1
Effect of High-intensity Interval Training in de novo heart Transplant recipients in 1
Scandinavia: 1-yr follow-up of the HITTS randomized, controlled study 2
(Short title: the HITTS study) 3
K. Nytrøena,b,h, K. Rolida,b,c,h, A. K. Andreassena,b, M. Yardleya,b,c, E. Gudea,h, D. O. Dahled, E.
4
Bjørkelunda, A.R. Authena, I. Grova, J. P. Wighe, C. H. Dallf, F. Gustafssong, K. Karasone, L.
5
Gullestada,b,h 6
7
Affiliations:
8
aDepartment of Cardiology, Oslo University Hospital Rikshospitalet, Norway. bFaculty of 9
Medicine, University of Oslo, Norway. cThe Norwegian Health Association. dDepartment of 10
Transplantation Medicine, Oslo University Hospital Rikshospitalet, Norway. eSahlgrenska 11
University Hospital, Gothenburg, Sweden. fDepartment of Cardiology, Bispebjerg University 12
Hospital, Copenhagen, Denmark. gRigshospitalet and University of Copenhagen, Denmark.
13
hKG Jebsen Center for Cardiac Research, University of Oslo, Norway and Center for Heart 14
Failure Research, Oslo University Hospital, Norway.
15 16
Corresponding author: Kari Nytrøen, Oslo University Hospital Rikshospitalet, Department of 17
Cardiology, postbox 4950, Nydalen, 0424 Oslo, Norway. E-mail:
18
kari.nytroen@medisin.uio.no 19
Phone: +47 951 89 935 20
21
Total wordcount (Introduction through Conclusion): 4987 22
23 24
2
ABSTRACT 25
Background:
26
There is no consensus on how, when, or at what intensity exercise should be performed after 27
heart transplantation (HTx). We have recently shown that high-intensity interval training 28
(HIT) is safe, well tolerated, and efficacious in the maintenance state after HTx, but studies 29
have not investigated HIT effects in the de novo HTx state. We hypothesized that HIT could 30
be introduced early after a HTx, and that it could lead to clinically meaningful increases in 31
exercise capacity and health-related quality of life (HRQoL).
32
Method:
33
This multicenter, prospective, randomized, controlled trial included 81 patients, mean 11 34
weeks (range 7- 16) after a HTx. Patients were randomized, 1:1, to either nine months of HIT 35
(4x4-min intervals at 85-95% of peak effort) or moderate intensity continuous training 36
(MICT) (60-80% of peak effort).
37
The primary outcome was the effect of HIT vs. MICT on the change in aerobic exercise 38
capacity, assessed as the VO2peak. Secondary outcomes included tolerability, safety, adverse 39
events, isokinetic muscular strength, body composition, HRQoL, left ventricular function, 40
hemodynamics, endothelial function, and biomarkers.
41
Results:
42
From baseline to follow-up, 96% of patients completed the study. There were no serious 43
exercise-related adverse events. The population comprised 73% men, and the mean ( SD) 44
age was 49 ( 13) years. At the 1-y follow-up, the HIT group demonstrated greater 45
improvements than those observed in the MICT group; the groups showed significantly 46
different changes in the VO2peak (mean difference between groups: 1.8 ml/kg/min), the 47
anaerobic threshold (0.28 L/min), the peak expiratory flow (11%), and the extensor muscle 48
exercise capacity (464 Joules). The 1.8 ml/kg/min difference was equal to approximately 0.5 49
3
metabolic equivalents, which is regarded as clinically meaningful and relevant. HRQoL was 50
similar between the groups, based on results from Short Form-36 (version 2), the Hospital 51
Anxiety and Depression scale, and a visual analogue scale.
52
Conclusion:
53
We demonstrated that HIT was a safe, efficient exercise method in de novo HTx recipients.
54
HIT, compared to MICT, resulted in a clinically significantly greater change in exercise 55
capacity, based on the VO2peak values (25% vs. 15%), the anaerobic threshold, the peak 56
expiratory flow, and muscular exercise capacity.
57 58
Clinical Trial Registration:
59
ClinicalTrial.gov identifier NCT01796379. URL:
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https://clinicaltrials.gov/ct2/show/NCT01796379?cond=heart+transplantation&cntry=NO&cit 61
y=oslo&rank=8 62
63
Keywords: Cardiopulmonary exercise testing, maximal oxygen consumption, VO2peak,
64
exercise, high-intensity interval training, muscle strength, heart transplantation, de novo heart 65
transplant recipients, health related quality of life, safety, tolerability, adverse events 66
67 68
4
Clinical Perspective 69
What is new?
70
• This randomized controlled trial was the first to show that the effect of nine months of 71
high-intensity training (HIT) in de novo recipients of heart transplants (HTx) produced 72
a clinically meaningful, significantly larger increase in VO2peak and muscular exercise 73
capacity, as compared to moderate intensity continuous training (MICT).
74
75
• This unique, cost-effective intervention was decentralized, and conducted in 76
cooperation with primary health care services: The one-on-one intervention in both 77
groups contributed to high adherence and high completion rates.
78
• These results are highly applicable to other patient groups.
79
What are the clinical implications?
80
• This novel project and the advanced measurements demonstrated that exercise training 81
is effective in most HTx patients and should start shortly after transplantation.
82
• High-intensity training is feasible in the de novo HTx patients and is more effective 83
than the current moderate training program.
84
• Exercise training can easily be implemented and performed supervised by local 85
physiotherapists close to the patient´s home, instead of more resource-demanding in- 86
hospital rehabilitation programs.
87
• HIT was feasible and safe in de novo HTx recipients and can be implemented readily 88
in clinical practice.
89 90
91
5
Introduction 92
Heart transplantation (HTx) is an established treatment for end stage heart disease. Despite 93
the improvement HTx offers in hemodynamic status, these patients have higher morbidity 94
rates and lower life expectancy,1, 2 health related quality of life (HRQoL),3 and functional 95
capacity 3, 4, compared to healthy subjects. These limitations are mainly due to the 96
development of early and late complications caused by the side effects of immunosuppressive 97
medications. 5, 6 Thus, there is a need to improve well-being and survival in HTx recipients.
98 99
A prominent limitation after HTx is impaired exercise tolerance, measured objectively as a 100
reduction in peak oxygen consumption (VO2peak). Previous studies have shown that VO2peak
101
was reduced by approximately 70% compared to age-matched healthy controls, 4 secondary to 102
both central and peripheral factors. 7, 8 Reduced exercise tolerance was associated with 103
reduced survival 9 and reduced HRQoL; 10, 11 thus, improving exercise capacity is a major 104
goal after HTx. Exercise is an essential part of most rehabilitation programs after HTx, but 105
surprisingly few randomized studies have studied the effects of this intervention. 3, 12-14 Of 106
those conducted, most have used traditional moderate training, which resulted in only a 107
moderate increase in the VO2peak.3, 4, 8, 12, 13
108 109
Previous studies have reported that high intensity training (HIT) was superior to moderate 110
intensity continuous training (MICT) in improving exercise capacity in healthy subjects 15 and 111
in patients with different cardiovascular disorders. 16-18 MICT induced several health benefits, 112
similar to those induced by HIT, but HIT had a superior effect, particularly related to stroke 113
volume. 15 A clear exercise-related effect on stroke volume remains to be studied in HTx 114
recipients. 19, 20 115
116
6
We have recently demonstrated that HIT is safe, well tolerated, and efficacious in HTx 117
recipients that are in maintenance status. 21-25 However, to date, no studies have investigated 118
the effects of HIT in de novo HTx recipients. One reason for this has been a concern that HIT 119
might induce adverse effects, due to the denervated state of the transplanted heart. However, 120
we and others have demonstrated that, during the first year after HTx, partial reinnervation 121
takes place and the heart rate (HR) response to exercise is nearly normalized. This 122
reinnervation might explain the tolerability to HIT exercise in the maintenance HTx state. 4, 8, 123
26 In contrast, the newly transplanted heart is denervated, and consequently, the HR response 124
is greatly reduced compared to healthy subjects. Moreover, studies have shown that different 125
factors are predictive of VO2peak in HTx recipients, depending on the time they are measured 126
after a HTx. For example, in the first months after a HTx, both central factors (i.e., stroke 127
volume and chronotropic responses) and peripheral factors seem to be predictive of VO2peak; 128
however, later on, peripheral factors (i.e., muscular strength and function) are the dominant 129
predictive factors. 7, 27-29 130
131
Although, in the early phase after HTx, central factors might be the leading cause of reduced 132
VO2peak, de novo HTx recipients are also frequently physically deconditioned, with low 133
muscular capacity, due to their heart failure history. This state is likely to contribute 134
additionally to a reduced VO2peak. 30 Thus, we hypothesized that HIT could be safely 135
introduced early after surgery, and that it would result in clinically meaningful increases in 136
exercise capacity and HRQoL. We tested this hypothesis in a multicenter, prospective, 137
randomized trial to test HIT vs. MICT treatments in de novo HTx recipients. 31 138
139 140 141
7
Methods 142
The data, analytic methods, and study materials will not be made available to other 143
researchers for purposes of reproducing the results or replicating the procedure, due to our 144
strict policies for data-sharing and privacy protection.
145 146
Study design 147
The main design of the HITTS study (High-intensity Interval Training in heart Transplant 148
recipients in Scandinavia) was described previously. 31 In short, the HITTS 1-y follow-up 149
study was a prospective, two-arm, multi-center, clinical study that enrolled de novo HTx 150
recipients. The collaborating centers were Copenhagen, Gothenburg, and Oslo; the latter 151
served as the core center. Included patients were randomized in a 1:1 allocation, to either HIT 152
or MICT (Figure 1). The intervention period, for both groups, started approximately three 153
months post HTx and lasted for nine months: up to the follow-up testing at 1-y post HTx.
154 155
Patients 156
For inclusion, patients had to be: clinically stable; aged >18 years; and receiving 157
immunosuppressive therapy according to local protocols (Supplementary table 1). Patients 158
also had to be willing and able to give written informed consent for study participation and 159
motivated to participate in the study for nine months. Patients were enrolled (after providing 160
written, informed consent) 6-8 weeks after surgery. Baseline testing was performed after 161
inclusion, at a mean of 11 weeks (range 7 - 16) post HTx. Allocation to the exercise group 162
was not revealed to study subjects or study personnel until after baseline tests had been 163
performed. At the follow-up exercise tests, all investigators were encouraged to use similar 164
instructions and motivational phrases irrespective of which exercise group the participant 165
belonged to.
166
8 167
Intervention 168
Patients from both groups were supervised and followed in the same manner. Each patient 169
was given general advice about life style changes, including a healthy diet, regular exercise, 170
no smoking, and how to avoid infections. For exercise, they were followed in the primary 171
health care setting; in their local communities by local physical therapists, in a 1:1 setting, at 172
the physical therapist´s facilities. Each therapist was frequently in contact with the main 173
research center via e-mail and telephone. According to protocol, all patients were advised to 174
exercise 2-3 times per week during the intervention period; at that rate, each patient would 175
perform approximately a total of 72 supervised exercise sessions, and each session was 176
planned to last about 40 min (both groups; Figure 2). Thus, the only difference in protocol 177
between the groups was the intensity of the exercise. All the patients in both groups were 178
provided with a Polar FT1 HR monitor (Polar Electro Oy, Kempele, Finland). A detailed 179
description of the two intervention arms is presented in Supplementary table 2.
180 181
High intensity training. The HIT intervention mainly consisted of 2- to 4-min intervals at 85- 182
95% of peak effort (85-95% of peak HR or approximately 81-93% of VO2peak). This intensity 183
corresponded to a rating of perceived exertion (RPE) of 16-18 (according to the Borgs scale) 184
(Figure 2A). The 9-month intervention was divided into three main periods, and the HIT 185
protocol became progressively more difficult (increases in interval lengths and intensities) in 186
each period, as previously described. 31 Briefly, the first period (3-6 months post HTx) 187
consisted of one HIT session, one resistance training session (core musculature and large 188
muscle groups), and one combined session per week. The second period (6-9 months post 189
HTx) consisted of two HIT sessions and one resistance training session (the last with or 190
without supervision) per week. The last 2-3 months of the intervention (up to the first annual 191
9
follow-up at 12 months post HTx) consisted of three HIT-sessions per week. All the sessions 192
were supervised and logged by the physical therapists, who recorded the exercise frequency, 193
duration, and intensity (data from the HR monitor).
194 195
Moderate intensity, continuous training. The control group performed the same amount of 196
supervised physical activity (2-3 times per week), but followed standard care procedures 197
consisting of MICT, which was performed at 60-80% of peak effort (Figure 2B), regular core 198
strengthening exercises, and exercises for large muscle groups. Like the HIT intervention, all 199
sessions were supervised and carefully monitored. The physical therapists logged the exercise 200
type, frequency, duration, and intensity. They also recorded the maximum and mean HR and 201
RPE (Borg scale) in each session.
202 203
Adherence was measured continuously. For each patient, the number of supervised sessions 204
was recorded weekly throughout the intervention period. There was close and regular contact, 205
via e-mail and telephone, between the in-hospital physical therapist and the local physical 206
therapists, and between the local physical therapist and the patient. As per-protocol, the in- 207
hospital physical therapist had a face-to-face consultation with all patients at six months post 208
HTx. Additionally, all patients were invited to call the in-hospital physical therapist to discuss 209
any problems or questions.
210 211
Outcomes 212
The primary endpoint was the change in VO2peak from baseline to follow-up, and the mean 213
change was compared between groups. Secondary and exploratory outcomes conducted at 214
baseline and at 12 months after HTx included: muscular capacity, measured as the maximum 215
muscular strength and muscular exercise capacity; chronotropic responses; right heart 216
10
catheterization hemodynamics; lung function; cardiac dimension and function, assessed with 217
echocardiography; arteriovenous oxygen difference (a-v O2 diff); endothelial function;
218
HRQoL; tolerability; safety; and exercise-related adverse events. All study end points were 219
read and controlled by personnel who were blinded for the intervention.
220 221
Cardiopulmonary exercise test (CPET) 222
The CPET was performed mean 11 weeks (range 7 -16) post HTx, either on a treadmill 223
(Norway) or a bicycle ergometer (Sweden, Denmark). The criteria for passing the test were a 224
respiratory exchange ratio (RER) 1.05 for the treadmill and 1.10 for the bicycle ergometer 225
test. For both tests, a passing Borg scale was > 18. The other equipment and protocols used 226
were described previously. 31 227
228
Muscular strength 229
Muscle strength was measured in the lower limbs; both extensors and flexors were measured 230
isokinetically. As previously described, 31 the three centers used different instruments, but 231
each patient used the same instrument at baseline and follow-up. Overall, maximal strength 232
was measured as the mean value of five repetitions at a low angular velocity (approximately 233
60⁰/s (Newton meter), and muscular exercise capacity was the sum (Joules) of 30 repetitions 234
at a high angular velocity (240⁰/s).
235 236
Hemodynamics, echocardiography, and endothelial function 237
Right catheterization was performed as described by Gude et al. 32 Standard Doppler- 238
echocardiography was performed by experienced technicians and assessed by cardiologists to 239
determine myocardial size and function. Endothelial function was assessed by brachial artery 240
flow-mediated dilatation (FMD) and the fingertip reactive hyperemia index (RHI). The 241
11
EndoPat apparatus was described by Dahle et al. 33 The echocardiography and right heart 242
catheterization were performed as clinical routine (performed by different clinicians) and the 243
clinicians were blinded to the randomization, including the single clinician who performed the 244
EndoPat.
245 246
Arteriovenous oxygen difference (a-v O2 diff) 247
The a-v O2 diff was calculated according to Fick´s equation, based on the resting VO2 values 248
from the CPET and cardiac output (CO) measurements acquired during right heart 249
catheterization.
250 251
Lung function 252
Different lung function variables were measured both at rest and during exercise. Spirometry 253
was performed at rest before the CPET: to obtain the peak expiratory flow (PEF); forced 254
expiratory volume at 1 min (FEV1); and forced vital capacity (FVC). During exercise, the 255
maximum ventilation (Vmax) and ventilatory efficiency (VE/VCO2) were calculated.
256 257
Health-related quality of life (HRQoL) 258
HRQoL was measured with the generic questionnaire Short Form-36, version 2 (SF-36v2).
259
Unlike a disease-specific questionnaire, a generic HRQoL questionnaire can be used in the 260
healthy population as well as in specific patient populations. 34 Subscales were aggregated 261
into two summed-scores: the physical component summary (PCS) and the mental component 262
summary (MCS). Scores were transformed to norm-based scores with a mean of 50 ± 10. 34 263
Symptoms of anxiety and depression were measured with the generic Hospital Anxiety and 264
Depression Scale (HADS). 35 Additionally, the patients rated usefulness and their overall 265
satisfaction of the intervention on a visual analogue scale (VAS).
266
12 267
Approval and ethics 268
This study was approved by the South-East Regional Committee for Medical and Health 269
Research Ethics in Norway, and the Committee for medical and health research ethics, in 270
Sweden and Denmark. This study was conducted in accordance with recommendations in the 271
Helsinki Declaration. This study was registered at ClinicalTrial.gov: identifier NCT01796379.
272
All participants provided written informed consent prior to inclusion in the study.
273 274
Statistical analysis 275
All data were analyzed with IBM SPSS, version 25.0 (IBM corporation, USA). Continuous 276
data are expressed as the mean ± standard deviation (SD) or the median interquartile range 277
(IR). Categorical data are presented as percentages. Within-group comparisons were 278
performed with paired samples t-tests and the Wilcoxon signed rank test. Comparisons of the 279
mean changes between groups were performed with an independent samples t-test or Mann- 280
Whitney U test, where appropriate. Baseline-adjusted ANCOVA tests was also performed for 281
verification of, and comparison with, the t-test analyses (Supplementary table 3). The Chi- 282
square or Fisher´s Exact test was used for comparing categorical data.
283 284
Clinically relevant predictors (age and sex) and other potential explanatory variables, based 285
on a statistically significant (p < 0.05) association with the dependent variable on univariate 286
analyses, were included in the multiple regression analysis to identify the degree of 287
association with the mean difference in VO2peak. The final model was built with a series of 288
multiple regression analyses, performed with the enter method (forced entry). Assumptions 289
were checked for normality and linearity, and none of the models were over-fitted with 290
respect to the total n.
291
13 292
We also performed a multiple regression analysis to compare previously published baseline 293
predictors 29 to the VO2peak level, at follow-up. As described previously, 31 the power 294
calculation was based on an estimated mean VO2peak difference between groups of 3 295
mL/kg/min, a SD of 5 mL/kg/min, an alfa of 5%, and a power of 80%; the analysis indicated 296
that at least 44 patients were required in each group. Due to the fact that fewer HTxs were 297
performed than expected at our collaborating centers during the inclusion period and due to 298
logistic problems, the final analysis included a total of 81 patients.
299 300
Results 301
A total of 155 de novo HTxs were assessed for eligibility during the inclusion period, from 302
2013 to 2017. As illustrated in the flowchart, 72 patients were excluded for various reasons 303
(Figure 1). Eighty-one were tested at baseline, and three dropped out during the intervention 304
period. Thus, 78 patients successfully completed the 1-y follow-up: 37 in the HIT group and 305
41 in the MICT group. The two drop-outs in the HIT group were due to hospitalization (one 306
had nose and throat related issues, one did not comply with the exercise protocol and chose to 307
withdraw from the study). In the MICT group, one patient dropped out, due to a brain 308
arteriovenous malformation (Figure 1).
309 310
Clinical characteristics 311
Among the total study population (n=78), the mean (SD) age was 49 13 years, and men 312
comprised 73% of the cohort. Baseline testing was performed at 11 2 weeks post HTx. The 313
clinical characteristics are presented in Table 1, according to group. Although the baseline 314
VO2peak was numerically lower in the HIT group at baseline (Table 2), the difference between 315
groups was not significant. All baseline variables in Tables 1-3 were tested for between-group 316
14
differences. The only significant difference in baseline characteristics between the two groups 317
was the 24h-h overall HR (Table 3).
318 319
Compliance, safety, and adverse events 320
Both the HIT and the MICT groups (n=78) performed a mean ( SD) of 58 22 exercise 321
sessions during the 9-month intervention. Thus, of the initially planned 72 exercise sessions, 322
81% was accomplished. In the HIT group, the mean exercise session length increased from 323
the first to the third and last period: The mean ( SD) length of the interval bouts increased 324
from 2.3 0.7 min in the first period to 3.6 0.7 min in the last period Accordingly, the mean 325
( SD) peak HR increased from 124 14 to 142 17 beats/min. In the MICT group, the mean 326
exercise sessions length was similar throughout the intervention period (56 13 minutes), but 327
this measurement included also all warm-up and stretching time. In this group, the average 328
HR per session increased from a mean ( SD) of 111 15 in the first exercise period to a 329
mean of 121 16 beats/min in the last period (Figure 3, Supplementary table 4). No serious 330
exercise-related adverse event occurred in either group during the intervention period. The 331
intervention could not be completed at 100% every week by all participants, because some 332
inactive periods occurred, due to cytomegalovirus (CMV) lung infections, other infections, 333
one ankle fracture, two spinal compression fractures, one arrhythmia (atrial flutter), 334
hospitalizations (elevated troponin T and proBNP (suspected rejections), nephrectomy, 335
hernia), gastroenteritis, transplant rejections grades 1 and 2, one deep vein thrombosis, 336
musculoskeletal problems (back, knee, trochanter bursitis, and Achilles tendon), headache, 337
family-related issues, insufficient time for exercise, symptoms of depression, and lack of 338
motivation. Detailed reasons for not being able to complete all the 72 planned exercise 339
sessions are presented in Supplementary table 5.
340 341
15
Cardiopulmonary exercise test 342
At the 1-y follow-up (Table 2), there was a significantly larger increase in VO2peak in the HIT 343
group compared to the MICT group (Figure 4). The mean [95% CI] difference between 344
groups in the VO2peak change was 1.8 ml/kg/min [0.05, 3.5], or half of one metabolic 345
equivalent. The result was verified in an ANCOVA analysis, adjusted for the baseline values 346
(Supplementary table 3). Thus, the primary study objective was achieved. In addition, the HIT 347
and MICT groups improved their VO2peak levels by 25% and 15%, respectively (Table 2, 348
Supplementary table 7). The anaerobic threshold increased more in the HIT group vs. the 349
MICT group, with a significant mean [95% CI] change between groups of 0.28 [0.08, 0.46]
350
L/min. The mean ( SD) RER was similar between groups, at both baseline and the 1-y 351
follow-up (1.19 0.09 vs. 1.22 0.09 in the HIT and MICT groups, respectively); both 352
groups had RER ratios >1.10, which indicated maximal levels of effort at both baseline and 1- 353
y follow-up. However, only the HIT group showed a significant improvement in the O2 pulse 354
(Table 2), which suggested an improved stroke volume. 36, 37 Chronotropic responses 355
improved in both groups, but the peak HR was higher in the HIT group than in the MICT 356
group at the 1-y follow-up (Table 2). Group-based correlations between the VO2peak and the 357
O2 pulse and peak HR are shown in Supplementary figure 2.
358 359
Sub-group analyses between subjects tested on the cycle ergometer versus the treadmill 360
showed no differences in the mean change in VO2peak at follow-up, either in the HIT or the 361
MICT group (data not shown).
362 363
Determinants of the change in aerobic capacity 364
Multiple linear regression analysis showed that the mean changes from baseline to the 1-y 365
follow-up in HR reserve and O2 pulse, including age and sex, accounted for 90% of the 366
16
variance (adjusted R2 square) in the mean change in VO2peak (L/min). All four variables 367
contributed significantly to the model, in the following order of importance: O2 pulse > HR 368
peak > sex >age (Supplementary table 6). We also evaluated several other variables that were 369
significant in the univariate regression. Additionally, we evaluated other clinically relevant 370
predictors, such as treatment arm, body mass index (BMI), muscular exercise capacity, 371
biomarkers, endothelial function, spirometry, resting a-v O2 diff, measures from 372
echocardiography, and right catheterization, but these did not show statistical significance in 373
the multiple regression analyses.
374 375
Secondary and exploratory endpoints 376
Both groups showed improvements in muscular strength (Nm) and muscular exercise capacity 377
(Joules). However, compared to the MICT group, the HIT group showed a significantly 378
higher mean change [95% CI] in muscular exercise capacity at the 1-y follow-up; the 379
difference in improvement between groups was 464 [63, 863] Joules (Figure 5). This 380
difference was further underscored by the correlation between VO2 and muscular exercise 381
capacity which was stronger in the HIT group (r=0.541) than in the MICT group (r=0.400) 382
(Supplementary figure 2). Neither group showed changes in echocardiographic variables (e.g., 383
the left ventricular dimension and ejection fraction) or the right heart catheterization data 384
obtained at rest (e.g., pulmonary artery or wedge pressures, cardiac output, pulmonary 385
vascular resistance, or systemic vascular resistance), except that the HIT group showed a 386
significant increase in the left ventricular systolic dimension at the 1-y follow up (Table 3).
387
Indices of myocardial stretch (NT-proBNP) and ischemia/myocardial necrosis (hs-Troponin 388
T) decreased from baseline to follow-up in both groups, but the mean changes were not 389
significantly different between groups. Additionally, the changes in endothelial function were 390
not different between groups (Table 3). The estimated a-v O2 difference at rest increased 391
17
significantly in the HIT group, but this change was not significantly different from the change 392
observed in the MICT group at the 1-y follow-up (Table 2). Pulmonary function, assessed by 393
PEF, increased significantly more in the HIT group than in the MICT group (mean [95% CI]) 394
difference between groups: 11 [2, 20] %). The changes in FEV1 were similar between groups 395
(Table 3).
396 397
HRQoL, assessed with the SF-36v2, HADS and a VAS scale, revealed no significant 398
differences between the groups regarding patient satisfaction and self-reported usefulness of 399
the intervention (Table 3). At baseline, both groups had higher scores in the SF-36v2 MCS 400
than in the PCS, but at the 1-y follow-up, both groups showed significant improvements in the 401
PCS (p<0.001) (Table 3). The HIT group had a numerically higher score on the VAS scale at 402
follow-up, but the difference between groups was not significant. HADS scores were low in 403
both groups, at both time points (Table 3); this finding indicated a low degree of anxiety and 404
depression symptoms during the course of the study. There was no significant difference in 405
HADS scores between the groups.
406 407
Discussion 408
The most important finding in this study was that HIT was a safe, efficient method of exercise 409
in de novo HTx recipients. We introduced this 9-month HIT-intervention as early as 8-12 410
weeks post HTx. We found that, compared to MICT, HIT resulted in clinically meaningful, 411
significantly larger increases in the VO2peak, AT, PEF, and muscular exercise capacity (Table 412
2 and 3). In addition, only the HIT group showed significant improvements in the resting a-v 413
O2 diff and the O2 pulse (within-group statistics).
414 415
18
As expected, exercise capacity increased significantly in both groups during the first year 416
following HTx. 19, 26, 38, 39 Moreover, we found that the improvement in the VO2peak was 1.8 417
ml/kg/min greater with HIT compared to MICT. The magnitude of this VO2peak increase was 418
equal to or greater than those found in large studies in patients with heart failure that were 419
treated with exercise alone (e.g., the HF-ACTION study showed an improvement at 3-months 420
follow-up of 0.6 ml/kg/min in the exercise group vs. 0.2 in the control group, and at 12- 421
months follow-up: 0.7 in the exercise group vs. 0.1 in the control group), 40 or patients treated 422
with betablockers, 41 angiotensin receptor blockers, 42 or cardiac resynchronization therapy. 43 423
The mechanism of this exercise effect remains unclear, but it is probably not related to 424
exercise adherence or duration. High intensity appears to be a key factor in increasing the 425
VO2peak, which suggests that HIT has unique effects on associated central factors, peripheral 426
factors, or both. 15, 16, 28, 44
427 428
The HIT intervention has not been conducted previously in de novo HTx recipients.
429
Therefore, it was encouraging to find that none of the three patients that dropped out during 430
the intervention reported any serious exercise-related adverse events. Our results underscore 431
that a de-centralized intervention model seems feasible. It also required less resources than 432
many other intervention models.
433 434
Both groups had a mean MCS score above the norm values, and none of the groups had mean 435
scores that indicated any symptoms of anxiety or depression during the course of the study.
436
Throughout the intervention period, the lower baseline PCS scores improved significantly 437
within both groups at the 1-y follow-up. Moreover, although patient satisfaction with the 438
exercise program was not significantly different between groups, the HIT group scored higher 439
on the VAS scale at follow-up, indicating somewhat better patient satisfaction (Table 3).
440
19
Additionally, there were important differences between the HITTS study and larger studies 441
such as SMART-EX and HF-ACTION, 40, 45 regarding the organization, exercise protocol, 442
and overall design. Typically, HTx exercise studies are relatively small, the population is 443
relatively healthy, and the subjects are usually highly motivated to perform exercise training.
444
In our study, the patients were actively involved in selecting where and with whom the 445
exercise should be carried out. They also participated in planning the progression of the 446
exercise. We are convinced that exercising in a 1:1 setting with a physical therapist was a key 447
factor in achieving optimal adherence, exercise intensity, and health benefits. The exercise 448
adherence was poorer and the increase in peak oxygen consumption in the intervention arm 449
was smaller in the much larger HF-ACTION study than in our study. Smaller studies, 450
particularly in a 1:1 setting, facilitate the management of monitoring and documenting the 451
actual intensity achieved during exercise sessions, and this information is essential for true 452
evaluations and firm conclusions on effects of different exercise modes.
453 454
A recent review by Tucker et al 7 addressed performance limitations in HTx recipients. They 455
concluded that HTx recipients have reduced VO2peak through central and peripheral 456
limitations, and that exercise training increases VO2peak via peripheral adaptions. Consistent 457
with that conclusion, in an earlier study on HTx recipients that were in maintenance status (1- 458
8 years post HTx), we demonstrated that predictors of baseline VO2peak were mainly of 459
peripheral origin. 27 Moreover, we found that the effects of a HIT intervention in that cohort 460
were largely due to peripheral adaptations. 20, 21 Similarly, a non-randomized study conducted 461
by Haykowsky et al. in 18 de novo HTx recipients concluded that the exercise-induced 462
increased in aerobic capacity was not associated with favorable improvements in left 463
ventricular systolic function. 19 However, measuring cardiac allograft function during exercise 464
20
is highly challenging, and performing echocardiography during submaximal exercise 465
probably would not reveal the full impact of exercise on stroke volume.
466 467
In the current de novo cohort, the baseline VO2peak level was determined by both central (O2
468
pulse and HR reserve) and peripheral (muscular exercise capacity) factors. 29 Many 469
researchers have considered O2 pulse, derived from CPET, a surrogate for stroke volume. 46-48 470
In the current study, we have taken O2 pulse to represent a central factor. However, O2 pulse 471
also depends on peripheral oxygen extraction.
472 473
In the present study, we performed multiple regression analyses to compare our previously 474
published baseline predictors, 29 with the follow-up values of the exact same predictors. The 475
regression model sustained: with O2 pulse, HR reserve, age, muscular exercise capacity, BMI, 476
and sex (in order of importance) explaining 86% (adjusted R2 square) of the variance in 477
VO2peak (L/min).
478 479
However, when we evaluated factors that might explain the effect of exercise (the mean 480
change in VO2peak at the 1-y follow-up) in a multiple regression analysis, we found that the 481
effect was more dependent on alterations in central factors (HR peak and O2 pulse) than on 482
peripheral factors. Indeed, the change in muscular exercise capacity did not contribute 483
significantly to the variance of the dependent variable (the mean change in VO2peak)
484
(Supplementary table 6). As described in the Results section, several other variables were also 485
evaluated for their potential contribution to the change in VO2peak, but they did not reach 486
statistical significance. These results might suggest that central factors, not surprisingly, 487
dominate in the first phase after a HTx and that peripheral factors become more important 488
after the first year. However, although in this cohort, we could not see any significant 489
21
exercise-mediated changes between groups in, for instance, the resting a-v O2 diff or 490
endothelial function, we could not rule out the possibility that those findings might have been 491
evident in a larger, sufficiently powered cohort. The other central factors we tested (other than 492
those mentioned above) were not significantly different between the groups at follow-up, 493
including the change in chronotropic responses and measures derived from right 494
catheterization or echocardiography (Tables 2 and 3).
495 496
The current study showed significantly greater mean changes in muscular exercise capacity in 497
the HIT group than in the MICT group. This difference implicates positive changes in skeletal 498
muscle function, skeletal muscle oxidative metabolism, and favorable peripheral vascular 499
changes. These differences were further underscored by the strong correlation between the 500
change in VO2peak and the change in muscular exercise capacity (Supplementary figure 2).
501
These types of peripheral adaptations are consistent with findings in a recent study, which 502
demonstrated that HIT induced a rise in pro-angiogenic mediators that promoted new vessel 503
formation. 44 The significant difference in PEF between groups at the 1-y follow-up might 504
have contributed to the greater change in VO2peak and the improved cardiorespiratory fitness 49 505
in the HIT group compared to the MICT group.
506 507
It is well known that exercise improves the VO2peak, and exercise is a key aspect of 508
rehabilitation after HTx. Recently, our research group also showed that improvements in the 509
VO2peak were related to better survival. 9 However, the mechanisms underlying an improved 510
VO2peak, and how they might be related to the differences between the HIT and MICT groups 511
remain somewhat unclear. We require a better understanding of the central and peripheral 512
contributions to the effects of exercise in HTx recipients, and how these contributions might 513
22
change with time after a HTx. With that understanding, we might be prepared to prescribe 514
timed, individually-tailored interventions to achieve optimal results with exercise.
515 516
Limitations 517
A central limitation of this study was the small sample size. Indeed, we did not attain the 518
planned inclusion number, according to the power analysis A higher “n” would probably have 519
strengthened the mean difference in VO2peak values and the exploratory secondary end-points 520
values at follow-up. Moreover, this limitation will likely affect results in the upcoming 3-y 521
follow-up. Another limitation was that many of the evaluated variables were collected at rest 522
(such as the measures from echocardiography, right catheterization, and the a-v O2 diff).
523
Measurements at rest might not have reflected true changes that could have occurred during 524
(peak) exercise. Furthermore, using O2 pulse as a surrogate for stroke volume is a clear 525
limitation and should be interpreted with caution. Additionally, only supervised exercise was 526
recorded in both groups. The performance of un-supervised exercise in both groups might 527
have been useful information. Furthermore, a quadriceps muscle biopsy would have provided 528
valuable insight regarding changes in different muscle fiber types, capillarization, muscle 529
activity, and energy expenditure.
530 531
In conclusion, we found that HIT was a feasible, safe, effective method of exercise in this 532
cohort of de novo HTx recipients. Our findings suggested that implementing HIT could 533
contribute to optimal general health outcomes and prognoses in this group of patients.
534 535
Acknowledgments 536
First, we would like to thank all the patients and local physical therapists that dedicated nearly 537
a year of their lives to participate in this study. We would also like to thank professor Eva 538
23
Prescott for the international cooperation and for contributing to patient management. For 539
assistance with the muscle strength testing, among the Swedish participants, we thank the 540
PhD student, Andreas Lundberg Zachrisson, and Professor Stefan Grau, from the University 541
of Gothenburg.
542 543
Sources of Funding 544
This work was supported by grants from the Norwegian Health Association, the South- 545
Eastern Norway Regional Authority, and Scandiatransplant.
546 547
Disclosures 548
The authors declare no conflict of interest.
549 550
Author contributions 551
The first two authors, Nytrøen K and Rolid K, contributed equally to this paper.
552 553
Affiliations 554
From the Department of Cardiology, Oslo University Hospital Rikshospitalet, Norway: (K.N., 555
K.R., A.K.A., M.Y., E.G., E.B., A.R.A., I.G., L.G.); Department of Transplantation Medicine, 556
Oslo University Hospital Rikshospitalet, Norway: (D.O.D), Faculty of Medicine, University 557
of Oslo, Norway: (K.N., K.R., A.K.A., M.Y., L.G.). From the Norwegian Health Association:
558
(K.R., M.Y.). Sahlgrenska University Hospital, Gothenburg, Sweden (K.K., J.P.W.);
559
Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark (C.D.);
560
Rigshospitalet and University of Copenhagen, Denmark (F.G.). KG Jebsen Center for Cardiac 561
Research, University of Oslo, Norway, and Center for Heart Failure Research, Oslo 562
University Hospital, Norway (K.N., K.R., E.G.,L.G.).
563
24 564 565
Figure Legends, Tables and Figures are uploaded as a separate document.
566 567 568 569 570
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