Effects of Aortic Constriction During Experimental Acute Right Ventricular Pressure Loading
Further Insights Into Diastolic and Systolic Ventricular Interaction
Background Acute right ventricular (RV) hypertension may result in hemodynamic collapse. The associated reduction in left ventricular (LV) end-diastolic volume is thought to result from reduced RV output (secondary to RV ischemia) and adverse direct ventricular interaction. Aortic constriction improves cardiac function in these circumstances; this has been attributed to a reversal of the RV ischemia caused by an increased coronary perfusion pressure. We hypothesized that altered ventricular interaction, potentially via altered septal mechanics, may also contribute to the beneficial effects of aortic constriction.
Methods and Results We instrumented nine dogs with ultrasonic dimension crystals to measure RV segment length, septum–to–RV free wall and septum–to–LV free wall diameters, and LV anteroposterior diameter. Catheter-tipped manometers were used to measure LV and RV pressures. Pericardial pressure was measured with flat, liquid-containing balloon transducers. Inflatable cuff constrictors were placed on the pulmonary artery (PA) and aorta, and a flow probe was placed on the PA. The right coronary artery (RCA) was perfused independently by a roller pump calibrated for flow. During moderate PA constriction, while RCA pressure was maintained at control level, RCA flow did not change significantly (15.8±6.2 to 16.9±11.5 mL/min) and was similar during severe PA constriction (18.6±9.8 mL/min). During severe PA constriction, RV stroke volume decreased from a control value of 10.3±4.9 to 2.3±1.4 mL/beat (P<.05). When aortic constriction was added while RCA pressure was maintained at control level, there was an increase in RV stroke volume to 4.5±2.0 mL/beat (P<.05) with no associated change in RCA flow (17.8±9.5 mL/min). However, pressure-dimension loops clearly demonstrated changes in diastolic and systolic ventricular interaction; with aortic constriction, there was a large increase in the transseptal pressure gradient associated with a rightward septal shift. During either isolated severe PA constriction or simultaneous severe PA and aortic constriction, RCA flow was increased until RCA pressure was approximately equal to that in the aorta. This produced an increase in RCA flow of 50% (P<.05); however, this increase in coronary flow was ineffective in improving any measure of RV function.
Conclusions In this model of acute RV hypertension, aortic constriction improves cardiac function, at least in part, by altering ventricular interaction independent of changes in RCA flow. Changes in RCA flow do not appear to have a significant impact on cardiac function in this model in which coronary artery pressure was maintained at normal or increased levels.
Acute severe pulmonary hypertension, such as occurs in pulmonary embolism or experimental pulmonary artery (PA) constriction, may result in hemodynamic collapse. The underlying mechanisms have been studied extensively with suggestions including decreased right ventricular (RV) output (series interaction) and leftward shift of the ventricular septum and increased pericardial constraint (both contributing to altered direct interaction). Together, these alterations result in decreased left ventricular (LV) filling and consequently, output.1 2 3 4 5 6 7 8 9 10 11 RV ischemia is considered to be an important contributing factor to the observed RV decompensation.12 13 14 15 16 It has been attributed to the combination of an increase in myocardial oxygen requirements and a decrease in coronary artery perfusion pressure secondary to systemic hypotension and increased resistance to coronary flow during both systole and diastole. Thus, although coronary artery flow increases during moderate PA constriction, it decreases to control levels during severe constriction; these findings are associated with metabolic markers of RV ischemia.12
Both aortic constriction and administration of phenylephrine have been shown to improve cardiac function during severe PA constriction.12 13 14 15 17 18 This benefit has been attributed to increased coronary artery perfusion pressure and thus, flow. This conclusion has been supported by the reversal of metabolic indicators of ischemia,12 although aortic constriction has not consistently resulted in increased flow.18 When the ischemia has been reversed by independently increasing coronary flow (to the same level observed during aortic constriction), RV function improved and the degree of tolerated obstruction increased.12 15 However, improvement has not been as great as that occurring during aortic constriction,15 suggesting that other factors may also contribute to the response.
Preliminary work in experimental pulmonary embolism in our laboratory and work by others18 suggest that systolic as well as diastolic ventricular interaction may contribute to the responses to aortic constriction. We therefore performed a study in a canine model of acute pulmonary hypertension in which right coronary artery (RCA) pressure and thus, flow, could be independently controlled. We were then able to assess the independent contribution of ventricular interaction to the responses to aortic and PA constriction.
This study conformed to the guiding principles of the American Physiological Society. Thoracotomy was performed through a midsternal approach in nine mongrel dogs (weight, 20 to 25 kg) that were premedicated with morphine sulfate (0.75 mg/kg). General anesthesia was induced with sodium thiopental (10 to 15 mg/kg) and maintained with Fentanyl (50 μg/kg over 5 minutes followed by an infusion of 20 to 50 μg/kg per hour) while the animals were ventilated with a constant-volume respirator (model 607, Harvard Apparatus) using a 70% nitrous oxide and 30% oxygen mixture. The pericardium was incised transversely along the base of the heart and widely retracted for instrumentation. Septum–to–LV free wall and septum–to–RV free wall diameters, LV anteroposterior diameter, and RV free wall segment length were measured by sonomicrometry (Triton Technology) with crystals implanted on the LV and RV free walls, in the ventricular septum, and in the RV free wall as previously described.1 To independently control RCA pressure and flow, the proximal artery was cannulated. An occlusive roller pump (Cole-Parmer Instruments) was connected to a carotid artery and primed with the animal’s blood. The outflow of the pump was connected to the RCA via a Y-connector, through which coronary perfusion pressure was measured. (The coronary artery cannula had been calibrated in that the relation of the transcannula pressure drop to the flow was determined. In each case, the cannula was large enough that, at subsequent flows, the pressure drop was negligible.) The RCA perfusion pressure was continuously monitored, and the pump output was adjusted such that perfusion pressure had the desired relation to mean aortic pressure. The resultant flow was recorded using a voltage-generating tachometer that was coupled to the roller pump.
Flat, liquid-containing balloon transducers were loosely attached to the LV and RV free walls to measure pericardial pressures as previously described.3 Inflatable cuff constrictors were implanted on the PA and proximal aorta. An ultrasonic flow probe (Transonic Systems Inc) was also implanted on the PA. The heart was then returned to the pericardial sac, the edges of which were loosely reapproximated with several individual sutures, taking care to avoid decreasing the pericardial volume. LV and RV pressures were measured with manometer-tipped catheters (model PR279, Millar Instruments) inserted through a femoral artery and internal jugular vein, respectively. Right atrial and aortic pressures were measured with catheters inserted through an internal jugular vein (fluid-filled) and femoral artery (manometer-tipped), respectively.
The effects of aortic constriction alone were assessed in a separate group of six animals that were instrumented similarly, except that the RCA was not cannulated and a cuff constrictor was not placed on the PA.
Cross-sectional echocardiography was performed for 10-second periods during control and peak responses to each of the interventions (Sonos 500, Hewlett-Packard). A hand-held 2.5-MHz transducer was applied as lightly as possible to minimize distortion of the shape of the right ventricle; pressures and dimensions from sonomicrometry were not analyzed from recordings obtained while the transducer was applied.
Conditioned signals (model VR16, PPG Biomedical Systems) were recorded and subsequently analyzed on a personal computer (IBM Corporation) using a special software package developed in our laboratory (cvsoft, Odessa Computer Systems Ltd, Calgary, Alberta). The analog signals were passed through antialiasing low-pass filters with a cutoff frequency of 100 Hz and were sampled at a frequency of 200 Hz.
In the first group of six animals, the aortic constrictor was inflated to increase aortic pressure to approximately 180 mm Hg (in increments of 20 mm Hg) to determine the response to aortic constriction alone. The study protocol in the experimental group of nine animals is outlined in Fig 1⇓. After a period of stabilization, mean RCA pressure was reduced from the control perfusion pressure (similar to the control mean aortic pressure) until RV ischemia was present, as indicated by typical alteration of the RV pressure–segment length loop (Fig 2⇓). Coronary pressure was then returned to baseline. An ischemic loop was usually evident at a mean RCA pressure of approximately 20 mm Hg. After recovery from ischemia (at least 5 minutes after return of the RV pressure–segment length loop and hemodynamics to control), PA constriction was performed to induce “moderate” hemodynamic changes (peak PA and aortic systolic pressures of approximately 40 to 50 and 80 to 90 mm Hg, respectively; stroke volume decreased from approximately 10 to 6 mL/beat). RCA pressure was maintained at control level. Graded aortic constriction was then performed in increments of 20 mm Hg to increase LV systolic pressure to 160 to 220 mm Hg while observing changes in RV stroke volume (estimated on-line from the flow probe on the PA). RCA pressure was maintained at control level. After data collection, the aortic constrictor was deflated. The PA was then constricted further to effect “severe” PA constriction (systolic aortic pressure of approximately 60 to 70 mm Hg with RV stroke volume reduced to 1 to 4 mL/beat). With careful adjustments, it was possible to maintain reasonable stability of these hemodynamic parameters with no spontaneous improvement or rapid deterioration for periods of 2 to 4 minutes. Incremental aortic constriction was then performed, with titration being primarily against observed increases in RV stroke volume. Then, in six experiments, while the effects of aortic constriction were stable, RCA flow was increased until mean RCA pressure was approximately that in the aorta. In six experiments, RCA pressure was increased to a similar level during severe PA constriction but in the absence of aortic constriction.
Only data collected at end expiration were analyzed. Transmural LV and RV pressures were calculated as intracavitary pressure minus pericardial (balloon) pressure over the corresponding ventricle. The transseptal pressure gradient (TSG) was calculated as instantaneous intracavitary LV pressure minus RV pressure. The product of the LV minor axis diameters (anteroposterior multiplied by septum–to–LV free wall) was used as an index of LV area and hence volume. LV area stroke work (the integrated area of the LV pressure–area index loop) was used as an index of LV systolic function. To assess systolic septal function in relation to the right ventricle, instantaneous RV transmural pressure-diameter loops were constructed and areas calculated. In addition, septal position (DRV) was measured (septum–to–RV free wall diameter divided by septum–to–LV free wall plus septum–to–RV free wall diameters), and TSG-DRV loops were constructed to assess septal function in relation to the combined diameters of both ventricles. The TSG–RV diameter loop area (TSG stroke work) was used as an index of the septal contribution to RV stroke work. RV pressure–segment length loops were also constructed to reflect free wall work. Finally, fractional and absolute shortening of RV segment length and septum–to–RV free wall diameter were calculated.
The significance of responses to each of the interventions was tested by repeated-measures two-way ANOVA with specified comparisons by the Student-Newman-Keuls test. Data in the tables are expressed as mean±SD; the data presented in Fig 3⇓ are mean±SEM. A probability value of less than .05 was considered significant.
Aortic Constriction Group
As shown in Table 1⇓, aortic constriction in the first group of six animals increased peak LV systolic pressure from 108±21 to 177±13 mm Hg and peak RV systolic pressure from 33±4 to 40±18 mm Hg; stroke volume decreased from 10.6±1.5 to 7.4±2.6 mL/min, and heart rate increased from 108±27 to 123±29 beats per minute; those changes were all statistically significant. RV end-diastolic pressure was unchanged, but LV end-diastolic pressure, transmural LV end-diastolic pressure (from 2±2 to 6±6 mm Hg), and end-diastolic TSG increased significantly. Septum–to–LV free wall and LV anteroposterior diameters increased significantly, and septum–to–RV free wall diameter decreased significantly by a similar amount. These changes were associated with a significant increase in LV area and a significant decrease in area stroke work. There was no change in absolute or fractional shortening of the RV segment length, and the increases in absolute and fractional shortening of the septum–to–RV free wall diameter were not significant.
RCA flow was reduced from 15.8±6.2 to 4.1±5.7 mL/min to produce an ischemic pattern on the RV pressure–RV segment length loop. This resulted in an approximately 25% decrease in RV stroke volume and LV area stroke work (P<.05). Other significant changes include a decrease in RV systolic pressure, a slight increase in transmural RV end-diastolic pressure, a marked decrease in segment length stroke work, increased RV segment length, and reduced absolute and fractional shortening of the segment length. All measurements returned to control values after ischemia was reversed (see Figs 2⇑ and 3⇑).
Moderate PA Constriction Followed by Aortic Constriction
Compared with the initial control state, moderate PA constriction resulted in an increase in heart rate, a decrease in RV stroke volume (10.3±4.9 to 6.6±2.8 mL/beat), and increased RV systolic pressure (30±3 to 44±9 mm Hg), all statistically significant. The decreases in LV area, septum–to–LV free wall and anteroposterior diameters, the increase in septum–to–RV free wall diameter, and the decrease in LV area stroke work were not statistically significant. The small increase in RCA flow was also not significant (RCA pressure had been maintained). With aortic constriction during moderate PA constriction, the small decrease in stroke volume was not significant. The increases in LV end-diastolic pressure, transmural LV end-diastolic pressure and RV end-diastolic pressure, and end-diastolic and end-systolic TSG were significant. The septum–to–LV free wall diameter increased, and the septum–to–RV free wall diameter decreased (both P<.05). LV area increased, but the decrease in LV area stroke work and slight increase in RCA flow were not significant (RCA pressure had been maintained). The changes in RV segment length and septum–to–RV free wall shortening, fractional shortening of RV segment length and septum–to–RV-free wall diameter, and TSG stroke work were not significant (see Fig 3⇑).
Severe PA Constriction Followed by Aortic Constriction
After deflation of the aortic constrictor, a greater degree of PA constriction resulted in no significant change in heart rate, but RV stroke volume decreased further (to 2.3±1.4 mL/beat, P<.05), as did LV systolic pressure (to 55±8 mm Hg, P<.05); RV end-diastolic pressure and transmural RV end-diastolic pressure increased significantly, and both end-diastolic and end-systolic TSG decreased (to −4.4±2.3 and 5±5 mm Hg, respectively, P<.05). The additional changes in septum–to–LV free wall diameter (decrease), septum–to–RV free wall diameter (increase), and LV area were statistically insignificant. LV area stroke work decreased substantially (P<.05). The increases in RV segment length and segment length stroke work were not significant. The slight increase in RCA flow was not significant. During subsequent aortic constriction, heart rate was unchanged, peak LV (55±8 to 209±28 mm Hg) and RV (47±6 to 68±17 mm Hg) systolic pressures increased significantly, and stroke volume approximately doubled (2.3±1.4 to 4.5±2.0 mL/beat, P<.05). Transmural RV end-diastolic pressure decreased slightly (2.5±2.8 to 1.5±2.4 mm Hg), LV end-diastolic pressure increased (6±3 to 16±9 mm Hg), transmural LV end-diastolic pressure increased (0±2 to 8±7 mm Hg), and end-diastolic TSG increased (−4.4±2.3 to 7.4±8.9 mm Hg), all significantly. Septum–to–LV free wall diameter and LV area increased, septum–to–RV free wall diameter decreased, and LV area stroke work increased (all P<.05); however, RCA flow did not increase (18.6±9.8 to 17.8±9.5 mL/min, P=NS). There was a slight decrease in RV segment length (P<.05), but there were no significant changes in RV segment length and diameter shortening (except for a slight decrease in absolute shortening of the RV diameter) or fractional shortening of the RV segment length and diameter. There was also no significant change in TSG stroke work.
An example of the changes that were observed echocardiographically during pulmonary and aortic constriction is illustrated in Fig 4⇑. As shown, there is a decrease in end-diastolic LV size and septal flattening during PA constriction compared with control and a reversal of these changes during aortic constriction with sustained PA constriction (also see Figs 3⇑, 5⇑, and 6⇑).
Increased Coronary Artery Flow
When mean RCA pressure was increased during severe PA constriction with (from 87±10 to 153±8 mm Hg, n=6) or without (from 83±13 to 140±18 mm Hg, n=6) simultaneous aortic constriction, flow increased significantly from 14.6±5.5 to 26.7±9.5 mL/min (PA constriction, no aortic constriction) and from 17.9±11.3 to 28±12.7 mL/min (simultaneous PA and aortic constriction); there was no suggestion of hemodynamic improvement. The slight but significant decreases in transmural RV end-diastolic pressure, segment length stroke work, and RV diameter work during PA constriction alone and the slight decrease in LV area and segment length work during simultaneous PA and aortic constriction did not reflect improvement in RV function.
RV Pressure–Segment Length and Pressure-Diameter Relations
Fig 5A⇑ shows representative RV pressure–segment length loops during control, PA constriction, and PA constriction plus aortic constriction, with RCA pressure maintained throughout at control level. An ischemic loop such as that observed during reduced coronary flow alone was not observed during PA constriction (see Fig 2⇑). End-diastolic RV segment length changed little during simultaneous PA and aortic constriction. The loops varied in shape among animals during aortic constriction, shifting to the left (five animals) or to the right (three animals); in one animal, there was no shift.
Typical changes in the RV pressure-diameter loops are illustrated in Fig 5B⇑. PA constriction shifted the RV pressure/septum–to–RV free wall diameter loop to the right (increased RV diameter) and upward (increased systolic pressure). Aortic constriction shifted the loop back to the left (smaller RV end-diastolic diameter and greater RV systolic pressure than during PA constriction alone). There was a positive loop in seven of nine animals; in the two with a negative loop, the control loop was also negative. In the seven animals with an initially positive loop, the loop area increased in only three; in three it remained positive, and in one it became slightly negative. Thus, increased RV stroke output occurred at a smaller end-diastolic diameter (and therefore volume) and at a greater afterload without an increase in intracavitary end-diastolic (but small decrease in transmural) RV pressure.
Representative loops depicting the TSG–RV diameter relations are shown in Fig 6⇑. As shown, severe PA constriction caused a marked decrease in TSG throughout the cardiac cycle associated with an increase in RV diameter. Aortic constriction caused a marked increase in the TSG throughout the cycle and a marked shift of the septum (decreased septum–to–RV free wall diameter and DRV beyond control in six of nine animals). As was the case with the RV pressure-diameter loops, the loops were positive in seven of the nine animals and were negative only in the animals with negative control loops. Loop area changes were also inconsistent.
The primary purpose of this study was to determine if ventricular interaction contributes to the beneficial effects of aortic constriction during acute RV hypertension. This would be in addition to the previously demonstrated benefit derived from reversal of RV ischemia. Independent control of RCA pressure during these interventions allowed us to discriminate between these two mechanisms. Since RCA pressure was maintained at normal or increased levels, the potential contribution of RV ischemia at low coronary artery pressures during PA constriction was not specifically addressed. When PA constriction caused severe hemodynamic deterioration, maintenance of RCA pressure at control levels was associated with an insignificant increase in coronary flow compared with control. An ischemic RV pressure–segment length loop was not observed, suggesting that ischemia may not contribute importantly to RV decompensation in this model. Aortic constriction approximately doubled RV stroke volume and LV stroke work despite the absence of an increase in RCA flow. Furthermore, a 50% increase in RCA flow during either isolated PA constriction or simultaneous PA and aortic constriction did not alter any of our measurements of cardiac function in a beneficial way. Thus, it is clear that improved cardiac function during aortic constriction in this model was not dependent on increased RCA flow and that other mechanisms must be considered. Differences between our model (independent control of RCA pressure) and other models12 13 14 15 16 17 18 might suggest that the role of RV ischemia may be different in the present study. While that may be true, RCA flow was increased only slightly and insignificantly from control to severe PA constriction in the present study. This is similar to previously reported changes,12 suggesting that the differences between models may not be great. The increase in RV stroke output was achieved despite a greater RV afterload; end-diastolic RV segment length decreased slightly, segment length work actually decreased in most animals, and RV end-diastolic diameter (and therefore volume) decreased because of the rightward septal shift. Therefore, the Frank-Starling mechanism was not directly responsible for the improvement in RV function.
Mechanism of Hemodynamic Deterioration During Acute RV Hypertension
Previous studies, including several from our laboratory,1 2 3 have clearly demonstrated that hemodynamic collapse during acute RV hypertension is at least partially related to direct diastolic ventricular interaction. Leftward septal shift, a phenomenon augmented by an intact pericardium, results in decreased LV size (preload) and therefore output by the Frank-Starling mechanism. The relative contribution of the series mechanism (decreased RV output) is uncertain, but we recently demonstrated that the right ventricle may still have the capacity to increase output at the time of hemodynamic collapse and that LV underfilling due to direct (septal plus pericardial) interaction may be a critical determinant of when hemodynamic collapse occurs.1 2 Thus, when the pericardium is intact, less embolism is required to cause deterioration, volume loading causes greater hemodynamic deterioration, and subsequent removal of volume improves function. The opposite occurs during volume loading and removal when the pericardium is opened; function improves during loading and deteriorates during phlebotomy. Thus, when the pericardium is closed, direct interaction appears to cause hemodynamic collapse despite obvious RV functional reserve.
Mechanism of Beneficial Effects of Aortic Constriction
The present study demonstrates that aortic constriction during PA constriction shifts the septum back to the right and thus increases LV end-diastolic volume and filling. The otherwise uncompromised left ventricle is able to increase its stroke output despite the increased afterload. Thus, there is the expected increase in LV area stroke work associated with the increase in LV area. However, it is not clear from our data why RV function improves despite apparently disadvantageous loading conditions (decreased preload and increased afterload). Changes in RV pressure-diameter and TSG–septal position loops during the interventions performed indicate that direct systolic ventricular interaction is dramatically altered. Although qualitative changes in these loops suggest that the septal contribution to RV function may be important, this potential mechanism was not validated quantitatively because of the absence of consistent increases in loop areas during aortic constriction. Thus, quantitation of loop area changes did not provide a clear explanation of the mechanism(s) by which benefit is achieved. Quantitation of other measurements of RV function also did not clarify the issue.
Previous studies have shown that changes in LV developed pressure can alter RV function19 20 21 22 23 24 25 26 27 just as increased RV end-diastolic volume or afterload can augment LV function through direct systolic interaction.25 27 The decrease in LV systolic pressure associated with an acute increase in RV afterload is not inconsistent with those findings; LV stroke work at given LV end-diastolic volumes is greater during PA constriction than at similar volumes during inferior vena caval constriction.25 Thus, decreased LV systolic pressure during PA constriction appears to account for some of the reduction in RV developed pressure and output independent of diastolic interaction.21 The potential contribution of LV contraction to RV function was clearly demonstrated recently by using different pacing sequences in both ventricles with an electrically isolated right ventricle.20 Approximately two thirds of pressure development and flow in the right ventricle occurred in the first beat after cessation of RV pacing. In the present study, the dramatic increase in the TSG throughout systole during aortic constriction and the resulting increase in RV pressure suggest that the potential gain to RV function by this mechanism may be substantial. The relative contributions of shared myocardial fibers of both ventricles, of buttressing of RV function by the less compliant septum, and of left-to-right ventricular augmentation of function by altered septal function remain to be clarified; however, the pressure-diameter loops suggest that the latter may have been important in at least seven of the nine animals. We cannot account for the improved RV function by any of our other measurements of septum–to–free wall diameter or segment-length function, a finding consistent with results from a previous study.18
While aortic constriction during moderate PA constriction caused changes that were qualitatively similar to those observed during severe PA constriction, RV stroke volume did not increase. The reason(s) for this is not clear but may be related to less diastolic and systolic interaction (particularly, less systemic hypotension) during moderate PA constriction and therefore less potential for reversal of these interactions. Clearly, aortic constriction does not augment RV stroke output in the control state, nor is there benefit unless PA constriction causes severe hemodynamic compromise.
Thus, aortic constriction appears to improve RV function during PA constriction by a combination of mechanisms. Reversal of myocardial ischemia, as has been previously demonstrated, is a factor, although our data suggest that ischemia and its reversal may be less important than previously thought. Altered diastolic ventricular interaction (increased LV end-diastolic volume due to rightward septal shift) has the potential to improve LV function by the Frank-Starling mechanism, since LV contractility is not altered by PA constriction.3 As a consequence, the right ventricle can increase its output, since some functional reserve is usually present. Augmentation of RV function by LV developed systolic pressure (increased systolic TSG) appears to play an important role as well. Our results suggest that function of both ventricles is better matched during diastole and systole by appropriate degrees of aortic constriction and is improved overall despite increased afterload to both ventricles.
As the mechanisms involved in ventricular interaction become clarified, potential clinical implications become apparent. Thus, volume loading after acute pulmonary embolism, frequently promoted as beneficial because of increased RV preload, may actually be harmful because it may reduce LV preload.2 28 29 The present study provides some insight into the mechanisms by which systemic vasoconstriction may be beneficial after pulmonary embolism in circumstances where volume loading and inotropic agents are less likely to be effective.28 29 30 The data are consistent with our previous work, which suggested that RV functional reserve is not completely exhausted at the point of hemodynamic collapse during acute RV hypertension, and support the view that systemic vasoconstriction may be beneficial and that other ways of altering diastolic and systolic interaction should be explored for potential clinical benefit.
Although our data suggest a limited role of myocardial ischemia during PA and aortic constriction, we have not excluded the possibility that more sensitive markers (eg, biochemical) of ischemia might uncover ischemia that was not evident using pressure–segment length loops. In addition, we did not assess the potential for RV subendocardial ischemia during maintained or increased coronary flow. Therefore, although it appears unlikely, it remains possible that RV ischemia played a significant role in our model.
Dr Tyberg is a Medical Scientist of the Alberta Heritage Foundation for Medical Research, which supported the study through an establishment grant. This study was also supported by grants from the Alberta Heart and Stroke Foundation. The authors wish to acknowledge the expert technical assistance of Cheryl Meek and Gerald Groves and thank Gwen Hubscher for typing the manuscript.
- Received December 5, 1994.
- Accepted January 17, 1995.
- Copyright © 1995 by American Heart Association
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