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(Circulation. 1996;93:1533-1541.)
© 1996 American Heart Association, Inc.

Articles

Adverse Influence of Systemic Vascular Stiffening on Cardiac Dysfunction and Adaptation to Acute Coronary Occlusion

David A. Kass, MD; Akio Saeki, MD; Richard S. Tunin, MS; Fabio A. Recchia, MD

From the Division of Cardiology, Department of Internal Medicine, and the Department of Biomedical Engineering, the Johns Hopkins Medical Institutions, Baltimore, Md.

Correspondence to David A. Kass, MD, Halsted 500, Division of Cardiology, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287.

	Abstract

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Background Age is an independent risk factor for increased mortality from ischemic heart disease. Arterial stiffening with widening of the pulse pressure may contribute to this risk by exacerbating cardiac dysfunction after total coronary artery occlusion.

Methods and Results To test the above hypothesis, 14 open-chest dogs underwent surgery in which the intrathoracic aorta was bypassed with a stiff plastic tube. Directing ventricular outflow through the bypass widened the arterial pulse pressure from 41 to 115 mm Hg at similar mean pressure and flow. Hearts ejecting into the native aorta (NA) exhibited only modest dysfunction after 2 minutes of mid–left anterior descending coronary artery occlusion. However, the same occlusion applied during ejection into the bypass tube (BT) induced far more severe cardiodepression (ie, systolic pressure fell by -41±10 mm Hg for BT versus -15±3 mm Hg for NA, and end-systolic volume rose by 15±3 versus 6±2 mL), with a threefold greater decline in ejection fraction. This disparity was not due to higher baseline work loads because total pressure-volume area was similar in both cases. Furthermore, marked increases in basal work load and wall stress induced by angiotensin II infusion (in four additional studies) did not reproduce this behavior. Although peak systolic chamber stress was greater with the BT, this did not increase systolic dyskinesis as measured in the central ischemic zone. However, the total mass of myocardium that was rendered severely ischemic (ie, flow reduced by 80%) was twice as large with BT ejection, likely expanding the region of dyskinesis. This disparity may relate to altered phasic coronary flow during BT ejection, which displays marked enhancement of systolic flow and renders the heart more vulnerable to diminished mean and systolic perfusion pressures.

Conclusions Cardiac ejection into a stiff systemic vasculature augments cardiac dysfunction and ischemia due to coronary occlusion by tightening the link between cardiac systolic performance and myocardial perfusion. This may contribute to the higher mortality risk from ischemic heart disease due to age.

Key Words: aging • blood pressure • ischemia • regional blood flow • risk factor

	Introduction

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Mortality from ischemic heart disease rises progressively with age, with 80% of deaths occurring in patients older than 65.^{1 2} Age appears to be a major independent risk factor for in-hospital and postdischarge mortality in patients who have had their first myocardial infarction.^{3 4 5} These deaths are often associated with more severe clinical heart failure symptoms, worse ventricular function, and a higher incidence of cardiac rupture.³ Autopsy data have failed to reveal age-dependent disparities in the extent of coronary artery disease^{3 6 7} ; thus, attention has shifted to other abnormalities of cardiovascular function.

One prominent change that occurs with aging is vascular stiffening due to deterioration of the elastic components within the arterial walls.^{8 9 10} Vascular stiffening produces systolic hypertension and pulse pressure widening, increasing both left ventricular systolic stress and metabolic demands while compromising diastolic pressures. It is often suggested that this interaction leads to a cardiac supply/demand imbalance. However, using an experimental bypass model of aortic stiffening, we recently reported that basal myocardial flow can actually be enhanced under these conditions, even at matched work loads, primarily due to augmentation of coronary flow during systole.¹¹ Furthermore, neither contractile function nor chamber efficiency (the latter defined by the relation between oxygen consumption and PVA¹² ) was acutely compromised.¹³ This compensation was achieved at a cost because hearts coupled to the stiff bypass utilized more oxygen to generate a given cardiac output¹³ and displayed a higher sensitivity of myocardial flow to altered mean and systolic arterial pressures.¹¹ This more tightly coupled the systolic pump performance of the heart with its own perfusion,¹² which could exacerbate ventricular dysfunction when performance is limited by coronary occlusion.

The present study was designed to test the hypothesis that cardiac ejection into a stiff vasculature augments ventricular dysfunction and adversely influences cardiac adaptations to an acute coronary occlusion. Several mechanisms for such influences were explored, including the role of increased baseline systolic stress; systolic dyskinesis within the central ischemic zone; the total mass of critically hypoperfused myocardium and, by extension, the overall extent of regional dysfunction; and the baseline phasic coronary flow pattern.

	Methods

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Preparation
The experimental model of arterial stiffening by means of thoracic aorta bypass has been reported in detail^{11 13} and is shown in Fig 1. The protocol was performed in accordance with the Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Council (Department of Health and Human Services publication No. NIH 85-21, revised 1985). The protocol was approved by the Animal Care and Use Committee of the Johns Hopkins University.

View larger version (29K): [in this window] [in a new window]   Figure 1. Surgical bypass preparation. Stiff plastic tubing is surgically interposed between the ascending thoracic aorta and the abdominal aorta (just above the iliac bifurcation). Clamping the NA just beyond the proximal anastomosis and at the diaphragm excluded the dominant source of vascular compliance (thoracic aorta) and resulted in enhanced pulsatile loading. Placement of the clamps on the proximal and distal bypass directed flow through the NA. Aortic pressure and flow were measured by micromanometer and ultrasound sensors, respectively. A volume catheter was advanced through the apex to measure left heart volume, and a micromanometer was placed through the free wall to measure chamber pressure. A second flow probe was placed around the mid-LAD to measure coronary flow. Sonomicrometer crystals were inserted into the anterior wall to measure regional shortening. See text for additional details.

Briefly, adult mongrel dogs (14) of either sex were anesthetized with pentobarbital (30 mg/kg IV bolus, followed by infusion at a rate of 3 mg/kg per hour) and ventilated with a volume respirator with enhanced inspired oxygen. Animals underwent a midline sternotomy, and the heart was suspended in a pericardial cradle. A portion of the mid-LAD (after the first major diagonal branch) was isolated and instrumented with an ultrasound flow probe (No. 2F, Transonics), and a ligature tie was placed just distal to the probe. The proximal ascending aorta was cleansed 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 allowed isolation of a portion of the aortic wall, onto which a vascular graft (synthetic polyester textile fiber [Dacron], 1 to 1.5 cm ID) was sewn with 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 ligated. A T-tube cannula was inserted into the aorta at this site, abdominal flow was reestablished, and the cavity was closed. The extravascular port of the T tube was linked with the ascending aorta graft by a 50-cm-long 1-cm ID plastic tube (Tygon) to complete the bypass. This tube had a linear compliance of 3x10^-3 mL/mm Hg over the physiological pressure range, which is less than 1% of NA compliance.

Additional instrumentation was as follows. Ventricular pressure-volume data were determined with use of a micromanometer (model SPC-320, Millar) and conductance catheter¹⁴ (Sigma V, CardioDynamics). The latter was inserted through the LV apex and advanced so that its distal end was 1 cm above the aortic valve. Individual pressure-volume segments displaying counterclockwise motion (ie, intracavitary) were combined to measure total volume. Proximal aortic pressure and flow were measured with a second ultrasonic flow probe placed between the aortic root and the proximal bypass graft anastomosis, and a micromanometer catheter was introduced through the left brachiocephalic artery. A left atrial catheter was placed for administration of radiolabeled microspheres. Last, a pair of ultrasound crystals was inserted into the midanterior wall (LAD territory) to measure regional segment length.

On completion of the surgery, autonomic reflexes were blocked with hexamethonium chloride (10 mg/kg IV) to avoid altered vagal or sympathetic tone during BT ejection. The efficacy of blockade was assessed by testing for an absence of heart rate response to varying preload or arterial pressure. Supplemental hexamethonium (5 to 10 mg/kg) was provided if reflex activation recurred. After blockade, pharmacological support of contractility and blood pressure was required and provided by low-dose epinephrine (1 to 3 µg·kg^-1·min^-1) infusion. The dose was titrated to achieve physiological arterial pressures, cardiac output, and coronary flows during NA perfusion. Once established, this epinephrine dose was not altered throughout the experiment.

Protocol
Cardiac output was directed into either NA or stiff BT (random order) by placement of vascular clamps. Clamping proximal and distal BT anastomosis sites directed blood through only the NA. Placement of clamps on the native thoracic aorta just distal to the Dacron anastomosis and at the diaphragm directed flow into the bypass. Under this condition, only the intrathoracic aorta was excluded from the systemic arterial circulation, whereas all other organs were perfused. Data were measured with one of the two ejection conditions after establishment of stable hemodynamics. Radiolabeled microspheres (New England Nuclear) were injected to measure baseline flow and flow distribution. In addition to steady state data, recordings were made during transient reduction of ventricular preload by bicaval occlusion to determine LV pressure-volume relations.¹⁴

Once baseline measurements were made, the mid-LAD was occluded for 2 minutes. Repeat hemodynamic recordings and microsphere injections were made at this time. The coronary artery was then reperfused, and the heart was allowed at least 1 hour to recover. The alternative ejection mode was then established, and the protocol was repeated. Baseline and ischemia data for both NA and BT ejection modes were obtained in 10 of the 14 studies. In the remaining hearts, only one ejection mode could be studied, yielding a total of 12 observations under each condition. On conclusion of the study, animals were euthanized, and the heart was removed and weighed. The LV was divided into four or five slices each with 10 to 16 epicardial and endocardial segment pairs. Tissue radioactivity was counted, and flows were determined and expressed as milliliters per gram per minute.

Angiotensin II Infusion Studies
To more directly test the influence of baseline work load and systolic stress on the acute response to coronary occlusion, four additional animals received angiotensin II (5 to 40 ng·kg^-1·min^-1 IV) to match the systolic pressure increase observed during BT ejection. These experiments were performed with the NA ejection mode only, both with and without angiotensin II infusion (randomized order), and animals were then exposed to 2-minute coronary occlusion as described above.

Data Analysis
The conductance catheter signal was calibrated as previously reported.¹¹ The linear offset constant was estimated with the use of the rapid hypertonic saline injection technique and analysis of data according to minimum-vs-maximum and isochronal signal methods.¹⁵ Injections for which both analysis methods yielded similar estimates (within 15%) were accepted,¹⁵ and the results of three to five estimates were then averaged. Previous studies have shown that the parallel conductance (V_p) is not significantly altered during acute regional ischemia.¹⁶ We also tested whether this offset was changed by ejection into the BT versus NA loads. Results from six animals revealed that the two estimates were nearly identical: V_p(BT)=0.96xV_p(NA)+1.7 (SEE=3.7 mL, r=.97). V_p(NA) was used for the overall study as it was measured in every animal. The calibration slope was set equal to the ratio of SV determined by flow probe to that derived from the uncalibrated catheter signal.¹¹

Aortic input impedance changes induced by the bypass model have been previously characterized in detail.^{11 13} These data have shown that the bypass model markedly lowers net vascular compliance by 60% to 80% (estimated according to the method of Liu et al¹⁷ ) at the same or near-identical mean arterial pressure and peripheral vascular resistance. The model also enhances systolic wave reflections but has minimal influence on characteristic impedance.

Aortic pressures and flows, LV end-systolic and end-diastolic pressures and volumes, SV, SW, and dP/dt_max were derived from steady state data that were signal-averaged with 5 to 10 sequential beats with ventilation temporarily suspended. Total LV work load was indexed by the PVA.^{12 18} We have previously shown that the linear correlation between PVA and MO₂ per beat is unchanged between NA and BT modes.¹³

Ventricular contractile function was assessed with the use of the end-systolic pressure-volume relation. Maximal chamber systolic wall stress (_max) was estimated according to the method of Arts et al,¹⁹ in which _max=max{3P_lv/ln(1+[V_w/V_lv])}, where P_lv and V_lv are ventricular pressure and volume, respectively, and V_w is chamber wall volume (estimated from LV mass). Regional function in the ischemic zone was expressed by end-diastolic (EDL) and end-systolic (ESL) segment lengths and fractional shortening ([EDL-ESL]/EDLx100).

Statistical Analysis
All data are presented as mean±SEM. Differences between baseline and coronary occlusion responses for NA and BT ejection modes were compared with the use of a two-sided unpaired Student's t test. This was used because data for both NA and BT were not obtained in every animal. Changes induced during coronary occlusion were related to the preceding baseline and compared with paired t tests. Differences between NA and BT ischemia responses were analyzed by two-way ANOVA. Microsphere flow distribution data were obtained in seven hearts and were compared with Wilcoxon nonparametric test. Significance is reported when P<.05.

	Results

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Vascular and Ventricular Responses to Flow Into Aortic Bypass
Table 1 provides mean arterial and ventricular hemodynamic parameters measured under compliant (NA) and stiff aortic bypass (BT) flow conditions. Peak aortic pressure increased by 46±15.4 mm Hg and diastolic pressure decreased by -28±15.6 mm Hg (both P<.001), widening the arterial pulse pressure nearly threefold. Mean aortic pressure and flow and peripheral resistance were not significantly altered, whereas total estimated arterial compliance declined substantially from 0.6±0.24 to 0.11±0.04 mL/mm Hg (P<.001).

View this table: [in this window] [in a new window]   Table 1. Baseline Hemodynamics for Native and Bypass Aorta

Fig 2 shows examples of aortic pressure and flow and corresponding pressure-volume loops for NA and BT conditions. NA ejection generated a narrow arterial pulse pressure, early rapid increase in systolic flow, and a square-shaped pressure-volume loop. For BT ejection, the pulse pressure widened markedly, peak flow diminished, and the pressure-volume loop displayed a late systolic peak. Baseline work load indexed by PVA was not significantly changed. The acute transition from NA to BT ejection has been previously shown to increase PVA.^{11 13} However, in the present study, these data were separated by an ischemic episode, at least 1 hour recovery, and, often, volume adjustments. The net effect was a minimal difference in baseline PVA. SW, ejection fraction, dP/dt_max, and segment length and percent shortening were also similar between ejection modes.

View larger version (16K): [in this window] [in a new window]   Figure 2. Examples of aortic pressure, aortic flow, and LV pressure-volume (PV) loops for native (solid lines) and stiff bypass (dashed lines) aorta conditions. Ejection into the bypass widened the arterial pulse pressure at the same mean pressure, and lowered peak aortic flow. PV loops changed from a square to trapezoidal shape, with a late systolic peak in the pressure waveform.

Basal coronary flow in the LAD territory was 58.8±10.1 mL/min during NA ejection (corresponding to 1.6±0.7 mL·g^-1·min^-1 for the myocardium) and 61.1±9.7 mL/min during BT ejection (P=NS). These ultrasound flow data have been shown to correlate with simultaneously measured flows by radiolabeled microspheres with both ejection modes.¹¹ Endocardial-to-epicardial flow ratios were also similar at baseline for the two conditions (1.13±0.05 for NA, 1.17±0.05 for BT, P=NS).

Response to Regional Ischemia
Fig 3 displays pressure-volume loops at baseline and during the initial 30 seconds of acute coronary occlusion for a sample experiment. Both NA and BT data were obtained in the same animal. The loops seen in Fig 3 demonstrate the major findings of this study. Under both ejection modes, acute coronary occlusion resulted in a rightward shift of the pressure-volume loops with higher ESVs. However, this change was far more pronounced when hearts ejected into the stiff bypass. There was a similar disparity in the extent of cardiac diastolic dilation. Although cardiac output was maintained under both conditions, systolic pressure declined more with BT ejection.

View larger version (27K): [in this window] [in a new window]   Figure 3. Pressure-volume response to acute coronary occlusion for NA (left) and stiff bypass aorta (right) ejection modes. With cardiac ejection into the normally compliant aorta, acute ischemia resulted in a rightward shift of the loops to higher diastolic and systolic volumes and in a slight reduction in systolic pressures. When the identical coronary occlusion was performed as hearts ejected into the stiff vascular model, there was greater cardiac dilation, with a more rightward shift of the ESV and a larger decline in systolic pressure.

The group data (Table 2) support these observations. End-diastolic pressure, EDV, and ESV all increased during regional ischemia, but this change was more than twofold greater when hearts ejected into the stiff bypass. As a result, ejection fraction decreased threefold more during BT ejection (P<.05). Furthermore, despite greater cardiac dilation, peak systolic pressures declined nearly threefold with BT compared with NA ejection.

View this table: [in this window] [in a new window]   Table 2. Change From Baseline After 2 Minutes LAD Occlusion

Contractile function indexed by dP/dt_max declined during coronary occlusion with both ejection modes. Less preload-dependent analysis with end-systolic pressure-volume relations, however, revealed a greater decline in end-systolic elastance with BT ejection. The positive shift in the volume axis intercept of end-systolic pressure-volume relations during ischemia also tended to be greater (P=.06). In three BT experiments, 2 minutes of total coronary occlusion was sufficient to produce progressive and profound cardiodepression, yielding 60% declines in both cardiac output and mean arterial pressure. Such severe functional depression was not observed when ejection was directed into the compliant NA.

Role of Systolic Hypertension or Increased Baseline Work Load
To probe the potential contribution of increased baseline systolic pressures and stresses on the disparate ischemia responses, four additional studies were performed with and without pressure augmentation by angiotensin II infusion. Angiotensin II was titrated to match the peak systolic pressure elevation observed with BT ejection (163±14.4 mm Hg with angiotensin II versus 168±16.6 mm Hg with BT). With angiotensin II, arterial diastolic pressure also increased, maintaining the same pulse pressure. Cardiac output and heart rate were not altered; however, resting diastolic volumes, peak chamber systolic stress, and PVA were all markedly increased by angiotensin II infusion (Table 3).

View this table: [in this window] [in a new window]   Table 3. Effect of Angiotensin II on Baseline Hemodynamics

Fig 4 displays impedance frequency spectra for NA versus BT conditions (Fig 4A) and NA with and without angiotensin II infusion (Fig 4B) and demonstrates the principal differences in net arterial load imposed by each intervention. With BT ejection, the impedance modulus at zero frequency (ie, mean resistance) remained similar to that with NA but then declined more slowly, reaching its first minimum at a much higher frequency. An analogous rightward shift was observed in the first negative-to-positive zero-phase crossover (Fig 4A, bottom). These changes are consistent with reduced compliance and are similar to those previously reported with this model.¹³ In contrast, angiotensin II primarily influenced the mean resistance (zero-frequency term) and had minimal influence on the moduli of higher frequency terms. The slight rightward shift of the phase data was consistent with an increase in pulse wave velocity due to the higher mean arterial pressure. Thus, mean rather than pulsatile loading was influenced much more by angiotensin II.

View larger version (21K): [in this window] [in a new window]   Figure 4. Examples of aortic input impedance spectra from NA and BT (left) versus NA (-A II) and NA (+A II) conditions (right). Top, Impedance modulus; bottom, phase. BT ejection had a major influence on the decline in the impedance modulus that was more gradual and reached the first minimum at a substantially higher frequency. The corresponding phase plot shows an analogous rightward shift of the first zero-phase crossover point. This is consistent with a reduction in compliance. In contrast, angiotensin II had its dominant effect on the zero-frequency term (ie, mean resistance), influencing the pulsatile components of the impedance load much less.

Despite a substantial increase in resting cardiac work load due to angiotensin II, the response to coronary occlusion was very similar to that measured in NA controls. Systolic pressure declined by -17.8±4.7 mm Hg without angiotensin II versus -19.8±1.9 mm Hg with angiotensin II (P=NS), and the increases in end-diastolic pressure (2.9±1.6 mm Hg without and 4.0±1.7 mm Hg with angiotensin II) and EDV (9.4±1.8 mL without and 11.8±4.3 mL with angiotensin II) were also quite similar. Thus, increasing baseline work load with angiotensin II infusion did not duplicate the disparity between ischemia responses observed for NA and BT ejection modes. This highlights the pulsatile load as a key contributor to the disparity between NA and BT ischemia data.

Systolic Dyskinesis Within the Central Ischemic Zone
Another potential mechanism for greater dysfunction after coronary occlusion during BT ejection was that critically hypoperfused myocardium became stretched more during systole (ie, enhanced dyskinesis) due to greater systolic stresses. Fig 5A displays pressure-segment length loops measured in the central ischemic zone shown at varying preload volumes at baseline and during ischemia for NA and BT ejection. These loops were directed counterclockwise under control conditions and became clockwise (systolic bulging) after occlusion. Despite higher systolic loads, the rightward shift of these data during ischemia and the magnitude of paradoxic bulging were similar.

View larger version (29K): [in this window] [in a new window]   Figure 5. A, Regional pressure-length loops and relations before (solid lines) and during (dashed lines) coronary occlusion for native and stiff bypass ejection modes. In both circumstances, the loops were directed clockwise during ischemia (ie, systolic bulging). Despite much higher systolic pressures developed with the bypass ejection, the extent of bulging was similar. During ischemia, the right sets of loops became nearly vertical above a systolic pressure of 50 mm Hg, suggesting that the myocardium could not be further stretched. B, Summary data are shown for end-diastolic and systolic lengths (EDL and ESL) and percent fractional shortening (%FS). *P<.05 vs baseline condition, #P<.05 vs NA.

Mean results are provided in Fig 5B. End-diastolic and end-systolic lengths both increased during ischemia, with slightly greater diastolic dimensions observed with BT ejection, consistent with the EDV disparity (compare with Table 2). However, negative fractional shortening was similar for the two conditions (-20.8±2.5% for NA and -19.7±3.9% for BT).

Extent of Critical Hypoperfusion
Results for ischemic zone size based on microsphere flow data are presented in Table 4. The percent mass of myocardium with flow reduced to less than 50%, 30%, 20%, or 10% of baseline was determined; and at each threshold level, there was approximately twice as much myocardium with compromised flow during BT as during NA ejection. Importantly, this disparity held for territories with very critical flow reductions (ie, <10% or 20% residual flow). Prior studies have shown that systolic bulging is observed when flow is reduced to such low levels.^{20 21} Thus, although the absolute magnitude of systolic dyskinesis in the central ischemic zone was not increased with BT ejection, it was very likely that systolic bulging became more widespread. Ischemic bed size was not increased with the angiotensin II infusion studies (Table 4), indicating that greater baseline systolic stresses alone were insufficient to produce this behavior.

View this table: [in this window] [in a new window]   Table 4. Influence of Bypass Ejection or Angiotensin II Infusion on the Amount of Hypoperfused Myocardial Tissue

Phasic Coronary Perfusion
Phasic coronary flow patterns were very different between NA and BT ejection modes, and this may have contributed to the expanded ischemic bed size observed with BT. Specifically, nearly half of antegrade epicardial flow occurred during systolic ejection with BT, as opposed to 25% when ejection was directed into the NA (Fig 6). Angiotensin II infusion, which elevated systolic pressures without widening the pulse pressure, did not reproduce this flow pattern. We have previously shown that the altered coronary flow pattern observed with BT ejection is associated with an enhanced sensitivity of coronary perfusion to mean and systolic pressures.¹¹ Thus, for the same decline in mean arterial pressure and work load, coronary flow is disproportionately reduced with BT compared with NA ejection. In the present study, mean and systolic pressures declined more with BT than with NA ejection (Table 2), which would predict even greater flow reduction and an expanded ischemic zone. This prediction is consistent with the flow results provided in Table 4.

View larger version (25K): [in this window] [in a new window]   Figure 6. A, Phasic epicardial coronary flow waveforms for three experimental conditions. Condition abbreviations are as in Fig 4. In each flow curve, the onset and end of the systolic ejection period (OS and ES, respectively) are denoted. With BT ejection, there was a marked rise in flow measured during systole, whereas with NA (with and without angiotensin II infusion), flow was predominantly diastolic. B, Summary data showing the percentage of flow measured during the systolic ejection period under the four experimental conditions.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study, we compared the ventricular response to acute coronary artery occlusion under two systemic vascular loading conditions. When hearts ejected into the normal compliant systemic vasculature, occlusion of the mid-LAD was well tolerated, with only modest changes in chamber volumes, diastolic and systolic pressures, and ejection fraction. However, when hearts were subjected to the same occlusion while ejecting into the stiff aortic bypass, acute cardiodepression was greatly exacerbated and adaptive responses were compromised. Ventricles developed nearly three times the magnitude of systolic and diastolic chamber dilation, had a far greater decline in systolic pressure, and had more widespread ischemia. This disparity was not mirrored by first increasing baseline systolic stresses and pressures with a systemic vasoconstrictor. Rather, the data pointed to the pulsatile nature of the vascular load and the importance of changes it induced in the coronary flow pattern that more tightly linked cardiac performance with myocardial perfusion.

Comparison With Prior Studies
This is the first direct demonstration of an adverse influence of cardiac ejection into a stiff arterial system on acute LV decompensation with acute coronary occlusion. To the best of our knowledge, only one prior study has evaluated somewhat analogous issues, with the use of a pacing-demand ischemia model.²² Watanabe et al²² chronically stiffened the descending aorta with bandages and then measured myocardial flow distribution and regional function during rapid pacing superimposed on a subcritical coronary stenosis. Bandaging yielded more modest changes in pulsatile load (systolic/diastolic pressures of 102/72 mm Hg for control and 112/63 mm Hg for bandaged) than those generated in the present study with BT ejection. Despite this, the investigators reported lower endocardial flows at baseline that declined further during demand ischemia in the bandaged animals. However, there was minimal impact on global LV function. Furthermore, ventricular work load was not assessed or controlled in this study.

We extended these findings and explored several potential mechanisms in more detail. By bypassing the ascending as well as descending thoracic aorta, we produced much greater effective arterial stiffening and enhancement of the pulsatile load at similar mean pressure and flow. This model is perhaps a more extreme example of vascular stiffening, but the data are consistent with pressure waveforms from elderly patients, particularly during moderate exercise when pulse pressure is often enhanced above baseline.^{23 24}

Mechanisms for Adverse Effect of Vascular Stiffening
Several mechanisms were explored for the adverse influence of vascular stiffening on the cardiac functional response to coronary occlusion. One potential mechanism was that baseline cardiac work load and systolic stresses were increased by ejection into the stiff vasculature, limiting the adaptive responses to ischemia. However, basal metabolic demand indexed by PVA was similar for the two sets of occlusions. PVA linearly correlates with total MO₂,^{12 18} and this dependence has been found to be unchanged between NA and BT conditions.¹³ Furthermore, when systolic pressures, PVA, and stresses were all increased by angiotensin II infusion, the response to coronary occlusion was similar to that of control. This indicated that the pulsatile loading from BT rather than baseline metabolic demand per se was a key factor for exacerbating cardiac dysfunction during ischemia.

A second mechanism was that the central ischemic region that became dyskinetic during NA ejection bulged even more during systole with BT ejection because of higher developed systolic pressures and greater stresses. However, this was not observed. Furthermore, it is unlikely that greater stresses alone exacerbated dyskinesis in more peripheral zones because pretreatment with angiotensin II did not worsen the ischemic response despite increasing systolic stress above that achieved with BT ejection. At chamber pressures of more than 40 to 50 mm Hg (stresses >80 g/cm²), myocardial distensibility becomes greatly diminished^{20 25} due to stretch of structural components. Such behavior was reflected in the near-vertical pressure-length relations at high pressures in the present study (Fig 5). Because peak chamber stress during NA ejection was already 260 g/cm², further increases with BT ejection would unlikely stretch the myocardium much more.

Although the absolute magnitude of systolic dyskinesia in the central ischemic zone did not increase during BT ejection, the total mass of tissue exhibiting such wall-motion abnormalities undoubtedly increased. This follows from the microsphere flow data that indicated nearly twice the mass of very critically hypoperfused myocardium, ie, flow reduced to 10% to 20% of baseline. Such severe flow limitations consistently produce negative systolic thickening²⁰ or shortening.²¹ More widespread systolic bulging would in part explain the disproportionate increase in chamber ESV. However, other factors, such as a compensatory redistribution of blood volume to the heart, also likely played a role. This is suggested by the magnitude of ESV increase with BT ejection, which exceeded total baseline SV. Thus, even if 100% of the ventricle had become dyskinetic, this alone could not account for the observed rise in ESV. Because the actual extent of systolic dyskinesis was much less than 100%, a fair proportion of the ESV (as well as EDV) increase must have reflected fluid redistribution. Although acute volume expansion can be adaptive (cardiac output was maintained with both NA and BT modes), chronically increased chamber volumes would be anticipated to exacerbate ventricular dysfunction.

Last, we observed a markedly altered phasic coronary flow during BT ejection, and propose that this is an important contributor to the disparity in ischemic zone size. Coronary flow was maintained with BT ejection despite lower mean diastolic pressures; this was due in part to a doubling of the flow measured during systolic ejection (Fig 6). At slightly higher diastolic pressures, we have previously shown that flow can be increased by 15% to 20% with BT ejection, even when total MO₂ is held constant.¹¹ An important consequence of this change in phasic flow, however, is that myocardial perfusion becomes more sensitive to lowering arterial mean and systolic pressures and not just to altering diastolic pressure. This suggests that ejection into a stiff vasculature more tightly couples the systolic pump performance of the heart with its own perfusion. In the present study, mean and systolic coronary perfusion pressures declined more during ischemia in hearts ejecting into the BT versus the NA load; thus, the effect on myocardial flow would have been magnified. Because angiotensin II infusion did not alter phasic coronary pressure or flow waveforms, it also did not duplicate this behavior (compare with Table 4).

Ischemic Myocardial Dysfunction in the Elderly
Advancing age is an independent risk factor for increased morbidity and mortality after a first myocardial infarction.^{1 2 3 4} In a study of nearly 10 000 patients, Maggioni et al³ reported that greater mortality of older patients was associated with worse cardiac dysfunction and heart failure symptoms, electromechanical dissociation, and cardiac rupture. This both highlighted the role of the ventricular response to the increased risk and suggested that hearts had greater chamber dilation. This and other studies^{6 7 8} have not found disparities in the severity of coronary lesions to explain this effect.

In the present study, we measured cardiac responses to 2 minutes of total coronary occlusion, not to myocardial infarction, and there were admittedly many physiological aspects of human aging that were not modeled by our preparation. Nevertheless, the exacerbated functional deterioration and chamber dilation we observed after acute coronary occlusion with BT ejection may be relevant to these clinical data. A heart perfused by a wide pulse pressure is more sensitive to declines in systolic and mean perfusion pressures¹¹ and thus to decrements of systolic function. Systolic arterial pressure is important to maintain adequate renal and cerebral perfusion in the elderly,^{26 27 28 29} and treatment that lowers systolic pressure too much (<130 mm Hg) may increase morbidity and mortality, partially due to inadequate organ perfusion. The heart is normally perfused primarily during diastole, and systolic pressure and flow have been considered to be less important. However, the present results coupled with our other recent data¹¹ suggest otherwise. A decline in systolic pressure from 180 to 130 mm Hg, as may occur in an elderly patient after an acute myocardial infarction, may not be as benign as often thought. Although increasing systolic pressures would probably be counterproductive, earlier interventions with aortic counterpulsation or reduction of myocardial demand with ß-blockers might be helpful.

Study Limitations
There were several limitations to the present study; one was that vascular stiffening (simulating changes seen with aging) was achieved acutely by means of the aortic bypass, whereas this is normally a chronic process requiring decades to develop. Aging also influences the ventricle, resulting in slowed rates of contraction and relaxation,^{30 31 32} loss of myocytes³³ with both cellular hypertrophy and an increase in the interstitial space, and reduced responsiveness to ß-adrenergic stimulation.³⁴ The coronary vasculature displays reduced endothelium-dependent vasodilator response to acetylcholine.³⁵ These changes would likely exacerbate rather than ameliorate the behavior we observed.

Second, studies were performed in the presence of autonomic reflex blockade, which may have influenced the results. Blockade was necessary to inhibit reflexes activated on switching between NA and BT ejection modes. In a prior study performed in dogs ejecting into an NA, we demonstrated slightly more contractile depression after coronary occlusion in the presence of autonomic blockade.¹⁶ Thus, with active reflexes, cardiac dysfunction during BT ejection and regional ischemia might have been less pronounced. However, elderly patients with stiff vasculatures have diminished chronotropic and inotropic responses to adrenergic stimulation,³⁴ so reflex-mediated contractile support might be blunted. This would only widen disparities seen in ischemic responses of younger and older individuals. Reflex blockade might also have influenced phasic coronary flow; however, it is unlikely that any such effects were significant. Basal coronary tone and LV and arterial pressures, the factors that principally determine the phasic coronary waveform,³⁶ were all within the normal range, as was the resulting phasic waveform.

Last, regional wall-motion analysis was limited to a single location intentionally positioned within the central ischemic zone. An expanded analysis of wall motion would have likely revealed more widespread systolic bulging during BT ejection, consistent with the increased mass of critically hypoperfused myocardium (Table 4). However, this was not attempted because of technical limitations imposed by an already complex surgical preparation.

Conclusions
Cardiac dysfunction and the compensatory adaptive response after acute coronary occlusion are adversely influenced when the heart ejects into a stiff arterial system. The most likely mechanism is that this pathological ventriculovascular interaction tightens the link between cardiac performance and myocardial perfusion, making the heart more vulnerable to insults that compromise pump function. The result is an expanded territory of critically hypoperfused myocardium, enhanced systolic dysfunction, a greater need for LV volume compensation, and a higher risk of cardiac failure. These data support recent clinical evidence that age itself increases mortality risk after myocardial infarction and may provide a mechanistic direction for future attempts to reduce this risk.

	Selected Abbreviations and Acronyms

 

BT = bypass tube EDV = end-diastolic volume ESV = end-systolic volume LAD = left anterior descending coronary artery LV = left ventricular MO2 = myocardial oxygen consumption NA = native aorta PVA = pressure-volume area SV = stroke volume SW = stroke work

	Acknowledgments

 
These studies were supported by National Health Service Grant HL47511 (D.A.K.) and American Heart Association (Maryland) Fellowship Grant (F.A.R.). Dr Kass is an Established Investigator of the American Heart Association.

Received August 16, 1995; revision received November 6, 1995; accepted November 7, 1995.

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