Afterload Pressure and Left Ventricular Contractility Synergistically Affect Left Atrial Pressure During Veno-Arterial Extra-Corporeal Membrane Oxygenation

Afterload Pressure and Left Ventricular Contractility Synergistically Affect Left Atrial Pressure During Veno-Arterial Extra-Corporeal Membrane Oxygenation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Afterload Pressure and Left Ventricular Contractility Synergistically Affect Left Atrial Pressure During Veno-Arterial Extra-Corporeal Membrane Oxygenation Jacky Jiang, Pankaj Jain, Audrey Adji, Michael Stevens, Gabriel Matus Vazquez, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2379607/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) may cause adverse effects including increased left ventricular (LV) filling pressure, LV distension and pulmonary oedema. We aimed to quantify the effects of ECMO flow, LV contractility, aortic pressure (AoP) and ECMO configuration on left atrial pressure (LAP) during VA-ECMO for cardiogenic shock in a mock circulatory loop (MCL). Methods: An MCL simulated a normal state, LV failure, right ventricular failure and biventricular failure. The ECMO return cannula was placed in the femoral artery (retrograde flow) or ascending aorta (antegrade flow). ECMO flow was incrementally increased from 0 to 5L/min. LAP, mean AoP, ECMO flow and total cardiac output were measured at steady state. Results: During VA-ECMO, LAP increased linearly with AoP, with the slope greater in the presence of LV impairment compared to preserved LV function. When AoP was held constant, as is the goal of therapy in clinical management, ECMO flow had no effect on LAP. In multivariable linear regression, AoP and LV contractility (p<0.001 for each) correlated independently with LAP, but ECMO flow did not. ECMO return flow direction had no effect on LAP. Conclusion: AoP and LV contractility, but not circuit flow or direction, independently determine LAP under VA-ECMO support. By controlling each of these inputs, vasodilator and inotrope management may combine synergistically to prevent VA-ECMO-related complications. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) is a cornerstone in the management of patients with severe cardiogenic shock 1 – 3 . Despite its use having increased substantially, survival with VA-ECMO remains poor with approximately 40% of patients surviving to hospital discharge 1 . While VA-ECMO is able to provide full cardiopulmonary support, it is also associated with a range of adverse haemodynamic and clinical effects, including left ventricular (LV) distension, thrombus formation and pulmonary oedema 4 . These effects are thought to be primarily driven by increased afterload due to retrograde flow from the VA-ECMO return cannula, resulting in reduced LV stroke volume and subsequent elevation of diastolic LV pressure and volume 1 , 5 , 6 . Important questions remain unanswered however, including: whether afterload and LV contractility have synergistic effects; whether the direction of ECMO return flow is significant; and whether ECMO flow itself is an independent determinant of LV filling pressure. Several measures are already utilised in the clinical setting to mitigate the risk of LV distension and its associated complications. These range from simple measures such as reducing ECMO flow and administration of vasodilators and/or inotropes, to progressively more invasive and costly measures including intra-aortic balloon pump, transvalvular microaxial ventricular assist devices, and direct surgical ‘venting’ of the LV 7 , 8 . A more complete understanding of the effects of hemodynamic and VA-ECMO operating conditions on LV preload is necessary to ensure optimal efficacy and resource utilization associated with these measures. Mock circulatory loops (MCLs) allow for precise control of a number of hemodynamic and circuit-related variables and systematic assessment of the interactions between mechanical circulatory support devices and the cardiovascular system, and have previously been used to investigate the effects of different VA-ECMO unloading techniques and cannula properties 9 – 12 . We sought to utilize an MCL to systematically assess the effects of changes in afterload pressure, ventricular contractility, and ECMO flow and direction on left atrial pressure (LAP) during VA-ECMO support. Methods Mock Circulatory Loop Design The MCL used in this study has been previously described in detail by Shehab et al 13 . Briefly, the left and right ventricles were constructed using a truncated ellipsoid-shaped deformable silicon diaphragm encased inside a transparent sealed air chamber. Ventricular contractility was achieved by external electropneumatic (EP) compression using a proprietary programmed air delivery system (Simulink, The MathWorks Inc, Natick MA). The EP regulators were programmed to deliver cyclic air pressure waveforms to each ventricle to create realistic systolic and diastolic pressures. These waveforms were then scaled by a multiplier (LV and RV Gain) to achieve pathologic ventricular function. Four identical hermetically sealed, cylinder-shaped Windkessel chambers (100mm diameter x 320mm height) were used to simulate aortic, systemic venous, pulmonary arterial and pulmonary venous compliance. The circuit in this study included separate upper and lower body systemic circulations. Systemic (SVR) and pulmonary vascular resistance (PVR) were created using tuning clamps placed on the systemic and pulmonary arterial limbs respectively. The MCL was filled with 5L of 40–60%wt glycerol-water solution, maintained at 37°C by a JB Nova JBN12 Water Bath (Grant Instruments Ltd, Cambridge, UK) to simulate the viscosity of blood with a haematocrit of 34%. The MCL included an ECMO circuit consisting of PVC Tygon tubing, draining from the right atrium and with arterial return limbs to the femoral artery and proximal aorta. Tuning clamps were placed on each arterial return limb, allowing for switching between retrograde and antegrade ECMO flow. A HeartWare HVAD (Medtronic, Minneapolis, MN) was placed within the circuit to simulate the centrifugal pump in an ECMO system. This HVAD was connected to a controller and monitor which allowed for adjustment of pump speed from 1800 to 4000 revolutions per minute (RPM). A schematic of the MCL in conventional VA-ECMO configuration is shown in Fig. 1 . ECMO flow and cardiac output were measured by BioProTT Clamp-On Transducers (em-tec GmbH, Finning, Germany) one placed distal to the HVAD pump within the ECMO circuit, and the other between the systemic venous compliance chamber and the right ventricle. Aortic pressure (AoP), left atrial pressure (LAP), and right atrial pressure (RAP) were measured using fluid-filled pressure transducers. Experimental Method The MCL was run in steady state, with real-time flow waveforms and pressures monitored by dSpace ControlDesk (dSpace GmbH, Paderborn, Germany). Four cardiac conditions were simulated: 1) normal function (LAP and RAP between 5–10 mmHg), 2) left ventricular failure (LVF) (LAP > 20mmHg, RAP < 10mmHg), 3) right ventricular failure (RVF) (LAP 20mmHg), and 4) biventricular failure (BVF) (LAP and RAP > 20mmHg). These conditions were achieved by altering LV and RV contractilities, SVR, PVR and compliances. Heart rate was maintained at 60 beats per minute. Mean AoP prior to commencement of VA-ECMO flow was set to either 50, 70 or 90mmHg by adjusting SVR. In each experiment, ECMO flow was varied by adjusting HVAD pump speed, to targets of 0, 2, 3, 4 and 5L/min. Four experiments were performed. In Experiment 1, ECMO flow was incrementally increased and SVR, while compliances and contractility were kept constant within each heart failure state. In experiment 2, SVR was adjusted to maintain constant AoP with increasing ECMO flow. In experiment 3, LV contractility was incrementally reduced from reduced from normal to severely impaired by scaling down the voltage delivered to the LV EP by 33%. In experiment 4, return flow was adjusted from retrograde to antegrade while resistances, compliances and contractility were kept constant. Table S1 in the Supplementary Appendix summarizes these experiments, and the specific combinations of heart failure state, ECMO configuration, ECMO flow direction, mean AoP, and ECMO flow rate examined in each. Data Acquisition and Analysis Flow and pressure waveforms were recorded using dSpace ControlDesk while pump speed was recorded from the HVAD controller. All data was processed in MATLAB (MathWorks, Natick, MA) and analysed using SPSS Statistics 29 (IBM, Armonk, New York). The means of the pressures and flows within each experiment were calculated and used for comparison. The primary dependent variable of interest was LAP. To compare means between groups, paired t-test or one-way analysis of variance (ANOVA) were used as appropriate. Simple linear regressions were used to ascertain relationships between continuous variables. Multiple linear regression was used to determine independent predictors of the dependent variable. For all statistical tests, a p-value < 0.05 was considered statistically significant. Results Left Atrial Pressure and Aortic Pressure The relationship between LAP and AoP is illustrated in Fig. 2 . In Fig. 2 A, data from Experiment 1 is divided in binary fashion, into ‘LV Normal’ (comprising ‘Normal’ and ‘RVF’ states) and ‘LV Impaired’ (comprising LVF and BVF states). Within each subgroup, LAP increases linearly with increased AoP (r 2 = 0.814 for LV Normal; r 2 = 0.855 for LV impaired, p < 0.001 for each). The slope of this relationship is nearly threefold higher for the LV Impaired subgroup (0.41) compared to the LV Normal subgroup (0.15). In Experiment 3, LV contractility was adjusted incrementally from normal (LV Gain 2.4) to severely impaired (LV Gain 1.6). There is a corresponding increase in the slope of the LAP-AoP relationship (Fig. 2 B), consistent with effect modification of contractility on this linear relationship. Left Atrial Pressure and ECMO Flow Rate The relationship between LAP and VA-ECMO flow rate is summarized in Fig. 3 . When SVR is held constant and mean AoP is uncontrolled, increased ECMO flow is associated with a numerical but not statistically significant increase in LAP (p = 0.684, Fig. 3 A). However, when SVR is varied to allow constant mean AoP with increased ECMO flow, there is no corresponding increase in LAP (p = 0.999, Fig. 5B). Left Atrial Pressure and Right Atrial Pressure In Experiment 1, LAP decreased linearly as RAP increased (r 2 = 0.327, p < 0.001). When the data was stratified according to LV function, both ‘LV Normal’ and ‘LV impaired’ subgroups demonstrated a negative, linear association between LAP and RAP (r 2 = 0.682 for LV normal; r 2 = 0.523 for LV impaired, p < 0.001 for both). The slope of this linear relationship was steeper in the LV impaired subgroup (-0.60 vs -0.22) consistent with greater sensitivity of the impaired LV to changes in RAP. Retrograde and Antegrade VA-ECMO flow The effects of ECMO return flow direction on LAP were explored in Experiment 4. There was no significant difference between retrograde and antegrade return flow in terms of LAP (p = 0.11), mean AoP (p = 0.06) or total cardiac output (p = 0.06). There was a small but statistically significant increase in ECMO flow with antegrade return compared to retrograde return (3.5 vs 3.4L/min, p = 0.001). Multivariable model to predict LAP A multiple linear regression model using data from Experiment 1 incorporated AoP, LV gain, ECMO flow rate and RAP as independent variables. AoP ((β = 0.556, p < 0.001) and LV gain (β = -0.695, p < 0.001), but not RAP (β = -0.114, p = 0.242) or ECMO flow rate (β = -0.069, p = 0.326) were independent predictors of LAP (r 2 for model = 0.852, p < 0.001). These results are summarized in Fig. 4 . Discussion Despite its role as a cornerstone of the management of severe cardiogenic shock, VA-ECMO continues to be associated with a high mortality and complication rate. Complications associated with impaired LV ejection and elevated LV filling pressure – including thrombus formation and pulmonary oedema – are well recognized. Understanding the haemodynamic and circuit-related factors that contribute to elevation of LV filling pressure is critical to the rational, pre-emptive application of mitigation strategies, including mechanical unloading devices. In the absence of hemodynamic data beyond in-silico simulations, use of these devices is guided by expert opinion. This has resulted in a high degree of inter-institutional variability, and a sharp recent increase in the use of percutaneous left ventricular assist devices (pVADs) with their associated increased cost and complication rates 7 . More robust physical data – in-vitro and in-vivo – is needed. In this context, the primary findings of this MCL study are: 1) under VA-ECMO support, aortic pressure and LV contractility independently correlate with LAP; 2) the effect of aortic pressure is mediated by LV contractility; 3) VA-ECMO flow rate does not independently affect LAP; and 4) direction of VA-ECMO flow does not affect LAP. AoP and LV contractility independently predict LAP during VA-ECMO Using an in-silico model, Dickstein demonstrated that, assuming a constant Frank-Starling relationship, the increase in pulmonary capillary wedge pressure (PCWP) following VA-ECMO initiation is dependent on both baseline LV function and the degree of AoP elevation 6 . In our study, LV contractility and AoP were independent predictors of LAP, confirming the findings of Dickstein in a physical model of the circulation. Of note, the consistency of findings between Dickstein’s model and ours occurred despite our model not incorporating Frank-Starling forces. Our results extend those of Dickstein, by demonstrating an incremental steepening of the slope of the linear AoP-LAP relationship with reduction in LV contractility. These findings suggest that LV contractility acts as an effect modifier on the AoP-LAP relationship, pointing to a synergistic effect between LV contractility and AoP on the risk of elevated LV filling pressure. In the clinical setting, these results highlight the important role of inotropes and vasodilators – in combination where possible – to reduce LV pressures on VA-ECMO support. In our study, the slope of the AoP-LAP relationship in the setting of LV impairment was 0.40, suggesting that a reduction in AoP by 12.5mmHg is sufficient to achieve a clinically meaningful, 5mmHg reduction in LAP. Importantly however, clinical use of vasodilators and inotropes as first-line therapies can be limited by vasoplegia or ongoing myocardial ischaemia, respectively 1 . In-vivo pre-clinical and clinical data are needed to determine a dose-response relationship between afterload and LV filling pressure reduction, and to determine the optimal target AoP and inotrope dose. Flow rate and direction do not predict LAP during VA-ECMO When AoP was held constant, increased ECMO flow rate had no effect on LAP. Furthermore, in multivariable analysis, ECMO flow did not independently predict LAP. The putative effect of ECMO flow on LAP – demonstrated numerically in our study only when AoP was uncontrolled – can therefore be attributed solely to its effect on AoP. Changing the direction of ECMO return flow similarly had no effect on LAP. Taken together, these findings challenge the conventional orthodoxy that it is the retrograde nature of ECMO flow – and by extension, the amount of retrograde ECMO flow – that directly imparts afterload on the LV, therefore causing LV distension and increased filling pressure. Rather, consistent with the arguments of Dickstein 6 , our study suggests it is increased AoP, irrespective of the origin of this increase , that primarily drives changes in filling pressure. Clinically, our findings suggests that, rather than reducing ECMO flow to reduce LAP as is standard practice, the same effect could be achieved simply through pharmacologic reduction in SVR without sacrificing ECMO flow. Limitations This MCL was not designed to simulate complex regulatory adaptations, such as the baroreceptor reflex and Frank-Starling mechanism, nor the ability of VA-ECMO to produce adequate myocardial and peripheral tissue oxygenation and correct metabolic disturbance. Numerical models, hybrid MCLs and in-vivo studies may more accurately represent these biological effects 14 . Additionally, the ventricles in our MCL were connected ‘in-series’, without a common interventricular septum. Therefore, we were unable to examine the effects of ventricular interdependence, which may significantly attenuate the effects of VA-ECMO on LAP through changes in ventricular compliance 15 – 18 . Further studies simulating direct biventricular interactions and exploring the effects of VA-ECMO on biventricular pressure-volume relationships are needed. Finally, we used a HeartWare HVAD in our VA-ECMO circuit instead of a dedicated ECMO pump, although these are both centrifugal pumps and obey similar physiological and engineering principles. Implications and Future Directions These findings highlight the critical role of afterload pressure and LV contractility in determining LV preload under VA-ECMO support. In terms of clinical translation, they highlight the critical and synergistic role of vasodilators and inotropes as first-line therapies to prevent pulmonary oedema in this setting. Conversely, our results do not support the practice of altering ECMO flow in order to reduce LAP. Pre-clinical and clinical in-vivo studies are needed to establish a dose-response relationship of reduced afterload and positive inotropy on LAP, determine optimal therapeutic targets, and identify patients most likely to require escalation to more invasive measures such as mechanical unloading. Conclusion In this MCL study, LV function and afterload pressure, but not circuit flow or direction, synergistically affect LV filling pressure during VA-ECMO support. Further in-vivo studies are needed to confirm these findings and guide strategies to improve VA-ECMO outcomes. Declarations Conflict of interest statement There are no conflicts of interest relevant to this study for any authors on this manuscript Funding: There were no sources of funding for this research. Competing Interests: The authors have no relevant financial or non-financial interests to disclose. Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jacky Jiang, Pankaj Jain, Audrey Adji, Michael Stevens, Gabriel Matus Vazquez, Sumita Barua and Christopher Hayward. The first draft of the manuscript was written by Jacky Jiang and Pankaj Jain, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics Approval: This was an in-vitro mock circulatory loop study; no ethics approval was required. References Rao P, Khalpey Z, Smith R, Burkhoff D, Kociol RD (2018) Venoarterial Extracorporeal Membrane Oxygenation for Cardiogenic Shock and Cardiac Arrest. Circulation: Heart Failure 11(9):e004905 Makdisi G, Wang IW (2015) Extra Corporeal Membrane Oxygenation (ECMO) review of a lifesaving technology. J Thorac Dis 7(7):E166–E176 King CS, Roy A, Ryan L, Singh R (2017) Cardiac support: emphasis on venoarterial ECMO. Crit Care Clin 33(4):777–794 Donker DW, Sallisalmi M, Broomé M (2021) Right–Left Ventricular Interaction in Left-Sided Heart Failure With and Without Venoarterial Extracorporeal Membrane Oxygenation Support—A Simulation Study. ASAIO J 67(3):297–305 Burkhoff D, Sayer G, Doshi D, Uriel N (2015) Hemodynamics of Mechanical Circulatory Support. J Am Coll Cardiol 66(23):2663–2674 Dickstein ML (2017) The Starling Relationship and Veno-Arterial ECMO: Ventricular Distension Explained. ASAIO J 64:1 Grandin EW, Nunez JI, Willar B et al (2022) Mechanical Left Ventricular Unloading in Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation. J Am Coll Cardiol 79(13):1239–1250 Tepper S, Masood MF, Baltazar Garcia M et al (2017) Left Ventricular Unloading by Impella Device Versus Surgical Vent During Extracorporeal Life Support. Ann Thorac Surg 104(3):861–867 Azimi M, Liao S, Vatani A, Burrell A, Gregory SD (2022) Improved Flow Dynamics of Extracorporeal Membrane Oxygenation via Design Modification of Dual-Lumen Cannulas. ASAIO J. Farag J, Stephens AF, Juene Chong W, Gregory SD, Marasco SF (2022) Intra-aortic Balloon Pump Use With Extra Corporeal Membrane Oxygenation-A Mock Circulation Loop Study. ASAIO J 68(5):669–675 Stephens AF, Wanigasekara D, Pellegrino VA et al (2021) Comparison of Circulatory Unloading Techniques for Venoarterial Extracorporeal Membrane Oxygenation. ASAIO J 67(6):623–631 Stephens AF, Wickramarachchi A, Burrell AJC, Bellomo R, Raman J, Gregory SD (2022) Hemodynamics of small arterial return cannulae for venoarterial extracorporeal membrane oxygenation. Artif Organs 46(6):1068–1076 Shehab S, Allida SM, Davidson PM et al (2017) Right Ventricular Failure Post LVAD Implantation Corrected with Biventricular Support: An In Vitro Model. ASAIO J 63(1):41–47 Cappon F, Wu T, Papaioannou T, Du X, Hsu PL, Khir AW (2021) Mock circulatory loops used for testing cardiac assist devices: A review of computational and experimental models. Int J Artif Organs 44(11):793–806 Brinker JA, Weiss JL, Lappé DL et al (1980) Leftward septal displacement during right ventricular loading in man. Circulation 61(3):626–633 Damiano RJ Jr, La Follette P Jr, Cox JL, Lowe JE, Santamore WP (1991) Significant left ventricular contribution to right ventricular systolic function. Am J Physiol 261(5 Pt 2):H1514–1524 Summer WR, Permutt S, Sagawa K, Shoukas AA, Bromberger-Barnea B (1979) Effects of spontaneous respiration on canine left ventricular function. Circ Res 45(6):719–728 Weyman AE, Wann S, Feigenbaum H, Dillon JC (1976) Mechanism of abnormal septal motion in patients with right ventricular volume overload: a cross-sectional echocardiographic study. Circulation 54(2):179–186 Supplementary Files TableS1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2379607","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":162043101,"identity":"daef5002-3f2d-4f57-b4b0-d3825a633cd2","order_by":0,"name":"Jacky Jiang","email":"","orcid":"","institution":"University of New South Wales","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jacky","middleName":"","lastName":"Jiang","suffix":""},{"id":162043102,"identity":"5ce5f757-b591-448f-869c-7019f284a5e4","order_by":1,"name":"Pankaj Jain","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYHACZgYGHgk5+/YGINvAgmgtFsYGPAdAWiSI1cJQkbhBIgHEIUKLOfvZwwY/ZCSMzSWfX93wo0CCgb+9OwGvFsuevOTEHqBfLGfnlN3sATpM4szZDXi1GBzIMT7AwyNhzHA7J+0GD1CLgUQuAS3n3xgf/MMjkdhw80zazT9EabmRY5wMtCVxww32Y7eJssVyxhtjYxmgwyR7cthuyxhI8BD0izl/jrHk2546OX72489uvvljI8ff3kvAYSCCsQdE8oDZPHiVw7Uw/AAR7A8Iqh4Fo2AUjIKRCQC6GkSDJ+o3KwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-4867-1773","institution":"University of New South Wales","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Pankaj","middleName":"","lastName":"Jain","suffix":""},{"id":162043103,"identity":"48cd9293-6845-4c35-9cbd-9bc19622b228","order_by":2,"name":"Audrey Adji","email":"","orcid":"","institution":"University of New South Wales","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Audrey","middleName":"","lastName":"Adji","suffix":""},{"id":162043104,"identity":"edb59ecf-f693-43fd-b700-4b3b4d879b45","order_by":3,"name":"Michael Stevens","email":"","orcid":"","institution":"University of New South Wales","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Stevens","suffix":""},{"id":162043105,"identity":"7bdef9ac-4de7-4fb5-ba1f-1f922f9bfad2","order_by":4,"name":"Gabriel Matus Vazquez","email":"","orcid":"","institution":"University of New South Wales","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gabriel","middleName":"Matus","lastName":"Vazquez","suffix":""},{"id":162043106,"identity":"1cff81dd-248d-4626-b989-3d1e76557f92","order_by":5,"name":"Sumita Barua","email":"","orcid":"","institution":"University of New South Wales","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sumita","middleName":"","lastName":"Barua","suffix":""},{"id":162043107,"identity":"fa9fb202-1c15-42bc-b51f-2c665a850d5e","order_by":6,"name":"Christopher Hayward","email":"","orcid":"https://orcid.org/0000-0003-4036-1890","institution":"University of New South Wales","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Hayward","suffix":""}],"badges":[],"createdAt":"2022-12-15 00:40:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2379607/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2379607/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":30852266,"identity":"61311f9a-26b2-42f7-9ceb-422022a7c259","added_by":"auto","created_at":"2022-12-28 16:16:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":110788,"visible":true,"origin":"","legend":"\u003cp\u003eMock Circulatory Loop Schematic. AoC – aortic compliance; ECMO – extracorporeal membrane oxygenation; HVAD – HeartWare Ventricular Assist Device; LV – left ventricle; PAC – pulmonary arterial compliance; PVC – pulmonary venous compliance; PVR – pulmonary vascular resistance; RV – right ventricle; SVC – systemic venous compliance; SVR – systemic vascular resistance; VAD – ventricular assist device\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2379607/v1/d1c5278cf0d48253d595eeef.jpg"},{"id":30852267,"identity":"d4081c13-89e8-469e-a76e-1430ba85e2f5","added_by":"auto","created_at":"2022-12-28 16:16:42","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":208762,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between left atrial pressure and aortic pressure. 2A (left): Experiment 1 data stratified by left ventricular function (normal vs impaired). 2B (right) Experiment 3 data stratified by left ventricular contractility. Higher gain corresponds to greater contractility.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2379607/v1/de5614f39f471ab2c3d1ee0a.jpg"},{"id":30852265,"identity":"3aa02672-359c-4d7e-bed4-3ba6ba3211db","added_by":"auto","created_at":"2022-12-28 16:16:42","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86551,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between VA-ECMO flow and left atrial pressure. 3A (left): Experiment 1 data showing numerical increase in LAP with increased ECMO flow when aortic pressure is not controlled. 3B (right): Experiment 2 data showing no increase in LAP with increased ECMO flow when aortic pressure is held constant. Error bars represent 95% confidence intervals. AoP – aortic pressure; LAP – left atrial pressure; ECMO – extracorporeal membrane oxygenation.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2379607/v1/a91f30bc4c8a117e5d0fc978.jpg"},{"id":30852268,"identity":"3eae4629-8b67-4392-9585-1c458a83d303","added_by":"auto","created_at":"2022-12-28 16:16:42","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":121625,"visible":true,"origin":"","legend":"\u003cp\u003eMultivariable linear regression model to predict LAP. 4A (left): Standardized coefficients. 4B (right): Predicted vs actual LAP using the regression model. Error bars and lines represent 95% confidence intervals. ECMO – extracorporeal membrane oxygenation; LAP – left atrial pressure; LV- left ventricular; mAoP – mean aortic pressure; RAP – right atrial pressure. \u0026nbsp;* p\u0026lt;0.001\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2379607/v1/d7b6ebf684ca08a66914006c.jpg"},{"id":35062667,"identity":"7cce33dc-51e0-4793-bbe2-56a73b9ea072","added_by":"auto","created_at":"2023-03-30 21:23:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":557315,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2379607/v1/60da7e09-ade4-4910-9537-cf90dd7bbed5.pdf"},{"id":30852264,"identity":"54d7c9aa-9610-48b1-9a8f-81ba347d6cee","added_by":"auto","created_at":"2022-12-28 16:16:42","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16063,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2379607/v1/3cc56fe883e8dfd74b14b5b7.docx"}],"financialInterests":"","formattedTitle":"Afterload Pressure and Left Ventricular Contractility Synergistically Affect Left Atrial Pressure During Veno-Arterial Extra-Corporeal Membrane Oxygenation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVeno-arterial extra-corporeal membrane oxygenation (VA-ECMO) is a cornerstone in the management of patients with severe cardiogenic shock\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Despite its use having increased substantially, survival with VA-ECMO remains poor with approximately 40% of patients surviving to hospital discharge\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhile VA-ECMO is able to provide full cardiopulmonary support, it is also associated with a range of adverse haemodynamic and clinical effects, including left ventricular (LV) distension, thrombus formation and pulmonary oedema\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. These effects are thought to be primarily driven by increased afterload due to retrograde flow from the VA-ECMO return cannula, resulting in reduced LV stroke volume and subsequent elevation of diastolic LV pressure and volume\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Important questions remain unanswered however, including: whether afterload and LV contractility have synergistic effects; whether the direction of ECMO return flow is significant; and whether ECMO flow itself is an independent determinant of LV filling pressure.\u003c/p\u003e \u003cp\u003eSeveral measures are already utilised in the clinical setting to mitigate the risk of LV distension and its associated complications. These range from simple measures such as reducing ECMO flow and administration of vasodilators and/or inotropes, to progressively more invasive and costly measures including intra-aortic balloon pump, transvalvular microaxial ventricular assist devices, and direct surgical \u0026lsquo;venting\u0026rsquo; of the LV\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. A more complete understanding of the effects of hemodynamic and VA-ECMO operating conditions on LV preload is necessary to ensure optimal efficacy and resource utilization associated with these measures.\u003c/p\u003e \u003cp\u003eMock circulatory loops (MCLs) allow for precise control of a number of hemodynamic and circuit-related variables and systematic assessment of the interactions between mechanical circulatory support devices and the cardiovascular system, and have previously been used to investigate the effects of different VA-ECMO unloading techniques and cannula properties\u003csup\u003e\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. We sought to utilize an MCL to systematically assess the effects of changes in afterload pressure, ventricular contractility, and ECMO flow and direction on left atrial pressure (LAP) during VA-ECMO support.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMock Circulatory Loop Design\u003c/h2\u003e \u003cp\u003eThe MCL used in this study has been previously described in detail by Shehab et al\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Briefly, the left and right ventricles were constructed using a truncated ellipsoid-shaped deformable silicon diaphragm encased inside a transparent sealed air chamber. Ventricular contractility was achieved by external electropneumatic (EP) compression using a proprietary programmed air delivery system (Simulink, The MathWorks Inc, Natick MA). The EP regulators were programmed to deliver cyclic air pressure waveforms to each ventricle to create realistic systolic and diastolic pressures. These waveforms were then scaled by a multiplier (LV and RV Gain) to achieve pathologic ventricular function. Four identical hermetically sealed, cylinder-shaped Windkessel chambers (100mm diameter x 320mm height) were used to simulate aortic, systemic venous, pulmonary arterial and pulmonary venous compliance. The circuit in this study included separate upper and lower body systemic circulations. Systemic (SVR) and pulmonary vascular resistance (PVR) were created using tuning clamps placed on the systemic and pulmonary arterial limbs respectively. The MCL was filled with 5L of 40\u0026ndash;60%wt glycerol-water solution, maintained at 37\u0026deg;C by a JB Nova JBN12 Water Bath (Grant Instruments Ltd, Cambridge, UK) to simulate the viscosity of blood with a haematocrit of 34%.\u003c/p\u003e \u003cp\u003eThe MCL included an ECMO circuit consisting of PVC Tygon tubing, draining from the right atrium and with arterial return limbs to the femoral artery and proximal aorta. Tuning clamps were placed on each arterial return limb, allowing for switching between retrograde and antegrade ECMO flow. A HeartWare HVAD (Medtronic, Minneapolis, MN) was placed within the circuit to simulate the centrifugal pump in an ECMO system. This HVAD was connected to a controller and monitor which allowed for adjustment of pump speed from 1800 to 4000 revolutions per minute (RPM). A schematic of the MCL in conventional VA-ECMO configuration is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eECMO flow and cardiac output were measured by BioProTT Clamp-On Transducers (em-tec GmbH, Finning, Germany) one placed distal to the HVAD pump within the ECMO circuit, and the other between the systemic venous compliance chamber and the right ventricle. Aortic pressure (AoP), left atrial pressure (LAP), and right atrial pressure (RAP) were measured using fluid-filled pressure transducers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eExperimental Method\u003c/h2\u003e \u003cp\u003eThe MCL was run in steady state, with real-time flow waveforms and pressures monitored by dSpace ControlDesk (dSpace GmbH, Paderborn, Germany). Four cardiac conditions were simulated: 1) normal function (LAP and RAP between 5\u0026ndash;10 mmHg), 2) left ventricular failure (LVF) (LAP\u0026thinsp;\u0026gt;\u0026thinsp;20mmHg, RAP\u0026thinsp;\u0026lt;\u0026thinsp;10mmHg), 3) right ventricular failure (RVF) (LAP\u0026thinsp;\u0026lt;\u0026thinsp;10 mmHg, RAP\u0026thinsp;\u0026gt;\u0026thinsp;20mmHg), and 4) biventricular failure (BVF) (LAP and RAP\u0026thinsp;\u0026gt;\u0026thinsp;20mmHg). These conditions were achieved by altering LV and RV contractilities, SVR, PVR and compliances. Heart rate was maintained at 60 beats per minute. Mean AoP prior to commencement of VA-ECMO flow was set to either 50, 70 or 90mmHg by adjusting SVR. In each experiment, ECMO flow was varied by adjusting HVAD pump speed, to targets of 0, 2, 3, 4 and 5L/min.\u003c/p\u003e \u003cp\u003eFour experiments were performed. In Experiment 1, ECMO flow was incrementally increased and SVR, while compliances and contractility were kept constant within each heart failure state. In experiment 2, SVR was adjusted to maintain constant AoP with increasing ECMO flow. In experiment 3, LV contractility was incrementally reduced from reduced from normal to severely impaired by scaling down the voltage delivered to the LV EP by 33%. In experiment 4, return flow was adjusted from retrograde to antegrade while resistances, compliances and contractility were kept constant. Table S1 in the Supplementary Appendix summarizes these experiments, and the specific combinations of heart failure state, ECMO configuration, ECMO flow direction, mean AoP, and ECMO flow rate examined in each.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData Acquisition and Analysis\u003c/h2\u003e \u003cp\u003eFlow and pressure waveforms were recorded using dSpace ControlDesk while pump speed was recorded from the HVAD controller. All data was processed in MATLAB (MathWorks, Natick, MA) and analysed using SPSS Statistics 29 (IBM, Armonk, New York). The means of the pressures and flows within each experiment were calculated and used for comparison. The primary dependent variable of interest was LAP.\u003c/p\u003e \u003cp\u003eTo compare means between groups, paired t-test or one-way analysis of variance (ANOVA) were used as appropriate. Simple linear regressions were used to ascertain relationships between continuous variables. Multiple linear regression was used to determine independent predictors of the dependent variable. For all statistical tests, a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eLeft Atrial Pressure and Aortic Pressure\u003c/h2\u003e \u003cp\u003eThe relationship between LAP and AoP is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, data from Experiment 1 is divided in binary fashion, into \u0026lsquo;LV Normal\u0026rsquo; (comprising \u0026lsquo;Normal\u0026rsquo; and \u0026lsquo;RVF\u0026rsquo; states) and \u0026lsquo;LV Impaired\u0026rsquo; (comprising LVF and BVF states). Within each subgroup, LAP increases linearly with increased AoP (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.814 for LV Normal; r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.855 for LV impaired, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for each). The slope of this relationship is nearly threefold higher for the LV Impaired subgroup (0.41) compared to the LV Normal subgroup (0.15). In Experiment 3, LV contractility was adjusted incrementally from normal (LV Gain 2.4) to severely impaired (LV Gain 1.6). There is a corresponding increase in the slope of the LAP-AoP relationship (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), consistent with effect modification of contractility on this linear relationship.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eLeft Atrial Pressure and ECMO Flow Rate\u003c/h2\u003e \u003cp\u003eThe relationship between LAP and VA-ECMO flow rate is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. When SVR is held constant and mean AoP is uncontrolled, increased ECMO flow is associated with a numerical but not statistically significant increase in LAP (p\u0026thinsp;=\u0026thinsp;0.684, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). However, when SVR is varied to allow constant mean AoP with increased ECMO flow, there is no corresponding increase in LAP (p\u0026thinsp;=\u0026thinsp;0.999, Fig.\u0026nbsp;5B).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eLeft Atrial Pressure and Right Atrial Pressure\u003c/h2\u003e \u003cp\u003eIn Experiment 1, LAP decreased linearly as RAP increased (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.327, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). When the data was stratified according to LV function, both \u0026lsquo;LV Normal\u0026rsquo; and \u0026lsquo;LV impaired\u0026rsquo; subgroups demonstrated a negative, linear association between LAP and RAP (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.682 for LV normal; r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.523 for LV impaired, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both). The slope of this linear relationship was steeper in the LV impaired subgroup (-0.60 vs -0.22) consistent with greater sensitivity of the impaired LV to changes in RAP.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eRetrograde and Antegrade VA-ECMO flow\u003c/h2\u003e \u003cp\u003eThe effects of ECMO return flow direction on LAP were explored in Experiment 4. There was no significant difference between retrograde and antegrade return flow in terms of LAP (p\u0026thinsp;=\u0026thinsp;0.11), mean AoP (p\u0026thinsp;=\u0026thinsp;0.06) or total cardiac output (p\u0026thinsp;=\u0026thinsp;0.06). There was a small but statistically significant increase in ECMO flow with antegrade return compared to retrograde return (3.5 vs 3.4L/min, p\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMultivariable model to predict LAP\u003c/h2\u003e \u003cp\u003eA multiple linear regression model using data from Experiment 1 incorporated AoP, LV gain, ECMO flow rate and RAP as independent variables. AoP ((β\u0026thinsp;=\u0026thinsp;0.556, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and LV gain (β = -0.695, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but not RAP (β = -0.114, p\u0026thinsp;=\u0026thinsp;0.242) or ECMO flow rate (β = -0.069, p\u0026thinsp;=\u0026thinsp;0.326) were independent predictors of LAP (r\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e for model\u0026thinsp;=\u0026thinsp;0.852, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These results are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite its role as a cornerstone of the management of severe cardiogenic shock, VA-ECMO continues to be associated with a high mortality and complication rate. Complications associated with impaired LV ejection and elevated LV filling pressure \u0026ndash; including thrombus formation and pulmonary oedema \u0026ndash; are well recognized. Understanding the haemodynamic and circuit-related factors that contribute to elevation of LV filling pressure is critical to the rational, pre-emptive application of mitigation strategies, including mechanical unloading devices. In the absence of hemodynamic data beyond in-silico simulations, use of these devices is guided by expert opinion. This has resulted in a high degree of inter-institutional variability, and a sharp recent increase in the use of percutaneous left ventricular assist devices (pVADs) with their associated increased cost and complication rates\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. More robust physical data \u0026ndash; in-vitro and in-vivo \u0026ndash; is needed.\u003c/p\u003e \u003cp\u003eIn this context, the primary findings of this MCL study are: 1) under VA-ECMO support, aortic pressure and LV contractility independently correlate with LAP; 2) the effect of aortic pressure is mediated by LV contractility; 3) VA-ECMO flow rate does not independently affect LAP; and 4) direction of VA-ECMO flow does not affect LAP.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eAoP and LV contractility independently predict LAP during VA-ECMO\u003c/h2\u003e \u003cp\u003eUsing an in-silico model, Dickstein demonstrated that, assuming a constant Frank-Starling relationship, the increase in pulmonary capillary wedge pressure (PCWP) following VA-ECMO initiation is dependent on both baseline LV function and the degree of AoP elevation\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In our study, LV contractility and AoP were independent predictors of LAP, confirming the findings of Dickstein in a physical model of the circulation. Of note, the consistency of findings between Dickstein\u0026rsquo;s model and ours occurred despite our model not incorporating Frank-Starling forces.\u003c/p\u003e \u003cp\u003eOur results extend those of Dickstein, by demonstrating an incremental steepening of the slope of the linear AoP-LAP relationship with reduction in LV contractility. These findings suggest that LV contractility acts as an effect modifier on the AoP-LAP relationship, pointing to a synergistic effect between LV contractility and AoP on the risk of elevated LV filling pressure. In the clinical setting, these results highlight the important role of inotropes and vasodilators \u0026ndash; in combination where possible \u0026ndash; to reduce LV pressures on VA-ECMO support. In our study, the slope of the AoP-LAP relationship in the setting of LV impairment was 0.40, suggesting that a reduction in AoP by 12.5mmHg is sufficient to achieve a clinically meaningful, 5mmHg reduction in LAP. Importantly however, clinical use of vasodilators and inotropes as first-line therapies can be limited by vasoplegia or ongoing myocardial ischaemia, respectively\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. In-vivo pre-clinical and clinical data are needed to determine a dose-response relationship between afterload and LV filling pressure reduction, and to determine the optimal target AoP and inotrope dose.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eFlow rate and direction do not predict LAP during VA-ECMO\u003c/h2\u003e \u003cp\u003eWhen AoP was held constant, increased ECMO flow rate had no effect on LAP. Furthermore, in multivariable analysis, ECMO flow did not independently predict LAP. The putative effect of ECMO flow on LAP \u0026ndash; demonstrated numerically in our study only when AoP was uncontrolled \u0026ndash; can therefore be attributed solely to its effect on AoP. Changing the direction of ECMO return flow similarly had no effect on LAP. Taken together, these findings challenge the conventional orthodoxy that it is the retrograde nature of ECMO flow \u0026ndash; and by extension, the amount of retrograde ECMO flow \u0026ndash; that directly imparts afterload on the LV, therefore causing LV distension and increased filling pressure. Rather, consistent with the arguments of Dickstein\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, our study suggests it is increased AoP, \u003cem\u003eirrespective of the origin of this increase\u003c/em\u003e, that primarily drives changes in filling pressure. Clinically, our findings suggests that, rather than reducing ECMO flow to reduce LAP as is standard practice, the same effect could be achieved simply through pharmacologic reduction in SVR without sacrificing ECMO flow.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis MCL was not designed to simulate complex regulatory adaptations, such as the baroreceptor reflex and Frank-Starling mechanism, nor the ability of VA-ECMO to produce adequate myocardial and peripheral tissue oxygenation and correct metabolic disturbance. Numerical models, hybrid MCLs and in-vivo studies may more accurately represent these biological effects\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Additionally, the ventricles in our MCL were connected \u0026lsquo;in-series\u0026rsquo;, without a common interventricular septum. Therefore, we were unable to examine the effects of ventricular interdependence, which may significantly attenuate the effects of VA-ECMO on LAP through changes in ventricular compliance\u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Further studies simulating direct biventricular interactions and exploring the effects of VA-ECMO on biventricular pressure-volume relationships are needed. Finally, we used a HeartWare HVAD in our VA-ECMO circuit instead of a dedicated ECMO pump, although these are both centrifugal pumps and obey similar physiological and engineering principles.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eImplications and Future Directions\u003c/h2\u003e \u003cp\u003eThese findings highlight the critical role of afterload pressure and LV contractility in determining LV preload under VA-ECMO support. In terms of clinical translation, they highlight the critical and synergistic role of vasodilators and inotropes as first-line therapies to prevent pulmonary oedema in this setting. Conversely, our results do not support the practice of altering ECMO flow in order to reduce LAP. Pre-clinical and clinical in-vivo studies are needed to establish a dose-response relationship of reduced afterload and positive inotropy on LAP, determine optimal therapeutic targets, and identify patients most likely to require escalation to more invasive measures such as mechanical unloading.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this MCL study, LV function and afterload pressure, but not circuit flow or direction, synergistically affect LV filling pressure during VA-ECMO support. Further in-vivo studies are needed to confirm these findings and guide strategies to improve VA-ECMO outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eConflict of interest statement\u003c/h3\u003e\n\u003cp\u003eThere are no conflicts of interest relevant to this study for any authors on this manuscript\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThere were no sources of funding for this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003e\u003cem\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jacky Jiang, Pankaj Jain, Audrey Adji, Michael Stevens, Gabriel Matus Vazquez, Sumita Barua and Christopher Hayward. The first draft of the manuscript was written by Jacky Jiang and Pankaj Jain, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval:\u0026nbsp;\u003c/strong\u003eThis was an \u003cem\u003ein-vitro\u003c/em\u003e mock circulatory loop study; no ethics approval was required.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRao P, Khalpey Z, Smith R, Burkhoff D, Kociol RD (2018) Venoarterial Extracorporeal Membrane Oxygenation for Cardiogenic Shock and Cardiac Arrest. Circulation: Heart Failure 11(9):e004905\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMakdisi G, Wang IW (2015) Extra Corporeal Membrane Oxygenation (ECMO) review of a lifesaving technology. J Thorac Dis 7(7):E166\u0026ndash;E176\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKing CS, Roy A, Ryan L, Singh R (2017) Cardiac support: emphasis on venoarterial ECMO. Crit Care Clin 33(4):777\u0026ndash;794\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDonker DW, Sallisalmi M, Broom\u0026eacute; M (2021) Right\u0026ndash;Left Ventricular Interaction in Left-Sided Heart Failure With and Without Venoarterial Extracorporeal Membrane Oxygenation Support\u0026mdash;A Simulation Study. ASAIO J 67(3):297\u0026ndash;305\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurkhoff D, Sayer G, Doshi D, Uriel N (2015) Hemodynamics of Mechanical Circulatory Support. J Am Coll Cardiol 66(23):2663\u0026ndash;2674\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDickstein ML (2017) The Starling Relationship and Veno-Arterial ECMO: Ventricular Distension Explained. ASAIO J 64:1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrandin EW, Nunez JI, Willar B et al (2022) Mechanical Left Ventricular Unloading in Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation. J Am Coll Cardiol 79(13):1239\u0026ndash;1250\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTepper S, Masood MF, Baltazar Garcia M et al (2017) Left Ventricular Unloading by Impella Device Versus Surgical Vent During Extracorporeal Life Support. Ann Thorac Surg 104(3):861\u0026ndash;867\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzimi M, Liao S, Vatani A, Burrell A, Gregory SD (2022) Improved Flow Dynamics of Extracorporeal Membrane Oxygenation via Design Modification of Dual-Lumen Cannulas. ASAIO J.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFarag J, Stephens AF, Juene Chong W, Gregory SD, Marasco SF (2022) Intra-aortic Balloon Pump Use With Extra Corporeal Membrane Oxygenation-A Mock Circulation Loop Study. ASAIO J 68(5):669\u0026ndash;675\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStephens AF, Wanigasekara D, Pellegrino VA et al (2021) Comparison of Circulatory Unloading Techniques for Venoarterial Extracorporeal Membrane Oxygenation. ASAIO J 67(6):623\u0026ndash;631\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStephens AF, Wickramarachchi A, Burrell AJC, Bellomo R, Raman J, Gregory SD (2022) Hemodynamics of small arterial return cannulae for venoarterial extracorporeal membrane oxygenation. Artif Organs 46(6):1068\u0026ndash;1076\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShehab S, Allida SM, Davidson PM et al (2017) Right Ventricular Failure Post LVAD Implantation Corrected with Biventricular Support: An In Vitro Model. ASAIO J 63(1):41\u0026ndash;47\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCappon F, Wu T, Papaioannou T, Du X, Hsu PL, Khir AW (2021) Mock circulatory loops used for testing cardiac assist devices: A review of computational and experimental models. Int J Artif Organs 44(11):793\u0026ndash;806\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrinker JA, Weiss JL, Lapp\u0026eacute; DL et al (1980) Leftward septal displacement during right ventricular loading in man. Circulation 61(3):626\u0026ndash;633\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDamiano RJ Jr, La Follette P Jr, Cox JL, Lowe JE, Santamore WP (1991) Significant left ventricular contribution to right ventricular systolic function. Am J Physiol 261(5 Pt 2):H1514\u0026ndash;1524\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSummer WR, Permutt S, Sagawa K, Shoukas AA, Bromberger-Barnea B (1979) Effects of spontaneous respiration on canine left ventricular function. Circ Res 45(6):719\u0026ndash;728\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeyman AE, Wann S, Feigenbaum H, Dillon JC (1976) Mechanism of abnormal septal motion in patients with right ventricular volume overload: a cross-sectional echocardiographic study. Circulation 54(2):179\u0026ndash;186\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2379607/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2379607/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) may cause adverse effects including increased left ventricular (LV) filling pressure, LV distension and pulmonary oedema. We aimed to quantify the effects of ECMO flow, LV contractility, aortic pressure (AoP) and ECMO configuration on left atrial pressure (LAP) during VA-ECMO for cardiogenic shock in a mock circulatory loop (MCL).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e An MCL simulated a normal state, LV failure, right ventricular failure and biventricular failure. The ECMO return cannula was placed in the femoral artery (retrograde flow) or ascending aorta (antegrade flow). ECMO flow was incrementally increased from 0 to 5L/min. LAP, mean AoP, ECMO flow and total cardiac output were measured at steady state.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eDuring VA-ECMO, LAP increased linearly with AoP, with the slope greater in the presence of LV impairment compared to preserved LV function. When AoP was held constant, as is the goal of therapy in clinical management, ECMO flow had no effect on LAP. In multivariable linear regression, AoP and LV contractility (p\u0026lt;0.001 for each) correlated independently with LAP, but ECMO flow did not. ECMO return flow direction had no effect on LAP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003eAoP and LV contractility, but not circuit flow or direction, independently determine LAP under VA-ECMO support. By controlling each of these inputs, vasodilator and inotrope management may combine synergistically to prevent VA-ECMO-related complications.\u003c/p\u003e","manuscriptTitle":"Afterload Pressure and Left Ventricular Contractility Synergistically Affect Left Atrial Pressure During Veno-Arterial Extra-Corporeal Membrane Oxygenation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-12-28 16:16:37","doi":"10.21203/rs.3.rs-2379607/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a752ad4f-994c-4fb0-94d1-fb0b21f6b11c","owner":[],"postedDate":"December 28th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-03-30T21:23:35+00:00","versionOfRecord":[],"versionCreatedAt":"2022-12-28 16:16:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2379607","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2379607","identity":"rs-2379607","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}