Heart Transplantation Clinical Trial
Official title:
Evaluation of Non-invasive Methods for the Detection of Acute Rejection in Heart Transplant Patients: Use of Echocardiography and Magnetocardiography (MCG) -Pilot Study
The purpose of this research study is to apply new non-invasive, no-risk techniques to a
cardiac transplant population for assessment of their reliability in detecting heart
transplant rejection.
Graft rejection remains a major factor limiting long-term survival despite continued
advancement in the use of immunosuppression. Aggressive surveillance for the detection of
acute rejection is therefore necessary. Repeated endomyocardial biopsy (EMB) (at least 11
times the first year after 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. Therefore, it would be very important for
patient care if new no-risk methods would prove to be effective in surveillance of
rejection.
This research study is designed to measure non-invasive ways to assess rejection along with
the standard planned endomyocardial biopsies you will have after heart transplantation.
First, the investigators plan to test the effectiveness of the investigational use of the
CMI 2406 Magnetocardiograph that has been approved by the U.S Food and Drug Administration
(FDA). While the device used in the study is FDA-approved for the non-invasive measurements
and recordings of the heart's magnetic field reflecting the heart's electrical currents, it
is not yet approved for the specific use of detection of transplant rejection.
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).
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