performed to assess the correlation of vascular stiffing parameters with left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR) and 24 h urinary albumin to creatinine ratio (UACR). The least absolute shrinkage and selection operator (LASSO) regression model were conducted to select the potential influencing factors, and the univariate and multivariate logistic analysis were used to identify the potential risk factors. Results: The mean age of included patients (female 43.4%) was 51.24 years, and the proportion of TOD was 78.13% (643/823). Compared with PA patients without TOD, those with TOD were older in age, had higher systolic blood pressure, diastolic blood pressure, brachial-ankle pulse wave velocity (BaPWV), UACR and LVMI, and lower eGFR. BaPWV was positively correlated with LVMI (r=0.20, P<0.001) and UACR (r=0.27, P<0.001) but inversely correlated with eGFR (r=0.29,P<0.001). Multivariate adjusted logistic analysis suggested that BaPWV was markedly associated with TOD (odds ratio [OR] =1.134; 95% confidence interval [CI]: 1.055-1.220; P=0.001), left ventricular hypertrophy (LVH) (OR=1.069, 95%CI: 1.011-1.131; P=0.019) and renal injury (OR=1.100, 95%CI: 1.039-1.165; P=0.001). Conclusions: BaPWV was significantly associated with TOD, LVH and renal injury in Chinese newly confirmed PA patients. The present study emphasized the important role of BaPWV in early recognition of TOD in newly confirmed PA patients, which may improve the clinical outcomes via early intervention.

Abstract 2040: Rapamycin Extends Life Of Matrix Gla Protein Knockout Mice Independent Of Vascular Calcification Content.

Background: Peripheral artery disease (PAD) is characterized by the narrowing and blockage of the vessels in lower extremities. While atherosclerosis has been the assumed culprit of PAD recent data now shows that medial arterial calcification (MAC) is the cause of below-the knee ischemia. MAC promotes thrombosis via inward remodeling, reduced elasticity, and arterial stiffness. The mechanisms driving MAC pathogenesis are unclear. Matrix Gla Protein (MGP) is an inhibitor of vascular calcification and present in arterial vessel walls. MGP -/- mice exhibit extensive MAC throughout their vasculature and die within 5-7 weeks due to aortic rupture or heart failure. The drug rapamycin functions as an inhibitor of cell proliferation and an activator of autophagy. Hypothesis: That rapamycin reduces MAC in MGP -/- mice via inhibiting inward remodeling and activating autophagy. Methods: MGP +/+ and MGP -/- mice treated with vehicle or rapamycin (5mg/kg, 3x weekly) starting at 10 days old for 2 weeks. Calcification was quantified via micro-computed tomography (uCT). Collagen structure and elastin quality were assessed histological staining. Markers of proliferation (Ki-67), cell death (Caspase 3), autophagy (LC3), and calcification (Runx2) were quantified via immunofluorescence staining. Western blot was used to assess autophagy flux and proliferation in smooth muscle cells (SMCs) isolated from MGP +/+ and MGP -/- mice. Results: While rapamycin treatment doubled the life-expectancy of MGP -/- mice, the calcification content was unchanged compared to the vehicle. However, rapamycin caused a significant decline in mineral density. Higher collagen content and improved elastin structure were observed in MGP -/- treated with rapamycin compared to vehicle. Runx2 and Ki-67 were elevated in MGP -/- mice compared to MGP +/+ , but there was no difference in response to rapamycin treatment. No difference was observed in caspase 3 levels. Under rapamycin treatment, MGP -/- SMCs exhibited higher autophagy flux than MGP +/+ SMCs. Conclusion: While rapamycin did not reduce MAC, our data suggest that rapamycin potentially preserves the integrity of the aortic vessel wall by inducing autophagy, which requires further investigation.

Racial Disparity in Microvascular Function in Men with Newly Diagnosed Prostate Cancer

BACKGROUND:Cardiovascular disease (CVD) is a leading cause of death in men with prostate cancer. In addition, non-Hispanic Black (NHB) men experience worse CVD-related mortality compared to their non-Hispanic White (NHW) counterparts, although the reason for this racial disparity remains unclear. Notably, vascular endothelial dysfunction often precedes the emergence of overt CVD. Indeed, conduit-vessel dysfunction, micro-vascular dysfunction, and arterial stiffness are independent predictors of CVD risk. Thus, the purpose of this study was to comprehensively assess vascular health in recently diagnosed NHB and NHW men with prostate cancer. Methods: Twenty-eight men (10 NHW, 18 NHB) with a new clinical diagnosis of prostate cancer (within 3 months) participated in this study. Flow-mediated dilation (FMD) was performed to represent conduit-vessel vascular endothelial function. Cutaneous post occlusive reactive hyperemia (PORH) with local thermal heating (LTH) and iontophoresis of acetylcholine were performed to represent various mechanisms regulating microvascular function. Lastly, pulse wave velocity (PWV) and pulse wave analysis (PWA) were performed to assess central and aortic stiffness, respectively. Data are reported as mean ± SD. Results: A 4-year age difference ( p=0.131) was observed between NHB (65±7 years) and NHW (69±6 years) men. No differences in BMI or clinical laboratory values were observed between NHB and NHW patients (all p>0.05). NHB men exhibited significantly lower microvascular function compared to NHW men, including PORH (NHB: 117±44 PU vs NHW: 207±47 PU; p<0.001), LTH (NHB: 180±73 PU vs NHW: 281±65 PU; p=0.003), and iontophoresis (NHB: 67±28 PU vs NHW: 136±38 PU; p<0.001). No differences in FMD ( p=0.596), PWV ( p=0.695), or PWA ( p=0.883) were observed between groups. CONCLUSION: The results of the current study provide compelling evidence that microvascular dysfunction is present in NHB men who are recently diagnosed with prostate cancer compared to their NHW counterparts. Given that NHB men were 4 years younger, these data support that the microvascular dysfunction may accelerate vascular aging and contribute to the racial disparity in CVD following prostate cancer diagnosis. Supported by: AHA SFRN 863621 (RAH). 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.

O-GlcNAcylation regulates angiotensin II-dependent induction of thrombospondin 1

O-Linked attachment of β-N-acetylglucosamine (O-GlcNAc) on serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins is a highly dynamic and ubiquitous post-translational modification that plays an important role in altering the function, activity, subcellular localization, and stability of target proteins. It has been proposed that physiologically, O-GlcNAcylation serves primarily to modulate cellular signaling and transcription regulatory pathways in response to nutrients and stress. However, in the vascular physiology literature, O-GlcNAc has predominantly been shown to be detrimental. Our preliminary data has shown that O-GlcNAcylation can cause aortic stiffness, however, the mechanisms underlying this phenotype remain to be elucidated. The predominant mechanisms by which O-GlcNAcylation contributes to alterations in proteostasis include competition with other post-translational modifications as well as regulation of gene expression. Thrombospondin-1 (TSP1) is a multifunctional matrix glycoprotein that impacts extracellular function (ECM) and cell adhesion, migration, proliferation, and cell-cell interaction. Therefore, we hypothesized that TSP1 could be an important downstream mediator of O-GlcNAcylation in aortic vascular smooth muscle cells (VSMCs). To test this hypothesis, primary VSMCs from the thoracic aorta were isolated from 12-week-old female Wistar rats and submitted to angiotensin (ANG) II treatment (100 nM, 3h). Some cells were also treated in the presence of ANG II type 1 (AT1)-receptor antagonist losartan (10−5 M, 30 min). ANG II was chosen because it is a physiological stressor known to cause arterial stiffening. O-GlcNAcylation (RL2 antibody), O-GlcNAcase (OGA), and TSP1 protein amounts were analyzed by Western blot, and the results were expressed in arbitrary units (AU) and mean ±standard error mean. Unpaired Student's test T was used and p<0.05 was considered statistically significant. Genetic and pharmacological inhibition of O-GlcNAc was achieved through OGT silencing and inhibition with a shRNA (FunGene6) and OSMI-4 (10−5 M, 30 min), respectively. As hypothesized, ANG II significantly increased O-GlcNAc in aortic VSMC (0.3±0.03 vs 0.5±0.03 AU n=8, p<0.05) which was inhibited by losartan (0.1±0.02). Moreover, ANG II significantly decreased OGA expression (0.16±0.04 vs 1.16±0.19 AU n=4, p<0.05), the enzyme responsible for removing O-GlcNAc motifs, supporting the observed increase in O-GlcNAc expression. Importantly, ANG II also increased TSP1 protein expression (0.2±0.04 vs 2.0±0.4 n=4, p<0.05), however, shRNA (0.7±0.05) for OGT and OSMI-4 (0.06±0.08) prevented this increase. Overall, these data indicate that Ang II-AT1R signaling can cause O-GlcNAcylation and that TSP1 could be an important downstream mediator of O-GlcNAc-mediated aortic stiffness. National Institutes of Health (R00HL151889, P20GM109091-Pilot Project, and P20GM103641-Pilot Project). University of South Carolina Offce of Research ASPIRE Award (180950-23-64136). American Heart Association Postdoctoral Fellow (916031). 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.