Download Nonuniformity: A physiologic modulator of contraction and relaxation

lACC Vol. 9. No.2
February 19~7:341-8
341
BASIC CONCEPTS IN CARDIOLOGY
Arnold M. Katz, MD, FACC, Guest Editor
Nonuniformity: A Physiologic Modulator of Contraction and
Relaxation of the Normal Heart
DIRK L. BRUTSAERT, MD, FACC
Antwerp. Belgium
Nonunlformity of mechanical performance is inherent
to the multicellular nature and specific geometry and
configuration of the ventricle of the heart. Although the
concept of nonuniformity of the diseased heart is not
new. ventricular function and the performance of the
heart as a muscular pump cannot be understood unless
nonuniform behavior is taken into account, even under
normal conditions. Along with the loading conditions
throughout the cardiac cycle and the time courses of
activation and inactivation, the nonuniform behavior of
load and of activation and inactivation in space and in
time constitutes a third important determinant of mechanical performance and efficiencyof the ventricle dur-
To produce efficient pumping the complex mass of
myocardial fibers must contract more or less
simultaneously .... the contracting myocardium
propels outflowing blood with a sudden impulse like a
piston struck with a mallet.
Rushmer
(I)
Blood is not merely pressed out by a decrease in
ventricular cavity; it is virtually wrung out.
Wiggers (2)
The muscular ventricular walls squeeze down on the
contained blood much as onc would milk a cow or
squeeze a lemon in a clenched fist.
Sarnoff and Mitchell
(3)
The mechanisms underlying the contractile performance of
the heart as a muscular pump during systole are as yet not
completely understood. The systolic contraction phase of
the cardiac cycle is controlled by two distinct, though not
entirely separable, mechanisms. These are a) control by the
From the Department of Physiology and Medicine and the University
Hospital. University of Antwerp. Antwerp. Belgium.
Manuscript received February 20. 1986: revised manuscript received
July 28. 1986. accepted September 2. 1986.
Address for reprints: Dirk L. Brutsaert, MD. PhD, University of Antwerp, Groenenborgerlaan. 171, 2020 Antwerp. Belgium.
01987 by the
American College
of Cardiology
ing both contraction and relaxation. Hence, a triad (load,
activation-inactivation, nonuniformity) of controls regulates systolic function of the normal ventricle.
In the diseased heart, even when loading and activation-inactivationare normal, the modulating role played
by this nonuniformity can become imbalanced because
of abnormal cavity size or shape or because of regional
dysfunction. Such an imbalance would diminish external
efficiency (the ratio of work performed to oxygen utiIized) of the ventricle and result in incoordinate contraction and relaxation. These abnormalities, in turn,
could exacerbate manifest cardiac failure,
(J Am Colt Cardiol 1987;9:341-8)
loading conditions (pressure and volume; heterornetric autoregulation 13); secondary coefficients 12]). and b) control
by all processes related to activation (contractility; homeometric autoregulation [3]; primary coefficients [2]) (Fig.
I). Similarly. the systolic relaxation phase of the cardiac
cycle is also governed by load and changes in load, and this
load dependence (or load sensitivity) is modulated by the
degree and rate of inactivation (Fig. I) (4-12).
In addition to this dual control of contraction and relaxation, the additional influence of some degree of nonunifonnity of ventricular performance has been obvious to many
investigators (tertiary coefficients) (2). Wiggers (2) emphasized that the spreading (electrical) impulse induces a series
This article is part of a series of informal teaching reviews devoted to subjects in basic cardiology that are of
particular interest because oftheir high potentialfor clinical
application. The series is edited by Arnold M. Katz. MD.
FACC. a leading proponent of the view that basic science
can be presented in a clear and stimulating fashion. The
intent of the series is to help the clinician keep abreast of
important advances in our understanding of the basic mechanisms underlying normal and abnormal cardiac function.
0735- J097/S7/$3.50
BRUTSAERT
NONUNIFORMITY OF THE CHART
342
JACC Vol. 9. No.2
February 1987:341-8
TRIPLE C O NTROL
of S YS T OLE
J
\~_
f
~----'/
t
IC EJECTION
,CONTRACTION~
IR
I::':
DIAST AS IS IATRIAL
......,...
CONTR
s '1 ,--=-=-=---,,
;RELAXATION
load
o
o inactiva tio n'
o load
o ac tivation
Comp liance
Figure 1. Triple control of the normal heart as a muscular pump.
The time course of the cardiac cycle is depicted as force (f) and
length (1) traces of an afterloaded contraction of an isolated cardiac
muscle (with isometric-isotonic, sequenced physiologic relaxation), synchronized in time (t) with pressure (P) and volume (V)
traces of an ejecting intact left ventricle. S = systole, from the
Greek word cnxrtosr; (a drawing together or contraction); it has
come to mean "the contraction or period of contraction of the
heart, especially that of the ventricles, sometimes divided into
components, as preejection and ejection periods, or isovolurnic,
ejection and relaxation periods." 0 = diastole, from the Greek
word OtC({]'ToAYJ (a drawing asunder, expansion); it has come to
mean' 'the dilatation or period of dilatation of the heart, especially
that of the ventricles, coinciding with the interval between the 2nd
and 1st heart sounds" (from Dorland's Medical Dictionary. 26th
ed. Philadelphia: WB Saunders, 1981). This medical interpretation
is only one of several possible interpretations of the two Greek
words; for example. according to Webster's Dictionary two other
equally valid interpretations of the word diastole are I) a lengthening of a short quantity or syllable, 2) a mark like a comma,
placed between the parts of certain words to distinguish them from
other words of the same form. In these two latter interpretations
temporal rather than spatial (as was used in the medical context)
separation is emphasized. Accordingly, another etymologically
justified interpretation of the word diastole could be a division,
notch or separation between two contraction-relaxation cycles.
This latter interpretation would be conceptually more appropriate
for an integrated muscle-pump system (5). In this sense, the term
relaxation periods in Dorland's interpretation of systole would also
include the rapid filling phase (RFP). Diastole would merely mean
separation of or standstill between two active cardiac cycles. Only
this latter interpretation of systole and diastole, as depicted in this
figure. will be considered in this review. IC = isovolumic contraction; IR = isovolumic relaxation; CONTR = contraction.
o
(non)uniformity
of
..liliiii distribut ion of ....
reg ional
lemporal "'IIIlI
load
, . (In)ac tl vatl on
of local fractionate contractions responsible for the initial
slow rise of intraventricular pressure. Moreover, the spiral
arrangement of the muscle fibers would make ventricular
contraction particularly efficacious by allowing the blood to
be wrung out. Yet, despite these earlier observations, nonuniformity has never been systematically incorporated as
part of the normal homeostatic mechanisms of cardiac function. Instead, in most studies on ventricular function investigators have tacitly assumed that contraction and relaxation phases of systole proceed in a uniform fashion. To
generate a sufficiently powerful impulse, in which the ventricle must develop forces about five times the force of
gravity, Rushmer (I) and many others believed that the
myocardial walls must contract almost synchronously.
Rushmer's view stemmed from his observation in the intact
heart of the high rates of pressure rise and dimension changes,
which induce an extremely high acceleration of blood with
an early peak flow velocity, suggesting an effective mechanism for pumping blood against high pressures.
Rushmer also emphasized that these rates of pressure
rise, dimension changes and flow can be readily altered
under different conditions, for example. changes in heart
rate, exercise, sympathetic stimulation, catecholamines, and
so on. He showed that these subtle alterations in rate were
to a large extent mediated through alterations in the degree
of synchronization in activation and in the rate of tension
development in the individual muscle fibers across the ventricular wall. Nevertheless, the possible role of variations
in synchrony of contraction as a factor in modulating myocardial performance was as yet not well appreciated. Among
others (2), Sarnoff and Mitchell (3) emphasized the important physiologic modulating role of some degree of nonuniformity in the performance of the muscle-pump function
of the heart. They showed that ventricular systole was prolonged and stroke work decreased when the heart was paced
from a ventricular rather than an atrial pacing site. Ever
since, experimental evidence from different disciplines, both
morphologic and functional. has continued to emphasize the
potential importance of nonuniformity of the ventricle both
in space and in time.
BRUTSAERT
NONUNIFORMITY OF THE CHART
JACC Vol. 9. No.2
February 1%7:341-8
Architectural Nonuniformity
The left ventricle does not conform to a simple geometric
shape, because the various myocardial "bundles" are oriented in different directions and describe circles of different
diameters (13,14). Fiber orientation through the ventricular
wall is characterized by a smooth change of direction of
muscle fibers across the wall as in an open Japanese fan
(15), not only spiraling in the longitudinal direction. but
changing directions by almost 180 from epicardium to endocardium. The thickness of the wall varies from a few
millimeters at the left ventricular apex to greater than 2 cm
at the attachments of the papillary muscles.
The geometry and configuration of the ventricle are major determinants of the force within the ventricular wall.
'This principle is an embodiment of the Laplace relation.
which states that the tensile stress within any shell is a
function of the distending pressure, radius of curvature and
wall thickness. Although regional stresses within the heart
have not been directly measured, several investigators ( 16-19)
have calculated that important nonuniform distribution in
circumferential and longitudinal stress should be taken into
account in the normal heart at rest; for example, endocardial
stress by far exceeds epicardial circumferential stress. This
results in nonuniform distribution of load over the different
myocardial cells in the ventricular wall both at rest and
during contraction (20-25).
Role of individual myocardial cells. Although regional
specialization of function exists (see later), morphologic
myocyte diversity has not been seen with conventional anatomic or electron microscopic techniques. Furthermore, the
slack (unloaded) sarcomere length of rest living cardiac cells
isolated from various regions of the normal heart was shown
to be distributed uniformly in different regions of these
single cells, regardless of the region of origin within the
ventricular wall, that is, left versus right ventricle or endocardial versus epicardial layers (26,27). These properties,
of course, may be altered because these cells at rest are
loaded in the intact ventricular wall in vivo. Accordingly.
any regional differences in the passive mechanical properties
of the wall of the intact normal heart are probably related
to regional differences in geometry or wall architecture, or
both, rather than to intrinsic differences in properties of the
individual myocardial cells in the ventricular wall.
0
Electrical Nonuniformity
Electrical excitation is facilitated by the rapidly conducting His-Purkinje system. This system is responsible for
the rapid spread of excitation to all portions of the ventricular
wall so that the ensuing contraction of the various regions
of the ventricle can be sufficiently simultaneous to produce
an effective pumping action (2). The spread of electrical
343
activity is, however, not entirely uniform. Fibers in different
parts of the heart are activated at relatively disparate times,
attaining differences of up to 80 to 100 ms in the normal
heart because the wave of excitation penetrates the ventricularwall from the endocardial to the epicardial surface (28,29).
In the intact ventricle, summation of slightly asynchronous
fiber forces would be expected to yield a more slowly rising
total force than would occur if the fibers were activated
more synchronously.
In in vitro experiments, asynchronous activation of pairs
of papillary muscles in series decreased the combined force
of both muscles (30). Increased synchronicity of contraction
could therefore result from an increased velocity of excitation through the specialized conduction tissue. It is unlikely. however, that a slight initial asynchrony plays any
significant regulatory role, for little or no increases in conduction velocity in Purkinje tissue and only very modest
conduction changes in ventricular muscle have been reported under normal conditions, for example, as a result of
sympathetic stimulation. On the other hand, when the effects
of altering the site of electrical activation on responses to
isoproterenol and treadmill exercise were examined in dogs,
a normal electrical activation of the left ventricle was required for optimal performance of the myocardium during
sympathetic stimulation (31).
Nonuniformity of Activation-Contraction and
Inactivation-Relaxation Coupling
Important nonuniformities exist in the excitation-contraction coupling (excitation-contraction coupling encompasses activation-contraction and inactivation-relaxation
coupling) both within a single cell and among cells taken
from different parts of the heart (Fig. 2).
Regional differences in action potential duration.
Several reports have shown that action potential duration
differs in different regions of the ventricle, being longer at
the base than at the apex and longer in endocardial than in
epicardial myocytes (32), Mechanical perturbations in various regions of the ventricle and differences in the type of
contraction depending on loading (that is, ventricular wall
stress) could easily explain such differences (33,34). Yet,
a marked heterogeneity of the action potential duration was
also found in single cardiac cells isolated from different
regions of rat ventricle, with much longer action potentials
generally being seen in cells from the left ventricle than in
cells from the right ventricle, and action potentials from the
base being longer than those from the apical region (35).
These regional differences in action potential duration are
accentuated in hypertrophied ventricles, in which the prolongation of the action potential that accompanies hypertrophy is not uniform, affecting endocardial, papillary muscle and epicardial fibers to a different degree (36).
BRUTSAERT
NONUNIFORMITY OF THE CHART
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JACC Vol. 9. No.2
February 1987:341-8
ACTIVATION · CONTRACTION
and
INACTIVATION · RELAXATION
COUPLI NG
NON · UNIFORMITY at
CELLULAR LEVEL
ELECTROPHYSIOLOGY
· Time -dependent spread 01 AP
· Spatial non-uniformi ty
AP duration : · lI Ve :. RtVe
. base » apex
. f (loading)
2
Ca KINETICS
· Ca content : Rt Ve:.Lt Ve.septal
• Ca uptake rate constant: septal:.lI Ve
3
AEQUORIN
=?
Aff init y of troponin for Ca· ' . f (loading)
I
Ca ++ •
I
•
4 ENERGETICS
I
I
• Oxld. capacity of mitochondria :
endoc .lI Ve :. ep ic .LI Ve
TROPONIN
•
ACTIN • MYOSIN
•
5
MYOSIN ISOZY MES
6
· Content : heterogenous (V, . V3• or VI . V3)
• Distr lbu , n: · eaual in one cardiac c ell
• V, in RtVe:.lIVeopic.llVe ondOC
• V3 in pap .m. :. liVe wall
MECHANICS
Figure 2. Schematic representation of nonuniformities
at a cellular level. The left part of the figure illustrates
in a schematic and simplified way the various sequences (from above to below) of normal activationcontraction and inactivation-relaxation coupling.
AP = action potential; Ca = calcium; endoc = endocardial; epic = epicardial; f = force; I = length;
LIVe = left ventricle; Oxid. = oxidative; pap.m.
papillary muscle; RtVe = right ventricle.
· Single cardia c c ells :
uniform contraction & relaxation
• Multicellular cardiac muscle :
non uniformity : • at high loads
. during relaxation
Regional differences in cellular calcium content and
exchange. Saari and Johnson (37) reported differences in
the Ca 2 + decay and uptake curves for individual heart segments. These investigations found significant variations in
the Ca 2 + content for the various segments in a decreasing
order: atrial> right ventricular> left ventricular = septal,
and differences in the uptake rate constants of Ca 2 + exchange in a decreasing order: septal > left ventricular >
right ventricular> atrial. Moreover, recent evidence indicates that in heart muscle in apparently steady state, there
may be large oscillations in myoplasmic calcium (38). Although no consistent differences in the myoplasmic calcium
transient derived from aequorin measurements have been
reported in different regions of the heart, Housmans et al.
(39) and Lab et al. (40) showed that changes in loading
conditions, as may occur in different regions of the heart
depending on wall stress, can modulate calcium binding to
the contractile proteins.
The oxidative capacity of the mitochondria, in particular
the specific activity of isocitric dehydrogenase, has been
found to be higher in the endocardial than in the epicardial
layers of the left ventricle, providing further support for a
greater contractile performance in the endocardial layers
(41 ).
Regional distribution and cellular heterogeneity of
myosin isoenzyme distribution. The myosin content is
heterogenous in different cells of the rat ventricle which can
contain either V I (high adenosine triphosphatase [ATPase]
activity) or V 3 (low ATPase activity), or mixed VI + V 3
isoenzyme (42). Within different regions of a given rabbit
heart, the percent V I was greatest for the right ventricular
papillary muscle, less for the right ventricular free wall and
least for the left ventricle (free wall plus septum), with
higher values for V I in the epicardium than the endocardium
(43,44). The V 3 content appears to be higher in the papillary
muscle than in the left ventricular wall (42). On the other
hand, the distribution of V I to V3 is always equal within a
single cardiac cell except in aging (45) and during reperfusion after ischemia (42). Although the significance of
regional distribution and of cellular heterogeneity of myosin
isoenzyme distribution in the heart is not known, these results suggest the existence of differences in contractile state
that may be due to changes in isoenzyme composition. Rabbit cardiac muscles that contain 100% V I myosin shorten
at zero load about six times faster than muscles that contain
100% V3 myosin, indicating that changes in the relative
amounts of V I and V 3 myosin isoenzymes are responsible
for alterations or regional differences in myocardial mechanical performance (45). Moreover, the abbreviated contraction and greater shortening velocity of right versus left
ventricular myocardium, which imply a higher intrinsic contractile state of the right than of the left ventricle (Rouleau
et al. unpublished observations 1986), correlated with a
higher V ltV3 ratio of myosin isoenzyme in the right ventricle
l ACC Vul. 9. Nil. 2
February I <J ~7:34 1 -~
(46). Winegrad (47) speculates that rapid changes in the
cellular regulatory state can occur through activation of fast
myosin (V I) from an off-state to an on-state.
In some regions of the ventricle, cells may have a variable
V I N.\ ratio with a constant VI + V~ content (cell type I)
whereas others may have a constant V ,N ~ ratio with a
variable VI + VI content (cell type 2) (47). This would
imply nonuniform myosin ATPase activity; as a result. cells
in various regions of the ventricle may function on different
force-velocity curves. For example, one would expect variable and high muscle shortening velocity (Vmax) values
with constant maximal force of contractile element (Po )
values in cell type I, and variable and high Po but constant
Vmax in cell type 2. Moreover, rapid changes in forcevelocity properties could occur within one single cell. These
changes may differ from cell to cell as a consequence, for
example, of mechanical demands or a variety of humoral
factors (47). Accordingly. the ventricle could modify the
efficiency with which it does work by selecting the appropriate myosin isoenzyme distribution along the ventricular
wall in accordance to regional stress distribution (44 ,45).
oxygen requirement. blood supply. catecholamine availability (48), thyroxine levels (45) and so on. Biochemical
modulation of nonuniformity could thus contribute a homeostatic mechanism in either the normal or diseased heart.
Mechanical Nonuniformity
Normal Heart: Physiologic Nonuniformity
In the intact ventricle some physiologic degree of mechanical nonuniformity must be taken into account to fully
explainoptimal and efficient muscle-pump performance during
both contraction and relaxation already under normal conditions.
Myocardial cell. Several studies (26.27,49-51) have
indicated that cell length and sarcomere length in different
regions of intact unloaded single cardiac cells decrease and
increase uniformly during twitch contraction. However. under some conditions. various degrees of nonuniformity can
be detected or elicited in these single cell cardiac preparations (26.38,49,50). Single cardiac cells, when leaky. contract asynchronously. most likely because of an incoordinated spread of activation in the presence of inhomogenous
sarcolemmal damage (26,49). With an appropriate calciumbuffering system. spontaneous asynchronous contractions
can be initiated by calcium-induced calcium release from
the sarcoplasmic reticulum. In skinned fibers. oscillatory
contractions can be elicited that manifest nonuniform cellular behavior; here, at borderline low calcium activation.
different groups of sarcomeres contract at the expense of
others. In some cells. spontaneous and reversihle oscillations can be triggered by loading the cell.
Accordingly, in the normal intact single cell, the sar-
BRUTSAERT
NON UNI FORMI T Y OF T HE CHART
345
colemmal membranes probably synchronize activation and
the ensuing contraction-relaxation cycle in both time and
space. This uniform mechanical behavior is lost when these
membranes are damaged. The presence of such cellular
nonunifonnities in the diseased (for example, ischemic) heart
has as yet not been demonstrated.
Myocardial muscle, In contrast to the remarkably uniform contractile performance in intact single cardiac cells,
an increasing degree of nonuniformity can be observed under normal conditions as the myocardial tissue becomes
more complex, such as in multicellular cardiac muscle preparations (52-54). This nonuniforrnity is more pronounced
at higher loading conditions. being most marked during
relaxation (53). Nonuniformity in these preparations is a
major determinant of the level and slope of the ascending
portion of the length-tension relation and of the entire forcevelocity-length surface. Factors that may contribute to this
nonuniform contractile behavior include spiral arrangements
of the fiber cells along the preparation . shear stresses at the
intercellular connections and nonuniform shifts in the myosin
isoenzyme (V I versus V, ) distribution pattern depending on
regional stress differences.
Accordingly. in normal cardiac muscle. along with loading, that is, preload. afterload, geometry and configuration.
and activation-inactivation kinetics. nonuniformity constitutes a third important determinant of performance that can
participate in the normal homeostatic control of cardiac
function.
Intact ventricle, The shape and geometry of the ventricle, arrangement of the fiber bundles in the ventricular
wall. the multicellular nature of the ventricular wall and the
nonuniform stress distribution at rest are all major determinants of the ventricular contraction-relaxation pattern.
These structural features result in important nonuniform
configurational changes during systole, when the left ventricle changes from an ellipsoid to a more conical shape (2).
The mechanical performan ce of the myocardium in di][ere nt layers of the ventricular wall is not uniform. Marked
differences in amplitude and contour of intramyocardial force
traces have been described; for example. endocardial forces
developing during systole are almost twice those of the
epicardial values (24). An early " endocardial kick" (55)
with high stress would thus initiate the cardiac contractile
cycle. preceding a more slowly developing but longer lasting
epicardial contraction. Moreover. more shortening (20,21)
and more systolic wall thickening (56) have been observed
in the inner than in the outer layer of the ventricle.
Considerable regional nonuniform distribution c[ wall
stress in normal ventricles during systole has also been
estimated f rom two-dimensional erhocurdiographv (57).
Haendchen er al. (23). who measured sectional function of
the left ventricle in normal humans using echocardiography,
demonstrated significant variations in regional myocardial
performance. with the extent of tiber shortening progres-
346
BRUTSAERT
NON UNIFORMITY OF TH E CHA RT
sively increasing from base to apex. Similar observations
were made in normal dog hearts, with systolic wall thickening increasing from base to apex (25). Nonuniform regional wall motion was also observed during relaxation in
normal human ventricles, with anterior wall segments
lengthening earlier and more rapidly than inferior wall segments (58) and with the base of the anterior left ventricular
free wall lengthening before the midportion and apex (59).
The fu nctional importance of nonuniformity call be better
appreciated ill the norma! right ventricle (60 ). where the
inflow tract shortens first at a time when the outflow tract
expands. The outflow tract, which shortens later, remains
contracted longer than the inflow tract. This lag between
inflow and outflow tract shortening makes the outflow tract
functionally distinct from the inflow tract. The intrinsic contractile state of right ventricular myocardium is also greater
than that of the left ventricle (46).
The significance of acute changes ill nonuniformity of
ventricular performance has been demonstrated in several
experimental studies (6 1-63). lizuka (61) showed that injection of isoproterenol or heated saline solution into the
distal part of the left anterior descending coronary artery
transiently abbreviated the duration of regional contraction
while simultaneously prolonging overall ventricular relaxation . Impaired relaxation by these experimentally induced
nonuniformities was much less pronounced after injection
of calcium or ouabain, which caused no regional changes
in contraction duration. Similarly, llebekk et al. (63) showed
that the increase in aortic flow was more marked when
isoproterenol was added to the systemic circulation than
when it was injected into a coronary branch, where isoproterenol induced striking nonuniformity of contraction and
relaxation in different regions of the ventricular wall.
Accordingly, in the normal intact ventricle, spatial and
temporal nonuniform distribution of load and of activation
and inactivation, constitutes, along with load and with activation and inactivation themselves, an important physiologic control mechanism. Throughout the cardiac cycle, this
mechanism maintains ventricular performance within a narrow but optimal range of mechanical efficiency as part of
the normal homeostatic control of cardiac function. Hence,
a triple control regulates ventricular function of the normal
heart (5, 12).
Diseased Heart: Inappropriately Increased
Nonuniformity (Fig . 3)
In various pathologic conditions, for example, conduction disturbances, ischemic and hypertrophic cardiomyopathy and drug intervention, the " optimal tuning" of
the control of muscle-pump performance by some physiologic degree of nonuniformity may become imbalanced.
Although normal global pump function may be maintained
by compensatory interactions among myocardial segments,
lACC Vo!. 'i. No. ~
February I'iX7:)4 1- X
dyskinesia (hypokinesia, ak inesia)
dyssynchrony (asynchrony)
dyssynergy (asynergy)
incoordinate contraction relaxation
regional (segmental) wan motion abnormalities
regional ventricular disease (dysfunction)
inhomogeneity • heterogeneity
PHYSIOLOGIC
PATHOPHYSIOLOGIC
HOMEOSTASIS \
(i n) activation
DYSFUNCTION
(
temporal
1NON - UNIFORMITY 1-------load ..-----
/
MUSCLE
------------- spat·raI
\.
PUMP
Figure 3, Terms used to describe abnormal contraction or relaxation patterns in the diseased heart. Some of these terms refer to
space . others refer to time (73). some refer to pump performance,
others to muscle properties. Only /10111111i/ (mnity is the more appropriate general term. It simultaneously encompasses the physiologic degree of spatial and temporal nonuniformity of load and
of activation and inactivation in musc le and pump, and the inappropriately increased nonun iformity encountered in the diseased
heart.
imbalanced or inappropriately increased nonuniformity may
result in an imbalance of forces that reduce mechanical
efficiency during contraction and, especially, during relaxation. It follows from the preceding discussion that no single
mechanism can explain all examples of inappriopriately increased nonuniformity. Architectural changes, electrical
disturbances, deficiencies in activation-contraction and inactivation-relaxation coupling and mechanical abnormalities, such as paradoxic septal motion induced by right ventricular overload, could each act alone or in concert to disturb
the physiologic modulating role of nonuniformity under different pathologic conditions.
Myocardial ischemia. In the ischemic and hypertrophic
heart, relaxation of the ventricle may be impaired long before contraction abnormalities occur (64). This early impairment of relaxation may result from inappropriately increased nonuniformity even when loading conditions or
activation and inactivation are unaltered (5. 12). Given the
regional or segmental nature of ischemic heart disease. inappropriately increased nonuniforrnity may induce or further
increase early relaxation abnormalities or incoordinate relaxation (5,11,12 ). Experimental proof of nonuniformity
after coronary ligation has been provided by several investigators (6 1,62,65). who showed transient changes in isovolumic left ventricular pressure decay induced by nonuniform interactions between normal and ischemic zones of the
ventricle. Similar transient nonuniformities have been observed clinically during percutaneous transluminal balloon
coronary angioplasty (66,67). Contraction-relaxation patterns obtained by Tyberg et al. (68) and later by Wiegner
et al. (69), who studied the interaction of myocardial segments of different strengths by arranging (68) or modeling
BRUTSAERT
NONUNIFORMITY OF THE CHART
lACC Vol. 9. NO.2
February 1987:341-8
(69) the contraction of normal and hypoxic muscle in series,
have provided useful explanations of most of these regional
abnormalities in the ischemic ventricle (6, II).
Ventricular hypertrophy. Inappropriate spatial and
temporal nonuniformity of loading and inactivation may also
help to explain delayed relaxation early in hypertrophy (5,64).
Here, changed geometry, regional variations of wall thickness, interstitial fibrosis, loss of myocardial contractile elements and loss of normal intercellular connections can further increase nonuniform distribution of load and inactivation
in the hypertrophied ventricular wall. In asymmetric forms
of hypertrophy, disruption of force distribution could further
enhance nonuniformity because some myocyte disarray would
be expected to develop in areas where shortening predominates as compared with areas where contraction is more
isometric (70).
Pharmacologic implications. Problems related to nonuniformity may also have important pharmacologic implications (71,72). The therapeutic benefit of a drug on pump
performance of the intact heart should not necessarily be
equated with a positive inotropic effect of the drug at a
myocardial level; improved pump performance after drug
administration can result both from increased contractility
and from a diminished degree of nonuniformity. Conversely, independent of its effect on loading, activation or
inactivation, a positive inotropic drug can easily compromise pump efficiency by merely increasing the difference
between normal and abnormal regions of the ventricle.
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