Non-invasive Evaluation of Heart Transplant Rejection- Pilot Study

Objectives:

The objectives of this study are to test the hypotheses that:

1. Tissue Doppler Imaging, Real time 3D segmental volume measurements, Magnetocardiographic Imaging plus serum markers and T-cell response change when transplant rejection occurs.
2. Tissue Doppler Imaging, Real time 3D segmental volume measurements, Magnetocardiographic Imaging plus serum markers and T-cell response remain stable when no rejection occurs

Background:

General:

Heart transplantation is an advantageous procedure for selected patients with end-stage heart failure. All patients remain on lifetime calcineurin immunosuppressive medications such as cyclosporine or tacrolimus to prevent rejection and extend graft function. Currently, the common practice in managing these patients has been titration of immunosuppressive medications to establish trough levels and clinical response. However, despite the diligent efforts to balance "adequate" immunosuppressive levels with prevention of end-organ toxicity or opportunistic infection; patients still experience acute rejection.

Graft rejection remains a major factor limiting long-term survival despite continued advancement in the use of immunosuppression. Aggressive surveillance using the gold standard of endomyocardial biopsy (EMB) for the detection of acute rejection is therefore necessary. Repeated EMB (a minimum of 11 times the first year after heart transplantation) remains the only reliable surveillance method available. EMB is expensive, invasive, inconvenient to the patient, and associated with a significant incidence of serious complications.

Hyperacute rejection occurs rarely since screening of recipient for anti-donor antibodies has been introduced. However, the focal or diffuse acute cellular rejection is more common and is diagnosed by EMB. The degree or severity of rejections is graded on a scale from 0 to 4 with a grade 3 or more being considered severe. Most acute cellular rejections occur within the first year after transplant. Chronic rejection or allograft arteriopathy occurs later and is monitored by coronary angiography.

Echocardiogram:

Echocardiograms are routinely performed in transplant patients. The findings of increased wall thickness decreased isovolumetric relaxation time and decreased compliance as well as decreased right ventricular (RV) or left ventricular (LV) ejection fraction may indicate rejection, and these parameters may normalize when the rejection resolves.

Tissue Doppler imaging (TDI) measurements are relatively new Doppler techniques for assessing left ventricular diastolic function. Selective measurements of tissue contraction and relaxation velocities at the mitral annulus can detect left ventricular dysfunction more accurately than conventional echocardiography. As left ventricular diastolic dysfunction is an early event during allograft rejection, these techniques may be useful for detecting rejection non-invasively. Few studies have shown that Doppler tissue imaging of the mitral annulus is useful in diagnosing heart transplant rejection (1-3).

Real time 3-dimensional (3D) echocardiography (RT-3D) may be a useful tool in evaluation of patients with coronary artery disease, left ventricular apical thrombi, valvular disease, in guiding intracardiac catheter placement and mitral valvuloplasty. RT-3D, which has recently become widely available, provides dynamic pyramidal data structures that encompass the entire heart and allows four-dimensional assessment of cardiac anatomy and function. It has been shown that this technique is very precise in determination of LV volume, mass and EF measurement and is well correlating with MRI (4-6). Mild changes in LV volume, LV mass and function occur during acute cardiac rejection. This very sensitive technique for assessment of regional volumetric changes has not yet been used for heart transplants monitoring.

Magnetocardiogram:

The Magnetocardiograph (MCG) is a novel imaging modality that may provide a sensitive and objective means to assess alterations in the heart tissue. Because the acute inflammatory process of rejection deleteriously affects myocyte structure and function, we hypothesize that either or both the de- and re-polarization changes will occur in the cardiac cycle with subsequent changes in the cardiac magnetic fields and may give altered readings in the affected patient over time.

Magnetocardiography (MCG) is a new modality which utilizes superconducting quantum interference devices for the detection of the weak magnetic fields (picoTesla range) generated by the heart's electrical currents. The magnetic field map picture, which is created by the measurements of the magnetic field, reflects the electrophysiological state of the heart. When there is an abnormality in cardiac depolarization or repolarization, such as in ischemia or myocarditis, this is reflected in an abnormality in the magnetic field map (7). Although MCG and ECG both measure the cardiac depolarization and repolarization patterns, they have fundamental differences. MCG is most sensitive to tangential currents whereas ECG is most sensitive to radial currents in relation to the chest surface (7-10). Cardiac abnormalities, which interfere with the normal activation and deactivation sequence, such as may occur in acute rejection, increase the contribution of tangential currents. In addition, the MCG detects the vortex currents which are not evident by ECG. Finally, the MCG is less affected by conductivity variations caused by lungs, skin, and muscles and there is no skin electrode contact problem since the device does not come in direct contact with the skin. Therefore, the MCG may be able to detect differences in depolarization and repolarization in a different manner and with a higher sensitivity than the ECG. We speculate that the variation in the magnetic field pattern is due to early subtle changes in cellular mechanisms or metabolism. These changes create a heterogeneous repolarization pattern probably caused by local currents appearing at the border zones between normal and diseased myocardium. This implies that changes in the MCG may appear even earlier in the cascade of rejection than wall motion abnormalities, ECG changes, or changes in serum markers such as troponin.

Schmitz et al reported a sensitivity of 91% and a specificity of 93% for the detection of acute rejection episodes in 15 transplant patients (11). Another study, utilizing a different analysis method, found a sensitivity and specificity of 83% and 84%, respectively for the diagnosis of graft rejection in 12 patients and 6 controls (12).