Analyses statistiques

Les analyses statistiques ont été effectuées à l’aide du logiciel SPSS version 22. Nous avons comparé nos deux groupes pré-traitement et post-traitement à l’aide d’un test t pour variables indépendantes afin de vérifier si les groupes étaient comparables initialement et à la fin du traitement. Nous avons comparé les valeurs initiales dans chaque groupe aux valeurs obtenues en fin de traitement par un test t pour échantillons appariés. Nous avons fait de même pour nos valeurs de VFC. Un test de chi-carré a été effectué afin de comparer l’histoire médicale des participants de nos deux groupes. Nos données sont exprimées en moyenne ± l’écart-type. Nous avons effectué des corrélations de Pearson entre les variables de VFC moyenne sur 24h et les mesures d’adiposité viscérale et sous-cutanée pour nos deux groupes. Les corrélations ont été effectuées à partir des valeurs absolues initiales, des valeurs absolues finales, des valeurs de variations absolues (Δ) (déterminées par la différence entre les paramètres initiaux et finaux) ainsi qu’à l’aide des données de variations relatives en pourcentage.

Nous avons vérifié s’il n’y aurait pas des corrélations entre les différents paramètres de VFC (SDNN, rMSSD, pNN50, TBF, BF et HF) et 1) les autres mesures anthropométriques (IMC, poids corporel et CT), et 2) les paramètres biochimiques (HDL, AGL, TG, CRP, adiponectine, leptine, Hb1Ac, insuline et HOMA-IR). Une valeur de p < 0,05 a été considérée comme étant statistiquement significative.

Chapitre 7

7. Article scientifique

Résumé

L’obésité est associée à une augmentation des risques de maladies cardiovasculaires. La rosiglitazone, un agoniste au récepteur nucléaire PPARγ, augmente le poids corporel. OBJECTIFS : 1) Évaluer l’impact d’un traitement de 12 mois sur la distribution adipeuse, et 2) évaluer si les changements de la distribution adipeuse sont associés à ceux de la variabilité de la fréquence cardiaque chez des patients diabétiques de type 2 avec pontage aorto-coronarien. Au total, 125 patients (117 hommes et 8 femmes) ont été sélectionnés. Soixante-deux patients ont été traités avec la rosiglitazone alors que 63 patients ont reçu un traitement à l’aide d’un placebo. RÉSULTATS : Dans le groupe rosiglitazone, nous avons observé une augmentation significative (p ≤ 0,001) du poids corporel (3,5 ± 3,5 kg), de l’indice de masse corporelle (1,3 ± 1,3 kg/m2_{), de la circonférence de taille (2,1}

± 4,8 cm) et du tissu adipeux sous-cutané (253,4 ± 266,0 cm3_{). Il n’y a aucun}

changement des paramètres de la variabilité de la fréquence cardiaque pour le groupe rosiglitazone et placebo ainsi qu’aucune corrélation entre ceux-ci et les changements de la distribution adipeuse.

Rosiglitazone affects the distribution of adipose tissue without deleterious impact on heart rate variability in post-CABG patients with type 2 diabetes

Audrey Grenier1,3 _{BSc ; Patrice Brassard}1,2 _{PhD ; Olivier F. Bertrand}1 _{MD PhD ;}

Jean-Pierre Després1,2 _{PhD ; Olivier Costerousse}1 _{PhD ; Natalie Alméras}1 _{PhD ; et}

Paul Poirier1,3 _{MD PhD}

From the 1 _{Institut universitaire de cardiologie et de pneumologie de Québec,}

Canada ; 2 _{Faculty of Medicine ;} 3 _{Faculty of pharmacy, Laval University, Québec,}

Canada.

Corresponding author:

Paul Poirier MD, PhD, FRCPC, FACC, FAHA Professor/Laval University Faculty of Pharmacy

Institut universitaire de cardiologie et de pneumologie de Québec 2725 Chemin Sainte-Foy

Québec City, QC, Canada, G1V 4G5

Phone: 418-656-4767 Fax: 418-656-4581 E-mail: paul.poirier@criucpq.ulaval.ca

Word count of text: 2 892

Abstract

Obesity is associated with decreased heart rate variability (HRV). Rosiglitazone, a PPARγ agonist, generally increases body weight. Objectives: 1) To assess the impact of a 12-month treatment with rosiglitazone on the distribution of abdominal adipose tissue [visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT)] and, 2) to evaluate if rosiglitazone-associated changes in abdominal fat distribution are associated with modification in HRV in patients with type 2 diabetes after coronary artery bypass graft surgery (CABG). Methods: One hundred twenty- five patients with diabetes between 40 and 75 years who had CABG surgery were studied. Anthropometric measurements: 1) body mass index (BMI), 2) waist circumference (WC), 3) abdominal computed tomography (CT) scan, and HRV (using a 24h Holter) were performed at baseline and after 12 months. Patients were randomized to rosiglitazone or placebo treatment. Results: In the rosiglitazone group vs. placebo group, we observed significant increases in body weight (3.5 ± 3.5 vs. 0.2 ± 2.5 kg, p ≤ 0.001), BMI (1.3 ± 1.3 vs. 0.1 ± 0.9 kg/m2_{, p ≤}

0.001), WC (2.1 ± 4.8 vs. 0.4 ± 3.4 cm, p ≤ 0.001) and SAT (253.4 ± 266.0 vs 6.4 ± 119.2 cm3_{, p ≤ 0.001) without statistically significant changes in VAT (-21.6 ± 280.4}

vs 56.9 ± 235.4 cm3_{). There was no change in HRV in either group after 12}

months. There was no correlation between changes of HRV parameters and fat distribution. Conclusion: Our results show that rosiglitazone treatment for 1-yr is associated with increases in body weight, BMI, WC and SAT without changes in VAT. The increment in SAT did not influence HRV in post-CABG patients with type 2 diabetes.

Key words: subcutaneous adipose tissue; thiazolidinediones; fat distribution; heart rate variability

Abbreviations: HRV, heart rate variability; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; CABG, coronary artery bypass graft surgery; VICTORY, VeIn Coronary aTherOsclerosis and Rosiglitazone after bypass surgerY; BMI, body mass index; WC, waist circumference; CT, computed tomography; CVD, cardiovascular disease; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; BLSA, Baltimore Longitudinal Study of Aging; TZDs, thiazolidinediones; T2D, type 2 diabetes; HbAlc, glycated hemoglobin; DEXA, dual-energy X-ray absorptiometry; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CRP, C- reactive protein; FFA, free fatty acids; TNF-α, tumor necrosis factor α; Il-6, interleukin 6; SDNN, standard deviation of all normal-to-normal (NN) interval; SDANN, standard deviation of the averages of NN intervals in all 5 min segments of the entire recording; rMSSD, square root of the mean of the squared differences between adjacent NN intervals; SDSD, standard deviation of differences between adjacent NN intervals; NN50, number of pairs of adjacent NN intervals differing by more than 50 ms in the entire recording; pNN50, NN50 divided by the total number or all NN intervals; VLF, very low frequencies; LF, low frequencies; HF, high frequencies.

1. Introduction

An estimated 17.3 million people, or 30% of the world's population, die from cardiovascular disease (CVD) every year [1]. High blood pressure, smoking, diabetes, visceral obesity, high cholesterol, physical inactivity and unhealthy dietary pattern are all major modifiable risk factors associated with CVD development [2-6]. The CVD risk level linked with visceral obesity can be clinically assessed using waist circumference (WC), which includes visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) depot [7]. Visceral adipose tissue is located around the viscera, whereas SAT is stored between the muscle and the skin.

Reduced heart rate variability (HRV) is also associated with an increase in CVD risk [8]. It could be defined as subtle changes in heart rate between two consecutive heart beats [9]. Heart rate variability represents the heart ability to adapt to the environment and to the demands of daily life in order to maintain homeostasis [9]. Heart rate variability provides information on cardiovascular health by providing information on the balance between the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS) [9].

Adiposity/obesity measurements seem to be differently associated with HRV. Different obesity indices have been associated with specific HRV parameters and there are associations between HRV and glucose metabolism [10, 11]. The association between adiposity indices and HRV has been evaluated in The Baltimore Longitudinal Study of Aging (BLSA) [12]. The objective of BLSA study was to determine if VAT, estimated by WC, affected more the autonomic nervous system than the SAT, assessed by body mass index (BMI). The authors reported that WC was associated with decreased HRV and there was no association between BMI and HRV [12]. These studies were transversal in nature and no study have assessed how changes in fat depot distribution or obesity indices may

influence HRV.

Among the drug treatments available to treat diabetes stands the class of thiazolidinediones (TZDs) which increases insulin sensitivity [13], and uptake of glucose by muscles and adipose tissue, concomitantly with a decrease in hepatic glucose production [14]. In addition, TZDs may lower blood pressure, improves dyslipidemia and helps restoring endothelial function [14]. On the other hand, rosiglitazone increases total body weight by promoting accumulation preferentially of SAT [14]. While an increase in visceral adiposity seems to be associated with lower HRV in patients with type 2 diabetes (T2D) after a CABG procedure [11], the influence of an increase in SAT induced by rosiglitazone treatment in these patients remains to be determined.

Our objective was to evaluate if the use of rosiglitazone would alter HRV in post- CABG patients with T2D using a more precise evaluation of body fat distribution. We evaluated whether rosiglitazone would have any significant impact on HRV considering the expected increase in total body weight and body fat.

2. Materials and methods