Cardiac transplantation: a review.

Cardiac transplantation is now an accepted treatment for end-stage cardiac disease. To ameliorate the deconditioning that results from the preoperative disease state and to counteract or lessen the severity of the sequelae of postoperative immunosuppression, physical therapists are active participants in the rehabilitation of cardiac transplant recipients. This involvement requires a level of knowledge and understanding of the surgical procedures, pharmacology, and postoperative management with which the therapist may have, heretofore, been unexposed. This article reviews the development of cardiac transplantation and presents an overview of the current state of the art, with emphasis on preoperative considerations, surgical and immediate postoperative care, and the effects of complications on selected exercise-related responses. [Sadowsky HS. Cardiac transplantation: a review. Phys Ther. 1996;76:498-515.

Cardiac transplantation has grown from a scientific curiosity into an accepted medical intervention for a broad spectrum of patients with end-stage heart disease. Cardiac transplantation is taking place at a great number of facilities, and a great many physical therapists are participating in the rehabilitation of transplant recipients. This article reviews the development of cardiac transplantation and then presents an overview of the present state of the art, with emphasis on preoperative considerations, surgical and immediate postoperative care, complications, and transplantation effects on selected exercise-related responses.

Historical Review

Carrel and Guthrie[1] were the first to describe cardiac transplantation (using a canine model) in their 1905 discussion of surgical anastomotic techniques. Carrel was awarded the Nobel Prize for Medicine and Physiology in 1912, in large part for this work, but little more occurred with regard to experimental cardiac transplantation in any model until 1933, when Mann and colleagues[2] refined the technique for cervical cardiac transplantation sufficiently to permit limited circulatory loading of the right ventricle of the heterotopically (ie, in other than the normal or usual position) transplanted heart. From the 1930s through the 1950s, cervical anastomosis of the "donor" heart was considered the most feasible means of accomplishing cardiac transplantation in the dog model (Fig. 1). Mann et al2 can be credited with clarifying several technical aspects of the surgical procedure, and they astutely observed that failure of the transplanted heart is likely due "to some biologic factor" and not always to flawed surgical technique,

There were few important developments regarding cardiac transplantation until the 1950s. In 1951, Marcus and coworkers[3] described circulatory loading of both ventricles of a transplanted canine heart (Fig. 1). This achievement led them to speculate on future prospects for application in human cardiac transplantation. In 1953, Downie[4] decried the dismal record of cardiac transplant survival and called for a concerted effort to expand the understanding of what is now called immunology. In 1957, Webb and Howard[5] reported that myocardial viability could be maintained for up to 8 hours with a combination of cardioplegic arrest and surface cooling in a heterotopic intrathoracic cardiac transplantation model. A year later, Goldberg and colleagues[6] described a successful procedure for orthotopic (ie, in the normal or usual position) cardiac transplantation in the canine model that used a cuff formed from a portion of the recipient heart's left atrium to avoid separate pulmonary venous anastomoses. In 1959, Cass and Brock[7] reported a further modification of the surgical procedure that used a right atrial cuff to avoid separate superior and inferior vena caval anastomoses (Fig. 2B).

Shumway and colleagues[8-10] concluded that the surgical requirements had been perfected to such an extent that the transplanted heart would be likely to function adequately for the normal life span of the animal if the host's immune system could be prevented from destroying the donor heart. In 1965, Lower and coworkers[11] reported long-term survival of dogs after transplantation following the successful treatment of cardiac graft rejection (as diagnosed by R-wave amplitude reduction on the electrocardiogram) with azathioprine and "pulsed" (ie, intermittently increased above baseline) doses of steroids.

The first clinical application of cardiac transplantation in a human occurred in 1964 at the University of Mississippi.[12] Unfortunately, because of the traditional definition of death (cessation of heart beat and breathing) adhered to at the time, the need for the donor organ preceded its availability; consequently, a large chimpanzee heart was used. The transplanted organ was unable to sustain the necessary circulation, and the patient died within an hour after the cardiopulmonary bypass was discontinued. In late 1967, Christiaan Barnard, in Cape Town, South Africa, performed the first human-to-human cardiac transplantation, Although the recipient succumbed to a Pseudomonas pneumonitis after 18 days, in the ensuing 12-month period, 101 cardiac transplantations were performed in 24 countries by 64 different groups.[13] By late 1969, however, due to abysmal success rates (30% survival at 2 years), there were few centers that continued cardiac transplantation.[14,15]

By focusing on the postoperative management of cardiac transplant recipients, a team led by Shumway, at Stanford University, continued to make advances on the basis of applied clinical and laboratory research throughout the early and mid 1970s. The development and clinical use of the Caves biopsy forceps,[16-18] which facilitated the direct transvenous acquisition of endocardial tissue samples, (Fig. 3), the Billingham histologic grading system for endocardial biopsy samples,[19-22] and antithymocyte globulin (ATG), a potent immunosuppressant used to treat acute allograft rejection,[23-26] contributed to an improvement in 1-year survival from 22% (10 transplants) in 1968 to 70% (21 transplants) in 1976. By 1980, the 5-year survival rate at Stanford University was stable at about 40%.[27-29]

The introduction of cyclosporin A (cyclosporine) into the immunosuppressant regimen of cardiac transplant recipients at Stanford University in 1980 marked the beginning of the "modern era of cardiac transplantation."[13] The impact of cyclosporin A on 1-year survival statistics was profound.[30] In 1981, only 90 cardiac transplants were performed worldwide, but by 1984, the number of cardiac transplants had grown to 440 and by 1988, the annual rate of cardiac transplant procedures exceeded 2,000.[31-34] Currently, the 1- and 5-year survival rates for cardiac transplant recipients are from 80% to 90% and from 60% to 70%, respectively.[35,36]

Since 1988, the number of centers performing cardiac transplants has increased more than 16% in the United States.[37] In 1992, there were 2,171 cardiac transplants performed in the United States.[37] Tremendous strides have been made with regard to cardiac transplant surgical technique and postoperative survival. Despite the fact that cardiac transplantation is not a cure, it is no longer considered an experimental curiosity; rather, cardiac transplantation is now the accepted treatment of choice for many patients with end-stage heart disease. Because inadequate donor availability makes transplantation impossible for all potential recipients, the selection of candidates must be based on a determination of which patients are most likely to demonstrate the greatest symptomatic improvement, functional gain, and life expectancy after transplantation.[38]

Since passage of the National Organ Transplantation Act, the United Network for Organ Sharing (UNOS) has been given the responsibility for maintaining the national prioritization and allocation system and for certifying transplant centers and local organ procurement organizations (OPOs) in the United States. The 50 states have been divided into 11 regions containing approximately the same size populations. Local OPOs regulate allocation to the appropriate recipient within the region. The highest priority (UNOS status 1) is given to potential recipients who are dependent on intensive medical care and require intravenous inotropic or mechanical circulatory support. If the donor heart cannot be matched to a recipient within the region, it is offered to any recipient in the nation. The limited availability of suitable organs for transplantation, coupled with the subjective and interdisciplinary process of selecting recipient candidates, necessitates a committee structure. At most transplant centers, the committee includes transplant surgeons, cardiologists and experts in relevant disciplines (eg, infectious disease, nursing, physical therapy).

Recipient Candidacy Criteria

Potential recipients are either New York Heart Association (NYHA) Classification (Tab. 1)[39] Class IV or ambulatory Class III patients. Numerous additional criteria have been established to identify the best recipient candidates.[38,40-59] Unless cured or controlled, infection and malignancy appear to be absolute contraindications to transplantation because the postoperative immuno-suppressive regimen would facilitate the spread of an active infection and might accelerate the growth of some malignancies. Most transplant centers require patients with pulmonary infarction to be treated with anticoagulants and monitored for at least 6 to 12 weeks before they are placed on the potential recipient list. Although careful selection of elderly candidates can yield benefits that are comparable to those for younger recipients, most centers limit the upper age limit for potential recipients to less than 65 years. Most transplant centers will not accept candidates with an elevated pulmonary vascular resistance or transpulmonary gradient ([mean pulmonary artery pressure] -- [pulmonary capillary wedge pressure]). Patients with diabetes mellitus will generally present problems for controlling blood glucose due to the use of corticosteroids in postoperative immunosuppression. Careful exclusion of end-organ damage is required, therefore, before people with diabetes are accepted for transplantation. Infants, children, and adolescents present additional unique requirements.[60,61] Table 2 presents common attributes that might contribute to the formulation of a general guideline for cardiac transplant recipient candidate selection.

Table 2.
Attributes(a) That Might Contribute to the Formulation of a
General Guideline for Cardiac Transplant Recipient
Candidacy[40-45,47-49,52-55,57]

NYHA class IV or III with [VO.sub.2]max < 14 mL [multiplied by]
[kg.sup.-1] [multiplied by] [min.sup.-1]
Left ventricular ejection fraction >20%
Age <65 y
Without active infection or malignancy
Without pulmonary infarction (or 6-12 wk postinfarction)
Pulmonary vascular resistance <4-6 mm Hg [multiplied by] [L.sup.-1]
[multiplied by] [min.sup.-1]
Transpulmonary gradient (mean PAP - mean PCWP) < 15 mm Hg
Without concomitant moderate or severe hepatic or renal disease
Without diabetic end-organ involvement
FVC >50% predicted and [FEV.sub.1] >1 L
Without current evidence of substance abuse
Ability and willingness to comply with medical regimen
Capable of meeting financial requirements
(a) NYHA=NEW York Heart Association, [VO.sub.2]max=maximal oxygen consumption,
PAP=pulmonary artery pressure, PCWP=pulmonary capillary wedge pressure,
FVC=forced vital capacity, [FEV.sub.1] =forced expiratory volume in 1 second

Donor Selection Criteria

Despite an estimated availability of between 6,900 and 10,700 cardiac donors per year,[62] 10% to 40% of potential recipients die while waiting for transplantation due to a shortage of donors.[63,64] Potential cardiac donors must be evaluated meticulously.[57,65,67] Suggested criteria for adult cardiac donor selection are presented in Table 3.[38,65,67] Doroshow and associates,[68] however, have suggested that the application of adult donor selection criteria for infants is inappropriate. Donors and recipients must be ABO blood group identical or compatible. Likewise, an attempt is made to match the major histocompatability complexes (eg, human leukocyle antigens [HLAs]) to reduce the chances of postoperative allograft rejection. Due to the physiological changes in myocardial tissue and the increased risk of cardiovascular disease associated with the aging process, adult donors are typically younger than 55 years of age. Persons with diagnosed or suspected malignancies are usually unacceptable as donors because the postoperative immunosuppressive regimen greatly facilitates the spread of established proliferative diseases. Cardiac Transplantation Operative Procedure Although heterotopic transplantation continues to be an option, most surgeons perform orthotopic cardiac transplantations.[69] Although individual surgeons may make minor variations in the technique, the following describes the general operative procedure for orthotopic transplantation.[69-73]

Table 3.
Criteria for Selection of Cardiac Donors and Guidelines for Matching
With Recipients[38,65,67]

Donor selection criteria
Acceptable ventricular function (after normalization of
  intravascular volume)
Age between 40 and 50 y
No evidence of malignancy
No evidence of significant cardiac disease and low probability
  of its development
No evidence of significant cardiac trauma
No serologic evidence of HIV(a) or hepatitis B
No severe infection
Donor/recipient matching criteria
ABO blood-type compatibility
Allograft ischemic time less than 4-5 hr
Body weight within [+ or -] 20%
Negative prospective cytotoxic T-cell crossmatch (not often
fiasible, although retrospective crossmatching is performed at
most centers)
(a) HIV=human immunodeficiency virus.

After heparinization, the donor heart is harvested by first separating and ligating the superior vena cava. The inferior vena cava is then separated just above the diaphragm, and the heart is permitted to beat until empty. An aortic crossclamp is applied just below the innominate artery, and cardioplegic solution is administered. Once cardioplegia has been established, the pulmonary veins are separated at their pericardial reflections and the pulmonary trunk is divided at the level of its bifurcation. Lastly, the aorta is severed beyond the origin of the innominate artery, and the heart is then stored in a sterile saline solution at a temperature of about 4[degrees]C.

Once the donor procurement team informs the recipient team that the donor heart is acceptable, the recipient is anesthetized. The median sternotomy and removal of the recipient's heart are generally not performed until the donor heart is present in the operating room. The excision is begun with an incision through the right atrium along the atrioventricular groove (but posterior to the atrial appendage) and extending posteriorly through the coronary sinus (Fig. 2A). A similar incision is made above the atrioventricular groove for the left atrium, leaving an atrial cuff (the size of which is dictated by the pulmonary veins). The great vessels are separated at the commissures of their semilunar valves. The recipient heart is then removed (Fig. 2B).

The left atrium of the donor heart is opened by connecting incisions through the pulmonary veins, creating a large posterior atrial cuff that is anastomoged to the recipient's left atrial cuff (Fig. 2C). The donor right atrium is then opened from the inferior vena cava upward into the base of the right atrial appendage, avoiding the nodal areas. Anastomosis of the donor heart's right atrial flaps with the recipient's right atrium is then begun from the lower end of the interatrial septum. The pulmonary arterial anastomosis is then completed with care, to avoid kinking. Finally, the aortic anastomosis is completed, and de-airing maneuvers are performed before the aortic crossclamp is removed. Before sternal closure, pleural and mediastinal drainage tubes are placed and epicardial pacing wires are affixed to the right atrium and ventricle. Ideally, total donor heart ischemic time should not exceed 4 hours.[49] Figure 2D depicts the positions of donor and recipient tissues following completion of the procedure.

Heterotopic cardiac transplantation is often complicated postoperatively by right lower-lobe atelectasis because of the nature of the procedure and the ultimate location of the donor heart.[70] Moreover, there is a greater actuarial risk of mortality associated with the procedure.[49,50,55,67] Nonetheless, heterotopic cardiac transplantation has been proposed as a means to expand the donor pool,[74] and may be indicated when the recipient's pulmonary vascular resistance is irrevocably high or the donor heart is too small to support the recipient alone.[70] The typical procedure is performed as follows.

After procurement, the donor heart is prepared by oversewing the inferior vena cava and right pulmonary veins; the left pulmonary veins are joined to form a single orifice. A right atrial flap is created with an incision along the superior vena cava that extends into the base of the right atrium.

Total cardiopulmonary bypass is established, and cardioplegic arrest of the recipient's heart is achieved. The recipient's left atrium is incised at the right superior pulmonary vein, and the single left pulmonary venous appendage from the donor heart is anastomosed (Fig. 4A). The donor's right atrial flap is then anastomosed to an incision made through the recipient's superior vena cava and right atrium. An end-to-side anastomosis of the donor's aorta is then made to the recipient's aorta. Finally, the pulmonary arterial anastomosis is completed (also end-to-side), but a Dacron(*) graft often has to be interposed (Fig. 4B).

Postoperative Care

The immediate postoperative care following cardiac transplantation is not dissimilar from that for patients after any other open-heart surgery. Most patients are weaned from mechanical ventilatory assistance within 24 to 36 hours, with endotracheal and orogastric tubes being removed at that time. Typically, isoproterenol is titrated to maintain a heart rate of about 110 beats per minute for the first 72 hours and is then tapered off. Likewise, low-dose dopamine (0.5-2 [mu]g/kg/min) is continued for 72 hours to facilitate diuresis. Postoperative pulmonary vascular resistance is closely monitored and is regulated for the first few days with intravenous vasodilators (eg, sodium nitroprusside), as necessary.

Reverse isolation rooms are rarely used; good hand washing and simple masking are generally sufficient for the recipient's protection. The patient's chest drainage tubes are typically removed after 2 days, and prophylactic antibiotics are usually discontinued at the same time. An oral diet is begun as soon as the patient can tolerate it. The pacing wires are usually removed and the first endomyocardial biopsy is performed 7 to 10 days after transplantation. Endomyocardial biopsy usually takes less than 20 minutes to complete, and in a typical procedure the bioptome is inserted via the internal jugular vein and advanced into the apex of the right ventricle (Fig. 3). Three to five tissue specimens of approximately 2 mm diameter are generally obtained from different sites for histological examination and immunological study of cellular subpopulations.

Postoperative cardiovascular physiology is dramatically affected by denervation,[75] donor-recipient size mismatch,[76] rejection, and immunosuppression. The extrinsic nervous supply (ie, parasympathefic fibers via the vagus nerve, sympathetic fibers via rami of the sympathetic trunk) to the donor heart is severed during the procurement surgery and, consequently, there is no direct neural control of the function of the transplanted heart. Moreover, the depolarization wave of the remaining native heart is not transmitted beyond the anastomotic suture (and subsequent scar) line to the transplanted donor myocardium. Thus, the immediate regulation of cardiac output is a consequence of circulating catecholamine levels and the Frank-Starling principle. The donor-recipient size relationship also affects cardiovascular function; without reasonable comparability of donor and recipient body mass, the postoperative consequences could be dire.

A brief review of the function of the immune system should facilitate a better understanding of immunosuppression and allograft rejection. The immune system is composed of several subsystems--histocompatibility complexes--that function to protect an individual from organisms or toxins that might cause damage.77,78 Almost all cells and toxins possess one or more specific chemical elements (antigens) that uniquely identify them.[79,80] Antigens provoke immune activity. Once activated, the immune system functions in two different ways: (1) destruction of the antigen by phagocytosis, a property of innate (nonspecific) immunity, or (2) formation of antibodies and sensitized lymphocytes, either or both of which may destroy the antigen, a property of acquired immunity. This latter activity--the acquired immune response--is responsible for allograft rejection.

Acquired immunity derives from the formation of antibodies (immunoglobulins) and sensitized lymphocytes as a specific humoral or cellular response to a unique antigenic stimulus (Fig. 5). Immature lymphocytic stem cells are formed in the bone marrow and released into the blood. Those lymphocytic stem cells that will ultimately be responsible for cell-mediated immunity are processed in the thymus--hence, the name T lymphocytes; those that will ultimately be responsible for antibody formation are processed in the liver and spleen, where they are transformed into B lymphocytes; still others continue to circulate and mature into macrophages.[77,78]

When activated by an antigen, B lymphocytes (B cells) enlarge and become lymphoblasts.[79] The lymphoblasts change into plasmablasts, which mature into plasma cells. The plasma cells produce the antibodies that are eventually secreted into the lymphatic circulation and ultimately reach the blood. The antibodies, in conjunction with elements of the complement system in the blood, then bind to and neutralize the antigens by means of agglutination, precipitation, opsonization, or lysis.[77-80]

When T lymphocytes are activated by an antigen, they proliferate and release a vast quantity of different types of T cells into the lymphatic circulation and, thereby, into the blood.[79] The different T cells can be classified into three basic groups: (1) helper T cells, (2) cytotoxic (killer) T cells, and (3) suppressor T cells. The helper T cells (phenotypic marker [CD4.sup.+]) are most numerous and are primarily responsible for regulating immune functions by forming lymphokines (interleukins, interferons, and so on). The lymphokines act to facilitate or inhibit the activity of both B cells and T cells. Cytotoxic T cells (phenotypic marker [CD8.sup.+]) directly attack the offending antigen, particularly "foreign" cells. Suppressor T cells are believed to modulate immune reactions and may play a role in autoimmune disorders.

Allograft Rejection

The manifestations of acute cardiac rejection are quite variable. Malaise, reduced exercise tolerance, and low-grade fever are sometimes associated with episodes of rejection. Unless it is suppressed, the immune reaction to the allograft will damage (and ultimately destroy) the cells of the transplanted heart, hindering cardiac function (Fig. 6).

Transplant rejection is best diagnosed by means of periodic endomyocardial biopsies, with the histologic findings interpreted as described by Billingham.[22,81] After the initial biopsy, routine biopsies are performed biweekly for the first three months, monthly for 6 months, and then every 3 months. After the first 2 years, biopsies arc performed on an annual basis. Episodes of rejection can drastically alter the ultimate number of biopsies that may be required. Endomyocardial biopsies are performed on an "as needed" basis for infants because the attendant risks outweigh the benefits of routine sampling.[60,82] Therefore, biopsies are usually done only to confirm noninvasive evidence of possible cardiac rejection in infants weighing less than 5 kg.[60,82]

Clinically, mild to moderate rejection is not associated with any reliable signs or symptoms (ie, signs or symptoms, such as angina, that are clearly associated with a particular pathology). In moderate to severe rejection, the signs and symptoms may include new cardiac arrhythmias, hypotension, fever, fatigue, malaise, or shortness of breath. Mild rejection is characterized by limited perivascular lymphocytic infiltration and accompanying interstitial edema. Rejection is called moderate when the lymphocytic infiltrate extends into the interstitium. Severe rejection is characterized by diffuse lymphocytic infiltrate, the presence of polymorphonuclear leukocytes, interstitial hemorrhage, and myocytic necrosis. Chronic rejection manifests itself as accelerated graft atherosclerosis and is generally not apparent in endomyocardial biopsies. The diagnosis is typically made with corona angiography or on autopsy.[81]

Immunosuppressive Therapy

Immunosuppressive therapy is often begun perioperatively with the administration of cyclosporine (which inhibits the proliferation of T lymphocytes) and azathioprine (which inhibits purine synthesis).[78,83-85] Cortico-steroids (which inhibit T-cell activation), are started intraoperatively with intravenous infusion of methyprednisolone and are continued until the patient can take prednisone orally. Although this "triple-drug" regimen constitutes the backbone of immunosuppressive therapy for cardiac transplant recipients,[78,83-85] at several centers polygonal anti-T-cell agents or low-dose total lymphoid irradiation is used in place of corticosteroids.[26,86,87] At most centers, however, polyclonal (eg, antilymphocyte globulin, antithymocyte globulin) or monoclonal (eg, muromonab-CD3) anti-T-cell agents are typically reserved for the treatment of acute episodes of rejection.[83,88,89] A new drug-FK 506 (which inhibits T-cell proliferation)--may further alter traditional approaches to the management of the immunosuppressive regimen.[90,91] There are several investgational drugs that also are used in an effort to reduce graft rejection episodes.[92-97] Table 4 summarizes the most common agents used in immunosuppressive and antirejection therapies for cardiac tranplant recipients.

Although allograft rejection is only the second leading cause of mortality for cardiac transplant recipients, immunosuppression is the primary source of morbidity. For example, cyclosporine has frequently been associated with leukopenia, hypertension, tremor, nephrotoxicity, hepatotoxicity, hirsutism, and increased susceptibility to infection; azathioprine has been associated with leukopenia, bone marrow suppression, hepatotoxicity, and pancreatitis; and prednisone has been associated with insomnia, congestive heart failure, hypertension, peptic ulcers, osteoporosis, muscle weakness, and increased susceptibility to infection Consequently, numerous additional medications--antihypertensives, diuretics, antacids, and antibiotics--are prescribed to counteract the untoward effects of immunotherapy. Clearly, the major foci of postoperative care must be directed at assessment of cardiac function, surveillance of rejection, titration of immunosuppression, and identification and treatment of the adverse effects related to immunosuppression.

Postoperative Complications

Rejection

Acute cardiac allograft rejection represents a failure of the immunosuppressive maintenance regimen to prevent activation of immune effector cells. Almost all cardiac transplant recipients will experience episodes of graft rejection at some point postoperatively. The importance of clinical physiological monitoring, therefore, cannot be overemphasized. Therapists and patients alike must be vigilant to the signs and symptoms of activity intolerance. It is rarely necessary, however, for the exercise regimen to be curtailed during episodes of mild to moderate rejection. During episodes of moderate rejection, when there are new arrhythmias, hypotension, or fever, exercise is reduced to unresisted symptom-limited modes of activity. During severe rejection, activity is often limited to self-care and may need to be more limited. In general, the long-term prognosis is poorer as the frequency and severity of rejection episodes increase.

Transplant Vasculopathy

Chronic rejection appears to manifest itself as accelerated graft atherosclerosis.[78,98,99] The incidence of this problem is reported to be about 10% to 15% by the end of the first year and between 35% and 50% by the fifth year postoperatively.[77,100,101] Unlike the typical form of atherosclerosis, accelerated graft atherosclerosis does not produce discrete plaques. Instead, evidence suggests that denervation leads to an "up-regulation" of muscarinic receptors that promotes increased calcium influx in the coronary arteries of the transplanted heart, facilitating a more insidious, diffuse, circumferential narrowing of arterial lumenal diameters. This form of coronary artery disease is the major factor that limits long-term survival of cardiac transplant recipients, but recent studies suggest that calcium channel blockers may ameliorate the problem.[100,102]

Infection

Infection (eg, mediastinitis, pneumonia, urinary tract infection, or intravenous catheter-induced sepsis) is the leading cause of postoperative death among cardiac transplant recipients.[36,103-105] The problem appears to be most troublesome during the first 2 years following transplantation.[98,104,106] Bacterial and viral infections are most common (47% and 41% of infections), with fungi and protozoa accounting for 12% of posttransplant morbidity.[103] The most frequent infecting organism is cytomegalovirus.[103,105-107] The most important contribution physical therapists can make toward infection control is washing their hands for a full 10 seconds before and after direct contact with any patient.

Hypertension

Most cardiac transplant recipients develop cyclosporine-related hypertension.[38,108,109] This posttransplant hypertension is most likely the result of cyclosporine-induced renal vasoconstriction superimposed on chronic renal hypoperfusion (as a consequence of congestive heart failure), third-spacing of fluids (as a consequence of extracorporeal circulation), and an abnormal distribution of blood flow (as a consequence of anesthesia and inotropic medications).[38,110,111] Therefore, cardiac transplant recipients' blood pressure should be closely monitored, with morning blood pressure values being used to guide antihypertensive therapy.[38] Because hypertension and associated problems can be so devastating, several methods have been suggested for treating these problems.[83,98,108,112-114] Cyclosporine is believed to elicit afferent glomerular arteriolar vasoconstriction via an increase in transmembrane calcium flux in mesangial. and vascular smooth muscle cells.[115,116] Consequently, alternative cyclosporine dosing schemes, calcium channel antagonists, and angiotensin-converting enzyme inhibitors are advocated in an effort to promote arteriolar dilation.[115-118]

Other Problems

Numerous other complications have been associated with the postoperative course of cardiac transplant recipients. Among them are hypercholesterolemia,[119,120] valvular insufficiency,[121] weight gain,[122,123] lymphoma,[124] exercise intolerance,[125] muscular weakness,[126] nephropathy, [117,119] and osteoporosis.[114] Finally, even the effect of donor and recipient gender on morbidity and mortality following transplantation must be considered. Female recipients and recipients of grafts from female donors exhibit a higher incidence of death from acute rejection. [127,128] There is no important difference in outcome, however, between male and female donors in terms of infection, late rejection, or overall survival.[129,130]

Effect of Transplantation on Selected Cardiovascular and Pulmonary Variables (Table 5)

[TABULAR DATA 5 OMITTED]

Heart Rate

At rest, cardiac transplant recipients exhibit higher heart rates than do individuals without cardiac transplants. [125,131-133] The most accepted rationale for this phenomenon is the loss of vagal tone associated with the surgical procedure.[134-138] At the outset of exercise, heart rate may increase slightly (as the result of either the Bainbridge reflex[139] or the increased rate of ventricular work[140]). There is usually, however, a 3- to 5-minute delay in the onset of cardiac acceleration. The gradual heart rate increase may even continue into the recovery period, and there is a slower-than-normal return to preexercise heart rate values.[132,141] The peak heart rate achieved during maximal exercise is markedly lower in cardiac transplant recipients than in age-matched control subjects.[131,132,141,142] This abnormal cardioacceleratory response limits the usefulness of exercise prescriptions based on target heart rate.

Stroke Volume/Cardiac Output

Resting stroke volume of patients following cardiac transplantation is less than that of individuals without transplantation,[143] but cardiac output is relatively normal.[133,143] Typically, there is a rapid increase in stroke volume of about 20% at the outset of exercise.[131,133,144,145] Later increases in stroke volume or cardiac output during prolonged submaximal exercise are mediated by inotropic responses to circulating catecholamines.[125,133,143,146-149] Observed values for peak cardiac output are lower in cardiac transplant recipients than control subjects.132,133,150,151

Blood Pressure

Both systolic and diastolic blood pressures are higher than expected, but the pulse pressure (the difference between systolic and diastolic blood pressures) is essentially normal at rest.[143,147,148] Diastolic blood pressure may decline early in submaximal exercise due, in large part, to reduced peripheral resistance, which is nonetheless still high relative to power output.[125,148,149,152] The peak systolic blood pressure of cardiac transplant recipients is less than that of individuals without cardiac transplants, but diastolic blood pressure is not much different.

Oxygen Consumption

In absolute terms, oxygen consumption during submaximal exercise is less in cardiac transplant recipients than age-matched control subjects.[146,153-157] Likewise, oxygen consumption at the anaerobic threshold is markedly lower than that of individuals without cardiac transplants or age-matched general surgery patients.[153,154,157] Braith et al[126] have suggested that the decrement in peak oxygen consumption observed in heart transplant recipients is partially due to skeletal muscle weakness.

Despite the formidable physiological ramifications of cardiac transplantation, patients exhibit training effects with persistent participation in regular exercise regimens.[158] The use of steady-state heart rate to gauge exercise intensity is not recommended, however, because of the progressive, slow increase in heart rate throughout an exercise session.[159] Other measures of exercise intensity that might prove more beneficial include blood pressure reserve,[160,161] perceived exertion,[160,162] or the dyspnea index.[163]

Blood pressure reserve is the difference between the maximal systolic (or diastolic) blood pressure and the resting systolic (or diastolic) blood pressure. By monitoring the transplant recipient's blood pressure during a graded exercise test, the blood pressure reserve can be determined. Then, a simple substitution of blood pressure for heart rate in Karvonen's formula yields a target blood pressure range for the patient's exercise prescription. Anecdotally, this technique has been of benefit in the acute rehabilitative phase for hypertensive transplant patients.

The rating of perceived exertion (RPE) has been widely used as a self-monitoring tool for transplant recipients. The Borg scale, as presented in Table 6, is most frequently used in clinical practice to establish an RPE level for training. When appropriately used in the establishment of an exercise prescription, the majority of patients train at an RPE of between 11 and 13.

Table 6.
Borg Scale for Rating of Perceived Exertion(a)
Rating    Description of Effort
7         Very, very light
9         Very light
10
11        Fairly light
12
13        Somewhat hard
14
15        Hard
16
17        Very hard
18
19        Very, very hard
20
(a) Reprinted with permission from Borg GV. Psychological basis of perceived
exertion. Med Sci Sports Exerc. 1982; 14:377-38 1.

The dyspnea, or ventilatory, index (Tab. 7) is a means of monitoring exercise intensity based on an individual's ventilatory response to exercise. A patient is instructed to breathe normally during exercise. Following a normal inhalation, the patient is asked to count aloud to 15 (taking about 8 seconds to complete the count); the patient may take a breath whenever necessary to complete the sequence. The number of breaths taken during the counting sequence establishes the dyspnea (ventilatory) level. Following an appropriate warm-up period, the patient is instructed to exercise at an intensity that requires him or her to take two to three breaths (levels 2-3).

Table 7.
Ventilatory Index Scale(a)
Level   Description
0       Able to count aloud to 15 without taking a breath
1       Must take one breath in order to complete counting
         aloud to 15
2       Must take two breaths in order to complete counting
         aloud to 15
3       Must take three breaths in order to complete
         counting aloud to 15
4       Must take more than three breaths in order to
         complete counting aloud to 15

(a) The patient/client is asked to breathe normally; following a normal
inhalation, the patient/client counts aloud to 15 over a 7.5- to 8-second
period, taking additional breaths as necessary; a "+" sign may be used to
indicate a "hurried" count. (Modified from the Rancho Los Amigos Dyspnea
Scale as presented in Physical Therapy Management of Patients With Pulmonary
Disease Downey, Calif: Rancho Los Amigos Professional Staff Association; 1980.

In general, the goal of exercise for cardiac transplant recipients is no different from that for any patient in a cardiac rehabilitation program.[160,164,165] The majority of cardiac transplant recipients return to an NYHA Class I status. [166]

Summary

Cardiac transplantation has become an accepted treatment for end-stage cardiac disease. Physical therapists are active participants in the rehabilitation of cardiac transplant recipients. Such involvement requires a level of knowledge and understanding of surgical procedures, pharmacology, and postoperative management with which the therapist may have, heretofore, been unexposed. This article, therefore, reviewed the development of cardiac transplantation and presented an overview of the present state of the art, with emphasis on preoperative considerations, surgical and immediate postoperative care, complications, and effects on selected exercise-related responses.

[Figures 1 to 6 ILLUSTRATION OMITTED]

(*) El du Pont de Nemours & Co Inc, 1007 Market St, Wilmington, DE 19898.

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HS Sadowsky, RRT, PT, CCS, is Associate Professor, Department of Physical Therapy, School of Health and Social Work, California State University, Fresno, CA 93740. Address all correspondence to Mr Sadowsky at 1665 E Houston Ave, Fresno, CA 93720 (USA) ([e-mail]).