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.

Randomized Trial of Cholesterol Lowering With Evolocumab for Cardiac Allograft Vasculopathy in Heart Transplant Recipients.

BACKGROUND: Cardiac allograft vasculopathy is characterized by increased coronary intimal thickness and is a leading cause of death in heart transplant (HTx) recipients despite the routine use of statins. The experience with inhibitors of proprotein convertase subtilisin-kexin type 9 in HTx recipients is limited. Our hypothesis was that lowering cholesterol with the proprotein convertase subtilisin-kexin type 9inhibitor evolocumab would reduce coronary intimal thickness in these patients without compromising safety. OBJECTIVES: This double blind, randomized trial was conducted to test whether evolocumab reduces the burden of cardiac allograft vasculopathy. METHODS: Patients who had received a cardiac allograft at one of the Nordic transplant centers within the prior 4 to 8 weeks were randomized to monthly subcutaneous injections of evolocumab 420 mg or matching placebo. The primary endpoint was the baseline-adjusted maximal intimal thickness as measured by intracoronary ultrasound after 12 months' treatment. RESULTS: The trial enrolled 128 patients between June 2019 and May 2022. Matched pairs of coronary ultrasound images were available for 56 patients assigned to evolocumab and 54 patients assigned to placebo. At 12 months, the adjusted mean difference in the maximal intimal thickness between the 2 arms was 0.017 mm (95% CI: -0.006 to 0.040; P = 0.14). The mean reduction in low-density lipoprotein cholesterol with evolocumab compared with placebo was 1.11 mmol/L (95% CI: 0.86-1.37 mmol/L). The use of evolocumab was not associated with an increase in adverse events. CONCLUSIONS: Twelve months of treatment with evolocumab substantially reduced low-density lipoprotein cholesterol but did not reduce maximal coronary intimal thickness in HTx recipients. (Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients [EVOLVD]; NCT03734211).

Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.

BACKGROUND: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. METHODS: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). FINDINGS: (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. INTERPRETATION: Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage. FUNDING: South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867).

The Alternative Complement Pathway Is Activated Without a Corresponding Terminal Pathway Activation in Patients With Heart Failure.

Objective: Dysregulation of the complement system has been described in patients with heart failure (HF). However, data on the alternative pathway are scarce and it is unknown if levels of factor B (FB) and the C3 convertase C3bBbP are elevated in these patients. We hypothesized that plasma levels of FB and C3bBbP would be associated with disease severity and survival in patients with HF. Methods: We analyzed plasma levels of FB, C3bBbP, and terminal C5b-9 complement complex (TCC) in 343 HF patients and 27 healthy controls. Results: Compared with controls, patients with HF had elevated levels of circulating FB (1.6-fold, p < 0.001) and C3bBbP (1.3-fold, p < 0.001). In contrast, TCC, reflecting the terminal pathway, was not significantly increased (p = 0.15 vs controls). FB was associated with NT-proBNP, troponin, eGFR, and i.e., C-reactive protein. FB, C3bBbP and TCC were not associated with mortality in HF during a mean follow up of 4.3 years. Conclusion: Our findings suggest that in patients with HF, the alternative pathway is activated. However, this is not accompanied by activation of the terminal pathway.

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response. OBJECTIVES: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. METHODS: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. RESULTS: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups. CONCLUSIONS: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).

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.