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Background Elevated level of plasma uric acid (PUA) has been associated with cardiovascular disease, but whether uric acid is an independent risk factor or merely a marker remains controversial. Methods We investigated in a cross-sectional setting the association of PUA with hemodynamics in 606 normotensive and never-medicated hypertensive subjects (295 men, 311 women, age range 19–73 years) without cardiovascular disease or gout. In all except 15 individuals, PUA was within the normal range. Supine hemodynamics were recorded using whole-body impedance cardiography and radial tonometric pulse wave analysis. Results The mean concentrations of PUA in age, sex and body mass index adjusted quartiles were 234, 278, 314, and 373 µmol/l, respectively. The highest PUA quartile presented with higher aortic to popliteal pulse wave velocity (PWV) than the lowest quartile (8.7 vs. 8.2 m/s, p = 0.026) in analyses additionally adjusted for plasma concentrations of C-reactive protein, low density lipoprotein cholesterol, triglycerides, and mean aortic blood pressure. No differences in radial and aortic blood pressure, wave reflections, heart rate, cardiac output, and systemic vascular resistance were observed between the quartiles. In linear regression analysis, PUA was an independent explanatory factor for PWV (β = 0.168, p 2 of the model 0.591), but not for systolic or diastolic blood pressure. When the regression analysis was performed separately for men and women, PUA was an independent predictor of PWV in both sexes. Conclusions PUA concentration was independently and directly associated with large arterial stiffness in individuals without cardiovascular disease and PUA levels predominantly within the normal range. Trial registration ClinicalTrials.gov NCT01742702.

OBJECTIVES: Most studies about upright regulation of blood pressure have focused on orthostatic hypotension despite the diverse hemodynamic changes induced by orthostatic challenge. We investigated the effect of passive head-up tilt on aortic blood pressure. METHODS: Noninvasive peripheral and central hemodynamics in 613 volunteers without cardiovascular morbidities or medications were examined using pulse wave analysis, whole-body impedance cardiography and heart rate variability analysis. RESULTS: In all participants, mean aortic SBP decreased by -4 (-5 to -3) mmHg [mean (95% confidence intervals)] and DBP increased by 6 (5--6) mmHg in response to upright posture. When divided into tertiles according to the supine-to-upright change in aortic SBP, two tertiles presented with a decrease [-15 (-14 to -16) and -4 (-3 to -4) mmHg, respectively] whereas one tertile presented with an increase [+7 (7-- 8) mmHg] in aortic SBP. There were no major differences in demographic characteristics between the tertiles. In regression analysis, the strongest explanatory factors for upright changes in aortic SBP were the supine values of, and upright changes in systemic vascular resistance and cardiac output, and supine aortic SBP. CONCLUSION: In participants without cardiovascular disease, the changes in central SBP during orthostatic challenge are not uniform. One-third presented with higher upright than supine aortic SBP with underlying differences in the regulation of systemic vascular resistance and cardiac output. These findings emphasize that resting blood pressure measurements give only limited information about the blood pressure status. publishedVersion

Purpose: The underlying causes of primary hypertension are not fully understood. Evidence on the relation of plasma calcium concentration with blood pressure (BP) is inconsistent and relies largely...

Parathyroid hormone has been related with the risk of hypertension, but the matter remains controversial. We examined the association of parathyroid hormone with central blood pressure and its determinants in 622 normotensive or never-treated hypertensive subjects aged 19–72 years without diabetes, cardiovascular or renal disease, or cardiovascular medications. The methods were whole-body impedance cardiography and analyses of pulse wave and heart rate variability. Cardiovascular function was examined in sex-specific tertiles of plasma parathyroid hormone (mean concentrations 3.0, 4.3 and 6.5 pmol/L, respectively) during head-up tilt. Explanatory factors for haemodynamics were further investigated using linear regression analyses. Mean age was 45.0 (s.d. 11.7) years, BMI 26.8 (4.4) kg/m2, seated office blood pressure 141/90 (21/12) mmHg, and 309 subjects (49.7%) were male. Only five participants had elevated plasma parathyroid hormone and calcium concentrations. Highest tertile of parathyroid hormone presented with higher supine and upright aortic diastolic blood pressure (P < 0.01) and augmentation index (P < 0.01), and higher upright systemic vascular resistance (P < 0.05) than the lowest tertile. The tertiles did not present with differences in pulse wave velocity, cardiac output, or measures of heart rate variability. In linear regression analyses, parathyroid hormone was an independent explanatory factor for aortic systolic (P = 0.005) and diastolic (P = 0.002) blood pressure, augmentation index (P = 0.002), and systemic vascular resistance (P = 0.031). To conclude, parathyroid hormone was directly related to central blood pressure, wave reflection, and systemic vascular resistance in subjects without cardiovascular comorbidities and medications. Thus, parathyroid hormone may play a role in the pathophysiology of primary hypertension.

Aldosterone-to-renin ratio (ARR) is a screening tool for primary aldosteronism (PA), but the significance of ARR when the PA criteria are not met remains largely unknown. In this cross-sectional study we investigated the association of ARR with haemodynamic variables in 545 normotensive and never-medicated hypertensive subjects (267 men, 278 women, age range 19–72 years) without suspicion of PA. Supine haemodynamic data was recorded using whole-body impedance cardiography and radial tonometric pulse wave analysis. In sex-adjusted quartiles of ARR, determined as serum aldosterone to plasma renin activity ratio, the mean values were 282, 504, 744 and 1467 pmol/µg of angiotensin I/h, respectively. The only difference in haemodynamic variables between the ARR quartiles was higher pulse wave velocity (PWV) in the highest quartile versus other quartiles (p = 0.004), while no differences in blood pressure (BP), heart rate, wave reflections, cardiac output or systemic vascular resistance were observed between the quartiles. In linear regression analysis with stepwise elimination, ARR was an independent explanatory factor for PWV (β = 0.146, p 2 of the model 0.634). In conclusion, ARR was directly and independently associated with large arterial stiffness in individuals without clinical suspicion of PA. Therefore, ARR could serve as a clinical marker of cardiovascular risk.Trial registration: ClinicalTrails.gov: NCT01742702.

Background: Telomeres are short segments in chromosome ends, the length of which is reduced during cell life-cycles. We examined the association of leukocyte telomere length and short telomere proportion with hemodynamic variables. Methods: Altogether 566 subjects (279 women and 287 men) without cardiovascular disease and medications with direct cardiovascular influences were subjected supine recordings for 5 minutes. Haemodynamics were captured using continuous tonometric pulse wave analysis and whole-body impedance cardiography. The analyses were adjusted for age, body mass index (BMI), alcohol use, smoking, plasma chemistry, and estimated glomerular filtration rate (eGFR). Results: In univariate analyses, leukocyte telomere length correlated with age, BMI, eGFR, aortic blood pressure, augmentation index, pulse wave velocity, and systemic vascular resistance (p < 0.05 for all). Short telomere proportion correlated with age, BMI, eGFR, aortic systolic blood pressure, augmentation index, and pulse wave velocity (p < 0.05 for all). In linear regression analyses of all hemodynamic variables, leukocyte telomere length was only an independent explanatory factor for augmentation index (Beta −0.006, p = 0.032), while short telomere proportion was not an explanatory factor for any of the hemodynamic variables, in contrast to age, BMI and several cardiovascular risk factors. Conclusion: Augmentation index was predominantly related with chronological aging, but also with leukocyte telomere length, suggesting that this variable of central wave reflection is a moderate marker of vascular biological aging.

BACKGROUND: The diagnostics of primary aldosteronism (PA) are usually carried out in patients taking antihypertensive medications. We compared haemodynamics between medicated PA, medicated essential hypertension (EH), never-medicated EH and normotensive controls (n = 130 in all groups). METHODS: The hypertensive groups were matched for age (53 years), sex (84 male/46 female) and body mass index (BMI) (30 kg m-2 ); normotensive controls had similar sex distribution (age 48 years, BMI 27 kg m-2 ). Haemodynamics were recorded using whole-body impedance cardiography and radial pulse wave analysis, and the results were adjusted as appropriate. Radial blood pressure recordings were calibrated by brachial blood pressure measurements from the contralateral arm. RESULTS: Radial and aortic systolic and diastolic blood pressure was similar in PA and never-medicated EH, and higher than in medicated EH and normotensive controls (P ≤ 0.001 for all comparisons). Extracellular water balance was ~ 4% higher in PA than in all other groups (P < 0.05 for all), whilst cardiac output was ~ 8% higher in PA than in medicated EH (P = 0.012). Systemic vascular resistance and augmentation index were similarly increased in PA and both EH groups when compared with controls. Pulse wave velocity was higher in PA and never-medicated EH than in medicated EH and normotensive controls (P ≤ 0.033 for all comparisons). CONCLUSIONS: Medicated PA patients presented with corresponding systemic vascular resistance and wave reflection, but higher extracellular water volume, cardiac output and arterial stiffness than medicated EH patients. Whether the systematic evaluation of these features would benefit the clinical diagnostics of PA remains to be studied in future. publishedVersion

Telomeres are short segments in chromosome ends, the length of which is reduced during cell lifecycles. We examined the association of mean leukocyte telomere length (LTL) and short telomere proportion (STP) with hemodynamic variables in normotensive and never-treated hypertensive volunteers (n=566, 19-72 years). STP and mean LTL were determined using Southern blotting, and supine hemodynamics recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. The analyses were adjusted for age, body mass index (BMI), alcohol use, smoking, plasma chemistry, and estimated glomerular filtration rate (eGFR). In univariate analyses, mean LTL and STP both correlated with age, BMI, eGFR, aortic blood pressure, augmentation index, and pulse wave velocity (p

Background Resting heart rate (HR) and its variability (HRV) reflect cardiac sympathovagal balance that can stimulated by head-up tilting. HRV is significantly influenced by the level of HR, but how much HRV offers additional information about cardiac autonomic tone than HR alone remains unresolved. We examined the relation of resting HR with short term HRV during passive head-up tilt.Methods Hemodynamics of 569 subjects without medications with direct cardiovascular effects and known cardiovascular diseases were recorded using whole-body impedance cardiography, continuous radial pulse wave analysis and electrocardiography based HRV analysis in supine and upright positions. For statistical analyses the study population was divided into tertiles of resting heart rate according to sexes.Results Higher low frequency to high frequency ratio (LF/HF) of HRV (reflecting sympathovagal balance) was associated with higher HR in supine (p

Background and aim: Low density lipoprotein cholesterol (LDL-C) is a primary risk factor for atherosclerosis, but it is also associated with elevated blood pressure (BP) and future development of hypertension. We examined the relationship between LDL-C and haemodynamic variables in normotensive and never-treated hypertensive subjects. Methods: We recruited 615 volunteers (19–72 years) without lipid-lowering and BP-lowering medication. Supine haemodynamics were recorded using continuous radial pulse wave analysis, whole-body impedance cardiography, and single channel electrocardiogram. The haemodynamic relations of LDL-C were examined using linear regression analyses with age, sex, body mass index (BMI) (or height and weight as appropriate), smoking status, alcohol use, and plasma C-reactive protein, sodium, uric acid, high density lipoprotein cholesterol (HDL-C), triglycerides, estimated glomerular filtration rate, and quantitative insulin sensitivity check index as the other included variables. Results: The mean (SD) characteristics of the subjects were: age 45 (12) years, BMI 27 (4) kg/m2, office BP 141/89 (21/13) mmHg, creatinine 74 (14) µmol/l, total cholesterol 5.2 (1.0), LDL-C 3.1 (0.6), triglycerides 1.2 (0.8), and HDL-C 1.6 (0.4) mmol/l. LDL-C was an independent explanatory factor for aortic systolic and diastolic BP, augmentation index, pulse wave velocity (PWV), and systemic vascular resistance index (p Conclusions: LDL-C is independently associated with BP via systemic vascular resistance and wave reflection. These results suggest that LDL-C may play a role in the pathogenesis of primary hypertension.

Background and Aim: Low density lipoprotein cholesterol (LDL-C) is a primary risk factor for atherosclerosis, but it is also associated with elevated blood pressure (BP) and future development of hypertension. We examined the relationship between LDL-C and haemodynamic variables in normotensive and never-treated hypertensive subjects. Methods: Altogether 615 volunteers (19–72 years) without lipid- and BP-lowering medication were recruited. Supine haemodynamics were recorded using continuous radial pulse wave analysis, whole-body impedance cardiography, and single channel electrocardiogram. The haemodynamic relations of LDL-C were examined using linear regression analyses with age, sex, body mass index (BMI) (or height and weight as appropriate), smoking status, alcohol use, and plasma C-reactive protein, sodium, uric acid, high density lipoprotein cholesterol (HDL-C), triglycerides, estimated glomerular filtration rate, and quantitative insulin sensitivity check index as the other included variables. Results: The mean (SD) characteristics of the subjects were: age 45 (12) years, BMI 27 (4) kg/m2, office BP 141/89 (21/13) mmHg, creatinine 74 (14) μmol/l, total cholesterol 5.2 (1.0), LDL-C 3.1 (0.6), triglycerides 1.2 (0.8), and HDL-C 1.6 (0.4) mmol/l. LDL-C was an independent explanatory factor for aortic systolic and diastolic BP, aortic pulse pressure, augmentation index, pulse wave velocity (PWV), and systemic vascular resistance index (p ≤ 0.013 for all). When central BP was included in the model for PWV, LDL-C was no more an explanatory factor for PWV. Conclusions: LDL-C is independently associated with BP via systemic vascular resistance and wave reflection. These results suggest that LDL-C may play a role in the pathogenesis of primary hypertension.

Treatment with beta-blockers appears to show inferior reduction in central versus peripheral blood pressure. We aimed to examine simultaneous changes in central and peripheral blood pressure, vascular resistance, cardiac function and arterial stiffness during beta-blockade. Haemodynamics were investigated after 3 weeks of bisoprolol treatment (5 mg/day) in a double-blind, randomized, placebo-controlled cross-over trial in never-treated 16 Caucasian males with grade I-II primary hypertension using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Bisoprolol decreased radial (134/80 versus 144/89 mmHg) and aortic blood pressure (122/80 versus 130/90 mmHg) and heart rate (57 versus 68 beats/min) when compared with placebo (p < 0.05 for all). Ejection duration (336 versus 316 ms) and stroke volume (109 versus 98 ml) were increased (p < 0.01 for all), while cardiac output was not significantly changed (6.2 versus 6.6 l/min). Bisoprolol decreased pulse wave velocity (7.8 versus 8.9 m/s, p < 0.001), but after adjustment for blood pressure, the decrease was not significant (8.16 versus 8.52 m/s, p = 0.464). The treatment reduced pulse pressure amplification from central to peripheral circulation (30 versus 38%, p = 0.002). No differences were observed in systemic vascular resistance, augmentation index, aortic characteristic impedance or total arterial stiffness after bisoprolol versus placebo. Bisoprolol decreased central and peripheral blood pressure and pulse wave velocity in male individuals with grade I to grade II hypertension. The decrease in pulse wave velocity was related to the antihypertensive effect. Reduced pulse pressure amplification indicates that peripheral blood pressure was reduced more efficiently than central blood pressure.

Background: Men and women differ in the risk of cardiovascular disease, but the underlying mechanisms are not completely understood. We examined possible sex-related differences in supine and upright cardiovascular regulation. Methods: Hemodynamics were recorded from 167 men and 167 women of matching age (∼45 years) and body mass index (∼26.5 kg/m2) during passive head-up tilt. None had diabetes, cardiovascular disease other than hypertension, or antihypertensive medication. Whole-body impedance cardiography, tonometric radial blood pressure, and heart rate variability were analyzed. Results were adjusted for height, smoking, alcohol intake, mean arterial pressure, plasma lipids and glucose. Results: Supine hemodynamic differences were minor: lower heart rate (−4%) and higher stroke volume (+7.5%) in men than women (p55 years). Heart rate variability analyses showed higher low frequency to high frequency ratio in supine (p

Background Augmentation index, a marker of central wave reflection, is influenced by age, sex, height, blood pressure, heart rate, and arterial stiffness. However, the detailed haemodynamic determinants of augmentation index, and their relations, remain uncertain. We examined the association of augmentation index with vascular resistance and other haemodynamic and non-haemodynamic factors. Methods Background information, laboratory values, and haemodynamics of 488 subjects (239 men, 249 women) without antihypertensive medication were obtained. Indices of central wave reflection, systemic vascular resistance, cardiac function, and pulse wave velocity were measured using continuous radial pulse wave analysis and whole-body impedance cardiography. Results In a regression model including only haemodynamic variables, augmentation index in males and female subjects, respectively, was associated with systemic vascular resistance (β = 0.425, β = 0.336), pulse wave velocity (β = 0.409, β = 0.400) (P

Background In a cross-sectional study we examined whether the haemodynamic response to upright posture could be divided into different functional phenotypes, and whether the observed phenotypes were associated with known determinants of cardiovascular risk. Methods Volunteers (n = 470) without medication with cardiovascular effects were examined using radial pulse wave analysis, whole-body impedance cardiography, and heart rate variability analysis. Based on the passive head-up tilt induced changes in systemic vascular resistance and cardiac output, the principal determinants of blood pressure, a cluster analysis was performed. Results The haemodynamic response could be clustered into 3 categories: upright increase in vascular resistance and decrease in cardiac output were greatest in the first (+45 % and -27 %, respectively), smallest in the second (+2 % and -2 %, respectively), and intermediate (+22 % and -13 %, respectively) in the third group. These groups were named as ‘constrictor’ (n = 109), ‘sustainer’ (n = 222), and ‘intermediate’ (n = 139) phenotypes, respectively. The sustainers were characterized by male predominance, higher body mass index, blood pressure, and also by higher pulse wave velocity, an index of large arterial stiffness, than the other groups (p

Background Men and women differ in the risk of cardiovascular disease, but the underlying mechanisms are not completely understood. We examined possible sex‐related differences in supine and upright cardiovascular regulation. Methods and Results Hemodynamics were recorded from 167 men and 167 women of matching age (≈45 years) and body mass index (≈26.5) during passive head‐up tilt. None had diabetes mellitus or cardiovascular disease other than hypertension or used antihypertensive medication. Whole‐body impedance cardiography, tonometric radial blood pressure, and heart rate variability were analyzed. Results were adjusted for height, smoking, alcohol intake, mean arterial pressure, plasma lipids, and glucose. Supine hemodynamic differences were minor: Men had lower heart rate (−4%) and higher stroke index (+7.5%) than women ( P P 55 years). Heart rate variability analyses showed higher low:high frequency ratios in supine ( P P =0.003) positions in men. Conclusions The foremost difference in cardiovascular regulation between sexes was higher upright hemodynamic workload for the heart in men, a finding not explained by known cardiovascular risk factors or hormonal differences before menopause. Heart rate variability analyses indicated higher sympathovagal balance in men regardless of body position. The deviations in upright hemodynamics could play a role in the differences in cardiovascular risk between men and women. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT 01742702.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Nitrates may facilitate syncope through various pathways, but the precise mechanism of nitrate-induced syncope is still under debate. The purpose of the present study was to compare the underlying haemodynamic mechanisms in subjects without and with presyncopal symptoms during a nitroglycerin-stimulated tilt-table test. WHAT THIS STUDY ADDS • A major decrease in systemic vascular resistance was documented in subjects with presyncope during 0.25 mg nitroglycerin-stimulated tilt-table test, in the absence of changes in cardiac output. These findings indicated that even a small dose of nitroglycerin significantly decreased arterial resistance and cardiac afterload. AIMS The mechanism of nitrate-induced syncope remains controversial. We examined the haemodynamic changes in healthy volunteers during nitroglycerin-stimulated tilt-table test. METHODS Continuous radial pulse wave analysis, whole-body impedance cardiography and plethysmographic finger blood pressure were recorded in a supine position and during head-up tilt in 21 subjects with presyncopal symptoms (6 male/15 female, age 43 ± 3 years) after 0.25 mg sublingual nitroglycerin and 21 control subjects (6 male/15 female, age 43 ± 2 years). The drug was administered in the supine position and a passive head-up tilt followed 5 min later. Additionally, nitroglycerin was only administered during head-up tilt in 19 subjects and the haemodynamics were recorded. RESULTS Supine and upright haemodynamics were similar before nitroglycerin administration in the two groups. During the nitroglycerin-stimulated tilt test, aortic and radial mean blood pressure decreased significantly more in the presyncope group when compared with the controls (P= 0.0006 and P= 0.0004, respectively). The decreases in systemic vascular resistance (P= 0.0008) and heart rate (P= 0.002), and increase in aortic reflection time (P= 0.0002) were greater in the presyncope group, while the change in cardiac index was not different between the groups (P= 0.14). If nitroglycerin was administered during the upright tilt and not in supine position, the haemodynamic changes were quite corresponding. CONCLUSIONS Presyncopal symptoms during nitrate-stimulated tilt test were explained by decreased systemic vascular resistance and increased aortic reflection time, while cardiac output remained unchanged. These findings indicated reduced arterial resistance in nitroglycerin-induced presyncope.

Background: The effect of upright posture on the level of augmentation index (AIx) remains controversial [1–3]. Phenotypic differences in AIx responses to upright posture are unknown. Methods: Altogether 323 women and 315 men without cardiovascular disease and medications with direct cardiovascular influences were subjected to passive head-up tilt (5-min supine, 5-min upright). Haemodynamics were recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Results: Mean (SD) age was 45.6 (1.2) years, BMI 26.8 (4.4) kg/m2, and average blood count, plasma lipids and creatinine were normal. AIx decreased from supine 22.7% (11.9) to upright 13.8% (12.2) (p < 0.001), while heart rate related AIx@75 decreased from 17.9% (11.8) to 13.9% (11.0) (p < 0.001), respectively. In stepwise linear regression analyses, the explanatory variables for upright reduction in AIx were changes in ejection duration (β = 0.744), aortic reflection time (β = −0.491), and stroke volume (β = 0.117); and supine ejection duration (β=0.312), systemic vascular resistance (SVR) (β = −0.271), pulse wave velocity (PWV) (β = −0.203), and systolic blood pressure (β=0.081) (p≤0.001 for all). When divided to quartiles according to the supine-to-upright change in AIx 1) the quartile with lowest supine AIx had highest upright AIx, lowest supine SVR and PWV, and lowest upright heart rate; 2) the quartile with highest supine AIx had lowest upright AIx, highest supine SVR and PWV, and highest upright heart rate. Conclusions: The level of AIx is decreased in the upright position. The phenotypic differences in the supine-to-upright change in AIx may explain why this variable has not predicted cardiovascular events in all endpoint studies.

To non-invasively measure central haemodynamics, arterial stiffness, cardiac function and vascular resistance, with the subject in the supine position and during head-up tilt, in order to examine the haemodynamic changes associated with alterations in the augmentation index, and to investigate repeatability and reproducibility of the measurement protocol.Thirty-three healthy volunteers (21-51 years) were investigated using continuous pulse wave analysis from the radial artery with a tonometric sensor, whole-body impedance cardiography and plethysmographic blood pressure (BP) recordings from the fingers. The measurements were performed with the subject supine and during passive head-up tilt, and repeated during the same session and on four separate days.During the head-up tilt, diastolic BP (5.2+/-0.6%), heart rate (27.6+/-1.9%) and vascular resistance (12.5+/-1.7%) increased (all p0.05), while systolic BP (-3.2+/-0.6%), aortic pulse pressure (-23.3+/-1.4%), augmentation index (-11.6+/-0.7%), aortic reflection time (-7.0+/-1.0%), ejection duration (-21.4+/-0.7%), stroke volume (-26.1+/-1.2%) and cardiac output (-5.0+/-1.5%) decreased (all p0.05). Augmentation index at rest correlated with aortic systolic BP (r = 0.423), aortic reflection time (r = -0.647), pulse wave velocity (r = 0.287) and age (r = 0.480). The change in augmentation index during head-up tilt correlated with the change in aortic systolic BP (r = 0.469), aortic pulse pressure (r = 0.606), ejection duration (r = 0.374) and heart rate (r = -0.445). According to Bland-Altman and repeatability index analyses, repeatability and reproducibility of the measurements were good during the same session and on separate days.Combined pulse wave analysis and impedance cardiography with the subject in the supine position and during head-up tilt is a repeatable and reproducible method for comprehensive investigation of the cardiovascular function.

Aim: To examine whether treatment of secondary hyperparathyroidism with paricalcitol provides benefits to arteries in uremic rats. Methods: 5/6-nephrectomized rats were treated (NX+Pari) or not treated (NX) with paricalcitol (200 ng/kg, thrice weekly) for 12 weeks. Aortic histology and isolated segments of the main and 2nd-order mesenteric arterial branches were studied. Results: Creatinine clearance was reduced by 54–61%, plasma phosphate increased 2.1- to 2.5-fold, and blood pressure by 40 mm Hg in both NX groups. PTH increased 13-fold in NX and 5-fold in NX+Pari rats. Calcification in aortic cross-sections increased from 2.1 to 7.1% after paricalcitol. In the large mesenteric artery, vasoconstriction to noradrenaline was reduced in NX+Pari rats. In the large and small arteries, vasorelaxation to acetylcholine was impaired in NX rats and unaffected by paricalcitol. In the small artery, paricalcitol increased nitric oxide synthase inhibition-resistant relaxation to acetylcholine, and maximal relaxation to levcromakalim. The small arteries of NX rats featured increased wall cross-sectional area, while paricalcitol further increased wall thickness and the wall:lumen ratio. Conclusion: Paricalcitol treatment showed both benefits and harmful effects in uremic rats: in the large artery vasoconstriction was reduced but calcification increased, while in the small artery vasorelaxation via potassium channels was moderately improved but hypertrophic remodeling was aggravated.

Cardiac repolarization is regulated, in part, by the KCNH2 gene, which encodes a rapidly activating component of the delayed rectifier potassium channel. The gene expresses a functional single nucleotide polymorphism, K897T, which changes the biophysical properties of the channel. The objective of this study was to evaluate whether this polymorphism influences two indices of repolarization--the QT interval and T-wave alternans (TWA)--during different phases of a physical exercise test.The cohort consisted of 1,975 patients undergoing an exercise test during which on-line electrocardiographic data were registered. Information on coronary risk factors and medication was recorded. The 2690AC nucleotide variation in the KCNH2 gene corresponding to the K897T amino acid change was analysed after polymerase chain reaction with allele-specific TaqMan probes.Among all subjects, the QTc intervals did not differ between the three genotype groups (por =0.31, RANOVA). Women with the CC genotype tended to have longer QT intervals during the exercise test, but the difference was statistically significant only at rest (p = 0.011, ANOVA). This difference was also detected when the analysis was adjusted for several factors influencing the QT interval. No statistically significant effects of the K897T polymorphism on TWA were observed among all subjects (p = 0.16, RANOVA), nor in men and women separately.The K897T polymorphism of the KCNH2 gene may not be a major genetic determinant for the TWA, but the influence of the CC genotype on QT interval deserves further research among women.

Objectives: Liquorice consumption elevates blood pressure [1–3], but the liquorice-induced haemodynamic changes in the upright position are unknown. We investigated haemodynamics after liquorice exposure in healthy volunteers during orthostatic challenge. Methods: Haemodynamics were recorded from 22 normotensive subjects during passive 10- minute head-up tilt before and after two weeks of liquorice consumption (glycyrrhizin dose 290–370 mg/day) using radial pulse wave analysis, whole-body impedance cardiography, and spectral analysis of heart rate variability. Thirty age-matched healthy subjects maintaining their habitual diet served as controls. Results: Liquorice ingestion elevated radial systolic (p < 0.001) and diastolic (p = 0.018) blood pressure and systemic vascular resistance (p = 0.037). During orthostatic challenge, heart rate increased less after the liquorice versus control diet (p = 0.003) and low frequency power of heart rate variability decreased within the liquorice group (p = 0.034). Liquorice intake increased central pulse pressure (p < 0.001) and augmentation index (p = 0.002) supine and upright, but in the upright position the elevation of augmentation index was accentuated (p = 0.007). Liquorice diet also increased extracellular fluid volume (p = 0.024) and aortic to popliteal pulse wave velocity (p = 0.027), and aortic characteristic impedance in the upright position (p = 0.002). Conclusions: In addition to increased extracellular fluid volume and large arterial stiffness, two weeks of liquorice ingestion elevated systemic vascular resistance and augmentation index. Measurements performed at rest may underestimate the haemodynamic effects of liquorice ingestion, as enhanced central wave reflection and reduced chronotropic response were especially observed in the upright position.

The authors examined the association between estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C equation, and hemodynamics in 556 normotensive or never-treated hypertensive patients without kidney disease (mean age, 46 years). Hemodynamic variables were recorded using pulse wave analysis and whole-body impedance cardiography. The mean eGFR was 98 mL/min/1.73 m(2) (range, 64-145 mL/min/1.73 m(2) and one third of the patients had values below 92, while none had proteinuria. In linear regression analyses adjusted for differences in age, weight:height ratio, low-density lipoprotein cholesterol, and sex, significant associations were found between lower eGFR and higher systolic (P=.001) and diastolic blood pressure (P

Background Liquorice ingestion often elevates blood pressure, but the detailed haemodynamic alterations are unknown. We studied haemodynamic changes induced by liquorice consumption in 20 subjects versus 30 controls with average blood pressures of 120/68 and 116/64 mmHg, respectively. Methods Haemodynamic variables were measured in supine position before and after two weeks of liquorice consumption (daily glycyrrhizin dose 290–370 mg) with tonometric recording of radial blood pressure, pulse wave analysis, and whole-body impedance cardiography. Thirty age-matched healthy subjects maintaining their normal diet were studied as controls. Results Two weeks of liquorice ingestion elevated peripheral and central systolic and diastolic blood pressure (by 7/4 and 8/4 mmHg, 95% confidence intervals [CI] 2-11/1-8 and 3-13/1-8, respectively, P ClinicalTrials.gov NCT01742702

OBJECTIVE Hypertension is characterized by increased vascular resistance and arterial stiffness, but information about upright hemodynamics is scarce. We compared hemodynamics in hypertensive versus normotensive patients at rest and during passive head-up tilt. METHODS Volunteers (n = 387, 19-72 years) without antihypertensive medication were recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Seated office blood pressure was 4/10 mmHg (systolic/diastolic) higher than average supine values during hemodynamic measurements. As there is no accepted cut-off for hypertension during tilt-table tests, supine level at least 135/85 mmHg defined hypertension (n = 155) versus normotension (n = 232). Age, BMI, and proportion of men were higher among hypertensives (49 vs. 42 years, 28 vs. 25, 55 vs. 38%, respectively), and analyses were adjusted for these differences. RESULTS Both at rest and during head-up tilt radial and aortic blood pressure and pulse pressure, cardiac index (CI) and work, systemic vascular resistance (SVR), and augmentation pressure were higher in hypertensive patients (P

Objective: Our aim was to evaluate the influence of mild impairment in kidney function on hemodynamics and cardiac autonomic tone. Methods: We studied 561 (50% male) normotensive and hypertensive subjects without kidney or other cardiovascular diseases or antihypertensive treatment. Supine and upright hemodynamics were recorded using continuous pulse wave analysis, whole body impedance cardiography and heart rate variability analysis. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI cystatin C equation. Results: Mean eGFR was 99 (range 53–152) ml/min/1.73 m2 and one third of the patients had values below 90. After adjustments for age, sex, body mass index and low density lipoprotein cholesterol level, regression analysis indicated significant associations between lower eGFR and higher systolic (p

A repolarization abnormality manifested as T-wave alternans (TWA) in electrocardiogram (ECG) predicts cardiovascular mortality. A common variant in the NOS1AP gene is associated with mortality and QT interval duration, possibly in a gender-specific manner, but data is lacking on potential association with TWA. This study tested association between rs10494366 in NOS1AP and both TWA and 4-year mortality.A total of 1963 Finnish Cardiovascular Study participants (36.6% female, 57.1 ± 13.0 years) were genotyped and their maximal TWA values were measured from continuous ECG recordings during clinical exercise test at rest, exercise and recovery.We observed a significant gender-specific effect of NOS1AP genotype on TWA. In all subjects, there was no statistically significant difference between the three genotypes (TT, TG, GG) in the responses of TWA over the entire exercise test (time-by-genotype interaction p = 0.057). In women, after adjustment for age, coronary heart disease and β-blocker medication status, changes of TWA over different phases of exercise test were significantly associated with NOS1AP genotype (time-by-genotype interaction p = 0.001). In men, NOS1AP rs10494366 was not associated with TWA. During follow-up (mean 47 months), 113 patients died. NOS1AP rs10494366 was not a statistically significant predictor of mortality.The NOSIAP variant rs10494366 influences TWA and TWA response during clinical exercise test in females. Gender-specific effects have also been previously reported for the influence of the variant on QT interval. If replicated, these findings should prompt studies to further elucidate the mechanisms underlying the gender differences in NOS1AP effects on repolarization.

Background: Vitamin D receptor activation with paricalcitol can modulate the transcription of renin-angiotensin system components in the surgical 5/6 nephrectomy rat model (5/6 NX) of chronic renal insufficiency. We tested the hypothesis whether dietary modification of phosphate influences kidney renin-angiotensin system gene expression at the mRNA level in 5/6 NX rats. Methods: Fifteen weeks after surgery, rats were given control diet (0.3% calcium, 0.5% phosphate), phosphate-lowering diet (3% calcium as carbonate) or high-phosphate diet (1.5%) for 12 weeks. Sham-operated rats were on control diet. Results: Blood pressure, plasma phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were increased in remnant kidney rats, whereas creatinine clearance was decreased. Phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were further elevated by the high-phosphate diet, but were reduced by the phosphate-lowering diet. Plasma calcium was increased with the phosphate-lowering diet and decreased with the high-phosphate diet. Remnant kidney rats on control diet showed upregulated kidney angiotensin-converting enzyme (ACE) and angiotensin (Ang) IV receptor (AT4) transcription, while ACE2, Ang II type 2 receptor and renin receptor transcription were downregulated in comparison with sham rats. Phosphate-lowering diet reduced whereas high-phosphate diet increased kidney ACE, and these effects were observed at both mRNA and protein levels. Dietary phosphate loading also resulted in lower AT1a gene transcription. Conclusion: Dietary phosphate loading was associated with elevated kidney ACE expression, increased tissue damage and lower AT1a transcription in 5/6 NX rats. Phosphate binding with 3% calcium carbonate had opposite effects on ACE and kidney damage.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Haemodynamic effects of endothelial stimuli induced by salbutamol and L-arginine in humans have been previously studied predominantly at rest in selected vascular beds. • We studied the effects of salbutamol, L-arginine and nitroglycerin on cardiac and vascular function by continuous recording of pulse wave analysis and impedance cardiography both in the supine position and during passive head-up tilt. WHAT THIS STUDY ADDS • The divergent effects of the research drugs in supine position and during head-up tilt indicate that human haemodynamics should also be studied in the upright position. • Since inhaled salbutamol induced more pronounced changes in haemodynamics, it provides a clinically more applicable tool than infused L-arginine for the assessment of endothelial function in humans. AIMS To examine the effects of salbutamol and L-arginine, two compounds acting largely on the endothelium, and the endothelium-independent agent nitroglycerin on blood pressure, arterial compliance, cardiac function and vascular resistance. METHODS Continuous radial pulse wave analysis, whole-body impedance cardiography, and plethysmographic blood pressure from fingers in the supine position and during head-up tilt were recorded in nine healthy subjects. Data were captured before and after L-arginine (10 mg mg−1 min−1) or saline infusion, salbutamol (400 µg) or placebo inhalation, and sublingual nitroglycerin (0.25 mg) or placebo resoriblet. RESULTS The results of all measurements were comparable before drug administration. The effects of inhaled salbutamol were apparent in the supine position: systemic vascular resistance (−9.2 ± 2.6%) and augmentation index (−4.0 ± 1.5%) decreased, and heart rate (8.6 ± 2.5%) and cardiac output (8.8 ± 3.1%) increased. L-arginine had no clear effects on supine haemodynamics, but during head-up tilt blood pressure was moderately decreased and reduction in aortic reflection time prevented, indicating improved large arterial compliance. Nitroglycerin reduced supine vascular resistance (−6.7 ± 1.8%) and augmentation index (−7.4 ± 1.6%), and increased cardiac output (+9.2 ± 2.7%). During head-up tilt, nitroglycerin increased cardiac output (+10.6 ± 5.6%) and heart rate (+40 ± 7.5%), decreased vascular resistance (−7.8 ± 5.8%) and augmentation index (−18.7 ± 3.2%), and prevented the decrease in aortic reflection time. CONCLUSIONS Inhaled salbutamol predominantly changed supine haemodynamics, whereas the moderate effects of L-arginine were observed during the head-up tilt. In contrast, small doses of nitroglycerin induced major changes in haemodynamics both supine and during the head-up tilt. Altogether, these results emphasize the importance of haemodynamic measurements in both the supine and upright positions.

Objective Ageing is associated with increased postural blood pressure changes and attenuated cardiovascular reactivity. As the background of these changes remains uncertain, we examined arterial stiffness, cardiac function and vascular resistance in healthy subjects in supine position and during orthostatic challenge. Methods Haemodynamics of 179 normotensive subjects (109 female and 70 male, 21–59 years) were examined using continuous radial pulse wave analysis, whole-body impedance cardiography, and plethysmographic finger blood pressures. Results Both in supine position and during head-up tilt central and peripheral blood pressure and augmentation index (amplitude of the reflected pressure wave divided by pulse pressure) increased, and time of pulse wave reflection decreased with age. Supine pulse wave velocity progressively increased with age. There were only minor differences in supine and upright systemic vascular resistance, cardiac index, stroke index, and heart rate that were not systematically related to age. In regression analysis, the explanatory factors for a more pronounced decrease in central systolic blood pressure during the head-up tilt were in the age of 50–59 years, higher baseline pulse wave velocity and central systolic BP. None of the changes in other haemodynamic variables during tilt were related to age. Conclusion As no systematic age-related differences were observed in cardiac function or vascular resistance, these results support the view that progressive reduction of large arterial compliance contributes to the exaggerated age-related decrease in central systolic blood pressure in response to head-up tilt.

T-wave alternans (TWA) in electrocardiography (ECG) is a marker of cardiac repolarization, the molecular regulation of which is incompletely understood. High TWA and prolonged QT intervals are both associated with ventricular arrhythmias and sudden death. Therefore, we tested the hypothesis of whether the same mutations that influence the QT interval also affect TWA variation. We examined the effect of 3 ion channel gene single nucleotide polymorphisms (SNPs), rs1805127, rs727957 KCNE1, and rs1805124 SCN5A, on TWA during a clinical exercise test. A total of 2008 subjects from the Finnish Cardiovascular Study underwent an exercise test with online ECG recording. TWA was measured by using the time-domain, modified moving average method. Maximum values at rest, during maximal exercise, and during recovery were used as outcome measures in statistical analysis. Moreover, 4-year survival data were collected and ion channel SNPs were determined. TWA was lowest in subjects with the TT genotype of rs1805127 during all phases of the exercise test (RANOVA main effect for genotype, P = 0.018). The result remained significant after adjustment for age, existing coronary heart disease, and β-blocker medication status (RANCOVA, P = 0.035). Of the polymorphisms studied, only rs1805127 had a significant association with mortality ( P = 0.047). The most common G-C haplotype, formed by rs727957 and rs1805127, was associated with TWA (RANOVA, P = 0.007) but not with mortality. The rs1805124 polymorphism was not associated with TWA. The common KCNE1 gene variant rs1805127 is associated with TWA during an exercise test in a Finnish population, which provides additional evidence that KCNE1 genetics may influence cardiac repolarization and cardiovascular mortality.

Background High resting heart rate (HR) is associated with increased cardiovascular risk in general populations, possibly due to elevated blood pressure (BP) or sympathetic over-activity. We studied the association of resting HR with cardiovascular function, and examined whether the hemodynamics remained similar during passive head-up tilt. Methods Hemodynamics were recorded using whole-body impedance cardiography and continuous radial pulse wave analysis in 522 subjects (age 20–72 years, 261 males) without medication influencing HR or BP, or diagnosed diabetes, coronary artery, renal, peripheral arterial, or cerebrovascular disease. Correlations were calculated, and results analysed according to resting HR tertiles. Results Higher resting HR was associated with elevated systolic and diastolic BP, lower stroke volume but higher cardiac output and work, and lower systemic vascular resistance, both supine and upright (p