It is an axiom of coronary care medicine that infarct size is a pivotal determinant of the prognosis of patients with acute myocardial infarction (AMI). When one is able to limit the size of an AMI, one is rewarded with a reduction in the number of potentially life-threatening complications such as pulmonary edema, cardiogenic shock, ventricular septal defects, papillary muscle rupture, and ventricular tachyarrhythmias.1 Salvage of even a rim of epicardial tissue as the wave front of necrosis spreads from the endocardium might prevent infarct expansion, ventricular remodeling, and congestive heart failure.2 3
Myocardial Necrosis and Reperfusion Injury
Reperfusion that is sufficiently early (within 15 to 20 minutes) after AMI may prevent ischemic zones of myocardium from progressing to infarction. However, with the possible exceptions of an AMI that develops during cardiac catheterization, of patients who receive prehospital thrombolysis, or of the rare patient who occludes a coronary artery in the Emergency Department or coronary care unit and receives extraordinarily prompt and successful thrombolysis, reperfusion in cases of human AMI results in a mixture of necrotic and salvaged myocytes. The amount of myocardium that is irreversibly damaged (area of necrosis divided by area at risk) is directly related to the duration of occlusion. Interventions that delay cell death (eg, β-blockers) may help to protect ischemic myocytes and leave a greater quantity of viable cells that can subsequently be rescued by reperfusion.
More than a decade ago, Braunwald and Kloner2 emphasized that reperfusion therapy, while beneficial in terms of myocardial salvage, may come at a cost because of a process referred to as reperfusion injury. Four aspects of reperfusion injury have been recognized4 : (1) lethal reperfusion injury (reperfusion-induced death of cells that were still viable at the moment of restoration of blood flow), (2) vascular reperfusion injury (no-reflow phenomenon and loss of vasodilatory reserve), (3) stunned myocardium (prolonged postischemic contractile dysfunction), and (4) reperfusion arrhythmia. While experimental and clinical data are consistent with the occurrence of vascular reperfusion injury, stunning, and reperfusion arrhythmia, the concept of lethal reperfusion injury remains controversial. The pathogenesis of reperfusion injury is probably multifactorial, and leading theories include intracellular calcium overload and generation of oxygen-derived free radicals.4 5 6 7 Injured myocytes develop defects in sarcolemmal integrity and in their ability to regulate cell volume. The processes noted above may be interrelated, because a decrease in cytosolic magnesium levels and an increase in cytosolic calcium levels contribute to local release of myocardial catecholamines and generation of oxygen-derived free radicals—sarcoplasmic reticulum dysfunction and loss of selective permeability of the sarcolemmal membrane then occur.2 4 6 8 9 10 11 Elevated cytosolic free calcium levels can activate degradative proteases that compromise plasma membrane integrity, allowing calcium overload and irreversible damage to mitochondria.12 13
It is important to emphasize that in contrast to the time-dependent spread of the wave front of necrosis when a coronary is occluded, the explosive deleterious processes producing reperfusion injury of viable tissue begin immediately on restoration of coronary blood flow. Any attempt to reduce their impact with adjunctive agents must be introduced before, or coincident with, restoration of perfusion. Probably even better is the prophylactic administration of a protective agent before coronary occlusion.2
Magnesium, Ischemic Heart Disease, and Myocardial Injury
Data are accumulating that indicate that the magnesium cation may be a promising agent for protection of ischemic myocardium and modulation of reperfusion injury. Magnesium is a critical cofactor in more than 300 intracellular enzymatic processes, many of which are integrally involved in mitochondrial function, energy production, maintenance of transsarcolemmal ionic gradients, cell volume control, and resting membrane potential.14 15 16 The cardiovascular consequences of magnesium deficiency in animal and clinical studies have been summarized by Seelig17 and include multifocal necrosis with calcium accumulation in mitochondria in a pattern reminiscent of myocardial ischemia and catecholamine-induced cardiomyopathy, atherogenesis, a heightened tendency to platelet aggregation, increased coronary and peripheral vascular resistances, sinus tachycardia and repolarization abnormalities, and ventricular tachyarrhythmia. A review of epidemiologic studies has highlighted an inverse relation between the magnesium content of drinking water and ischemic heart disease–related mortality in various populations.16 Intravenous infusions of magnesium in patients have been reported to reduce coronary and systemic vascular resistance, inhibit platelet aggregation, and terminate episodes of torsades de pointes–type ventricular tachycardia.14 18 19 20
Experimental models involving manipulation of extracellular magnesium levels shed additional light on the role this cation plays in response to cellular stresses. Dickens and coworkers21 challenged cell cultures of bovine aortic endothelial cells with oxygen-derived free radicals under conditions of normal or deficient extracellular magnesium. The magnesium-deficient cells exhibited greater oxidative endothelial injury than the magnesium-replete cells, suggesting that tissues subjected to oxidative stress in the setting of magnesium deficiency sustain greater damage owing to intracellular lipid peroxidation. Using a Langendorff-perfused working rat heart model, du Toit and Opie22 studied the impact of various agents that modulate calcium flux administered during the first 2 minutes of reperfusion (early) and 15 minutes after reperfusion (late) on the severity of reperfusion-induced stunning. Calcium influx was inhibited by use of agents such as magnesium, and reperfusion stunning was attenuated only when these agents were administered within 2 minutes after reperfusion; these agents were ineffective when administered after as little as 15 minutes of reperfusion had elapsed.22 The duration of myocardial stunning in a swine model of brief coronary occlusion (8 minutes) and reperfusion was exacerbated by magnesium deficiency and ameliorated by pretreatment with intravenous magnesium.23 24A
As reported recently, intracellular magnesium levels are reduced in patients with AMI.24B This deficiency is not adequately reflected in serum measurements, since magnesium is predominantly an intracellular ion and less than 1% of total body magnesium is found in the intravascular compartment. Patients with AMI may be deficient in magnesium because of a low dietary intake, advanced age, prior diuretic use, or trapping of free magnesium in adipocytes, because soaps are formed when free fatty acids are released by catecholamine-induced lipolysis with the onset of infarction.16 25 26 The stress of AMI can intensify a patient’s magnesium requirement because of myocardial and urinary losses of magnesium.27 28 Therefore, benefit from supplemental magnesium administration should be evident in models in which magnesium is administered before occlusion, during occlusion, at the time of reperfusion, or during a short window of time after reperfusion but not late after reperfusion.
The articles published in this issue of Circulation by Christensen et al29 and Herzog et al30 when viewed in the context of six other reports of in vivo animal models of coronary occlusion and reperfusion31 32 33 34 35 36 are important contributions to the emerging database on the potential benefits of magnesium in ischemic heart disease (see the Table⇓⇓). These eight reports span four different animal species, are complementary, and provide data on magnesium loading at various times along a continuum from a point well before coronary occlusion (equivalent to primary prevention in patients) to time points just before, during, and after coronary occlusion that ranged from 45 minutes to 72 hours. The duration of coronary occlusion in all these models is longer than those previously reported in experiments on myocardial stunning23 24A and more closely mimics human AMI treated with thrombolysis or percutaneous transluminal coronary angioplasty (PTCA) rather than a bout of unstable angina.24A The treatment regimens are likely to have yielded blood or tissue concentrations of magnesium generally consistent with those observed in patients with AMI who received magnesium in clinical trials.37 Magnesium infusions can cause a multitude of cardiovascular and local cellular effects. Some investigators observed modest reductions in heart rate and arterial pressure that may have played a protective role but are unlikely to be the sole explanation for the ability of magnesium to reduce infarct size.35 36 Under the experimental conditions of Christensen et al29 and Herzog et al,30 no differences in hemodynamics or myocardial blood flow were seen in the magnesium-treated versus control animals, suggesting that any differences observed were likely to be due to a myocellular effect of magnesium.
Implications of the experimental data summarized in the Table⇑ are that magnesium deficiency at the time of coronary occlusion is associated with a larger infarct;31 short-term administration of supplemental magnesium just before coronary occlusion, during the time when the coronary is occluded, at the time of reperfusion, or within 15 to 45 minutes of reperfusion, limits the size of the infarct.29 30 32 34 36 The benefits of supplemental magnesium are lost either when there is a delay of >15 to 45 minutes after the onset of reperfusion or when reperfusion is sufficiently late such that only negligible amounts of myocardial tissue are available for salvage.29 30 35 If the coronary artery is subtotally occluded and distal perfusion is maintained, no incremental benefit of magnesium is observed.33 Confirmation of these observations is found in the reports of a greater infarct size in magnesium-deficient animals and of reduced infarct size in animals pretreated with magnesium in which AMI is produced by another method, isoproterenol infusion.38 39
While the latest experiments of Christensen et al29 and Herzog et al30 lend support to the intriguing notion that early treatment with magnesium limits infarct size by as much as 50%, they do not conclusively establish the mechanism by which magnesium exerts its benefit. The available data40 suggest that a combination of mechanisms may act additively or even synergistically to protect myocytes: (1) reduced vulnerability to oxygen-derived free radicals,21 (2) decreased cytosolic calcium levels by inhibition of inward flux of calcium ions through sarcolemmal calcium channels and possibly intracellular sites as well,11 22 33 (3) reduced myocardial oxygen demand via sinus slowing and lowering of arterial pressure,35 (4) coronary vasodilation and enhancement of collateral development,18 41 and (5) inhibition of platelet aggregation19 and prevention of coronary thrombosis.
The reduction of infarct size with magnesium has profound research and clinical implications. Do these latest experiments by Christensen et al29 and Herzog et al30 in conjunction with the other studies cited provide indirect evidence that lethal reperfusion injury occurs in experimental animals and can be ameliorated by supplemental magnesium? Since it is not possible to know in advance the moment of coronary occlusion in patients, the eight experiments in the Table⇑ taken together with the Langendorff model of du Toit and Opie22 suggest that to achieve cardioprotective effects with magnesium, the blood level must be elevated either before or within a short interval after reperfusion of a totally occluded coronary artery by thrombolysis or PTCA or after spontaneous reperfusion.42 Since thrombolysis and spontaneous reperfusion are both characterized by stuttering cycles of reperfusion and reocclusion until sustained reperfusion is achieved, magnesium regimens that include a loading bolus and infusion are probably necessary. In addition to limitation of myocardial necrosis, such a regimen might also offer protection against stunning and more necrosis should late reocclusion of the infarct-related artery occur. Finally, during the critical early hours of AMI it is imperative to maintain an adequate coronary perfusion pressure; magnesium-loaded boluses that are too large, delivered too rapidly, or given in conjunction with other vasodilating agents, such as nitrates, may cause a decrease in arterial pressure leading to a reduction in subendocardial perfusion.
Clinical Trial Results
On the basis of the experimental data on magnesium in AMI, it is possible to formulate hypotheses to help frame future studies to resolve some of the confusing and controversial results of clinical trials reported to date. To place these arguments in perspective, it is important to recall that 15 years ago DeWood and colleagues43 performed coronary arteriograms within the first 24 hours of AMI and determined that the incidence of total occlusion relative to the onset of chest pain was as follows: 0 to 4 hours, 87.3%; 4 to 6 hours, 85.3%; 6 to 12 hours, 68.4%; and 12 to 24 hours, 64.9%.
One of the earliest studies that showed a beneficial effect of magnesium in the prethrombolytic era was conducted by Rasmussen at a hospital in Copenhagen that was served by a highly efficient ambulance service such that patients with AMI were admitted in <1 hour from the onset of chest discomfort (H. Rasmussen, personal communication, 1995). The 30-day mortality rate was reduced from 17.0% in the control group to 6.7% in the magnesium-treated group. Since Rasmussen administered magnesium <3 hours after admission, one might deduce that the majority of patients in the trial had an occluded infarct-related artery at the time magnesium was infused and that the plasma level was therefore elevated when spontaneous reperfusion occurred.44
The LIMIT-2 trial randomized 2316 patients a median of 3 hours from the onset of chest pain (74% were actually randomized within 6 hours).37 It was a protocol requirement that magnesium be infused coincident with thrombolysis: a treatment that was administered to 36% of patients. Thus, LIMIT-2 investigators were likely to have achieved an elevated magnesium level at the time of reperfusion in those patients undergoing thrombolysis; the relatively early enrollment of patients not receiving thrombolysis combined with prompt administration of magnesium after enrollment also makes it likely that magnesium levels were elevated when spontaneous reperfusion occurred in patients not undergoing pharmacological reperfusion. All-cause mortality was reduced by 24% at 28 days (control group, 10.3%; magnesium-treated group, 7.8%). Survival curves from the trial show that the majority of the mortality reduction took place in the first week of follow-up.37 Indirect evidence consistent with a limitation of infarct size as a mechanism by which magnesium reduced mortality in LIMIT-2 is the 25% lower rate of congestive heart failure observed during the hospital phase of treatment and the >20% reduction in ischemic heart disease–related mortality during long-term follow-up that now extends to a mean of 4.5 years.37 40
The ISIS-4 trial randomized 58 050 patients a median of 8 hours from the onset of chest pain (only ≈40% were randomized within 6 hours) and reported no mortality benefit at 35 days in all randomized patients (control group, 7.24%; magnesium group, 7.64%) or any subgroup of patients.45 However, it was a protocol design element of ISIS-4 that thrombolytic therapy be administered before magnesium was infused; the window for infusion of magnesium was up to 24 hours from the onset of chest pain. Although the time from chest pain to randomization was recorded for each patient in ISIS-4, the actual number of hours from onset of chest pain to thrombolysis (a treatment administered to 70% of patients in the trial) was not recorded and neither was the time from randomization to actual infusion of magnesium. In the 30% of patients who did not receive a thrombolytic agent, the median time to randomization was 12 hours, an interval by which a substantial number of patients would have achieved spontaneous reperfusion. Given the low mortality rate in the control group, the late enrollment of patients in ISIS-4, especially in the subset not receiving thrombolysis, and the fact that magnesium infusions were delayed 1 to 2 hours after thrombolytic therapy, it is possible that the majority of patients in ISIS-4 were at low risk of mortality and did not have an elevated magnesium blood level until well beyond the narrow time window for salvage of myocardium or prevention of reperfusion injury suggested by experimental data. Use of the number of hours from chest pain to randomization as a surrogate estimate of the time of magnesium administration in ISIS-445 may be too imprecise in view of the critical relation between elevated extracellular magnesium levels and reperfusion as illustrated by the animal models of Christensen et al29 and Herzog et al.30
Shechter et al46 recently reported a series of 198 patients who were not candidates for thrombolysis and who were randomized an average of 7 hours after the onset of chest pain to receive either a magnesium infusion or matched placebo. (This was an average of 5 hours earlier than the comparable subgroup in ISIS-4.) The magnesium-treated group experienced a mortality rate of 4.2% compared with 17.3% in the control group; much of this mortality benefit appeared to be accomplished by a reduction in the incidence of cardiogenic shock and congestive heart failure—findings that are consistent with the hypothesis that magnesium limited infarct size.26 46
Where Do We Go From Here?
Clinicians now find themselves in an unusual position. Isolated tissue experiments and in vivo models offer a consistent mechanistic message—magnesium limits the amount of dysfunctional myocardium after AMI, but to accomplish this extracellular magnesium levels must be elevated when coronary blood flow is restored. The ability of magnesium to block calcium overload and limit oxygen-derived free radical injury makes it an even more attractive candidate as an adjunctive agent than superoxide dismutase, which appears to act predominantly on the latter source of cellular damage and has been disappointing in human trials to date.47 48
Meta-analyses49 50 of small-scale clinical trials were concordant with the animal data and showed a reduction in mortality with magnesium that appeared to be confirmed by an intermediate-size trial (LIMIT-2). When one factors in the inexpensive nature of the agent and inserts the LIMIT-2 data in a Markov model, a highly favorable incremental cost-effectiveness ratio is calculated for prescribing magnesium in AMI (K.E. Fleischmann, MD, unpublished observation, 1995). Many therapies in medicine are in use today with a far less impressive portfolio than that assembled for magnesium.
It is also clear that the extremely large sample size of ISIS-4 and its disappointing findings regarding magnesium despite the preceding positive trial results have convinced many physicians that magnesium is ineffective51 52 . Fewer than 10% of clinicians currently report using magnesium in AMI in the ongoing National Registry of Myocardial Infarction-2 (E.M. Antman, MD, unpublished observation, 1995). It should be noted, however, that an attempt to pool ISIS-4 in a meta-analysis with all preceding trials by use of a fixed-effects model that does not account for potentially critical intertrial differences such as timing of administration may produce misleading conclusions.26
One might conclude at this point that one of two possibilities must be the case: (1) ISIS-4 was correct and magnesium is ineffective51 52 or (2) the animal models and smaller clinical trials are correct and magnesium reduces mortality in AMI. However, I believe an alternative explanation more accurately fits the available data—magnesium decreases myocardial damage and reduces mortality if it is administered before reperfusion occurs. Experimental models and clinical trials show progressively smaller benefits and eventually no benefit the later magnesium is given after reperfusion. Mortality reduction with magnesium is greatest in patients with the highest baseline risk (as in the Rasmussen et al44 and Shechter et al46 trials).26 Thus, ISIS-4 appears to provide biologically important and clinically useful information that is congruent with the animal models—late administration of magnesium to inherently low-risk patients is of no benefit and may expose patients to the risk of coronary hypoperfusion if arterial pressure is reduced.
Despite the large sample size of the ISIS-4 trial, the question of the role of magnesium in AMI especially with early administration to higher risk patients remains an open one that needs to be settled by another clinical trial. An NIH-sponsored trial (MAGIC) that will be underway shortly hopefully will provide important information to resolve the question of the role of magnesium in the management of acute myocardial infarction. We can either continue to develop future therapeutic strategies in medicine by taking promising observations from the bench and testing them at the bedside in clinical trials of a practical sample size or clinicians will insist on seeing the results of megatrials before making definitive therapeutic recommendations. The answer for the role of magnesium in AMI is important by itself and has broader implications as to how we should allocate research dollars in the future.
The author wishes to acknowledge the valuable editorial suggestions of Drs Mildred Seelig, Robert Kloner, Kent Woods, Thomas W Smith, and Eugene Braunwald.
- Copyright © 1995 by American Heart Association
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