High-intensity interval training and health-related quality of life in de novo heart transplant recipients – results from a randomized controlled trial

The intervention is described elsewhere [22, 23]. Briefly, the participants were randomized 1:1, to either nine months of HIT or MICT at 11 ± 2 weeks after HTx. Participants in both groups exercised 2–3 times per week in the 9-month long intervention. The HIT consisted of 2–4 interval bouts at an intensity of 85–95% of maximal effort (corresponding to a rated perceived exertion (RPE) of 16–18). Between the HIT bouts, there was an active rest period (RPE 11–13). The goal for the HIT group was to be able to perform 4 interval bouts of 4 min length in the last intervention period. The MICT group followed the standard-of care exercise recommendations in recently HTx recipients, with an exercise intensity of 60–80% of maximal effort (corresponding to an RPE of 12–15) for a duration of 25 min. Both interventions included a 10 min warm up and a cool-down period of 5 min at the end of the exercise session. In addition, both groups performed strength training. All exercise sessions were performed in the participants’ local communities, supervised by health personnel and all exercise sessions in both groups were logged and monitored with a heart rate monitor. Of 72 planned sessions, the HIT group completed median (interquartile range (IR)) 60 (28) sessions and the MICT group completed 56 (37) (p for difference 0.858).

HRQoL was assessed by the generic questionnaire SF-36v2, [24] frequently used in HTx populations [1, 25]. The SF-36 is divided into eight subscales; Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. The eight subscales aggregate into two summary scores; a Physical Component and a Mental Component; higher score indicating better HRQoL. In this study, all scores were transformed to norm-based values with a standardized mean of 50 and a standard deviation (SD) of 10. A change of 2–4 points on any item is considered to be of clinical significance [24].

Symptoms of anxiety and depression were measured with the Hospital Anxiety and Depression Scale (HADS) [26]. The participants’ socio-demographic background was assessed by a simple questionnaire at baseline and at follow-up. Additionally, at follow-up, all the participants recorded: “To what extent do you feel participation in this study had a positive impact on your general health and well-being” on a numeric visual analogue scale (VAS), ranging from “not at all” to “to a very great extent”.

All the questionnaires were self-administered and filled out during the study visits at both time points (Fig. 2). The Physical Functioning subscale from SF-36v2 was selected to represent self-reported physical function.

All participants underwent a cardiopulmonary exercise test (CPET) with measurements of VO_2peak at baseline and at follow-up. Most of the Norwegian participants (n = 70) in were tested on a treadmill with breath-by-breath gas analysis (Jaeger® Masterscreen® CPX, Carefusion), and four of the particpants were tested on a bicycle (Schiller Cardiovit® CS-200 Excellence). The participants from Sweden and Denmark (n = 7) were tested on a bicycle (Jaeger®,Oxy Con Pro® and Jaeger® Vyntus® CPX). The CPET tests was performed with an individualized protocol with a gradual increase in workload until exhaustion [22, 27]. Isokinetic muscle strength and muscular exercise capacity in the lower limbs were measured with a dynamometer (Cybex 6000) [22, 23, 28].

All participants provided written informed consent prior to inclusion. The study was approved by the regional ethic committees in Norway, Sweden and Denmark. The study is conducted according to the Helsinki Declaration. https://​clinicaltrials.​gov/​ identifier NCT01796379.

Continuous data are expressed as mean ± SD, or median (IR). Categorical data are presented as number and percentages. An intention-to-treat analysis were conducted. Differences between the two groups were investigated with independent Student t -tests and with Mann-Whitney U tests where appropriate. The change (delta value) for each participant between baseline and 1-year follow-up was calculated by subtracting the results at 1-year follow-up with the results at baseline [Change = 1-year follow-up – baseline]. The change was assessed by independent t-tests to calculate the mean difference in change between the two groups in normally distributed variables, and by Mann-Whitney U tests for variables with skewed distribution. Within-group differences were analyzed with Paired-Sample t-tests and Wilcoxon Signed Rank tests. We assessed associations between HRQoL scores and parameters reflecting exercise capacity using Pearson’s and Spearman’s correlations. Missing data in the SF-36v2 were handled by the “half-scale” rule, which means that a scale score was calculated if at least half of the items of that specific scale were answered [24]. For the two HADS scales, scores were calculated for those with complete data only. All data were analyzed using IBM SPSS 25.0 (IBM Corporation, United States). P values < 0.05 (two-sided) were considered statistically significant.

There was little missing data. At baseline there were 1.3% missing for the following SF-36 subscales; Role Physical, Vitality and Mental Health and 2.6% missing for the Role Emotional subscale and each of the two SF-36 sum scores. At follow-up there were 1.3% missing for all of the SF-36 subscales except of General Health and Social Functioning, while there were 2.6% missing for each of the two SF-36 sum scores and for each of the HADS scores.

The high baseline HRQoL scores may reflect an above average healthy population and may also have affected the impact of the intervention on HRQoL. For obvious reasons, the sickest patients could not be enrolled in the trial. Thus, our results may not be valid for the entire HTx population. HRQoL was a secondary, but prespecified endpoint in the HITTS (High-intensity Interval Training in De Novo Heart Transplant Recipients in Scandinavia) study [22, 23]. With only 78 participants we may face a type II error due to insufficient statistical power.

A disease-specific HRQoL questionnaire could have been more sensitive to detect differences between groups. So far, no disease-specific questionnaires in Norwegian are available for the HTx population. In a prior HTx study, we experienced a ceiling effect using the heart failure-specific Kansas City Cardiomyopathy Questionnaire [30] and decided not to use this questionnaire in this study.

The HITTS trial [22, 23] was not designed to assess the participants´ daily activities and the roles they were hoping to assume. This limits our ability to explain the between-group difference in the Role Emotional scale.

Interventions for good and stable HRQoL, both short- and long-term after HTx, are needed. Exercise yields better physical function and makes it easier to engage in various activities of everyday life. However, despite improved VO_2peak with the HIT intervention, HRQoL was similar in both intervention arms. The development of an organ transplant-specific HRQoL questionnaire is warranted for future research in this field, [25] as it probably will be more accurate to detect changes in health status associated with organ transplant issues.