Heart transplant (HTx) recipients usually have reduced exercise capacity with reported VO 2peak levels of 50-70% predicted value. Our hypothesis was that highintensity interval training (HIIT) is an applicable and safe form of exercise in HTx recipients and that it would markedly improve VO 2peak.Secondarily, we wanted to evaluate central and peripheral mechanisms behind a potential VO 2peak increase. Forty-eight clinically stable HTx recipients >18 years old and 1-8 years after HTx underwent maximal exercise testing on a treadmill and were randomized to either exercise group (a 1-year HIIT-program) or control group (usual care). The mean ± SD age was 51 ± 16 years, 71% were male and time from HTx was 4.1 ± 2.2 years. The mean VO 2peak difference between groups at follow-up was 3.6 [2.0, 5.2] mL/kg/min (p < 0.001). The exercise group had 89.0 ± 17.5% of predicted VO 2peak versus 82.5 ± 20.0 in the control group (p < 0.001). There were no changes in cardiac function measured by echocardiography. We have demonstrated that a long-term, partly supervised and community-based HIIT-program is an applicable, effective and safe way to improve VO 2peak , muscular exercise capacity and general health in HTx recipients. The results indicate that HIIT should be more frequently used among stable HTx recipients in the future.Key words: Aerobic exercise, chronotropic response, heart transplantation, maximum oxygen uptake, muscle strength, VO 2peak Abbreviations: % HR max , percent of age-predicted maximum heart rate; AT, anaerobic threshold (ventilatory threshold); BIA, bioelectrical impedance analysis; CG, control group; CO, cardiac output; CRI, chronotropic response index; CRP, C-reactive protein; DXA, dual-emission X-ray absorptiometry; EG, exercise group; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; HF, heart failure; HIIT, high-intensity interval training; HR, heart rate; HR max , maximum heart rate; HRQoL, health-related quality of life; HTx, heart transplant; J, Joule; LV, left ventricle; LVe', left ventricle early diastolic mitral annular velocity; LVEF, left ventricle ejection fraction; Nm, Newtonmeter; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; RER, respiratory exchange ratio; RPE, rated perceived exertion; VAS scale, visual analog scale; VE max , maximum ventilation; VO 2peak , peak oxygen uptake.

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 (V o 2 peak). 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 V o 2 peak (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 V o 2 peak values (25% versus 15%), anaerobic threshold, peak expiratory flow, and muscular exercise capacity. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier NCT01796379.

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.

Chronotropic incompetence is not a limiting factor for exercise capacity in a population of relatively fit HTx patients. The most significant predictors, representing only peripheral factors, are similar to those often determining VO2peak in healthy, non-athletic individuals. Our findings emphasize the importance of a low percentage of body fat and high muscular exercise capacity in order to attain a sufficient VO2peak level after HTx.

PurposeHeart transplantation causes denervation of the donor heart, but the consequences for cardiovascular homeostasis remain to be fully understood. The present study investigated cardiovascular autonomic control at supine rest, during orthostatic challenge and during isometric exercise in heart transplant recipients (HTxR).MethodsA total of 50 HTxRs were investigated 7–12 weeks after transplant surgery and compared with 50 healthy control subjects. Continuous, noninvasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 60° head-up tilt and during 1 min of 30% of maximal voluntary handgrip. Plasma and urine catecholamines were assayed, and symptoms were charted.ResultsAt supine rest, heart rate, blood pressures and total peripheral resistance were higher, and stroke volume and end diastolic volume were lower in the HTxR group. During tilt, heart rate, blood pressures and total peripheral resistance increased less, and stroke volume and end diastolic volume decreased less. During handgrip, heart rate and cardiac output increased less, and stroke volume and end diastolic volume decreased less. Orthostatic symptoms were similar across the groups, but the HTxRs complained more of pale and cold hands.ConclusionHTxRs are characterized by elevated blood pressures and total peripheral resistance at supine rest as well as attenuated blood pressures and total peripheral resistance responses during orthostatic challenge, possibly caused by low-pressure cardiopulmonary baroreceptor denervation. In addition, HTxRs show attenuated cardiac output response during isometric exercise due to efferent sympathetic denervation. These physiological limitations might have negative functional consequences.

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Background. Heart transplantation (HTx) surgically transects all connections to the heart, including the autonomic nerves. We prospectively examined signs, timing and consequences of early sympathetic and parasympathetic sinoatrial reinnervation, as well as explored indirect evidence of afferent cardiopulmonary reinnervation. Methods. Fifty HTx recipients were assessed at 2.5, 6, and 12 mo after HTx. For comparison, 50 healthy controls were examined once. Continuous, noninvasive recordings of hemodynamic variables and heart rate variability indices were performed at supine rest, 0.2 Hz controlled breathing, 60° head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. Results. In HTx recipients, supine low-frequency heart rate variability gradually increased; supine high-frequency variability did not change; heart rate variability indices during controlled breathing remained unaltered; heart rate responses during tilt and isometric exercise gradually increased; the tachycardia response during Valsalva maneuver increased, while the bradycardia response remained unchanged; and indices of baroreflex sensitivity improved. Responses remained low compared to healthy controls. A negative correlation between indices of preload and heart rate response during head-up tilt emerged at 12 mo. Conclusions. Results suggest that sympathetic reinnervation of the sinoatrial node starts within 6 mo after HTx and strengthens during the first year. No evidence of early parasympathetic reinnervation was found. Indirect signs of afferent reinnervation of cardiopulmonary low-pressure baroreceptors emerged at 12 mo. Better sympathetic sinoatrial control improved heart rate responsiveness to orthostatic challenge and isometric exercise, as well as heart rate buffering of blood pressure fluctuations.

Heart transplant recipients have reduced exercise capacity despite preserved graft function. The IronIC trial was designed to test the hypothesis that intravenous iron therapy would improve peak oxygen consumption in these patients. METHODS AND RESULTS: This randomized, placebo-controlled, double-blind trial was performed at our national center for heart transplantation. One hundred and 2 heart transplant recipients with a serum ferritin <100 mg/liter or 100 to 300 mg/liter, in combination with transferrin saturation of <20%, and hemoglobin level >100 g/liter were enrolled ≥1 year after transplantation. A cardiopulmonary exercise test was performed before administration of the study drug and at 6 months follow-up. The primary endpoint was peak oxygen consumption. Key secondary outcomes included iron status, handgrip strength, quality of life, and safety. Fifty-two patients were randomized to receive ferric derisomaltose 20 mg/kg, and 50 to placebo. The between-group difference in baseline-adjusted peak oxygen consumption was 0.3 ml/kg/min (95% confidence interval -0.9 to 1.4, p = 0.66). In patients with a baseline ferritin <30 mg/liter, peak oxygen consumption was significantly higher in the ferric derisomaltose arm. At 6 months, iron stores were restored in 86% of the patients receiving ferric derisomaltose vs 20% in patients receiving placebo (p < 0.001). Quality of life was significantly better in patients receiving ferric derisomaltose. Twenty-seven adverse events occurred in the intravenous iron group vs 30 in the placebo group (p = 0.39). CONCLUSION: Intravenous iron treatment did not improve peak oxygen consumption in heart transplant recipients with ferritin <100 mg/liter or 100 to 300 mg/liter in combination with transferrin saturation <20%. TRIAL REGISTRATION NUMBER: http//www.clinicaltrials.gov identifier NCT03662789.