49 Rehabilitation after Cardiac Transplantation

Heart transplantation has been performed as definitive therapy for endstage heart failure since the early 1980s. According to the inter- national registry the annual number of patients is probably well over 4000 worldwide. Any special rehabilitation program for this group will depend on sufficient local concentration of heart transplant recipients (HTRs). Since 60%

of all patients are reported from centers with less than 30 patients per year, going without any formal rehabilitation is a reality for many.

On the other hand, one can hardly imagine a group of patients that is so obviously in need of rehabilitation because of the multifaceted physical and mental problems to be encountered pre- and postoperatively.

This chapter contains a concise overview of group-specific issues and can hopefully contribute to further improve rehabilitation of these patients, whose 5-year-survival is now close to 70%. Of all patients surviving the first year, 50% will live more than 12 years.

Since short-term survival is no longer the key issue for HTRs, a return to func- tional lifestyle with good quality of life becomes the desired outcome.

The core components of cardiac rehabilitation will be discussed with emphasis on the differing aspects in transplant recipients: baseline patient assessment, exercise training and physical activity counseling, risk factor management, nutritional counseling, psychosocial management, and voca- tional counselling.

Baseline assessment requires knowledge of the anatomical and physiological reasons for limited exercise tolerance, which will be described first.

Central Limitations to Exercise Tolerance

The denervated heart exhibits unique characteris- tics relevant to exercise performance. Resting heart rate is equal to or above 100 beats/min 6 weeks after surgery,

with a slow decrease over the years to the range of 80 to 90 beats/min. This intrinsic heart rate, in the absence of parasympa- thetic and sympathetic nerve fibers, is modulated almost entirely by circulating catecholamines.

Thus rate response to exercise is typically sluggish, peak heart rate reaches only 70–80% of the value of age-matched controls and deceleration during recovery is delayed, as shown in Figure 49-1.

Interestingly, cardiac output as assessed via VO

during spiroergometry anticipates heart rate response. The limited chronotropic response seems to be compensated for by increased stroke volume due to augmented venous return. Thus the Frank–Starling mechanism is of much greater importance in transplanted hearts than usual.

Heart rate reserve is limited to 20 to 30 beats/min in some patients, rarely exceeding 40–50% of resting heart rate.

The resulting chronotropic incompetence is the main contribu- tor to exercise intolerance.

During the first year, peak heart rate increases according to Mercier et al.

from 58% of age-matched values at 1 month to 72% at 6 months. Givertz et al.

found no significant improvement in peak heart rate after the first year up to 5 years, which suggests the absence of functionally significant cardiac rein- nervation during this time. Some HTRs, however,

49

Rehabilitation after Cardiac Transplantation

Carsten B. Cordes

407

by performing strenuous long-term exercise pro- grams are able to reach peak heart rate values close to age-matched controls.

For many years denervation of the donor heart was thought to be permanent. Nowadays it is gen- erally accepted that in some HTRs there is partial reinnervation heterogeneously distributed in the myocardium and sometimes reaching the sinoa- trial node.

This is supported by Bengel et al.,

who found improved heart rate response and con- tractile function in the group of HTRs with PET- demonstrated signs of sympathetic reinnervation.

Nevertheless the functional significance, inci- dence, and time course of reinnervation are still not fully understood.

The second major contributor to exercise intol- erance in HTRs is diastolic dysfunction due to altered left ventricular compliance with slower relaxation, probably linked to the absence of sympathetic innervation. Additional contributing factors may be mismatch between donor’s heart size and the recipient’s body size, molecular damage associated with brain death, number of rejection episodes, hypertension and myocardial ischemia from cardiac allograft vasculopathy.

Cardiac output at rest is normal or only mildly reduced due to the fact that markedly reduced left ventricular end-diastolic volume and stroke volume (minus 20–40%) are compensated for by elevated resting heart rate.

Pulmonary diffusing capacity (DLCO) is abnor- mal in chronic heart failure patients and persists after transplantation but is commonly not the lim- iting factor. Only when the measured value is 50%

lower than predicted does it lead to relevant exer- cise-induced hypoxemia.

Peripheral Limitations to Exercise Tolerance

Chronic heart failure leads to muscle atrophy, decreased mitochondrial content, decreased oxidative enzymes, and a shift towards less fatigue-resistant type IIb fibers. These changes seem to persist for some time. In addition capil- lary/fiber ratio in skeletal muscle is reduced even late after transplantation by 27%.

Delayed oxygen recovery kinetics in mild heart failure are only partially reversed after heart transplanta- tion.

Skeletal muscle strength as measured by knee extension of HTRs with a mean age of 50 is comparable to the values of untrained and seden- tary 70- to 79-year-old volunteers.

Specific limi- tations arise from the use of corticosteroids promoting muscle atrophy and from ciclosporin, which leads to impaired NO synthesis by endothe- lial damage. So the characteristic high peripheral vascular resistance is due to the coaction of antecedent chronic heart failure and detrimental

0 2 4 6 8 10 stop 2 4 6

graded exercise and recovery (minutes) 80

90 100 110 120 130

heartrate (beats/minute)

HTR Control

F IGURE 49-1. Typical heart rate response of HTRs early after operation with elevated resting pulse, delayed and flat increase towards a

relatively low peak rate occurring after termination of exercise. Deceleration is slow and prolonged.

side-effects of immunosuppression. Central and peripheral limitations lead to a higher rate of per- ceived exertion for HTRs at any given level of activity and peak VO

will not exceed 60% of the value of age-matched controls with similar level of physical activity.

Figure 49-2 summarizes central and peripheral limitations to exercise tolerance.

Exercise Training

The rationale for chronic dynamic exercise and resistance training is prevention of side-effects of immunosuppressive therapy and reduction of car- diovascular risk factors, thus improving quality of life. The former is directed against increasing body weight, insulin resistance, hypertension, and hypercholesterolemia. The latter may prevent glu- cocorticoid-induced osteoporosis and skeletal muscle myopathy. Both interact in increasing oxygen extraction by muscle, which decreases the need for cardiac output at a given level of muscu- lar work,

whereas peak cardiac output itself is not significantly affected by exercise training.

Training programs have proved to be beneficial in the early postoperative period as well as 5 years after transplant. Kobashigawa et al.

could show in a randomized controlled trial that an individu-

alized 6-month program consisting of an average of 17 session of at least 30 minutes of muscular- strength and aerobic training at moderate inten- sity improved workload by 59% (35 W) compared to 18% (12 W) in the control group with no super- vision. Also the relative increase in peak oxygen consumption (49%) was almost three times as high. Tegtbur et al.

started 5 years after trans- plant and instructed patients to use a computer- assisted cycle ergometer at home. After 12 months and an average of 114 training sessions with an intensity 10% below anaerobic threshold, contin- uous power output rose by 43% from 46 ± 12 to 66

± 16W. Quality of life improved and peak oxygen consumption increased by 12% whereas the control group lost 4%, which is consistent with Douard et al.

who found an annual decline of approximately 5% without exercise training after transplant.

Considering the fact that 60–80% of HTRs still have corticosteroids included in their immuno- suppressive regime for a considerable period and that 30–50% of these will sustain osteoporotic fractures, effective countermeasures are definitely needed.

So far medical treatment has been dis- appointing. Only resistance exercise has been proved to restore bone mineral density to pre- transplant level,

making this mode of training an

Exercise intolerance

Diastolic dysfunction Limited

Frank- Starling mechanism Reducedpeak cardiacoutput

Chronotropic incompetence

Reduced oxygen uptake

Reduced muscular strength

Endothelial dysfunction

Abnormal muscular metabolism

F IGURE 49-2. Summary of the most important factors contributing centrally (left) and peripherally (right) to exercise intolerance of HTRs.

indispensable part of any exercise prescription for HTRs.

A summary of effects of exercise train- ing

is given in Table 49-1.

Effects of Exercise Training in Heart Transplant Recipients

Exercise intensity is best measured by rate of perceived exertion (RPE). Using the original Borg scale, RPE should be 12 to 14, which corre- sponds to the ventilatory threshold and a heart rate of usually between 60% and 80% of maximum. For testing protocols small increments of 10 W per minute are recommended to allow for the slow adaptation of heart rate in HTRs.

Aerobic exercise may be started in the second or third week after transplant but should be discontinued during corticosteroid bolus therapy for rejection.

Resistance exercise should be added after 6 to 8 weeks. A practical approach to Aerobic exercise has been used by Kavanagh et al.,

who instructed patients with a mean age of 47 to start walking 1.6 km five times weekly at a pace that resulted in a perceived exertion of 13 to 14 on the Borg scale.

The pace should be increased over time to jogging with the objective to finally run 4.8 km in 36 minutes (8 km/h) within 6–8 months. This led to improvement of VO

from 22.2 to 27.9 mL/kg per minute and of peak power output from 107 to 161 W. Gains were equivalent to the reversal of the cumulative effects of 12 years’ aging. Unfortu- nately these gains in physical fitness of HTRs cannot be preserved. They are lost over time despite training at a rate of normal aging. Activity counseling should emphasize the absolute necessity of regular exercise training of at least 30–40 min daily, including slowly progressing warm-up, closed-chain resistive activities (e.g.

bridging, half-squats, toe raises, use of therapeutic bands) and walking/jogging/cycling in order to make up for the period of prolonged physical deconditioning, counteract some of the effects of immunosuppression, and maintain good quality of life.

Risk Factor Management

Mortality during the first year is 1.4 times that of the next 4 years combined.

Whereas rejection and infection dominate during the first months, mor-

Parameter Compared to normal Change by training

Resting heart rate +25–50% Decreased

Peak heart rate − 20–40% Increased

Peak VO

− 30–40% Increased 12–44%

Peak cardiac output − 30–40% None

Left ventricular ejection fraction at rest Near normal None Left ventricular stroke volume at peak − 20–30% None Pulmonary capillary wedge pressure (PCW) +25–50% None

at peak

Right atrial pressure (RAP) at peak +80–100% None

Left ventricular end-diastolic pressure Increased Possibly reduced Left ventricular end-diastolic diameter −20–30% None

Anaerobic threshold Reduced Increased 13–28%

Peak power output Reduced Increased 50–60%

Peak syst systolic arterial blood pressure (PR) −20% Increased Rate of perceived exertion at given workload Increased Reduced

Lean body mass Reduced Increased 4%

Bone mineral density Reduced Restored to pre-transplant

level

Muscular strength Reduced Increased

Muscular oxidative capacity Reduced Increased

Muscular capillary network Reduced None

tality thereafter is mainly due to the development of cardiac allograft vasculopathy (CAV) and malignancies.

Measures Against Rejection

Basic medical therapy to reduce the incidence of acute rejection includes two or three of the follow- ing immunosuppressants: ciclosporin, azathio- prine, corticosteroids. Ciclosporin, a calcineurin inhibitor, specifically acts on T-cell and B-cell acti- vation and has markedly improved survival in the first 2 years after transplant. However, due to its negative effects on blood pressure, renal function, lipid and glucose metabolism, it had little positive impact on the determinants of long-term survival such as cardiac allograft vasculopathy (CAV). The patient may notice hypertrophic gingivitis, hyper- trichosis, and tremor and headache. It decreases oxidative enzymes and may thus further limit oxidative capacity in HTR.

Tacrolimus, equally effective against acute rejection, is increasingly substituted for ciclosporin because of a lower inci- dence of hypertension and hyperlipidemia;

however, there is a trend for more cases of new- onset diabetes.

Other side-effects are similar to ciclosporin, but it lacks the potential for hirsutism and gingival hyperplasia.

Azathioprine used to be the second pillar of immunosuppressive therapy. Its major side-effect is dose-dependent myelosuppression. Now it has widely been substi- tuted by mycophenolate mofetil (MMF, CellCept), which acts more specifically on the lymphocytes and has shown to be more effective in reducing the number of rejection episodes.

It is usually well tolerated, but may sometimes lead to dose-depen- dent nausea, vomiting, or diarrhea. During the first year, 80% of HTRs are on a triple-drug-regime including corticosteroids gradually decreasing to about 60% in the fifth year with a maintenance dosage of usually 5 mg prednisolone per day.

Three days of high-dose prednisone (100–1000 mg) are the usual treatment for acute rejection grade 2 of the seven-grade biopsy-classification of the International Society of Heart and Lung Trans- plantation (ISHLT). Some long-term side-effects are well known. Osteopenia occurs in 100% of HTRs, osteoporotic fractures in 30–50%. There has been less focus on myopathy, but its impact on exercise intolerance because of muscular weak- ness of arms and legs should not be underesti-

mated. Cosmetic effects like acne, hirsutism, moon face, and truncal obesity are particularly troubling to many patients.

Since quick, appropriate treatment is necessary to handle acute rejection, patients are instructed to practice self-monitoring. An unusually low blood pressure, a change of heart rate, unex- plained weight gain or fatigue may be early signs of rejection even when there is no feeling of being sick. Adherence to the medical regime as well as careful self-monitoring including taking one’s temperature twice daily is of vital importance.

Measures Against Infection

During periods of increased immunosuppression within the initial 6 to 12 months, most centers prescribe medical prophylaxis against cyto- megalovirus, herpes simplex reactivation, pneu- mocystis, aspergillus and candida species. It should be stressed, however, that the recipient of a transplant is expected to show an increased responsibility for himself by complying with the recommendations of his transplant center con- cerning personal hygiene and general measures to avoid those infections that are not due to latent viruses (Table 49-2). Medical personnel dealing with HTRs should be aware of the immunosup- pression-induced impairment of the inflamma- tory response, which attenuates the signs and symptoms of invasive infection.

Active immunization with live virus is generally not recommended. Vaccination against flu and

T ABLE 49-2. General measures to reduce the risk of infection 1. Good dental hygiene, no toothbrush older than 4 weeks 2. Frequent handwashing using liquid soap

3. Avoidance of close contact with people with infectious diseases (measles, chickenpox, mumps, mononucleosis, common cold, flu) 4. Avoidance of contact with persons having received oral polio

vaccination for 8 weeks

5. If indispensable, pets in the household only under strict precautions limiting contact

6. No gardening without gloves

7. No contact with decaying plants, fruits, vegetables 8. No stay near construction work and compost heaps 9. No mold inside the home

10. Hydroculture (hydroponics) is better than potting compost in the home

11. Avoidance of swimming in public baths during the first months

12. Avoidance of hot tub, sauna, and whirlpool

pneumococcal pneumonia is deemed helpful by most centers to avoid serious infections.

Increasing numbers of transplant recipients are active intercontinental travelers. They should receive special counseling from their transplant center.

Female HTRs suffering from increased growth of facial and body hair are not advised to use the new method of electrolysis for permanent depilation because of the risk of infection.

Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV), the main determinant of long-term survival, is a rapidly progressive form of atherosclerosis that occurs uniquely in HTRs, characterized by concentric intimal proliferation in early stages (58% by one year), later developing diffuse narrowing in prox- imal and distal portions of the coronary tree (50%

by 5 years). Occlusion of smaller arteries can go unnoticed, and chest pain is usually absent. In- stead congestive heart failure, ventricular arrhyth- mias, and sudden death are the first clinical manifestations.

The published studies on cardiac rehabilita- tion for heart transplantation so far have not addressed CAV. Although exercise training would theoretically delay or prevent coronary artery disease progression in the transplanted heart, this still has to be studied.

Risk factors for the development of CAV on the donor’s side are hypertension and higher age, on the recipient’s side coronary artery disease, number of rejection episodes in first year, symp- tomatic and asymptomatic cytomegalovirus infection, young age, hyperlipidemia, obesity, smoking, hypertension, and diabetes.. The latter five are amenable to lifestyle changes, exercise training, and adequate medication. Hypercholes- terolemia is present in 52% by 1 year and 90% by 7 years.

Statins (pravastatin, simvastatin) not only lowered LDL cholesterol levels but also decreased the incidence of CAV and significantly improved survival. In addition, pravastatin reduced the number of rejection episodes.

Statins are now part of standard therapy, but dose-related myo- pathy and myolysis due to interaction with ciclosporin has not only been a theoretical danger.

Most centers prefer pravastatin in doses up to 40 mg because its metabolism is less dependent on

CYP3A4 and the risk of relevant drug interaction appears to be lower. Obesity can be controlled by daily exercise and a healthy diet. Cessation of smoking is a prerequisite for transplantation in most centers but psychological support may be needed not to resume old habits. Hypertension is linked to immunosuppressive therapy and dener- vation of cardiac volume receptors. It is very common and affects 73% by 1 year and 97% by 7 years.

It is sensitive to a low-sodium diet. Treat- ment with diltiazem and ACE inhibitors led to improved coronary artery diameter and less intimal thickening. Antihypertensive therapy is usually completed by diuretics. Beta-blockers should not be used as they hamper the already delayed chronotropic response of the denervated heart.

The cumulative incidence of new-onset dia- betes after transplantation is 32% at 5 years. Risk factors are family history of diabetes, pre-trans- plant blood glucose level and post-transplant cor- ticosteroid dose. There is mounting evidence that diabetes may play a pivotal role in the develop- ment of CAV. Regular screening, early diagnosis, and a stepwise therapeutic approach once A

exceeds 6.5% are recommended according to the International Consensus Guidelines.

Target blood pressure is 130/80 mmHg.

Malignancies

Whereas the incidence of solid organ malignancy is similar to that in the general population, skin cancer is increased by a factor of 20. It occurs in 18% of 7-year survivors. Next are lymphoprolifer- ative disorders, bringing the overall cumulative incidence of post-transplant malignancies to 24%.

Since etiology is linked to immunosuppres- sion, there is no prevention available other than reducing sun exposure. Early detection of any suspicious skin changes as well as of enlarged lymph nodes or any swelling beneath the skin is important.

Pharmacology of the Denervated Heart

Pharmacological distinctions due to denervation

of the heart

that should be known to all medical

personnel dealing with HTRs are listed in Table

49-3.

( <10% of calories) replaced by monounsaturated fat (oleic acid as in olive oil and rapeseed oil), no concentrated carbohydrates, and a wide variety of healthy fresh food. There are good reasons to follow this Mediterranean style diet,

even though controlled studies in HTRs to assess the influence of nutrition on CAV or survival have not been published.

To prevent infection with toxoplasma, listeria, salmonella, staphylococci and fungi to name the most important agents, a list of foods to be avoided as far as possible is given in Table 49-4.

The level of evidence is of course rather limited and regional conditions have to be taken into account, which explains the considerable variance between centers in this regard. Fresh fruit and salad should be cleaned very carefully, especially during the first 6 months. For different reasons grapefruit juice should be avoided. It may decrease ciclosporin metabolism to an unpre- dictable extent.

Psychosocial Management

Cardiac transplantation is a process, not an event.

It continues for the remainder of the recipient’s life and it means a new set of problems in place of the old ones. There are some typical stages of adjustment.

A postoperative phase of euphoria usually comes to an end with the first rejection or other setback, conveying a feeling of vulnerability.

Depression and anxiety may follow, after which the patient eventually settles into a more realistic acceptance of opportunities and limits. In our early experience with HTRs between 20 and 60 days after surgery we found that well-meaning medical information and advice on life after transplant had often turned into enduring concern and apprehensiveness as detected by the choice of topics HTRs discussed with psycholo- gists.

This showed that careful presentation of recommendations is necessary, leaving the choice up to the patient and offering every possible support he or she may need to adjust. Subsequent to initial postoperative recovery poor medical compliance may account for significant morbidity and for up to 25% of deaths occurring. Risk of CAV was elevated 5-fold by persistent depression, 7-fold by medication non-compliance, 8-fold by

Nutritional Counseling

There are four major goals regarding nutrition after heart transplantation: avoidance of over- weight, balancing of side-effects of immunosup- pressants, limitation of classical cardiovascular risk factors, and avoidance of infection.

Overweight is a risk factor for diabetes, hyper- tension, hyperlipidemia, and CAV. A history of pre-transplant obesity or the correction of prior malabsorption by transplant may contribute to its development. Excessive caloric intake can be caused by an increased appetite due to corticos- teroids. Patients have to be aware of the need to accept strict calorie control in relation to their energy consumption. Corticosteroids also lead to salt and fluid retention as well as elevation of blood sugar and cholesterol. Post-transplant nutrition should therefore contain low sodium, low total fat ( <30% of calories), low saturated fat T ABLE 49-3. Pharmacology of the denervated heart

Digitalis Positive inotropic effect preserved No vagus-dependent dromotropic effect Not helpful to control ventricular rate in atrial

fibrillation

Beta-blockers Slows heart rate response to exercise even further Due to antagonism of circulating catecholamines Verapamil Dromotropic effect preserved due to direct action

on atrioventricular node Helpful in atrial fibrillation Chinidin No vagolytic effect

Helpful in atrial fibrillation Atropine No vagolytic effect

Rare paradoxical effect with complete heart block and sinus arrest

Vasodilators No reflex tachycardia

Epinephrine Positive inotropic and chronotropic effect (adrenaline),

norepinephrine (noradrenaline)

T ABLE 49-4. Dietary infection prophylaxis – food to be avoided 1. Raw meat

2. Raw seafood 3. Unpasteurized milk

4. Cheese from unpasteurized milk 5. Moldy cheese

6. Raw eggs

7. Soft ice

persistent anger–hostility, and 10-fold by obesity within 3 years after transplant.

Therefore edu- cational and psychotherapeutic interventions should be incorporated into the transplant team’s comprehensive care and follow-up of HTRs.

Family adjustment and stabilization of partner relationships pose a great challenge. Whereas during the pre-transplant period spouses, chil- dren and other relatives may have relieved the patient from daily responsibilities, when the patient returns home in better physical condition, roles have to be carefully re-established. Trying to live up to high expectations may pose emotional stress on the HTR. Recently, however, more focus has been put on the suffering of family and spouses, with the provision of partner-groups at rehabilitation clinics and follow-up centers being recommended.

Return to work rates vary widely from as low as 21% to as high as 79%. Obviously more factors are involved than successful surgery and good quality of life. In the United Kingdom, Kavanagh et al.

reported 69% employment at 5 years and 57% at 12 years post transplant.

In the German series by Hetzer et al., 34% of survivors of 9 to 13 years were employed.

To interpret this one has to under- stand the national differences in social security with different thresholds for benefits of unem- ployment, partial disability, and permanent dis- ability. Other important predictors are length of pre-transplant disability, employment history, education, and state of the economy. HTRs below the age of 65 are generally encouraged by the transplant team to resume work with very few exceptions (like construction work). Social workers should assist in reducing misconceptions about employment of HTRs on the part of the former or prospective employer.

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