title: Simvastatin treatment attenuates increased respiratory variability and apnea/hypopnea index in rats with chronic heart failure.
abstract: Cheyne-Stokes respiration and cardiac arrhythmias are associated with increased morbidity and mortality in patients with chronic heart failure (CHF). Enhanced carotid body chemoreflex (CBC) sensitivity is associated with these abnormalities in CHF. Reduced carotid body (CB) nitric oxide and nitric oxide synthase (NOS) levels play an important role in the enhanced CBC. In other disease models, Simvastatin (statin) treatment increases endothelial NOS, in part, by increasing Krüppel-like Factor 2 expression. We hypothesized that statin treatment would ameliorate enhanced CBC sensitivity as well as increased respiratory variability, apnea/hypopnea index, and arrhythmia index, in a rodent model of CHF. Resting breathing pattern, cardiac rhythm, and the ventilatory and CB chemoreceptor afferent responses to hypoxia were assessed in rats with CHF induced by coronary ligation. CHF was associated with enhanced ventilatory and CB afferent responses to hypoxia as well as increased respiratory variability, apnea/hypopnea index, and arrhythmia index. Statin treatment prevented the increases in CBC sensitivity and the concomitant increases in respiratory variability, apnea/hypopnea index, and arrhythmia index. Krüppel-like Factor 2 and endothelial NOS protein were decreased in the CB and nucleus tractus solitarii of CHF animals, and statin treatment increased the expression of these proteins. Our findings demonstrate that the increased CBC sensitivity, respiratory instability, and cardiac arrhythmias observed in CHF are ameliorated by statin treatment and suggest that statins may be an effective treatment for Cheyne-Stokes respiration and arrhythmias in patient populations with high chemoreflex sensitivity.
authors: Department of Cellular and Integrative Physiology, 985850 Nebraska Medical Center, Omaha, NE 68198. hschultz@unmc.edu.
authors: Karla K V
authors: KK
authors: Haack
authors: Noah J
authors: NJ
authors: Marcus
authors: Rodrigo
authors: R
authors: Del Rio
authors: Irving H
authors: IH
authors: Zucker
authors: Harold D
authors: HD
authors: Schultz
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D002344:Carotid Body / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D006333:Heart Failure / Q000150:complications*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012119:Respiration / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use*; D012891:Sleep Apnea Syndromes / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C543921:Klf2 protein, rat; D051741:Kruppel-Like Transcription Factors; D044140:Receptor, Angiotensin, Type 1; D009569:Nitric Oxide; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III
keywords: Cheyne–Stokes Respiration; carotid body; simvastatin; systolic heart failure