Increase In Pulse Wave Velocity Research Articles

PHARMACOLOGICAL TREATMENT OF ARTERIAL HYPERTENSION GUIDED BY PERIPHERAL OR CENTRAL BLOOD PRESSURE: COMPARISON OF THE TWO STRATEGIES IN THE INCIDENCE OF INTERMEDIATE OUTCOMES

Objective: To compare the parameters of central and peripheral blood pressure measurements, arterial stiffness, target organ damage (TOD), biochemical and renal profiles among participants who had the therapeutic strategy guided by central (CG) and peripheral (PG) blood pressure values. Design and method: Randomized study in two groups: CG and PG. Five visits were carried out, the first (V1) being selection and randomization followed by intermediate visits, every 3 months, to assess blood pressure and adjust antihypertensive drugs. The procedures performed in the initial and final visit (V5) were: measurement of central arterial pressure and pulse wave velocity (PWV) (mobil-o-graph) and peripheral (OMRON HEM1100), carotid ultrasound, echodopplercardiogram and laboratory tests. Paired and unpaired t and chi-square tests were used. Adopted significance level of 5% and a confidence interval of 95%. Results: A total of 59 participants were evaluated (30 from the CG and 29 from the PG). Age, BMI, central and peripheral blood pressure measurements, PWV, left ventricular mass index (LVMI), carotid intimal mean thickness, biochemical profile and glomerular filtration rate did not differ between the two groups (p > 0.05) in randomization. The augmentation index (AIx) was higher in the CG than in the PG at randomization (27.3% ± 12.2% vs 20.3% ± 13.3% p 0.041). After 1 year of follow-up, in the analysis between the groups, the central diastolic pressure was lower in the CG (78.9mmHg ± 9.7mmHg vs 84.3 ± 10.4mmHg, p 0.024) and the difference in AIx between the groups ceased to exist. When intra-group comparisons were made before and after the intervention, a reduction in the PWV (p < 0.001) and LVMI (p = 0.018) was observed in the CG. In PG there was an increase in PWV (p < 0.001) and LVMI (p = 0.003). Conclusions: The intervention guided by central pressure, after 1 year of follow-up, was able to reduce the central diastolic pressure and correct the AIx parameter and, in the intra-group analysis, it promoted a reduction in PWV and LVMI. There was no difference between the two groups regarding the improvement of outcomes related to central and peripheral blood pressure, cardiac and vascular TOD, biochemical and renal profile.

439-P: Disparate Effects of Menopause on Cardiovascular Risk in Women with Type 1 Diabetes

Introduction: Women with type 1 diabetes (T1D) are at increased risk for cardiovascular disease (CVD) , and menopause increases CVD risk. However, little is known about menopause and CVD risk in T1D. Methods: Women with (N=64) and without T1D (n=63) ages 47-55 years were examined for CVD risk factors and surrogate CVD markers: pulse wave velocity (PWV) , augmentation pressure (AP) and pulse height (PH) , brachial artery distensibility (BrachD) , and subendocardial viability index (SVI) . Body composition was measured by Dual Xray Absorptiometry. Menopausal status was determined by self-report. CVD markers were examined by diabetes and menopausal status using linear regression models adjusted for age. Results: Mean ± SD age was 51±2.5 years in women with T1D and 51 ± 2.4 years in women without diabetes (p=0.32) . The percentage postmenopausal did not differ (30% vs. 32%, p=0.8) between T1D and nondiabetes women. As shown in the table, women with T1D had higher systolic blood pressure and measures of arterial stiffness (PWV, AP, PH, and BrachD) and lower SVI than women without diabetes. Menopause was associated with a greater loss in fat free mass and a greater increase in PWV and AP among women with T1D compared to women without diabetes. Conclusions: Women with T1D have worse CVD markers, and menopause is associated with greater increases in arterial stiffness and loss in lean body mass than in nondiabetes women, independent of age. Disclosure H.K.Wise: None. E.Malecha: None. C.J.Chartier-logan: None. L.Pyle: None. A.Keshawarz: None. J.K.Snell-bergeon: Stock/Shareholder; GlaxoSmithKline plc. Funding American Diabetes Association (7-13-CD-10)

INCREASED PULSE WAVE VELOCITY AND ASSOCIATED FACTORS IN BRAZILIAN HYPERTENSIVE PATIENTS

Objective: The increase in pulse wave velocity (PWV) reflects arterial stiffness and indicates an increased risk of cardiovascular disease (CVD). Several factors have been associated with increased PWV in different populations and some of them are poorly studied or have controversial results. The objective of this study was to identify the sociodemographic, laboratory and blood pressure factors associated with the increase in PWV in participants of the I Brazilian Registry of Hypertension (I RBH). Design and method: Cross-sectional, multicenter and national study with data taken from the baseline of the I RBH. Participants with central blood pressure measured were nalyses. A questionnaire was applied with demographic data, personal medical history, lifestyle and biochemical tests. The PWV value considered as changed was > or = 10 m/s. Statistical nalyses were performed using Stata 15, comparisons established with chi-square and correlations with Spearman or Pearson tests, p < 0.05 adopted. Results: 44 participants were evaluated: 62.5% women, 63.8 ± 14.4 years, PWV 9.5 ± 2.2 m/s and 40.7% had PWV > or = 10 m/s. Higher frequency of altered PWV was presented in those aged > or = 60 years (62.8%) and with > or = three cardiovascular risk facts (p < 0.001). Age (r = 0.907), central systolic blood pressure (SBP) (r = 0.223), peripheral SBP (r = 0.237) and HDL (r = 0.240) were correlated with PWV. Conclusions: We identified a higher frequency of PWV > or = 10m/s in patients with 60 years or more, patients with three or more risk factors and a positive correlation of age, PASc, PASp and HDL with PWV in hypertensive patients of the I RBH.

Global Aortic Pulse Wave Velocity is Unchanged in Bicuspid Aortopathy With Normal Valve Function but Elevated in Patients With Aortic Valve Stenosis: Insights From a 4D Flow MRI Study of 597 Subjects.

Aortopathy is common with bicuspid aortic valve (BAV), and underlying intrinsic tissue abnormalities are believed causative. Valve-mediated hemodynamics are altered in BAV and may contribute to aortopathy and its progression. The contribution of intrinsic tissue defects versus altered hemodynamics to aortopathy progression is not known. To investigate relative contributions of tissue-innate versus hemodynamics in progression of BAV aortopathy. Retrospective. Four hundred seventy-three patients with aortic dilatation (diameter ≥40 mm; comprised of 281 BAV with varied AS severity, 192 tricuspid aortic valve [TAV] without AS) and 124 healthy controls. Subjects were 19-91 years (141/24% female). 1.5T, 3T; time-resolved gradient-echo 3D phase-contrast (4D flow) MRI. A surrogate measure for global aortic wall stiffness, pulse wave velocity (PWV), was quantified from MRI by standardized, automated technique based on through-plane flow cross-correlation maximization. Comparisons were made between BAV patients with aortic dilatation and varying aortic valve stenosis (AS) severity and healthy subjects and aortopathy patients with normal TAV. Multivariable regression, analysis of covariance (ANCOVA), Tukey's, student's (t), Mann-Whitney (U) tests, were used with significance levels P < 0.05 or P < 0.01 for post-hoc Bonferroni-corrected t/U tests. Bland-Altman and ICC calculations were performed. Multivariable regression showed age with the most significant association for increased PWV in all groups (increase 0.073-0.156 m/sec/year, R2 =0.30-48). No significant differences in aortic PWV were observed between groups without AS (P=0.20-0.99), nor were associations between PWV and regurgitation or Sievers type observed (P=0.60, 0.31 respectively). In contrast, BAV AS patients demonstrated elevated PWV and a significant relationship for AS severity with increased PWV (covariate: age, R2 =0.48). BAV and TAV patients showed no association between aortic diameter and PWV (P=0.73). No significant PWV differences were observed between BAV patients with normal valve function and control groups. However, AS severity and age in BAV patients were directly associated with PWV increases. 3 TECHNICAL EFFICACY: Stage 3.

Subclinical atherosclerosis associates with diabetic retinopathy incidence: a prospective study.

The prospective correlation between subclinical atherosclerosis and diabetic retinopathy (DR) incidence in Chinese patients with type 2 diabetes mellitus (T2DM) remains elusive. Prospective data were obtained from 2781 patients with diabetes, among whom 1,964 and 2,180 T2DM patients without any and referable DR at baseline, respectively, were included in the analysis. Multivariate analyses were performed using the Cox proportional hazards model. Over a median follow-up of 22.2months (interquartile range 12.7-27.7), 282 (14.36%) and 125 (5.73%) patients developed any and referable DR, respectively. After adjustment for confounders, each standard deviation (SD) increase in brachial-ankle pulse wave velocity (ba-PWV) was associated with 31% (95% confidence interval 1.15-1.50) and 38% (1.14-1.66) higher risks of incident any and referable DR, respectively. Compared with the lowest ba-PWV quartile, the highest ba-PWV quartile had 135% (1.48-3.72) and 293% (1.83-8.44) higher risks of developing any and referable DR, respectively. Per SD increase of pulse pressure (PP) was associated with 22% (1.09-1.38) and 22% (1.02-1.46) higher risks of incident any and referable DR, respectively. The restricted cubic spline models further indicated a significant linear association of baseline subclinical atherosclerosis with referable DR, and a nonlinear association with any DR. In addition, adding the ba-PWV to the prognostic model for DR incidence improved the C-statistic value, the integrated discrimination improvement value, and the net reclassification improvement value (all P < 0.05). Baseline subclinical atherosclerosis was significantly associated with an increased risk of DR incidence, and elevated ba-PWV independently predicted incident DR in T2DM patients.

Effect of spironolactone on vascular stiffness in hemodialysis patients: a randomized crossover trial.

BackgroundThe role of spironolactone treatment in hemodialysis patients is debated, but a survival benefit is suggested. Mineralocorticoids and chronic kidney disease have been linked to cardiovascular fibrosis. Therefore, we hypothesized that spironolactone would affect vascular stiffness, cardiac systolic, and diastolic function in hemodialysis patients.MethodsThis was a randomized crossover study in hemodialysis patients supplemented with an echocardiographic case series. All outcomes reported here were secondary in the trial and were assessed without blinding. Block randomization and allocation determined treatment order. Participants received 50 mg spironolactone daily for 12 weeks and untreated observation for another 12 weeks. Pulse wave velocity (PWV) was measured before and after treatment and observation. Doppler-echocardiography was conducted before and after treatment. Systemic arterial compliance indexed to body surface area (SACi), left ventricular ejection fraction (LVEF), the peak early diastolic mitral inflow velocity (E), the peak late diastolic mitral inflow velocity (A), and the peak early diastolic myocardial lengthening velocity (E’) were measured. E/A and E/E’ were then calculated. Statistical analyses were conducted per protocol. A generalized linear mixed model with random participant effects was used for PWV. The Wilcoxon signed-rank test was used for echocardiographic variables.ResultsThirty participants were recruited, 18 completed follow-up, and 17 were included in PWV-analyses. Spironolactone treatment showed a tendency toward an increase in PWV of 1.34 (95% confidence interval: −0.11 to 2.78) m/s, which was not statistically significant (P = 0.07). There were no significant changes in any of the other variables (LVEF, E/A, E/Eʹ, or SACi).ConclusionsWe found no evidence supporting an effect of 12-week administration of spironolactone 50 mg daily on vascular stiffness, cardiac systolic, or diastolic function in hemodialysis patients.

Intravenous sodium thiosulphate for vascular calcification of hemodialysis patients-a systematic review and meta-analysis.

Vascular calcification (VC) is a common comorbidity among patients with chronic kidney disease (CKD), indicating major cardiovascular events. This study aimed to evaluate the effects and safety of intravenous sodium thiosulphate (STS) for VC in CKD patients. Electronic databases were searched for clinical trials that provided data comparing outcomes among patients treated with and without STS. The PRISMA guidelines were followed. Efficacy was assessed using calcification scores and arterial stiffness. Safety was examined by analyzing adverse symptoms, electrolytes and bone mineral density (BMD). Random-effects models were performed. Meta-regression and sensitivity analysis were done. The risk of bias was assessed using the Cochrane tools. Among the 5601 publications, 6 studies involving 305 participants (mean age: 56 years, male: 56.6%) with all participants on maintenance hemodialysis met eligibility criteria. For efficacy, the progression in Agatston scores in the coronary arteries [107 patients, mean difference (MD): -241.27, 95% confidence interval (95% CI): -421.50 to -61.03] and iliac arteries (55 patients, MD: -382.00, 95% CI: -751.07 to -12.93) was lower in the STS treated group compared with controls. The increase in pulse wave velocity was lower in the STS group (104 patients, MD: -1.29m/s, 95% CI: -2.24to -0.34m/s). No association was found between the change in calcification scores and STS regimen. For safety, gastrointestinal symptoms (e.g. nausea) and increased anion gap acidosis were noted. No reduction in BMD by STS was observed. Intravenous STS may attenuate the progression of VC and arterial stiffness in hemodialysis patients. Large and well-designed randomized controlled trials are warranted.

Cardiovascular Risk Factors and Target Organ Damage in Adolescents: The SHIP AHOY Study.

Development of cardiovascular disease in adults has been directly linked to an adverse metabolic phenotype. While there is evidence that development of these risk factors in childhood persists into adulthood and the development of cardiovascular disease, less is known about whether these risk factors are associated with target organ damage during adolescence. We collected data from 379 adolescents (mean age 15.5, 60% male) with blood pressure between the 75th and 95th percentile to determine if there is a metabolic phenotype that predicts cardiovascular changes (left ventricular mass, systolic and diastolic function, pulse wave velocity, and renal function). We determined the number of risk factors for cardiovascular disease (hypertension, dyslipidemia, obesity, and insulin resistance) present in each participant. Generalized linear models were constructed to determine if the number of cardiovascular risk factors (CVRFs) were associated with measures of target organ damage. The number of CVRFs present were associated with statistically significant differences in increased left ventricular mass index, increased pulse wave velocity, decreased peak longitudinal strain, urine albumin to creatine ratio and echocardiographic parameters of diastolic dysfunction. Generalized linear models showed that dyslipidemia and insulin resistance were independently associated with markers of diastolic dysfunction (P ≤ .05) while increased blood pressure was associated with all makers of target organ damage (P ≤ .03). These data suggest the of the number of CVRFs present is independently associated with early changes in markers of target organ damage during adolescence.

Effects of Exercise on Aortic Stiffness Associated with 5‐Flurouracil in Rats

Background5‐fluorouracil (5‐FU) is a chemotherapy drug that is often prescribed in treatment regimens for malignancies of the gastrointestinal tract, breast, and head/neck. However, despite its clear efficacy in cancer treatment, it is also the second most common chemotherapeutic implicated in the development of short and/or long‐term cardiotoxicity that can lead to a less efficacious cancer treatment regimen. Specifically, 5‐FU is associated with increases in arterial stiffness, leading to increased risks for developing heart failure and cardiovascular disease. Exercise, both acutely and following long‐term training, has exhibited cardiovascular health benefits and protection in healthy and disease populations, including reductions in e.g., pulse wave velocity (PWV), a clinical measure of arterial stiffness. Therefore, the purpose of this study was to investigate 5‐FU induced arterial stiffness (via PWV) and evaluate the efficacy of multiple acute bouts of exercise to mitigate arterial stiffness associated with 5‐FU. Further, we utilized reverse phase protein analysis (RPPA) to investigate mechanisms associated with 5‐FU induced arterial stiffness.MethodsMale Sprague Dawley rats aged 6‐8 months (n=26) were used in this series of experiments. All animals were first acclimated to treadmill exercise, and randomized into four groups: Control (CON, n=8), 5‐FU only (5‐FU=7), exercise (EX, n=4), and 5‐FU with exercise (5‐FUEX, n=7). All animals were surgically instrumented with catheters in the external jugular vein and tail artery. Animals received a clinically relevant dose of 5‐FU with the combination of a bolus (50mg/kg), followed immediately by a 2h continuous infusion of 5‐FU (265mg/kg) through the jugular catheter. This was done to better imitate clinical drug delivery rather than i.p injections typically used in pre‐clinical models. Baseline and 2h measurements of PWV were made from the descending to lower abdominal aorta. Both exercise groups underwent four, 20–30‐minute acute bouts of moderate intensity exercise (20m/min, 5% incline) on consecutive days, 24h apart, with the last being ~10 minutes before surgical instrumentation. RPPA analysis was performed on abdominal aorta from each animal for analysis of changes in protein expression.ResultsThere were no differences in PWV between groups at either time point (p&gt;0.05). However, a significant increase in PWV from baseline to the 2h time point was evident in the 5‐FU group alone (CON ‐1.1±4.9, 5‐FU 14.8±4.4, EX 4.6±5.7, 5‐FUEX 5.4.9±2.2%, p&lt;0.05). Preliminary RPPA analysis indicated 1.5log2fold changes in 5‐FU animals in multiple factors, several of which have been associated with increased vascular stiffness including Steroid Receptor Co‐activator (SRC‐1) and mitogen‐activated protein kinase (MAPK1/MAPK3) that will require further investigation.ConclusionThis study suggests that 5‐FU induces aortic stiffness in rats that can be attenuated with prior acute bouts of exercise. These findings provide further efficacy of exercise therapy in cancer standards of care besides its established benefits for reducing fatigue and improving quality of life in cancer patients. Lastly, the potential to mitigate cardiovascular complications of 5‐FU therapy is clinically important as it can possibly prevent early cessation or reductions of this efficacious therapy.

Involvement of Lysyl Oxidase in the Pathogenesis of Arterial Stiffness in Chronic Kidney Disease

RationaleIncreased vascular stiffness is a key mediator of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Increased vascular stiffness in CKD is thought to be the consequence of long‐standing hypertension and vascular calcification. However, vascular stiffness is increased early in patients with CKD, even before metabolic complications develop. Lysyl Oxidase (LOX) is a key mediator of collagen crosslinking and matrix remodeling. Up‐regulation of LOX has been associated with increased tissue stiffness in cancer and wound healing. We hypothesize that increased LOX might be a key mechanism for increased vascular stiffness in CKD. β‐aminopropionitrile (BAPN), a LOX inhibitor, was used to test the hypothesis.Methods5/6 nephrectomy (Nx) or Sham surgery was performed in 8‐weeks old male C57BL/6 mice. 2‐weeks after Nx, mice were randomized to BAPN (300 mg/kg/day in water) or vehicle for 4‐weeks. Vascular stiffness was assessed by pulse wave velocity (PWV). LOX levels were measured by ELISA and qPCR. Collagen crosslinking was measured by mass spectrometry. Comparisons between groups were made using one‐way ANOVA, p‐Value &lt;0.05 was accepted as significant.ResultsNx resulted in decreased renal function at 8 weeks but no change in blood pressure or calcification. (~2‐3‐fold increase in creatinine, urea, and cystatin C) compared to control mice. Nx surgery resulted in increase in PWV (Con:179±32, Nx: 306 ± 47 cm/s, p&lt;0.001). This was associated with an increased LOX in aorta (Con:118±8, Nx: 311±13 pg/mg dry weight, p&lt;0.001). Mice with Nx surgery had an increased total collagen contents (183%, p&lt;0.001) as well as cross‐linked collagen (DPD; 83%, p&lt;0.05, PYD: 270% p&lt;0.01). BAPN treatment significantly attenuates PWV (211± 49 cm/s, p&lt;0.01), LOX (256±21 pg/mg dry weight, p&lt;0.05) and total collagen contents (23%, p&lt;0.01). BAPN treatment reduced the crosslinked collagens (DPD and PYD) but this did not reach statistical significance.ConclusionOur findings suggest: a) Increased vascular stiffness in CKD is independent of BP and calcification b) LOX mediated changes in extracellular matrix are at least in part responsible for the pathogenesis of arterial stiffness in CKD. Inhibition of excessive LOX may have therapeutic potential in alleviating increased vascular stiffness in CKD.

Aging and G Protein‐Coupled Estrogen Receptor Exacerbates Carotid Artery Structural Remodeling

Aging is a nonmodifiable risk factor for cardiovascular disease associated with arterial stiffening and cardiac dysfunction. We previously showed an important role for G protein‐coupled estrogen receptor (GPER) in modulating female protection from arterial stiffening. In this study, we hypothesized that aging would decrease vascular compliance in GPER knockout (ko) mice to a greater extent than wildtype (wt) mice. Adult (25 weeks) and middle‐aged (57 weeks) mice were subjected to high frequency ultrasound for pulse wave velocity (PWV), and structural remodeling in the carotid artery was assessed with biaxial pressure myography followed by constitutive modeling. Data was analyzed by 3‐way ANOVA and Sidak’s post hoc tests. As we previously showed, PWV was significantly lower in adult female wt mice versus their male counterparts (1.4 ± 0.05 vs. 1.1 ± 0.02 m/s; P=0.0004) but was not different in adult ko mice (1.6 ± 0.07 vs 1.4 ± 0.08, P=0.20). Interestingly, PWV increased with aging in female but not male wt mice, so that the sex difference was lost (1.7 ± 0.03 vs 1.7 ± 0.06, P=0.99). Despite the lower PWV, circumferential linearized material stiffness in passive conditions was elevated in adult female wt versus male wt (1.9 ± 0.2 vs. 1.4 ± 0.2 MPa; P=0.02), but this sex difference was lost in middle‐aged wt mice (1.3 ± 0.1 vs. 1.2 ± 0.1 MPa; P=0.87). Aging significantly increased the ratio of thick to thin collagen only in male wt and female ko groups. We found that females but not males experience an increase in PWV at middle‐age along with a decrease in circumferential stiffness. In contrast, female GPER mice already display a higher PWV as adults, indicating that GPER deletion in females is a model of accelerated vascular aging.

Early Life Stress (ELS) Accelerates Autoimmunity and Synergistically Increases Risk for Cardiovascular Disease (CVD) in the Pristane‐Induced Model of Systemic Lupus Erythematosus (SLE) in Mice

ELS is defined as exposure to childhood adversity such as maltreatment (e.g., verbal and physical abuse), sexual abuse, and household dysfunction occurring prior to age 18. ELS is associated with increased risk of CVD and poorer health outcomes earlier in adulthood. SLE is an autoimmune disease with high CVD burden and influenced by environmental factors including psychosocial stress such as ELS. We hypothesized that a mouse model of ELS, maternal separation with early weaning, MSEW, would develop autoimmunity in response to the pristane‐induced model of SLE earlier and at higher levels than normally reared (NR) SLE mice. We further hypothesized that MSEW+SLE mice would have earlier onset of increased CVD risk determined by aortic stiffness and vascular dysfunction. MSEW entails separating pups from the dam 4h/day (postnatal, PD 2 to 5) and 8h/day (PD 6 to 16) followed by weaning at PD17. NR litters remain with the dam and are weaned at PD21. The pristane‐induced model of SLE uses a single intraperitoneal (i.p.) injection to induce SLE‐like symptoms in female mice that include autoantibody production, vascular dysfunction, kidney damage, and increased blood pressure. At 6‐8 weeks of age, female mice were grouped accordingly: NR control (NR+CON) received an i.p. saline injection, while NR+SLE and MSEW+SLE received an i.p. pristane injection. To measure autoimmunity, anti‐Smith autoantibodies associated with the pristane model and IgG antibodies were measured at 4 months post‐pristane injection. MSEW+SLE mice developed significantly higher levels of anti‐Smith autoantibodies while NR+SLE mice had similar levels to NR+CON mice (total arbitrary units; MSEW+SLE: 2.7, NR+SLE: 1.4, NR+CON:1.5, p=0.04). At five months post‐pristane injection, MSEW+SLE and NR+SLE mice had similar levels of anti‐Smith autoantibody levels (p=0.76). Similarly, at 4 months post‐pristane injection Total Igg was increased in MSEW SLE animals compared to N+CON, but not in NR+SLE mice(OD 450; MSEW+SLE: 0.72, NR+SLE: 0.47, NR+CON:0.24, p=0.01). Aortic stiffness (increased pulse wave velocity, PWV) is a CVD risk marker and was assessed at 4 months post‐pristane injection. PWV was significantly increased in MSEW+SLE mice (mm/sec; NR+CON: 1.5, NR+SLE: 1.5, MSEW+SLE 2.7, p=&lt;0.0001). To assess aortic dysfunction, concentration response curves to phenylephrine (PE)‐mediated constriction and acetylcholine (Ach)‐mediated relaxation were completed from MSEW+SLE and NR+SLE mice at 7 months post‐pristane injection. MSEW+SLE mice showed increased sensitivity to PE (log[PE], M; MSEW+SLE: ‐6.5, NR+SLE: ‐6.11, p=0.02), but no differences in Ach relaxation were observed. These results show that MSEW mice exposed to the environmental trigger for SLE, pristane, develop autoimmunity earlier and to a higher level as well as increased aortic stiffness compared to NR+SLE mice. This mouse model of ELS and SLE will allow in‐depth studies to understand the ELS‐specific mechanisms driving early development of autoimmunity and CVD risk. In conclusion, ELS accelerates autoimmunity and is associated with CVD risk which models the impact of ELS on humans with SLE.

Abstract 481: Regulatory Role Of Endothelial PHD2 On Hypertensive Arterial Stiffness And Vascular Calcification

Arterial stiffness is the center feature of hypertension and has significant impact upon disease etiology and outcomes. Up to date, there is no therapy available to efficiently target arterial stiffness. Emerging evidence indicates that prolyl hydroxylase protein-2 (PHD2) is a novel target of vascular remodeling. Although endothelial PHD2 has been shown to contribute to pulmonary hypertension, the role of PHD2 on arterial stiffness and calcification remains elusive. Here, we investigated the underlying mechanisms of endothelial PHD2 on arterial stiffness and calcification. Using Doppler ultrasound to measure pulse-wave velocity (PWV), we found that PHD2 EC KO mice had a significant increase in arterial stiffness at 7 month old age. PWV was further increased in the PHD2 EC KO mice at 12 month old age, but this was not seen in the control mice. We then further tested whether PHD2 EC KO mice sensitized hypertension-induced arterial stiffness by infusion with angiotensin II for 4 weeks. Infusion of control mice with Ang-II resulted in a time-dependent increase in PWV. Ang-II-induced PWV was further elevated in the PHD2 EC KO mice. H&amp;E staining showed that the aorta media thickness was significantly increased in the aorta of PHD2 EC KO mice. Infusion of mice with Ang-II for 4 weeks resulted in a significant increase in media thickness. The aorta media thickness was significantly increased in the aorta of PHD2 EC KO mice + Ang-II as compared to control mice + Ang II. Mechanistically, the arginase-2 expression and activity were significantly upregulated in the aorta of PHD2 EC KO mice. Deficiency of PHD2 in EC further promoted Ang-II-induced arginase activity. In addition, knockout of PHD2 in EC resulted in a five- fold increase in SOX9 expression in the mouse aorta as compared to PHD2 f/f (WT) control. Similarly, BMP2 expression was increased in the aorta of PHD2 EC KO mice. Co-staining of alkaline phosphatase (ALP) with BMP2 further showed an increased co-staining ALP/BMP2 in the aorta of PHD2 EC KO mice. Alizarin Red staining revealed a significant increase in area (%) of calcification in the aorta of PHD2 EC KO mice. Our study indicates a novel role of endothelial PHD2 in the regulation of arterial stiffness and calcification.

Abstract 371: The Role Of Scleraxis In Inducing Vascular Stiffness

Vascular dysfunction underlies numerous significant diseases including diabetes, atherosclerosis and hypertension. Vascular dysfunction can be a result of altered smooth muscle contraction/relaxation, and impaired endothelial cell function within the vessel wall. Vascular fibrosis involves an increase in the thickness of vessel wall. This contributes to either an increase in extracellular matrix (ECM) synthesis or induced vascular smooth muscle proliferation within the vessel wall, or both, causing stiffer vessels with impaired tone and reduced lumen diameter.Our lab identified the transcription factor scleraxis as a novel master regulator of fibrotic signaling in the myocardium, showing scleraxis is sufficient to induce fibroblast to myofibroblast phenotype conversion, a critical step in the development of fibrosis, and directly up-regulates ECM genes in cardiac fibroblasts. Angiotensin II (AngII) was reported to induce vascular fibrosis via activation of the transcription factor Smad3 in aortic vascular smooth muscle cells. Our lab has shown that Smad3 physically interacts with scleraxis, and critically requires scleraxis to drive TGFβ/Smad fibrotic signaling in cardiac fibroblasts.Our preliminary data has revealed that scleraxis is detectable in the arterial wall, and scleraxis expression is elevated in high pressure versus low pressure regions of vessels. Loss of scleraxis in the aortas of scleraxis knock-out mice reveals a discontinuation and disarrangement in the structure of vascular wall. We thus hypothesize that scleraxis is sufficient and necessary to induce vascular fibrosis.Pressure myography data reveals an increase in vascular stiffness and thickness of 3rd order mesenteric arteries of smooth muscle-specific scleraxis overexpression mice. Also, our data shows that vascular stiffness is significantly increased in AngII-induced scleraxis overexpression mice with a relative increase in telemetry blood pressure measurements and pulse wave velocity. Histological sections suggest a reduction of the translamellar ECM accumulations in AngII-induced scleraxis overexpression aortas. To summarize, scleraxis may contribute to vascular stiffness by inducing vascular smooth muscle proliferation.

АРТЕРИАЛЬНАЯ ЖЕСТКОСТЬ ПРИ СЕМЕЙНОЙ ГИПЕРХОЛЕСТЕРИНЕМИИ: ЕСТЬ ЛИ РИСКИ В ДЕТСКОМ ВОЗРАСТЕ?

The most common monogenic hereditary disease is familial hypercholesterolemia (FH), in which an abnormal increase in blood cholesterol levels has been observed since childhood and can lead to the development of premature atherosclerosis. Indicators of arterial stiffness can be used as independent markers of structural and morphological changes in the vascular wall. Objective of the study: to study the features of arterial stiffness in children with heterozygous FH. Materials and methods of research: an open prospective cohort single-center study was conducted from January 2017 to August 2021. It involved 87 children aged 5 to 17 years [median 11 years (7.0–15.0 years)], of which 44 children (21 boys and 23 girls) were diagnosed with FH, heterozygous form (set in accordance with Simon Broome British criteria), who did not undergo lipid-lowering therapy (the main group), and 43 healthy children (22 boys and 21 girls) included in the control group. Group differences in age and gender were not statistically significant (p=0.99 and p=0.749, respectively). All children underwent daily monitoring of blood pressure equipped with the option of measuring arterial stiffness Vasotens («Peter Telegin» LLC, Nizhny Novogorod). The pulse wave velocity in the aorta (PWVao), augmentation index (AIx), and the maximum rate of pressure rise (dp/dt) were evaluated. Results: children with FH showed a statistically significant increase in aortic pulse wave velocity (PWVao) compared to healthy peers: minimal [3.85 (3.3–5.25) m/s versus 3.3 (2.8–3.9) m/s, p=0.009], medium [6.8 (5.8–8.6) m/s versus 4.3 (3.7–5.1) m/s, p&lt;0.001] and maximum per day [8.25 (7.2–11.2) m/s versus 6.3 (5.15–7.25) m/s, p&lt;0.001]. In the FH group, compared with the control group, a statistically significant increase in the minimum [–69.61±8.08 (–72.07–(–67.16))% and –73.05±7.32 (–75.3–(–70.8))%, respectively, р=0.041] and the daily average augmentation index [–44.5 (–39.0–(–34.0))% and –50.0 (–59.5–(–44.0))% respectively, р&lt;0.001], medium [628.0 (582.0–730.0) mmHg/s and 569.0 (387.0–644.0) mmHg/s, respectively, p=0.001] and the maximum per day maximum rate of pressure rise [1109.5 (1030.8–1475.0) mmHg/s and 965.0 (667.5–1002.5) mmHg/s, respectively, p&lt;0.001]. Correlation analysis in the FH group showed statistically significant direct correlation between low density lipoprotein (LDL) content in the blood serum and maximum PWVao (r=0.485, p&lt;0.001) as well as between the LDL content in the blood serum and the average PWVao (r=0.492, p&lt;0.001). Conclusion: the results show, along with the increase in arterial stiffness in patients with FH, their relationship to the level of LDL, which allows to consider them as a possible additional method of determining cardiovascular risk in children with FH and assessing disease progression.

CHARACTERISTICS OF ARTERIAL WALL STIFFNESS IN PATIENTS WITH CHRONIC HEART FAILURE WITH PRESERVED SYSTOLIC FUNCTION OF THE LEFT VENTRICLE

Modern methods of acute myocardial infarction (AMI) treatment allow to avoid early postinfarction remodeling, but increase the number of patients with chronic heart failure (CHF) and preserved systolic heart function. The stiffness of the main arteries in patients with CHF and preserved left ventricular (LV) ejection fraction (EF) after AMI has been found to be increased. The severity of CHF depends on the increase in pulse wave velocity. The relationship between increased arterial stiffness and BNP and NT-pro BNP levels in patients with CHF with preserved LV EF 1 year after AMI was revealed.

Inhibition of sphingomyelinase attenuates diet – Induced increases in aortic stiffness

Sphingomyelinases ensure ceramide production and play an integral role in cell turnover, inward budding of vesicles and outward release of exosomes. Recent data indicate a unique role for neutral sphingomyelinase (nSMase) in the control of ceramide-dependent exosome release and inflammatory pathways. Further, while inhibition of nSMase in vascular tissue attenuates the progression of atherosclerosis, little is known regarding its role on metabolic signaling and arterial vasomotor function. Accordingly, we hypothesized that nSMase inhibition with GW4869, would attenuate Western diet (WD) - induced increases in aortic stiffness through alterations in pathways which lead to oxidative stress, inflammation and vascular remodeling. Six week-old female C57BL/6L mice were fed either a WD containing excess fat (46%) and fructose (17.5%) for 16 weeks or a standard chow diet (CD). Mice were variably treated with GW4869 (2.0 μg/g body weight, intraperitoneal injection every 48 h for 12 weeks). WD feeding increased nSMase2 expression and activation while causing aortic stiffening and impaired vasorelaxation as determined by pulse wave velocity (PWV) and wire myography, respectively. Moreover, these functional abnormalities were associated with aortic remodeling and attenuated AMP-activated protein kinase, Sirtuin 1, and endothelial nitric oxide synthase activation. GW4869 treatment prevented the WD-induced increases in nSMase activation, PWV, and impaired endothelium dependent/independent vascular relaxation. GW4869 also inhibited WD–induced aortic CD36 expression, lipid accumulation, oxidative stress, inflammatory responses, as well as aortic remodeling. These findings indicate that targeting nSMase prevents diet – induced aortic stiffening and impaired vascular relaxation by attenuating oxidative stress, inflammation and adverse vascular remodeling.

The Effect of a Single Bout of Resistance Exercise with Blood Flow Restriction on Arterial Stiffness in Older People with Slow Gait Speed: A Pilot Randomized Study.

Purpose: Low-intensity resistance exercise with moderate blood-flow restriction (LIRE-BFR) is a new trending form of exercises worldwide. The purpose of this study was to compare the acute effect of a single bout of traditional resistance exercise (TRE) and LIRE-BFR on arterial stiffness in older people with slow gait speeds. Methods: This was a randomized, controlled clinical study. Seventeen older adults (3 men; 14 women; 82 ± 5 years old) completed a session of TRE (n = 7) or LIRE-BFR (n = 10). At baseline and after 60 min post-exercise, participants were subject to blood pressure measurement, heart rate measurements and a determination of arterial stiffness parameters. Results: There was no significant difference between the TRE and LIRE-BFR group at baseline. Pulse-wave velocity increased in both groups (p < 0.05) post-exercise with no between-group differences. Both exercise modalities did not produce any adverse events. The increase in systolic blood pressure, pulse pressure, augmentation pressure and pulse wave velocity (all p > 0.05) were similar after both TRE and LIRE-BFR. Conclusion: TRE and LIRE-BFR had similar responses regarding hemodynamic parameters and pulse-wave velocity in older people with slow gait speed. Long-term studies should assess the cardiovascular risk and safety of LIRE-BFR training in this population.

Arterial Stiffness Parameters and Subendocardial Viability Ratio in Patients with Arterial Hypertension Affected by Subclinical and Clinical Atherosclerosis

Aim. Assessment the arteries' stiffness parameters and subendocardial viability ratio in hypertensive patients with various degrees of severity of the atherosclerotic process manifestation.Material and methods. 133 hypertensive patients were divided into 3 groups, similar in age and sex, depending on the severity of the atherosclerotic process: hypertensive patients without atherosclerosis (n=42; 53.3±7.6 years); patients with hypertension and subclinical atherosclerosis (SА) (n=52; 56.5±8.0 years); patients with hypertension and coronary artery disease (CAD) (n=39; 57.4±6.8years) and control group which consisted of individuals without cardiovascular diseases (n=33; 54.6±8.4 years). All participants underwent 24-hour blood pressure monitoring with assessment of arterial stiffness parameters and subendocardial viability ratio (SERV).Results. Subjects from all groups with hypertension have significantly higher mean systolic blood pressure (SBP) (131.1±11.9, 127.8±14.8, 128.6±15.3 respectively; p&lt;0.001), as well as central systolic blood pressure (SBPao) (122.0±11.0, 118.8±12.7, 119.9±13.3 respectively; p&lt;0.001), pulse pressure (PP) (46.4±9.8, 45.6±10.6, 48.9±12.0 respectively; p&lt;0.05) and central pulse pressure (PPao) (35.5±8.5, 34.9±8.5, 38.5±9.6 respectively; p&lt;0.05), pulse wave velocity in aorta (PWVao) (11.3±1.5, 12.3±1.8, 11.5±1.7 respectively; p&lt;0.05) compared with control group (SBP 116.3±7.3; SBPao 108.9±6.4, PP 39.9±6.5, PPao 30.9±5.4, PWVao 10.4±1.3). In hypertensive patients with SA, PWVao was significantly higher compared to other groups (p&lt;0.05). With bringing the indicator to SBP 100 mmHg and HR=60 beats/min, there were no differences between the control group and the group with hypertension (p=0.3), also groups with hypertension+SA and hypertension+CAD did not significantly differ from each other (p=0.6). SERV in subjects with hypertension+SA was significantly lower than in patients with hypertension (p&lt;0.05) and no significant differences were detected with the group with hypertension+CAD (p=0.77).Conclusions. In hypertensive patients with SA, a decrease in subendocardial perfusion is associated with an increase in pulse wave velocity in aorta. Moreover, such a decrease in perfusion approaches to the values of patients suffering from coronary artery disease, which indicates significant changes in the small vessels of the heart that form the coronary reserve.

Association between arterial stiffness and sleep apnoea in patients with resistant hypertension.

Resistant Hypertension (RHT) is associated with a higher risk of Obstructive Sleep Apnoea (OSA). OSA and aortic stiffness (AS) measured by Pulse Wave Velocity (PWV) are independent risk factors for cardiovascular events. We assessed, in a cross-sectional study, the association between AS measured by PWV and OSA severity in patients with RHT. All patients were submitted to polysomnography, PWV measure and 24 h ABPM. Bivariate analysis compared patients with and without moderate/severe OSA. Multivariate analysis was performed to assess the independent correlates of moderate/severe OSA. A total of 376 patients were included, 31% were men with a mean age of 63 ± 10 years. Moderate/severe OSA was diagnosed in 214 patients (57%), 63 patients (17%) presented AS. Uncontrolled ABPM (true RHT) was found in 215 patients (57.2%) and among them 113 were diagnosed with moderate/severe OSA. Evaluating AS in patients with mild, moderate and severe apnoea, we observed a progressive increase in PWV (8.19 ± 1.55, 8.51 ± 1.84, 8.67 ± 1.68, respectively). Classifying them in 2 groups: (1) without apnoea/mild apnoea and (2) moderate/severe apnoea, we found higher values in group 2 (8.21 ± 1.52 m/s vs. 8.60 ± 1.75 m/s, p = 0.02), especially among true RHT patients (8.28 ± 1.62 vs. 8.81 ± 1.86, p = 0.029), women (8.13 ± 1.49 vs. 8.55 ± 1.73, p = 0.036), and uncontrolled nocturnal systolic BP (8.49± 1.63 vs. 8.58 ± 1.78, p = 0.04). In conclusion, in this RHT cohort, although with borderline results, the more severe the apnoea, the greater the arterial stiffness, mainly among women, true RHT and patients with an adverse nocturnal BP profile.