Cardioprotection of ischaemic preconditioning is associated with inhibition of translocation of MLKL within the plasma membrane
June 19, 2018
Necroptosis, a form of cell loss involving the RIP1‐RIP3‐MLKL axis, has been identified in cardiac pathologies while its inhibition is cardioprotective. We investigated whether the improvement of heart function because of ischaemic preconditioning is associated with mitigation of necroptotic signaling, and these effects were compared with a pharmacological antinecroptotic approach targeting RIP1. Langendorff‐perfused rat hearts were subjected to ischaemic preconditioning with or without a RIP1 inhibitor (Nec‐1s). Necroptotic signaling and the assessment of oxidative damage and a putative involvement of CaMKII in this process were analysed in whole tissue and subcellular fractions. Ischaemic preconditioning, Nec‐1s and their combination improved postischaemic heart function recovery and reduced infarct size to a similar degree what was in line with the prevention of MLKL oligomerization and translocation to the membrane. On the other hand, membrane peroxidation and apoptosis were unchanged by either approach. Ischaemic preconditioning failed to ameliorate ischaemia–reperfusion‐induced increase in RIP1 and RIP3 while pSer229‐RIP3 levels were reduced only by Nec‐1s. In spite of the additive phosphorylation of CaMKII and PLN because of ditherapy, the postischaemic contractile force and relaxation was comparably improved in all the intervention groups while antiarrhythmic effects were observed in the ischaemic preconditioning group only. Necroptosis inhibition seems to be involved in cardioprotection of ischaemic preconditioning and is comparable but not intensified by an anti‐RIP1 agent. Changes in oxidative stress nor CaMKII signaling are unlikely to explain the beneficial effects.
Cardiovascular Magnetic Resonance in Acute ST-Segment-Elevation Myocardial Infarction: Recent Advances, Controversies, and Future Directions
April 30, 2018
Heerajnarain Bulluck , Derek J. Hausenloy
Although mortality after ST-segment elevation myocardial infarction (MI) is on the decline, the number of patients developing heart failure as a result of MI is on the rise. Apart from timely reperfusion by primary percutaneous coronary intervention, there is currently no established therapy for reducing MI size. Thus, new cardioprotective therapies are required to improve clinical outcomes after ST-segment–elevation MI. Cardiovascular magnetic resonance has emerged as an important imaging modality for assessing the efficacy of novel therapies for reducing MI size and preventing subsequent adverse left ventricular remodeling. The recent availability of multiparametric mapping cardiovascular magnetic resonance imaging has provided new insights into the pathophysiology underlying myocardial edema, microvascular obstruction, intramyocardial hemorrhage, and changes in the remote myocardial interstitial space after ST-segment–elevation MI. In this article, we provide an overview of the recent advances in cardiovascular magnetic resonance imaging in reperfused patients with ST-segment–elevation MI, discuss the controversies surrounding its use, and explore future applications of cardiovascular magnetic resonance in this setting.
Realizing the therapeutic potential of novel cardioprotective therapies: The EU-CARDIOPROTECTION COST Action – CA16225
April 1, 2018
The EU-CARDIOPROTECTION COST Action - CA16225 MC Members
Acute myocardial infarction (AMI) and the heart failure (HF) that often follows are the leading causes of death and disability in Europe and worldwide. As such, new treatment strategies are needed to protect the heart against acute ischemia/reperfusion injury (IRI) in order to preserve cardiac function and prevent adverse left ventricular remodeling and HF – a strategy termed “cardioprotection.” Despite intensive experimental and clinical research since the discovery of the remarkable cardioprotective effect of ischemic preconditioning more than 3 decades ago, there are currently no effective cardioprotective therapies in clinical practice. The challenge has been to successfully translate novel cardioprotective therapies discovered in experimental studies into the clinical setting for patient benefit.
This EU-CARDIOPROTECTION COST Action CA16225 will address this challenge by setting up a pan-European research network of leading experts in experimental and clinical cardioprotection, to jointly develop innovative strategies for translating novel cardioprotective therapies into the clinical setting. This will be achieved through 4 main research objectives, each linked to the activities of a Working Group (WG): (1) WG1 New Targets: to use innovative strategies to discover novel targets for cardioprotection, given that many of the established cardioprotective targets have so far failed; (2) WG2 Combination Therapy: to investigate the effects of using combination therapy directed to multiple targets as an innovative cardioprotective strategy, given that single-targeted approaches to cardioprotection have so far failed; (3) WG3 Confounders: to use more clinically relevant animal AMI/HF models for testing novel cardioprotective therapies which take into account the confounding effects of co-morbidities and co-medications, given that many of the failed clinical studies have been based on therapies developed using juvenile healthy animal models; and (4) WG4 Consortium: to set up a European network of research centers (called the European Cardioprotection Consortium (ECC)) for multi-center randomized placebo-controlled testing of novel cardioprotective therapies in small/large animal AMI/HF models, and in AMI/HF patients, in order to improve the rigor of pre-clinical and clinical testing of novel cardioprotective therapies. In summary, the overall objective of the EU-CARDIOPROTECTION COST Action CA16225 will be to improve the translation of novel cardioprotective therapies into the clinical setting for patient benefit.
Cardioprotection research must leave its comfort zone
May 2, 2018
The translation from mechanistic, more reductionist basic science research to clinical outcome studies is not a linear, rational process but fraught with many surprises such that the prediction of a clinically meaningful endpoint even from a robust preclinical endpoint is difficult.
Guidelines for experimental models of myocardial ischemia and infarction
April 9, 2018
Myocardial infarction is a prevalent major cardiovascular event that arises from myocardial ischemia with or without reperfusion, and basic and translational research is needed to better understand its underlying mechanisms and consequences for cardiac structure and function. Ischemia underlies a broad range of clinical scenarios ranging from angina to hibernation to permanent occlusion, and while reperfusion is mandatory for salvage from ischemic injury, reperfusion also inflicts injury on its own. In this consensus statement, we present recommendations for animal models of myocardial ischemia and infarction. With increasing awareness of the need for rigor and reproducibility in designing and performing scientific research to ensure validation of results, the goal of this review is to provide best practice information regarding myocardial ischemia-reperfusion and infarction models.