598
Coronary Hypertension and Diastolic
Compliance in Isolated Rabbit Hearts
Laura F. Wexler, William N. Grice, Mary Huntington, Jonathan F. Plehn, and Carl S. Apstein
Acute pulmonary edema during hypertensive crisis has been attributed to acute left ventricular
systolic failure secondary to increased afterload. We tested the hypothesis that the increase in
coronary artery perfusion pressure associated with systemic hypertension could also contribute
to increased left ventricular filling pressures by acutely increasing coronary intravascular
volume and decreasing left ventricular diastolic compliance. Isolated isovolumic (balloon in left
ventricle) normal rabbit hearts (n=13) with pericardium removed and right ventricle vented
were blood perfused at an initial coronary artery perfusion pressure of 100 mm Hg; left
ventricular balloon volume was adjusted to produce an initial left ventricular end-diastolic
pressure of 15±1 mm Hg; left ventricular systolic pressure was 102±3 mm Hg. When coronary
perfusion pressure was increased to 130±l mm Hg to simulate a hypertensive crisis, coronary
flow increased from 2.0±0.2 to 3.0±0.2 ml/min/g left ventricle (/><0.001), left ventricular
systolic pressure increased to 116±4 mm Hg, and isovolumic left ventricular end-diastolic
pressure increased to 21±1 mm Hg (p<0.001), which indicated a decrease in left ventricular
diastolic compliance. When coronary perfusion pressure was decreased to a physiological level
of 70 mm Hg, coronary flow rate decreased to 1.4±0.1 ml/min/g left ventricle (p<0.001), left
ventricular systolic pressure fell to 82±4 mm Hg, and left ventricular end-diastolic pressure fell
to 14±1 mm Hg (p<0.001). The left ventricular diastolic pressure-volume curve was shifted
upward and to the left at a coronary perfusion pressure of 130 mm Hg relative to the curve
generated at a coronary perfusion pressure of 70 mm Hg, confirming that left ventricular
diastolic compliance decreased when coronary perfusion pressure was elevated. Coronary
hypertension also resulted in an increase in left ventricular wall thickness as assessed by
two-dimensional echocardiogram. Mean endocardial-to-epicardial wall thickness was 5.1±0.6
mm at a coronary perfusion pressure of 130 mm Hg and 4.1±0.4 mm at a coronary perfusion
pressure of 70 mm Hg (p<0.05). Neither peak negative rate of change of pressure (—dP/dt) nor
the exponential time constant of ventricular relaxation changed when coronary perfusion
pressure was decreased from 130 to 70 mm Hg, which suggests that early diastolic relaxation
was unaffected over the range of coronary perfusion pressure studied. The correlation between
coronary hypertension, decreased left ventricular diastolic compliance, and increased wall
thickness in the normal isolated isovolumic blood-perfused rabbit heart suggests that coronary
vascular turgor may be a significant factor altering diastolic compliance of the left ventricle
during acute hypertension. (Hypertension 1989; 13: 598-606)
H
ypertensive crisis frequently results in congestive heart failure and may precipitate
acute pulmonary edema. The acute rise in
From the Cardiac Muscle Research Laboratory, Cardiovascular Institute, Boston University School of Medicine and The
Cardiology Section of the Thorndike Memorial Laboratory,
Boston City Hospital, Boston, Massachusetts.
Supported by Special Emphasis Research Career Award AM/
HL-01114 from the National Heart, Lung, and Blood Institute
and the National Institute of Arthritis, Diabetes, Digestive, and
Kidney Diseases (L.F.W.) and by US Public Health Service
research grants HL-31807 and HL-18318 (C.S.A.).
Address for reprints: Laura F. Wexler, MD, Division of
Cardiology, VA Medical Center, 3200 Vine Street, Cincinnati,
OH 45220.
Received June 20, 1988; accepted December 19, 1988.
pulmonary capillary pressure that leads to pulmonary congestion is usually attributed to acute left
ventricular systolic failure secondary to an acute
increase in afterload, that is, afterload mismatch.1
However, the increase in coronary perfusion pressure and flow associated with an acute rise in aortic
pressure may also directly affect left ventricular
diastolic function.
Previous work from this2-5 and other6-7 laboratories has demonstrated a direct relation between left
ventricular diastolic compliance and coronary artery
perfusion pressure and flow. In this report we have
adopted the terminology of Gaasch et al8 who use
the term ventricular compliance to indicate changes
in diastolic pressures at a common or fixed diastolic
Wexler et al
volume or parallel shifts in the position of the
diastolic pressure-volume curve. Thus, reduced
ventricular compliance refers to an increase in left
ventricular end-diastolic pressure at a fixed left
ventricular volume or a parallel shift of the left
ventricular diastolic pressure-volume curve upward
and to the left. The term compliance is to be
distinguished from the term chamber stiffness or
chamber distensibility, which, by current usage,
imply assessment of the slope of the diastolic pressure-volume curve.
During states of reduced coronary artery perfusion
pressure andflow(ischemia), ventricular compliance
initially increases in association with a decrease in
left ventricular diastolic wall thickness. Conversely,
during states of increased coronary flow induced by
vasodilation, left ventricular compliance decreases
to a small degree in concert with an increase in
diastolic wall thickness.2-7-9 These findings support
the concept initially proposed by Salisbury et al10 in
1960 that distensibility of the left ventricle is directly
affected by coronary vascular turgor, that is, the
degree to which the coronary vascular tree is distended with blood. Therefore, we hypothesized that
an acute increase in both coronary artery perfusion
pressure andflowassociated with acute aortic hypertension would substantially decrease ventricular diastolic compliance and contribute directly to increasing left ventricular diastolic filling pressure. We
tested this hypothesis in the isolated, isovolumic
blood-perfused normal rabbit heart in which we
could impose acute aortic and coronary hypertension in the absence of acute systolic failure.
Materials and Methods
Isolated Isovolumic Blood-Perfused Heart
Heparinized male albino New Zealand rabbits (12 kg) were anesthetized with sodium pentobarbital
(50 mg/kg). The thorax was opened, the pericardium cut, and the heart isolated. A perfusion cannula was positioned in the aortic root directly above
the aortic valve; the coronary arteries were perfused with fresh whole heparinized rabbit blood. A
separate heparinized rabbit served as the blood
donor, contributing 80-100 ml fresh whole blood to
which 2 mg of gentamicin was added to prevent
bacterial growth. The interval between isolation of
the heart and initiation of coronary perfusion was
less than 10 seconds. The perfusion system (Figure
1) consisted of a venous reservoir, a variable-flow
pump, an oxygenator, a water-jacketed arterial reservoir, and a filter. The arterial reservoir was pressurized so that coronary perfusion pressure could
be controlled by a valve, which adjusted the pressure inside the reservoir; coronary blood flow was
allowed to vary according to coronary vasomotor
autoregulation.
After being pumped from the venous reservoir,
the blood passed through an oxygenator into the
pressurized arterial reservoir and then through a
Coronary Hypertension and LV Compliance
599
Blood Line
Pressu
Regulato:
Syringe
Intra-LV Balloon
Apical Drain
FIGURE 1. Diagram of isovolumic blood-perfused working rabbit-heart preparation. Heparinized blood from a
donor rabbit was pumped through an oxygenator and filter
to coronary arteries through a cannula in the aortic stump.
Coronary perfusion pressure (CPP) was controlled by a
pressure regulator, and coronary flow was determined by
coronary vascular autoregulation. A thin-walled latex balloon filled left ventricular cavity and was attached to a
fluid-filled catheter for measurement of left ventricular
pressure (LVP). Left ventricular compliance was assessed
by measuring changes in left ventricular pressure at a
constant balloon volume and by analyzing diastolic
pressure-volume curves (see text for full description).
filter (40 ^.m pore size) before entering the aortic
cannula. The oxygenator was made by coiling
approximately 7.5 m silastic tubing (0.58 mm i.d. by
0.77 mm o.d) as has been reported previously from
this laboratory.2 The silastic tubing was placed
inside a large beaker that was covered and equilibrated with a gas mixture of 20% O2, 3% CO2, and
77% N2 to maintain arterial pc^ at 90-110 mm Hg
and pH 7.35-7.42. Hematocrit of the blood ranged
from 29 to 33%. Glucose was monitored every 30
minutes with Chemstnp reagent strips (Boehringer
Mannheim Diagnostics, Indianapolis, Indiana), and
glucose was added as needed to maintain blood
glucose levels within a range of 80-120 mg/dl
throughout each experiment.
After initiation of coronary perfusion, the left
atrium was cut, and a drainage cannula was placed
in the apex of the left ventricle to decompress that
chamber of any Thebesian drainage. A drainage
cannula was positioned in the right ventricle via the
pulmonary artery to collect all venous effluent, keep
the right ventricle decompressed, and eliminate any
influence of right ventricular volume or pressure on
left ventricular compliance. The distal pulmonary
artery and all venae cavae were ligated. A thermistor and pacing electrode were inserted into the
right ventricle via the right atrium. All hearts were
paced at 3.5 Hz, which consistently exceeded the
600
Hypertension
Vol 13, No 6, Part 1, June 1989
endogenous heart rate of each rabbit. Recording
electrodes were fixed to the right atrium. A doublecannulated collapsed latex balloon was placed in
the left ventricle. Both cannulas exited through the
mitral valve orifice and were tied in place at the
atrioventricular groove. One cannula was connected to a pressure transducer; the second cannula
was connected to a calibrated syringe, which was
used to adjust balloon volume. The balloon was
larger than the left ventricular cavity and completely filled it so that no measurable pressure was
generated by the balloon itself over the range of
volumes used in these experiments.
The preparation was submerged in warmed saline
inside a water-jacketed chamber, and temperature
was maintained constant at 37° C. The stability of
this preparation has been reported.11
Hemodynamic Measurements
Coronary perfusion pressure was measured from
a side arm of the aortic perfusion cannula, which
was connected to a Statham (Gould-Statham,
Oxnard, California) P23Db pressure transducer.
Isovolumic left ventricular pressure was measured
from a short length of stiff fluid-filled polyethylene
tubing connecting the intraventricular balloon to a
Statham P23Db transducer. The damping characteristics and natural resonant frequency response of
this system have been reported previously3 and
satisfy the range shown by Falsetti et al12 to be
required for accurate measurement of ventricular
pressure. The effect of coronary artery perfusion
pressure on left ventricular compliance was assessed
by measurement of changes in left ventricular diastolic pressure at a fixed left ventricular volume5 as
well as by measurement of changes in the position
of the left ventricular diastolic pressure-volume
curve. Pressure-volume curves were generated by
progressive filling of the left ventricular balloon
with 0.2-ml increments of saline and measurement
of the corresponding left ventricular diastolic pressure, beginning with a completely collapsed (zero
volume) balloon and increasing the balloon volume
until end-diastolic pressure was 20-25 mm Hg. To
avoid any contribution of hysteresis or stress relaxation to observed shifts in the pressure-volume
relation, left ventricular diastolic pressure was
always measured 7-10 seconds after each addition
of volume to the balloon and only during filling (not
emptying) of the balloon. We have previously documented the reproducibility offillingcurves obtained
in this manner.4
Left ventricular relaxation was assessed by two
methods: peak negative rate of change of pressure
(-dP/dt) and the exponential time constant of left
ventricular pressure decay, calculated by the derivative method (from the linear regression of -dP/dt
vs. pressure).13-14
Left ventricular isovolumic systolic pressure and
peak positive rate of change of pressure (+dP/dt)
were recorded at each coronary perfusion pressure.
Maximum developed pressure was measured from
the complete pressure-volume curve at each perfusion pressure.
Coronary flow rate was measured by timed samples of coronary venous effluent collected from the
pulmonary artery cannula.
Measurement of Left Ventricular Wall Thickness
Two-dimensional echocardiographic imaging of
the isolated, perfused heart was performed by aiming a 5.0 MHz medium-focus mechanical transducer, coated with ultrasound gel, through a membranous latex aperture in the surrounding water
jacket. The transducer was manipulated until a
clear, circular short-axis view of the left ventricle
was obtained at a level just below the tips of the
mitral leaflets, with the collapsed right ventricle
positioned posteriorly. The transducer was then
clamped into position for the duration of the
experiment.
All studies were recorded on standard ¥i in.
videotape, and wall thickness was later measured
from digitized images by means of video calipers on
a dedicated microcomputer. Wall thickness determination was made at the time of the R wave peak
by measurement of the left ventricular free wall at
the anterior (12 o'clock) position from endocardial
(trailing edge) to epicardial (leading edge) borders.
Measurements were made by an observer who was
blinded to the conditions of each experiment.
In a subset of experiments, change in epicardial
length was also measured under isovolumic conditions. We have previously shown that changes in
isovolumic epicardial length correlate with changes
in wall thickness measured by epicardial and endocardial ultrasonic crystals.2 A mercury-in-silastic epicardial length gauge,15 10 mm unstressed length,
was sutured to the epicardial surface of the left
ventricular free wall in a horizontal orientation
along the equatorial circumference of the heart
midway between the base and apex. The gauges
were mounted with a slight degree of initial stretch
so that slack in the gauge would not compromise
measurement of segment length. Strain gauge length
was recorded simultaneously with the aortic and
left ventricular pressure signals; data is reported as
change in length, in millimeters.
Experimental Protocol
All hearts (n=18) underwent a 30-minute warmup period at a coronary artery perfusion pressure of
100 mm Hg with left ventricular balloon volume
adjusted to produce a left ventricular diastolic pressure of 15 mm Hg. Balloon volume at this diastolic
pressure became the control balloon volume for
each heart for the duration of the experiment. Initial
measurements of coronary flow and left ventricular
pressure were obtained.
Wexler et al
Coronary Hypertension and LV Compliance
601
TABLE 1. Changes in Left Ventricular End-Diastollc Pressure and Wall Thickness During and After Reversal of
Coronary Artery Hypertension
Coronary flow
CPP
LVSP
LVEDP
(mm Hg)
(mm Hg)
(mm Hg)
(ml/min/g left ventricle)
Hypertensive followed by normotensive coronary artery perfusion pressure
3.0+0.2
116±4
21 + 1
130
70
1.4±0.1
82±4
14±1
p<0.0025
p<0.01
p<0.01
Normotensive followed by hypertensive coronary artery perfusion pressure
71±9
11±1
70
l.l±0.3
3.9+0.9
100±7
21 + 1
130
p<0.025
p<0.01
p<0.01
Echo h
(mm)
Segment length
change (mm)
5.1+0.6
4.1 ±0.4
p<0.005
-0.32±0.10mm
p<0.05
+0.38±.06mm
p<0.005
CPP, coronary artery perfusion pressure; LVSP, peak left ventricular systolic pressure; LVEDP, left ventricular
end-diastolic pressure; Echo h, echocardiographic wall thickness. All p values are for paired t test.
Acute Coronary Hypertension
Coronary perfusion pressure was increased (over
3-5 minutes) to 130 mm Hg or until coronary perfusion pressure began to exceed peak left ventricular systolic pressure. The level of imposed hypertension was limited to 140 mm Hg or less to avoid
the possibility of excessive edema formation.16 When
left ventricular pressure had stabilized (approximately 5 minutes), measurements of coronary flow
rate, left ventricular isovolumic systolic and diastolic pressure, and epicardial segment length were
obtained. A two-dimensional echocardiogram was
recorded on videotape, and a left ventricular filling
curve was generated.
Reversal of Coronary Hypertension
After left ventricular balloon volume was returned
to the control volume, coronary perfusion pressure
was reduced to 70 mm Hg. When left ventricular
pressure had stabilized (approximately 5 minutes),
measurements of coronary flow, left ventricular
isovolumic systolic and diastolic pressure, and segment length were obtained; a two-dimensional
echocardiogram was recorded, and a left ventricular filling curve was generated. At the conclusion of
the experiment, the heart was removed from the
apparatus, the left ventricle was dissected free, and
wet weight/dry weight ratio was determined.
Reversed Sequence of Perfusion
Pressure Changes
In a second series of hearts (n=5), after a period
of baseline control perfusion at a coronary perfusion pressure of 100 mm Hg, the coronary perfusion
pressure was first decreased to 70 mm Hg and then
increased to 130 mm Hg. Coronary flow rate, left
ventricular isovolumic systolic and diastolic pressure, segment length, two-dimensional echocardiographic wall thickness, andfillingcurves were measured at each level of coronary artery perfusion
pressure. At the end of each experiment, the left
ventricle was isolated for wet and dry weight determination.
Assessment of Myocardial Edema
To assess the possible contribution of coronary
hypertension-induced myocardial edema to observed
changes in left ventricular compliance, we compared
wet weight/dry weight ratios of hearts exposed to high
coronary artery perfusion pressure with a series of
hearts exposed only to normal levels of perfusion
pressure. A separate series of similarly prepared isolated hearts (n=5) were perfused at a coronary perfusion pressure of 70 mm Hg for 45 minutes such that
the total duration of perfusion was comparable with
the total duration of the acute hypertension protocols.
The wet weight/dry weight ratio in these hearts was
compared with the wet weight/dry weight ratio of
hearts subjected to both hypertension protocols
described above, that is, hypertension followed by
normalization of perfusion pressures and normal perfusion followed by hypertension.
Statistical Analysis
Data are expressed as the mean±SEM. Comparisons of the means of parameters measured at
different coronary artery perfusion pressures were
by Student's paired t test. Left ventricular diastolic
pressure-volume curves were analyzed by linear
regression of the equation:
LVEDP=a(LV vol)+b
where LVEDP is the left ventricular end-diastolic
pressure and LV vol is the left ventricular balloon
volume.2 The means of the constants a and b,
representing slope and position, respectively, of the
curves obtained at each level of coronary artery
perfusion pressure were compared by Student's
paired / test.
Results
At the end of the control warm-up period, during
which the heart was perfused at a coronary artery
perfusion pressure of 100 mm Hg, coronary flow
rate was 2.0±0.2 ml/min/g left ventricular wet wt.
The volume of the left ventricular balloon was
adjusted to produce an end-diastolic pressure of
602
Hypertension
Vol 13, No 6, Part 1, June 1989
I?
li15
$i
CPP-130 mm Hg
CPP-70 mm Hg
n-10
10
.4
.6
8
1.0
Left Ventricular Balloon Volume
2. Line graph of effect of reversal of hypertensive coronary artery perfusion pressure (CPP) on left
ventricular end-diastolic pressure-volume curve. Position
of diastolic pressure-volume curve shifted significantly
downward and to right when coronary artery perfusion
pressure was decreased from hypertensive levels (130
mm Hg) to physiological levels (70 mm Hg). The means
ofx values were 0.89 and 1.0 for data points obtained at
coronary perfusion pressures of 130 and 70 mm Hg,
respectively. These values were calculated by fitting
pressure-volume data to linear regression equation
LVEDP=a(LV vol)+b where LVEDP is left ventricular
end-diastolic pressure and LV vol is left ventricular
balloon volume. Balloon volumes were normalized to
largest volume obtained for each heart; that is, a value of
1.0 was assigned to balloon volume at a left ventricular
end-diastolic pressure of 25 mm Hg and a coronary
perfusion pressure of 70 mm Hg.
FIGURE
15±1 mm Hg; left ventricular systolic pressure was
102±3 mm Hg.
The effects of coronary hypertension on left ventricular diastolic compliance are shown in Table 1
and Figure 2. The change in coronary blood flow,
left ventricular isovolumic systolic and diastolic
pressure, echocardiographic left ventricular wall
thickness, and epicardial segment length after coronary artery perfusion pressure was decreased from
hypertensive to physiological levels is shown in
Table 1. During coronary hypertension (coronary
artery perfusion pressure of 130 mm Hg), coronary
flow rate was 3.0±0.2 ml/min/g left ventricular wet
wt; left ventricular systolic pressure was 116±4
mm Hg, and left ventricular end-diastolic pressure
was 21 ± 1 mm Hg. When coronary artery perfusion
pressure was reduced to a physiological level of 70
mm Hg, coronary artery flow rate fell to 1.4±0.1
ml/min/g left ventricle (p<0.001). Left ventricular
systolic pressure decreased to 82±4 mm Hg
(p<0.001), and left ventricular end-diastolic pressure decreased to 14±1 mm Hg (p<0.001). Coronary hypertension was associated with a significant
increase in wall thickness (Figure 3). Mean echocardiographic wall thickness was 5.1 ±0.6 mm at a
coronary artery perfusion pressure of 130 mm Hg
compared with 4.1 ±0.4 mm at a coronary perfusion
pressure of 70 mm Hg (p<0.05). Isovolumic epicar-
dial length decreased by 0.32±0.1 mm (p<0.05)
after reversal of coronary hypertension, confirming
the decrease in wall thickness demonstrated by
echocardiography.
When the sequence of alterations in coronary
artery perfusion pressure was reversed such that
hearts were first perfused at a physiological pressure of 70 mm Hg followed by hypertension at 130
mm Hg, comparable changes in end-diastolic pressure and segment length were observed (Table 1).
Figure 2 shows left ventricular diastolic pressurevolume curves obtained from 10 hearts, each subjected to hypertensive levels followed by physiological levels of coronary artery perfusion pressure.
When analyzed by fitting the pressure-volumecurve data points at each coronary artery perfusion pressure to the linear regression equation
LVEDP=a(LV vol)+b, there was no significant
difference in the means of the slopes (a) of the
curves; however, the means of the y intercepts (b)
were significantly different at a coronary perfusion
pressure of 130 mm Hg (—34.7±6) compared with a
coronary artery perfusion pressure of 70 mm Hg
(-47.1 ±6, /7<0.05). Thus, the position of the diastolic pressure-volume curve obtained at a coronary
artery perfusion pressure of 130 mm Hg was shifted
significantly upward and to the left relative to the
curve obtained at a physiological coronary artery
perfusion pressure of 70 mm Hg, consistent with a
decrease in left ventricular compliance at the higher
coronary artery perfusion pressure. When the
sequence of alterations in coronary artery perfusion
pressure was reversed (70 mm Hg followed by 130
mm Hg), a similar shift in the position of the left
ventricular diastolic pressure-volume curve was seen.
There were no significant changes in rate of early
left ventricular relaxation at different coronary perfusion; neither peak -dP/dt nor the exponential
time constant of left ventricular relaxation (from the
linear regression of —dP/dt vs. pressure) were significantly different when measured at a coronary
perfusion pressure of 130 mm Hg versus 70 mm Hg
(Table 2).
Left ventricular systolic performance improved
when coronary perfusion pressure was increased.
Peak +dP/dt was significantly higher at a coronary
perfusion pressure of 130 mm Hg than at 70 mm Hg
(1,644±76 vs. 1,335±58 mm Hg/sec, p<0.001), and
maximum developed pressure increased (93± 15 vs.
80±12mm Hg, p<0.05).
We considered the possibility that coronary hypertension might induce interstitial edema and that this
might contribute to the observed changes in left
ventricular compliance. We compared the wet weight/
dry weight ratios of three groups of hearts (Table 3).
Group 1 was exposed to the sequence of decreasing
perfusion pressure (130-70 mm Hg); group 2 was
exposed to the sequence of increasing perfusion
pressure (70-130 mm Hg); group 3 was exposed to a
similar total duration of perfusion (45 minutes) but at
a stable perfusion pressure of 70 mm Hg. There were
Wexler et al Coronary Hypertension and LV Compliance
FIGURE 3.
CPP(mm Hg)
= <05
Wall thickness
(mm)
no significant differences in wet weight/dry weight
ratios among the three groups, which suggests that
there was no significant increase in edema formation
associated with the levels of coronary artery perfusion pressure used in these experiments.
Discussion
In the isolated isovolumic blood-perfused rabbit
heart, an increase in mean aortic perfusion pressure
comparable with that observed during acute hypertensive episodes (from 70 mm Hg to 130 mm Hg)
was associated with a decrease in left ventricular
compliance, that is, with a shift in the left ventricular
diastolic pressure-volume relation upward and to the
left such that left ventricular end-diastolic pressure
was significantly increased for any level of diastolic
volume. This reversible decrease in ventricular compliance induced by coronary hypertension occurred
in association with a reversible increase in diastolic
wall thickness, demonstrated both by echocardiography and by epicardial segment-length gauge.
Directionally similar changes in left ventricular
compliance and wall thickness were observed when
coronary perfusion pressure was varied between 70
and 100 mm Hg, but the measured changes in
isovolumic left ventricular end-diastolic pressure,
left ventricular wall thickness, and position of the
left ventricular diastolic pressure-volume curve did
not reach statistical significance.
TABLE 2. Effect of Coronary Artery Perfusion Pressure on Left
Ventricular Relaxation
CPP
(mm Hg)
130
70
T
(msec)
54±6
48±4
NS
Peak -dP/dt
(mm Hg/sec)
-1104±51
-1012±47
NS
CPP, coronary artery perfusion pressure; T, time constant of
left ventricular pressure decay calculated by the derivative
method12-13; NS, not significant.
603
Echocardiograms
of changes in wall thickness
during coronary hypertension. Left panel shows short
axis view of an isolated heart
perfused at a coronary perfusion pressure (CPP) of 70
mm Hg. Right panel shows the
same heart perfused at a coronary perfusion pressure of
130 mm Hg. Arrows indicate
anterior (12 o'clock) location
where epicardial to endocardial wall thickness was measured. Right ventricle is posterior and to left (between 6
o'clock and 9 o'clock). Data
represents mean±SEM of six
hearts.
Although not the focus of this study, we also
observed changes that suggested a small improvement in systolic function in response to coronary
artery hypertension. Isovolumic left ventricular systolic pressure, peak +dP/dt, and maximum developed pressure were significantly greater at a coronary artery perfusion pressure of 130 mm Hg than
at 70 mm Hg. Two mechanisms may contribute to
this observation: the Frank-Starling mechanism and
the Anrep effect. Arnold and colleagues1718 suggested that distension of coronary vessels during
coronary hyperperfusion (the "garden-hose" effect)
increased myocardial fiber length, thus enhancing
mechanical function by the Frank-Starling mechanism. Many investigators19-24 have demonstrated a
positive inotropic response to an increase in aortic
pressure, an effect first described by Von Anrep23
(and by Knowlton and Starling26) in 1912. The
mechanism of the Anrep effect is unclear. Vatner
and colleagues21 suggested that the effect is a consequence of hyperemia after transient subendocardial ischemia induced by the acute increase in aortic
pressure. However, this effect is not entirely dependent on an increase in coronary flow since the
phenomenon can be demonstrated, albeit to a more
modest extent, in models in which aortic pressure is
acutely increased while coronary flow is held
constant,22-23 and force-velocity analyses suggest that
TABLE 3. Comparison of Wet Weight/Dry Weight Ratios In Three
Groups of Hearts
Group
Coronary artery
perfusion pressures
Wet/dry weight ratio
1
130 mm Hg-70 mm Hg
2
70 mm Hg-130 mm Hg 5.0+0.10 (/i= 13)
5.3+.0.2 (n=5)
NS
NS
NS
3
70mmHg
NS, not significant.
5.1+0.05 (n=5)
604
Hypertension
Vol 13, No 6, Part 1, June 1989
the increase in systolic performance represents a
true net positive inotropic effect.19 This effect does
not appear to be mediated by release of catecholamines as it has been observed after 0-adrenergic
blockade.2124
Most textbooks attribute the acute pulmonary
congestion associated with hypertensive crisis to
systolic failure secondary to excessive afterload.1
However, this concept may not explain the sole
mechanism of pulmonary congestion in acute hypertensive states. The decrease in left ventricular compliance associated with increased wall thickness at
increased coronary artery perfusion pressures provides an alternative or additional mechanism of acute
pulmonary congestion in acute hypertensive states.
Previous work has suggested that coronary artery
perfusion pressure and flow can significantly modify
left ventricular diastolic properties although none
have specifically addressed hypertensive states. In
1960, Salisbury et al10 reported that coronary artery
perfusion pressure was inversely proportional to
left ventricular diastolic distensibility in isovolumic
contracting dog hearts. They speculated that a
passive increase in coronary blood volume retained
within the coronary arteries and veins (turgor) would
change the resiliency of the coronary vascular tree
and thus change the elastic properties of the heart.
Additional studies27-30 have confirmed this hypothesis about the relations among coronary flow, myocardial blood volume, and wall thickness, and
several 2 - 931 - 34 have related these changes to alterations in left ventricular diastolic pressure-volume
relations.
During states of increased coronary artery blood
flow induced either by vasodilators,29-34 postischemic hyperemia, 367 or hyperemia induced by
hypoxemia, 2 - 5734 ventricular compliance has been
shown to decrease. However, in each of these
studies, the coronary perfusion pressure either
decreased or was held constant as part of the
experimental protocol. Verrier and colleagues34
demonstrated a small shift in the left ventricular
diastolic pressure-dimension curve compatible with
reduced compliance in intact dog hearts when
coronary blood flow was increased by druginduced vasodilation; however, coronary perfusion pressure declined in this study, and the
authors speculated that the effect may have been
much greater had coronary perfusion pressure not
decreased.
The effects of increased coronary artery perfusion pressure on left ventricular diastolic properties
have been investigated previously but with conflicting results. Olsen and colleagues33 reported a
leftward shift in the left ventricular diastolic pressure-dimension curve in arrested dog hearts on
right ventricular bypass when coronary artery pressure was increased from 40 to 120 mm Hg although
they noted that the greatest changes occurred below
the autoregulatory range (^80 mm Hg). Alderman
and Glantz35 showed in humans that the left ven-
tricular pressure-volume curve shifted upward and
to the left when aortic pressure was increased to
hypertensive levels by angiotensin infusion. They
speculated that external mechanical loading conditions (right-left ventricular interaction and pericardial restraint) and the viscoelastic properties of the
cardiac muscle were the key factors altering the left
ventricular diastolic pressure-volume relation. In
contrast to these studies, Abel and Reis32 reported
no change in isovolumic left ventricular end-diastolic
pressure in an intact balloon-in-left ventricle canine
model on right ventricular bypass either when coronary artery perfusion pressure was decreased to
ischemic levels or increased to 150 mm Hg. With use
of a similar model, Templeton and colleagues31
reported no change in either the position or slope of
the left ventricular diastolic pressure-volume curve
in isovolumic dog hearts when coronary perfusion
pressure was increased. However, only a modest
increase in coronary perfusion pressure from 60 to 95
mm Hg was imposed, and this is consistent with our
observation that the decrease in compliance was
significant only when coronary perfusion pressure
was increased from 70 to 130 mm Hg and was not
statistically significant over the range of 70-100
mm Hg.
In the present study, we have demonstrated a
significant, rapidly reversible decrease in left ventricular compliance associated with coronary artery
perfusion pressures in the hypertensive range. Left
ventricular end-diastolic pressure was significantly
increased at a fixed diastolic volume, and there was
a parallel shift upward and to the left of the diastolic
pressure-volume curve. We did not observe any
change in the slope of the diastolic pressure-volume
curve so that calculated chamber stiffness, as defined
by Gaasch et al,8 was unchanged over the range of
perfusion pressures we studied. We have previously observed that both the position and the slope
of the pressure-volume curve change when the
heart is subjected to injury by hypoxia or protracted
ischemia. However, alterations in pressure and flow
induced by adenosine shifted only the position of
the diastolic pressure-volume curve and had little if
any effect on the slope.2 Parallel shifts in the position of the diastolic pressure-volume curve in the
absence of changes in slope have been described by
others during acute interventions in intact
animals35-36 and have been primarily ascribed to
external forces, such as pleural and pericardial
pressure or right-left ventricular interaction, which
can be discounted in our model. The reversible
increase in wall thickness we observed suggests
that the decrease in ventricular compliance resulted,
at least in part, from an increase in coronary vascular turgor, that is, in decreased distensibility of
the ventricular wall secondary to vascular engorgement. However, several other factors that might
modify diastolic properties of the left ventricle in
this model should be considered.
Wexler et al
Coronary Hypertension and LV Compliance
605
Myocardial Interstitial Edema Formation
Cross and colleagues30 demonstrated in the isolated blood-perfused dog heart that myocardial interstitial edema (>4-5% heart weight) reduced left
ventricular compliance. However, Salisbury et al16
did not find evidence of significant edema formation
in blood-perfused hearts when the degree of hypertension was limited to less than 140 mm Hg. It is
possible that the small gradient between maximum
coronary artery perfusion pressure and peak left
ventricular systolic pressure that developed in some
hearts may have magnified the coronary vascular
engorgement or permitted accumulation of interstitial edema at coronary perfusion pressures of less
than 140 mm Hg. However, we did not find evidence
of increased myocardial edema formation associated
with hypertension. The wet weight/dry weight ratios
of hearts perfused at a stable coronary artery perfusion pressure of 70 mm Hg was not significantly
different from those hearts subjected to periods of
coronary hypertension at 130 mm Hg, consistent
with the findings of Salisbury et al.16 Furthermore,
there was no correlation between the degree of
leftward shift of the diastolic pressure-volume curve
and presence or absence of a small gradient between
hypertensive coronary artery perfusion pressure and
peak left ventricular systolic pressure.
increasing coronary vascular diastolic distending pressure to enhance early diastolic relaxation.
In clinical hypertensive crisis, in which there is a
greater increase in peak systolic pressure than occurs
in our isolated heart model, the role of impaired
relaxation secondary to increased afterload may be
more significant. Furthermore, since hypertensive
crisis usually occurs in patients with a history of
sustained hypertension, a variable degree of left
ventricular hypertrophy may have a key role in
determining diastolic compliance during acute hypertensive states. Increased total coronary resistance
per gram of left ventricle in the hypertrophied heart
may minimize the effect of acute increases in coronary perfusion pressure, and hypertrophy would
attenuate the increase in wall stress. However,
inherent differences in myocardial relaxation in the
hypertrophied heart may make it more susceptible
to further worsening of chamber compliance during
acute coronary hypertension. Hypertensive crisis in
a hypertrophied heart may be more likely to cause
subendocardial ischemia than in a nonhypertrophied heart because of borderline subendocardial
perfusion and limited subendocardial coronary vasodilator reserve. Thus, in hypertrophied hearts, hypertensive crisis may alter diastolic compliance by
several mechanisms, including increased coronary
perfusion pressure and subendocardial ischemia.
Effects of Increased Afterload
The velocity of early diastolic relaxation is reduced
when wall stress, that is, afterload, is increased
throughout the period of tension development in the
isovolumic heart.37-41 Changes in wall stress can be
estimated from changes in the components of the
Laplace relation, stress=Pr/2h where P is intraventricular pressure, r is the midwall radius of the sphere,
and h is wall thickness. During the coronary hypertension experiments, peak left ventricular systolic
pressure increased only modestly; left ventricular
balloon volume was held constant, so that endocardia]
radius was not changed, but wall thickness increased
so that midwall and epicardial radius were increased.
It is not clear whether increased wall thickness induced
by coronary vascular engorgement diminishes wall
stress and stress imposed on the myocytes, as it does
in left ventricular hypertrophy, or increases it, due to
increased diastolic fiber length. Furthermore, it has
been suggested that an acute increase in coronary
artery perfusion pressure may actually enhance the
rate of early diastolic relaxation by imposition of an
early distending pressure on the myocardium as the
coronary vasculaturefillsunder increased pressure.42-43
We compared the rate of early diastolic relaxation at
coronary perfusion pressures of 70 mm Hg and at 130
mm Hg. No differences were observed in either the
time constant of left ventricular pressure decay or in
peak -dP/dt (Table 2). It is possible that in this
experimental model the effects of the modest increase
in afterload to decrease the rate of early diastolic
relaxation were exactly counteracted by the effects of
In summary, acute coronary vascular engorgement
associated with hypertensive coronary artery perfusion pressures in normal isolated blood-perfused rabbit hearts leads to a significant decrease in left ventricular compliance, which is rapidly reversible when
coronary artery perfusion pressure is lowered. This
phenomenon may contribute to development of acute
pulmonary edema in hypertensive crisis in that the
acute increase in systemic arterial pressure may affect
not only systolic performance by acute afterload
mismatch but may also alter diastolic compliance
directly as a result of coronary vascular engorgement.
The mechanism of rapid improvement in pulmonary
congestion commonly observed with vasodilator therapy may be related to decompression of coronary
vascular engorgement and improved diastolic compliance as well as to left ventricular unloading and
improved systolic function.
Acknowledgments
We thank Dr. James J. Ferguson III for his
assistance with the analysis of left ventricular relaxation. We also thank Dr. Margaret Ferrell for her
contributions to this research and Nancy Ahonen
for her help in preparing the manuscript.
References
1. Cohn JN: Blood pressure and cardiac performance, in Laragh
JH (ed): Hypertension Manual. New York, Yorke, 1973, pp
257-276
2. Vogel WM, Apstein CS, Briggs LL, Gaasch WH, Ahn J:
Acute alterations in left ventricular diastolic chamber stiffness: Role of the "erectile effect" of coronary arterial
606
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Hypertension
Vol 13, No 6, Part 1, June 1989
pressure and flow in normal and damaged hearts. Circ Res
1982;51:465-478
Vogel WM, Briggs LL, Apstein CS: Separation of Inherent
diastolic myocardial fiber tension and coronary vascular
erectile contributions to wall stiffness of rabbit hearts damaged by ischemia, hypoxia, calcium paradox and reperfusion. J Mol Cell Cardiol 1985;17:57-70
Wexler LF, Weinberg EO, Ingwall JS, Apstein CS: Acute
alterations in left ventricular chamber distensibility: Mechanistic differences between hypoxemia and ischemia in isolated perfused rabbit and rat hearts. Circ Res 1986^9:515-528
Serizawa T, Vogel WM, Apstein CS, Grossman W: Comparison of acute alterations in left ventricular relaxation and
diastolic chamber stiffness induced by hypoxia and ischemia. J Clin Invest 1981;68:91-102
Gaasch WM, Bing OHL, Franklin A, Rhodes D, Bernard
SA, Weintraub RM: The influence of acute alterations in
coronary blood flow on left ventricular diastolic compliance
and wall thickness. Eur J Cardiol 1978;7(suppl): 147-161
Gaasch WM, Bernard SA: The effect of acute changes in
coronary blood flow on left ventricular end-diastolic wall
thickness. An echocardiographic study. Circulation 1977;
56:593-598
Gaasch WH, Apstein CS, Levine HJ: Diastolic properties of
the left ventricle, in Levine HJ and Gaasch WH (eds): The
Ventricle. Boston, Martinus Nijhoff, 1985, pp 147-148
Apstein CS, Grossman W: Opposite initial effects of supply
and demand ischemia on left ventricular diastolic compliance: The ischemia-diastolic paradox. J Mol Cell Cardiol
1987;19:119-128
Salisbury PF, Cross CE, Rieben PA: Physiological factors
influencing coronary artery pressure upon myocardial elasticity. Circ Res 1960;8:794-800
Isoyama S, Apstein CS, Wexler LF, Grice W, LoreU BH:
Acute decrease in left ventricular diastolic chamber distensibility during simulated angina in isolated hearts. Circ Res
1987;61:925-933
Falsetti HJ, Mates RE, Caroll RJ, Gupta RL, Rell SE:
Analysis correction of fluid wave distortion in fluid filled
catheter systems. Circulation 1974;49:165-172
Raff GL, Glantz SA: Volume loading slows left ventricular
isovolumic relaxation rate. Circ Res 1981;48:813-824
Eichorn P, Grimm J, Koch R, Hess O, Carroll J, Krayenbuehl HP: Left ventricular relaxation in patients with left
ventricular hypertrophy secondary to aortic valve disease.
Circulation 1982;65:1395-1404
Parrish D, Strandness DE Jr, Bell JW: Dynamic response
characteristics of a mercury-in-silastic strain gauge. J Appl
Physio! 1964;19:363-365
Salisbury PF, Cross CE, Katsuhara K, Rieben PA: Factors
which initiate or influence edema in the isolated dog heart.
Circ Res 1961;9:601-606
Arnold G, Dosch EF, Messner E, Neitzer TA, Lochner W:
The importance of perfusion pressure in the coronary arteries for the contractility and the oxygen consumption of the
heart. Pflugers Arch 1968^99:339-356
Arnold G, Morgensteiner C, Lochner W: The autoregulation
of the heart work by the coronary perfusion pressure.
Pflugers Arch 1970;321:34-55
Clancy RL, Graham TP Jr, Ross J Jr, Sonnenblick EH,
Braunwald E: The influence of aortic pressure-induced
homeometric autoregulation on myocardial performance.
Am J Physiol 1968;214:1186-1192
Furnival CM, Linden RJ, Snow HM: Inotropic changes in
the left ventricle: The effect of changes in heart rate, aortic
pressure, and end-diastolic pressure. J Physiol 1970;
11:359-387
Vatner SF, Monroe RG, McRitchie RJ: Effects of anaesthesia, tachycardia and autonomic blockade on the Anrep effect
in intact dogs. Am J Physiol 1974;226:1450-1456
22. Rosenblueth AJ, Lopez AE, Rubrio R: The adaptation of
ventricular muscle to different circulatory conditions. Arch
Intern Physiol 1959;67:358-373
23. Sarnoff SJ, Mitchell JH, Gilmore JP, Remensnyder JP:
Homeometric autoregulation of the heart. Circ Res 1960;
8:1077-1091
24. Gamble WJ, LaFarge CG, Fyler DC, Weisul J, Monroe RG:
Regional coronary venous saturation and myocardial oxygen
tension following abrupt changes in ventricular pressure in
the isolated dog heart. Circ Res 1974;34:672-681
25. Von Anrep G: On the part played by the suprarenals in the
normal vascular reactions of the body. J Physiol 1912;
45:307-317
26. Knowlton FP, Starling EH: The influence of variations in
temperature and blood pressure on the performance of the
isolated mammalian heart. J Physiol 1912;44:206-219
27. Salisbury PF, Cross CE, Rieben PA: Physiological factors
influencing coronary blood volume in isolated dog hearts.
Am J Physiol 1961;200:633-636
28. Morgenstem C, Holjes U, Arnold G, Lochner W: The
influence of coronary pressure and coronary flow on intracoronary blood volume and geometry of the left ventricle.
Pflugers Arch 1973;340:101-111
29. Scharf SM, Bromberger-Barnea B: Influence of coronary
flow and pressure on cardiac function and coronary vascular
volume. Am J Physiol 1973;224:918-925
30. Cross CE, Rieben PA, Salisbury PF: Influence of coronary
perfusion and myocardial edema on pressure-volume diagram of left ventricle. Am J Physiol 1961 ;201:102-108
31. Templeton GH, Wildenthal K, Mitchell JH: Influence of
coronary blood flow on left ventricular contractility and
stiffness. Am J Physiol 1972;223:1216-1220
32. Abel RM, Reis RL: Effects of coronary blood flow and
perfusion pressure on left ventricular contractility in dogs.
Circ Res 1970^7:961-969
33. Olsen CO, Aharian DE, Jones RN, Hill RC, Sink JD, Lee
KL, Wechsler AS: The coronary pressure-flow determinants
of left ventricular compliance in dogs. Circ Res 1981;
49:856-865
34. Verrier ED, Bristow JD, Hoffman JIE: Coronary vasodilation shifts the diastolic pressure-dimension curve of the left
ventricle. J Mol Cell Cardiol 1986; 18:579-584
35. Alderman EL, Glantz SA: Acute hemodynamic interventions shift the diastolic pressure volume curve in man.
Circulation 1976^4:662-671
36. Mirsky I, Ranken JS: The effects of geometry, elasticity and
external pressures of the diastolic pressure-volume and
stiffness-stress relations. How important is the pericardium?
Circ Res 1979;44:601-611
37. Kariiner JS, LeWinter MM, Mahler F, Engler R, O'Rourke
RA: Pharmacologic and hemodynamic influences on the rate
of isovolumic left ventricular relaxation in the normal conscious dog. J Clin Invest 1977 ;60:511-521
38. Gaasch WH, Blaustein AS, Andrias CS, Avitall B: Myocardial relaxation. II. Hemodynamic determinants of the rate of
left ventricular isovolumic pressure decline. Am J Physiol
198O;239:H1-H6
39. Gaasch WH, Blaustein AS, Adam D: Myocardial relaxation.
IV. Mechanical determinants of the time course of left
ventricular pressure decline during isovolumic relaxation.
Eur J Cardiol 1980;l(suppl A): 111-117
40. Raff GL, Glantz SA: Volume loading slows left ventricular
isovolumicrelaxationrate: Evidence of load-dependent relaxation in the intact dog heart. Circ Res 1981;48:813-824
41. Brutsaert DL, Rademakers FE, Sys SV: Triple control of
relaxation: Implications for the cardiac patient. Circulation
1984;69:190-196
42. Hoffman JIE: Determinants and prediction of transmural
myocardial perfusion. Circulation 1978^58:601—611
43. Brutsaert DL, Housmans PR, Goethals MA: Dual control of
relaxation. Circ Res 1980;47:637-652
KEYWORDS • left ventricular diastolic compliance • coronary
perfusion • hypertensive crisis • pulmonary edema