Free radicals and myocardial protection: A surgical viewpoint

doi:10.1016/0003-4975(89)90047-7

The Annals of Thoracic Surgery

Volume 47, Issue 6, June 1989, Pages 939-945

https://doi.org/10.1016/0003-4975(89)90047-7 Get rights and content

Abstract

Oxygen-derived free radicals are now considered important contributors to tissue injury associated with ischemia and reperfusion. Transition metals primarily iron, greatly enhance the generation of these active species, which can destroy a large variety of biomolecules, in particular the lipid components of cell membranes. This review tries to demonstrate why cardiopulmonary bypass and aortic cross-clamping are situations that predispose to oxygen free radical production, and how “antifree radical” agents such as enzymatic scavengers, antioxidants, and iron chelators may prove to be useful therapeutic radicals in the clinical setting of open heart surgery.

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Cited by (64)

Cardiac surgery: Myocardial energy balance, antioxidant status and endothelial function after ischemia-reperfusion
2002, Biomedicine and Pharmacotherapy
Myocardial and endothelial damage is still a widely debated problem during the ischemia–reperfusion sequence in heart surgery. We evaluated myocardial purine metabolites, antioxidant defense mechanisms, oxidative status and endothelial dysfunction markers in 14 patients undergoing coronary artery by-pass graft (CABG). Heart biopsies were taken before aortic cross-clamping (t1), before clamp removal (t2) and 30 min after reperfusion (t3); perchloric extracts of the tissue were analyzed for glutathione, NAD, nucleotide nucleoside and base content by capillary electrophoresis (CE). In plasma samples from the coronary sinus we evaluated: nitrate and nitrite concentrations by CE, plasma glutathione peroxidase (plGPx) by ELISA, endothelin-1 (ET-1) by RIA and reactive oxygen metabolites (ROM) by colorimetric assay. During the ischemic period (t2) we observed a reduction in cellular NAD and GSH levels, as well as nitrate, nitrite and plGPx. ATP and GTP levels decreased and their catabolic products AMP, GMP, IMP, adenosine, inosine and hypoxanthine accumulated. The energy charge, ATP/ADP ratio, and nucleotide/(nucleoside + base) ratios decreased. At t3, levels of plasma ET-1 increased and monophosphate nucleotides tended to return to basal values. The energy charge did not increase but the nucleotide/(nucleoside + nucleobase) ratio recovered to some extent. Levels of nitrates plus nitrites continued to decrease. No significant variation in ROM levels was observed. Our data indicate that oxidative stress and endothelial damage are major events during CABG, overwhelming the scavenging capacity of the myocyte and preventing restoration of the normal energy balance for 30 min after reperfusion. The AMP deaminase pathway leading to IMP production is active during ischemia and adenosine is not the main compound derived from ATP break-down in the human heart. The possible role of extracorporeal circulation is also discussed.
Endothelial damage during myocardial preservation and storage
2002, Annals of Thoracic Surgery
Citation Excerpt :
Moreover, hypoxia affects the production of oxygen-derived free radicals also at very low oxygen tensions. The consequent reduction in the availability of tissue antioxidants [12] may cause endothelial cell activation or disruption. The impairment of endothelial barrier function [7, 13] may thus result in perivascular and tissue edema with consequent alterations in the distribution of cardioplegic or storage solutions, as well as reduction of coronary flow after reperfusion, promoting graft dysfunction.
Preservation and storage techniques represent two major issues in routine cardiac surgery and heart transplantation. Historically, these methods were conceived to prevent ischemic injury to myocardium after cardiac arrest during heart operations. Evidence shows that endothelium plays a critical role in the maintenance of normal heart function after cardiac operation, mainly by controlling the coronary circulation. Methods for preservation and storage, developed initially to protect cardiomyocyte function, may be deleterious for vascular endothelium and compromise myocardial protection. In this review article the present knowledge about endothelial injury secondary to preservation and storage techniques is discussed.
cGMP is decreased after acute ischemia in chronically ischemic canine limbs
1999, Journal of Surgical Research
Background. A chronic partially ischemic state may alter the skeletal muscle response to acute ischemia and free radical formation.
Methods. In order to investigate this hypothesis, a chronic ischemic state was established by ligating the right femoral artery of four mongrel dogs. ABIs were decreased from 1.05 ± 0.25 preligation to 0.54 ± 0.14 at 6 weeks (P = 0.04). At the end of 8 weeks, the hindlimb was subjected to 3 h of acute ischemia by clamping the iliac artery. The clamp was then released for 2 h of reperfusion. Plasma samples from the right iliac vein were taken during the ischemia–reperfusion period for analysis of cGMP. Tibialis anterior biopsies for Western analysis of eNOS and iNOS were taken upon completion of reperfusion. Comparisons to control dogs subjected to the acute ischemia and reperfusion without prior femoral artery ligation were made.
Results. cGMP levels were increased in the controls at 3 h of ischemia (3539 ± 350) and 2 h of reperfusion (2880 ± 269). The chronic ischemia group did not develop a corresponding increase in cGMP at 3 h of ischemia (2762 ± 251) or after 2 h of reperfusion (2102 ± 130). Western analysis of eNOS and iNOS revealed similar levels in both groups. Analysis of eNOS revealed 0.6429 ± 0.086 and 0.5916 ± 0.072 (densitometric units ± SEM) for study and control dogs, respectively. Analysis of iNOS revealed 0.3401 ± 0.067 and 0.2475 ± 0.066 for study and control dogs, respectively.
Conclusion. Previous ligation of the femoral artery resulting in chronic partial ischemia in this model demonstrated no increase in cGMP following acute ischemia that was not accompanied by a change in eNOS or iNOS levels. Nitric oxide activity is reflected by cGMP levels, which may increase in response to free radicals in the acute setting of complete ischemia.
Detection of oxidative DNA damage to ischemic reperfused rat hearts by 8-hydroxydeoxyguanosine formation
1998, Journal of Molecular and Cellular Cardiology
Reactive oxygen species that are generated in the ischemic heart upon reperfusion, play a significant role in the pathogenesis of reperfusion injury. Although DNA is a well known target for free radical attack, little attention has been paid to the injury of DNA molecules associated with ischemia and reperfusion. In this study, the formation of 8-hydroxydeoxyguanosine (8-OHDG), a product of hydroxyl radical (OH^.)-DNA interaction, was monitored in the post-ischemic myocardium. A simple high performance liquid chromatography (HPLC), with uv detection, detected pmol levels of 8-OHDG in the pre-ischemic heart which increased steadily and progressively as a function of reperfusion time. A similar rise in 8-OHDG was noticed when isolated hearts were perfused with a OH^.-generating system. Corroborating with the increased 8-OHDG formation, increased amount of creatine kinase was released from the coronary effluent indicating increased tissue injury. The formation of 8-OHDG was completely blocked when hearts were preperfused with oxygen-free-radical scavenger, 1,3-dimethyl-2-thiourea (DMTU) which also significantly reduced the appearance of CK in the coronary effluent, suggesting that oxidative DNA damage play a role in the pathophysiology of ischemic reperfusion injury.
Minimally diluted tepid blood cardioplegia
1998, Annals of Thoracic Surgery
Background. To evaluate the effects of minimally diluted tepid blood cardioplegia, a prospective, randomized study was undertaken.
Methods. Thirty-seven patients undergoing isolated primary coronary artery bypass grafting were randomized to receive standard 4:1 diluted tepid blood cardioplegia (4:1 group, n = 18) or minimally diluted tepid blood cardioplegia (Mini group, n = 19). Cardioplegic solution was delivered in an intermittent antegrade fashion in both groups. Myocardial oxygen and lactate metabolism, release of the MB isoenzyme of creatine kinase and thiobarbituric acid reactive substances, and cardiac function were measured during and after the operation.
Results. Myocardial oxygen consumption was significantly greater and lactate release was significantly lower in the Mini group than in the 4:1 group during cardioplegia. Minimally diluted blood cardioplegia resulted in more prompt resumption of lactate extraction, lower levels of release of the myocardial-specific isoenzyme of creatine kinase and thiobarbituric acid reactive substances during reperfusion, and better postoperative left ventricular function compared with the standard 4:1 cardioplegia.
Conclusions. Minimally diluted tepid blood cardioplegia may provide superior myocardial protection than the standard 4:1 dilution technique by optimizing the aerobic environment through an increase in oxygen supply during intermittent cardioplegia.
Effect of preoperative antioxidant supplements on perioperative myocardial injury [4] (multiple letters)
1997, Journal of Thoracic and Cardiovascular Surgery

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Current reviewFree radicals and myocardial protection: A surgical viewpoint

Abstract

J Am Coll Cardiol

J Mol Cell Cardiol

J Mol Cell Cardiol

J Free Radic Biol Med

J Mol Cell Cardiol

J Mol Cell Cardiol

J Mol Cell Cardiol

FEBS Lett

J Mol Cell Cardiol

Life Sci

J Mol Cell Cardiol

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Ann Thorac Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Free radicals and tissue injury

Lab Invest

Are free radical a major culprit?

Free radicals and myocardial injury: pharmacologic implications

J Am Coll Cardiol

Inhibition of the iron-catalysed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine

Biochem J

The activity of xanthine oxidase in heart and liver of rats, guinea pigs, pigs, rabbit, and human beings [Abstract]

Circulation

Allopurinol in prevention of reperfusion injury of hypoxically stored rat hearts

J Heart Transplant

Myocardial alterations due to free-radical generation

Am J Physiol

Evidence of myocardial free radical injury during elective repair of tetralogy of Fallot

Circulation

The role of lipid peroxidation in pathogenesis of ischemic damage and the antioxidant protection of the heart

Basic Res Cardiol

Glutathione redox cycle protects cultured endothelial cells against lysis by extracellularly generated hydrogen peroxide

J Clin Invest

Lipid peroxidation and scavenger mechanism in experimentally induced heart infarcts

Basic Res Cardiol

Current review
Free radicals and myocardial protection: A surgical viewpoint