PHYSIOLOGICAL REVIEWS
Vol. 79, No. 3, July 1999
Printed in U.S.A.
Development of Cardiac Sensitivity to Oxygen Deficiency:
Comparative and Ontogenetic Aspects
BOHUSLAV OSTADAL, IVANA OSTADALOVA, AND NARANJAN S. DHALLA
Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic; and Institute of
Cardiovascular Sciences, St. Boniface General Hospital Research Center, University of Manitoba,
Faculty of Medicine, Winnipeg, Canada
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I. Introduction
II. Cardiac Hypoxia and Ischemia
A. Definition
B. Early consequences of oxygen deprivation
C. Reperfusion injury, stunning, and hibernation
III. Development of Oxygen and Energy Supply
A. Development of myocardial blood supply
B. Development of myocardial energy supply
IV. Development of Cardiac Sensitivity to Oxygen Deprivation
A. Comparative aspects
B. Ontogenetic aspects
V. Protection of the Developing Heart
A. Adaptation to chronic hypoxia
B. Ischemic preconditioning
C. Pharmacological interventions
D. Cardioplegia
VI. Conclusions and Perspectives
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Ostadal, Bohuslav, Ivana Ostadalova, and Naranjan S. Dhalla. Development of Cardiac Sensitivity to Oxygen
Deficiency: Comparative and Ontogenetic Aspects. Physiol. Rev. 79: 635– 659, 1999.—Hypoxic states of the cardiovascular system are undoubtedly associated with the most frequent diseases of modern times. They originate as a
result of disproportion between the amount of oxygen supplied to the cardiac cell and the amount actually required
by the cell. The degree of hypoxic injury depends not only on the intensity and duration of the hypoxic stimulus, but
also on the level of cardiac tolerance to oxygen deprivation. This variable changes significantly during phylogenetic
and ontogenetic development. The heart of an adult poikilotherm is significantly more resistant as compared with
that of the homeotherms. Similarly, the immature homeothermic heart is more resistant than the adult, possibly as
a consequence of its greater capability for anaerobic glycolysis. Tolerance of the adult myocardium to oxygen
deprivation may be increased by pharmacological intervention, adaptation to chronic hypoxia, or preconditioning.
Because the immature heart is significantly more dependent on transsarcolemmal calcium entry to support
contraction, the pharmacological protection achieved with drugs that interfere with calcium handling is markedly
altered. Developing hearts demonstrated a greater sensitivity to calcium channel antagonists; a dose that induces
only a small negative inotropic effect in adult rats stops the neonatal heart completely. Adaptation to chronic
hypoxia results in similarly enhanced cardiac resistance in animals exposed to hypoxia either immediately after birth
or in adulthood. Moreover, decreasing tolerance to ischemia during early postnatal life is counteracted by the
development of endogenous protection; preconditioning failed to improve ischemic tolerance just after birth, but it
developed during the early postnatal period. Basic knowledge of the possible improvements of immature heart
tolerance to oxygen deprivation may contribute to the design of therapeutic strategies for both pediatric cardiology
and cardiac surgery.
I. INTRODUCTION
Clinical-epidemiological studies have shown that the
risk factors of serious cardiovascular diseases, such as
0031-9333/99 $15.00 Copyright © 1999 the American Physiological Society
atherosclerosis and ischemic heart disease, are present
during the early phases of ontogenetic development (57)
(Fig. 1). Some of them, including excessive food intake
and an increased level of cholesterol, operate directly
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greater capability for anaerobic glycolysis (for review, see
Ref. 203), in 1987 several publications provided some
indications that the immature heart might in fact be more
susceptible to ischemic injury than the adult one (e.g.,
Refs. 175, 250). Unfortunately, the ontogenetic conclusions are often based on a simple comparison of the adult
myocardium with a randomly selected and poorly defined
developmental stage (e.g., “fetal,” “newborn”). The possible developmental changes between selected (and not
exactly defined) points thus remain undetermined (152).
Moreover, such an approach is not acceptable for neonates, because rapid changes in cardiac development take
place during the first postnatal week (166, 168, 170).
Although it is impossible to agree fully with the statement that the ontogenetic development is a replication of
phylogeny, comparative studies (more correct than “phylogenetic,” since the researcher is comparing not the
whole evolutionary range but only some classes, i.e., a
synecdochic approach) have contributed significantly to
our understanding of the function of the vertebrates cardiovascular system (33, 181). From the point of view of
developmental cardiology, the advantage of comparative
studies lies in the possibility of studying selected developmental periods as stable situations, which is impossible
for the rapidly changing mammalian ontogeny. Better understanding of the development of both sides of the essential equation of cardiac homeostasis, i.e., oxygen supply 5 oxygen consumption, may serve as a typical
example; it would be unthinkable without significant contribution of a comparative approach.
Therefore, in this review, our intention is to deal with
comparative and ontogenetic aspects of the development
of systems responsible for myocardial oxygen supply and
myocardial oxygen consumption and to stress their role in
the variations in cardiac sensitivity to oxygen deprivation.
FIG. 1. Risk factors of atherosclerosis and ischemic heart disease during ontogenetic development in humans. [Data
from Fejfar (57).]
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after birth, whereas genetic factors are present even before birth. Thus atherosclerosis and ischemic heart disease can no longer be considered the diseases of the fifth
and higher decades of life, but their origin and consequences may be essentially influenced by risk factors
acting already during development. It follows that experimental studies of the pathogenic mechanisms of these
disturbances must shift to the early ontogenetic periods.
Accordingly, it is not surprising that the interest of theoretical and clinical cardiologists in the developmental
approach keeps increasing. The advances of molecular
biology (226, 227) as well as the developing possibilities
of prenatal cardiology (221) have substantially accelerated this trend.
The most frequent (and hence the most widely studied) cardiovascular diseases of modern times undoubtedly include hypoxic states. They originate as a result of
disproportion between the amount of oxygen supplied to
the cardiac cell and the amount actually required by the
cell. The degree of injury depends, however, not only on
the intensity and duration of the hypoxic stimulus, but
also on the level of cardiac tolerance to oxygen deprivation. In recent years, the attention of cardiac research
laboratories has concentrated on the theoretical basis of
rational prevention and therapy of cardiovascular problems, such as myocardial ischemia and chronic hypoxia,
leading to the development of cor pulmonale. Although
abundant data are available concerning the effects of
ischemia and hypoxia on the adult myocardium, very little
is known about the influence of oxygen deprivation on the
developing cardiac muscle. Furthermore, the available
literature on ontogeny is scarce and rather controversial.
Whereas up to 1987 there had been a consensus that the
immature heart was more resistant to oxygen deprivation
than the adult one, possibly as a consequence of its
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CARDIAC SENSITIVITY TO OXYGEN DEFICIENCY
Particular attention is paid to the possible endogenous
protection of the immature heart against oxygen deprivation (adaptation to chronic hypoxia, preconditioning) as
well as to the developmental limitations of exogenous
protection provided by pharmacological interventions.
The clinical implications of hypoxemic congenital heart
disease, intraoperative exposure of the immature heart to
ischemia, cardioplegia, and possible risks for the clinical
use of inotropic drugs in obstetrics and pediatric cardiology are also emphasized.
II. CARDIAC HYPOXIA AND ISCHEMIA
As stated in section I, myocardial hypoxia is the
result of disproportion between oxygen supply and demand. Because of the high coronary arteriovenous difference, the myocardium is not able to bring about a substantial improvement in the oxygen supply by increased
extraction of oxygen from the blood, and thus the only
way of meeting the high demands is through an increased
blood supply. Oxygen consumption depends on the heart
rate, contractile performance, and tension of the ventricular wall, as a result of the pressure-volume relationship
in the ventricle itself (78). Theoretically, any of the known
mechanisms leading to tissue hypoxia can be responsible
for a reduced oxygen supply in the myocardium, but the
most common causes are undoubtedly 1) ischemic hypoxia (often described as “cardiac ischemia”) induced by
reduction or interruption of the coronary blood flow and
2) systemic (hypoxic) hypoxia (“cardiac hypoxia”) characterized by a drop in PO2 in the arterial blood but adequate perfusion. Anoxia is the absence of oxygen supply
despite adequate perfusion. For the sake of completeness,
we could add 3) anemic hypoxia in which the arterial PO2
is normal but the oxygen transport capacity of the blood
is decreased and 4) histotoxic hypoxia resulting from
reduced intracellular utilization of oxygen in the presence
of adequate saturation and an adequate blood flow (e.g.,
inhibition of oxidative enzymes in cyanide poisoning).
The most frequent causes of high oxygen consumption
are increased physical activity, mental stress, or administration of a substance with a positive inotropic and chronotropic effect. In healthy subjects, these high oxygen
requirements are adequately met by an increase in the
coronary blood flow.
It should be emphasized that the terms hypoxia and
ischemia are unfortunately often used interchangeably in
the literature despite the fact that the consequences of the
two mechanisms at the cellular level are very different
(153). In ischemia, there is not only a drop in the supply
of oxygen and substrates, but also a significant reduction
in the clearance of metabolites, in particular of lactic acid
B. Early Consequences of Oxygen Deprivation
With a reduction in oxygen supply, the adult as well as
immature myocardium switches from the aerobic to the
1. The most frequently used experimental models
of cardiac hypoxia and ischemia
TABLE
In Vitro
In Vivo
Hypoxia (2 PO2 in medium)
Isolated perfused heart
Isolated papillary muscle
Isolated myocytes
Ischemia (2 coronary flow)
Isolated perfused heart
Hypoxia (acute and chronic)
Normobaric/hypobaric hypoxia
Ischemia
Acute
Coronary artery ligation
Balloon catheter
Chronic
Atherosclerosis
Ameroid
2, Decrease.
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A. Definition
and hydrogen ions; the intracellular pH falls rapidly as the
acid products of glycolysis accumulate. In contrast, in
cardiac hypoxia, perfusion results in the washing out of
the acid products of glycolysis, thereby retarding the rate
of development of acidosis (197). Systemic hypoxia is
usually a generalized phenomenon diffusely involving the
whole myocardium, whereas ischemia is confined to the
area supplied by the affected coronary artery. Ischemic
hypoxia is clinically manifested primarily in ischemic
heart disease and its acute form, myocardial infarction,
whereas systemic hypoxia is associated with chronic cor
pulmonale of varying origin, cyanosis due to a hypoxemic
congenital heart disease, and changes induced in the cardiopulmonary system by a decrease in barometric pressure at high altitudes. In two cases, however, systemic
hypoxia can be qualified as physiological: 1) the fetal
myocardium that is adapted to hypoxia corresponding to
an altitude of 8,000 m (“Mount Everest in utero”) (202)
and 2) the myocardium of subjects living permanently at
high altitudes. In both situations, the myocardium is significantly more resistant to acute oxygen deficiency, but
in populations living in lowlands, this property is lost
soon after birth (72, 137).
Unfortunately, there is still no existing experimental
model that adequately reproduces all the functional,
structural, and metabolic changes that are characteristic
for hypoxic states of the human cardiopulmonary system.
The basic problem is that in most models, we are working
with an intact animal in which the systems responsible for
the supply and consumption of oxygen are not affected by
pathological process. Furthermore, mainly for the methodological reasons, not all experimental models of adult
hearts are applicable to the immature myocardium. The
most frequently used experimental models of cardiac hypoxia and ischemia are summarized in Table 1.
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contractile proteins, which contribute to the raised enddiastolic resting tension (for review, see Refs. 46, 58, 144,
151).
Energy depletion, oxygen radical accumulation, and
loss of calcium homeostasis, although major contributors
to the cascade of events induced by reduction in oxygen
supply, have to be coupled with the consequences of the
loss of osmotic control that develops at the same time
(144). The accumulation of intracellular substances, including lactate, phosphate, protons, and ammonium ions,
presents the myocytes with an “osmotic shock” at a time
when the sarcolemma is becoming increasingly fragile.
Membrane disruption is the inevitable consequence (90).
C. Reperfusion Injury, Stunning, and Hibernation
All the changes described in section IIB are time
dependent. Transient reversible ischemia followed by
reperfusion can result in increased production of superoxide radicals (243); they attack proteins and polyunsaturated fatty acids, causing enzyme inactivation and lipid
peroxidation, respectively. In reversible ischemia, the intensity of this damage is not sufficient to cause cell death
but is sufficient to produce dysfunction of some key cell
organelles (e.g., sarcolemma and sarcoplasmic reticulum). This would result in impaired calcium homeostasis:
increase of free cytosolic calcium and excitation-contraction uncoupling. The ultimate consequence is a reversible
depression of contractility (21). In contrast, reperfusion
after prolonged periods of ischemia, at a time when the
energy reserves are depleted, the cytosolic calcium level
has risen substantially, osmotic equilibrium has been disturbed, and the natural pool of oxygen radical scavengers
is depleted, can hasten the death of those cells that were
already injured but are potentially salvageable (144).
As stated above, short-lasting myocardial ischemia
followed by reperfusion induces contractile abnormalities. This “postischemic stunning” is defined as a mechanical dysfunction that persists after reperfusion despite the
absence of irreversible damage and despite restoration of
normal or near-normal coronary flow (for review, see
Refs. 23, 69). The factors responsible for myocardial stunning consist of two components: a component that develops during ischemia and another component that develops after reperfusion. Myocardial stunning is thus
probably a multifactorial process that involves 1) abnormalities of calcium homeostasis occurring during ischemia and reperfusion and 2) generation of oxygen-derived
free radicals upon reperfusion. From the effects of antioxidants in models of myocardial stunning, the reperfusion injury component appears to be greater than the
ischemic injury component (21). These facts support the
important concept (214) that the severity of the reperfusion injury component of myocardial stunning is propor-
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anaerobic mode (for review, see Refs. 90, 144). The capacity
of the myocytes to generate energy in the form of ATP and
creatine phosphate becomes severely depleted, to such an
extent (only 3 mol of ATP are produced for every mole of
glucose instead of 38 mol that are generated during oxidative metabolism) that the high-energy stores become rapidly
depleted (196). The heart ceases to contract within seconds
from the onset of oxygen deprivation. However, the precise
mechanism of the impairment of the ventricular systolic
function has not been defined. The possible etiology includes the ability of hydrogen ions to displace calcium ions
from their binding sites on the myofibrils and the failure of
calcium transients. Thus the actin-myosin interaction is impaired and contractility is reduced (29). Despite the fact that
lack of oxygen depletes ATP from the myocardium, impairment of function is not closely related to depression of
overall ATP content, which declines more slowly and is
associated with progressive intracellular hypoxia and acidosis (119). Potassium ions migrate from the inside to the
outside of the muscle cells, and sodium ions move in the
opposite direction. These are important changes, since extracellular accumulation of potassium ion has a profound
effect on the transmembrane potential difference, and intracellular accumulation of sodium ions leads to myocardial
swelling. Interestingly, the form of oxygen deprivation may
modify the events; for example, anaerobic glycolysis is activated and persistent in hypoxic preparations but is depressed to zero in low-flow ischemic preparations (150).
Soon after the onset of oxygen deprivation, cytosolic
calcium increases, leading to an intracellular calcium
overload (for review, see Refs. 58, 144). This multifactorial event is of both intracellular and extracellular origin.
The extracellular component probably involves the entry
of a small amount of calcium in exchange for sodium. The
major component is, however, of intracellular origin;
mechanisms that are involved include enhanced calcium
release from the sarcoplasmic reticulum (possibly because of damage caused by free radical production) (216),
failure of the calcium uptake by sarcoplasmic reticulum
(because of energy depletion), failure of ATP-dependent
sarcolemmal calcium pump responsible for extruding calcium ions across the sarcolemma, and proton-driven efflux of calcium from the mitochondria. As the duration of
the hypoxic/ischemic episode progresses, the sarcolemma may become leaky, possibly because of free radical formation and the effect of these newly formed radicals on the architecture of the membrane-located
phospholipids. The consequences of this rise in cytosolic
calcium include activation of lysosomal proteases and
phospholipases, resulting in ultrastructural injury; stimulation of oxygen radical production; activation of latent
calcium-dependent ATPases, which hastens depletion of
residual ATP reserves; calcium accumulation in mitochondria leading to a defect in energy production; and
calcium accumulation in the cytosol in the vicinity of the
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CARDIAC SENSITIVITY TO OXYGEN DEFICIENCY
III. DEVELOPMENT OF OXYGEN AND
ENERGY SUPPLY
As mentioned in section I, the degree of myocardial
injury depends not only on the intensity and duration of
hypoxic (ischemic) stimulus, but also on the degree of
cardiac sensitivity to oxygen deficiency. This variable is
determined by the relationship between myocardial oxygen supply and demand, i.e., myocardial blood flow and
the oxygen-carrying capacity of blood, on the one hand,
and the functional state of cardiac muscle (level of contractile function, systolic wall tension, heart rate, and
external work) and basal metabolism, on the other hand
(2, 3). Because most of these determinants change significantly during phylogenetic and ontogenetic development,
it is not surprising that significant developmental changes
also underlie their common consequence, cardiac resistance to oxygen deprivation (33). It may, therefore, be of
interest to analyze how the developmental changes in
oxygen-supplying and oxygen-consuming systems influence the changes in cardiac sensitivity to hypoxia or
ischemia. From this point of view, two evolutionary situations seem to be most important: the transition from
poikilothermy to homeothermy in adult vertebrates and
the perinatal period in homeotherms.
The comparison of experimental and clinical ontogenetic studies is, however, difficult, to some extent as a
consequence of the inconsistent terminology (203). The
absence of commonly agreed definitions for individual
developmental periods (e.g., newborn, neonate, infant,
and immature) has undoubtedly hampered clarification in
this field, particularly in animal studies. Because the ma-
jority of the experimental studies referred to in this survey have been carried out in the rat, we will, for the sake
of consistency, use the following definitions: neonate
(newborn), ,1 wk old; suckling, up to 2 wk old; weaning,
2– 4 wk old; sexual maturation, 4 – 8 wk old; adult, 8 wk
old and beyond (8). Results from species other than rat
are also discussed, and we will adopt the definitions used
by the respective authors.
A. Development of Myocardial Blood Supply
1. Comparative aspects
Performance of the heart as a pump must be precisely adapted to the oxygen consumption of the total
active body mass. As a result, the heart size in different
species of vertebrates, expressed as a ratio of heart
weight to body weight (i.e., relative heart weight), varies
considerably (39, 75, 186), by as much as 20-fold (185).
The relative heart weight is highest in birds, followed by
mammals and by poikilotherms; fish appear to have the
lowest heart weight among all vertebrates. The maximum
acceleration of heart growth during phylogeny occurs
when the metabolic activity of animal tissues has substantially increased, i.e., during transition from poikilothermy
to homeothermy (53, 186) (Fig. 2).
It is obvious that phylogenetic differences in cardiac
size, performance, and energy demand are reflected in the
construction of an oxygen pathway from the blood to
mitochondria. The first coronary vessels appeared in
some fish at least 500 million years ago (181, 182). Their
development is closely related to the transformation of
the musculature from a spongy avascular myocardium to
a compact myocardium supplied from coronary arteries.
Although the heart of adult homeotherms consists entirely of a compact musculature with coronary blood
supply, the ventricular myocardium of most species of
cold-blooded vertebrates is formed by two different muscular layers: the inner avascular spongious musculature,
supplied by diffusion from the ventricular lumen, is covered by an outer compact layer with a coronary blood
supply (18, 156, 161–163, 186) (Fig. 3). Quantitative analysis of the terminal blood bed has revealed that poikilotherms with a low relative heart weight (e.g., fish) have a
significantly lower lacunar capacity than animals with a
higher relative heart weight, such as amphibians and reptiles (160). Recently, Kohmoto et al. (99) have demonstrated a high degree of direct myocardial perfusion from
the ventricular cavity in the endocardial region of alligator
hearts. The high density of channels and thin sheets of
myocardium permit reasonable diffusion distances between myocytes and the ventricular cavity.
The myocardial blood supply of certain lower vertebrates appears to be “primitive” and “inefficient.” However, there may well be good reasons for the principles
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tional to the severity of the ischemic injury component.
Accordingly, any intervention that attenuates the severity
of ischemic injury will also, indirectly, attenuate the severity of the subsequent reperfusion injury.
Myocardial stunning should be distinguished from
the concept of “hibernating myocardium.” This can be
defined as a persistent (for at least several hours) contractile dysfunction that is associated with reduced coronary flow but preserved myocardial viability (22, 70, 76).
This phenomenon is teleologically postulated to be an
adaptive response of the heart to low flow, whereby oxygen demand is downregulated to the point that the reduced oxygen supply can be tolerated for an extended
period of time without cell death and without clinical or
metabolic evidence of ischemia. Once coronary flow is
restored, the dysfunction is completely reversed. Thus
stunning and hibernation have one thing in common; in
both cases, the ventricular dysfunction is reversible. The
major difference is that blood flow is normal or near
normal in stunned myocardium, whereas it is reduced in
hibernating myocardium (22).
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Volume 79
FIG. 2. Relative heart weight in individual classes of vertebrates. [Data from
Hesse (75).]
2. Ontogenetic aspects
It is obvious that the type of blood supply changes
significantly during phylogenetic development and that
coronary arteries play a dominant role only in adult homeotherms, birds, and mammals. In this connection, an
obvious question arises about the time course of development of myocardial blood supply during the ontogeny
of warm-blooded animals.
The development of the vascular bed in the heart of
homeotherms has been summarized by Rakusan (191),
Hudlicka et al. (83), and Tomanek (229). Recent studies
have shown that capillaries form via vasculogenesis, i.e.,
from precursor cells, which migrate to the epicardium
from the liver region and then form tubes (132, 179).
These structures first appear 13 days after conception in
rats (206) and during the fourth week of pregnancy in
humans (148). The vascular tubes mature and become
associated with pericytes; these vessels subsequently
grow by angiogenesis, a process which consists of disrup-
FIG. 3. Different types of myocardial blood
supply. a: Spongious musculature supplied from
ventricular lumen. b: Inner spongious layer is
covered by an outer compact musculature with
vascular supply. c: As in b, but capillaries are
present also in some trabecels of spongylike
musculature. d: Compact musculature supplied
from coronary vessels. [Adapted from Ostadal
et al. (160).]
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concerned to inform clinicians who treat heart disease
(28). Medical researchers seeking treatment for blocked
coronary arteries are now becoming interested in the
spongy myocardium of fishes and reptiles. The information obtained represents a significant step toward achieving transmyocardial blood flow in patients. Surgeons have
already begun using lasers to punch holes in the left
ventricle to permit some oxygenation directly from the
luminal blood, a technique known as transmyocardial
revascularization (82). This operative technique may improve myocardial perfusion in patients in whom the standard method of revascularization is counterindicated.
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CARDIAC SENSITIVITY TO OXYGEN DEFICIENCY
coronary vessels is completed the blood supply is effected
mostly from coronary arteries.
B. Development of Myocardial Energy Supply
1. Comparative aspects
For the understanding of developmental changes in
cardiac sensitivity to oxygen deprivation, a basic knowledge of the development of cardiac metabolism is of
crucial importance. Decisive differences in cardiac energy
metabolism in adult vertebrates are the result of changes
in metabolic activities of animal tissues, the most obvious
one taking place during transition from poikilothermy to
homeothermy (for review, see Ref. 49). Thermoregulating
mammals and birds have a relative heart weight and total
metabolic capacity that is, on average, four times whereas
arterial blood pressure is six times higher than in poikilotherms (97, 181). In terms of anaerobic metabolism, all
requisite enzymes of glycolysis are routinely detected in
vigorous activities. Hexokinase, which catalyzes the first
step in the utilization of exogenously supplied glucose, is
about five times more active in hearts of poikilotherms
than homeotherms (49). The mitochondrial enzymes of
the poikilotherm and homeotherm heart are similar in
their structure and functional properties, but their activity
per milligram tissue or tissue protein is considerably
lower in cold-blooded hearts (53, 84, 247); for example,
reptiles possess only 20 –50% of the mammalian capacity
(52, 53). The ratio of creatine kinase to cytochrome-c
oxidase, a rough estimate of aerobic capacity and cellular
energy turnover, is significantly increased in poikilotherms (38). When challenged by hypoxia, this high level
may represent an enhanced efficiency to attenuate the
impact of a depressed energy liberation. Moreover, poikilothermic hearts possess a high relative glycolytic capacity as indicated by a high pyruvate kinase-to-cytochrome-c
oxidase ratio.
Significant metabolic differences exist between the
compact and the spongious layer of the poikilothermic
heart (15). The activities of enzymes that are connected
with aerobic oxidation (citrate synthase, malate dehydrogenase) and glucose phosphorylation (hexokinase) are
higher in the spongious than in the compact layer. Similarly, the content of phospholipids is higher in the spongious musculature, the greatest difference being in the
content of diphosphatidylglycerol (50). Furthermore,
Maresca et al. (121) and Greco et al. (63) have demonstrated that differences in enzyme activities are accompanied by different mitochondrial populations in the two
layers. It is interesting to note that the myosin ATPase
activity (calcium activated) is significantly higher in the
compact musculature as compared with the spongious
layer of the carp heart (15).
In conclusion, significant metabolic differences exist
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tion of the basement membrane and migration and proliferation of endothelial cells to form new channels (229).
After early capillarization, plexes of vessels with venular
dimensions appear; in contrast, the formation of the arterial system is a later event (77, 209). The major coronary
arteries form by coalescence of microvessels that grow
toward and penetrate the aorta (20). The coronary arteries connect to the aorta in humans as early as after 44
days of pregnancy (77). The development of the arterial
vasculature continues after birth; there is an increase in
the number of branches and an increase in the length of
arterial segments (44, 198). Similarly, the early postnatal
period is characterized by a rapid rate of coronary capillary formation; close to one-half of all adult capillaries in
the rat heart are formed during the first 3– 4 postnatal
weeks, and after 45 days of age in rats, capillary growth
stops (149, 194). The ultrastructural differentiation of capillary endothelium in rats is completed by the end of the
second postnatal week (163), but the development of
various enzymes characteristic of capillary endothelium
(ATPase, alkaline phosphatase, and dipeptidyl peptidase
IV) is only completed after weaning (116). It is well established that the process of vascularization is influenced
by growth factors, the extracellular matrix, and mechanical forces; however, there are few experimental data
concerning this issue (229).
The main quantitative changes of the coronary capillary bed during the subsequent period are a decrease in
the muscle fiber-to-capillary ratio and a decrease in capillary density; the number of myocytes supplied by a
single capillary decreases from four to six in the neonatal
period to one in adult hearts from humans, rabbits, and
rats; simultaneously, the number of muscle fibers per
square millimeter decreases, whereas their diameter increases (182, 193). A decrease in capillary density with
increasing age and cardiac mass occurs in all mammalian
hearts. It follows that the capillary domain, i.e., the area
supplied by a single capillary in a tissue cross section,
increases with increasing cardiac mass and is similar in
both rats and humans (192).
It may be concluded that changes in the heart size
during ontogenetic development of homeotherms are, as
during phylogeny, accompanied by the gradual transformation of the avascular spongious musculature into a
compact myocardium supplied through coronary vessels.
Ontogenetic development of the myocardial blood supply
can be thus divided into three periods (164): 1) lacunar,
up to the development of coronary arteries the myocardium is entirely spongious and supplied from ventricular
cavity; 2) transient, from the beginning of the arterial
stem development to the time when the definite coronary
vasculature is formed during which the myocardium may
be supplied both from the lumen and from the developing
coronary bed; and 3) coronary, when the development of
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between the poikilothermic and homeothermic heart and
even between the two layers of the same heart of lower
vertebrates. It is likely that these differences play a crucial role in the different sensitivity of the poikilo- and
homeothermic heart to oxygen deficiency.
2. Ontogenetic aspects
lar myocardium, whereas that of hexokinase was higher
in the atrial tissue. This suggests that the ventricle is
amply equipped for utilization and oxidation of all major
nutrients (lactate, fatty acids, and glucose), whereas the
atrium predominantly utilizes glucose.
Ontogenetic development is characterized by quantitative and qualitative changes in the cardiac mitochondria. There are twofold increases in volume density, size,
and number of mitochondria per cell between days 0 and
5 in rats (149) and months 0 and 2 in dogs (109). Moreover, developmental changes in mitochondrial oxygen utilization have been demonstrated (213, 222, 244, 253); as a
result, the respiratory control ratio (a measure of the
dependence of respiratory rate on ADP) is greater in the
mitochondria of fetal and neonate hearts, suggesting that
the higher respiratory rates in immature hearts are a
reflection of a high level of electron transport.
In conclusion, cardiac metabolism changes in response to oxygen and substrate availability during development. The fetus is relatively more dependent on anaerobic glycolysis, using glucose as its major source,
whereas the mature heart is almost exclusively aerobic,
with nonesterified fatty acids as the predominant substrate. The fact that the fetal heart relies on carbohydrate
metabolism can therefore be regarded as adaptation to
hypoxia.
IV. DEVELOPMENT OF CARDIAC SENSITIVITY
TO OXYGEN DEPRIVATION
A. Comparative Aspects
Of the experimental models commonly used for
studying the effect of oxygen deprivation in homeotherms
(see Table 1), only a limited number are suitable for the
cold-blooded heart. The absence of, or a partially developed, coronary circulation excludes, for instance, the
possibility of using acute or chronic regional ischemia.
The most frequently used models are, therefore, systemic
and histotoxic hypoxia.
As discussed in section IIIB, the poikilothermic heart,
which is frequently exposed to oxygen deficiency in an
aquatic environment, is better equipped biochemically to
cope with oxygen deprivation than the mammalian one.
Data comparing the sensitivity of the poikilothermic and
homeothermic heart to oxygen deficiency are relatively
scarce. The anaerobic capacity of cardiac muscle in different chordates from cyclostome (hagfish) to humans
has been reviewed by Poupa (181) and Driedzic and
Gesser (49). Force development of isometric cardiac
strips in vitro under roughly similar conditions was measured when respiration was blocked by cyanide (histotoxic hypoxia). The highest tolerance to lack of oxygen was
observed in the reptilian (monitor lizard) and cyclostome
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Whereas the heart of adult homeotherms can utilize a
wide spectrum of substrates for the provision of energy,
including lipids, carbohydrates, and amino acids with
long-chain fatty acids as the predominant source, fetal
metabolism is primarily anaerobic, and this adaptive
property is retained during the neonatal period. The high
stores of glycogen that characterize the fetal and newborn
myocardium are essential for enhancing tolerance to hypoxia, but these decrease rapidly after birth; anaerobic
production of energy may also be related to enhanced
stores of amino acids that allow substrate level phosphorylation (92). The immature heart mainly depends on glycolysis because the capacity to use fatty acids is impaired
due to either delayed maturation of enzymes associated
with mitochondrial fatty acid transport and metabolism
or to deficiency of carnitine (30, 31, 235–237). In addition
to the enzymes associated with fatty acid metabolism,
several other enzymes, such as those of the citric acid
cycle and the respiratory chain, together with creatine
kinase and various cytochromes, have been shown to
have a low activity in the immature heart (48, 80, 232,
237). Postnatal development of enzyme activities depends
on the degree of maturation of individual species at birth.
In rats, highly immature at birth, enzyme activities exhibit
three different developmental patterns. 1) The mitochondrial enzymes of aerobic metabolism (citrate synthase,
3-hydroxyacyl-CoA dehydrogenase) and the cytoplasmic
glycerophosphate dehydrogenase increase steadily from
the end of prenatal life up to adulthood. Similarly, cytochrome-c oxidase activity increases during postnatal development in rats (232), but these changes are not necessarily related to developmental changes in different
subunits (122). 2) Lactate dehydrogenase and malate dehydrogenase decrease during late prenatal life and then
increase as in the former group. 3) Hexokinase (which
brings glucose into metabolism) and triosephosphate dehydrogenase (used in the later part of glycolysis) oscillate
around the adult value without significant developmental
changes. In contrast to the rat heart, the developmental
differences in the guinea pig, which is more mature at
birth, were significantly less pronounced (A. Bass, B.
Ostadal, M. Stejskalova, and A. Stiejlerova, unpublished
observations; and Ref. 80). Significant differences in enzyme activities were found between the atrial and ventricular myocardium (17, 231); the activity of enzymes,
connected with aerobic metabolism, lactate, and fatty
acid metabolism, was significantly higher in the ventricu-
Volume 79
July 1999
CARDIAC SENSITIVITY TO OXYGEN DEFICIENCY
dial cells in fish (212). The functional significance of
myocardial sarcoplasmic reticulum in poikilotherms is
unclear and may differ between atrium and ventricle (49).
In conclusion, it appears that the adult poikilothermic heart as a whole (i.e., without separation into the
compact and spongious layer) is significantly less sensitive to oxygen deprivation as compared with the homeothermic one, probably because of higher anaerobic capacity and the developmental differences in systems
responsible for calcium handling. The important question
regarding the relationship between the type of myocardial
blood supply (lacunar vs. coronary) and sensitivity to
oxygen deprivation was, unfortunately, not addressed in
studies done in vitro and remains to be answered.
B. Ontogenetic Aspects
As stated in section IVA, oxygen deprivation in the
mammalian myocardium is predominantly induced by
ischemia or systemic hypoxia. However, they do not represent equivalent insults. Whereas all flow is terminated in
ischemia, hypoxia involves the exposure of the myocardium to a perfusate with low PO2. The latter condition
provides a continuous supply of substrate, whereas removal of lactate from the hypoxic heart prevents the
intracellular acidosis that occurs with ischemia. Thus, by
anaerobic glycolysis, the energy stores and ionic gradients can be maintained in the hypoxic heart for a considerable period of time (187). Over the past years, many
experimental studies have compared the tolerance of the
mature and immature heart to hypoxia and ischemia (for
review, see Ref. 203). These studies were stimulated by
the increasing clinical interest in the immature heart of
children who have undergone open-heart surgery in
which the myocardium is subjected to ischemic arrest and
by the early ontogenetic occurrence of the risk factors for
ischemic heart disease.
1. Cardiac sensitivity to hypoxia
Early evidence for an age-dependent decrease in resistance to hypoxia is found in studies on the survival
time of the rat, cat, dog, guinea pig, and rabbit in anoxic
environments (56, 62). It was found that in each species
the survival time was inversely related to age and to the
maturity of the newborn. The survival time in rabbits
decreased day by day even during the first week of life
and reached adult values at 2 wk of age (62). The capability of the newborn to withstand hypoxia has been
attributed to the high glycogen content in the heart and
liver. However, because these studies were performed in
the intact animals, the effect of hypoxia on the central
nervous system, peripheral resistance, and acid-base balance could indirectly affect myocardial function.
The concept of greater tolerance of the neonatal
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(hagfish) heart; the force development was reduced by no
more than 30% and recovered slowly toward initial values.
Large differences were found in fish; contractile force in
free-swimming cod was reduced by 90%, whereas that in
bottom-dwelling flounder was reduced by only 50% (within 45 min after the onset of hypoxia). The highest sensitivity was observed in homeotherms (humans); a decline
of contractile force occurred immediately (within 5 min)
and was irreversible. In poikilotherms, the sensitivity to
histotoxic hypoxia was increased upon increasing the
temperature of the perfusion medium (35). Myocardial
cells of poikilotherms, similar to as in homeotherms, may
be irreversibly damaged by hypoxia (110); highly resistant
reptilian heart should be noted as a probable exception
(238 –240).
Acidosis protects the reptilian heart against contractile dysfunction induced by hypoxia, but no similar effect
was observed in the fish heart (60). The ability of the heart
to work at high PCO2 is probably another cause of the high
resistance of the reptilian myocardium to hypoxia and
cannot be explained either by a different tissue pH or by
buffering capacity. In view of the fact that calcium competes with protons, it can be speculated that the effect of
CO2 is counteracted by calcium activation (181). Because
enhanced sarcolemmal calcium influx or increased calcium release from the sarcoplasmic reticulum as a calcium source were excluded in these studies, mitochondrial calcium was proposed as a tentative candidate; by
blocking the mitochondrial sodium/calcium exchange, the
protective effect of acidosis on reptilian heart was abolished (60). Furthermore, the poikilothermic heart is, in
comparison with the homeothermic one, resistant to the
calcium paradox. This phenomenon, i.e., the development
of mechanical impairment when the heart is reperfused
with normal calcium after a brief period of cardiac arrest
during perfusion with calcium-free medium (258), has not
been observed in ventricular strips from several different
species of cold-blooded animals (183).
Because it is well known that calcium plays an important role in the development of ischemia and/or hypoxia-induced myocardial injury, the phylogenetic differences in systems involved in calcium handling have to be
taken into consideration as a possible explanation of the
difference in the sensitivity of poikilothermic heart to
oxygen deprivation. The cardiac coupling mechanism in
lower vertebrates relies heavily on sarcolemmal calcium
fluxes, whereas the sarcoplasmic reticulum is of little or
no importance, e.g., in amphibians (55, 128). In many fish,
the sarcoplasmic reticulum certainly conforms to this
amphibian pattern, but there are other species in which
the sarcoplasmic reticulum is undoubtedly better developed (134, 212). On the other hand, a t-tubular system has
never been observed in fish myocardial cells, and thus the
concept of functional couplings between cisternae a t
tubules in mammals and birds does not apply to myocar-
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OSTADAL, OSTADALOVA, AND DHALLA
FIG. 4. Ontogenetic development of cardiac tolerance to acute hypoxia (expressed as recovery of isotonic contraction of isolated right
ventricle after 20 min of acute anoxia in vitro) in male and female rats.
[Data from Ostadal et al. (157).]
FIG. 5. Tolerance of isolated perfused rat heart to global ischemia
during first week of life expressed as recovery of developed force (DF)
after ischemia (percentage of baseline values). [Data from Ostadalova et
al. (170).]
2. Cardiac sensitivity to ischemia
As with hypoxia, the immature myocardium also appears to be relatively resistant to ischemia in the rabbit (9,
27, 64, 146), pig (10), dog (91), and rat (204, 205, 252). Riva
and Hearse (205) have observed that the age-dependent
changes in resistance to global ischemia in the isolated rat
heart (expressed as postischemic recovery of developed
pressure) showed a biphasic pattern with increasing tolerance from 5 to 23 days of age, followed by a decline to
adulthood. These observations were similar to our experiments on cardiac resistance to acute nitrogen anoxia in
vitro (157). Detailed analysis of the tolerance of the isolated rat heart to global ischemia during the first week of
life has, however, revealed a significant decrease from
day 1 to day 7 (170) (Fig. 5), suggesting a possible triphasic pattern of the ontogenetic development of cardiac
sensitivity to ischemia. The sensitivity of neonatal myocardium may be species dependent. Baker et al. (10) have
shown that the neonatal pig heart is more susceptible to
ischemia than the neonatal rabbit heart.
In this connection, it is necessary to mention studies
showing that the immature heart might be more susceptible to ischemic injury than the adult heart (37, 187, 250).
The above studies reporting similarities between findings
under hypoxic and ischemic conditions suggest that the
differences between the form of oxygen deprivation used
are not sufficient to account for the conflicting results.
According to the results of Quantz et al. (189), the reported conclusions were contradictory, primarily because
of the different end point used to assess the tolerance.
Those who used time to onset of ischemic contracture
(TIC) as the end point found it to be shorter in neonatal
hearts and thus concluded that the immature hearts are
more susceptible to ischemic injury. In contrast, those
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heart has been supported by Su and Friedman (225) and
Jarmakani and co-workers (86, 89). By using the perfused
myocardium, they have shown that 30 min of anoxia
(perfusate equilibrated with 95% N2-5% CO2) had a minimum effect on myocardial function in the newborn rabbit
(0 –2 days) and dog (0 –9 days); the effect of hypoxia on
the contractile function was, in both species, inversely
related to age. Moreover, the increase in lactate production during hypoxia was significantly greater in the newborn than in the adult, indicating that the newborns are
capable of maintaining adult levels of myocardial ATP.
Several other studies have shown a greater posthypoxic
preservation of variables, such as calcium handling (88,
141) and mitochondrial function in the newborn heart
(254). Similar age-dependent tolerance to hypoxia was
observed in rats (157); the resistance of the isolated right
ventricle expressed as the recovery of contractility after
20 min nitrogen anoxia (the mixture of 95% O2-5% CO2
was replaced with 95% N2-5% CO2; Ref. 127) was significantly higher in newborn males than in adults. The ontogenetic changes showed a biphasic pattern. The relatively
high cardiac resistance at birth even increased up to the
30th day of life (i.e., up to the end of the weaning period)
in both male and female hearts; however, this value decreased in males from the 30th to the 60th day but remained unchanged in females. The adult female heart was
thus significantly more resistant to hypoxia (Fig. 4).
It may be concluded that cardiac sensitivity to hypoxia or anoxia changes significantly during ontogenetic
development; however, the time course is different in
males and females. Detailed information about the development of cardiac tolerance to hypoxia during early postnatal period is unfortunately still lacking.
Volume 79
CARDIAC SENSITIVITY TO OXYGEN DEFICIENCY
July 1999
who evaluated the recovery of ventricular function when
ischemia was followed by a period of reperfusion concluded that the immature heart regained a better function
and thus is more tolerant to ischemic insults. The onset of
ischemic contracture is thought to mark the beginning of
irreversible damage and correlates with the depletion of
high-energy phosphates. However, TIC does not reflect
events after reperfusion and does not, in fact, indicate the
irreversible damage to the global ventricular function.
Therefore, TIC is not a good index of ischemic injury.
Studying functional recovery after an ischemic insult as
the end point seems to be more closely related to situations in cardiac surgery.
The mechanisms of the higher resistance of the immature heart to oxygen deprivation have not yet been
satisfactorily clarified. It may be speculated that an explanation for the phenomenon lies in the lower energy
demand, greater anaerobic glycolytic capacity, and higher
glycogen reserves of the neonatal heart (79, 254) (Table
2). The ontogenetic difference would also be consistent
with biochemical maturation, since many of the striking
differences with respect to substrate utilization and energy metabolism are lost soon after birth. The tolerance of
the immature heart to ischemia may also be related to
amino acid utilization by transamination (92). Moreover,
the ATP catabolic pathways change during development
(81, 139, 223). During normoxia, the adult heart releases
80% of total purine as urate and 7% as inosine, whereas
the immature heart releases 64% as hypoxanthine and 15%
as inosine. Hypoxanthine and inosine produced by the
immature heart can be recycled into the ATP pool,
whereas urate is not recyclable. As a consequence, ATP
depletion occurs more rapidly in the mature heart. In
addition, AMP accumulates in the immature heart during
ischemia, which allows a rapid replenishment of ATP on
reperfusion. On the other hand, de novo synthesis of ATP
is required in the mature heart. These observations suggest that the immature heart is better adapted to ATP
2. Possible mechanisms of the higher tolerance
of the immature heart to oxygen deficiency
TABLE
2 Energy demand
1 Anaerobic capacity
1 Glycogen reserves
2 Free fatty acids uptake
Amino acid transamination
ATP catabolic pathways
2 Free radical production
Transmembrane calcium transport
2 Sensitivity to acidosis
1, Increase; 2, decrease.
synthesis than to its breakdown, the situation that may be
advantageous in conditions of low substrate availability.
The immature heart thus suffers less ischemic injury than
the mature heart after the same ischemic insult (223).
Another factor that may contribute to the increased
tolerance of the immature heart is the age-related change
in calcium handling (143, 145, 234, 254). Calcium homeostasis is closely related to cell metabolism and is an
accepted determinant of tissue injury during both oxygen
deprivation and repletion. Calcium handling in the neonate is different from that in the adult. The contraction of
mammalian myocardium is known to depend on both
transsarcolemmal calcium influx and calcium release
from the sarcoplasmic reticulum (54). However, the relative contribution of the two mechanisms varies significantly during development. The contraction of neonatal
myocardium where the sarcoplasmic reticulum is not
fully developed depends to a large extent on the influx of
calcium across the sarcolemma via the calcium channels.
During further development, the ability of sarcoplasmic
reticulum to accumulate calcium increases, and there is a
progressive maturation of calcium release from the sarcoplasmic reticulum (228). Similarly, calcium sensitivity
of cardiac myofilaments increases, reaching the adult values in rats starting from the 15th day of postnatal life
(233). An analogous developmental trend has the cardiac
sensitivity to isoproterenol-induced calcium overload
(169). The role of acidosis may also be important; the
negative inotropic effect of low pH was strikingly smaller
in the neonatal rabbits (142) which, according to Solaro et
al. (221), can be accounted for by a lower myofibrillar
calcium sensitivity to low pH in this age group. None of
these observations can, however, fully explain the day-byday changes in cardiac tolerance to ischemia we have
observed in rats during the first week of life (170).
Another determinant of tissue injury is oxygen free
radicals. According to Southworth et al. (223), the immature heart exposed to an ischemic insult suffers less injury
than the mature heart and, as a consequence, produces
fewer free radicals on reperfusion. They found that the
adult guinea pig heart produced more oxygen radicals
than the immature heart (3 days premature delivered by
caesarean section) over the range of ischemic durations
examined (0 – 60 min). The largest difference was observed after 20-min ischemia when the mature heart produced four times more free radicals than the immature
heart. Because the major source of oxygen radicals in this
model involves xanthine oxidase, developmental differences in the capacity for free radical production on reperfusion can be explained in terms of priming for the xanthine oxidase system during ischemia. It is not clear,
however, if similar developmental changes occur in the
other free radical-generating mechanisms that may be
important in the pathogenesis of ischemia-reperfusion
injury. Moreover, the exact relationship between free rad-
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3. Possible mechanisms of the higher tolerance of the
immature heart
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OSTADAL, OSTADALOVA, AND DHALLA
V. PROTECTION OF THE DEVELOPING HEART
From the foregoing discussion it is evident that the
degree of hypoxic injury depends not only on the intensity
and duration of the hypoxic stimulus but also on the level
of cardiac tolerance to oxygen deprivation. It is, therefore, not surprising that the interest of many experimental
and clinical cardiologists during the past 35 years has
been focused on the question of how cardiac tolerance to
oxygen deprivation might be increased. In this regard,
there are three possibilities: 1) pathophysiological interventions that may be long lasting (adaptation to chronic
hypoxia) or short lasting (i.e., preconditioning) to counteract the adverse effects of reduced oxygen supply, 2)
pharmacological interventions that either increase the
myocardial oxygen supply (vasodilators) or reduce oxygen demand (negative inotropes), and 3) cardioplegia, a
special type of pharmacological protection, often combined with hypothermia and used in cardiac surgery.
Whereas a substantial amount of data are available concerning protection of the adult myocardium, much less is
known about this phenomenon in the developing heart.
The data in the literature are scarce and often contradictory. The present review summarizes the results and hy-
potheses dealing with the ontogenetic differences and
limitations in endogenous and exogenous protection of
the hypoxic/ischemic heart.
A. Adaptation to Chronic Hypoxia
Adaptation to chronic hypoxia is characterized by a
variety of functional changes that help to maintain homeostasis with minimum energy expenditure (51). Such
adjustment may protect the heart under conditions that
require enhanced work and consequently increased metabolism. In addition to such protective effects, adaptation to chronic hypoxia may also exert adverse influences
on the cardiopulmonary system, including the development of pulmonary hypertension and right ventricular
hypertrophy, which may result in congestive heart failure
(for review, see Refs. 26, 100, 137, 154, 165).
1. Protective effect of adaptation
In chronic hypoxia, the myocardium must maintain
an adequate contractile function despite the lower oxygen
tension in coronary circulation. It was reported in the late
1950s (85) that the incidence of myocardial infarction is
lower in people who live at high altitude (Peru, 4,000 m).
In addition to chronic hypoxia however, relatively increased physical activity and reduced obesity have to be
taken into consideration when explaining the protective
effects of living at high altitudes. Epidemiological observations on the protective effect of high altitude are consistent with the results of experimental studies using
acute anoxia in vitro, necrogenic doses of isoproterenol,
and acute ischemia for testing the myocardial resistance
in acclimatized animals. In this connection, it must be
pointed out that the pioneer experimental studies on the
protective effect of high altitude on cardiac muscle were
carried out in Prague by Kopecky and Daum in 1958 (106)
and by Poupa et al. in 1966 (184). They demonstrated that
the isolated right ventricular myocardium of rats acclimatized for at least 6 wk to an intermittent simulated altitude
of 7,000 m (24 h every other day) recovers its contractility
in vitro after nitrogen anoxia better than the same preparation from normoxic animals. These findings were later
confirmed by McGrath and Bullard (126) and Meerson et
al. (129). Furthermore, it has been reported (127, 246) that
a similar protective effect can be induced by a relatively
short intermittent exposure of rats to simulated high altitude (4 h/day, a total of 24 exposures to 7,000 m).
Recently, an increased tolerance to global ischemia, manifested as improved recovery of the contractile function
following reperfusion, was shown in isolated perfused
hearts of adult rats acclimatized to permanent normobaric hypoxia. Furthermore, adaptation to high altitude
had a pronounced antiarrhythmic effect under conditions
of acute myocardial ischemia (131) and attenuated the
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ical production on reperfusion and the recovery of contractile function remains unclear. It has been shown that
the recovery of the contractile function is closely related
to ischemic duration rather than to the profile of radical
production (223). This suggests that ischemic injury is a
more important factor in influencing recovery of cardiac
function than is free radical production.
In this connection, it is relevant to explore whether
differential susceptibility to reperfusion-induced injury
may be partly responsible for the differences in postischemic recovery between neonates and adults (203). Nakanishi et al. (143) compared the consequences of reoxygenation after 40 min of hypoxia (95% N2) in isolated,
arterially perfused, septal preparations of adult and neonatal (3–7 days) rabbits. They have observed that enzyme
release during hypoxia and reoxygenation in the newborn
was significantly less than in the adult, suggesting less
sarcolemmal damage in the young animals. Because the
extent of reperfusion-induced injury depends on the severity of the preceding hypoxia or ischemia (59, 71), the
likely interpretation of these results is that the neonate
sustained less injury during the 40 min of hypoxia than the
adult and was thus less vulnerable to reperfusion injury
(203). To determine the tolerance to reperfusion-induced
injury in the neonatal hearts, studies in which interventions designed to overcome reperfusion-induced injury
are given at the time of reperfusion would be desirable
(203). To our knowledge, no such studies have been reported in developing hearts.
Volume 79
July 1999
CARDIAC SENSITIVITY TO OXYGEN DEFICIENCY
FIG. 6. Effect of adaptation to intermittent high-altitude hypoxia
(7,000 m, 8 h/day, 5 days/week, a total of 24 exposures) on cardiac
resistance to acute hypoxia (expressed as recovery of isotonic contractions of isolated papillary muscle, percentage of baseline values) in
young (exposed from 4th day of postnatal life) and adult (exposed from
12th week) rats. ** P , 0.01. [Data from Ostadal et al. (155).]
hypoxic injury in both adult and immature hearts. Because most of these effects were observed in acclimatized
rats, the behavior of larger immature species under conditions of chronic hypoxia needs to be examined in future
investigations.
2. Possible protective mechanisms
A) BLOOD OXYGEN TRANSPORT CAPACITY. An increase in
hemoglobin increases the blood oxygen concentration.
Indeed, mammals and birds introduced to high altitudes
develop variable degrees of polycythemia (199), associated with a shift to oxygen dissociation curve to the right
due to increased concentration of 2,3-diphosphoglycerate
(135). On the other hand, mammals and birds genotypically adapted to high altitude show a modest or no increase in hematocrit values (12). It can be concluded,
therefore, that an increased blood oxygen content may
not necessarily be an adaptive parameter. Several studies
demonstrated an increased concentration of myoglobin in
chronically hypoxic myocardium (for review, see Ref.
137), but significant differences exist depending on species and age.
B) TISSUE OXYGEN TRANSPORT. There is disagreement with
respect to the development of myocardial capillaries in
animals exposed to hypobaric hypoxia. Whereas Rotta
(207), Clark and Smith (40), and Smith and Clark (219)
found a decrease in the ventricular capillary density in
chronically hypoxic guinea pigs and rats, Miller and Hale
(133) found an increased capillary density in both ventricles. Turek et al. (230) described an increase in the hypertrophied right ventricle and no change in the left ventricle. Moravec et al. (136) as well as Banchero et al. (12)
found a similar increase only in the left ventricle. Finally,
Rakusan et al. (195) and Pietschmann and Bartels (178)
found no evidence of increased myocardial capillary density in animals exposed to high altitude. Mathieu-Costello
et al. (123–125) showed that correction for sarcomere
length is critical to the interpretation of results; capillary
length per volume of muscle fiber was not significantly
different between lowland and highland deer mouse. Such
a variability in results may be due to the selection of
experimental animals, their age, as well as duration of
chronic hypoxia. Nevertheless, it seems that coronary
angiogenesis and increased coronary flow are effective
compensatory mechanisms at the beginning of the process of acclimatization; later, their importance may decrease. This view is supported by normal or even decreased coronary blood flow in residents living at high
altitude (137).
C) ENERGETIC METABOLISM. The protective effect of
chronic hypoxia may involve increased capacity of cardiac anaerobic metabolism, increased energy utilization
capacity, and possibly selection of metabolic pathways or
substrates with a higher energy efficiency that would
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development of systemic hypertension and left ventricular hypertrophy in spontaneously hypertensive rats (73).
A few authors have compared the tolerance of chronically hypoxic versus normoxic immature myocardium.
We (155) observed that intermittent high-altitude hypoxia
resulted in similarly enhanced cardiac resistance (expressed as the recovery of contractile function of the
isolated right ventricle after acute nitrogen anoxia in
vitro) in rats exposed to hypoxia either from the fourth
day of postnatal life or in adulthood (Fig. 6). Adaptation to
chronic hypoxia increased the tolerance in both sexes,
but the sex difference (i.e., increased tolerance in females) was maintained (158). An important feature of
adaptation to chronic hypoxia is that the protective effect
persists even 4 mo after the removal of rats from the
hypoxic environment (154). This finding needs further
detailed experimental investigation; nevertheless, it suggests further possibilities in the search for effective protection of the myocardium against various types of hypoxic injury. Baker et al. (11) demonstrated that
adaptation to chronic hypoxia from birth in a normobaric
chamber increased the tolerance of the developing rabbit
heart (day 7 to day 28). Recovery of postischemic aortic
flow at these stages was better in chronically hypoxemic
hearts compared with age-matched controls. Furthermore, metabolic adaptation to hypoxemia has been observed in the myocardium of children with congenital
cardiac malformations producing hypoxemia (210). The
aerobic capacity of the energetic metabolism was significantly reduced in hypoxemic hearts as compared with
normoxemic patients.
It may be, therefore, concluded that adaptation to
chronic hypoxia increases cardiac resistance to acute
647
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OSTADAL, OSTADALOVA, AND DHALLA
Similarly, the possible role of heat shock proteins (130),
remodeling of the ventricles (130), sex hormones, and
antioxidant reserve is not fully established. Recently, Kolar et al. (101) have demonstrated that the ATP-dependent
potassium channel blocker glibenclamide practically
abolished the antiarrhythmic effect of adaptation, suggesting that these channels appear to be involved in the
cardioprotection mechanism of chronic hypoxia. The optimum degree of hypoxia and length of acclimatization for
cardioprotection are, however, still unclear.
Unfortunately, despite the fact that the first experimental study on the cardioprotective effect of adaptation
to chronic hypoxia was published more than 35 years ago,
no satisfactory explanation of this important phenomenon has yet been proposed. Furthermore, most of the
above hypotheses are based on results from adult animals; the possible age-related differences in the mechanisms involved are still unexplained.
3. Adverse effects of adaptation
The literature concerning the influence of age on
chronic hypoxia-induced cardiopulmonary changes is neither sufficient nor consistent. Smith et al. (220) reported
that young rats exposed to chronic hypobaric hypoxia
showed a lower right ventricular hypertrophy than adult
animals. Rabinowitch et al. (190) compared cardiopulmonary changes in rats exposed to permanent hypoxia corresponding to the altitude of 5,000 m starting either on the
ninth day of life or in adults. These investigators found
that the age difference in pulmonary hypertension and
right ventricular hypertrophy was not statistically significant. In our experiments (105, 155), an intermittent highaltitude hypoxia (hypobaric chamber, equivalent to 7,000
m, 8 h/day, a total of 24 exposures) induced chronic
pulmonary hypertension and right ventricular enlargement in animals exposed either from the fourth day of life
or in adulthood. Whereas the pressure elevation in the
pulmonary circulation was expressed more in adult hypoxic animals, the right ventricular enlargement was
greater in the young group of rats. Right ventricular
weight increased linearly with the rise in pulmonary
blood pressure in young hypoxic animals (r 5 0.72); this
relationship was, however, very loose in adult rats (r
5 0.16). The close correlation between these two parameters in young hypoxic animals may be the consequence
of the higher plasticity of the developing heart (e.g., hyperplastic growth of myocytes just after birth). Chronic
hypoxia also modulates changes of collagenous proteins.
The proportion of this fraction significantly increased,
whereas the collagen I-to-III ratio was decreased; this
suggested an increased synthesis of collagen III. The elevation of collagen III in young rats was significantly higher
(177). It should be mentioned that even severe chronic
hypoxia-induced pulmonary hypertension and right ven-
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decrease the oxygen requirements (137). This view is
supported by our findings in chronically hypoxic rats (16)
in which both ventricles had a significantly higher capacity for glucose utilization as well as for the synthesis and
degradation of lactate. On the other hand, the ability of
the heart to break down fatty acids decreased significantly. Chronic hypobaric hypoxia increased the number
of cardiac mitochondria and slightly decreased their
mean volume (43). Novel-Chate et al. (147) have shown
that chronic hypoxia increased cardiac function-to-oxygen consumption ratio and induced phosphocreatine
overshoot after b-adrenoreceptor stimulation. Furthermore, acclimatization to high altitude lowers the specific
activities of several sarcolemmal ATPases and, at the
same time, increases their affinity for ATP (257), which
permits a more efficient utilization of ATP and helps to
prevent membrane transport function under conditions of
low energy production. It should be mentioned, however,
that it is often impossible to distinguish the direct effect
of chronic hypoxia from those of hypertrophy and from
other factors, including the nutritional state associated
with exposure to high altitude (14).
D) NEUROHUMORAL REGULATIONS. Despite increased sympathetic activity (66), chronic hypoxia is associated with
impaired response to adrenergic stimulation due to downregulation of myocardial b-adrenergic receptors (19, 94).
One potential mechanism of desensitization to catecholamines in chronic hypoxia appears to involve a decreased functional activity of the G protein a-subunit (93).
Chronic hypoxia may also lead to increased degradation
of catecholamines as indicated by the elevated activity of
catechol-O-methyltransferase (118). Chronic hypoxia-induced decreased sensitivity to catecholamines can be
seen to be antiarrhythmic and may be responsible for the
protective effect of adaptation on isoproterenol-induced
necrotic lesions (184). On the other hand, Kacimi et al.
(95) have found that chronic hypoxia increases the muscarinic receptor affinity and density, which may contribute to the blunted responsiveness of the heart to catecholamines.
Chronic hypoxia-induced hypothyroidism may be
one of the cardioprotective mechanisms, since the hypothyroid myocardium is less susceptible to hypoxia (120).
Furthermore, adaptation to high altitude significantly increased the myocardial level of prostaglandins (188). In
fact, a single dose of 7-oxo-prostacyclin increased cardiac
tolerance to acute nitrogen anoxia in vitro in control and
chronically hypoxic rats (256). The protective effect of
acclimatization and prostacyclin were, however, additive,
suggesting that different mechanisms may be involved.
Adaptation to chronic hypoxia has also been shown to
induce a decrease in adenosine receptor density without
any change in the affinity for the agonist (95), but the
possible involvement of adenosine in the protective effect
of adaptation to chronic hypoxia is poorly understood.
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CARDIAC SENSITIVITY TO OXYGEN DEFICIENCY
tricular hypertrophy were completely reversible after removal of rats from the hypoxic atmosphere for a sufficiently long period of time (.4 wk; Refs. 16, 74, 103, 165,
201).
B. Ischemic Preconditioning
ical protection with adenosine and A1-selective agonists
and muscarinic agonist, may have a different ontogenetic
development.
Some information on the neonatal hearts has also
been obtained in cultured cells; Webster at al. (242) demonstrated that neonatal rat cardiac myocytes preconditioned by a 25-min exposure to hypoxia followed by
reoxygenation were protected against membrane damage
for up to 6 h of prolonged severe hypoxia, as determined
by arachidonic acid release and contractile recovery. In
contrast, nonpreconditioned myocytes exhibited a significant hypoxic damage after 2– 4 h. It is obvious that contractile failure in tissue culture occurs much more slowly
in response to hypoxia than in the working heart, perhaps
because of differences in the balance of energy supply
and demand between these two situations. Similarly,
Ovelgönne at al. (171) have shown that preconditioning
can be induced in cultured neonatal myocytes after a
60-min exposure to hypoxia but not by heat shock proteins. The experimental protocol leading to cardioprotection in culture is, however, significantly different from
classical preconditioning, and the information thus obtained is difficult to compare with our results.
The precise mechanisms of preconditioning are still
unclear but almost certainly involve the initial release of
“endogenous myocardial protective substances” (173,
253), which probably include adenosine, bradykinin, prostacyclin, and nitric oxide, as well as the translocation of
protein kinase C (PKC) to sarcolemmal and nuclear membranes (255) and, possibly, an effect on ATP-dependent
potassium channels (65). The evidence for this hypothesis
includes the prevention of preconditioning by inhibition
of the activity or translocation of PKC (114, 224) as well
as the fact that activators of PKC can mimic the effects of
ischemic preconditioning (41, 114). Protein kinase C is a
family of closely related serine-threonine protein kinases
that can be classified into two major categories. The
conventional PKC isoforms (e.g., a, g) are characterized
enzymatically by their requirement for calcium for activation, and the novel PKC isoforms (e.g. d, e, z) are structurally related to the conventional PKC but do not require
calcium for maximum activation. Protein kinase C isoform expression in the rat heart, however, changes significantly during ontogenetic development (208); PKC-a, -d,
and -z were detected in 2-day-neonatal hearts, but only a
slight immunoreactivity was detected in extracts from the
adult hearts. The decline in PKC-a and -d occurred during
the first two postnatal weeks, whereas PKC-z had declined even by the second postnatal day. On the other
hand, PKC-e was detected in neonatal as well as in adult
hearts. We have observed (170), in accordance with the
above results, that PKC isoforms a, d, z, and e were
expressed during the first postnatal week. Moreover, the
levels of PKC-a and -d changed significantly during this
period, whereas PKC-a was expressed at a higher level on
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The most efficient form of temporal protection of the
adult myocardium is ischemic preconditioning, first described by Murry et al. (138). This phenomenon was defined as an enhanced tolerance of the heart to a prolonged
period of ischemia that is achieved by prior exposure to
much shorter periods of the same insult. Preconditioning
is manifested by a reduction of myocardial cell injury
(138), marked suppression of ventricular arrhythmias
(174, 217), and enhanced recovery of contractile function
(36) during reperfusion, after a period of prolonged ischemia. Whereas extensive data are available on ischemic
preconditioning in the adult myocardium, information on
this protective mechanism in the immature heart is very
inadequate. We have shown (167, 170) that classical ischemic preconditioning, at least in rats, is not present at
birth, and the enhanced recovery of contractile function
develops only at the end of the first postnatal week (day
7). The decreasing tolerance of the neonatal heart to
ischemia is thus counteracted by the development of an
endogenous protective mechanism. Because there were
no data on ischemic preconditioning in the immature
heart, we have used an experimental protocol (three
3-min periods of global ischemia, each separated by a
5-min period of reperfusion) which in adult rats improved
the recovery of contractile function and reduced the infarct size as well as the number of ventricular arrhythmias
(113). Nevertheless, it seems that our findings were not
influenced by the age-dependent differences in the threshold for protection, since a prolongation of the ischemic
episodes from 40 to 60 min did not lead to the development of preconditioning in 1-day-old animals (170). Similarly, Awad et al. (6) have shown that loss of preconditioning in the immature isolated rat heart cannot be
overridden by an increased preconditioning stimulus (5min ischemia 1 5-min reperfusion vs. 4 3 5-min ichemia
and 5-min reperfusion). In addition, they (7) subjected a
4-day-old heart to the pharmacological stimulus of phenylephrine that also failed to protect the immature heart.
On the basis of these results, it cannot be excluded,
however, that ischemic preconditioning with another index of injury (e.g., infarct size, number of arrhythmias) or
in different animal species might have a different developmental time course. Recently, Liu et al. (112) observed
that ischemic preconditioning can be induced in 4- to
7-day-old isolated perfused rabbit hearts. Data on the
newborns are, however, lacking. Similarly, some “new”
methods of preconditioning (108), such as pharmacolog-
649
650
OSTADAL, OSTADALOVA, AND DHALLA
C. Pharmacological Interventions
There are, in general, two pharmacological possibilities for improving the oxygen homeostasis in the hypoxic
3. Comparison of cardiac protection by
adaptation to chronic hypoxia and by ischemic
preconditioning
TABLE
Protection
Duration
Mechanism
1, low; 111, high.
Chronic Hypoxia
Preconditioning
1
111
?
11
1
?
or ischemic myocardium; these include increasing the
oxygen supply by increasing coronary flow (vasodilators)
and reducing the oxygen consumption by decreasing the
cardiac contractile function (negative inotropic drugs).
The clinical use of this second group in pediatric cardiology is, however, markedly limited because significant ontogenetic differences exist in cardiovascular sensitivity to
inotropic agents (for review, see Refs. 4, 47, 152). In this
review, we therefore focus on negative inotropic drugs
that affect transsarcolemmal calcium fluxes in cardiac
muscle.
The contraction of the adult mammalian myocardium
is known to be dependent on both transsarcolemmal calcium influx and calcium release from the sarcoplasmic
reticulum (55). However, as has been shown in section
IVB3, the relative contribution of the two mechanisms
varies significantly during development. It was proposed
that if the immature heart is relatively more dependent on
transsarcolemmal calcium entry, then the developing
heart may be more sensitive to the negative inotropic
effect of calcium channel antagonists (25, 104, 168, 218,
245).
Gibson et al. (61) were the first to report that verapamil depressed cardiac output in intact puppies to a
greater extent than that observed in adult dogs. Boucek et
al. (25) and Artman et al. (5) demonstrated that the immature rabbit heart has a greater sensitivity not only to
the negative inotropic effects of verapamil but also to the
effects of nifedipine and diltiazem. Their conclusions
were based on a comparison of newborn and adult hearts,
where the observed difference was prominent. Skovranek
et al. (218) found that the mortality of verapamil-treated
rats was age dependent. The negative inotropic response
of the rat isolated right ventricular myocardium was significantly greater in 3-day-old animals than in all older
groups (15-, 30-, and 90-day-old rats) (Fig. 7). Similar
age-related changes were observed in experiments on
isolated perfused rat heart (104); this ontogenetic difference was found under the conditions of both constant
perfusion pressure and constant flow and is thus independent of the state of coronary circulation. It seems that
ontogenetic differences in the effect of calcium antagonists are not the result of changes in the density and the
affinity of nitrendipine-binding sites because they attain
the adult values in the rat myocardium already during the
first week of life. Similarly, the binding characteristics in
the rabbit heart did not differ in neonatal and adult age
(24, 200). On the other hand, significant ontogenetic differences have been described in the subcellular localization and surface density of dihydropyridine and ryanodine
receptors (245).
Thus it may be concluded that the higher sensitivity
of the isolated developing heart to calcium channel blockade is a consequence of a higher functional dependence of
the immature myocardium on transsarcolemmal calcium
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day 1 and PKC-d only on day 7. On the other hand, no sign
of translocation of any PKC isoforms under study was
observed on day 7, i.e., on the first day of postnatal life
when ischemic preconditioning appeared. On the basis of
this observation, the role of PKC in the mechanism of
preconditioning cannot be excluded; a study of further
postnatal development of this protective phenomenon
would be decisive in this respect. Furthermore, the simultaneous presence of at least four different isoforms of
PKC in the neonatal heart and of only two different isoforms of PKC in the adults might suggest a high degree of
age-dependent specificity and flexibility of the signal
transduction mechanisms. Webster et al. (242) found that
the PKC activator phorbol ester mimics the effect of brief
episodes of hypoxia in providing protection of neonatal
cultured myocytes against prolonged hypoxia.
Repeated brief coronary occlusions depress systolic
function and result in prolonged contractile impairment
despite the absence of irreversible damage. This postischemic myocardial stunning (23), which occurred also in
our experiments, was thought to limit the myocardial
oxygen demand and thereby preserve cellular viability.
There is now, however, sufficient evidence to state conclusively that preconditioning is not a consequence of
myocardial stunning (172). Our results (170) support this
conclusion, since stunning was present even on postnatal
days 1 and 4 when preconditioning was not observed.
Thus it may be concluded that ischemic preconditioning as a potent cardioprotective mechanism is, at least
in rats, not a genotypic phenomenon but that it develops
very early during postnatal life (Table 3). It is, however,
too early to reach a definitive conclusion on whether the
mechanisms involved in the preconditioning of the immature heart differ or are identical to those of the adult
myocardium. It is hoped that further studies of the ontogenetic development of cardiac protection will assist in
characterizing the role of key events during ischemic
preconditioning of the immature heart.
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CARDIAC SENSITIVITY TO OXYGEN DEFICIENCY
influx. Further information would be, however, necessary
for an understanding of the developmental changes in
cardiovascular sensitivity to calcium antagonists in intact
animals. The answer may be, namely, the result of combined reactions of developing myocardial cells (inotropy),
developing nodal cells (chronotropy), and developing vascular smooth muscle cells (vasodilation). We presume
that despite significant interspecies differences, ontogenetic changes in cardiac sensitivity to calcium antagonists
may exist in all mammals including humans, depending,
however, on the time course of maturation of the systems
involved in myocardial and vascular calcium handling.
Thus we should like to point to the possible negative
consequences of the clinical use of calcium antagonists in
the youngest, very sensitive, age group. The clinical importance of this problem results from the repeatedly observed complications of verapamil treatment during the
early postnatal period in children: hypotension and shock
(1, 180), atrioventricular block and bradycardia (215), and
cardiac arrest in hypocalcemic infants (63). All these
reported complications were observed in patients up to 1
yr of life.
D. Cardioplegia
Cardioplegia has revolutionized open-heart surgery.
This technique, which was developed on the basis of a
theoretical approach to the manipulation of ischemic injury, has markedly increased the tolerance to ischemia
which in turn has improved operating conditions. Associated with this has been an improvement in postischemic
recovery and a reduction of mortality (67, 98, 252). How-
ever, this success has been largely in the field of adult
cardiac surgery, whereas protection of the immature myocardium during cardiac surgery remains a significant clinical problem. Bull et al. (32) found no difference in the
degree of myocardial protection seen in pediatric patients
by St. Thomas’ Hospital cardioplegic solution compared
with that provided by reperfusion between intermittent
periods of aortic cross-clamping. The explanation of inadequate myocardial protection in young hearts may be
related in part to cyanosis increasing the vulnerability of
the heart to ischemic injury and to the developmental
differences in metabolic profiles of adult and immature
hearts. Del Nido et al. (45) and Lofland et al. (115) have
suggested that the greater drop in ATP content in the
young hearts during reperfusion indicates reperfusion injury as a major mechanism of myocardial damage in the
young hearts. This rather complicated and controversial
topic was reviewed in detail by Riva and Hearse (203).
The results of experimental studies on cardioplegic
protection of the immature rabbit heart have revealed that
single-dose cardioplegia plus hypothermia is more or
equally effective as hypothermia alone (e.g., Ref. 27),
whereas multidose cardioplegia plus hypothermia seems
to be detrimental (117). According to Magovern et al.
(117), the cardioplegic solution used (St. Thomas’ Hospital) has adverse effects in immature hearts at 10°C that
are not seen at 28°C. Similarly, Baker et al. (9) demonstrated at 14°C that the St. Thomas’ Hospital solution
improved postischemic recovery of function in the mature rabbit heart but decreased it in the immature heart.
Analogous results were obtained in immature pigs (42)
and guinea pigs (241) which showed that hypothermic
potassium cardioplegia inadequately protects the ischemic myocardium. Species-related changes in the deleterious effect of cold multidose crystalloid cardioplegia
have been claimed to occur (10); St. Thomas’ Hospital
solution protected neonatal pig myocardium, but it appeared to damage the neonatal rabbit heart. For an explanation of these controversial results, the different time
course of cardiac maturation has to be taken into consideration. The composition of cardioplegic solutions may
play an important role; their formulation was derived
from adult animals and based on the normal ionic composition of the extracellular fluid, with sodium and calcium concentrations, the main determinants of cellular
calcium exchange, optimally present at moderately reduced levels (9). Because calcium handling and voltagedependent calcium channel activity differ in neonates (87,
96, 140, 168), the calcium component of the cardioplegic
solution may be responsible for different susceptibility
and degree of protection. Furthermore, hypertrophy and
cyanosis, which are often present in young hearts undergoing cardiac surgery, may alter not only the sensitivity of
the heart to ischemia, but also its responsiveness to cardioplegia. In view of the relatively high mortality and
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FIG. 7. Negative inotropic effect of calcium antagonist verapamil on
isolated right ventricle in rats of different age. [Data from Skovranek et
al. (218).]
651
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OSTADAL, OSTADALOVA, AND DHALLA
VI. CONCLUSIONS AND PERSPECTIVES
The importance of the developmental approach for
experimental and clinical cardiology is indisputable. It
offers new possibilities in the experimental studies of
pathogeny, prevention, and therapy of serious cardiovascular diseases; hypoxic states of the cardiovascular system may serve as a typical example.
What can we gain from studying the heart of lower
vertebrates for analysis of pathogenetic mechanisms involved in the hypoxic/ischemic tolerance of the immature
mammalian heart? Their cardiovascular system, which in
many superficial ways resembles anatomically different
ontogenetic periods of homeotherms, shows an amazing
morphological functional and metabolic diversity. Surprisingly complex and unexpected patterns of oxygensupplying systems have been revealed during the last 30
years that cannot be regarded as primitive or inefficient;
some of them are, however, still poorly described. The
poikilothermic heart represents a unique model for com-
parison of the tolerance to oxygen deprivation in two
precisely defined, developmentally stable layers of the
same heart, differing in their structure (compact, spongious), type of blood supply (lacunar, coronary), as well
as the capacity of energetic metabolism. Moreover, this
complex system is very susceptible to changes in cardiac
growth, work load, and metabolic demand. Furthermore,
comparative studies have clearly shown that the adult
poikilothermic heart is significantly less sensitive to hypoxia as compared with the homeothermic one. The possible mechanisms involve higher anaerobic capacity and
developmental differences in system responsible for calcium handling, i.e., a situation resembling the immature
mammalian heart. Although it seems that the type of
blood supply (coronary, lacunar) does not play a decisive
role in the sensitivity to myocardial injury, precise information on the lacunar myocardial blood supply might be
surprisingly useful for the development of new techniques
for the treatment of human ischemic heart disease. Unfortunately, the data on cardiac structure, function, and
metabolism in lower vertebrates have only infrequently
been exploited for insights by investigators studying the
mechanisms of cardiac sensitivity to oxygen deprivation
in developing hearts of homeotherms. We, however, do
hope that developmental cardiologists might come to a
new appreciation of the amazing physiological potential
of supposedly “simple” cardiovascular systems of lower
vertebrates.
Ontogenetic research in the field of cardiac hypoxia
and ischemia can generally be divided into four closely
related areas: 1) study of normal structural, functional,
and biochemical development of the cardiovascular system; 2) study of the tolerance of the developing heart to
oxygen deprivation; 3) possibilities of protective interventions; and 4) late effects of early hypoxic damage of the
cardiovascular system. The great majority of experimental data indicate that the immature mammalian heart is
more resistant to oxygen deficiency as compared with
adults. There are, however, many controversies concerning the mechanisms of developmental variation in cardiac
responsiveness; the obvious discrepancies may be partly
due to the different experimental procedures used for
studying different animal species with a different time
course of maturation. Precise knowledge of individual
developmental periods that are critical for cardiac ontogeny is thus crucial for the prediction and explanation of
cardiac reactions to oxygen deficiency. Furthermore, experimental data on ontogenetic differences in cardiac
responsiveness to hypoxia/ischemia were obtained almost exclusively from healthy individuals. However, such
an approach is far from the clinical situations, where
interventions applied in the critical developmental periods may have serious consequences for further maturation. The complications observed after the clinical use of
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morbidity associated with pediatric surgery, it is undoubtedly important to clarify these possibilities and to learn
more about the mechanisms of developmental changes
underlying different sensitivity of immature and adult
myocardium to cardioplegia.
As mentioned earlier, cardioplegia is mostly combined with hypothermia. Cooling slows heart rate and
metabolism which, in turn, results in a decrease in oxygen
consumption (68, 251). Systemic hypothermia with or
without circulatory arrest continues to be used for cardiac protection during pediatric heart surgery; it has been
reported that in the neonatal heart, hypothermia permits
a “safe” ischemic period for at least 90 min (107). Despite
this, clinical studies have reported a 10% mortality using
deep (15°C) hypothermia, with 50% of these deaths ascribed to acute cardiac insufficiency (111). It would appear, therefore, that not all hearts are afforded equal
protection by hypothermia. Wittnich (248) undertook a
study of the metabolic effects of various clinically employed levels of hypothermia (25, 19, and 12°C) on 3-dayold piglet heart. As expected, each level of hypothermia
extended the time before the onset of ischemic injury in
these neonatal hearts. Even with the deepest hypothermia, however, ATP depletion by as much as 25% was seen
in the first 30 min of ischemia (249). Although this was
significantly less than during 30 min of normothermic
ischemia (50%), some ATP use was still present. In a
group of hearts that had 50% less ATP than normal, the
safe ischemic time afforded by the use of deep hypothermia was significantly reduced. This suggests that hypothermia does not offer equal protection in all immature
hearts, especially those with lower ATP levels, including
neonatal hearts exposed to severe hypoxia.
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CARDIAC SENSITIVITY TO OXYGEN DEFICIENCY
negative inotropic drugs during early cardiac development may serve as warning examples.
Developmental cardiology is now in a molecular era,
and our understanding of cardiogenesis expands exponentially. Recent advances of new methodology, particularly molecular biology and genetics, may substantially
help in the laborious search for a better understanding of
the pathogenetic mechanisms that determine the degree
of cardiac tolerance to oxygen deprivation as well as
mechanisms responsible for different types of cardiac
protection. Nevertheless, molecular analysis in developmental cardiology is unthinkable without a comprehensive and well-integrated view of the field.
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