Increase In Aortic Stiffness Research Articles

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

We have found that T cells contribute to age-related large artery stiffness. The T-box transcription factor, Eomes is an important regulator of CD8+ (Cytotoxic) T cell differentiation from a naïve to a memory phenotype. We previously reported that these effector memory CD8+ T cells accumulate in the aorta of old mice. We aimed to investigate whether inhibiting CD8+ T cell memory differentiation in mice, specifically through T cell-specific Eomes deletion, would protect these animals from high-fat diet (HFD)-induced large artery stiffness. Mice with a CD8 driven Cre Recombinase were bred with mice with loxp sites surrounding the Eomes gene resulting in wild type (CD8 Eomes+/+) and T cell specific Eomes deleted (CD8 Eomesf/f) mice. Mice were randomly divided into a normal chow (NC) and HFD. Resulting in 8 mice of each genotype and diet. The NC group was given a normal diet containing 4% fat and the HFD group was given a high-fat diet containing 60% fat. At 4-8 months of age, doppler pulse wave velocity was used to assess large artery stiffness. Following euthanasia, aortic T cell phenotype was assessed using flow-cytometry. Group differences were assessed by two-way ANOVA and Tukey’s post-hoc test. Data shown as mean ± SD. Regardless of genotype, HFD had a significant impact on pulse wave velocity (PWV), indicating elevated aortic stiffness. In the HFD group, both CD8 Eomesf/f and CD8 Eomes+/+ mice exhibited higher PWV values (330.08±72.33 cm/s;312.5±53.74 cm/s) compared to their counterparts in the NC group (256.4±63.67 cm/s;259.2±66.36 cm/s, p=0.0172). To determine whether HFD-induced increases in aortic stiffness are accompanied by changes in aortic T cell phenotype, flow cytometric analysis was performed on the aorta. First, we observed, regardless of mouse genotype, HFD had a significant impact on CD4+ (Helper T) naïve cells, resulting in a blunted percentage of these cells. This dietary effect was observed in both CD8 Eomesf/f and CD8 Eomes+/+ mice (NCD CD8 Eomesf/f: 70.92±5.912%; NCD CD8 Eomes+/+ mice: 56.46±20.62%; HFD CD8 Eomesf/f: 47.5±7.865%; HFD CD8 Eomes+/+ mice: 50.58±13.907%; p=0.0206). In contrast, the percentages of CD8+ naïve cells did not display a significant change in response to the high-fat diet (p=0.6303). HFD significantly influenced CD4+ memory cells, resulting in an increase in percentages, regardless of mouse genotype (NCD CD8 Eomesf/f: 29.09± 5.909%; NCD CD8 Eomes+/+ mice: 44.27±19.17%; HFD CD8 Eomesf/f: 52.47±7.875%; HFD CD8 Eomes+/+ mice: 49.44±13.9%; p=0.02). However, HFD did not produce any significant alterations in CD8+ memory cell percentages (p=0.6). These results suggest that contrary to our hypothesis, T cell specific Eomes deletion is not suffcient to protect against diet induced large artery stiffness. However, this may be due to greater proportions of CD4+ memory cells in the aorta with high fat feeding. Funding: AHA 940023, NIH R01AG060395, K01AG061271. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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

High altitude exposure challenges the cardiovascular system to compensate for barometric pressure-mediated reductions in arterial oxygen content. Reductions in oxygen content elicit simultaneous increases in sympathetic nervous system activity and vasodilation that may have competing effects on changes in large artery stiffness. The objective of this study was to examine changes in aortic and carotid stiffness during high altitude sojourn in healthy, young adults. We hypothesized that short-term high-altitude sojourn would increase both aortic and carotid stiffness. 17 Generally healthy adults (23±4 yrs, 25.0±3.0 BMI, n=9 females) underwent vascular assessments in the supine position at 1400 m and after an 8-day incremental ascent to 4300 m. Aortic stiffness and carotid β-stiffness were derived from carotid-femoral pulse wave velocity (cfPWV) via applanation tonometry and right common carotid artery ultrasonography, with blood pressure assessed via oscillometry. Ascent from 1400 m to 4300 m resulted in decreased arterial oxygen saturation (-11±4 %, p<0.001) and carotid β-stiffness (-4.48±2.73 au, p<0.001), and increased cfPWV, (+54.98±78.10 cm/s, p=0.01) and mean arterial pressure (+4±7 mmHg, p=0.02). Changes in cfPWV, arterial oxygen saturation, and blood pressure were moderately to strongly correlated (r=-0.425-0.503, p=0.09-0.04). Our data suggest that short term exposure to high altitude has differential effects on carotid versus aortic stiffness despite increases in mean blood pressure. Increases in aortic stiffness appear related to hypoxia-induced reductions in arterial oxygen saturation and concomitant increases in blood pressure, while reductions in carotid stiffness may stem, in-part, from compensatory carotid artery dilation necessary to increase cerebral blood flow at high altitude. Additional research is necessary to further understand mechanisms underlying differential changes in large artery stiffness during high altitude sojourn. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intermittent oral supplementation with fisetin improves arterial function in doxorubicin chemotherapy-treated mice by suppressing cellular senescence

Introduction. Arterial dysfunction (endothelial dysfunction and aortic stiffening) is a key antecedent to the development of cardiovascular diseases. Cellular senescence, a state of nearly irreversible cell cycle arrest, develops in arteries following doxorubicin (Doxo) chemotherapy treatment and induces arterial dysfunction. Fisetin is a natural senolytic (senescent cell clearing compound) that improves arterial function in old mice. However, it is unknown if fisetin supplementation can decrease cellular senescence to reverse Doxo-induced arterial dysfunction. Purpose. To determine if fisetin supplementation can improve arterial function following Doxo treatment by decreasing cellular senescence. Methods & Results. Cell culture. Human aortic endothelial cells were treated with fisetin for 48 hr (0.25, 0.5, 1 uM) following Doxo-induced cellular senescence (200 nm Doxo for 48 hr). 1 uM fisetin lowered senescence burden (senescence-associated β-galactosidase staining) by ~50% ( P = 0.0003). Animals. Young adult (4 mo) male/female p16-3MR mice received Doxo (10 mg/kg) or sham (saline) intraperitoneally. Four weeks later (established time-point of Doxo-induced arterial dysfunction), animals were treated daily with vehicle (V; 10% EtOH, 30% PEG400, 60% Phosal 50 PG) or fisetin (F; 100 mg/kg) via oral gavage using an intermittent 1 week on - 2 weeks off - 1 week on dosing paradigm, yielding 4 groups (Sham-V; Sham-F; Doxo-V; Doxo-F). Data from Sham-V and Sham-F groups were similar for all outcomes. Data are combined due to no sex differences. Endothelial function. Endothelial function (carotid artery endothelium dependent dilation [EDD] to acetylcholine [ACh]) and nitric oxide (NO)-mediated EDD (± L-NAME) were measured following fisetin (or vehicle) supplementation. Doxo-V mice had lower peak EDD relative to Sham-V (73 ± 2 v. 89 ± 2 %; P = 0.003), and this difference was ameliorated in Doxo-F animals (88 ± 3 %). Likewise, Doxo-V mice had lower NO-mediated EDD compared to Sham-V (39 ± 7% v. 55 ± 8%, P = 0.047), and this difference was ameliorated in Doxo-F mice (66 ± 7%). Incubation of carotid arteries ex vivo with ganciclovir (GCV) to clear p16+ senescent cells in p16-3MR mice normalized peak EDD (Sham-V, 93 ± 1; Doxo-V, 93 ± 2; Doxo-F, 91 ± 2%), suggesting that reducing cellular senescence is the mechanism by which fisetin supplementation improved endothelial function. Aortic stiffness. The Doxo-induced increase in aortic stiffness (aortic pulse wave velocity [PWV]) (Doxo-V, 426 ± 20 vs. Sham-V, 332 ± 5 cm/sec; P < 0.0001) was reversed following fisetin supplementation in Doxo-F mice (pre-fisetin: 426 ± 10 v. post-fisetin: 345 ± 5 cm/sec; P = 0.001). The differences in PWV were associated with corresponding differences in ex vivo aortic intrinsic mechanical wall stiffness (Doxo-V, 5991 ± 362 v. Doxo-F, 3996 ± 415 vs. Sham-V, 4813 ± 133 kPa; P = 0.010). Ex vivo incubation of aorta rings with GCV for 48h ameliorated group differences in aortic intrinsic mechanical wall stiffness, suggesting a causal role for suppression of cellular senescence in the response. Conclusion: Intermittent fisetin supplementation may be a novel strategy to favorably modulate cellular senescence, a key cellular signaling pathway mediating arterial dysfunction with Doxo chemotherapy. R21 AG078408 & K99 HL159241. 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.

Study Protocol of a Prospective, Monocentric, Single-Arm Study Investigating the Correlation of Endograft Properties with Aortic Stiffness in Abdominal Aortic Aneurysm Patients Subjected to Endovascular Aortic Repair.

The number of endovascular aortic repairs (EVARs) has surpassed the number of open surgical repairs of abdominal aortic aneurysms (AAAs) worldwide. The available commercial endoprostheses are composed of materials that are stiffer than the native aortic wall. As a consequence, the implantation of stent-graft endoprostheses during EVAR increases aortic rigidity and thus aortic stiffness, resulting in a decrease in abdominal aorta compliance. EVAR has been found to have a possibly harmful effect not only on heart functions but also on other vascular beds, including kidney function, due to the decrease in aortic compliance that it causes. Aortic stiffness is measured by various hemodynamic indices like the pulse wave velocity (PWV), the central aortic pressure (CAP), and the augmentation index (AIx). In the literature, there are increasing numbers of studies investigating the properties of endografts, which are strongly related to increases in aortic stiffness. However, there is a lack of data on whether there is a correlation between the length of various endografts implanted during EVAR and the increase in the PWV, CAP, and AIx postoperatively compared to the preoperative values. The aim of this prospective, observational, monocentric, single-arm study is to investigate the correlation between endograft length and the postoperative increase in the PWV, CAP, and AIx in patients subjected to EVAR. Additionally, this study intends to identify other endograft properties related to increases in the PWV, CAP, and AIx. Other endpoints to be studied are the existence of immediate postoperative myocardial and kidney injury after EVAR. The prediction of cardiovascular events caused by endograft-related increased aortic stiffness could contribute to the improvement of various endograft properties so that the impact of endografts on the native aortic wall can be minimized.

Association of aortic stiffness with abdominal vascular and coronary calcifications in patients with stage 3 and 4 chronic kidney disease

Rationale and objectivesIncreased central (aortic) arterial stiffness has hemodynamic repercussions that affect the incidence of cardiovascular and renal disease. In chronic kidney disease (CKD) there may be an increase in aortic stiffness secondary to multiple metabolic alterations including calcification of the vascular wall (VC).The objective of this study was to analyze the association of central aortic pressures and aortic stiffness with the presence of VC in abdominal aorta (AAC) and coronary arteries(CAC). Materials and methodsWe included 87 pacientes with CKD stage 3 and 4. Using applanation tonometry, central aortic pressures and aortic stiffness were studied. We investigated the association of aortic pulse wave velocity (Pvc-f) and Pvc-f adjusted for age, blood pressure, sex and heart rate (Pvc-f index) with AAC obtained on lumbar lateral radiography and CAC assessed by multidetector computed tomography. AAC and CAC were scored according to Kauppila and Agatston methods, respecti-vely. For the study of the association between Pvc-f index, Kauppila score, Agatston score, central aortic pressures, clinical parameters and laboratory data, multiple and logistic regression were used. We investigated the diagnosis performance of the Pvc-f index for prediction of VC using receiver-operating characteristic (ROC). ResultsPvc-f and Pvc-f index were 11.3 ± 2.6 and 10.6 m/s, respectively. The Pvc-f index was higher when CKD coexisted with diabetes mellitus (DM). AAC and CAC were detected in 77% and 87%, respectively.Albuminuria (β = 0.13, p = 0.005) and Kauppila score (β = 0.36, p = 0.001) were independently associated with Pvc-f index. In turn, Pvc-f index (β = 0.39, p = 0.001), DM (β = 0.46, p = 0.01), and smoking (β = 0.53; p = 0.006) were associated with Kauppila score, but only Pvc-f index predicted AAC [OR: 3.33 (95% CI: 1.6−6.9; p = 0.001)].The Kauppila score was independently associated with the Agatston score (β = 1.53, p = 0.001). The presence of AAC identified patients with CAC with a sensitivity of 73%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 38%.The Vpc-f index predicted the presence of CAC [OR: 3.35 (95% CI: 1.04−10.2, p = 0.04)]. In the ROC curves, using the Vpc-f index, the AUC for AAC and CAC was 0.82 (95%CI: 0.71−0.93, p = 0.001) and 0.81 (95% CI: 0.67–0.96, p = 0.02), respectively. ConclusionsWhen stage 3–4 CKD coexists with DM there is an increase in aortic stiffness determined by the Vpc-f index. In stage 3–4 CKD, AAC and CAC are very prevalent and both often coexist. The Vpc-f index is independently associated with AAC and CAC and may be useful in identifying patients with VC in these territories.

The relationship between Brucella infection and aortic stiffness in children.

In this study, it was aimed to show whether Brucella infection, which causes various cardiovascular complications in children, can lead to an increase in aortic stiffness with a noninvasive method, echocardiography. Children who were diagnosed with Brucella infection and who had tachycardia, chest pain and murmur that were not related to body temperature increase during the treatment were evaluated cardiologically and had echocardiographic examination, were included in the study. Aortic strain, aortic distensibility measurement results and aortic stiffness index of the patients in the patient and control groups were calculated. Our study included 53 cases with a mean age of 11.43±4.13 years in the patient group and 68 cases with a mean age of 10.16±3.61 years in the control group. We found that systolic blood pressure was lower in the patient group than in the control group (p=0.014). In the analysis of laboratory parameters, blood glucose level was found to be significantly higher in the patient group (p=0.001). In the statistical evaluation of aortic strain, aortic stiffness index and aortic distensibility measurement results between the patient and control groups, no statistically significant difference was found between the groups (p=0.287, p=0.784, p=0.208). In our study, where we tried to show a new parameter that could contribute to the increase in aortic stiffness, the results showed that Brucella infection was not a factor that increased aortic stiffness in the pediatric age group.

Alterations in aortic elasticity indices among type 2 diabetes patients in a low and middle income country using M-mode echocardiography: A cross-sectional comparative study.

Diabetes is one of the leading causes of noncommunicable diseases worldwide. It is known to induce cardiovascular remodeling, which can result in a variety of complications, including a considerable increase in aortic stiffness. While studies in Western populations have explored these effects, data on Asians, mainly Vietnamese, are limited. This study aimed to assess aortic elasticity in type 2 diabetes mellitus (T2DM) patients compared to healthy individuals. This quantitative, cross-sectional study compared aortic elasticity indices between individuals with T2DM and healthy controls in Vietnam. Aortic elasticity indices were assessed for all participants using M-mode echocardiography. A comparison between the healthy and T2DM groups revealed substantial differences in aortic elasticity indices. The aortic stiffness index (ASI) was significantly greater in the T2DM group than in the control group, with median values of 6.10 (3.64-12.47) and 3.79 (2.40-8.50), respectively (p = 0.003). Aortic strain (AS) was substantially lower in the T2DM group than in the control group, with median values of 8.21% (4.24-13.07) and 10.66% (6.01-18.23), respectively (p = 0.039). Furthermore, the median aortic compliance (AC, 10-2mm/mmHg) and aortic distensibility (AD, 10-3mmHg-1) in individuals with T2DM were 4.07 (2.28-7.44) and 3.08 (1.57-5.26), respectively, lower than those in the control group, with median values of 6.40 (3.08-10.75) and 5.33 (2.80-9.79). A longer diabetes duration was linked to a greater ASI (r = 0.43, p < 0.05), while the AS decreased (r = -0.37, p < 0.05). Substantial variations in aorta elasticity indices were found in patients with T2DM using M-mode echocardiography. These differences highlight the impact of T2DM on vascular health. More research is needed to investigate the consequences of these discrepancies and their significance for clinical purposes.

Abstract 18373: Differential Effects of Hypertension and Aneurysm on Stiffness Properties of the Abdominal Aorta

Introduction: The serum and glucocorticoid inducible kinase-1 (SGK-1) can contribute to matrix remodeling in murine models of hypertension (HTN) and abdominal aortic aneurysm (AAA), a potential biomechanical link between these aortopathies. Utilizing aortic stiffness as a marker of pathologic remodeling. Hypothesis: We hypothesize that HTN causes an SGK-1 dependent increase in aortic stiffness to amplify AAA growth. Methods: AngiotensinII (AngII) infusion induced HTN in C57Bl/6 mice (WT;1.46mg/kg/day) with subset groups treated + periadventitial CaCl2 to induce AAA and + infusion of the specific SGK-1 inhibitor EMD638683 (2.5mg/kg/day;n=2-4 each). Abdominal aortic ultrasound was conducted on Day 0 and Day 21 to measure stiffness parameters (radial strain(RS), distensibility(D), pulse propagation velocity(PPV)). Aortic diameter (AoD) was obtained by ultrasound and systolic blood pressures (SBP) were measured by Coda tail cuff. Results: This HTN model has consistently resulted in &gt;30% increase in SBP and AAA induction did not effect SBP. Although the WT+AngII+AAA mice had 66+8% increase in AoD, dilation was not amplified beyond that of the WT+AAA mice (72+7%, p=NS). Treatment with EMD had no impact on SBP, but did significantly reduce AAA growth (WT+AAA+EMD=29+5%; WT+AngII+AAA+EMD= 24+3%), therefore despite ongoing mechanical tension, SGK-1 inhibition abrogated a pathway necessary for degenerative remodeling. Accordingly, aortic stiffness was differentially altered in HTN versus AAA. As indictors of increased stiffness, D decreased with HTN (p&lt;0.05 vs Day 0) and RS decreased with AAA (p&lt;0.05 vs Day 0), but SGK-1 inhibition had no effect, indicating that the matrix remodeling driving these mechanical parameters was not SGK-1 dependent. Conversely, PPV was increased in both aortopathies (WT+AAA, WT+AngII, WT+AngII+AAA; each p&lt;0.05 vs Day 0) but EMD infusion prevented elevation in PPV, suggesting SGK-1-dependent preservation of contractility. Conclusions: Although concurrent induction of HTN and AAA did not amplify AAA growth, these aortopathies differentially impacted aortic stiffness. Tracking PPV as an indicator of pathologic SGK-1 activity may represent a pharmacological target to abrogate dysfunctional aortic remodeling.

Association between Biomarkers of Inflammation and 10-Year Changes in Aortic Stiffness: The Multi-Ethnic Study of Atherosclerosis.

Background. Chronic inflammation is associated with incident cardiovascular events. We study the association between biomarkers of inflammation and subclinical vascular dysfunction measured as proximal aortic stiffness. Methods. MRI imaging was performed in the Multi-Ethnic Study of Atherosclerosis (MESA) at baseline (2000) and at the 10-year follow-up. Aortic arch pulse wave velocity (PWV) and ascending and descending aorta distensibility (AAD, DAD) were measured in 1223 asymptomatic individuals at both exams. Linear regression was used to study the association of baseline inflammation-C-reactive protein (CRP), interleukin-6 (IL6), and fibrinogen (Fib)-with baseline and 10-year changes in aortic stiffness (PWV, AAD, DAD). Results. The mean age of the participants was 59 ± 9 years, 47.8% of them were men, 32.6% were hypertensive at baseline, and 7.6% were diabetic. At baseline and follow-up, the mean AAD values were, respectively, 1.73 × 10-3 mmHg-1 and 1.57 × 10-3 mmHg-1, the mean DAD values were 2.19 × 10-3 mmHg-1 and 1.99 × 10-3 mmHg-1, and the mean PWV values were 8.10 m/s and 8.99 m/s. At baseline, the AAD (in 10-3 mmHg-1) and DAD (in 10-3 mmHg-1) were inversely associated with CRP (in mg/L) (AAD coeff: -0.047, p-value: 0.011, DAD coeff: -0.068, p-value: <0.001) and IL6 (in pg/mL) (AAD coeff: -0.098, p-value: 0.003, DAD coeff: -0.14, p-value: <0.001) in a univariable analysis but not after adjustment for demographic variables or cardiovascular risk factors. The baseline DAD was inversely associated with Fib (in mg/dL) (coeff: -0.334, p-value: 0.001). The baseline PWV (in m/s) was positively associated with IL6 (in pg/mL) in a univariable analysis (coeff: 0.054, p-value: 0.014). In a longitudinal analysis, the 10-year changes in DAD were inversely associated with CRP, even after adjustment for demographics and risk factors (DAD coeff: -0.08, p-value 0.044). Conclusions. Higher CRP levels at baseline were independently associated with a 10-year increase in aortic stiffness, measured as decreased aortic distensibility.

Association Between Aortic Stiffness and Exercise Tolerance in Patients at the Risk Stage of Heart Failure.

The number of patients with heart failure (HF) has increased, and it is crucial to prevent the development of HF in patients at risk of HF. The present study aimed to risk stratify patients in Stage A and B HF based on associations between exercise-induced changes in aortic stiffness and exercise tolerance. Patients in Stage A and B HF who performed a cardiopulmonary exercise test were enrolled in the study (n=106; median age 65.0 years [interquartile range 52.8-73.0 years]). Exercise tolerance was examined by the percentage of predicted peak oxygen consumption (%V̇O2peak). The ascending aortic pressure waveform was estimated non-invasively. Aortic stiffness was assessed using the augmentation index (AIx) and reflection magnitude (RM). Multivariable regression analysis showed that AIx measured both before and after exercise was significantly associated with %V̇O2peak (β=-0.221 [P=0.049] and β=-0.342 [P=0.003], respectively). When participants were divided into %V̇O2peak subgroups using a cut-off value of 60%, RM decreased immediately after exercise and remained lower 5 min after exercise in the group with preserved exercise tolerance, but recovered to baseline levels 5 min after exercise in the group with reduced exercise tolerance. Exercise-induced increases in aortic stiffness were associated with exercise tolerance in patients at risk of HF, suggesting that exercise-induced changes in aortic stiffness may be useful to stratify high-risk patients.

Asociación de la rigidez aórtica con calcificaciones vasculares abdominales y coronarias en pacientes con enfermedad renal crónica estadios 3 y 4

Rationale and objectivesIncreased central (aortic) arterial stiffness has hemodynamic repercussions that affect the incidence of cardiovascular and renal disease. In chronic kidney disease (CKD) there may be an increase in aortic stiffness secondary to multiple metabolic alterations including calcification of the vascular wall (VC).The objective of this study was to analyze the association of central aortic pressures and aortic stiffness with the presence of VC in abdominal aorta (AAC) and coronary arteries (CAC). Materials and methodsWe included 87 patients with CKD stage 3 and 4. Using applanation tonometry, central aortic pressures and aortic stiffness were studied. We investigated the association of aortic pulse wave velocity (Pvc-f) and Pvc-f adjusted for age, blood pressure, sex and heart rate (Pvc-f index) with AAC obtained on lumbar lateral radiography and CAC assessed by multidetector computed tomography. AAC and CAC were scored according to Kauppila and Agatston methods, respectively. For the study of the association between iPvc-f index, Kauppila score, Agatston score, central aortic pressures, clinical parameters and laboratory data, multiple and logistic regression were used. We investigated the diagnosis performance of the Pvc-f index for prediction of VC using receiver-operating characteristic (ROC). ResultsPvc-f and Pvc-f index were 11.3±2.6m/s and 10.6m/s, respectively. The Pvc-f index was higher when CKD coexisted with diabetes mellitus (DM). AAC and CAC were detected in 77% and 87%, respectively.Albuminuria (β=0.13, p=0.005) and Kauppila score (β=0.36, p=0.001) were independently associated with Pvc-f index. In turn, Pvc-f index (β=0.39, p=0.001), DM (β=0.46, p=0.01), and smoking (β=0.53; p=0.006) were associated with Kauppila score, but only Pvc-f index predicted AAC [OR: 3.33 (95% CI: 1.6–6.9; p=0.001)].The Kauppila score was independently associated with the Agatston score (β=1.53, p=0.001). The presence of AAC identified patients with CAC with a sensitivity of 73%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 38%.The Vpc-f index predicted the presence of CAC [OR: 3.35 (95% CI: 1.04–10.2, p=0.04)]. In the ROC curves, using the Vpc-f index, the AUC for AAC and CAC was 0.82 (95% CI: 0.71–0.93, p=0.001) and 0.81 (95% CI: 0.67–0.96, p=0.02), respectively. ConclusionsWhen stage 3–4 CKD coexists with DM there is an increase in aortic stiffness determined by the Vpc-f index. In stage 3–4 CKD, AAC and CAC are very prevalent and both often coexist. The Vpc-f index is independently associated with AAC and CAC and may be useful in identifying patients with VC in these territories.

MARKED INCREASES IN PROXIMAL AORTIC CHARACTERISTIC IMPEDANCE AND HENCE FORWARD WAVE PRESSURES BEYOND BRACHIAL BLOOD PRESSURE IN ANGIOGRAPHIC PROVEN CORONARY ARTERY DISEASE

Objective: Although indexes of aortic stiffness increase the risk for coronary artery disease (CAD), the extent to which proximal aortic stiffness increases enhance central arterial forward wave pressures beyond changes in peripheral pressures, is uncertain. We aimed to determine whether increases in proximal aortic stiffness, as indexed by aortic characteristic impedance (Zc) translate into an enhanced central arterial pressure for a given brachial BP. Design and method: From central pressure, aortic velocity and outflow tract diameter measurements and echocardiography, we determined Zc and arterial pressure wave morphology in 71 patients with angiographic proven CAD and all other cardiac pathology excluded. We compared central arterial function in these patients with 230 age and sex-matched controls from a community study, and in patients with stroke and CLI (n = 287) diagnosed in a hospital setting. Results: Adjusting for confounders, including mean arterial pressure, and aortic root diameter, as compared to controls, both Zc and the pressures generated by the product of peak aortic flow (Q) and Zc (PQxZc) were markedly increased in patients with CAD (p&lt;0.0001) and those with stroke or CLI (p&lt;0.005). Moreover, compared to patients with stroke and CLI, those with CAD also had marked increases in both Zc and PQxZc (p&lt;0.0001). Consequently, with adjustments for the same confounders, pressures generated by forward wave pressures (Pf) were markedly increased in patients with CAD as compared to controls and to patients with alternative arterial diseases (p&lt;0.0001). Importantly, after further adjustments for brachial PP or SBP, the higher Pf values in patients with CAD were retained (p&lt;0.005 to &lt;0.0001). However, with adjustments for brachial SBP and confounders, central aortic PP did not differ between groups. Conclusions: Independent of confounders and aortic root diameter, a marked increase in proximal aortic Zc occurs in patients with CAD as compared to both controls and patients with arterial disease in alternative beds. This translates into a greater central arterial pulsatile load determined by forward travelling pressure waves, but not peak central PP than that predicted by brachial BP measurements. These data support a need for intense brachial BP lowering in CAD.

Vascular function in women: when studying perimenopause is peri important.

Vascular function in women: when studying perimenopause is peri important.

Circulating Markers Of Matrix Homeostasis Are Dysregulated In Hypertension-induced Aortic Stiffness

Increased aortic stiffness due to remodeling of the extracellular matrix is a known predictor of cardiovascular morbidity and mortality. Assessment of aortic stiffness has not been widely adopted, likely due to the need for specialized equipment. We hypothesize that plasma markers associated with matrix homeostasis correlate to an increase in aortic stiffness.

Estimated pulse wave velocity and incident heart failure and its subtypes: Findings from the multi-ethnic study of atherosclerosis

Age-associated increase in aortic stiffness, measured as carotid-femoral pulse wave velocity (PWV), is an important effector of cardiac damage and heart failure (HF). Pulse wave velocity estimated from age and blood pressure (ePWV) is emerging as a useful proxy of vascular aging and subsequent cardiovascular disease risk. We examined the association of ePWV with incident HF and its subtypes in a large community sample of 6814 middle-aged and older adults from the Multi-Ethnic Study of Atherosclerosis (MESA). MethodsParticipants with an ejection fraction ≤40 % were classified as HF with reduced ejection fraction (HFrEF) while those with an ejection fraction ≥50 % were classified as HF with preserved ejection fraction (HFpEF). Cox proportional hazards regression models were used to calculate hazard ratios (HR) and 95 % confidence intervals (CI). ResultsOver a mean follow-up period of 12.5 years, incident HF was diagnosed in 339 participants: 165 were classified as HFrEF and 138 as HFpEF. In fully adjusted models, the highest quartile of ePWV was significantly associated with an increased risk of overall HF (HR 4.79, 95 % CI 2.43–9.45) compared with the lowest quartile (reference). When exploring HF subtypes, the highest quartile of ePWV was associated with HFrEF (HR 8.37, 95 % CI 4.24–16.52) and HFpEF (HR 3.94, 95 % CI 1.39–11.17). ConclusionsHigher ePWV values were associated with higher rates of incident HF and its subtypes in a large, diverse cohort of men and women.

Proximal aortic stiffness modifies the relationship between heart rate and backward wave and hence central arterial pulse pressure.

A lower heart rate (HR) increases central blood pressure through enhanced backward wave pressures (Pb). We aimed to determine whether these relationships are modified by increases in aortic stiffness. Using non-invasive central pressure, aortic velocity and diameter measurements in the outflow tract (echocardiography), we assessed the impact of aortic stiffness on relationships between HR and arterial wave morphology in 603 community participants < 60 years of age, 221 ≥ 60 years, and in 287 participants with arterial events [stroke and critical limb ischemia (CLI)]. As compared to community participants < 60 years, those ≥ 60 years or with events had increased multivariate adjusted proximal aortic characteristic impedance (Zc) and carotid femoral pulse wave velocity (PWV) (p < 0.05 to < 0.0001). Community participants ≥ 60 years and those with events also had a greater slope of the inverse relationship between HR and Pb (p < 0.001 for comparison). While in community participants < 60 years, no interaction between indexes of aortic stiffness and HR occurred, in those ≥ 60 years (p < 0.02) and in those with arterial events (p = 0.001), beyond aortic root diameter, an interaction between Zc and HR, but not between PWV and HR independently associated with Pb. This translated into stepwise increases in the slope of HR-Pb relationships at incremental tertiles of Zc. Although HR was inversely associated with the systemic reflection coefficient in community participants ≥ 60 years (p < 0.0001), adjustments for the reflection coefficient failed to modify HR-Pb relations. Beyond the impact on systemic wave reflection, increases in proximal aortic stiffness enhance the adverse effects of HR on Pb and hence central BP.

Impact of 60 days of head-down bed rest on large arteries.

The long-term cardiovascular consequences of microgravity on large arteries are a threat for long-term space missions. We hypothesized that changes in arterial properties differ according to the arterial territory (upper or lower body), and arterial structure (elastic vs. muscular arteries), in response to 60-day head-down bed rest (HDBR). Twenty healthy male volunteers were included and received a daily multivitamin supplementation in a double-blind fashion. At baseline, 29 and 52 days during strict HDBR, then 12 and 30 days after HDBR, aortic stiffness was measured using carotid-to-femoral pulse wave velocity (cf-PWV) and aortic MRI. Carotid, femoral, brachial and popliteal arteries were studied by ultrasound echo tracking, central blood pressure (BP) by tonometry and endothelial function by flow-mediated dilatation. Cf-PWV increased during HDBR (+0.8 and +1.1m/s, at D29 and D52, respectively, P = 0.004), corresponding to an increase in vascular age up to +11 years (P = 0.003). Changes were similar to those observed on MRI (+0.8 m/s at D52, P < 0.01) and were independent of BP and heart rate changes. After HDBR, cf-PWV showed a substantial recovery at R12 but still remained higher than baseline at R30 (+0.8 m/s, P = 0.018), corresponding to +6.5 years of vascular aging (P = 0.018). Thoracic aorta diameter increased significantly (+6%, P = 0.0008). During HDBR, femoral and popliteal arteries showed dimensional changes, leading to femoral inward hypotrophic remodeling (femoral diameter: -12%, P < 0.05; wall cross-sectional area: -25%, P = 0.014) and popliteal inward eutrophic remodeling (popliteal diameter: -25%, P < 0.05; wall cross-sectional area: -3%, P = 0.51). After HDBR, both arterial territories of the leg recovered. We did not observe any significant changes for carotid arteries nor for endothelial function during and after HDBR. Multivitamin supplementation did not affect vascular changes. HDBR was associated with an important increase in aortic stiffness, which did not completely recover 1 month after the end of HDBR. The thoracic aorta and the lower body muscular arteries underwent significant changes in dimensions whereas the common carotid arteries were preserved. These results should raise caution for those exposed to microgravity, real or simulated.

Suppression of trimethylamine N-oxide with DMB mitigates vascular dysfunction, exercise intolerance, and frailty associated with a Western-style diet in mice.

Consumption of a Western-style diet (WD; high fat, high sugar, low fiber) is associated with impaired vascular function and increased risk of cardiovascular diseases (CVD), which could be mediated partly by increased circulating concentrations of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO). We investigated if suppression of TMAO with 3,3-dimethyl-1-butanol (DMB; inhibitor of microbial TMA lyase) in mice could prevent: 1) WD-induced vascular endothelial dysfunction and aortic stiffening and 2) WD-induced reductions in endurance exercise tolerance and increases in frailty, as both are linked to WD, vascular dysfunction, and increased CVD risk. C57BL/6N mice were fed standard chow or WD (41% fat, ∼25% sugar, 4% fiber) for 5 mo beginning at ∼2 mo of age. Within each diet, mice randomly received (n = 11-13/group) normal drinking water (control) or 1% DMB in drinking water for the last 8 wk (from 5 to 7 mo of age). Plasma TMAO was increased in WD-fed mice but suppressed by DMB. WD induced endothelial dysfunction, assessed as carotid artery endothelium-dependent dilation to acetylcholine, and progressive increases in aortic stiffness (measured serially in vivo as pulse wave velocity), both of which were fully prevented by supplementation with DMB. Endurance exercise tolerance, assessed as time to fatigue on a rotarod test, was impaired in WD-fed mice but partially recovered by DMB. Lastly, WD-induced increases in frailty (31-point index) were prevented by DMB. Our findings indicate DMB or other TMAO-lowering therapies may be promising for mitigating the adverse effects of WD on physiological function, and thereby reducing risk of chronic diseases.NEW & NOTEWORTHY We provide novel evidence that increased circulating concentrations of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) contribute to vascular dysfunction associated with consumption of a Western-style diet and that this dysfunction can be prevented by suppressing TMAO with DMB, thereby supporting translation of this compound to humans. Furthermore, to our knowledge, we present the first evidence of the role of TMAO in mediating impairments in endurance exercise tolerance and increased frailty in any context.

Abstract P3126: Sphingomyelinase Participates Diet - Induced Increases In Aortic Stiffness And Cardiac Dysfunction

Excessive accumulation of ceramides induces mitochondria dysfunction and promotes toxicity in multiple types of cells, including endothelial cells and cardiomyocytes. Neutral sphingomyelinase (nSMase) is thought to increase ceramide levels through sphingomyelin hydrolysis, and the resultant increase in ceramides plays a role in the pathogenesis of a number of disorders, such as atherosclerosis and heart failure. While inhibition of nSMase attenuates the progression of atherosclerosis and heart failure, little is known regarding its role in correcting impaired metabolic signaling, arterial dysfunction and metabolic cardiomyopathy. Accordingly, we hypothesized that nSMase inhibition with GW4869, attenuates Western diet (WD) - induced increases in aortic stiffness and cardiac dysfunction through effects on pathways which lead to oxidative stress and inflammation. 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 treated with GW4869 (2.0 μg/g body weight, intraperitoneal injection every 48 hours for 12 weeks). WD consumption increased plasma nSMase activation and tissue nSMase2 expression in concert with aortic stiffening and impaired vasorelaxation as determined by pulse wave velocity (PWV) and wire myography, respectively. WD fed mice exhibited reduced EF (systolic dysfunction) and increased E/E’ and IVRT (diastolic dysfunction) determined by in vivo Doppler ultrasound. Moreover, these functional abnormalities were associated with attenuated AMP-activated protein kinase, Sirtuin 1, and endothelial nitric oxide synthase activation. These functional and metabolic abnormalities were blunted by in vivo GW4869 treatment. These findings indicate that targeting nSMase prevents diet - induced aortic stiffening and cardiac dysfunction by correction of impaired metabolic signaling.

CORRELATION BETWEEN VASCULAR INFLAMMATION MARKERS, DIASTOLIC DYSFUNCTION AND CARDIOVASCULAR RISK IN PATIENTS WITH TAKAYASU ARTERITIS

Objective: Takayasu arteritis (TAK) increases vascular stiffness and arterial resistance. Abnormal immune response is a crucial factor in the pathogenesis of TAK. Here, we investigated I) vascular and cardiac ultrasonography parameters as increased cardiovascular risk in TAK patients, compared to atherosclerotic patients; ii) Treg and Th17 cells frequencyin TAK-refractory patients treated with infliximab Design and method: Clinical, instrumental and biochemical data in patients with active TAK were compared in a case control study were compared to age- and sex-matched atherosclerotic patients. In a subpopulation of TAK patients, Treg/Th17 cells percentage was measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were carried out in all patients. Histological and immunohistochemical analysis were performed to correlate vessel wall patho-morphology and clinical/laboratory results Results: TAK patients displayed increased aortic valve dysfunction and diastolic dysfunction compared to atherosclerosis. Moderate-to-severe aortic regurgitation correlates with the highest serum levels of uric acid in TAK patients. A significant increase in aortic stiffness was associated with peripheral T lymphocyte levels. Increase in CD3+CD4+ and CD8+ infiltration and High-mobility group box 1 (HMGB1) was significantly higher in TAK group. CD15+ neutrophils were significantly higher in TAK, suggesting an association with inflammation-related vascular damage. Flow cytometric Tregs percentage was significantly reduced in TAK patients. Interestingly, in patients treated with infliximab, this value significantly increased at T18 compared to T0. Concomitantly, the frequency of CD3+CD4+IL-17+ cells behaved in the opposite way: the higher number of Th17 cells observed in TAK patients at T0 compared to controls significantly decreased at T18 compared to T0. Supporting the specific pathogenetic mechanisms of vessel damage in TAK, we found an increased risk of cardiovascular disease that correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Conclusions: These observations strengthen the clinical efficacy of infliximab in TAK patients, supporting the idea that biologic therapy may achieve a better control of TAK progression and help to stabilize the Treg/Th17 score toward values similar to those found in atherosclerotic patients