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Ranolazine in the prevention of anthracycline cardiotoxicity
Francesco Corradi1, Luca Paolini1, Raffaele De Caterina2
1Institute of Cardiology and Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, Italy.
Abstract:
Ranolazine is a selective inhibitor of the cardiomyocyte late inward sodium current, INaL, and features anti-ischemic, antiarrhythmic and ATP-sparing actions. Extensive laboratory data show that anthracyclines can induce the production of reactive oxygen species (ROS). Other laboratory data show that ROS can hyperactivate the cardiac isoform of calmodulin-dependent protein kinase II (CaMKII δ), in turn inducing a hyperactivation of the cardiac late sodium current (INaL) and a resulting cytosolic calcium overload. This, as a consequence of the related sodium overload, can induce a mitochondrial calcium depletion that, in turn, triggers a chronic vicious cycle characterized by mitochondrial H2O2 production (increased oxidative stress), and NAD(P)H and ATP depletion (energetic stress), both sustaining ROS production. We hypothesize that anthracyclines may induce both INaL hyperactivation and an oxidative/energetic vicious cycle in cardiomyocytes. These sustained oxidative and energetic stresses may induce low-level cardiomyocyte and cardiac stem cell death by various mechanisms, leading to heart failure in the presence of genetic factors, age, ischemic and arrhythmic events, harmful dietary behaviors, and concomitant diseases. By reducing INaL in a myocardium particularly vulnerable to apoptotic stress and ischemia ranolazine might thus exert cardioprotection interfering with the vicious cycle of anthracycline cardiotoxicity.
Insights
Ranolazine may protect the heart from anthracycline toxicity by inhibiting the late sodium current (INaL). This action could disrupt a vicious cycle of oxidative and energetic stress in cardiomyocytes, potentially preventing heart failure.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Anthracyclines can induce reactive oxygen species (ROS) production in cardiomyocytes.
- ROS can lead to hyperactivation of the cardiac late sodium current (INaL), causing calcium overload and mitochondrial dysfunction.
- This initiates a vicious cycle of oxidative and energetic stress, contributing to cardiomyocyte death and heart failure.
Purpose of the Study:
- To investigate the potential cardioprotective effects of ranolazine against anthracycline-induced cardiotoxicity.
- To explore the role of the late sodium current (INaL) in the mechanism of anthracycline cardiotoxicity.
- To determine if ranolazine can interfere with the oxidative and energetic vicious cycle induced by anthracyclines.
Main Methods:
- Laboratory data analysis on anthracycline effects on cardiomyocytes.
- Examination of reactive oxygen species (ROS) and their impact on cardiac ion currents and cellular energy.
- Hypothesizing the mechanism of anthracycline cardiotoxicity involving INaL and oxidative/energetic stress.
Main Results:
- Anthracyclines induce ROS, leading to INaL hyperactivation, calcium overload, and mitochondrial dysfunction.
- A vicious cycle of oxidative and energetic stress is established, promoting cardiomyocyte and cardiac stem cell death.
- Ranolazine, as an INaL inhibitor, is hypothesized to counteract this cycle and offer cardioprotection.
Conclusions:
- Anthracyclines may induce cardiotoxicity through INaL hyperactivation and a detrimental oxidative/energetic cycle.
- Ranolazine's ability to reduce INaL suggests a potential therapeutic role in mitigating anthracycline-induced heart failure.
- Targeting INaL may be a viable strategy for cardioprotection in vulnerable myocardium.
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