Do high doses of AT1-receptor blockers attenuate central sympathetic outflow in humans with chronic heart failure?

Abstract

In patients with CHF (chronic heart failure) sympathetic activity increases as cardiac performance decreases and filling pressures increase. We hypothesized that in patients with mild-to-moderate CHF, higher than conventional doses of an AT1-receptor [AngII (angiotensin II) type 1 receptor] antagonist would achieve greater central AT1-receptor blockade, resulting in diminished MSNA (muscle sympathetic nerve activity) and augmented MSNA variability, two indices of central effects on sympathetic outflow. In total, 13 patients with ischaemic cardiomyopathy [NYHA (New York Heart Association) class II-III] were weaned off all pharmacological RAS (renin-angiotensin system) modifiers, and then randomized to receive a low (50 mg/day) or high (200 mg/day) dose of losartan. Central haemodynamics, MSNA and its variability, plasma catecholamines, AngI (angiotensin I) and AngII and aldosterone were assessed both before and 3 months after randomization. Neither dose altered BP (blood pressure), PCWP (pulmonary capillary wedge pressure) or CI (cardiac index) significantly. Compared with 50 mg daily, losartan 200 mg/day decreased MSNA significantly (P<0.05), by approximately 15 bursts/min, and increased MSNA variability within the 0.27-0.33 Hz high-frequency range by 0.11 units(2)/Hz (P=0.06). PNE [plasma noradrenaline (norepinephrine)] fell in parallel with changes in MSNA (r=0.62; P<0.05). These findings support the hypothesis that higher than conventional doses of lipophilic ARBs (AT1-receptor blockers) can modulate the intensity and variability of central sympathetic outflow in patients with CHF. The efficacy and safety of this conceptual change in the therapeutic approach to heart failure merits prospective testing in clinical trials.

Exercise Training Can Prevent Cardiac Hypertrophy Induced by Sympathetic Hyperactivity with Modulation of Kallikrein-Kinin Pathway and Angiogenesis

“…Sympathetic activity increases in a wide range of cardiac diseases, such as ischemic heart failure [42]. Importantly, pronounced sympathetic activation has been shown to be inversely correlated with survival [43].…”

Statins and the autonomic nervous system

“…Indeed, the only human trial not to demonstrate a statistically significant reduction in MSNA used a similar dose of atorvastatin (10 mg/day) [104]. The concept that higher doses of lipophilic agents may be required to act on central neural sites has been put forth for AT 1 receptor blockers [143]. The issue of lipophilicity and statin penetration is complicated by evidence that hydrophilic statins are capable of reducing circulating isoprenoid levels as a result of hepatic HMG-CoA reductase inhibition [144].…”

Effects of CPAP on Blood Pressure and Sympathetic Activity in Patients With Diabetes Mellitus, Chronic Kidney Disease, and Resistant Hypertension

“…After patients' vital signs were determined, they underwent an assessment of MSNA by peroneal nerve microneurography, as described in detailed previously. 30 MSNA was calculated from a 5-minute recording after 30 minutes of rest in a supine position in a quiet room with dim lights. At the end of this 5-minute period, blood samples for the assessment of plasma catecholamines, renin, and aldosterone were collected, processed, and evaluated as described previously.…”

“…At the end of this 5-minute period, blood samples for the assessment of plasma catecholamines, renin, and aldosterone were collected, processed, and evaluated as described previously. 30 Patients then completed 24-hour ABPM with the SpaceLabs 90217 (Snoqualmie, WA). This was done at baseline and 6 weeks after CPAP initiation (therapeutic or subtherapeutic, as assigned).…”