Author(s): Maricarmen Cruz-Jimenez, MD, Isabel Borras-Fernandez, MD, Suzette Arias-Mejias, MD, MS, Lorena Rivera-Gonzalez, MD
Originally published: September 20, 2013 Last updated: January 4, 2023
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Disease/ Disorder

Definition

Heart transplantation (HT) is the procedure in which a failing heart is replaced by a healthy heart from a suitable donor to re-establish myocardial function and systemic blood flow.

Etiology

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  Other indications may be related to the secondary impact of a failing heart to other organs (i.e., renal function) when managing medications, worsening right ventricular function, rising pulmonary artery pressure, and rising natriuretic peptide levels, among some.3

Epidemiology including risk factors and primary prevention

The number of adults in the world suffering hypertension increased from 594 million people (1975) to 1.13 billion people (2015). In 2020, it was reported that 47% of the United States population suffered from hypertension, contributing to a higher risk for stroke and heart disease. The World Health Organization reports that 42% of adults with hypertension are diagnosed and treated, and that of those treated about 21% have it controlled. Poorly managed hypertension may lead to heart failure, (WW) but advanced heart failure may be the result of congenital and acquired heart disease. In acquired etiologies, primary prevention is based on managing healthy lifestyles that may include nutritional, physical activity, tobacco avoidance, primary condition management, among some.4

Heart transplantation is considered the treatment for advanced heart failure for a selected group of patients. There is an unbalance between demand and organ availability so the heart allocation will require outweighing the benefits for the individual against the pool of others on the waiting list. The decision will consider the impact this procedure has on improving quality of life and survival rate.3

The median heart allograft donor age in 2010 was 31 years in the U.S. compared to 42 years in Europe.5 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.6

Patho-anatomy/physiology

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.7  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.8

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.9 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).10

Heart Transplantation is indicated when end stage heart disease cannot be managed through conservative means. Since the first cardiac transplant procedure (1967) 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, but even with historic treatment advances, 5-year mortality rate is reported as high as 40%.11,12

Patients’ outcomes are affected by pre-existing conditions, especially HTN, diabetes mellitus (DM) and obesity, and the development of secondary complications.10 Other factors that influence the evolution of the disease are immunosuppressive therapies.

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.

The major cause of mortality in the first 30 days post-transplant is primary graft failure. In the early post-operative period, common complications include left ventricular failure, hyperacute rejection, tricuspid regurgitation, arrhythmias, coagulopathies, and cardiac tamponade, among some.13 In the first year after the transplant the most common complication includes graft failure, rejection and infection; after the first year, complications include cancer and cardiac allograft vasculopathy.14  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.5

Essentials of Assessment

History

After a heart transplantation, symptoms that are commonly encountered include:

  • Chest pain
  • Shortness of breath
  • Persistent cough
  • Fatigue
  • Palpitations
  • Limitations in physical activity, associated with angina or not
  • Anxiety
  • Depression
  • Sleeping problems
  • Nausea
  • Constipation
  • Edema

History should also explore on the cardiac history including surgeries and associated complications, medications and compliance, diet, toxic habits, comorbidities and family history. Functional status including, prior functional level and interference of symptoms in ambulation and ADL, 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.15

Physical examination

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).7
  • 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.

Functional assessment

Tools used for clinical functional assessments in HF patients mostly focus on measuring quality of life and symptom burden, such as the Minnesota Living with Heart Failure Questionnaire, the Sickness Impact Profile, and the Sense of Coherence Scale.16

Laboratory studies

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 (e.g., calcineurin inhibitors and mammalian target of rapamycin inhibitors (mTORs); maintenance doses are adjusted using the trough level).

Imaging

Essential imaging studies include electrocardiogram (previous myocardial infarct, conduction block), 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).17

Pre transplant echocardiography provides more specific information about biventricular function and valvular disease; echo can provide estimates too of the pulmonary artery systolic pressure. Right heart catheterization provides information on heart filling pressures. Right heart dysfunction is associated to a poorer prognosis.3 Awareness of these values should alert the physician when establishing precautions and goals of care in the rehabilitation plan.

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.7

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 prior to cardiac transplant. Poor prognostic factors include:

  • Peak oxygen consumption of less than 10 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
  • Natriuretic peptide levels, 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 abuser
  • Reduced functional capacity whether estimated by NYHA class or exercise testing.18,19

The Seattle Heart Failure Model and the Heart Failure Survival Score are two instruments used in advanced heart failure that are associated to 1-year survival prognostication.3

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.

It has been shown that interventions by medical providers even 1 day prior to surgery, which include discussing an individualized plan and providing emotional support, can have a significant impact. Social support in terms of whether the patient has family / friend they can depend on specially during their recovery, is important as it can affect outcomes.21

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.21

Professional Issues

There is a limited number of donors when compared to the demand. The number of heart transplants has increased through the years with 3715 cases performed in 2020 in the USA. Most transplants receivers are ages 50 to 65, nonetheless, statistics show a recent and ongoing rise in transplants in people over 65 years of age. However, during the past few years due to COVID-19 pandemic, the number of enlisted candidates has decreased slightly with 4000 new listings in 2020 as compared to 4087 in 2019.22

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.23

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. Preoperative interventions, such as pre-rehabilitation, aim to improve patients’ physical, metabolic, and psychosocial capacities in preparation for surgery.24 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
  • Corticosteroids

A well-established starting point to optimize patients before surgery is supervised pre-rehabilitation programs for at least three months prior to elective surgery.24 However, because of the transplant waiting list, patients who are able to participate in a home exercise program may be more appropriate. Cardiac rehabilitation programs could extend from 4 weeks to 6 months, depending on the patient’s postoperative course.

Pediatrics25

As medical and surgical management for patients with congenital heart disease improves, the survival rate of pediatric heart transplant patients has increased. Motor, exercise capacity, feeding, speech, and/or cognition may be affected in this population. As a result, in contrast to adults, rehabilitation goals extend beyond increasing endurance and functional capacity. Age-appropriate exercise programs that emphasize muscle strength, range of motion, sensory/proprioception, coordination, balance, gross motor abilities, and developmental skills should be implemented. In addition, the pediatric population with heart related disease has shown increased difficulty in their speech development as well as swallowing problems; both of which should ideally be treated by a speech pathologist.

At different disease stages

  • Pretransplant stage:16
    • 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/acute:26
    • 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.
  • Sub-acute:27
    • 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.
  • Chronic/stable:
    • 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.
  • Preterminal or end of life care:26
    • 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.
  • Suspected organ rejection:28,29
    • Rejection may occur at any time after the transplant and throughout the patient’s life (e.g., low stress tolerance, shortness of breath, edema, arrythmias, temperature changes).
    • It is advised to measure and record body temperature, blood pressure, fluid balance, and weight every day, at least for a few weeks to months, to detect these events early on.
    • The patient may continue with their current exercise program during a moderate severity graft rejection episode, but they should not progress until the graft rejection has been adequately treated.
    • Suspension of all physical activity, with the exception of passive range of motion exercises, is recommended during severe acute graft rejection.

Coordination of care

Coordination of care seems challenging with great opportunities for improvement.30 Disease unpredictability challenges providers in forming enduring relationships.31 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 psychological counselor.21 Coordination should integrate both hospitalized and community-based patients.

In the pediatric population, close coordination with school programs should be taken into consideration as part of the integration into the functional goals.

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.

Cutting Edge/ Emerging and Unique 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.32

An important advancement in the last decade is cardiac allograft rejection monitoring; this emphasizes a non-invasive approach for monitoring allograft rejection. Currently the gold standard for monitoring rejection is endomyocardial tissue biopsy (EMB), however alternatives that are being evaluated include liquid biopsy and emerging biomarkers among others. Even though these techniques have shown promising results, further research is still needed. EMB remains the fold standard.33

Another unprecedented concept is the COVID-19 pandemic and its impact on the heart transplantation process and population. It has affected the transplantation waiting list and donor-pre-transplant screening adding COVID testing/exposure for both the donor and recipient. It has also impacted the appropriate timing for surgical intervention which is impacted according to screening test results and rapid turnover of the test. The intermediate post-transplant management has been affected in different ways including ensuring dedicated nursing staff, hospital rooms so that patients are not at a higher risk of complications during the post-op phase by contacting multiple health care providers. In the ambulatory post-transplant management, the challenges faced include patient/family hygiene as well as use of personal protective equipment and/or social distancing. For those patients that were being monitored from previous transplant, there was a delay in routine rejection testing including echo and endomyocardial biopsies.34

Another unique concept is related to the healthcare disparities. Despite recent improvements in the last decade, there is still evidence that minority groups undergo and are referred less frequently for heart transplantation as compared to other racial groups. In addition, African Americans and Hispanic Latinos have a worse outcome than other racial groups. Even though the exact cause of this disparity is not clear, socioeconomic status, access to care, racial and ethnic differences, immunologic mechanisms and genetic mismatch are considered major contributors.35,36

Gaps in the Evidence-Based Knowledge

COVID 19 has created significant gaps in knowledge including the impact of the viral infection itself as well as the impact of the therapies used for the treatment of the infection. Heart manifestations include myocardial injury, heart failure, myocarditis, tachyarrhythmias among others.37

Patients with heart failure and those who have had heart transplants (HT) may have particular difficulties as a result of COVID-19, which can exacerbate presentation, care, and prognosis.38 Clinical presentation in HT patients with COVID-19 is variable, just like in the general population. However, myocarditis symptoms (high troponin levels, ECG changes, and new left ventricular dysfunction) can be misinterpreted as rejection of graft.39 Early detection and treatment can prevent further complication with regards to heart graft. The use of hearts from COVID-19 positive donors for transplant is controversial, however the most recent research appears to support the use of organs from COVID-19 positive donors with favorable results and no indication of transmission of infection.40 Future research on long term outcomes is needed.

During an acute COVID-19 infection, HT patients should be handled with particular focus on immunosuppressive medication.41 In moderate to severe COVID-19 presentations, the International Society for Heart and Lung Transplantation (ISHLT) guidelines recommend discontinuing immunosuppressive drugs such as mycophenolate, mofetil or azathioprine.42 However, there are no guideline on how to adjust exercise program in HT patient undergoing a COVID-19 infection.

There are concerns about the risk of adverse events, including bleeding and thromboembolic events with recent miniaturization of the LVADs. However, there is evidence that these devices positively impact life expectancy and in certain cases functional capacity. More experience and evidence-based results are needed.43

The long-term outcome data on the benefits of exercise-based rehabilitation is still limited, therefore gaps still exist in benefits, health-related quality of life, and healthcare costs.44 This lack of evidence impacts the development of a consensus statement for the rehabilitation care after heart transplant.

References

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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. 9/20/2013.

Previous Revision(s) of the Topic

Maricarmen Cruz-Jimenez, MD, Francisco Merced-Ortiz, MD, Isabel Borras-Fernandez, MD. Cardiac rehabilitation before and after cardiac transplantation. 10/29/2019.

Author Disclosure

Maricarmen Cruz, MD
VA Office of Rural Health to VA Caribbean Healthcare System; Research grant; Healthcare disparity research project

Isabel Borras, MD
Office of Rural Health, Veterans Administration; Research Grant; CoPi in research study in Telehealth in TBI
Office of Rural Health, Veterans Administration; Research Grant; CoPi in research study in Sociodemographic and mortality in TBI

Suzette Arias-Mejias, MD, MS
Nothing to Disclose

Lorena Rivera-Gonzalez, MD
Nothing to Disclose