Immediately after transplantation the cardiac output and diastolic compliance are diminished, attributable to the anoxic period experienced from the time of harvest to transplantation.

In the Twenty-four to forty-eight hours postoperatively the contractily, ventricular compliance, and cardiac performance improve, but rate and contractility must be supported by exogenous catecholamine. Since cell mediated immunity shouldn't begin before 4-5 days, any rejection leading to diminished ventricular performance would likely be a humorally mediated process.

Early in the phase of the of post-transplanted life both right and left filing pressures are increased only to slowly receed with time. The right heart pressures begin to fall as the pulmonary pressures fall, ischemic periods are reversed, and tricuspid regurgitaion is minimized. The left sided filling pressures decline as the heart recovers from the ischemia of transplantaion.

Six or more months post operatively the patients on azothioprine and prednisone have normal cardiac output, normal to elevated pulmonary wedge pressure, normal pulmonary artery pressure, normal EF, and normal blood pressure. With the introduction of cylcosporine came a variety of hemodynamic abnormalities. Most patients have some systemic hypertension, which may lead secondarily to high left ventricular filling pressures, high pulmonary capillary wedge pressures and high right atrial pressures.

Myocardial contractility remains comprable to normal native hearts.

The resting heart rate is controlled by the intrinsic pacemaker system and the autonomic system. It is this delicate balance that keeps the heart functioning at the appropriate rate. It is also the modification of these systems that is responsible for the change in heart rate in the appropriate direction. It has been shown that the parasympathetics are the predominate in the resting state and down-regulate the rate of the heart rate. Early after transplantation, the rate must be supported by exogenous chronotropes or pacing. Later, circulating endogenous catecholamines support the resting heart rate. In the transplanted denervated heart the resting rate is faster than normal due to the loss of parasympathetic inhibition.

The transplanted heart responds to exercise as expected by increasing its rate, but the rate of increase is delayed just as the decrease of heart rate. The mechanism implicated in the increase of heart rate is the release of catacholamines from the peripheral nervous system. There is some evidence for reinnervation in a small percentage of cases.

There is an increase in cardiac output in the exercise state, however the mechanisms involved in the increase are different in the early stages than in the late stages of execrise. As opposed to normal hearts which initially increase output predominantly using rate, at the begining of exercise, transplant patients increase output using Frank-Starling mechanisms by increasing the stroke volume(SV) and end-diastolic volume(EDV). This is of course mediated through the autonomic nervous system which still controls the splancnic bed. At maximal exercise the EDV is equal to that of resting state. There is an increase in the heart rate, ejection fraction,and stroke volume all due to the increase of circulating catacholamines.

There are three types of rejection that the transplanted heart is susceptible to: hyperacute, acute, and chronic rejection.

Hyperacute rejection is a humorally mediated response which occurs when the host has been previously sensitized (preformed antibodies)to the donor's I-MHC antigens. This is a vascular phenomenon and typically occurs during or shortly after implantation. Thrombosis and whole organ ischemic necrosis occurs with or without antibody deposition in the parenchyma. This is a rare condition with dismal thearapuetic promises.

Acute rejection is a cell mediated response which occurs most commonly during the first three months after transplantation and is the consequence of the activation of the native T-cells and their proliferation. This is the phenomenon usually referred to by the phrase "Rejection", and it is a treatable condition for which standard immunosuppression is routinely used.

Chronic rejection probably occurs in response to vascular antigens other than HLA antigens. This results in fibrointimal proliferation leading to diffuse vascular occlusion, ischemia,and infarction. The actual mechanism responsible for the initiation of the process is poorly understood.

Diagnosis

The most important aspect of managing and optimizing the performance of the transplanted heart is early diagnosis of the rejction process and the immediate inhibition of destruction by administration of the appropriate immunosuppressive regimen. Currently, there is no reliable noninvasive test for acute rejection. Endomyocardial biopsies are performed beginning shortly after surgery using a biotome inserted percutaneously through the right internal jugular vein. Small samples of the right ventricular wall are examined microscopically for evidence of and severity of rejection.

The allograft is sampled periodically with a higher frequency at first and less later, since the likelihood acute of rejection deminishes with time. There are histological features that have been described for acute rejection that are used to grade the progress.

Mild acute rejection is defined by the presence of perivascular or mild interstitial lymphocytic infiltrates without myocyte destruction. It is generally unaccompanied by any hemodynamic compromise.

Moderate acute rejection is characterized by marked perivascular, endocardial, and intertial lymphocytic infiltrates with loss of myocytes.

Severe acute rejection is characterized by the presence of marked myocyte necrosis, hemorrhage, and neutrophil infiltration characteristic of acute inflammation.

With the current immunosuppressive treatments and prolonged transplant survival it has become evident that accelerated atherosclerotic disease of the donor heart has become the new hurdle in the fight for long term survival. The disease presents with characteristic diffuse, concentric lesions of the coronary arteries, with myointimal proliferatation, and disturbed internal elastic lamina affecting the muscular arteries of the graft. Often the penatrating myocardial arteries become occluded causing an infarct before the occlusion of the larger epicardial arteries. Because the heart is denervated, these events are frequently asymptomatic until heart failure ensues.

The cause of this process is unknown. There are currently three theories speculating the etiology of this disease.(1)The treatment of rejection by cyclosporine and corticosteroids has been implicated in either directly or indirectly injuring the vasculature.(2)In the immunocompromised patient, various organisms(viruses) may hasten the "nontransplant atherosclerosis" by simply damaging the vessels.(3)Finally, the immune system itself is implicated. It is claimed that the process occurs as a result of the chronic low-grade rejection process.