Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo

Abstract

Clinical observations are highly inconsistent with the use of the antidiabetic rosiglitazone regarding its associated increased risk of myocardial infarction. This may be due to its hidden cardiotoxic properties that have only become evident during post-marketing studies. Therefore, we aimed to investigate the hidden cardiotoxicity of rosiglitazone in ischemia/reperfusion (I/R) injury models. Rats were treated orally with either 0.8 mg/kg/day rosiglitazone or vehicle for 28 days and subjected to I/R with or without cardioprotective ischemic preconditioning (IPC). Rosiglitazone did not affect mortality, arrhythmia score, or infarct size during I/R. However, rosiglitazone abolished the antiarrhythmic effects of IPC. To investigate the direct effect of rosiglitazone on cardiomyocytes, we utilized adult rat cardiomyocytes (ARCMs), AC16, and differentiated AC16 (diffAC16) human cardiac cell lines. These were subjected to simulated I/R in the presence of rosiglitazone. Rosiglitazone improved cell survival of ARCMs at 0.3 μM. At 0.1 and 0.3 μM, rosiglitazone improved cell survival of AC16s but not that of diffAC16s. This is the first demonstration that chronic administration of rosiglitazone does not result in major hidden cardiotoxic effects in myocardial I/R injury models. However, the inhibition of the antiarrhythmic effects of IPC may have some clinical relevance that needs to be further explored.

Droplet Digital PCR Is a Novel Screening Method Identifying Potential Cardiac G-Protein-Coupled Receptors as Candidate Pharmacological Targets in a Rat Model of Pressure-Overload-Induced Cardiac Dysfunction

“…To enable the identification of drugs that are possible candidates of drug repurposing for a novel indication in HF, we aimed to identify GPCRs that show significantly different expression in TAC vs. SHAM hearts, as GPCRs are the largest family of targets for already-approved drugs—agonists, antagonists or partial agonists—currently available on the market. Given the general need for increasing translational value and success of preclinical studies in the field of cardiology [ 29 , 30 , 31 , 32 , 33 ], we aimed to conduct a systematic screening of cardiac GPCRs with reduced risk of subjective bias. To this end, we first assessed the cardiac GPCR gene expression both by bulk RNA sequencing and ddPCR, and filtered only for those candidates that (i) were identified by both methods to be significantly differentially expressed in TAC vs. SHAM rat hearts, and (ii) show significant correlation in levels of gene expression measured by both methods.…”

Effects of Bempedoic Acid in Acute Myocardial Infarction in Rats: No Cardioprotection and No Hidden Cardiotoxicity

“…Previously, our group has shown that using preclinical models of I/R injury could be suitable to detect hidden cardiotoxic effects of drugs. In a rat model of myocardial I/R injury, 28 days of rofecoxib pretreatment was found to increase the mortality and irreversible ventricular fibrillations during cardiac ischemia [ 3 ]; thus, it showed hidden cardiotoxic effects according to our definition, while we have found that the PPAR-γ agonist antidiabetic drug, rosiglitazone, does not show major hidden cardiotoxic effects, but it interferes with the antiarrhythmic effect of ischemic preconditioning [ 23 ].…”

Cardioprotective efficacy of limb remote ischaemic preconditioning in rats: discrepancy between a meta-analysis and a three-centre in vivo study

“…the ISs (as proportions of AARs in %) and AARs (as proportions of total left ventricular areas in %), was measured with computer planimetry by independent and blinded investigators using InfarctSize software (version 2.4b, Pharmahungary Group, Szeged, Hungary) in the Budapest and Szeged study centres, or SigmaScan Pro 5 (Systat software, San Jose, CA) in the Amsterdam study centre, as described in previous publications of the workgroups. [27][28][29][30][31][32][33][34][35]…”