Download Metabolic Response during Impending Myocardial

Metabolic Response during Impending
Myocardial Infarction
II.
Clinical Implications
By M. F. OLIVER, M.D.
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SUMMARY
The immediate local metabolic response of the myocardium to acute regional
ischemia is determined by an interaction of various influences. These include: (1)
the extent of and the variability in reduction of blood flow; (2) the degree and persistence of hypoxia; and (3) the effects of local release of catecholamines, particularly
in relation to loss of intracellular potassium.
The subsequent metabolic response of the myocardium is partly dependent on the
degree of impairment locally of normal myocardial metabolism and partly on the
systemic reaction to increased catecholamine activity and hence on: (1) adipose
tissue lipolysis; (2) hepatic and muscle glycogenolysis; (3) insulin suppression; and
(4) growth hormone and cortisol activity. These determine the extent of the uptake
from blood of FFA and glucose by the ischemic myocardium.
There is increasing evidence that high arterial concentrations of FFA can depress
myocardial performance by leading to ventricular arrhythmias and decreased contractility. This effect probably depends on a critical interaction between the local concentration of FFA, catecholamines, and hypoxia.
Metabolic intervention in the management of heart attacks should accordingly be
directed toward reducing mobilization of adipose tissue FFA and increasing myocardial
glycolytic activity.
THE IMMEDIATE MYOCARDIAL and
systemic metabolic responses to a "heart
attack" result from acute myocardial ischemia
rather than from myocardial infarction. The
essential difference between these conditions
is that ischemia can disappear spontaneously
and is potentially reversible therapeutically.
There are difficulties in studying the immediate consequences of myocardial ischemia in
man, since many episodes probably occur
without recognizable symptoms and many
patients die before they can summon medical
aid. Indeed, the median time of death after
the onset of symptoms of impending infarction is about 2 hours,l and well before the
morphologic characteristics of myocardial infarction can be identified. It is just for this
reason that understanding of the metabolic
and electrophysiologic consequences of acute
From the Department of Cardiology,
Infirmary, Edinburgh, Scotland.
Circulation, Volume XLV, February 1972
myocardial ischemia is so vital. The problem is
compounded by the fact that most studies of
experimentally-induced myocardial ischemia
have little analogy with ischemia occurring
spontaneously in the aging and extensively
arteriosclerotic human heart. Further, angina
induced by exercise, pacing, or hypoxia does
not lead to the same degree of systemic
disturbance as prolonged ischemia due to
acute coronary occlusion.
The purpose of this paper is to review, in
the context of acute heart attacks in man, the
probable immediate local metabolic response
in the myocardium, the general systemic
metabolic response, and the effect of each on
myocardial rhythmicity and contractility.
Immediate Local Metabolic Response
This is primarily determined by acute
myocardial ischemia and secondarily by local
catecholamine release.
Royal
491
492
Ischemia
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In the acutely ischemic and inifareting
myocardium, there is likely to be hypoxia of
xvarying degrees rather than extensive anoxia.
The myocardium beyond the site of coronary
artery occlusion probably undergoes rapid
changes wvith collateral vessels opening and
closing as thrombi occur locally, with some
areas of poor perfusion recovering as intravascular pressure improves and with others
becoming temporarily or permanently starved
as flow ceases altogether. There can be little
static in the-myocardium during the first hour
after occlusion, and this is emphasized by the
heterogeneity of pathologic change after
experimental coronary artery occlusion.' Perfusion of viable myocardial tissue depends on
the interaction of many influences and the
balance obtained between opposing forces.
For example, the immediate decrease in local
pressure in the arteries distal to the area of
partial or complete block will directly reduce
perfusion and stimulate inflow from collateral
vessels. Again, metabolic changes (see below)
can cause vasodilatation through release of
adenosine, and catecholamines can cause
vasodilation and vasoconstriction. Spreading
thrombus formation in arteries under low
pressure, a decrease in stroke output, and
raised left ventricular systolic and diastolic
pressure can all impair local perfusion.
The high oxygen content of venous blood
leaving the ischemic area and the reasonably
well-maintained epicardial (but not endocardial) oxygen tension emphasize that it is
hvpoxia rather than anoxia that determines
the immediate local metabolic response. In
addition, it is regional hypoxia compounded
by reduction and not cessation in coronary
flow-in other words, regional myocardial
ischemia in a heart where flow to other areas
is not impaired. The persistence of myocardial
ischemia, the degree of adaptation to it, and
the critical nature of certain affected sites
(Purkinje tissue) may all be more important
than its- extent in relation to the subsequent
onset of ventricular arrhvthmias and acute
failure.
In an accompanying paper, Opie` has
OLIVER
described the metabolism of glucose and free
fatty acids (FFA) in the normally oxygenated
heart and the adjustments that probably occur
in ischemia. The evidence for accelerated
glycolysis and anaerobic energy production is
reviewved. One of the difficulties we haxve at
present is understanding exactly how these
intracellular metabolic events trigger off ain
arrhvthibia or lead to acuite heart failure. Two
resultant acute changes which require emplhasis are reduction in extriacellular pH4 aind release of mvocardial catecholamine stores. Reduction of pH is probably due mostly to
release of hydrogen ions during hydrolysis of
ATP at a greater rate thaln it is synthesized and
perhaps from accumulation of hydrogen ions
associated with lactate release aind accumulation of FFA. Very little is known about changes
in intracellular pH but reduction could oc'CuIrl
v ery locally and lead to local cellulai damnacge.
Acidosis has been shown to suppress pacemaker and contractile perfor mance in the
anoxic isolated rat heart.) Release of imivocardial catecholamines maya be theo mlost important of all the adverse influences and responsible for many of the local metabolic changes.
Local Catecholamine Release
Experimentally it has been showin that
activation of sympathetic receptors in the
mvocardium can occuI immediately as a resuilt
of mvocardial isehemia or of an1 inicrease in
coronlary artery pressure: a very rapid spinlal
reflex, abolished by sectioninig of differeint
fibers to the stellate ganglia, takes place witlh
stimulation of differenit sympathetic fibers
to the myocardium.; Release occurs of
epinephriie anid inorepiinephrinie, stored in
granules on the preterminal svmpathetic
fibers. Catecholamines are released within
minutes into the circulation in most dogs after
coronary artery ligation.7 Depletion of catecholamines from ischemic and infarcted areas
of the myocardium wJas first reported in man
from histochemical studies," and this has been
observed experimentally as sooin as half an
hour after ligation of a coronary arterv.10 The
view that local catecholamine activity can lead
to early myocardial damage seems reasonable
in consideration of the many reports of
Circulation, VoluwIe XLV. Februar 1972
METABOLIC RESPONSE DURING MI ( II )
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morphologic changes following the administration of catecholamines.1 1 2 Catecholamine
stimulation of phosphorylase activity is well
described8 and can occur within 1 min of
producing total myocardial ischemia..'8 Together with a rise in orthophosphate, this is
probably the immediate and initial stimulus
to glycogeniolysis. Catecholamine stimulation
also leads to anl inicrease in succinlic and lactic
dehydrogeniase activity in the ischemic area of
the myocardium with efflux inlto the coronary
sinlus. Histochemical or morphologic changes
do niot occur wheni coronary artery ligationi is
not associated wvith catecholaminie release.14
Certain local metabolic changes could result
from local catecholamine activity. These
include glycogenolysis and glycolysis. Hydrolvsis of stored triglyceride can occur since
catecholamines activate a myocardial lipase.'5
This local effect of catecholamines may be
particularly important in humans, since there
is much more triglyceride stored in our hearts
compared with that in most animals." In the
presence of severe hypoxia, an increase in the
intracellular concentration of FFA could
result. Any decrease in carrier protein would
exaggerate the effects of intracellular FFA
accumulation. Weakly bound FFA could
combine with acyl-CoA and also form cation
salts. It has been hypothesized that these
could harm cell and mitochondrial membranes
as a result of detergent action.'7 Increased
concentrations of FFA can also depress
mitochondrial oxidative metabolism.'`8
There is much evidence linking increased
catecholamine activity with serious arrhythmias in experimental animals19-22 and in man,
and measures designed to reduce the action of
catecholamines on the myocardium such as
cardiac denervation 2 or ,8-adrenergic blockade'!' decrease the arrhythmogenic tendency.
The mechanisms through which these changes
trigger an arrhythmia are not clear. During
mvocardial isehemia, potassium and phosphate loss occurs24 but this loss of ions is
enihaniced by large conicenitrationis of norepinephrinie although reversed by low concentrationls of norepiinephrine.25 Presumably there is
irregularity of potassium loss, anid marked
(irculation. Volume XLV, February 1972
493
difference in the gradienits of cationl conlcenltration across cell membranes may xvell exaggerate the temporal discrepancy in recovery
of excitability kniowiv to exist between Purkinje
tissue anid venitricular muscle and to the initiationi of arrhythmias.21" A further factor of
importaince is the movemeAnt of extracellular
fluid inlto the ischemic cell causinlg sxvellinlg
anid further reductioni of initracellular potassium concenitration.Systemic Metabolic Response
This is mainly determined by increased
plasma catecholaminie concentrationls (fig. 1).
When acute coronary artery occlusion leads
to symptoms, aid this is not always the case,
there is stimulation of postganglionic sympathetic nerve endings with release of norepinephrine, and of the adrenal medulla with
release of epinephrine. Both catecholarmines
are present in high concentrations in plasma28
and urine2t} during the first 24-48 hours after
the onset of symptoms. The concentrations of
these catecholamines in plasma reach high
levels withini the first fexv hours after the onset
of symptoms and later appear to be related to
the severity of the infarct. Norepiniephrine
acts through ,3-adreenergic receptors to activate
the adeniylcyclase system in adipose tissue
causing conversioni of ATP to cyclic AMP, and
cyclic AMP activates a lipolytic system leading
to hydrolysis of stored triglycerides to diglycerides, FFA, and also glycerol. While some
reesterification of FFA occurs, the net effect is
release of FFA and glycerol into the eirculation.") In acute myocardial infarction, plasma
FFA concentrations are elevated xvithin 4
hours of the onset of symptoms.:' The highest
values are found on the first day, and by the
sixth day normal values are usually reached.32
Glycerol levels are also elevated. There is a
close relationship betweein blood catecholamine anid FFA values in myocardial infare-
tionl.34
Epinephrine has a weak effect on adipose
tissue lipolysis but its main action at this time
is to stimulate glycogenolysis in liver and
muscle 'with elevation of blood glucose levels.
Epinephrine also suppresses f-cell activity in
OLIVER
494
Acute mvocardial ischemia
.Pain and "stress"
of,
ACTH-
Cortisol
Adrenal medulla
Postganglionic
sympathetic
I
nerves
Norepinephrine
Epinephrine
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Gluconeogenesis
Suppiression
of insulin
secretion
Growth hormione
Adipose tissue lipolysis
Hepatic and
muscle glycogenolysis
Plasma free fatty acids +
Plasn3a glycerol +
Plasma glucose +
Figure 1
Schemratic diagram illustrating some of the systemic metabolic responses which occur during
inmpending myocardial infarction. Many of these interact, and the diagram is deliberately
simplified.
the pancreas35 with a decrease in insulin
secretion leading to further elevation of blood
glucose. Thus, hyperglycemia occurs after
acute myocardial infarction, and more than
half of these patients have an abnormal
glucose tolerance test during the first 72 hours
of the attack.36, Reduction of insulin secretion
has been demonstrated in patients after acute
myocardial infarction following an intravenous glucose load37 and an intravenous
tolbutamide test.38 The degree of failure in
these responses has been positively correlated
with the severity of the illness and with the
presence of cardiogenic shock. Cortisol secretion 39 and plasma growth-hormone levels40 are
increased during the first 24 hours after the
onset of acute myocardial infarction. As the
clinical condition improves, the degree of
glucose intolerance diminishes and insulin
secretion increases. In the second week plasma
insulin levels are above normal,40 and at this
stage the anabolic effect of insulin in enhancing the transport of amino acids into cells and
their incorporation into protein is important
for repair of the injured myocardium. Cortisol
stimulates the breakdown of protein for
gluconeogenic purposes and also the key
gluconeogenic enzymes, but it is doubtful
whether these actions operate until the acute
period has passed.
These increases in plasma FFA and glucose
usually allow ischemic myocardial cells to be
perfused with sufficient concentrations of
substrates to ensure the survival of many.
However, an excessive response, which rnay
no longer he optimal, can occur in some
patients. Plasma FFA can be elevated
beyond the concentration when they are
carried by the two principal binding sites on
albumin-a 2:1 molar ratio is exceeded when
plasma FFA levels are greater than 1200
jgEq/liter, and occasionally levels in the
Circulation, Volunie XLV, February 1972
METABOLIC RESPONSE DURING MI (II)
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region of 2000 ,Eq/liter have been recorded.
When the FFA/albumin ratio increases, fatty
acids are progressively more weakly bound to
albumin, and there is an exponential relationship between increases in FFA/albumin ratio
and FFA entry into the cell.41 In dogs during
extensive myocardial ischemia, there is a
proportionately greater myocardial uptake of
FFA when compared with that of glucose and
pyruvate and with myocardial oxygen consumption despite reduced coronary flow.24
This relatively larger uptake of FFA is
reflected in an increase in the oxygenextraction ratio for FFA from 77% in the
control period to 101% during ischemia and a
decrease in the oxygen-extraction ratio for
glucose from 33 to 25%. In patients with a
severe systemic response to acute myocardial
infarction, insulin suppression can be almost
complete, and this will reduce the availability
of glucose to myocardial cells in spite of the
rise which occurs in plasma glucose levels. In
addition, there is recent evidence that glucose
uptake by the myocardium in normal resting
man is inversely related to FFA levels42 and
perhaps less dependent on insulin than was
previously thought. Thus, ischemic myocardial
cells may in some patients be exposed to an
unusually high FFA/glucose ratio as a result
of a marked systemic metabolic response.
Effect of Local and Systemic Metabolic
Response on Myocardial Performance
The two chief complications of myocardial
ischemia or infarction are serious ventricular
arrhythmias and pump failure. The former
occur soon after the onset of symptoms and
the latter may either occur early as so-called
cardiogenic shock when it is associated with a
poorly understood set of vascular reflexes or
later as left or progressive right ventricular
failure. In this section, consideration will be
given to the relationship of the local and
general metabolic changes on the development of arrhythmias and on myocardial
contractility.
Arrhythmias
Reference has already been made to the
relationship between increased catecholamine
Circulation, Volume XLV, February 1972
495
activity and arrhythmias, and in recent years
the possibility has arisen that high plasma
FFA levels may have an independent arrhythmogenic action. This is a potentially
important concept and is based on the
following evidence. In patients with acute
myocardial infarction, a positive relationship
has been reported between the incidence of
serious ventricular arrhythmias and of early
deaths with plasma FFA levels above 1200
,iEq/liter,31'43 although this has not been
observed by all investigators.21 44 In similar
patients, a positive correlation between plasma
glycerol levels and arrhythmias has also been
observed.33 FFA can cause arrhythmias in
other species without changes in catecholamine activity. In the normal dog, intravenous
infusions of FFA as their sodium salts can
cause conduction defects45 although not ventricular arrhythmias; in geese, elevation of
FFA by glucagon produced ventricular arrhythmias and myocardial necrosis;46 and, in
isolated perfused rat-heart preparations, octanoate produced arrhythmias.47
Investigations had been made of the effects
on cardiac rhythm of increased arterial FFA,
elevated by heparin induction of plasma lipolysis independently of catecholamine activity, in dogs in which myocardial infarction was
produced experimentally. In studies in which
occlusion of the circumflex coronary artery was
produced in a closed-chest preparation with
subsequent infarction of the lateral wall of the
left ventricle, marked elevation of plasma
FFA was usually associated with the development of frequent ventricular ectopic systoles
and sometimes with ventricular tachycardia or
even ventricular fibrillation.48' 4 In a comparable set of studies, however, conducted in
dogs in which an apical branch of the anterior
descending artery was ligated with consequent production of a small infarct at the apex
of the left ventricle, marked elevation of
plasma FFA by use of the same system for
inducing plasma lipolysis was not associated
with any increase in the incidence of serious
ventricular arrhythmias.50 An explanation for
these apparently contradictory results is not
immediately forthcoming. It is important to
496
OLIVER
Table 1
Main Differences in Experimental Design between Edinburgh and London in Relation
to Induction of Arrhythniias by Elevation of Arterial FFA and through Administration of
Initralipid and Heparin
Parameter
Lonnlon
Edinburgh
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FFA levels (,uEq, liter) 2t0-)() 6000
2000-600(0
ArrihyTthmia
Yes
No
AI omgrels (sometimes ii idernlouirished) Greyhounds (differeint life
Subj ects
historv, exercise, habits,
physiologic hypertrophy
of heart, anid perhaps
differ enit feeding)
AMaterial
Closed-chest preparation
Openi-chest and pericardectomy
Maini (circultmflex
Branich of aniterior desceniding
Ar.tery
Treatmenit
Occlusion of artery with
Ligation of artery
balloon catheter
Initerruption of arterial
?Stimntiatiuln of arterial sympathetic
sympat.hetic nerves
imer-ves bv stretching
?In crease
Local cateeholaminle
?D1)ecrease
concentration
Hea.rt rate (beats m-rniii) 120-1-)0
160-180
3.6 4.0
Serutm potassiuim
3.2-3.7
(mEq/liter)
Seruim albutmin (g/liter) 2 -3)
recognize that there were marked differences
in the experimental models and systems of
study. These are illustrated in table 1.
Differences of potential importance are that
Opie and colleagues5" may have conducted
their experiments in conditions of reduced
sensitivity to the induction of arrhythmias, as
a result of pericardectomy which reduces
contractile force,51 of reduced local catecholamine concentration due to interruption of
the sympathetic supply during ligation of the
artery, and of the higher heart rate which
could prevent complete manifestation of a
parasystolic focus originating in an accelerated "automatic" cell in the Purkinje system.
Small doses of norepinephrine, which
elevated FFA but did not lead to any hemodynamic changes, reduced the incidence of ventricular ectopic activity and enhanced contractility in dogs with extensive myocardial
infarction.24 Whether this can be regarded as
evidence against the arrhythmogenic activity
of FFA is not clear, since the egress of
potassium ions that usually occurs in acute
ischemia was reduced in the same experiments. Recently, it has been shown that in-
4-4.5
fusions of FFA/ albumin complex to dogs
with experimental myocardial infarction will
raise arterial FFA to levels comparable to
those seen in patients and lead to serious
ventricular arrhythmias.52 Positive findings
have been recorded in a majority of dogs. No
arrhythmias occurred in dogs with myocardial
infarction given plasma infusions under comparable conditions without elevation of FFA.
In these studies, no heparin, catecholamine, or
lipid emulsion was used. The raised arterial
FFA decreased exponentially with time and
appear to be utilized physiologically. If
further studies confirm these preliminary
findings, the case is strong for regarding elevated plasma FFA as arrhythmogenic in the
presence of myocardial ischemia.
Final interpretation of the various experiments described is not yet possible and should
certainly take into account the type of
preparation studied, the degree of ischemia
(the absolute level of oxygen is crucial to the
metabolism of FFA), the extracellular concentrations of FFA, glucose, and insulin, and the
chain length of the fatty acids. Metabolically,
the conducting system is like white muscle
Circulation, Volume XLV, February 1972
497
METABOLIC RESPONSE DURING MI ( II )
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and has a lowver capacity to metabolize fatty
acids, and more are likely to accumulate there
when compared with the rest of the myocardium. This accumulation of FFA in myocardial cells might be exaggerated if there is
much leakage and sequestration of albumin in
extracellular tissue. Increase in arterial FFA
and increased uptake by the ischemic myocardium may be followed by triglyceride deposition if oxidation is incomplete and if there is
glucose 3-phosphate available for esterification
to take place. Fatty infiltration of the ischemic
and infarcted myocardium has been described
years ago,53 and experimental evidence is now
available of a positive relationship between the
degree of elevation of arterial FFA and
triglyceride deposition in the ischemic myocardium.54
Myocardial Contractility
Myocardial oxygen consumption (MVo,) is
determined by a number of factors including
intramyocardial tension, the contractile state
of the heart, heart rate, the external work
performed by the heart, the energy required
to activate contraction, and the metabolic
status of the myocardium. All of these can be
changed sharply by increased catecholamine
activity, thus increasing MVo.,. Any marked
increase in MV0., could be deleterious to
certain critically ischemic areas of myocardium. High levels of FFA can also increase
MVo,,. This has been shown in the isolated
perfused heart55) and in intact dogs through
studies of the effect of high concentrations of
arterial FFA produced by plasma lipolysis;i)",
local metabolic rate in the left ventricular wall
is also increased by elevated arterial FFA."7
The effects of FFA and dextrose on
contractility have been compared by studying
rat papillary muscle.58 Contractility under
well-oxygenated conditions was not altered by
equivalent concentrations of FFA or dextrose,
but under hypoxic conditions contractility was
depressed by concentrations of FFA in the
region of 2:1 albumin molar ratio and
increased by dextrose. Similarly, dextrose
improved mechanical performance in isolated
perfused hearts when hypoxic, although not
when adequately oxygenated.59 High concenCirculation, Volume XLV, February 1972
trations of FFA in the region of 6:1 FFA/albumin molar ratio depressed myocardial
contractility in perfused isovolumic heart
preparations. In addition, diastolic pressure
increased.';0 A comparable synergism on myocardial contractility has been shown between
FFA, using octanoate, and glucose in isolated
perfused rat hearts.47 From studies using a
nonmetabolized FFA (pent-4-enoic acid), this
depression of contractility appears to be
mediated directly by FFA or acyl-CoA derivatives rather than their metabolic products.';1
High arterial levels of FFA may therefore
induce arrhythmias and depress myocardial
contractility during acute myocardial ischemia,
particularly if there is a relatively small increase in glucose uptake by the myocardium
and marked hypoxia. Additionally, high concentration of FFA can decrease coronary blood
flow62 and cause platelet aggregation.63
Metabolic Intervention
Control of the extent of the metabolic
response might contribute to the management
of cardiac arrhythmias and of acute pump
failure in myocardial ischemia. The aim
should be to reduce elevated plasma FFA
levels and to increase intracellular glucose
concentrations.
One therapeutic approach, not fully explored in man, is to reduce arterial concentrations of FFA. This might be achieved by
drugs which reduce adipose tissue lipolysis.
,/-Adrenergie blockade is unlikely to be a
satisfactory means of controlling the metabolic response since the inotropic and chronotropic effects of catecholamines can be critically important in the early stages of acute
myocardial infarction. A ,8-blocker which has
a specific effect in preventing cathecholamine
activation of adipose tissue lipolysis would
however be of interest. Nicotinic acid also has
such an effect,64 but it is usually associated with
flushing. The effects of nicotinic acid analogs
require to be studied, and one has been shown
to have an antiarrhythmic action.49
An alternative approach is to increase the
uptake of glucose by the myocardium. The
intravenous use of glucose, insulin, and
498
OLIVER
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potassium to improve uptake of glucose and
prevent depletion of potassium is superficially
attractive. However, hypervolemia can occur
and the results of clinical trials are not impressive.65 This may be due to the fact that
these trials have been conducted in unselected
groups of patients with acute myocardial infarction. The patients who would be expected
to respond optimally are those with a high
plasma FFA/glucose ratio. Further, the concentrations of glucose, insulin, and potassium
which have been used have been lower than
those theoretically and experimentally desirable.66 Increased glucose uptake might also
be achieved by the use of glucagon. This substance has been shown to have a positive
inotropic action in the management of cardiac
failure and following acute myocardial infaretion.Y67 This effect might be due to increased
uptake of glucose by myocardial cells or to
increased myocardial calcium stores. Potassium and magnesium salts of dl-aspartic acid
increase glucose utilization68 and potassium
aspartate and tris-aspartate have been reported to lower heparin-induced elevation of
plasma FFA. This might be another approach
worthy of study.
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(To be continued in March CIRCULATION)
Circulation, Volume XLV, February 1972
Metabolic Response during Impending Myocardial Infarction: II. Clinical
Implications
M. F. OLIVER
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Circulation. 1972;45:491-500
doi: 10.1161/01.CIR.45.2.491
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