Hidden Cardiotoxicity of Rofecoxib Can be Revealed in Experimental Models of Ischemia/Reperfusion

Cardiac adverse effects are among the leading causes of the discontinuation of clinical trials and the withdrawal of drugs from the market. The novel concept of ‘hidden cardiotoxicity’ is defined as cardiotoxicity of a drug that manifests in the diseased (e.g., ischemic/reperfused), but not in the healthy heart or as a drug-induced deterioration of cardiac stress adaptation (e.g., ischemic conditioning). Here, we aimed to test if the cardiotoxicity of a selective COX-2 inhibitor rofecoxib that was revealed during its clinical use, i.e., increased occurrence of proarrhythmic and thrombotic events, could have been revealed in early phases of drug development by using preclinical models of ischemia/reperfusion (I/R) injury. Rats that were treated with rofecoxib or vehicle for four weeks were subjected to 30 min. coronary artery occlusion and 120 min. reperfusion with or without cardioprotection that is induced by ischemic preconditioning (IPC). Rofecoxib increased overall the arrhythmias including ventricular fibrillation (VF) during I/R. The proarrhythmic effect of rofecoxib during I/R was not observed in the IPC group. Rofecoxib prolonged the action potential duration (APD) in isolated papillary muscles, which was not seen in the simulated IPC group. Interestingly, while showing hidden cardiotoxicity manifested as a proarrhythmic effect during I/R, rofecoxib decreased the infarct size and increased the survival of adult rat cardiac myocytes that were subjected to simulated I/R injury. This is the first demonstration that rofecoxib increased acute mortality due to its proarrhythmic effect via increased APD during I/R. Rofecoxib did not interfere with the cardiprotective effect of IPC; moreover, IPC was able to protect against rofecoxib-induced hidden cardiotoxicity. These results show that cardiac safety testing with simple preclinical models of I/R injury uncovers hidden cardiotoxicity of rofecoxib and might reveal the hidden cardiotoxicity of other drugs.

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Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.280.5.h2313 ◽

2001 ◽

Vol 280 (5) ◽

pp. H2313-H2320 ◽

Cited By ~ 221

Author(s):

Zhongyi Chen ◽

Chu Chang Chua ◽

Ye-Shih Ho ◽

Ronald C. Hamdy ◽

Balvin H. L. Chua

Keyword(s):

Coronary Artery ◽

Lactate Dehydrogenase ◽

Transgenic Mice ◽

Ischemia Reperfusion ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Fragmentation Pattern ◽

Area At Risk ◽

Antiapoptotic Protein

To test whether the antiapoptotic protein Bcl-2 prevents apoptosis and injury of cardiomyocytes after ischemia-reperfusion (I/R), we generated a line of transgenic mice that carried a human Bcl-2 transgene under the control of a mouse α-myosin heavy chain promoter. High levels of human Bcl-2 transcripts and 26-kDa Bcl-2 protein were expressed in the hearts of transgenic mice. Functional recovery of the transgenic hearts significantly improved when they were perfused as Langendorff preparations. This protection was accompanied by a threefold decrease in lactate dehydrogenase (LDH) released from the transgenic hearts. The transgenic mice were subjected to 50 min of ligation of the left descending anterior coronary artery followed by reperfusion. The infarct sizes, expressed as a percentage of the area at risk, were significantly smaller in the transgenic mice than in the nontransgenic mice (36.6 ± 5 vs 69.9 ± 7.3%, respectively). In hearts subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion, Bcl-2 transgenic hearts had significantly fewer terminal deoxynucleodidyl-transferase nick-end labeling-positive or in situ oligo ligation-positive myocytes and a less prominent DNA fragmentation pattern. Our results demonstrate that overexpression of Bcl-2 renders the heart more resistant to apoptosis and I/R injury.

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Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0412 ◽

2020 ◽

Author(s):

Richard S Varga ◽

Tibor Hornyik ◽

Zoltán Husti ◽

Zsófia Kohajda ◽

Gábor Krajsovszky ◽

...

Keyword(s):

Torsades De Pointes ◽

Coronary Artery Occlusion ◽

Canine Model ◽

Artery Occlusion ◽

Class I ◽

Class Iii ◽

Drug Induced ◽

Pharmacological Management ◽

Repolarization Reserve ◽

Electrophysiological Effects

Cardiovascular diseases are the leading causes of mortality. Sudden cardiac death is most commonly caused by ventricular fibrillation (VF). Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and heart failure. Pharmacological management of VF and AF remains suboptimal due to limited efficacy of antiarrhythmic drugs and their ventricular proarrhythmic adverse effects. In this study, the antiarrhythmic and cardiac cellular electrophysiological effects of SZV-270, a novel compound, were investigated in rabbit and canine models. SZV-270 significantly reduced the incidence of VF in rabbits subjected to coronary artery occlusion/reperfusion, reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged frequency corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations and blocked IKr in isolated cardiomyocytes (Class III effects), reduced maximum rate of depolarization (Vmax) at cycle lengths smaller than 1000 ms in ventricular preparations (Class I/B effect). Importantly, SZV-270 did not provoke Torsades de Pointes arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. In conclusion, SZV-270 with its combined Class I/B and III effects can prevent re-entry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes.

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The role of reactive oxygen species in the infarct-limiting effect of hypoxic preconditioning

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2021-20-2-87-91 ◽

2021 ◽

Vol 20 (2) ◽

pp. 87-91

Author(s):

A. S. Sementsov ◽

N. V. Naryzhnaya ◽

M. A. Sirotina ◽

L. N. Maslov

Keyword(s):

Reactive Oxygen Species ◽

Coronary Artery ◽

Ischemia Reperfusion ◽

Reactive Oxygen ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Hypoxic Preconditioning ◽

Male Rats ◽

Oxygen Species ◽

Infarct Size Reduction

Introduction. Increased resistance of the heart to ischemia/reperfusion (I/R) is an urgent aim of physiology, pharmacology, and cardiac surgery, since I/R injury of the heart is often the cause of cardiogenic shock and subsequent death of patients in the postoperative period. Materials and methods. The study was carried out in male rats which were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). Before coronary occlusion, early hypoxic preconditioning (HP) was modeled. The rats were subjected to six sessions of hypoxia (8 % O2, 10 min) and reoxygenation (21 % O2, 10 min) 30 min before coronary artery occlusion. The rats were injected with the following drugs: 1,3-dimethylthiourea (DMTM), 2-mercaptopropionyl glycine (2-MPG), deferoxamine. Results. It was found that HP contributes to infarct size reduction by 30 %. Preliminary administration of DMTM, 2-MPG, deferoxamine eliminated the infarct-reducing effect of HP. Conclisuon. The obtained data indicate that reactive oxygen species are involved in the cardioprotective effect of HP.

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Abstract 13764: Chronic Electronic Cigarette Vapor Exposure Leads to Impaired Cardiac Function in Experimental Rat Myocardial Ischemia/reperfusion Model

Circulation ◽

10.1161/circ.142.suppl_3.13764 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Wangde Dai ◽

Jianru Shi ◽

Juan Carreno ◽

Lifu Zhao ◽

Michael T Kleinman ◽

...

Keyword(s):

Coronary Artery ◽

Cardiac Function ◽

Wall Thickness ◽

Ischemia Reperfusion ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Risk Zone ◽

Arterial Resistance ◽

No Reflow ◽

Impaired Cardiac Function

Background: We investigated the effects of long-term electronic cigarettes with nicotine (eC) vaping on cardiac function and structure in rats subjected to myocardial infarction (MI). Methods: After 8 weeks of exposure to either pure air (n=20) or eC (n=20), rats were anesthetized, and were subjected to 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. Cardiac function was assessed by echocardiogram and pressure measurements of the aorta and left ventricle (LV). Cardiac output (CO) was measured using a thermodilution catheter. At 3 hours of reperfusion, ischemic risk zone, no-reflow and infarct areas were determined. Results: Prior to coronary artery occlusion, chronic eC exposure was associated with a lower CO (45 ± 2 ml/min ) compared to air (55 ± 4 ml/min; p<0.05)) and a decrease in +dP/dt (5226 ± 294 mmHg/s versus 6062 ± 271 mmHg/s; p=0.05). After 30 minutes of coronary occlusion and 2.5 hours of reperfusion, CO and LV + dp/dt fell in both groups, but remained significantly lower in eC compared to the pure air group (Table). LV systolic and diastolic dimensions were significantly smaller in the E-Cig group compared to the air group. Systolic and diastolic anterior LV wall thickness were significantly thicker in the eC group after reperfusion. The ischemic risk size was comparable between the 2 groups. MI size was 48.8 ± 4.8% of the ischemic risk zone in the air group and 45.4 ± 4.4 % in the eC group (p=0.603). The area of no reflow was 26.7 ± 4.0% of the ischemic risk zone in the air group and 21.1 ± 3.5% in the E-C group (p=0.298). Chronic eC exposure did not change heart rate and blood pressure, but the significantly increased the systemic arterial resistance. Conclusions: Chronic exposure to eC significantly impaired cardiac function in rats prior to and during ischemia/reperfusion, increased arterial resistance, but did not increase infarct size or no-reflow zone. Increased LV wall thickness of the risk zone suggested that eC may have increased edema.

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Metoprolol blunts the time-dependent progression of infarct size

Basic Research in Cardiology ◽

10.1007/s00395-020-0812-4 ◽

2020 ◽

Vol 115 (5) ◽

Cited By ~ 3

Author(s):

Manuel Lobo-Gonzalez ◽

Carlos Galán-Arriola ◽

Xavier Rossello ◽

Maribel González‐Del‐Hoyo ◽

Jean Paul Vilchez ◽

...

Keyword(s):

Infarct Size ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Coronary Artery Occlusion ◽

Primary Angioplasty ◽

Primary Outcome Measure ◽

Artery Occlusion ◽

Area At Risk ◽

Perfusion Computed Tomography ◽

Myocardial Ischemia Reperfusion

Abstract Early metoprolol administration protects against myocardial ischemia–reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.

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Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00971.2003 ◽

2004 ◽

Vol 286 (5) ◽

pp. H1649-H1653 ◽

Cited By ~ 136

Author(s):

Yiru Guo ◽

Adam B. Stein ◽

Wen-Jian Wu ◽

Wei Tan ◽

Xiaoping Zhu ◽

...

Keyword(s):

At Risk ◽

Infarct Size ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Effective Means ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Water Soluble ◽

Arterial Blood

Although carbon monoxide (CO) has traditionally been viewed as a toxic gas, increasing evidence suggests that it plays an important homeostatic and cytoprotective role. Its therapeutic use, however, is limited by the side effects associated with CO inhalation. Recently, transition metal carbonyls have been shown to be a safe and effective means of transporting and releasing CO groups in vivo. The goal of the present study was to test whether a water-soluble CO-releasing molecule, tricarbonylchloro(glycinato) ruthenium (II) (CORM-3), reduces infarct size in vivo when given in a clinically relevant manner, i.e., at the time of reperfusion. Mice were subjected to a 30-min coronary artery occlusion followed by 24 h of reperfusion and were given either CORM-3 (3.54 mg/kg as a 60-min intravenous infusion starting 5 min before reperfusion) or equivalent doses of inactive CORM-3, which does not release CO. CORM-3 had no effect on arterial blood pressure or heart rate. The region at risk did not differ in control and treated mice (44.5 ± 3.5% vs. 36.5 ± 1.6% of the left ventricle, respectively). However, infarct size was significantly smaller in treated mice [25.8 ± 4.9% of the region at risk ( n = 13) vs. 47.7 ± 3.8% ( n = 14), P < 0.05]. CORM-3 did not increase carboxyhemoglobin levels in the blood. These results suggest that a novel class of drugs, CO-releasing molecules, can be useful to limit myocardial ischemia-reperfusion injury in vivo.

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Comparative Effects of Verapamil, Nicardipine, and Nitroglycerin on Myocardial Ischemia/Reperfusion Injury

Anesthesiology Research and Practice ◽

10.1155/2011/521084 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Hitoshi Yui ◽

Uno Imaizumi ◽

Hisashi Beppu ◽

Mitsuhiro Ito ◽

Munetaka Furuya ◽

...

Keyword(s):

Infarct Size ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Rabbit Model ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Control Group ◽

Area At Risk ◽

Group A

The aim of this experiment was to establish whether verapamil, nicardipine, and nitroglycerin have (1) infarct size-limiting effects and (2) antiarrhythmic effects inin vivorabbit hearts during ischemia/reperfusion. Rabbits received regional ischemia by 30 min of left anterior descending coronary artery occlusion followed by 3 hours of reperfusion under ketamine and xylazine anesthesia. The animals were randomly assigned to the following 4 treatment groups: a control group, a verapamil group, a nicardipine group, and a nitroglycerin group. A continuous infusion of verapamil, nicardipine, or nitroglycerin was initiated 5 min prior to ischemia. Infarct size/area at risk decreased in verapamil, and nitroglycerin. The incidence of ischemia-induced arrhythmia decreased in nicardipine, verapamil and nitroglycerin. The incidence of reperfusion-induced arrhythmias decreased in verapamil and nitroglycerin. From the present experimental results, verapamil and nitroglycerin rather than nicardipine did afford significant protection to the heart subjected to ischemia and reperfusion in a rabbit model.

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Exercise-induced activation of cardiac sympathetic nerve triggers cardioprotection via redox-sensitive activation of eNOS and upregulation of iNOS

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01102.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. H2051-H2059 ◽

Cited By ~ 40

Author(s):

Yuzo Akita ◽

Hajime Otani ◽

Seiji Matsuhisa ◽

Shiori Kyoi ◽

Chiharu Enoki ◽

...

Keyword(s):

Oxidative Stress ◽

Coronary Artery ◽

Sympathetic Nerve ◽

Ischemia Reperfusion ◽

Sympathetic Nerves ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Cardiac Sympathetic Nerve ◽

Exercise Induced ◽

Oxide Synthase

We investigated the mechanism of exercise-induced late cardioprotection against ischemia-reperfusion (I/R) injury. C57BL/6 mice received treadmill exercise (60 min/day) for 7 days at a work rate of 60–70% maximal oxygen uptake. Exercise transiently increased oxidative stress and activated endothelial isoform of nitric oxide synthase (eNOS) during exercise and increased expression of inducible isoform of NOS (iNOS) in the heart after 7 days of exercise. The mice were subjected to regional ischemia by 30 min of occlusion of the left coronary artery, followed by 2 h of reperfusion. Infarct size was significantly smaller in the exercised mice. Ablation of cardiac sympathetic nerve by topical application of phenol abolished oxidative stress, activation of eNOS, upregulation of iNOS, and cardioprotection mediated by exercise. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine during exercise also inhibited activation of eNOS, upregulation of iNOS, and cardioprotection. In eNOS−/− mice, exercise-induced oxidative stress was conserved, but upregulation of iNOS and cardioprotection was lost. Exercise did not confer cardioprotection when the iNOS selective inhibitor 1400W was administered just before coronary artery occlusion or when iNOS−/− mice were employed. These results suggest that exercise stimulates cardiac sympathetic nerves that provoke redox-sensitive activation of eNOS, leading to upregulation of iNOS, which acts as a mediator of late cardioprotection against I/R injury.

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Differential effects of postconditioning on myocardial stunning and infarction: a study in conscious dogs and anesthetized rabbits

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00124.2006 ◽

2006 ◽

Vol 291 (3) ◽

pp. H1345-H1350 ◽

Cited By ~ 35

Author(s):

Nicolas Couvreur ◽

Laurence Lucats ◽

Renaud Tissier ◽

Alain Bize ◽

Alain Berdeaux ◽

...

Keyword(s):

Coronary Artery ◽

Infarct Size ◽

Myocardial Stunning ◽

Ischemia Reperfusion ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Left Ventricular ◽

Segment Length ◽

Wall Thickening ◽

Area At Risk

Postconditioning, i.e., brief intermittent episodes of myocardial ischemia-reperfusion performed at the onset of reperfusion, reduces infarct size after prolonged ischemia. Our goal was to determine whether postconditioning is protective against myocardial stunning. Accordingly, conscious chronically instrumented dogs (sonomicrometry, coronary balloon occluder) were subjected to a control sequence (10 min coronary artery occlusion, CAO, followed by coronary artery reperfusion, CAR) and a week apart to postconditioning with four cycles of brief CAR and CAO performed at completion of the 10 min CAO. Three postconditioning protocols were investigated, i.e., 15 s CAR/15 s CAO ( n = 5), 30 s CAR/30 s CAO ( n = 7), and 1 min CAR/1 min CAO ( n = 6). Left ventricular wall thickening was abolished during CAO and similarly reduced during subsequent stunning in control and postconditioning sequences (e.g., at 1 h CAR, 33 ± 4 vs. 34 ± 4%, 30 ± 4 vs. 30 ± 4%, and 33 ± 4 vs. 32 ± 4% for 15 s postconditioning, 30 s postconditioning, and 1 min postconditioning vs. corresponding control, respectively). We confirmed this result in anesthetized rabbits by demonstrating that shortening of left ventricular segment length was similarly depressed after 10 min CAO in control and postconditioning sequences (4 cycles of 30 s CAR/30 s CAO). In additional rabbits, the same postconditioning protocol significantly reduced infarct size after 30 min CAO and 3 h CAR (39 ± 7%, n = 6 vs. 56 ± 4%, n = 7 of the area at risk in postconditioning vs. control, respectively). Thus, contrasting to its beneficial effects on myocardial infarction, postconditioning does not protect against myocardial stunning in dogs and rabbits. Conversely, additional episodes of ischemia-reperfusion with postconditioning do not worsen myocardial stunning.

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The Diabetic Heart: Too Sweet for Its Own Good?

Cardiology Research and Practice ◽

10.1155/2012/845698 ◽

2012 ◽

Vol 2012 ◽

pp. 1-15 ◽

Cited By ~ 37

Author(s):

Hannah J. Whittington ◽

Girish G. Babu ◽

Mihaela M. Mocanu ◽

Derek M. Yellon ◽

Derek J. Hausenloy

Keyword(s):

Diabetes Mellitus ◽

Animal Model ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Experimental Models ◽

Diabetic Heart ◽

Ischemia And Reperfusion ◽

Ischemic Conditioning ◽

Animal Data ◽

Patients With Diabetes

Diabetes mellitus is a major risk factor for ischemic heart disease (IHD). Patients with diabetes and IHD experience worse clinical outcomes, suggesting that the diabetic heart may be more susceptible to ischemia-reperfusion injury (IRI). In contrast, the animal data suggests that the diabetic heart may be either more, equally, or even less susceptible to IRI. The conflicting animal data may be due to the choice of diabetic and/or IRI animal model. Ischemic conditioning, a phenomenon in which the heart is protected against IRI by one or more brief nonlethal periods of ischemia and reperfusion, may provide a novel cardioprotective strategy for the diabetic heart. Whether the diabetic heart is amenable to ischemic conditioning remains to be determined using relevant animal models of IRI and/or diabetes. In this paper, we review the limitations of the current experimental models used to investigate IRI and cardioprotection in the diabetic heart.

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