- Heart transplant recipients (HTR) have decreased aerobic power (peak V˙O2) that is due to a lower cardiac output (due to cardiac allograft denervation, diastolic dysfunction, and impaired vascular function) and arteriovenous oxygen difference (due to decreased skeletal muscle oxidative fibers, enzymes, and capillarity).
- Short-term (≤1 yr) exercise training improves peak V˙O2 primarily through favorable skeletal muscle adaptations.
- Endurance-trained HTR who perform long-term (>2 yr) training can achieve a peak heart rate (HR) (due to cardiac allograft reinnervation) and peak V˙O2 similar to healthy age-matched individuals. Finally, a select group of highly endurance-trained HTR can achieve a peak V˙O2 similar to age-matched endurance athletes and can successfully complete premier endurance and ultraendurance races.
- Future studies are required to determine the role that exercise volume and intensity contribute to the improvement in peak V˙O2 across the heart transplantation (HT) continuum.
Heart transplantation (HT) is a lifesaving surgical intervention for select individuals with end-stage refractory heart failure (HF). The first human-to-human HT surgery was performed 5 decades ago by Dr. Christiaan Barnard at the Groote Schuur Hospital in Cape Town, South Africa. Since this time, more than 120,000 adult HTs have been performed, and the survival rate has improved significantly (median survival is 10.7 yr (1)) as a result of refinements in recipient and donor selection, advances in surgical techniques, organ preservation strategies, and immunosuppressive therapy (2).
Despite normalization or improvement of left ventricular (LV) ejection fraction, heart transplant recipients (HTR) have reduced exercise tolerance, measured objectively as decreased peak aerobic power (peak V˙O2) (3). As shown in Figure 1, compared with pre-HT, the greatest improvement in peak V˙O2 occurs within the first year postsurgery (≈7 ml·kg−1·min−1) (4–9); however, it remains 40% to 50% lower than age-, sex-, and activity-matched healthy controls (4,5,7,9).
In accordance with the Fick principle and law of diffusion (10,11), the reduced peak V˙O2 is due to decreased oxygen delivery to and utilization by the exercising muscle (Fig. 2). This review provides the perspective that the impaired peak V˙O2 after HT is due to both central (cardiac) and peripheral (vascular, skeletal muscle) abnormalities, and the improvement with short-term (12 months or less) exercise training, in previously deconditioned HTR, is primarily due to favorable peripheral adaptations (17). We also contend that the superior peak V˙O2 found in highly endurance-trained HTR is due to reinnervation of the cardiac allograft coupled with skeletal muscle adaptations.
DECREASED PEAK V˙O2: ROLE OF IMPAIRED CARDIAC FUNCTION
Heart transplant recipients’ peak exercise cardiac output (CO) is 30%–40% lower than age-matched healthy controls (3,12,18,19). In turn, the decreased CO is due, in part, to surgical denervation of the cardiac allograft, which results in a higher than normal resting HR and a delayed and blunted increase during exercise (20) (Fig. 2). A review of more than 1,700 adult HTR (mean age: 48 yr; mean peak V˙O2: 21 ml·kg−1·min−1) reported an average weighted peak HR of 140 bpm (≈80% of age-predicted peak HR) (3). The magnitude of the HR impairment is related to the extent of cardiac allograft reinnervation and underlying physical activity and fitness level (19,21). Specifically, Bengel et al. (21,22), using positron-emission tomography with catecholamine analogue 11C hydroxyephedrine, reported a modest positive univariate association between sympathetic reinnervation and time postsurgery, and that reinnervated HTR (higher overall hydroxyephedrine retention) had a significantly greater peak exercise power output, HR, LV ejection fraction, and LV ejection fraction reserve (peak minus rest) compared with denervated HTR. Our group extended these findings by demonstrating a positive relation between functional sympathetic reinnervation (measured as reserve HR) and peak V˙O2 in HTR (19).
Despite a greater time for diastolic filling due to a blunted exercise HR, peak exercise end-diastolic volume and stroke volume are approximately 20% lower in HTR versus age-matched controls (12,18,19). The lower end-diastolic volume is the result of altered LV relaxation kinetics coupled with increased LV chamber stiffness (12,13). An early invasive hemodynamic exercise study by Paulus et al. (13) showed that the rest-to-peak exercise change in time constant of LV pressure decay (tau) was 2.5-fold slower in HTR compared with normal controls (Fig. 2). Furthermore, the depressed acceleration of LV relaxation during exercise also was associated with a 2.3- and 1.5-fold increase in LV minimum diastolic pressure and LV end-diastolic pressure, respectively (13). Kao and colleagues (12) extended these findings and reported that the pulmonary capillary wedge pressure (PCWP)/end-diastolic volume index ratio during upright maximal cycle exercise was 1.7-fold higher in sedentary HTR versus age-matched sedentary normal controls (Fig. 2). Finally, it recently has been shown that despite preserved LV ejection fraction, HTR with an elevated peak exercise mean PCWP (34 mm Hg) had a significantly greater impairment in LV global longitudinal strain and peak systolic mitral annular velocity compared with HTR with normal LV filling pressure (23). Moreover, the mean PCWP/peak exercise power output ratio was inversely related to peak exercise cardiac index.
The mechanism responsible for cardiac allograft diastolic dysfunction is unclear but may be related to decreased adrenergic tone associated with denervation, donor recipient heart size mismatch, ischemic injury associated with graft retrieval, or afterload-induced cardiac hypertrophy associated with immunosuppression therapy (13). Diastolic dysfunction also may be due to myocardial ischemia associated with cardiac allograft vasculopathy (CAV), a unique and aggressive form of atherosclerosis that is believed to be caused by endothelial injury mediated through immune mechanisms (3). This endothelial damage causes smooth muscle proliferation and intimal thickening, which may eventually result in coronary obstruction and allograft failure (24). As such, HT patients with significant CAV exhibit markedly reduced exercise capacity (peak V˙O2) and pronounced ventilation-perfusion mismatch (25).
In summary, lower peak exercise CO post-HT is primarily the result of cardiac denervation-mediated chronotropic and allograft diastolic dysfunction (12,13,19).
DECREASED PEAK V˙O2: ROLE OF IMPAIRED VASCULAR FUNCTION
Heart transplant recipients’ peak exercise systemic vascular resistance (SVR) is 50% higher than healthy age-matched individuals (12,19). Impaired endothelial-dependent vasodilation of peripheral conduit arteries (14,26,27) and resistance arterioles (28,29) may contribute to elevated maximal exercise SVR. Andreassen et al. (30) reported that peak V˙O2 correlated with the vasodilatory response to endothelial-dependent acetylcholine infusion in HTR, and Patel et al. (31) found a strong correlation between exercise time after reaching anaerobic threshold and brachial artery endothelial function. Endothelial dysfunction also has been linked to the progression of CAV, the main cause of death at 5 yr post-HT (32,33), and contributes to reduced peak V˙O2 post-HT (8).
The magnitude of the impairment in endothelial function seems to be related to antecedent HF etiology (14,34–37). Specifically, Patel et al. (14) showed that endothelial function was improved, and normalized relative to healthy age-matched controls, in HTR with antecedent nonischemic cardiomyopathy but not in ischemic cardiomyopathy. Our group (38) extended these finding by showing HTR with previous ischemic HF had slower pulmonary V˙O2 kinetics compared with nonischemic HTR and attributed this finding to a greater impairment in skeletal muscle blood flow in the former group.
Chronic immunosuppressant therapy also may adversely affect the vasculature in HTR. Tacrolimus and cyclosporine (immunosuppressant drugs) have been linked to increased vascular dysfunction with increased time posttransplant (36,39,40). Long-term HT survivors also have elevated resting and exercise muscle sympathetic nerve activity (MSNA) (41–45). An exaggerated sympathetic response during exercise causes peripheral vasoconstriction, which results in reduced oxygen delivery to the active muscles (19,41–43). Houssiere et al. (43) demonstrated that excessive metaboreflex (measured by the muscle sympathetic nerve activity in response to isometric handgrip and postexercise cuff occlusion) and peripheral chemoreceptor sensitivity (assessed by MSNA and ventilatory responses to hypoxia) are related to exercise intolerance in long-term HTR.
In summary, endothelial dysfunction and elevated sympathetic activation increase exercise SVR limiting oxygen delivery to skeletal muscle and contributes to reduced peak V˙O2. The magnitude of vascular impairment is influenced by HF etiology and post-HT immunosuppression therapy.
DECREASED PEAK V˙O2: ROLE OF IMPAIRED SKELETAL MUSCLE FUNCTION
Given that the majority of oxygen consumed during exercise occurs in the active muscle, a reduction in skeletal muscle mass may contribute to reduced exercise tolerance post-HT. Indeed, a series of studies by Braith et al. (46,47) found that HTR have significantly reduced total body and leg lean mass and muscle strength that was associated with reduced peak V˙O2 in HTR compared with healthy, sedentary age-matched controls (46).
Heart failure is associated with skeletal muscle abnormalities including decreased percent type I (oxidative) fibers, mitochondrial volume, capillary density, and oxidative enzyme capacity (16,48). Skeletal muscle biopsies of the vastus lateralis before and 2–12 months post-HT demonstrate a persistent reduction in the percentage of type I fibers (15,49,50) (Fig. 2). Muscle fiber size (cross-sectional area) and mitochondrial volume density increase post-HT reaching levels below (49) or equal to healthy age-matched individuals (51); however, reductions in capillary density persist post-HT (49–51). These myopathic effects are partially attributable to long-term corticosteroid and cyclosporine use, which damage the microvasculature and inhibit pathways associated with capillarization and expression of oxidative fibers (46,47,52–56). In addition, cyclosporine administration has been shown to reduce skeletal muscle mitochondrial respiration and impair endurance exercise performance (57,58). Taken together, immunosuppression therapy seems to have deleterious effects on skeletal muscle morphology and function, which may contribute to the reduced peak exercise V˙O2 observed in HT patients. Finally, skeletal muscle oxidative enzymatic capacity (measured by citrate synthase activity) is significantly reduced before HT (49,50,59) and is unchanged (15,50) or improved to subnormal levels post-HT (49).
A consequence of the skeletal muscle abnormalities is that it results in decreased oxygen utilization by the active muscles. Kao et al. (12) were the first to report that maximal exercise arterial-venous oxygen difference was significantly lower (−24%) in HTR versus age-matched healthy controls. Moreover, our group (60) showed that HTR have prolonged pulmonary V˙O2 kinetics and decreased peak exercise skeletal muscle oxygen extraction during small muscle mass (1-leg knee extension) exercise, where the limiting role of the heart was minimized.
In summary, persistent abnormalities in skeletal muscle mass, morphology, and oxidative capacity are important contributors to the reduced peak V˙O2 post-HT.
EXERCISE TRAINING AND IMPROVEMENT IN PEAK V˙O2 POST-HEART TRANSPLANT
The few randomized controlled exercise intervention trials performed to date have shown that endurance or combined endurance and strength training significantly increases HTR peak V˙O2 (≈2.5 ml·kg−1·min−1) (59,61–70). The magnitude of the improvement in peak V˙O2 seems related to the underlying training intensity and duration of training. For example, Dall et al. (63), using a crossover design, compared the effects of 12 wk of high-intensity interval training versus traditional moderate-intensity continuous training on peak V˙O2 in 16 HTR (time post-HT: 6.4 yr). Both training programs increased peak V˙O2; however, the magnitude of change was greater after high-intensity interval compared with moderate-intensity continuous training (4.9 ml·kg−1·min−1 vs 2.6 ml·kg−1·min−1, respectively).
Richard et al. (71) were the first to report that middle-aged male HTR (n = 14, mean time post-HT: 46 mo) who perform long-term endurance training (4 h·wk−1, mean duration: 3 yr) are capable of achieving a peak HR and V˙O2 similar to age-predicted values. A later report by Pokan et al. (72) found that male HTR who perform high-intensity and volume endurance training (≥2 yr-training performed between 7 and 20 h·wk−1) had a peak V˙O2 (45 ml·kg−1·min−1) that was 29% higher than age-matched healthy sedentary males. Finally, Haykowsky et al. (73) recently reported the highest ever peak V˙O2 in a male HTR (64 ml·kg−1·min−1 measured 32 months post-HT with functional evidence of cardiac reinnervation) who, before being diagnosed with HF (nonischemic cardiomyopathy) was a professional cyclist (peak V˙O2: 71–75 ml·kg−1·min−1). The mechanisms for this remarkable peak V˙O2 were attributed to a greater stroke volume and oxygen extraction and may suggest a “legacy effect,” whereby a high peak aerobic power pre-HT may dictate the upper limits of trainability after successful HT (73).
Taken together, these studies and cases demonstrate functional evidence of cardiac (sympathetic) reinnervation and restoration of chronotropic potential after long-term, high-intensity and volume endurance training in HTR. Furthermore, endurance-trained HTR are able to attain a peak exercise V˙O2 that is similar to or greater than age-matched sedentary healthy individuals, and in the case of the former professional cyclist, equal to age-matched endurance-trained athletes.
IMPROVEMENT IN PEAK V˙O2 POSTTRAINING: ROLE OF CARDIAC FUNCTION
Studies performed to date, in previously untrained HTR, have shown that 6–52 wk of exercise training does not significantly change resting LV end-diastolic or end-systolic volume, stroke volume, ejection fraction, or cardiac output (61,74–76). Furthermore, resting HR is either unchanged (59,62,65,67,74,76,77) or is significantly lower after training (66,75). Exercise training does not seem to reverse allograft diastolic dysfunction because resting PCWP (and end-diastolic volume) and Doppler-derived isovolumic relaxation time and deceleration time remain unaltered after training (61,74,76,77).
Currently, no study has measured exercise hemodynamics during peak exercise; therefore the mechanisms underpinning the training-mediated increase in peak V˙O2 are not well understood. Kavanagh et al. (75) examined the effects of exercise training (mean duration = 16 mo) on peak V˙O2 and submaximal exercise cardiac output (CO2 rebreathing technique, measured at 45% and 74% of posttraining peak V˙O2) in 36 male HTR (mean age = 47 yr, time posttransplant = 7.4 mo). Peak V˙O2 (liters/minute) and HR increased significantly by 27% and 9%, respectively, with no change in submaximal stroke volume or cardiac output. Finally, peak V˙O2, and submaximal cardiac output during workloads 1 and 2 were 30%, 24%, and 20% lower than age- and sex-matched healthy controls, respectively.
Geny et al. (74) measured LV filling pressures, cardiac output, and systemic vascular resistance during submaximal exercise and peak V˙O2 before and after 6 wk of exercise training in 7 HTR (6 males, mean age = 42 yr, time post-HT = 11 mo). Exercise training significantly increased peak V˙O2 (+12%) with no change in peak HR, or submaximal HR, stroke volume, cardiac output, right atrial pressure, pulmonary artery pressure, PCWP, or systemic vascular resistance after exercise training (74).
Our group (64) and others (76) found that the improvement in peak V˙O2 with training was not associated with a significant change in submaximal exercise LV systolic annular velocity, early diastolic mitral velocity (E), early diastolic annular velocity (e’), E/e’, stroke area, or fractional area change (64,76). Taken together, evidence to date suggests that in previously deconditioned HTR, exercise training performed for less than 1 yr is not associated with an improvement in resting and exercise cardiac output.
IMPROVEMENT IN PEAK V˙O2 POSTTRAINING: ROLE OF VASCULAR FUNCTION
The few studies that examined the effects of exercise training on vascular function remain equivocal (59,64,65,78–80). In a retrospective, cross-sectional analysis, Schmidt et al. (80) reported that endothelial function (measured with brachial artery flow–mediated dilation) was significantly higher in HTR who performed regular exercise versus those who did not. In agreement with these findings, Hermann et al. (65) showed that 8 wk of high-intensity interval training significantly improved endothelial function measured with brachial artery flow-mediated dilation. In contrast, Haykowsky et al. (64) and Braith et al. (78) found no change in endothelial-dependent vasodilation after 12 wk of exercise training. Currently, only one study has assessed changes in resting and submaximal systemic SVR after exercise training (74). Using invasive hemodynamic monitoring, Geny et al. (74) reported no change in resting or submaximal SVR after 6 wk of continuous endurance and interval training.
IMPROVEMENT IN PEAK V˙O2 POSTTRAINING: ROLE OF SKELETAL MUSCLE FUNCTION
In previously deconditioned HTR, exercise training is associated with favorable skeletal muscle adaptations including increased mitochondrial volume density (81), oxidative enzyme capacity (82), and a shift toward a greater percentage of type I (oxidative) muscle fibers (82). In contrast to observations in healthy individuals, exercise training did not alter capillary density and capillary-to-fiber ratio present in HTR, a finding that may be due to immunosuppression therapy (83). Both endurance (75) and combined endurance and strength training (64,82) also increase lean body mass. Moreover, Braith et al. (78) showed that 6 months of aerobic and strength training significantly increases type I (oxidative) myosin heavy chain isoform and citrate synthase and lactate dehydrogenase activity in vastus lateralis skeletal muscle.
A consequence of these favorable changes in skeletal muscle morphology and oxidative enzyme activity is that they may result in increased O2 utilization by the active muscles. Nytroen et al. (66) recently reported that the significant improvement in peak V˙O2 after 12 months of high-intensity exercise training was due to favorable peripheral adaptations. Specifically, alterations in body composition (reduced body fat) and muscle exercise capacity (total work completed during 30 isokinetic contractions) were strong predictors of change in peak V˙O2, whereas the change in HR reserve predicted less than 5% of the change in peak V˙O2. To date, only one study has measured whole-body arteriovenous oxygen difference after exercise training (74) and found that it was unchanged during submaximal exercise. However, not unlike HF patients, it is possible that the muscle delivery and utilization may be higher during peak exercise after training (84).
In summary, in previously deconditioned HTR, the improvement in peak V˙O2 after training is primarily driven by favorable skeletal muscle adaptations.
IMPROVEMENT IN CLINICAL OUTCOMES WITH EXERCISE TRAINING POST-HEART TRANSPLANT
In addition to the improvements in peak V˙O2 associated with exercise-based cardiac rehabilitation (CR), two recent retrospective analyses (85–87) reported that HTR who participate in early CR programs after HT have a lower risk of hospital readmission and improved long-term survival. Specifically, a retrospective analysis by Bachmann et al. (85) of 595 Medicare beneficiaries who received HTs in the United States in 2013 revealed that participation in an exercise-based CR program was associated with a 29% decrease in 1-yr hospital readmissions among HT patients. Similarly, Rosenbaum et al. (87) recently showed that participation in early CR after HT was associated with improved long-term survival (1-, 5-, 10-yr survival) after adjusting for baseline debility in 201 HT patients at the Mayo Clinic. Most impressively, this reduction in mortality was observed with a mean of 14 CR sessions attended, which is far lower than standard CR programs. Indeed, attending as few as 8 CR sessions was associated with improved survival, with incrementally greater survival for each session attended beyond 8 (86,87).
UPPER LIMITS OF ENDURANCE PERFORMANCE POST-HEART TRANSPLANT
Several case reports published in the mid-to-late 1980s demonstrated that select HTR can successfully complete a 20-km run (2 h and 46 min), Boston marathon (5 h and 57 min), or an Olympic distance triathlon (1.5-km swim, 40-km bike, 10-km run in 4 h and 12 min) within a 15-month period post-HT (88–90). Haykowsky et al. added to these unique reports by demonstrating the superior athletic ability of two highly endurance-trained male HTR (73,91–94).
The first HTR, a 45-yr-old male who underwent HT surgery in June 2012, has competed in more than 60 sporting events during the last 4 yr (73). Notably, he has successfully finished some of the most arduous endurance and ultraendurance races including an Ironman triathlon (n = 3; in 2014, he became the first to complete the Ironman World Championship), supratrail run (84 km with 4131 climbing meters), cycle marathon (238 km with 5500 climbing meters), Transalpine-bike (537 km over 7 days; 16,820 m total ascent/descent), Transalpine-run (257 km over 7 days; 28,582 m total ascent/descent), and Cape Epic mountain bike race (654 km over 8 days; 14,550 climbing meters) (94). Between the 10th and 62nd month post-HT, he performed 13 cardiopulmonary exercise tests, and his average peak V˙O2 was 51 ml·kg−1·min−1. Remarkably, his pre- to post-HT change in peak V˙O2 (47 ml·kg−1·min−1) is the highest ever reported among this population, and is nearly sevenfold greater than that reported for sedentary HTR tested during the same time period (73) (Fig. 1).
The second HTR’s surgery was performed in August 1986, when he was aged 26 yr (73,91–93). Eighteen years post-HT, he began performing structured endurance training, and between 2005 and 2017, he has competed in 36 endurance events (73). Twenty-two years post-HT, he became the first HTR to finish an Ironman triathlon (race time: 15.6 h), and he also competed in the 2013 (>25 miles when the race was cancelled) and 2014 Boston marathon (4 h and 33 min). More recently (31 yr posttransplant) his average HR during a 10-km training run was equal to 85% of his age-predicted maximal HR (91–93).
The two HTR highlighted earlier are examples of the remarkable human endurance capacity that can be achieved in the short- (<5 yr) and long-term period (>2 decades) post-HT. The mechanisms responsible for their superior aerobic power and endurance performance is due, in part, to reinnervation of the cardiac allograft. Indeed, these individuals’ HR during continuous exercise performed between 11 h (HTR case 1) and 15 h (HTR case 2) is similar to that which more than 1,700 HTR can only achieve for 1 min during maximal exercise (3).
CONCLUSIONS AND FUTURE DIRECTIONS
Heart transplant recipients have severely reduced peak V˙O2 secondary to a lower peak exercise CO (due to cardiac allograft denervation and diastolic dysfunction coupled with increased SVR) and arterial-venous oxygen difference (secondary to decreased oxidative fibers, enzymes, and capillarity). Our group, and others, have shown that short-term (≤1 yr) exercise training, in previously deconditioned HTR, improves peak exercise V˙O2 primarily through skeletal muscle adaptations (increased lean mass, oxidative enzyme capacity, and greater proportion of type I fibers). In contrast, some endurance-trained (>2-yr training experience) HTR are able to achieve a peak HR and V˙O2 similar to age-matched healthy individuals. Notably, a select group of HTR endurance athletes are capable of achieving a peak V˙O2 similar to age-matched endurance athletes and are able to compete in premier endurance (Boston marathon, Ironman triathlon) and ultraendurance races (Cape Epic, Transalpine).
To date, studies investigating improvements in cardiac and peripheral function after exercise training in HTR have only measured resting and submaximal function. Future studies are required to determine the mechanisms responsible for the improvement in peak V˙O2 and the role that exercise volume and intensity contribute to this improvement. A better understanding of these contributions will provide mechanistic insight and allow us to better tailor exercise interventions to enhance peak V˙O2 in this patient population. In addition, the impact that intense and prolonged exercise has on cardiac allograft function and coronary vasculopathy including microvascular function requires further study. Finally, the legacy effect that pre-HF fitness level and pretransplant exercise training has on cardiovascular health outcomes requires further study.
The authors would like to thank Andre Human for creating the graphic illustrations that appear at the top of Figure 2.
Dr. Haykowsky is supported by the Moritz Chair in Geriatrics at the University of Texas at Arlington, and NIH R15NR016826-01 grant. Dr. Nelson is supported by American Heart Association 1GSDG27260115 and Harry S. Moss Heart Trust grants. Drs. Nelson and Haykowsky also are supported by University of Texas at Arlington Interdepartmental Research Grant.
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