Heart transplantation (HT) is the procedure in which a failing heart is replaced by a healthy heart from a suitable donor in order to re-establish myocardial function and systemic blood flow.
Common causes leading to a heart transplantation are: nonischemic cardiomyopathy (54%), ischemic cardiomyopathy (37%), valvular heart disease (3%), congenital heart disease (3%), hypertension (HTN), rhythm disorders, infections, alcohol/drug use, and unknown.1 General indications for evaluation and referral for heart transplant listing includes cardiogenic shock requiring intravenous inotropic support and/or mechanical support, refractory NYHA class III/IV heart failure, recurrent ventricular arrhythmias with hemodynamic compromise or refractoriness, and revascularization.2
Epidemiology including risk factors and primary prevention
There are approximately 2300 new cases of HT in the United States yearly, and 3742 worldwide.3 The median heart allograft donor age in 2010 was 31 years in the U.S. compared to 42 years in Europe.4 Seventy five percent of heart transplant candidates are men. Recipients’ survival risk is affected by the need of requiring a ventilator or left ventricular assist device prior to transplantation, a previous transplant, coronary artery disease or cardiomyopathy, and older age. Although heart transplantation is considered the gold standard treatment for patients with advanced heart failure failing medical and device therapies, there are barriers to this therapeutic option. We have seen great advance in the last decades in terms of pharmacological and device therapies (e.g. resynchronization therapies) that have translated in better survival of patient with heart failure. This survival implies an increase in the number of patients living with end-stage heart failure in a scenario were the number of cardiac allograft available for donation has remained constant, limiting the availability of organs for transplantation.5
As the heart is failing and systemic perfusion is impaired, end organ function is affected creating a vicious cycle that compromises and affects the prognosis of the patient (renal and liver failure, intestinal ischemia and edema with disruption of the intestinal barrier and translocation of endotoxins as well reduction in muscle mass). The musculoskeletal system is subject to deconditioning and muscle atrophy associated with decreased mitochondrial content, decreased oxidative enzymes, and a shift toward less fatigue-resistant type IIb fibers.6 In the lungs, there is ventilation/perfusion mismatch with a severity related to the same as heart failure (HF); after transplant, forced expiratory volume at1 second (FEV1), forced vital capacity, and total lung capacity normalize; however, decreased diffusing capacity may persist because of vascular and parenchymal abnormalities.7
Cardiac transplantation results in postganglionic denervation, leading to the inability to respond to the parasympathetic nervous system. The denervated heart presents with higher systolic and diastolic blood pressures, elevated heart rate (HR) at rest, lower maximal myocardial oxygen consumption, lower heart rate reserve, and decreased exercise duration.8 Physiologic changes in exercise response are catecholamine dependent, thus delaying recovery after exercise.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
HT candidates present with deteriorating cardiac function that has not responded to conventional medical therapy and fall into the New York Heart Association (NYHA) disease class III (moderate) or IV (severe). 9
Since the first cardiac transplant procedure was performed, the survival has improved steadily during the last decades. According to the report from the ISHLT registry, 1- year survival is almost 90% with a conditional half-life of 13.2 years.10 Patients’ outcomes are affected by pre-existing conditions, especially HTN, diabetes mellitus (DM) and obesity, and the development of secondary complications. 9 Other factors that influence the evolution of the disease are immunosuppressive therapies. The most common complication in the first year after the transplant includes graft failure, rejection and infection. After the first year, complications include cancer and cardiac allograft vasculopathy. 11 In general, the overall 10-year mortality is about 50%. From a functional and emotional point of view, the patient’s quality of life is significantly improved, and approximately 90% of patients report not having any activity limitations within the first 5 years after a HT. 4
Specific secondary or associated conditions and complications
Expected conditions and complications include pulmonary HTN, DM, HTN, acute rejection, cardiac allograft vasculopathy, renal dysfunction/failure, opportunistic infection, wound dehiscence, peripheral neuropathy, myopathy, obesity, severe peripheral vascular, cerebrovascular disease, and malignancy.
2. ESSENTIALS OF ASSESSMENT
Symptoms that are commonly encountered include:
- Persistent cough
- Limitations in physical activity, associated with angina or not
- Sleeping problems
History should also include the following: duration of symptoms, prior functional level, home and community environmental barriers, musculoskeletal complaints, symptoms consistent with neurologic and/or vascular diseases, a psychosocial assessment, use of assistive devices, and postsurgical complications.
A thorough comprehensive physical examination is of outmost importance in this population. Signs observed during the examination reflect the physiologic changes and consequences of deconditioning and of a denervated heart and should include monitoring of the following:
- General medical status including hypotension, fever, shortness of breath, edema, and fatigue (signs of acute rejection).6
- Hemodynamic status including resting HTN, elevated resting HR, and decreased chronotropic response.
- Cardiopulmonary status including jugular-venous distention, rales, displaced apical pulse, third and fourth heart sounds, hepatomegaly, edema, abdominal distension, and hyperventilation.
- Musculoskeletal status including decreased muscle mass and strength, contractures, pain, proximal weakness (myopathy secondary to corticosteroid use), edema, pigmentation of skin, and diminished pulses (peripheral vascular resistance).
- Neurologic status including decreased reflexes, impaired sensation, proximal muscles weakness, and impaired balance.
Tools used for clinical functional assessments in HF patients mostly focus on measuring quality of life and symptoms, such as the Minnesota Living with Heart Failure Questionnaire, the Sickness Impact Profile, and the Sense of Coherence Scale.12
Side effects related to chronic immunosuppression should be followed (leukopenia, thrombocytopenia, renal dysfunction, hyperglycemia, hyperlipidemia, opportunistic infection, and malignancies) using the following tests:
- Complete blood count
- Comprehensive metabolic panel
- Lipid profile
- Trough levels of immunosuppressive medications (eg, calcineurin inhibitors and mammalian target of rapamycin inhibitors (mTORs); maintenance doses are adjusted using the trough level).
Essential imaging studies include: electrocardiogram (previous myocardial infarct), echocardiograms (cardiac structure and function), heart catheterizations (including right atrial and right/left ventricular assessment), metabolic stress tests (severity of cardiac functional impairment and risk stratification pretransplant), holter monitoring (arrhythmias), endomyocardial biopsy, and coronary angiography (for cardiac allograft vasculopathy evaluation).13
Supplemental assessment tools
- The six-minute walk test measures functional exercise capacity.
- The Borg Rate of Perceived Exertion Scale determines the perceived exertion during various levels of exercise intensity.6
Early predictions of outcomes
No single tool has enough predictive power to stratify patients in advanced HF, in part related to the variability in the clinical course previous to cardiac transplant. Bad prognostic factors include: peak oxygen consumption of less than 14 mL/kg/min, or less than 50% of predictive value for older age (>70 y); being a woman (worse prognosis); age (>70 y); etiology of heart disease (coronary artery disease, cardiomyopathy); longer duration of illness; obesity (body mass index >30); active infections; severe DM with end organ damage; peripheral vascular or cerebrovascular diseases; creatinine greater than 2.5 mg/dL or creatinine clearance less than 25 mL/min; bilirubin greater than 2.5 mg/dL; serum transaminases greater than 3 times the reference ranges; international numeric ratio greater than 1.5 off warfarin; severe pulmonary dysfunction with FEV1 less than 40% predicted; recent pulmonary infarction within 6 to 8 weeks; uncontrolled HTN; neuromuscular disorders; mental illness; substance abuse; and reduced functional capacity whether estimated by NYHA class or exercise testing.14, 15
Explore architectural (stairs, hills), transportation, and mobility barriers.
Social role and social support system
A holistic approach, including psychologic, social, and spiritual assessment is recommended. Depression, anxiety, sleeping difficulties, and adjustment disorders are commonly seen. Psychiatric history or history of substance abuse may contribute to functional limitations and affect compliance to treatment posttransplant. Transportation barriers can interfere with continuity of care; family involvement is key home management support. Poor medical compliance after the postoperative recovery may account for significant morbidity and for up to 25% of deaths.16
Only 2200 transplants are performed each year in the U.S., because there is a shortage of donors, making research and follow-up challenging. 14
To ensure a fair system of distribution of donor hearts, the United Network for Organ Sharing (UNOS) created a system that uses wait time, severity of illness and geographic distance between the donor hospital and the transplant center.17
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
A multidisciplinary approach should be used in the treatment, management and rehabilitation of this population. Heart transplant candidates should initiate an exercise routine prior to surgery. Posttransplant, patients will be deconditioned, with impaired functionally capacity, decreased cardiac output, and decreased maximal oxygen capacity.
Reasons for persistent abnormal exercise capacity may include the following:
- Marked deconditioning before heart transplant
- Surgical denervation
- Skeletal muscle weakness
Cardiac rehabilitation programs could extend from 4 weeks to 6 months, depending on the patient’s postoperative course.
At different disease stages
- Pretransplant stage12:
- Left ventricular assist devices (LVADs) can serve as a viable bridge before transplantation, allowing an opportunity to recondition through aerobic training that can include treadmill or free ambulation.
- New onset/acute18:
- Physical conditioning should begin during the inpatient phase, once hemodynamic stabilization has been achieved.
- Exercise programs should include aerobic exercises in cycle-ergometer or walking with progressive increase on duration and intensity and articular mobility, flexibility, and resistance of large muscular groups. Monitoring should include HR and blood pressure, and subjective fatigue with the Borg Scale.
- On discharge, patients should be able to walk on leveled surfaces; the use of the upper limb to assist in a pull-to-stand and transfers should be limited to protect the sternum.
- Programs can begin as early as 2 weeks post-surgery. Structured-supervised programs demonstrate superior outcomes over home-based programs in a physical work capacity and activities of daily living.
- Walking is recommended on alternate days; the exercise program should progress to include: closed-chain resistive activities (bridging, half squats, toe raises), abdominal exercises (curl ups and pelvic tilts), flexibility exercises (chest expansion and thoracic mobility, side stretch, trunk twist, scapular squeezes, shoulder rolls), and aerobic exercises (treadmill walking or pedaling on bicycle ergometer). The duration and intensity shall progressively increase to meet the patient’s tolerance with a goal of 30 minutes of continuous aerobic exercise at moderate intensity for each session.
- Patients suspected of organ rejection must be halted from training until endomyocardial biopsy shows resolution of rejection.
- Cardiac transplant patients may survive for more than 25 years.
- Chronic immunosuppression may lead to infections, malignancy, and renal deterioration.
- Exercise routines should be adopted daily.
- Exercise must be halted if organ rejection is suspected.
- Preterminal or end of life care18:
- An interdisciplinary approach is used to address patient and family needs.
- Providers need to educate patient/family about disease progression, functional decline, advanced care planning, and end of life decisions.
- Goals are targeted to maximize quality of life, focusing on symptoms management. These include pain relief, affirming life and regarding dying as a normal process, and offering a support system to help patients live as actively as possible.
Coordination of care
Coordination of care seems challenging with great opportunity for improvement. 20 Disease unpredictability challenges providers in forming enduring relationships. 21 Interdisciplinary coordination of care should begin pretransplant before end-stage heart disease occurs and led by a physician. The team should include specialists in HF, rehabilitation, palliative care, social work, and a spiritual and psychologic counselor. 16 Coordination should integrate both hospitalized and community-based patients.
Patient & family education
Education to the patient and family is core to the short- and long-term process. After the heart transplant, the patient must monitor signs of infection, weight changes, pulse, changes in blood pressure and sugar levels. Patients must adhere to nutritional recommendations, medications and the exercise routine. Adjustment to the post-transplant process can require psychosocial intervention.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
HT patients require an effective education program where they become aware of the course of their recovery, including understanding of the medication regimes need and potential side effects. Clinicians need to closely monitor medications interaction and their side effects. Unusual neuropathies can be observed post-surgically, such as peroneal, axillary, and radial, among others.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
Stem cell and regenerative therapy continues to be a promising field seeking therapeutics options for patients with cardiovascular disease and heart failure. Those theories contributing to the observed benefits have changed in the past decade, and these include the release of cardioprotective paracrine factors that lead to repair. Physicians must know that this is not yet ready for clinical application.22
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
It is recognized that the incidence and types of immune suppression-associated malignancies vary with extent and completeness of follow-up.23
The long‐term data on the benefits of exercise rehabilitation is limited, so this is a field where gaps still exist on the long-term benefits of exercise on health‐related quality of life, and healthcare costs.24
There are concerns about the risk of adverse events, including bleeding and thromboembolic events with recent miniaturization of the LVADs. More experience is needed.25
- Jurt U, Delgado D, Malhotra K, Bishop H, Ross H. Cardiology patient pages. Heart transplant: what to expect. Circulation. 2002;106:1750-1752.
- Jon A. Kobashigawa et al, Evaluation of Heart Transplant Candidacy. Clinical Guide to Heart Transplantation, by Springer Berlin Heidelberg, 2017, pp. 21–35.
- United Network of Organ Sharing (UNOS) and The Registry of the International Society of Heart and Lung Transplantation (ISHLT) (www.ishlt.org/registries/heartlung registry.asp). The registry of the International Society of Heart and Lung Transplantation: twenty-fifth annual report. Journal of Heart and Lung Transplantation. 2008; 27:937-983.
- Stehlik J, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society of Heart and Lung Transplantation MS: 29th official adult heart transplant report–2012. Journal of Heart and Lung Transplantation. 2012:31:1052-1064.
- Kittleson M, Kobashigawa J. Cardiac Transplantation Current Outcomes and Contemporary Controversies. Journal of the American College of Cardiology (JACC): Heart Failure Vol. 5, No. 12, 2017:857–68.
- Cordes C. Rehabilitation after cardiac transplantation. In: Perk J, Mathes P, Gohlke H, et al, eds. Cardiovascular Prevention and Rehabilitation. London, UK: Springer-Verlag; 2007:407-415.
- Ravenscraft SA, Gross CR, Kubo SH, et al. Pulmonary function after successful heart transplantation–one year follow up. Chest. 1993;103:54-58.
- Wilson RF, Johnson, TH, Haidet GC, et al. Sympathetic reinnervation of the sinus node and exercise hemodynamics after cardiac transplantation. Circulation. 2000;101:2727-2733.
- Botta DM, Mancini M. Heart transplantation. 2012. Available at: Emedicine.medscape.com/article429816. Accessed June 14, 2012.
- Lund LH, Edwards LB, Dipchand AI, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation report-2016; focus theme: primary diagnostic indications for transplant. Journal of Heart and Lung Transplantation 2016;35: 1158–69.
- Harris C, Cao C, Croce B, Munkholm-Larsen S. Heart transplantation. Annals of Cardiothoracic Surgery. 018 Jan; 7(1):172.
- Piña IL, Apstein CS, Balady GJ, et al. Exercise and heart failure: a statement from the American Heart Association committee on exercise, rehabilitation and prevention. Circulation. 2003;107:1210-1225.
- Abrahams Z, Mullens W, Boyle A. Cardiac transplantation. In: Griffin BP, Topol EJ, eds. Manual of Cardiovascular Medicine. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:171-190.
- Mancini, D, Lietz K. Contemporary reviews in cardiovascular medicine: selection of cardiac transplant patients 2010. Circulation. 2010;122:173-183.
- Constanzo MR, Augustine S, Bourge R, et al. Selection and treatment of candidates for heart transplantation. Circulation. 1995;92:3593-3612.
- Jaarsma T, Beattie JM, Ryder M, et al. Palliative care in heart failure: a position statement from the palliative care workshop of the Heart Failure Association of the European Society of Cardiology. European Journal of Heart Failure. 2009;11:433-443.
- Eisen HJ, Hunt SA, Yeon SB. Patient education (beyond the basics). https://www.uptodate.com/contents/heart-transplantation-beyond-the-basics. July 2019. Browsed on August 4, 2019.
- Guimaraes GV, d’Avila VM, Chizzola PR, et al. Physical rehabilitation in heart transplantation. Revista Brasileira de Medcina do Esporte. 2004;10:412-415.
- Kobashigawa JA, Leaf DA, Lee N, et al. A controlled trial of exercise rehabilitation after heart transplantation. New England Journal of Medicine. 1999;340:272-277.
- Engelhardt JB, Rizzo VM, Della Penna RD, et al. Effectiveness of care coordination and health counseling in advancing illness. American Journal of Managed Care. 2009;15:817-825.
- Stewart S, McMurray JJ. Palliative care for heart failure. Editorial. British Medical Journal. 2002;325:915-916.
- Nguyen PK, Thee JW, Wu JC. Adult Stem Cell Therapy and Heart Failure, 2000 to 2016: A Systematic Review. JAMA Cardiology. 2016 Oct 1;1(7):831-841.
- Strecker T, Rösch J, Weyand M, Agaimy A. Frequency and spectrum of metachronous malignancies in heart transplant recipients: a 11-year-experience at a German heart center. International Journal of Clinical and Experimental Pathology. 2013;6:411-420.
- Anderson L, Nguyen TT, Dall CH et al. Exercise-based cardiac rehabilitation in heart transplant recipients. Cochrane Database Syst Rev. 2017. Apr 2017.
- Heack ML, Hoogslag GE, Rodrigo SF et al. Treatment options in end-stage heart failure: where to go from here? Netherlands Heart Journal. 2012;20:167-175.
Original Version of the Topic
Maricarmen Cruz, MD, Isabel Borras-Fernandez, MD, Xavier Aviles-Guzman, MD, Cristina Isabel Sepulveda-Alamo, MD. Cardiac rehabilitation before and after cardiac transplantation. 09/20/2013.
Maricarmen Cruz-Jimenez, MD
Nothing to Disclose
Francisco Merced-Ortiz, MD
Nothing to Disclose
Isabel Borras-Fernandez, MD
Nothing to Disclose