Supplemental dataset on the influence of cardiac resynchronisation therapy in pacing-induced cardiomyopathy and concomitant central sleep Apnea

This article contains supplemental data to the publication “Central Sleep Apnea and Pacing-Induced Cardiomyopathy” [1], which was the most recent publication of the “UPGRADE” study. It provides in-depth analysis of the effects of cardiac resynchronisation therapy (CRT) in patients suffering from pacing-induced cardiomyopathy (PICM) on cardiac remodeling as well as functional cardiac parameters in comparison to continuous right ventricular pacing (RVP). Furthermore, it also covers additional data on several sleep parameters, which were not presented in the main article including the index for obstructive sleep apnea (OSA), the index for mixed sleep apnea and the oxygen saturation measurements during polysomnography. Further, Kaplan-Meier curves are presented for major adverse cardiac events (MACE) and overall mortality by severity of sleep apnea. Generally, the “UGRADE” study was a single-center prospective double-blinded randomized controlled trial lasting from 2014 to 2020. The methodology included a cross-over design giving the possibility to detect differences while CRT was activated and while continuous RVP was applied. The presented data should aid clinicians in daily practice as upgrading to CRT is not limited to improvement in cardiac parameters, but also modifies sleep apnea in patients with PICM, a generally sparsely studied entity of heart failure.

double-blinded randomized controlled trial lasting from 2014 to 2020. The methodology included a cross-over design giving the possibility to detect differences while CRT was activated and while continuous RVP was applied. The presented data should aid clinicians in daily practice as upgrading to CRT is not limited to improvement in cardiac parameters, but also modifies sleep apnea in patients with PICM, a generally sparsely studied entity of heart failure.
© 2020 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) Table   Subject Medicine and Dentistry Specific subject area Cardiology and Cardiovascular Medicine Type of data Figure  How

Value of the Data
• The additional data provides further insights of the cardiac remodeling process as well as several other sleep parameters including the respiratory status after activation of CRT in patients with PICM compared to continuous right ventricular pacing. • These results should provide guidance to clinicians working regularly with cardiac pacemakers facing patients with PICM. An amelioration of several cardiac, but also sleep parameters can be achieved by upgrading to CRT. • The data described should help to understand the complex interplay between heart failure and sleep apnea. It further underlines the open issues to be adressed in future trials, but also helps to estimate the treatment effect for power analysis.

Experimental Design, Materials and Methods
The UPGRADE study (ClinicalTrials.gov Identifier: NCT01970423) was an investigator-driven single-center prospective double-blinded randomized controlled study. The major purposes of this trial were the validation of the AP scan®, a novel algorithm implemented in cardiac pacemakers to screen for sleep apnea [2] , and to evaluate the effects of CRT upgrading in patients suffering from PICM and concomitant CSA. Inclusion criteria were heart failure symptoms despite guideline directed medical therapy (New York Heart Failure Association Class II, III or ambulatory IV), a LVEF below 40% and the need of right ventricular pacing above 40% despite optimal device programming. Exclusion criteria were end-stage heart failure (vasopressor dependent or low output syndrome), a glomerular filtration rate below 30 ml/min/1.73 m2, a life expectancy below one year, women with childbearing potential, drug abuse, hyperthyroidism, and intolerance of contrast agent. The enrolment phase started in 2014 and was completed in 2019, the last patient completed the follow-up in 2020. A detailed description of the conduction of study specific examinations as well as the follow-up schedule is presented in the related research article [1] . Following formulas were used to calculate index for OSA [(number of obstructive apneas) × 60 / total sleep time (in minutes)] and the index for mixed apnea [number of mixed apneas × 60 / total sleep time (in minutes)]. Statistical analysis was conducted using IBM SPSS, version 24 (IBM Corporation, Armonk, NY, USA), graphics were designed using GraphPad PRISM, version 5 (GraphPad Software, Inc., La Jolla, CA, USA). Continuous variables are displayed as median (interquartile range), categorical variables are expressed as number (percentage). Distribution of continuous variables was assessed by inspection of histograms and using the Kolmogorov-Smirnov test. Differences in repeated measurements were analysed either with the paired t -test or the Wilcoxon test, according to their distribution. Analysis of MACE and survival were estimated with the Kaplan-Meier method, differences were assessed with the log-rank test. Whiskers in the boxplot demonstrate the 95% percentile (2.5-97.5). p -values ≤ 0.05 were regarded statistically significant.

Ethics Statement
The protocol of this trial was approved by the local ethics committee. The study was conducted in accordance with the "Declaration of Helsinki", verbal and written informed consent was obtained from each patient enrolled into the study.

Declaration of Competing Interest
This study has received a grant by the Austrian National Bank "Jubiläumsfondsprojekt Nr. 15,974 . Further it was supported by an unlimited scientific grant from the Boston Scientific Investigator Sponsored Research (ISR) Committee, Boston Scientific, St. Paul, MN, USA. Both grants were assigned to Wolfgang Dichtl.