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© 1995 American Heart Association, Inc.
Articles |
Systolic Flow Augmentation in Hearts Ejecting Into a Model of Stiff Aging Vasculature
Influence on Myocardial Perfusion-Demand Balance
Correspondence to David A. Kass, MD, Carnegie 538, Department of Cardiology, The Johns Hopkins Medical Institutions, 600 N Wolfe St, Baltimore, MD 21287.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Abstract Age-related arterial stiffening and widening of the pulse pressure elevates ventricular systolic wall stress while it lowers diastolic coronary perfusion pressure. These changes are thought to adversely alter the balance between myocardial work load and blood supply. To test this hypothesis, the native compliant thoracic aorta was surgically bypassed by a stiff tube in reflex-blocked anesthetized dogs. Ventricular outflow was directed into either native aorta or the bypass; the latter resulting in an increase in arterial pulse pressure from 37.8 to 107.5 mm Hg (P<.001), with minimal change in mean pressure and flow. Cardiac work load was assessed by pressure-volume area (PVA), which combines external and internal left ventricular work and is linearly related to myocardial oxygen consumption (M
O2), and by
MO2 itself. Regional phasic and mean
coronary flow were measured in the left anterior descending coronary
artery, and global flow was assessed by radiolabeled microspheres.
Myocardial supply-demand balance was assessed by comparing flow at
matched PVA or MO2, flow-PVA relations,
and endocardial-to-epicardial flow ratios. When blood flow was directed
into the stiff bypass tube, peak systolic pressure, wall stress, and
PVA all rose nearly 50%, yet diastolic perfusion pressure fell by 20
mm Hg (all P<.01). Rather than being compromised, however,
mean coronary flow rose by 34%, maintaining the same
endocardial-to-epicardial flow ratio (
1.1). Flow augmentation
persisted when data were compared at matched work load (PVA or
MO2) and mean arterial pressure, as well
as over a range of work loads (P<.001 from ANCOVA of
flow-PVA relations). The increased flow resulted from enhanced systolic
perfusion, which nearly equaled diastolic flow when ejection passed
into the stiff bypass. These data counter the notion that cardiac
coupling with a stiff arterial system (as with aging) necessarily
compromises myocardial flow versus metabolic demand. However, the data
highlight a greater role of systolic flow under such conditions and
also raise the novel suggestion that enhanced pulsatility of the
arterial pressure waveform may itself augment coronary perfusion.
Key Words: coronary flow • pressure-volume area • arterial compliance • systolic hypertension • aging
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human aging results in lowered arterial compliance, which is largely due to a progressive degeneration of the elastic components within the walls of major proximal conduit vessels.1 2 As a consequence, the arterial pulse pressure widens, systolic hypertension develops, and ventricular wall stress and metabolic demand are increased while mean diastolic pressures may be reduced.3 4 5 6 7 8 Since most myocardial flow normally occurs during diastole, these abnormalities are thought to limit cardiac function by adversely influencing the myocardial supply-demand balance.6 7 9 However, such adverse cardiac effects of enhanced pulsatile load remain speculative.
To investigate this issue, we developed an experimental model in which the native thoracic aorta (NA) is surgically bypassed by a stiff plastic conduit linking the proximal ascending aorta to the subdiaphragmatic abdominal aorta.10 Cardiac outflow can be directed into either the compliant NA or the stiff bypass "aorta" (bypass tube [BT]). With flow through the BT, total peripheral resistance is little changed, whereas arterial compliance is markedly reduced. As a consequence, arterial pulse pressure increases nearly threefold at the same mean pressure and flow, and the resulting arterial pressure-flow and ventricular pressure-volume waveforms are physiological and quite similar to those observed in elderly individuals.10 In the present study, this preparation was used to determine whether increased pulsatile load due to vascular stiffening adversely alters the relation between cardiac work load and perfusion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preparation
The thoracic aorta bypass preparation has been previously reported in detail.10 The protocol was reviewed and approved by the Animal Care and Use Committee of the Johns Hopkins University. Briefly, adult mongrel dogs (n=14) of either sex were anesthetized with pentobarbital (30 mg/kg IV) and ventilated on a volume respirator, along with enhanced inspired oxygen. Ventilation was guided by periodic checks of arterial blood gas levels, and adjustments were made accordingly to maintain a PO2 of
60
mm Hg. Both carotid and femoral arteries were cannulated by
fluid-filled catheters to allow arterial blood sampling and pressure
monitoring and to provide a route for cerebral perfusion after aortic
bypass. A central venous cannula was placed for injection of hypertonic
saline used for volume signal calibration (see below). Animals underwent a midline sternotomy. The pericardium was opened, and the heart was suspended in a pericardial cradle. A micromanometer catheter (SPC 350, Millar Instruments) was passed through the mid left ventricular (LV) free wall to measure intracavity pressure and secured by a pursestring suture. An ultrasonic flow probe (No. 2R, Transonics) was placed around the left anterior descending coronary artery (LAD) (after the first major diagonal branch) for phasic and mean blood flow recording. The proximal ascending aorta was cleaned of fat and adventitia and then partially occluded with a C clamp at or just proximal to the base of the right brachiocephalic artery. This isolated a portion of the aortic wall onto which a vascular graft (Dacron, 1- to 1.5-cm internal diameter) was sewn by end-to-side anastomosis. Femoral arterial pressure was monitored to ensure adequate distal aortic flow during suturing. Next, the abdominal cavity was entered through a midline incision, an 8- to 10-cm portion of the aorta extending from the iliac bifurcation to the inferior mesenteric artery was isolated, and all side branches were ligated. A T tube cannula was inserted into the aorta at this site, abdominal flow was then reestablished, and the cavity was closed. The extravascular port of the T tube was linked with the ascending aorta graft by a plastic tube (50 cm long; internal diameter, 1 cm; Tygon), thereby completing the bypass. This tube had a linear compliance of 3x10-3 mL/mm Hg over the physiological pressure range, 1% of the NA compliance.
Additional instrumentation was as follows: Ventricular volume data were
measured by a conductance catheter11 12 13 method (Sigma V,
CardioDynamics), with the catheter inserted through the apex and placed
so that its distal end was 1 cm above the aortic valve. All
individual pressure-volume segments displaying counterclockwise motion
(ie, intracavitary) were identified, and only these segments were
combined to assess total volume. The catheter was secured by an apical
pursestring suture. Proximal aortic pressure and flow were measured by
a second ultrasonic flow probe placed between the aortic root and the
proximal bypass graft anastomosis and by a micromanometer catheter
introduced through the left brachiocephalic artery and secured at the
same site. In four of the animals, an additional catheter was advanced
into the coronary sinus. Blood was continuously extracted and compared
with arterial blood to measure the arterial-venous oxygen difference
(
AVo2) (AVOX Systems).
Once the preparation was completed, autonomic reflexes were blocked by hexamethonium chloride (10 mg/kg IV). The adequacy of blockade was assessed by testing for the absence of a heart rate response to varying preload or arterial pressure. Supplemental hexamethonium (5 to 10 mg/kg) was given if reflex activation recurred. After blockade, pharmacological support of contractility and blood pressure was needed, and this was provided by low-dose continuous infusion of epinephrine (1 to 3 µg · kg · min-1). The dose was titrated to achieve physiological arterial pressure and flow with NA perfusion. Once established, this dose was not altered during the experiment.
Protocol
Cardiac output was directed into either the NA or BT by
positioning occlusion clamps. Fig 1
shows schematic
diagrams for the two flow patterns. Placement of clamps at the proximal
and distal BT anastomosis sites (Fig 1A, sites a and b) directed blood
only through the NA. When these clamps were repositioned on the NA just
beyond the bypass anastomosis and at the diaphragm (Fig 1B, sites c and
d), flow passed only through the BT. Under this condition, nearly the
entire intrathoracic aorta was excluded from the systemic arterial
circulation; however, all other organs were perfused. Data were
measured under each ejection condition after stable steady state
hemodynamics were established (at least 10 minutes). Signals were
digitized at 200 Hz, displayed, and recorded by use of custom-designed
software.
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In addition to these baseline data, measurements were made at varying
levels of total cardiac work load. Work load was either altered
transiently, by left atrial hemorrhage into a reservoir or by bi–vena
caval occlusion (n=12), or at steady state, also achieved by hemorrhage
(n=4). These steady state data were supplemented by results obtained
from animals used in a previous study10 (n=9). Data
recorded during these preload changes were used to assess coronary
blood flow (CBF) at matched levels of total ventricular work load and
myocardial oxygen consumption (MO2) for
both NA and BT conditions. They were also used to examine
CBF–myocardial demand relations.
Endocardial-to-epicardial (endo/epi) flow ratios and verification of the regional LAD flow data were obtained by flow analysis using radiolabeled microspheres. Approximately 2x106 15-µm labeled spheres (New England Nuclear) were suspended in 10% dextran plus Tween, vortex-mixed for 20 minutes, and injected into the left atrium. Simultaneous withdrawal of peripheral arterial blood enabled regional flow calibration by standard technique.14 At the study conclusion, animals were euthanatized, the heart was removed and weighed, and the LV was divided into four or five slices each with 10 to 16 epicardial and endocardial segment pairs. The tissue was counted, and flows were expressed as milliliters per minute per gram. Reported microsphere flow data are the average results from all segments.
Volume Signal Calibration
Calibration of the conductance catheter required both slope and
offset determination. The offset was estimated by the hypertonic saline
method.12 13 Data were analyzed by methods of Baan et
al14 and Lankford et al,12 and only
concordant runs were used. Three to five separate estimates were
averaged. The calibration slope was the ratio of stroke volume
determined by flow probe to that of the uncalibrated catheter signal.
This ratio was determined for each beat measured during transient or
steady state preload reductions, and the results were
averaged.10 Slope and offset calibration parameters were
then applied to the volume signal to yield absolute chamber volume.
Verification of Flow Analysis
Myocardial perfusion was primarily assessed by the mid-LAD
ultrasound flow signal. These flows were assumed to be in fixed
proportion to total myocardial flow, determined anatomically by the
ratio of mass perfused by the mid-LAD to total LV mass. These
assumptions were tested in four animals in which regional ultrasound
flow (in milliliters per minute) was directly compared with
microsphere-derived total LV flow. Data were measured under varying
conditions (NA versus BT, high versus low preload). Fig 2 shows typical results from one dog, with a high
correlation between the flow measurements. Group regression
analysis yielded a similar result with
R2=.98. The average ratio of regional
to total flow from these data was 23±4% (similar to a 22% value
reported previously15 ), with a coefficient of variation of
10%. This supports the assumptions underlying analysis of the
mid-LAD flows.
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Data Analysis
Arterial vascular properties were measured from aortic
pressure-flow data. Impedance spectra were determined by Fourier
analysis of baseline steady state data under the two ejection
conditions. Characteristic impedance was calculated as the average
modulus from 5 to 12 Hz, and total resistance was calculated as the
zero-frequency modulus. Peripheral resistance was calculated as the
difference between mean resistance and characteristic impedance.
Arterial compliance was estimated by the area method of Liu et
al.16 A limitation of this or any method that assumes a
simplified Windkessel model is that it implies no wave reflections.
Reflections were present in the bypass preparation, and
interpretations of compliance values must keep this limitation in mind.
Nonetheless, the results provide a reasonable indication of overall
compliance changes.17
Total ventricular work load was indexed by pressure-volume area (PVA)
and MO2. PVA is the sum of ventricular
external and internal work and linearly correlates with
MO2 per beat.18 The
PVA-MO2 relation is fairly insensitive
to changes in LV load,18 19 including reduced compliance
generated by the present aortic bypass preparation.10
Fig 3 displays an example of PVA determination and the
relation between PVA and myocardial flow. Ventricular pressure-volume
loops are shown at varying preloads, and these data define end-systolic
and end-diastolic boundaries (Fig 3A). End-systolic
relations were often nonlinear and therefore fit to quadratic
curves.20 The diastolic relation was fit by a
monoexponential. At each preload, PVA was equal to the sum of stroke
work and potential energy (PE), the latter equal to the area bounded by
systolic and diastolic pressure-volume relations between end-systolic
volume and Vo (the volume axis intercept of the
end-systolic pressure-volume relation) (Fig 3B). PE was determined by
analytic integration of the pressure-volume curve fits. From these
data, beats could be selected at the highest matched PVA for
comparison. In addition, by combining several such beats, relations
between PVA and CBF were obtained (Fig 3C). Fig 3 shows results from a
transient LV preload reduction, and similar data were also obtained by
using steady state preload change.
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In a subset of animals, ventricular work load was directly assessed by
MO2. In four animals, this was
determined by on-line AVo2 analysis combined
with mid-LAD flows. In an additional nine animals, total coronary sinus
blood flow and AVo2 were measured. Measurements
were also made over a range of steady state work loads.
Ventricular function assessment included assessment of midwall fiber
stress (
f) and strain (
f) estimated by
the method of Arts et al.21 Stress was calculated as
follows:
f=3Plv/ln(1+[Vw/Vlv]),
where Plv and Vlv are ventricular pressure and
volume, respectively, and Vw is chamber wall volume. Mean
ejection and peak systolic stresses were calculated. Strain was
estimated as follows:
f=1/3 · ln(1+3Vlv/Vw). Plots
of f-f loops during preload reduction
yielded a highly linear end-systolic f-f
relation, from which end-systolic myocardial stiffness (slope) was
derived. Since end-systolic pressure-volume relations were curvilinear
in the majority of animals, contractile function was more easily
assessed by the highly linear relation between stroke work and
end-diastolic volume,20 as well as by the
maximal derivative of pressure measured at the highest matched
end-diastolic volume obtained for both vascular loading
conditions. This last index assumed that dP/dtmax occurred
before the onset of ejection in both NA and BT modes. This was true in
all cases, with ejection starting an average of 12 to 16 milliseconds
after dP/dtmax.
Myocardial supply-demand balance was assessed three ways. The
first compared mean regional blood flow at the highest matched level of
PVA or MO2 for both NA and BT
conditions. The second compared relations between CBF and PVA,
determined from variable preload data as shown in Fig 3C
. A downward
and/or rightward shift of this relation was interpreted as a fall in
blood supply for any given demand level. Results were obtained under
both transient and steady state loading conditions. The third method
was based on the ratio of diastolic to systolic pressure-time integrals
(DPTI/SPTI), as described by Buckberg and coworkers.22 23
SPTI is the area under the systolic portion of the arterial pressure
wave, and DPTI is the difference between areas under diastolic portions
of arterial and ventricular pressure waveforms, respectively.
Data are provided as mean±SD. Baseline conditions and data at matched
PVA (or MO2) were compared by paired
t test. Statistical tests for an influence of ejection
pattern (NA versus BT) on PVA–myocardial flow relations were made by
ANCOVA for each heart. Combined data were analyzed by multivariate
regression; dummy variables were used to code for interanimal variation
about the mean.24 Statistical significance is reported at
P<.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vascular and Ventricular Responses
Arterial loading changes associated with directing flow through the BT were similar to those previously reported with this model.10 Peak aortic pressure increased and diastolic pressure decreased by +61.8 and -17.9 mm Hg, respectively, whereas mean aortic pressure and flow did not change significantly (Table 1
). Pulse pressure widened from 37.8±8.4 to 107.5±26.5
mm Hg (P<.001). Peripheral resistance and characteristic
impedance were not significantly altered, likely reflecting the fact
that both very proximal and distal components of the arterial tree were
unchanged by the bypass. In contrast, estimated total arterial
compliance was markedly reduced. The enhanced pulsatile load also
increased LV metabolic demand (PVA) and peak and mean systolic wall
stress (Table 1). Systolic contractile function rose modestly, as
assessed by the slope (stroke work–end-diastolic relation)
whereas dP/dtmax measured at the same
end-diastolic volume did not significantly change.
End-systolic myocardial stiffness rose from 32.8±14.7 to 49.1±14.9
g · cm-2 · 10-2 (P<.05).
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Fig 4 shows representative examples of aortic
pressure, flow, and corresponding pressure-volume loops for NA and BT
conditions. The principal features of NA ejection were a narrow
arterial pulse pressure, early rapid rise of systolic flow, and a
square-shaped pressure-volume loop. For the BT, the pulse pressure
widened markedly, peak flow diminished, and pressure-volume loop shape
became trapezoidal, reflecting late-systolic pressure rise. A late rise
in diastolic pressure due to reflected waves was often observed with
BT. This would only tend to increase arterial compliance estimated by
the area method,16 so actual compliance was likely even
lower.
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Coronary Perfusion
Despite the fall in mean diastolic aortic pressure, myocardial
perfusion was enhanced when ejection was directed through the BT.
Mid-LAD regional flow was 34.3±11.3 mL/min (corresponds to total LV
perfusion of 1.2 mL min-1 · g-1) when
ejection was directed into the NA. This rose to 45.9±15.6 mL/min when
ejection passed through the BT. This 36% rise in mean flow measured in
the LAD territory was virtually the same as the flow increase
determined for the whole heart (35±25%) by use of radiolabeled
microspheres.
To determine whether higher CBF simply reflected increased ventricular
demand, data were analyzed at similar PVA (Table 2) or
MO2 (Fig 5). To match
PVA, data at high preload for NA ejection were compared with results at
slightly reduced preload for BT ejection by using beats obtained during
transient load reduction. Even at matched PVA and at the same mean
arterial pressure, mean flow was 21% higher with BT. This occurred
despite a 25-mm Hg decline in mean aortic diastolic pressure.
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Indexing demand by PVA assumed that it adequately reflected
MO2 and that this correspondence was
similar for NA and BT conditions, as previously found.10
The results then predicted that AVo2 should
decline in order to have higher flow at the same metabolic demand.
These assumptions and the prediction were directly tested in 13
additional hearts by comparing steady state cardiac cycles for both NA
and BT conditions at similar levels of
MO2. The results displayed in Fig 5
support the PVA-matched data, showing a 15% rise in mean CBF with BT
ejection as well as a decline in AVo2 (-10%)
(both P<.05).
To further probe the nature of increased flow with BT ejection, phasic
CBF patterns were systematically studied. This revealed that the mean
flow increase was primarily due to higher flows during systole. Fig 6 displays phasic CBF waveforms for two examples
(including the animal shown in Fig 3). When ejection passed through the
NA, CBF was predominantly diastolic. In contrast, ejection into the
stiff BT led to a marked rise in systolic flow nearly equaling that
during diastole. By integrating flow during systolic ejection versus
nonejection (diastole), the percentage of systolic CBF was determined
(Table 2). This averaged 25.8±9.2% for NA and 45.8±13.0% for flow
via the BT (P<.01). One component of this enhanced flow
related to lengthening of the systolic ejection period (from 41% to
48% of cycle length, P<.001); however, peak flow rates
also rose markedly. Diastolic flow remained virtually unchanged despite
a 20-mm Hg fall in mean diastolic pressure.
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Enhanced flow at matched PVA was not restricted to the epicardium.
Table 3 provides endo/epi flow ratios measured in nine
hearts at similar mean arterial pressure. The ratios were minimally
different between NA and BT conditions. Previous studies have suggested
that DPTI/SPTI could serve as an index of the adequacy of endocardial
perfusion.22 23 The ratio is normally 1.2 to 1.5, and when
it falls below 0.6, the endo/epi flow ratio also declines to 
0.6,
consistent with subendocardial ischemia.22 Interestingly,
this earlier finding did not hold for the present data. Although
the DPTI/SPTI ratio was 1.22±0.3 for NA flow and fell to 0.55±0.24
for BT flow, this did not result in a reduced endo/epi ratio or to
contractile dysfunction suggestive of ischemia.
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Perfusion–Work Load Relations
To test whether the rise in CBF at a single matched PVA or
MO2 persisted over a range of work
loads, PVA-CBF (or MO2-CBF) relations
for NA and BT ejection were compared. For data obtained during
transient preload reduction (eg, see Fig 3C), ANCOVA revealed
significant differences between the relations in 10 of 12 animals
(Table 4), with the relations shifting upward with BT.
Fig 7A shows an example of these results. Since
transient preload reduction may not have provided fully adequate time
for CBF to adapt to the change in work load, data were also obtained
using steady state changes in preload from a different group of
animals.10 As shown by example in Fig 7B, the results were
similar. Both examples were supported by group analyses. Multivariate
regression indicated a significant elevation in the CBF-PVA relation
due to BT ejection. For the transient preload data, the
regression equation was as follows:
CBF=13.75+0.0094 · PVA+4.2 · GRP, where GRP, a
categorical variable, is 0 for NA and 1 for BT (r=.977,
P<.001). For the steady state data, the regression was as
follows: CBF=36.0+0.036 · PVA+9.2 · GRP (r=.976,
P<.001). The relative percent change in the offset due to
BT ejection was similar for the two data sets. Differences in their
slopes reflected use of regional LAD flow for transient data versus
global flow for steady state data.
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Direct comparisons between results measured during steady state and
transient preload changes were obtained in two additional animals, with
cardiac demand assessed by MO2.
MO2 for transient load reduction assumed
a constant AVo2 equal to the value measured at
initial rest volume. Both sets of data responded similarly to the
switch from NA to BT vasculatures (Fig 8) and were
consistent with the preceding group analysis.
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Potential Role of Enhanced Systolic Flow
The increased contribution of systolic CBF with BT ejection
suggested that total coronary perfusion under this condition might be
more sensitive to a given change in mean arterial pressure. To test
this, we also compared data at a 40% lower PVA (Table 5). At this load, mean coronary pressure was also
reduced similarly for NA and BT data, although this was achieved with a
disproportionate decline in systolic pressure for BT ejection.
Interestingly, CBF fell 56% more with BT than with NA ejection. One
component of this was a greater decline in diastolic flow, likely due
to diastolic pressures falling below the autoregulating range. However,
there was also a marked disparity in systolic flow reduction, which was
nearly 100% greater with BT ejection. Thus, BT ejection increased the
sensitivity of myocardial perfusion to changes in mean arterial
pressure.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vascular stiffening and systolic hypertension are important risk factors for increased morbidity and mortality from cardiovascular disease.2 6 25 26 Among the mechanisms for this association is thought to be an adverse coupling between the heart and arterial tree. Hearts ejecting into a low-compliance vascular system must generate a wide pulse pressure, simultaneously increasing systolic chamber wall stress while lowering diastolic coronary perfusion pressure. Since a dominance of diastolic coronary perfusion is assumed, this combination would be expected to compromise myocardial perfusion relative to demand. The present study tested this hypothesis and found, somewhat surprisingly, that coronary perfusion actually rose with greater pulsatile load despite the same mean pressure and total metabolic demand (measured by PVA or M
O2). This enhanced perfusion was due to
a near doubling of systolic flow and maintenance of diastolic
perfusion. Significantly, however, ejection into a stiff arterial load
resulted in a greater sensitivity of perfusion to changes in mean
arterial pressure. These results suggest that systolic pressures may
play a greater role in overall myocardial perfusion in elderly
individuals. They also provide novel evidence that pulsatile loading,
perhaps from the shape of the arterial pressure waveform itself, can
influence CBF.
Myocardial Flow-Demand Balance
In a prior study using a similar experimental
model,10 we reported that imposition of an acute increase
in pulsatile load neither adversely affected contractile function nor
energetic efficiency. This seemed surprising, particularly if
myocardial perfusion was compromised as a consequence of the disparity
between systolic load and diastolic perfusion pressure. The present
study provides insight into the mechanism for this preserved function,
showing that flow is not compromised but often enhanced even at a
similar work load and that the endo/epi flow ratio remains normal. Both
findings argue against an imbalance between myocardial supply and
demand. The lack of change in the endo/epi flow ratio is important for
several reasons. It indicates that the increment in overall myocardial
flow does not solely pertain to outer muscle layers. This makes it
unlikely that endocardial flow versus work load was compromised. It
also suggests that a substantial rise in systolic stress without
simultaneous critical reduction in diastolic pressure, as is often
found in elderly humans, is unlikely to compromise endocardial
perfusion.
Interestingly, this result was not predicted by the analysis of
DPTI/SPTI. Buckberg et al22 reported that canine hearts
exposed to supra-aortic banding with rapid pacing or to an
arteriovenous fistula had a decline in the DPTI/SPTI ratio from 1.5 to
0.5 along with a fall in the endo/epi flow ratio from 1.0 to 0.4.
Although the marked reduction of arterial compliance in the present
study produced a similar decline in DPTI/SPTI, there was no evidence of
endocardial hypoperfusion. Differences in the interventions may explain
this discrepancy. In the earlier study, supra-aortic constriction
markedly increased left atrial pressure (near 40 mm Hg), suggesting
that altered chamber diastolic loading may have compromised endocardial
perfusion. In contrast, end-diastolic pressure was low and
minimally altered by the switch between NA and BT ejection modes (Table 1). For the arteriovenous fistula data, the aortic diastolic pressure
was very low (40 mm Hg), and this likely contributed to reduced
endocardial perfusion.
Our data are compatible with a recent chronic study reported by Watanabe et al.27 In this investigation, aortic compliance was reduced by bandaging the descending thoracic aorta and left brachiocephalic trunk with nylon tape. After 4 weeks, arterial systolic and diastolic pressure changes were modestly altered, but compliance fell from 0.5 to 0.24 mL/mm Hg, and mean flow measured in the left circumflex artery rose by 42%. However, these data were not obtained at matched work loads; therefore, some enhanced flow may have been due to greater metabolic demand. Our data clarify this observation, indicating that a component of the enhanced flow may not reflect higher work load.
Pulsatile Pressure and Coronary Flow
Myocardial flow is influenced by both cardiac energy requirements
and coronary perfusion pressure. As reviewed by Feigl et
al,28 these interdependencies can be represented on a
three-dimensional surface, with a positive relation between CBF and
MO2 that itself shifts upward with
increments in mean coronary perfusion pressure. To our knowledge, the
present data are the first to suggest a fourth dimension, that of
the arterial pulse pressure itself. At the same mean aortic perfusion
pressure and PVA or MO2, a wider pulse
pressure appears capable of augmenting CBF. The relative role of
mechanical or biochemical mechanisms to augmented flow remains unknown
and is beyond the scope of the present investigation. However, it
is noteworthy that studies have reported that nitric oxide plays an
important role in flow-mediated endothelial relaxation in epicardial
vessels29 30 and that pulsatile flow itself can further
enhance this effect.31 It is conceivable that enhanced
epicardial release of such substances influences downstream resistance
vessels in an autocrine fashion, contributing to enhanced myocardial
perfusion.
Increased pulsatile load also raised systolic wall stress, and this is traditionally anticipated to increase the systolic myocardial flow impediment particularly in the endocardium. However, recent studies have suggested that ventricular stiffness rather than stress may better define how myocardial properties dictate the balance between systolic and diastolic flow.32 33 34 These investigators propose that intramyocardial blood volume is pressurized during systole as a consequence of increasing myocardial stiffness and that this pressure counters forward coronary pressure to determine the extent of antegrade perfusion. A greater systolic stiffness would therefore impede flow more.
In the present experiments, both systolic stress and end-systolic stiffness increased when ejection was directed into the stiff BT. By either model, one would predict a greater systolic flow impediment, yet systolic flow nearly doubled. Thus, the systolic pressure augmentation was sufficient to overcome any increase in flow impediment. This raises a cautionary note in trying to predict how changes in arterial pulse pressure will influence the balance of the forces that generate forward and backward flow. What our results indicate is that even for exaggerated pulsatile loading, systolic perfusion pressure rise exceeds that of ventricular stress or stiffness, such that antegrade systolic perfusion is actually enhanced and not impeded.
The present study may have implications for management of arterial blood pressure in the elderly. The shift to a less compliant aorta resulted in a greater dependence on systolic flow, and with similar reductions of PVA and mean and diastolic coronary pressures, myocardial flow declined disproportionately. When blood pressure is clinically regulated, it is usually the mean and diastolic pressures that receive the greatest attention. Our data suggest that systolic pressure should also be carefully considered, because excessive lowering of systolic pressure may result in an acute adverse limitation of myocardial perfusion. This could be particularly important for hearts with reduced coronary flow reserve, which is also found with aging35 or with coronary stenoses. One important caveat is that the present data were measured in normal (not elderly) ventricles and with an acute rather than chronic imposition of a high pulsatile load. Chronic adaptations and changes in the aging myocardium and vasculature could alter these responses, and further studies will be needed.
Methodological Issues
The present study was conducted by using a preparation
in which ventricular work load and coronary perfusion were directly
coupled. This was necessary to determine whether enhanced pulsatile
loading of the ventricle would indeed compromise coronary perfusion
relative to energy demand. However, this meant that we could not test
for independent influence of pulsatile coronary perfusion on coronary
flow and that we could not test whether pulsatile pressures alter
myocardial autoregulation. These are questions for ongoing
investigations in which pulsatile coronary perfusion can be
independently controlled.
Because of the complexity of the on-line measurements and the
integrated physiology, it was nearly im- possible to match cardiac work
load (either PVA or MO2) for both NA and
BT conditions at the time of study. Rather, cardiac cycles were
obtained over a range of loads and from beats selected among these to
obtain the highest similar work load. Preload change was used to vary
demand, although this simultaneously lowered mean arterial perfusion
pressure. Significantly, and as shown in Tables 2 and 4, mean coronary
pressures were similar for the two conditions at matched work load and
remained well above a potential ischemic range. The similarity of
results obtained by transient compared with steady state preload
changes further supports the dominance of metabolic demand over
perfusion pressure in mediating the flow response. Transient loading
changes might be expected to be more sensitive to changes in arterial
pressure, yet results were qualitatively and quantitatively similar to
those measured with steady state preload alteration. Prior studies have
shown that CBF can respond quickly to changes in work
load.36 If anything, flow may have lagged slightly behind
changes in demand but would influence both NA and BT data.
Conclusion
We report that marked reductions in arterial compliance
resulting in systolic hypertension, reduced diastolic pressures, and
increased ventricular wall stress do not necessarily limit myocardial
perfusion relative to total energy demand. On the contrary, in normal
hearts with normal coronary vessels, myocardial flow can rise above
that required by metabolic demand, largely because of the augmented
flow during systole. This suggests that the pressure waveform itself
may have an influence on myocardial flow. Finally, although arterial
stiffening did not compromise myocardial supply-demand balance at rest,
there was a greater sensitivity of flow to changes in mean arterial
pressure. This may have important implications to the management of
arterial pressure in the elderly.
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Acknowledgments |
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This study was supported by Public Health Service grant HL-44545 (Dr Kass) and an American Heart Association, Maryland Affiliate, Inc, Fellowship Award (Dr Recchia). Dr Kass is an Established Investigator of the American Heart Association. Dr Saeki is a visiting fellow from Osaka (Japan) Medical College. The authors gratefully thank Richard Tunin for his excellent technical assistance in performing these studies.
Received February 22, 1994; accepted September 16, 1994.
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