Acute myocardial infarction, reperfusion injury, and intravenous magnesium therapy: Basic concepts and clinical implications

doi:10.1016/S0002-8703(96)90339-7

American Heart Journal

Volume 132, Issue 2, Part 2, August 1996, Pages 478-482

https://doi.org/10.1016/S0002-8703(96)90339-7 Get rights and content

Abstract

The concept of reperfusion-induced injury has aroused special interest during the past decade as thrombolysis and direct angioplasty were introduced for early restoration of coronary blood flow in patients with acute myocardial infarction. There is experimental and clinical evidence that oxygen-derived free radicals (oxyradical hypothesis), activation of the complement system (complement hypothesis), and disturbance in calcium homeostasis (calcium hypothesis) may account for the development of reperfusion injury. Data from numerous animal experiments and clinical trials suggest that magnesium, a physiologic calcium blocker, may be efficacious for reduction of reperfusion injury. Despite encouraging results from previous clinical trials that revealed beneficial effects of intravenous magnesium therapy with respect to mortality, left ventricular function, and infarct size, a recently published large-scale trial (ISIS-4) provided conflicting data and caused major controversy. Further clinical trials, well-designed and carefully conducted, should elucidate the beneficial effects of magnesium in acute myocardial infarction, especially in conjunction with new and aggressive reperfusion techniques.

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Cited by (25)

Magnesium reduces free radical concentration and preserves left ventricular function after direct current shocks
2003, Resuscitation
Objective: Our objective was to determine if magnesium reduces free radicals generated by direct current countershock and preserves left ventricular contractile function. Background: We have previously shown that magnesium reduces free radicals in a coronary occlusion-reperfusion model, and therefore also might reduce free radical generation by direct current shocks. Methods: In eight swine weighing 18–27 kg (mean: 22 kg), using electron paramagnetic resonance, we monitored continuously the coronary sinus concentration of ascorbate free radical, a measure of free radical generation (total oxidative flux). Epicardial shocks (30 J) using a truncated exponential biphasic waveform (5/5 ms) were administered. Each animal received two shocks, one without and one with magnesium, 80 mg/min IV, beginning 10 min before the shock and continuing to 15 min after the shock. Percent fractional area shortening of the left ventricular cavity was determined by 2-dimensional echocardiography. Results: Magnesium shocks resulted in a significantly lower increase in the ascorbate free radical concentration (0.6±4.6%) than no-magnesium shocks (16±3.3%, P<0.05) at 12 min after the shock. Total radical flux was reduced 72% (P<0.05), and left ventricular fractional area shortening was preserved: baseline: 69±2.6%, no-magnesium shocks: 41±2.8% (P<0.05, versus baseline) and magnesium shocks 61±3.7%. Conclusions: Magnesium pre-treatment reduced oxygen free radicals generated by direct current shocks; post-shock left ventricular contractile function was not impaired. Magnesium may be cardioprotective during epicardial (‘surgical’) defibrillation.
Objectivo: O nosso objectivo foi determinar se o magnésio reduz os radicais livres gerados por uma corrente de choques directa e se preserva a função contráctil do ventriculo esquerdo. Contexto: Evidenciamos préviamente que o magnésio reduz os radicais livres num modelo coronário de oclusão-reperfusão, e portanto também pode diminuir a produção de radicais livres por choques de corrente directa. Método: Monitorou-se de forma contı́nua, utilizando a ressonância electrónica paramagnética, a concentração de radicais livres de ascorbato no seio coronário, uma medição da produção de radicais livres (fluxo oxidativo total) em oito porcos pesando 18–27 kg (média=22 kg). Foram administrados choques epicárdicos (30 J) utilizando ‘ondas bifásicas exponenciais e truncadas’ (5/5 ms). Cada animal recebeu dois choques, um sem e outro com magnésio, 80 mg/min, iniciado 10 min antes do choque e continuado até 15 min. depois do choque. Foi determinada, por ecocardiograma bidimensional, a fracção de encurtamento do ventrı́culo esquerdo. Resultados: Os choques com magnésio resultaram num aumento significativamente menor da concentração de radicais livre ascorbato (0.6±4.6%) do que os choques sem magnésio (16±3.3%; P<0.05) aos 12 min após o choque. O fluxo total de radicais foi reduzido a 72% (P<0.05), e a fracção de encurtamento do ventrı́culo esquerdo foi preservada: linha de base: 69±2.6%, choques sem magnésio: 41±2.8% (P<0.05, versus linha de base) e choques com magnésio 61±3.7%. Conclusões: O pré-tratamento com magnésio reduz a produção de radicais livres de oxigénio produzidos por choques de corrente directa; a função ventricular esquerdo após o choque não foi alterada. O magnésio pode ser cardioprotector durante a desfibrilhação epicárdica (‘cirúrgica’).
Objetivo^: Nuestro objetivo fue determinar si acaso el magnesio reduce los radicales libres generados por la descarga de corriente directa y preserva la función contráctil del ventrı́culo izquierdo. Antecedentes: Hemos mostrado previamente que el magnesio reduce los radicales libres en un modelo oclusión coronaria-reperfusión, y por lo tanto podrı́a también reducir la generación de radicales libres por descarga de corriente directa. Métodos: Por medio de resonancia paramagnética en 8 cerdos que pesaban 18–27 kg (promedio 22 kg), hicimos monitoreo contı́nuo de concentración de radicales libres de ascorbato en el seno coronario, una medida de la generación de radicales libres (flujo oxidativo total). Se administraron descargas epicárdicas (30 J) usando corriente en una onda bifásica exponencial truncada (5/5 ms). Cada animal recibió dos descargas, una sin y una con magnesio, 80 mg/min ev, empezando 10 minutos antes de la descarga y continuado hasta 15 min después de la descarga. Se determinó el acortamiento porcentual del área de la cavidad del ventrı́culo izquierdo con ecografı́a bidimensional. Resultados: Los pacientes con magnesio y descarga presentaron un aumento en la concentración de los radicales libres de ascorbato (0.6±4.6%) significativamente menor que los pacientes que no recibieron magnesio(16±3.3%, P<0.05) al medirlo 12 minutos después de la descarga. El flujo total de radicales se redujo 72% (P<0.05), y el acortamiento fraccional de área de ventriculo izquierdo se mantuvo: linea basal: 69±2.6%, sin bolos de MG, 41±2.8% (P<0.05 versus basal), con magnesio 61±3.7%. Conclusiones: El pretratamiento con magnesio reduce los radicales libres generados por descargas de corriente directa; la función contráctil ventricular izquierda no se daño. El magnesio puede ser cardioprotector durante desfibrilación epicárdica (quirurgica).
Pro: Magnesium should be administered to all coronary artery bypass graft surgery patients undergoing cardiopulmonary bypass
2000, Journal of Cardiothoracic and Vascular Anesthesia
Citation Excerpt :
From 1981 through 1991, a series of small studies were performed examining empiric magnesium administration in this patient population. Meta-analysis of more than 1,300 patients enrolled in these studies showed a decreased mortality with magnesium administration in the setting of a myocardial infarction.6,14,17,18 These results were followed by the 1994 Second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2), a single-center, randomized, double-blind, placebo-controlled study designed to test the hypothesis that doubling serum magnesium concentration would reduce the mortality rate in patients with an acute myocardial infarction.17
Adenosine for myocardial protection in acute myocardial infarction
1997, American Journal of Cardiology
Although reperfusion therapy for acute myocardial infarction is known to reduce infarct size, improve left ventricular function, and reduce mortality, the full potential benefit may be limited by acceleration of damage resulting from reperfusion, or “reperfusion injury.” Evidence of a variety of mechanisms of reperfusion injury has led to a wide range of proposed therapeutic interventions, including agents to prevent oxygen free radical damage, inhibit white blood cell function, reduce calcium influx, improve microvascular blood flow, inhibit sympathetic stimulation, and improve energy stores. A multitude of agents have been shown to limit infarct size in animals when administered before or during reperfusion. Unfortunately, most have been disappointing when tested clinically. Adenosine, a theoretically attractive agent for preventing reperfusion injury, has shown promise in small, clinical studies, and appears to be an endogenous substance involved in the protective effect of ischemic preconditioning. When studied in the setting of angioplasty for acute myocardial infarction, adenosine was associated with small infarct size and improved coronary flow. As myocardial preservation with reperfusion during bypass surgery shares pathophysiologic characteristics with the reperfused myocardium in acute infarction, early results of adenosine during bypass surgery presented at this symposium support the concept that adenosine may be beneficial. Two ongoing Phase II trials of adenosine in acute myocardial infarction—one with thrombolysis and one with direct angioplasty—will provide important information about the potential benefits of adenosine in the context of reperfusion.
Myocardial-reperfusion injury in cardiac surgery with cardiopulmonary bypass. Biochemical aspects
2018, Cirugia Cardiovascular
Desde los inicios de la cirugía cardiaca con circulación extracorpórea, el daño de isquemia-reperfusión miocárdico ha sido reconocido como uno de los principales causantes de morbimortalidad.
Revisión bibliográfica sobre isquemia-reperfusión miocárdica a nivel experimental y clínico utilizando Pubmed y otras bases y fuentes de datos incluyendo Teseo.
Se realiza una revisión actualizada de los aspectos celulares y bioquímicos de la isquemia-reperfusión miocárdica. Se exponen los cambios celulares durante la isquemia, los cambios celulares durante la reperfusión, los radicales libres de oxígeno, la activación del sistema del complemento, la activación de las citocinas proinflamatorias y la interacción neutrófilo-endotelio. Se adjunta una tabla con un listado de fármacos y compuestos que a nivel experimental y clínico que han sido usados para tratar el daño de isquemia-reperfusión miocárdico.
En el momento actual se sigue investigando de forma activa en este campo y hay estudios clínicos en marcha encaminados a probar la eficacia de fármacos para reducir el daño de isquemia-reperfusión miocárdico. El cirujano cardiaco debe de estar bien informado en nuevos métodos de cardioprotección en cirugía cardiaca.
Since the beginning of the cardiac surgery with cardiopulmonary bypass, myocardial-reperfusion injury has been recognized as one of the leading causes of morbidity and mortality related with this type of surgery.
A bibliographic review in Pubmed and other data base including Teseo has been carried out.
Fundaments of the cellular changes during the ischemic time, cellular changes in the reperfusion time, release of oxygen free radicals, complement activation, proinflammatory cytokines activation and neutrophil-endothelium interaction are exposed. A table with a selected list of drugs and compounds used against the myocardial ischemic -reperfusion injury syndrome is included.
At present, the myocardial reperfusion injury syndrome is an active line of research. There are many trials and studies on investigating new agents .The cardiac surgeon should be well informed in new strategies in myocardial protection in cardiac surgery.
155 words
Magnesium reduces myocardial infarct size via enhancement of adenosine mechanism in rabbits
2002, Cardiovascular Research
Cellular calcium homeostasis during ischemia; a thermodynamic approach
2000, Cardiovascular Research

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Acute myocardial infarction, reperfusion injury, and intravenous magnesium therapy: Basic concepts and clinical implications

Abstract

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

J Moll Cell Cardiol

J Am Coll Cardiol

Am Heart J

Am J Cardiol

Blood

J Moll Cell Cardiol

Am J Cardiol

Am J Clin Nutr

FEBS Lett

J Mol Cell Cardiol

Am Heart J

Am J Cardiol

Lancet

Am J Cardiol

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

Ann Thorac Surg

J Am Coll Cardiol

Reperfusion in acute myocardial infarction

New developments in the management of ischemic heart disease

Curr Opin Cardiol

Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction

Lancet

Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study

Lancet

A prospective trial of intravenous streptokinase in acute myocardial infarction (ISAM): mortality, morbidity, and infarct size at 21 days

N Engl J Med

Randomized trial of late thrombolysis in patients with suspected acute myocardial infarction

Lancet

The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction

N Engl J Med

Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients

Lancet

A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction: The Primary Angioplasty in Myocardial Infarction Study Group

N Engl J Med

Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction: The Mayo Coronary Care Unit and Catheterization Laboratory Groups

N Engl J Med

A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction

N Engl J Med

Outcome of patients with acute myocardial infarction who are ineligible for thrombolytic therapy

Ann Intern Med

Myocardial stunning in man

Circulation

Exacerbation of reperfusion arrhythmias by sudden oxidant stress

Circ Res

Early afterdepolarization induced in vivo by reperfusion of ischemic myocardium

Circulation

Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of reperfusion injury

Circulation

Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival

Deterious effects of oxygen radicals in ischemia/reperfusion: resolved and unresolved issues

Circulation

Cardiac reperfusion injury

Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog

Canine myocardial reperfusion injury: its reduction by the combined administration of superoxide dismutase and catalase

Circ Res