Myocardial Ischemia and Arrhythmia: Under the auspices of the Society of Cooperation in Medicine and Science (SCMS), Freiburg, Germany

302 Pages·1994·10.34 MB·English

by  Prof. Dr. med. J. Holtz

Myocardial Ischemia and Arrhythmia
M. Zehender, T. Meinertz, H. Just
(Editors)
Myocardial Ischemia
and Arrhythmia
Under the auspices of the Society of Cooperation in
Medicine and Science (SCMS), Freiburg, Germany
.~
Steinkopff Darmstadt
~
Springer New Y ork
The Editors:
PD Dr. M. Zehender Prof. Dr. T. Meinertz
Prof. Dr. H. Just Innere Medizin
Medizinische Universitiitsklinik Universitatskrankenhaus Eppendorf
Abt. Innere Medizin III MartinistraBe 52
Hugstetter StraBe 55 20246 Hamburg
79106 Freiburg
Die Deutsche Bibliothek - CIP-Einheitsaufnahme
Myocardial ischemia and arrytbmiajM. Zehender ... (Ed.). Under the auspices of the Society of Coopera
tion in Medicine and Science (SCMS), Freiburg, Germany. - Darmstadt: Steinkopff; New York: Springer,
1994
ISBN-13 : 978-3-642-72507-4 (Steinkopff) Gb. e-ISBN-13: 978-3-642-72505-0
DOl: 10.1007/978-3-642-72505-0
NE: Zehender, Manfred [Hrsg.]
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Copyright © 1994 by Dr. Dietrich SteinkopffVeriag GmbH & Co. KG, Darmstadt
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Softcover reprint of the hardcover 1st edition 1994
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Preface
During recent years, it has become evident that ventricular arrhythmias may arise
from myocardial ischemia and that they may be harbingers of sudden cardiac death.
On the other hand, ventricular arrhythmias may occur without any prognostic
significance and sudden cardiac arrhythmic death may strike without any warning
arrhythmia. The role of ischemia in the genesis of ventricular arrhythmias and of
sudden cardiac death has been observed beyond doubt. However, the mechanism by
which ischemia leads to the appearance of ventricular arrhythmias and/or sudden
cardiac death has remained rather poorly understood, inspite of rather remarkable
research efforts on the one hand, and the magnitude of the problem on the other
hand.
We have therefore set out to assemble scientists from around the world in order to
define the current state of our knowledge on myocardial ischemia and arrhythmia.
Well in line with the tradition of the Gargellen Conferences, we assembled clinicians
and basic scientists for the 7th Gargellen Conference. This book presents the proceed
ings of the Symposium in the attempt to define the current status of our understand
ing of this significant problem. The Symposium was organized by the Society for
Cooperation in Medicine and Science (SCMS) and was generously sponsored by
Astra Chemicals, Wedel; Bayer AG, Leverkusen; Boehringer-Mannheim; CPI-Lilly,
Giessen; Janssen GmbH, Neuss; Minden Pharma, Minden; Rahm Pharma, Weiter
stadt; Schering AG, Berlin, and Siemens AG, Erlangen. The publication of this book
would not have been possible without the enthusiastic support of the publisher
SteinkopffVerlag, in particular Mrs. Sabine Ibkendanz. To her and her associates at
Steinkopff, we extend our sincere thanks for expert help and friendly cooperation.
M. Zehender
T. Meinertz
H. Just
Introduction
Myocardial ischemia is characterized by ionic and biochemical alterations which
may lead to malignant ventricular arrhythmias. At the same time, the ischemic
myocardium shows both reentry and non-reentrant mechanisms contributing to the
initiation and the maintenance of ventricular tachycardias or flutter and fibrillation.
The basis may be both anatomical, e.g., scarring, as well as functional through electric
inhomogeneity due to various reasons. The complex interaction between reentry and
non-reentrant mechanisms may lead to acceleration and the development of mUltiple
reentrant circuits, thus setting the stage for ventricular fibrillation and thereby
circulatory standstill.
The nature of the non-reentrant mechanism remains to be clarified, but may be
due to delayed after-depolarizations resulting from altered calcium homoeostasis, as
occurs in the ischemic state, as well as with the more chronically occurring phenotype
change of the failing human heart.
It shall not go unnoticed that alterations of the sympathetic innervation signifi
cantly contribute to the lowering of fibrillation threshold and to the initiation of
ventricular arrhythmias.
The general sequence of events is characterized by rapid decrease in tension
development. Within seconds, contractile performance is lost. The ischemic region of
the myocardium instead stretches and bulges to the outside under the influence of the
intraventricular pressure. Within a few minutes there is a rapid decrease in high
energy phosphates, a near complete depletion of creatinine phosphate, whereas
AT P declines at a slower rate. The ischemic myocardium turns hypoxic and
acidotic. Stagnation of blood flow leads to accumulation of ions and metabolites
in the interstitial fluid, which may contribute to the development of lethal arrhyth
mias. In addition, the autonomic nervous system and the sympathetic end organs
are activated and may both systemically, as well as locally, contribute to arrhyth
mogenesis.
Let us consider in the following several arrhythmogenic mechanisms which may
act either separately or conjointly:
Numerous observations have established beyond doubt that myocardial ischemia
may precede the appearance of ventricular ectopy and/or of ventricular tachyar
rhythmias by minutes or seconds, thereby indicating that acutely occurring changes
in the state of ischemia may be responsible for the lethal arrhythmia.
VIII Introduction
Hypoxia
Myocardial ischemia induces a rapid fall of P0 in the ischemic myocardium. As
2
a consequence, electrophysiologic alterations by means of shortening of the action
potential are seen together with a decrease in resting membane potential and of z max
of phase 0 of depolarization. Voltage clamp studies have shown that the hypoxia
induced decrease in repolarization time results from an increase in the time indepen
dent potassium current. The slow inward calcium current does not seem to be
effective. Hypoxia also augments the internal longitudinal resistence, thereby in
fluencing conductive properties. The electrophysiological alterations are exaggerated
in the presence of low glucose. The effective hypoxia may be linked to the decreased
AT P production via glycolysis.
Acidosis
Ischemia induces a decrease in both intracellular and extracellular pH. The extra
cellular hydrogen ion concentration falls to a plateau between 5.5 and 6.0. Acidosis in
itself already leads to a decrease of both z max of phase 0 depolarization and of
conduction velocity. At the same time, internal longitudinal resistance increases.
Acidosis will also significantly modify the activity of several intercellular enzymes,
catabolizing substances known to accumulate in the state of ischemia.
Mechanisms leading to premature ventricular contractions
and ventricular tachycardia.
Early myocardial ischemia is accompanied by premature ventricular contractions
and a bout of ventricular tachycardia. In more than 3/4 of the cases these can be
linked to intramyocardial reentry. Marked conduction delay of the preceding sinus
beat in the subendocardium could lead to reactivation of adjacent subendocardial
tissue proximal to the block. The intramural location of the reentrant pathway has
been demonstrated repeatedly. Maintenance of ventricular tachycardia often occurs
due to intramural reentry, dependent on the continued presence of activation, which
is sufficiently delayed in order to permit the adjacent tissue to recover and to become
reexcitable upon return of the depolarization wave. The run of ventricular tachy
cardia often terminates, even in the presence of continuous marked conduction delay,
if there is a significant change in the reentrant pathway and delayed activation of the
terminal beat occurring in a region in which excitability has not recovered. Several
studies have indicated that ventricular tachycardia can also arise from non-reentrant
~echanisms. A non-reentrant mechanism is one that operates distant from the site of
termination of the preceding beat without intervening electrical activity. In terms of
the action potential, this rests upon increased velocity of depolarization during phase
4 or is due to delayed early after depolarizations.
The non-reentrant excitation arises in almost any part of the myocardium. In
chronically overloaded myocardium, especially in the presence of heart failure,
Introduction IX
myocardial phenotype changes occur which lead to characteristic derangements of
calcium homoeostasis. Here the reduced capacity of the sarcoplasmic reticulum
calcium ATPase seems to playa major role: with decreased reuptake capacity free
cytosolic calcium at the end of systole increases, leading to prolonged contraction
and delayed diastolic relaxation. If the condition exists over any longer period of
time, then upregulation of the sarcolemmal sodium calcium exchanger may occur.
The consequence is a loss of calcium to the outside with subsequent decrease in
sarcoplasmic reticulum calcium store and, therefore, a reduction in calcium ions
being available at the onset of excitation contraction coupling. At the same time,
however, for each calcium ion lost to the outside of the cell, two sodium ions do enter
the cytosol. This, of course, may lead to a propensity towards increased after
depolarizations and therefore non-reentrant ectopic activity.
Since myocardial ischemia quite often occurs on the basis of a chronically
overloaded and oftentimes failing myocardium, this condition may playa significant
role quite frequently, not withstanding the possibility that other mechanisms may
lead to the initiation of ectopic beats and their perpetuation outside the well
established reentrant mechanisms.
Under conditions of ischemia several authors have observed an increased free
cytosolic calcium concentration, which was considered to mediate electrophysiologic
alterations characteristic for early ischemia. This observation finds support in the
antifibrillatory effect of calcium channel blocking agents.
Potassium changes during myocardial ischemia
Myocardial ischemia is accompanied by a number of ionic and biochemical alter
ations contributing to arrhythmogenesis. Among them, the extracellular potassium
increases in the ischemic myocardial zone may be significant: They occur as early as
30 s after coronary occlusion and show a characteristic triphasic response. The initial
rise occurs over the first 48 min and is easily reversed. Thereafter follows a plateau
phase. The third phase occurs approximately 30 min after the onset of ischemia and
consists of an increase of extracellualr potassium, probably arising from cell death in
the state of necrosis. Extracellular potassium may reach 50 mmol or more in the
central ischemic zone. In the ischemic border zones potassium alterations may be
rather inhomogeneous. They can, however, considerably contribute to the potential
difference between endocardium and epicardium and thereby to the conditions that
increase electrical inhomogeneity. The increase in extracellular potassium appears to
correlate directly to the extent of cellular damage. On the other hand, the rise in
extracellular potassium cannot be held solely responsible for the profound elec
trophysiological alterations characteristic of myocardial ischemia. The mechanisms
responsible for the early increase in extracellular potassium in hypoxic cell injury has
not been sufficiently clarified. The inhibition of the sodium potassium ATPase may
be one mechanism. Enhanced potassium effiux may contribute. It is also possible,
that ATP-dependent potassium channels may contribute, especially since gliben
clamide, a sulfonyl urea which blocks the AT P-dependent potassium channel, has
antiarrhythmic activity during early ischemia and seems to be independent of the
x Introduction
direct effects of glycolysis. Another possibility is that other concomitant effects of
ischemia, such as lysophosphoglycerides or long chain acylcarnitins accumulate in
the membranes in ischemic myocardium. It may interact with membrane bound
AT P-sensitive potassium channels. However, this awaits clarification.
Sympathetic nervous system
Ischemia leads to alterations and activations of myocardial sympathetic afferences
and thereby induces an increase in afferent sympathetic nerve activity. Reflexly
efferent sympathetic nerve activity is increased as well. Asymmetric sympathetic
input may occur and can be potentially arrhythmogenic due to inhomogenous
alterations of ventricular conduction, rejlOlarization and automaticity. Through the
sympathetic nervous systems both reentrant as well as non-reentrant mechanisms
may lead to increased ectopic activity and/or ventricular fibrillation. Several observa
tions suggest that asymmetric (right-to-Ieft) sympathetic innervation may signifi
cantly increase ventricular vulnerability and the incidence of ventricular fibrillation.
It has remained unclear if norepinephrine released from intramyocardial nerve
terminals within the ischemic zone contributes in any significant way to the appear
ance of arrhythmias and/or the propensity to develop ventricular fibrillation. Over
all, the release of norepinephrine into the venous effluent of the myocardium during
a state of ischemia is not very pronounced. Nevertheless, an enhanced release of
norepinephrine almost invariably occurs during ischemia. It is likely that the release
of intramyocardial catecholamines occurring during early ischemia may contribute
significantly to arrhythmogenesis.
Under normal physiologic conditions adrenergic control of the myocardium
is mediated through the beta-adrenergic receptors. Intercellular mediation of the
sympathetic activity operates through a stimulation of the adenylatecyclase and
activation of the CAMP-dependent proteinkinases. This interaction between the
beta-adrenergic receptor and the activation of adenylatecyclase is functionally
coupled by a guaninnucleotide binding protein (G-protein). Cycling AMP-depending
proteinkinase has been shown to phosphorylate sarcolemmal calcium channels. This
activates the slow inward current for calcium besides the direct receptor-mediated
opening of sarcolemmal calcium channels. Beta-adrenergic receptor stimulation
appears to regulate intracellular calcium concentrations through a CAMP-dependent
influence upon the calcium channels in addition to the aforementioned mechanism.
In the state of myocardial ischemia an increase in sinus rate may increase the extent
of conduction delay and functional conduction block. Furthermore, an increase in
the slow inward calcium current may lead to an enhancement of the degree of slow
conduction and block. Finally, an inhomogeneous reduction in the refractory period
between the ischemic and non-ischemic cells may induce electrical inhomogeneity
and thereby lower fibrillation threshold.
Beta-adrenergic receptor blockade, in turn, has been shown to reduce the
occurrence of both ventricular tachycardia and fibrillation in the state of ischemia.
The mechanism of action of beta-receptor blockade has not fully been clarified,
however.
Introduction XI
The arrhythmogenic effect of beta-adrenergic stimulation during ischemia may be
enhanced by an increase in beta-adrenergic receptors. Such an increase may occur
within a few minutes after the onset of ischemia. It is still unclear if the receptor
downregulation, as commonly seen in chronic heart failure, has any significant
influence upon ventricular vulnerability. It needs to be mentioned, however, that in
the chronic failing human myocardium the propensity to develop ventricular fibrilla
tion is especially high!
Alpha-adrenergic receptor stimulation does not seem to playa significant role in
electrical vulnerability. Nevertheless, an increase of the repolarization time and
refractory periods and a decrease in automaticity are seen in isolated Purkinje fibres
in vitro. These electrophysiological effects, however, could be expected to be antiar
rhythmic rather than arrhythmogenic.
In contrast, under the conditions of niyocardial ischemia the effects of myo
cardial alpha-adrenergic stimulation may be enhanced and may even be arrhyth
mogenic. The enhanced alpha I-adrenergic responsiveness of early myocardial
ischemia may be mediated by an increase in the density of alpha I-adrenergic
receptors and/or the intracellular coupling. Enhanced alpha I-adrenergic respon
siveness during ischemia may be related to an increase in number of the recep
tors and/or to increased coupling to intracellular signal proteins, such as IP3.
Under the conditions of ischemia the fibrillation threshold in response to nore
pinephrine concentration seems to be markedly lowered. Alpha I-adrenergic
blockade may inhibit the development of delayed after-depolarizations induced
by hypoxia. It remains, however, open to further studies if alterations of the
alpha-sympathetic tone may contribute to ventricular vulnerability in a clinically
significant manner.
Electrophysiological alterations of ischemia
The aforementioned ionic and metabolic changes lead to characteristic changes in
electrophysiologic behavior of the myocardial syncytium: Marked changes are seen
within minutes of the onset of ischemia. Transmembrane action potential from the
epicardial surface of the ischemic heart demonstrates a marked decrease in resting
membrane potential, the action potential amplitude, the rate of upstroke of phase 0,
and of action potential duration. Similar observations are seen in the subendocar
dium as well.
Within 10 min the action potential demonstrates changes in amplitude and
duration with subsequent development of inexcitability and conduction block in the
central ischemic zone. During longer periods of ischemia excitability begins to return.
However, after more than 30 min of ischemia complete inexcitability is seen. Immedi
ately after, the onset of ischemia refractory period in the ischemic zone decreases.
Action potential lengthens, only to finally exceed the values seen in the non-ischemic
control state. This, however, is accompanied by a marked dispersion of the refractory
periods between the ischemic and the non-ischemic myocardial zone. The refractory
periods in the ischemic zone continue to increase with a development of post
repolarization refractoriness.
XII Introduction
The rapidity and severity of the electro physiologic alterations during the interval
after acute ischemia are recognizable in a decrease in amplitude and a variable
increase duration of the bipolar electrogram. Activation time is markedly delayed
and extracellular electro grams become more asynchronous and fractionated. At
times, continuous electrical activity is seen, spanning the interval between a normal
sinus beat and the initiation of a ventricular ectopic beat. It has been concluded that
continuous reentry can be established under these conditions. Marked slowing of
conduction velocity, as seen in early myocardial ischemia, could be due to an increase
in extra- and intracellular longitudinal resistance, as well as to a reduction of action
potential amplitude and upstroke velocity during phase 0 of depolarization.
The most striking observation in myocardial ischemia is the marked degree of
electrical inhomogeneity. There is, for one, a considerable variation in the refractory
period between the ischemic and non-ischemic zones. This becomes even more
pronounced as post repolarization refractoriness develops. There is also spatial
dissociation due to cell death and temporal dissociation with development of con
duction delay due to the aforementioned electrophysiological abnormalities.
Heterogeneity is most evident between the ischemic and the non-ischemic regions in
the border zones. Myocardial mapping has demonstrated characteristic spread of the
wave fronts over the epicardial and endocardial layers.
All the factors mentioned attest to the fact that myocardial ischemia and electrical
vulnerability are intimately related.
Recent clinical observations during myocardial mapping in the ischemic state, as
well as direct observations with Holter-ECG recordings during spontaneously occur
ring or induced myocardial ischemic events have demonstrated with increasing
clarity that life-threatening ventricular arrhythmias have a tendency to occur prefer
entially under the conditions of acute myocardial ischemia.
The situation, however, continues to be only incompletely understood. Partial
understanding of the electrophysiologic, ionic, and biochemical mechanisms on the
one hand, and scanty clinical observations on the other hand calls for further
clarification, especially in view of necessary therapeutic consequences.
H. Just, Freiburg