Rationale The opening of the mitochondrial permeability transition pore (mPTP) is a critical determinant of ischaemia-reperfusion injury, and preventing its opening confers powerful cardioprotection in non-diseased myocardium. Whether this cardioprotective effect is present in the setting of hypertrophic cardiomyopathy (HCM) is unknown and is investigated in this study.
Methodology Local UCLH/UCL ethical committee approval had been granted for this study. Human adult ventricular cardiomyocytes were isolated from left ventricular septal tissue, harvested from consenting patients undergoing surgical myectomy for obstructive HCM. The cells were loaded with the fluorescent dye TMRM which localises to the mitochondria, generates oxidative stress within the mitochondria on confocal imaging, resulting in mPTP opening, as indicated by the collapse of the mitochondrial membrane potential. The time taken to induce the loss of mitochondrial membrane potential was used as a measure of mPTP opening sensitivity. Cells were randomised to the following: (1) DMSO 0.01% vehicle control (N=8/group); (2) cells pre-treated with ciclosporin-A (CsA)(0.2 μM) for 15 min (N=7/group); (3) cells pre-treated with atorvastatin (25 μM)(N=7/group).
Results In the control group, mPTP opening was induced after 188.7%±22.7 s of oxidative stress, providing evidence for a functional mPTP in the setting of HCM. Furthermore, pretreatment with the known mPTP inhibitor, CsA, and atorvastatin, delayed the onset of mPTP opening by 51%±10% (p<0.001) and 35%±7% (p<0.05), respectively.
Conclusions For the first time in diseased human ventricular myocytes, we have demonstrated that the mPTP is functional and that its opening can be inhibited by cardioprotective agents such as CsA and atorvastatin.
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