Arterial Stiffness Research Articles

Mechanistic insights into cardiovascular effects of ultrafine particle exposure: A longitudinal panel study

BackgroundUltrafine particle (UFP) has been linked with higher risks of cardiovascular diseases; however, the biological mechanisms remain to be fully elucidated. ObjectivesThis study aims to investigate the cardiovascular responses to short-term UFP exposure and the biological pathways involved. MethodsA longitudinal panel study was conducted among 32 healthy, non-smoking young adults in Shanghai, China, who were engaged in five rounds of follow-ups between December 2020 and November 2021. Individual exposures were calculated based on the indoor and outdoor real-time measurements. Blood pressure, arterial stiffness, targeted biomarkers, and untargeted proteomics and metabolomics were examined during each follow-up. Linear mixed-effect models were applied to analyze the exposure and health data. The differential proteins and metabolites were used for pathway enrichment analyses. ResultsShort-term UFP exposure was associated with significant increases in blood pressure and arterial stiffness. For example, systolic blood pressure increased by 2.10 % (95 % confidence interval: 0.63 %, 3.59 %) corresponding to each interquartile increase in UFP concentrations at lag 0–3 h, while pulse wave velocity increased by 2.26 % (95 % confidence interval: 0.52 %, 4.04 %) at lag 7–12 h. In addition, dozens of molecular biomarkers altered significantly. These effects were generally present within 24 h after UFP exposure, and were robust to the adjustment of co-pollutants. Molecular changes detected in proteomics and metabolomics analyses were mainly involved in systemic inflammation, oxidative stress, endothelial dysfunction, coagulation, and disturbance in lipid transport and metabolism. DiscussionThis study provides novel and compelling evidence on the detrimental subclinical cardiovascular effects in response to short-term UFP exposure. The multi-omics profiling further offers holistic insights into the underlying biological pathways.

THE PREVALENCE, CHARACTERISTICS, AND PREDICTORS OF HYPERTENSION PHENOTYPES IN A CHINESE POPULATION

Objective: Different phenotypes of hypertension are associated with varying degrees of cardiovascular risk. However, there is limited data available regarding the features and predictors of hypertension phenotypes in Chinese populations. This study aimed to evaluate the prevalence, characteristics, and predictors of different patterns of hypertension in a Chinese population. Design and method: In this study, a cross-sectional design was employed, and a total of 13,073 community participants were included. Hypertension phenotypes were defined as isolated systolic hypertension (ISH, systolic blood pressure (SBP) no less than 140 mmHg and diastolic blood pressure (DBP) less than 90 mmHg), isolated diastolic hypertension (IDH, SBP less than 140 mmHg and DBP no less than 90 mmHg), and systolic-diastolic hypertension (SDH, SBP on less than 140 mmHg and DBP no less than 90 mmHg). Univariate and multivariate logistic regression analyses were utilized to investigate the predictors of various hypertension phenotypes. Results: The mean age of participants was 56.1 years, and 8625 (66%) were women. The prevalence rates of normotension, ISH, IDH, and SDH were 77.7%, 15.6%, 1.2%, and 5.6%, respectively. Compared with the normotensive group, participants with ISH were more likely to be older, men, overweight, obese, presenting with abdominal obesity, artery stiffness, and diabetes, as well as having lower levels of serum creatinine. Patients with IDH demonstrated a higher likelihood of being younger, men, presenting with abdominal obesity, and having higher levels of heart rate compared to normotensive individuals. Furthermore, male gender, alcohol consumption, overweight, obesity, abdominal obesity, artery stiffness, and higher levels of heart rate were predictors for SDH compared to normotension. Conclusions: Male gender and abdominal obesity were identified as common risk factors for three phenotypes of hypertension. However, age had a varying effect on the prevalence of distinct patterns of hypertension.

NON-INVASIVE CENTRAL BLOOD PRESSURE AND INTRACRANIAL WAVEFORM ASSESSMENT IN HYPERTENSIVE PATIENTS

Objective: Hypertension (HT) remains as the leading cause of death around the globe and brain diseases, such as cognitive decline. The association between HT and cerebrovascular diseases is strong, mainly with stroke and cognitive impairment, but the mechanistic bases remain to be established. The objective of this study is to observe central blood pressure, arterial stiffness and intracranial pressure in long-term chronic hypertensive patients. Design and method: Patients above 18 years were assessed from November 2022 to August 2023 with non-invasive central blood pressure and intracranial pressure waveform measurements in a cross-sectional analysis. Peripheral and central blood pressure parameters were obtained using a validated oscillometric device (Mobil-O-Graph). Non-invasive intracranial pressure measurement was performed with the validated Brain4Care (B4C) sensor. Using the B4C non-invasive evaluation, the cut-off point identified to define ICHT by the P2/P1 ratio was > 1.2, and the cut-off for time to peak (TTP) was > 0.25 seconds. To compare P2/P1 and TTP values between the categories of quantitative variables, the chi-square test was used; the Mann Whitney or ANOVA tests were used for bivariate analyses; and for correlations, the Spearman test was used. It was adopted as significant at p < 0,05. Results: Non-invasive central blood pressure, arterial stiffness, and intracranial pressure waveform assessment were performed in 145 patients with essential long-term hypertension over a period of ten months. The median age was 69.0 (61.8 – 75.7) years, 77.9% were female, and the median BMI was 29.0 (25.4 – 33.1) kg/m2. The average time since the hypertension diagnosis was 20.0 years. The median value of P2/P1 ratio for all cohort was 1.4 (1.2 – 1.5) and TTP 0.24 (0.21 – 0.29) seconds. A bivariate analysis was performed considering ICHT or not and the parameters of central BP and PWV assessments, with findings of higher central SBP, central DBP, and peripheral DBP among patients with ICHT by the parameter of P2/P1. Conclusions: Central systolic blood pressure levels are more linked to intracranial hypertension, while diastolic blood pressure values are similar, raising questions about the most suitable blood pressure assessment method for brain disorders.

Associations of between- and within-day patterns of physical activity accumulation with arterial stiffness and indices of microvascular health-Evidence from The Maastricht study.

While physical activity (PA) is understood to promote vascular health, little is known about whether the daily and weekly patterns of PA accumulation associate with vascular health. Accelerometer-derived (activPAL3) 6- or 7-day stepping was analyzed for 6430 participants in The Maastricht Study (50.4% women; 22.4% Type 2 diabetes mellitus (T2DM)). Multivariable regression models examined associations between stepping metrics (average step count, and time spent slower and faster paced stepping) with arterial stiffness (measured as carotid-femoral pulse wave velocity (cfPWV)), and several indices of microvascular health (heat-induced skin hyperemia, retinal vessel reactivity and diameter), adjusting for confounders and moderators. PA pattern metrics were added to the regression models to identify associations with vascular health beyond that of stepping metrics. Analyses were stratified by T2DM status if an interaction effect was present. Average step count and time spent faster paced stepping was associated with better vascular health, and the association was stronger in those with compared to those without T2DM. In fully adjusted models a higher step count inter-daily stability was associated with a higher (worse) cfPWV in those without T2DM (std β = 0.04, p = 0.007) and retinal venular diameter in the whole cohort (std β = 0.07, p = 0.002). A higher within-day variability in faster paced stepping was associated with a lower (worse) heat-induced skin hyperemia in those with T2DM (std β = -0.31, p = 0.008). Above and beyond PA volume, the daily and weekly patterns in which PA was accumulated were additionally associated with improved macro- and microvascular health, which may have implications for the prevention of vascular disease.

EFFECTS OF ALLISARTAN ON URIC ACID, LEFT ATRIAL, LEFT VENTRICULAR AND ARTERY STIFFNESS IN MILD-TO-MODERATE ESSENTIAL HYPERTENSION

Objective: Our study aimed to explore the effects of allisartan on blood pressure, uric acid (UA), left atrial, left ventricular structure and function and artery stiffness in mild-to-moderate essential hypertension. Design and method: Our study is a randomised, double-blind, crossover design involving 98 patients with mild-to-moderate essential hypertension. Participants were administered allisartan (240mg) or olmesartan (20mg) once daily for 12 weeks each in varying sequences. Results: Both allisartan and olmesartan led to a significant decrease in systolic blood pressure (SBP) levels from baseline, with no significant difference between the two drugs (δ= 6.5mmHg, P<0.001 and δ= 5.64mmHg, P=0.002). Notably, allisartan exhibited a more pronounced reduction in diastolic blood pressure compared to olmesartan (δ= 3.66mmHg, P=0.001), with superior efficacy in lowering diastolic blood pressure (DBP) (δ= 3.39mmHg, P=0.016). Allisartan significantly dropped serum UA levels (δ= 26.37 μmol/L, P<0.001), whereas olmesartan did not achieve a significant reduction compared to allisartan (δ= 33.63 μmol/L, P<0.001). In terms of cardiac and artery stiffness, allisartan demonstrated significant reductions in left atrial volume index (LAVI) (δ= 2.86 ml/m2, P<0.001), left ventricular mass index (LVMI) (δ= 4.82 g/m2, P=0.010) and ankle-brachial pulse wave velocity (baPWV) (δ= 154.49 cm/s, P<0.001), all-surpassing olmesartan significantly (all P<0.01). Conclusions: In conclusion, compared to olmesartan, allisartan demonstrates significant reductions in serum UA, blood pressure, LAVI, LVMI and baPWV in patients with mild to moderate essential hypertension. This study provides new evidence supporting the efficacy of allisartan in treating mild-to-moderate essential hypertension and reducing serum UA levels in this population.

THE ARTERIAL STIFFNESS AS RISK FACTOR FOR THE OCCURRENCE OF ARTERIAL HYPERTENSION IN POSTOPERATIVE CRITICALLY ILL PATIENTS

Objective: The aim of the present study is to investigate the predictive value of arterial stiffness in the occurrence of arterial hypertension in critically ill patients. Also, the study investigates the risk factors of arterial hypertension in ICU patients. Design and method: This is a prospective observational study. The study included postoperative patients who were admitted to the ICU. We collected demographic characteristics of the patients, their clinical characteristics (i.e. hemodynamic status), clinical severity (APACHE II, SOFA score), lifestyle data (i.e. smoking, alcohol, drugs), and medical history (diabetes mellitus, cardiovascular diseases). Arterial stiffness assessment is performed by recording and analyzing the pulse wave in postoperative patients during the first 24 hours of admission to the ICU. The Sphygmocor software was used for pulse wave analysis and IBM SPSS v.27.0 software was used for statistical analysis. Results: The sample of the study consisted of 74 patients. Most of them were males (70.3%) aged 59.3±18.6 yrs and the rest were females (29.7%) aged 63.3±16.9 yrs. Totally, 54.1% of patients had emergency surgery, 60.8% survived and discharged from ICU, 52.7% had arterial hypertension, 70.3% had diabetes mellitus, 58.1% were smoking, and 63.5% had hypercholesterolemia. The APACHE II score of patients was found 21.2±7.2 and the SOFA score 7.5±2.8 The value of peripheral systolic blood pressure (PSBP) was 138.7±19.4 mmHg, peripheral diastolic blood pressure (PDBP) was 67.1±13.2 mmHg, mean peripheral blood pressure (MPBP) was 90.7±14.6 mmHg, pulse pressure (PP) was 53.1±15.3 mmHg and AIX@75 was 22.3±13.1%. Older patients (69.1±14.9 vs. 52.7±17.3, p=0.001), patients with diabetes mellitus (92.3% vs. 7.7%, p=0.001), patients with hypercholesterolemia (92.3% vs. 7.7%, p=0.001), patients with higher value of Albumin (2.9±0.5 vs. 2.5±0.6, p=0.025), and patients with a higher value of AIX@75 (26.8±10.5 vs. 18.3±14.1, p=0.004) had statistically significant higher percentages of arterial hypertension. Higher AIX values are associated with a greater likelihood of arterial hypertension (OR: 1.027; 95%CI: 1.004-1.049, p=0.018). Conclusions: The arterial stiffness is an independent risk factor for arterial hypertension in postoperative critically ill patients.

Estudio de la asociación de marcadores de rigidez arterial central y periférica con la función renal en pacientes con hipertensión arterial, diabetes mellitus y enfermedad renal crónica

Rationale and objectivesIncreased aortic or central arterial stiffness (CAS) is a major factor in cardiovascular morbidity and mortality in patients with vascular risk factors. Decreased glomerular filtration rate (GFR) and increased urinary albumin excretion (uALB) are associated with lethal and non-lethal cardiovascular events. The pathophysiological mechanisms of this association are not fully defined.The aim of this study was: 1.- To analyze the CAS, comparing several markers, in subjects with arterial hypertension (HTN), diabetes mellitus (DM), chronic kidney disease (CKD) and their combination. 2.- To study the possible association of CAS with renal dysfunction (decrease in GFR and increase in uALB). Material and methodsA total of 286 subjects were included, divided into several groups: Control (n: 38); HTN (n:51); DM without CKD (n:26); CKD without DM (n:77); CKD with DM (n:94). Several indices obtained by applanation tonometry were used to determine the CAS: carotid-femoral pulse velocity (VPc-f); central pulse pressure (cPP); augmentation index standardized to a cardiac frequency of 75 l/min (IA75); peripheral / aortic arterial stiffness gradient (ASGp-a). As a marker of peripheral arterial stiffness, the carotid-radial pulse velocity (PVc-r) was determined. The ASGp-a was calculated from the PVc-r /PVc-f ratio. The subendocardial viability index (iBuckberg) was obtained from the aortic pulse wave.Multiple regression, binary logistic regression, and multinomial regression were used to study the association between arterial stiffness markers and renal function. ResultsThe adjusted values of the PVc-f [(median (interquartile range) (m/sec)] were significantly higher in subjects with DM [(9 (1.2)], CKD [(9.4 (0.7)] and DM with CKD [(10.9 (0.7)] than in the control group [(8.2 (1.3)] and group with HTN [(8.3 (0.9)], (p:0.001). Patients with DM with CKD had higher PVc-f values than all other groups (p: 0.001). The ASGp-a of the patients was significantly lower than that of the controls, and the group with DM with CKD had significantly lower values than the other groups. The cPP in the DM with CKD group was significantly higher than in the other groups. All patients had an AI75 higher than the control group.When all aortic stiffness markers were introduced together in the regression, PV c-f was the only one that, after multivariate adjustment, was independently and inversely associated with GFR (β; –4, p:0.001) and predicted the presence of GFR decrease (< 60mL/min/1.73 m2), [(OR (95%CI): 1.50 (1.17-1.92; p:0.001]. The PVc-f was the only index directly associated with albuminuria (β: 0.15, p: 0.02) and predicted the existence of abnormal albuminuria (> 30mg/g), [(OR; 1.66 (1.25-2.20), p:0.001)]. The PVc-f was also associated with the iBuckberg (β: -2.73, p: 0.01).Multinomial regression confirmed that PVc-f is a significant determinant of GFR and uALB. On the other hand, the increase in PVc-f and the presence of DM contribute significantly to the magnitude of albuminuria. ConclusionsAortic stiffness increases in the presence of vascular risk factors such as hypertension, DM and CKD. This increase is greater when DM and CKD coexist. Increased aortic stiffness is inversely associated with GFR and directly with uALB, and is predictive of decreased GFR and abnormal uALB. The VPc-f is the parameter of aortic stiffness that is most consistently associated with renal dysfunction. Increased aortic stiffness could be one of the pathomechanisms linking renal dysfunction to cardiovascular events.

Evaluating the Role of LOXL2 in Post-menopausal Arterial Stiffening

Introduction: Cardiovascular disease (CVD) is the number one cause of death for both men and women. Even though pre-menopausal women are relatively protected from CVD, a disproportionate increase in CVD risk and incidence occurs after menopause. Aortic stiffening, as occurs in aging, is predictive of major adverse cardiovascular events, independent from the traditional CVD risk factors. Epidemiological studies have shown that older, post-menopausal women exhibit an accelerated pace of aortic stiffening, eventually surpassing age-matched men, with exacerbated isolated systolic hypertension, diastolic dysfunction, and left ventricular remodeling. The hormonal shift, particularly loss of estrogen, present in post-menopausal women has also been widely studied; however, it is increasingly clear that estrogen loss alone is not responsible for the elevated CVD risk. More recently, a shift to androgen signaling has emerged as a key facet in post-menopausal women's health. Thus, mechanistic differences and manifestations of arterial stiffness in men and women require further investigation to help identify and develop novel risk assessment tools and therapeutic targets. Here we propose LOXL2, a key matrix remodeling enzyme, as a potential therapeutic target. In this study, we determined if post-menopausal females present accelerated arterial stiffening, and an abrupt and larger increase in LOXL2. We also studied the effect of sex hormones in LOXL2 activation. Methods and results: Male and female C57Bl/6J mice were used. Female mice underwent ovariectomy (OVX) or sham surgery at 10 weeks old. Three groups were compared: 1) OVX, 2) sham control females, and 3) age-matched males. Body weight, pulse wave velocity (PWV, the gold-standard index of in vivo arterial stiffening), and blood pressure (BP) were measured non-invasively from 12 to 53 weeks old. Results showed a significant increase in both body weight and PWV in the OVX females compared to sham females and males. BP remained similar for all groups, with a slight increase in OVX females. Mice were dissected, and aorta and heart were extracted and prepared for Western blotting measurements. OVX mice showed a low heart to body weight ratio. Western blotting (pilot data) revealed an increasing trend in LOXL2, ERα, and ERβ in the aorta and heart of OVX females. To test LOXL2 activation by sex hormones in vitro, human aortic smooth muscle cells (HASMC) and human aortic endothelial cells (HAEC) were exposed to dihydrotestosterone (DHT) and estradiol (E2) concentrations that mimic the hormonal levels of menstruating women, post-menopausal women, and men (post-puberty) for 16h. Western blotting showed highest levels of LOXL2 when mimicking the post-menopausal women hormonal levels in HASMCs but not in HAECs. Conclusion: Vascular stiffness is exacerbated in OVX females compared to sham females and males. OVX mice present a higher LOXL2 protein abundance in the aorta and heart, as well as increased ERα and ERβ. LOXL2 is modulated by sex hormones, showing significant increase when mimicking post-menopausal women’ hormonal levels. Future studies will continue to: 1) determine the molecular mechanisms underlaying increased arterial stiffness in females after menopause, 2) identify and test novel targets to stop and/or reverse this increase in vascular stiffening, and 3) study the role of hormonal shift in old females in arterial aging. NHLBI grant R01HL148112 01 (L.S.). 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.

Kidney Stem Cell Reprogramming Drives Spontaneous Hypertension via Exosomes

The spontaneously hypertensive rat (SHR) is a commonly used animal model for studying primary hypertension. However, the precise mechanism of these rats developing hypertension remains to be defined. Here, we have first demonstrated that kidney stem cell reprogramming is a driver for the development of hypertension in SHR rats. In this study, we treated 5-week-old SHR rats with WKY-kidney stem cell-derived exosomes (WKY-Exo) and 5-week-old WKY rats with SHR-Exo, respectively, via i.p. injections. Notably, WKY-Exo effectively blocked the development of hypertension and arterial stiffening in SHRs. It is fascinating that WKY rats developed hypertension and arterial stiffening due to treatment of SHR-Exo. We confirmed that both WKY- and SHR-Exo were up taken into aortic endothelial and smooth muscle cells after i.p. delivery of CD63/GFP-labelled exosomes. We demonstrated that WKY-Exo can improve vascular functions and arterial compliance of SHR rats as evidenced by preventing the development of arterial stiffness and restoring renal artery endothelial function. We also demonstrated that the vascular functions were impaired in WKY rats after SHR-Exo treatment. Furthermore, our data show that expression of Elastin, Emilin1, and Myh11 was significantly downregulated in the aorta of SHR rats, which can be repaired by WKY-Exo treatment. SHR-Exo decreased expression of Elastin and Emilin1 without affecting Myh11 in the aorta of WKY rats, suggesting that Elastin and Emilin1 deficiency could contribute to arterial stiffening leading to the development of spontaneous hypertension. Proteomic analysis reveals the enrichment of protein-protein interaction network for elastic fiber assembling, blood vessel development, and regulation of angiogenesis in WKY-Exo vs SHR-Exo. In conclusion, our data first demonstrates that kidney stem cell reprograming is a driver for the development of spontaneous hypertension in SHR rats. WKY-KSCs-derived exosome contains a proteome profile promoting arterial repair, which may provide a therapeutic means to prevent and treat primary hypertension. NIH. 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.

Proximal convoluted tubule cells-derived exosomes attenuate aging-related vascular dysfunction

Aging is an identified risk factor for cardiovascular disease. Aging is associated with increased prevalence of endothelial dysfunction and arterial stiffening. Exosomes are bi-lipid nanoscale vesicles that play important roles in intercellular communications. The purpose of this study was to determine whether administration of renal proximal convoluted tubule cells (PCT)-derived exosomes affects vascular and renal function in aging mice. Aging (24 months old) and young mice (3 months old) were treated with PCT-derived exosomes via non-invasive injection into the kidney 3 times a week for 2 weeks. Administration of PCT-derived exosomes did not affect blood pressure or urinary Na+, K+, and Ca2+ excretions, indicating that PCT-derived exosomes did not affect kidney function. Pulse wave velocity (PWV) was increased in aging mice, indicating arterial stiffening. Interestingly, treatment with PCT-exosomes effectively reduced aging-associated arterial stiffening. In addition, aortic endothelium-dependent relaxing (EDR) responses to acetylcholine (Ach) were reduced in aging mice, indicating endothelial dysfunction. Treatment with PCT-derived exosomes rescued aging-associated aortic endothelial dysfunction. Mechanistically, aortic expression of VCAM1, ICAM1, TNFα, and MCP-1 was upregulated in aging mice, indicating vascular inflammation. Notably, aging-associated vascular inflammation was largely attenuated by delivery of PCT-derived exosomes. Our results suggest that PCT-derived exosomes improves aging-associated arterial stiffening and vascular dysfunction partly via inhibiting vascular inflammation. The findings may help develop novel therapeutic strategies for aging-associated vascular dysfunction using PCT-derived exosomes. This work is supported by NIH research grants R01 HL154147 and AG062375. 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.

XX Sex Chromosome Complement Promotes Arterial Stiffening and High Blood Pressure in Female Mice

Arterial stiffness measured by pulse wave velocity (PWV) increases precipitously during menopausal transition due to estradiol decline. Longitudinal studies show a steep increase in PWV of postmenopausal women compared to age-matched men. Previously, we have demonstrated increased PWV in ovariectomized and middle-aged female mice. Additionally, we showed increased oxidative stress in female than male vascular cells treated with angiotensin II in hormone-free charcoal-stripped media. We hypothesize that a decline in estradiol unleashes the female sex chromosomes effect that promotes arterial stiffening. In this study, we used the four core genotype mice (n=6-10/group) comprising females with either XX or XY sex chromosome complement that were left intact or ovariectomized for 8 weeks. Arterial stiffening was assessed with pulse wave Doppler and 24-hour blood pressure by radiotelemetry. Carotid artery passive myography and vascular reactivity of 2nd order mesenteric artery were assessed by pressure myography. To induce hypertension, ovariectomized XX and XY mice were treated with deoxycorticosterone acetate (DOCA; 50 mg/pellet) for 21 days and 1% saline as drinking water. PWV was significantly increased in ovariectomized than in gonadal intact XX and XY mice (main effect: p&lt;0.001). However, an interaction effect was indicated with higher PWV in XX than XY ovariectomized mice (4.9±0.1 vs. 4.2±0.2 m/s; p&lt;0.001), indicating a sex chromosome effect. Carotid artery stress-strain curves showed a leftward shift of XX than XY ovariectomized mice, suggesting increased structural stiffness. Masson’s trichrome staining of the aorta showed increased collagen in the adventitia of XX than XY ovariectomized mice (30±0.01 vs. 26±0.02 %; P=0.005). Higher systolic blood pressure (SBP) was indicated in ovariectomized XX than in XY mice (Baseline; 123±3 vs. 116±4 mmHg; P=0.02). DOCA-induced hypertension blunted the PWV difference between OVX XX and XY mice; however, SBP was higher in XX than in XY mice (Week 1: 135±13 vs.127±3 mmHg; P=0.3), (Week 2: 148±4 vs.140±1 mmHg; P=0.08), and (Week 3: 137±9 vs.127±4 mmHg; P=0.4). We observed impaired acetylcholine-mediated relaxation in mesenteric arteries of hypertensive ovariectomized XX than XY mice (47±6 % vs. 24±6 %; P=0.03). Our data suggested that ovariectomized female mice with XX sex chromosome complement promote arterial stiffening and blood pressure. However, DOCA-induced hypertension promotes endothelial dysfunction and blunts PWV in ovariectomized XX and XY mice. Future studies will identify elements in the XX sex chromosome complement contributing to arterial stiffening and high blood pressure. R00HL155841 and R25HL105400. 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.

Ovariectomy-Induced Arterial Stiffening Differs From Vascular Aging and Is Reversed by GPER Activation.

Arterial stiffness is a cardiovascular risk factor and dramatically increases as women transition through menopause. The current study assessed whether a mouse model of menopause increases arterial stiffness in a similar manner to aging and whether activation of the G-protein-coupled estrogen receptor could reverse stiffness. Female C57Bl/6J mice were ovariectomized at 10 weeks of age or aged to 52 weeks, and some mice were treated with G-protein-coupled estrogen receptor agonists. Ovariectomy and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while ovariectomy increased material stiffness without altering vascular geometry. RNA-sequencing analysis revealed that ovariectomy downregulated smooth muscle contractile genes. The enantiomerically pure G-protein-coupled estrogen receptor agonist, LNS8801, reversed stiffness in ovariectomy mice to a greater degree than the racemic agonist G-1. In summary, ovariectomy and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling, while ovariectomy-induced material stiffness independent of geometry and a loss of the contractile phenotype. This study enhances our understanding of the impact of estrogen loss on vascular health in a murine model and warrants further studies to examine the ability of LNS8801 to improve vascular health in menopausal women.

Utility of waist-to-height ratio, waist circumference and body mass index in predicting clustered cardiometabolic risk factors and subclinical vascular phenotypes in children and adolescents: A pooled analysis of individual data from 14 countries

AimsThe clinical utility of waist-to-height ratio (WHtR) in predicting cardiometabolic risk factors (CMRFs) and subclinical markers of cardiovascular disease remains controversial. We aimed to compare the utility of WHtR with waist circumference (WC) and body mass index (BMI) in identifying children and adolescents (youths) at risk for cardiometabolic outcomes, including clustered CMRFs, high carotid intima-media thickness (cIMT), and arterial stiffness (assessed as high pulse wave velocity, PWV). MethodsWe analyzed data from 34,224 youths (51.0 % boys, aged 6–18 years) with CMRFs, 5004 (49.5 % boys, aged 6–18 years) with cIMT measurement, and 3100 (56.4 % boys, aged 6–17 years) with PWV measurement from 20 pediatric samples across 14 countries. ResultsWHtR, WC, and BMI z-scores had similar performance in discriminating youths with ≥3 CMRFs, with the area under the curve (AUC) (95 % confidence interval, CI)) ranging from 0.77 (0.75–0.78) to 0.78 (0.76–0.80) using the modified National Cholesterol Education Program (NCEP) definition, and from 0.77 (0.74–0.79) to 0.77 (0.74–0.80) using the International Diabetes Federation (IDF) definition. Similarly, all three measures showed similar performance in discriminating youths with subclinical vascular outcomes, with AUC (95 % CI) ranging from 0.67 (0.64–0.71) to 0.70 (0.66–0.73) for high cIMT (≥P95 values) and from 0.60 (0.58–0.66) to 0.62 (0.58–0.66) for high PWV (≥P95 values). ConclusionsOur findings suggest that WHtR, WC, and BMI are equally effective in identifying at-risk youths across diverse pediatric populations worldwide. Given its simplicity and ease of use, WHtR could be a preferable option for quickly screening youths with increased cardiometabolic risk in clinical settings.

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

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

CAROTID-FEMORAL PULSE WAVE VELOCITY PROGRESSION IN HYPERTENSIVE PATIENTS IS ASSOCIATED WITH SUBSEQUENT CV OUTCOMES

Objective: Arterial stiffness (Pulse Wave Velocity-PWV) is associated with CV events and mortality. However, little is known on the relationship of its progression (δ PWV) over time with CV outcomes. The aim of our study was to evaluate the relationship between PWV progression and all-cause mortality and CV events in hypertensive subjects. Design and method: We enrolled 402 consecutive hypertensive outpatients. At baseline anamnestic, clinical, BP, laboratory data and PWV were assessed. We performed a PWV follow-up examination at a median time of 3.7±0.5 years. Patients were subsequently followed for a median time of 10.1 (IQR 9.5-10.5) years recording all-cause mortality and CV events. Results: At baseline the mean age was 53.2±13.0 years, SBP and DBP were 141.8±17.5 and 86.8±10.5 mmHg and PWV was 8.5±1.9 m/s. Despite an improvement in BP control (-9.2±19.5 and -8.0±12.3 for SBP and DBP respectively), at follow-up the population showed a PWV increase (δPWV +0.6±1.9 m/s). Progressors (δ PWW &gt; 0.5 m/s, 204 patients, 50.7%) had a significantly lower survival probability and higher cumulative incidence of composite events, while no differences were seen for CV events (unadjusted analysis). At cox multivariable analysis neither δ PWV &gt; 0.5 m/s (progressors) nor δ PWV (as a spline function) were associated with CV events and with all-cause mortality. However, the association with survival probability and cumulative incidence of CV events, as a composite outcome, was significant (HR = 2.32, 95% CI: 1.33 – 4.04, p=0.003). Conclusions: In conclusion, our study shows that PWV progression of at least 0.5 m/s is frequent in hypertensive patients and that it is associated with a significantly higher risk of developing CV events or dying (composite outcome).

ASSOCIATION BETWEEN ESTIMATED PULSE WAVE VELOCITY AND INCIDENT NONALCOHOLIC FATTY LIVER DISEASE IN KOREAN ADULTS

Objective: Nonalcoholic fatty liver disease (NAFLD) is associated with vascular dysfunction, one of the signs of which is arterial stiffness. Carotid–femoral pulse wave velocity (PWV), which is considered the gold standard measure of arterial stiffness, can be estimated using two commonly assessed clinical variables: age and blood pressure. This study aimed to evaluate the association between estimated PWV (ePWV) and the prevalence and incidence of NAFLD among Korean adults. Design and method: This study used data from the Ansan–Ansung Cohort Study, a subset of the Korean Genome and Epidemiology Study, and included 8,336 adult participants with and without NAFLD at baseline. The participants were subdivided into three tertile groups according to ePWV. Results: At baseline, the prevalence of NAFLD was 10.5, 27.5, and 35.0% in the first (lowest), second, and third (highest) tertiles of ePWV, respectively. During the 18-year follow-up period, 2,467 (42.9%) incident cases of NAFLD were identified among 5,755 participants who did not have NAFLD at baseline. After adjustment for clinically relevant variables, participants in the second (adjusted hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.12–1.40) and third (adjusted HR, 1.42; 95% CI, 1.24–1.64) tertiles of ePWV had a significantly higher risk of incident NAFLD than those in the first tertile. Conclusions: Higher ePWV independently associated with an elevated risk of NAFLD in the general population.

RELATIONS BETWEEN WHITE COAT EFFECT OF BLOOD PRESSURE AND ARTERIAL STIFFNESS

Objective: The aim of this study was to analyze the relationship between brachial-ankle pulse wave velocity (b-a PWV) and white coat effect (WCE), that is the difference between the elevated office blood pressure (BP) and the lower mean daytime pressure of ambulatory BP, in a mixed population of normotention, untreated sustained hypertension, sustained controlled hypertension, sustained uncontrolled hypertension, white coat hypertension, white coat uncontrolled hypertension. Design and method: A total of 444 patients with WCE for systolic BP (54.1% female, age 61.86±13.3 years) were enrolled in the study. Patients were separated into low white coat effect (&lt; 9.5 mm Hg) and high white coat effect (&gt;=9.5 mm Hg) according to the median of WCE. Results: The subjects with a high WCE showed a greater degree of arterial stiffness than those with a low WCE for systolic BP values (P&lt; .05). The b-a PWV were 17.2±3.3m/s and 18.4±3.4 m/s in low WCE and high WCE, respectively. The b-a PWV increased with the increase of WCE, showing a positive correlation between them (P&lt; .05 for non-linearity). The significant association between the high WCE and the b-a PWV was confirmed by the results of multiple regression analysis after adjusting for confounding factors (beta=0.78, 95% Cl 0.25-1.31, P=. 004). Similar results were observed in subgroups. Conclusions: In conclusion, WCE is significantly associated with arterial stiffness. More research is needed to determine the WCE and target organ damage.

Macrophage Targeted Dendrimer-Tesaglitazar Therapy for Atherosclerosis

Background: Atherosclerosis is a leading contributor to cardiovascular disease, the number one cause of death globally. Although atherosclerosis is clearly a multicellular disease that also affects endothelial cells as well as smooth muscle cells of arteries, it is increasingly recognized as an inflammatory disease. Our goal is to determine if targeting immune cells implicated in atherosclerosis can halt plaque accumulation and resulting derangement of vascular cells in the aorta. Peroxisome proliferator activated receptors (PPARs) within macrophages present a promising therapeutic target as PPAR-α and PPAR-γ agonists have been shown to improve lipid metabolism and inhibit macrophage foam cell formation. However, due to high doses required and associated side effects, clinical translation was halted. We target anti-atherogenic pathways in immune cells using the novel treatment D-Tesa, a dendrimer conjugate of a dual PPAR-α/γ agonist, Tesaglitazar. Methods: 25-week-old, male, apolipoprotein E knockout (ApoE−/−) mice were fed high fat diet (HFD) for 16 weeks to induce atherosclerosis and randomized into two groups: 1) treatment group: D-Tesa for 6 weeks (20μg/kg twice weekly by oral gavage and 2) untreated group. HFD was continued for the duration of the study. Pulse wave velocity (PWV: Doppler), blood pressure (BP: tail cuff on trained, conscious mice), and body weight were monitored. Dendrimer mediated delivery of drug payload to plaque macrophages was studied using D-Cy5, a fluorescently labeled dendrimer, in an atherosclerotic mouse. Aortas were isolated and used for vasoreactivity studies and western blot analysis. THP-1 cell derived foam cells were used to study D-Tesa’s mechanism of action in vitro. Results: Immunofluorescence staining and confocal microscopy revealed that D-Cy5 localized in macrophages within the atherosclerotic plaque in ApoE−/− mice on HFD, indicating that the dendrimer can deliver drugs specifically into the plaque. D-Tesa slowed plaque progression, preserved endothelial function, and decreased arterial stiffness. BP was similar and unchanged between groups. D-Tesa surprisingly decreased body weight, which was the opposite effect observed from the free drug in clinical trials. Western blotting of aorta revealed that D-Tesa treated mice experienced an upregulation of PPAR-α, PPAR-γ, and ABCA1. The in vitro studies with THP-1 derived foam cells confirmed the upregulation of the cholesterol efflux pathway and anti-inflammatory benefit of D-Tesa. Conclusion: D-Tesa offers a novel therapy to ameliorate multiple damaging consequences of atherosclerosis on the cardiovascular system including improvements in plaque burden, endothelial function, arterial stiffness, and body weight in an ApoE−/− model of atherosclerosis. Excitingly, these effects were seen at 2-15 times lower doses despite continued HFD than those reported in literature with a combination of free Tesa and low-fat diet. Thus, D-Tesa offers great translational relevance because of potential reduction in negative side effects and higher patient benefit due to noted lack of compliance with dietary changes in the clinic. Further research is ongoing to evaluate sex differences, dose response, and long-term effects of this highly promising therapy. This work was supported by a NHLBI grant R01HL148112 01 (L.S.) and the Traystman Endowment (S.K.). 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.

166. Arterial Stiffness as an Index of Inflammation in Patients With Treatment Resistant Bipolar Depression

166. Arterial Stiffness as an Index of Inflammation in Patients With Treatment Resistant Bipolar Depression

REDUCED AEROBIC FITNESS IS ASSOCIATED WITH IMPAIRED CEREBROVASCULAR FUNCTION IN INDIVIDUALS WITH ATRIAL FIBRILLATION

INTRODUCTION &amp; AIMS Lower aerobic fitness (V̇O2peak) is associated with higher risk of cerebrovascular disease. However, the relationship between V̇O2peak and cerebrovascular function and cerebral blood velocity at rest and during exercise has not been investigated in adults with atrial fibrillation (AF). We aimed to compare resting and exercise cerebral blood velocity responses and cerebrovascular function in individuals with AF to healthy controls. METHODS Eight inactive adults either with AF or healthy age-matched controls (AF: n=4, 64±6 years, 50% female; control: n=4, 66±4 years, 75% female) completed a maximal graded exercise test to measure V̇O2peak. Transcranial Doppler was used to measure bilateral middle cerebral artery velocity (MCAv). Vascular function was assessed by measuring MCAv increases and time to peak following a 30s hypercapnia stimulus (9% CO2, 21% O2, and balanced nitrogen), and MCAv during aerobic exercise (3-minute stages at 40%, 60% and 80% V̇O2peak). Blood pressure, heart rate and end-tidal gases were collected alongside MCAv. RESULTS Compared to controls, individuals with AF (both P&amp;lt;0.01) had higher BMI (AF: 31.8±2.0 kg/m2; control: 27.3±0.6 kg/m2), lower V̇O2peak (AF: 19.9±2.5 mL/kg/min; control: 33.7±5.8 mL/kg/min), and similar blood pressure. Resting right and left MCAv was higher in the AF group (R: 66.6±34.0 cm/s; L: 44.2±10.1 cm/s) compared to the control (R: 36.1±6.7 cm/s; L: 34.9±8.7 cm/s); this was not significant (P=0.121 and 0.258). Right MCAv was higher than left MCAv in individuals with AF but this was not significant (P=0.247). Hypercapnia and exercise induced MCAv and time to peak were similar between groups (P&amp;gt;0.05). CONCLUSION Lower V̇O2peak may be associated with increased resting MCAv in individuals with AF. Furthermore, there may be regional disparities in MCAv in individuals with AF. Future studies with larger sample sizes investigating potential mechanisms and volumetric cerebrovascular changes (e.g., vessel diameter, arterial stiffness) in AF are warranted.