Marie-Pier Desjardins

Aortic-Brachial Pulse Wave Velocity Ratio: A Blood Pressure-Independent Index of Vascular Aging.

Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV (R2=0.10 and 0.08; P<0.001 and P=0.003) and MAP and carotid–radial PWV (R2=0.22 and 0.12; P<0.001 and P<0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio (R2=0.0002 and 0.0001; P=0.8 and P=0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging.Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV ( R 2=0.10 and 0.08; P <0.001 and P =0.003) and MAP and carotid–radial PWV ( R 2=0.22 and 0.12; P <0.001 and P <0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio ( R 2=0.0002 and 0.0001; P =0.8 and P =0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging. # Novelty and Significance {#article-title-24}

Levels of Angiopoietin-Like-2 Are Positively Associated With Aortic Stiffness and Mortality After Kidney Transplantation

BACKGROUND Angiopoietin‐like‐2 (ANGPTL2) is a secreted proinflammatory glycoprotein that promotes endothelial dysfunction, atherosclerosis, and cardiovascular disease (CVD). Circulating ANGPTL2 is increased in chronic kidney disease (CKD), where the risk of CVD is amplified. The objectives of the present study were to (i) examine whether kidney transplantation (KTx) reduces ANGPTL2 levels, (ii) identify the determinants of ANGPTL2 after KTx, (iii) study the association of ANGPTL2 with aortic stiffness, and (iv) assess the impact of ANGPTL2 on mortality after KTx. METHODS In 75 patients, serum ANGPTL2 levels were measured at baseline and 3 months after KTx. Aortic stiffness was determined by carotid‐femoral pulse wave velocity, glomerular filtration rate was estimated by CKD‐EPI formula, and serum cytokines and endothlin‐1 levels were determined 3 months after KTx. Survival analysis was performed using Kaplan‐Meier and Cox regression after a median follow‐up of 90 months. RESULTS After 3 months of KTx, ANGPTL2 levels decreased from 71 ng/ml (53‐95) to 11 ng/ml (9‐15) (P < 0.001). In multivariate analysis, age, lower renal function, and endothelin‐1 were independently associated with higher post‐KTx ANGPTL2 levels. ANGPTL2 was positively associated with aortic stiffness after KTx, even when adjusted for mean blood pressure (standardized &bgr; = 0.314; P = 0.008). During follow‐up, 13 deaths occurred. The group of patients with higher post‐KTx ANGPTL2 levels had a hazard ratio for mortality of 3.9 (95% confidence interval: 1.07‐14.4; P = 0.039). CONCLUSION KTx significantly reduced serum ANGPTL2 levels. The positive association between post‐KTx ANGPTL2, aortic stiffness and mortality, suggests that ANGPTL2 may play a biological role in CKD‐related CVD.

Reduction of Arterial Stiffness After Kidney Transplantation: A Systematic Review and Meta‐Analysis

Background End‐stage kidney disease is associated with increased arterial stiffness. Although correction of uremia by kidney transplantation (KTx) could improve arterial stiffness, results from clinical studies are unclear partly due to small sample sizes. Method and Results We conducted a systematic review and meta‐analysis of before‐after design studies performed in adult KTx patients with available measures of arterial stiffness parameters (pulse wave velocity [PWV], central pulse pressure [PP], and augmentation index) before and at any time post‐KTx. Mean difference of post‐ and pre‐KTx values of different outcomes were estimated using a random effect model with 95% confidence interval. To deal with repetition of measurement within a study, only 1 period of measurement was considered per study by analysis. Twelve studies were included in meta‐analysis, where a significant decrease of overall PWV by 1.20 m/s (95% CI 0.67‐1.73, I2=72%), central PWV by 1.20 m/s (95% CI 0.16‐2.25, I2=83%), peripheral PWV by 1.17 m/s (95% CI 0.17‐2.17, I2=79%), and brachial‐ankle PWV by 1.21 m/s (95% CI 0.66‐1.75, I2=0%) was observed. Central PP (reported in 4 studies) decreased by 4.75 mm Hg (95% CI 0.78–10.28, I2=50%). Augmentation index (reported in 7 studies) decreased by 10.5% (95% CI 6.9‐14.1, I2=64%). A meta‐regression analysis showed that the timing of assessment post‐KTx was the major source of the residual variance. Conclusions This meta‐analysis suggests a reduction of the overall arterial stiffness in patients with end‐stage kidney disease after KTx.

Aortic-Brachial Pulse Wave Velocity Ratio: A Measure of Arterial Stiffness Gradient Not Affected by Mean Arterial Pressure

Background: Aortic stiffness, measured by carotid-femoral pulse wave velocity (cf-PWV), is used for the prediction of cardiovascular risk. This mini-review describes the nonlinear relationship between cf-PWV and operational blood pressure, presents the proposed methods to adjust for this relationship, and discusses a potential place for aortic-brachial PWV ratio (a measure of arterial stiffness gradient) as a blood pressure-independent measure of vascular aging. Summary: PWV is inherently dependent on the operational blood pressure. In cross-sectional studies, PWV adjustment for mean arterial pressure (MAP) is preferred, but still remains a nonoptimal approach, as the relationship between PWV and blood pressure is nonlinear and varies considerably among individuals due to heterogeneity in genetic background, vascular tone, and vascular remodeling. Extrapolations from the blood pressure-independent stiffness parameter β (β0) have led to the creation of stiffness index β, which can be used for local stiffness. A similar approach has been used for cardio-ankle PWV to generate a blood pressure-independent cardio-ankle vascular index (CAVI). It was recently demonstrated that stiffness index β and CAVI remain slightly blood pressure-dependent, and a more appropriate formula has been proposed to make the proper adjustments. On the other hand, the negative impact of aortic stiffness on clinical outcomes is thought to be mediated through attenuation or reversal of the arterial stiffness gradient, which can also be influenced by a reduction in peripheral medium-sized muscular arteries in conditions that predispose to accelerate vascular aging. Arterial stiffness gradient, assessed by aortic-brachial PWV ratio, is emerging to be at least as good as cf-PWV for risk prediction, but has the advantage of not being affected by operating MAP. Key Messages: The negative impacts of aortic stiffness on clinical outcomes are proposed to be mediated through attenuation or reversal of arterial stiffness gradient. Aortic-brachial PWV ratio, a measure of arterial stiffness gradient, is independent of MAP.

[OP.7C.12] IMPACT OF KIDNEY TRANSPLANTATION ON AORTIC PULSE WAVE VELOCITY AND AORTIC STIFFNESS INDEX B0

Objective: Patients with chronic kidney disease are at increased risk of aortic stiffness and cardiovascular disease. We have previously shown that aortic pulse wave velocity (PWV) improves as early as 3 months post-kidney transplantation (KTx). Arterial stiffness index &bgr;0 has been proposed to be an intrinsic blood pressure independent parameter of vascular wall property. The aim of this study is to examine 1) the early versus late changes in aortic PWV and stiffness index &bgr;0 and 2) to define the characteristics of patients with favorable and unfavorable trajectories of stiffness index &bgr;0. Design and method: In this longitudinal study, 79 patients who underwent KTx were enrolled and followed-up before, 3, 6 and 24 months after KTx. Aortic stiffness was determined non-invasively by the assessment of carotid-femoral pulse wave velocity (cf-PWV) (Complior) while central mean blood pressure was obtained from applanation tonometry (SphygmoCor). Aortic stiffness index &bgr;0 was calculated using the following formulae: &bgr;0 = (PWV2)*2&rgr;)/Pd-ln(Pd/Pref) in which Pref refers to reference pressure (Pref = 100mmHg), &rgr; to blood mass density (&rgr; = 1050 kg/m3) and Pd to brachial diastolic blood pressure (mmHg). Cytokines profile was measured in plasma by ELISA using a Multiplex array. Results: There was an early reduction of &bgr;0 3 months after KTx (from 29.0 ± 17.7 to 25.8 ± 10.6 (P = 0.014)) outweighed by an increase at 6 and 24 months (27.8 ± 12.0 to 28.2 ± 11.2). There were no late changes of aortic PWV at 6 and 24 months. The faster progression of &bgr;0 after an initial improvement was not related to renal function, age, comorbidities or kidney donor characteristics. Nonetheless, the accelerated progression of &bgr;0 was associated with higher levels of pro-inflammatory cytokines, such as interleukin-6 (P = 0.029), interleukine-8 (P = 0.040) and interleukin-10 (P = 0.032). Figure. No caption available. Conclusions: The early improvement of aortic stiffness index &bgr;0 after KTx suggests that KTx leads to an early improvement of the intrinsic mechanical properties of aorta. However, this improvement is followed by a later progression of &bgr;0, which is associated with increased pro-inflammatory cytokines, suggesting that activation if immune system may be involved in arterial wall remodelling in kidney transplant recipients.

[PP.19.17] AORTIC RESERVOIR FUNCTION, REGIONAL ARTERIAL STIFFNESS AND AORTIC-TO-BRACHIAL STIFFNESS GRADIENT IN DIALYSIS POPULATION

Objective: A decreased aortic reservoir function is associated with increased cardiovascular events. Patients with chronic kidney disease in need of dialysis have an accelerated progression of aortic stiffness and reversal of the aortic-to-brachial stiffness gradient. We previously observed an annual reduction in brachial stiffness which was partly explained by a greater stiffness of the aorta. The aim of this study was to determine the relationship between aortic reservoir pressure, regional arterial stiffness and aortic-to-brachial stiffness gradient. Design and method: Among 310 patients with chronic kidney disease on dialysis, aortic and brachial stiffness were measured by determination of pulse wave velocity of carotid-femoral (cf-PWV) and carotid-radial (cr-PWV) segments (Complior). The aortic-to-brachial stiffness gradient was calculated by the ratio of cf-PWV to cr-PWV (PWV ratio). Reservoir pressure (RP), its integral (AUC-RP) and excess pressure parameters (XSP, AUC-XSP) were derived from radial pressure waveforms (radial tonometry-without generalized transfer function). Results: Reservoir pressure parameters were significantly associated with cf-PWV (stdz &bgr; of RP = 0.194, stdz &bgr; of AUC-RP = 0.168) and PWV ratio (stdz &bgr; of RP = 0.283, stdz &bgr; of AUC-RP = 0.310) in multivariate models taking into account mean arterial pressure, age, sex, hemodialysis status, diabetes, height and heart rate, all with p < 0.001. An inverse association was observed in multivariate models between reservoir pressure and cr-PWV (stdz &bgr; of RP = −0.153, stdz &bgr; of AUC-RP = −0.221). In contrast, excess pressure parameters were not significantly associated with regional stiffness and PWV ratio in multivariable models. Conclusions: In a dialysis population, aortic reservoir function was associated with aortic stiffness and PWV ratio and negatively associated with brachial stiffness in multivariate models. In contrast, no association was observed between excess pressure parameters and PWV after adjustments for potential confounders.

Aortic–Brachial Pulse Wave Velocity RatioNovelty and Significance

Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV (R2=0.10 and 0.08; P<0.001 and P=0.003) and MAP and carotid–radial PWV (R2=0.22 and 0.12; P<0.001 and P<0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio (R2=0.0002 and 0.0001; P=0.8 and P=0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging.Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV ( R 2=0.10 and 0.08; P <0.001 and P =0.003) and MAP and carotid–radial PWV ( R 2=0.22 and 0.12; P <0.001 and P <0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio ( R 2=0.0002 and 0.0001; P =0.8 and P =0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging. # Novelty and Significance {#article-title-24}

Aortic–Brachial Pulse Wave Velocity RatioNovelty and Significance: A Blood Pressure–Independent Index of Vascular Aging

Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV (R2=0.10 and 0.08; P<0.001 and P=0.003) and MAP and carotid–radial PWV (R2=0.22 and 0.12; P<0.001 and P<0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio (R2=0.0002 and 0.0001; P=0.8 and P=0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging.Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV ( R 2=0.10 and 0.08; P <0.001 and P =0.003) and MAP and carotid–radial PWV ( R 2=0.22 and 0.12; P <0.001 and P <0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio ( R 2=0.0002 and 0.0001; P =0.8 and P =0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging. # Novelty and Significance {#article-title-24}

[OP.1C.03] REGIONAL VASCULAR STIFFNESS IN RESPONSE TO NITROGLYCERIN AND THEIR IMPACT ON ARTERIAL STIFFNESS GRADIENT.

Objective: In dialysis patients, we have shown that aortic-brachial stiffness gradient outperforms cf-PWV for the prediction of mortality. We hypothesized that arterial stiffness gradient increases after administration of vasodilatory drugs. The aim of this study is to examine the impact of nitroglycerin (GTN) on arterial stiffness gradient using aortic-brachial (AB-PWV ratio) and aortic-femoral PWV ratios (AF-PWV ratio) in non-dialysis subjects. Design and method: This cross-sectional study was conducted in 35 adult patients. The mean age was 66 ± 10, 77% were men, 17% and 14% of the subjects had diabetes and cardiovascular disease. Aortic, brachial and femoral stiffness were respectively measured by determination of carotid-femoral (cf-PWV), carotid-radial (cr-PWV) and femoral-dorsalis pedis pulse wave velocity (fd-PWV), at baseline and 5 minutes post-GTN 0.4 mg s.l.. Direct distance measures were used to determine PWV. AB-PWV ratio and AF-PWV ratio were respectively obtained by dividing cf-PWV by cr-PWV or fd-PWV. Generalized estimating equations were used to evaluate the impact of GTN on changes of regional stiffness (cf-PWV, cr-PWV and fd-PWV) and arterial stiffness gradients (AB-PWV ratio and AF-PWV ratio) after adjustments for mean blood pressure (MBP). Results: At baseline, cf-PWV, cr-PWV and fd-PWV were, respectively, 11.8 ± 2.1 m/s, 9.0 ± 1.4 m/s and 8.2 ± 1.6 m/s resulting in an AB-PWV ratio of 1.34 ± 0.28 and an AF-PWV ratio of 1.50 ± 0.41. After GTN, there was a decrease in MBP of 2.1 mmHg (p = 0.016), without any changes in cf-PWV (11.8 ± 2.3 m/s). However, there were a significant reduction in cr-PWV by 0.54 m/s (p < 0.001) and fd-PWV by 1.20 m/s (p < 0.001), which resulted in a significant increase in AB- and AF-PWV ratios by 0.10 (p = 0.001) and by 0.24 (p < 0.001), respectively. Adjustments for MBP did not affect the effect size nor the significance of changes in AB- and AF-PWV ratios. Conclusions: The present study shows that aortic-brachial and aortic-femoral stiffness gradients are adversely affected by GTN administration. The differential impact of various anti-hypertensive drugs on the vascular stiffness gradient needs to be further studied.

[PP.37.04] EVOLUTION OF ARTERIAL STIFFNESS AFTER KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS

Objective: Chronic kidney disease is associated with increased arterial stiffness. Correction of the uremic milieu by kidney transplantation may be improve arterial stiffness. However, the results from clinical studies are not uniformly convincing. This could be related to small sample size of studies, heterogeneity in methods and timing of assessment of arterial stiffness after transplantation. The objective of the present study is to measure the impact of renal transplantation on the reduction of arterial stiffness. Design and method: Observational studies and randomized controlled trials with measurements of arterial wave velocity (PWV) were extracted from MEDLINE, EMBASE, COCHRANE LIBRARY, and Web of Science from their inception to January 2016. Two reviewers independently identified eligible studies comparing PWV before and after kidney transplantation and extracted data including population characteristics, interventions and outcomes. Results: 11 studies with 408 subjects were available for comparing pre- to post-transplant PWV. There was a mean change of PWV by -1.28 m/s (95% CI, - 2.01 to - 0.55) post-transplantation (I2 = 72 %). When subgroup analysis was performed only for studies that had assessed aortic PWV (5 studies, 163 patients), there was a non-significant mean changes of PWV by -0.74 m/s (95% CI, -1.49 to 0.02) post-transplantation (I2 = 61%) (FIGURE). The subgroup analysis of the studies with brachial-ankle PWV (BA-PWV), which included 4 studies and 168 patients, showed a significant reduction in PWV by -2.48 m/s (95% CI, - 4.36 to - 0.60) (I2 = 84 %). Limiting analysis to the studies that have measured BA-PWV after at least 3 months of transplantation (3 studies, 151 patients) showed similar results but reduced heterogeneity (I2 = 13%). Figure. No caption available. Conclusions: There is a significant reduction in overall PWV after kidney transplantation. There was a great heterogeneity in the among studies. Further analysis is required to examine the importance of changes in different vascular beds taking into account changes in blood pressure.