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European journal of heart failure (2020). doi:10.1002/ejhf.1749, Published by Wiley, Oxford

Cardiovascular disease associated with metabolic syndrome has a high prevalence, but the mechanistic basis of metabolic cardiomyopathy remains poorly understood. We characterised the cardiac transcriptome in a murine metabolic syndrome (MetS) model (LDLR-/-; ob/ob, DKO) relative to the healthy, control heart (C57BL/6, WT) and the transcriptional changes induced by ACE-inhibition in those hearts. RNA-Seq, differential gene expression and transcription factor analysis identified 288 genes differentially expressed between DKO and WT hearts implicating 72 pathways. Hallmarks of metabolic cardiomyopathy were increased activity in integrin-linked kinase signalling, Rho signalling, dendritic cell maturation, production of nitric oxide and reactive oxygen species in macrophages, atherosclerosis, LXR-RXR signalling, cardiac hypertrophy, and acute phase response pathways. ACE-inhibition had a limited effect on gene expression in WT (55 genes, 23 pathways), and a prominent effect in DKO hearts (1143 genes, 104 pathways). In DKO hearts, ACE-I appears to counteract some of the MetS-specific pathways, while also activating cardioprotective mechanisms. We conclude that MetS and control murine hearts have unique transcriptional profiles and exhibit a partially specific transcriptional response to ACE-inhibition. ispartof: SCIENTIFIC REPORTS vol:8 issue:1 ispartof: location:England status: published

Background: Fibroblast growth factor (FGF) 23 is a hormone that increases urinary phosphate excretion and regulates renal sodium reabsorption and plasma volume. We studied the role of plasma FGF23 in therapy optimization and outcomes in patients with new-onset and worsening heart failure (HF).Methods: We measured plasma C-terminal FGF23 levels at baseline in 2399 of the 2516 patients included in the BIOlogy Study to Tailored Treatment in Chronic HF (BIOSTAT-CHF) trial. The association between FGF23 and outcome was evaluated by Cox regression analysis adjusted for potential confounders.Results: Median FGF23 was 218.0 [IQR: 117.1-579.3] RU/ml; patients with higher FGF23 levels had a worse NYHA class, more signs of congestion, and were less likely to use an ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARBs) at baseline (all P Conclusions: In patients with new-onset and worsening HF, higher plasma FGF23 levels were independently associated with volume overload, less successful uptitration of ACEi/ARBs and an increased risk of all-cause mortality and HF hospitalization. (c) 2017 Elsevier B.V. All rights reserved.

Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the renal protective effect of RAAS-blockade is incomplete. Short-term clinical studies have demonstrated that dietary sodium restriction potentiates the antiproteinuric effect of RAAS-blockade. More recently, it was shown that this effect is accompanied by a lower risk of end-stage renal disease and adverse cardiovascular outcomes. The modulation of RAAS-blockade efficacy by sodium intake is likely multifactorial, and is mediated by effects of sodium on local tissue RAAS in kidney, vasculature and brain, and by effects on the immune system. Despite the evidence showing the beneficial effects of even a moderate sodium restriction (similar to 2.5 g/d), it remains difficult to realize in clinical practice. In an analysis based on 24-h urinary sodium excretion data from more than 10,000 CKD patients and renal transplant recipients, we found that sodium intake in these patients is on average 3.8 g/d, closely resembling the global general population (3.95 g/d). Behavioral approaches including the use of online dietary coaching (ehealth) and feedback using data from 24-h urine collections may be useful to successfully lower dietary sodium intake, aiming to improve cardio-renal outcomes in patients with CKD. (C) 2016 Elsevier Ltd. All rights reserved.

Galectin-3 activation is involved in the pathogenesis of renal damage and fibrogenesis. Limited data are available to suggest that galectin-3-targeted intervention is a potential therapeutic candidate for the prevention of chronic kidney disease. Homozygous TGR(mREN)27 (REN2) rats develop severe high blood pressure (BP) and hypertensive end-organ damage, including nephropathy and heart failure. Male REN2 rats were treated with N-acetyllactosamine [galectin-3 inhibitor (Gal3i)] for 6 wk; untreated REN2 and Sprague-Dawley rats served as controls. We measured cardiac function with echocardiogram and invasive hemodynamics before termination. BP and proteinuria were measured at baseline and at 3 and 6 wk. Plasma creatinine was determined at 6 wk. Renal damage was assessed for focal glomerular sclerosis, glomerular desmin expression, glomerular and interstitial macrophages, kidney injury molecule-1 expression, and α-smooth muscle actin expression. Inflammatory cytokines and extracellular matrix proteinases were quantified by quantitative real-time PCR. Systolic BP was higher in control REN2 rats, with no effect of Gal3i treatment. Plasma creatinine and proteinuria were significantly increased in control REN2 rats; Gal3i treatment reduced both. Renal damage (focal glomerular sclerosis, desmin, interstitial macrophages, kidney injury molecule-1, α-smooth muscle actin, collagen type I, and collagen type III) was also improved by Gal3i. All inflammatory markers (CD68, IL-68, galectin-3, and monocyte chemoattractant protein-1) were elevated in control REN2 rats and attenuated by Gal3i. Markers of extracellular matrix turnover were marginally altered in untreated REN2 rats compared with Sprague-Dawley rats. In conclusion, galectin-3 inhibition attenuated hypertensive nephropathy, as indicated by reduced proteinuria, improved renal function, and decreased renal damage. Drugs binding to galectin-3 may be therapeutic candidates for the prevention of chronic kidney disease.

Background: There is increased interest in using alternative end points for trials of kidney disease progression. The currently established end points of end-stage renal disease and doubling of serum creatinine level, equivalent to a 57% decline in estimated glomerular filtration rate (eGFR), are late events in chronic kidney disease (CKD), requiring large clinical trials with long follow-up. As part of a comprehensive evaluation of lesser declines in eGFR as alternative end points, we describe the consistency of treatment effects of intervention on the alternative and established end points in past trials.Study Design: Diagnostic test study.Setting & Population: 9,488 participants from 37 randomized controlled trials of CKD progression across 5 intervention types.Index Test: Alternative end points including percentage change in eGFR from baseline (20%, 30%, 40%, and 57%) throughout study duration and to 12, 18, and 24 months. eGFR change confirmed versus nonconfirmed at the next visit.Reference Test: The historically established end point of time to composite of treated kidney failure (end-stage renal disease), untreated kidney failure (GFR Results: Over a median of 3.62 years' follow-up, there were 3,070 established end points. Compared to the established end point, the number of alternative end points was greater for smaller versus larger declines in eGFR and longer versus shorter follow-up intervals. There was a general trend toward attenuation of the treatment effect with end points defined by a lesser eGFR decline, with greater attenuation with nonconfirmed end points, except for the low-protein-diet intervention, for which a stronger treatment effect was observed. The ratio (95% credible interval) of the HR for the alternative to established end point for the 5 intervention types ranged from 0.91 (0.64-1.43) to 1.12 (0.89-1.40) for 40% decline and from 0.88 (0.63-1.39) to 1.15 (0.88-1.54) for 30% decline for the overall study duration, indicating consistency of treatment effects.Limitations: Limited variety of interventions tested and low statistical power for many CKD clinical trials.Conclusions: These results provide some support for the use of lesser eGFR declines as a surrogate end point, with stronger support for the 40% than 30% decline. (C) 2014 by the National Kidney Foundation, Inc.

Supplemental Digital Content is available in the text, Purpose of review Restriction of dietary sodium is recommended at a population level as well as for groups at high cardiovascular risk, and chronic kidney disease (CKD). This review addresses recent evidence for the protective effect of dietary sodium restriction in CKD patients specifically. Recent findings Sodium intake in CKD populations is generally high, and often above population average. Recent data demonstrated that moderately lower sodium intake in CKD patients is associated with substantially better long-term outcome of renin–angiotensin–aldosterone system (RAAS)-blockade, in diabetic and nondiabetic CKD, related to better effects of RAAS-blockade on proteinuria, independent of blood pressure. This is in line with better short-term efficacy of RAAS-blockade during moderate sodium restriction in diabetic and nondiabetic CKD. This effect of sodium restriction is likely mediated by its effects on volume status. Sustainable sodium restriction can be achieved by approaches on the basis of behavioral sciences. Summary Moderate restriction of dietary sodium can substantially improve the protective effects of RAAS-blockade in CKD, by specific renal effects apparent from proteinuria reduction. The latter precludes straightforward extrapolation of data from nonrenal populations to CKD. Concerns regarding the adverse effects of a very low sodium intake should not distract from the protective effects of moderate sodium restriction. Prospective studies should assess the efficacy and sustainability of different strategies to target high sodium intake in CKD, along with measures at population level. Video abstract http://links.lww.com/CONH/A14

Purpose of reviewRestriction of dietary sodium is recommended at a population level as well as for groups at high cardiovascular risk, and chronic kidney disease (CKD). This review addresses recent evidence for the protective effect of dietary sodium restriction in CKD patients specifically.Recent findingsSodium intake in CKD populations is generally high, and often above population average. Recent data demonstrated that moderately lower sodium intake in CKD patients is associated with substantially better long-term outcome of renin-angiotensin-aldosterone system (RAAS)-blockade, in diabetic and nondiabetic CKD, related to better effects of RAAS-blockade on proteinuria, independent of blood pressure. This is in line with better short-term efficacy of RAAS-blockade during moderate sodium restriction in diabetic and nondiabetic CKD. This effect of sodium restriction is likely mediated by its effects on volume status. Sustainable sodium restriction can be achieved by approaches on the basis of behavioral sciences.SummaryModerate restriction of dietary sodium can substantially improve the protective effects of RAAS-blockade in CKD, by specific renal effects apparent from proteinuria reduction. The latter precludes straightforward extrapolation of data from nonrenal populations to CKD. Concerns regarding the adverse effects of a very low sodium intake should not distract from the protective effects of moderate sodium restriction. Prospective studies should assess the efficacy and sustainability of different strategies to target high sodium intake in CKD, along with measures at population level.

In autosomal dominant polycystic kidney disease (ADPKD), activation of the renin-angiotensin aldosterone system (RAAS) may contribute to hypertension and disease progression. Although previous studies have focused on circulating RAAS components, preliminary evidence suggests that APDKD may increase urinary RAAS components. Therefore, our aim was to analyze circulating and urinary RAAS components in ADPKD. We cross-sectionally compared 60 patients with ADPKD with 57 patients with non-ADPKD chronic kidney disease (CKD). The two groups were matched by sex, estimated glomerular filtration rate (eGFR), blood pressure, and RAAS inhibitor use. Despite similar plasma levels of angiotensinogen and renin, urinary angiotensinogen and renin excretion were five- to sixfold higher in ADPKD ( P < 0.001). These differences persisted when adjusting for group differences and were present regardless of RAAS inhibitor use. In multivariable analyses, ADPKD, albuminuria, and the respective plasma concentrations were independent predictors for urinary angiotensinogen and renin excretion. In ADPKD, both plasma and urinary renin correlated negatively with eGFR. Total kidney volume correlated with plasma renin and albuminuria but not with urinary renin or angiotensinogen excretions. Albuminuria correlated positively with urinary angiotensinogen and renin excretions in ADPKD and CKD. In three ADPKD patients who underwent nephrectomy, the concentrations of albumin and angiotensinogen were highest in plasma, followed by cyst fluid and urine; urinary renin concentrations were higher than cyst fluid. In conclusion, this study shows that, despite similar circulating RAAS component levels, higher urinary excretions of angiotensinogen and renin are a unique feature of ADPKD. Future studies should address the underlying mechanism and whether this may contribute to hypertension or disease progression in ADPKD.

Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added to RAAS blockade on residual albuminuria in patients with type 2 diabetic nephropathy.In this multicentre, double-blind, placebo-controlled, crossover randomised trial, we included patients with type 2 diabetic nephropathy. Main entry criteria were microalbuminaria or macroalbuminuria, and creatinine clearance of 30 mL/min or higher with less than 6 mL/min decline in the previous year. We tested the separate and combined effects of sodium restriction (dietary counselling in the outpatient setting) and hydrochlorothiazide (50 mg daily), added to standardised maximal angiotensin-converting enzyme (ACE) inhibition (lisinopril 40 mg daily), on albuminuria (primary endpoint). Patients were given hydrochlorothiazide (50 mg per day) or placebo during four treatment periods of 6 weeks. Both treatments were combined with regular sodium diet or sodium restriction (target sodium intake 50 mmol Na(+) per day). The 6-week treatment periods were done consecutively in a random order. Patients were randomised in blocks of two patients. The trial was analysed by intention to treat. The trial is registered with TrialRegister.nl, number 2366.Of 89 eligible patients, 45 were included in the study. Both sodium restriction and hydrochlorothiazide significantly reduced albuminuria, irrespective of treatment sequence. Residual geometric mean albuminuria with baseline treatment was 711 mg per day (95% CI 485-1043); it was significantly reduced by sodium restriction (393 mg per day [258-599], p=0·0002), by hydrochlorothiazide (434 mg per day [306-618], p=0·0003), and to the greatest extent by their combination (306 mg per day [203-461], p0·0001). Orthostatic complaints were present in two patients (4%) during baseline treatment, five (11%) during addition of sodium restriction, five (11%) during hydrochlorothiazide treatment, and 12 (27%) during combination treatment. No serious adverse events occurred.We conclude that sodium restriction is an effective non-pharmacological intervention to increase RAAS blockade efficacy in type 2 diabetic nephropathy.None.

Chronic immunosuppressive therapy is often complicated by the development of both arterial hypertension and renal dysfunction. The principal aim of this study was to assess the effects of dual inhibition of renin-angiotensin system (RAS) and other antihypertensive treatment on blood pressure and renal function in normotensive and hypertensive Fawn-Hooded (FH) strains during chronic calcineurin inhibitor (CNI) administration. Combinations of perindopril (5 mg kg(-1) per day) and losartan (50 mg kg(-1) per day) or amlodipine (6 mg kg(-1) per day) and metoprolol (80 mg kg(-1) per day) were administered to normotensive (FHL) and hypertensive (FHH) rats, fed with diet containing tacrolimus (Tac; 12 mg kg(-1) per day). Tac-induced arterial hypertension in both animal strains (FHL: 151±4; FHH: 198±6 mm Hg) was prevented by dual RAS inhibition (FHL: 132±3 mm Hg, P0.05; FHH: 153±3 mm Hg, P0.05) as well as by a combination of amlodipine and metoprolol (FHL: 136±3 mm Hg, P0.05; FHH: 166±4 mm Hg, P0.05). However, significant nephroprotection was observed only in animals on dual RAS inhibition where albuminuria was reduced in both FHL (51.1±3.9 vs. 68.3±4.5 μg per day; P0.05) and FHH rats (13.1±0.3 vs. 18.8±0.7 mg per day; P0.05). We also found Tac-induced enhancement in renal angiotensin II activity that was significantly reduced by dual RAS inhibition in both FHL (63.5±3.2 vs. 23.1±3.0 fmol g(-1)) and FHH (79.8±8.5 vs. 32.2±5.8 fmol g(-1)). In addition, histological analysis revealed that RAS inhibition noticeably diminished glomerulosclerosis and tubulo-interstitial injury. This study indicates that dual blockade of RAS significantly attenuates Tac-induced arterial hypertension and nephrotoxicity in FH rats and further supports the notion that RAS inhibitors display efficient renoprotective properties during CNI treatment.

Objective:Sodium restriction potentiates the efficacy of the rennin-angiotensin-aldosterone system (RAAS)-blockade and improves long-term cardiovascular and renal protection, even independent of the better blood pressure control. The mechanisms underlying the potentiation of cardiorenal protection by sodium restriction are incompletely understood. RAAS-blockade with angiotensin-converting enzyme (ACE) inhibitors increases circulating levels of the anti-inflammatory and antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which is assumed to contribute to its therapeutic effects. We hypothesized that sodium restriction on top of RAAS-blockade further increases AcSDKP, as a possible explanation for the enhanced effects of RAAS-blockade during sodium restriction.Methods:To test this hypothesis, we performed a secondary analysis of a randomized clinical trial investigating 46 nondiabetic chronic kidney disease (CKD) patients (age 5013 years, 80% men) with overt proteinuria and mild to moderate renal insufficiency. Patients were subjected, in a crossover design, to four double-blind 6-week study periods with either regular sodium diet (19449mmol Na(+/)day) or low sodium diet (102 +/- 52mmol Na+/day) on top of either lisinopril (40mg/day; single RAAS-blockade) or lisinopril plus valsartan (320mg/day; dual RAAS-blockade).Results:Sodium restriction significantly increased circulating levels of AcSDKP during single and dual RAAS-blockade (P=0.032 and 0.042, respectively). Linear mixed-model analysis confirmed that AcSDKP levels were increased in response to sodium restriction, irrespective of sex, age, creatinine clearance, blood pressure, BMI, single or dual RAAS-blockade, treatment sequence and other dietary factors, that is calcium and protein (P=0.020).Conclusion:In patients with nondiabetic CKD, we demonstrated that sodium restriction, on top of single and dual RAAS-blockade, increases circulating levels of the anti-inflammatory and antifibrotic peptide AcSDKP. The rise in AcSDKP may contribute to the increased protection of RAAS-blockade during sodium restriction.

Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and development of end-stage renal disease (ESRD) remain major concerns in diabetes. In addition, diabetic patients with microalbuminuria have an increased cardiovascular mortality. Therefore, new treatment modalities or strategies are needed to prevent or slow the progression of diabetic nephropathy and prevent cardiovascular disease in diabetes. In this review we describe current concepts in pathophysiology, treatment goals and we discuss future developments in the treatment of diabetic nephropathy. Common risk factors for diabetic nephropathy and its progression are longer duration, poor glycaemic control, hypertension and the presence of albuminuria. Available treatment options, especially renin-angiotensin aldosterone system (RAAS) blockade, but also better blood pressure and blood glucose control, decrease the incidence of cardiovascular disease and renal disease in diabetes. It is important that treatment goals are tailored to the individual patient with individual treatment goals of glycaemic control and blood pressure, depending on age, type of diabetes and diabetes duration. Aggressive treatment of glucose control and blood pressure might not always be best practice for every patient. Since the proportion of ESRD due to diabetic nephropathy remains high, optimisation of RAAS blockade is advocated and can be achieved by adequate sodium restriction and/or diuretic treatment. Moreover, aldosterone blockade might be a valuable strategy, which has potency to slow the progression of diabetic renal disease. Other possible future interventions are under investigation, but large clinical trials have to be awaited to confirm the safety and efficacy of these drugs.

I Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years. Despite the proven efficacy of RAAS blockade, however, the reduction in proteinuria is insufficient in many patients, and does not prevent further deterioration of renal function. Short-term studies have shown that a variety of treatment intensification strategies have a beneficial effect on blood pressure and proteinuria, including RAAS blockade using either dose escalation or multiple drugs, and restriction of dietary sodium. Large clinical trials have shown that RAAS blockade with multiple drugs does not improve patients' long-term renal or cardiovascular outcome. By contrast, two post-hoc analyses of landmark trials in nephrology show beneficial renal and cardiovascular effects from avoiding excessive dietary sodium intake during single-agent RAAS blockade therapy. The effects of dietary sodium restriction on renal or cardiovascular outcome still require prospective confirmation. However, current data support the implementation of lifestyle changes to reduce dietary sodium intake in combination with single-agent RAAS blockade, rather than dual-agent RAAS blockade, as a potent and feasible strategy to mitigate the burden of renal and cardiovascular disease in patients with CKD. Lambers Heerspink, H. J. et al. Nat. Rev. Nephrol. 9, 112-121 (2013); published online 18 December 2012; doi:10.1038/nrneph.2012.281

I Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years. Despite the proven efficacy of RAAS blockade, however, the reduction in proteinuria is insufficient in many patients, and does not prevent further deterioration of renal function. Short-term studies have shown that a variety of treatment intensification strategies have a beneficial effect on blood pressure and proteinuria, including RAAS blockade using either dose escalation or multiple drugs, and restriction of dietary sodium. Large clinical trials have shown that RAAS blockade with multiple drugs does not improve patients' long-term renal or cardiovascular outcome. By contrast, two post-hoc analyses of landmark trials in nephrology show beneficial renal and cardiovascular effects from avoiding excessive dietary sodium intake during single-agent RAAS blockade therapy. The effects of dietary sodium restriction on renal or cardiovascular outcome still require prospective confirmation. However, current data support the implementation of lifestyle changes to reduce dietary sodium intake in combination with single-agent RAAS blockade, rather than dual-agent RAAS blockade, as a potent and feasible strategy to mitigate the burden of renal and cardiovascular disease in patients with CKD. Lambers Heerspink, H. J. et al. Nat. Rev. Nephrol. 9, 112-121 (2013); published online 18 December 2012; doi:10.1038/nrneph.2012.281

Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared to non-RAASi, the trend in risk for renal events was significantly reduced by 43%, not changed, or increased by 37% for each tertile of increased sodium intake, respectively. The trend for cardiovascular events was significantly reduced by 37%, increased by 2% and 25%, respectively. Thus, treatment effects of ARB compared with non-RAASi-based therapy on renal and cardiovascular outcomes were greater in patients with type 2 diabetic nephropathy with lower than higher dietary sodium intake. This underscores the avoidance of excessive sodium intake, particularly in type 2 diabetic patients receiving ARB therapy. Kidney International (2012) 82, 330-337; doi:10.1038/ki.2012.74; published online 21 March 2012

Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the renal protective effect of RAAS-blockade is incomplete. Short-term clinical studies have demonstrated that dietary sodium restriction potentiates the antiproteinuric effect of RAAS-blockade. More recently, it was shown that this effect is accompanied by a lower risk of end-stage renal disease and adverse cardiovascular outcomes. The modulation of RAAS-blockade efficacy by sodium intake is likely multifactorial, and is mediated by effects of sodium on local tissue RAAS in kidney, vasculature and brain, and by effects on the immune system. Despite the evidence showing the beneficial effects of even a moderate sodium restriction (similar to 2.5 g/d), it remains difficult to realize in clinical practice. In an analysis based on 24-h urinary sodium excretion data from more than 10,000 CKD patients and renal transplant recipients, we found that sodium intake in these patients is on average 3.8 g/d, closely resembling the global general population (3.95 g/d). Behavioral approaches including the use of online dietary coaching (ehealth) and feedback using data from 24-h urine collections may be useful to successfully lower dietary sodium intake, aiming to improve cardio-renal outcomes in patients with CKD. (C) 2016 Elsevier Ltd. All rights reserved.

Albuminuria has been associated with increased risk of multiple adverse outcomes, including ESRD, acute kidney injury, cardiovascular disease, and death. Some clinicians advocate for population-based screening of this condition, as a means of identifying individuals at high risk for morbidity and mortality. Several factors influence the potential implementation of screening for albuminuria in the general population, including the type of test used, the threshold for albuminuria, the validity and prognostic value of testing, frequency of follow-up testing, and associated costs of screening. This review discusses the available literature addressing these issues, and suggests an approach to screening patients for albuminuria. (C) 2011 by the National Kidney Foundation, Inc. All rights reserved.

Intervention in the RAAS (renin-angiotensin-aldosterone system) is one of the leading pharmacotherapeutic strategies, among others, used for the treatment of cardiovascular disease to improve the prognosis after myocardial infarction and to reduce hypertension. Recently, regenerative progenitor cell therapy has emerged as a possible alternative for pharmacotherapy in patients after myocardial infarction or ischaemic events elsewhere, e.g. in the limbs. Angiogenic cell therapy to restore the vascular bed in ischaemic tissues is currently being tested in a multitude of clinical studies. This has prompted researchers to investigate the effect of modulation of the RAAS on progenitor cells. Furthermore, the relationship between hypertension and endothelial progenitor cell function is being studied. Pharmacotherapy by means of angiotensin II type I receptor antagonists or angiotensin-converting enzyme inhibitors has varying effects on progenitor cell levels and function. These controversial effects may be explained by involvement of multiple mediators, e.g. angiotensin II and angiotensin-(1-7), that have differential effects on mesenchymal stem cells, haematopoietic progenitor cells and endothelial progenitor cells. Importantly, angiotensin II can either stimulate endothelial progenitor cells by improvement of vascular endothelial growth factor signalling, or invoke excessive production of reactive oxygen species causing premature senescence of these cells. On the other hand, angiotensin-(1-7) stimulates haematopoietic cells and possibly also endothelial progenitor cells. Furthermore, aldosterone, bradykinin and AcSDKP (N-acetyl-Ser-Asp-Lys-Pro) may also affect progenitor cell populations. Alternatively, the variability in effects of angiotensin II type I receptor and angiotensin-converting enzyme inhibition on cardiovascular progenitor cells might reflect differences between the various models or diseases with respect to circulating and local tissue RAAS activation. In the present review we discuss what is currently known with respect to the role of the RAAS in the regulation of cardiovascular progenitor cells.

Important biochemical constituents of the fibrinolytic system include tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). In the current review, we aim to describe the genetic architecture of t-PA and PAI-1. Several genetic polymorphisms in the t-PA and PAI-1 gene have been found to be associated with t-PA and PAI-1 levels in different patient cohorts. However, these genetic variations explain only, a minor part of the heritability of t-PA and PAI-1, suggesting that genes in other pathways may influence t-PA and PAI-1 levels, and that epistasis and gene-environment interactions may play an important role in determining plasma levels of t-PA and PAI-1. Several studies reported that interindividual variation in plasma levels of t-PA and PAI-1 are significantly influenced by common polymorphisms in genes from the renin-angiotensin and bradykinin systems. In addition, we and others documented several gene-environment interactions and epistatic effects of genetic polymorphisms in the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels. In future studies, we need to consider high-order interactions and additional polymorphisms in genes from other (unknown) pathways detected by genome-wide association studies to fully understand the complex genetic architecture of these important intermediate quantitative traits and thereby thrombosis.

Background: To evaluate the effect of supraphysiological levels of angiotensin II and selective angiotensin II type 1 receptor ( AT1-receptor) blockade on neointimal formation and systemic endothelial function after stent implantation in the rat abdominal aorta.Methods: Male Wistar rats were randomized to one of three groups; control (n = 8), angiotensin II infusion (n = 9, 200 ng/kg/min), or candesartan cilexetil (n = 8, AT1-receptor blocker; rats received 14.4 mg kg(-1) day(-1)). Stents were implanted in the abdominal aorta. Histological analyses were performed at 4 weeks. Endothelial function was determined in isolated thoracic aortic rings.Results: Neointimal area was increased in the angiotensin II treated group versus the control group, 0.88 mm(2) +/- 0.21 versus 0.66 mm(2) +/- 0.16 (P Conclusions: Supraphysiological levels of angiotensin II aggravates neointimal formation in the stented rat abdominal aorta, and in parallel decreases endothelial function. AT1-receptor blockade does not reduce neointimal formation in rats without supraphysiological angiotensin II levels. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Because no controlled clinical studies are available about the possible role of angiotensin II receptor blockers in preventing effort myocardial ischemia, we evaluated the effect of angiotensin II receptor blocker/losartan in preventing exercise-induced myocardial ischemia in patients with coronary artery disease. Twenty-four sedentary patients with chronic stable ischemia were prospectively randomized to 28 days (double blind) of losartan 100 mg or losartan placebo in 2 divided doses. In each patient the treatment was crossed over to the alternative regimen (28 days, double blind) after a 1-week placebo period (single blind). At the end of each phase a new exercise stress test was performed. At baseline, systolic blood pressure was significantly decreased after losartan 100 mg compared with losartan placebo. At submaximal exercise, systolic blood pressure and rate-pressure product were lower after losartan 100 mg administration compared with losartan placebo, and these findings remained significant at 1-mm ST depression and at peak exercise. Losartan 100 mg administration versus losartan placebo significantly delayed the time to 1-mm ST-depression onset and decreased ST-segment depression at peak exercise and time to recovery of ST-segment depression. Losartan 100 mg administration compared with losartan placebo was able to significantly increase exercise duration and maximal workload during exercise stress testing. In conclusion, in our study, losartan decreased electrocardiographic parameters of myocardial ischemia in patients with coronary artery disease, suggesting a possible role of this drug in treatment of patients with effort myocardial ischemia.

There is convincing evidence that angiotensin II, through activation of the angiotensin II type 1 (AT1) receptor, is involved in the atherosclerotic process. Similarly, angiotensin receptor blockers decrease vascular inflammation, hypertrophy and thrombosis, which are the key components of the progression of atherosclerosis. In addition, in several animal models, angiotensin receptor blockade was able to inhibit atherosclerosis. However, the effects of angiotensin receptor blockers on clinical outcome in cardiovascular patients remains to be established. Contradictory results have been found on the reduction of the risk on myocardial infarctions and in-stent restenosis, although there is solid evidence for cerebroprotective effects of these receptor blockers. These differences may be related to the role of the AT2 receptor. This review discusses the role of angiotensin II and angiotensin receptor blockers in the atherosclerotic process and its translation into clinical practice.

There is convincing evidence that angiotensin II, through activation of the angiotensin II type 1 (AT1) receptor, is involved in the atherosclerotic process. Similarly, angiotensin receptor blockers decrease vascular inflammation, hypertrophy and thrombosis, which are the key components of the progression of atherosclerosis. In addition, in several animal models, angiotensin receptor blockade was able to inhibit atherosclerosis. However, the effects of angiotensin receptor blockers on clinical outcome in cardiovascular patients remains to be established. Contradictory results have been found on the reduction of the risk on myocardial infarctions and in-stent restenosis, although there is solid evidence for cerebroprotective effects of these receptor blockers. These differences may be related to the role of the AT2 receptor. This review discusses the role of angiotensin II and angiotensin receptor blockers in the atherosclerotic process and its translation into clinical practice.

The endogenous fibrinolytic system describes a complex process resulting in the hydrolytic cleavage of fibrin by plasmin to promote clot dissolution and generate fibrin degradation products. This system helps protect the circulation from intravascular fibrin formation and thrombosis that would otherwise lead to vessel occlusion and tissue ischemia[1;2]. The efficacy of plasminogen activation and fibrin degradation is largely determined by the balance between local concentrations of tissue-type plasminogen activator (t-PA) and it’s cognate inhibitor, plasminogen activator inhibitor type 1 (PAI-1). There is substantial evidence indicating that plasma t-PA and PAI-1 are regulated in part by the renin-angiotensin system (RAS)[3]. Angiotensin II promotes the synthesis of PAI-1 in vitro[4;5]. Furthermore, ACE inhibitors have been shown to reduce plasma PAI-1 levels in patients post-myocardial infarction[6], in hypertensive subjects[7], and in postmenopausal females[8]. Conversely, bradykinin is a potent stimulator for t-PA in humans[9], and ACE-inhibition augments bradykinin induced t-PA release from the arterial vasculature[10;11]. Interactions between the RAS, bradykinin and fibrinolytic systems on t-PA and PAI-1 levels may explain at least part of the relationship between those systems and cardiovascular disease and the beneficial effects of ACE-inhibition on thrombotic events. Indeed, prior studies demonstrated interactions between genes from the fibrinolytic system and RAS on levels of t-PA and PAI-1[12–14]. However, these studies were either performed in selected high-risk populations or had small sample sizes. In addition, no study has yet investigated the interplay between genes from the RAS, bradykinin, and fibrinolytic systems on plasma levels of t-PA and PAI-1 in a single study. Therefore, the aim of the present study was to investigate the effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma levels of t-PA and PAI-1 in a large population-based sample, explicitly examining two-way epistatic interactions.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor I (PAI-I) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-I levels in a large population-based sample from the PREVEND study in Groningen, the Netherlands (n = 2,527). We measured polymorphisms from genes of the fibrinolytic system, the renin-angiotensin system (RAS), and the bradykinin system. We found that males had higher levels of natural-log transformed t-PA, and PAI-I (P

Declining kidney function predicts increasing cardiovascular risk in people with hypertension. Microalbuminuria is a marker for cardiovascular risk and declining kidney function. Agents that block the renin-angiotensin-aldosterone system (RAAS), notably angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), reduce proteinuria and microalbuminuria, lower blood pressure and slow the progression of proteinuric kidney disease. Evidence is accumulating that the combination of an ACE inhibitor and an ARB is the optimal means of RAAS blockade in this setting, slowing the progression of nephropathy independently of blood pressure lowering to a greater degree than can be achieved using maximum approved doses of either agent alone. However, the emerging therapeutic potential of ACE inhibitor/ARB combination therapy in hypertensive kidney disease requires further characterization. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events trial aims to determine definitively whether the combination therapy of an ARB, irbesartan and an ACE inhibitor, ramipril, is more effective than ramipril alone in reducing the urinary albumin excretion rate in patients at high cardiovascular risk with hypertension and proteinuria or microalbuminuria.

Microalbuminuria is an early sign of progressive cardiovascular and renal disease in individuals with and without diabetes. Despite compelling data, at present only a minority of patients with diabetes and rarely individuals without diabetes are screened for albuminuria in a systematic way. All of the criteria to implement systematic albuminuria screening are fulfilled in diabetes, and most are nearly fulfilled for microalbuminuria screening in individuals without diabetes. Because of the growing evidence that treatment of microalbuminuria in individuals without diabetes may offer A cost-effective benefit to prevent cardiovascular disease, nephrologists and other health care providers should pay more attention to the early detection and subsequent treatment of individuals with microalbuminuria.

The incidence of end stage renal disease in patients who have not experienced a classic primary renal disease is dramatically increasing. Chronic kidney disease (CKD) in these patients is due to diabetes, mostly type 2, hypertension and generalised atherosclerosis. As these patients are frequently diagnosed as having renal function impairment only in the late phase, more effort should be undertaken to diagnose them earlier, that is, at a time when renoprotective measures can still be undertaken. For that purpose, measurement of the estimated glomerular filtration rate (GFR) might be helpful. To properly interpret those measurements, however, we need to be aware of the pros and cons of the use of formulas to estimate the GFR. Most likely, a better way to detect subjects at risk of CKD in the early phase is screening by dipstick proteinuria or preferably by testing for (micro-) albuminuria. Because microalbuminuria not only indicates increased renal but also enhanced cardiovascular risk, the benefits of such screening programmes may have a much greater affect than only preventing renal disease.

Weight gain, when it leads to overweight or obesity, is nowadays one of the major health problems. ACE, FTO, AKR1C2, TIMP4 and MMP2 genes have been implicated in previous studies on weight regulation. This study investigated the contribution of polymorphisms in these five candidate genes to the risk of weight gain over a 10-year time period. Two groups were selected from participants of the Doetinchem cohort study who were followed over a 10-year period: A stable weight group (±2 kg/10 year; n = 259) and a weight gainers group who increased their body weight by roughly 10 % (>8 kg/10 year; n = 237). Starting BMI was between 20 and 35 kg/m2 and baseline age between 20 and 45 years. Selected SNPs and insert/deletion in candidate genes were measured in each group. In men, the allelic distribution of FTO rs9939609 (χ 2 p = 0.005), ACE rs4340 (χ 2 p = 0.006) and AKR1C2 rs12249281 (χ 2 p = 0.019) differed between the weight stable and weight gainers group. Interaction between FTO rs9939609 and ACE rs4340 was observed. In women, the allelic distribution of MMP2 rs1132896 differed between the weight stable and weight gainers group (χ 2 p = 0.00001). The A-allele of FTO was associated with a 1.99× higher risk of gaining weight in men (OR 1.99, p = 0.020), while in women, the C-allele of MMP2 was associated with a 2.50× higher risk of weight gain (OR 2.50, p = 0.001) over the 10-year period. We found that FTO in men and MMP2 in women are associated with weight gain over a 10-year follow-up period.

Heart failure after myocardial infarction (MI) is associated with endothelial dysfunction. There is conflicting evidence on the exact nature of this endothelial dysfunction and how endothelium-dependent vasodilation is affected by angiotensin-converting enzyme inhibitor (ACE-I) therapy. Furthermore, consequences of acute ACE-I withdrawal are largely unknown. Therefore, we studied the contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to the effects of ACE-I therapy and its withdrawal on endothelial function in MI rats. Rats were subjected to coronary ligation to induce MI and were assigned to quinapril or vehicle from 2 weeks to 8 months post-MI. In parallel, MI rats treated for 14 months with quinapril were subjected to treatment withdrawal for 0, 4, and 6 weeks. Acetylcholine (ACh)-induced relaxation and underlying endothelium-derived mediators were studied in isolated aortic rings. Long-term quinapril (8 months) resulted in markedly improved endothelium-dependent vasodilation in rats with myocardial infarction, which could be attributed to marked improvement in non-NO/prostanoid-mediated relaxation (ie, EDHF). After 14 months of follow-up, maximum vasodilation was still preserved by quinapril. Withdrawal after 14 months of treatment caused significantly impaired ACh-induced EDHF-mediated relaxation within 4 weeks. A marked reduction in EDHF-mediated relaxation caused this impairment. NO-mediated relaxation was unaffected. These findings highlight the importance of EDHF impairment in development of endothelial dysfunction after myocardial infarction and the possibility of improving EDHF-mediated vasodilation with chronic ACE inhibitor therapy. In addition, withdrawal of chronic ACE inhibition after MI should be considered carefully, as profound endothelial dysfunction may develop rapidly.

Heart failure after myocardial infarction (MI) is associated with endothelial dysfunction. There is conflicting evidence on the exact nature of this endothelial dysfunction and how endothelium-dependent vasodilation is affected by angiotensin-converting enzyme inhibitor (ACE-I) therapy. Furthermore, consequences of acute ACE-I withdrawal are largely unknown. Therefore, we studied the contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to the effects of ACE-I therapy and its withdrawal on endothelial function in MI rats. Rats were subjected to coronary ligation to induce MI and were assigned to quinapril or vehicle from 2 weeks to 8 months post-MI. In parallel, MI rats treated for 14 months with quinapril were subjected to treatment withdrawal for 0, 4, and 6 weeks. Acetylcholine (ACh)-induced relaxation and underlying endothelium-derived mediators were studied in isolated aortic rings. Long-term quinapril (8 months) resulted in markedly improved endothelium-dependent vasodilation in rats with myocardial infarction, which could be attributed to marked improvement in non-NO/prostanoid-mediated relaxation (ie, EDHF). After 14 months of follow-up, maximum vasodilation was still preserved by quinapril. Withdrawal after 14 months of treatment caused significantly impaired ACh-induced EDHF-mediated relaxation within 4 weeks. A marked reduction in EDHF-mediated relaxation caused this impairment. NO-mediated relaxation was unaffected. These findings highlight the importance of EDHF impairment in development of endothelial dysfunction after myocardial infarction and the possibility of improving EDHF-mediated vasodilation with chronic ACE inhibitor therapy In addition, withdrawal of chronic ACE inhibition after MI should be considered carefully, as profound endothelial dysfunction may develop rapidly.

Introduction. Animal studies demonstrated an interaction between angiotensin 11 (Ang 11) responsiveness And endothelium-dependent relaxation (EDR). However, this relation has not been well described in humans. Therefore, we investigated the relation between Ang 11 responsiveness and EDR in isolated human Arteries. Materials and Methods. Segments of the internal mammary artery (IMA) were harvested from 89 patients undergoing coronary bypass surgery. Rings of these segments were exposed in organ bath experiments to metacholine (ME; 10 nmol/L -0.1 mmol/L) after precontraction with phenylephrine (PE; 10 mu mol/L), And secondly to increasing concentrations of Ang 11 (0.1, nmol/L -1 mu mol/L). Results. Patients with the highest contraction to Ang 11 showed the lowest ME relaxation (r=0.312; p=0.003). Angiotensin-converting enzyme (ACE)-inhibition significantly increased Ang 11 sensitivity (p=0.03). This increase was accompanied by a tendency toward decreased EDR (p=0.07). The inverse relation between Ang responsiveness and endothelitium-dependent relaxation could not be explained by an increased tissue or serum ACE-inhibition in patients with a higher endothelium-dependent relaxation. Conclusions. High Ang 11 responsiveness inversely correlates to EDR in IMA's of patients with established coronary Artery disease. Short-term treatment with an ACE-inhibitor increased the response to Ang 11, but had ail adverse effect on EDR.

Both angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) interfere with the activity of the renin-angiotensin system (RAS) in a different way. Theoretically, one might expect beneficial effects when they are used in combination, as a more complete suppression of the RAS can be achieved. But can this additional effect still be seen in patients on full-dose ACE-inhibition? Several controlled trials demonstrated that combination therapy can have additional benefits in hypertensive patients, in chronic heart failure patients, and in both diabetic and non-diabetic nephropathy patients. However, the clinical benefit was not always as pronounced as expected and not every patient will benefit from dual blockade of the RAS. There is some evidence of a less pronounced effect of combination therapy when a full dose of the ACE-inhibitor is given. However, it is well known that ACE-inhibitors cannot completely suppress the formation of angiotensin II, in particular, when the RAS is activated. Indeed, clinical trials indicated that add-on therapy with an ARB was especially of use when the RAS remained activated despite full-dose ACE-inhibitor treatment. In summary, combination of a full-dose ACE-inhibitor and an ARB can be a rational choice in selected patients.

Impaired endothelial function is recognised as one of the earliest events of atherogenesis. Endothelium-dependent vasomotion has been the principal method to assess endothelial function. In this article, we will discuss the clinical value of the different techniques to evaluate endothelium-dependent vasomotion. To date, there seems not to be a simple and reliably endothelial function test to identify asymptomatic subjects at increased risk for cardiovascular disease in clinical practice. Recent studies indicate that pharmacological interventions, in particular with ACE-inhibitors and statins, might improve endothelial function. However, there is no solid evidence that improvement of endothelial function is a necessity for the observed reduction in cardiovascular events by these compounds. Overall, at this moment, there is no place in clinical practice for the use of endothelial function as a method for risk assessment or target of pharmacological interventions. (c) 2005 Elsevier Inc. All rights reserved.

Impaired endothelial function is recognised as one of the earliest events of atherogenesis. Endothelium-dependent vasomotion has been the principal method to assess endothelial function. In this article, we will discuss the clinical value of the different techniques to evaluate endothelium-dependent vasomotion. To date, there seems not to be a simple and reliably endothelial function test to identify asymptomatic subjects at increased risk for cardiovascular disease in clinical practice. Recent studies indicate that pharmacological interventions, in particular with ACE-inhibitors and statins, might improve endothelial function. However, there is no solid evidence that improvement of endothelial function is a necessity for the observed reduction in cardiovascular events by these compounds. Overall, at this moment, there is no place in clinical practice for the use of endothelial function as a method for risk assessment or target of pharmacological interventions. (c) 2005 Elsevier Inc. All rights reserved.

The occurrence of in-stent restenosis is a major drawback of percutaneous transluminal coronary angioplasty with stent placement. Target vessel revascularization is necessary in 15% of patients who receive a stent. Recent advances in the development of drug-eluting stents have reduced these numbers tremendously. However refinement of antirestenotic therapies remains obligatory. The emerging interest in more physiological antirestenotic therapies might unchain an interest in the well-known inhibitors of the rennin-angiotensin system (RAS), the angiotensin-converting enzyme inhibitors, and the angiotensin II type I receptor blockers. Contradictory results overshadow the discussion of whether intervention in the RAS could prevent in-stent restenosis. This review discusses the pathophysiology of in-stent restenosis, the role of the RAS in in-stent restenosis, and the possible role of RAS intervention in the prevention of in-stent restenosis.

Although it is generally accepted that the efficacy of imidapril, an angiotensin-converting enzyme inhibitor, in congestive heart failure (CHF) is due to improvement of hemodynamic parameters, the significance of its effect on gene expression for sarcolemma (SL) and sarcoplasmic reticulum (SR) proteins has not been fully understood. In this study, we examined the effects of long-term treatment of imidapril on mortality, cardiac function, and gene expression for SL Na+/K+ATPase and Na+–Ca2+exchanger as well as SR Ca2+pump ATPase, Ca2+release channel (ryanodine receptor), phospholamban, and calsequestrin in CHF due to myocardial infarction. Heart failure subsequent to myocardial infarction was induced by occluding the left coronary artery in rats, and treatment with imidapril (1 mg·kg–1·day–1) was started orally at the end of 3 weeks after surgery and continued for 37 weeks. The animals were assessed hemody nam ically and the heart and lung were examined morphologically. Some hearts were immediately frozen at –70 °C for the isolation of RNA as well as SL and SR membranes. The mortality of imidapril-treated animals due to heart failure was 31% whereas that of the untreated heart failure group was 64%. Imidapril treatment improved cardiac performance, attenuated cardiac remodeling, and reduced morphological changes in the heart and lung. The depressed SL Na+/K+ATPase and increased SL Na+–Ca2+exchange activities as well as reduced SR Ca2+pump and SR Ca2+release activities in the failing hearts were partially prevented by imidapril. Although changes in gene expression for SL Na+/K+ATPase isoforms as well as Na+–Ca2+exchanger and SR phospholamban were attenuated by treatments with imidapril, no alterations in mRNA levels for SR Ca2+pump proteins and Ca2+release channels were seen in the untreated or treated rats with heart failure. These results suggest that the beneficial effects of imidapril in CHF may be due to improvements in cardiac performance and changes in SL gene expression.Key words: sarcolemmal Na+/K+ATPase, Na+–Ca2+exchange, sarcoplasmic reticulum, heart failure, ACE inhibition.

Coronary vasomotor function plays an important role in onset and progression of coronary artery disease. Suwaidi [Circulation 101 (2000) 948] and Schächinger [Circulation 101 (2000) 1899] demonstrated that vasomotor dysfunction has a significant impact on events in patients with minimal coronary artery disease. Endothelial specific testing can be performed in coronary as well as peripheral arteries. However, non-coronary tests have a low correlation with the coronary vasomotor response, as assessed by acetylcholine. In large clinical prospective placebo-controlled trials, angiotensin-converting enzyme (ACE) inhibitors and lipid-lowering drugs reduce morbidity and mortality after myocardial infarction or myocardial infarction-induced heart failure. The same drugs restore endothelial dysfunction after myocardial infarction, as was demonstrated in small experimental and clinical studies. Recent studies in patients with coronary artery disease showed a relation with endothelial dysfunction and the occurrence of adverse coronary events. For this reason, it is important to develop methods to evaluate endothelial function.

In heart failure., a deficient oxygen supply often is a primary cause for myocardial dysfunction. The reverse however, may also be true; the changes that occur in the failing heart may predispose for the existence of tissue hypoxia, which further affects the function of the heart. Specifically, myocardial by ertrophy and accelerated heart rhythm enhance oxygen demand, while supply is hampered short by endothelial dysfunction and diffusion barriers (such as fibrosis, arterial hyperplasia, and myocyte hypertrophy). Another contributory factor may be deficient growth of the microvasculature that does riot keep pace with the rate of myocardial hypertrophy. Fewer microvessels have been observed in many forms of cardiomyopathies. On the other hand, some distinct forms of cardiomyopathics are characterized by the compensatory growth of microvessels, or even excess angiogenesis. This review summarizes the knowledge that has been gathered on this topic thus far and discusses factors that mediate myocardial microvessel growth. Furthermore, a paradigm is presented in which the rate of microvessel growth predicts, at least in part, the degree of myocardial dysfunction. Therapies aimed at the restoration of the microcirculation are proposed to preserve and improve myocardial function.

Renin-angiotensin system (RAS) overactivity has been implied in progressive renal function loss. We investigated whether changes in the renal expression of RAS components are specifically associated with the proteinuric kidney.Unilateral adriamycin-induced proteinuria was obtained by clamping the left renal artery before injection of adriamycin. In control animals, both left and right renal arteries were clamped. Twelve weeks later, mRNA expression of RAS components was determined in both kidneys. In the affected and non-affected kidney of the unilateral proteinuric rat, we demonstrate up-regulation of angiotensin-converting enzyme (ACE) mRNA (213%+/-22 and 188%+/-24 of controls, respectively), up-regulation of transforming growth factor P (TGF-beta) mRNA (956%+/-229 and 418%+/-56) and down-regulation of angiotensin type 2 receptor (AT(2)-R) mRNA (24%+/-5 and 20%+/-5). The expression of angiotensin type 1 receptor (AT(1)-R) mRNA and inositol 1,45-trisphosphate receptor type I (IP3R-I) mRNA were unchanged.In conclusion, renal expression of ACE, AT(2)-R, and AT(1)-R mRNA is not mediated by protein leakage Local intrarenal protein leakage did influence renal TGF-beta mRNA expression.

Aims Information regarding the cardiorenal axis in patients after a myocardial infarction (MI) is limited. We examined the change in renal function after a first MI, the protective effect of angiotensin converting enzyme (ACE) inhibition and the prognostic value of baseline renal function. Methods and results The study population consisted of 298 patients with a first anterior wall MI who were randomized to the ACE inhibitor captopril or placebo after completion of streptokinase infusion. Renal function, by means of glomerular filtration rate (GFR), was calculated using the Cockroft–Gault equation (GFRc). In the placebo group, renal function (GFRc) declined by 5.5mlmin−1within 1 year, vs only 0.5mlmin−1in the ACE inhibitor group \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((P{ 103mlmin−1was 1.86 (95% CI 1.11–3.13; \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P=0.019\) \end{document}). Conclusions Renal function markedly deteriorates after a first MI, but is significantly preserved by ACE inhibition. Furthermore, an impaired baseline renal function adds to the prognostic risk of developing CHF in patients after a first anterior MI.

Objective: To study the effects of increased levels of myocardial angiotensin II type I (AT,) receptor on microvascular growth following myocardial infarction (MI). Methods: MI was created in transgenic rats (TGR) with a cardioselective overexpression of the AT(1) receptor. We used Sprague-Dawley (SD) rats as controls. Some of the rats were treated with the selective AT(1) receptor blocker losartan (Los). Rats were sacrificed after 3 weeks. Results: MI caused left ventricular (LV) hypertrophy and LV dysfunction in both SD and TGR, which was prevented by AT, receptor blockade. Furthermore, MI decreased microvessel density in the non-infarcted myocardium (SD MI: 1653+/-37 /mm(2), p

Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II (Ang II), AT(1)-receptor blockers (ARB) is the cornerstone of renoprotective therapy. Still, the number of patients with end-stage renal disease is increasing worldwide, prompting the search for improved renoprotective strategies. In spite of proven efficacy at group level, the longterm renoprotective effect of RAAS blockade displays a marked between-patient heterogeneity, which is closely linked to between-patient differences in the intermediate parameters of blood pressure, proteinuria and renal haemodynamics. Of note, the between-patient differences by far exceed the between-regimen differences, and thus may provide a novel target for exploration and intervention. The responsiveness to RAAS blockade appears to be an individual characteristic - as demonstrated by studies applying a rotation-schedule design. The type and severity of renal disease, obesity, insulin-resistance, glycaemic control, and genetic factors may all be involved in individual differences in responsiveness, as well as dietary factors, such as dietary sodium and protein intake. Several strategies, such as dietary sodium restriction and diuretic therapy, close-titration for proteinuria, and dual RAAS blockade with ACE-I and ARB, can improve the response to therapy at a group level. However, when analysed for their effect in individuals, it appears that these measures do not allow poor responders to catch up with the good responders, i.e. in spite of their efficacy at group level, the available measures are usually not sufficient to overcome individual resistance to RAAS blockade. We conclude that between-patient differences in responsiveness to renoprotective intervention should get specific attention as a target for intervention. Unravelling of the underlying mechanisms may allow development of specific intervention. Based on the currently available data, we propose that response-based treatment schedules, with a multidrug approach titrated and adapted at individual responses rather than fixed treatment schedules, may provide a fruitful strategy for more effective renoprotection.

Data from recent clinical trials show that lowering of BP reduces the rate of renal function loss in chronic renal disease. There is evidence supporting the assertion that BP lowering obtained by intervention in the renin-angiotensin-aldosterone system (RAAS) has an additive renoprotective effect in both diabetic and nondiabetic renal diseases. However, to dissociate BP-dependent and non-BP-dependent action of RAAS blockade, the relevant trials are in many cases flawed by design, resulting in BP differences between the comparative anti hypertensive strategies. This review discusses whether the relevant literature allows for the conclusion that RAAS intervention has renoprotective effects in addition to its effects on BP. In particular, the main evidence for a specific renoprotective action of RAAS blockade is provided by its consistent antiproteinuric action, which cannot completely be attributed to the reduction in BP. Indeed, other strategies that lower proteinuria without having an antihypertensive effect, such as lowering dietary protein intake or the use of nonsteroidal antiinflammatory drugs, appear to have a renoprotective effect as well. Interestingly, a consistent finding across different intervention studies is that the more proteinuria is reduced the better the kidney appears to be protected. Therefore, it is concluded that agent-characteristics of RAAS intervention (i.e., antiproteinuric properties) independently influence renal function loss in addition to its BP-lowering effect. Future studies should further explore the renoprotective benefit of non-anti hypertensive intervention measures, alone and in combination with antihypertensive strategies.

Background. The antiproteinuric effect of combining the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the angiotensin II (Ang II) antagonist losartan was compared to that of the optimal antiproteinuric doses of monotherapy. Methods. To this purpose, lisinopril and losartan were studied in 9 nondiabetic renal patients with median proteinuria 4.5 g/day (95% Cl, 3.5, 6.4), creatinine clearance of 80 mL/ min (95% CI, 66, 96), and mean arterial pressure (MAP) of 102 mm Hg (95 % CI, 93, 112). First, in two protocols with six-week treatment periods per dose, the optimal antiproteinuric dose of each drug was established in each patient. Losartan and lisinopril were used in randomized order, each preceded by a baseline period without medication. The doses of losartan (mg/day) were 50, 100, 150, and again 50. The lisinopril doses were 10, 20, 40, and again 10. After the second protocol, patients were treated with a combination, using the optimal antiproteinuric doses established for the individual drugs. Results. The antiproteinuric response by losartan was optimal at 100 mg (-46%; 95% CI, -60, -24%), being larger than at the 50 mg dose (-27%; 95% CI, -42, -4%, P

Background. ACE inhibition exerts an antiproteinuric and renoprotective effect. However, residual proteinuria is often present. As residual proteinuria is associated with a poor renal outcome, identification of its determinants is important. We found previously that the systemic sequelae of proteinuria enhance renal damage in untreated nephrotic rats. The impact of systemic nephrosis on renal therapy response, however, is unclear. In the present Study we therefore investigated whether the severity of systemic nephrosis, estimated from plasma cholesterol, predicts residual proteinuria during ACE inhibition. Methods. Sixty male Wistar rats with established adriamycin nephrosis were studied. Six weeks after the induction of nephrosis, rats were stratified for proteinuria and treated for 2 weeks with lisinopril (75 mg/l) or vehicle. Results. At the start of treatment, median proteinuria was 744 mg/day (95% confidence interval (CI) 609 860) and plasma cholesterol was 10.4 mmol/l (95% CI 8.0 12.6), reflecting the state of systemic nephrosis. Lisinopril, but not vehicle, reduced blood pressure and proteinuria (-62%; range -70 to -48; P

Aims To predict the long-term left ventricular volume index early after myocardial infarction and to investigate the relationship between long-term left ventricular dilatation risk and clinical outcome.Methods and Results By applying a previously developed dilatation model, we predicted the 6-month left ventricular volume index early after myocardial infarction (median 9 days) in 13 679 GISSI-3 patients, to identify patients at high risk of long-term left ventricular dilatation. The left ventricular systolic and diastolic volume indexes at 6 months were predicted with r=0.72 and r=0.68. respectively. in the subgroup of patients in whom a pre-discharge echo was available (n=7842). Patients predicted to be at risk for long-term left ventricular dilatation had an increased risk of mortality (R.R. 1.87. 95% CI: 1.48 to 2.36) and heart failure at 6 months (RR 2.59, 95% CI:2.04 to 3.28), but no increased risk of reinfarction at 6 months (RR 1.12, 95% CI: 0.87 to 1.45) or of angina pectoris (RR 1.07, 95% CI: 0.95 to 1.20).Conclusion Our prediction of long-term left ventricular dilatation, obtained by applying our new dilatation model in over 13 000 GISSI-3 patients, correlated well with mortality and heart failure after myocardial infarction, Therefore, our new dilatation model may contribute to more efficient risk stratification early after myocardial infarction. (C) 2001 The European Society of Cardiology.

The presence of an altered renal function in essential hypertension, advanced heart failure (HF) and after a myocardial infarction (MI) is associated with higher cardiovascular morbidity, and mortality. Indices of altered renal function (e.g., microalbuminuria, increased serum creatinine concentrations, decrease in estimated creatinine clearance or overt proteinuria) are independent predictors of cardiovascular morbidity, and mortality in any, of the three clinical situations. These parameters should then be routinely evaluated in clinical practice. These facts have several therapeutic implications. First, although there is no evidence-based information on the level of blood pressure that confers optimal renal protection, levels substantially, lower than past recommendations are advisable, Second, hypertensive kidney, damage should be prevented by, early treatment of hypertensive patients, particularly those with microalbuminuria. Finally, to avoid further aggravation of high cardiovascular risk, antihypertensive agents devoid of unwanted metabolic side effects should be used for the treatment of hypertensive vascular damage, In HF, the combination of an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker seem to be the most renoprotective. Renal outcome is also improved by, ACE inhibition after an MI. Finally,, renal and cardiovascular outcome seem to run in parallel in all these situations. (J Am Coll Cardiol 2001;38:1782-7) (C) 2001 by the American College of Cardiology.