The characteristics of elevated blood pressure in abdominal obesity correspond to primary hypertension: a cross-sectional study.

BACKGROUND: Obesity-related hypertension and the associated metabolic abnormalities are considered as a distinct hypertensive phenotype. Here we examined how abdominal fat content, as judged by waist:height ratio, influenced blood pressure and hemodynamic profile in normotensive subjects and never-treated hypertensive patients. METHODS: The 541 participants (20-72 years) underwent physical examination and laboratory analyses and were divided into age and sex-adjusted quartiles of waist:height ratio. Supine hemodynamics were recorded using whole-body impedance cardiography, combined with analyses of radial tonometric pulse wave form and heart rate variability. RESULTS: Mean waist:height ratios in the quartiles were 0.46, 0.51, 0.55 and 0.62. Radial and aortic blood pressure, systemic vascular resistance, pulse wave velocity, markers of glucose and lipid metabolism, leptin levels and C-reactive protein were higher in quartile 4 when compared with quartiles 1 and 2 (p < 0.05 for all). Cardiac index was lower in quartile 4 versus quartile 1, while no differences were seen in heart rate variability, augmentation index, plasma renin activity, and aldosterone concentration between the quartiles. Linear regression analyses showed independent associations of abdominal obesity with higher aortic systolic and diastolic blood pressure, systemic vascular resistance, and pulse wave velocity (p < 0.05 for waist:height ratio in all regression models). CONCLUSION: Higher waist:height ratio was associated with elevated blood pressure, systemic vascular resistance, and arterial stiffness, but not with alterations in cardiac sympathovagal modulation or activation of the circulating renin-angiotensin-aldosterone system. Although obesity-related elevation of blood pressure has distinct phenotypic features, these results suggest that its main characteristics correspond those of primary hypertension. TRIAL REGISTRATION: ClinicalTrails.gov NCT01742702 (date of registration 5th December 2012).

Plasma total calcium concentration is associated with blood pressure and systemic vascular resistance in normotensive and never-treated hypertensive subjects.

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 on studies utilizing office BP measurements in populations using cardiovascular drugs. In many studies adjustment for confounders was not optimal. In this cross-sectional study we examined the association of plasma total calcium concentration with the haemodynamic determinants of blood pressure.Subjects and methods: Supine haemodynamics were recorded using pulse wave analysis, whole-body impedance cardiography, and heart rate variability analysis in 618 normotensive or never-treated hypertensive subjects (aged 19-72 years) without diabetes, cardiovascular or renal disease, or cardiovascular medications. Linear regression analysis was used to investigate factors associated with haemodynamic variables.Results: Mean age was 45.0 years, body mass index 26.8 kg/m2, seated office BP 141/89 mmHg, and 307 subjects (49.7%) were male. Mean values of routine blood and plasma chemistry analyses were within the reference limits of the tests except for low-density lipoprotein cholesterol (3.05 mmol/l). In the laboratory, mean supine radial BP was 131/75 mmHg, and both systolic and diastolic BP correlated directly with plasma total calcium concentration (r = 0.25 and r = 0.22, respectively, p < 0.001 for both). In regression analysis plasma total calcium concentration was an independent explanatory variable for radial and aortic systolic and diastolic BP, and systemic vascular resistance, but not for cardiac output, pulse wave velocity, or any of the heart rate variability parameters.Conclusion: Plasma total calcium concentration was directly associated with systolic and diastolic BP and systemic vascular resistance in normotensive or never-treated hypertensive subjects without comorbidities and cardiovascular medications. Higher plasma calcium concentration potentially plays a role in primary hypertension via an effect on vascular resistance.

Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency.

Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB) expressions after 12 and 27 weeks of 5/6 nephrectomy, and after 12 weeks of 0.3% adenine diet, representing proteinuric and interstitial inflammation models of CRI, respectively. Uric acid and calcium-phosphate metabolism were modulated after 5/6 nephrectomy, while ETA blocker and calcimimetic were given with adenine. Endothelin receptor mRNA levels were measured using RT-qPCR and protein levels using autoradiography (5/6 nephrectomy) or ELISA (adenine model). Both 12 and 27 weeks after 5/6 nephrectomy, kidney cortex ETA protein was increased by ~60% without changes in ETB protein, and the ETB:ETA ratio was reduced. However, the ETB:ETA mRNA ratio did not change. In the adenine model, kidney ETA protein was reduced by ~70%, while ETB protein was suppressed by ~95%, and the ETB:ETA ratio was reduced by ~85%, both at the protein and mRNA levels. The additional interventions did not influence the observed reductions in the ETB:ETA ratio. To conclude, unfavorable reduction in the ETB:ETA protein ratio was observed in two different models of CRI. Therefore, ETA blockade may be beneficial in a range of diseases that cause impaired kidney function.

Atherogenic index of plasma is related to arterial stiffness but not to blood pressure in normotensive and never-treated hypertensive subjects.

BACKGROUND AND AIMS: Atherogenic index of plasma (AIP), defined as the logarithm of triglycerides to high-density lipoprotein cholesterol (HDL-C) ratio, is a strong predictor of future cardiovascular disease. Our aim was to examine the association of AIP with haemodynamic variables in normotensive and never-treated hypertensive subjects in a cross-sectional study. METHODS: Supine haemodynamics in 615 subjects without antihypertensive and lipid-lowering medications were examined using whole-body impedance cardiography and radial pulse wave analysis. Linear regression analysis was applied to investigate the association of AIP with haemodynamic variables and age, sex, body mass index (BMI), smoking status, alcohol consumption, plasma C-reactive protein, electrolytes, uric acid, low density lipoprotein cholesterol (LDL-C), estimated glomerular filtration rate, and quantitative insulin sensitivity check index. RESULTS: The demographics and laboratory values of the study population were (mean ± 95% confidence interval): age 44.9 ± 1.0 years, BMI 26.8 ± 0.4 kg/m2, office blood pressure 140.6 ± 1.6/89.4 ± 1.0 mmHg, total cholesterol 5.2 ± 0.08, LDL-C 3.1 ± 0.08, triglycerides 1.2 ± 0.08, HDL-C 1.6 ± 0.04 mmol/l, and AIP -0.15 ± 0.02. Age (standardized coefficient Beta 0.508, p < .001) and aortic systolic blood pressure (Beta 0.239, p < .001) presented with the strongest associations with pulse wave velocity. However, AIP was also associated with pulse wave velocity (Beta 0.145, p < .001). AIP was not related with aortic or radial blood pressure, cardiac output, systemic vascular resistance, or augmentation index. CONCLUSIONS: AIP is directly and independently associated with arterial stiffness, a variable strongly related to cardiovascular risk. This supports more widespread use of AIP in standard clinical cardiovascular disease risk evaluation.

LDL cholesterol is associated with systemic vascular resistance and wave reflection in subjects naive to cardiovascular drugs.

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 < 0.05 for all). When central BP was included in the model for PWV, LDL-C was no longer 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.

Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency.

BACKGROUND: We studied whether endothelin receptor antagonist and calcimimetic treatments influence renal damage and kidney renin-angiotensin (RA) components in adenine-induced chronic renal insufficiency (CRI). METHODS: Male Wistar rats (n = 80) were divided into 5 groups for 12 weeks: control (n = 12), 0.3% adenine (Ade; n = 20), Ade + 50 mg/kg/day sitaxentan (n = 16), Ade + 20 mg/kg/day cinacalcet (n = 16), and Ade + sitaxentan + cinacalcet (n = 16). Blood pressure (BP) was measured using tail-cuff, kidney histology was examined, and RA components measured using RT-qPCR. RESULTS: Adenine caused tubulointerstitial damage with severe CRI, anemia, hyperphosphatemia, 1.8-fold increase in urinary calcium excretion, and 3.5-fold and 18-fold increases in plasma creatinine and PTH, respectively. Sitaxentan alleviated tubular atrophy, while sitaxentan + cinacalcet combination reduced interstitial inflammation, tubular dilatation and atrophy in adenine-rats. Adenine diet did not influence kidney angiotensin converting enzyme (ACE) and AT4 receptor mRNA, but reduced mRNA of renin, AT1a, AT2, (pro)renin receptor and Mas to 40-60%, and suppressed ACE2 to 6% of that in controls. Sitaxentan reduced BP by 8 mmHg, creatinine, urea, and phosphate concentrations by 16-24%, and PTH by 42%. Cinacalcet did not influence BP or creatinine, but reduced PTH by 84%, and increased hemoglobin by 28% in adenine-rats. The treatments further reduced renin mRNA by 40%, while combined treatment normalized plasma PTH, urinary calcium, and increased ACE2 mRNA 2.5-fold versus the Ade group (p < 0.001). CONCLUSIONS: In adenine-induced interstitial nephritis, sitaxentan improved renal function and tubular atrophy. Sitaxentan and cinacalcet reduced kidney renin mRNA by 40%, while their combination alleviated tubulointerstitial damage and urinary calcium loss, and increased kidney tissue ACE2 mRNA.

Vasopeptidase Inhibition Corrects the Structure and Function of the Small Arteries in Experimental Renal Insufficiency.

BACKGROUND: We studied whether vasopeptidase inhibition corrects the structure and function of the small arteries in experimental chronic renal insufficiency (CRI). METHODS: After 5/6 nephrectomy (NX) surgery was performed on rats, there was a 14-week follow-up, allowing CRI to become established. Omapatrilat (40 mg/kg/day in chow) was then given for 8 weeks, and the small mesenteric arterial rings were investigated in vitro using wire and pressure myographs. RESULTS: Plasma and ventricular B-type natriuretic peptide (BNP) concentrations were increased 2- to 2.7-fold, while systolic blood pressure (BP) increased by 32 mm Hg after NX. Omapatrilat treatment normalized the BNP and reduced the BP by 45 mm Hg in the NX rats. Endothelium-dependent vasorelaxation was impaired but the response to acetylcholine was normalized after omapatrilat treatment. Vasorelaxations induced by nitroprusside, isoprenaline and levcromakalim were enhanced after omapatrilat, and the responses were even more pronounced than in untreated sham-operated rats. Arterial wall thickness and wall-to-lumen ratio were increased after NX, whereas omapatrilat normalized these structural features and improved the strain-stress relationship in the small arteries; this suggests improved arterial elastic properties. CONCLUSION: Omapatrilat treatment reduced BP, normalized volume overload, improved vasorelaxation and corrected the dimensions and passive elastic properties of the small arteries in the NX rats. Therefore, we consider vasopeptidase inhibition to be an effective treatment for CRI-induced changes in the small arteries.

Effects of oxonic acid-induced hyperuricemia on mesenteric artery tone and cardiac load in experimental renal insufficiency.

BACKGROUND: Recent studies suggest a causal role for increased plasma uric acid in the progression of chronic renal insufficiency (CRI). However, uric acid also functions as an antioxidant with possible beneficial effects. METHODS: We investigated the influence of hyperuricemia on mesenteric arterial tone (main and second order branch) and morphology in experimental CRI. Forty-four Sprague-Dawley rats were 5/6 nephrectomized (NX) or Sham-operated and fed 2.0% oxonic acid or control diet for 9 weeks. RESULTS: Oxonic acid feeding elevated plasma uric acid levels 2.4 and 3.6-fold in the NX and Sham groups, respectively. Plasma creatinine and urea were elevated 2-fold and blood pressure increased by 10 mmHg in NX rats, while hyperuricemia did not significantly influence these variables. Right and left ventricular weight, and atrial and B-type natriuretic peptide mRNA content were increased in NX rats, but were not affected by hyperuricemia. In the mesenteric artery, hyperuricemia did not influence vasoconstrictor responses in vitro to norepinephrine or potassium chloride. The small arteries of NX rats featured hypertrophic remodeling independent of uric acid levels: wall to lumen ratio, wall thickness and cross-sectional area were increased without changes in lumen diameter. In the main branch, vasorelaxations to acetylcholine were impaired in NX rats, but were not affected by hyperuricemia. In contrast, relaxations to the large-conductance Ca(2+)-activated K(+)-channel (BKCa) opener NS-1619 were reduced by oxonic acid feeding, whereas responses to nitroprusside were not affected. CONCLUSIONS: Experimental hyperuricemia did not influence cardiac load or vascular remodeling, but impaired BKCa -mediated vasorelaxation in experimental CRI.

Phosphate binding reduces aortic angiotensin-converting enzyme and enhances nitric oxide bioactivity in experimental renal insufficiency.

BACKGROUND: Disturbed calcium-phosphorus metabolism is associated with increased kidney angiotensin-converting enzyme (ACE) in experimental chronic renal insufficiency (CRI). However, information about the effects of phosphate binding and loading on vascular ACE is lacking. METHODS: Fifteen weeks after 5/6 nephrectomy (NX), rats were placed on a phosphate-binding (NX+Ca, 3.0% Ca), phosphate-loading (NX+Pi, 1.5% Pi), or control diet for 12 weeks (NX and sham). RESULTS: Aortic ACE, blood pressure, plasma phosphate, and parathyroid hormone were increased in the NX and NX+Pi groups, but were reduced with phosphate binding. Endothelium-mediated relaxations of isolated mesenteric conduit artery rings to acetylcholine were impaired in the NX and NX+Pi groups, but did not differ from sham in NX+Ca rats. Experiments with nitric oxide (NO) synthase inhibition in vitro suggested that the NO-mediated component of acetylcholine response was lower in the NX and NX+Pi groups, but did not differ from sham in NX+Ca rats. In all NX groups, aortic endothelial NO synthase (eNOS) was reduced, while plasma and urine concentrations of NO metabolites were increased. Aortic nitrated proteins and calcification were increased in the NX and NX+Pi groups when compared with the NX+Ca and sham groups. CONCLUSION: Hypertension in the NX model of CRI was associated with reduced vasorelaxation, decreased eNOS, and increased ACE and nitrated proteins in the aorta. Phosphate binding with calcium carbonate enhanced vasorelaxation via endogenous NO and suppressed elevation of ACE and nitrated proteins, suggesting reduced vascular oxidative stress. Our findings support the view that correction of the calcium-phosphorus balance prevents CRI-induced vascular pathophysiology.

Moderate hyperuricaemia ameliorated kidney damage in a low-renin model of experimental renal insufficiency.

Uric acid has promoted renal fibrosis and inflammation in experimental studies, but some studies have shown nephroprotective effects due to alleviated oxidative stress. We studied the influence of experimental hyperuricaemia in surgically 5/6 nephrectomized rats. Three weeks after subtotal nephrectomy or sham operation, the rats were allocated to control diet or 2.0% oxonic acid (uricase inhibitor) diet for 9 weeks. Then blood, urine and tissue samples were taken, and renal morphology and oxidative stress were examined. Inflammation and fibrosis were evaluated using immunohistochemistry and real-time PCR (RT-PCR). Remnant kidney rats ingesting normal or oxonic acid diet presented with ~60% reduction of creatinine clearance and suppressed plasma renin activity. Oxonic acid diet increased plasma uric acid levels by >80 µmol/L. In remnant kidney rats, moderate hyperuricaemia decreased glomerulosclerosis, tubulointerstitial damage and kidney mast cell count, without influencing the fibrosis marker collagen I messenger RNA (mRNA) content. In both sham-operated and 5/6 nephrectomized rats, the mast cell product 11-epi-prostaglandin-F2α excretion to the urine and kidney tissue cyclooxygenase-2 (COX-2) levels were decreased. To conclude, hyperuricaemic remnant kidney rats displayed improved kidney morphology and reduced markers of oxidative stress and inflammation. Thus, moderately elevated plasma uric acid had beneficial effects on the kidney in this low-renin model of experimental renal insufficiency.

Dietary phosphate binding and loading alter kidney angiotensin-converting enzyme mRNA and protein content in 5/6 nephrectomized rats.

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 (AT(4)) 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 AT(1a) gene transcription. CONCLUSION: Dietary phosphate loading was associated with elevated kidney ACE expression, increased tissue damage and lower AT(1a) transcription in 5/6 NX rats. Phosphate binding with 3% calcium carbonate had opposite effects on ACE and kidney damage.

Left ventricular periostin gene expression is associated with fibrogenesis in experimental renal insufficiency.

BACKGROUND: Cardiovascular diseases are the most important cause of death in patients with impaired kidney function. Left ventricular hypertrophy (LVH), cardiac interstitial fibrosis and cardiovascular calcifications are characteristic of chronic renal insufficiency (CRI). Periostin is a fibrogenesis- and calcification-related matricellular protein re-expressed in adult tissues undergoing remodelling in response to pathological stimuli. The role of periostin in CRI-induced LVH is unknown. METHODS: Rats were 5/6-nephrectomized (NX), and after 15 weeks of disease progression high-calcium, high-phosphate or paricalcitol treatment was given for 12 weeks. Cardiac tissue and blood samples were taken to study periostin gene expression and to determine factors contributing to its reactivation, respectively. Left ventricular (LV) periostin expression was also examined in response to angiotensin II or arginine(8)-vasopressin (AVP)-induced pressure overload and in spontaneously hypertensive rats. RESULTS: CRI resulted in a 6.5-fold increase in LV periostin messenger RNA (mRNA) levels. Positive extracellular immunostaining for periostin was detected in areas of infiltrated inflammatory cells and fibrotic lesions. There was a significant correlation between LV periostin mRNA levels and plasma biomarkers of impaired kidney function, LVH, fibrogenesis-related proteins osteopontin and osteoactivin, and anti-calcific matrix Gla protein. Moreover, LV periostin gene expression in CRI correlated positively with systolic blood pressure (BP) and was activated rapidly in response to angiotensin II or AVP infusions. CONCLUSIONS: Periostin is involved in fibrotic cardiac remodelling in CRI. The re-expression of periostin is localized to the fibrotic and inflammatory lesions and is most likely the consequence of elevated BP.

Posture-Related Differences in Cardiovascular Function Between Young Men and Women: Study of Noninvasive Hemodynamics in Rural Malawi.

Background Cardiovascular risk is higher in men than in women, but little information exists about sex-related differences in cardiovascular function from low-income countries. We compared hemodynamics between sexes in rural Malawi in a cohort followed up since their birth. Methods and Results Supine, seated, and standing hemodynamics were recorded from 251 women and 168 men (mean age, 21 years; body mass index, 21 kg/m2) using oscillometric brachial waveform analyses (Mobil-O-Graph). The results were adjusted for estimated glomerular filtration rate, and plasma potassium, lipids, and glucose. Men had higher brachial and aortic systolic blood pressure and stroke index regardless of posture (P<0.001), and higher upright but similar supine diastolic blood pressure than women. Regardless of posture, heart rate was lower in men (P<0.001), whereas cardiac index did not differ between sexes. Women presented with lower supine and standing systemic vascular resistance index (P<0.001), whereas supine-to-standing increase in vascular resistance (P=0.012) and decrease in cardiac index (P=0.010) were higher in women. Supine left cardiac work index was similar in both sexes, whereas standing and seated left cardiac work index was higher in men than in women (P<0.001). Conclusions In young Malawian adults, men had higher systolic blood pressure, systemic vascular resistance, and upright cardiac workload, whereas women presented with higher posture-related changes in systemic vascular resistance and cardiac output. These findings show systematic sex-related differences in cardiovascular function in a cohort from a low-income country with high exposure to prenatal and postnatal malnutrition and infectious diseases.

Parathyroid hormone may play a role in the pathophysiology of primary hypertension.

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.

Team-based "Get-a-Grip" lifestyle management programme in the treatment of obesity.

This study examined weight loss during an extensive 1-year lifestyle programme in primary care in Finland in overweight subjects (n = 134, age 18-69 years; BMI > 30, or BMI > 25 with a comorbidity that would benefit from weight loss) between 2009 and 2013 in a single arm design. The programme included four medical doctor visits, five sessions by a dietitian (advice on diet and on-location shopping behaviour), cooking classes, exercise supervised by personal trainer, and group discussions. A motivational interview method was applied. Of the 134 participants, 92 (69%) completed the 1-year programme. Among the participants 44% lost ≥ 5%, while 21% lost ≥ 10% of their initial body weight. In intention-to-treat-analyses, the mean weight loss during one year was 4.8 kg (p < 0.001). Mean BMI decreased by 1.7 kg/m2 (p < 0.001) and waist circumference by 5.6 cm (p < 0.001). Mean muscle mass increased by 3.3% (p < 0.001), and body fat decreased by 5.0% (p < 0.001). After the programme mean visceral fat content was reduced by 6.4%, systolic blood pressure by 8 mmHg (p < 0.001), and diastolic blood pressure by 6 mmHg (p < 0.001). In conclusion, retention to the team-based lifestyle management programme resulted in moderate but significant weight loss with beneficial changes in body composition, and the trend to lose weight was maintained throughout the year. Trial registration: Clinicaltrials.gov identifier NCT04003259.

Adverse influence of bisoprolol on central blood pressure in the upright position: a double-blind placebo-controlled cross-over study.

Treatment with beta-blockers is characterized by inferior reduction of central versus peripheral blood pressure. We examined changes in blood pressure, cardiac function, and vascular resistance after 3 weeks of bisoprolol treatment (5 mg/day) during passive head-up tilt in 16 never-treated Caucasian males with grade I-II primary hypertension. A double-blind, randomized, placebo-controlled cross-over design was applied, and hemodynamics were recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Bisoprolol decreased blood pressure in the aorta (~8/10 mmHg, p ≤ 0.032) and radial artery (~10/9 mmHg, p ≤ 0.037), but upright aortic systolic blood pressure was not significantly reduced (p = 0.085). Bisoprolol reduced heart rate and left cardiac work, and increased subendocardial viability index in supine and upright positions (p ≤ 0.044 for all). Bisoprolol increased stroke volume in the supine (~11 ml, p = 0.02) but not in the upright position, while only upright (~1 l/min, p = 0.007) but not supine cardiac output was reduced. Upright elevation in systemic vascular resistance was increased 2.7-fold (p = 0.002), while upright pulse pressure amplification was decreased by ~20% (p = 0.002) after bisoprolol. Aortic augmentation index, augmentation pressure, and pulse pressure were not changed in the supine position but were increased in the upright position (from 9% to 17%, 3-6 mmHg, and 30-34 mmHg, respectively, p ≤ 0.016 for all). In conclusion, although bisoprolol treatment reduced peripheral blood pressure, central systolic blood pressure in the upright position was not decreased. Importantly, the harmful influences of bisoprolol on central pulse pressure and pressure wave reflection were manifested in the upright position.

Changes in hemodynamics associated with metabolic syndrome are more pronounced in women than in men.

The increase in cardiovascular risk associated with metabolic syndrome (MS) seems higher in women than in men. We examined hemodynamics during head-up tilt in 252 men and 250 women without atherosclerosis, diabetes, or antihypertensive medication, mean age 48 years, using whole-body impedance cardiography and radial pulse wave analysis. MS was defined according to Alberti et al. 2009. Men and women with MS presented with corresponding elevations of systolic and diastolic blood pressure (10-14%, p ≤ 0.001) versus controls. Supine pulse wave velocity (16-17%, p < 0.001) and systemic vascular resistance (7-9%, p ≤ 0.026), and upright cardiac output (6-11%, p ≤ 0.008) were higher in both MS groups than controls. Elevation of supine aortic characteristic impedance was higher in women than in men with MS (16% vs. 8%, p = 0.026), and in contrast to men, no upright impedance reduction was observed in women. When upright, women but not men with MS showed faster return of reflected pressure wave (p = 0.036), and smaller decrease in left cardiac work (p = 0.035) versus controls. The faster upright return of reflected pressure, lower upright decrease in left cardiac work, and higher elevation of aortic characteristic impedance may contribute to the greater increase in MS-related cardiovascular risk in women than in men.

Liquorice ingestion attenuates vasodilatation via exogenous nitric oxide donor but not via ß2-adrenoceptor stimulation.

We examined the effect of liquorice ingestion on haemodynamic responses to exogenous nitric oxide donor (nitroglycerin) and ß2-adrenoceptor agonist (salbutamol), and 11ß-hydroxysteroid dehydrogenase activity, in 21 volunteers and 21 reference subjects. Haemodynamic data was captured before and after sublingual nitroglycerin (0.25 mg) and inhaled salbutamol (400 µg) during orthostatic challenge utilising radial pulse wave analysis and whole-body impedance cardiography. The recordings were performed at baseline and following two weeks of liquorice intake (290-370 mg/d glycyrrhizin). Urinary cortisone and cortisol metabolites were examined. Liquorice intake elevated aortic systolic and diastolic blood pressure and systemic vascular resistance when compared with the reference group. Following research drug administration the liquorice-induced increase in systemic vascular resistance was observed in the presence of nitroglycerin (p<0.05) but no longer in the presence of salbutamol. Liquorice ingestion decreased cardiac chronotropic response to upright posture (p = 0.032) in unadjusted analysis, but when adjusted for age and sex the difference in the upright change in heart rate was no longer significant. The urinary cortisone to cortisol metabolite ratio decreased from 0.70 to 0.31 (p<0.001) after liquorice intake indicating significant inhibition of the 11ß-hydroxysteroid dehydrogenase type 2. In the reference group the haemodynamic variables remained virtually unchanged. These results suggest that liquorice exposure impaired vasodilatation in vivo that was induced by exogenous nitric oxide donor but not that induced by ß2-adrenoceptor stimulation. Trial registration: EU Clinical Trials Register 2006-002065-39 ClinicalTrials.gov NCT01742702.

Oxonic acid-induced hyperuricemia elevates plasma aldosterone in experimental renal insufficiency.

BACKGROUND: Hyperuricemia is associated with renal insufficiency and may predispose to Na retention and hypertension. Whether hyperuricemia plays a causal role in the pathogenesis of cardiovascular disease remains controversial. OBJECTIVE: We examined the effects of hyperuricemia on circulating and renal components of the renin-angiotensin-aldosterone system in experimental renal insufficiency. METHODS: Three weeks after 5/6 nephrectomy or sham-operation, rats were put on 2.0% oxonic acid diet for 9 weeks. Blood pressure was monitored using tail-cuff, and blood, urine, and kidney samples were taken, as appropriate. Kidney angiotensin-converting enzyme, angiotensin-converting enzyme 2 and angiotensin II receptors (AT1R, AT2R) were examined using real-time reverse transcriptase-PCR and autoradiography. RESULTS: Oxonic acid diet increased plasma uric acid by 80-90 micromol/l, while blood pressure was elevated only in hyperuricemic 5/6 nephrectomy rats (18 mmHg). Creatinine clearance was reduced by 60% in both 5/6 nephrectomy groups and by 25% in hyperuricemic Sham rats. The 5/6 nephrectomy group showed over 90% suppression of plasma renin activity, whereas the Sham + oxonic acid diet group showed 1.2 and 1.4-fold, and 5/6 nephrectomy + oxonic acid diet group 2.5 and 2.3-fold increases in plasma renin activity and plasma aldosterone, respectively. Hyperuricemia increased K and decreased Na excretion in Sham and 5/6 nephrectomy rats, leading to a more than 1.6-fold increase in urine K to Na ratio. No changes in kidney angiotensin-converting enzyme, angiotensin-converting enzyme 2, AT1R or AT2R were detected that could explain the hyperuricemia-induced alteration in Na-K balance. CONCLUSION: As oxonic acid diet increased plasma renin activity, plasma aldosterone, and urine K to Na ratio, these changes may play a significant role in the harmful cardiovascular actions of hyperuricemia.

Paricalcitol treatment and arterial tone in experimental renal insufficiency.

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.