Heart Transplantation Clinical Trial
Official title:
Advanced Cardiac Imaging in Cardiac Allograft Vasculopathy
Cardiac allograft vasculopathy (CAV) is a process of both immune and non-immune mediated
thickening of the heart arteries of transplanted hearts. CAV limits the long term survival
of heart transplant patients and is one of the common causes of death in the late post
transplant period. Current methods of detecting CAV rest with invasive cardiac
catheterization which carry repeated risks, as this test needs to be performed periodically
through the life of a heart transplant patient. Traditional methods of coronary angiography
identify CAV late in its course and is a crude method of evaluating coronary anatomy in
heart transplant patients. Intravascular ultrasound is an additive tool that is able to
detect early CAV before it becomes angiographically apparent, but still requires invasive
cardiac catheterization to perform. However, it also limits assessment to the major
epicardial arteries and does not give any information regarding the smaller branch vessels
and cardiac microvasculature. Advances in cardiac CT and cardiac MRI hold potential to
evaluate for CAV non-invasively. In addition, perfusion techniques may provide additional
functional information regarding the status of the microvascular.
In this pilot study, we aim to demonstrate the feasibility of cardiac CT and cardiac MRI
with and without perfusion protocols, in patients post-heart transplant and to describe and
compare CT and MRI findings in patients with established CAV versus those with no CAV, as
diagnosed by standard invasive methods.
Heart transplantation is a viable treatment option for select patients with end-stage heart
failure, with 1-year survival rates for heart transplantation approximating 85%. Of those
who survive the first year, >90% are alive at 5 years. In the early post-transplant period,
rejection of the donor heart due to activation of the recipients immune system, is the most
worrisome complication and most common cause of morbidity and mortality. With time, the risk
of rejection declines and cardiac allograft vasculopathy (CAV) represents the most common
cause of heart failure and death in heart transplant recipients. CAV is a form of coronary
artery disease in the transplanted heart. It develops due to a variety of immune and
non-immune mediated mechanisms. It differs significantly from coronary artery disease in
normal hearts, in that it affects arteries of all sizes (not just the main arteries visible
by coronary angiography) and it involves thickening of the inner layer of the arteries,
rather than the surface lining of the arteries as in traditional coronary artery disease.
Early CAV is clinically silent. Patients are most often diagnosed by routine coronary
angiographic surveillance (standard of care), or by declining heart function by surveillance
imaging (standard of care), with no evidence of any organ rejection.
Coronary angiography and assessment of heart function remain the cornerstone for diagnosis
of CAV. The main limitation of angiography is its inability to identify mild or early
disease, as an apparently normal angiogram can underestimate the presence of CAV.
Intra-vascular ultrasound (IVUS) at coronary angiography has been evaluted as an adjunctive
mordality for assessing and diagnosing early CAV. Certain IVUS parameters have been
correlated with high risk for development of CAV and overall worse prognosis long term.
Detection of CAV has important therapeutic and prognostic implications. Once detected by
angiography, the likelihood of progression to severe CAV within 5 years is 19%. The overall
likelihood of death or re-transplantation as a result of CAV is approximately 50% for severe
CAV. Changes are made to medical therapy targeted at slowing or halting CAV progression and
patients are evaluated for re-transplantation sooner rather than later, depending on the
rate of progression.
Currently, CAV is diagnosed by cardiac catheterization performed at routine intervals post
transplant, with or without the use of IVUS. This is an invasive test with complications
including bleeding, vascular damage, renal failure, stroke, heart attack or death. It has
low sensitivity for identifying early CAV. Recent advances in cardiac magnetic resonance
imaging (CMR) and cardiac CT imaging (CCT) present a unique opportunity to investigate these
non-invasive modalities in CAV. To date, there are no studies in this field.
We propose to evaluate whether functional CCT and/or CMR perfusion abnormalities, calcium
scoring by CCT, and late gadolinium enhancement by CMR, is feasible in heart transplant
patients and whether these modalities can detect abnormalities that correlate to cardiac
catheterization results and detect early CAV before it becomes angiographically apparent.
This pilot study will be the first of its kind in the heart transplant population. We aim to
demonstrate feasibility and safety of CCT/CMR in heart transplant patients and correlate
specific CMR/CCT abnormalities to established angiographic apparent CAV. This will allow
further prospective evaluation of this exciting non-invasive modality in CAV detection with
larger research studies by our group.
The clinical implications are significant in that we may reduce the number of invasive
procedures performed and identify CAV earlier, leading to the institution of earlier
therapies, such as proliferation signal inhibitors, that may alter the natural history of
this disease in effort to prolong the life of the transplanted heart.
Specific Objectives:
Primary Objectives:
1. The number of patients with adverse events from CCT and CMR
2. Determine recruitment rates for future studies, logistics of testing, and the ability
to perform the tests
Secondary Objectives:
1. Describe the CCT and CMR imaging findings in CAV
1. Identify and describe structural and functional CMR abnormalities in established
angiographically apparent CAV using novel imaging protocols, including stress-rest
perfusion imaging.
2. Identify and describe structural and functional cardiac CT abnormalities in
established angiographically apparent CAV using novel imaging protocols, including
stress-rest perfusion imaging.
2. Correlation between intimal thickening by IVUS imaging at cardiac catheterization and
CCT/CMR perfusion abnormalities at one year post heart transplant.
3. Correlation between CCT/CMR perfusion abnormalities at one year post heart transplant
with the development of angiographically apparent CAV, graft dysfunction, cardiac
adverse events, and overall survival long term, and compare CCT to CMR in this regard
(Cohort 1 & 2 below)
Study Design: Patients will be recruited into 1 of 3 cohorts from the heart transplant
program at the QE II Health Science Center, Halifax Infirmary site, using a protocol
approved by the institutional research ethics board. Eligible patients are those scheduled
for routine invasive coronary angiography, > 18 years of age, > 12 months post-transplant
and be able to undergo both CCT and CMR. Exclusion criteria include a creatinine clearance
(CrCl) calculated < 45ml/min, contraindications or inability to administer intravenous
beta-blockers or calcium channel blockers and standard contraindications to CMR, contrast
media, and adenosine. Patients will be identified by Dr. Brian Clarke who is involved the
care of all heart transplant patients at the QE II Health Science Centre
Data will be analyzed as follows:
1. Feasibility will be determined based on successful rate of recruitment and completion
of CCT/CMR scans in cohort 3.
2. Patients eligible for cohort 3 require the diagnosis of CAV 1 at any time point
post-transplant. The attending transplant cardiologist involved makes this assessment.
More advanced CAV is excluded. These patients will be analyzed without a comparator
group. For CCT, calcium scoring, intimal thickening, and perfusion abnormalities will
be described and analyzed for their correlation to angiographic findings. CMR imaging
will describe late gadolinium enhancement, structural changes, and perfusion
abnormalities and be analyzed for their correlation to angiographic findings. In a
separate analysis, these patients will also be compared with those in cohort 2 to
determine the non-invasive imaging differences between CAV1 and CAV0 patients.
3. Cohort 1 will be analyzed separately; comparing those with MIT <0.5mm to those with MIT
> 0.5mm for differences in CCT/CMR imaging and perfusion abnormalities. CCT will be
compared with CMR in both MIT subgroups. We anticipate to identify perfusion
abnormalities in the MIT > 0.5mm group and no perfusion abnormalities in the MIT <
0.5mm. Patients in cohort 1 will be followed long term for the development of
angiographically apparent CAV, adverse cardiac events, graft dysfunction, and death.
Results will be reported mainly in a descriptive manner, so that data will be summarized in
percentage, mean or median, where applicable.
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Observational Model: Cohort, Time Perspective: Prospective
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