Protecting the Mitochondria in Cardiac Disease

Cardiac disease is a broad cluster of several diseases, which include coronary artery disease, valve disease, congenital heart disease, arrhythmia, and cardiomyopathy [...].

to different diseases [15,16]. As these sex differences are attributed to hormones, Kalkhoran and Kararigas [17] review the role of oestradiol (an oestrogen steroid hormone) in regulating mitochondrial dynamics in cardiovascular and nervous systems and position this hormone as a potential therapeutic target.
Over the past decade, several cardioprotective agents which can directly or indirectly prevent mitochondrial dysfunction have been identified. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that modulate myocardial lipid metabolism and energy homeostasis. Interestingly, the activation of PPARs has been shown to be cardioprotective in the setting of IR injury through the modulation of nonmetabolic pathways [18,19]. Extending our knowledge of their mode of action, Papatheodorou and colleagues [20] demonstrated that PPARβ/δ activation elevated antioxidant enzymes and aldehyde dehydrogenase-2 (ALDH2), which in turn decreased reactive oxygen species (ROS) production and 4-Hydroxynonenal (4-HNE) adducts, respectively. Consistent with being a metabolic modulator, PPARβ/δ activation also stimulated PGC-1α and elevated Krebs cycle enzymes, with the subsequent preservation of myocardial energetics that was associated with reduced infarct size and arrhythmias as well as improved cardiac recovery post-IR injury.
The opening of the mitochondrial permeability transition pore (mPTP) is widely recognised as the final step of IR injury due to the induction of mitochondrial swelling and cardiomyocyte death [21]. Targeting the mPTP has been challenging due to a limited understanding of its components, structure, regulation, and function. Interestingly, Lewis and colleagues [22] demonstrated that immature hearts are better protected against IR injury than adult hearts, and this was attributed to a reduced tendency for mPTP opening in the former. Further studies on why immature hearts display innate resistance towards IR injury may help to unravel novel targets that could potentially protect the adult heart from injury.
In the setting of pulmonary arterial hypertension (PAH), the leading cause of death is right ventricular failure (RVF). Since an increase in ROS has been implicated in the development of RV hypertrophy (RVH) and in the transition to RVF, Hirschhäuser and colleagues [23] investigated the role of the hydrogen peroxide-generating protein p66shc in disease pathogenesis. The genetic deletion of p66shc did not alter mitochondrial ROS production nor influence cardiac function in the setting of RV pressure overload, although an impairment in RV cardiomyocyte shortening was observed. Collectively, these findings imply that p66shc-derived ROS may not be a key mediator of RVH and RVF.
An ideal treatment for advanced HF is heart transplantation. However, during this procedure, the temporary reduction in oxygen supply dampens high-energy phosphate (HEP) reserves in cardiomyocytes and elicits cell death due to the ischaemic state. As such, Ahmed and colleagues [24] investigated whether pre-treated hearts with the immunosuppressant fingolimod (FTY720) could demonstrate better cardiac performance following transplantation. Interestingly, FTY720 pre-treatment was shown to improve hemodynamics, coronary blood flow, and HEP reserves in heterotopic transplanted hearts, with accompanying reductions in peroxynitrite levels and caspase activity, which may imply a decrease in cell death following IR.
In summary, this series of articles clearly illustrates that mitochondria mediate and prevent cardiac disease, and while mitoprotective agents have been shown to attenuate cardiac insults and improve contractile function in pre-clinical animal models, results from upcoming clinical trials (NCT03586414) will reveal whether these agents can be considered as therapeutic modalities for improving health outcomes in cardiac patients.

Conflicts of Interest:
The authors declare no conflict of interest.