Effect of High-Intensity Interval Training in De Novo Heart Transplant Recipients in Scandinavia.

BACKGROUND: There is no consensus on how, when, or at what intensity exercise should be performed after heart transplantation (HTx). We have recently shown that high-intensity interval training (HIT) is safe, well tolerated, and efficacious in the maintenance state after HTx, but studies have not investigated HIT effects in the de novo HTx state. We hypothesized that HIT could be introduced early after HTx and that it could lead to clinically meaningful increases in exercise capacity and health-related quality of life. METHODS: This multicenter, prospective, randomized, controlled trial included 81 patients a mean of 11 weeks (range, 7-16 weeks) after an HTx. Patients were randomized 1:1 to 9 months of either HIT (4×4-minute intervals at 85%-95% of peak effort) or moderate-intensity continuous training (60%-80% of peak effort). The primary outcome was the effect of HIT versus moderate-intensity continuous training on the change in aerobic exercise capacity, assessed as the peak oxygen consumption (Vo2peak). Secondary outcomes included tolerability, safety, adverse events, isokinetic muscular strength, body composition, health-related quality of life, left ventricular function, hemodynamics, endothelial function, and biomarkers. RESULTS: From baseline to follow-up, 96% of patients completed the study. There were no serious exercise-related adverse events. The population comprised 73% men, and the mean±SD age was 49±13 years. At the 1-year follow-up, the HIT group demonstrated greater improvements than the moderate-intensity continuous training group; the groups showed significantly different changes in the Vo2peak (mean difference between groups, 1.8 mL·kg-1·min-1), the anaerobic threshold (0.28 L/min), the peak expiratory flow (11%), and the extensor muscle exercise capacity (464 J). The 1.8-mL·kg-1·min-1 difference was equal to ≈0.5 metabolic equivalents, which is regarded as clinically meaningful and relevant. Health-related quality of life was similar between the groups, as indicated by results from the Short Form-36 (version 2), Hospital Anxiety and Depression Scale, and a visual analog scale. CONCLUSIONS: We demonstrated that HIT was a safe, efficient exercise method in de novo HTx recipients. HIT, compared with moderate-intensity continuous training, resulted in a clinically significantly greater change in exercise capacity based on the Vo2peak values (25% versus 15%), anaerobic threshold, peak expiratory flow, and muscular exercise capacity. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier NCT01796379.

Long-term effects of high-intensity training vs moderate intensity training in heart transplant recipients: A 3-year follow-up study of the randomized-controlled HITTS study.

The randomized controlled High-Intensity Interval Training in De Novo Heart Transplant Recipients in Scandinavia (HITTS) study compared 9 months of high-intensity interval training (HIT) with moderate intensity continuous training in de novo heart transplant recipients. In our 3-year follow-up study, we aimed to determine whether the effect of early initiation of HIT on peak oxygen consumption (VO2peak ) persisted for 2 years postintervention. The study's primary end point was the change in VO2peak (mL/kg/min). The secondary end points were muscle strength, body composition, heart rate response, health-related quality of life, daily physical activity, biomarkers, and heart function. Of 78 patients who completed the 1-year HITTS trial, 65 entered our study and 62 completed the study tests. VO2peak increased from baseline to 1 year and leveled off thereafter. During the intervention period, the increase in VO2peak was larger in the HIT arm; however, 2 years later, there was no significant between-group difference in VO2peak . However, the mean change in the anaerobic threshold and extensor muscle endurance remained significantly higher in the HIT group. Early initiation of HIT after heart transplantation appears to have some sustainable long-term effects. Clinical trial registration number: NCT01796379.

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

BACKGROUND: Studies on the effect of high-intensity interval training (HIT) compared with moderate intensity continuous training (MICT) on health-related quality of life (HRQoL) after heart transplantation (HTx) is scarce. No available studies among de novo HTx recipients exists. This study aimed to investigate the effect of HIT vs. MICT on HRQoL in de novo recipients. METHODS: The HITTS study randomized eighty-one de novo HTx recipients to receive either HIT or MICT (1:1). The HIT intervention were performed with 2-4 interval bouts with an intensity of 85-95% of maximal effort. The MICT group exercised at an intensity of 60-80% of their maximal effort with a duration of 25 min. HRQoL was assessed by the Short Form-36 version 2 (SF-36v2) and the Hospital Anxiety and Depression Scale, mean 11 weeks after surgery and after a nine months' intervention. The participants recorded their subjective effect of the interventions on their general health and well-being on a numeric visual analogue scale. Clinical examinations and physical tests were performed. Differences between groups were investigated with independent Student t-tests and with Mann-Whitney U tests where appropriate. Within-group differences were analyzed with Paired-Sample t-tests and Wilcoxon Signed Rank tests. Correlations between SF-36 scores and VO2peak were examined with Pearson's correlations. RESULTS: Seventy-eight participants completed the intervention. Both exercise modes were associated with improved exercise capacity on the physical function scores of HRQoL. Mental health scores remained unchanged. No differences in the change in HRQoL between the groups occurred except for Role Emotional subscale with a larger increase in the HIT arm. Better self-reported physical function was associated with higher VO2peak and muscle strength. CONCLUSION: HIT and MICT resulted in similar mean changes in HRQoL the first year after HTx. Both groups experienced significant improvements in the physical SF-36v2. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01796379 Registered 18 February 2013.

Long-term effects of high-intensity interval training in heart transplant recipients: A 5-year follow-up study of a randomized controlled trial.

BACKGROUND: Previous studies have demonstrated that high-intensity interval training (HIT) is superior to moderate-continuous exercise in general and in cardiovascular diseases. Recently, we also found HIT safe and efficient after heart transplantation (HTx). This study reports the 5-year long-term effects. DESIGN AND METHODS: Forty-one HTx patients who had completed the previous 12-month randomized controlled trial, comparing HIT intervention with usual care, were eligible. In particular, we measured VO2peak , muscular capacity, intravascular ultrasound, and questionnaires measuring physical and mental health. RESULTS: The baseline mean±SD values were as follows: age; 49.1±16.5 years, men; 68%, time since HTx: 4.1±2.2 years. Within the HIT group, initial VO2peak increased significantly from 27.7±5.7 to 31.2±5.3 mL/kg/min. However, during the next 4 years, VO2peak decreased to 26.0±6.2 mL/kg/min. The control group showed slightly decreasing VO2peak values during the entire 5-year period. The HIT group reported significantly less anxiety symptoms, but there were no long-term differences in VO2peak , muscular capacity, or cardiac allograft vasculopathy between the groups. The similar VO2peak values correspond to our findings of similar everyday activity. CONCLUSION: Our findings suggest that intermittent periods of HIT may be necessary to maintain the initial benefits gained from the intervention. However, HIT probably reduces the burden of anxiety, which is a frequent health issue following HTx.

Design and rationale of the HITTS randomized controlled trial: Effect of High-intensity Interval Training in de novo Heart Transplant Recipients in Scandinavia.

There is no consensus on how, when, and at what intensity exercise should be performed and organized after heart transplantation (HTx). Most rehabilitation programs are conducted in HTx centers, which might be impractical and costly. We have recently shown that high-intensity interval training (HIT) is safe, well tolerated, and efficacious in maintenance HTx recipients, but there are no studies among de novo patients, and whether HIT is feasible and superior to moderate training in HTx recipients is unclear. A total of 120 clinically stable HTx recipients older than 18 years will be recruited from 3 Scandinavian HTx centers. Participants are randomized to HIT or moderate training, shortly after surgery. All exercises are supervised in the patients' local communities. Testing at baseline and follow-up includes the following: VO2peak (primary end point), muscle strength, body composition, quality of life, myocardial performance, endothelial function, biomarkers, and progression of cardiac allograft vasculopathy. A subgroup (n = 90) will also be tested at 3-year follow-up to assess long-term effects of exercise. So far, the HIT intervention is well tolerated, without any serious adverse events. We aim to test whether decentralized HIT is feasible, safe, and superior to moderate training, and whether it will lead to significant improvement in exercise capacity and less long-term complications.

Peak oxygen uptake and self-reported physical health are strong predictors of long-term survival after heart transplantation.

BACKGROUND: Peak oxygen uptake (VO2peak ) is known as the gold standard measure of cardiopulmonary fitness. We therefore hypothesized that measures of physical health would predict long-term survival in heart transplant recipients (HTx). METHODS: This retrospective study investigated survival in two HTx populations; the cardiopulmonary exercise test (CPET) cohort comprised 178 HTx patients who completed a VO2peak test during their annual follow-up (1990-2003), and the SF-36 cohort comprised 133 patients who completed a quality of life questionnaire, SF-36v1 (1998-2000). RESULTS: Mean (SD) age in the CPET cohort was 52 (12) yr and 54 (11) yr in the SF-36 cohort. Mean observation time was, respectively, 11 and 10 yr. Mean (SD) VO2peak was 19.6 (5.3) mL/kg/min, and median (IR) physical function (PF) score was 90 (30). VO2peak and PF scores were both significant predictors in univariate Cox regression. Multiple Cox regression analyses adjusted for other potential predictors showed that VO2peak , age, and cardiac allograft vasculopathy (CAV) were the most important predictors in the CPET cohort, whereas age, PF score, smoking, and CAV were the most important predictors in the SF-36 cohort. In Kaplan-Meier analysis, VO2peak and PF scores above the median value were related to significant longer survival time. CONCLUSION: Peak oxygen uptake and self-reported physical health are strong predictors for long-term survival in HTx recipients. VO2peak is a crucial measurement and should be more frequently used after HTx.

Effect of high-intensity interval training in young heart transplant recipients: results from two randomized controlled trials.

BACKGROUND: Little is known about the effect of exercise in young heart transplant recipients, and results on group level is lacking. This study summarizes the findings of the youngest participants in two previous randomized controlled trials. METHOD: This is a hypothesis-generating study reporting the main results from the youngest participants in two larger randomized controlled trials investigating the effect of high-intensity interval training (HIT). The article summarizes the main results from 28 young participants (< 40 year of age) who have participated in two previous studies which evaluated the effect of HIT vs. controls in adult heart transplant recipients. One of the studies included de novo heart transplant recipients and the other included maintenance heart transplant recipients.All study tests were performed in-hospital, in the specialist health care setting, but the exercise intervention was carried out locally, in cooperation with the primary health care. In both studies the exercise intervention lasted for 9-12 months. In one study, HIT (85-95% of peak effort) was compared to controls (no specific intervention), and in the other study HIT was compared to moderate, continuous exercise (MICT, 60-80% of peak effort). The main outcome measure was peak oxygen uptake (VO2peak) and a secondary endpoint was muscle strength. RESULTS: The summarized findings from the youngest heart transplant recipients in these two studies demonstrated mainly that the improvement in peak oxygen uptake among the younger recipients (< 40 years) was much larger (4.7 vs. 1.2 ml/kg/min and 7.0 vs. 2.2 ml/kg/min) compared to the improvement among the older recipients (≥ 40 years), and in accordance with results from adult heart transplant populations: HIT, compared to MICT, induced the largest improvement in peak oxygen consumption, also in the younger heart transplant recipients. CONCLUSIONS: These results suggest that young heart transplant recipients have a greater effect of HIT than of MICT and may also suggest that younger recipients benefit more from high-intensity interval training than their older co-patients. However, larger randomized studies focusing on the young heart transplant population is strongly needed to confirm this hypothesis. TRIAL REGISTRATION: Clinical trial registrations: NCT01796379 and NCT01091194.

Importance of physical capacity and the effects of exercise in heart transplant recipients.

One of the most important prognostic factors in heart failure patients is physical capacity. Patients with very poor physical performance and otherwise eligible, may be listed as candidates for heart transplantation (HTx). After such surgery, life-long immunosuppression therapy is needed to prevent rejection of the new heart. The dark side of immunosuppression is the increased risk of infections, kidney failure, cancer and advanced atherosclerosis (cardiac allograft vasculopathy), with the two latter conditions as the main causes of later mortality. In a worldwide perspective, 50% of the HTx patients survive past 10 years. Poor aerobic capacity prior to graft deterioration is not only limited to the failing heart, but also caused by peripheral factors, such as limited function in the skeletal muscles and in the blood vessels walls. Exercise rehabilitation after HTx is of major importance in order to improve physical capacity and prognosis. Effects of high-intensity interval training (HIT) in HTx recipients is a growing field of research attracting worldwide focus and interest. Accumulating evidence has shown that HIT is safe and efficient in maintenance HTx recipients; with superior effects on physical capacity compared to conventional moderate exercise. This article generates further evidence to the field by summarizing results from a decade of research performed at our center supported by a broad, but not strict formal, literature review. In short, this article demonstrates a strong association between physical capacity measured after HTx and long-term survival. It describes the possible "HIT-effect" with increased levels of inflammatory mediators of angiogenesis. It also describes long-term effects of HIT; showing a positive effect in development of anxiety symptoms despite that the improved physical capacity was not sustained, due to downregulation of exercise and intensity. Finally, our results are linked to the ongoing HITTS study, which investigates safety and efficiency of HIT in de novo HTx recipients. Together with previous results, this study may have the potential to change existing guidelines and contribute to a better prognosis for the HTx population as a whole.

Clinical features and determinants of VO2peak in de novo heart transplant recipients.

AIM: To study exercise capacity and determinants of early peak oxygen consumption (VO2peak) in a cohort of de novo heart transplant (HTx) recipients. METHODS: To determine possible central (chronotropic responses, cardiopulmonary and hemodynamic function) and peripheral factors (muscular exercise capacity and body composition) predictive of VO2peak, a number of different measurements and tests were performed, as follows: Cardiopulmonary exercise testing (CPET) was performed mean 11 wk after surgery in 81 HTx recipients > 18 years and was measured with breath by breath gas exchange on a treadmill or bicycle ergometer. Metabolic/respiratory measures include VO2peak and VE/VCO2 slope. Additional measures included muscle strength testing, bioelectrical impedance analysis, echocardiography, blood sampling and health-related quality of life. Based on the VO2peak (mL/kg per minute) median value, the study population was divided into two groups defined as a low-capacity group and a high-capacity group. Potential predictors were analyzed using multiple regression analysis with VO2peak (L/min) as the dependent variable. RESULTS: The mean ± standard deviation (SD) age of the total study population was 49 ± 13 years, and 73% were men. This de novo HTx cohort demonstrated a median VO2peak level of 19.4 mL/kg per min at 11 ± 1.8 wk post-HTx. As compared with the high-capacity group, the low-capacity group exercised for a shorter time, had lower maximal ventilation, O2 pulse, peak heart rate and heart rate reserve, while the VE/VCO2 slope was higher. The low-capacity group had less muscle strength and muscular exercise capacity in comparison with the high-capacity group. In order of importance, O2 pulse, heart rate reserve, muscular exercise capacity, body mass index, gender and age accounted for 84% of the variance in VO2peak (L/min). There were no minor or major serious adverse events during the CPET. CONCLUSION: Although there is great individual variance among de novo HTx recipients, early VO2peak measures appear to be influenced by both central and peripheral factors.

Immediate response in markers of inflammation and angiogenesis during exercise: a randomised cross-over study in heart transplant recipients.

Background: The present study explored and compared the immediate responses in markers of inflammation and angiogenesis in maintenance heart transplant (HTx) recipients before, during and after sessions of high-intensity interval training (HIT) versus moderate-intensity continuous training (MICT). The study aimed to explain some of the trigger mechanisms behind HIT in HTx recipients. Methods: This cross-over study included 14 HTx patients (mean±SD age: 53±13 years; time since HTx, 3±2 years). All participants underwent baseline blood samples and a cardiopulmonary exercise test during their first visit. The next two visits included one HIT session and one MICT session, in randomised order. Blood samples were taken during and after each exercise session. Myokines and inflammatory markers related to vascular inflammation, blood-platelet activation and modulation of angiogenesis were analysed. Results: The main findings in this study were (1) exercise, regardless of intensity, induced a significant immediate response in several vascular, angiogenetic and in particular platelet-derived inflammatory mediators in HTx recipients. (2) HIT showed trends to induce an increased response in von Willebrand factor, vascular endothelial growth factor-1 and angiopoetin-2, and a decreased response in growth differentiation factor-15, compared with MICT. Conclusions: This pattern and in particular the trend towards an increased angiogenetic mediator response could contribute to the beneficial effects of HIT in HTx recipients. Trial registration number: NCT02602834.