Williams, Barbara

Percutaneous transluminal renal angioplasty and stenting (PTRS) for RVH may not revert the secondary cardiac dysfunction and remodeling. In experimental RVH, infusion of the tetrapeptide Bendavia (that inhibits mitochondrial permeability transition pore opening) during PTRS attenuated stenotic kidney inflammatory injury and improved its function. We hypothesized that adjunct Bendavia during PTRS would also attenuate cardiac remodeling after reversal of RVH. RVH was induced in 18 pigs, of which 6 were sham treated (RVH) and 12 underwent PTRS plus a 4h IV infusion of Bendavia (0.05 mg/kg) or vehicle (n=6, each); 6 normal pigs served as controls. Cardiac oxygenation and function were assessed 4 wks later by blood oxygen level‐dependent (BOLD)‐MRI and CT, and tissue studies performed. PTRS normalized blood pressure (Table). Systolic function was unchanged. Apoptotic activity (caspase‐3), hypoxia (BOLD‐R2*), inflammation (TNF‐α, IL‐6), and fibrosis (trichrome) remained elevated and diastolic function (E/A) impaired in PTRS+Vehicle, but all improved in PTRS+Bendavia (Figure). Thus, novel cardioprotective properties of Bendavia enhance cardiac recovery after reversal of experimental RVH, and may provide a novel therapeutic option.

Background Renovascular hypertension ( RVH ) impairs cardiac structure and left ventricular ( LV ) function, but whether mitochondrial injury is implicated in RVH ‐induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury. Methods and Results After 12 weeks of hypercholesterolemic ( HC )‐ RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial‐targeted peptide ( MTP ), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner‐membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector‐computed tomography and oxygenation by blood‐oxygen‐level–dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic‐reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert‐butyl hydroperoxide ( tBHP ) untreated or treated with MTP . Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin‐sensitive sarcoplasmic reticulum Ca 2+ ‐ ATP ase activity that declined in HC ‐ RVH normalized in MTP ‐treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP ‐treated pigs. In tBHP ‐treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics. Conclusions Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC ‐ RVH , suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy.