ARTICLE
Auteur(s) : Ronald Smetana, H. Georg Sthlinger,
Katharina Kiss, Dietmar H. Glogar
Introduction
Coronary artery disease (CAD) ranks top in mortality and
morbidity indices for humans. A number of risk factors such as
hypertension, diabetes mellitus, hyperlipidemia, obesity, smoking,
physical inactivity and stress are known to contribute to the
development of CAD.
Over the past decade several reviews have focused on the relevance
of magnesium in cardiovascular disease [1-11]. Special interest has
developed regarding the importance of magnesium as a
pharmacological agent in the treatment of acute myocardial
infarction (AMI). Evidence exists that magnesium could diminish or
even prevent reperfusion injury in AMI [12-15]. Appreciation of the
qualitative and quantitative role of magnesium in CAD and AMI is
continuously increasing ; nevertheless, there is still a need
for further studies.
After the 2nd Leicester Intravenous Magnesium
Intervention Trial (LIMIT-2) and the 4th International
Study on Infarct Survival (ISIS-4) the doubts on the efficacy of
intravenous magnesium in AMI still remain [16, 17]. The present
clinical study Magnesium in Coronaries (MAGIC) will hopefully
answer the open questions [18].
Physiological and pathophysiological cardiac mechanisms
The activation of the sympathetic nervous system has to be
considered as a compensatory mechanism to maintain perfusion
pressure for vital organs and enhance myocardial contractility [19,
20]. Nevertheless, one of the most important actions of
catecholamines is to alter the cardiac electrolyte metabolism.
Adrenaline stimulates the beta-adrenergic receptors, and this leads
to increased intracellular cyclic adenosine monophosphate, which
activates the membrane-bound, magnesium and adenosine triphosphate
(ATP) dependent sodium-potassium pump in order to maintain membrane
stability. This sequence is a physiological mechanism of the vital
myocardium that turns into a pathophysiological pattern in case of
ischemia followed by intracellular loss of potassium and
magnesium.
The ischemic myocardium
Myocardial perfusion is mainly determined by arterial blood
pressure and diastolic coronary perfusion. Ischemia in the course
of AMI leads to progressive myocardial necrosis dependent on the
duration of occlusion.
CAD is characterised pathomorphologically by arteriosclerosis and
is expressed clinically by reduced coronary blood flow with
consecutive myocardial ischemia and hypoxemia. Myocardial
dysfunction is accompanied by increased catecholamine
concentrations in blood and urine. The increase in catecholamine
concentration is related to the severity of CAD and/or to the
performance of the left ventricle.
In the case of coronary occlusion and consecutive myocardial
necrosis activation of the sympathetic nervous system is enhanced
and leads to increased release of catecholamines. In order to
maintain magnesium dependent cardiac energy metabolism the
requirements of magnesium are elevated. The persistence of this
status leads to an imbalance of the intra/extracellular ion
concentration and consecutively to a reduction of activity of the
magnesium dependent membrane bound sodium-potassium pump, which
leads to an increased influx of calcium.
Catecholamines and systemic stress
In relation to the duration and severity of CAD stress and
magnesium deficiency are mutually enhancing [21]. Thus, a vicious
circle may develop resulting in adrenergic overstimulation. The
enhanced catecholamine output in CAD requires an increased
magnesium supply to maintain intracellular energy-bound metabolic
processes. Therefore, physical and psychological stress increases
the amount of magnesium required. The catecholamines cause movement
of magnesium from intra- to extracellular compartments.
Consequently, the electric membrane becomes unstable and membrane
permeability increases, followed by cellular loss of magnesium and
potassium and an increased risk of developing ventricular ectopic
beats, with the risk of more severe arrhythmias and a low threshold
for ventricular tachycardia and fibrillation [22]. Additionally,
the loss of myocardial magnesium is associated with the uptake of
calcium that proceeds cardiac damage by calcium accumulation [21,
23].
Acute myocardial infarction and reperfusion injury
In AMI the restoration of coronary blood flow by pharmacological
or mechanical interventions is essential for the survival of the
ischemic myocardium. Cardiac reperfusion, however, may be followed
by complications such as myocardial stunning, arrhythmias and even
lethal cell injury [23, 26].
The possible pathomechanisms underlying reperfusion injury
according to the current knowledge are: oxygen radicals, generated
by the restoration of blood flow, ischemia induced activation of
the complement system, and disturbance of calcium homeostasis in
addition to oxidative stress and complement-mediated damage in the
myocardium. The development of myocardial stunning is related to
cytosolic calcium overload at the onset of reperfusion [26].
Magnesium is a physiological calcium blocker modulating the
transmembrane shift of calcium and the calcium transport across the
sarcoplasmic reticulum. Since calcium overload plays an important
role in the pathogenesis of reperfusion injury, the channel
blocking properties of magnesium may have beneficial effects in
patients with AMI. The intravenous administration of magnesium
leads to an increase in extracellular magnesium and may reduce the
infarct size through the following mechanisms: reduction of calcium
overload in myocardial mitochondria and conservation of
intracellular ATP as magnesium-ATP, improved coronary blood flow
through coronary vasodilatation, reduction of arrhythmias, and
reduction of catecholamine influence on the myocardium.
Magnesium
There is currently no class I evidence for the use of magnesium
in AMI, although several large trials have shown essential benefits
for intravenous magnesium therapy with regard to reduction of
life-threatening arrhythmia and left ventricular failure [12, 13,
16]. Magnesium acts as cofactor for over 350 enzymes and
metabolic processes in the human body. Its function as a cofactor
of the cellular energy metabolism as magnesium-ATP is of obvious
importance. During ischemia caused by impaired coronary blood flow
the need for magnesium augments, necessitating increased
utilization of intracellular reserves. As the equilibrium of the
electrolyte fluxes is very sensitive to changes of the ionic
stability, an increased influx of calcium is taking place. Growing
instability of the cell membrane to the point of membrane leakage
and loss of magnesium into the extracellular compartment follows
this disturbance of cellular homeostasis. These incidents are
followed by increasing loss of function of the myocyte, leading to
development of systemic stress and to a further rise in
catecholamine output. A vicious circle consisting of increased
catecholamine stimulation, extended activation of the energy
metabolism of the cell and therefore augmented need for magnesium
develops, finally leading to the total loss of cell function and
cell lysis [21, 26]. Magnesium may therefore play a pivotal role in
the prevention of reperfusion injury by membrane stabilization and
reduction of calcium overload in the myocardial mitochondria and by
conservation of ATP as magnesium-ATP. The use of intravenous
magnesium in AMI is a stimulating option in the scope of future
strategies in therapeutic regimen.
What is evidence
Experimental and clinical studies have shown that the
application of magnesium in pharmacological dosage improves the
myocardial energy metabolism, stabilises cell membranes and leads
to vasodilatation of coronary arteries as well as peripheral
arteries [25-28].
Based on these studies LIMIT-2 was performed. LIMIT-2 provided
data on more than 2,300 patients. In contrast to earlier
studies patients receiving thrombolytic therapy were included. The
study protocol demanded that magnesium was given as soon as
possible after the onset of symptoms. In case of thrombolytic
intervention magnesium had to be administered before thrombolysis.
The results showed an impressive reduction in short-term mortality
of 24% for the magnesium group compared to the placebo group.
Furthermore, in a follow up of LIMIT-2 a 20% reduction in long-term
mortality after 4.5 years could be demonstrated [29].
Based on the results of LIMIT-2 the intravenous application of
magnesium in AMI was investigated in ISIS-4, together with
captopril and isosorbid-mononitrate. Thrombolytic intervention was
a part of this study protocol as well. ISIS-4 was an international
multicenter clinical trial with more than 58,000 patients. The
publication of the results induced the “ISIS-CRISIS”, since the
data showed no positive effect of magnesium on mortality.
Additionally the study documented the risks of magnesium
administration like the occurrence of bradycardia and
hypotension.
As it has been pointed out in several critical reviews, the
crucial aspect leading to the success or failure of magnesium
application in AMI is the timing of magnesium
therapy – on average, magnesium was given 5 hours
later in ISIS-4 than in LIMIT-2.
In another important prospective, double-blind, placebo controlled
trial, magnesium was given intravenously in patients with AMI who
were considered unsuitable for thrombolytic therapy because of late
arrival at the hospital, i.e. more than 6 hours after onset of
symptoms, and an age of more than 70 years [30]. The results
of this study suggested that high-risk patients clearly benefit
from an infusion of magnesium.
The recently published Second National Registry in Myocardial
Infarction in the USA contains conflicting data from randomised
controlled trials [31]. The study evaluated the use and impact on
mortality of intravenous magnesium in the treatment of patients
with AMI. The results revealed that only 5.1% of more than
173000 patients received intravenous magnesium within the
first 24 hours after an AMI and the outcome of magnesium use
was associated with increased mortality. However, multivariate
analyses testing interaction effects in this study suggest that
intravenous magnesium may benefit patients who receive thrombolytic
therapy.
Thus, similar to the guidelines of thrombolytic intervention,
there is evidence, however incomplete, that the early
administration of intravenous magnesium, at the latest before
myocardial reperfusion has started, may have beneficial effects, as
expressed by a reduced incidence of left ventricular failure during
the acute phase of myocardial infarction and a reduction in
mortality at the early stage of the post-infarction period
[32].
MAGIC
The conflicting results of prior trials mean that the
effectiveness of magnesium remains uncertain. Analyses of the
varying results suggest that timing of therapy and patient risk
level are key factors in determining magnesium effectiveness
[33].
MAGIC has been designed as the pivotal trial. The National Heart,
Lung and Blood Institute of the National Institute of Health in the
USA supports the clinical project MAGIC conducted by the Harvard
Medical School.
MAGIC is a multicenter, randomised, double blind,
placebo-controlled trial. The projected length of patient enrolment
is two years. Centers in 15 countries are expected to include
a total of 6100 patients. Eligible patients presenting with a
suspected myocardial infarction are being included. If patients are
eligible for reperfusion therapy (either thrombolysis or
percutaneous transluminal coronary angioplasty), they will be
included only if they are ≥ 65 years of age (to treat high
risk patients) and if treatment can be administered within six
hours of the onset symptoms. Patients not eligible for reperfusion
therapy will be eligible for randomisation irrespective of age,
provided treatment can be administered within six hours of the
onset of symptoms. Study drug treatment – magnesium as
magnesium sulphate and placebo – will be administered
intravenously as a bolus of 8 mmol magnesium over
15 minutes followed by an infusion of 69 mmol magnesium
for 24 hours. All other treatments should follow standard care
for AMI as outlined in existing publications such as the American
College of Cardiology/American Heart Association Practice
Guidelines [34, 35]. The primary endpoint in this trial is 30-day
all cause mortality.
Conclusion
Intravenous magnesium therapy can reduce mortality in patients
with AMI as documented in various studies. There is evidence that
magnesium may prevent myocardial reperfusion injury and reduce
infarct size. The critical point of intravenous magnesium therapy
is most likely the timing of administration. Magnesium evidently
has to be given no later than 6 hours after onset of anginal
pain and before thrombolytic therapy is initiated. In view of the
current knowledge there is general agreement that new clinical
trials must be performed to point out future directions for the
management of intravenous magnesium therapy in AMI. The focus must
certainly be on the high-risk patient. The answer to the unresolved
issues could be “MAGIC”.
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