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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.

SUBMITTER: Haack KK

PROVIDER: S-EPMC3993007 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Simvastatin treatment attenuates increased respiratory variability and apnea/hypopnea index in rats with chronic heart failure.

Haack Karla K V KK Marcus Noah J NJ Del Rio Rodrigo R Zucker Irving H IH Schultz Harold D HD

Hypertension (Dallas, Tex. : 1979) 20140210 5

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 e ...[more]

PMID: 24516105

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Project description:BackgroundThe relationship between the Epworth sleepiness scale (ESS) and the apnea-hypopnea index (AHI) is uncertain and even poor. The major problem associated with the ESS might be a lack of consideration of weight in prediction in clinical practice. Would awarding different item-scores to the four scales of ESS items to develop a weighted ESS scoring system improve the accuracy of the AHI prediction? It is warranted to explore the intriguing hypotheses.MethodsSeven hundred fifty-six adult patients with suspicion of obstructive sleep apnoea syndrome (OSAS) were prospectively recruited to a derivation cohort. This was tested against a prospective validation cohort of 810 adult patients with suspected OSAS. Each ESS item’s increased odds ratio for the corresponding AHI was calculated using univariate logistic regression. The receiver operating characteristic curves were created and the areas under the curves (AUCs) were calculated to illustrate and compare the accuracy of the indices.ResultsThe higher the ESS item-score, the closer the relationship with the corresponding AHI. The odds ratios decreased as a result of the increased AHI. The ESS items were of unequal weight in predicting the corresponding AHI and a weighted ESS was developed. The coincidence rates with the corresponding AHI, body mass indices, and neck circumferences rose as the scores increased, whereas nocturnal nadir oxygen saturations decreased, and the weighted ESS was more strongly associated with these indices, compared with the ESS. The capability in predicting the patients without OSAS or with severe OSAS was strong, especially the latter, and the weighted ESS orchestrated manifest improvement in screening the patients with simple snoring. The patterns of sensitivities, specificities, and Youden’s indices of the four ranks of weighted ESS for predicting the corresponding AHI were better than those of the ESS, and the AUCs of weighted ESS were greater than the corresponding areas of ESS in the two cohorts.ConclusionsThe weighted ESS orchestrated significant improvement in predicting the AHI, indicating that the capability in predicting the patients without OSAS or with severe OSAS was strong, which might have implications for clinical triage decisions to prioritize patients for polysomnography.

Project description:ObjectivesThe aim of this study was to identify correlations between sleep apnea severity and tongue volume or posterior airway space measured via three-dimensional reconstruction of volumetric computerized tomography (CT) images in patients with obstructive sleep apnea (OSA) for use in predicting OSA severity and in surgical treatment. We also assessed associations between tongue volume and Mallampati score.MethodsSnoring/OSA male patients (n = 64) who underwent polysomnography, cephalometry, and CT scans were enrolled in this retrospective study. OSA was diagnosed when the apnea-hypopnea index (AHI) was greater than 5 (mild 5-14; moderate 15-29; severe>30). The patients were also categorized into the normal-mild group (n = 22) and the moderate-severe group (n = 42). Using volumetric CT images with the three-dimensional reconstruction technique, the volume of the tongue, posterior airway space volume, and intra-mandibular space were measured. The volumes, polysomnographic parameters, and physical examination findings were compared, and independent factors that are related to OSA were analysed.ResultsNo associations between tongue volume or posterior airway space and the AHI were observed. However, multivariate linear analyses showed that tongue volume had significantly negative association with lowest O2 saturation (r = 0.365, p = 0.027). High BMI was related to an increase in tongue volume. Modified Mallampati scores showed borderline significant positive correlations with absolute tongue volume (r = 0.251, p = 0.046) and standardized tongue volume (absolute tongue volume / intramandibular area; r = 0.266, p = 0.034). Between the normal-mild and moderate-severe groups, absolute tongue volumes were not different, although the standardized tongue volume in the moderate-severe group was significantly higher.ConclusionAbsolute tongue volume showed stronger associations with lowest O2 saturation during sleep than with the severity of AHI. We also found that high BMI was a relevant factor for an increase in absolute tongue volume and modified Mallampati grading was a useful physical examination to predict tongue size.

Project description:BackgroundOne of the key mechanisms underlying OSA is reduced pharyngeal muscle tone during sleep. Data suggest that pharmacologic augmentation of central serotonergic/adrenergic tone increases pharyngeal muscle tone.Research questionWe hypothesized that venlafaxine, a serotonin-norepinephrine reuptake inhibitor, would improve OSA severity.Study design and methodsIn this mechanistic, randomized, double-blind, placebo-controlled crossover trial, 20 patients with OSA underwent two overnight polysomnograms ≥ 4 days apart, receiving either 50 mg of immediate-release venlafaxine or placebo before bedtime. Primary outcomes were the apnea-hypopnea index (AHI) and peripheral oxygen saturation (Spo2) nadir, and secondary outcomes included sleep parameters and pathophysiologic traits with a view toward understanding the impact of venlafaxine on mechanisms underlying OSA.ResultsOverall, there was no significant difference between venlafaxine and placebo regarding AHI (mean reduction, -5.6 events/h [95% CI, -12.0 to 0.9]; P = .09) or Spo2 nadir (median increase, +1.0% [-0.5 to 5]; P = .11). Venlafaxine reduced total sleep time, sleep efficiency, and rapid eye movement (REM) sleep, while increasing non-REM stage 1 sleep (Pall < .05). On the basis of exploratory post hoc analyses venlafaxine decreased ("improved") the ventilatory response to arousal (-30%; P = .049) and lowered ("worsened") the predicted arousal threshold (-13%; [P = .02]; ie, more arousable), with no effects on other pathophysiologic traits (Pall ≥ .3). Post hoc analyses further suggested effect modification by arousal threshold (P = .002): AHI improved by 19% in patients with a high arousal threshold (-10.9 events/h [-3.9 to -17.9]) but tended to increase in patients with a low arousal threshold (+7 events/h [-2.0 to 16]). Other predictors of response were elevated AHI and less collapsible upper airway anatomy at baseline (|r| > 0.5, P ≤ .02).InterpretationIn unselected patients, venlafaxine simultaneously worsened and improved various pathophysiologic traits, resulting in a zero net effect. Careful patient selection based on pathophysiologic traits, or combination therapy with drugs countering its alerting effects, may produce a more robust response.Trial registryClinicalTrials.gov; No.: NCT02714400; URL: www.clinicaltrials.gov.

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Simvastatin treatment attenuates increased respiratory variability and apnea/hypopnea index in rats with chronic heart failure.

Publications

Simvastatin treatment attenuates increased respiratory variability and apnea/hypopnea index in rats with chronic heart failure.

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