Non-responsiveness to cardioprotection by ischaemic preconditioning in Ossabaw minipigs with genetic predisposition to, but without the phenotype of the metabolic syndrome

Abstract

The translation of successful preclinical and clinical proof-of-concept studies on cardioprotection to the benefit of patients with reperfused acute myocardial infarction has been difficult so far. This difficulty has been attributed to confounders which patients with myocardial infarction typically have but experimental animals usually not have. The metabolic syndrome is a typical confounder. We hypothesised that there may also be a genuine non-responsiveness to cardioprotection and used Ossabaw minipigs which have the genetic predisposition to develop a diet-induced metabolic syndrome, but before they had developed the diseased phenotype. Using a prospective study design, a reperfused acute myocardial infarction was induced in 62 lean Ossabaw minipigs by 60 min coronary occlusion and 180 min reperfusion. Ischaemic preconditioning by 3 cycles of 5 min coronary occlusion and 10 min reperfusion was used as cardioprotective intervention. Ossabaw minipigs were stratified for their single nucleotide polymorphism as homozygous for valine (V/V) or isoleucine (I/I)) in the γ-subunit of adenosine monophosphate-activated protein kinase. Endpoints were infarct size and area of no-reflow. Infarct size (V/V: 54 ± 8, I/I: 54 ± 13% of area at risk, respectively) was not reduced by ischaemic preconditioning (V/V: 55 ± 11, I/I: 46 ± 11%) nor was the area of no-reflow (V/V: 57 ± 18, I/I: 49 ± 21 vs. V/V: 57 ± 21, I/I: 47 ± 21% of infarct size). Bioinformatic comparison of the Ossabaw genome to that of Sus scrofa and Göttingen minipigs identified differences in clusters of genes encoding mitochondrial and inflammatory proteins, including the janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway. The phosphorylation of STAT3 at early reperfusion was not increased by ischaemic preconditioning, different from the established STAT3 activation by cardioprotective interventions in other pig strains. Ossabaw pigs have not only the genetic predisposition to develop a metabolic syndrome but also are not amenable to cardioprotection by ischaemic preconditioning.

Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy

“…injections. One explanation may lie in the distinct genetic backgrounds of the utilized strains, as several studies have consistently demonstrated that lineage-specific effects determine the susceptibility of experimental animal models to cardiotoxicity as well as cardioprotection [ 3 , 22 , 25 , 26 ]. Nonetheless, both acute models, utilizing a single high dose, and chronic models, employing repetitive injections of small doses, have been widely used to study AICM in mice [ 44 ].…”

Cardioprotection and its Translation: A Need for New Paradigms? Or for New Pragmatism? An Opinionated Retro- and Perspective

“…Preparations, models and protocols which did not result in infarct size reduction were discarded and most often not reported. Only recently, with the recognition of the translational gap, have studies in rats 73,74 and pigs 75,76 reported failure of infarct size reduction by ischaemic conditioning. 77 Primordial non-responsiveness to cardioprotection by a given intervention, which is possibly determined by the genome, has been neglected so far and may account for some of the translational gap.…”

Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning

“…A recent study in Ossabaw minipigs which are prone to develop a full metabolic syndrome, including insulin resistance with progression to type 2 diabetes, hyperlipidemia, obesity, and hypertension with the subsequent development of coronary atherosclerosis and occasional spontaneous myocardial infarction, demonstrated loss of protection by ischemic PreC in these pigs even before they had developed the diseased phenotype; the loss of protection was associated with lack of activation of STAT3 and a primordial genetic difference in mitochondrial function and STAT signaling from other pig strains. Thus, lack of cardioprotection can even become manifest before a metabolic syndrome has developed ( Kleinbongard et al, 2022 ).…”