The Human Explanted Heart Program: A translational bridge for cardiovascular medicine

Abstract

The progression of cardiovascular research is often impeded by the lack of reliable disease models that fully recapitulate the pathogenesis in humans. These limitations apply to both in vitro models such as cell-based cultures and in vivo animal models which invariably are limited to simulate the complexity of cardiovascular disease in humans. Implementing human heart tissue in cardiovascular research complements our research strategy using preclinical models. We established the Human Explanted Heart Program (HELP) which integrates clinical, tissue and molecular phenotyping thereby providing a comprehensive evaluation into human heart disease. Our collection and storage of biospecimens allow them to retain key pathogenic findings while providing novel insights into human heart failure. The use of human non-failing control explanted hearts provides a valuable comparison group for the diseased explanted hearts. Using HELP we have been able to create a tissue repository which have been used for genetic, molecular, cellular, and histological studies. This review describes the process of collection and use of explanted human heart specimens encompassing a spectrum of pediatric and adult heart diseases, while highlighting the role of these invaluable specimens in translational research. Furthermore, we highlight the efficient procurement and bio-preservation approaches ensuring analytical quality of heart specimens acquired in the context of heart donation and transplantation.

Keywords: Heart failure; Human explanted heart; Pediatric heart diseases; Tissue biobank; Translational research; Ventricular assist device.

Graphical abstract

Fig. 1

Schematic of the collection and dissection of the explanted heart tissue and dissection. A. Etiology of heart disease in explanted hearts and apical cores. Numbers represent total hearts collected within that group as of May 2020. Mixed etiology describes patients that fit into multiple categories, such as DCM with CAD; other etiology describes conditions that do not fall into these categories, for example chemotherapy-induced and restrictive cardiomyopathies. B. Visual representation of the non-ischemic explanted heart sample collection (left) and the resultant tissue samples for the ischemic group (right). C. The range of distinct sample sections collected for each explanted heart with the myocardium collected differently according to the infarct area. DCM: dilated cardiomyopathy; CAD: coronary artery disease; HCM: hypertrophic cardiomyopathy; TV: transplant vasculopathy; CHD: congenital heart defects; AC: arrhythmogenic cardiomyopathy; LAD: left anterior descending artery; LCX: left circumflex artery; RCA: right coronary artery; LCC/RCC/NCC: left/right/non-coronary cusp, EAT: epicardial adipose tissue; OCT: optimal cutting temperature-mounted; EM: electron microscope.

Fig. 2

Transplant listing criteria and the relation to the Human Explanted Heart Program (HELP). A. Conceptual diagram depicting the heart transplant listing eligibilities for both recipients (left) and donors (right), and the sources of failing and non-failing hearts for HELP biobank. Left: Flow chart illustrating the eligibility, detailed evaluations, and referral status for being listed as heart transplant candidates. Right: The inclusion criteria, specific assessments, and types of donor hearts are delineated. Note that transplantations were limited by the scarcity of matched ideal donor hearts, with the potential to improve by extending the clinical acceptance of donor hearts. HELP biobank: Our heart pools are composed of native failing hearts from transplant recipients, the apical core from patients receiving an LVAD, and non-failing (namely marginal, and unmatched ideal) hearts. B. Imbalanced heart donor-recipient matching in Canada. The HF population was divided into adult (blue lines) and pediatric (green lines) subpopulations; accordingly, the statistics recorded the annual numbers of patients needing heart transplants (round marker) and the ones got transplanted (square marker) from 2006 to 2018. C. Clinical potentials of expanded application of “marginal hearts”. Annual total numbers of HF patients (including adult and pediatrics) were collected at both national (dash lines) and provincial (solid lines) levels. The data from 2014 to 2018 demonstrated the advantageous outcomes in terms of increased heart transplant cases (red lines) and simultaneously reduced number of patients awaiting (brown lines) at the national level, while the heart transplant rate remained relatively stable in Alberta during the past five years. Statistics were obtained from the Canadian Organ Replacement Register affiliated with the Canadian Institute for Health Information [39,40]. CA: Canada; AB: Alberta.

Fig. 3

Adult human explanted heart gallery. A. Adult failing hearts with various types of cardiomyopathies including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM) and arrhythmogenic cardiomyopathy (AC). B. Other etiologies that led to end-stage HF including ischemic heart disease (IHD), valvular heart disease (VHD), congenital heart defects (CHD) and transplant vasculopathy. C. Unmatched ideal hearts, and marginal hearts were harvested into our non-failing control pool. Age and gender-matched selection was adopted while seeking the best reference group in our research. D. Apex during LVAD insertion and native failing heart following transplant were both procured. Scale bar = 1 cm.

Fig. 4

Pediatric human explanted heart gallery. A. The common types of cardiomyopathy contributing to pediatric HF such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM). B. Congenital heart diseases with a variety of etiologies, such as hypoplastic left heart syndrome (HLHS), transposition of great artery (TGA), Tetralogy of Fallot (TOF), and pulmonary atresia. Scale bar = 1 cm.

Fig. 5

Quality control practices to manage and maintain the HELP biobank, and experimental applications. A. A visual representation of the dissected pieces of explanted heart tissues on a metal plate full of ice. B. Representative pictures showing optimized biopreservation methods leading to appropriately prepared TFM sample (1), paraffin-embedded blocks were systematically color-coded based on the structures (2), buffers for isolating cardiac cells or fixing tissues for histological examination (3), and embedded myocardial samples for ultrastructural study using an electron microscope (4). C. Experimental applications on the heart samples such as immunofluorescent light microscopy and confocal microscopy. D. A capture of the cryogenic long-term storage facility for appropriate depositing of different tissue samples. E. Systems biology analysis using advanced multi-omics techniques. Tissue sampling and processing (1), transcriptome from cells and nuclei delineating whole cardiac cell profiles by UMAP (2), spatial visualization of cell types probed by RNAscope (3), distribution of specific cell population after subclustering analysis (4). Modified from Litvinukova et al. [37] and reproduced with permission from Nature.