Although heart transplantation (HTx) is a life-saving treatment for select cases of end-stage heart failure,¹ the post-transplantation course is frequently challenging. In general, solid organ transplant recipients often struggle with obesity, reduced exercise tolerance, muscle weakness, and reduced aerobic activity due to extended hospital courses, medication side effects, and metabolic syndrome.² More specific to HTx, lifelong immunosuppression increases the risk of advanced atherosclerosis and malignancy.¹ Compared to healthy controls, HTx recipients have lower life expectancy, higher morbidity, decreased health-related quality of life (QoL), and worsened functional capacity.³ Despite the survival benefit that HTx affords end-stage heart failure patients, the average life expectancy post-transplant is only 12.5 years.⁴ Thus, for HTx physicians, the question remains: how can we improve the life expectancy and long term well-being of our patients?¹

Theoretical Benefits of Exercise in HTx
In the general population, regular exercise has numerous health benefits.⁵ Less is known about the benefits of exercise in the HTx population; in fact, for many years, exercise was recommended with caution in HTx recipients due to concerns about inappropriate heart rate responses following cardiac denervation.^3,6 More recently, however, studies have suggested that partial sympathetic reinnervation of the transplanted heart occurs in the year following transplantation and that the heart rate response to exercise trends towards normal over time.³ Currently, participation in a cardiac rehabilitation exercise program (CREP) is considered safe for HTx patients and may also be effective in slowing or even preventing some of the adverse events associated with transplantation and chronic immunosuppression, such as muscle atrophy.^1,6 Further, several studies have noted that post-HTx patients who begin a CREP within 12 weeks after transplantation suffered no adverse events and were safely able to complete an extended CREP.⁷ What remains uncertain is: (1) what type of exercise should be encouraged, (2) what specific health benefits can be expected by following an exercise program, and (3) the duration of exercise needed to see health improvement.

Objective Improvements in Exercise Capacity
Peak oxygen uptake (VO_2peak) measured during cardiopulmonary exercise testing is considered the gold standard assessment of physical capacity, and has been validated as a strong predictor of survival in healthy cohorts, those with coronary artery disease (CAD), and in the advanced heart failure community.¹ The same metric has been used to measure changes in physical activity in HTx patients over time and with different exercise routines.⁸ Studies of exercise in HTx have also assessed variables like anaerobic threshold, muscle endurance, self-reported QoL, and anxiety and depression scores to better understand the impact of exercise routines on the well-being and health of HTx patients.^{1–3,6,7,9–11}

While CREPs traditionally offer graduated, moderate intensity training (MIT) regimens, recent data show that high-intensity interval training (HIIT) programs may be better for post-HTx patients.⁸ Nytrøen and colleagues recently reported on the measured VO_2peak values in post-HTx patients who participated in either HIIT or MIT CREP for 9 months post-HTx. They found that not only was HIIT training safe and well tolerated, but also associated with a greater VO_2peak increase (25%) compared to that in the MIT group (15%).³ HIIT participants also benefitted from a greater improvement in peak expiratory flow, anaerobic threshold, and muscular endurance.³ Further, when these patients were followed for 2 additional years, the HIIT group maintained a higher anaerobic threshold and better extensor muscle endurance than control peers.⁹

Quality of Life
Although a growing body of evidence supports substantial improvements in exercise capacity for cardiac rehabilitation and HIIT activity in the post-HTx population, the data on improvements in QoL and mental health are more equivocal. Importantly, despite patient-reported improvements in QoL after HTx, the perceived QoL of a HTx patient remains lower than that of a healthy control.¹ A meta-analysis identified two older studies that had found improvements in self-reported physical QoL and self-reported symptoms of anxiety and depression in post-HTx patients who participated in exercise training when compared to post-HTx patients who did not exercise. This led many to hope that regular exercise could help post-HTx patients report improved QoL comparable to that of a healthy, non-HTx person.² However, a more recent Cochrane review of the benefits of CREP post-HTx did not find a significant difference in patient-reported QoL between those patients who participated in exercise training compared to those who did not exercise, nor was there any significant difference between patients who participated in HIIT versus MIT.¹² As such, the data on QoL improvements with exercise are mixed at best, and the benefits in exercise capacity with regular training may not be perceived to be as significant to patients as they are to their HTx physicians.

"Use It or Lose It": Minimal Long-term Benefits of Short-term HIIT
Another limitation of exercise training is that improved VO_2peak with regular activity are sustained only while the patient is actively participating in the exercise program. The same study by Nytrøen et al., which found improvements in VO_2peak after a 9-month HIIT program, did not find sustained improvement in VO_2peak 2 years after completion of the program. In fact, by 2 years after completion of either the HIIT or MIT program, there was no difference in change of VO_2peak from baseline between the HIIT and MIT groups. Although the HIIT group did show significant and sustained improvements in anaerobic threshold and extensor muscle endurance compared to the MIT group, less is known about whether these markers are associated with any long-term health or longevity benefits.

Next Steps
There is ample opportunity for research into optimal exercise programs for post-HTx patients.  The safety of CREPs early in the post-operative course for HTx patients has been validated.  While HIIT programs can increase a patient's VO_2peak, anaerobic threshold, and muscle endurance when compared to MIT exercise, less is known about the meaningful long-term benefits of these exercise markers in HTx patients. It would seem logical to extrapolate that the survival benefits conferred by increased VO_2peak seen in non-HTx cohorts of healthy controls, CAD patients, and severe heart failure groups would also be seen in the post-HTx population. However, important differences in cardiovascular physiology and long-term immunosuppression requirements in the HTx population pose significant limitations in comparison to other patient populations.¹ Finally, the studies referenced above document the safety of supervised exercise programs, but whether the results can be extrapolated to unsupervised programs in the post HTx population remains unclear. More research is needed to validate the benefits of both long-term and independent exercise habits in this unique population.

References

1. Yardley M, Gullestad L, Nytrøen K. Importance of physical capacity and the effects of exercise in heart transplant recipients. World J Transplant 2018;8:1-12.
2. Didsbury M, McGee RG, Tong A, et al. Exercise training in solid organ transplant recipients: a systematic review and meta-analysis. Transplantation 2013;95:679-87.
3. Nytrøen K, Rolid K, Andreassen AK, et al. Effect of high-intensity interval training in de novo heart transplant recipients in Scandinavia. Circulation 2019;139:2198-2211.
4. Khush KK, Cherikh WS, Chambers DC, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult heart transplantation report - 2019; focus theme: donor and recipient size match. J Heart Lung Transplant 2019;38:1056-66.
5. Myers J. Cardiology patient pages. Exercise and cardiovascular health. Circulation 2003;107:e2-e5.
6. Choi H-E, Kim C, Park S-H. One-year follow-up of heart transplant recipient with cardiac rehabilitation: a case report. Medicine (Baltimore) 2020;99:e19874.
7. Rolid K, Andreassen AK, Yardley M, et al. Clinical features and determinants of VO2peak in de novo heart transplant recipients. World J Transplant 2018;8:188-97.
8. Parker AM, Corotto P, Bergin JD. Competitive athletics after heart transplant. http://www.acc.org.. Nov 28, 2016. Accessed October 30, 2020. https://www.acc.org/latest-in-cardiology/articles/2016/11/21/07/44/competitive-athletics-after-heart-transplant .
9. Rolid K, Andreassen AK, Yardley M, et al. 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. Am J Transplant 2020;20:3538-49.
10. Nytrøen K, Rolid K, Yardley M, Gullestad L. Effect of high-intensity interval training in young heart transplant recipients: results from two randomized controlled trials. BMC Sports Sci Med Rehabil 2020;12:35.
11. Tucker WJ, Beaudry RI, Samuel TJ, et al. Performance limitations in heart transplant recipients. Exerc Sport Sci Rev 2018;46:144-51.
12. Anderson L, Nguyen TT, Dall CH, Burgess L, Bridges C, Taylor RS. Exercise-based cardiac rehabilitation in heart transplant recipients. Cochrane Database Syst Rev 2017;4:CD012264.

Clinical Topics: Cardiac Surgery, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Sports and Exercise Cardiology, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Transplant, Interventions and Coronary Artery Disease, Exercise, Sports and Exercise and ECG and Stress Testing

Keywords: Sports, Athletes, Heart Transplantation, Quality of Life, Exercise Tolerance, Exercise Test, Anaerobic Threshold, Cardiac Rehabilitation, Coronary Artery Disease, Self Report, Mental Health, Metabolic Syndrome, Life Expectancy, Muscle Weakness, Heart Rate, Depression, Heart Failure, Exercise Therapy, Anxiety, Atherosclerosis, Muscular Atrophy, Immunosuppression, Neoplasms, Morbidity, Oxygen, Hospitals

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