Realizing the therapeutic potential of novel cardioprotective therapies: The EU-CARDIOPROTECTION COST Action – CA16225

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

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

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.

Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities

Acute myocardial infarction (AMI) and the heart failure that often follows, are major causes of death and disability worldwide. As such, new therapies are required to limit myocardial infarct (MI) size, prevent adverse left ventricular (LV) remodeling, and reduce the onset of heart failure following AMI. The inflammatory response to AMI, plays a critical role in determining MI size, and a persistent pro-inflammatory reaction can contribute to adverse post-MI LV remodeling, making inflammation an important therapeutic target for improving outcomes following AMI. In this article, we provide an overview of the multiple players (and their dynamic roles) involved in the complex inflammatory response to AMI and subsequent LV remodeling, and highlight future opportunities for targeting inflammation as a therapeutic strategy for limiting MI size, preventing adverse LV remodeling, and reducing heart failure in AMI patients.

STAT3 as a common signal of ischemic conditioning: a lesson on “rigor and reproducibility” in preclinical studies on cardioprotection.

Ischemic conditioning before (ischemic preconditioning, IPC) or after (ischemic postconditioning, POCO) sustained myocardial ischemia/reperfusion (I/R), induced locally or remotely from the heart (remote IPC, RIPC), reduces infarct size. However, none of the identified signaling steps of ischemic conditioning was robust across models and species to be successfully translated to humans. In prior separate studies in pigs, activation of signal transducer and activator of transcription 3 (STAT3) was causal for infarct size reduction by IPC, POCO, and RIPC but it remains unclear whether or not STAT3 is truly a common denominator of cardioprotective signaling. We therefore, now analyzed the phosphorylation of STAT3 and other signaling proteins in left ventricular biopsies from our prior studies on IPC, POCO and RIPC in one approach. We developed a strategy for the quantification of protein phosphorylation in multiple samples from many experiments on different gels/membranes by Western blot. Along with reduced infarct size, the ratio of STAT3tyr705 phosphorylation/total STAT3 protein at early reperfusion was significantly increased by IPC (IPC 2.0 ± 0.3 vs. I/R 1.2 ± 0.2 arbitrary units), but only trendwise by POCO and RIPC (1.3 ± 0.2; 1.4 ± 0.2 arbitrary units); storage time for IPC samples was shorter than for POCO and RIPC samples. No other signaling protein phosphorylation was associated with reduced infarct size. We confirmed STAT3 phosphorylation with IPC. For POCO and RIPC we could not reproduce the findings from our earlier more focused studies. At this point, we can not distinguish between lack of robustness of the biological signal and methodological issues of our retrospective approach.