Cardiac MRI - Approaches for New Diagnostic Noninvasive Tools for the Detection of Cardiac Allograft Rejection

Background Heart transplantation is a treatment for select patients with end-stage heart failure. Improvements in immunosuppressive therapies and patient management have increased the life expectancy of heart transplant patients. One-year survivals are 90% and 80%, with 65 % and 49% of pediatric and adult patients surviving 8 - 15 years after transplantation in Finland, respectively. Despite this success, rejection remains the "Achilles heel" of heart transplantation. The early detection of acute rejection and cardiac allograft vasculopathy (chronic rejection) are paramount to avoiding graft loss. Unlike in kidney and liver transplantation, there are no clinically validated biomarkers for detecting heart transplant rejection.

Biopsy and invasive coronary angiography are widely accepted as the gold standard for diagnosing acute graft rejection and chronic rejection (vasculopathy) in both pediatric and adult heart transplant recipients, respectively. However, biopsies are invasive, and they carry a significant risk of complication regarding that majority of endocardial biopsies are performed in asymptomatic patients. In addition, the histologic assessment of biopsies is often subjective. Due to the lack of consensus, biopsy protocols are center-specific and depend on the experience and personal preference of the transplant team. Helsinki pediatric transplant protocol can be considered as high-intensity biopsy center. At best, the routine surveillance biopsies can detect late episodes of moderate to severe rejection in children with an 8% - 10% annual incidence up to 11 years after transplantation. However, there is no correlation between the intensity of biopsies and the incidence of rejection or 4-year mortality in the pediatric population, suggesting the need for other monitoring practices for rejection.

Cardiac MRI. Advanced multimodality imaging techniques, such as cardiac magnetic resonance imaging (MRI), may provide a future alternative to the monitoring practices for children and adults following heart transplantation. This has the potential to decrease the frequency of biopsies and radiation, especially in low-risk patients. Cardiac MRI can assess myocardial changes over time after transplantation. In heart transplant patients, MRI facilitates the detection of acute and chronic rejection and allows monitoring of gradual adverse remodeling. Volumetric assessment of the ventricles can further independently predict hospitalizations and mortality. The most widely investigated MRI parameters for detecting acute rejection are the T2 (indicates myocardial edema) and T1 relaxation times (indicates extracellular volume fraction (ECV) and fibrosis). Further, the assessment of global left ventricular function, myocardial strain analysis as well as late gadolinium enhancement (LGE) have been used for detection of chronic myocardial changes. Except for LGE and ECV, all of them can be measured noninvasively without the need for gadolinium contrast.

Even biopsy results may fail to predict rejection. A retrospective study of adults found that T2 time of ≥56 ms had a 97% negative predictive value for detecting acute rejection grade > 2. Interestingly, up to 80% of patients with a simultaneous negative biopsy but prolonged T2 relaxation time developed acute rejection in the next 30 days. The study suggested that T2 time measurement may be equal, or even superior to biopsy. However, the use of T2 relaxation time early after transplantation is limited, as it may be elevated in the first 25 days after transplantation regardless of the rejection status.

Contrast-enhanced MRI with gadolinium may provide additional information to T2 and T1 relaxation times and further limit the need for biopsies. It can identify areas of myocardial inflammation, scarring, and diffuse fibrosis, as well as assess myocardial perfusion. The prevalence of late gadolinium enhancement increases with the severity of rejection, whereas early gadolinium enhancement reflects extracellular space expansion secondary to acute necrosis and edema. Both myocardial edema (identified on T2- weighted imaging) and early myocardial contrast enhancement distinguish patients with International Society for Heart and Lung Transplantation (ISHLT) grade 2R rejection from those with grades 1R and 0R. Further, it has been reported that late enhancement in serially assessed transplant patients is associated with major adverse cardiac events and mortality. A recent study in 20 pediatric heart transplant patients showed that MRI-derived fibrosis markers correlate with the severity of fibrosis on biopsy. Although replacement fibrosis is irreversible, other MRI measurements change over time. Therefore, serial imaging can provide insight not only into disease progression but also on the efficacy of treatment. This is particularly relevant in acute rejection where the evaluation of myocardial edema with T2 mapping and interstitial expansion or fibrosis (T1 mapping ) can be accomplished with and without the administration of contrast agents and could easily limit the number of biopsies.