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 units2/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.
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Research Article|
January 21 2013
Do high doses of AT1-receptor blockers attenuate central sympathetic outflow in humans with chronic heart failure?
Marcel Ruzicka;
*Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
†Division of Nephrology, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
Correspondence: Dr Marcel Ruzicka (email [email protected]).
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John S. Floras;
John S. Floras
‡Division of Cardiology, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
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Andrew J. G. McReynolds;
Andrew J. G. McReynolds
‡Division of Cardiology, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
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Elizabeth Coletta;
Elizabeth Coletta
*Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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Haissam Haddad;
Haissam Haddad
*Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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Ross Davies;
Ross Davies
*Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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Frans H. H. Leenen
Frans H. H. Leenen
*Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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Publisher: Portland Press Ltd
Received:
August 14 2012
Revision Received:
November 07 2012
Accepted:
November 19 2012
Accepted Manuscript online:
November 19 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 124 (9): 589–595.
Article history
Received:
August 14 2012
Revision Received:
November 07 2012
Accepted:
November 19 2012
Accepted Manuscript online:
November 19 2012
Citation
Marcel Ruzicka, John S. Floras, Andrew J. G. McReynolds, Elizabeth Coletta, Haissam Haddad, Ross Davies, Frans H. H. Leenen; Do high doses of AT1-receptor blockers attenuate central sympathetic outflow in humans with chronic heart failure?. Clin Sci (Lond) 1 May 2013; 124 (9): 589–595. doi: https://doi.org/10.1042/CS20120437
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