Cardiac Mitochondrial Function After Heart Transplantation

Background

The prognosis after heart transplantation (HTx) has improved considerably since the first HTx was performed in 1967. Studies from our group have shown both left and right ventricular function is affected immediately after heart transplantation, but this seems to recover to some extent over the first year. This immediate effect on the graft organ following HTx is associated with tissue ischemia and reperfusion injury causing cellular energy depletion, mitochondrial failure and subsequent apoptosis. The condition may progress into full blown primary graft failure (PGF) with a need for mechanical cardiovascular support or inotropes which is seen in 3-30 % of HTx patients. The cardiac injury will consequently increase the risk of morbidity as well as mortality. In addition to acute PGF, a chronic rejection owing to coronary arterial vasculopathy (CAV) may develop. Hence, despite advances in peritransplantation treatment and immunosuppression, PGF and CAV remain the major heart related mortality causes following HTx and additional assessment and treatments are therefore needed.

Graft rejection is diagnosed, and the severity graded based on endomyocardial biopsies (EMB) taken percutaneously through the jugular or femoral veins. These biopsies are routinely performed at our institution to ensure prober immunosuppression following HTx.1 Acute cellular rejection (ACR) may occur in approximately 25% of the patients which is associated with PGF, CAV and later chronic rejection. However, mitochondrial function and integrity may prove to be a more sensitive marker of allograft rejection. In heart failure, mitochondria density changes while function and integrity is impaired linking the failing heart to energy deprivation. Animal studies demonstrate that deterioration in total mitochondrial function precedes histopathological changes during cardiac graft rejection following HTx. Therefore, assessment of mitochondrial function following HTx may allow for earlier detection of rejection and allograft dysfunction. This may be of particular importance as emerging treatments are targeting both energy substrate supply for adenosine-triphosphate (ATP) generation produced by the mitochondria as well as mitochondrial function in the failing heart. At our institution, we have established methods to evaluate mitochondrial function in myocardial tissue, and pilot studies have demonstrated feasibility with the use of EMB. In addition, by use of non-invasive 11C-acetate positron-emission tomography (PET), we can assess myocardial external energy efficiency (MEE) calculated by the ratio of myocardial external work (EW) and oxidative metabolism (MVO2). Thus, enabling quantification of coupling between mitochondrial energy production and mechanical work.

Despite the overt association between graft dysfunction/rejection and mitochondrial function, it remains unsettled whether mitochondrial content and function associate with PGF, ACR and CAV. Such findings may be of prognostic importance and even elucidate a new treatment target.

Hypotheses