Download Cardiac Responses to Increased Afterload

Cardiac Responses to Increased Afterload
State-of-the-Art Review
ROBERT C. TARAZI, M.D.,
AND MATTHEW N. LEVY,
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B
EFORE the advent of effective antihypcrtensive therapy, heart failure was the most
common cause of death from hypertension.1
Today, hypertension remains the most common cause
of left ventricular (LV) hypertrophy in adults*- • and
the most common precursor of congestive heart
failure.4- • It has usually been assumed that the link between increased arterial pressure and cardiac dysfunction was straightforward, a mechanical proposition between an increased load and an overworked
pump. As happens so often, the relationship proved
much more complex.
It has been proven that the heart does not respond
similarly to all types of overload,6 that cardiac hypertrophy is not a homogenous entity,*1' and that
arterial pressure is not linearly related to cardiac dysfunction in all types or at all stages of hypertension.8"10 Pressure overload evokes cardiac responses
that are different from volume overload8 or intense
exercise.*1 n Whether all types of pressure overload
evoke the same type of cardiac responses is one of the
questions we address, as is the closely related question of whether all types of hypertension are associated with the same pattern of cardiac hypertrophy.
The proposition that hypertension is not a single or
homogeneous disease is universally accepted in discussions of the genesis and mechanisms of the rise in
arterial pressure; it has not usually been advanced in
the analysis of its cardiac consequences.
This discussion is not only of theoretical value; its
clinical implications may lead to a fundamental
reevaluation of our therapeutic aims and guidelines.
The recent observations of significant cardiac hypertrophy in borderline hypertension1*1 u showed that
structural myocardial changes are not limited to advanced stages of the disease, and that cardiac prob-
M.D.
lems may be present from the earliest stages. The
demonstration that cardiac hypertrophy can be
reversed by medical antihypertensive therapy*114~17 is
lending urgency to the question of whether cardiac
hypertrophy is advantageous or the first step to
failure. Basic to these questions is the nature of the increased cardiac load in hypertension. Stepped-care
therapy is based on diastolic blood pressure levels; it is
questionable whether this variable describes adequately the load that the heart must bear when arterial pressure is elevated.
Definition of Afterload
The "afterload" for any contracting muscle is the
total force that opposes shortening, minus the stretching force that existed prior to contraction. For cardiac muscle, the afterload is the force against which
the myocardial fibers must contact during the ejection phase of systole. Force equals pressure times
area, by definition. The total force opposing LV contraction (i.e., the afterload) is the product of the LV
pressure and the internal surface area of the LV
cavity.
In hypertensive subjects, of course, the arterial and
LV pressures are abnormally high during systole and,
therefore, the LV afterload tends to be high. The internal surface area of the LV varies directly with the volume of blood in the ventricle. If the hypertensive subject also has a dilated LV, the internal area of the LV
will be greater than that for a normal subject. Hence,
for any given pressure, the afterload tends to increase
as the ventricular volume becomes greater. The internal surface area of the ventricular cavity is extremely
difficult to measure precisely. Furthermore, both pressure and area change continually throughout ejection.
Therefore, it is difficult to assess afterload accurately.
From the Research Division, Cleveland Clinic Foundation, and
Division of Investigative Medicine, Mt. Sinai Medical Center and
Case Western Reserve University, Cleveland, Ohio.
Supported in part by the National Heart, Lung, and Blood Institute (grants NHLBI-6835 and NHLBI-15758) and the American
Heart Association, Northeast Ohio Affiliate.
Address for reprints: Robert C. Tarazi, M.D., Research Division,
Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio
44106.
(Hypertension4(suppl U): II-8-II-18,1982)
Alternatire Criteria of Afterload
Because of the difficulties of assessing LV afterload
precisely, various alternative criteria have been used.
Most commonly, the peak (or systolic) aortic pressure is taken as an index of afterload mainly because it
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CARDIAC RESPONSES TO INCREASED AFTERLOAD/7a«jz/ and Levy
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can be measured so readily. However, other indices
have also been used. Each index has certain advantages for specific applications.
Milnor1* has strongly advocated the arterial impedance as the critical measure of ventricular afterload. The advantages of this criterion is that the impedance depends exclusively on the characteristics
(i.e., resistance, compliance, and geometry) of the external system into which the ventricle must eject
blood. The arterial impedance does not depend on the
characteristics of the heart itself, whereas all of the
other criteria of afterload do depend in part on the
performance of the heart. For example, the peak systolic aortic pressure depends as much on ventricular
performance as it does on peripheral resistance or arterial compliance.1*
However, the arterial impedance is difficult to
measure and even to express. High-fidelity pressure
and flow curves must be obtained, and must be subjected to a complicated harmonic (Fourier) analysis
and other mathematical manipulations. The results
are then represented by two complicated curves: one,
the amplitude of the impedance as a function of frequency, the other the phase of the inpedance as a function of frequency. In addition to these obvious problems related to complexity, the arterial impedance
may not be the best criterion to apply to the question
of the effect of increased afterload on the heart in
hypertensive subjects. The physician treating a hypertensive patient wishes to know what effects the
afterload has on cardiac output, on the energy requirements of the myocardium, and on the tendency to
induce myocardial hypertrophy. These effects depend
at least as much on cardiac as on vascular factors.
Pronounced and equivalent increases in arterial impedance can occur, for example, in hypovolemic
shock, as in severe hypertension." The same high arterial impedance will be associated with markedly
different cardiac outputs, myocardial oxygen consumptions, and tendencies toward hypertrophy in
these two different cardiovascular states.
Other criteria of afterload that have been found
useful for specific purposes are the LV pressure at the
end of ejection and the area of the LV pressure curve
throughout ejection. The end-systolic pressure is a
critical determinant of stroke volume, as explained
below (see p 11-12). The area under the systolic portion of the LV pressure curve has been termed the
"tension-time index" and has been found to correlate
well with the myocardial oxygen consumption."
An estimate of the force opposing LV contraction
could be obtained from the calculation of myocardial
wall stress. The latter (a) is a function of pressure (P),
internal radius (R), and wall thickness (h) of the LV,
as expressed in the simplified formula: a = PR/2h . . .
(Eq. 1). Left ventricular wall stress obviously changes
continuously throughout the cardiac cycle, describing
a curve that might be quite different from intraventricular pressure curves." Some values (peak systolic
stress, end-systolic stress, and average systolic stress)
have been used as estimates of afterload;11'" of par-
II-9
ticular significance for clinical investigations is the
possibility of obtaining them noninvasively from cuff
systolic pressure and echocardiographic tracings."1M
Calculation of stress has added a new dimension to
clinical evaluation of the cardiac effects of hypertension. The demonstration that antihypertensive drugs
could have divergent effects on blood pressure and
ventricular hypertrophy1- "• ** implies that LV stress
could increase, decrease, or remain unchanged, depending on the relative variations of P, R, and h during treatment and that these changes in stress might
not be predicted from determinations of pressure
alone.
In more practical terms, physicians have to be content only with determinations of arterial pressure. The
essential accuracy of auscultatory readings has been
confirmed if meticulous attention is given to details of
this deceptively simple method.1 Indeed, it has been
shown that calculations of LV systolic wall stress
using cuff systolic pressure closely matched those
derived from intraventricular pressure records by
Millar catheters.11'" Cardiac work is related to systolic rather than diastolic arterial pressure load.1*
Against this background, it is obvious that the traditional reliance on diastolic or mean arterial pressure
to evaluate the cardiac effects of hypertension does not
take into account the other important determinants of
afterload. If for clinical purposes one has to depend on
determination of arterial pressure alone, then the systolic not diastolic level is the value closest to a correct
evaluation of the load imposed on the heart by hypertension.15 This indeed was shown to be the case in all
studies correlating cardiac hypertrophy with arterial
pressure levels.1*"1*
In summary, cardiac afterload can be calculated in
a variety of ways; the choice of a particular index will
depend in part on the function examined and on the
degree of precision required. Practical considerations
may impose clinical constraints, but under these conditions, it is time to recognize in practice the particular significance of systolic as opposed to diastolic
pressure levels.
Mechanical Effects of Increased Afterload
Isolated Myocardial Strips
The immediate effects of a change in afterload on
the contraction of cardiac muscle can be appreciated
by observing the contratile responses of isolated myocardial strips. Figure 1 displays the results of experiments conducted by Sonnenblick** on cat papillary
muscle; velocity of shortening, extent of shortening,
work, and power vary with the total load against
which the cardiac muscle strip contracts. In each of
the four panels, a given curve represents the changes
obtained for a given preload, which is the stretching
force applied prior to contraction. The total load,
plotted along the abscissa, is the sum of this given
preload plus the variable afterload.
Panel B in figure 1 shows that for a given preload,
the extent of shortening diminishes as the afterload
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1981 BLOOD PRESSURE COUNCIL
SUPP II, HYPERTENSION, VOL 4, No 3, MAY-JUNE 1982
(and hence, the total load) is increased; this is illustrated by each of the three curves in the panel.
However, as the diastolic length of the muscle is increased by augmenting the preload, the extent of
shortening during an induced contraction is increased
for any given total load. Myocardial work and power
increase progressively with total load up to some optimum level; with greater loads, these functions then
diminish progressively. Work equals force times distance (extent of shortening). Hence, zero work is done
either when the load is zero or when the load is so
great that the muscle cannot shorten (isometric contraction). Power equals the time rate of change of
work; when work is zero, power also is zero. The
muscle strip is capable of shortening against greater
total loads as the preload is increased (fig. 1, Panels C
and D). Also, the optimum total load increases as
the preload is raised.
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Whole Heart Preparations
FIGURE 1. Changes in velocity of shortening, extent of
shortening, work, and power in a cat papillary muscle that
was induced to contract from preloads of 0.2, 0.4, and 0.6 g.
At each preload, the muscle was made to contract against a
range of afterloads from zero to that against which it was no
longer able to shorten. Total load, plotted along the
abscissa, is the sum of the pre- and afterloads. (Reprinted
with permission from Am J Physiol 202: 931, 1962.)
Several groups of investigators have succeeded in
determining the influence of variations in afterload on
cardiac performance prior to the onset of adaptive
changes. Monroe and French" and Imperial et al.11
changed arterial impedance abruptly during ventricular diastole and observed the influence on ventricular performance during the next ventricular systole;
the greater the impedance, the greater the peak ventricular systolic pressure and the lesser the stroke volume. Responses to increased afterload resembled
those obtained in isolated myocardial strips (e.g., fig.
1, Panel B) in that the peak ventricular systolic pressure is analogous to the total loss and the stroke volume is analogous to the extent of shortening. Ross et
al." changed LV afterload by rapidly injecting blood
into or withdrawing blood from the aorta between
beats. As the afterload was increased (fig. 2), peak LV
systolic pressure increased and stroke volume
af:/v f\,
ECG
AofV
r
;
LVEDPr.
\-AJ\J-JVAAAA
i
11 n n t\ f i ri n
FIGURE 2. Changes in aortic flow,
electrocardiogram, aortic pressure,
left ventricular (LV) pressure, LV
end-diastolic pressure, and L V dp/dt
in a dog in which the aortic pressure
was suddenly changed during diastole.
In each panel, the first beat occurred
under control conditions, the second
beat against altered afterload. In the
panels from left to right, the
afterloads during the second beat
were progressively greater. (Reprinted with permission from Circulation Research 18: 149, 1966.)
CARDIAC RESPONSES TO INCREASED AFTERLOAD/Tarazi and Levy
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decreased. The peak aortic flow is analogous to the
peak velocity of shortening of a myocardial strip; the
progressive reduction in peak aortic flow with increasing afterload is equivalent to the inverse force-velocity
relationship in cardiac muscle strip.
More recent studies have helped to define precisely
the influence of afterload changes on the volume of the
ventricles during ejection. Studies from several laboratories'*"** have shown that the volume reached by the
ventricles at the end of ejection (the end-systolic volume) depends on the afterload and contractility, but is
independent of the end-diastolic volume and the
stroke volume. For a given state of contractility, the
end-systolic volume is delimited by the isovolumic
pressure-volume relationship. In isovolumetric contractions (i.e., with no change in volume), the peak
pressure generated by the ventricle varies with the enddiastolic volume; this is a manifestation of the wellknown Frank-Starling mechanism, or the normal ventricle, it has been found that, under these conditions,
the pressure-volume relationship is virtually linear
over the physiological range of end-diastolic
pressures.*4"**
When the ventricle contracts and ejects blood, the
concomitant changes in pressure and volume may be
displayed as a pressure-volume loop. The end-systolic
pressure-volume coordinates of these ejecting beats
falls on or slightly below the isovolumetric pressurevolume curve. The prevailing pressure and volume at
the end of ejection closely approximate the values obtained at the peak of an isovolumetric contraction
originating from a comparable volume. In a study by
Weber and Janicki," the heart was caused to contract
from a constant end-diastolic fiber length (fig. 3, Point
a) against three different afterloads; Curves 1,2, and 3
in figure 3 represent the response to high, intermediate, and low afterloads respectively. The wall forces
11-11
and circumferential fiber lengths at the end of systolic
(Points d, c,, and c,) varied directly with the afterload,
but the stroke volumes (as reflected by the differences
between end-diastolic and end-systolic fiber lengths)
varied inversely with the afterload. The dashed line indicated the peak force-length relationship that was obtained for the same heart when it was caused to contract isovolumetrically over a range of volumes. Note
how closely Points c,, c,, and c, fall to this dashed line.
The ventricular myocardium develops a force during ejection that depends on the prevailing level of
pressure and on the ventricular dimensions. A myocardial fiber can no longer shorten when it attains a
force that is maximal for its prevailing length; this
marks the end of ejection. The maximum force for a
given fiber length is attained by an isometric contraction. Hence, the pressure-volume coordinates at the
end of ejection are virtually identical to the values attained during an isovolumetric contraction that occurs
at the corresponding end-systolic volume for the ejecting beat.
Cardiac Hypertrophy in Response to
Increased Afterload
Cardiac hypertrophy is the usual response to prolonged or repeated increases in afterload; it is one of
the pathological hallmarks of hypertension. However,
rather than being a late and irreversible complication
of the disease, it has recently been shown to be an
early response that can play an important role in the
evolution of the disease. Folkow** has demonstrated
how closely intertwined in the progress of hypertension are the structural cardiovascular alterations and
functional neurohumoral influences, each exerting important interactions on the other. The rate at which
the heart can adapt its design when exposed to changes
in pressure was found to be rapid enough'- "• *•• *•
2.2
O
O1
HI
O 1.1
0.0
15.0
16.3
LENGTH cm
17.5
FIGURE 3. Force length loops for an isolated, supported
dog heart contracting against three different loading conditions, but from a constant end-diastolic length (Point aj.
Curves 1, 2, and 3 represent responses to high, intermediate, and low afterloads, respectively. As the ventricle
shortened against progressively small afterloads, there was a
progressively greater stroke volume (as reflected by the
differences between end-systolic and end-diastolic fiber
lengths). Note that the end-systolic forces and lengths
(Points cu c,, and c,) fall along the force-length curve
(dashed line) derived from a series of isovolumetric contractions. (Reprinted, with modification, from Am J Physiol
232: H-241, 1977.)
II-12
1981 BLOOD PRESSURE COUNCIL
to suggest that structural alterations must be taken
in account as dynamic participants in the response to
hypertension and its treatment.
The exact stimulus initiating cardiac hypertrophy is
not known, although it is likely to be related to 'an
increase in myocardial tension as the ventricle contracts against a greater resistance."1 *° Biochemical
changes in the myocardium can follow very rapidly
(within hours) the imposition of an extra load on the
heart. 41 - u Their nature and rate of progress differ
widely depending on the initiating stimulus and type of
consequent hypertrophy.48' **
Ventricular Hypertrophy in Clinical Hypertension
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The development of LVH is an important landmark in the clinical evolution of hypertension. 1 '' The
presence of LVH, as detected by the EKG, was found
to be an extremely lethal risk attribute in the Framingham study;* within 5 years of its appearance, 35% of
the men and 20% of the women with this finding were
dead. Even higher figures for 5 years mortality were
reported by Sokolow and Perloff" from a study of
hypertension antedating the advent of effective antihypertensive therapy. In the Framingham study, the
risk of cardiac failure in patients with EKG criteria
for LVH was three times higher than that associated
with hypertension in general.
Although hypertension is the most common cause
of pressure overload hypertrophy, our concepts of cardiac performance in that situation have been mostly
derived from studies of aortic stenosis or of experimental banding of the large vessels.4*"48 Studies of cardiac involvement by hypertension have all too often
been restricted, largely because of ethical reasons, to
determinations of cardiac output which could not by
themselves allow a full understanding of myocardial
responses to the increased load.50"" However, it is not
certain whether one can, with any degree of assurance,
extrapolate directly to hypertension the results obtained from studies of other types of hypertrophy
(even those due to pressure overload). There are too
many differences between aortic narrowing and increased systemic pressure, and these disparities could
directly or indirectly modify cardiac responses. Some
of these differences are:
1.
2.
3.
4.
Duration of load
Role of large vessels
Driving pressure of coronary circulation
Peripheral vascular disease
a) Influence on impedance
b) Coronary vascular disease
5. Associated neurohumoral disturbance.
Noninvasive ultrasound or radioisotopic techniques are rapidly modifying our understanding of
cardiac responses to hypertension. Before their advent, most of our knowledge was based on EKG
studies."" Although, electrocardiographic patterns
do to some extent reveal changes in LV mass, they are
not very sensitive signs of LVH." On the other hand,
echocardiography has introduced a new dimension in
SUPP II, HYPERTENSION, VOL 4, No 3, MAY-JUNE 1982
this domain by allowing a more precise look at ventricular geometry and some quantitation of LV wall
thickness and mass. It has revealed a more complex
picture of LVH than simple concentric hypertrophy." 5 * LVH was found to occur quite early in
s.ome adolescents with borderline blood pressure elevation,11- l I a finding similar to that described by our
group and others in spontaneously hypertensive
rats.*1 ** Unexpectedly rapid changes in wall thickness
and mass were reported to occur with antihypertensive therapy;18' ** assymetric septal hypertrophy was
reported to occur,1* particularly in early hypertension," not necessarily due to a genetically transmitted
cardiomyopathy but secondary to LV pressure overload.61 Obviously, much remains to be established,
particularly as regards to the factors modulating the
development of hypertrophy and the clinical significance of changes in ventricular mass."
Arterial Pressure Levels and Left Ventricular Hypertrophy
Both the incidence and degree of LVH were found
to correlate poorly with arterial pressure levels.*"10- "• "
This is not surprising, since arterial pressure is not per
se an accurate measure of afterload. The significance
of that fact, however, was often overlooked in part because of the then developing concept of hypertension
as a quantitative deviation from normal 1 and of the
assumption that cardiac hypertrophy was simply a
graded response to the increasing pressure levels. Exceptions to that rule were attributed to coexisting coronary arterial disease or cardiomyopathy." These explanations have been challenged for both animal*"10
and human80-*• hypertension. In animals, where cardiac weight and other variables could be defined more
precisely than in man, the relationship between arterial pressure and LV weight was found to vary
widely among different types of hypertension. A close
relationship was found in renovascular hypertension*6
but not with DOCA hypertension, * while cardiac
hypertrophy was noted even before significant hypertension in SHR.*' *° The conclusions derived from the
development of hypertensive hypertrophy were substantiated by observations made during its reversal by
antihypertensive measures. Drugs that were equipotent with respect to blood pressure control had
divergent effects on left ventricular mass.*- u Thus,
neither the development nor reversal of hypertrophy
appeared to be simple expressions of quantitative
alterations in blood pressure levels.
Functional Consequences of Left Ventricular Hypertrophy
Whether LVH is a useful compensatory process or
the first step toward depressed contractility and eventual decompensation is still debated.4*1 a The implications of any answer to that problem are of enormous importance in hypertension, where reversal of
myocardial hypertrophy can be obtained by some
antihypertensive drugs.14
The functional consequences of LVH can be viewed
from two aspects, the effect of hypertrophy on intrin-
CARDIAC RESPONSES TO INCREASED AFTERLO AD/Tarazi and Levy
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sic myocardial contractility and its mechanical consequences on myocardial wall stress. Studies of the first
aspect showed a wide array of findings depending on
the type of pressure load and its duration. Earlier
studies with papillary muscles from animals with aoric or pulmonary artery constriction indicated a
reduced inotropic state, a evidenced by depressed
force-velocity curves.4'"1* However, later studies suggested that this depression might be only transient and
that myocardial contractility returned to normal
about 2 to 2.5 months following pulmonary artery
banding in cats" or aortic constriction in dogs.70 A
somewhat different pattern emerged from similar
studies of hypertensive models; not only did they differ
from the above but they also appeared to differ according to the experimental model of hypertension.
The main findings in the early state (8 weeks) of
Goldblatt hypertension in rats snowed a decrease in
shortening velocity at zero load but no change in maximum instantaneous power. Papillary muscles from
hearts of the same model with significant ventricular
hypertrophy (+50% in weight) showed significant prolongation of isometric time to peak tension and of
time to half-relaxation but were still able to maintain
normal levels of peak isometric tension." However, as
hypertensive rats were followed for 6 months, the
maximum instantaneous power was gradually reduced
below the control norm over the same period."
In contrast, the LV papillary muscles of younger
SHR showed normal contractility and relaxation
parameters." Only at about 40 weeks of age was the
first sign of depressed contractility seen (depressed isotonic shortening velocity). At age 60 to 80 weeks,
maximum isometric tension was significantly reduced.
The inscription of cardiac function curves by rapid
volume expansion has likewise revealed a time dependent reduction in cardiac performance during the
evolution of hypertension.10- u A conflict persists as
regard to the results obtained in younger SHRs. Spcch
et al." reported a reduced maximal pumping capacity
in SHR age 17 to 29 weeks, whereas Pfeffer ct al.74
and others" found that cardiac function was well
maintained during the developmental phase of cardiac hypertrophy and well through the first 12 to 18
months of life. It is not easy to reconcile these differences, many of which may be due to technical reasons.
In favor of the latter's conclusion, however, is its general agreement with the results obtained by Bflrger
and Strauer" in papillary muscle studies. The important point remains that cardiac performance, which
might be normal in the early stages of hypertrophy,
eventually falls at some later point in its evolution.
The ability of the heart to increase its output obviously depends on both preload conditions and the level
of resistance to ejection, as well as on myocardial
muscle mass. In a sequence of impressive studies,
HallbSck and her collaborators7*"" have shown that
the performance of the hypertrophied ventricle of the
SHR varies in comparison with that of normal controls, depending on both filling pressure and afterload
conditions. The hypertrophied ventricles performed
better than control when working against a high
11-13
pressure load. Conversely, at low preload levels, the
stroke volume was lower in SHR than in normotensive rats at their respective in vivo pressure levels.
Under those conditions, the higher pressure against
which the SHR was working reduced its stroke volume. At high cardiac filling pressures, however, when
the full resources of the hypertrophied ventricle are
mobilized, cardiac performance was superior in SHR
compared to controls.77
These results indicate that it is not really possible to
describe the full spectrum of the cardiac consequences of hypertrophy from a description of cardiac
function curves alone. There are many mechanisms by
which the hypertrophied LV could compensate for the
higher load it has to carry. These include dependence
on higher preload,77- "• *° mobilization of adrenergic
support,80' " and alterations in ventricular geometry."
With regard to the first, the studies of the GOteborg
group,77- " as well as those of Saragoca and Tarazi,*0
showed that both in SHR and renovascular hypertension the hypertrophied heart responded to a volume or
pressure overload by higher LV filling pressure. This
increased end-diastolic pressure was not due to a
reduction in LV distensibility but signified a greater
end-diastolic volume." - *°
Simultaneously, with this greater dependence on
heterometric autoregulation, myocardial inotropic
responses to isoproterenol were blunted in direct correlation with the increase in ventricular weight (fig.
4).*°' M That reduction in responsiveness, which was
documented by many,**"*8 seemed to imply a reduced
ability to depend on adrenergic support. Consonant
with this are recent reports of reduced density of cardiac beta-adrenergic receptors in various types of
hypertensive hypertrophy.**'" Saragoca and Tarazi*0
have postulated, therefore, that there occurs in hypertensive cardiac hypertrophy a subtle shift toward
greater dependence on the Frank-Starling mechanism.
The central relocation of intravascular volume seen in
human" and experimental77' ** hypertension would
seem to agree with the concept.
120 -
y110.2- 20.9x
r - 0 . 6 7 7 , p<0.00
o SHAMS
• RHR
100
80
o
°
60
s.
•o
<
40
20
s
1
1
'
1
1
1
1
1
1
1
1
2.0 .2 .4 .6 .8 3.0 .2 .4 .6 .8 4.0
VENTRICULAR WEIGHT
(mg/gm body weight)
FIGURE 4. Inotropic response to isoproterenol infusion (as
determined from &dP/dt/Pw at developed LV pressure of
40 mm Hg) was inversely correlated with ventricular weight
in rats with renovascular hypertension (RHR) and shamoperated controb. (Reprinted with permission from Hypertension 3 (suppl I): 1-171, 1981.)
U-14
1981 BLOOD PRESSURE COUNCIL
Cardiac Hypertrophy and Myocardial Wall Stress
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The stress imposed on the myocardial wall is one of
the main determinants of myocardial oxygen requirements and could well be one of the important factors
in the evolution of hypertrophy. The level of stress
obviously depends on the way by which hypertrophy
alters the geometry of the LV. Grossman et al. ai and
Gaasch" have clearly demonstrated the dependence of
LV function on the ratio of wall thickness to radius of
the ventricle; Strauer*0 came to the same conclusions
utilizing the ratio of LV volume to its mass. Whatever the index of function used, the velocity of circumferential fiber shortening (Vcf) or the ejection
fraction, the results from many centers have been
remarkably consistent; the greater the dilation of the
heart's cavity in relation to thickening of its wall, the
more marked the depression of its function.
These observations are readily explained by the
effect of myocardial hypertrophy on wall stress; Equation 1 implies that the greater the LV dilation, the
higher the stress on its wall, unless this is counterbalanced by greater thickness of the wall. Although
unavoidable simplications and assumptions are involved in the extrapolation to the complicated
geometry of the LV of calculations based on simple
ellipsoid or spherical models," the remarkable uniformity of results from many centers underlines the
basic validity of this approach. Hypertrophy could,
therefore, be viewed as a compensatory process to
reduce the higher tension imposed by higher pressure
levels.
The clinical implications are obvious; whereas concentric hypertrophy could be viewed as a potentially
useful compensatory process, eccentric ventricular
hypertrophy was associated with greater stress and
depressed performance. Few would doubt the second
half of this statement; dilation in excess of hypertrophy (inadequate ventricular hypertrophy) is associated with reduced ventricular function. The net
effect of concentric hypertrophy, however, has proven
more difficult to define; reduction of wall stress by the
increased thickness of the myocardium is a direct consequence of the interaction of forces described in
Equation 1. However, hypertrophy has other consequences such as reduced compliance of the increased
ventricular mass, alterations in myocardial composition, and secondary changes in coronary perfusion —
all of which may interfere with different aspects of cardiac function in systole or diastole. The progression
from concentric hypertrophy to ventricular dilation in
heart failure has been predicated more on the basis of
group comparisons" than on direct evidence of progression in man. The frequency of that progression or
the factors influencing it still remains to be determined.
Since the measurements needed for the calculation
of stress and cardiac performance depended to a great
extent on invasive techniques, the initial concepts were
derived from studies of aortic stenosis and cardiomyopathy. Their application to hypertension lagged
because of the legitimate ethical concerns regarding
SUPP II, HYPERTENSION, VOL 4, No 3, MAY-JUNE 1982
LV catheterization in asymptomatic subjects. Moreover, questions arose regarding the applicability to
hypertension of conclusions derived from aortic stenosis or experimental coarctation. The differences
between these types of pressure load are many, as
listed above (see p 11-12). Possibly adding to these
differences is also the possible impact of altered sympathetic tone or of activation of the renin-angiotensin
system in hypertension. Even within hypertension,
cardiac catecholamine concentration differed markedly from one model of the disease to another.67
However, as echocardiographic techniques were
developed and studies of the heart in hypertension increased rapidly, the early conclusions seemed to confirm the basic concepts developed from other models.
The spectrum of cardiac involvement in hypertension,
however, appeared wider than originally postulated.
Guazzi et al." described a clear differentiation in indices of performance among hypertensive patients
based on: (1) presence of echocardiographic signs of
LVH; (2) thickness of posterior LV wall and; (3)
magnitude of the LV short axis diameter. Fouad et
al." found that among hypertensive patients, the variable most closely related to cardiac performance was
end-systolic stress, which showed a highly significant
inverse correlation with both the degree (% shortening) and velocity (Vcf) of LV contraction (r = -0.80
and -0.74 respectively, p < 0.001 for both) (figs. 5
and 6). This correlation was found consistently in the
whole group of patients investigated, whether treated
*
SHOBT
r--0.80
(XO.OOI
(n-65)
40 ,
30
• •
N
N
20
•
10
20
40
60
80
100
120
MO
100
ESS (103 dynen/cm2)
FIGURE 5. The degree of shortening of the left ventricular
minor axis (% shortening) was inversely related to end-systolic stress in this group of 65 hypertensive patients; end-systolic stress was calculated from ausculatory systolic pressure and from simultaneous echocardiographic recording, as
described by Wilson et al. (see ref. 22). The data were
derived from Fouad et al. (see ref. 92).
CARDIAC RESPONSES TO INCREASED AFTERLOAD/Tarazi and Levy
Vcf
1.8r=-0.740
p 0.001
(n=65)
1.5 t
0.5
50
100
170
1-15
hypertensive patients. The presence of heart failure or
obvious cardiomegaly is a serious risk for sympatholytic therapy; apart from these classical signs, however, we did not find it possible to separate by simple
clinical hemodynamic or ECG examination those
patients who tolerated well guanethidine or propranolol from those whose cardiac performance was
depressed by sympathetic blockade.**
Given the importance of adrenergic blockade in the
treatment of hypertension, the importance of determining its effect on cardiac performance in patients
with cardiac hypertrophy hardly needs stressing. Recent studies have suggested that reversal of hypertensive cardiac hypertrophy is favored by those antihypertensive drugs that interfere with, or at least do
not stimulate, sympathetic activity.*1 Mi *' The interaction of blood pressure fluctuations, cardiac performance, and level of cardioadrenergic drive obviously needs better definition in hypertension.
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ESS (103 dynes/cm2)
FIGURE 6. The same inverse relationship described in
figure 5 was also found between the velocity of shortening
(Vcf) and end-systolic stress. The data were derived from
Fouad et al. (see ref 92.)
or not, and seemed to describe the relationship expected between afterload and ventricular performance."
In contrast, the correlations between the same indices of cardiac performance and other levels of LV
stress (peak or average systolic stress) were much
weaker or did not even attain statistical significance.
These results emphasize the diagnostic value of the
end-systolic pressure/volume relationship for assessment of myocardial contractility.""*7 Another aspect
of these results worth emphasizing is the relatively
high value of the correlation between end-systolic
stress and LV contraction (% shortening) (r1 = 64%).
This correlation was obtained irrespective of concomitant sympatholytic or other forms of therapy and
suggests the biologic importance of the mechanical
conditions under which the heart operates.
Factors Other Than Wall Stress
Important as these biophysical considerations are,
however, they are not the only determinants of cardiac function in hypertensive patients. Alterations in
myocardial contractility, in cardioadrenergic drive,
and coincident coronary atherosclerosis may all have
significant influences, and it is not always easy to
define the relative roles they play. The heart's ability
to sustain an increased pressure load is remarkably dependent on the level of sympathetic activity.*1 That
level varies considerably among hypertensive patients"- ** and so does the dependence of the heart on
adrenergic drive to meet any added stress.**1 ** Little is
known about factors that govern this dependence in
Coronary Blood Flow and Left Ventricular Hypertrophy in
Hypertension
Clinicians have long suspected that myocardial perfusion might be impaired in hypertension. Initial
studies, however, showed rather consistently that coronary blood flow per unit mass of myocardium was
within normal limits." 1 •• Only recently has the problem been examined in more detail, particularly the
response of coronary vessels to vasodilator stimuli and
the distribution of flow between the endocardium and
epicardium.**110°
Most studies have indeed confirmed that coronary
flow in pressure LVH was usually normal at rest (in
proportion to myocardial mass). However, in response
to vasodilator stimuli, there was often, albeit not
always, a reduced capacity for coronary vasodilation.**110* Apparently, a greater portion of that capacity must have been used to maintain an adequate
myocardial perfusion at rest, leaving a reduced coronary vascular reserve. The extent of that reduction
differed widely amongst various studies, but this is not
surprising given the large number of factors that can
influence coronary vasodilation. These include the
relation of coronary perfusion pressure to degree of
LVH and the extent of structural changes in the coronary vessels.80 In cases with reduced coronary reserve, the coronary flow might not be able to meet the
additional demands imposed by increased cardiac
work. Under these conditions, the subendocardial
region would be at particular risk of ischemic injury.101
Antihypertensive therapy can influence coronary
blood flow in many ways; fears that therapeutic lowering of a raised blood pressure would lead to coronary
insufficiency or to myocardial infarction have not, in
our experience, been substantiated. On the contrary,
reduction of the pressure load and therefore of the excessive myocardial oxygen requirements will help
relieve coronary insufficiency and reduce anginal episodes. It is important, however, to avoid in patients
with cardiac disease or in older patients the reflex
11-16
1981 BLOOD PRESSURE COUNCIL
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tachycardia and hyperkinetic circulation that occur
with some vasodilators, such as hydralazine diazoxide
or minoxidil. One must also consider, in addition to
these early pharmacologic effects, the long-term consequences of antihypertensive therapy on cardiac
hypertrophy and on the coronary vessels.
Wicker and Tarazi104 found that, in rats with renovascular hypertension, reversal of LVH led to restoration of coronary vascular reserve if the latter had been
reduced by the hypertrophy. Of particular importance was the relation between arterial pressure and
myocardial mass. Parallel changes in both did not
greatly alter coronary blood flow per gram ventricular weight, but reduction of blood pressure without
reversal of hypertrophy was associated with a significant reduction in the coronary flow response to maximal vasodilation. It is obvious that much remains to
be elucidated regarding the coronary effects of prolonged antihypertensive therapy. The situation becomes even more complex if coronary atherosclerosis
is added to the effects of hypertension and cardiac
hypertrophy. Interference with the vasodilating
capacity of coronary vessels may then aggravate the
effects of a coronary stenosis or obstruction.
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Hypertension. 1982;4:8-18
doi: 10.1161/01.HYP.4.3_Pt_2.8
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