ESC Working Group Cellular Biology of the Heart: Position Paper: improving the preclinical assessment of novel cardioprotective therapies

Abstract

Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia–reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes.

Acute Myocardial Injury: A Perspective on Lethal Reperfusion Injury

“…Hundreds of interventions have been performed in experimental studies with a view to limit ischemic injury but to date, interventions intended to improve patient outcomes have been disappointing. This may be due to various factors including, among others, poorly designed pre-clinical studies prior to embarking on clinical trials, inadequate pharmacological studies, complexities of the human in vivo model, and inadequate design of clinical studies to test cell protection therapies [101][102][103][104]. A short summary of emerging treatments is provided here; however, we recommend the reader consult the wealth of scientific publications on this subject already available in the literature.…”

At the crossroads from bench to bedside: luteolin is a promising pharmacological agent against myocardial ischemia reperfusion injury

“…Over the past 3 decades, a number of pharmacological cardioprotection strategies were discovered in experimental studies (9). Researches involved conditioning mechanisms have revealed multiple receptors, pathways and end effectors, all of which can be pharmacologically stimulated, such as agents acting on cardiomyocyte receptors (adenosine, bradykinin, opioids, glucagon-like peptide 1, atrial natriuretic peptide, erythropoeitin, insulin), agents acting on intracellular signal transduction pathways (phosphodiesterase-5 inhibitors, glyceryl trinitrate or nitroglycerin, atorvastatin, delcasertib, nicorandil) and agents acting on the mitochondria (cyclosporine-A) (10)(11)(12)(13).…”

“…However, none has been translated into clinical practice with the exception of early reperfusion (14)(15)(16). The reasons for the failure to translate pharmacologic conditioning strategies of cardioprotective effects from the bench to bedside have been extensively discussed in the literatures (3,(8)(9)(10)(11)(14)(15)(16)(17)(18)(19). Some experts concluded that the causes of failure can be attributed to inadequacy animal IRI models used in the preclinical cardioprotection studies.…”

“…Some experts concluded that the causes of failure can be attributed to inadequacy animal IRI models used in the preclinical cardioprotection studies. Nonetheless, in the position paper which published in 2013 (3), the experts concluded that the failure was not be due to a shortage of potential cardioprotective strategies discovered in the pre-clinical experimental setting (14), but was be due to the inability to successfully translate these promising therapies into interventions that actually improved the outcomes in patients (3,(8)(9)(10)(11)(14)(15)(16)(17)(18)(19).…”

“…Lut was chosen as a tool to mimic pharmacologic conditioning because it is a multiple targets agent. The reason can be attributed to a number of factors: (I) Pharmacologic conditioning has different working sites (10)(11)(12)(13). In the commentary, Cokkinos (2) has also reviewed that Lut is effective on multi-signalling pathway (NF-κB, PI3K/Akt pathway).…”