Fontan Circulation and Aortic Stiffness: Insights into Vascular Dynamics and Haemodynamic Interplay.

Increased aortic stiffness predisposes cardiac afterload and influences cardiac function. Congenital heart diseases involving aortic arch malformation and extended cardiovascular surgery, i.e. univentricular heart diseases, can lead to increased aortic stiffness. This study aimed to investigate whether Fontan patients (FO) have increased aortic stiffness within distinct aortic segments, and whether these parameters relate to Fontan-specific haemodynamics. In a prospective case-control study, 20 FO and 49 heart-transplanted control subjects with biventricular circulation underwent invasive cardiac catheterisation. We invasively measured pulse wave velocity (PWV) in the ascending aorta and along the entire aorta. Haemodynamic parameters, including end-diastolic pressure, pulmonary artery pressure, the cardiac index and systemic vascular resistance index were also assessed. FO exhibited significantly higher ascending aorta PWV (aPWV) than controls (FO: 7.2 ± 2.4 m/s|Controls: 4.9 ± 0.7 m/s, p < 0.001) and compared to the inner group central aorta PWV (cPWV; FO: 5.5 ± 1.2 m/s|Controls: 5.3 ± 1.0 m/s). Multivariate analysis confirmed this aPWV elevation in FO even after adjusting for age and BMI. aPWV and cPWV were almost identical within the control group. Correlation analyses revealed associations between cPWV and blood pressure in controls, while correlations were less apparent in FO. We detected no significant association between the aPWV and other haemodynamic parameters in any of our groups. FO exhibit increased aPWV, indicating specific vascular stiffness in the ascending aorta, while their overall aortic stiffness remains comparable to controls. Further research is needed to understand the implications of these findings on Fontan circulation and long-term cardiovascular health. CENTRAL MESSAGE: Fontan patients show increased aortic arch pulse wave velocity, suggesting specific vascular stiffness. PERSPECTIVE STATEMENT: Our study offers rare insights into pulse wave velocity in Fontan patients, highlighting increased arterial stiffness in the aortic arch. Vascular stiffness was particularly increased in the area of surgical reconstruction. This indicates the need for further research on vascular stiffness in Fontan circulation to understand its impact on cardiovascular health. CLINICAL TRIAL REGISTRATION: German clinical trial registration, DRKS00015066.

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.

BACKGROUND: 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. PURPOSE: To investigate relative contributions of tissue-innate versus hemodynamics in progression of BAV aortopathy. STUDY TYPE: Retrospective. SUBJECTS: 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). FIELD STRENGTH/SEQUENCE: 1.5T, 3T; time-resolved gradient-echo 3D phase-contrast (4D flow) MRI. ASSESSMENT: 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. STATISTICAL TESTS: 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. RESULTS: 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). DATA CONCLUSION: 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. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Quantitative Thermal Stimulation Using Therapeutic Ultrasound to Improve Cerebral Blood Flow and Reduce Vascular Stiffness.

It is important to improve cerebrovascular health before the occurrence of cerebrovascular disease, as it has various aftereffects and a high recurrence rate, even with appropriate treatment. Various medical recommendations for preventing cerebrovascular diseases have been introduced, including smoking cessation, exercise, and diet. However, the effectiveness of these methods varies greatly from person to person, and their effects cannot be confirmed unless they are practiced over a long period. Therefore, there is a growing need to develop more quantitative methods that are applicable to the public to promote cerebrovascular health. Thus, in this study, we aimed to develop noninvasive and quantitative thermal stimulation techniques using ultrasound to improve cerebrovascular health and prevent cerebrovascular diseases. This study included 27 healthy adults in their 20s (14 males, 13 females). Thermal stimulation using therapeutic ultrasound at a frequency of 3 MHz was applied to the right sternocleidomastoid muscle in the supine posture for 2 min at four intensities (2.4, 5.1, 7.2, and 10.2 W/cm2). Diagnostic ultrasound was used to measure the peak systolic velocity (PSV), heart rate (HR), and pulse wave velocity (PWV) in the right common carotid artery (CCA), and the physiological changes were compared between intervention intensities. Compared to pre-intervention (preI), the PSV showed a significant increase during intervention (durI) at intensities of 7.2 W/cm2 and 10.2 W/cm2 (p = 0.010 and p = 0.021, respectively). Additionally, PWV showed a significant decrease for post-intervention (postI) at 7.2 W/cm2 and 10.2 W/cm2 (p = 0.036 and p = 0.035, respectively). However, the HR showed no significant differences at any of the intensities. The results demonstrate that an intervention at 3 MHz with an intensity of 7.2 W/cm2 or more can substantially increase cerebral blood flow and reduce arterial stiffness. Therefore, the use of therapeutic ultrasound of appropriate intensity is expected to improve the cerebral blood flow and reduce vascular stiffness to maintain cerebral blood flow at a certain level, which is closely related to the prevention and treatment of cerebrovascular diseases, thereby improving cerebrovascular health.

Arterial Aging Best Reflected in Pulse Wave Velocity Measured from Neck to Lower Limbs: A Whole-Body Multichannel Bioimpedance Study.

Pulse wave velocity is a commonly used parameter for evaluating arterial stiffness and the overall condition of the cardiovascular system. The main goal of this study was to establish a methodology to test and validate multichannel bioimpedance as a suitable method for whole-body evaluations of pulse waves. We set the proximal location over the left carotid artery and eight distal locations on both the upper and lower limbs. In this way, it was possible to simultaneously evaluate pulse wave velocity (PWV) in the upper and lower limbs and in the limbs via four extra PWV measurements. Data were acquired from a statistical group of 220 healthy subjects who were divided into three age groups. The data were then analysed. We found a significant dependency of aortic PWV on age in those values measured using the left carotid as the proximal. PWV values in the upper and lower limbs were found to have no significant dependency on age. In addition, the PWV in the left femoral artery shows comparable values to published already carotid-femoral values. Those findings prove the reliability of whole-body multichannel bioimpedance for pulse wave velocity evaluation and provide reference values for whole-body PWV measurement.

Load Position Estimation Method for Wearable Devices Based on Difference in Pulse Wave Arrival Time.

With the increasing use of wearable devices equipped with various sensors, information on human activities, biometrics, and surrounding environments can be obtained via sensor data at any time and place. When such devices are attached to arbitrary body parts and multiple devices are used to capture body-wide movements, it is important to estimate where the devices are attached. In this study, we propose a method that estimates the load positions of wearable devices without requiring the user to perform specific actions. The proposed method estimates the time difference between a heartbeat obtained by an ECG sensor and a pulse wave obtained by a pulse sensor, and it classifies the pulse sensor position from the estimated time difference. Data were collected at 12 body parts from four male subjects and one female subject, and the proposed method was evaluated in both user-dependent and user-independent environments. The average F-value was 1.0 when the number of target body parts was from two to five.

Plasma metabolites associated with arterial stiffness in patients with type 2 diabetes.

BACKGROUND: Although an increased arterial stiffness has been associated with traditional coronary risk factors, the risk factors and pathology of arterial stiffness remain unclear. In this study, we aimed to identify the plasma metabolites associated with arterial stiffness in patients with type 2 diabetes mellitus. METHODS: We used the metabolomic data of 209 patients with type 2 diabetes as the first dataset for screening. To form the second dataset for validation, we enlisted an additional 31 individuals with type 2 diabetes. The non-targeted metabolome analysis of fasting plasma samples using gas chromatography coupled with mass spectrometry and the measurement of brachial-ankle pulse wave velocity (baPWV) were performed. RESULTS: A total of 65 annotated metabolites were detected. In the screening dataset, there were statistically significant associations between the baPWV and plasma levels of indoxyl sulfate (r = 0.226, p = 0.001), mannitol (r = 0.178, p = 0.010), mesoerythritol (r = 0.234, p = 0.001), and pyroglutamic acid (r = 0.182, p = 0.008). Multivariate regression analyses revealed that the plasma levels of mesoerythritol were significantly (ß = 0.163, p = 0.025) and that of indoxyl sulfate were marginally (ß = 0.124, p = 0.076) associated with baPWV, even after adjusting for traditional coronary risk factors. In the independent validation dataset, there was a statistically significant association between the baPWV and plasma levels of indoxyl sulfate (r = 0.430, p = 0.016). However, significant associations between the baPWV and plasma levels of the other three metabolites were not confirmed. CONCLUSIONS/INTERPRETATION: The plasma levels of indoxyl sulfate were associated with arterial stiffness in Japanese patients with type 2 diabetes. Although the plasma levels of mannitol, mesoerythritol, and pyroglutamic acid were also associated with arterial stiffness, further investigation is needed to verify the results.

Vascular age.

Age can be evaluated according to many criteria. Of course the objective measure is the calendar age which may differ from the biological age. The biological age more or less correlates with the vascular age. The concept of vascular age is based on the statement that “An individual is as old as his blood vessels”. The process of vascular aging already starts in childhood. Arterial aging may essentially be viewed from two standpoints. First, it involves stiffening of arteries and loss of their elasticity; second, degenerative changes and formation of atherosclerotic plaques occur, being the cause of ischemia, especially in case of the development of atherothrombosis. Both these processes can be monitored: The change of elasticity (arteriosclerosis) mainly by examination of pulse wave velocity (PWV), atherosclerosis then primarily with non-invasive methods, ultrasound or CT angiography examination. From the clinical point of view it is particularly important whether we can influence vascular age in some way. Evidence is available now that atherosclerosis can be affected by hypolipidemic treatment, arteriosclerosis then in particular by ACE inhibitors. The aforementioned possibility of influencing vascular age brings us to another problem, which is compliance of patients. With regard to that it is good that in a situation where we have two drugs affecting vascular age, we can use their fixed combination. It is available as a combination of atorvastatin and perindopril.

Arterial Stiffness in CKD: A Review.

This narrative review summarizes a decade of experience examining the cross-sectional and longitudinal relationships of arterial stiffness, as assessed using carotid-femoral pulse wave velocity, with outcomes in patients with chronic kidney disease enrolled in the Chronic Renal Insufficiency Cohort. Our goal is to review the importance of the pulse wave contour and pulse wave velocity and present data on the reproducibility of pulse wave velocity measurements, determinants of pulse wave velocity, and the relationship that velocity measurements have with longitudinal kidney and cardiovascular outcomes. Measures of arterial stiffness have contributed substantially to our understanding of mechanisms of cardiovascular disease, kidney disease progression, and all-cause mortality. Given the independent relationship of arterial stiffness to a variety of outcomes, it is our hope that future developments in behavioral, nutritional, and pharmacologic approaches to vascular destiffening will provide interventions that benefit patients with chronic kidney diseases.

Mineralocorticoid Antagonism and Vascular Function in Early Autosomal Dominant Polycystic Kidney Disease: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Vascular dysfunction, characterized by impaired vascular endothelial function and increased large-elastic artery stiffness, is evident early in autosomal dominant polycystic kidney disease (ADPKD) and is an important predictor of cardiovascular events and mortality. Aldosterone excess has been implicated in the development of endothelial dysfunction and arterial stiffness, in part by causing increased oxidative stress and inflammation. We hypothesized that aldosterone antagonism would reduce vascular dysfunction in patients with early-stage ADPKD. STUDY DESIGN: Prospective, randomized, controlled, double-blind, clinical trial. SETTING & PARTICIPANTS: 61 adults aged 20 to 55 years with ADPKD, estimated glomerular filtration rate ≥ 60mL/min/1.73m2, and receiving a renin-angiotensin-aldosterone system inhibitor. INTERVENTION: Spironolactone (maximum dose, 50mg/d) or placebo for 24 weeks. OUTCOMES: Change in brachial artery flow-mediated dilation (FMDBA) was the primary end point and change in carotid-femoral pulse-wave velocity (CFPWV) was the secondary end point. RESULTS: 60 participants completed the trial. Participants had a mean age of 34±10 (SD) years, 54% were women, and 84% were non-Hispanic white. Spironolactone did not change FMDBA (8.0% ± 5.5% and 7.8% ± 4.3% at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 8.4% ± 6.2% and 8.0% ± 4.6%; P=0.9for comparison of change between groups) or CFPWV (640±127 and 603±101cm/s at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 659±138 and 658±131cm/s; P=0.1). Brachial systolic blood pressure was reduced with spironolactone (median change, -6 [IQR, -15, 1] vs -2 [IQR, -7, 10] mm Hg in the placebo group; P=0.04). Spironolactone did not change the majority of circulating and/or endothelial cell markers of oxidative stress/inflammation and did not change vascular oxidative stress. LIMITATIONS: Low level of baseline vascular dysfunction; lack of aldosterone measurements. CONCLUSIONS: 24 weeks of aldosterone antagonism reduced systolic blood pressure without changing vascular function in patients with early-stage ADPKD. FUNDING: NIDDK, NIH National Center for Advancing Translational Sciences, and the Zell Family Foundation. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01853553.

Multi-Site Photoplethysmographic and Electrocardiographic System for Arterial Stiffness and Cardiovascular Status Assessment.

The development and validation of a system for multi-site photoplethysmography (PPG) and electrocardiography (ECG) is presented. The system could acquire signals from 8 PPG probes and 10 ECG leads. Each PPG probe was constituted of a light-emitting diode (LED) source at a wavelength of 940 nm and a silicon photomultiplier (SiPM) detector, located in a back-reflection recording configuration. In order to ensure proper optode-to-skin coupling, the probe was equipped with insufflating cuffs. The high number of PPG probes allowed us to simultaneously acquire signals from multiple body locations. The ECG provided a reference for single-pulse PPG evaluation and averaging, allowing the extraction of indices of cardiovascular status with a high signal-to-noise ratio. Firstly, the system was characterized on optical phantoms. Furthermore, in vivo validation was performed by estimating the brachial-ankle pulse wave velocity (baPWV), a metric associated with cardiovascular status. The validation was performed on healthy volunteers to assess the baPWV intra- and extra-operator repeatability and its association with age. Finally, the baPWV, evaluated via the developed instrumentation, was compared to that estimated with a commercial system used in clinical practice (Enverdis Vascular Explorer). The validation demonstrated the system's reliability and its effectiveness in assessing the cardiovascular status in arterial ageing.

Associations Between Kidney Disease Measures and Regional Pulse Wave Velocity in a Large Community-Based Cohort: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Arterial stiffness is suggested as a mediator of cardiorenal interaction. However, previous studies reported inconsistent associations between chronic kidney disease (CKD) and arterial stiffness and were limited by using either estimated glomerular filtration rate (eGFR) or albumin-creatinine ratio (ACR) and examining arterial stiffness at limited segments. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 3,424 Atherosclerosis in Communities (ARIC) Study participants aged 66 to 90 years during 2011 to 2013. PREDICTORS: eGFR and ACR. OUTCOME: Pulse wave velocity (PWV) at 6 segments: carotid-femoral (cfPWV), heart-carotid (hcPWV), and heart-femoral (hfPWV), reflecting central stiffness; heart-ankle (haPWV) and brachial-ankle (baPWV), representing both central and peripheral stiffness; and femoral-ankle (faPWV), indicating peripheral stiffness. ANALYTICAL APPROACH: Multiple linear and logistic regression models to quantify the associations of eGFR and ACR with continuous PWV and elevated PWV (in the highest quartile), respectively. RESULTS: After adjusting for age, sex, and race, higher cfPWV and hfPWV were consistently associated with lower eGFR and higher ACR. Higher haPWV and baPWV were also observed with higher ACR. The independent association of both CKD measures with elevated cfPWV remained consistent after adjusting for additional confounders (ORs of elevated cfPWV were 1.09 [95% CI, 1.01-1.18] per 15-mL/min/1.73m2 lower eGFR and 1.20 [95% CI, 1.07-1.33] per 4-fold higher ACR). Higher ACR was also associated with elevated hfPWV and haPWV (ORs per 4-fold higher ACR were 1.25 [95% CI, 1.12-1.39] for elevated hfPWV and 1.19 [95% CI, 1.06-1.33] for elevated haPWV). Lower eGFR was associated with lower odds of elevated baPWV and faPWV (ORs per 15-mL/min/1.73m2 lower eGFR were 0.92 [95% CI, 0.84-0.99] and 0.91 [95% CI, 0.85-0.99], respectively). LIMITATION: Unable to address temporality between CKD measures and arterial stiffness. CONCLUSIONS: Both lower eGFR and higher ACR are independently associated with measures of central arterial stiffness, with stronger associations for ACR over eGFR. Our findings suggest that central arterial stiffness may be an important pathophysiologic phenotype of vascular disease in CKD.

Association of Periodontitis and Arterial Stiffness in Type 2 Diabetic Patients.

BACKGROUND: periodontitis is a major cause of chronic infection in diabetic patients. Diabetic patients have four-fold risk of having cardiovascular disease. Chronic inflammation caused by periodontitis, a non-traditional cardiovascular risk factor is widely known to play a major role in atherogenesis. Among non-diabetics, an association has been found between periodontitis and arterial stiffness, but in diabetic patients the result is inconsistent. No study has investigated either the proportion of periodontitis or its correlation with arterial stiffness in type 2 diabetes population in Indonesia. METHODS: this study was a cross-sectional study involving 97 patients with type 2 diabetics, who were recruited on Endocrinology Clinic from April to August 2017. Periodontitis was measured for pocket depth, clinical attachment loss and bleeding on probing by a periodontist. Carotid-femoral PWV (Pulse Wave Velocity) was measured using SphygmoCor Xcel with cuff-based tonometry technique. RESULTS: periodontitis was found in 99% type 2 diabetic subjects and 78% of them had severe periodontitis. There was no significant correlation found between pocket depth, clinical attachment loss and cfPWV (r=0.024, p=0.407 and r=0.011, p=0.456); whereas there was a weak positive correlation between pocket depth and PWV (r=0.294, p=0.041) in well-controlled type 2 diabetics. CONCLUSION: most of type-2 diabetics had severe periodontitis; however, the correlation between periodontitis and arterial stiffness could not be concluded in this study.

Noninvasive Regional Aortic Stiffness for Monitoring the Early Stage of Abdominal Aortic Aneurysm in Mice.

BACKGROUND: Abdominal aortic aneurysm (AAA) affects more than 5% of the population in developed countries. To study the formation and progression of AAA, we developed a non-invasive method to analyse regional aortic stiffness to monitor the formation and progression of AAA. METHODS: Saline or Angiotensin II (AngII) was subcutaneously infused in apolipoprotein E knockout (ApoE-/-) mice for 28 days; a high-resolution imaging system was used to identify changes in arterial stiffness measured by pulse-wave velocity (PWV) and aortic lumen diameter in the suprarenal aorta. RESULTS: Both regional PWV and luminal diameter in the suprarenal aorta did not change significantly in saline-treated ApoE-/- mice for 28 days. In contrast, AngII treatment for 28 days rapidly increased both regional PWV and luminal diameter. The difference in luminal diameter could be identified at 14 days. However, regional PWV significantly increased within the first 7 days after AngII perfusion as compared with saline treatment. However, in ApoE-/- diabetic mice, both regional PWV and aortic diameter did not differ between AngII and saline treatment at 7 or 28 days. CONCLUSIONS: Regional PWV may be used to monitor AAA development and was improved after AngII infusion in ApoE-/- mice.

CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is an independent risk factor for hypertension, coronary artery disease, and diabetes mellitus. Epicardial fat has been recently recognized as a new risk factor and active participant on cardiometabolic risk. The aim of this study was to assess an independent relationship between sleep apnea severity, metabolic and vascular markers, and epicardial fat, at baseline and after 3 months of continuous positive airway pressure (CPAP) therapy. MATERIALS AND METHOD: Our study group consisted of 48 patients with suspected OSAHS and no prior history of cardiovascular disease or diabetes mellitus. All patients underwent full overnight polysomnography. Thickness of epicardial and visceral adipose tissue, brachial artery flow-mediated dilation (FMD), carotid intima media thickness (cIMT), pulse wave velocity (PWV), plasma C-reactive protein (CRP) levels, fasting glucose levels, HbA1c, homeostatic model assessment of insulin resistance index (HOMA), and lipid profile were measured at baseline and after 3 months of CPAP use in patients with moderate to severe OSAHS. RESULTS: In OSAHS patients (Apnea-hypopnea index (AHI) ≥15/h, N = 28), epicardial fat correlated with fasting glucose (rho = 0.406, p = 0.04) and HOMA (rho = 0.525, p = 0.049) but was not associated with visceral fat (rho = 0.126, p = 0.595). Epicardial adipose tissue (EAT) (p = 0.022) increased across AHI severity along with PWV (p = 0.045) and carotid intima media thickness (IMT) (p = 0.034) while FMD (p = 0.017) decreased. Therapy with CPAP reduced both epicardial (p < 0.001) and visceral fat (p = 0.001). Alterations in epicardial fat across the follow-up were associated with changes in PWV (p = 0.026) and HOMA (p = 0.037) independently of major confounders. CONCLUSIONS: Epicardial fat thickness was associated with OSA severity and may be an additional marker of cardiovascular risk as well as of future diabetes in these patients. CPAP therapy reduced epicardial fat, suggesting its potentially beneficial role in reducing cardiometabolic risk in OSA patients.

Rationale and study design of the prospective, longitudinal, observational cohort study "rISk strAtification in end-stage renal disease" (ISAR) study.

BACKGROUND: The ISAR study is a prospective, longitudinal, observational cohort study to improve the cardiovascular risk stratification in endstage renal disease (ESRD). The major goal is to characterize the cardiovascular phenotype of the study subjects, namely alterations in micro- and macrocirculation and to determine autonomic function. METHODS/DESIGN: We intend to recruit 500 prevalent dialysis patients in 17 centers in Munich and the surrounding area. Baseline examinations include: (1) biochemistry, (2) 24-h Holter Electrocardiography (ECG) recordings, (3) 24-h ambulatory blood pressure measurement (ABPM), (4) 24 h pulse wave analysis (PWA) and pulse wave velocity (PWV), (5) retinal vessel analysis (RVA) and (6) neurocognitive testing. After 24 months biochemistry and determination of single PWA, single PWV and neurocognitive testing are repeated. Patients will be followed up to 6 years for (1) hospitalizations, (2) cardiovascular and (3) non-cardiovascular events and (4) cardiovascular and (5) all-cause mortality. DISCUSSION/CONCLUSION: We aim to create a complex dataset to answer questions about the insufficiently understood pathophysiology leading to excessively high cardiovascular and non-cardiovascular mortality in dialysis patients. Finally we hope to improve cardiovascular risk stratification in comparison to the use of classical and non-classical (dialysis-associated) risk factors and other models of risk stratification in ESRD patients by building a multivariable Cox-Regression model using a combination of the parameters measured in the study. CLINICAL TRIALS IDENTIFIER: ClinicalTrials.gov NCT01152892 (June 28, 2010).

A genetic marker of uric acid level, carotid atherosclerosis, and arterial stiffness: a family-based study.

BACKGROUND: Hyperuricemia associates with atherosclerosis complications, but it is uncertain whether this relationship is causal in nature. The urate transporter GLUT9 (encoded by the SLC2A9 gene) is a major genetic determinant of serum uric acid level in humans. Because polymorphisms are distributed randomly at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and atherosclerosis. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Family-based study including 449 individuals in 107 families in a genetically homogeneous population in Southern Italy. FACTOR: Serum uric acid level, rs734553 allele, and age. OUTCOME: Ultrasound biomarkers of atherosclerosis (intima-media thickness [IMT] and internal diameter) and pulse wave velocity (PWV). RESULTS: Serum uric acid level was dose-dependently associated with the T allele of rs734553, a polymorphism in SLC2A9 (P=8×10(-6)). Serum uric acid level was a strong modifier of the relationship between age and IMT in fully adjusted analyses (ß=0.33; P=0.01), whereas no such relationship was found for internal diameter (ß=-0.15; P=0.3) or PWV (ß=0.10; P=0.6). The T allele coherently associated with carotid IMT, internal diameter, and PWV and emerged as an even stronger modifier of the age-IMT and age-internal diameter relationships in both crude and fully adjusted (ß=0.40 [P<0.001] and ß=0.48 [P=0.003], respectively) analyses. LIMITATIONS: This is a hypothesis-generating study. CONCLUSIONS: Results in this family-based study implicate uric acid as an important modifier of the age-dependent risk for atherosclerosis. Trials testing uric acid-lowering interventions are needed to prove this hypothesis.

Aerobic or Resistance Training and Pulse Wave Velocity in Kidney Transplant Recipients: A 12-Week Pilot Randomized Controlled Trial (the Exercise in Renal Transplant [ExeRT] Trial).

BACKGROUND: Cardiovascular disease remains the leading cause of death in kidney transplant recipients. This pilot study examined the potential effect of aerobic training or resistance training on vascular health and indexes of cardiovascular risk in kidney transplant recipients. STUDY DESIGN: Single-blind, randomized, controlled, parallel trial. SETTING & PARTICIPANTS: 60 participants (mean age, 54 years; 34 men) were randomly assigned to aerobic training (n=20), resistance training (n=20), or usual care (n=20). Participants were included if they had a kidney transplant within 12 months prior to baseline assessment. Patients were excluded if they had unstable medical conditions or had recently started regular exercise. INTERVENTION: Aerobic training and resistance training were delivered 3 days per week for a 12-week period. The usual-care group received standard care. OUTCOMES & MEASUREMENTS: Pulse wave velocity, peak oxygen uptake (Vo2peak), sit-to-stand 60, isometric quadriceps force, and inflammatory biomarkers were assessed at 0 and 12 weeks. RESULTS: The anticipated 60 participants were recruited within 12 months. 46 participants completed the study (aerobic training, n=13; resistance training, n=13; and usual care, n=20), resulting in a 23% attrition rate. Analyses of covariance, adjusted for baseline values, age, and dialysis vintage pretransplantation, revealed significant mean differences between aerobic training and usual care in pulse wave velocity of -2.2±0.4 (95% CI, -3.1 to -1.3) m/s (P<0.001) and between resistance training and usual care of -2.6±0.4 (95% CI, -3.4 to -1.7) m/s (P<0.001) at 12 weeks. Secondary analyses indicated significant improvements in Vo2peak in the aerobic training group and in Vo2peak, sit-to-stand 60, and isometric muscle force in the resistance training group compared with usual care at 12 weeks. There were no reported adverse events, cardiovascular events, or hospitalizations as a result of the intervention. LIMITATIONS: Pilot study, small sample size, no measure of endothelial function. CONCLUSIONS: Both aerobic training and resistance training interventions appear to be feasible and clinically beneficial in this patient population.

Reduced Cardiovascular Reserve in Chronic Kidney Failure: A Matched Cohort Study.

BACKGROUND: Patients with chronic kidney failure (CKF) experience impaired functional cardiovascular reserve with reduced oxygen consumption at peak exercise (VO(2peak)). No studies have examined whether this is related to impaired cardiovascular compliance as a consequence of loss of adaptive structural alterations, resulting from chronic uremia or hypertension. STUDY DESIGN: Prospective matched-cohort study. SETTING & PARTICIPANTS: We assessed CKF in parallel with patients with essential hypertension but without cardiovascular disease. Patients with CKF were either scheduled for kidney transplantation or transplant waitlisted. 80 patients with CKF and 80 with essential hypertension matched in age, sex, and body mass index were evaluated. 61 patients with CKF (76.3%) were dialysis dependent. PREDICTOR: CKF versus essential hypertension without cardiovascular disease. MEASUREMENTS & OUTCOMES: VO(2peak) was measured during maximal exercise testing. 2-dimensional echocardiography and arterial applanation tonometry were performed prior to exercise testing. To evaluate for the difference in VO(2peak) between study groups, statistically significant predictors of VO(2peak) in multiple regression models were additionally assessed by fitting models comprising the interaction term of patient group with the predictor variable of interest. RESULTS: VO(2peak) was significantly lower in patients with CKF than those with essential hypertension (18.8 vs 24.5 mL/min·kg; P<0.001). Independent predictors of VO(2peak) for CKF included left ventricular (LV) filling pressure (E/mean e'; unstandardized regression coefficient: change in VO(2peak) [in mL/min·kg] per 1-unit change of variable = -5.1) and pulse wave velocity (-4.0); in essential hypertension, these were LV mass index (0.2), LV end-diastolic volume index (0.4), peak heart rate (0.2), and pulse wave velocity (-8.8). The interaction effect of VO(2peak) between patient groups with LV mass index (P<0.001), LV end-diastolic volume index (P<0.001), and peak heart rate (P<0.01) were significantly stronger in the hypertension group, whereby higher values led to greater VO(2peak). LIMITATIONS: Skeletal muscle strength was not assessed. CONCLUSION: This study suggests that maladaptive LV changes, as well as blunted chronotropic response, are important mechanistic factors resulting in reduced cardiovascular reserve in patients with CKF, beyond predominantly vascular changes associated with hypertension.

Aortic Stiffness, Ambulatory Blood Pressure, and Predictors of Response to Antihypertensive Therapy in Hemodialysis.

BACKGROUND: Arterial stiffness is associated with elevated blood pressure (BP), but it is unclear whether it also makes hypertension more resistant to treatment. Among hypertensive dialysis patients, this study investigated whether aortic stiffness determines ambulatory BP and predicts its improvement with therapy. STUDY DESIGN: Post hoc analysis of the Hypertension in Hemodialysis Patients Treated With Atenolol or Lisinopril (HDPAL) trial. SETTINGS & PARTICIPANTS: 179 hypertensive hemodialysis patients with echocardiographic left ventricular hypertrophy. PREDICTOR: Baseline aortic pulse wave velocity (PWV). OUTCOME: Baseline and treatment-induced change in 44-hour ambulatory BP at 3, 6, and 12 months. MEASUREMENTS: Aortic PWV was assessed with an echocardiographic-Doppler technique (ACUSON Cypress, Siemens Medical), and 44-hour interdialytic ambulatory BP monitoring was performed with a Spacelabs 90207 monitor. RESULTS: Mean baseline aortic PWV was 7.6±2.7 (SD) m/s. Overall treatment-induced changes in ambulatory systolic BP (SBP) were -15.6±20.4, -18.9±22.5, and -20.0±19.7 mmHg at 3, 6, and 12 months. Changes in SBP were no different among tertiles of baseline PWV. Aortic PWV was associated directly with baseline ambulatory SBP and pulse pressure (PP) and inversely with diastolic BP (DBP). After adjustment for several cardiovascular risk factors, each 1-m/s higher PWV was associated with 1.34-mm Hg higher baseline SBP (ß=1.34±0.46; P=0.004) and 1.02-mm Hg higher PP (ß=1.02±0.33; P=0.002), whereas the association with DBP was no longer significant. Baseline PWV did not predict treatment-induced changes in SBP (Wald test, P=0.3) and DBP (Wald test, P=0.7), but was a predictor of an overall improvement in PP during follow-up (Wald test, P=0.03). LIMITATIONS: Observational design; predominantly black patients were studied. CONCLUSIONS: Because aortic PWV is not a predictor of treatment-induced change in ambulatory BP among hypertensive dialysis patients, it indicates that among these patients, hypertension can be controlled successfully regardless of aortic stiffness.

Effect of exercise training on estimated GFR, vascular health, and cardiorespiratory fitness in patients with CKD: a pilot randomized controlled trial.

BACKGROUND: Exercise capacity, which is predictive of all-cause mortality and cardiovascular disease risk, is reduced significantly in patients with non-dialysis-dependent chronic kidney disease. This pilot study examined the effect of moderate-intensity exercise training on kidney function and indexes of cardiovascular risk in patients with progressive chronic kidney disease stages 3 to 4. STUDY DESIGN: Single-blind, randomized, controlled, parallel trial. SETTING & PARTICIPANTS: 20 patients (aged 18-80 years; 17 men) randomly assigned to rehabilitation (n=10) or usual care (n=10). Participants were included if they were 18 years or older and had evidence of rate of decline in creatinine-based estimated glomerular filtration rate (eGFRcr)≥2.9mL/min/1.73m(2) per year for 12 months preintervention. Patients were excluded if they had unstable medical conditions or had recently started regular exercise. INTERVENTION: The rehabilitation group received resistance and aerobic training (3 days per week) for a 12-month period. The usual care group received standard care. OUTCOMES: Kidney function assessed by comparing mean rate of change in eGFRcr (mL/min/1.73m(2) per year) from a 12-month preintervention period against the 12-month intervention period. Pulse wave velocity (PWV), peak oxygen uptake (Vo2peak), and waist circumference assessed at 0, 6, and 12 months. MEASUREMENTS: eGFR assessed using creatinine, cystatin C (eGFRcys), and a combination of both values (eGFRcr-cys). RESULTS: 18 participants (rehabilitation, 8; usual care, 10) completed the study. A significant mean difference in rate of change in eGFRcr (+7.8±3.0 [95% CI, 1.1-13.5] mL/min/1.73m(2) per year; P=0.02) was observed between the rehabilitation and usual care groups, with the rehabilitation group demonstrating a slower decline. No significant between-group mean differences existed in absolute eGFRcr, eGFRcr-cys, or eGFRcys at 12 months of study intervention. Significant between-group mean differences existed in PWV (-2.30 [95% CI, -3.02 to -1.59] m/s), waist circumference (-7.1±12.8 [95% CI, -12.4 to -3.2] cm), and Vo2peak (5.7 [95% CI, 1.34-10.10] mL/kg/min). Change in eGFRcr was correlated inversely with PWV (r=-0.5; P=0.04) at 12 months. LIMITATIONS: Small sample size, inconsistency between primary and secondary measures of kidney function. CONCLUSIONS: The effect of a 1-year exercise intervention on progression of kidney disease is inconclusive. A larger study with longer follow-up may be necessary.