Exercise as a modality to improve heart transplantation-related functional impairments: An article review

Abstract

Heart transplantation (HT), the treatment choice of advanced heart failure patients, is proven effective in increasing the survival and functional status of the recipients. However, compared to normal controls, functional status is lower in HT recipients. Exercise given in cardiac rehabilitation has been shown to improve exercise capacity as measured with peak oxygen uptake (VO2 peak) and muscle strength after completion of the program and cessation of exercise results in loss of exercise benefits. Several factors related to cardiac denervation and the use of immunosuppressive agents in HT recipients result in functional impairments including cardiovascular, pulmonary, exercise capacity, psychological, and quality of life (QoL) problems. High-intensity interval training (HIIT) is the most common type of exercise used in HT recipients and given as a hospital-based program. Improvement of functional impairments was found to have occurred due to primarily musculoskeletal adaptations through improvement of muscle structure and aerobic capacity and cardiovascular adaptations. In general, exercise given after transplantation improved VO2 peak significantly and improvement was better in the HIIT group compared to moderate intensity continuous training or no-exercise groups. Improvement of QoL was ascribed to improvement of exercise capacity, symptoms, pulmonary function, physical capacity improvement, anxiety, and depression.

Key Words: Cardiac rehabilitation, Exercise tolerance, Functional status, Heart transplantation, High-intensity interval training, Muscle strength, Quality of life

Core Tip: Heart transplantation is proven effective in increasing the survival and functional status of the recipients, but compared to normal controls, their functional status is lower. Exercise is shown to improve exercise capacity and its cessation causes the loss of its benefits. Cardiac denervation and immunosuppressive agents used in heart transplantation recipients result in cardiovascular, pulmonary, exercise capacity, psychological, and quality of life problems. Functional improvement is mainly due to musculoskeletal and cardiovascular adaptations. The greatest improvement in exercise capacity was found in recipients given supervised high-intensity training. Quality of life improvement resulted from the improvement of exercise capacity and symptoms.

INTRODUCTION

Heart transplantation (HT) is the treatment choice of advanced heart failure (HF) patients in those for whom the recommended optimal medical treatment fails to control symptoms and halt the progression of the underlying pathology[1]. HT is proven effective in increasing survival rate, particularly for advanced HF with New York Heart Association (NYHA) class IV, stage D, whose survival rate was zero[2]. The 1-year and 5-year survival rates after HT are approximately 90% and 70%, respectively. The main causes of death are malignancy, vasculopathy of the coronary arteries, and graft failure. Some patients experience left ventricular dysfunction and antibody-mediated rejection[1].

The goal of HT is to restore an active lifestyle and improve the quality of life (QoL). In the first year, 45% of recipients are readmitted to the hospital, and after one year 20%-25% of recipients need yearly hospitalization for diagnosis[3]. The benefits of HT on functional status are enabling most patients to return to normal life, and prevent limitations in daily activity by reducing symptoms and improving exercise capacity[4]. Although the benefits of HT are widely proven, compared to healthy controls, exercise capacity and physical performance of HT recipients were lower. The same result was shown in the QoL, especially in work performance[5-9].

Cardiac rehabilitation (CR) is a multidisciplinary approach recommended for HT patients, both before and after surgery. Exercise given in CR has proven benefits in improving patients’ functional status, reducing the severity of cardiac allograft vasculopathy (CAV), reducing risk and complications of other cardiovascular diseases, and decreasing rehospitalization and even death[10]. A decreased risk of readmission one year after discharge is considered a benefit of CR. However, the participation rate among HT recipients in the United States is only approximately 50%[11].

HT recipients have abnormal physiological responses to both acute and regular exercise due to pathological changes in the cardiovascular and musculoskeletal systems. The underlying HF and hospital admission after the surgery contributed to these responses[7,12]. The abnormal physiological responses to exercise are associated with chronotropic incompetence that decreases heart rate (HR) response to exercise and peak HR post HT[13]. Studies regarding the physiological effects of exercise in HT recipients have shown that exercise capacity as measured with peak oxygen uptake (VO2 peak) and muscle strength increased after completion of the program. Despite that, there is also evidence that the benefits of exercise will decrease or be lost after cessation of exercise. These findings should become a consideration to continue exercise to maintain long-term effects[14-16]. Extensive literature has described exercise in HT recipients and this review seeks to describe exercise from a physical and rehabilitation medicine point of view by describing functional disorders in HT recipients and how exercise can improve their condition.

HEART TRANSPLANTATION AND ITS COMPLICATIONS

HT is indicated to HF patients with cardiogenic shock with a low probability of recovery, NYHA classification of class IIIb or IV, severe functional limitations, coronary artery disease with refractory angina with Canadian Cardiovascular Score class II or IV despite optimal therapy, localized cardiac tumors with a low probability of metastasis, and recurrent life-threatening ventricular arrhythmias despite optimal therapy[2]. Left ventricular ejection fraction (LVEF) < 35%, acute myocarditis, restrictive cardiomyopathy or severe symptomatic hypertrophic, congenital heart disease with no complication of severe and fixed pulmonary hypertension, aerobic capacity (VO2max) of < 50% predicted and/or ≤ 12–14 mL/kg/min, and/or the minute ventilation/carbon dioxide production (VE/VCO) slope > 35 during cardiopulmonary exercise testing (CPET) are also indications for HT[17].

Long-term complications of HT include CAV, rejection, arrhythmias, infection, and side effects of immunosuppressive agents such as malignancy, nephrotoxicity, and drug-drug interaction[1,2,17]. Progressive graft vasculopathy and peripheral vasculopathy are associated with increased cardiovascular risk and death in HT recipients. These pathologies are associated with endothelial dysfunction due to a reduction in arterial compliance that is caused by deterioration of peripheral vasodilatation, deposition of collagen, decreased elastin, and sympathetic hyperactivity[18]. Transplant rejection is also considered as the major cause of death, and the use of immunosuppressive agents to prevent organ rejection results in further worse complications[1,4]. About 30% of deaths within the first year after transplantation occur due to infection[4]. CPET is suggested to be performed during the first annual screening of HT recipients because it can identify patients at high risk of developing advanced CAV[19].

FUNCTIONAL IMPAIRMENTS IN HEART TRANSPLANTATION RECIPIENTS

Cardiovascular function

Cardiovascular alterations in HT recipients are chronotropic incompetence, impaired diastolic function, high resting HR, reduced maximum cardiac output (CO), endothelial dysfunction, increased sympathetic activation, and increased peak exercise systemic vascular resistance[7]. A reduced HR response and reduction of peak HR after transplantation resulted in lower VO2max in HT recipients than in normal controls. This was associated with chronotropic incompetence due to cardiac denervation[13]. Cardiac denervation results in a higher normal resting HR and a delayed and blunted increase during exercise[20].

At supine rest, HT recipients have a high total peripheral resistance and blood pressure, while, during an orthostatic challenge, HT recipients are found to have preserved total peripheral resistance and blood pressure responses. In a standing position, HT recipients are unable to increase their HR and cardiac output further, causing attenuation of the cardiac output resulting in symptoms and a cold hand[21]. HR recovery in HT recipients is impaired. A study found that HR recovery at the first minute and the second minute was 7 beats and 14 beats, respectively. This is equivalent to fourfold lower than normal individuals with 30 beats and 52 beats in the first minute and the second minute, respectively[15].

HT recipients have a 50% elevation of systemic vascular resistance (SVR) resulting from impaired endothelial-dependent vasodilation and higher peak SVR than healthy age-matched controls. The magnitude of endothelial dysfunction is related to HF etiology where the non-ischemic cardiomyopathy is better than the ischemic one. Pulmonary VO2 kinetics was found slower in ischemic HF. Vascular dysfunction is also adversely affected by chronic use of immunosuppressive agents. Elevated sympathetic nerve activity causes increased peripheral vasoconstriction during exercise and reduced oxygen delivery to the exercising muscles, resulting in exercise intolerance[20].

Pulmonary function

HF is associated with a restrictive pattern of pulmonary disorders presented as a decrease in pulmonary function[22]. Severe chronic lung disease in HT patients increases HT complications and decreases functional capacity and survival rate after transplantation. Pulmonary dysfunction due to immunosuppressive agents results in increased pulmonary infection risk. Lower pulmonary function was also associated with prolonged ventilator use[2]. As per response to exercise, HF causes an excessive ventilatory response to exercise due to an increase in wasted ventilation[13].

A study found that HT surgery results in an improvement of forced expiration volume in one second and forced vital capacity. However, respiratory muscle strength remained below the normal predicted value as presented by maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and peak cough flow (PCF)[22]. Another study found that HT increased pulmonary function to normal or near normal values, but transfer factors and transfer coefficient remained low. The presence of pulmonary edema before HT was considered as a cause[13]. Pulmonary function changes after HT are decreased lung diffusion capacity for carbon monoxide and abnormal gas exchange, which further limit exercise capacity, leading to exercise-induced hypoxemia and exercise intolerance[8].

Exercise capacity

Exercise capacity is defined as the maximum amount of physical exertion that can be sustained by an individual, which reflects the cardiovascular system function. Exercise intolerance, on the other hand, is defined as the inability to perform physical activities without symptoms of dyspnea and/or fatigue due to impaired exercise capacity, which is the main impairment found in patients with HF. Exercise capacity can be measured by CPET which is the gold standard measurement because it allows a non-invasive assessment for exercise capacity limitations. Peak oxygen uptake during a maximal exercise test or VO2 peak is a key parameter of exercise capacity[23,24]. Another term to reflect exercise capacity is VO2max. VO2max refers to the oxygen consumption of an individual when exercising to the maximum exertion. Achieving a plateau VO2 during a graded maximal exercise test is an accurate measurement of VO2max. However, the high inter-subject variability in achieving their maximum effort may cause a lower value of VO2[25]. The VO2 peak is considered the best predictor of survival and mortality in HF patients with preserved ejection fraction[26].

HT recipients have a below-predicted VO2 peak due to several factors. A decrease in exercise capacity in HT recipients is schematically described in Figure 1[7,20,21]. Cardiovascular and skeletal muscle abnormalities result in lower exercise capacity in HT recipients[7,17,20]. Surgical excision in HT results in the denervation of parasympathetic and sympathetic nerve fibers in the heart. Cardiac denervation is responsible for decreased CO, exercise capacity, nocturnal decline in blood pressure, a slower increase in HR during exercise, and higher resting HR early post-HT. Cardiac denervation decreases the catecholamine stores in the myocardium and as a result, the heart relies on non-cardiac circulating catecholamines. Therefore, HT recipients may experience more arrhythmias and have abnormal responses to adrenergic medications. The denervated heart must increase its stroke volume to increase cardiac output, even during mild exercise, to compensate for chronotropic incompetence[17,20]. A delayed chronotropic response and decreased maximum HR in HT recipients are associated with decreased exercise capacity[22]. Lower CO is caused by diastolic dysfunction and impaired vascular function, while decreased arteriovenous oxygen difference is caused by decreased skeletal muscle oxidative fibers, enzymes, and capillarity. These abnormalities lead to decreased VO2 peak in HT recipients, which is 40% to 50% lower than that of sex-, age-, and activity-matched healthy controls[7,20]. Cardiac allograft diastolic dysfunction is related to cardiac denervation and CAV. CAV is an aggressive development of atherosclerosis resulting from the immune mechanism that mediates endothelial injury[20].

Figure 1  Pathophysiology of decreased aerobic capacity in heart transplantation recipients.

Total body and leg mass and muscle strength were associated with decreased exercise capacity[20,22]. Decreased skeletal muscle function contribute to exercise intolerance because the majority of oxygen consumption during exercise occurs in the exercising muscles. Maximal arteriovenous oxygen difference was lower in HT recipients than in normal age-matched healthy controls[20].

Muscular fitness

The underlying HF causes pre-transplantation skeletal muscle dysfunction, which results in decreased muscle strength[7]. Skeletal muscle dysfunction presents as fiber atrophy and contractile dysfunction. The mechanisms that contribute to skeletal muscle atrophy in HF are dysregulation of myokine expression, inability to activate pro-hypertrophic pathway or anabolic resistance, impaired mitochondrial dynamics in regulating energy metabolism, and impairment of satellite cells responsible for muscle growth. Aging and physical inactivity in HF patients also contribute to skeletal muscle dysfunction[27,28]. One study found that skeletal muscle dysfunction was associated with reduced exercise capacity in HF patients, both with reduced or preserved ejection fraction[28].

In HT recipients, muscle atrophy is caused mainly by adverse immunosuppressive agent effects and postoperative restrictions[22]. Musculoskeletal changes in HT recipients are decreased total body mass, reduced type 1 oxidative fiber, decreased oxidative enzyme capacity, decreased capillary/fiber ratio, decreased peak exercise arteriovenous oxygen difference, and decreased bone density[7].

A study found decreased skeletal muscle oxidative and beta-oxidative enzyme activities and glycolytic enzyme activity 2 mo after HT compared with those before transplantation. At one year, no restoration of skeletal muscle or oxidative or beta-oxidative enzyme activities occurred, while decreased oxidative muscle fibers, increased glycolytic enzyme activity, and increased glycolytic fatigable fibers were found. This finding suggests that skeletal muscle dysfunction persists within one year after HT[29].

Psychological problems and quality of life

In HT candidates, several factors cause a decrease in QoL, such as the burden of symptoms, the disabling consequences of the treatment protocol, and HF itself which will affect daily lives[30]. Specifically, psychological and social dysfunctions, persistent congestion, activation of neurohormonal response and inflammation, skeletal muscle dysfunction, decreased kidney function, right ventricular dysfunction, severely compromised hemodynamic state, and cachexia were found to be associated with decreased QoL. QoL decreased as NYHA classification worsened and exercise tolerance contributed to a marked decrease in QoL[31].

QoL is a parameter used to evaluate the long-term result of HT. Many HT recipients reported functional impairments in several aspects of QoL at one year after surgery. In addition to disorder in work performance, eating, social interaction, ambulation, home management, and recreation were also reported. There was only approximately a quarter of HT recipients who returned to work within one year and more than half (59%) among them reported problems that affected their work performance. Factors that contributed to this issue were the presence of symptoms, neurological problems, stress, depression, older age, female sex, and lower LVEF[7-9]. Hospital and intensive care unit admission also affect QoL domains. One study found that patients requiring extracorporeal membrane oxygenation pre- or post-HT had impaired physical function and leg complications at intensive care unit discharge[32]. Compared to advanced HF patients, HT recipients demonstrated higher scores in all QoL domains. The improvement of symptoms of dyspnea and exercise intolerance, a decrease in psychological problems, and an improvement in functional ability limitations are considered the reasons[33].

EXERCISE TO IMPROVE FUNCTIONAL STATUS OF HEART TRANSPLANTATION RECIPIENTS

Rationale of exercise

Exercise-based CR is recommended both before (pre-habilitation) and after HT. The reasons for this recommendation are: (1) HT recipients have a poor exercise capacity and deconditioning syndrome; (2) inactivity before and after HT causes deconditioning, which impairs the healing process and causes skeletal muscle dysfunction; and (3) the use of corticosteroid medications causing skeletal muscle dysfunction[4,10,34]. Exercise-based CR is shown to decrease the rehospitalization rate among HT recipients[4]. In addition, participation in exercise-based CR for ≥ 23 sessions was proven beneficial in reducing major adverse cardiovascular events[34].

Recommendation of exercise

Exercise in HT recipients is given as a part of CR that encompasses pre-rehabilitation to phase III CR. Exercise in pre-rehabilitation periods aims at reducing HT-related complications such as intensive care unit-acquired weakness and cardiac cachexia in addition to maintaining a higher fitness level[7,35]. Phase I CR is given to prevent the deleterious effects of prolonged bed rest with early mobilization. Early mobilization can be started soon after extubating. The program given includes kinesiotherapy and the prevention of respiratory infection. In-bed exercise such as passive range of motion can be given initially and progress to seated exercise, standing, and walking. Exercise with cycle ergometry, starting with resistance-free and slow-pace treadmill walking, can be given after in-bed exercise is tolerated by the patients. Regular exercise program given in phase II CR may begin early after HT (from the second or third week) and be given for 6-8 wk. Phase III CR is an intervention that aims to maintain the benefits of exercise given in phase II and promote life-long healthy behavior. Exercise is provided in the form of a home exercise program with activities similar to early phase II CR[7,36].

Resistance exercise is given along with aerobic exercise to counteract the effect of immunosuppressive agents on skeletal muscles[37]. Aerobic exercise recommendation for HT recipients can be given with a frequency of 3–5 d per week, with an intensity of 80%-90% of maximum HR or 60% to 70% of VO2 peak. The duration of initial exercise is 20-60 min. Exercise at the beginning should be supervised, which then continues to non-supervised exercise[38]. Other components of CR given to HT recipients aim at maintaining a balanced diet, monitoring blood pressure, avoidance of hyperlipidemia, limiting sodium intake, appropriate medication use, smoking cessation, and psychosocial management[7].

Exercise protocol

Prescription of exercise must be tailored to the patients based on their recovery rate and current exercise capacity. Exercise programs should include aerobic and strengthening exercises for major muscle groups. Exercise dose (frequency, intensity, and duration) should progress gradually[10]. High-intensity interval training (HIIT) is the most common type of exercise given to HT recipients and given as a hospital-based program (Table 1).

Table 1 Summary of exercise protocols in heart transplantation recipients.

Ref.	Exercise intervention	Exercise protocol
		Frequency	Intensity and time	Type	Warm-up	Cool-down	Program duration
Torto et al[53], 2022	Single-leg vs double-leg HIIT	3 sessions per week	Two kinds of HIIT, done alternately. 4-min exercise bouts at high intensity alternated by 3-min rest at low intensity, 4 sets, 12 bouts. 2-min exercise bouts at high intensity alternated by 2-min rest at low intensity, 6 sets, 12 bouts	Ergocycle, pedaling frequency 60-75 RPM	5 min	5 min	8 wk
Rustad et al[40], 2014	HIIT vs usual exercise	3 sessions per week	4-min exercise bouts at 85%-95% of HR peak alternated by 3-min rest equal to Borg scale of 11-13, 4 bouts	Treadmill uphill walking or running	10 min		3 episodes of 8-wk exercise
Dall et al[15], 2014	HIIT vs MICT	3 sessions per week	HIIT: 4-, 2-, and 1-min bouts of exercise at > 80% of VO2 peak alternated by a 2-min rest at 60% of VO2 peak, 32 min	Ergocycle	10 min	10 min	12 wk
			MICT; 60%-70% of VO2 peak, 45 min
Yardley et al[14], 2017	HIIT vs usual care	3 sessions per week	4-min exercise bouts at 85%–95% of HR max alternated by 3-min active recovery periods equal to Borg scale of 11–13, 4 bouts	Treadmill or ergocycle	10 min	10 min	12 mo
Nytrøen et al[51], 2012	HIIT vs usual care	3 sessions per week	4-min exercise bouts at 85%–95% of HR max alternated by 3-min active recovery periods equal to Borg scale of 11–13, 4 bouts	Treadmill	10 min		3 episodes of 8-wk exercise
Hermann et al[43], 2011	HIIT vs no exercise	3 sessions per week	Initial HIIT 4-min, 2-min, 30-s exercise bouts at 80%, 85%, and 90% of VO2 peak consecutively, equal to Borg scale of 18–19, followed by half a minute of recovery period. After HIIT, 10-min staircase running with an intensity of 80% of VO2 peak. Total time: 42 min	Bicycle and staircase running	10 min	10 min	8 wk
Nytrøen et al[16], 2012	HIIT vs MICT and no exercise	3 sessions per week	HIIT: Exercise bouts at 85%-95% of peak effort	Treadmill			9 mo
			MICT: Exercise bouts at 60%-80% of peak effort
Haykowsky et al[41], 2009	Aerobic and strengthening exercises	Aerobic: 5 sessions per week during the first 8 wk. 3 sessions per week during the final 4 wk	Aerobic: During the first 8 wk: Exercise at HR equal to 60%-80% of VO2 peak for 30-45 min During the final 4 wk: Exercise at HR equal to 80% of VO2 peak for 45 min	Ergocycle			12 wk
		Strengthening: 2 sessions per week	Strengthening: 50% of maximal strength, 1-2 sets, 10-15 repetitions	Chest press, arm curls, latissimus dorsi pulldown, and leg press
Karapolat et al[42], 2008	Flexibility, aerobic, strengthening, breathing, and relaxation exercises	3 sessions per week, 1.5 h exercise per session	Flexibility: Stretching and range of motion exercise	Applied to the trunk, upper extremities, and lower extremities joints			8 wk
			Aerobic: Exercise at 60%-70% of the VO2 peak equal to a Borg scale of 13-15, 30 min	Treadmill or ergocycle
			Strengthening: Lightweight of 250-500 g, 2 wk after performing aerobic exercise	Abdominal, upper extremities, and lower extremities muscle groups
				Pursed-lip breathing, synchronization of thoracic and abdominal movement, and expiratory abdominal augmentation
				Jacobson’s progressive muscle relaxation
Hsu et al[52], 2011	Hospital-based-aerobic exercise	3 sessions per week	Exercise at 50%-80% of VO2 peak, 25-30 min	Combination of ergocycle and treadmill	10 min	10 min	12 wk

HIIT: High-intensity interval training; RPM: Revolutions per minute; HR: Heart rate; MICT: Moderate-intensity continuous training; VO2 peak: Peak oxygen uptake.

Safety of exercise

Data regarding the efficacy and safety of exercise in HT recipients, especially data on cardiovascular mortality, hospitalization rates, and side effects, are limited[5]. One study reported no adverse event related to exercise during the follow-up period[15]. A case study reported no complications or life-threatening events during CR that was given long-term with the HIIT protocol[22]. A systematic review and meta-analysis found that none of the included studies reported either cardiovascular or all-cause mortality. An adverse event of myocardial infarction in the usual care group was reported in one study that caused participants to be withdrawn from the study. No considerable adverse event was reported in the remaining studies[39].

EFFECT OF EXERCISE ON FUNCTIONAL STATUS OF HEART TRANSPLANTATION RECIPIENTS

Cardiovascular function

Previous studies found that heart function parameters such as systolic and diastolic functions, left ventricular systolic function, and chronotropic variables were not significantly improved after exercise[40-42]. One study found an improvement in cardiovascular functions in the form of decreased systolic blood pressure by 5 mmHg, decreased resting HR by one beat, increased HR peak by four beats, and increased HR by five beats after exercise. These improvements are suggested to be due to increased exercise-induced catecholamine and allograft sensitivity[15]. Ultrasound examination found a reduction of 50% in the progression of CAV after exercise. This may result from a reduction of the pro-inflammatory state[39].

In terms of improvement in HR recovery, a study found that HIIT resulted in a modest improvement. HIIT improved heightened reaction and shortened reaction time of the sinus node, leading to a faster HR recovery and higher HR peak, which is considered as a marked decrease of vagal activity. The HR recovery is also considered as an independent and powerful predictor of death. Improvement in HR recovery also occurred in the moderate intensity continuous training (MICT) group, but the improvement was marked in the HIIT group[15]. The impact of exercise on chronotropic function is due to an increase in chronotropic response and partial improvement in autonomic imbalance secondary to prevention of overactivation of the sympathetic system and improvement in HR variability, baroreflex sensitivity, and HR recovery[42]. Studies that examined vascular function in HT recipients were limited. Flow-mediated dilatation (FMD) was found to increase significantly in the HIIT group[43]. However, endothelial-independent and -dependent vasodilatation was unchanged in the group given a combination of aerobic and resistance exercises and no exercise[41].

Pulmonary function

Studies regarding pulmonary function in HT recipients are limited. Breathing exercises given to HT recipients were found to improve pulmonary function test parameters[44]. Another study that gave a combination of both HIIT and MICT aerobic and resistance exercises found no difference between groups on pulmonary function changes from baseline to 3-year follow-up. However, no data on changes in pulmonary function are available[45]. A previous case report found that aerobic exercise improved MIP, MEP, and PCF. The mechanism by which pulmonary function improves is increasing respiratory muscle strength, thoracic mobility, and the balance between chest and lung elasticity[22].

Exercise capacity

The physiological mechanisms of exercise capacity improvement are suggested to be due to the improvement of peripheral adaptations such as an increase in energy synthesis in skeletal muscle leading to an increase in mitochondrial density, an increase in the ability to utilize and extract oxygen, and a decrease in inflammation[15,40,46]. Short-term exercise (< 1 year) improves VO2 peak primarily through skeletal muscle adaptations, while long-term exercise (> 2 years) acts through cardiac allograft reinnervation[20]. Exercise-based CR improved peripheral skeletal muscle performance, leading to improved exercise capacity in the elderly with HT. There is a possible beneficial effect of HIIT given for ≥ 1 year in the elderly with HT on improving peak HR[37]. Improvement of cardiac function, such as left ventricular end-systolic and diastolic volume, stroke volume, and LVEF, was not significant in the previous study. This explains that peripheral factors are more related to the improvement of VO2 peak compared to central factors such as improvement of cardiac output as obtained in patients with other cardiovascular diseases[46,47]. However, compared to patients using left ventricular assistive devices, HT recipients may have a greater ability to increase their cardiac output as a response to exercise[48].

The VO2 peak in HT recipients is 40%-50% lower than that of normal healthy subjects. VO2 peak is a powerful prognosticator for patients with HT because it is associated with long-term survival. Participation in CR was associated with a reduction of 29% in readmission after one year. However, studies showed that the benefit of exercise on VO2 peak dropped or was lost after 5-mo or 4-year cessation of exercise[39].

A previous study found that VO2 peak increased significantly in HT recipients who attended CR, with an average increase in VO2 peak of 10.2% compared to those who did not[49]. One study gave a 3-mo CR and found an increase in VO2 peak of 10.5 mL/min/kg compared to baseline up to 1 year after HT[22].

The variation of increased exercise capacity value depends on the exercise intensity, baseline exercise capacity, and HT procedure including surgical techniques, drugs, and postoperative management[22]. HIIT was found superior to MICT in improving VO2 peak (Table 1). Improvement of VO2 peak was greater in the group receiving HIIT compared to MICT in the follow-up period of 12 wk[15]. The superiority of HIIT was assumed due to long exercise duration and high-intensity exercise bouts, as well as higher HR reserve and peak HR obtained with HIIT[50]. In addition to a greater improvement in VO2 peak, HIIT was superior to MICT due to greater improvement in peak heart rate and FMD. However, improvement in FMD was little both in HIIT and MICT[46]. The mechanisms underlying the improvement of exercise capacity with HIIT in addition to improvement of chronotropic response with increased HR are reduction of body fat mass and decreased incidence rate of CAV and its progressivity[42].

The increase in VO2 peak with exercise in HT recipients may be due to cardiac changes such as reinnervation induced by exercise and skeletal muscle changes. HT recipients with reinnervation have greater exercise capacity than those without. Karapolat et al[42] found that the CR program for 8 wk provided a 19% increase in VO2 peak. In their study, the hospital exercise group had a better increase in VO2 peak than the home exercise group. Lack of improvement after exercise in the home-exercise group was suggested to be due to improper technique in conducting exercises.

Exercise has been proven to improve vascular endothelial function in addition to VO2 peak in chronic HF patients and those with impaired vascular endothelial function. Exercise also improves VO2 peak via increased bioavailability of nitric oxide, suppression of oxidative stress, and induction of vasodilation[7].

Muscular fitness

Muscle strength and muscular exercise capacity were the common parameters used in previous studies. When compared to MICT, the HIIT group demonstrated a higher maximum muscle strength at 1-year follow-up, but improvement in muscular exercise capacity was not significant in either group. This result was similar in the HIIT group compared to the no-exercise group[16]. In contrast to this result, another study found that quadriceps and hamstring muscle capacity significantly improved by 15% and 19% in the exercise group and control group, respectively, while, in the control group, no change was found[51]. A study on muscular endurance found that muscular endurance at 1-year and 3-year follow-ups was higher in the HIIT group compared to the MICT group[45]. Regarding body composition changes, Haykowsky et al[41] found that leg lean mass was significantly higher in the group given a combination of aerobic and resistance exercises compared to no exercise. Muscle exercise capacity and improvement in lean body mass were considered to have a role in increased exercise capacity[20]. The changes in skeletal muscle morphology and oxidative enzyme capacity after aerobic and resistance exercises increased oxygen utilization by the exercising muscles, resulting in greater improvement in exercise capacity[41].

Psychological problems and quality of life

Previous studies found varying results regarding QoL (Table 2). In studies that found significant changes in QoL after the intervention or during the follow-up periods, improvement of QoL was suggested to be due to increased exercise capacity, decreased symptoms as a result of pulmonary function and physical capacity improvement, improvement in anxiety and depression, and a relatively good physical fitness at the beginning of the study[14,44,45,52]. One study found no significant changes in QoL sum scores, but, in the general health sub-score, there was a significant between-group difference. Participants in the exercise group had a higher subjectively measured general health score[51]. A previous review stated that aerobic exercise in the form of HIIT is proven as an effective means to improve exercise capacity, resulting in improvement in the QoL and a reduction in anxiety and depression[47]. However, one systematic review and meta-analysis did not find a consistent effect of exercise-based CR on QoL. The beneficial effect of HIIT on short- and long-term anxiety is well-established in this study[39].

Table 2 Summary of research on exercise in heart transplantation recipients.

Ref.	Aim(s)	Subjects	Outcomes	Results
Torto et al[53], 2022	To compare the effect of SL HIIT and DL HIIT on pulmonary VO2 and HR kinetics in three groups of transplanted patients	33 subjects underwent heart, kidney, and liver transplantation	Pulmonary VO2; HR kinetic; Exercise capacity	During moderate-intensity exercise: SL and DL were effective in improving pulmonary VO2 and HR kinetics; No difference between SL and DL in pulmonary VO2 and HR kinetics; During heavy–intensity exercise, SL was as effective as DL in improving exercise capacity
Rustad et al[40], 2014	To investigate the effect of HIIT on exercise capacity and cardiac function	52 subjects, 1-8 years after heart transplantation randomized equally to the exercise group (EG) and control group (CG)	Exercise capacity; Cardiac function (systolic and diastolic) was determined by echocardiography	HIIT effectively improved exercise capacity; No clinically important improvement in systolic and diastolic functions with HIIT
Dall et al[15], 2014	To compare the effect of HIIT on VO2 peak, BP, HR rest, HR peak, HR recovery, HR reserve, and workload during exercise test	17 adult stable HT recipients (≥ 12 mo after HT) were randomized into HIIT and CON	Primary outcome: VO2 peak; Secondary outcomes: BP, HR rest, HR peak, HR recovery, and HR reserve during exercise testing	The effect of HIIT on VO2 peak was superior to CON; Improved HR reserve and HR peak were only found in the HIIT group; Improved HR recovery in both groups; A marked loss of effects after 5 mo
Yardley et al[14], 2017	To evaluate the continuity of HIIT and maintenance of exercise benefits on physical capacity long term after the intervention ended	41 stable heart transplant recipients who underwent 12-mo HIIT were followed until 5 years	Physical activity; Physical capacity; Exercise variables; Muscular exercise capacity; Body composition and metabolic profile; HRQoL; Depression and anxiety	Both groups maintained moderate physical activity levels after 5 years; Both groups demonstrated equal aerobic performance and daily activities after 5 years; HIIT was associated with a significant increase in VO2 peak after 1 year and a smaller decline in VO2 peak after 5 years; No difference between the two groups at 5-year follow-up in decreased VO2 peak; There was a non-clinically significant increase in VE/VCO2 slope in the HIIT group after 5 years; No difference in muscular exercise capacity between the two groups after 5 years; HRQoL score was good and prevalence of depression was low in both groups after 5 years; Long-term anxiety symptoms was reduced in the HIIT group
Nytrøen et al[51], 2012	To prove that HIIT would improve VO2 peak with a higher percent of predicted than previously shown in most studies; To investigate possible peripheral and central mechanisms behind an increase in VO2 peak	52 stable heart transplant recipients were randomized into HIIT and control groups	VO2 peak; Muscle strength and muscular exercise capacity; Body composition; HRQoL	VO2 peak was significantly improved in the HIIT group and no changes in the control group. A predicted VO2 peak level of 89% was achieved and higher than previous studies; Muscular exercise capacity was significantly improved; No significant difference between groups in changes in body composition at the follow-up; No significant changes in HRQoL sum scores in both groups at the follow-up, but the general health sub-score was significantly different between groups
Hermann et al[43], 2011	To investigate the long-term effect of HIIT on VO2 peak, FMD, BP, inflammation markers, and natriuretic peptide in HT recipients	30 HT recipients at 12 mo of transplantation were randomized into exercise and control groups	VO2 peak; FMD; BP; Inflammation markers; Natriuretic peptide	VO2 peak and FMD increased significantly in the HIIT group compared to the control group; No correlation was noted between BP reduction and improvement in FMD in the HIIT group; CRP was significantly decreased in the HIIT group while there was no change in the control group; TNF-alpha and IL-6 concentrations were unchanged in both groups; No significant decrease in pro-BNP and a significant decrease in pro-ANP in the HIIT group; No change in the natriuretic peptide concentration in the control group
Nytrøen et al[16], 2012	To report the effect of HITT vs MICT or no exercise among young HT recipients	28 young subjects (< 40 years) from the previous two studies	The primary outcome was VO2 peak; Secondary outcomes were maximum muscle strength and muscular endurance	HIIT vs MICT: Increased VO2 peak and maximum muscle strength were higher in HIIT than MICT after 1 year; No significant difference between the two groups in muscular exercise capacity
				HIIT vs no exercise: Increased VO2 peak and maximum muscle strength were higher in HIIT compared to the no exercise group; No significant difference between the two groups in muscular exercise capacity
Haykowsky et al[41], 2009	To investigate the effect of supervised aerobic exercise combined with strength training (SET) vs control with no training (NT) on VO2 peak, peripheral vascular function, LV systolic function, maximum strength, and lean mass in stable HT recipients	43 stable HT recipients at 0.5 years or more post-surgery were randomized into two groups	Primary outcome: VO2 peak; Secondary outcomes: Brachial artery endothelial function, LV systolic function, maximum strength, and lean mass	VO2 peak and peak power output were higher in SET than in NT; LV systolic function was not different after intervention in both groups; Endothelial-independent or -dependent vasodilation was unchanged in both groups; Chest- and leg-press maximum strength was significantly increased after SET and no change in arm curl strength or latissimus dorsi pulldown; The lean mass of the leg was significantly higher after SET than NT
Karapolat et al[42], 2008	To explore the effects of home-based (Group 1) and hospital-based exercise (Group 2) on chronotropic variables and exercise capacity in HT recipients	42 subjects, randomized into two groups	Exercise capacity; Metabolic function; Chronotropic variables (chronotropic response and HR recovery)	Group 1: A significant difference in post-exercise VO2 peak and metabolic function; The difference between HR reserve pre- and post-exercise was significant; No significant differences in other chronotropic variables
				Group 2: No significant change in all outcomes after the exercise
Karapolat et al[44], 2013	To investigate the effects of CR on pulmonary functions, exercise capacity, HRQoL, and psychological state of HF, HT, or LVAD patients	46, 40, and 11 subjects diagnosed with end-stage HF, HT, and LVAD, respectively	Exercise capacity (VO2 peak); Pulmonary function (PFT); HRQoL (SF-36); Psychological state (BDI) and State-Trait Anxiety Inventory (STAI)	Pre- and post-exercise VO2 peak, pulmonary function test (FEV 1% and FVC%), SF-36, and depressive symptoms were significantly different in all three groups, but the ratio of FEV 1 to FVC was not significantly different; No significant differences in VO2 peak, PFT, SF-36, or BDI scores among the three groups; STAI scores in intergroup and intragroup assessments of the three groups were not significantly different
Rolid et al[45], 2020	To compare effects of HIIT and MICT on biomarkers, pulmonary function, heart function, VO2 peak, muscle strength, daily PA, symptoms of anxiety and depression, and HRQoL after 1 year and 3 years	78 HT recipients completed 1-year follow-up and 65 subjects completed 3-year follow-up	Biomarkers; Pulmonary function; Heart function; VO2 peak; Muscle strength; Daily PA; Symptoms of depression and anxiety; HRQoL	Changes in biomarker, pulmonary function, heart function, VO2 peak, daily PA, and mental and physical summary scores were not significantly different between groups from baseline to 3 years; No differences between the two groups from 1 year to 3 years; Both groups had a stable exercise capacity with a small decline in VO2 peak; HIIT group showed a higher change in VO2 peak from baseline to 1 year; Muscle endurance improved significantly from baseline to 1 year and remained significantly higher at 3 years in both groups. An improvement was higher in the HIIT group; The median value of HRQoL in physical and mental components was > 50 in both groups. Physical component scores were changed in both groups, while mental component scores remained high and stable after 3 years. Symptoms of anxiety were low in both groups and no between-group difference from baseline to the 3-year follow-up
Hsu et al[52], 2011	To investigate the effect of the phase 2 CR program on exercise capacity and HRQoL; To test the hypothesis (the peak physical capacity achieved after training is not a major determinant of HRQoL)	45 clinically stable HT recipients and 34 CABG patients who completed a phase II CR	VO2 peak; HRQoL	An early CR program improved VO2 peak and HRQoL significantly; Improvement of HRQoL was greater in the HT group compared to CABG; The relative increase in physical capacity is the major determinant of HRQoL

HIIT: High-intensity interval training; SL: Single-leg; DL: Double-leg; HR: Heart rate; VO2peak: Peak oxygen uptake; BP: Blood pressure, HT: Heart transplantation; CON: Continued moderate exercise; HRQoL: Health-related quality of life; VE/VCO2 slope: Ventilation/carbon dioxide production slope; FMD: Flow-mediated dilation; TNF-α: Tumor necrosis factor-α; IL-6: Interleukin 6; pro-BNP: Pro-brain natriuretic peptide; pro-ANP: Pro-atrial natriuretic; MICT: Moderate-intensity continuous training; SET: Strength and endurance training; NT: No training; LV: Left ventricle; CR: Cardiac rehabilitation; HF: Heart failure; LVAD: Left ventricular assist device; PFT: Pulmonary function test; SF-36: Short-form 36 items; BDI: Beck’s Depression Inventory; STAI: State-Trait Anxiety Inventory; FEV1: Forced expiration volume in one second; FVC: Forced vital capacity; PA: Physical activity; CABG: Coronary artery bypass graft.

CONCLUSION

Several factors related to cardiac denervation and the use of immunosuppressive agents in HT recipients result in functional impairment, including cardiovascular, pulmonary, exercise capacity, and psychological problems, as well as the QoL. HIIT is the most common type of exercise used in HT recipients and is given as a hospital-based program. Improvement of functional impairments has been shown to be due to physiological effects of exercise primarily musculoskeletal adaptations through improvement of muscle structure and aerobic capacity and cardiovascular adaptations. In general, exercise given after HT improved VO2 peak significantly and improvement was better in the HIIT group compared to MICT or no-exercise groups. Improvement of QoL was suggested as being due to increased exercise capacity, decreased symptoms as a result of pulmonary function and physical capacity improvement, improvement in anxiety and depression, and relatively good physical fitness at the beginning of the study.

ACKNOWLEDGEMENTS

The author would like to thank Padjadjaran University for database facilitation.