Therapeutic Advances in Cardiovascular Disease current issue

Changes seen in the aging kidney and the effect of blocking the renin--angiotensin system

Tue, 06 Oct 2009 09:21:11 PDT

Background: The objective was to evaluate structural changes of glomeruli during aging and the role of chronic renin—angiotensin system inhibition (RASi) on these changes; starting RASi on Wistar rats at two different moments: the first group after weaning and the second at the midpoint of their lifespan (12 months).

Methods: Thirty rats were divided, after weaning, into three groups of 10: group 1: control (C); group 2 : 30 mg/kg/day losartan (L); group 3 : 10 mg/kg/day enalapril (E). At 18 months, rats were placed in metabolic cages to evaluate proteinuria, then killed. Another group of 24 rats, 12 months old, were divided into three groups of eight: group 1: C; group 2: L; group 3: E. At 18 months the same procedure described above was carried out. Finally, a third group of 20 rats was studied as healthy controls and killed: 10 rats at 7 months and ten at 12 months of age. Tissue samples were collected after sacrifice. To evaluate glomerular fibrotic changes, both focal and periglomerular sclerosis, and mesangial matrix expansion, a scoring scale was established. We also evaluated anti--SM-actin and anti-collagen-III immunolabeling. Glomerular area was measured using an image analyzer.

Results: Proteinuria and serum creatinine increased with age but were reduced in treated animals. Main glomerular changes present in 18-month-old rats were reduced by half in treated animals. Glomerular area showed significant increase with normal aging and all treatment strategies protected against it.

Conclusion: RAS plays a central role in natural process of renal aging, probably by producing effects influencing the biology of aging, the effects of which can be attenuated by RASi.

Low dietary sodium intake is associated with enhanced vascular endothelial function in middle-aged and older adults with elevated systolic blood pressure

Jablonski, K. L., Gates, P. E., Pierce, G. L., Seals, D. R. — Tue, 06 Oct 2009 09:21:11 PDT

Background: Age and increasing systolic blood pressure (BP) are associated with vascular endothelial dysfunction, but the factors involved are incompletely understood. We tested the hypothesis that vascular endothelial function is related to dietary sodium intake among middle-aged and older adults (MA and O) with elevated systolic BP.

Methods: Data were analyzed on 25 otherwise healthy adults aged 48—73 years with high normal systolic BP or stage I systolic hypertension (130—159 mmHg). Self-reported sodium intake was <100 mmol/d in 12 (7 M) subjects (low sodium, 73±6 mmol/d) and between 100 and 200 mmol/d in 13 (9 M) subjects (normal sodium, 144±6 mmol/d).

Results: Groups did not differ in other dietary factors, age, body weight and composition, BP, metabolic risk factors, physical activity and maximal aerobic capacity. Plasma concentrations of norepinephrine, endothelin-1, oxidized low-density lipoproteins (LDL), antioxidant status and inflammatory markers did not differ between groups. Brachial artery flow-mediated dilation (FMD) was 42% (mm ) to 52% (% ) higher in the low versus normal sodium group (p < 0.05). In all subjects, brachial artery FMD was inversely related to dietary sodium intake (FMD mm r =—0.40, p < 0.05; %r =—0.53, p < 0.01). Brachial artery FMD was not related to any other variable. In contrast, endothelium-independent dilation did not differ between groups (p ≥ 0.24) and was not related to sodium intake in the overall group (p ≥ 0.29).

Conclusions: Low sodium intake is associated with enhanced brachial artery FMD in MA and O with elevated systolic BP. These results suggest that dietary sodium restriction may be an effective intervention for improving vascular endothelial function in this high-risk group.

Aggressive statin therapy in multicenter and effectiveness for the reduction of intra-myocardial damage caused by non-ST elevation acute coronary syndrome: AMERICA study

Tue, 06 Oct 2009 09:21:11 PDT

Background: While preprocedural statin treatment for acute coronary syndrome (ACS) is widely regarded as beneficial, there has been no prospective randomized multicenter trial of patients with non-ST elevation ACS in the Japanese population to examine the efficacy of preprocedural aggressive statin use. The aim of this study was to confirm this effect by prospective randomized multicenter design.

Methods: Fifty patients who presented with non-ST elevation ACS were enrolled, and randomly assigned to aggressive statin administration before percutaneous coronary intervention (PCI). Troponin-T (TnT), creatine phosphokinase (CK), CK-myocardial band (CK-MB), high-sense C-reactive protein (hs-CRP), and brain natriuretic peptide (BNP) were measured at baseline and/ or after procedure.

Results: Three days after PCI, the statin group had significantly less CK elevation compared with the nonstatin group (84±17 IU/l versus 180±68 IU/l, respectively, p = 0.02). CK-MB elevation also tended to be lower in the statin group than in the nonstatin group (3.2±1.9 versus. 7.0±3.0, respectively, p = 0.07), as was BNP level (3.2±1.9 versus 7.0±3.0 pg/ml, respectively, p = 0.07). The change of serum LDL cholesterol was significantly correlated with CK (p = 0.01) and TnT (p = 0.02) at 1 day after PCI.

Conclusions: Aggressive statin usage before PCI to Japanese patients with non-ST elevation ACS appears to reduce myocardial damage after procedure. The degree of serum lipid level reduction may reflect the vulnerability of atheromatous plaques that could cause cardiac damage after PCI.

Some mechanical aspects of arterial aging: physiological overview based on pulse wave analysis

Hashimoto, J., Ito, S. — Tue, 06 Oct 2009 09:21:11 PDT

Aging has a striking impact on the arterial structure and function. The principal structural change with age is medial degeneration that leads to a progressive stiffening of the large elastic arteries. Large artery stiffening increases aortic systolic and pulse pressures through an increase in the forward incident wave and an early return of the backward reflected wave. Peripheral muscular arteries/arterioles are only minimally affected in structure by aging itself, but impaired vasomotor function can alter their impedance properties and thereby increase reflection magnitude. An augmented aortic pressure due to enhanced wave reflection increases wasted left ventricular effort and causes cardiac hypertrophy. Increased pulsatile pressure and flow stresses extend to the vulnerable microcirculation of vasodilated organs such as the brain and kidneys, and can predispose to cerebral lacunar infarction and albuminuria. Although most currently available vasodilators appear to have little direct effect on degenerated elastic arteries, they can act instead on less-degenerated muscular arteries to markedly reduce peripheral wave reflection magnitude and central aortic pressure, and thus contribute to the regression of left ventricular hypertrophy. Further studies are necessary to examine whether the effect of vasodilator therapy on reducing wave reflection contributes similarly to the prevention of microvascular damage in the brain and kidneys.

Blocking aldosterone in heart failure

Shafiq, M. M., Miller, A. B. — Tue, 06 Oct 2009 09:21:11 PDT

Fifty years after its discovery, aldosterone continues to stimulate interest as a therapeutic target. Early studies focused on aldosterone’s actions on hypertension, the kidney, and electrolyte handling. More recently, its actions on the heart and cardiovascular system have become more apparent. Aldosterone causes cardiac fibrosis and remodeling, and stimulates neurohormonal systems that adversely affect the cardiovascular system. Aldosterone antagonism attenuates these negative effects. Clinical studies have applied this science and demonstrated improved morbidity and mortality with aldosterone blockade, specifically in patients with chronic heart failure and patients who are postmyocardial infarction and with depressed left ventricular function. This article will address the pathophysiology of aldosterone in cardiac fibrosis and remodeling, review the current clinical trial data, and explore the application of aldosterone blockade in an expanded heart failure population. The Randomized Aldactone Evaluation Study showed that the aldosterone antagonist spironolactone reduced mortality when compared to placebo in patients with chronic advanced heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study demonstrated a significant reduction in mortality and hospitalizations for patients randomized to the aldosterone antagonist eplerenone. A more provocative question is whether aldosterone antagonism will afford the same protection in patient populations with heart failure and preserved left ventricular function. Clinical trials are underway, and results are eagerly awaited.

Treating type 2 diabetes: incretin mimetics and enhancers

Nori Janosz, K. E., Zalesin, K. C., Miller, W. M., McCullough, P. A. — Tue, 06 Oct 2009 09:21:11 PDT

As a consequence of excess abdominal adiposity and genetic predisposition, type 2 diabetes is a progressive disease, often diagnosed after metabolic dysfunction has taken hold of multiple organ systems. Insulin deficiency, insulin resistance and impaired glucose homeostasis resulting from beta-cell dysfunction characterize the disease. Current treatment goals are often unmet due to insufficient treatment modalities. Even when combined, these treatment modalities are frequently limited by safety, tolerability, weight gain, edema and gastrointestinal intolerance. Recently, new therapeutic classes have become available for treatment. This review will examine the new therapeutic classes of incretin mimetics and enhancers in the treatment of type 2 diabetes.

Therapeutic efficacy of renin--angiotensin blockade in patients receiving dialysis

Suzuki, H. — Tue, 06 Oct 2009 09:21:11 PDT

Observational data in dialysis patients has indicated an increased cardiovascular mortality. One pathophysiological cause of this cardiovascular mortality in these patients is volume overload. In addition, an inappropriately activated renin—angiotensin system (RAS) has been proposed as another possible mechanism for the increased cardiovascular mortality. With these possible causes in mind, blockade of the RAS with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) have both emerged as means of preventing cardiovascular events in this population. This review focuses on clinical evidence of the beneficial effects of ACE inhibitors and ARBs in dialysis patients with regard to the improvement of cardiovascular events as well as blood pressure control and maintenance of dialysis therapy.