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The study of myocardial ischemia-reperfusion treatment through computational modelling

Wan Ab Naim WN, Mohamed Mokhtarudin MJ, Chan BT, Lim E, Ahmad Bakir A, Nik Mohamed NA

J Theor Biol, 2021 01 21;509:110527.
PMID: 33096094 DOI: 10.1016/j.jtbi.2020.110527

Reperfusion of the blood flow to ischemic myocardium is the standard treatment for patients suffering myocardial infarction. However, the reperfusion itself can also induce myocardial injury, in which the actual mechanism and its risk factors remain unclear. This work aims to study the mechanism of ischemia-reperfusion treatment using a three-dimensional (3D) oxygen diffusion model. An electrical model is then coupled to an oxygen model to identify the possible region of myocardial damage. Our findings show that the value of oxygen exceeds its optimum (>1.0) at the ischemic area during early reperfusion period. This complication was exacerbated in a longer ischemic period. While a longer reperfusion time causes a continuous excessive oxygen supply to the ischemic area throughout the reperfusion time. This work also suggests the use of less than 0.8 of initial oxygen concentration in the reperfusion treatment to prevent undesired upsurge at the early reperfusion period and further myocardial injury. We also found the region at risk for myocardial injury is confined in the ischemic vicinity revealed by its electrical conductivity impairment. Although there is a risk that reperfusion leads to myocardial injury for excessive oxygen accumulation, the reperfusion treatment is helpful in reducing the infarct size.

Matched MeSH terms: Myocardial Reperfusion Injury*
Current Updates on Potential Role of Flavonoids in Hypoxia/Reoxygenation Cardiac Injury Model

Ali SS, Noordin L, Bakar RA, Zainalabidin S, Jubri Z, Wan Ahmad WAN

Cardiovasc Toxicol, 2021 08;21(8):605-618.
PMID: 34114196 DOI: 10.1007/s12012-021-09666-x

Clinically, timely reperfusion strategies to re-establish oxygenated blood flow in ischemic heart diseases seem to salvage viable myocardium effectively. Despite the remarkable improvement in cardiac function, reperfusion therapy could paradoxically trigger hypoxic cellular injury and dysfunction. Experimental laboratory models have been developed over the years to explain better the pathophysiology of cardiac ischemia-reperfusion injury, including the in vitro hypoxia-reoxygenation cardiac injury model. Furthermore, the use of nutritional myocardial conditioning techniques have been successful. The cardioprotective potential of flavonoids have been greatly linked to its anti-oxidant, anti-apoptotic and anti-inflammatory properties. While several studies have reviewed the cardioprotective properties of flavonoids, there is a scarce evidence of their function in the hypoxia-reoxygenation injury cell culture model. Hence, the aim of this review was to lay out and summarize our current understanding of flavonoids' function in mitigating hypoxia-reoxygenation cardiac injury based on evidence from the last five years. We also discussed the possible mechanisms of flavonoids in modulating the cardioprotective effects as such information would provide invaluable insight on future therapeutic application of flavonoids.

Matched MeSH terms: Myocardial Reperfusion Injury/drug therapy*; Myocardial Reperfusion Injury/metabolism; Myocardial Reperfusion Injury/pathology; Myocardial Reperfusion Injury/physiopathology
Non-coding RNAs as therapeutic targets for preventing myocardial ischemia-reperfusion injury

Ong SB, Katwadi K, Kwek XY, Ismail NI, Chinda K, Ong SG, et al.

Expert Opin Ther Targets, 2018 03;22(3):247-261.
PMID: 29417868 DOI: 10.1080/14728222.2018.1439015

INTRODUCTION: New treatments are required to improve clinical outcomes in patients with acute myocardial infarction (AMI), for reduction of myocardial infarct (MI) size and preventing heart failure. Following AMI, acute ischemia/reperfusion injury (IRI) ensues, resulting in cardiomyocyte death and impaired cardiac function. Emerging studies have implicated a fundamental role for non-coding RNAs (microRNAs [miRNA], and more recently long non-coding RNAs [lncRNA]) in the setting of acute myocardial IRI. Areas covered: In this article, we discuss the roles of miRNAs and lncRNAs as potential biomarkers and therapeutic targets for the detection and treatment of AMI, review their roles as mediators and effectors of cardioprotection, particularly in the settings of interventions such as ischemic pre- and post-conditioning (IPC & IPost) as well as remote ischemic conditioning (RIC), and highlight future strategies for targeting ncRNAs to reduce MI size and prevent heart failure following AMI. Expert opinion: Investigating the roles of miRNAs and lncRNAs in the setting of AMI has provided new insights into the pathophysiology underlying acute myocardial IRI, and has identified novel biomarkers and therapeutic targets for detecting and treating AMI. Pharmacological and genetic manipulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients.

Matched MeSH terms: Myocardial Reperfusion Injury/genetics; Myocardial Reperfusion Injury/prevention & control*
S-allylcysteine improves ischemia/reperfusion alteration on cardiac function, antioxidant, and mitochondrial permeability

Aziz NF, Ramalingam A, Latip J, Zainalabidin S

Life Sci, 2021 Mar 15;269:119080.
PMID: 33465387 DOI: 10.1016/j.lfs.2021.119080

S-Allylcysteine (SAC) is an extensively studied natural product which has been proven to confer cardioprotection. This potentiates SAC into many clinical relevance possibilities, hence, the use of it ought to be optimally elucidated. To further confirm this, an ischemia/reperfusion model has been used to determine SAC at 10 mM and 50 mM on cardiac function, cardiac marker, and mitochondrial permeability. Using Langendorff setup, 24 adult male Wistar rats' hearts were isolated to be perfused with Kreb-Henseleit buffer throughout the ischemia/reperfusion method. After 20 min of stabilization, global ischemia was induced by turning off the perfusion for 35 min followed by 60 min of reperfusion with either Kreb-Henseleit buffer or SAC with the dose of 10 mM or 50 mM. The cardiac function was assessed and coronary effluent was collected at different timepoints throughout the experiment for lactate dehydrogenase (LDH) measurement. The harvested hearts were then used to measure glutathione while isolated mitochondria for mPTP analysis. SAC-reperfused hearts were shown to prevent the aggravation of cardiac function after I/R induction. It also dose-dependently upregulated glutathione reductase and glutathione level and these were also accompanied by significant reduction of LDH leakage and preserved mitochondrial permeability. Altogether, SAC dose-dependently was able to recover the post-ischemic cardiac function deterioration alongside with improvement of glutathione metabolism and mitochondrial preservation. These findings highly suggest that SAC when sufficiently supplied to the heart would be able to prevent the deleterious complications after the ischemic insult.

Matched MeSH terms: Myocardial Reperfusion Injury/drug therapy*; Myocardial Reperfusion Injury/metabolism; Myocardial Reperfusion Injury/pathology
Fulltext DJ-1 protects against cell death following acute cardiac ischemia-reperfusion injury

Dongworth RK, Mukherjee UA, Hall AR, Astin R, Ong SB, Yao Z, et al.

Cell Death Dis, 2014 Feb 27;5:e1082.
PMID: 24577080 DOI: 10.1038/cddis.2014.41

Novel therapeutic targets are required to protect the heart against cell death from acute ischemia-reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson's disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia-reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1(L166P) and DJ-1(Cys106A) mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n≥7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection.

Matched MeSH terms: Myocardial Reperfusion Injury/genetics; Myocardial Reperfusion Injury/metabolism; Myocardial Reperfusion Injury/pathology; Myocardial Reperfusion Injury/prevention & control*
Fulltext Impact of prolonged nicotine administration on myocardial function and susceptibility to ischaemia-reperfusion injury in rats

Ramalingam A, Mohd Fauzi N, Budin SB, Zainalabidin S

Basic Clin Pharmacol Toxicol, 2021 Feb;128(2):322-333.
PMID: 32991780 DOI: 10.1111/bcpt.13500

This study investigated the impact of prolonged nicotine administration on myocardial susceptibility to ischaemia-reperfusion (I/R) injury in a rat model and determined whether nicotine affects mitochondrial reactive oxygen species (ROS) production and permeability transition in rat hearts. Sprague-Dawley rats were administered 0.6 or 1.2 mg/kg nicotine for 28 days, and their hearts were isolated at end-point for assessment of myocardial susceptibility to I/R injury ex vivo. Rat heart mitochondria were also isolated from a subset of rats for analysis of mitochondrial ROS production and permeability transition. Compared to the vehicle controls, rat hearts isolated from nicotine-administered rats exhibited poorer left ventricular function that worsened over the course of I/R. Coronary flow rate was also severely impaired in the nicotine groups at baseline and this worsened after I/R. Nicotine administration significantly increased mitochondrial ROS production and permeability transition relative to the vehicle controls. Interestingly, pre-incubation of isolated mitochondria with ROS scavengers (superoxide dismutase and mitoTEMPO) significantly abolished nicotine-induced increase in mitochondria permeability transition in isolated rat heart mitochondria. Overall, our data showed that prolonged nicotine administration enhances myocardial susceptibility to I/R injury in rats and this is associated with mitochondrial ROS-driven increase in mitochondrial permeability transition.

Matched MeSH terms: Myocardial Reperfusion Injury/chemically induced*; Myocardial Reperfusion Injury/metabolism; Myocardial Reperfusion Injury/pathology; Myocardial Reperfusion Injury/physiopathology
Development of an In Vitro Cardiac Ischemic Model Using Primary Human Cardiomyocytes

Hafez P, Chowdhury SR, Jose S, Law JX, Ruszymah BHI, Mohd Ramzisham AR, et al.

Cardiovasc Eng Technol, 2018 09;9(3):529-538.
PMID: 29948837 DOI: 10.1007/s13239-018-0368-8

Developing experimental models to study ischemic heart disease is necessary for understanding of biological mechanisms to improve the therapeutic approaches for restoring cardiomyocytes function following injury. The aim of this study was to develop an in vitro hypoxic/re-oxygenation model of ischemia using primary human cardiomyocytes (HCM) and define subsequent cytotoxic effects. HCM were cultured in serum and glucose free medium in hypoxic condition with 1% O2 ranging from 30 min to 12 h. The optimal hypoxic exposure time was determined using Hypoxia Inducible Factor 1α (HIF-1α) as the hypoxic marker. Subsequently, the cells were moved to normoxic condition for 3, 6 and 9 h to replicate the re-oxygenation phase. Optimal period of hypoxic/re-oxygenation was determined based on 50% mitochondrial injury via 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and cytotoxicity via lactate dehydrogenase (LDH) assay. It was found that the number of cells expressing HIF-1α increased with hypoxic time and 3 h was sufficient to stimulate the expression of this marker in all the cells. Upon re-oxygenation, mitochondrial activity reduced significantly whereas the cytotoxicity increased significantly with time. Six hours of re-oxygenation was optimal to induce reversible cell injury. The injury became irreversible after 9 h as indicated by > 60% LDH leakage compared to the control group cultured in normal condition. Under optimized hypoxic reoxygenation experimental conditions, mesenchymal stem cells formed nanotube with ischemic HCM and facilitated transfer of mitochondria suggesting the feasibility of using this as a model system to study molecular mechanisms of myocardial injury and rescue.

Matched MeSH terms: Myocardial Reperfusion Injury/metabolism*; Myocardial Reperfusion Injury/pathology
Fulltext Targeting mitochondrial reactive oxygen species-mediated oxidative stress attenuates nicotine-induced cardiac remodeling and dysfunction

Ramalingam A, Budin SB, Mohd Fauzi N, Ritchie RH, Zainalabidin S

Sci Rep, 2021 07 05;11(1):13845.
PMID: 34226619 DOI: 10.1038/s41598-021-93234-4

Long-term nicotine intake is associated with an increased risk of myocardial damage and dysfunction. However, it remains unclear whether targeting mitochondrial reactive oxygen species (ROS) prevents nicotine-induced cardiac remodeling and dysfunction. This study investigated the effects of mitoTEMPO (a mitochondria-targeted antioxidant), and resveratrol (a sirtuin activator) , on nicotine-induced cardiac remodeling and dysfunction. Sprague-Dawley rats were administered 0.6 mg/kg nicotine daily with 0.7 mg/kg mitoTEMPO, 8 mg/kg resveratrol, or vehicle alone for 28 days. At the end of the study, rat hearts were collected to analyze the cardiac structure, mitochondrial ROS level, oxidative stress, and inflammation markers. A subset of rat hearts was perfused ex vivo to determine the cardiac function and myocardial susceptibility to ischemia-reperfusion injury. Nicotine administration significantly augmented mitochondrial ROS level, cardiomyocyte hypertrophy, fibrosis, and inflammation in rat hearts. Nicotine administration also induced left ventricular dysfunction, which was worsened by ischemia-reperfusion in isolated rat hearts. MitoTEMPO and resveratrol both significantly attenuated the adverse cardiac remodeling induced by nicotine, as well as the aggravation of postischemic ventricular dysfunction. Findings from this study show that targeting mitochondrial ROS with mitoTEMPO or resveratrol partially attenuates nicotine-induced cardiac remodeling and dysfunction.

Matched MeSH terms: Myocardial Reperfusion Injury/chemically induced; Myocardial Reperfusion Injury/metabolism; Myocardial Reperfusion Injury/prevention & control
Fulltext Mediation of Cardiac Macrophage Activity via Auricular Vagal Nerve Stimulation Ameliorates Cardiac Ischemia/Reperfusion Injury

Chung CH, Bretherton B, Zainalabidin S, Deuchars SA, Deuchars J, Mahadi MK

Front Neurosci, 2020;14:906.
PMID: 33013299 DOI: 10.3389/fnins.2020.00906

Background: Myocardial infarction (MI) reperfusion therapy causes paradoxical cardiac complications. Following restoration of blood flow to infarcted regions, a multitude of inflammatory cells are recruited to the site of injury for tissue repair. Continual progression of cardiac inflammatory responses does, however, lead to adverse cardiac remodeling, inevitably causing heart failure.
Main Body: Increasing evidence of the cardioprotective effects of both invasive and non-invasive vagal nerve stimulation (VNS) suggests that these may be feasible methods to treat myocardial ischemia/reperfusion injury via anti-inflammatory regulation. The mechanisms through which auricular VNS controls inflammation are yet to be explored. In this review, we discuss the potential of autonomic nervous system modulation, particularly via the parasympathetic branch, in ameliorating MI. Novel insights are provided about the activation of the cholinergic anti-inflammatory pathway on cardiac macrophages. Acetylcholine binding to the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages polarizes the pro-inflammatory into anti-inflammatory subtypes. Activation of the α7nAChR stimulates the signal transducer and activator of transcription 3 (STAT3) signaling pathway. This inhibits the secretion of pro-inflammatory cytokines, limiting ischemic injury in the myocardium and initiating efficient reparative mechanisms. We highlight recent developments in the controversial auricular vagal neuro-circuitry and how they may relate to activation of the cholinergic anti-inflammatory pathway.
Conclusion: Emerging published data suggest that auricular VNS is an inexpensive healthcare modality, mediating the dynamic balance between pro- and anti-inflammatory responses in cardiac macrophages and ameliorating cardiac ischemia/reperfusion injury.

Matched MeSH terms: Myocardial Reperfusion Injury