Introduction: Orthotopic cardiac xenotransplantation has seen substantial advancements in the last years. In preclinical experiments, donor organ overgrowth has been a major hurdle, resulting in loss of the transplant. Various intrinsic (e.g., species-specific organ growth) and extrinsic factors (e.g., interspecies differences of hemodynamic parameters and hormone levels) have been identified as causes. A better understanding of the pathogenesis and pathophysiology of cardiac overgrowth after xenotransplantation is necessary before clinical application.

Method: Hearts from genetically modified (GGTA1-KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n=3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n=9) was additionally treated with mTOR inhibitor, anti-hypertensive medication, and fast corticoid tapering. Left ventricular (LV) growth was assessed by echocardiography, and hemodynamic measurements were recorded by a wireless implant via probes attached to the apex of the LV and the ascending aorta. 

Results: Group I hearts tripled their LV mass within 4 weeks (222±66% increase), caused by non-physiological LV wall enlargement; dynamic pressure gradients between LV and the aorta developed (up to 99.8mmHg). Additional signs of subvalvular left ventricular outflow tract (LVOT) obstruction (pulsus bisferiens, Brockenbrough-Braunwald-Morrow-Sign) were also seen. In group II, LV geometry was preserved during the first 3 months and pressure gradients were absent; afterwards, slow progression towards LV hypertrophy (167±4% LV mass increase after 6 months) and the development of LVOT pressure gradients (up to 158.3mmHg) similar to group I were observed.

Conclusion: After orthotopic xenotransplantation, untreated porcine hearts show signs of dynamic LVOT obstruction, resembling hypertrophic obstructive cardiomyopathy (HOCM) in humans. This xenogeneic form of LVOT obstruction (xHOCM), caused by a vicious cycle of species-specific organ growth and afterload-induced myocardial hypertrophy, leads to graft failure without growth inhibition. A growth inhibitory treatment with mTOR inhibitor, anti-hypertensive medication, and fast corticoid tapering can only delay development of xHOCM. With genetic modifications aiming to reduce donor organ sizes (e.g., growth hormone receptor-KO) or the selection of smaller pig species (e.g., Auckland Island pigs), xHOCM might be completely prevented.