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Keywords:

  • Aerobic exercise;
  • chronotropic response;
  • heart transplantation;
  • maximum oxygen uptake;
  • muscle strength;
  • VO2peak

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References

Heart transplant (HTx) recipients usually have reduced exercise capacity with reported VO2peak levels of 50–70% predicted value. Our hypothesis was that high-intensity interval training (HIIT) is an applicable and safe form of exercise in HTx recipients and that it would markedly improve VO2peak.

Secondarily, we wanted to evaluate central and peripheral mechanisms behind a potential VO2peak 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 VO2peak 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 VO2peak 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 VO2peak, 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.


Abbreviations: 
% HRmax

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

HRmax

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

VEmax

maximum ventilation

VO2peak

peak oxygen uptake

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References

Exercise capacity improves after a heart transplant (HTx), but continues to be subnormal compared with healthy individuals (1,2). Among factors considered to explain these abnormalities are reduced cardiac output due to chronotropic incompetence or reduced stroke volume, myocardial diastolic dysfunction and peripheral abnormalities (e.g. reduced muscle strength and oxidative capacity, abnormal blood supply because of impaired vasodilatation/capillary density) (2,3).

Several studies demonstrate a positive effect of aerobic exercise after HTx (4–6), but almost all have used exercise with moderate intensity, and the peak oxygen uptake (VO2peak) remain below normal ranging from 50% to 70% of predicted values (1,2). High-intensity interval training (HIIT) has been shown to be an efficient form of exercise to improve physical capacity in patients with coronary artery disease and heart failure (HF) (7,8). However, except for the study by Hermann et al. (9), HTx recipients have not been exposed to this type of exercise mainly because it has been considered “unphysiological” due to chronotropic incompetence. We have previously shown that the heart rate (HR) response is not a limiting factor in HTx recipients’ exercise capacity (10,11) and recent studies suggest that peripheral factors, rather than the heart, may limit exercise capacity in these patients (6). It has also been shown that VO2peak in HTx recipients is independent of the exercise protocol (12). Thus, we reasoned that HIIT would improve VO2peak in HTx recipients, and result in a higher percent of predicted VO2peak than previously shown in most studies. Secondarily, we wanted to investigate possible mechanisms behind a potential increase in VO2peak.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References

Patients and settings

We prospectively recruited 57 clinically stable HTx patients during their annual follow-up between 2009 and 2010 (Figure 1). The inclusion criteria were: age >18 years; 1–8 years after HTx; optimal medical treatment; stable clinical condition; ability to perform maximal exercise test on a treadmill; willingness and ability to perform a 1-year HIIT-program; and provision of written informed consent. Exclusion criteria were: unstable condition; need for revascularization or other intervention; infection; physical disability preventing participation and exercise capacity limited by other disease or illness. All participants were treated according to our immunosuppressive protocol with a calcineurin inhibitor, corticosteroids and mycophenolate mofetil or azathioprine, as well as statins (Table 1).

image

Figure 1. Flow chart of the study population. Exercise group (n = 24), Control group (n = 24).

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Table 1.  Baseline characteristics of the heart transplant (HTx) study population
 Exercise group (EC) n = 24Control group (CG) n = 24t-test, p-Value EG vs. CG
  1. Data are expressed as mean ± SD, median (interquartile range) or percentage.

  2. aX2/Fischer exact test. bMann–Whitney U test.

  3. HTx = heart transplantation; HR = heart rate; EF = ejection fraction; LVEDD = left ventricular end diastolic diameter; CO = cardiac output; LVe′= left ventricle early diastolic mitral annular velocity; ARB = angiotensin II receptor blocker; ACE = angiotensin converting enzyme; eGFR = estimated glomerular filtration rate; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; CRP = C-reactive protein; HbA1c= hemoglobin A1c.

Sex (% men)67711.000a
Age (years)48 ± 1753 ± 140.306
Donor age (years)34 ± 1238 ± 130.251
Ischemic time (min)179 ± 82 159 ± 95 0.446
Time after HTx (years)4.3 ± 2.43.8 ± 2.10.443
Years of HF prior to HTx4.2 ± 5.03.8 ± 2.60.766
Smoking (%)
 Yes/No/Exsmoker4/63/330/71/290.760
Echocardiography
 EF (%)52.3 ± 5.7 54.8 ± 7.3 0.217
 LVEDD (cm)4.8 ± 0.55.0 ± 0.50.266
 CO (L/min)5.6 ± 1.25.0 ± 1.00.060
 LVe′ (cm/s)8.1 ± 1.78.1 ±1.7 0.993
Medication (%)
 Ciclosporine/Tacrolimus/Everolimus92/8/1380/13/210.416/1.000/0.701a
 Mycophenolate/Azatioprine92/096/41.000/1.000a
 Prednisolone96880.609a
 Beta blocker17250.724a
 Calcium blocker17330.559a
 ARB/ACE inhibitors33380.763a
 Diuretics29330.755a
 Statins100100
Blood samples
 Hemoglobin (g/dL)13.9 ± 1.313.9 ± 1.2 0.895
 eGFR (mL/min/1.73m2)55 ± 859 ± 4 0.050
 NT-proBNP (pmol/L)35.0 (24)29.5 (54)0.551b
 CRP (mg/L)0.9 (1.3)1.8 (3.1)0.886b
 HbA1c (%)5.7 (0.6)5.7 (0.6)0.864b

Of the 57 initially recruited patients, five were excluded (Figure 1), and 52 patients underwent baseline testing and were randomized, using computer generated randomization sequences, to either intervention group (HIIT) or control group (usual care). There were no significantly different baseline characteristics between the study population and the rest of the HTx cohort (n = 135), not included in the study (data not shown). The study was approved by the South-East Regional Ethics Committee in Norway (ClinicalTrial.gov identifier: NCT 01091194).

Intervention

The exercise intervention was HIIT performed on a treadmill. Each patient was assigned to a local, cooperating physiotherapist for individual supervision of every HIIT-session. The intervention was divided into three 8-week periods of exercise with three sessions every week. Additionally, the patients were encouraged to continue any physical activity on their own. All participants were provided with their own HR monitor and both the supervised sessions and their solo training were monitored and logged. The HIIT-sessions consisted of 10 min warm-up, followed by four 4 min exercise bouts at 85–95% of maximum heart rate (HRmax), interposed by 3 min active recovery periods (Figure 2) corresponding to ∼11–13 on the Borg, 6–20 rated perceived exertion (RPE), scale. HRmax, recorded during the maximal exercise test at baseline, was used to determine each patient's training zone. Speed and/or increased inclination of the treadmill were adjusted individually to reach the desired HR. No intervention was given to the control group other than basic, general care given to all HTx patients.

image

Figure 2. Level of intensity (% of maximum heart rate) during high-intensity interval training.*Error-bars represent 1 SD. Exercise group (n = 24), Control group (n = 24).

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Exercise testing

We used a modified test protocol from the European Society of Cardiology (13). The treadmill test protocol was carried out as previously described (10). Test termination criteria were respiratory exchange ratio (RER) > 1.05 and/or Borg 6–20 RPE scale > 18. Effect of exercise at submaximal levels is presented as the difference in HR and RER between the exact same time points of the baseline and follow-up test, corresponding to 60% and 80% of maximal exercise at the baseline test.

Muscle strength and muscular exercise capacity

Quadriceps (extension) and hamstrings (flexion) muscle strength and muscular exercise capacity were tested isokinetically (Cybex 6000, Lumex Inc, Ronkonkoma, NY, USA). The test was performed in a sitting position, testing one leg at a time. Muscle strength was tested at an angular velocity of 60°/sec. Five repetitions were performed, with the mean peak value in Newton meter (Nm) calculated for each patient. As a measure of muscular exercise capacity, total work during 30 isokinetic contractions at 240°/sec were measured, with total work in Joule (J) calculated as the sum of all repetitions.

Biochemistry

Regular blood screening was performed in the morning, in fasting site, for all patients by routine laboratory methods. Platelet-poor EDTA plasma for measurements of inflammatory and myocardial markers were collected and stored as previously described (10). N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) were analyzed as described elsewhere (14). Interleukin (IL)-6, IL-8 and IL-10 were analyzed by enzyme immunoassays (R&D Systems, Minneapolis, MN, USA).

Health-related quality of life

Health-related quality of life (HRQoL) was measured with the generic questionnaire Short Form 36 (SF-36), version 2. The results were aggregated into two sum-scores: Physical Component Summary (PCS) and Mental Component Summary (MCS), reported on a standardized scale with a mean of 50 and a SD of 10, based on the 1998 US general population. Patients were also asked to subjectively rate on a VAS scale how much participation in this study had improved their HRQoL.

Miscellaneous

Echocardiography and bioelectrical impedance analysis were performed as previously described (10).

Statistical analysis

Continuous data are expressed as mean ± SD or median (interquartile range), and categorical data are presented as counts/percentages. In-group comparisons were made using paired samples t or Wilcoxon signed rank tests, and between-group comparisons were made using unpaired t or Mann–Whitney U tests, as appropriate. For categorical data, χ2 or Fischer's exact tests were used. Correlations, univariate and multiple regression analysis (hierarchical, enter method) were used to evaluate the association between the change in VO2peak at follow-up and the change in different predictors. The following potential predictors were evaluated for its effect on the change in VO2peak: age; sex; LVEF; CO; LVe′; change in peak HR; %HRmax; HR reserve; CRI; BMI; body fat; muscle strength; eGFR; NT-proBNP and CRP. p-values < 0.05 (two-sided) were considered statistically significant.

The power analysis were based on an expected change in VO2peak of 25% in the EG, and a SD of change without intervention of 4 mL/kg/min. With an alpha of 5% and power of 80% we would need at least 14 patients in each group. We included a total of 52 patients in order to compensate for dropouts and to be able to look into secondary end points.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References

Four of the 52 initially included patients were lost to follow-up due to their health condition or missing data (Figure 1) leaving 48 patients eligible for further analysis. Baseline characteristics are given in Table 1 with no significant differences between the exercise group (EG) and the control group (CG).

Compliance with exercise

Of the 72 planned HIIT-sessions, 69 ± 6 sessions were performed with an intensity of 91.5 ± 2.5% of HRmax. Each exercise-bout lasted 3.9 ± 0.2 minutes (Figure 2). During the weeks between the supervised periods, 66 ± 20 solo training sessions of various activities were performed, with an average HR of 76 ± 6% HRmax.

The last 3 months before follow-up testing, 37.5% in the CG had exercised once or less per week, 37.5%—two to three times per week and 25% four times or more per week, with an exercise duration >30 minutes and a RPE >14 on the Borg 6–20 scale.

Effect of HIIT on responses during maximal exercise

VO2peak increased in the EG with no significant change in the CG, resulting in a significant difference of 3.6 [95% CI 2.0, 5.2] mL/kg/min between the groups at follow-up (Table 2, Figure 3(A)). In line with this, at follow-up VO2peak was 89.0 ± 17.5% and 82.5 ± 20.0% of predicted in the EG and CG, respectively (Table 2). Also, VEmax increased in the EG, but not in the CG, resulting in a significant difference in changes between the groups (Table 2). After HIIT, %HRmax and HR reserve were higher in the EG compared with the CG (Table 2).

Table 2.  Effect of exercise in the two groups
 Exercise group (EG)Control group (CG)Mean difference between groups [95% CI]t-test p-Value
BaselineFollow-upBaselineFollow-up
  1. Data are expressed as mean ± SD. *p < 0.05 and **p < 0.001 within group at follow-up.

  2. HR = heart rate; SBP/DBP = systolic/diastolic blood pressure; RER = respiratory exchange ratio; RPE = rated perceived exertion; CRI = chronotropic response index; VEmax= maximum ventilation; AT = anaerobic threshold; Nm = Newton meter; J = Joule.

Rest
  HR rest (during echocardiography)85 ± 1183 ± 1179 ± 1181 ± 13−5 [−9, 0]0.040
  SBP (mmHg)130± 17136 ± 16131 ± 20129 ± 148 [−3, 19]0.155
  DBP (mmHg)80 ± 1082 ± 981 ± 1582 ± 171 [−7, 10]0.763
Peak exercise (treadmill)
  VO2peak (mL/kg/min)27.7 ± 5.530.9 ± 5.3**28.5 ± 7.028.0 ± 6.73.6 [2.0, 5.2]<0.001
 % of predicted VO2peak80.0 ± 20.089.0 ± 17.5**82.5 ± 20.082.0 ± 19.09.4 [4.5, 14.4]<0.001
  VO2peak (L/min)2.34 ± 0.512.57 ± 0.51**2.29 ± 0.562.25 ± 0.540.26 [0.15, 0.37]<0.001
  RER1.07 ± 0.061.08 ± 0.041.06 ± 0.051.07 ± 0.050.007 [−0.019, 0.032]0.602
  Borg scale (peak RPE)18.5 ± 0.518.8 ±0.4*18.4 ± 0.618.5 ±0.90.2 [−0.3, 0.7]0.385
  Test duration (min)10.6 ± 2.714.1 ± 3.0**12.2 ± 4.713.0 ± 5.92.9 [1.5, 4.3]<0.001
  Peak HR159 ±14163 ± 13*154 ±15153 ±175 [0, 10]0.035
 %HRmax93 ±1296 ± 10*92 ±1092 ± 103 [0, 6]0.050
  HR reserve (beats/min)74 ±1481 ± 13*75 ± 1772 ± 1710 [4, 16]0.002
  CRI0.89 ± 0.230.95 ± 0.19*0.88 ± 0.190.88 ± 0.180.06 [0.01, 0.12]0.019
  Peak SBP (mmHg)181 ± 33211 ± 66*197 ± 22191 ± 3235 [3, 67]0.034
  Peak DBP (mmHg)71 ± 1580 ± 14*83 ± 1491 ± 350 [−14, 15]0.930
  O2 pulse (mL/beat)15.3 ± 3.216.1 ± 2.5*14.5 ± 3.914.7 ± 3.00.6 [−0.6, 1.8]0.290
  VEmax (L)88.1 ± 18.998.4 ± 18.0**83.0 ± 19.382.4 ± 18.510.8 [5.3, 16.3]<0.001
  VE/VCO2 slope29.4 ± 3.428.7 ± 2.629.1± 3.228.8 ± 3.7−0.9 [−1.6, 1.4]0.906
  Submaximal exercise: AT (L/min)1.39 ± 0.271.64 ± 0.36*1.45 ± 0.371.51 ± 0.330.19 [−0.07, 0.45]0.138
Heart rate recovery
  Beats at 30 sec−6 ± 5−8 ± 5−7 ± 5−7 ± 4−3 [−5, 0]0.054
  Beats at 1 min−15 ± 7−16 ± 5−14 ± 8−15 ± 90 [−3, 3]0.918
  Beats at 2 min−24 ± 7− 27 ± 6−25 ± 12− 26 ± 11−2 [−6, 3]0.401
Muscle strength (Nm) and muscular exercise capacity (J)
  Quadriceps (Nm)129 ± 44130 ± 42119 ± 40111 ± 37*8 [0, 17]0.063
  Hamstrings (Nm)68 ± 2471 ± 2771 ± 2567 ± 286–2, 14]0.117
  Quadriceps + hamstrings (Nm)394 ± 131402 ± 135380 ± 121359 ± 123*29 [1, 57]0.043
  Quadriceps (J)2984 ± 14833446 ± 1231**2887 ± 10533035 ± 1088313 [−13, 639]0.059
  Hamstrings (J)1530 ± 8391822 ± 813**1539 ± 5901610 ± 738221 [−26, 468]0.078
Quadriceps + hamstrings (J)4514 ± 22625286 ± 1979**4426 ± 15484645 ± 1735534 [39, 1029]0.035
Body composition
  Body mass index27.2 ± 4.526.5 ± 4.126.3 ± 4.226.3 ± 4.7−0.7 [−1.6, 0.2]0.106
  Body fat (%)26.1 ± 10.325.2 ± 9.524.6 ± 10.125.0 ± 9.7−1.4 [−3.2, 0.5]0.152
  Weight (kg)86.3 ± 16.184.3 ± 15.882.3 ± 15.282.2 ± 15.1−1.9 [−4.5, 0.7]0.143
image

Figure 3. VO2peak (A) and muscular exercise capacity (B) at baseline and follow-up in the exercise and control group.*Error-bars represent 1 SD. Exercise group (n = 24), Control group (n = 24).

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Systolic, but not diastolic, blood pressure (BP) at peak exercise was higher in the EG than in the CG with a significant difference in changes between the groups (Table 2). Although O2-pulse, which reflects stroke volume, improved significantly in the EG after HIIT, the changes between the groups were not significant (Table 2), and all variables reflecting systolic or diastolic function, including NT-proBNP values remained unchanged in both groups (data not shown).

Effect of HIIT on responses during sub-maximal exercise

HR and RER decreased significantly during submaximal exercise intensities (60% and 80% of baseline maximal exercise) in the EG, but not in the CG, resulting in significant differences in the changes of these variables (Figure 4). AT improved from 1.39 to 1.64 L/min, occurring at 64% of the actual VO2peak at follow-up in the EG, while there was no change in the CG, but the difference in changes did not reach statistical significance (Table 2).

image

Figure 4. Change in HR (A) and RER (B) during submaximal stages at follow-up.*Error-bars represent 1 SD. Exercise group (n = 24), Control group (n = 24).

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Effect of HIIT on responses during rest

During the study, resting HR decreased slightly in the EC and increased slightly in the CG, resulting in a significant difference at follow-up (Table 2). This difference was confirmed by the 24 h Holter recordings (data not shown), which showed a significant reduction of minimum HR in the EG; 69 versus 66 beats/min at baseline and follow-up, respectively (p < 0.05). Numerically, HR declined more rapidly after exercise in the EG after 30 sec (p = 0.054 comparing EG and CG), with no differences at 1 and 2 min (Table 2). Systolic and diastolic BP at rest was similar (Table 2). Echocardiographic parameters of myocardial function and pulse-wave analysis of arterial compliance were similar between the groups (data not shown).

Effect of HIIT on muscle strength and muscular exercise capacity

Quadriceps maximal strength did not change in the EG, while it was reduced in the CG (Table 2). There were no changes in hamstrings maximal strength. Quadriceps and hamstrings muscular exercise capacity increased significantly by 15% and 19%, respectively, in the EG, while remaining unchanged in the CG (Table 2), resulting in a significant difference in the change in total work (J) in both quadriceps and hamstrings between the groups (Figure 3B).

Effect of HIIT on body composition, biochemistry and HRQoL

Numerically, the EG had positive changes in their body composition, but there were no significant differences in changes between the study groups at follow-up (Table 2). Lipid profile, glycemic control, NT-proBNP or plasma levels of IL-6, IL-8 and CRP were also similar (data not shown).

Both groups had high HRQoL scores and there were no significant changes in any of the sum-scores (data not shown). However, there was a significant difference between the EG and the CG on the SF-36 General Health subscale at follow-up: 54 versus 49, respectively (p < 0.05). As for subjectively improved health, the EG reported 65 on the VAS scale versus 26 in the CG (p < 0.001).

Determinants of the change in VO2peak

In the multiple regression analysis (Table 3), the change in %body fat and increased muscular exercise capacity (%) together explained 48% (R2 change = 0.48) of the variance of the change in VO2peak. HR reserve added another 5% to the explained variance (R2 change = 0.05).

Table 3.  Multiple linear regression analysis (hierarchical, enter model) of the change in VO2peak (mL/kg/min) at follow-up
VO2peak change atfollow-up predictors (n = 48) B[95%CI], p-ValueR2 change, p-ValueModel summary R2 (Adjusted R2)Model summary p-Value
Change in body fat (%)−0.61 [−0.85, −0.38], <0.0010.337, <0.0010.529 (0.472)<0.001
Change in muscular exercise capacity (%)0.02 [0.01, 0.04], 0.0180.146, <0.001  
Change in HR reserve (beats)0.06 [−0.003, 0.13], 0.0610.048, 0.042  
Age (years)−0.01 [−0.06, 0.05], 0.7740.001, 0.783  
Sex (male)0.10 [−1.53, 1.74], 0.8970.000, 0.897  

Safety parameters

One patient in the CG suffered from an MI resulting in HF and was lost to follow-up (Figure 1). There were no other serious adverse events in any of the groups during the time of follow-up and there were no incidences of musculoskeletal injuries in the EG.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References

HIIT has traditionally been avoided in HTx patients mainly due to concerns over chronotropic insufficiency and safety. The present study has, however, demonstrated that such training is applicable and safe in HTx patients. More importantly, the HIIT-program significantly improved VO2peak, as compared to no changes in the CG. The EG reached a predicted VO2peak level of 89% that is higher than shown in most other studies. This increase in VO2peak was accompanied by a significant improvement in muscular exercise capacity, a decrease in resting HR, an increase in HR reserve and increase in VEmax, without any changes in parameters of systolic and diastolic myocardial function or parameters of inflammation. Importantly, the improvement in peak VO2 in the present study is considered clinically significant as 3.5 mL equals 1 metabolic equivalent, and is greater than that found in most rehabilitation programs among HTx patients (4,15) or what has been observed with an introduction of ACE-inhibitors (16), beta blockers (17) or cardiac resynchronization therapy (18), among HF patients.

Due to chronotropic incompetence in the denervated heart, most centers have used exercise programs with long warm-up, followed by a gradual increase in intensity toward 50–80% of peak effort. HIIT, with repeated bouts of exercise, with a rapid increase in intensity to 85–95% of peak HR sustained for some minutes, followed by a sudden decline in intensity, has been considered unphysiological in HTx patients. However, our study supports a recent study among HTx patients that such exercise training is safe and well-tolerated, and results in a significant improvement in exercise capacity (9). In addition, we have shown that such training can be done decentralized, near the patients’ home environment, supervised by local physiotherapists. At last, while most other exercise interventions have lasted for weeks to some months, our study lasted a whole year, primarily because we wanted to see if such training could be sustained by the participant for such a long time.

In contrast to findings in HF patients where HIIT has been found to induce a significant antiremodeling effect and improved myocardial function (8), HIIT did not induce any improvement in markers of myocardial function in the present study. Although there was an increase in O2-pulse in the EG after HIIT, without any significant changes between the groups, all other variables of systolic and diastolic function were similar during follow-up. Also, there were no changes in NT-proBNP in either the EG or the CG. These findings may suggest that the effect of HIIT on the myocardium is different in HF patients as compared with HTx recipients.

Chronotropic incompetence due to denervation is repeatedly regarded as one of the most central VO2peak limiting factors in HTx recipients (19,20). In our previous work (10,11) we found that the chronotropic responses were close to normal in two different HTx study populations and thus, potentially not a significant determinant of VO2peak. However, in the present randomized trial, we found that HIIT significantly increased HR reserve as a result of both a higher peak HR and a lower resting HR. Thus, while HIIT had no effect on myocardial performance and remodeling in HTx recipients, it seems to have a beneficial chronotropic effect. The reason for this is at present unclear, but might be due to improved autonomic nervous control (11,20–22).

Muscle diffusion capacity, mitochondrial enzyme levels and capillary density are potential peripheral sites for VO2peak limitation (23). Although most research support cardiovascular delivery of O2 to be the central component in VO2peak, the importance of skeletal muscle function should not be underestimated, especially not in HTx recipients on immunosuppressive medication that induces skeletal muscle dysfunction. Long-term use of cyclosporine causes muscle atrophy and a shift toward a larger amount of fast-twitch muscle fibers at the expense of the slow-twitch fibers (24), while corticosteroids result in mitochondrial dysfunction (25). Both at baseline (10) and at follow-up in the current study, we found muscular exercise capacity as a strong predictor of VO2peak. This is in accordance with other studies on HTx recipients with emphasis on the role of skeletal muscle function and microcirculation in physical capacity (5,6,26).

Limitations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References

The inclusion criteria and type of intervention may have led to a selection bias. Participants were defined as stable and healthy, and could have a higher-than-average motivation for exercise, and a baseline higher HRQoL score. In addition, the study population was relatively small and we lacked complete data on reasons for excluding patients from the initial screened population. Over 90% of the patients were still on low-dosage steroids, and based on their negative influence on muscle function, this may have affected the results. Also, the mean baseline VO2peak was relatively high. However, as the values were normally distributed, this likely represents normal group heterogeneity, rather than solely well-trained subjects. Most importantly, since the CG did not undergo another exercise strategy we cannot conclude that HIIT is better than usual, moderate training, but only state that HIIT is an effective and safe form of exercise in this population.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References

In summary, we have demonstrated that a long-term, partly supervised and community-based HIIT-program is an applicable, effective and safe way to improve VO2peak, muscular exercise capacity and general health in HTx patients. The results suggest that HIIT should be introduced and more frequently used among stable HTx recipients. However, it remains to be determined whether this intervention translates into a better prognosis in this patient group. Forthcoming studies should also address the optimal period for HIIT intervention following transplantation.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References

We especially thank the HTx nurses Anne Relbo, Ingelin Grov and Sissel Stamnesfet for valuable help in coordinating this project, May-Britt Skaale for editing the Holter recordings and Wenche Stueflotten for blood sampling. This work was funded by a grant from the South-East Health Region in Norway (Helse Sør-Øst).

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusion
  9. Acknowledgments
  10. Disclosure
  11. References