Remote Ischemic Preconditioning Ameliorates Anthracycline-induced Cardiotoxicity and Preserves Mitochondrial Integrity

Anthracyclines exert their cytotoxic effect via topoisomerase II inhibition and intercalation of DNA. The effective antitumor mechanism is nonselective and may have cardiotoxic consequences. Currently no effective therapies are able to prevent anthracycline-induced cardiotoxicity, so present treatments rely on conventional heart failure therapies. The mechanisms by which anthracyclines generate cardiotoxicity seem to converge on damage to mitochondria. Despite promising preclinical results, a number of interventions including antioxidants, iron chelators targeting mitochondrial processes have failed to demonstrate a clinical benefit.

In the presents study, the authors applied remote ischemic conditioning. i.e. the process whereby brief, reversible episodes of ischemia and reperfusion in one vascular bed (e.g. an arm) confers a global protection that renders remote tissues and organs resistant to injury. A central mechanism underlying the benefits of remote ischemic conditioning is mitochondrial protection. The authors used pigs to demonstrate that remote ischemic conditioning given before doxorubicin injections (0.45 mg/kg) at weeks 0, 2, 4, 6, and 8 blunted left ventricular ejection fraction depression up to 16 weeks after the first doxorubicin treatment compared to pigs receiving no pretreatment (41.5±9.1% vs 32.5±8.7%, p=0.04) as evaluated by cardiac magnetic resonance imaging. In a separate series of 10 pigs, transmission electron microscopy at week 6 showed fragmented mitochondria with severe morphological abnormalities and up-regulation of fission and autophagy proteins in doxorubicin treated pigs. These abnormalities were reduced in remote condition treated pig, which also had less severe myocardial interstitial fibrosis.

Several studies in small animal models have shown beneficial effects by remote conditioning against anthracycline induced cardiotoxity. This is the first study to document a beneficial effect in a large animal model by serial cardiac magnetic resonance evaluation. The findings are of importance along road to translate experimental findings into clinical usage. Remote ischemic conditioning also had consistent beneficial effects against ischemia reperfusion injury in experimental models of acute myocardial infarction and even in proof-of-concept clinical studies by documenting infarct size reduction. Due to low clinical event rates among uncomplicated acute myocardial infarction patients, translation into a clinical benefit remains challenging, so remote conditioning should probably be given to high-risk patients. Cancer patients undergoing anthracycline therapy may be patients with high risk of cardiotoxity and should be a target population. An advantage may be that anthracycline administration in cancer patient is a fully programmed event, unlike acute myocardial infarction, and it is thus possible to schedule remote ischemic preconditioning. Although the present studies have some limitations, e.g. the intracoronary route for doxorubicin injection used in the experimental study does not mimic the clinical scenario and is a highly aggressive model and the pigs studied were juvenile and free of comorbidity that may attenuate the effect of remote condition, the results are encouraging. We eagerly await the results of two ongoing proof-of-concept clinical studies investigating the effect of remote conditioning on anthracycline induced cardiotoxity (NCT02471885 and NCT03166813).