729-1 Modulation of Cardiac Hypertrophy by Blockade of the Renin Angiotensin System: Effects on LVH Regression, Gene Expression, and Survival

The aim of the present study was to investigate the contribution of the renin angiotensin system to maintenance of pressure overload left ventricular hypertrophy (LVH). Rats with fixed ascending aortic stenosis were treated with either vehicle (VEH, n=36), hydralazine (HYD, 20mg/kg/d, n=35). ramipril (RAM, 10mg/kg/d, n=35), or losartan (LOS, 40mg/kg/d, n=16) during weeks 6–12 after banding. We have previously demonstrated that compared to sham (n=36), VEH and HYD rats were characterized by a 1.8–1.9-fold increase of left ventricular to body weight ratios (LV/BW). whereas those aortic stenosis rats treated with RAM or LOS displayed a blunted increase of LV/BW (14-fold; p<0.05, each vs. HYD). We now extend these observations demonstrating that myocyte cross sectional widths were increased by 150% in VEH and HYD rats (p<0.001, vs. sham), whereas ramipril and losartan treatment resulted in myocyte widths that were only mildly elevated (53% and 28%, respectively). Furthermore, VEH and HYD displayed a 14–15 fold increase of LV atrial natriuretic peptide (ANP) mRNA as well as a 44% decrease of sarcoplasmatic reticulum (SR) Ca2+-ATPase (p<0.001, vs. sham). In contrast, alterations of ANP and SR-Ca2+-ATPase mRNA levels were significantly blunted by both RAM and LOS. The attenuation of LVH by RAM or LOS was not explained by blood pressure reduction that was similar in the HYD group. Finally, RAM and LOS decreased mortality (6 out of 51 animals; 11%)as compared to 20% in HYD and 31% in VEH groups (p<0.05).In summary, blockade of the renin angiotensin system may promote regression of pressure overload LVH on the macro-, and microscopical, as well as the molecular level by mechanisms that are, in part, independent of hemodynamic drug effects. LVH regression may improve survival despite persisting pressure overload

Effects of hypoxia on renin secretion and renal renin gene expression

Effects of hypoxia on renin secretion and renal renin gene expression. Plasma renin activity (PRA) and renal renin mRNA levels were measured in male rats exposed to hypoxia (8% O2) or to carbon monoxide (CO; 0.1%) for six hours. PRA increased fourfold and 3.3-fold, and renin mRNA levels increased to 220% and 200% of control, respectively. In primary cultures of renal juxtaglomerular (JG) cells, hypoxia (lowering medium O2 from 20% to 3% or 1%) for 6 or 20hours did not affect renin secretion or gene expression. Renal denervation did not prevent stimulation of the renin system by hypoxia. Because norepinephrine increased 1.7-fold and 3.2-fold and plasma epinephrine increased 3.9-fold and 7.8-fold during hypoxia and CO inhalation, respectively, circulating catecholamines might mediate the stimulatory effects of hypoxia on renin secretion and renin gene expression. Stimulation of β-adrenergic receptors by continuous infusion of 160 μg/kg/hr isoproterenol increased PRA 17-fold and 20-fold after three and six hours, respectively, and renin mRNA by 130% after six hours. In rats with a stimulated renin system (low-sodium diet), isoproterenol did not stimulate PRA or renal renin mRNA further. In summary, both arterial and venous hypoxia can stimulate renin secretion and renin gene expression powerfully in vivo but not in vitro. These effects seem not to be mediated by renal nerves or by a direct effect on JG cells but might be mediated by circulating catecholamines

Improvement of the cardiac marker N-terminal-pro brain natriuretic peptide through adjustment for renal function: a stratified multicenter trial

Background: N-terminal-pro brain natriuretic peptide (NT-proBNP) is a useful cardiac marker that is also influenced by renal dysfunction. It was our objective to assess the relationship between NT-proBNP concentrations in plasma and worsening renal function, and to attempt adjustment of NT-proBNP for renal dysfunction in a prospective, stratified multi-center study. Methods: We stratified 203 male patients according to their cardiac status and the estimated glomerular filtration rate (eGFR). Cardiac disease was assessed by medical history, physical examination and standardized echocardiography. Patients were stratified according to the following: absence of cardiac history and abnormalities (control, CTRL, n=66), cardiac history without left ventricular hypertrophy (LVH) or left ventricular systolic dysfunction (LVD) (history, n=30), LVH without systolic dysfunction (LVH, n=68), and LVD [ejection fraction (EF) <40%, LVD, n=39]. Renal disease was stratified according to the eGFR: 15–30 mL/min (n=52), 31–75 mL/min (n=99), and >75 mL/min (n=52). Results: NT-proBNP was correlated with eGFR in the entire study population and for all levels of cardiac disease (all p<0.01). Regression analysis allowed adjustment of NT-proBNP for eGFR in a continuous manner, and this adjustment significantly improved the predictive value (receiver operating characteristic curve for symptomatic LVD from 0.80 to 0.86, p<0.01; sensitivity from 74% to 83% and specificity from 68% to 79%). Conclusions: NT-proBNP correlates inversely and significantly with eGFR throughout all levels of cardiac strata. We propose for the first time a continuous adjustment algorithm which markedly improves the predictive values of NT-proBNP in male patients with impaired renal function. Clin Chem Lab Med 2010;48:121–8.Peer Reviewe

Improvement of the cardiac marker N-terminal-pro brain natriuretic peptide through adjustment for renal function: a stratified multicenter trial

Background: N-terminal-pro brain natriuretic peptide (NT-proBNP) is a useful cardiac marker that is also influenced by renal dysfunction. It was our objective to assess the relationship between NT-proBNP concentrations in plasma and worsening renal function, and to attempt adjustment of NT-proBNP for renal dysfunction in a prospective, stratified multi-center study. Methods: We stratified 203 male patients according to their cardiac status and the estimated glomerular filtration rate (eGFR). Cardiac disease was assessed by medical history, physical examination and standardized echocardiography. Patients were stratified according to the following: absence of cardiac history and abnormalities (control, CTRL, n=66), cardiac history without left ventricular hypertrophy (LVH) or left ventricular systolic dysfunction (LVD) (history, n=30), LVH without systolic dysfunction (LVH, n=68), and LVD [ejection fraction (EF) 75 mL/min (n=52). Results: NT-proBNP was correlated with eGFR in the entire study population and for all levels of cardiac disease (all p<0.01). Regression analysis allowed adjustment of NT-proBNP for eGFR in a continuous manner, and this adjustment significantly improved the predictive value (receiver operating characteristic curve for symptomatic LVD from 0.80 to 0.86, p<0.01; sensitivity from 74% to 83% and specificity from 68% to 79%). Conclusions: NT-proBNP correlates inversely and significantly with eGFR throughout all levels of cardiac strata. We propose for the first time a continuous adjustment algorithm which markedly improves the predictive values of NT-proBNP in male patients with impaired renal function