© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Right ventricular dysfunction persists following brief right ventricular pressure overload
San Francisco Department of Veterans Affairs Medical Center and the Department of Medicine, Cardiology Section, University of California, San Francisco, CA, USA
* Corresponding author. Cardiology (111C), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA. Tel.: +1 (415) 221-4810, ext. 3751; fax: +1 (415) 750-6950; e-mail: greyson@cardio.ucsf.edu
Received 28 August 1996; accepted 16 January 1997
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objective: Acute pulmonary hypertension may cause right ventricular (RV) contractile failure. While it has been assumed that restoration of normal loading conditions after acute pulmonary hypertension is sufficient for complete recovery of RV function, this has not been rigorously examined. The purpose of this study was to test the hypothesis that acute RV pressure overload produces RV contractile dysfunction that persists following restoration of control loading conditions. Methods: We subjected 18 autonomically-blocked, chloralose-anesthetized, open-chest pigs to 1 h of pulmonary artery constriction to increase RV systolic pressure from 35±1 to 55±1 mmHg, followed by 2 h of measurements after pulmonary artery constriction release. We determined regional RV free wall function from pressure–segment length loops and preload recruitable stroke work relations, and global RV function from stroke work vs. end-diastolic pressure relations. Results: As expected, RV free wall systolic shortening diminished during pulmonary artery constriction, but the endo/epi blood flow ratio, lactate uptake, and coronary venous pH were not significantly changed. Following release of pulmonary artery constriction, RV systolic and diastolic pressures returned to control values. Nonetheless, contractile dysfunction persisted, with depressed RV free wall systolic shortening (70±22% of control), RV regional external work (59±11% of control at control end-diastolic length), and global RV stroke work (56±14% of control at control end-diastolic pressure). Depressed regional work was due to a parallel, rightward shift of the preload recruitable stroke work relation. Five pigs identically instrumented but not subjected to pulmonary artery constriction showed no significant changes over 3 h. Conclusions: Acute pulmonary hypertension causes RV contractile dysfunction that persists at least 2 h after restoration of control loading conditions. Contractile dysfunction is not attributable to RV ischemia during pressure overload.
KEYWORDS Right ventricular function; Pressure–volume relation; Pressure overload; Pig, anesthetized
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Acute pulmonary artery hypertension, resulting from hypoxic pulmonary vasoconstriction [1], massive pulmonary embolism [2], acute left ventricular dysfunction [3], or acute mitral regurgitation [4], may lead to right ventricular (RV) contractile failure. Although it has been assumed that restoration of normal RV loading conditions is a sufficient condition for prompt and complete recovery of RV function, this supposition has never been subjected to rigorous investigation.
The primary goal of this study was to test the hypothesis that RV systolic function remains persistently depressed when control loading conditions are restored following a brief period of acute pressure overload. Because previous experimental studies have found evidence of ischemia of the RV free wall during severe acute RV pressure overload [5, 6], an additional aim of this study was to determine whether RV free wall ischemia during pressure overload might contribute to persistent contractile dysfunction following relief of pressure overload.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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This investigation conformed with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). It was approved by the Animal Studies Subcommittee of the San Francisco Department of Veterans Affairs Medical Center.
2.1 Experimental preparation
Twenty-three female Yorkshire-Landrace pigs weighing 30–42 kg were anesthetized with ketamine HCl (20 mg/kg i.m.) and 
-chloralose (100 mg/kg i.v., Sigma Chemical Co., St. Louis); anesthesia was maintained with -chloralose (30–50 mg/kg-h i.v.). The pigs were placed on a recirculating hot water blanket and wrapped in towels to prevent hypothermia. Normal saline with 5% dextrose was infused continuously at 150–250 ml/h i.v. Pigs were intubated via tracheotomy and ventilated with an air/O2 mix using a pressure-cycled ventilator adjusted to maintain pCO2 between 35 and 45 mmHg, pH between 7.35 and 7.45, and pO2 greater than 100 mmHg.
Fig. 1 illustrates the instrumentation of the heart. A fluid-filled catheter was placed in the aortic arch via a carotid artery for systemic blood pressure monitoring and arterial blood sampling. After exposure via a midline sternotomy and right lateral thoracotomy, the heart was suspended in a pericardial cradle. A solid-state micromanometer catheter (Millar Instruments, Houston, TX) was introduced into the RV via an internal jugular vein. Bipolar pacing wires were affixed to the left atrial appendage. Hydraulic occluders were placed around the main pulmonary artery (PA) and the inferior vena cava (IVC). Two pairs of piezoelectric crystals were implanted in the RV free wall for determination of segment shortening using a sonomicrometer (Triton Technology, San Diego, CA). One set was placed in the region of the inflow tract, and one set in the region of the outflow tract. The crystals were aligned as shown in Fig. 1, parallel to the principal axes of shortening in each region, as determined by Meier et al. [7]. An intramyocardial electrogram was recorded from the crystal leads and used for timing of cardiac events.
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In 16 pigs (Groups 2 and 3, defined below), a transit-time ultrasonic flow probe (Transonic Systems, Ithaca, NY) was placed around the pulmonary artery, a catheter was inserted into the left atrium for injection of fluorescent dye-labeled microspheres (Molecular Probes, Seattle, WA), and a tributary cardiac vein draining the RV free wall was cannulated with a heparinized 24 g Teflon catheter for withdrawal of coronary venous blood samples.
2.2 Experimental groups
Initial experiments were performed in 7 pigs (Group 1) that underwent measurements of regional right ventricular function under baseline conditions, during 1 h of acute RV pressure overload, and for 1 h following relief of pressure overload. In subsequent experiments, 11 pigs (Group 2) underwent measurements of global ventricular function and myocardial metabolism in addition to the measurements of regional right ventricular function. In these pigs, measurements were obtained for 2 h following relief of RV pressure overload. To verify stability of the preparation in the absence of RV pressure overload, 5 additional pigs (Group 3) underwent the same surgical instrumentation and series of measurements as Group 2 pigs but without RV pressure overload.
2.3 Experimental protocol
Autonomic blockade was produced with atropine (0.2 mg/kg i.v.) and propranolol (1.0 mg/kg i.v.), repeated every 2 h. Adequate autonomic blockade was evidenced by absence of reflex tachycardia during transient hypotension due to IVC constriction. The heart was paced at approximately 10 bpm faster than the spontaneous heart rate to minimize changes in heart rate during the experimental protocol. Lignocaine (40 mg i.v.) was occasionally used to reduce the frequency of ventricular arrhythmias during pulmonary artery constriction. Group 2 and 3 pigs were pretreated with indomethacin 30 mg i.v. to eliminate the transient pulmonary hypertension and systemic hypotension otherwise commonly observed after initial administration of microspheres (which are suspended in dilute Tween-20). Indomethacin was given at least 2 h before the beginning of the experimental protocol. Baseline measurements of hemodynamics, regional and global RV function, and myocardial metabolism were made after verifying stability of the preparation for 30 min.
The PA occluder was gradually constricted over 15 min to increase RV systolic pressure from the control level of 35±1 mmHg to the maximum RV systolic pressure obtainable (mean 55±1 mmHg) without provoking progressive systemic hypotension. In previous studies from our laboratory, myocardial blood flow distribution and lactate uptake did not indicate the presence of ischemia at this level of pressure overload [8]. RV pressure overload was maintained at this level for 1 hr. The hydraulic occluder was then released and measurements obtained over a 1 h (Group 1) or 2 h (Groups 2 and 3) period.
2.4 Hemodynamic measurements
Pressure segment–length loops were recorded during 10 s occlusions of the IVC with mechanical ventilation suspended. Three to 6 IVC occlusions were performed under each experimental condition, spaced at intervals of at least 2–3 min.
Hemodynamic data were digitized at 200 Hz and recorded using a data acquisition system consisting of a Macintosh IIfx computer (Apple Computer, Cupertino, CA), a 12-bit high-speed analog-to-digital converter (NBMIO16X-H, National Instruments Corporation, Austin, TX), and custom software developed using the LabView programming language (National Instruments Corporation).
2.5 Hemodynamic data analysis
Hemodynamic data, including pressure, segment length, segment shortening and pulmonary flow were all determined under steady-state conditions and during dynamic IVC occlusions. End-diastole was defined as the point corresponding to the peak of the QRS complex of the intramyocardial electrogram. End-systole was defined as the point of maximum negative RV dP/dt. Systolic shortening was defined as the difference between end-diastolic and end-systolic segment length, divided by the end-diastolic segment length.
Dynamic IVC occlusion data were analyzed according to the following procedure. First, individual cardiac cycles were automatically identified from the intramyocardial electrocardiogram signal. Next, the area of the pressure–segment length loop recorded during each cardiac cycle (which serves as an index of regional external work) was plotted against its corresponding end-diastolic segment length (EDL) to derive the preload recruitable stroke work (PRSW) relation. The data points for the 3–6 IVC occlusions collected under each experimental condition were combined for analysis, and the slope and length-axis intercept of the PRSW relation determined. The slope of the PRSW relation has been used by other investigators as an index of regional contractility [9], while the length-axis intercept corresponds to the end-diastolic segment length at which no external work would be performed.
Global RV stroke work (Groups 2 and 3) was determined by integrating the instantaneous product of pulmonary artery flow (determined using the pulmonary artery flow probe) and RV pressure over each cardiac cycle during IVC occlusions. The stroke work for each cardiac cycle was then plotted against its corresponding end-diastolic pressure (EDP), which was used as a surrogate for end-diastolic RV volume, to generate a global RV PRSW relation.
Regional external work and global RV stroke work following release of PA constriction were calculated from the PRSW relations by setting EDL and EDP to their control values. These preload-adjusted values were then compared with the corresponding control values. Those data derived from sonomicrometry measurements that are dependent on the intercrystal distance (i.e., regional PRSW intercept, PRSW slope and work) were normalized to control values, since the preparation-dependent intercrystal distance varied somewhat from experiment to experiment.
2.6 Regional blood flow and substrate consumption
In Groups 2 and 3, regional myocardial blood flow was determined using the fluorescent microsphere technique [10]. During each experimental condition, 
3 million well-mixed, sonicated, 15-µm-diameter, fluorescent-dye-labeled latex microspheres (blue-green, green, orange, red, or crimson) were injected into the left atrium during simultaneous timed withdrawal of a reference blood sample from a carotid artery. Blue-green and green microspheres were not used in the same experiment. Reference blood samples were heparinized and immediately mixed with equal volumes of distilled water. At the conclusion of the experiment, the heart was removed, and the areas of myocardium encompassing the sites of the inflow and outflow crystals were excised and divided into 2 transmural layers (approximately 1.5 g each).
The reference blood samples were centrifuged and the supernatant discarded. Tissue and blood samples were digested in 40 ml 2.0 N methanolic KOH for 48 h, and then sequentially centrifuged and washed in 0.2% Tween followed by methanol. After the final centrifugation, samples were air-dried for 72 h, then resuspended in 1.0 ml ethoxyethyl acetate (Sigma). Fluorescence, with correction for background fluorescence, was determined using a Perkin-Elmer fluorescence spectrometer equipped with an automated well-plate reader.
Coronary venous and carotid artery blood samples were obtained just before each microsphere injection. Arterial and coronary venous blood oxygen contents were determined from the sum of the hemoglobin-bound and dissolved oxygen contents [11]. Coronary venous pH was measured using an automated blood gas analyzer (Radiometer, Copenhagen, DK). To determine lactate concentrations, arterial and coronary venous blood samples were mixed with cold 7% perchloric acid and centrifuged; the protein-free supernatant was then removed and stored at –4°C until lactate concentrations were determined enzymatically [12]. Regional RV free wall lactate and oxygen consumption (MVO2) were calculated by multiplying the arterial-coronary venous blood content differences by the transmural blood flow.
2.7 Statistical analysis
Hemodynamics and metabolic variables, and the slopes and intercepts of the PRSW relations, were compared using repeated measures ANOVA (StatView, Abacus Concepts, Berkeley, CA). When significant differences were identified with the F-test, individual comparisons were performed using Student's t-test and the Bonferroni correction for multiple comparisons. All data are reported as mean±s.e.m.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Table 1 shows steady-state hemodynamic data under each experimental condition. Regional RV function and hemodynamics did not differ significantly between Group 1 and Group 2. As expected, pulmonary artery constriction (PAC) increased RV systolic pressure (from 34±1 to 55±1 mmHg). PAC also produced a modest but significant increase in RV end-diastolic pressure, and a decrease in mean aortic pressure. Following release of PAC, RV systolic and diastolic pressures did not differ significantly from control.
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The effect of PAC on regional RV function did not differ between the RV inflow and outflow tracts. Therefore, all reported results for regional function are averages of the inflow and outflow tract measurements. During pulmonary artery constriction, RV systolic shortening fell to 0.11±0.01 from the baseline of 0.18±0.01, as anticipated due to the increased afterload. Following release of PAC, RV loading conditions returned to control values, but systolic shortening remained persistently depressed at 0.13±0.01. This persistent impairment in contractile function occurred despite an increase in end-diastolic segment length (to 105±3% of control), which otherwise would have been expected to result in greater systolic shortening through the Frank-Starling mechanism. Similarly, cardiac output and stroke volume in Group 2 both declined slightly from their control values 2 h after release of PAC, without a significant change in end-diastolic pressure and despite a significant increase in end-diastolic segment length.
Fig. 2A (see figure legend for details) shows representative pressure–segment length loops obtained by constriction of the inferior vena cava during a single experiment under control conditions and 1 h following release of PAC. Note that the loop areas, which are an index of regional external work, are smaller for any given EDL 1 h post-PAC (gray lines), compared with control (black lines). Fig. 2B shows the preload-recruitable stroke work (PRSW) relations derived from the data in Fig. 2A, demonstrating a parallel, rightward shift in the relation 1 h after release of PAC compared with control.
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Table 2 summarizes the derived indices of systolic function during the control and post-PAC periods. Derived indices are not reported during pressure overload because the PRSW relations were not sufficiently linear at these RV pressures. Since regional external work and global RV stroke work are strongly dependent on preload, we determined these with EDL (for regional external work) and EDP (for global RV stroke work) matched to control values (steady-state, pre-PAC). Regional external work 2 h after release of PAC was persistently reduced at 59±11% of the control value. Even unadjusted for the increased EDL, steady-state regional external work 2 h after release of PAC was decreased compared with control (85% and 89% of control in Groups 1 and 2, respectively), despite nearly identical PA systolic pressure. Global RV stroke work 2 h after release of PAC remained depressed to a similar extent as regional RV stroke work, at 56±14% of the control value at matched EDP.
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Table 3 shows measurements of transmural RV free wall blood flow, the endocardium-to-epicardium blood flow ratio, lactate consumption, and coronary venous pH under each experimental condition. Regional myocardial blood flow and MVO2 rose during RV pressure overload, without a change in the endocardium-to-epicardium blood flow ratio. RV free wall lactate consumption increased slightly during PAC, and coronary venous pH showed no change. These findings indicate that significant ischemia of the RV free wall did not occur during PAC. Following release of PAC, regional myocardial blood flow and MVO2 were higher, and regional mechanical efficiency (regional work index divided by MVO2) 23% lower than during control conditions, although these differences did not achieve statistical significance.
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Tables 1–3
show hemodynamic and metabolic measurements in the 5 sham-operated pigs (Group 3). Measurements in sham pigs at 1, 2 and 3 h correspond temporally to PAC, 1 h post-PAC and 2 h post-PAC in pigs subjected to RV pressure overload. RV systolic pressure increased slightly during the sham protocol, but the intercept of the regional PRSW relation, regional external work at matched EDL, cardiac output and stroke volume, and metabolic measurements were all unchanged for the duration of the protocol. |
4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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RV contractile dysfunction is commonly observed during clinical conditions of acute pressure overload, such as hypoxic pulmonary vasoconstriction [1], massive pulmonary embolism [2], acute left-ventricular dysfunction [3], and acute mitral regurgitation [4]. However, no previous study has investigated the question of whether restoration of normal RV loading conditions is a sufficient condition for the recovery of RV function.
We found that restoration of control loading conditions was not sufficient to normalize RV function after 1 h of acute RV pressure overload. Reduced regional RV function in both the inflow and the outflow tracts of the RV free wall was paralleled by a quantitatively similar reduction of global RV function, that persisted for at least 2 h. At any given RV end-diastolic segment length or pressure, less regional and global external work was performed after PAC than before.
Some investigators have reported that RV ischemia contributes to RV contractile failure during severe acute pulmonary hypertension [5, 6]. Thus, post-ischemic contractile dysfunction, or stunning, could conceivably result from acute RV pressure overload. In those studies, however, RV ischemia occurred concomitant with severe systemic hypotension and progressive hemodynamic instability. In our study, we were careful to limit the severity of PAC to avoid severe systemic hypotension and hemodynamic instability. Indeed, our data do not support the hypothesis that ischemia of the RV free wall provoked by PAC resulted in post-ischemic dysfunction after release of PAC. Absolute RV free wall blood flow increased by 75% during PAC, without a change in the endocardium-to-epicardium blood flow distribution ratio, evidence of myocardial lactate production or coronary venous acidosis. We cannot exclude the possibility that small regions of myocardial ischemia were interspersed among better-perfused areas but could not be detected by the methods employed. Even so, it is unlikely that limited or mild RV free wall ischemia could have resulted in the marked reduction of RV free wall contractile function observed post-PAC.
It is unlikely that reduced high-energy phosphate concentrations or increased inorganic phosphate following release of PAC could account for the persistently depressed contractile function. In a previous study, we found that the phosphocreatine-to-ATP ratio in the right ventricular free wall, which is depressed during acute RV pressure overload, normalizes soon after release of PAC [13].
We investigated the possibility that humoral factors released during prolonged RV pressure overload and depressed cardiac output could have contributed to generalized myocardial depression affecting both the RV and the LV. We instrumented 4 additional pigs with sonomicrometry crystals and micromanometer-tipped catheters in both the left and right ventricles and subjected them to 1 h of PAC followed by 1 h observation post-PAC. In these pigs, RV systolic dysfunction and a rightward shift in the RV PRSW relation occurred in the post-PAC period without any significant changes in the left ventricular PRSW relation. Thus, it is unlikely that the observed depression of RV function post-PAC reflects a generalized myocardial depressant effect. Nor is it likely that the use of lignocaine contributed to the observed systolic dysfunction, since in these 4 pigs there were no changes in systolic function or the PRSW relation from control following bolus administration of 3 mg/kg of lignocaine (which was more than the total administered to Groups 1–3 over a 3 h period).
Depressed regional external work post-PAC was not due to a decline in the slope of the PRSW relation, but rather to an increase in the length-axis intercept of the PRSW relation, as illustrated by the pressure–segment length loops in Fig. 2. Pressure–segment length loops A (control) and B' (post-PAC) have nearly identical end-diastolic segment lengths. However, the area (i.e., external work) of loop B' is reduced primarily because of the rightward shift in the intercept of the PRSW relation.
The physiologic basis for an increase in the length-axis intercept of the PRSW relation has not yet been determined. Such an increase might reflect diminished contractility or an abnormality of active contractile processes. However, most investigators have found the intercept of the PRSW relation to be relatively independent of changes in inotropic state [14–16]. Other investigators have found a rightward shift in the length-axis intercept of the PRSW relation during interventions that decreased contractility [17, 18], but such a rightward shift was generally accompanied by a large decrease in the PRSW slope, which has been considered to be a sensitive index of regional contractility [14, 16]. We found no change in the slope of the PRSW relation in the post-PAC period, despite the significant increase in the PRSW intercept.
An alternative explanation for the parallel, rightward shift in the PRSW relation is that it reflects non-elastic deformation of myocardium [19]. For example, high systolic stress leading to deformation of structural elements that help coordinate contraction (e.g., endomysial collagen struts, the intermediate filament system or Z-band proteins [20–22]) could result in depressed systolic function [19, 23]. Any potential ultrastructural basis for the changes in ventricular function relations observed in this study remains to be determined.
We considered using the slope of the end-systolic pressure–segment length relation to assess regional contractile function. However, these relations were less linear and more variable than the regional PRSW relation. Furthermore, Karunanithi et al. found that the global right ventricular PRSW relation was more sensitive to changes in inotropic state and less sensitive to changes in loading conditions than the end-systolic pressure–volume relation [16]. Similarly, Pagel et al. found that the regional PRSW relation was superior to the end-systolic pressure–segment length relation for assessment of regional contractile function in the left ventricle [17].
4.1 Limitations
We employed an open-chest, open-pericardium model; thus, it is possible that unrestrained RV dilatation contributed more to systolic dysfunction than would have been expected if the pericardium were intact. However, the effects of pericardial restraint are modest until RVEDP exceeds 10 mmHg [24]. In our experiments, RVEDP was no more than 10 mmHg during PAC in all but 3 pigs. Moreover, Dell'Italia found no evidence for a significant effect from pericardial restraint in a model of acute pulmonary embolus and pulmonary hypertension in closed-chest dogs [25]. Thus, it is unlikely that an intact pericardium would have substantially affected our results.
Because of the complex shape and heterogeneous thickness of the RV free wall, there was no method available to determine RV wall stress in these experiments. Thus, we cannot exclude the possibility that fractional systolic shortening, regional external stroke work or global stroke work post-PAC were depressed partly as a consequence of an increase in systolic wall stress that might accompany RV dilatation or shape changes. However, such an effect would have been more likely to decrease the PRSW relation slope than to increase its intercept.
Tricuspid regurgitation due to RV dilatation following pressure overload could contribute to a decrease in measured global RV stroke work, since retrograde flow across the tricuspid valve would not be measured by the pulmonary artery flow probe. It is also possible that a shift in the position of the interventricular septum could contribute to the observed reduction of global RV stroke work post-PAC. We did not employ echocardiography to assess these effects. However, tricuspid regurgitation and shifts in septal position would not have been expected to cause the observed decline in regional RV free wall external work, which paralleled the decline in global RV stroke work. Indeed, reduced RV afterload due to tricuspid regurgitation would have been expected to result in increased regional segment shortening following release of PA constriction.
We did not detect any recovery of RV function over the 2 h post-PAC period; the potential for subsequent recovery of function remains uncertain. Finally, since we placed only one pair of crystals in each region, we did not assess potential anisotropic effects of PAC on RV free wall function.
Time for primary review 33 days.
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Acknowledgements |
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The authors are grateful to Ms. Maria Mayr for her assistance with the biochemical assays. Supported in part by NIH grants HL03475 (CG), HL49944 (GGS) and by the Department of Veterans Affairs Medical Research Service. Dr. Greyson was the recipient of a Clinician-Scientist Award from the American Heart Association.
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References |
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