Replacing the Endomyocardial Biopsy: Easier Said Than Done

Allograft rejection remains a fundamental challenge for all solid organ transplant recipients and programs. The development of the percutaneous endomyocardial biopsy (EMB) technique and later the standardization of allograft rejection by the International Society for Heart and Lung Transplantation (ISHLT)1 were major milestones. However, this gold standard is far from pure with discrepancies among pathologists, especially regarding intermediate severities of rejection being well documented.2,3 In addition, EMB is not without risk as well as expense to the various departments involved and ultimately the patient and healthcare payors. Noninvasive replacements for the EMB have been sought for >40 y with the recent advent of commercial tests such as gene expression profiling (Allomap, CareDx)4 and donor-derived cell-free DNA5 (CareDx, and Prospera). Both techniques have excellent negative predictive value for the presence of ISHLT grade 2R or worse rejection, relatively low positive predictive value, as well as significant expense and the requirement for central laboratory analysis. Alternative approaches including cardiac magnetic resonance imaging have also been gaining increasing interest, although access will likely be restricted to specialized centers and cost remains a concern, as well as availability with higher patient demand.6 There is clearly a need to consider alternative approaches that have lower cost and that may be available in local laboratories or with rapid results by commercial high-volume operations. In this issue of Transplantation, Pérez-Carrillo et al7 from the Health Research Institute Hospital at La Fe, in Valencia, Spain, report pilot data that give us a glimpse into potential future approaches. The group examined blood specimens with corresponding pathologic results including 40 paired samples from 24 patients focusing on gene expression profiling and specifically differential regulation of genes involved in the cardiac sarcomere. The authors noted that 17 of 59 sarcomeric genes were differentially expressed according to levels of mRNA, most notably alpha cardiac actin (ACTC-1), although there was dysregulation of other sarcomeric gene components. The authors then examined the protein expression corresponding to the mRNA findings in a set of 80 samples from 30 subsequent transplant patients. This was done with a commercially available sandwich ELISA. The group noted that elevated ACTC-1 protein levels correlated with ISHLT 2R rejection similarly to the commercially available gene expression profiling test Allomap (receiver operator curve area under the curve 0.702). However, this test was not predictive of more mild forms of rejection (ISHLT grade 1R). They concluded that ACTC-1 levels can be quantified by inexpensive, widely available techniques that may have broad applicability. What does the future look like for noninvasive surveillance of cardiac cellular rejection? Unfortunately, although the results of Pérez-Carrillo et al7 are interesting, they represent a small set of pilot data. The CareDx Allomap test and newer developments, such as donor-derived cell-free DNA have been studied more extensively with a variety of heart transplant patients and yet are far from the worldwide standard of care.4,5,8 Some of this is due to the cost and availability of these testing modalities that are not universal outside of the United States. However, there is tremendous clinical inertia as well, which maintains the usual status quo with EMB and hemodynamic assessment as fundamental aspects of surveillance especially in the first year following heart transplantation. Antibody-mediated rejection remains another issue that is less predictable and not clearly evaluated by noninvasive testing. Although there is a pathologic formulation to standardize biopsy grading, there is controversy over the treatment of asymptomatic mild cases or the management of donor-specific alloantibodies in the absence of tissue damage.9 Underlying all these noninvasive techniques is the lack of a gold standard for truth regarding cardiac allograft rejection. EMB may miss an area of rejection, ultimately being guided by fluoroscopy or echocardiography, but neither guides the operator to pathologic zones. Pathologists may disagree on interpretation of results, even among experts.2 Many cardiac biopsies are done on a protocolized basis as opposed to those accompanied by clinical signs of organ compromise, and therefore the incidental finding of mild asymptomatic rejection represents a therapeutic challenge. The end result is that many patients may be over immunosuppressed, with the benefit of the doubt principle and fear of fatal rejection leading to higher levels of immunosuppression. This may result in increased opportunistic infections such as cytomegalovirus, or chronic morbidities, such as those related to chronic steroids or calcineurin antagonist use. As a community, heart transplant clinicians tend to be reluctant to change practice, and unlike renal transplantation, failure of the heart is often rapidly fatal with few good options in immunosuppressed patients. Trials in heart transplantation are relatively small and increasingly infrequent with a dearth of interest in drug development in preference to more promising areas such as rheumatology and dermatology.10 One of the last major heart transplant trials, the Invasive Monitoring Attenuation Through Gene Expression trial was published more than a decade ago, and yet EMB remains a hallmark of the first post transplant year for many patients today.4,8 To make progress in the future will require several key steps: Willingness to trust noninvasive surveillance modalities in the context of a trial to assess the utility of a biopsy-based versus blood-based surveillance strategy early post transplant (14–90 d). Realignment of financial incentives that currently favor procedure-based surveillance performed by heart failure clinicians. Recognition that the target of surveillance varies over time with acute cellular and antibody-mediated rejection most important in the first 6–12 mo and the hazard of chronic underimmunosuppression more significant long term. This will require potentially different biomarkers for phases of post transplant care. Discovery of a biomarker that correlates with cardiac allograft vasculopathy (preferably at a time period that allows interventions to be tested to attenuate its development). Much has been accomplished in the first 50 y of clinical heart transplantation. Hopefully, the goals stated above will be addressed in the next decade, and widespread and robust noninvasive surveillance modalities will eventually be as commonplace as the bioptome used today for routine EMB. Until then, it will be easier to talk about post transplant life without routine biopsy than to actually live it.