* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Reservoir and Conduit Function of the Right Atrium - AJP
Survey
Document related concepts
Coronary artery disease wikipedia , lookup
Heart failure wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Myocardial infarction wikipedia , lookup
Cardiac surgery wikipedia , lookup
Hypertrophic cardiomyopathy wikipedia , lookup
Electrocardiography wikipedia , lookup
Lutembacher's syndrome wikipedia , lookup
Arrhythmogenic right ventricular dysplasia wikipedia , lookup
Mitral insufficiency wikipedia , lookup
Atrial fibrillation wikipedia , lookup
Atrial septal defect wikipedia , lookup
Quantium Medical Cardiac Output wikipedia , lookup
Dextro-Transposition of the great arteries wikipedia , lookup
Transcript
Articles in PresS. Am J Physiol Heart Circ Physiol (December 9, 2004). doi:10.1152/ajpheart.00566.2004 Reservoir and Conduit Function of the Right Atrium: Impact on Right Ventricular Filling and Cardiac Output Sydney L. Gaynor, MD, Hersh S. Maniar, MD, Sunil M. Prasad, MD, Paul Steendijk, PhD,* Marc R. Moon, MD From the Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri, and the Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands* Address for Correspondence: Marc R. Moon, MD Division of Cardiothoracic Surgery Washington University School of Medicine 3108 Queeny Tower #1 Barnes-Jewish Plaza St. Louis, Missouri 63110-1013 (314) 362-0993 FAX: (314) 362-0328 E-mail: [email protected] Short Running Title: RA Reservoir & Conduit Function … Keywords: Right Atrial Function, Conductance Catheter, Right Ventricular Afterload, Inotropic Stimulation, Pulmonary Artery Occlusion Copyright © 2004 by the American Physiological Society. Gaynor et al … Page 2 of 25 ABSTRACT The purpose of this study was to investigate the relationship between right atrial (RA) reservoir and conduit function and to determine how hemodynamic changes influence this relationship and its impact on cardiac output. In eleven open-chest sheep, RA reservoir and conduit function were quantified as RA inflow with the tricuspid valve closed versus open, respectively. Conduit function was separated into early (before A-wave), and late (after A-wave) components. The effects of inotropic stimulation, partial pulmonary artery occlusion, and pericardiotomy were tested. At baseline with the pericardium intact, reservoir function accounted for 0.56 ± 0.13 (mean ± one standard deviation) of RA inflow, early conduit for 0.29 ± 0.07, and late conduit (during RA contraction) for 0.16 ± 0.11. Inotropic stimulation decreased conduit function and increased reservoir function, but these effects did not reach statistical significance. With partial pulmonary artery occlusion, early conduit function fell to 0.20 ± 0.11 (P<0.04), and the conduitto-reservoir ratio decreased by 41% (P<0.03). Similarly, after pericardiotomy, early conduit function fell to 0.14 ± 0.09 (P<0.004), reservoir function increased to 0.72 ± 0.08 (P<0.04), and, consequently, the early conduit-to-reservoir ratio decreased by 63% (P<0.006). Cardiac output was inversely related to the conduit-to-reservoir ratio (r = 0.39, P<0.001). This study demonstrated that the right atrium adjusts its ability to act more as a reservoir versus a conduit in a dynamic manner. The RA conduit-to-reservoir ratio was directly related to the RVP-RAP gradient at the time of maximum RA volume, with increased ventricular pressures favoring conduit function, but it was inversely related to cardiac output, with an increase in the reservoir contribution favoring improved cardiac output. Gaynor et al … Page 3 of 25 The right atrium is a dynamic structure whose role is to assist filling of the right ventricle. Ideally, the right atrium should transfer a high volume of blood rapidly to the ventricle at low pressure to prevent peripheral edema and hepatic congestion. The three components of atrial function are: 1) reservoir function, storing blood when the tricuspid valve is closed and releasing stored blood when it opens, 2) conduit function, passive blood transfer directly from the coronary and systemic veins to the right ventricle when the tricuspid valve is open, and 3) booster pump function, atrial contraction in late diastole to complete ventricular filling (10,13,31). Previous studies have demonstrated that pathologically altered left atrial conduit-to-reservoir function is an important determinant of left-heart function and can profoundly affect cardiac performance (2,4,14-17,30,33,34,38), but studies examining right atrial (RA) reservoir and conduit function are limited. The mechanics of the right atrium are complex (5,8,24,26). In 1628, William Harvey was the first to identify the atrium as a “receptacle and store-house” and reported that the right atrium was “the first to live, and the last to die” (12). In an elegant computer model, Suga found that increased atrial compliance markedly improved cardiac performance and concluded that a “flexible atrium” (increased receptacle capabilities) would substantially improve the heart’s output (36). Others have predicted that early ventricular filling increases directly with atrial compliance (16,33,38); however, data is limited from intact subjects to support these theories. In addition, it remains completely unknown what factors influence the RA conduit-to-reservoir ratio and how physiologic adaptations impact this ratio to accommodate right ventricular (RV) needs in times of stress. The purpose of the current investigation was to examine the relationship of conduit-to-reservoir function in the normal right atrium and to determine how loss of pericardial integrity, increased inotropic state, acute pulmonary hypertension, and, ultimately, the atrioventricular (AV) pressure gradient influenced the composite functions of the right atrium and its impact on cardiac output. Gaynor et al … Page 4 of 25 Methods Eleven adult sheep (25-30 kg) were anesthetized with ketamine hydrochloride (27 mg/kg im) and pentothal sodium (6.8 mg/kg iv), and intubated and ventilated (Siemens; Munich, Germany) with supplemental inhalational isoflurane (1.5-3%). performed, leaving the pericardium intact. A median sternotomy was Ultrasonic flow probes (10-12-mm perivascular probes with a T206 Flowmeter, Transonic Systems; Ithaca, NY) were placed around the superior (SVC) and inferior (IVC) vena cava approximately 1-cm from the caval-atrial junction to measure RA inflow. Micromanometer-tipped pressure catheters (Millar Instruments, Houston, TX) were zeroed in a 37°C water bath for 30 min before insertion. A 1-cm incision was made in the pericardium over the anterior RV free wall, and a 7-Fr micromanometer was positioned in the mid-RV cavity to record RV pressure (RVP). A second 1-cm incision was made in the pericardium over the RA appendage, and a 6-Fr combined pressure-volume conductance catheter (Millar SPR-766) was positioned along the long axis of the right atrium so that its tip rested at the RA-IVC junction. This catheter was connected to a signal conditioner processor (Sigma 5DF, CD Leycom; Zoetermeer, The Netherlands) to convert instantaneous conductance measurements into relative RA volume as previously described (24). A micromanometer 2-cm from the distal end of the catheter allowed simultaneous measurement of RA pressure (RAP). A tourniquet was positioned around the distal main pulmonary artery (PA) to permit acute RV afterload manipulation via partial PA occlusion. A third 1-cm incision was made over the AV groove to place a vascular loop around the coronary sinus so that it could be occluded during data collection to prevent coronary venous return. Experimental Protocol. With the pericardium intact, data were recorded during steady-state baseline conditions. Between 3 and 10 steady-state beats were recorded during each study intervention, and data acquisition runs were repeated in triplicate. To alter inotropic state, a calcium chloride bolus (10 mg/kg iv) was given, and steady-state data were obtained. Acute pulmonary hypertension was Gaynor et al … Page 5 of 25 created by partial PA occlusion to produce a 50% rise in maximum RVP, and steady-state data were recorded. The PA tourniquet was released, and RVP returned to its baseline level. After a ten minute stabilization period, the pericardium was opened, and data were again recorded during steady-state conditions. Complete data with the pericardium intact was available in nine of the eleven animals, and complete data with the pericardium open was available in seven of the eleven animals. At the conclusion of the experiment, the animals were euthanized using pentothal sodium (1 g iv) followed (after 2 min) by potassium chloride (80 meq iv), and proper positioning of the catheters was confirmed. All animals received humane care in compliance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” prepared by the National Academy of Sciences and published by the National Institutes of Health. The study was approved by the Washington University School of Medicine Animal Studies Committee and conducted according to Washington University policy. Data Analysis. During each data acquisition run, ECG, RAP, RVP, SVC flow, IVC flow, and RA conductance signals were acquired at 200 Hz and processed using custom-designed computer software. The RAP and RVP signals were differentiated with respect to time to calculate maximum RA dP/dt and RV dP/dt, and relative RA volume was determined using the conductance catheter as previously described (24,35). The instantaneous pressure gradient across the tricuspid annulus (RVP-RAP gradient) was corrected for differences in the height of the RAP and RVP sensors (hydrostatic pressure gradient) (20). The average hydrostatic pressure gradient ( PH) was calculated as the difference between RAP and RVP at the time immediately before the electrocardiographic P wave (during diastasis), then subtracted from the pressure differential as follows: RVP-RAP gradient = RVP(t) – RAP(t) - PH. Gaynor et al … Page 6 of 25 RA reservoir and conduit function. Reservoir and conduit function of the right atrium were calculated by integrating RA inflow (combined SVC and IVC flow) during RV systole (reservoir) and RV diastole (conduit) (16,17,30). Since the tricuspid valve is closed during RV systole, all blood that enters from the cavae during this period is reserved in the atrium (coronary sinus return was temporarily interrupted during data collection). Thus, RA reservoir volume equals integrated RA inflow from the ECG R-wave to the time of maximum RA volume, which corresponds to the initiation of RA emptying and approximates the time of tricuspid valve opening (17). In contrast, RA conduit volume equals integrated RA inflow during RV filling when the tricuspid valve is open. Total conduit volume was separated into an early component, from the time of maximum RA volume to the beginning of atrial contraction (A-wave, time of maximum RA dP/dt), and a late component, from the A-wave to the end of RV filling (ECG Rwave). The late conduit component quantifies blood entry into the atrium against the force of the RA kick. Figure 1 illustrates typical hemodynamic data obtained from one animal at baseline. Integrated RA inflow volume during the reservoir and conduit phases was divided by total RA inflow volume (stroke volume) to yield reservoir and conduit (both early and late) function as a percentage of total RA inflow. Statistical Analysis. All data are reported as means ± SD. Hemodynamic data obtained during steady-state baseline conditions with the pericardium closed and after calcium chloride bolus, partial PA occlusion, and pericardiotomy were compared using repeated-measures ANOVA. When indicated by a significant F statistic (P<0.05), differences were isolated using Fischer’s protected least significant difference test. Multiple linear regression analysis was used to determine which hemodynamic factors most influenced reservoir and conduit function, and linear regression was used to determine the relationship between the conduit-to-reservoir ratio and cardiac output (stroke volume times heart rate). All statistical analyses were performed using SigmaStat 2.03 (SPSS Inc., Chicago, IL). Gaynor et al … Page 7 of 25 Results Table 1 summarizes the steady-state hemodynamic data during baseline (pericardium closed), inotropic stimulation (calcium chloride bolus), partial PA occlusion, and following pericardiotomy. With inotropic stimulation, maximum RVP increased by 38% (P<0.04), RV dP/dt increased by 26% (P>0.05), and there was a tendency for RA dP/dt to rise (P=0.06). With partial PA occlusion, maximum RVP similarly increased by 51% (P<0.004), but the changes in RV dP/dt and RA dP/dt did not reach statistical significance (P=0.10 and P=0.09, respectively). Following pericardiotomy, maximum RV dP/dt fell by 20% (P=0.06). There were no significant changes with any intervention in heart rate (P>0.60), P-R interval (P>0.13), RA filling time (reservoir time, P>0.75), RA emptying time (total conduit time, P>0.96), mean RA pressure (RAP) (P>0.28), total RA inflow (stroke volume, P>0.40), or cardiac output (P>0.32). Table 2 and Figures 2 and 3 summarize changes in reservoir and conduit function with each intervention. At baseline with the pericardium closed, reservoir function accounted for 0.56 ± 0.13 of RA inflow (21.1 ± 6.8 mL), early conduit function for 0.29 ± 0.07 (11.2 ± 5.5 mL), and late conduit function for 0.16 ± 0.11 (5.3 ± 2.4 mL). Inotropic stimulation decreased RA inflow volume during the late conduit phase to 3.0 ± 1.0 mL (P<0.02), but the fall in late conduit function to 0.09 ± 0.04 did not reach statistical significance (P=0.11). With partial PA occlusion, early conduit function fell by 31% (P<0.04) and there was a tendency for reservoir function to increase (p=0.09), resulting in a fall in the early conduit-to-reservoir ratio from 0.56 ± 0.22 at baseline to 0.33 ± 0.22 (P<0.03). Following pericardiotomy, there was a small increase in RA inflow during the late conduit phase (+0.6 mL, P<0.05) but a larger decrease during the early conduit phase (-5.4 mL, P<0.003). This coupled with a 29% increase in reservoir function (P<0.04), resulted in a fall in the early conduit-to-reservoir ratio to 0.21 ± 0.15 with the pericardium open (P<0.006). Linear regression analysis demonstrated that cardiac output was inversely related to the conduit-to-reservoir ratio (r = 0.39, P<0.001) (Figure 4). Gaynor et al … Page 8 of 25 In multilinear regression analysis, heart rate (P>0.10), stroke volume (P>0.10), maximum RA dP/dt (P>0.09), maximum RV dP/dt (P>0.30), and maximum RA volume (P>0.16) did not significantly influence reservoir and conduit function. Significant factors included RAP (P<0.004), RVP (P<0.003), and the RVP-RAP gradient (P<0.004) at the time of maximum RA volume, which corresponds to the initiation of RA emptying. Table 3 summarizes the impact of each significant factor on reservoir, early conduit, and late conduit function. The cutoff values analyzed included RAP at maximum RA volume = 4.2 mmHg, RVP at maximum RA volume = 5.8 mmHg, and RVP-RAP gradient at maximum RA volume = 0.53 mmHg, representing the median value for each parameter across all interventions in all animals. With increased RAP at maximum RA volume, reservoir function rose by 12% (P<0.001) and early conduit function fell by 25% (P<0.001), resulting in a fall in the early conduit-to-reservoir ratio from 0.65 ± 0.69 to 0.40 ± 0.49 (P<0.001). In contrast, with elevated RVP at maximum RA volume, reservoir function fell by 8% (P<0.02) and early conduit function rose by 23% (P>0.006), resulting in a rise in the early conduit-to-reservoir ratio from 0.43 ± 0.49 to 0.62 ± 0.69 (P<0.02). The RVP-RAP gradient at maximum RA volume had a similar effect, increasing the early conduit-to-reservoir ratio from 0.42 ± 0.50 to 0.64 ± 0.69 (P<0.004). Discussion Previous studies have demonstrated that pericardial integrity can have a profound effect on the interplay between various cardiac chambers and, when lost, can decrease the adaptive capacity of the atrium to stress (1,3,11,16). In an earlier report from this laboratory, it was noted that RA contractility (atrial kick) fell by 54% and RA compliance rose by 39% following pericardiotomy (24). In the current study, without pericardial restraint, the atrium acted more as a reservoir than a conduit; the RA early conduit-to-reservoir ratio fell from 0.56 ± 0.22 to 0.21 ± 0.15 (P<0.006). Likely, the pericardium has a greater effect on the thin-walled atria than on the thick-walled ventricles. Nagano and coauthors found in normal subjects that the left atrium was Gaynor et al … Page 9 of 25 less compliant than the left ventricle, facilitating blood transfer between the chambers during the early conduit phase (28). It is not surprising, however, that others have suggested that increased atrial compliance, which promotes reservoir function (17,37), would have a greater positive impact on cardiac output than would supplementation of conduit function (2,36). Hoit and colleagues examined left atrial mechanics during left ventricular dysfunction, comparing the compensatory response with a normal atrium versus a failing atrium (induced with rapid atrial pacing) (14). With a normal atrium, reservoir function increased by 19% and booster pump function (atrial contraction) nearly doubled to maintain cardiac output despite a fall in left ventricular ejection fraction from 0.57 to 0.32. In contrast, with a failing atrium, reservoir function fell by 30%, conduit function increased by 33%, and the atrial kick disappeared. The shift from reservoir to conduit function in Hoit’s study was inadequate to maintain cardiac output, which fell by 20%. In the current report, cardiac output was inversely related to the conduit-toreservoir ratio, increasing as the reservoir contribution increased (p<0.03). These findings support the theory of Suga and others that a “flexible atrium” would substantially improve the heart’s output (2,16,33,36,38). The proper physiologic explanation of right heart AV valve mechanics is that the valve leaflets open when ventricular pressure drops below atrial pressure and coapt and close when ventricular pressure exceeds atrial pressure during systole (9,39). In the current study, RA volume reached its maximum and began to fall when the RVP-RAP gradient was 0.53 mmHg on average. It is important to note, however, that the time of maximum RA volume does not necessarily correspond to the time of tricuspid valve opening. On the left side of the heart, Karlsson and associates, using myocardial markers on the mitral valve, demonstrated that the mitral valve moves towards its open position in the isovolumic phase, but that the leaflets do not separate until minimum LV pressure is obtained (21). A similar phenomenon could occur on the right side of the heart with the tricuspid valve, and the RA appendage may also play a role. Hoit and colleagues elegantly demonstrated the impact of the LA appendage on LA compliance and Gaynor et al … Page 10 of 25 LV filling (17). In the current study, the RA conductance catheter was placed into the atrium via the appendage and secured with a purse string. With this technique, we could not be certain that the entire contents contained within the appendage were included in the volume measured using the conductance catheter. Thus, it is possible that at the time of maximum RA volume, blood may have been moving from the chamber into the appendage, giving the illusion of RA emptying. In the current study, while there was a shift towards reservoir function with partial PA occlusion, it was noted that as the RVP-RAP gradient at the time of maximum RA volume increased, the atrium functioned more as a conduit than a reservoir. As the atrium fills during the reservoir phase, it has been suggested that, like the ventricle, the atrial myocardium stores elastic energy that is released when the tricuspid valve opens to aid early ventricular filling (2,10). Presumably, as the RVP-RAP gradient at the time of maximum RA volume increases, the atrium has to work harder to move the same amount of blood across the tricuspid valve. Acutely, the right atrium has not had time to adapt, and the elastic recoil stored during the reservoir phase may not be adequate to support ventricular filling. Potentially through a rise in RV suction, the ventricle could actively draw blood into itself through the atrium directly from its inflow source, the systemic venous circulation, expressed as an increase in RA early conduit function. Pressure clamping studies on the right side of the heart would be necessary to prove these theories (19,20,27,29). Nishikawa and coauthors demonstrated that with exercise, LA reservoir function increased by 37% and LA conduit function decreased by 23% (30). Although Nishikawa did not measure PA pressures, others have demonstrated that substantial pulmonary hypertension can develop during exercise, especially in subjects with abnormal hearts (7,18,23,32). For example, in heart transplant recipients, Pflugfelder and colleagues noted that peak exercise produced a 90% increase in mean PA pressure with a three-fold rise in RAP (32). In the current report, when RAP at the time of maximum RA volume exceeded 4.2 mmHg, reservoir function rose by 12%, early conduit function fell by 25%, and the early conduit-to-reservoir ratio decreased from 0.65 to 0.40. Gaynor et al … Page 11 of 25 The redistribution of conduit to reservoir function during exercise was similar to the findings of the current study during partial PA occlusion, in which the atrium acted more as a reservoir than a conduit. With partial PA occlusion, the early conduit-to-reservoir ratio fell from 0.56 ± 0.13 to 0.33 ± 0.22 (P<0.03). Grant and associates demonstrated that the left atrium acted as a short-term storage reservoir and that atrial reservoir function was four times more important than active atrial contraction in providing energy for the work of ventricular filling (10). Reservoir function also provides capacitance to dampen irregularities of atrial filling and prevent acute elevations of central venous pressure. With chronic exposure to elevated pulmonary pressures, changes in the biochemical properties and myocardial fiber structure of the right atrium likely occur to make it a more efficient capacitor, but future studies will be necessary to delineate the mechanistic adaptive response of the right atrium to chronic pulmonary hypertension (6,22). Potential Limitations. As with all open-chest physiology studies in anesthetized animals, there are potential difficulties in translating results to the closed-chest human clinical setting. However, pericardial integrity was maintained through most of the preparation in an attempt to best mimic the natural in vivo state, and although pericardial pressures were not measured, we suspect that the use of transmural pressures (subtracting pericardial pressure from intracavitary pressure) would have demonstrated similar results. In addition, while this study examined only subjects with acute pulmonary hypertension, we anticipate that subjects with chronic pulmonary hypertension and other diseases that impair the right heart may be even more dependent on the atrium’s ability to variably function more as a reservoir or a conduit. While we did not quantify booster pump function (atrial contraction) in the current report, its contribution to ventricular filling and cardiac output can be quite important. Active atrial contraction increases stroke volume by 10% to 20% (30,34), a contribution that increases via the Frank-Starling mechanism following ventricular ischemia (25) and becomes more important to maintain filling with advanced age and when the ventricle either dilatates or hypertrophies Gaynor et al … Page 12 of 25 (14,34). We have previously shown that atrial contraction increases with acute pulmonary hypertension to support ventricular filling, but falls when pericardial integrity is lost (24). The late conduit phase reported in the current study quantifies RA inflow during atrial contraction. On the left side of the heart, reversed flow is common in the pulmonary veins during the atrial kick, but it disappears with exercise (30). Nishikawa and associates found that the minimum pulmonary venous flow rate rose progressively with increasing levels of exertion (30). In the current report examining the right side of the heart, reversal of flow in the vena cavae was rare, occurring during the late conduit phase in only 29 of 653 (4%) steady-state beats, more often during inotropic stimulation (7 of 45 beats, 16%) and partial PA occlusion (12 of 166, 7%) than during baseline with the pericardium closed (8 of 267, 3%) or open (2 of 175, 1%). In summary, this study demonstrated that the right atrium adjusts its ability to act more as a reservoir versus a conduit in a dynamic manner, dependent not only on global physiologic changes, but on beat-to-beat changes in the pressure differential between the right-sided chambers. The RA conduit-to-reservoir ratio was directly related to the RVP-RAP gradient at the time of maximum RA volume, with increased ventricular pressures favoring conduit function, but it was inversely related to cardiac output, with an increase in the reservoir contribution favoring increased cardiac output. While this study examined subjects exposed to acute physiologic changes, we anticipate an even more profound impact of RA reservoir and conduit function on RV filling and cardiac output during chronic disease states that impair right heart mechanics. ACKNOWLEDGMENTS This study was supported by grant HL-69949 from the National Heart, Lung, and Blood Institute of the National Institutes of Health and by a Foundation Research Grant from the Thoracic Surgery Foundation for Research and Education. Drs. Gaynor and Maniar were also supported in part by grant T32-HL-07776 from the National Heart, Lung, and Blood Institute. The authors gratefully acknowledge Martha L. Lester, BS and Celeste M. Chu, BS for their assistance in the surgical preparation as well as the technical assistance of Diane Toeniskoetter and Kathy Fore. Gaynor et al … Page 13 of 25 REFERENCES 1. Applegate RJ, Johnston WE, Vinten-Johansen J, Klopfenstein HS, and Little WC. Restraining effect of intact pericardium during acute volume loading. Am J Physiol Heart Circ Physiol 262:H1725-H1733, 1992. 2. Barbier P, Solomon SB, Schiller NB, and Glantz SA. Left atrial relaxation and left ventricular systolic function determine left atrial reservoir function. Circulation 100:427436, 1999. 3. Bove AA and Santamore WP. Ventricular interdependence. Prog Cardiovasc Dis 23:365388, 1981. 4. Bowman AW and Kovacs SJ. The left atrial conduit volume is generated by deviation from the constant-volume state of the left heart: A combined MRI-echocardiographic study. Am J Physiol Heart Circ Physiol 2004 (in press). 5. Carlson DE, Burchard KW, and Gann DS. Right atrial volume during hemorrhage in the dog. Am J Physiol Heart Circ Physiol 250:H1136-H1144, 1986. 6. De Vroomen M, Steendijk P, Cardozo RHL, Brouwers HA, Van Bel F, Baan J. Enhanced systolic function of the right ventricle during respiratory distress syndrome in newborn lambs. Am J Physiol Heart Circ Physiol 280;H392-H400, 2001. 7. Elkayam U, Roth A, Weber L, Hsueh W, Nanna M, Freidenberger L, Chandraratna PA, and Rahimtoola SH. Isometric exercise in patients with chronic advanced heart failure. Hemodynamic and neurohumoral evaluation. Circulation 72:975-981, 1985. 8. Ferguson JJ, Miller MJ, Aroesty JM, Sahagian P, Grossman W, and McKay RG. Assessment of right atrial pressure-volume relations in patients with and without an atrial septal defect. J Am Coll Cardiol 13:630-636, 1989. 9. Fung YC. Biodynamic Circulation. 2nd Edition, New York, NY, Springer-Verlag, 1997, p.36-49. Gaynor et al … Page 14 of 25 10. Grant C, Bunnell IL, and Greene DG. The reservoir function of the left atrium during ventricular systole. An angiocardiographic study of atrial stroke volume and work. Am J Med 37:36-43, 1964. 11. Hamilton DR, Dani RS, Semlacher RA, Smith ER, Kieser TM, and Tyberg JV. Right atrial and right ventricular transmural pressures in dogs and humans. Effects of the pericardium. Circulation 90:2492-2500, 1994. 12. Harvey W. An Anatomical Study of the Movement of the Heart and Blood in Animals (1628). Translated by Leake CD. Baltimore, MD, Charles C. Thomas, 1928, p.123. 13. Hitch DC and Nolan SP. Descriptive analysis of instantaneous left atrial volume – with special reference to left atrial function. J Surg Res 30:110-120, 1981. 14. Hoit BD and Gabel M. Influence of left ventricular dysfunction on the role of atrial contraction. An echocardiographic-hemodynamic study in dogs. J Am Coll Cardiol 36:17131719, 2000. 15. Hoit BD, Shao Y, and Gabel M. Left atrial systolic and diastolic function accompanying chronic rapid pacing-induced atrial failure. Am J Physiol Heart Circ Physiol 275:H183H189, 1998. 16. Hoit BD, Shao Y, Gabel M, and Walsh RA. Influence of pericardium on left atrial compliance and pulmonary venous flow. Am J Physiol Heart Circ Physiol 264:H1781H1787, 1993. 17. Hoit BD, Shao Y, Tsai L, Patel R, Gabel M, and Walsh RA. Altered left atrial compliance after atrial appendectomy. Influence on left atrial and ventricular filling. Circ Res 72:167175, 1993. 18. Hosenpud JD, Morton MJ, Wilson RA, Pantely GA, Norman DJ, Cobanoglu MA, and Starr A. Abnormal exercise hemodynamics in cardiac allograft recipients one year after cardiac transplantation. Relation to preload reserve. Circulation 80:525-532, 1989. Gaynor et al … Page 15 of 25 19. Ingels NB, Daughters GT, Nikolic SD, DeAnda A, Moon MR, Bolger AF, Komeda M, Derby GC, Yellin EL, and Miller DC. Left atrial pressure-clamp servomechanism demonstrates LV suction in canine hearts with normal mitral valves. Am J Physiol Heart Circ Physiol 267:H354-H362, 1994. 20. Ingels NB, Daughters GT, Nikolic SD, DeAnda A, Moon MR, Bolger AF, Komeda M, Derby GC, Yellin EL, and Miller DC. Left ventricular diastolic suction with zero left atrial pressure in open-chest dogs. Am J Physiol Heart Circ Physiol 270;H1217-H1224, 1996. 21. Karlsson MO, Glasson JR, Bolger AF, Daughters GT, Komeda M, Foppiano LE, Miller DC, and Ingels NB. Mitral valve opening in the ovine heart. Am J Physiol Heart Circ Physiol 274;H552-H563, 1998. 22. Leeuwenburgh BPJ, Helbing WA, Steendijk P, Schoof PH, and Baan J. Biventricular systolic function in young lambs subject to chronic systemic right ventricular pressure overload. Am J Physiol Heart Circ Physiol 281;H2697-2704, 2001. 23. Mabee SW, Metra M, Reed DE, Dei Cas L, and Cody RJ. Pulmonary hypertension and systemic hypotension as limitations to exercise in chronic heart failure. J Card Fail 1:27-33, 1994. 24. Maniar HS, Prasad SM, Gaynor SL, Chu CM, Steendijk P, and Moon MR. Impact of pericardial restraint on right atrial mechanics during acute right ventricular pressure load. Am J Physiol Heart Circ Physiol 284:H350-H357, 2003. 25. Matsuda Y, Toma Y, Ogawa H, Matsuzaki M, Katayama K, Fujii T, Yoshino F, Moritani K, Kumada T, and Kusukawa R. Importance of left atrial function in patients with myocardial infarction. Circulation 67:566-571, 1983. 26. Miller MJ, McKay RG, Ferguson JJ, Sahagian P, Nakao S, Come PC, and Grossman W. Right atrial pressure-volume relationships in tricuspid regurgitation. Circulation 73:799808, 1986. Gaynor et al … Page 16 of 25 27. Moon MR, Bolger AF, DeAnda A, Komeda M, Daughters GT, Nikolic SD, Miller DC, and Ingels NB. Septal function during left ventricular unloading. Circulation 95:1320-1327, 1997. 28. Nagano T, Arakawa M, Tanaka T, Yamaguchi M, Takaya T, Noda T, Miwa H, Kagawa K, and Hirakawa S. Diastolic compliance of the left atrium in man. A determinant of preload of the left ventricle. Heart and Vessels 5:25-32, 1989. 29. Nikolic SD, Yellin EL, Tamura K, Vetter H, Tamura T, Meisner JS, and Frater RWM. Passive properties of canine left ventricle. Diastolic stiffness and restoring forces. Circ Res 62:1210-1222, 1988. 30. Nishikawa Y, Roberts JP, Tan P, Klopfenstein CE, and Klopfenstein HS. Effect of dynamic exercise on left atrial function in conscious dogs. J Physiol 481:457-468, 1994 31. Nolan SP, Dixon SH, Fischer RD, and Morrow AG. The influence of atrial contraction and mitral valve mechanics on ventricular filling. A study of instantaneous mitral valve flow in vivo. Am Heart J 77:784-791, 1969. 32. Pflugfelder PW, McKenzie FN, and Kostuk WJ. Hemodynamic profiles at rest and during supine exercise after orthotopic cardiac transplantation. Am J Cardiol 61:1328-1333, 1988. 33. Prioli A, Marino P, Lanzoni L, and Zardini P. Increasing degrees of left ventricular filling impairment modulate left atrial function in humans. Am J Cardiol 82:756-761, 1998. 34. Spencer KT, Mor-Avi V, Gorcsan J, DeMaria AN, Kimball TR, Monaghan MJ, Perez JE, Weinert L, Bednarz J, Edelman K, Kwan OL, Glascock B, Hancock J, Baumann C, and Lang RM. Effects of aging on left atrial reservoir, conduit, and booster pump function. A multi-institution acoustic quantification study. Heart 85:272-277, 2001. 35. Steendijk P, Staal E, Jukema JW, and Baan J. Hypertonic saline method accurately determines parallel conductance for dual-field conductance catheter. Am J Physiol Heart Circ Physiol 281:H755-H763, 2001. 36. Suga H. Importance of atrial compliance in cardiac performance. Circ Res 35:39-43, 1974. Gaynor et al … Page 17 of 25 37. Tabata T, Oki T, Yamada H, Iuchi A, Ito S, Hori T, Kitagawa T, Kato I, Kitahata H, and Oshita S. Role of left atrial appendage in left atrial reservoir function as evaluated by left atrial appendage clamping during cardiac surgery. Am J Cardiol 81:327-332, 1998. 38. Thomas JD, Choong CYP, Flachskampf FA, and Weyman AE. Analysis of the early transmitral Doppler velocity curve. Effect of primary physiologic changes and compensatory preload adjustment. J Am Coll Cardiol 16:644-655, 1990. 39. Wiggers CJ. Studies on the consecutive phases of the cardiac cycle. I. The duration of the consecutive phases of the cardiac cycle and the criteria for their precise determination. Am J Physiol 56:415-438, 1921. Gaynor et al … Page 18 of 25 TABLE 1. Hemodynamic effects of inotropic stimulation with calcium chloride, acute partial PA occlusion, and pericardiotomy. Baseline Pericardium Closed Pericardium Open Calcium PA Occlusion Baseline Heart rate (beats/min) 104 ± 32 105 ± 12 101 ± 20 119 ± 22 RA filling time (msec) 342 ± 67 344 ± 71 349 ± 31 363 ± 43 RA emptying time (msec) 208 ± 91 235 ± 64 228 ± 62 205 ± 51 Mean RA pressure (mmHg) 4.1 ± 1.7 4.6 ± 1.7 4.7 ± 1.7 5.2 ± 2.1 Maximum RV pressure (mmHg) 25 ± 6 35 ± 9* 38 ± 10* 22 ± 3 Maximum RA dP/dt (mmHg/s) 177 ± 56 225 ± 73 214 ± 68 1563 ± 188* 1472 ± 274 997 ± 173* 37.3 ± 9.6 36.8 ± 9.8 33.5 ± 6.5 38.8 ± 6.7 3.7 ± 1.2 3.8 ± 0.8 3.3 ± 0.8 4.5 ± 0.9 Maximum RV dP/dt (mmHg/s) 1245 ± 423 Total RA inflow (mL/beat) Cardiac output (mL/min) 223 ± 94 Values are means ± SD. n = 9 for pericardium closed and 7 for pericardium open. PA, pulmonary artery; RA, right atrial; RV, right ventricular. *P<0.05 versus pericardium closed baseline. Repeated measures ANOVA was used for all comparisons. Gaynor et al … Page 19 of 25 TABLE 2. Effects of inotropic stimulation with calcium chloride, acute partial PA occlusion, and pericardiotomy on RA reservoir and conduit function. Baseline Pericardium Closed Pericardium Open Calcium PA Occlusion Baseline reservoir volume (mL) 21.1 ± 6.8 23.2 ± 6.7 early conduit volume (mL) 11.2 ± 5.5 11.0 ± 6.0 late conduit volume (mL) 5.3 ± 2.4 reservoir function 21.5 ± 4.3 27.4 ± 3.9 7.0 ± 4.7* 5.8 ± 4.3* 3.0 ± 1.0* 5.4 ± 1.3 5.9 ± 2.6* 0.56 ± 0.13 0.63 ± 0.10 0.64 ± 0.08 0.72 ± 0.08* early conduit function 0.29 ± 0.07 0.29 ± 0.11 0.20 ± 0.11* 0.14 ± 0.09* late conduit function 0.16 ± 0.11 0.09 ± 0.04 0.17 ± 0.06 0.15 ± 0.07 0.56 ± 0.22 0.50 ± 0.26 0.33 ± 0.22* 0.21 ± 0.15* -------------------------------------- -------------------------------------early conduit-to-reservoir Values are means ± SD. n = 9 for pericardium closed and 7 for pericardium open. PA, pulmonary artery; RA, right atrial. *P<0.05 versus pericardium closed baseline. Repeated measures ANOVA was used for all comparisons. Gaynor et al … Page 20 of 25 TABLE 3. Effects of RA and RV hemodynamics at the time of maximum RA volume on RA reservoir and conduit function. Reservoir Early conduit Late conduit RA pressure at maximum RA volume < 4.2 mmHg 0.58 ± 0.18 0.28 ± 0.16 0.15 ± 0.13 > 4.2 mmHg 0.65 ± 0.15* 0.21 ± 0.11* 0.15 ± 0.12 RV pressure at maximum RA volume < 5.8 mmHg 0.64 ± 0.16 0.22 ± 0.12 0.15 ± 0.15 > 5.8 mmHg 0.59 ± 0.17* 0.27 ± 0.16* 0.15 ± 0.09 RV-RA pressure at maximum RA volume < 0.53 mmHg 0.66 ± 0.14 0.22 ± 0.12 0.13 ± 0.10 > 0.53 mmHg 0.57 ± 0.18* 0.27 ± 0.16* 0.17 ± 0.14* Values are means ± SD. n = 254 including all baseline, calcium chloride, and partial pulmonary artery occlusion runs with and without pericardial integrity. PA, pulmonary artery; RA, right atrial; RV, right ventricular. *P<0.05 for higher values versus lower values. ANOVA was used for all comparisons. Gaynor et al … Page 21 of 25 FIGURE LEGENDS FIGURE 1: Typical hemodynamic data with the pericardium intact during the baseline state in one animal from this study. Three steady-state beats are illustrated. The reservoir phase extends from the ECG R-wave to time of maximum RA volume (corresponding to tricuspid valve opening). The conduit phase contains two components, the early phase, from the time of maximum RA volume to the A-wave (maximum RA dP/dt), and the late phase, from the A-wave to the end of RV filling (the subsequent ECG R-wave). FIGURE 2: Effects of inotropic stimulation with calcium chloride, acute partial PA occlusion, and pericardiotomy on RA reservoir and conduit function. Data represent mean values for reservoir (black, bottom), early conduit (white, middle), and late conduit (grey, top) contribution as a percentage of total RA inflow during each intervention. FIGURE 3: Effects of inotropic stimulation with calcium chloride, acute partial PA occlusion, and pericardiotomy on RA early conduit-to-reservoir ratio. Values are means ± SD. * P<0.05 versus pericardium closed baseline (repeated measures ANOVA). FIGURE 4: Linear regression analysis comparing the RA conduit-to-reservoir ratio to cardiac output. As the RA conduit-to-reservoir ratio increased, cardiac output decreased. Gaynor et al … Page 22 of 25 Figure 1: Gaynor et al … Page 23 of 25 Figure 2: Gaynor et al … Page 24 of 25 Figure 3: Gaynor et al … Page 25 of 25 Figure 4: