Volume 7, Number 1, March 2006

POPULAR
TOPICPAPERDifferences Between Cardiac and Arterial Fibrosis and Stiffness in Aldosterone-Salt Rats: Effect of Eplerenone
Johnny Nehme, Nathalie Mercier, Carlos Labat, Athanase Benetos, Michel E Safar, Claude Delcayre, Patrick Lacolley

Background: Previous experiments have studied separately the development of either cardiac or aortic fibrosis and stiffness in aldosterone (Aldo)-salt hypertensive rats. Our aim was to determine in vivo the effects of Aldo and the Aldo receptor antagonist eplerenone (Epl) on simultaneous changes in cardiac and arterial structure and function and their interactions.
Methods and Results: Aldo was administered in uninephrectomised Sprague-Dawley rats receiving a high-salt diet from 8 to 12 weeks of age. Three groups of Aldo-salt rats were treated with 1 to 100 mg/kg-1. d-1 Epl by gavage. Arterial elasticity was measured by elastic modulus (Einc)-wall stress curves using medial cross-sectional area (MCSA). The cardiac and arterial walls were analysed by histomorphometry (elastin and collagen), immunohistochemistry (EIIIA fibronectin, Fn), and Northern blot (collagens I and III). Aldo caused increased systolic blood pressure (SBP), carotid Einc, MCSA, and EIIIA Fn with no change in wall stress or elastin and collagen densities. No difference in collagen mRNA levels was detected between groups. During the same period, cardiac mass and collagen mRNA and protein levels increased markedly in the myocardial tissue. Epl normalised collagen in the myocardium, Eincwall stress curves, MCSA, and EIIIA Fn in Aldo rats. These dose-dependent effects were not accompanied by a consistent reduction in SBP and cardiac mass.
Conclusions: In exogenous hyperaldosteronism in the rat, Aldo causes independently myocardial collagen and arterial Fn accumulation, the latter being responsible for increased intrinsic carotid stiffness. Epl prevents both cardiac and arterial effects but does not reduce consistently SBP.

JRAAS 2006;7:31-39.

PAPERBeneficial Effect of Eplerenone on Cardiac Remodelling and Electrical Properties of the Failing Heart
Walmor C De Mello

Introduction:The effect of chronic administration of eplerenone on cardiac remodelling and electrical properties was investigated in the failing heart of cardiomyopathic hamsters (TO-2) at five months of age.
Materials and Methods: Two-month-old hamsters were treated with eplerenone (200 mg/kg/day) administered into the chow for a period of three months. Measurements of membrane potential were performed with intracellular microelectrodes connected to a high impedance DC amplifier. The thickness of the ventricular wall as well as the area of fibrosis were measured. To investigate the influence of eplerenone on the electrogenic sodium pump myocytes were isolated from the ventricle and the pump current density was measured in voltage clamped cells using the whole cell clamp configuration.
Results: The results indicated that: 1) the width of the left and right ventricular wall was significantly reduced; 2) the heart weight/body weight ratio was decreased by 38±2.4% (n=24) (p<0.05); 3) the fibrotic area in the left ventricle (LV) was reduced by 12.6±2% (n=25) (p<0.05); 4) the incidence of cardiac arrhythmias was decreased from 58±3.8% (n=20) in the control to 40±4.1% (n=20) (p<0.05) in animals treated with eplerenone. Moreover, a significant reduction in the dispersion of the QT interval was found with the drug; 5) eplerenone increased the resting potential of ventricular fibres from 64.3±1.5 mV to 73.4±1.4 mV (n=30) (p<0.05), an effect related to the activation of an electrogenic sodium pump. The conduction velocity, in longitudinal direction, was enhanced from 50±2.2 cm/s (n=10) in the controls to 59±2.4 cm/s (n=13) (p<0.05) in animals treated with eplerenone.
Conclusions: Eplerenone reduces cardiac remodelling, the incidence of cardiac arrhythmias and improves impulse propagation, an effect in part related to the antifibrotic effect of the drug but also to the activation of the electrogenic sodium pump.

JRAAS 2006;7:40-46.

PAPERRenal Haemodynamics are not Related to Genotypes in Offspring of Parents with Essential Hypertension
Karin Skov, Jens Kristian Madsen, Hans Erik Hansen, Laura Zagato, Erik Frandsen, Giuseppe Bianchi, Michael John Mulvany

Introduction. The pathogenesis of essential hypertension (EH) has a major genetic component and is associated with renal abnormalities. Normotensive offspring of hypertensive parents are likely to develop EH and are a suitable population for identifying possible relations between genetic and renal abnormalities.
Methods: We investigated if renin-angiotensinaldosterone system associated genotypes (angiotensinogen [M235T] and ACE [I/D]) are related to blood pressure (BP), renal haemodynamics and sodium excretion in sex and age-matched (18–35 years) healthy Caucasian offspring of either two parents with EH (n=101, EH-offspring) or two normotensive parents (n=50, controls). The alpha-adducin polymorphism (G460W) was also investigated.
Results: Compared to controls, BP, heart rate, renal vascular resistance (RVR) and urinary sodium excretion were, respectively, 5%, 7%, 15% and 20% higher in EHoffspring. In controls, the TT-genotype of the M235T angiotensinogen polymorphism was associated with higher BP and higher plasma angiotensinogen. By contrast, in EHoffspring the TT-genotype was associated with lower BP and unchanged plasma angiotensinogen. Plasma angiotensinogen correlated positively with BP in EH-offspring, with a similar tendency (p=0.08) in controls. The distributions of the three candidate polymorphisms were similar in EH-offspring and controls. There were no associations between any of the polymorphisms and any of the renal parameters measured.
Conclusion: The markedly greater RVR, proportionally larger than the greater BP, supports a role for RVR in the pathogenesis of EH. The lack of association between the candidate polymorphisms and the investigated parameters, even in this homogenous and for hypertension strongly predisposed group, suggests that the polymorphisms investigated do not play important roles in the pathogenesis of hypertension.

JRAAS 2006;7:47-55.

POPULAR
TOPICEDITORIAL REVIEWRole of Angiotensin II in Cardiovascular Disease – Therapeutic Implications of More Than a Century of Research
Carlos M Ferrario

More than a century of research on the reninangiotensin system (RAS) has uncovered the widespread involvement of angiotensin II (Ang II) in the pathophysiology of cardiovascular diseases. A number of outcomes-based mega trials utilising hard clinical endpoints have revealed beneficial effects of angiotensin receptor antagonists (AIIAs/ARBs) in patients with hypertension, heart failure, diabetic nephropathy, and post-myocardial infarction (MI). The results of these studies not only emphasise the importance of Ang II in the pathophysiology of these diseases but have provided the basis for an evidence-based approach for the use of AIIAs in clinical practice. It is hoped that the next 100 years of research into the RAS will uncover hitherto unimaginable therapeutic opportunities.

JRAAS 2006;7:3-14.

POPULAR
TOPICEDITORIAL REVIEWAldosterone Inhibition Reduces the Risk of Sudden Cardiac Death in Patients with Heart Failure
Kishlay Anand, Aryan N Mooss, Syed M Mohiuddin

Sudden cardiac death (SCD) accounts for over 450,000 deaths annually in the USA. Sudden death is estimated to account for approximately 50% of all deaths from cardiovascular causes. Total cardiac mortality has decreased from 728,115 in 1989 to 719,456 in 1999 but the percentage of deaths that are sudden has actually increased from 38% to 47%. Prevention of SCD in patients with risk factors is a high priority for public health professionals. Aldosterone has been shown to be associated with myocardial inflammation, endothelial dysfunction and fibrosis. There is evidence from clinical trials suggesting the role of aldosterone inhibition in prevention of SCD. We reviewed the potential mechanisms and discuss the clinical implications of Randomised ALdactone Evaluation Study (RALES) and Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS). The use of aldosterone receptor blockers had an overall effect of 21% risk reduction in SCD. Appropriate monitoring and counselling is essential while using either of the aldosterone inhibitors.

JRAAS 2006;7:15-19.

POPULAR
TOPICCOMMENTARYAldosterone Blockade Over and Above ACE-Inhibitors in Patients with Coronary Artery Disease but without Heart Failure
Nimit C Shah, Stuart Pringle, Allan Struthers

Recent evidence points to a role for the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of atherosclerosis and its complications, including acute angina pectoris. Two large trials in heart failure have clearly demonstrated that blocking aldosterone improves mortality^1,2 and that this benefit occurs over and above standard therapy with angiotensin-converting enzyme (ACE) inhibitors. The question that naturally arises from these landmark studies is whether aldosterone blockade would produce the same benefits in patients with coronary artery disease (CAD) but no heart failure.
There are three reasons to believe this might be the case. Firstly, angiotensin II (Ang II) and aldosterone produce similar biological effects and Ang II withdrawal has been shown to benefit patients with angina; aldosterone blockade may therefore follow in the footsteps of ACE inhibitors, as it did in heart failure, and produce benefits in vascular patients without heart failure. Secondly, one of the main mechanisms which is thought to be responsible for the benefit of aldosterone blockade in the Randomised ALdactone Evaluation Study (RALES) and Eplerenone Post-AMI Heart Failure Survival Study (EPHESUS), is that it improves endothelial/vascular function^3,4 and endothelial/vascular dysfunction is the fundamental abnormality in angina pectoris.
Finally, aldosterone blockade has been shown to reduce atherosclerosis in animal studies of atherosclerosis without heart failure, which are analogous to CAD patients.⁵

JRAAS 2006;7:20-30.

RENIN REPORTSpotlight on Renin: Cardiovascular outcomes in chronic kidney disease and suppression of the renin-angiotensin system
Official publication of the members of the RENIN ACADEMY

JRAAS 2006;7:56-58.