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The prevalence of obesity has tripled over the past five decades. Obesity, especially visceral obesity, is closely related to hypertension, increasing the risk of primary (essential) hypertension by 65%–75%. Hypertension is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and its prevalence is rapidly increasing following the pandemic rise in obesity. Although the causal relationship between obesity and high blood pressure (BP) is well established, the detailed mechanisms for such association are still under research. For more than 30 years sympathetic nervous system (SNS) and kidney sodium reabsorption activation, secondary to insulin resistance and compensatory hyperinsulinemia, have been considered as primary mediators of elevated BP in obesity. However, experimental and clinical data show that severe insulin resistance and hyperinsulinemia can occur in the absence of elevated BP, challenging the causal relationship between insulin resistance and hyperinsulinemia as the key factor linking obesity to hypertension. The purpose of Part 1 of this review is to summarize the available data on recently emerging mechanisms believed to contribute to obesity-related hypertension through increased sodium reabsorption and volume expansion, such as: physical compression of the kidney by perirenal/intrarenal fat and overactivation of the systemic/renal SNS and the renin–angiotensin–aldosterone system. The role of hyperleptinemia, impaired chemoreceptor and baroreceptor reflexes, and increased perivascular fat is also discussed. Specifically targeting these mechanisms may pave the way for a new therapeutic intervention in the treatment of obesity-related hypertension in the context of 'precision medicine' principles, which will be discussed in Part 2. [ABSTRACT FROM AUTHOR]

Background Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH. Methods Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECM i) on cardiac MRI. Results Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs −0.53 [0.68] mL/min/g; P =.03) but not CFR by cardiac PET (0.01 [0.64] vs −0.07 [0.48]; P =.72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (−13 [28] vs 10 [26] mL; P =.03) and global circumferential strain (GCS; median [interquartile range 25th–75th]: −1.3% [−2.9%–1.0%] vs 2.3% [−0.4%–4.1%]; P =.03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = −0.65, P =.057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs −0.05 [0.36]; P =.04). Eplerenone prevented a small increase in troponin (0.00 [−0.13–0.00] vs 0.00 [0.00–0.74] ng/L; P =.03) without effects on ECM i (0.9 [−2.3–4.3] vs −0.7 [−2.2–−0.1] g/m2; P =.38). CD4+ T-cell count (127 [−38–286] vs −6 [−168–53] cells/μL; P =.02) increased in the eplerenone- versus placebo-treated groups. Conclusions RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo. Clinical Trials Registration NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1). [ABSTRACT FROM AUTHOR]

Background The effects of the renin–angiotensin–aldosterone system in cardiovascular system have been described based on small studies. The aim of this study was to evaluate the relationship between aldosterone and plasma renin activity (PRA) and cardiovascular structure and function. Methods We studied a random sample of Multi-Ethnic Study of Atherosclerosis participants who had aldosterone and PRA blood assays at 2003–2005 and underwent cardiac magnetic resonance at 2010. Participants taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were excluded. Results The aldosterone group was composed by 615 participants, mean age 61.6 ± 8.9 years, while the renin group was 580 participants, mean age 61.5 ± 8.8 years and both groups had roughly 50% females. In multivariable analysis, 1 SD increment of log-transformed aldosterone level was associated with 0.07 g/m2 higher left ventricle (LV) mass index (P = 0.04) and 0.11 ml/m2 higher left atrium (LA) minimal volume index (P < 0.01). Additionally, higher log-transformed aldosterone was associated with lower LA maximum strain and LA emptying fraction (P < 0.01). Aldosterone levels were not significantly associated with aortic measures. Log-transformed PRA was associated with lower LV end diastolic volume index (β standardized = 0.08, P = 0.05). PRA levels were not significantly associated with LA and aortic structural or functional differences. Conclusions Higher levels of aldosterone and PRA are associated with concentric LV remodeling changes. Moreover, aldosterone was related to deleterious LA remodeling changes. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Could circulating maternal prorenin serve as a proxy for oocyte and preimplantation embryo development, assessed by time-lapse parameters and clinical treatment outcomes? SUMMARY ANSWER High circulating maternal prorenin concentrations after ovarian stimulation associate with a larger oocyte area, faster cleavage divisions from the five-cell stage onwards and increased chance of successful implantation. WHAT IS KNOWN ALREADY After ovarian stimulation, circulating prorenin (renin's precursor), is largely ovary-derived. Prorenin may contribute to ovarian angiotensin synthesis, which is relevant in reproduction given its role in follicular development and oocyte maturation. STUDY DESIGN, SIZE, DURATION Prospective observational cohort study including couples requiring fertility treatment from May 2017 as a subcohort of the ongoing Rotterdam Periconception Cohort conducted in a tertiary referral hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS Between May 2017 and July 2020, 309 couples with an indication for IVF treatment or ICSI were included. Resulting embryos (n = 1024) were submitted to time-lapse embryo culture. Time of fertilization (t0), pronuclear appearance (tPNa), and fading (tPNf) as well as the exact timing of reaching the two- to eight-cell stage (t2–t8), the start of blastulation (tSB), reaching the full (tB), and expanded blastocyst (tEB) were retrospectively recorded. Oocyte area was measured at t0, tPNa, and tPNf. Prorenin was determined at the day of embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE After adjustment for patient- and treatment-related factors, linear mixed modeling showed that higher prorenin concentrations associate with a larger oocyte area at tPNa (β 64.45 µm2, 95% CI 3.26; 125.64, P  = 0.04), and faster progression from five-cell stage onwards (e.g. β8-cell −1.37 h, 95% CI −2.48; −0.26, P  = 0.02). Prorenin associated positively with pre-transfer outcomes (e.g. βfertilized oocytes 2.09, 95% CI 1.43; 2.75, P  < 0.001) and implantation (odds ratio+β-hCG-test: 1.79, 95% CI 1.06; 3.08, P  = 0.03), but not with live birth. LIMITATIONS, REASONS FOR CAUTION This prospective observational study provides associations and therefore residual confounding cannot be excluded and causality has to be shown in intervention studies. WIDER IMPLICATIONS OF THE FINDINGS Theca cell-derived factors, such as prorenin, may help to clarify the underlying endocrine mechanism of oocyte maturation and embryo development, with a special focus on the (patho)physiological reproductive role of prorenin and the identification of factors influencing its secretion and activity, which is of great added value for improving embryo selection and predicting implantation and pregnancy outcomes. This will bring us to investigate which determinants of oocyte quality and embryo development should take center stage in developing preconception care strategies. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands, and the Erasmus MC Medical Research Advisor Committee's 'Health Care Efficiency Research' program (OZBS72.16080). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Pregnancy is marked by the onset of rapid hemodynamic alterations in order to accommodate the needs of the developing fetus. Arterial stiffness is an independent predictor of cardiovascular events and mortality, and its measurement in clinical practice has been recommended. It follows a U-shaped curve in uncomplicated pregnancy, decreasing to a nadir in mid-pregnancy and rising at term. Systemic vasodilation occurs due to elevated nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor, estrogen, progesterone, and relaxin. Vascular resistance decreases to a nadir in mid-pregnancy, while endothelial function is enhanced starting in the first trimester. Plasma volume increases by about 50%, and total red blood cell mass increases by up to 40%. Cardiac output increases by up to 45%, at first due primarily to elevated stroke volume, then mainly due to increased heart rate. Along with echocardiography, cardiac magnetic resonance imaging is safe for use in pregnancy. It may assess cardiac function more accurately than echocardiography, and may be indicated in specific clinical cases. Moreover, blood pressure decreases to a nadir in mid-pregnancy and rises to near preconception values postpartum. An appreciation of the vascular changes occurring in healthy pregnancy can aid in the prediction and diagnosis of pregnancy complications, such as preeclampsia and other hypertensive disorders of pregnancy, and inform treatment. In particular, noninvasive arterial stiffness/hemodynamics assessment provides unique clinical information beyond blood pressure and traditional maternal characteristics, and can signal a need for further testing, or be used in combination with other tests to predict or diagnose complications of pregnancy. [ABSTRACT FROM AUTHOR]

Context The SARS-CoV-2 virus is dependent on components of the renin-angiotensin-aldosterone system for infectivity. Primary aldosteronism (PA) is a form of secondary hypertension mediated by autonomous aldosterone production. The intersection of COVID-19 and PA, both which may involve components of the renin-angiotensin-aldosterone system, remains unknown. Methods We assessed PA as a risk factor for COVID-19 infection and compared management, severity of disease, and outcomes during COVID-19 with a matched population of patients with essential hypertension (EH) by conducting a retrospective observational cohort study. Results Of the patients with PA, 81 had a negative PCR test for COVID-19, whereas 43 had a documented positive PCR test for COVID-19. Those patients with PA who tested positive for COVID-19 tended to be female (P =.08) and the majority of those with COVID-19 infection identified as non-White race (P =.02) and Hispanic ethnicity (P =.02). In a subanalysis, 24-hour urine aldosterone on initial PA diagnosis tended to be higher those in the PA group who developed COVID-19 compared with those in the PA group who did not develop COVID-19 [median (interquartile range): 36.5 (16.9, 54.3) vs 22.0 (15.8, 26.8) mcg, P =.049] and was an independent predictor of COVID-19 infection controlling for sex, race, and ethnicity. Angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and mineralocorticoid receptor antagonist use did not differ between those patients with PA who did and did not have COVID-19 infection. Comparing those patients with PA and matched patients with EH (n = 286) who were COVID-19 PCR positive, there was a significantly higher incidence of cardiovascular complications (12 vs 2%, P =.004) in the PA vs EH group. Conclusion These data begin to inform us as to whether PA should be a newly identified subpopulation at risk for COVID-19-related cardiovascular disease sequelae. [ABSTRACT FROM AUTHOR]

Background The effects of sodium (Na+) intakes on renal handling of potassium (K+) are insufficiently studied. Methods We assessed the effect of Na+ on renal K+ handling in 16 healthy males assigned to three 7-day periods on low salt diet [LSD, 3 g sodium chloride (NaCl)/day], normal salt diet (NSD, 6 g NaCl/day) and high salt diet (HSD, 15 g NaCl/day), with constant K+ intake. Contributions of distal NaCl co-transporter and epithelial Na+ channel in the collecting system on K+ and Na+ handling were assessed at steady state by acute response to 100 mg oral hydrochlorothiazide and with addition of 10 mg of amiloride to hydrochlorothiazide, respectively. Results Diurnal blood pressure slightly increased from 119.30 ± 7.95 mmHg under LSD to 123.00 ± 7.50 mmHg (P = 0.02) under HSD, while estimated glomerular filtration rate increased from 133.20 ± 34.68 mL/min under LSD to 187.00 ± 49.10 under HSD (P = 0.005). The 24-h K+ excretion remained stable on all Na+ intakes (66.28 ± 19.12 mmol/24 h under LSD; 55.91 ± 21.17 mmol/24 h under NSD; and 66.81 ± 20.72 under HSD, P   =   0.9). The hydrochlorothiazide-induced natriuresis was the highest under HSD (30.22 ± 12.53 mmol/h) and the lowest under LSD (15.38 ± 8.94 mmol/h, P   =   0.02). Hydrochlorothiazide increased kaliuresis and amiloride decreased kaliuresis similarly on all three diets. Conclusions Neither spontaneous nor diuretic-induced K+ excretion was influenced by Na+ intake in healthy male subjects. However, the respective contribution of the distal convoluted tubule and the collecting duct to renal Na+ handling was dependent on dietary Na+ intake. [ABSTRACT FROM AUTHOR]

Serum fibroblast growth factor 23 (FGF23) levels and the renin-angiotensin-aldosterone system (RAAS) are elevated in chronic kidney disease (CKD) patients, and their association with left ventricular hypertrophy (LVH) has been reported. However, whether the FGF23 elevation is the cause or result of LVH remains unclear. At 10 weeks, male C57BL/6J mice were divided into 4 groups: sham, CKD (5/6 nephrectomy), LVH (transaortic constriction), and CKD/LVH group. At 16 weeks, the mice were euthanized, and blood and urine, cardiac expressions of FGF23 and RAAS-related factors, and cardiac histological analyses were performed. Heart weight, serum FGF23 levels, and cardiac expression of FGF23 and RAAS-related factors, except for angiotensin-converting enzyme 2, were more increased in the CKD/LVH group compared to the other groups. A significant correlation between LVH and cardiac expressions of FGF23 and RAAS-related factors was observed. Furthermore, there was a significantly close correlation of the cardiac expression of FGF23 with LVH and RAAS-related factors. The coexisting CKD and LVH increased serum and cardiac FGF23 and RAAS-related factors, and there was a significant correlation between them. A close correlation of cardiac, but not serum FGF23, with LVH and RAAS suggests that local FGF23 levels may be associated with LVH and RAAS activation. [ABSTRACT FROM AUTHOR]

Subclinical myocardial dysfunction is prevalent among well-treated persons with HIV (PWH). We have previously demonstrated unique renin-angiotensin-aldosterone system physiology among PWH with metabolic dysregulation. Mineralocorticoid receptor blockade may be a targeted treatment strategy for subclinical heart disease in PWH. Forty-six PWH were randomized to receive either eplerenone 50 mg daily or placebo in a 6-month randomized, double-blinded, placebo-controlled trial. We assessed changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker of cardiac stretch, under controlled posture and dietary conditions. The eplerenone- and placebo-treated groups demonstrated a long duration of HIV with good immunological control. NT-proBNP levels were similar between the groups at baseline (41.1 [20.2, 97.9] vs 48.9 [29.2, 65.4] ng/L, P =.80) and decreased significantly more in the eplerenone- vs placebo-treated groups after 6 months (change NT-proBNP -9.6 [-46.8, 0.3] vs -3.0 [-17.0, 39.9] ng/L, P =.02 for comparison of change between groups). Decreases in NT-proBNP were independent of changes in systolic and diastolic blood pressure, and related to decreases in high-sensitivity C-reactive protein (ρ = 0.32, P =.05) and inversely to increases in serum aldosterone (ρ = -0.33, P =.04) among all participants. Treatment with eplerenone for 6 months vs placebo significantly decreases NT-proBNP levels among PWH, independent of eplerenone's known blood pressure-lowering effects. Further studies should elucidate whether lowering NT-proBNP in this at-risk metabolic population with subclinical heart disease will offer cardioprotection. Clinical Trial Registration NCT01405456 [ABSTRACT FROM AUTHOR]

The landscape of HIV medicine dramatically changed with the advent of contemporary antiretroviral therapies, which has allowed persons with HIV (PWH) to achieve good virologic control, essentially eliminating HIV-related complications and increasing life expectancy. As PWH are living longer, noncommunicable diseases, such as cardiovascular disease (CVD), have become a leading cause of morbidity and mortality in PWH with rates that are 50% to 100% higher than in well-matched persons without HIV. In this review, we focus on disease of the coronary microvasculature and myocardium in HIV. We highlight a key hormonal system important to cardiovascular endocrinology, the renin-angiotensin-aldosterone system (RAAS), as a potential mediator of inflammatory driven-vascular and myocardial injury and consider RAAS blockade as a physiologically targeted strategy to reduce CVD in HIV. [ABSTRACT FROM AUTHOR]

Obesity contributes 65–75% of the risk for human primary (essential) hypertension (HT) which is a major driver of cardiovascular and kidney diseases. Kidney dysfunction, associated with increased renal sodium reabsorption and compensatory glomerular hyperfiltration, plays a key role in initiating obesity-HT and target organ injury. Mediators of kidney dysfunction and increased blood pressure include (i) elevated renal sympathetic nerve activity (RSNA); (ii) increased antinatriuretic hormones such as angiotensin II and aldosterone; (iii) relative deficiency of natriuretic hormones; (iv) renal compression by fat in and around the kidneys; and (v) activation of innate and adaptive immune cells that invade tissues throughout the body, producing inflammatory cytokines/chemokines that contribute to vascular and target organ injury, and exacerbate HT. These neurohormonal, renal, and inflammatory mechanisms of obesity-HT are interdependent. For example, excess adiposity increases the adipocyte-derived cytokine leptin which increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway. Excess visceral, perirenal and renal sinus fat compress the kidneys which, along with increased RSNA, contribute to renin–angiotensin–aldosterone system activation, although obesity may also activate mineralocorticoid receptors independent of aldosterone. Prolonged obesity, HT, metabolic abnormalities, and inflammation cause progressive renal injury, making HT more resistant to therapy and often requiring multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes, and inflammation. More effective anti-obesity drugs are needed to prevent the cascade of cardiorenal, metabolic, and immune disorders that threaten to overwhelm health care systems as obesity prevalence continues to increase. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is associated with a high incidence of fractures. However, the pathophysiology of this disease is not fully understood, and limited therapeutic interventions are available. This study aimed to determine the impact of type 1 angiotensin II receptor blockade (AT‐1RB) on preventing CKD‐related fragility fractures and elucidate its pharmacological mechanisms. AT‐1RB use was associated with a lower risk of hospitalization due to fractures in 3276 patients undergoing maintenance hemodialysis. In nephrectomized rats, administration of olmesartan suppressed osteocyte apoptosis, skeletal pentosidine accumulation, and apatite disorientation, and partially inhibited the progression of the bone elastic mechanical properties, while the bone mass was unchanged. Olmesartan suppressed angiotensin II‐dependent oxidation stress and apoptosis in primary cultured osteocytes in vitro. In conclusion, angiotensin II‐dependent intraskeletal oxidation stress deteriorated the bone elastic mechanical properties by promoting osteocyte apoptosis and pentosidine accumulation. Thus, AT‐1RB contributes to the underlying pathogenesis of abnormal bone quality in the setting of CKD, possibly by oxidative stress. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Background Women with chronic kidney disease (CKD) are at increased risk of superimposed pre-eclampsia (SPE). Accurate identification of SPE is challenging. We hypothesized that specific components of the renin–angiotensin–aldosterone system (RAAS) would discriminate between CKD and SPE. The aim of the study was to establish differences in circulating and intrarenal RAAS in women with CKD with and without SPE and compare these to normotensive controls (NCs) and women with pre-eclampsia (PE). Methods White European NC women (n  = 20), women with PE (n  = 9), normotensive CKD without SPE (n  = 8) and with SPE (n  = 11) were recruited in the third trimester. Plasma renin, plasma and urine total angiotensinogen (AGT) concentrations were quantified by enzyme-linked immunosorbent assay, urinary tetrahydroaldosterone (TH-aldo) concentration by gas chromatography-mass spectrometry and placental growth factor (PlGF) by immunoassay. Results Urinary TH-aldo:creatinine ratios were lower in women with PE or SPE compared with NC or women with CKD (P   < 0.05 for all). The same group differences were observed for plasma active renin and PlGF concentrations (P   < 0.05 for all). Urine total AGT was higher in women with PE compared with NC (P   <   0.05) and urine TH-aldo:urine AGT was lower (P   < 0.05). However, women with SPE had lower urinary AGT concentrations compared with women with PE (P   < 0.05). No differences in plasma total AGT were observed between groups. Conclusions Women with SPE have a lower urinary TH-aldo:creatinine ratio, lower plasma active renin and lower PlGF concentrations than women with CKD, comparable to women with PE without pre-existing disease, suggestive of similar pathophysiology. These data suggest disruption of the RAAS pathway in SPE similar to PE. Exploration of the predictive value of RAAS components for adverse pregnancy events in women with CKD is required. [ABSTRACT FROM AUTHOR]

Background Cardiovascular mortality in patients receiving dialysis remains unacceptably high, with unexplained ancestry differences suggesting a genetic component. Methods We analyzed DNA samples from 37% of subjects enrolled in the EValuation Of Cinacalcet Hydrochloride (HCl) Therapy to Lower CardioVascular Events (EVOLVE) trial, a randomized trial conducted in patients receiving hemodialysis with secondary hyperparathyroidism, comparing cinacalcet to placebo on a background of usual care. DNA was analyzed for single-nucleotide polymorphisms (SNPs) in the genes encoding the angiotensin-converting enzyme receptor type I (AGTR1) and angiotensin-converting enzyme (ACE). Survival analyses were conducted separately in European Ancestry (EA) and African Ancestry (AfAn) due to known differences in cardiovascular events, minor alleles for the same variant and the frequency of minor alleles. Our primary determination was a meta-analysis across both races. Results Meta-analysis showed significant associations between rs5186 in AGTR1 and increased rates by 25–34% for the primary endpoint (composite of death or nonfatal myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event), all-cause mortality, cardiovascular mortality and heart failure; all P < 0.001. Three correlated SNPs in ACE were associated with lower rates of sudden cardiac death (SCD) in EA samples. One ACE SNP, rs4318, only found in the AfAn samples, was associated with a lower rate of SCD in the AfAn samples. Conclusions The C allele in rs5186 in AGTR1 was associated with higher rates of death and major cardiovascular events in a meta-analysis of EA and AfAn patients with end-stage kidney disease. SNPs in ACE were associated with SCD. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the relationship of lipocalin 2 to inflammation and cardiac injury with increased aldosterone in human immunodeficiency virus (HIV).Methods: A standardized 6-day low-sodium diet was used to stimulate renin-angiotensin-aldosterone system (RAAS) activation, and serum lipocalin 2 and biomarkers of inflammation and cardiac stretch were assessed among persons with or without HIV.Results: Lipocalin 2 levels increased with RAAS activation compared with suppression in the HIV group (median level [interquartile range], 71.3 [59.2-99.7] vs 67.0 [51.8-86.3] ng/mL; P = .01). During RAAS activation, lipocalin 2 was related to biomarkers of inflammation (tumor necrosis factor α [P = .007]), monocyte/macrophage activation (soluble CD163 [P = .005] and chemokine [C-C motif] ligand 2 [P = .03]), and markers of cardiac stretch (brain natriuretic peptide [P < .001] and N-terminal fragment of the prohormone brain natriuretic peptide [P = .001]) in HIV.Conclusion: Lipocalin 2 may be important in modulating aldosterone-induced inflammation, monocyte activation, and cardiac stretch during RAAS activation in HIV.Clinical Trial Registration: NCT01407237. [ABSTRACT FROM AUTHOR]

Background Fibroblast growth factor 23 (FGF23) is discussed as a new biomarker of cardiac hypertrophy and mortality in patients with and without chronic kidney disease (CKD). We previously demonstrated that FGF23 is expressed by cardiac myocytes, enhanced in CKD and induces cardiac hypertrophy via activation of FGF receptor 4 independent of its co-receptor klotho. The impact of FGF23 on cardiac fibrosis is largely unknown. Methods By conducting a retrospective case–control study including myocardial autopsy samples from 24 patients with end-stage CKD and in vitro studies in cardiac fibroblasts and myocytes, we investigated the pro-fibrotic properties of FGF23. Results The accumulation of fibrillar collagens I and III was increased in myocardial tissue of CKD patients and correlated with dialysis vintage, klotho deficiency and enhanced cardiac angiotensinogen (AGT) expression. Using human fibrosis RT2 Profiler PCR array analysis, transforming growth factor (TGF)-β and its related TGF-β receptor/Smad complexes, extracellular matrix remodeling enzymes and pro-fibrotic growth factors were upregulated in myocardial tissue of CKD patients. FGF23 stimulated cell proliferation, migration, pro-fibrotic TGF-β receptor/Smad complexes and collagen synthesis in cultured cardiac fibroblasts. In isolated cardiac myocytes, FGF23 enhanced collagen remodeling, expression of pro-inflammatory genes and pro-survival pathways and induced pro-hypertrophic genes. FGF23 stimulated AGT expression in cardiac myocytes and angiotensin II and aldosterone, as components of the renin–angiotensin–aldosterone system (RAAS), induced FGF23 in cardiac myocytes. Conclusions Our data demonstrate that activated RAAS induces FGF23 expression in cardiac myocytes and thereby stimulates a pro-fibrotic crosstalk between cardiac myocytes and fibroblasts, which may contribute to myocardial fibrosis in CKD. [ABSTRACT FROM AUTHOR]

Background. Renin-angiotensin-aldosterone system (RAAS) blockade provides renoprotective effects in chronic kidney disease (CKD); yet progressive renal function loss remains common. Dietary sodium restriction potentiates the renoprotective effects of RAAS blockade. Vitamin D receptor activator (VDRA) treatment reduces proteinuria, inflammation and fibrosis, but whether these effects depend on sodium intake has not been studied. We hypothesized that the renoprotective effects of VDRA treatment, with or without RAAS blockade, are modulated by sodiumintake. Methods. Six weeks after the induction of adriamycin nephrosis in Wistar rats, i.e. with established proteinuria, animals were treated with the VDRA paricalcitol, lisinopril, the combination, or vehicle; each treatment was given during either a high- (2% NaCl) or a low-sodium (0.05% NaCl) diet for 6 weeks. We assessed proteinuria, blood pressure, renal macrophage accumulation and renal expression of the pre-fibrotic marker alphasmooth muscle actin (a-SMA) at the end of the treatment. Results. Both paricalcitol and lisinopril individually, as well as in combination, reduced proteinuria and glomerular and interstitial inflammation during a low-sodium diet, but not during a high-sodium diet. All interventions also reduced focal glomerulosclerosis and interstitial expression of a-SMA during the lowsodium diet, while similar trends were observed during the high-sodium diet. The renoprotective effects of paricalcitol were not accompanied by blood pressure reduction. As proteinuria was already abolished by lisinopril during the low-sodium diet, the addition of paricalcitol had no further effect on proteinuria or downstream inflammatory or pre-fibrotic changes. Conclusion. The renoprotective effects of the VDRA paricalcitol are blood pressure independent but do depend on dietary sodium status. The combination of RAAS blockade, dietary sodium restriction and VDRA may be a promising intervention to further retard renal function loss in CKD. [ABSTRACT FROM AUTHOR]

Heart failure is one of the major public health challenges facing the Western world. Its prevalence is increasing as the population ages and modern techniques are implemented to manage cardiac disease. In response, there has been a sustained effort to develop novel strategies to address the high levels of associated morbidity and mortality. Indeed, agents that target the renin-angiotensin-aldosterone system (RAAS) have transformed the way in which we manage heart failure. Despite this, mortality in heart failure is poorer than in many malignancies and a large burden of morbidity and recurrent hospitalisation remains. Here, we review the role of RAAS modulation within the field of systolic heart failure. In particular, we provide practical guidance on using current RAAS blockade agents and focus on the recent emergence of new agents that promise additional substantial benefit to those living with left ventricular systolic dysfunction. [ABSTRACT FROM AUTHOR]

BACKGROUND The decrease in kidney perfusion as often observed in hypertensive individuals does not necessarily occur in a symmetrical fashion, thereby potentially introducing left–right differences in response to vasoactive agents. Increased aldosterone levels have been associated with reduced renal perfusion in normotensive and hypertensive individuals, but it is unknown whether both kidneys are equally affected in this respect and how angiotensin II is involved in this relationship. Therefore, our aim was to investigate the association of both aldosterone and the aldosterone–renin ratio with side-selective renal blood flow in essential hypertension. METHODS We studied 146 essential hypertensive patients with patent renal arteries who had undergone renal angiography for exclusion of renal artery stenosis. Prior to contrast administration, blood samples were drawn for the determination of renin and aldosterone levels, and side-selective renal blood flow was measured using the 133Xenon washout technique. RESULTS Left mean renal blood flow (MRBF) was significantly lower than right MRBF (227±74 vs. 250±76mL * min−1 * 100g kidney−1, P = 0.01). We could not demonstrate a correlation of ln aldosterone or ln renin with left or right kidney perfusion. Ln aldosterone–renin ratio (ARR), however, was inversely and independently associated with left MRBF (β = −13.993, P = 0.02; fully adjusted model) but not with right MRBF. CONCLUSIONS A higher ARR corresponds to reduced perfusion of the left kidney, yet is not associated with right kidney perfusion. Especially under circumstances of diminished right renal blood flow, this may affect blood pressure and kidney function. [ABSTRACT FROM AUTHOR]

Several health institutions recommend sodium intake be reduced to below 2,300 mg, which means that 6-7 billion individuals should alter their diet to accommodate. Such a radical recommendation should be based on solid evidence. However, this review reveals that (i) there are no randomized controlled trials (RCTs) allocating individuals to below 2,300 mg and measuring health outcomes; (ii) RCTs allocating risk groups such as obese prehypertensive individuals and hypertensive individuals down to (but not below) 2,300 mg show no effect of sodium reduction on all-cause mortality; (iii) RCTs allocating individuals to below 2,300 mg show a minimal effect on blood pressure in the healthy population (less than 1 mm Hg) and significant increases in renin, aldosterone, noradrenalin cholesterol, and triglyceride; and (iv) observational studies show that sodium intakes below 2,645 and above 4,945 mg are associated with increased mortality. Given that 90% of the worlds' population currently consumes sodium within the optimal range of 2,645-4,945 mg, there is no scientific basis for a public health recommendation to alter sodium intake. [ABSTRACT FROM AUTHOR]

BACKGROUND: Left ventricular (LV) hypertrophy (LVH) plays an important role in hypertensive heart disease, and may be accompanied by myocardial autophagy. However, the pattern of autophagy during evolution of LVH is unclear. We hypothesized that autophagy activation indicates advancing cardiac LVH with tissue remodeling. METHODS: Ten domestic pigs with a 10-week unilateral renovascular hypertension (HTN) were classified as mild or moderate HTN (n = 5 each group) based on the degree of renal artery stenosis (above or below 75%). Seven normal pigs served as controls. Left ventricular remodeling, function, and microvascular density were assessed using multi-detector- and micro-computed tomography and histology. Markers of myocardial autophagic and endoplasmic reticulum (ER) stress-related unfolded protein response (UPR), apoptosis, and fibrosis were examined ex vivo. RESULTS: Both HTN groups had increased myocyte cross-sectional area, but it was greater in moderate HTN, accompanied by elevated LV muscle-mass. Moderate, but not mild HTN, also showed impaired microvascular density and impaired myocardial perfusion. Autophagy mediators were unaltered in mild HTN but UPR markers were increased, while in moderate HTN they were all upregulated, whereas UPR markers were suppressed. Myocardial apoptosis and fibrosis were also greater in moderate HTN. Autophagic proteins were correlated with LVH and fibrosis. CONCLUSIONS: Autophagic activity is stimulated during the exacerbation of LVH, following a transient early increase in ER stress, and may be involved in the progression of cardiac remodeling in renovascular hypertensive heart disease. [ABSTRACT FROM AUTHOR]

The article focuses on a cross-sectional study concerning the use of angiotensinogen concentrations as a marker of cardiac diastolic dysfunction. It mentions that the researchers measured plasma angiotensinogen and performed tissue doppler imaging for assessing left ventricular diastolic function; analyzed plasma renin concentrations; and discusses the limitations of the study associated with cohort analysis and cross-sectional design.

Background. We conducted single-marker, gene- and pathway- based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort study participants. Methods. A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (SNPs) in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end-stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Geneand pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Results. Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m²/year, respectively, while renal events occurred in a respective 11.5 and 24.9% of participants. We identified strong gene- and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (both P < 1.00 × 10-6). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P < 1.00 × 10-6). No single-marker associations with CKD progression were observed. Conclusions. The current study provides strong evidence for a role of the RAAS in CKD progression. [ABSTRACT FROM AUTHOR]

Immune cells may take part in the renin-angiotensin-aldosterone system (RAAS), which plays a pivotal role in the regulation of vascular tone and blood pressure. The aim of the study was to analyse the expression and activity of angiotensin-converting enzyme type 1 (ACE1) and ACE2 in human monocytes (MO) and their subsets. The highest relative level of ACE1-, as well as ACE2-mRNA expression, was observed in CD14++CD16− (classical) MO. Moreover, in these cells, mean level of ACE2-mRNA was almost two times higher than that of ACE1-mRNA (11.48 versus 7.073 relative units, respectively). In peripheral blood mononuclear cells (PBMC), MO and classical MO, ACE1 and ACE2 protein expression was stronger compared to other MO subpopulations. The highest level of Ang II generated from Ang I in vitro was observed in classical MO. In this setting, generation of Ang-(1-9) by PBMC and classical MO was higher when compared to the whole MO population ( P < 0·05). The generation rate of vasoprotective Ang-(1-7) was comparable in all analysed cell populations. However, in CD14+CD16++ (non-classical) MO, formation of Ang-(1-7) was significantly greater than Ang II ( P < 0·001). We suggest that in physiological conditions MO (but also lymphocytes forming the rest of PBMC pool) may be involved in the regulation of vessel wall homeostasis via the RAAS-related mechanisms. Moreover, non-classical MO, which are associated preferentially with the vascular endothelium, express the vasoprotective phenotype. [ABSTRACT FROM AUTHOR]

The average salt intake of people in Canada, the United States, and Europe is about 3,400mg of sodium per day, which exceeds the recommended intake levels set by various health organizations. The World Health Organization recommends a worldwide reduction of sodium intake to less than 2,000mg per day. Most research to date has focused on the negative effects of high-sodium intake; however, little information is available on the metabolic effects of low-sodium intakes. This review focuses on the hormonal changes associated with low-sodium diets, specially the hormones involved in metabolism and cardiovascular and renal function. Based largely on rodent studies, low-sodium diets have been associated with changes in glycemic control, energy metabolism, cardiovascular disease risk, cholesterol concentrations, inflammation, and functioning of the renin-angiotensin-aldosterone system. Overall, research has revealed mixed results regarding the impact of dietary sodium intake on various hormones. Further research is required to assess the effects of sodium reduction on hormones and their associated pathways in order to determine the likelihood of any unintended effects. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease, characterized by progressive cyst growth and renal enlargement, resulting in renal failure. Hypertension is common and occurs early, prior to loss of kidney function. Whether hypertension in ADPKD is a primary vasculopathy secondary to mutations in the polycystin genes or secondary to activation of the renin–angiotensin–aldosterone system by cyst expansion and intrarenal ischemia is unclear. Dysregulation of the primary cilium causing endothelial and vascular smooth muscle cell dysfunction is a component of ADPKD. In this article, we review the epidemiology, pathophysiology and clinical characteristics of hypertension in ADPKD and give specific recommendations for its treatment. [ABSTRACT FROM AUTHOR]

Background Activation of the renin–angiotensin–aldosterone system (RAAS) is an important mediator of diabetic nephropathy. Urinary angiotensinogen, a novel biomarker of the intrarenal RAAS, is associated with progressive kidney injury. In this study, the authors investigated the determinants of urinary angiotensinogen and its associations with staging of diabetic nephropathy. Methods Random urine samples were collected from the patients with type 2 diabetes with normoalbuminuria (n = 52), microalbuminuria (n = 52) and macroalbuminuria (n = 51) for the measurement of angiotensinogen by sensitive and specific ELISAs. Control samples were collected from healthy volunteers (n = 20) who had normal albuminuria and renal function. Results Urinary angiotensinogen was higher in microalbuminuric and macroalbuminuric diabetes than in controls [63.44 (interquartile range, IQR: 22.08, 174.8) versus 398.38 (IQR: 205.03, 673.68) versus 9.12 (IQR: 3.76, 23.82) ng/mg creatinine, respectively, P < 0.001]. In diabetes with normoalbuminuria, urinary angiotensinogen was also higher than in controls [16.42 (IQR: 7.69, 34.71) versus 9.12 (IQR: 3.76, 23.82) ng/mg creatinine, P = 0.047]. The performance of the biomarker in differentiating each stage of type 2 diabetes from controls was illustrated by receiver-operating characteristic curves. The areas under the curve for the diagnosis of established normoalbuminuric, microalbuminuric and macroalbuminuric type 2 diabetes using urine angiotensinogen (ng/mg creatinine) were 0.62 (95% CI: 0.48–0.77), 0.85 (95% CI: 0.76–0.94) and 0.96 (95% CI: 0.92–1.00), respectively. In addition, the cut-off levels were 9.30 ng/mg (sensitivity 65.4%, specificity 55.0%), 12.32 ng/mg (sensitivity 55.8%, specificity 65.0%) and 17.44 ng/mg (sensitivity 44.2%, specificity 70.0%), respectively, for distinguishing normoalbuminuric type 2 diabetes from healthy controls. Conclusions The authors propose that angiotensinogen could be one of the potential urinary biomarkers for diagnosis in established diabetic nephropathy. It appeared even before the significant albuminuria in diabetic nephropathy. It might be useful as an early biomarker of activation of the renin–angiotensin system in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

The conventional antihypertensive therapies including renin–angiotensin–aldosterone system antagonists (converting enzyme inhibitors, receptor blockers, renin inhibitors, and mineralocorticoid receptor blockers), diuretics, β-blockers, and calcium channel blockers are variably successful in achieving the challenging target blood pressure values in hypertensive patients. Difficult to treat hypertension is still a commonly observed problem world-wide. A number of drugs are considered to be used as novel therapies for hypertension. Renalase supplementation, vasopeptidase inhibitors, endothelin antagonists, and especially aldosterone antagonists (aldosterone synthase inhibitors and novel selective mineralocorticoid receptor blockers) are considered an option in resistant hypertension. In addition, the aldosterone antagonists as well as (pro)renin receptor blockers or AT2 receptor agonists might attenuate end-organ damage. This array of medications has now been complemented by a number of new approaches of non-pharmacological strategies including vaccination, genomic interference, controlled breathing, baroreflex activation, and probably most successfully renal denervation techniques. However, the progress on innovative therapies seems to be slow and the problem of resistant hypertension and proper blood pressure control appears to be still persisting. Therefore the regimens of currently available drugs are being fine-tuned, resulting in the establishment of several novel fixed-dose combinations including triple combinations with the aim to facilitate proper blood pressure control. It remains an exciting question which approach will confer the best blood pressure control and risk reduction in this tricky disease. [ABSTRACT FROM PUBLISHER]

The progression of hypertensive involvement toward heart failure includes myocardial fibrosis and changes of left ventricular (LV) geometry. In the presence of these abnormalities, diastolic abnormalities occur and are defined as LV diastolic dysfunction (DD). They include alterations of both relaxation and filling, precede alterations of chamber systolic function and can induce symptoms of heart failure even when ejection fraction is normal. The prevalence of heart failure with normal ejection fraction (HFNEF) increased over time whereas the rate of death from this disorder remained unchanged. In this view, diagnosis, prognosis, and therapeutic management of DD and HFNEF in hypertensive patients is a growing public health problem. DD may be asymptomatic and identified occasionally during a Doppler-echocardiographic examination. This tool has gained, therefore, important clinical position for diagnosis of DD. Comprehensive assessment of diastolic function should be done not by a simple classification of DD progression but by estimating the degree of LV filling pressure (FP), a true determinant of symptoms and prognosis. This can be obtained by different ultrasound maneuvers/tools but the ratio between transmitral E velocity and pulsed tissue Doppler-derived early diastolic velocity (E/e′ ratio) is the most feasible and accurate. The identification of left atrial enlargement may be useful in uncertain cases. The recommended management of DD in hypertensive patients should correspond to blood pressure (BP) lowering and to the attempt of reducing LV mass and normalizing LV geometry. Prospective studies with well-defined entry criteria are needed to establish whether this approach could reflect a better prognosis.American Journal of Hypertension (2011). doi:10.1038/ajh.2010.235 [ABSTRACT FROM AUTHOR]

Background. Renin-angiotensin-aldosterone system (RAAS) activation plays an important role in cyclosporine (CsA)-induced nephropathy. The main aim of this study was to test whether the administration of green tea extract (GTE) prevents the development of CsA-induced nephrotoxicity.Methods. The rats were treated for 21 days and divided into four groups (n = 6/group): control group (0.9% saline injection), CsA group (30 mg/kg/day by intraperitoneal injection), CsA–GTE group (CsA plus GTE 100 mg/kg/day subcutaneous injection) and GTE group (GTE alone).Results. There were significant increased levels of serum blood urea nitrogen and creatinine in the CsA group compared with that of the control group and significantly improved in the CsA–GTE group. Biochemical analysis showed that the plasma renin activity (PRA) and serum concentration of aldosterone were significantly increased in the CsA group compared with the control group and significantly decreased in the CsA–GTE group compared with the CsA group. The total level of renin protein expression was significantly higher in the CsA group than in the control group, and it was lower in the CsA–GTE group than in the CsA group.Conclusions. CsA treatment increases the PRA and intrarenal renin levels and induces nephrotoxicity. The protective effects of GTE on CsA-induced structural and functional alternations of the kidney may be the blockage of RAAS. [ABSTRACT FROM AUTHOR]

Background. The haemodynamic responses to angiotensin II type 1 (AT1) receptor blockade may be mediated in part by interactions between angiotensin II and the angiotensin II type 2 receptor (AT2R). An AT2R G1675A gene polymorphism has been described, but the functional effects of this polymorphism are unknown.Methods. Haemodynamic function, circulating renin–angiotensin system mediators and norepinephrine were measured in young healthy subjects at baseline and at 2 and 4 weeks after treatment with irbesartan. Subjects were divided into two groups on the basis of the AT2R G1675A gene polymorphism: GG subjects (n = 12) and AA/GA subjects (n = 22).Results. AA/AG subjects exhibited hypotensive and renal vasodilatory responses to irbesartan at 4 weeks, but GG subjects did not. In accord with haemodynamic effects, circulating aldosterone levels were suppressed in AA/AG, while circulating norepinephrine levels were augmented only in GG subjects. In contrast, increases in circulating renin, angiotensin II and plasma renin activity after irbesartan were exaggerated in AA/AG subjects.Conclusions. The AT2R G1675A polymorphism is a determinant of haemodynamic responses to AT1 receptor blockade, an effect that may be due to influences on aldosterone escape. [ABSTRACT FROM AUTHOR]

Background. Inhibition of the renin–angiotensin–aldosterone system (RAAS) provides renoprotection in adriamycin nephropathy (AN), along with a decrease in overexpression of glomerular heparanase. Angiotensin II (AngII) and reactive oxygen species (ROS) are known to regulate heparanase expression in vivo. However, it is unknown whether this is also the case for aldosterone. Therefore, we further assessed the role of aldosterone, AngII and ROS in the regulation of glomerular heparanase expression. [ABSTRACT FROM PUBLISHER]

Inhibition of renin has been shown to be successful in managing hypertension and maintaining cardiac health. Canine models have played a key role in preclinical assessment of renin inhibitors. Here we report the cloning of canine prorenin gene. The amino acid sequence of mature canine renin was ∼70% identical to that of human renin. The full-length prorenin was expressed in HEK 293 cells, purified and converted to its active form by trypsin-mediated cleavage of the 43 residue propeptide. The mature enzyme was characterized by steady-state kinetics using a peptide corresponding to the canine angiotensinogen sequence, Ac–Asp–Arg–Val–Tyr–Ile–His–Pro–Phe–His–Leu–Leu–Val–Tyr–Ser–OH (cleavage between Leu10–Leu11). The reaction followed Michaelis–Menten kinetics with a KM of 120 µM and a second-order rate constant (kcat/KM) of 1.7 × 105 M−1s−1. The enzyme was inhibited by various human renin inhibitors, but at reduced potency compared to the human renin. The basis of the species specificity was investigated by mutagenesis. Based on primary sequence and structural alignments, three mutants were prepared (G149S-S150T, V286L, G149S-S150T-V286L). Each mutant yielded catalytically active enzymes with lower specific activities than native canine renin. V286L had the greatest effect on substrate specificity, while G149S, S150T mutations produced enzymes with inhibitor profiles similar to human renin. [ABSTRACT FROM PUBLISHER]

The relationship between cardiovascular and renal pathologies is well recognized in advanced nephropathy and heart failure, but in early disease it has received less attention. Consequently, microalbuminuria screening and interventions that treat early nephropathy remain under-utilized cardioprotective strategies in the hypertensive patient. Agents that delay the progression of renal disease are likely to be cardioprotective by lessening the systemic consequences of renal dysfunction and may have additional cardioprotective effects by exerting beneficial effects on endothelia elsewhere in the body and within the heart. A critical driving factor within both renal and wider cardiovascular pathologies is overactivation of the renin–angiotensin–aldosterone system (RAAS). Accordingly, RAAS-directed antihypertensive agents including both angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have been demonstrated to have renoprotective effects. In major prospective trials, two ARBs, losartan and irbesartan, have been demonstrated to be renoprotective in patients with frank proteinuria, and one ARB, irbesartan, has been shown to have renoprotective properties in patients with microalbuminuria. For patients with incipient or frank renal dysfunction, an aggressive RAAS-based approach to hypertension management, combining potent blood pressure control with proven renoprotection, may therefore constitute a key component of therapy targeted towards long-term cardioprotection. [ABSTRACT FROM PUBLISHER]

Aims The purpose of this study was to determine whether the deletion/insertion (D/I) polymorphism in the ACE-encoded angiotensin-converting enzyme or the pooled gene effect of five renin–angiotensin–aldosterone system (RAAS) polymorphisms were disease modifiers in a large cohort of unrelated patients with genotyped hypertrophic cardiomyopathy (HCM). [ABSTRACT FROM PUBLISHER]

The renin-angiotensin-aldosterone system (RAAS) regulates sodium balance, fluid volume, and blood pressure (BP). It is also implicated in the progression of heart failure, hypertension, and kidney disease; this is mediated by the binding of angiotensin II (ang II) to the ang II type 1 but not the ang II type 2 receptor. Preclinical and clinical studies have shown that blockade of the RAAS with ang II receptor blockers (ARB) is effective not only in controlling BP but also in preventing end-organ damage. Through their mechanism of action, ARB may offer benefit with respect to endothelial dysfunction and vascular remodeling, as well as cardiac and renal protection. In addition, both recent and ongoing clinical trials help to clarify further the mechanisms for the benefits of using ARB across the cardiovascular continuum. [Copyright &y& Elsevier]

Patients with autosomal dominant polycystic kidney disease (ADPKD) often develop hypertension before any abnormalities in renal function are detected clinically. Therefore, standard screening (serum creatinine and urinalysis) of young individuals with unexplained hypertension to exclude renal parenchymal disease would rarely detect ADPKD.Data from 516 subjects with ADPKD (217 male and 299 female), aged newbornto 55 years with a normal serum creatinine and no proteinuria based on urine dipstick, studied between 1985 and 2000, were compared with data from similar subjects from the National Health and Nutrition Examination Survey (NHANES) III (1988–1994) and NHANES IV (1999–2000) data, by gender.There was a highly significant occurrence of hypertension in young patients with ADPKD when compared to patients aged 20 to 34 years in the U.S. population. The hypertension in patients with ADPKD occurred in the absence of abnormal renal function or abnormal urinalysis.These data indicate that renal ultrasound screening of young hypertensive individuals (aged 20 to 34 years) should be considered when searching for causes of secondary hypertension. Identifying affected ADPKD individuals early in their disease will permit aggressive blood pressure treatment and early inhibition of the renin-angiotensin-aldosterone system, which has been shown to reverse left ventricular hypertrophy, an important cardiovascular risk factor. In the present era of renal replacement therapy, cardiovascular complications are the main cause of death in patients with ADPKD. [Copyright &y& Elsevier]

To determine the relationship between plasma immunoreactive atrial natriuretic peptide (i-ANP) and renin–angiotensin–aldosterone system (RAAS), plasma i-ANP, plasma renin activity (PRA) and plasma aldosterone (PA) were assayed in 29 patients (19 hypertensive and 10 normotensive) with chronic renal failure (CRF), and in 10 healthy subjects.Hypertensive patients had higher i-ANP values than normotensive patients and controls (P<0.05 and P<0.01 respectively).There was no significant correlation between plasma i-ANP and creatinine concentrations in hypertensive patients, whereas this correlation was statistically significant in normotensive patients (r = 0.70, P<0.01).Other positive correlations were between plasma i-ANP and systolic blood pressure in hypertensive patients (r = 0.69, P<0.01) and between plasma ANP and mean arterial pressure in normotensive patients (r = 0.63, P<0.01). There was significant negative correlation between plasma ANP and fractional sodium excretion (FENa) in hypertensive patients (r = −0.47, P<0.05), though there was significant positive correlation in normotensive patients (r = 0.80, P<0.01). Hypertensive patients, with the exception of one anuric patient and another with atrial fibrillation, had a significant negative correlation between FENa and systolic arterial blood pressure (r = 0.64, P<0.01).The patient group had increased PRA and PA values (P<0.01 and P<0.001 respectively) and showed positive correlation with mean arterial pressure (MAP) (r = 0.71, P<0.001 and r = 0.58, P<0.01 respectively).These results show that increased concentrations of immunoreactive ANP circulate in CRF together with activated RAAS. We demonstrate that elevated ANP cannot affect blood pressure and natriuresis in hypertensive patients with CRF, whose RAAS is activated. [ABSTRACT FROM PUBLISHER]

The hormones of the renin–angiotensin–aldosterone system were measured during regular haemodialysis with acetate or bicarbonate at dialysate sodium concentrations of 135, 140, 145, and 150 mmol/l. Plasma renin activity and aldosterone concentration were higher during acetate haemodialysis than during bicarbonate haemodialysis. At lower dialysate sodium concentrations, plasma renin activity (acetate dialysis and bicarbonate dialysis) and aldosterone concentration (only acetate dialysis) were higher than they were at higher dialysate sodium concentrations. Plasma renin activity increased during acetate dialysis, but did not change during bicarbonate dialysis. Aldosterone and potassium concentrations were positively correlated. Aldosterone decreased during haemodialysis (increase to predialysis values at the end of haemodialysis (4 h) at lower dialysate sodium concentrations). It is concluded that the renin-angiotensin-aldosterone system is activated more during acetate dialysis than during bicarbonate dialysis. Aldosterone concentrations seem to be related more closely to serum potassium than to renin–angiotensin–aldosterone system and to serum sodium intradialytically. [ABSTRACT FROM PUBLISHER]

AimThere is evidence that interaction between angiotensin II type 1 receptor A1166C gene polymorphism and angio-tensin I-converting enzyme Insertion/Deletion gene variation might have an effect on the risk of myocardial infarction. The study was carried out in a population of 2244 male Caucasians, whose coronary anatomy was defined by means of coronary angiography. We analysed the relationship, on the risk of ischaemic heart disease, of angiotensin II type 1 receptor A1166C gene variation, not only to myocardial infarction but also to coronary artery disease, and its potential interaction with angio-tensin I-converting enzyme Insertion/Deletion gene polymorphism.Methods and ResultsNo association was detected between angiotensin II type 1 receptor A1166C gene polymorphism and coronary artery disease. Similarly, there was no link to myocardial infarction, either in the total population or in low risk groups. In addition, most importantly, we found no interaction between angiotensin II type 1 receptor A1166C gene variation and angiotensin I-converting Insertion/Deletion polymorphism, either in connection with the risk of coronary artery disease or myocardial infarction.ConclusionThis angiotensin II type 1 receptor A1166C gene variation is not associated with any detectable increase in risk of ischaemic heart disease. The findings of the present study do not suggest that, as regards risk of coronary artery disease and myocardial infarction, there is interaction between gene polymorphism and angiotensin I-converting enzyme Insertion/Deletion gene variation.The European Society of Cardiology [ABSTRACT FROM PUBLISHER]

AimsThe purpose of this study was to examine, in chronically treated heart failure patients vs control subjects, the influence of neurohumoral activation and aldosterone escape on arterial elastic behaviour, assessed by non-invasive mathematical lumped-parameter modelling of the compliance of the arterial system.Methods and ResultsRadial arterial pulse waves were recorded non-invasively for 30s with an arterial tonometer sensor array in 13 chronic heart failure patients (mean age, 59±2·5 years) in New York Heart Association class II. The patients had been taking digoxin, furosemide, captopril and aspirin for more than 3 months. Thirteen healthy subjects (mean age, 50±4·0 years) acted as controls. Compliance of the proximal (aorta and major branches, C1) and distal parts (C2) of the circulation were derived from a third order four-element modified Windkessel model which can reproduce arterial pressure waveforms, including both exponential and oscillatory sections. Active renin, angio-tensin II and aldosterone levels were determined on venous blood samples in the supine position and after 30min active standing. There was decreased proximal (C1, 1·51±0·11ml.mmHg−1,P<0·01) and distal (C2, 0·050±0·011ml.mmHg−1) arterial compliance in the chronic heart failure patients vs controls (C1, 1·71±0·16ml.mmHg−1; C2, 0·054±0·006ml.mmHg−1). The chronic heart failure patients were characterized by an aldosterone escape phenomenon which was inversely correlated with the proximal arterial compliance in both supine (r=−0·795,P=0·002) and standing (r=−0·628,P=0·029) positions.ConclusionsIn chronically treated heart failure patients with full angiotensin-converting enzyme-inhibition and diuretics, there is decreased compliance of the aorta and its major branches, which is inversely correlated with the aldosterone escape phenomenon. [ABSTRACT FROM PUBLISHER]

In untreated congestive heart failure, aldosterone plasma concentrations are elevated in proportion to the severity of the disease and are further increased by the use of diuretic treatment. Angiotensin II, plasma potassium concentrations, and corticotropin are the major stimulators of aldosterone synthesis. During angiotensin converting enzyme (ACE) inhibition, the role of alternative major or minor regulatory mechanisms may become significant. This may explain why during continuous ACE inhibition, after an initial reduction, plasma aldosterone measurements may subsequently increase to pretherapeutic levels. In addition to causing sodium and water retention, aldosterone contributes to hypokalaemia and hypomagnesaemia, which may induce electrical instability and death of cardiac myocytes. Aldosterone is also one factor involved in cardiac hypertrophy and fibrosis, which, together with myocardial cell death, may underlie progressive adverse myocardial remodelling. Evidence for a direct vascular effect of aldosterone suggests that this hormone may contribute to generalized vasoconstriction. Elevated plasma aldosterone levels can also contribute to depression of barorefiex sensitivity, and they are associated with increased mortality in patients with severe heart failure. Experimental and clinical research should be further expanded to investigate the potential benefits of opposing the effects of aldosterone by use of specific antagonists or other potentially more potent pharmacological agents with favourable side-effect profiles. [ABSTRACT FROM PUBLISHER]

The results of studies in animals indicate that in left ventricular (LV) dysfunction and early heart failure, vasodilative-natriuretic mechanisms effectively antagonize vasoconstrictive-anti-natriure systems; this balancing effect contributes to preservation of circulatory and renal function. Progression to overt heart failure is characterized by a shift of this balance, with dysfunction of vasodilator systems and activation of vasoconstrictor systems. In patients, neurohumoral activation is observed early in asymptomatic LV dysfunction and is related to the severity of LV dysfunction in the progression of the syndrome. Neurohumoral activation precedes overt heart failure, and it has independent prognostic value for the development of heart failure. Activation of the renin-angiotensin system and of the sympathetic nervous system, as well as the possible stimulation of vasopressin secretion, may contribute to the transition from LV dysfunction to heart failure and may, therefore, provide targets for early pharmacological intervention. [ABSTRACT FROM PUBLISHER]

The Framingham heart study has shown that arterial hypertension is the major aetiological factor for the development of heart failure. In the presence of heart failure, various regulatory systems may be operative. These include the Frank-Starling mechanism, the neurohormonal system, regulation of cardiac growth and peripheral oxygen delivery. Recently, the interrelationship of the neuroendocrine system and cardiac growth has been examined.In the pressure or volume overloaded heart, growth of the myocardium involves the enlargement of cardiac myocytes, an adaptation governed by ventricular loading. Non-myocyte cell growth, including cardiac fibroblasts, may also occur. However, the haemodynamic load does not appear to be its major physiological stimulus. Cardiac fibroblast activation is responsible for the accumulation of type I and III collagens, the major fibrillar proteins of the myocardial collagen matrix, while vascular smooth muscle cell growth accounts for medial thickening of coronary resistance vessels. This structural remodelling of the cardiac interstitium represents a major determinant of pathological hypertrophy: it accounts for abnormal myocardial stiffness and impaired coronary reserve, thereby leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure.Several lines of evidence suggest that circulating and tissue renin-angiotensin-aldosterone systems are involved in the structural remodelling of the non-myocyte compartment, including the ‘cardioprotective’ effects of angiotensin converting enzyme (ACE) inhibition or the beneficial effects of anti-aldosterone treatment that were found to prevent myocardial fibrosis in renovascular hypertension due to unilateral renal ischaemia under experimental conditions. In spontaneously hypertensive rats, i.e. the analogous model for primary hypertension in man, with either early or advanced hypertensive heart disease, the ACE inhibitor lisinopril was able to restore myocardial structure and function to normal These ‘cardioreparative’ properties of chronic ACE inhibition may be valuable in reversing left ventricular dysfunction in hypertensive heart disease by treating the structural roots of heart failure. [ABSTRACT FROM PUBLISHER]

The anti-hypertensive effect of ketanserin, a new antagonist of 5-HT-serotonergic receptors, was evaluated in 10 patients with uncomplicated essential hypertension. At the end of 2 weeks of placebo wash-out and following 2 and 4 weeks of treatment with ketanserin (20 mg twice daily), blood pressure and heart rate were measured both in the supine and standing position. In addition, before and at the end of treatment, plasma renin activity ( PRA), plasma concentration of aldosterone and the nocturnal urinary excretion of 6-keto-PGF and TXB, the two metabolites that largely reflect the renal synthesis of prostacyclin and thromboxane, respectively, were determined. The study was carried out in a metabolic ward where the intake of sodium was adjusted to 100–120 mmol day. Ketanserin significantly reduced blood pressure both in the supine and standing position with no significant change of heart rate. The treatment did not produce any variation of PRA, aldosterone, urinary excretion of6-keto-PGF or TXB. These results indicate that ketanserin reduces blood pressure without interfering with the renin-angiotensin-aldosterone system or the renal synthesis of prostacyclin and thromboxane. [ABSTRACT FROM PUBLISHER]

Objectives: Endothelin-1 levels are elevated in a number of conditions characterised by impaired cardiovascular performance and abnormal vasoconstriction such as congestive cardiac failure and primary and secondary pulmonary hypertension. The aim of the present study was to assess the effects of the vasoconstrictor peptide endothelin-1 on pulmonary and systemic haemodynamics and cardiovascular performance in normal man. Methods: Ten healthy male volunteers were studied on two occasions in a randomised, double-blind, placebo-controlled, cross-over study and received systemic infusions of either endothelin-1 (0.75, 1.5 and 3 pmol·kg−1·min−1 for 30 min each) or saline placebo. Systemic and pulmonary haemodynamic parameters were monitored non-invasively by pulsed-wave Doppler, as were parameters of left and right ventricular diastolic filling and inotropic state. Effects on renin–angiotensin and natriuretic peptide system activity were also measured. Results: Endothelin-1 infusion produced dose-related falls in heart rate, stroke volume and cardiac output. Systemic vascular resistance (SVR) increased from 1156±57 to 1738±115 dyn·s·cm−5, and total pulmonary vascular resistance (TPR) increased from 142±12 to 329±22 dyn·s·cm−5. Endothelin-1 caused significant impairment of left and right ventricular diastolic filling, even at a low dose which had no pulmonary or systemic pressor effects. Electromechanical and Doppler acceleration indices of inotropic state were also significantly impaired. Activity of the renin–angiotensin system was suppressed by endothelin-1 whilst plasma levels of atrial natriuretic peptide (ANP) were unchanged. Conclusions: Thus, in addition to systemic and pulmonary pressor effects our results suggest that endothelin-1 impairs overall cardiovascular performance by causing diastolic dysfunction and acting as a negatively inotropic agent. These effects were associated with compensatory changes in the renin–angiotensin system. [ABSTRACT FROM PUBLISHER]

Objective: Cardiac preconditioning represents an important cardioprotective mechanism which limits myocardial ischaemic damage. The aim of this investigation was to assess the impact of preconditioning in hypertension, which is a major risk factor for ischaemic heart disease. Methods: Hearts isolated from male transgenic ((mREN-2)27) hypertensive (TGH) rats, and their normotensive controls (Hannover Sprague-Dawley; SD rats), were perfused at constant flow using the Langendorff technique, and were subjected to either ischaemic preconditioning (3×4 min ischaemia) or continuous perfusion. Global ischaemia was then induced for 30 min, followed by 60 min of reperfusion, during which time mechanical performance was assessed (left ventricular developed pressure (LVDP), heart rate, and end-diastolic pressure). Results: In the absence of preconditioning, mechanical performance was substantially depressed on reperfusion, and there was no difference between TGH hearts and SD hearts (area under the curve (AUC) for the LVDP (LVDP0–60) plot against time for reperfusion = 356±115 and 296±206 mmHg·min, respectively). Cardiac preconditioning caused significant protection in both groups, but this was significantly (P<0.05) greater (3-fold) in the TGH hearts (AUC for LVDP0–60 = 3349±610 mmHg·min) compared to the SD hearts (AUC for LVDP0–60 = 1153±527 mmHg·min). In both groups, preconditioning induced significant protection of diastolic function. The enhanced effects of preconditioning on mechanical performance in the TGH hearts were unaffected by the angiotensin AT1-receptor antagonist, losartan (3 μM). However, losartan did partially reverse the beneficial effects of preconditioning on post-ischaemic diastolic function in the TGH hearts. Conclusions: The results of the present investigation clearly show that cardiac preconditioning is substantially enhanced in hearts from TGH rats. Furthermore, the beneficial effects of preconditioning on diastolic function, but not mechanical performance, in TGH hearts is partially mediated by AT1-receptors. [ABSTRACT FROM PUBLISHER]

Objective: Angiotensin II has been suggested to be involved in the pathogenesis of diastolic dysfunction in left ventricular hypertrophy (LVH). The purpose of this study was to assess the effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on LV diastolic function in 16 normal control dogs and 20 LVH dogs with perinephritic hypertension. Methods: LV hemodynamics was studied before and after intravenous injection of enalaprilat (0.25 mg/kg) or L-158,809 (0.3 mg/kg). The hemodynamic data were analyzed in relation to the changes in myocardial blood flow (measured by radioactive microspheres) and in the circulating angiotensin II and norepinephrine levels. Results and Conclusions: At baseline, significant increases were observed for LV/body weight ratio as well as LV systolic and end-diastolic pressures in the LVH dogs (all P < 0.01 vs. the control group). In addition, LV relaxation time constant was prolonged and the chamber and myocardial stiffness constants were increased (P < 0.01) in the LVH dogs, suggesting an impairment of LV diastolic function. Administration of enalaprilat or L-158,809 improved LV stiffness constants in the LVH dogs (P < 0.05). The diastolic LV pressure-diameter relation shifted downwards in the LVH dogs whereas diastolic distensibility was not altered in the control dogs. Although the circulating angiotensin II levels were significantly decreased by enalaprilat in the LVH dogs, they did not correlate with the changes in the stiffness constants. Furthermore, the alterations of LV diastolic properties in the LVH group could not be attributed to myocardial perfusion, which was rather decreased by administration of enalaprilat and L-158,809. These results suggest that angiotensin II, particularly at the local level, is involved in the pathogenesis of diastolic dysfunction in pressure-overload LVH. The data also support the concept that ACE inhibitors and angiotensin II receptor blockers are potentially beneficial in the treatment of the hypertrophied heart. [ABSTRACT FROM PUBLISHER]

Objective: The aim was to study the effects of high dose systemic human C-type natriuretic peptide (CNP) infusion in man on systemic and pulmonary haemodynamics and the renin-angiotensin system before and after infusion of angiotensin II. Methods: Eight normal male volunteers were studied on two separate occasions when, after the subjects had been rested to reach a baseline haemodynamic state (T0), infusions of either human CNP (10 pmol·kg−1·min−1) or placebo (5% dextrose) were begun. After 30 min (T30) on each study day, a concomitant infusion of angiotensin II (6 ng·kg−1·min−1) was started, and both infusions ran together for a further 30 min (until T60). Measurements of systemic and pulmonary haemodynamic variables and the activity of the renin-angiotensin system were made at baseline (T0), after 30 min of CNP or placebo (T30), and after angiotensin II (T60). Results: Infusion of CNP had no significant effects on systemic or pulmonary haemodynamics or on baseline reninangiotensin system activity compared with placebo. Infusion of angiotensin II produced significant systemic and pulmonary pressor effects and also stimulated aldosterone secretion. There were, however, no significant differences between the changes induced by angiotensin II (expressed as the difference between T30 and T60) when CNP was infused compared with placebo: change in mean systemic arterial pressure with CNP 26.6(SEM 2.3) mm Hg v placebo 30.3(3.6) mm Hg; change in mean pulmonary artery pressure with CNP 11.7(2.5) mm Hg v placebo 10.9(1.0) mm Hg; change in aldosterone concentration with CNP 219(40) pmol·litre−1 v placebo 242(40) pmol·litre−1. Conclusions: At a dose of CNP which has previously been found to have marked haemodynamic effects in dogs, no effect on systemic or pulmonary haemodynamics was observed in man. Furthermore, CNP had no effect on the aldosterone or pressor responses to infused angiotensin II. The present study would suggest that CNP does not have a circulating endocrine role in cardiovascular homeostasis, although a paracrine role within vascular endothelium is perhaps more likely. [ABSTRACT FROM PUBLISHER]