ICR3 Supplement: Acute Cardiac Unloading and Recovery – Proceedings November 2022 by Radcliffe Cardiology

Spring 2024 • Sponsored supplement

Acute Cardiac Unloading and Recovery Proceedings of the 7th Annual Acute Cardiac Unloading and REcovery (A-CURE) symposium held on 4 November 2022 in Chicago The development of this supplement was funded by Abiomed

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Contents

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Foreword

The State of the Field in Cardiac Unloading: Annual Update

Impella Support for Recovery of Chronic Heart Failure

Cardiac State Optimisation to Promote Recovery During Extracorporeal Circulatory Support

Selected Talk: Cardiac Energetics and Systemic Perfusion with Veno-arterial Extracorporeal Membrane Oxygenation Versus ECMELLA for Cardiogenic Shock in a Large Animal Model

Selected Talk: An Analysis of Extracellular Matrix Proteins Involved in the Loaded and Unloaded Heart After Myocardial Infarction

Young Investigator Award: Transvalvular Unloading Reduces Anaerobic Glycolysis Before Reperfusion and Preserves Energy Substrate Utilisation After Reperfusion in Models of Acute MI

Best in Research Award: Mechanical Left Ventricular Unloading Increases Coronary Flow by Prolonging the Diastolic Phase

Is Unloading the Left Ventricle the Key to Improving Survival in Anterior Wall Acute MI?

From Door to Balloon to Unload: The STEMI Door-to-Unload (DTU) Clinical Trial Programme

PROTECT-Kidney Randomised Controlled Trial: MRI Pilot Study

Automatic Left Ventricular Unloading Using a Percutaneous Transvalvular Microaxial Flow Pump During Veno-arterial Extracorporeal Membrane Oxygenation Support

UNLOAD-ECMO Randomised Controlled Trial for Left Ventricular Unloading with Venoarterial Extracorporeal Membrane Oxygenation in Severe Cardiogenic Shock

CERAMICS Trial: Best Practices for Mechanical Circulatory Support Escalation and Management in Acute MI–Cardiogenic Shock

UNLOAD-HF Randomised Controlled Trial for Left Ventricular Unloading in Acute Heart Failure

Decompensated Heart Failure: Taking the Acute Out of Decompensation

Panel Discussion: Targeting Heart Recovery in a Real-world Setting

Selected Talk: A Novel Fluoroscopic Approach to Impella Percutaneous Ventricular Assist Device Positioning

Selected Talk: Left Ventricular Unloading Acutely Reduces Right Ventricular Preload in Patients with Acute Decompensated Heart Failure and Cardiogenic Shock

Role of Right Ventricle Reserve Assessment and Left Ventricular Unloading to Predict Right Heart Failure After Left Ventricular Assist Device Implantation

Panel Discussion: Advanced Surgical Uses of Percutaneous Ventricular Assist Device Support and Patient Management

Panel Discussion: Non-cardiac Surgery Interventions on Patients Receiving Impella Support © RADCLIFFE GROUP 2022 www.ICRjournal.com

A-CURE 7th Annual Symposium Foreword

This supplement presents a set of 18 original, CME-accredited talks and three panel discussions presented at the 7th Annual Acute Cardiac Unloading and REcovery (A-CURE) Symposium, held on 4 November 2022 in Chicago (IL, US). The symposium proceeded with four rich sessions, as detailed below. Session I covered ‘Advances in Basic and Preclinical Science of Acute Unloading and Myocardial Recovery’. This session featured four presentations with state-of-the-art preclinical work in cardiac unloading. Dr Bart Meyns opened the session with fascinating data on reverse remodelling in an ovine model of chronic heart failure (HF). Two talks on the topic ECPella followed, with Dr Steven Keller presenting his group’s careful haemodynamic work comparing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) combination with Impella versus intra-aortic balloon pump therapy and Dr Ann Banke presenting data on the impact of left ventricular unloading in cardiac energetics. Dr Spyros Marvropoulos then shared data on extracellular matrix modifications during cardiac unloading. The session closed with the keynote lecture delivered by Dr Biykem Bozkurt on ‘Decompensated Heart Failure, Taking the Acute out of Decompensation’. Dr Bozkurt educated the audience on the need to reconceptualise HF and proposed new ways to classify HF and optimise patient care. Session II consisted of five talks that examined the ‘Clinical Science and Evidence for Cardiac Unloading and Recovery’. Dr William O’Neill opened the session with an intriguing talk covering the roll-in experience of the STEMI-DTU pivotal trial, asking the question whether unloading the left ventricle is the key to improving survival in anterior wall acute MI. Dr Navin Kapur followed, with data from the STEMI-DTU pilot study that provided clinical evidence that delaying reperfusion by 30 min under active left ventricular unloading may reduce ischaemic symptoms and infarct size in anterior ST-elevation MI (STEMI). Following the two talks on the STEMI-DTU trial, Dr Ralf Westenfield presented pilot phase data from the PROTECT Kidney randomised controlled trial, revealing a positive signal towards improved renal outcomes in the Impella arm. The last two talks of the session covered the topic of device algorithms and data-driven metrics that can help optimise patient care. Dr Benedikt Schrage presented clinical data from the newly developed VA-ECMO mode, an Impella system algorithm that aids in simultaneous management of Impella and VA-ECMO. Dr Christian Moyer wrapped up the session with a talk on the development of the SmartPump system, which allows diagnostic measurement of various cardiac metrics with the Impella system, closing with a vision of the comprehensive management of critical care patients using smart digital tools. Session III featured three renowned cardiac specialists presenting the ‘Upcoming Trials in the Clinical Applications of Cardiac Unloading’. Dr Benedikt Schrage presented the UNLOAD-ECMO randomised controlled trial for left ventricular unloading with VA-ECMO in severe cardiogenic shock; Dr Mir Babar Basir presented the CERAMICS study to evaluate best practices for mechanical circulatory support escalation and management in acute MI–cardiogenic shock; and Dr Alex Nap presented the UNLOAD-HF randomised controlled trial for left ventricular unloading in acute HF. Session IV included three presentations and two panel discussions on the Frontiers in Surgical and Clinical Applications of Unloading. Dr Luca Baldetti opened with a talk highlighting the importance of correct positioning of Impella implantation to avoid device-related complications and to optimise its function using a novel fluoroscopic approach. Dr Kay Everett presented clinical data suggesting that maximal left ventricular unloading improves biventricular performance in patients with acute decompensated HF and cardiogenic shock. Dr Ryan Tedford followed on the topic of biventricular HF with his presentation, demonstrating that right ventricular reserve may be a useful measure of right ventricular function to predict right ventricular failure after left ventricular assist device implantation. In addition to the live talks, scientific posters were accepted for A-CURE 2022 from top-class researchers around the world. The posters can be viewed at the A-CURE website (https://a-cure.org/livestream/). Of the submitted abstracts, the A-CURE faculty selected two award winners: The Young Investigator Award went to Dr Lija Swain of Tufts Medical Center for her presentation ‘Trans-valvular Unloading Reduces Anaerobic Glycolysis Before Reperfusion and Preserves Energy Substrate Utilisation after Reperfusion in Models of Acute Myocardial Infarction’. The Best in Research Award went to Dr Tomoki Sakata of Icahn School of Medicine at Mount Sinai for his research presentation ‘Mechanical LV Unloading Increases Coronary Flow by Prolonging Diastolic Phase’. This supplement also contains summaries from the three faculty-led panel discussions. The first panel discussed Heart Recovery in the Real-world Setting with the global leaders in HF. The second panel addressed the topic of ‘Cutting-edge Surgical Applications of pVAD and Patient Management’ with a group of cardiac surgeons. The last panel discussion centred on ‘Non-cardiac Surgery Interventions on Patients Receiving Impella Support’, featuring the unique collaboration between cardiologists and general surgeons. The presentations highlighted exciting new developments and represented substantial advances in the field of acute myocardial unloading and heart recovery over the past year. The A-CURE Working Group meeting is unique in including a diverse group of experts from various disciplines within an open, constructive and intimate public setting. We hope that you find this supplement informative and interesting.

Citation: Interventional Cardiology 2024;19(Suppl 1):1–35. DOI: https://doi.org/10.15420/icr.2024.19.S1 © RADCLIFFE GROUP 2024 www.ICRjournal.com

A-CURE 7th Annual Symposium

Welcome to this special supplement devoted to the proceedings of the 7th Annual Acute Cardiac Unloading and REcovery (A-CURE) Symposium, which was held on 4 November 2022 (https://a-cure.org/annual-symposium/past-events/event-2022-2). The A-CURE Symposium is a platform to celebrate the research over the past decade in the space of cardiac unloading and heart recovery and to promote discussion of the latest discoveries in these fields.

The State of the Field in Cardiac Unloading: Annual Update Presented by Daniel Burkhoff, MD, PhD1,2 1. Cardiovascular Research Foundation, New York, NY, US; 2. Columbia University, New York, NY, US

Dr Dan Burkhoff opened the symposium with his state-of-the-field address highlighting the history of the A-CURE Symposium over the past 6 years. He presented an overview of some of the pivotal studies that emerged from collaborations at A-CURE, including: the pivotal STEMI-DTU (door-tounload) study, which is currently recruiting patients; the PROTECT Kidney study, which evaluates the impact of unloading on acute kidney injury and other end organs; VENUS-HF, an early feasibility study that assesses early efficacy signals for diuresis in acute decompensated heart failure patients; the IMPACT trial, which tests the prophylactic use of unloading in patients with a low ejection fraction undergoing cardiac surgery; and the SmartPump study, which examines the use of mechanical support devices as diagnostic tools.

and MI, where the patient is being treated with vasopressors and inotropes. Unloading the heart under these stress conditions allows cardiac output and blood pressure to be maintained with little input from the native heart. By taking over the workload of the heart, unloading potentially allows for the safe withdrawal of pressors and inotropes, which significantly impact myocardial oxygen consumption. Altogether, the effects of unloading on cardiac haemodynamics and energetics help reduce myocardial injury and prevent the remodelling process that follows an acute myocardial insult. Research by the A-CURE Working Group over the past years has further uncovered the cardioprotective effects of unloading beyond haemodynamics and energetics.2 Some of these studies will be presented at the A-CURE symposium, including mechanistic studies of the molecular players behind cardiac unloading and translational studies applying these concepts in the clinical arena to improve patient outcomes. In addition, there has been a growing appreciation of unloading beyond MCS, such as research around renal unloading, invasive monitoring to quantify the degree of unloading and catheter-based ventricular remodelling devices.3

The A-CURE Working Group previously defined ventricular unloading as ‘the reduction of the total mechanical power expenditure of the ventricle which correlates with reduction in myocardial oxygen consumption and haemodynamic forces that lead to ventricular remodelling’.1 Certain mechanical circulatory support (MCS) devices, such as the Impella pump, can achieve primary unloading of the ventricle that results in decreased left ventricular end diastolic pressure, stroke work, pressure–volume area and myocardial oxygen consumption while improving blood pressure, total cardiac output and myocardial perfusion. There are also secondary benefits of cardiac unloading, particularly in cases of cardiogenic shock 1.

Uriel N, Sayer G, Annamalai S, et al. Mechanical unloading in heart failure. J Am Coll Cardiol 2018;72:569–80. https:// doi.org/10.1016/j.jacc.2018.05.03; PMID: 30056830. 2. Curran J, Burkhoff D, Kloner RA. Beyond reperfusion: acute ventricular unloading and cardioprotection during

Dr Burkhoff invited the in-person and virtual audience to actively participate in the symposium featuring four sessions of the latest research in the space of cardiac unloading and recovery.

myocardial infarction. J Cardiovasc Transl Res 2019;12:95– 106. https://doi.org/10.1007/s12265-019-9863-z; PMID: 30671717. 3. Cerrud-Rodriguez R, Burkhoff D, Latib A, et al. A glimpse into the future of transcatheter interventional heart failure

therapies. J Am Coll Cardiol Basic Trans Science 2022;7:181– 91. https://doi.org/10.1016/j.jacbts.2021.09.012; PMID: 35257045.

Impella Support for Recovery of Chronic Heart Failure Presented by Bart Meyns, MD Katholieke Universiteit Leuven, Leuven, Belgium

Dr Meyns shared the results of his preclinical study testing the hypothesis that extended duration of direct cardiac unloading using the high-flow Impella 5.5 pumps can initiate reverse remodelling in chronic heart failure. The goals of this study were to describe the myocardial functional, cellular and subcellular-level effects of cardiac unloading and gain insights into the optimised mode of unloading.

The chronic heart failure model used in the study was generated by permanent ligation of the diagonal branches, combined with ischemia– reperfusion of the mid-section of the left anterior descending artery, in sheep. This model resulted in an ischaemic cardiomyopathy phenotype with infarct, border and remote zones in the myocardium, similar to a clinical presentation of ischaemic cardiopathy after MI. Over time, the injury led to

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A-CURE 7th Annual Symposium Table 1: Study Endpoints

a progressive increase in the left ventricular (LV) end-diastolic and endsystolic volumes, a reduction in the LV ejection fraction (LVEF), an increase in the sphericity index and hypertrophy of myocytes. At 8 weeks after injury, the sheep that developed chronic dilated cardiomyopathy with LVEF of <40% were included in the reverse remodelling study. Sheep that met the inclusion criteria were randomised to either Impella 5.5 support with maximum unloading (n=7) or a control group without Impella support (n=7). The sheep were supported for 3 months and sacrificed at the 5-month time point for tissue collection. Assessments, including cardiac MRI, haemodynamic measurements, biopsies and blood analysis, were taken prior to injury (baseline), at the point of randomisation (8 weeks) and at the end of the study (5 months). The study endpoints are listed in Table 1.

Functional

MRI (LVEDV, ESV, SV, EF contractility) Heart rate, haemodynamics Myocyte hypertrophy

Fibrosis and ECM remodelling

Gene expression, western blotting Histology and immunohistochemistry

Gene expression

Fetal gene programme Metabolism ECC, β-adrenergic signalling, PI3-K/AKT signalling

Blood biomarkers

BMP, ANP Renin, aldosterone Noradrenaline

ANP = atrial natriuretic peptide; BMP = basic metabolic panel; ECC = embryonal carcinoma cells; ECM = extracellular matrix; EF = ejection fraction; ESV = end-systolic volume; LVEDV = left ventricular end-diastolic volume; PI3-K = phosphatidylinositol 3-kinase; SV = systolic volume.

In his talk, Dr Meyns presented the results of the functional assessment. Structural changes were demonstrated via cardiac MRI from 8 weeks to 5 months. Although the magnitudes of impact varied, sheep who were supported by the Impella 5.5 showed an overall improvement in the enddiastolic and end-systolic volumes, with those that had the most dilated LV chambers showing the most reverse remodelling. Although there were significant reductions in the end-diastolic and end-systolic volumes in the Impella-supported group, there were no significant group effects on the overall stroke volume, sphericity index, cardiac output or LVEF.

myocytes in the remote zone. Dr Meyns clarified that further analyses on the functional and molecular aspects are pending, including analysis of plasma samples, biopsies, pressure–volume loops and Impella pressure sensor data. The data shown by Dr Meyns demonstrate that long-term unloading with Impella achieves reverse remodelling of the chronic failing heart with a significant reduction in the global end-diastolic and end-systolic volumes and cardiac hypertrophy. In addition, Impella support improved regional contractility in the remote zone. These findings offer hope for patients with chronic heart failure. Dr Meyns’ team is working on the molecular analysis of the tissue samples collected from this study to add to the current functional analysis.

In this model of chronic ischaemic cardiomyopathy, scar size did not change from 8 weeks to 5 months. Interestingly, regional analysis of the remote zone by MRI showed a significant improvement in function in the Impella-supported group: regional LVEF, wall thickening and wall volumes were reduced in the remote zone. This finding was confirmed by histology results, which showed a significant reduction in the mean number of

Cardiac State Optimisation to Promote Recovery During Extracorporeal Circulatory Support Presented by Steven Keller, MD, PhD, MPhil Johns Hopkins University, Baltimore, MD, US

Dr Keller opened his presentation with a clinical case to illustrate the challenges we currently face when treating patients with severe heart failure. He presented the case of a 25-year-old man with severe left ventricular (LV) dysfunction who experienced a cardiac arrest in the setting of cocaine use. After a brief arrest period, during which he received cardiopulmonary resuscitation, the patient experienced post-arrest haemodynamic instability. The patient was subsequently cannulated in the emergency department and placed on extracorporeal circulatory support via veno-arterial extracorporeal membrane oxygenation (VAECMO). After cannulation, an ECG showed the patient had a normal LV cavity with an LV ejection fraction (EF) of 10% and diffuse hypokinesis. However, over the following 24 hours, despite various efforts, minimal pulsatility persisted and the decision was taken to proceed with a venting strategy via placement of Impella CP to maintain forward flow. Unfortunately, formation of a large LV thrombus was detected in the apex, and the Impella could not be placed. The patient became asystolic and care was withdrawn at 48 hours.

This case demonstrates the lack of accurate assessment for the need for a venting strategy: the patient experienced a catastrophic outcome even though his initial chest X-ray before ECMO showed an improvement in interstitial oedema and no signs of LV dilation. Although VA-ECMO can restore systemic perfusion, it can also adversely impact on the failing LV by increasing the afterload (Figure 1). This is accompanied by a number of other adverse effects, including increased metabolic and mechanical stress on the failing heart. Venting strategies can be used to prevent the potential deleterious effects of VA-ECMO by mitigating the increase in the afterload. Dr Keller provided the example of two percutaneous mechanical circulatory support (MCS) devices available to vent the LV when used in combination with VA-ECMO: the intra-aortic balloon pump (IABP) and the percutaneous ventricular assist device (pVAD) that is Impella CP. However, there are limited data on how these devices function in response to the retrograde flow from the VA-ECMO.

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A-CURE 7th Annual Symposium Figure 1: Veno-arterial Extracorporeal Membrane Oxygenation Increases Afterload to the Left Ventricle

The joint collaboration between the Massachusetts Institute of Technology (MIT) and Abiomed aimed to address this data gap by conducting a preclinical study using the porcine model of acute cardiogenic shock to perform a physiological comparison between the different MCS venting strategies. Acute cardiogenic shock was induced in six pigs via serial embolisation of the left anterior descending (LAD) or left circumflex (LCx) coronary arteries with microbeads; the pigs were then randomised to either pVAD or IABP support after undergoing peripheral VA-ECMO. The pigs met the definition of shock if two or more of the following criteria were met: mean arterial pressure <50 mmHg; LV end-diastolic pressure (LVEDP) >16 mmHg; and/or mixed venous oxygen saturation <50%. By using LV pressure–volume loops that provide insights into ventricular physiological state and function, it was demonstrated that there was a decrease in contractility and increased LVEDP in the porcine experimental model upon the induction of shock, which is comparable to the clinical physiology of acute cardiogenic shock. Combined VA-ECMO and IABP resulted in increased LV volume and a modest change in LVEDP. Although the IABP generated the appearance of pulsatility as the IABP cycles, caution should be exercised because this may not mean the aortic valve is opening. Conversely, combined VAECMO and pVAD showed a reduction in stroke work and a significant lowering of LVEDP. The continuous flow throughout the cardiac cycle achieved an increase in diastolic pressure and a decrease in systolic pressure. Further, there was an increasing degree of LVEDP drop with higher Impella Performance (P) levels (ranging from a 35% reduction at P2 to a 60% reduction at P8 with 50 ml/kg/min ECMO flow), whereas IABP had minimal impact on filling pressure (<10% change). This benefit was shown to be preserved across the different ECMO flow rates and is a titration-dependent effect.

ECMO = extracorporeal membrane oxygenation.

upon failure to wean off ECMO. However, the patient’s haemodynamics continued to deteriorate over the following 7 days. Upon replacement of the IABP with an Impella CP, the patient began to recover, and he was rehabilitated and discharged 2 weeks later. Dr Keller was delighted to announce that the patient was still alive 2 years later without having undergone any further hospitalisation.

When used together with VA-ECMO, pVAD venting significantly reduced the drivers of myocardial oxygen consumption compared with IABP venting, including LVEDP, stroke work and dP/dtmax. pVAD venting also improved the metrics of coronary and systemic perfusion compared with IABP venting, including coronary perfusion, systemic perfusion and carotid artery blood flow.

In conclusion, Dr Keller highlighted the relevance of the study findings to complex clinical scenarios and the greater clinical benefits that a pVAD venting strategy, such as Impella CP, can offer over IABP venting when combined with VA-ECMO. He caveated that successful clinical use of an MCS device is dependent upon competent deployment. A clinical trial of the combined MCS approach is the next step to follow this preclinical evidence.

Dr Keller provided a second case example to demonstrate the application of the study findings to clinical practice. He presented the case of a 61-year-old man with coronary artery disease who had an IABP inserted preoperatively. The patient experienced a ventricular tachycardia arrest postoperatively and underwent VA-ECMO cannulation, after which the IABP was removed. On Day 2 postoperatively, the IABP was reinserted

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A-CURE 7th Annual Symposium

Selected Talk: Cardiac Energetics and Systemic Perfusion with Veno-arterial Extracorporeal Membrane Oxygenation Versus ECMELLA for Cardiogenic Shock in a Large Animal Model Peter Frederiksen, MD Presented by Ann Banke, MD, PhD Odense University Hospital, Odense, Denmark

Dr Banke’s research is based on patients with severe left ventricular (LV) dysfunction and cardiogenic shock (CS) after acute MI where mechanical circulatory support to provide end organ perfusion is necessary.

The definition of shock was at least a 50% reduction in cardiac output and/or at least a 50% reduction in SvO2 or an absolute SvO2 of <30%. Once CS had been induced, the animals were supported on VA-ECMO and underwent further embolisation until there was a decoupling of LV pressure and aortic pressure. Five animals entered the VA-ECMO arm, whereas seven animals entered the ECMELLA arm. Animals in both groups were monitored continuously for a further 4 hours on mechanical support.

Pharmacological support or minor invasive support devices alone are often insufficient to provide end organ perfusion for these patients, and more robust circulatory support, such as veno-arterial extracorporeal membrane oxygenation (VA-ECMO), may be necessary. Nonetheless, VAECMO comes with a number of factors to consider. One such factor is the watershed, a phenomenon in which the blood coming from the ECMO flows in the opposite direction to blood coming from the LV. This has the potential of compromising the oxygen supply to the coronary arteries, and potentially the central nervous system and upper body. Another issue to consider is inadequate emptying of the LV during VA-ECMO support.1

Dr Banke presented the study results. The mean (±SD) arterial pressure in the VA-ECMO and ECMELLA groups after CS was 51 ± 5 mmHg and 51 ± 4 mmHg, respectively. After 4 hours, mean arterial pressure was lower in the VA-ECMO than ECMELLA group (64 ± 8 mmHg versus 69 ± 21 mmHg, respectively; p=0.02). There was no difference in noradrenaline infusion between the two groups. The VA-ECMO flow was equal at the time of CS but decreased in the ECMELLA group during the support period to 3 l/min, compared with 3.7 l/min in the VA-ECMO group (p=0.001). Total cardiac work, calculated as pressure–volume area × heart rate, was significantly lower in the ECMELLA group, with the greatest reduction in the first hour of mechanical support, after which it stabilised (p=0.003). End organ perfusion, measured as arterial lactate concentration, was equally elevated in both groups. There was no statistically significant difference in mixed SvO2 between the two groups, but SvO2 increased during the mechanical support period. Carotid blood flow increased during the mechanical support period by an equal amount of 100 ml in both groups. There was no difference in renal SvO2 between the two groups, but SvO2 increased during the first hour of support before stabilising. Urine output was numerically higher in the ECMELLA group, but the difference was not statistically significant (p=0.8).

Dr Banke explained that the current study aimed to address how LV unloading can be achieved in VA-ECMO-supported patients. Dr Banke’s study hypothesis was that the combination of VA-ECMO and Impella CP (ECMELLA) improves cardiac energetics without compromising end organ perfusion compared with VA-ECMO alone in a porcine model of CS. The model used was the Danish landrace pig, weighing approximately 70 kg and administered amiodarone prior to instrumentation to avoid ventricular arrhythmias. A Doppler flow probe was used around the carotid artery to collect flow data throughout the study period. VA-ECMO was accessed via the femoral artery and there was renal vein access and arterial access for coronary angiogram and placement of the Impella CP. A midline incision was made to allow for echocardiographic imaging during the study. Data collected included the pressure–volume area, stroke work and LV enddiastolic volume obtained from the conductance catheter and continuous cardiac output and venous oxygen saturation (SvO2) from the pulmonary artery catheter; in addition, arterial, renal vein and pulmonary artery blood was sampled for arterial blood gas analysis.

Dr Banke concluded her presentation by summarising the key findings, which showed total cardiac work was lower in the ECMELLA compared with VA-ECMO group, indicating more appropriate cardiac energetics, while there was equal end organ perfusion in the two groups.

Following instrumentation, step-wise controlled CS was induced by embolisation in the left main coronary artery and was guided by SvO2.2 1.

Møller-Helgestad OK, Hyldebrandt JA, Banke A, et al. Impella CP or VA-ECMO in profound cardiogenic shock: left ventricular unloading and organ perfusion in a large animal model. EuroIntervention 2019;14:e1585–92. https://doi.org/10.4244/eij-d-18-00684; PMID: 30418160. 2. Møller-Helgestad OK, Ravn HB, Møller JE. Large porcine model of profound acute ischemic cardiogenic shock. Methods Mol Biol 2018;1816:343–52. https://doi.org/10.1007/978-1-4939-8597-5_27; PMID: 29987833.

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A-CURE 7th Annual Symposium

Selected Talk: An Analysis of Extracellular Matrix Proteins Involved in the Loaded and Unloaded Heart After Myocardial Infarction Presented by Spyros Mavropoulos, MD, PhD Icahn School of Medicine, Mount Sinai, New York, NY, US

In acute heart failure, unloading the left ventricle (LV) by percutaneous LV assist devices (pLVAD) reduces LV filling pressures and volumes, as well as cardiac workload and wall stress, which, in turn, reduces myocardial oxygen demand and increases coronary perfusion. Dr Mavropoulos shared previous mechanistic studies that examined the effects of unloading at the intracellular level, including changes in the expression of calcium-handling proteins, Ca2+-ATPase activity and mitochondrial dynamics.1,2

The LC-MS analysis showed that of 986 proteins identified in the ECM isolates, using cut-off values of a ≥50% increase or decrease in expression levels (p=0.05), 39 ECM proteins were identified as differentially expressed between the unloaded and overloaded hearts. For the 39 proteins identified, gene ontology analysis by molecular function showed there was increased protein expression of RNA- and lipid-binding proteins in the unloaded group. Gene ontology analysis by biological processes showed a relative increase in the expression of proteins involved in cell differentiation, vesicle transport and programmed cell death processes in the unloaded group.

Dr Mavropoulos described the cardiac extracellular matrix (ECM) as a dynamic scaffold of macromolecules surrounding the cells that can transmit the forces that act upon the heart and signals to the cardiomyocytes in response to these forces. The ECM acts as a modulator of cell signalling, adhesion, angiogenesis and fibrosis.

Dr Mavropoulos concluded that there were significant differences in the protein composition of the cardiac ECM between acutely overloaded and unloaded myocardium. The differentially expressed proteins are those largely involved with the molecular functions of RNA and lipid binding and the biological processes of cell differentiation, vesicle transport and programmed cell death. The study findings suggest that the possible initiation of changes in the cardiac cell phenotype is in response to the unloading process and that the benefits induced by pLVAD may persist beyond device removal.

In his current study, Dr Mavropoulos hypothesised that the change in the composition of LV ECM proteins is another mechanism underlying the benefits provided to the heart by acute LV unloading using a pLVAD. MI was induced in 10 Yorkshire pigs using an inflated balloon catheter in the mid-left anterior descending artery for 90 min. After 7 days, the pigs were split into two groups: one group was unloaded with Impella to create an unloaded state of the LV, and the other underwent mechanical induction of acute aortic regurgitation to create an overloaded state. After 2 hours, all pigs were killed and their cardiac tissues harvested for ECM protein extraction. The resulting denatured peptides were screened using liquid chromatography–mass spectrometry (LC-MS) and subjected to computational analysis (Figure 1).

Dr Mavropoulos concluded that this study calls for further characterisation of the effects of the differentially expressed proteins on the cardiac tissue, which could lead to identification of potential therapeutic targets, including the possible use of Impella for diagnostic and discovery purposes.

Figure 1: Schematic of the Study Protocol

AR = aortic regurgitation; ECM = extracellular matrix; LC = liquid chromatography; MS = mass spectrometry.

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A-CURE 7th Annual Symposium 1.

Wei X, Li T, Hagen B, et al. Short-term mechanical unloading with left ventricular assist devices after acute myocardial infarction conserves calcium cycling and improves heart function. JACC Cardiovasc Interv 2013;6:406–15. https://doi.org/10.1016/j.jcin.2012.12.122; PMID: 23523452. 2. Esposito ML, Zhang Y, Qiao X, et al. Left ventricular unloading before reperfusion promotes functional recovery after acute myocardial infarction. J Am Coll Cardiol 2018;72:501–14. https://doi. org/10.1016/j.jacc.2018.05.034; PMID: 30049311.

Young Investigator Award: Lija Swain, PhD Transvalvular Unloading Reduces Anaerobic Glycolysis Before Reperfusion and Preserves Energy Substrate Utilisation After Reperfusion in Models of Acute Myocardial Infarction Presented by Lija Swain, PhD Tufts Medical Center, Boston, MA, US

Dr Swain is the recipient of the Young Investigator Award awarded by the A-CURE Faculty for the scientific merit and innovation of her research.

A previous study showed that mechanical preconditioning with left ventricular (LV) unloading with a mechanical circulatory support device reduces infarct size and wall stress in acute preclinical models of MI compared with primary reperfusion, despite a delay in reperfusion by 60 min.1 Another recent research study found that transvalvular unloading and delayed reperfusion preserves myocardial energy substrate utilisation and protects mitochondrial structure and function in acute MI.2

Dr Swain outlined the molecular changes during ischaemia versus after reperfusion: ischaemia triggers metabolic changes within the cells and a switch to anaerobic glycolysis.3 This, in turn, increases glucose uptake, with an associated rise in lactate that lowers cellular pH, closing the mitochondrial permeability transition pores (MPTPs).3 Reperfusion washes out lactate and opens the MPTPs, increasing the loss of calcium and leading to cell hypoxia and apoptosis. Cellular signalling of oxygen is regulated by hypoxia-inducible factor (HIF)-1α.4

Figure 1: Experimental Scheme and Analysis

IR = ischaemia–reperfusion; LAD = left anterior descending artery; LC-MS/MS = liquid chromatography–tandem mass spectrometry; TVP = transvalvular pump.

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A-CURE 7th Annual Symposium The hypothesis of Dr Swain’s current study was that LV unloading reduces infarct size and promotes myocardial recovery by first reducing ischaemic injury and then further limiting reperfusion injury. Her study used the pig model of acute MI, with pigs divided into four groups. Group A underwent induction of a total of 210 minutes of left anterior descending coronary artery (LAD) occlusion without reperfusion; Group B underwent a total of 210 minutes of LAD occlusion, but with added LV unloading by Impella CP in the last 120 minutes of ischemia; Group C underwent a total of 210 minutes of LAD occlusion followed by 120 minutes of reperfusion; and Group D underwent 210 minutes of LAD occlusion with the last 120 minutes of LV unloading, and were then re-perfused for 120 minutes with continued LV unloading with Impella CP. At the end of the study, the myocardial infarct size of all pigs was quantified and tissue samples were collected. Tissues samples underwent liquid chromatography–mass spectrometry to identify the differential metabolites (Figure 1).

Based on the metabolomics data, concentrations of lactate and glucose, as markers of anaerobic glycolysis, were significantly lower in the hearts that had LV unloading during ischemia (Groups B and D), suggesting LV unloading reduces anaerobic glycolysis before reperfusion, meaning reduced ischaemic injury. Further, LV unloading during ischemia reduced energy demand, as indicated by lower concentrations of ATP and ADP, as well as their precursors, indicating reduced workload and metabolic demand. Levels of HIF-1α, a molecular marker of ischaemia, were measured in tissue samples. During ischaemia, HIF-1α levels were decreased in the LV unloading group (Group B versus Group A), but were unchanged in the reperfused groups (Group D versus Group C). Dr Swain’s findings suggest that LV unloading limits myocardial HIF-1α expression during ischemia, but stabilises HIF-1α levels after reperfusion. Analysis of other targets of HIF1α associated with glycolysis showed that LV unloading reduces anaerobic glycolysis before reperfusion.

Dr Swain presented the results of her study, which showed that hearts with LV unloading during ischemia (Groups B and D) had smaller infarct size whether or not there was reperfusion. The majority of myocardial injury occurs after reperfusion; however, by unloading the myocardium with a transvalvular device, the infarct size after reperfusion is significantly reduced.

Dr Swain concluded that her findings show that LV unloading for prolonged periods of time is likely to be well tolerated and safe by providing systemic haemodynamic support while normalising myocardium metabolism and thereby making myocardium recovery more likely.

Kapur NK, Qiao X, Paruchuri V, et al. Mechanical pre-conditioning with acute circulatory support before reperfusion limits infarct size in acute myocardial infarction. JACC Heart Fail 2015;3:873–82. https://doi.org/10.1016/j.jchf.2015.06.010; PMID: 26541785. 2. Swain L, Reyelt L, Bhave S, et al. Transvalvular ventricular unloading before reperfusion in acute myocardial infarction. J Am Coll Cardiol 2020;76:684–99. https://doi.org/10.1016/j.jacc.2020.06.031; PMID: 32762903. 3. Li X, Liu M, Sun R, et al. Protective approaches against myocardial ischemia reperfusion injury. Exp Ther Med 2016;12:3823–9. https://doi.org/10.3892/etm.2016.3877; PMID: 28101167. 4. Carroll VA, Ashcroft M. Targeting the molecular basis for tumour hypoxia. Expert Rev Mol Med 2005;7:1–16. https://doi.org/10.1017/s1462399405009117; PMID: 15831177.

Best in Research Award: Tomoki Sakata, MD, PhD Mechanical Left Ventricular Unloading Increases Coronary Flow by Prolonging the Diastolic Phase Presented by Tomoki Sakata, MD, PhD Icahn School of Medicine at Mt Sinai, New York, NY, US

Dr Sakata was awarded the Best in Research Award by the A-CURE Faculty as the author of the highest-scoring abstract from all abstract submissions.

At the 6th Annual A-CURE Symposium, Dr Sakata showed preclinical evidence that mechanical left ventricular (LV) unloading increases coronary perfusion of the infarct area.1 Study data suggested that mechanical LV unloading is more beneficial in post-MI patients with high diastolic pressure associated with increased LV stiffness and in those with worse cardiac contractility.1 However, there are other factors that are thought to increase coronary flow with LV unloading, including low cardiac output, low dP/dtmax, high left atrial pressure, high pulmonary capillary wedge pressure and high LV end-diastolic pressure. The exact mechanism by which LV unloading influences coronary flow remains to be determined.

It is within this context that Dr Sakata set out the hypothesis of his study that aimed to investigate how mechanical LV unloading increases coronary flow by modifying LV diastole. MI was induced in five Yorkshire pigs by mid-left anterior descending (LAD) coronary artery occlusion for 90 minutes followed by reperfusion for 60 minutes before the Impella CP was initiated to perform mechanical LV unloading. The pigs were catheterised to enable coronary pressure and flow monitoring. Coupled LV pressure and coronary flow– pressure data gated by the ECG were collected from each animal. Dr Sakata presented the study results: diastolic LV pressure was lower and the proportion of the diastolic phase was extended in the unloaded

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A-CURE 7th Annual Symposium compared with control group; coronary pressure fluctuated less and was consistently higher throughout the cardiac cycle with unloading; and coronary flow was higher throughout diastole in the unloaded group. Although the correlation was not significant, coronary flow tended to increase with lower LV end-diastolic pressure.

form.2 The results of Dr Sakata’s study demonstrate that the magnitude of the forward wave intensity was lower with LV unloading due to less variation in coronary pressure created by continuous pump flow in the aortic root. In addition, the results show that the duration between the backward suction wave and the backward pushing wave was extended with LV unloading, with the effect of prolonging the duration of the relaxation–contraction period.

Dr Sakata used wave intensity analysis to quantify the forces that create individual pressure and velocity waves within the coronary artery circulation to determine the contributors to these observed changes. Dr Sakata set out the four types of forces as forward and backward pushing waves, and forward and backward suction waves. The pushing wave is the dominant forward-travelling pushing wave and is created in the proximal aortic root by LV ejection; the backward-travelling pushing wave is created in the distal side by compression of the myocardial vasculature. The backward-travelling suction wave is caused by relief of myocardial microcirculatory compression.2

Dr Sakata summarised the mechanism of increased coronary flow speculated from his study as follows: the implementation of the Impella CP affects coronary haemodynamics by pump suction and pump flow effects. Suction in the LV works as LV unloading lowers diastolic LV pressure, and the continuous pump flow creates a constant and high coronary pressure. Together, these two phenomena modify myocardial relaxation and contraction, leading to a prolonged diastolic phase. The resulting extended diastolic phase increases coronary flow during diastole. Dr Sakata recognised that further studies are needed to verify these mechanisms.

Dr Sakata explained that, in simple terms, the total wave intensity is the sum of backward and forward wave intensities, which can also be calculated by changes in pressure and flow. In his study, Dr Sakata focused on the backward suction wave and the backward pushing wave because these waves are the beginning and end of the coronary wave

Dr Sakata concluded that mechanical LV unloading decreased LV pressure and extended the diastolic period, leading to increased coronary flow throughout diastole in the infarcted heart.

Sakata T, Watanabe S, Mazurek R, et al. Impaired diastolic function predicts improved ischemic myocardial flow by mechanical left ventricular unloading in a swine model of ischemic heart failure. Front Cardiovasc Med 2022;8:795322. https://doi.org/10.3389/fcvm.2021.795322; PMID: 35097014. 2. Davies JE, Whinnett ZI, Francis DP, et al. Evidence of a dominant backward-propagating ‘suction’ wave responsible for diastolic coronary filling in humans, attenuated in left ventricular hypertrophy. Circulation 2006;113:1768–78. https://doi.org/10.1161/circulationaha.105.603050; PMID: 16585389.

Is Unloading the Left Ventricle the Key to Improving Survival in Anterior Wall Acute MI? Presented by William O’Neill, MD Henry Ford Hospital, Detroit, MI, US

The concept of myocardial salvage has been described since the 1970s. Acute MI is survivable but its impact is time dependent because the ‘wavefront’ of tissue necrosis begins to spread from a small area of infarct after 40 minutes of coronary occlusion, plateauing at around 96 hours.1 Dr O’Neill commented on the difficulty researchers faced at the time to accurately measure infarct size in human patients to prove that a therapy could potentially reduce infarct, and recognised that a method to directly or indirectly measure infarct size was needed. In a 1981 study that used systolic time intervals to estimate left ventricular (LV) viability, it was found that patients who had preserved LV systolic function following MI had superior 5-year survival.2 These findings supported the notion that patients who survived acute MI with a large infarct scar had poor long-term prognosis and led to a scientific pursuit of therapies to decrease infarct size.

statistically significant improvement in LV function measured by LV ejection fraction (EF).3 Following this, a study conducted in 2005 examined advanced imaging techniques as a means to determine the size of infarction. That study demonstrated the time dependency of salvage in patients with anterior infarction.4 For patients who presented within 2 hours of symptom onset, infarct size remained relatively small and rapid reopening of the artery could effectively decrease infarct size. However, this window of opportunity to salvage the myocardium rapidly diminished after 3 hours, after which there was limited scope for improvement in infarct size.4 In the US, the median time from symptom onset to presentation is 4.0 (IQR 1.6–16.0) hours.5 With the recommended door-to-balloon (DTB) time of 90 minutes, the total time from onset to reperfusion can be between 3.0 and 17.5 hours from symptom onset.6 This may be one of the reasons why, even though DTB time has improved markedly in the US over the past 20 years, it has had minimum impact on long-term survival. Therefore, in Dr O’Neill’s opinion, the biggest challenge is to treat patients within the time frame in which reperfusion can make a difference.

Dr O’Neill shared his experience in his first randomised trial for streptokinase, conducted in 1983, that compared the intracoronary administration of streptokinase versus dextrose placebo within 6 hours from the onset of symptoms of acute MI in 40 patients.3 Although streptokinase achieved re-establishment of flow in 60% of patients, compared with 10% of patients in the control group, there was no

Given the practical difficulties in achieving this, an alternative strategy is to devise time-independent methods to decrease infarct size and improve

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A-CURE 7th Annual Symposium Figure 1: Study Population

myocardial function and salvage. In hearts with small infarcts, the apex may remain hypokinetic but the rest of the myocardium has the potential to positively remodel and recover. However, in hearts with large infarcts, both the apex and anterior wall become akinetic, with sequelae of adverse remodelling and ventricular dilation, leaving only a small potential for myocardial recovery.7 Therefore, the goal should be to decrease the infarct size enough so that the ventricle can positively remodel following the insult.

STEMI-DTU pilot study trial population 50 patients enrolled, randomised and unloaded

UR-IR (n=25)

Dr O’Neill discussed data from the CRISP-AMI randomised trial that showed that among patients with acute anterior ST-elevation MI (STEMI) without shock, intra-aortic balloon counter-pulsation plus primary percutaneous coronary intervention (PCI) compared with PCI alone did not result in reduced infarct size.8 In contrast, the AMIHOT I + II trials showed that among patients with anterior STEMI undergoing PCI within 6 hours of symptom onset, the infusion of supersaturated oxygen into the left anterior descending artery infarct territory resulted in a significant reduction in infarct size.9,10

Patients with 3–5 day CMR (n=41) 1 patient without contrast; no measured infarct size 1 patient lost to follow-up after 3–5 days Patients analysed in cohort (n=39)

Dr O’Neill presented the STEMI-DTU pilot study, a multicentre prospective randomised safety and feasibility trial.9 In all, 50 patients were enrolled and randomised 1 : 1 to LV unloading with the Impella CP followed by immediate reperfusion (UR-IR arm) versus delayed reperfusion after 30 minutes of unloading (UR-DR arm). Forty-one patients were assessed by cardiac MRI (CMR) at 3–5 days and 30 days after PCI; 39 were analysed for the final analysis (Figure 1).

Group 1 (IS ≤25%)

normal basal and nearly normal mid-cavity, with approximately 25% of patients with a hypokinetic or akinetic apex. In the group with large infarct size, the wall motion in the basal and mid-cavity at 90 days was largely hypokinetic, and the wall motion of the apex did not improve; 80% remained akinetic. These data show that if the anterior wall was akinetic in the period 3–5 days after injury, it was unlikely to be recoverable. The aim is that patients are discharged from hospital with infarct sizes ≤25% of their LV mass. Current STEMI-DTU roll-in experience shows that twothirds of patients enrolled are achieving infarct size ≤25%. Although not part of the original assessment, the study team will continue to monitor this.

Dr O’Neill also shared the echocardiogram-based wall motion analysis of the STEMI-DTU pilot cohort. The wall motion analysis showed that in patients with a larger infarct size (>25% LV mass), all three sections of the myocardium (basal, mid-cavity and apical) had significant proportions of hypokinesis and akinesis at 3–5 days. In the group with smaller (≤25% LV mass) infarct size, all three sections showed a significant proportion of hypokinesis, but a smaller proportion of akinesis and a larger proportion of normal wall motion compared with the group with larger infarct size. At 90 days, the group with smaller infarct size showed recovery to fully Reimer KA, Jennings RB. The ‘wavefront phenomenon’ of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest 1979;40:633–44. PMID: 449273. 2. Weissler AM, O’Neill WW, Sohn YH, et al. Prognostic significance of systolic time intervals after recovery from myocardial infarction. Am J Cardiol 1981;48:995–1002. https://doi.org/10.1016/0002-9149(81)90311-8; PMID: 7304466. 3. Khaja F, Walton JA Jr, Brymer JF, et al. Intracoronary fibrinolytic therapy in acute myocardial infarction. Report of a prospective randomized trial. N Engl J Med 1983;308:1305–11. https://doi.org/10.1056/ nejm198306023082201; PMID: 6341842. 4. O’Neill, W, Dixon, S, Grines, C. The year in interventional cardiology. J Am Coll Cardiol 2005;45:1117–34. https://doi.

Group 2 (IS >25%)

CMR = cardiac magnetic resonance; DTU = door-to-unload; IS = infarct size; STEMI = ST-elevation MI; UR-DR = left ventricular unloading with the Impella CP followed by delayed reperfusion after 30 min of unloading; UR-IR = left ventricular unloading with the Impella CP followed by immediate reperfusion.

In order to assess the impact of the initial infarct size on heart recovery, the pilot study subjects were divided according to their infarct size measured by CMR 3–5 days after PCI into two groups: those with an infarct size measuring ≤25% LV mass and those with infarct size >25% LV mass. Results from the 30-day CMR and 90-day echocardiogram showed that the group with smaller initial infarct size experienced a greater increase in LVEF. For those with an initial infarct size >25% LV mass, LVEF remained flat at 30 and 90 days. These individuals also exhibited a significant increase in LV end-systolic and end-systolic volumes, indicating that the ventricle began to adversely remodel and dilate.11

UR-DR (n=25)

Dr O’Neill summarised his presentation by reiterating that early revascularisation is the most potent intervention possible for improvement in survival outcomes, but unfortunately most patients do not present quickly enough to benefit from revascularisation. Multiple strategies have failed to limit infarct size, although intracoronary adenosine and supersaturated oxygen are potential therapeutic treatments. Dr O’Neill believes that unloading in the setting of STEMI offers enormous promise and feels optimistic about the findings that will come from the STEMI-DTU pivotal study.

org/10.1016/j.jacc.2005.01.006; PMID: 15808773 5. Peacock WF, Christenson R, Diercks DB, et l. Myocardial infarction can be safely excluded by high-sensitivity troponin I testing 3 hours after emergency department presentation. Acad Emerg Med 2020;27:671–680. https://doi. org/10.1111/acem.13922. PMID: 32220124. 6. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary. J Am Coll Cardiol 2013;61:485–510. https://doi.org/10.1016/j.jacc.2012.11.018 PMID: 23256913 7. Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348:2007–18. https://doi.org/10.1056/nejmra021498; PMID: 12748317. 8. Patel MR, Smalling RW, Thiele H, et al. Intra-aortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock: the CRISP AMI

randomized trial. JAMA 2011;306:1329–37. https://doi. org/10.1001/jama.2011.1280; PMID: 21878431. 9. Stone GW, Martin JL, de Boer MJ, et al. Effect of supersaturated oxygen delivery on infarct size after percutaneous coronary intervention in acute myocardial infarction. Circ Cardiovasc Interv 2009;2:366–75. https://doi. org/10.1161/circinterventions.108.840066; PMID: 20031745. 10. Schömig A, Kastrati A, Dirschinger J, et al. Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. N Engl J Med. 2000;343:385–91. https://doi.org/10.1056/nejm200008103430602; PMID: 10933737. 11. O’Neill WW, Wang DD, Polak S, et al. Left ventricular remodeling after anterior-STEMI PCI: imaging observations in the Door-To-Unload (DTU) pilot trial. J Invasive Cardiol 2022:e611–9. PMID: 35830361.

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A-CURE 7th Annual Symposium

From Door to Balloon to Unload: The STEMI Door-to-Unload (DTU) Clinical Trial Programme Presented by Navin Kapur, MD Tufts Medical Centre, Boston, MA, US

Figure 1: STEMI-DTU Pilot Trial Study Protocol

Dr Kapur opened with a case study of a 70-year-old active man who experienced chest pain during exercise. Electrocardiogram confirmed anterior ST-elevation MI (STEMI) with sum of ST elevation greater than 20 mm in leads V2–V5. The patient was admitted 1 hour from symptom onset. He consented to entry into the STEMI Door-to-Unload (DTU) clinical trial and was randomised to the control arm to receive standard of care for prompt revascularisation. Left ventricular (LV) assessment showed ejection fraction (EF) <30% and LV end-diastolic pressure 35 mmHg. Symptom-to-balloon time was 110 minutes and an optimal door-to-balloon time of <25 minutes was achieved. An ECG 3–5 days after percutaneous coronary intervention (PCI) showed restoration of LVEF to 50%; however, cardiac MRI (CMR) revealed that a massive anterior scar remained.

50 patients enrolled, randomised and unloaded

U-IR (n=25) No CMR completed (n=5) 1 expired 1 metallic prosthesis 2 large body mass index 1 outside time window

U-DR (n=25) No CMR completed (n=4) 1 expired 2 claustrophobic 1 chronic kidney disease

(n=20)

(n=21)

(n=19)

(n=21)

(n=25)

No CMR completed 1 outside time window

A population-based cohort study of 7,733 patients showed that a significant proportion of patients who experience their first MI after 65 years of age develops heart failure following revascularisation: 34% developed heart failure in hospital and 71% developed heart failure within 5 years.1 Dr Kapur used the case study and this reference to illustrate the disconnect between reperfusion and myocardial salvage: reperfusion alone may not achieve optimum myocardial salvage. These clinical observations led to the design of the STEMI-DTU trial, asking the central question of ‘Can we mitigate the onset of heart failure by further reducing the infarct size at the time of anterior STEMI and thereby preserving the myocardium for future years?’

CMR = cardiac MRI; U-DR = delayed reperfusion after 30 minutes of left ventricular unloading; U-IR = left ventricular unloading followed by immediate reperfusion

Dr Kapur shared that the trial achieved 100% compliance for the protocolised 30-minutes unloading time before reperfusion in the LV unloading plus delayed reperfusion (U-DR) arm, which was a reassuring signal that the study approach is feasible. Dr Kapur highlighted a key learning from the pilot study, which is becoming more apparent in the ongoing pivotal study, namely that U-DR reduces ischaemic symptoms. The STEMI-DTU trialists coined the proverbial term ‘door-to-snore’ to describe their observations that upon Impella insertion, the patient’s crushing chest pain resolved to the extent that the patient was able to fall asleep while their left anterior descending artery (LAD) was still occluded. The results from the pilot trial showed that the U-DR approach uncoupled coronary occlusion from myocardial infarct size by creating a window of time, 30 minutes, that did not exist before. This window of time where LAD occlusion and ischemia are uncoupled allows for additional strategies to optimise myocardial and metabolic recovery to be implemented.

Key prognostic factors to consider in STEMI patients include:

• infarct size and the extent of microvascular obstruction that occurs due to thrombotic debris;

• epithelium damage; • vasoconstriction; and • extrinsic compression of the microvasculature from oedema. The STEMI-DTU pilot trial evaluated infarct size and the degree of microvascular obstruction after PCI in patients who had immediate reperfusion with Impella unloading versus delayed reperfusion after 30 minutes of Impella unloading. Dr Kapur noted that this trial tests a disruptive hypothesis that delayed reperfusion plus LV unloading limits myocardial ischemia and reduces myocardial damage. This novel strategy is based on a body of growing evidence that delaying reperfusion by 30 minutes while unloading achieves the lowest infarct size.3

To understand the mechanism of U-DR, Dr Kapur and others conducted and published several preclinical mechanistic studies. A study of microcirculatory blood flow in an LAD infarct model showed that the U-DR approach enhanced coronary collateral flow before reperfusion and reduced the area of risk within the infarct zone.4 Using hypoxia-inducible factor (HIF)-1α as a biomarker of ischaemia, it was shown that LV unloading was associated with a decrease in HIF-1α expression prior to reperfusion that persisted over a period of 120 minutes.5 Metabolomics analysis of postinfarct myocardial tissue showed that transvalvular unloading triggers a global metabolic shift and reduces anaerobic glycolysis during coronary

The pilot phase of the STEMI-DTU trial addressed the feasibility and safety of the strategy with Impella CP by assessing major adverse cardiac and cerebrovascular events at 30 days. The primary efficacy endpoint of infarct size/total LV mass at 30 days evaluated whether delaying reperfusion before LV unloading increased infarct size. Fifty patients were enrolled and randomised as per the study protocol shown in Figure 1.

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A-CURE 7th Annual Symposium Figure 2: STEMI-DTU Study Protocol

occlusion, which is a critical mechanism for ischemia–reperfusion injury (unpublished data). The current STEMI-DTU trial was protocolised with LV unloading for 30 minutes prior to reperfusion, but preclinical data from the Kapur laboratory and others suggest that a longer period of LV unloading prior to reperfusion may be feasible without increasing the ischemic burden.

All patients present at STEMI-DTU study site with anterior STEMI

Patient meets all inclusion and no exclusion criteria

Informed consent

Results from the STEMI-DTU pilot trial showed that across different sizes of anterior MI, the primary efficacy endpoint of infarct size/total LV mass was reduced in the U-DR arm compared with the unloading with immediate reperfusion (U-IR) arm. In addition, both the U-DR and U-IR arms had smaller average infarct size (22–27% and 17–19%, respectively) compared with the average infarct size of 36% in the CRISP-AMI trial populations.6 Microvascular occlusion showed the same trends: the U-DR arm achieved 1.3–1.6% microvascular obstruction after PCI, compared with 3.5–5.6% in the U-IR arm. These results demonstrate that 30 minutes of active LV unloading prior to reperfusion improves myocardial salvage compared with immediate reperfusion.

Iliofemoral angiogram and left ventriculogram performed to rule out contraindication for Impella CP® placement and confirm patient is indicated for PCI

Randomisation

Treatment arm (n=344 subjects) Impella CP® implanted and support initiated for ≥30 min

Dr Kapur concluded his talk by sharing the design of the STEMI-DTU pivotal trial, which is a prospective randomised multicentre trial. The STEMI-DTU pivotal trial is designed to compare mechanical LV unloading with the Impella CP device for 30 minutes prior to primary PCI to primary PCI alone without LV unloading, and to evaluate whether delayed reperfusion reduces infarct size and improves prognosis in patients with STEMI. All patients in the pivotal study will receive a femoral angiogram and a ventriculogram to ensure high-quality enrolment.

Ezekowitz JA, Kaul P, Bakal JA, et al. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction. J Am Coll Cardiol 2009;53:13–20. https://doi.org/10.1016/j.jacc.2008.08.067; PMID: 19118718. 2. Symons R, Pontone G, Schwitter J, et al. Long-term incremental prognostic value of cardiovascular magnetic resonance after ST-segment elevation myocardial infarction: a study of the collaborative registry on CMR in STEMI. JACC Cardiovasc Imaging 2018;11:813–25. https://doi. org/10.1016/j.jcmg.2017.05.023; PMID: 28823746. 3. Kapur NK, Alkhouli MA, DeMartini TJ, et al. Unloading the left ventricle before reperfusion in patients with anterior

Coronary angiogram

PCI procedure

4–24 h Impella CP® support Impella CP® explant in cath lab

Clinical follow-up: 3–5 days echocardiogram and CMR 30 days clinical safety evaluation 6 months CMR and clinical evaluation Clinical evaluation at 12, 18 and 24 months and annually through 60 months

There was a significant study protocol non-adherence of 36% in the pilot trial due to the difficulties with study execution; for the pivotal trial, participating sites will have access to a community of clinicians available to provide support 24/7 to achieve greater study protocol adherence. The study protocol has been recently published (Figure 2),7 and recruitment is underway, with 250 subjects already enrolled. 1.

Control arm (n=344 subjects)

CMR = cardiac magnetic resonance; PCI = percutaneous coronary intervention; STEMI = ST-elevation MI.

ST-segment-elevation myocardial infarction. Circulation 2019;139:337–46. https://doi.org/10.1161/ circulationaha.118.038269; PMID: 30586728. 4. Briceno N, Annamalai SK, Reyelt L, et al. Left ventricular unloading increases the coronary collateral flow index before reperfusion and reduces infarct size in a swine model of acute myocardial infarction. J Am Heart Assoc 2019;8:e013586. https://doi.org/10.1161/jaha.119.013586; PMID: 31698989. 5. Swain L, Reyelt L, Bhave S, et al. Transvalvular ventricular unloading before reperfusion in acute myocardial infarction. J Am Coll Cardiol 2020;76:684–99. https://doi. org/10.1016/j.jacc.2020.06.031; PMID: 32762903.

6. Kapur NK, Pahuja M, Kochar A, et al. Delaying reperfusion plus left ventricular unloading reduces infarct size: subanalysis of DTU-STEMI pilot study. Cardiovasc Revasc Med 2023. https://doi.org/10.1016/j.carrev.2023.09.009; PMID: 37891053 epub ahead of press. 7. Kapur NK, Kim RJ, Moses JW, et al. Primary left ventricular unloading with delayed reperfusion in patients with anterior ST-elevation myocardial infarction: rationale and design of the STEMI-DTU randomized pivotal trial. Am Heart J 2022;254:122–32. https://doi.org/10.1016/j. ahj.2022.08.011; PMID: 36058253.

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A-CURE 7th Annual Symposium

PROTECT-Kidney Randomised Controlled Trial: MRI Pilot Study Presented by Ralf Westenfeld, MD University Hospital Düsseldorf, Düsseldorf, Germany

Figure 1: PROTECT-Kidney Study Overview

The PROTECT-Kidney trial was designed to address the important clinical issue of contrast-induced acute kidney injury (CI-AKI), which was shown to be associated with higher mortality in patients after percutaneous coronary intervention (PCI).1 CI-AKI ranks second among all causes of acute kidney injury (AKI) and contributes to inappropriately low rates of coronary angiography in patients with chronic kidney disease.2,3 There is a tendency for higher-risk patients to receive more conservative therapy for cardiovascular diseases, even though it has been shown that undergoing coronary angiography can reduce the risk of death by half for patients with chronic kidney disease from diseases such as non-ST-elevation MI and acute coronary syndrome.3 A study performed in 2019 found that the incidence of AKI during Impellasupported high-risk PCI in patients was lower than the predicted rates of AKI.4 These data led to the need for a prospective randomised trial to further explore the protective strategy of the Impella to prevent AKI during high-risk PCI.

HR-AKI patients • Urgent or elective PCI • Consecutive patients All patients will be assigned a preliminary value of ‘1’ for the Contrast Media variable Assign preliminary Mehran risk score

Enrolment Inclusion: elevated risk of AKI as defined by a preliminary Mehran risk score ≥10

The PROTECT-Kidney pilot trial is a prospective randomised study investigating the role of Impella to maintain kidney function in a highrisk cohort for CI-AKI. The Mehran score was used to quantify the risk of AKI after contrast administration and patients with a Mehran score of ≥10 were included in the trial.5 The incidence of CI-AKI was detected by serum creatinine concentrations, and MRI was used to assess kidney function. The PROTECT-Kidney pilot trial was designed with a sample size of 40 to assess safety and feasibility, and the PROTECT-Kidney trial was powered at n=200 to detect efficacy on CI-AKI. Patients in both the Impella and control arms underwent MRI before and after coronary angiography. The primary endpoint was the incidence of CI-AKI, as defined by the Acute Kidney Injury Network’s (AKIN) definition: an increase in creatinine ≥0.3 mg/dl from baseline within 48 h after the procedure (Figure 1).

Exclusion criteria: • Emergency intervention (STEMI, CGS) • Haemodynamic support required for procedure (dual physician review and agreement) • MCS already in place • On-going resuscitation • Mechanical ventilation • AKI within 7 days prior • CKD, Stage 5 • Pregnant • Haemoglobin <8.5 g/dl

PCI + optimal medical therapy

PCI + optimal medical therapy + Impella support

Assign final Mehran risk score based on actual procedural contrast media used

Primary endpoint: rate of AKI

AKI, acute kidney injury; CGS = cardiogenic shock; CKD, chronic kidney disease; HR-AKI = high-risk acute kidney injury; MCS, mechanical circulatory support; PCI = percutaneous coronary intervention; STEMI = ST-elevation MI.

Dr Westenfeld presented the preliminary results from the PROTECTKidney pilot trial. With 30 patients enrolled thus far, the mean (±SD) Mehran score was 13.0 ± 2.9 in both the Impella and control arms and there was an individual AKI risk of 27% in the Impella group, compared with 28% in the control group, predicted by the Mehran score. In the Impella and control groups, mean patient age was 77.0 ± 6.5 years and 78.0 ± 6.3 years, respectively, and 53% and 50% of patients, respectively, were on anticoagulation therapy. The Charlson Comorbidity Indexderived likelihood of 10-year survival was 15.0 ± 19.9 and 13.0 ± 23.6 in the Impella and control arms, respectively. Mean left ventricular (LV) ejection fraction was 41.0 ± 13.2% in the Impella group, compared with 48.0 ± 7.4% in the control group. Mean contrast volumes used were 140.0 ± 51.1 and 152.0 ± 59.5 ml in the Impella and control groups, respectively. The primary endpoint of AKI occurred in 43% of patients in the control group, compared with 20% in the Impella arm. Renal function remained unchanged after contrast administration for 14% of patients in the control arm, compared with 60% in the Impella arm. Based on these data, Dr Westenfeld predicted that if the trial is scaled up, the projected p-values for the primary endpoint will be significant for a sample size of 200.

Dr Westenfeld discussed the potential mechanisms of renal protection by Impella during high-risk PCI. From the haemodynamic and MRI data obtained from the pilot study, he showed that patients in the control arm experienced a rise in LV end-diastolic pressure after PCI, whereas patients in the Impella arm did not. Further, looking at the blood oxygenation level-dependent MRI measurement obtained before and after contrast use, patients in the control arm showed a heterogeneous but significant oxygenation drop of the renal medulla after contrast use, whereas oxygenation levels were largely preserved in patients in the Impella arm. Dr Westenfeld summarised that the interim analysis of the PROTECTKidney trial revealed less AKI (n.s.) and a higher proportion of patients with unchanged kidney function following contrast administration (p<0.05) in the Impella high-risk PCI group compared with control. The treatment groups were well matched for kidney function and the risk of AKI, and exhibited a low abundance of severely reduced LV function, although both groups had considerable comorbidities, these were well-balanced.

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A-CURE 7th Annual Symposium No safety concerns were detected in the pilot trial. Patients in the Impella arm were protected from an increase in LV end-diastolic pressure during catheterisation and displayed a trend for increased diastolic blood pressure along with stabilised oxygenation of the kidney medulla, which 1.

Dangas G, Iakovou I, Nikolsky E, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005;95:13–9. https://doi. org/10.1016/j.amjcard.2004.08.056; PMID: 15619387. 2. Fähling M, Seeliger E, Patzak A, Persson PB. Understanding and preventing contrast-induced acute kidney injury. Nat Rev Nephrol 2017;13:169–80. https://doi.org/10.1038/

was verified by MRI. Dr Westenfeld concluded that he expects the PROTECT-Kidney trial to demonstrate the nephroprotective effect of Impella, and the results will help decipher the potential underlying pathophysiology.

nrneph.2016.196; PMID: 28138128. 3. Chertow GM, Normand SL, McNeil BJ. ‘Renalism’: inappropriately low rates of coronary angiography in elderly individuals with renal insufficiency. J Am Soc Nephrol. 2004;15:2462–8. https://doi.org/10.1097/01. asn.0000135969.33773.0b; PMID: 15339996. 4. Flaherty MP, Moses JW, Westenfeld R, et al. Impella support and acute kidney injury during high-risk percutaneous

coronary intervention: the Global cVAD Renal Protection Study. Catheter Cardiovasc Interv 2020;95:1111–21. https://doi. org/10.1002/ccd.28400; PMID: 31355987. 5. MD+Calc. Mehran score for post-PCI contrast nephropathy. https://www.mdcalc.com/calc/10087/mehran-score-post-pcicontrast-nephropathy (accessed November 2023).

Automatic Left Ventricular Unloading Using a Percutaneous Transvalvular Microaxial Flow Pump During Veno-arterial Extracorporeal Membrane Oxygenation Support Paul Haller, MD and Presented by Benedikt Schrage, MD University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Dr Schrage opened his presentation by recapping the use of mechanical circulatory support (MCS) devices to prevent patients from deteriorating into cardiogenic shock (CS) by supporting the patient and providing end organ perfusion. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is one such device increasingly used in cases of severe CS. However, a major drawback associated with VA-ECMO is the increase in left ventricular (LV) afterload, which can result in subsequent LV overload and worsening of the dilatation.1,2 Recent retrospective clinical studies have shown that active LV unloading using a percutaneous transaortic LV assist device, namely Impella, in combination with VA-ECMO reduced LV afterload and was associated with better outcomes and lower mortality.2

generates additional patient management needs that must be considered. Factors to take into account when managing VA-ECMO and Impella devices simultaneously include:

Dr Schrage explained that adding the Impella to VA-ECMO, the ECPella configuration, presents an incredible opportunity to optimise LV unloading and facilitate recovery. However, adding a second MCS device also

Given this, there needs to be continuous monitoring and adjustment of the two devices by balancing the Impella P-level to the LV preload as well as the VA-ECMO flow. However, real-time device management can be

• balancing the Impella P-level versus ECMO flow: increasing the

Impella P-level will allow more active unloading, but may lead to suction events, which can lead to haemolysis; • assessment of the recovery status of the heart by monitoring the degree of inflow to the LV to monitor when is the time to wean or escalate; and • ventilation and volume settings of the patient.

Figure 1: Left Ventricular and Aortic Pressure Coupling and Decoupling

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A-CURE 7th Annual Symposium challenging while taking care of CS patients; a tool to help automate this process would be immensely helpful.

placement of VA-ECMO was able to achieve sufficient aortic pressure and mean arterial pressure. The patient, however, exhibited very low pulsatility and almost no native heart function. During this stage, the VA-ECMO Mode algorithm automatically controlled Impella flow and maintained the optimal decoupling factor with little P-level change. Over the next 2 days, as the patient’s native heart function started to recover and pulsatility returned, the VA-ECMO Mode algorithm dynamically adjusted the Impella P-levels to maintain the optimal decoupling and avoid suctioning. This traditionally would be performed manually by the care team. The advantage of the VAECMO Mode is that the algorithm can respond immediately to haemodynamic changes, whereas the care team cannot always be present to make immediate changes. In the last 3 days, the patient’s pulsatility stabilised and the care team started weaning the patient off VA-ECMO while the Impella remained in situ to provide ongoing support.

During systole, LV and aortic pressures are coupled: the LV pressure rises and matches the aortic pressure to open the aortic valve and push the blood into the systemic circulation. Impella achieves LV unloading by decoupling the LV pressure from the aortic pressure so that the LV pressure remains below the aortic pressure (Figure 1). This way, the LV can rest and recover while VA-ECMO and Impella support meet the circulatory needs. Using the degree of LV–aortic pressure decoupling as the metric of LV unloading, a new software algorithm to control Impella pump performance during simultaneous use of VA-ECMO was developed in collaboration with the Abiomed engineering team. The new software tool, named VA-ECMO Mode, is integrated into the Automated Impella Controller (AIC) to allow for automatic control of the Impella P-level to balance against the VA-ECMO flow and avoid suction events, while maximising the degree of LV unloading. This will help lighten the device management burden on the clinical care team and allow for real-time optimisation of the degree of LV unloading to facilitate the patient’s heart recovery. VA-ECMO Mode is currently being tested in a clinical study, with Dr Schrage’s centre being part of it.

After sharing the successful case of using the VA-ECMO Mode to manage an ECPella patient, Dr Schrage summarised his talk. These clinical experiences support that active LV unloading may improve outcomes for CS patients on VA-ECMO. With opportunities to improve patient outcomes, simultaneous use of two MCS devices also brings about the challenge of proper device management, such as the risk of too much (e.g. suction events, haemolysis) or too little unloading (e.g. non-effective application) unloading. The VA-ECMO Mode automatically decouples LV pressure from aortic pressure and optimises the degree of LV unloading. Dr Schrage closed by highlighting the potential for the VA-ECMO Mode to be used as a guide for device weaning decisions.

Dr Schrage provided a case example of the VA-ECMO mode used in a realworld CS patient with ECPella support. The time course of LV and aortic pressures, aortic pulsatility, the decoupling factor and the Impella pump speed over the 7 days of Impella support was shown. In the first 2 days,

1. Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in cardiogenic shock. Eur Heart J 2014;35:156–67. https://doi.org/10.1093/eurheartj/eht248; PMID: 24014384. 2. Schrage B, Burkhoff D, Rübsamen N, et al. Unloading of the left ventricle during venoarterial extracorporeal membrane oxygenation therapy in cardiogenic shock. JACC Heart Fail 2018;6:1035–43. https://doi.org/10.1016/j.jchf.2018.09.009; PMID: 30497643.

UNLOAD-ECMO Randomised Controlled Trial for Left Ventricular Unloading with Veno-arterial Extracorporeal Membrane Oxygenation in Severe Cardiogenic Shock Presented by Benedikt Schrage, MD University Hospital Eppendorf Hamburg, Hamburg, Germany

Dr Schrage opened his presentation by recapping that veno-arterial extracorporeal membrane oxygenation (VA-ECMO) provides circulatory support for cardiogenic shock (CS), but also increases left ventricular (LV) afterload, which can hamper myocardial recovery. In a recent multinational multicentre retrospective registry study, it was shown that if the LV afterload is reversed by active LV unloading using Impella in addition to VA-ECMO in the setting of CS, 30-day mortality was lower, although there were higher rates of complications, such as bleeding and ischaemia.1

Impella for active LV unloading on top of VA-ECMO (n=99) or the control arm with VA-ECMO alone (n=99). A blinded interim analysis will be performed after enrolment of 75% (n=148) of patients is achieved. The primary endpoint of the study is time to death from any cause within 30 days after randomisation; data from a 12-month follow-up for additional secondary efficacy endpoints and safety endpoints will also be collected. Dr Schrage highlighted that the trial includes patients with a number of key inclusion features. First, an arterial lactate concentration of >5 mmol/l, which is a higher threshold than previous randomised controlled trials on mechanical circulatory support, has been included to target a high-risk patient population and distinguish patients with high mortality even within the same Society for Cardiovascular Angiography and Interventions (SCAI) SHOCK stage.2 A second key inclusion criterion is systolic blood pressure <90 mmHg or the need for catecholamines to maintain blood pressure at this level. In addition, patients must display

Based on learnings from this data, Dr Schrage and his team designed a randomised clinical trial, the UNLOAD-ECMO trial, to test the hypothesis that active LV loading with Impella combined with VA-ECMO (ECPella strategy) improves 30-day survival in patients with severe CS compared with the strategy of VA-ECMO alone. The study population consists of patients with severe CS due to severe LV dysfunction. These patients will be randomised 1 : 1 to either the intervention arm for treatment with an

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A-CURE 7th Annual Symposium the signs of impaired organ perfusion with at least one of the following: impaired mental status or cold, clammy skin or oliguria with urine output <30 ml/h. Third, it has been decided to include patients who have undergone previous ECMO therapy for up to 6 hours before implantation of the Impella device, and a resuscitation time of up to 60 minutes is allowed. Finally, the study will include patients with both acute MI-CS and non-acute MI-CS because there appears to be no association between causes of CS and mortality after VA-ECMO. The trial encourages early active LV unloading by early implantation of Impella and early

explant in accordance with strict protocols. Due to the risk of complications arising from the use of two devices simultaneously, study procedures encourage the use of ultrasound-guided access and micropuncture sets to assist with device implantation. Dr Schrage clarified that at the present time the trial does not rely upon any objective criteria for LV dysfunction. Dr Schrage closed his presentation by announcing that enrolment is expected to commence imminently.

Schrage B, Becher PM, Bernhardt A, et al. Left ventricular unloading is associated with lower mortality in patients with cardiogenic shock treated with venoarterial extracorporeal membrane oxygenation: results from an international, multicenter cohort study. Circulation 2020;142(22):2095–106. https://doi.org/10.1161/circulationaha.120.048792; PMID: 33032450. 2. Jentzer JC, Schrage B, Patel PC, et al. Association between the acidemia, lactic acidosis, and shock severity with outcomes in patients with cardiogenic shock. J Am Heart Assoc 2022;11:e024932. https://doi.org/10.1161/jaha.121.024932; PMID: 35491996.

CERAMICS Trial: Best Practices for Mechanical Circulatory Support Escalation and Management in Acute MI–Cardiogenic Shock Presented by Babar Basir, DO Henry Ford Hospital, Detroit, MI, US

Table 1: Survival to Discharge Based on Cardiac Power Output/Inotropes in the Cath Lab

The National Cardiogenic Shock Initiative (NCSI) was assembled to assess the impact of early mechanical circulatory support (MCS) in patients with acute MI (AMI) and cardiogenic shock (CS) treated with percutaneous coronary intervention (PCI). Before establishment of the NCSI in 2016, there was significant variability in the use of MCS in AMI-CS. There were no standardised practices, and outcomes associated with the use of MCS in AMI-CS were variable. In addition, experience in the use of large-bore MCS placement, management and approval was only beginning to grow. There were also limited data on the association of right heart failure, intensive care unit (ICU) management of MCS, MCS weaning and escalation.

Survival to Discharge based on CPO/Inotropes in Cath Lab No. inotropes

CPO (W)

≥2

≤0.6

63% (n=19)

43% (n=21)

35% (n=17)

0.6 to <0.8

89% (n=18)

63% (n=24)

64% (n=11)

≥0.8

89% (n=35)

71% (n=42)

64% (n=14)

Data show the percentage (number) of patients surviving to discharge in each category. CPO = cardiac power output.

The NCSI addressed these needs by providing a uniform shock protocol to help healthcare systems obtain predictable outcomes and a set of standardised best practices based on foundational principles. The initiative offers a number of protocols to improve patient survival by encouraging the early use of Impella pre-PCI during optimal PCI techniques of the target artery or other large-bore vessels and avoiding escalating vasopressor and inotrope doses, which are associated with poorer outcomes. The initiative enables devices to be weaned based on invasive haemodynamics with right-sided heart catheterisation and offers hub-and-spoke models of care for the transfer of patients. Overall, the NCSI has consistently demonstrated survival in AMI-CS of over 70%.1

The Impella device can also help predict right-sided heart failure. Evidence obtained by the NCSI has shown that of the 92% of patients with right ventricular (RV) catheterisation, those who had RV failure (RVF) had an absolute mortality of approximately 14% more than those without RVF.4 However, despite these favourable outcomes, the NCSI found that the use of RV haemodynamic support devices for treatment escalation is <20% in practice.4 Similarly, instead of escalating treatment to mechanical support devices, patients in AMI-CS are often maintained on increasing doses of vasopressors and inotropes, which are associated with increased mortality independent of underlying cardiac power output.5,6 NCSI analysis found that the cause of death for the majority of patients is due to ongoing CS (58%) and multiorgan failure (18%), but only 19% of patients in CS receive escalation of treatment appropriate for worsening CS.2,3 The NCSI also found that there was a considerable variation in ICU-level care and the ability of sites to escalate MCS.2 Unless sites have the appropriate tools and devices, they are unable to effectively treat patients in CS with haemodynamic support and improve clinical outcomes.

Over the past few years, the NCSI has continued to collect data to improve its best practice protocols on the mechanical support management of these patients with AMI. This has included data from the Cardiogenic Shock Working Group on the use of invasive haemodynamics in guiding therapy, a practice that has been shown to improve survival in AMI-CS.2 Conversely, a delay in treatment and delivery of MCS is associated with higher mortality in AMI-CS.3 This finding is consistent with evidence that CS should be treated acutely and with minimum delay to reverse the CS state.

Taking all the learnings from the NSCI, Dr Basir and his team designed the study Can Escalation Reduce Acute Myocardial Infarction in Cardiogenic

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A-CURE 7th Annual Symposium Shock (CERAMICS). Twenty sites were selected, all with rapid MCS escalation capabilities, including Impella, RV MCS and ECPella support devices. Data were collected on the survival of all AMI-CS patients, including those not treated with Impella.

<2.2 l/min/m2 or cardiac power output <0.6 W. The NCSI protocol was adhered to, which includes escalation of treatment with quick implantation of the Impella CP, followed by revascularisation and right heart catheterisation for monitoring to rapidly reduce the use of inotropes. Escalation could occur at any time, but ideally as early as possible and preferably in the cardiac cath lab. Key triggers for escalation with an unloading strategy were guided by haemodynamics and aimed at achieving survival >80% (Table 1). The implementation of shock protocols alongside a team-based approach is associated with improved patient outcomes.

The sites participating in the trial used the same definitions as per the NCSI protocol, namely Society for Cardiovascular Angiography and Interventions (SCAI) SHOCK classes C, D and E. AMI was defined as ischaemic symptoms with ECG and/or biomarker evidence of ST-elevation MI (STEMI) or nonSTEMI. CS was defined as at least two of the following: hypotension (systolic blood pressure [SBP] <90 mmHg or the use of inotropes or vasopressors to maintain SBP); signs of end organ hypoperfusion, including cool extremities, oliguria/anuria, elevated lactate concentrations, altered mentation; and hypodynamic evidence of hypoperfusion, represented by a cardiac index 1.

Basir MB, Lemor A, Gorgis S, et al. Early utilization of mechanical circulatory support in acute myocardial infarction complicated by cardiogenic shock: the National Cardiogenic Shock Initiative. J Am Heart Assoc 2023;12:e031401.https:// doi.org/10.1161/JAHA.123.031401; PMID: 38014676. 2. Osman M, Syed M, Patel B, et al. Invasive hemodynamic monitoring in cardiogenic shock is associated with lower in-hospital mortality. J Am Heart Assoc. 2021;10:e021808. https://doi.org/10.1161/jaha.121.021808; PMID: 34514850.

Dr Basir closed his presentation by confirming that the foundations, strategy and principles of the NSCI will be studied further in the CERAMICS study, as well as in the RECOVER IV randomised controlled trial for AMI-CS patients.

3. Tehrani BN, Truesdell AG, Sherwood MW, et al. Standardized team-based care for cardiogenic shock. J Am Coll Cardiol 2019;73:1659–69. https://doi.org/10.1016/j. jacc.2018.12.084; PMID: 30947919. 4. Basir MB, Kapur NK, Patel K, et al. Improved outcomes associated with the use of shock protocols: updates from the National Cardiogenic Shock Initiative. Catheter Cardiovasc Interv 2019;93:1173–83. https://doi.org/10.1002/ ccd.28307; PMID: 31025538. 5. Basir MB, Lemor A, Gorgis S, et al. Vasopressors

independently associated with mortality in acute myocardial infarction and cardiogenic shock. Catheter Cardiovasc Interv 2022;99:650–7. https://doi.org/10.1002/ ccd.29895; PMID: 34343409. 6. Basir MB, Schreiber TL, Grines CL, et al. Effect of early initiation of mechanical circulatory support on survival in cardiogenic shock. Am J Cardiol 2017;119:845–51. https://doi. org/10.1016/j.amjcard.2016.11.037; PMID: 28040188.

UNLOAD-HF Randomised Controlled Trial for Left Ventricular Unloading in Acute Heart Failure Presented by Alex Nap, MD, PharmD, PhD Amsterdam University Medical Centre, Amsterdam, the Netherlands

Acute heart failure (AHF) is a common but serious condition associated with high morbidity and mortality. Unfortunately, the number of patients presenting with AHF is increasing, and most of these patients present with acute decompensated heart failure (ADHF) or acute on chronic heart failure (HF). Following diuretic treatment, most patients are discharged, but there are some patients who show signs and symptoms of worsening HF, which can result in escalation of therapy. Dr Nap referred to a recent study that showed that the patients who fare the worst are those with ADHF and signs of hypoperfusion and congestion; these signs can determine prognosis and affect renal, hepatic and pulmonary function, resulting in a multisystem disorder.1

Dr Nap proceeded with reference to the Society for Cardiovascular Angiography and Intervention (SCAI) SHOCK criteria for defining the stages of CS severity from A to E.5 Higher SCAI SHOCK stages are associated with higher risks of mortality. This clinical classification of CS can help guide therapy, indicate prognosis and determine the effect of intervention. Due to the tendency of patients to spiral down the stages of CS severity, there is a time limit for intervention, without which the patient may otherwise deteriorate, and there is then the risk that haemodynamic derangement will become a metabolic derangement. Dr Nap provided an overview of the treatment recommendations and their classifications as per the 2021 European Society of Cardiology guidelines and the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines.6,7 Intravenous inotropic support is recommended for patients in CS (class of recommendation [COR] 1/level of evidence [LOE] B-NR) to maintain systemic perfusion and preserve end organ performance. For COR 2a/ LOE B-NR in patients in CS, temporary mechanical circulatory support (MCS) is reasonable when end organ failure cannot be maintained by pharmacological means to support cardiac function. Both US and EU guidelines (COR IIa, LOE C) recommend short-term MCS in patients with CS or as a bridge-to-recovery, bridge-to-decision or bridge-to-bridge, and further indications include treatment of the cause of CS or long-term MCS or transplantation.6,7 Dr Nap suggested it may be appropriate to start

Dr Nap recapped the pathophysiology of ADHF, which includes reduced left ventricular (LV) function and activation of the sympathetic nervous and renin–angiotensin systems. This, in turn, triggers neurohumoral activation and has a detrimental effect on renal function, increasing central venous pressure and wedge pressures.2,3 This leads to ventricular remodelling and dilated ventricles, and Dr Nap presented the pressure–volume loops that illustrate this advanced stage of morbidity. As congestion prevails and other organs become involved, ADHF becomes a multisystem disorder. Cardiogenic shock (CS) represents an advanced state of morbidity along this pathophysiological pathway of end organ hypoperfusion caused by reduced cardiac output and blood pressure.4

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A-CURE 7th Annual Symposium patients with CS on MCS rather than inotropes, but there has been no randomised control trial showing inotropes have a positive effect on survival. He referred to a study that found that primary circulatory support with an intra-aortic balloon pump showed a significant increased in improved organ perfusion assessed by venous oxygen saturation (SvO2), compared with inotropes in decompensated HF and low output.8

of reduced LV ejection fraction <35%; persistent signs and symptoms of congestion and evidence of SCAI criteria for CS Stages B–C with the presence of any of the following: hypotension (SBP <90 mmHg or mean arterial pressure <60 mmHg or vasoactive agents to maintain normotension); oliguria (≤0.5 ml/kg/h, ≤720 ml/24 h); lactate >2.0 mmol/l; increase in creatinine ≥0.3 mg/dl during the first 24 hours or amino-ltransferase >200 U/l. All patients must be 18–75 years of age.

Dr Nap explained that this context led to the hypothesis that the UNLOADHF trial is going to test: primary introduction of Impella in patients with ADHF with evidence of perfusion (SCAI CS Stages B and C) will result in superior outcomes compared with patients treated with standard treatment with inotropes. The primary endpoints at 60 days will be: all-cause mortality; worsening HF (to SCAI Stages D or E); the need for mechanical ventilation; and other organ failure (e.g. intubation, renal transplant and rehospitalisation/urgent hospital visit). Key secondary endpoints at 48 hours will be pulmonary capillary wedge pressure (PCWP) + right atrial pressure <30 mmHg; PCWP –25 mmHg; and PCWP –5 mmHg.

Exclusion criteria include acute coronary syndrome, haemodynamic parameters/biochemistry as defined for SCAI CS Stages D or E; bradycardia and atrioventricular blocks necessitating pacemaker implantation; contraindications for Impella CP; bleeding diathesis or known coagulopathy; and inability to provide informed consent. Patients will be randomised into one of the two arms (either Impella ± inotropes or inotropes alone) and all patients will receive a pulmonary artery catheter to monitor pressures. Following the trial, patients will be weaned and commenced on guideline-directed medical therapy.

The study is a prospective randomised controlled open-label multicentre two-arm trial. One arm is Impella ± standard therapy with inotropes (intervention arm); the other arm is treatment with inotropes alone (control). The study is a two-stage design: Stage 1 includes two groups of 77 patients and Stage 2 includes two groups of 228 patients. Intention-totreat and protocol analyses will be performed. Inclusion criteria are ADHF (non-acute coronary syndrome) and evidence 1.

Espinosa B, Llorens P, Gil V, et al. Prognosis of acute heart failure based on clinical data of congestion. Rev Clin Esp (Barc) 2022;222:321–31. https://doi.org/10.1016/j. rceng.2021.07.004; PMID: 34756646. 2. ter Maaten JM, Valente MA, Damman K, et al. Diuretic response in acute heart failure – pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015;12:184–92. https://doi.org/10.1038/nrcardio.2014.215; PMID: 25560378. 3. Abraham J, Blumer V, Burkhoff D, et al. Heart failure-related cardiogenic shock: pathophysiology, evaluation and management considerations: review of heart failure-related cardiogenic shock. J Card Fail 2021;27:1126–40. https://doi.

Dr Nap summarised his presentation by confirming that ADHF is a serious condition with a high morbidity and mortality characterised by congestion, impaired cardiac output/cardiac index and high filling pressures. Unloading is an attractive treatment option in patients with HF-CS and the UNLOAD-HF trial aims to assess whether LV unloading reduces clinical events in ADHF SCAI shock Stages B–C compared with standard treatment with inotropes.

org/10.1016/j.cardfail.2021.08.010; PMID: 34625131. 4. Furer A, Wessler J, Burkhoff D. Hemodynamics of cardiogenic shock. Interv Cardiol Clin 2017;6:359–71. https:// doi.org/10.1016/j.iccl.2017.03.006; PMID: 28600090. 5. Kapur NK, Kanwar M, Sinha SS, et al. Criteria for defining stages of cardiogenic shock severity. J Am Coll Cardiol 2022;80:185–98. https://doi.org/10.1016/j.jacc.2022.04.049; PMID: 35835491. 6. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. https:// doi.org/10.1093/eurheartj/ehab368; PMID: 34447992.

Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/ HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022;79:e263–421. https://doi. org/10.1016/j.cardfail.2022.02.010; PMID: 35378257. 8. den Uil CA, Van Mieghem NM, Bastos MB, et al. Primary intra-aortic balloon support versus inotropes for decompensated heart failure and low output: a randomised trial. EuroIntervention 2019;15:586–93. https://doi. org/10.4244/EIJ-D-19-00254; PMID: 31147306.

Decompensated Heart Failure: Taking the Acute Out of Decompensation Presented by Biykem Bozkurt, MD, PhD Editor-in-Chief JACC: Heart Failure; Baylor College of Medicine, Houston, TX, US

Dr Bozkurt is one of the world’s leaders in heart failure (HF). She gave a groundbreaking talk on the trajectory she would like to see the field move towards, including reconsideration of the definition of decompensated HF, a vision of how to target success for treating decompensated HF and how to create phenotypical types to tailor treatment strategy to phenotype.

admission or emergency department (ED) visit. Step 3 requires an escalation of care: patients with AHF require urgent evaluation with subsequent initiation or intensification of treatment, including intravenous therapies or procedures. Dr Bozkurt noted that the definitions of AHF provided in the various guidelines do not always correspond to these three dimensions. For example, the US guidelines define AHF only on the basis of the location criteria and require the patient to be hospitalised.1 Most of the other decision pathways require all three dimensions to be met, but in differing ways. Dr Bozkurt showed how the AHF definitions relied upon for inclusion in clinical trials also differ and require different combinations of the three steps. For example, the PIONEER trial required a primary diagnosis of HF that included symptoms and signs of fluid overload.2 The GALACTIC-HF

Dr Bozkurt started her talk by providing the overarching definition of acute HF (AHF) based on three key steps. Step 1 requires a worsening of patient symptoms: HF is a syndrome of symptoms and signs and, by definition, AHF requires the symptoms and signs of HF to newly onset (de novo HF) or worsen (acute decompensated HF [ADHF]). Step 2 refers to location: AHF should manifest as a severe enough condition for the patient to seek urgent medical attention leading to an unplanned hospital

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A-CURE 7th Annual Symposium Figure 1: Patient Trajectory

GDMT = guideline-directed medical therapy. Source: Hollenberg et al, 2021.1 Used with permission from Elsevier.

trial required patients to be currently hospitalised for HF or have made an urgent visit to the ED for a primary diagnosis of HF with elevated B-type natriuretic peptide/N-terminal pro B-type natriuretic peptide (NT-proBNP).3 In the SOLOIST trial, patients must have been admitted to hospital or had an urgent care visit to the ED, the HF unit or the infusion centre for worsening HF associated with evidence of intravascular volume overload and have received intravenous diuretics.4

common denominator of terminology. Decompensation is not defined by factors such as a series of hospitalisations or the haemodynamics alone, but rather the requirement for an escalation or intensification of urgent therapy, be it in a primary or secondary setting. This is the proposed change in nomenclature that Dr Bozkurt wishes to promote and gain consensus on. She proposed that decompensated HF (DHF) in the new era can be defined as HF patients who: are refractory to standard/ optimised HF treatment with active deterioration; and require intensified/ escalated/urgent intravenous, advanced or rescue HF therapy that is not specified by location or requirement of hospitalisation. Dr Bozkurt made the distinction between worsening HF and DHF: worsening HF responds to interventions as an outpatient and its signs and symptoms can be managed by oral HF medication titration. However, DHF involves worsening symptoms and signs that require intensified, urgent and additional therapy.5

These examples illustrate the variations in concepts that make the construction of clinical trials for AHF all the more challenging. In contrast, where HF is an endpoint in the adjudication of clinical trials, the definition tends to be more specific. Diagnoses are often based on standard criteria, such as the ICD-10 codes, the presence of symptoms and signs, objective diagnostic criteria such as imaging or elevated natriuretic peptide (NP) levels and escalation of treatment via intravenous diuretics, mechanical circulatory support (MCS) or other interventions. In HF clinical trials, hospitalisation has frequently been used to increase the risk profile of AHF patients. Trials have adopted a strategy to incorporate patients who have a history of HF hospitalisations to target a population with higher event rates.

Proposal 2: Define the Decompensated Heart Failure Haemodynamic Subset and Treat

There have been numerous conceptualisations of phenotypic classification for HF over the past two decades. Gheorghiade et al laid out the clinical presentations of AHF in eight categories.6 Nieminenan et al and McDonagh et al further defined the phenotypes of AHF.7,8 Abraham et al showed how there can be overlapping phenotypes.9 The Society for Cardiovascular Angiography and Interventions (SCAI) SHOCK stage is also relied upon as an indication of shock severity and comprises one component of mortality risk prediction and treatment decisions in AHF patients with cardiogenic shock.

Proposal 1: Change in Nomenclature

Dr Bozkurt explained how the acuity of the presentation does not necessarily matter for AHF. For example, if a de novo HF patient is not decompensated, they may not be in AHF and may not require hospitalisation; not all de novo HF is ADHF. There can be three types of patients admitted for HF: patients with de novo HF, patients with acute decompensated de novo HF and patients with decompensation of chronic HF.

Combining knowledge from these former studies, Dr Bozkurt proposed a simplified classification of haemodynamic subsets for the selection of treatment for DHF. The two haemodynamic subsets are the congested (warm and wet) and the hypoperfused (cold and wet). Once the

Having appreciated that ‘acute’ is not a necessary requirement in decompensated HF, Dr Bozkurt explained that ‘decompensation’ is the

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A-CURE 7th Annual Symposium Proposal 4: Check the Patient Trajectory

Table 1: Heart Failure Guidelines: Optimisation of Guideline-directed Medical Therapy During Hospitalisation

The fourth step is tracking the trajectory of DHF patients based on their response to the initial DHF therapy. Despite the importance of patient trajectory, current administrative policies tend to prioritise discharge over improved long-term outcomes. Therefore, it is important that if patients require advanced therapies due to unresolved congestion, they are not discharged prematurely. Instead, they should only be discharged once they have achieved resolution of symptoms and signs and improvements in the diagnostic markers. The tricky part is to know what metric or markers of decongestion should be used for tracking the patient trajectory.

Recommendations for maintenance or optimisation of GDMT during hospitalisation Referenced studies that support the recommendations are summarised in the online data supplements19 COR

LOE

Recommendations

B-NR

1. In patients with HFrEF requiring hospitalisation, pre-existing GDMT should be continued and optimised to improve outcomes, unless contraindicated.

B-NR

2. In patients experiencing a mild decrease of renal function or asymptomatic reduction of blood pressure during HF hospitalisation, diuresis and other GDMT should not routinely be discontinued.

B-NR

3. In patients with HFrEF, GDMT should be initiated during hospitalisation after clinical stability is achieved.

B-NR

4. In patients with HFrEF, if discontinuation of GDMT is necessary during hospitalisation, it should be reinitiated and further optimised as soon as possible.

Reviewing the outcomes of the standard of care arm from the seven recent DHF trials, it was shown that two-thirds of patients achieve resolution of jugular vein distension (JVD) and pulmonary rales by discharge, and 50–75% have resolution of oedema by discharge. Interestingly, dyspnoea improves with standard HF treatment and weight loss is achieved with varying degrees; however, there was no apparent correlation between dyspnoea and weight loss.10–17 In addition, weight loss alone was not always associated with better long-term clinical outcomes. The ESCAPE trial showed that pulmonary artery catheter-guided therapy did not result in survival benefit; however, it is important to note that these patients were neither shock patients nor patients with marked elevated filling pressure.18 The GUIDE-IT trial targeted NP concentrations to guide HF therapy in ambulatory patients, but was unable to demonstrate that a strategy of NT-proBNP-guided therapy was more effective than the standard care strategy in improving outcomes.19 The PRIMA II trial built upon this and demonstrated that the guidance of HF therapy to reach an NT-proBNP reduction of >30% after clinical stabilisation did not improve 6-month outcomes.20 Instead, as demonstrated in the PIONEER trial, patients who improve on guideline-directed therapy see a corresponding reduction in NP levels. In this way, NP acts as a marker for responsiveness to therapy but is not a target for therapy in itself.2 The DOSE trial demonstrated that more complete decongestion is associated with better outcomes, and patients who had improvements in two or three objective markers of decongestion had improved clinical outcomes than those with improvement in no or one marker (39.0% versus 53.8%; p=0.03).21

COR = class of recommendation; GDMT = guideline-directed medical therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LOE = level of evidence. Source: Heidenreich et al, 2022.27 Used with permission from Elsevier.

haemodynamic subset has been defined, the patient can be appropriately treated according to their subset and urgency to achieve a positive change. The primary treatment goal for the congested haemodynamic subset should be to decongest, whereas for the hypoperfused haemodynamic subset the treatment goal should be to provide circulatory support with inotropes or MCS. Each haemodynamic subset can each be further subcategorised; for example, the congested haemodynamic subset can be subdivided into pulmonary congestion, systemic congestion and both, with each type requiring specific therapies. The hypoperfusion haemodynamic subset can divided into pre-shock (e.g. SCAI A and B) and cardiogenic shock (e.g. SCAI C, D and E) subsets that need pharmacological or mechanical support.

Dr Bozkurt’s proposal is to individualise therapy depending on the baseline and changes from baseline; one should look for improvement or resolution of symptoms, signs and diagnostic biomarkers (e.g. NP concentrations, haemodynamics, O2 saturation levels, filling pressures). Instead of using one or two metrics to track the patient response, an array of metrics should be used to accurately assess the patient’s decongestion response.

Proposal 3: Define Specific Aetiology, Phenotypes and Severity

The third step that Dr Bozkurt proposed is to define the specific aetiology, phenotype and the proximate cause of decompensation that needs specific treatment in addition to HF. This requires consideration of the primary cardiac diagnoses complicated with DHF (e.g. acute coronary syndrome, pulmonary embolism, hypertensive emergency, myocarditis) and non-cardiac diagnoses (e.g. pneumonia, chronic obstructive pulmonary disease exacerbation). There is also the need to specify the ventricle type of DHF (e.g. left ventricular failure, right ventricular failure, biventricular failure) and to specify the presentation severity that needs specific therapy (e.g. DHF with respiratory failure, DHF with diuretic resistance, DHF with repeated DHF episodes). It should be noted that diuretic resistance is important and is a change to be defined as an output or during the inpatient intervention.

Dr Bozkurt highlighted the need to beware of false alarms (e.g. acute kidney injury, cardiorenal syndrome) that can hinder clinical care and clinical trial design. This is because creatinine can rise with successful decongestion and is not associated with worse outcomes in ADHF patients.22 However, worsening creatinine with persistent congestion, not worsening HF alone, is associated with adverse outcomes. The ESCAPE trial showed that rising creatinine accompanied by haemoconcentration is associated with better outcomes,23 whereas the EVEREST trial showed that haemoconcentration is associated with worsening HF but better clinical outcomes.24 Dr Bozkurt explained one of the major problems in DHF patient management is a high rate of discontinuation of guideline-directed

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A-CURE 7th Annual Symposium medical therapy (GDMT), ranging from 23% to 42% of patients following hospitalisation.25 There is a need to respond appropriately to the trajectory of the patient’s response to DHF therapy and ‘rescue’ those patients who are deteriorating. Approximately one-third of patients in the congestion subset are refractory, whereas another one-third of patients are discharged with residual congestion. Approximately 6–10% of patients in the hypoperfusion subset are refractory or worsen.26

factors and preventing readmission/mortality. For patients who have had multiple admissions within the past few months (e.g. four admissions over the past 12 months or three admissions over the past 6 months), the aim is to decongest them, maintain their quality of life, optimise GDMT, prevent precipitating factors, use disease-modifying approaches and consider advanced care (e.g. transplant or MCS) or palliative care (Table 1). GDMT should always be initiated before discharge because it is safe and effective.25

Step 4, therefore, places an emphasis upon the patient’s trajectory over the course of hospitalisation (Figure 1).27 Refractory patients or patients who experience worsening HF after initial treatment require escalation of treatment. Dr Bozkurt defines ‘refractory’ as those patients whose condition fails to improve with initial DHF treatment or those who require escalation. Patients with worsening HF are a different population, comprising those who experience worsening HF signs or symptoms, pulmonary oedema or cardiogenic shock and those who require initiation of new, repeat or an increase in intravenous treatment, MCS or ventilatory support.

In summary, Dr Bozkurt’s lecture provided a pioneering vision of reconceptualising HF. In Dr Bozkurt’s proposal, the focus should be on the ‘decompensated’ aspect of HF rather than the ‘acuity’. Decompensated HF patients are those with active deterioration despite attempts to optimise HF treatment and who require intensified or urgent intravenous, advanced or rescue HF therapy. In Dr Bozkurt’s vision, DHF is not specified by location, hospitalisation or acuity of presentation. She proposes that haemodynamic subsets of DHF patients should be defined and treated accordingly, in addition to the proximate causes, to enable therapy to be tailored to the specific cause. She reminded us of the need to recognise a confounding presentation that can hijack the ability to treat the patient appropriately and to recognise chronic and acute trajectories to ensure patients are rescued if they are refractory or worsening. In these cases, patients can be escalated to initiate a higher level of care if their life trajectory implies an active deterioration.

Proposal 5: Look for the Long-term Trajectories for Decompensated Heart Failure

The long-term trajectory of DHF patients should be monitored and efforts should be taken to modify and change their trajectory. This step includes continuing and optimising GDMT, treating and preventing precipitating 1.

Hollenberg SM, Warner Stevenson L, Ahmad T, et al. 2019 ACC expert consensus decision pathway on risk assessment, management, and clinical trajectory of patients hospitalized with heart failure: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2019;74:1966–2011. https://doi. org/10.1016/j.jacc.2019.08.001; PMID: 31526538. 2. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin– neprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019;380:539–48. https://doi.org/10.1056/ NEJMoa1812851; PMID: 30415601. 3. Teerlink JR, Diaz R, Felker GM, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med 2021;384:105–16. https://doi.org/10.1056/ NEJMoa2025797; PMID: 33185990. 4. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117–28. https://doi.org/10.1056/ NEJMoa2030183; PMID: 33200892. 5. Zile MR, Bennett TD, St John Sutton M, et al. Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures. Circulation 2008;18:1433–41. https://doi.org/10.1161/ CIRCULATIONAHA.108.783910; PMID: 18794390. 6. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research. Circulation 2005;112:3958–68. https://doi. org/10.1161/CIRCULATIONAHA.105.590091; PMID: 16365214. 7. Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006;27:2725–36. https://doi.org/10.1093/eurheartj/ehl193; PMID: 17000631. 8. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. https:// doi.org/10.1093/eurheartj/ehab368; PMID: 34447992. 9. Abraham J, Blumer V, Burkhoff D, et al. Heart failure-related cardiogenic shock: pathophysiology, evaluation and management considerations: review of heart failure-related cardiogenic shock. J Card Fail 2021:1126–40. https://doi. org/10.1016/j.cardfail.2021.08.010; PMID: 34625131. 10. Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 2003;41:997–1003. https://doi.org/10.1016/s07351097(02)02968-6; PMID: 12651048.

11. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797–805. https://doi.org/10.1056/ NEJMoa1005419. PMID: 21366472. 12. Gattis WA, O’Connor CM, Gallup DS, et al. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004;43:1534–41. https://doi.org/10.1016/j. jacc.2003.12.040. PMID: 15120808. 13. Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAXAHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 2009;373:1429–39. https://doi.org/10.1016/S01406736(09)60622-X; PMID: 19329178. 14. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002;287:1531–40. https://doi. org/10.1001/jama.287.12.1531; PMID: 11911755. 15. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005;294:1625–33. https://doi.org/10.1001/ jama.294.13.1625. PMID: 16204662. 16. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013;381:29–39. https://doi.org/10.1016/S01406736(12)61855-8; PMID: 23141816 17. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675–83. https://doi.org/10.1016/j.jacc.2006.07.073; PMID: 17291932. 18. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005;294:1625–33. https://doi.org/10.1001/ jama.294.13.1625; PMID: 16204662. 19. Felker GM, Anstrom KJ, Adams KF, et al. Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2017;318:713–20. https://doi.org/10.1001/jama.2017.10565; PMID: 28829876.

20. Stienen S, Salah K, Moons AH, et al. NT-proBNP (N-terminal pro-B-type natriuretic peptide)-guided therapy in acute decompensated heart failure: PRIMA II randomized controlled trial (can NT-ProBNP-guided therapy during hospital admission for acute decompensated heart failure reduce mortality and readmissions?). Circulation 2018;137:1671–83. https://doi.org/10.1161/ CIRCULATIONAHA.117.029882; PMID: 29242350. 21. Kociol RD, McNulty SE, Hernandez AF, et al. Markers of decongestion, dyspnea relief, and clinical outcomes among patients hospitalized with acute heart failure. Circ Heart Fail 2013;6:240–5. https://doi.org/10.1161/ CIRCHEARTFAILURE.112.969246; PMID: 23250981. 22. Metra M, Davison B, Bettari L, et al. Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function. Circ Heart Fail 2012;5:54–62. https://doi. org/10.1161/CIRCHEARTFAILURE.111.963413; PMID: 22167320. 23. Testani JM, Chen J, McCauley BD, at al. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 2010;122:265–72. https://doi.org/10.1161/ CIRCULATIONAHA.109.933275; PMID: 20606118 PMCid:PMC3025294. 24. Greene SJ, Gheorghiade M, Vaduganathan M, et al. Haemoconcentration, renal function, and post-discharge outcomes among patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial. Eur J Heart Fail 2013;15:1401–11. https://doi.org/10.1093/ eurjhf/hft110; PMID: 23845795 PMCid:PMC4199468. 25. Savarese G, Kishi T, Vardeny O, et al. Heart failure drug treatment – inertia, titration, and discontinuation: a multinational observational study (EVOLUTION HF). JACC Heart Fail 2023;11:1–14. https://doi.org/10.1016/j. jchf.2022.08.009; PMID: 36202739. 26. Chioncel O, Mebazaa A, Maggioni AP, et al. Acute heart failure congestion and perfusion status – impact of the clinical classification on in-hospital and long-term outcomes; insights from the ESC-EORP-HFA Heart Failure Long-Term Registry. Eur J Heart Fail 2019;21:1338–52. https://doi.org/10.1002/ejhf.1492; PMID: 31127678. 27. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/ HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022;79:e263–421. https://doi. org/10.1016/j.jacc.2021.12.012; PMID: 35379503.

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A-CURE 7th Annual Symposium

Panel Discussion: Targeting Heart Recovery in a Real-world Setting Moderated by: Bobbi Bogaev Chapman, MD1 and Panellists: Manreet Kanwar, MD,2 Jane Wilcox, MD, MSc3 and Bart Meyns, MD4 1. Abiomed, Danvers, MA, US; 2. Allegheny General Hospital, Pittsburgh, PA, US; 3. Northwestern Medicine, Chicago, IL, US; 4. Katholieke Universiteit Leuven, Leuven, Belgium

Dr Bobbi Chapman from Abiomed welcomed everyone to this interactive panel discussion and introduced the panellists, starting with Dr Jane Wilcox, Chief of the Section of Heart Failure Treatment and Recovery at Northwestern University Feinberg School of Medicine in Chicago, US, and principal investigator of the Impella BTR™ Early Feasibility Study (BTR EFS), and then Dr Manreet Kanwar, Section Head of the AGH McGinnis Cardiovascular Institute at Allegheny General Hospital in Pittsburgh, US, and founding member of the Cardiogenic Shock Working Group, and Dr Bart Meyns, Professor and Chief of Cardiac Surgery at the University Hospital Leuven in Leuven, Belgium.

Dr Kanwar would like to see assistive technologies that can provide more information about the degree of reverse remodelling, including the response to active unloading and change in the degree of myocardial fibrosis. For her, the duration of support of any temporary mechanical circulatory support (MCS) device is key; 14 days, for example, may be insufficient time for recovery. Ideally, she would be looking for a device with a longer duration time and one that is associated with fewer adverse events. Dr Wilcox answered that the most important feature in a device for her is the stability of the platform. She generally uses the Impella 5.5 because it fulfils this criterion. The Impella 5.5 also offers the additional benefit of being inserted through axillary access, which allows for patient ambulation. Dr Wilcox noted the importance of monitoring native heart function during the period of support, along with monitoring of the patient’s trajectory. The goal is to get the patient out of CS and onto GDMT.

Dr Chapman opened the discussion by inviting each panellist to describe their approach to heart recovery in their own clinical practice and set out the circumstances in which they choose to use unloading as part of their strategy to achieve recovery. Dr Wilcox acknowledged that the notion of recovery is very broad and the identification of ‘recoverable’ patients does not yet have clear-cut guidelines. When patients with chronic worsening heart failure present, she first performs right heart catheterisation to monitor the pulmonary capillary wedge pressure (PCWP) and cardiac index. When patients with high PCWP and low cardiac index are identified, the first discussion centres around finding ways to optimise the patient with other means prior to considering advanced therapy. In particular, when Dr Wilcox sees a young patient with relatively preserved global longitudinal strain and no prior exposure to angiotensin receptor–neprilysin inhibitor (ARNI) or highdose beta-blockers, she sees an opportunity to attempt native heart recovery using temporary unloading alongside guideline-directed medical therapy (GDMT). For patients who have not yet been treated with ARNI, she would strongly consider temporary unloading and ARNI.

Dr Meyns would like to see a device that can be placed in a minimally invasive fashion, that enables a patient to be discharged home and that offers a support duration spectrum of 6–12 months. For him, the patient’s ability to tolerate MCS weaning is important in guiding decisions. Dr Meyns finds the Impella pumps particularly helpful in this respect because they can be run down to no flow or close to no flow to enable a trial weaning prior to explanting the device. In addition, temporary MCS preserves the apex muscle.

Dr Kanwar explained that her aim is always to look for a path to recovery, and that drives her strategy. Active unloading in cardiogenic shock (CS) is well supported. In addition, Dr Kanwar will try to identify any reversible underlying trigger of heart failure that can be treated.

Given that financial incentives to recover patients are lacking, the moderator next asked the panellists how they overcome this barrier within their own clinical teams and the hospital.

Dr Kanwar agreed that it typically takes 6–12 months to achieve recovery of over 40%. At this point in time, although complete normalisation of left ventricular function is rarely achieved, the hearts have recovered to the point that GDMT can be tolerated and the native ejection fraction of >30% allows for the patient to avoid transplant.

Dr Kanwar replied that in her clinical practice, with the active implementation of MCS devices, she is seeing the lowest rates of heart transplant and, conversely, high rates of recovery in CS patients. She believes these success rates are down to careful patient selection. Although she acknowledges that her institution is paying for this success financially, she believes patient outcomes should take priority.

Dr Meyns aims for recovery in all his patients. In his clinical practice, in appropriate patient populations, he considers a 6-month wait period with GDMT and reassesses the patient for signs of native heart recovery prior to heart transplant. He uses the axillary Impella support in his patients as a part of this approach. His goal is always recovery. Continuing from the panellists’ overriding pursuit of recovery for their patients, the moderator asked the panellists to outline what they would look for in an ideal recovery device. What features should it have to better wean patients, improve support and achieve recovery in more patients?

Dr Chapman thanked the panellists for their contributions to a highly productive discussion and closed by recapping that further work is required to improve the means of identifying which patients are recoverable; best practices should be developed to help others gain the maximal advantage with Impella technology in a variety of clinical settings, and there is a need to develop smarter pumps that are dischargeable.

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A-CURE 7th Annual Symposium

Selected Talk: A Novel Fluoroscopic Approach to Impella Percutaneous Ventricular Assist Device Positioning Alessandro Beneduce, MD1 and Presented by Luca Baldetti, MD2 1. Scientific Institute for Research, Hospitalization and Healthcare, Ospedale San Raffaele, Milan, Italy; 2. Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy

Dr Baldetti’s talk covered the importance of the correct positioning of Impella implantation to avoid device-related complications and to optimise its function. In his presentation, Dr Baldetti discussed how correct positioning is best achieved, and presented results from his study to improve assessment of Impella malrotation.

anatomical landmarks and do not provide clear visualisation of the LV apex. Therefore, there is a need for a standardised fluoroscopic protocol for assessment of device malrotation on implantation. Dr Baldetti presented his centre’s methods to achieve this aim. A patient with a malrotated Impella underwent a contrast-enhanced multidetector non-ECG-gated chest CT scan during Impella support, and the images were compared with those of a patient with a correctly positioned Impella. The CT scans provided imaging of the direction and location of the device that matched three- and four-chamber echocardiogram views. Although Dr Baldetti recognised that different imaging modalities methods can offer different implant views, he rationalised the choice of CT scans because they provide volumetric data, angulation reconstruction and can be translated to match fluoroscopy imaging.

Dr Baldetti set out the three conditions that need to be met in order to achieve correct positioning of the Impella on implantation. The first condition is correct positioning represented by the waveforms on the device console; the second is the correct shaft depth across the aortic valve; and the third condition requires the pigtail to be directed downward towards the left apex and away from the lateral left ventricle (LV) wall. Correct Impella positioning is only fully fulfilled when all three conditions are met. The gold-standard method to assess correct Impella positioning is transthoracic or transoesophageal echocardiography; however, these methods are not always used in clinical practice.

Dr Baldetti identified the mitral valve annulus as the most suitable anatomical landmark to rely upon to guide assessment of implant positioning and noted that it can be lined up with the Impella, using its ring as the marker. He applied the S-curve method to assess optimal implant views.2 By using a multiview approach, Dr Baldetti demonstrated that it is possible to assess the orientation of the Impella towards the LV apex, the depth of the device across the aortic valve and the laterality of the device (Figure 1).

Dr Boldetti explained that if only the first two conditions are fulfilled, this can result in Impella malrotation, and this is thought to occur in as many as 32% of cases. Compared with no malrotation, device malrotation is associated with higher rates of adverse in-hospital outcomes, including higher degrees and worsening degrees of aortic regurgitation during support (14.7% versus 68.8%; p<0.001) and an increase in MI (0% versus 12.5%; p=0.035), major bleeding (14.7% versus 43.8%; p=0.025) and stroke (0% versus 12.5%; p=0.035) while in hospital.1 However, Impella malrotation is not easy to detect relying on 2D fluoroscopy imaging alone because these images lack

Dr Baldetti provided the results of his proof-of-concept validation case that tested this approach in a real-world setting, which confirmed the device was appropriately positioned. The position was verified to be

Figure 1: Impella Malrotation: the S-curve Method

Fluoroscopic algorithm for Impella percutaneous ventricular assist device positioning. 3C = three chamber; 4C = four chamber; CAU = caudal; CRA = cranial; IVS, interventricular septum; LAO = left anterior oblique; LV, left ventricle; RAO = right anterior oblique. INTERVENTIONAL CARDIOLOGY: REVIEWS, RESEARCH, RESOURCES www.ICRjournal.com

A-CURE 7th Annual Symposium correct by ECG performed in the intensive care unit. Dr Baldetti concluded that the fluoroscopic implant approach for Impella allows for rapid assessment of pump positioning and may overcome the lack of ultrasound imaging availability in centres. The right anterior oblique and caudal views

may present the preferred implant fluoroscopic views, whereas multiple views may further refine assessment of device orientation within the LV. Dr Baldetti acknowledged that this approach was validated in only one patient; further validation is underway.

Baldetti L, Beneduce A, Romagnolo D, et al. Impella malrotation within the left ventricle is associated with adverse in-hospital outcomes in cardiogenic shock. JACC Cardiovasc Interv 2023;16:739–41. https://doi.org/10.1016/j.jcin.2023.01.020; PMID: 36990567. 2. Pighi M, Thériault-Lauzier P, Piazza N. Multimodality imaging for interventional cardiologists. EuroIntervention 2018;14:AB33–9. https://doi.org/10.4244/eij-d-18-00614; PMID: 30158094.

Selected Talk: Left Ventricular Unloading Acutely Reduces Right Ventricular Preload in Patients with Acute Decompensated Heart Failure and Cardiogenic Shock Presented by Kay Everett, MD, PhD Tufts Medical Center, Boston, MA, US

Acute decompensated heart failure (ADHF) and cardiogenic shock (CS) are signs of deterioration in patients experiencing heart failure (HF). The proportion of patients with CS who also have ADHF is increasing, and mortality rates have remained high over the past few decades at 30– 50%.1 Unfortunately, right ventricular (RV) dysfunction in these patients is associated with worse survival.2 The priority goals of managing these patients are supporting the systemic circulation, relieving decongestion and minimising myocardial workload. Ventricular unloading has emerged as a means of offering myocardial protection, but it remains to be determined whether maximum left ventricular (LV) unloading can improve RV performance in ADHF-CS. Up until now, understanding in this domain has been limited to computational analyses (i.e. simulations using computational modelling with patient haemodynamic data). Dr Everett’s study aimed to address this by directly collecting these data from human patients with ADHF and testing the hypothesis.

Dr Everett presented the study results, which showed a significant reduction in end-diastolic pressures (EDP) of both the LV and RV after Impella 5.5 activation in the acute setting (p<0.05). Dr Everett proposed that these findings show that LV unloading of patients with ADHF-CS can achieve a reduction in biventricular filling pressures. Further, all patients saw a significant reduction in LV PVA during Impella 5.5 activation. There was a more diverse response in RV PVA, with four (67%) patients experiencing a significant reduction during the acute setting with Impella activation; one patient experienced no change and one patient experienced an increase in RV PVA (p<0.05). Examination of pressure–volume loops showed that four of the six patients experienced a significant coupled reduction in LV and RV volumes, pressures and PVA. The two patients who experienced unchanged or increased RV volumes and PVA both required inhaled pulmonary vasodilators due to refractory LV failure. All patients tolerated the procedure well without complications and, by the end of the study, three patients had been weaned off vasoactive medications.

The hypothesis of the present study was that maximal transvalvular LV unloading decreases RV pressures and pressure–volume area (PVA) in patients with ADHF-CS. Dr Everett relied upon a clinical case series that has enrolled six patients to date. All six patients had ADHF and refractory CS and underwent Impella 5.5 implantation as a bridge to transplant or durable ventricular assist device. Invasive haemodynamics, including the biventricular pressure–volume loops, were performed at baseline and between 5 and 15 min after Impella activation to assess biventricular function. Analysis was performed on both the aggregate patient cohort and per patient.

Dr Everett closed her presentation by summarising the findings of her study that identified a reduction in biventricular filling pressures, decrease in LV PVA, variable RV response and PVA reduction in selected patients with ADHF-CS in response to Impella 5.5 activation. These findings support the hypothesis that maximal transvalvular LV unloading may improve biventricular performance in ADHF-CS. Dr Everett added that in ADHF-CS patients with refractory RV failure, additional devices to address right-side decongestion or additional time on support may be required. She acknowledged the limitations of her study, including its small sample size and single-centre basis. However, additional enrolment of patients with and without refractory RV failure is ongoing, and this study will inform better identification of patients who require biventricular support.

The mean (±SD) age of patients was 57.3 ± 5.9 years and 83% were male. Patients had, on average, three vasoactive agents, and 33% required pulmonary vasodilators. Mean (±SD) LV ejection fraction was 10.0 ± 4.2% and LV end-diastolic diameter was 6.0 ± 0.7 cm. Baseline haemodynamics showed significant biventricular congestion and high vascular resistance in all patients.

Abraham J, Blumer V, Burkhoff D, et al. Heart failure-related cardiogenic shock: pathophysiology, evaluation and management considerations: review of heart failure-related cardiogenic shock. J Card Fail 2021;27:1126–40. https://doi.org/10.1016/j.cardfail.2021.08.010; PMID: 34625131. 2. Jain P, Thayer KL, Abraham J, et al. Right ventricular dysfunction is common and identifies patients at risk of dying in cardiogenic shock. J Card Fail 2021;27:1061–72. https://doi.org/10.1016/j. cardfail.2021.07.013; PMID: 34625126. 1.

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A-CURE 7th Annual Symposium

Role of Right Ventricle Reserve Assessment and Left Ventricular Unloading to Predict Right Heart Failure After Left Ventricular Assist Device Implantation Presented by Ryan Tedford, MD Medical University of South Carolina, Charleston, SC, US

Dr Tedford opened his talk with a patient case: a 62-year-old man with non-ischaemic cardiomyopathy with a left ventricular (LV) end-diastolic diameter of 7.7 cm and a LV ejection fraction of 25%. The patient had severe mitral regurgitation and a dilated right ventricle (RV) with mild to moderate dysfunction and moderate tricuspid regurgitation. His renal and liver functions were normal and he had elevated pulmonary vascular resistance but was not on any inotropes. The patient was treated with nitroprusside. His Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile was 4. The patient’s right arterial pressure (RAP) was normal at 6 mmHg; pulmonary artery wedge pressure (PAWP) was elevated at 20 mmHg and his pulmonary artery pulsatility index (PAPi) was 3.33. These parameters did not signify a high risk of RV failure (RVF) and this patient would not be considered at high risk of RVF after implantation of a durable left ventricular assist device (LVAD) according to traditional criteria. However, the patient ended up experiencing acute RVF following HeartMate 3 implantation. This case study illustrates how hard it is to predict RVF prior to implant and yet RVF following LVAD implantation continues to be associated with poor outcomes.

Despite these ongoing efforts to predict and prevent RHF, it remains a leading cause of morbidity and mortality in heart failure patients, particularly after implantation of a durable LVAD. It is particularly challenging because multiple clinical factors and therapies impact RV function in pre-LVAD patients. Dr Tedford assembled a perspective in 2017 to summarise the potential mechanisms of RV dysfunction after implantation of a durable LVAD, including the decline in septal function from the reduced twist of the heart and a decline in RV contractibility due to LV unloading.4 The gold standard to assess RV function is pressure–volume analysis, but this is an invasive procedure and not always practical. Dr Tedford referred to a number of studies that aimed to identify RV function indicators. One study performed on a piglet model of pulmonary hypertension investigated whether RV–pulmonary artery coupling could be related to RV reserve.5 That study found that RV reserve was associated with ventricular–arterial coupling.5 Another clinical study showed that RV ejection fraction during submaximal exercise is an index of RV contractile reserve, and provides a better identification of RV dysfunction than resting measures.6 Finally, a study in six patients with biventricular failure who underwent dobutamine stress echocardiography within 30 days of mechanical circulatory support (MCS) implant showed that individuals who did not develop RHF had higher systolic pulmonary artery pressure and tricuspid annular plane systolic excursion that those who did.7 As a result of these efforts, a step was taken to redefine contractile reserve as the response of the RV to LV unloading with pharmacological (vasodilator) or temporary mechanical support.8

Dr Tedford outlined the traditional methods used to assess RVF, which include an array of haemodynamic, echocardiographic and MRI metrics (Table 1). However, no single metric in isolation is a good predictor to tell which patients will develop RV dysfunction. In further efforts to predict RVF, a considerable number of risk scores have been developed but independent validation cohorts have shown that these are also poor at predicting RVF.1,2 The European Registry for Patients with Mechanical Circulatory Support (EUROMACS) Right Heart Failure (RHF) risk score with a large derivation and validation cohort outperformed other risk scores and clinical predictors of early postoperative RHF, but even so, the C-index of the composite score was 0.70 in the derivation and 0.67 in the validation cohort.3

Using this definition, Dr Tedford presented an overview of his retrospective multicentre study performed on patients undergoing durable LVAD implantation.9 Seventy patients underwent right heart catheterisation (RHC) and vasodilator testing with nitroprusside as part of LVAD/transplant evaluation. Most patients had combined post- and precapillary pulmonary hypertension. The 2020 MCS Academic Research Consortium definition was used to define RHF,10 and a validation cohort of 10 consecutive patients was included. Of these patients, 39% met criteria for RVF and 20% required a right ventricular assist device, half of which were planned. Baseline demographics,

As an example, when various risk scores are applied to the opening patient case, none would have predicted RVF, with scores of 0 (low risk) on EUROMACS RHF, 0 (low risk) on the postoperative EUROMACS RHF, 0 (low risk) on the Kormos RV risk score and 1 (low risk) on the CRITT RV score.

Table 1: Methods and Metrics of Right Ventricle Assessment RHC

Echo

Cardiac MRI

• RAP/CVP • RAP:PAWO • PAPi (pulmonary pulse pressure/RAP) • RVSWI

• RV/RA size • TAPSE or S’ • RV FAC • RV strain • TAPSC/PASP

• RV/RA volumes • TAPSE • RVEF • SV/ESV • Strain

CVP = central venous pressure; ESV = end-systolic volume; FAC = fractional area change; LA = left atrium; LV = left ventricle; PAPi = pulmonary artery pulsatility index; PASP = pulmonary arterial systolic pressure; PAWP = pulmonary artery wedge pressure; RAP = right arterial pressure; RA = right atrium; RV = right ventricle; RVEF = right ventricular ejection fraction; RVSWI = right ventricular stroke work index; S’ = systolic velocity of the tricuspid annulus; SV = stroke volume; TAPSE = tricuspid annular plane systolic excursion.

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A-CURE 7th Annual Symposium Figure 1: Stroke Volume Index Predictability of Early Right Heart Failure

INTERMACS profiles, haemodynamics, echo parameters and laboratory parameters were similar between those who did and did not develop RHF. There was no difference between the most used RHF risk scores, including the EUROMACS RHC score. The results of Dr Tedford’s study showed that the difference in stroke volume index (SVI) in response to nitroprusside, and specifically peak SVI, was a better indicator of patients who went on to develop RHF compared with baseline SVI alone, as shown in Figure 1. If SVI was maintained above 22.10 ml/m2, the likelihood of the patient developing RHF was low.9

response by unloading with an Impella device and found that individuals with a significant decrease in right atrial pressure, or no increase in the RAP/PAWP ratio or an improvement in PAPi were less likely to develop RVF after LVAD implantation.13 Returning to the patient case described at the beginning of his presentation, Dr Tedford showed that after nitroprusside infusion the SVI was low at 19.8 ml/m2 and PAPi decreased from 3.33 to 2.0. These parameters suggest the patient had a lack of RV reserve prior to LVAD implantation.

Another recent study conducted at a single centre also found that SVI varied during peak nitroprusside infusion.11 This investigation additionally found that post-nitroprusside PAPi was improved in those patients who did not develop RHF. SVI and PAPi could provide independent predictors of RVF following LVAD implantation. In addition, Gonzalez et al. looked at the peak haemodynamic parameters to predict RVF and found that optimal PAPi was the best predicator of RVHF.12 Hsi et al. examined the RV 1.

Bellavia D, Iacovoni A, Scardulla C, et al. Prediction of right ventricular failure after ventricular assist device implant: systematic review and meta-analysis of observational studies. Eur J Heart Fail 2017;19:926–46. https://doi. org/10.1002/ejhf.733; PMID: 28371221. Kalogeropoulos AP, Kelkar A, Weinberger JF, et al. Validation of clinical scores for right ventricular failure prediction after implantation of continuous-flow left ventricular assist devices. J Heart Lung Transplant 2015;34:1595–603. https://doi.org/10.1016/j. healun.2015.05.005; PMID: 26123950. Soliman OII, Akin S, Muslem R, et al. Derivation and validation of a novel right-sided heart failure model after implantation of continuous flow left ventricular assist devices: the EUROMACS (European Registry for Patients with Mechanical Circulatory Support) right-sided heart failure risk score. Circulation 2018;137:891–906. https://doi. org/10.1161/circulationaha.117.030543; PMID: 28847897. Houston BA, Shah KB, Mehra MR, Tedford RJ. A new ‘twist’ on right heart failure with left ventricular assist systems. J Heart Lung Transplant 2017;36:701–7. https://doi.org/10.1016/j. healun.2017.03.014; PMID: 28416103. Guihaire J, Haddad F, Noly PE, et al. Right ventricular

Dr Tedford concluded his presentation by summarising that RV reserve is associated with the gold-standard measure of RV function, and vasodilator testing (or temporary MCS) to unload the LV may be another way to assess RV reserve and predict RV failure in patients after they undergo LVAD implantation. He acknowledged that prospective studies are needed to test these hypotheses.

reserve in a piglet model of chronic pulmonary hypertension. Eur Respir J 2015;45:709–17. https://doi. org/10.1183/09031936.00081314; PMID: 25504996. 6. Ireland CG, Damico RL, Kolb TM, et al. Exercise right ventricular ejection fraction predicts right ventricular contractile reserve. J Heart Lung Transplant 2021;40:504–12. https://doi.org/10.1016/j.healun.2021.02.005; PMID: 33752973. 7. Deswarte G, Kirsch M, Lesault PF, et al. Right ventricular reserve and outcome after continuous-flow left ventricular assist device implantation. J Heart Lung Transplant 2010;29:1196–8. https://doi.org/10.1016/j. healun.2010.05.026; PMID: 20620082. 8. Haddad F, Vrtovec B, Ashley EA, et al. The concept of ventricular reserve in heart failure and pulmonary hypertension: an old metric that brings us one step closer in our quest for prediction. Curr Opin Cardiol 2011;26:123–31. https://doi.org/10.1097/hco.0b013e3283437485. PMID: 21297465. 9. Read JM, Azih NI, Peters CJ, et al. Hemodynamic reserve predicts early right heart failure after LVAD implantation. J Heart Lung Transplant 2022;41:1716–26. https://doi. org/10.1016/j.healun.2022.07.003; PMID: 35934606.

10. Hall SA, Copeland H, Alam A, Joseph SM. The “right” definition for post-left ventricular assist device right heart failure: the more we learn, the less we know. Front Cardiovasc Med 2022;9:893327. https://doi.org/10.3389/ fcvm.2022.893327; PMID: 35557521; PMCID: PMC9087190. 11. Cacioli G, Polizzi V, Ciabatti M, et al. Prediction of right ventricular failure after left ventricular assist device implantation: role of vasodilator challenge. Eur Heart J Acute Cardiovasc Care 2022;11:629–39. https://doi.org/10.1093/ ehjacc/zuac085; PMID: 35866303. 12. Gonzalez MH, Wang Q, Yaranov DM, et al. Dynamic assessment of pulmonary artery pulsatility index provides incremental risk assessment for early right ventricular failure after left ventricular assist device. J Card Fail 2021;27:777–85. https://doi.org/10.1016/j. cardfail.2021.02.012; PMID: 33640481. 13. Hsi B, Joseph D, Trachtenberg B, et al. Degree of change in right ventricular adaptation measures during axillary Impella support informs risk stratification for early, severe right heart failure following durable LVAD implantation. J Heart Lung Transplant 2022;41:279–82. https://doi. org/10.1016/j.healun.2021.11.007; PMID: 34998630.

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A-CURE 7th Annual Symposium

Panel Discussion: Advanced Surgical Uses of Percutaneous Ventricular Assist Device Support and Patient Management Moderator: Mark Anderson, MD1 Panellists: Hermann Reichenspurner, MD, PhD2 and Alexander Bernhardt, MD2 1. Hackensack Meridian Health, Edison, NJ, US; 2. University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Presentation 1: Impella 5.0/5.5 in the Setting of Post-cardiotomy Failure Presented by: Hermann Reichenspurner, MD, PhD

Figure 1: Impella Support Options in Cardiac Surgery

Dr Reichenspurner started his presentation by listing the indications of Impella 5.0/5.5 as follows:

Preoperative Axillary insertion a few days preoperatively for optimisation Bridge-to-cardiac surgery candidacy

• Cardiogenic shock; • Weaning from extracorporeal membrane oxygenation (ECMO); • Bridge-to-bridge before left ventricular assist device (LVAD)

Intraoperative Axillary graft and Impella placement before sternotomy Axillary graft and wire placement after sternotomy and before CPB

Preventing post-cardiotomy failure

implantation or before heart transplant; • Bride to recovery: myocarditis, peripartum; and • Cardiac surgery • Mitral valve surgery; • Aortic valve surgery; and • Coronary artery bypass graft (CABG)/off-pump coronary artery bypass (OPCAB) with left ventricular (LV) ejection fraction (EF) <30%.

and the Impella explanted under local anaesthesia on Day 8. At this time, the patient was doing well with an EF of 30% and an LVEDD of 60 mm.

He emphasised the importance of avoiding low cardiac output syndrome (LCOS) following cardiac surgery (post-cardiotomy cardiogenic shock), which is caused by a transient decrease in systemic perfusion secondary to myocardial dysfunction. LCOS occurs in 10–15% of all cardiac surgery and is associated with poor clinical outcomes and mortality. Dr Reichenspurner referred to a study conducted on a population of 774,881 CABG patients from the Society of Thoracic Surgeon (STS) database that aimed to describe and test the STS risk model for CABG.1 That study found that patients with reduced EF undergoing cardiac surgery have an increased rate of LCOS.1

In a second patient case, a 74-year-old male patient had been experiencing dyspnoea for 4 weeks. A coronary angiogram confirmed triple-vessel disease, and the patient’s EF was 22% and LVEDD 68 mm. His cardiac output deteriorated to 2 l/min, but percutaneous coronary intervention (PCI) was not considered appropriate due to severe peripheral arterial vascular disease. The patient underwent a protected OPCAB graft with the use of Impella 5.5 during the procedure. Dr Reichenspurner has performed nine OPCABs with Impella so far and has achieved 100% complete revascularisation and in-hospital survival. His patients were able to be mobilised on support from Day 1 postoperatively.

There are numerous different ways in which Impella support can be used in cardiac surgery that aim to prevent post-cardiotomy failure or, if it has occurred, treat it (Figure 1). Preventing post-cardiotomy failure can be achieved by preoperative axillary insertion of the Impella for optimisation or as a bridge to cardiac surgery candidacy. The Impella can also be used intraoperatively via axillary graft placement pre-sternotomy or with axillary graft and wire placement after sternotomy and before cardiopulmonary bypass (CPB). In patients with failure to wean from CPB, the Impella pump can be placed directly either through the ascending aorta or the axillary artery.

Dr Reichenspurner outlined the trials that are coming up: IMPACT (Impella Protected Cardiac Surgery Trial) US was presented at the A-CURE 2022 annual symposium and IMPACT EU is an upcoming trial to examine the use of Impella in high-risk cardiac surgery.2 The PRIME (Protected CABG with Impella) trial is a German multicentre trial on OPCAB with the use of Impella under preparation. Dr Reichenspurner finished by looking forward to the results of these studies in the near future.

Dr Reichenspurner presented a patient case to illustrate the use of Impella in the treatment of post-cardiotomy failure: a 63-year-old male patient underwent aortic valve replacement (AVR) 10 years earlier. The patient deteriorated with an aortic valve opening area of 0.8 cm2, an EF of 62% and a left ventricular end-diastolic diameter (LVEDD) of 68 mm. Due to his coronary anatomy, the patient was not suitable for transcatheter aortic valve replacement (TAVR). He underwent a redo AVR and, due to the failure to wean off CPB, an Impella 5.0 was implanted. The patient was extubated after 4 h, fully mobilised on the device on Day 1 postoperatively

Dr Bernhardt reported the outcomes from the STS Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 2020 Annual Report that reviewed 25,551 patients undergoing primary isolated continuous-flow LVAD implantation per annum between 2010 and 2019.2 In 2019, 50% of patients were INTERMACS Profile 1 or 2 before durable LVAD, and 73% received an LVAD as destination therapy.2 The 1- and 2-year survival rates in the most recent era have improved compared with the period from 2010 to 2014 (82.3% and 73.1% versus 80.5% and 69.1%, respectively; p<0.0001).3 Major bleeding and infection continue to be the

Failure to wean from CPB/PCCS Direct Aortic LD Axillary 5.0 Axillary or Direct Aortic 5.5

Treating post-cardiotomy failure

CPB = cardiopulmonary bypass; PCCS = post cardiotomy cardiogenic shock.

Presentation 2: Impella 5.5/5.0 as a Bridge to Durable Left Ventricular Assist Device Presented by: Alexander Bernhardt, MD

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A-CURE 7th Annual Symposium leading adverse events. The incidence of stroke has declined in the current era to 12.7% at 1 year.3

Dr Anderson continued by asking the experts how they determine whether to insert the Impella upfront or intraoperatively, or whether they wean the patient before implantation.

Dr Bernhardt recapped the evidence that demonstrated Impella 5.0/5.5 is a feasible bridge-to-decision option for patients following extracorporeal life support (ECLS) implantation and allows further evaluation of a patient’s neurological state and future therapy needs.4 Dr Bernhardt proceeded with an overview of a multicentre retrospective study that gathered data on 531 patients who underwent durable mechanical circulatory support implantation after ECLS between January 2010 and August 2018 in 11 high-volume European centres.5 That study found that patients receiving durable mechanical circulatory support after ECLS experienced significant survival benefit with 1 year survival of 53%.5 Another study demonstrated the benefits of the Impella 5.0/5.5 device over ECLS as a bridging device before LVAD implantation, which included evaluation of right ventricle (RV) function and early mobilisation and optimisation of patients.6 Dr Bernhardt asserted that using Impella enables full haemodynamic assessment and facilitates better prognostic and therapeutic strategies.

Dr Reichenspurner expressed that we have learnt that the aortic balloon pump only works if used prophylactically, whether that is primarily or while on bypass, but he would not use it belatedly. Dr Anderson was in agreement with this approach. In response to Dr Reichenspurner’s enquiry about the use of Impella in off-pump coronary artery surgery, Dr Anderson replied by describing the advantages of avoiding bypass and reducing global ischaemic time. He confirmed that off-pump surgery can impair the RV during manipulation of the LV, but with Impella the LV is decompressed, which reduces compromise of the RV during cardiac manipulation. He added that it is, of course, always possible to put the patient on a pump acutely if necessary. Dr Bernhardt was in agreement with the views of Drs Reichenspurner and Anderson. He added that patients who decompensate in the ICU have the worst outcomes, so it is important to take steps to prevent post-cardiotomy cardiac failure for these patients in particular. One step he takes to minimise this risk is to use the Impella device intraoperatively. In this way, the Impella can help stabilise the patient not only intraoperatively, but also in the crucial 48 h after surgery. Further, he finds that the Impella improves renal function and can achieve early mobilisation of the patient, enabling surgeons to decide when to safely wean the patient off support.

This concept was subsequently proven in a feasibility study of nine patients who were implanted with an Impella 5.0 after ECLS.7 Survival of 90% was achieved. Following CE approval, the first 46 consecutive patients underwent Impella 5.5 implantation in six German centres between March 2018 and September 2019. Of those patients who underwent bridge-to-durable LVAD implantation, a 30-day survival rate of 89.5% was achieved.8

Dr Anderson asked the panellists about the pros and cons of direct aortic versus axillary insertion.

Building on this evidence, Dr Bernhardt set up a retrospective multicentre study in Germany to collect the outcomes and adverse events in patients who were bridged with axillary Impella pumps to durable LVAD. The goal of the registry is to assess the predictors of poor outcomes, especially right heart failure (RHF). Dr Bernhardt presented the preliminary results of this study, which have not yet been published. One-third of the study subjects were resuscitated, with 40% implanted with ECLS before Impella support. In this very sick patient population, the 1-year survival rate was >70%.

Dr Reichenspurner replied that the great advantage of axillary insertion over direct insertion is that its removal can be performed in the ICU rather than in the operating room. He offered a patient example in which the left axillary approach was taken because right side access was impossible. In his clinical practice, the aortic approach will always be the last choice. Dr Anderson added that there are alternatives to direct insertion when removing the graft because it is not always necessary to perform a redo sternotomy to explant it, and it is therefore helpful to have both options available.

Panel Discussion

Dr Anderson thanked the experts for their presentations and kicked off the discussion with the first question. In respect of high-risk cardiac surgery, patients are often steered towards high-risk PCI and surgery is left for the truly high-risk patients who have no alternative options. Dr Anderson asked the experts how they decide which patients are appropriate for high-risk PCI and which are appropriate for high-risk cardiac surgery.

Dr Anderson next enquired about the mechanism of pre-LVAD implantation and how it improves patient outcomes. Dr Bernhardt explained that the Impella 5.5 can be used as a bridging device to provide time to improve the overall condition of the patient and optimise other systemic issues, such as cardiac state, fluid status and end organ function. This means that the patient can be brought out of the acute phase of cardiogenic shock and the risk of infection can be mitigated so that the patient is left only with LV-sided failure prior to durable LVAD implantation.

Dr Reichenspurner responded that, in his clinical experience, the majority of high-risk patients are generally better off with PCI, but there is a proportion of high-risk patients for whom PCI is not suitable or they have contraindications. He believed that a defined strategy is required for this population of very high-risk patients. Dr Reichenspurner is interested in the results of the IMPACT pilot trial because it examines this high-risk patient group and compares prophylactic Impella with standard care to determine whether Impella will improve current outcomes of high-risk cardiac surgery.

Dr Reichenspurner added that, at present, durable LVADs are implanted into INTERMACS Profile 1 and 2 patients, and half of these patients survive but half do not. In order to make the LVAD more acceptable as a treatment, he believes it is important to stabilise and improve the patient condition before implantation, in the same way patients are stabilised prior to undergoing heart transplant. The Impella 5.5 achieves this by buying the patient time during which they can recover and mobilise. The better the condition the patient is in, the better the outcomes are likely to be after LVAD implantation.

Dr Anderson anticipated that Impella will make a difference and agreed that the results from the IMPACT pilot trial will be exciting. He anticipated not only positive survival rates, but also a positive impact on acute renal injury, ventilator time and duration in the intensive care unit (ICU).

INTERVENTIONAL CARDIOLOGY: REVIEWS, RESEARCH, RESOURCES www.ICRjournal.com

A-CURE 7th Annual Symposium Dr Anderson enquired about the techniques used by the panellists to minimise axillary artery injury and the risk of stroke during the explant of the Impella device during durable LVAD implantation.

he has not experienced any incidents of stroke using this updated practice method. Dr Reichenspurner agreed with this recommendation. He considered removing the Impella via the apex a useful change of technique to use whenever the opportunity presents, and especially if the support duration was for a prolonged period of time.

Dr Bernhardt replied that in his practice the extraction technique has recently been updated and he now recommends extraction of the implant from the apex instead of the axillary artery. He advised closing by manipulation of the carotids to minimise the risk of stroke. In his practice, 1.

Shahian DM, O’Brien SM, Filardo G, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 1 – coronary artery bypass grafting surgery. Ann Thorac Surg 2009;88(1 Suppl):S2–22. https://doi.org/10.1016/j. athoracsur.2009.05.053; PMID: 19559822. 2. Benke K, Korça E, Boltjes A, et al. Preventive Impella® support in high-risk patients undergoing cardiac surgery. J Clin Med 2022;11:5404. https://doi.org/10.3390/jcm11185404. PMID: 36143050. 3. Molina EJ, Shah P, Kiernan MS, et al. The Society of Thoracic Surgeons INTERMACS 2020 annual report. Ann Thorac Surg 2021;111:778–92. https://doi.org/10.1016/j.

athoracsur.2020.12.038; PMID: 33465365. 4. Bernhardt AM, Zipfel S, Reiter B, et al. Impella 5.0 therapy as a bridge-to-decision option for patients on extracorporeal life support with unclear neurological outcomes. Eur J Cardiothorac Surg 2019;56:1031–6. https:// doi.org/10.1093/ejcts/ezz118; PMID: 31038672. 5. Saeed D, Potapov E, Loforte A, et al. Transition from temporary to durable circulatory support systems. J Am Coll Cardiol 2020;76:2956–64. https://doi.org/10.1016/j. jacc.2020.10.036; PMID: 33334424. 6. Houston BA, Shah KB, Mehra MR, Tedford RJ. A new ‘twist’ on right heart failure with left ventricular assist systems. J

Heart Lung Transplant 2017;36:701–7. https://doi.org/10.1016/j. healun.2017.03.014; PMID: 28416103. 7. Bertoldi LF, Pappalardo F, Lubos E, et al. Bridging INTERMACS 1 patients from VA-ECMO to LVAD via Impella 5.0: De-escalate and ambulate. J Crit Care 2020;57:259– 63. https://doi.org/10.1016/j.jcrc.2019.12.028; PMID: 32061461. 8. Bernhardt AM, Potapov E, Schibilsky D, et al. First in man evaluation of a novel circulatory support device: early experience with the Impella 5.5 after CE mark approval in Germany. J Heart Lung Transplant 2021;40:850–5. https:// doi.org/10.1016/j.healun.2021.04.001; PMID: 34030970.

Panel Discussion: Non-cardiac Surgery Interventions on Patients Receiving Impella Support Moderated by: Mark Anderson, MD1 Panellists: Nicolas Brozzi, MD, Raul Rosenthal, MD,2 Jaime Hernandez-Montfort, MD,3 Ramachandra Reddy, MD3 and Radha Gopalan, MD4 2

1. Hackensack Meridian Health, Edison, NJ, US; 2. Cleveland Clinic Florida, Weston, FL, US; 3. Baylor Scott & White Health, Dallas, TX, US; 4. Banner University Medical Center, Phoenix, AZ, US

Presentation 1: Non-cardiac Interventions in Patients With High Profile Temporary Transvalvular Pumps Presented by: Jaime Hernandez-Montfort, MD

temporary MCS device like Impella 5.5, which can offer ambulatory, haemodynamic and end organ stability, assistance with perioperative bleeding, reduced duration in the intensive care unit and lower need for organ replacement.

Dr Hernandez-Montfort opened by presenting the discussion goals as follows:

Dr Hernandez-Montfort provided an example of a non-cardiac case that may require heart support.

• to emphasise the unmet need among high-risk patients with impaired myocardial function requiring non-cardiac interventions

The patient was a 66-year-old woman with multiple comorbidities, including hypertension, hyperlipidaemia and coronary artery disease, and presented with bloody diarrhoea, unintentional weight loss and a fall. She experienced refractory shock on noradrenaline, vasopressin and phenylephrine. Her white blood cell count was 18,000/mm3 and lactate was 4.3mmol/l. An echocardiogram showed severe left ventricular (LV) dysfunction with a stress-induced cardiomyopathy pattern, free air and a sigmoid colon mass. Given the colonic perforation with refractory shock, it was decided to proceed with exploratory laparotomy and stabilise the patient upfront with Impella 5.5 with heparin-free purge fluid. After the patient’s conditions resolved, she demonstrated LV remission, normal LV size and normal LV systolic function with an ejection fraction of 55–60%. She underwent rehabilitation before discharge home.

• to review case-based programmatic approaches to patients with impaired myocardial function requiring non-cardiac surgical interventions.

To achieve best possible outcomes, an effective advanced heart disease recovery and replacement programme requires access to an advanced heart failure (HF) specialist, comprehensive therapy with remote monitoring and interdisciplinary teams for cardiogenic shock (CS). As with most cardiac recovery programmes, an interdisciplinary team approach is required to decide the best intervention for the patient. Given that there are multiple mechanical circulatory support (MCS) options available, it is necessary to define the intended transition and haemocompatibility to tailor the device to the patient and optimise the patient’s condition for the next step.

This is one example of a procedure in which the Impella 5.5 was used as a bridge to recovery/replacement by providing cardiac support. Other non-cardiac procedures, such as laparoscopic nephrectomy, cystoscopy and bladder mass resection, lung and liver biopsy and upper and lower

Dr Hernandez-Montfort clarified that determining the next step may require non-cardiogenic profiling.1 He set out the advantages of a

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A-CURE 7th Annual Symposium endoscopy with biopsy, may benefit from the use of heparin-free Impella support.2

Impella performance. Dr Brozzi closed his presentation by acknowledging that this is just the beginning, and further research is required.

Impella 5.5 is safe and feasible for patients with underlying HF who need to undergo non-cardiac interventions, but more clinical data need to be collected to better understand this patient population and appropriate usage.

Presentation 3: Benefits of Bariatric Surgery and Rapid Weight Loss on Cardiac Health Presented by: Raul Rosenthal, MD

Dr Rosenthal’s presentation provided an outline of the benefits of bariatric surgery and rapid and durable weight loss on cardiac health. Due to its particular anatomical location and its proximity to the coronary arteries, pericardial fat is linked to coronary pathology (e.g. coronary atherosclerosis).4

Presentation 2: Application of Transvalvular Axial Flow Pumps to Support Advanced Heart Failure Patients Undergoing Abdominal Surgery Presented by: Nicolas Brozzi, MD

Dr Brozzi shared that more than 10 million major non-cardiac surgical procedures are performed each year in the US and the number of patients with HF is increasing.3 Furthermore, patients presenting with advanced HF and LV dysfunction are facing increased mortality risk during major abdominal surgery. Patients with CS are often not considered appropriate candidates for non-cardiac surgeries. Transvalvular axial flow pumps, such as the Impella 5.0 and 5.5, can offer robust haemodynamic support for these patients with severe LV failure.

Dr Rosenthal obtained a linear measurement of pericardial fat thickness from 113 patients 1.07 years before and 1.3 years after undergoing bariatric surgery. Measurements were performed on CT examinations that were reformatted into the sagittal plane. Measurements before and after bariatric surgery were compared and related to the risk of developing coronary artery disease (CAD) by the Framingham Heart Study parameters and predictors of CHD at 10 years.5 The patients had a mean (±SD) age of 56 ± 14 years and had commodities associated with CAD, including diabetes type 2 and hypertension. The results demonstrated a significant decrease in pericardial fat thickness after the bariatric procedure (from 5.64 ± 1.90 to 4.68 ± 4.68 mm after bariatric surgery; p=0.0001). This benefit translated into a decreased risk of CAD after procedure (12.43% versus 10.25%) with a reduction in RR of 17.43%.

Dr Brozzi provided an overview of his study, which was a retrospective review of patients undergoing abdominal surgery under Impella. He collected data on basic demographics, type of abdominal surgery, time on Impella support, transition to other support devices and outcomes, including major complications and mortality. The devices used were Impella CP, 5.0 and 5.5.

Dr Rosenthal’s study also showed improvements in ventricular conduction after reduction in pericardial fat triggered by rapid weight loss in patients with severe obesity undergoing bariatric interventions. This was investigated by a retrospective review of ECG changes. Dr Rosenthal compared changes in pericardial fat thickness and ECG components before and after bariatric surgery. The results showed that as pericardial fat decreased after surgery, both the QT interval (401.93 ± 32.31 versus 389.00 ± 35.62 ms before and after bariatric surgery, respectively; p=0.017) and QTc interval (438.74 ± 29.01 versus 426.88 ± 25.39 ms before and after bariatric surgery, respectively; p=0.006) improved in this patient population.

Dr Brozzi presented data from four patient cases. All four patients had a long history of cardiomyopathy and were relatively young (aged 22, 26, 32 and 64 years). All were receiving inotropic treatment and were readmitted in CS. Three patients received an intra-aortic balloon pump in an attempt to stabilise them, and all four were transitioned onto the Impella device. The surgeries performed were one nephrectomy, two sleeve gastrostomies and one cholecystectomy. Two patients required transitional support; one required extracorporeal membrane oxygenation (ECMO), but then proceeded to Society for Cardiovascular Angiography and Interventions (SCAI) SHOCK Stage E before eventually being transplanted. Another patient proceeded to HeartMate 3 because they could not be weaned off Impella. There were three successful transplants in total.

In his study, Dr Rosenthal also looked at LV ejection fraction (LVEF) by conducting a retrospective review of echocardiographic changes in systolic function in patients with obesity who underwent bariatric surgery at his institution. LVEF before bariatric surgery was compared to that 12 months after surgery when maximum weight loss occurs, and patients with preoperative HF were compared to those without preoperative HF. Results showed that bariatric surgery and rapid and durable weight loss improved LVEF after 12 months in patients with severe obesity and HF: LVEF in patients without and with HF was 59.90 ± 7.58% and 38.79 ± 13.26%, respectively, before bariatric surgery (p=0.001), compared with 59.88 ± 7.85% and 48.47± 14.57%, respectively, after bariatric surgery (p=0.0001). In addition, Dr Rosenthal examined the cardiac geometry and found that weight loss following bariatric surgery resulted in improved heart ventricular function and structure. Most of the patients with obesity presented with significant concentric remodelling before surgery and improved to normal geometry of chambers after bariatric surgery.

Dr Brozzi set out the surgical and anaesthetic considerations that were taken into account in each case. The procedures were conducted under cardiac anaesthesia with invasive monitoring via a left arterial line, SwanGanz catheter and transoesophageal echocardiogram to optimise patient management intraoperatively. The procedures involved cardiac surgeons remaining on stand-by , along with ECMO, in the operating room during device implantation. Systemic heparin was discontinued 4–6 h prior to surgery and the patients were administered bicarbonate purge solution at the time of transition to Impella and throughout the course of Impella support until 12–24 h after surgery. Systemic heparin was restarted postoperatively if there was no evidence of bleeding. Dr Brozzi concluded that his initial experience of using Impella for patients requiring haemodynamic support for advanced HF CS was satisfactory, with 75% (n=3) of his patients successfully transplanted. He made the point that implantable LV assist devices have set a precedence for this strategy in non-cardiac operations and the adoption of alternative anticoagulation strategies in the perioperative period do not affect

Dr Rosenthal found there was an improvement in LV mass index and ventricular contractility in patients with obesity following rapid weight loss after bariatric surgery: LV fractional shortening improved from 31.05 ± 8.82% before to 36.34 ± 8.21% after surgery (p=0.007); posterior wall thickness improved from 1.16 ± 0.23 mm before to 1.04 ± 0.22 mm after

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A-CURE 7th Annual Symposium surgery (p=0.01); and the LV mass index improved from 101.3 ± 38.3 g/m2 before to 86.70 ± 26.6 g/m2 after surgery (p=0.005).

Dr Brozzi responded by stating that an Impella 5.0 or 5.5 will provide more support for the high-risk patient with decompensated HF. He offered an extreme example of one patient with small artery anatomy and a BMI of 52 kg/m2 for whom his team had to use Impella CP, which proved sufficient to support the patient through the non-cardiac surgery.

Dr Rosenthal explained that obesity and excessive visceral adiposity have been considered key mediators in metabolic and cardiovascular diseases. His study aimed to report the changes in interatrial fat after bariatric surgery and its effect on the risk of developing new-onset AF using CT and ECG parameters. The results showed a decrease in interatrial fat formation following rapid weight loss after bariatric surgery (3.93 ± 1.38 versus 2.97 ± 0.97 mm before and after bariatric surgery, respectively; p=0.001) that was associated with a lowering of the risk of new-onset AF in patients with severe obesity (9.08 ± 10.04% versus 7.48 ± 8.74% before and after bariatric surgery, respectively; p=0.341). Dr Rosenthal concluded that obesity and excess visceral adiposity are risk factors for AF and bariatric surgery decreases interatrial fat thickness in patients with obesity, resulting in a lower risk for new-onset AF.

Dr Hernandez-Montfort replied that in his practice he uses the Impella 5.5 to prepare patients with LV unloading for further transition, such as additional profiling, remission, recovery or replacement. Dr Reddy emphasised it is important to get the patient ambulatory, which can be achieved with Impella 5.5. In his practice, he also uses Impella 5.5 to provide the patient with maximum support upfront. Dr Anderson agreed with these positions and confirmed it makes sense to use the most powerful pump for all these reasons. Dr Anderson expressed his intrigue with the use of Impella to change phenotypes and achieve rapid weight loss after bariatric surgery. He enquired whether patients who need bariatric surgery can go on to receive guideline-directed medical therapy, LVAD or heart transplant.

Dr Rosenthal also conducted a retrospective analysis of the US National (Nationwide) Inpatient Sample (NIS) database to assess whether rapid and durable weight loss had an impact on hospital admissions in patients with diastolic HF and severe obesity.6 The results showed that in this retrospective case-control study of a large, representative national sample of patients with severe obesity, bariatric surgery was associated with significantly reduced hospitalisations for diastolic HF when adjusted for baseline cardiovascular disease risk factors. Bariatric surgery was also found to reduce the incidence of diastolic HF in high-risk patients with hypertension and CAD.

Dr Brozzi reminded us that these patients are high-risk end-stage HF patients with INTERMACS profile 2 and 3, so they will all eventually need either LVAD or heart transplant. However, in actual practice only 30% of the patients who need bariatric surgery in order to receive the next therapy actually receive bariatric surgery and were subsequently successful in transplantation. According to his analysis of the Nationwide Inpatient Sample database of 7 million hospitalisations in 2018, one million patients had reported BMI and 3,000 patients with BMI >35 kg/m2 were admitted with end-stage HF or CS. Therefore, this is evidence that there is a significant number of patients whose care may be being neglected, and this presents an opportunity to address these patients’ needs. Dr Brozzi continued that this opportunity will bring challenges, but nonetheless the initial experience is encouraging. For example, patient adherence to therapies and dietary restrictions after bariatric surgery is required if the patient is to have the prospect of a transplant.

Panel Discussion

Dr Anderson opened the discussion by expressing his appreciation of the extension of the therapeutic indications of MCS devices as highlighted in the presentations. He queried whether there is need for any legitimate concern of infection risk associated with the introduction of a foreign body, like the Impella device, into a patient with sepsis. He asked the experts to comment on the associated infection risks of a contaminated device, including endocarditis, wound infection, persistent bacteraemia and abdominal sepsis, during non-cardiac procedures.

Dr Anderson reflected that the Impella pumps are highly haemocompatible, but wondered whether the experts had experienced any post-procedural issues with anticoagulation or bleeding complications.

Dr Hernandez-Montfort replied that in his experience, a procedure like exploratory laparotomy is an extreme case and would be rare. The patient would be on prophylactic antibiotics prior to procedure and support would not persist for longer than 1 or 2 weeks. In his opinion, the risks need to be weighed up and the potential outcomes of potential recovery versus death thoroughly discussed with the patient and their family to arrive at a shared decision. In his practice to date, surveillance cultures have all come back negative.

Dr Hernandez-Montfort confirmed that he has not experienced any anticoagulation problems save one case of haemolysis that was due to device malposition. His centre has seen positive results with bicarbonatebased solution as the Impella purge solution. He explained that to mitigate the risk of deep vein thrombosis, he sometimes administers prophylactic subcutaneous heparin or low-molecular-weight heparin. However, he clarified that in his clinical practice he has not experienced any incidents of pump or device thrombosis. He confirmed that he has also successfully removed the device without the need for heparin.

Dr Reddy clarified that in his practice, an abdominal procedure would only be performed with multidisciplinary team agreement. Because the Impella is only a temporary device and not permanent, in his practice he does not staple it in place, which means the graft can be removed in entirety with little risk of wound sepsis. Dr Reddy added that the lack of need for heparin systemically or in the pump has made a positive difference too, and he now only uses heparin subcutaneously.

The question was asked whether the patients undergoing bariatric surgery had mostly been inpatients, elective admissions or placements? Dr Hernandez-Montfort confirmed that all his patients to date have been inpatients and there have been no elective indications.

Dr Anderson next asked the experts how they decide between an Impella CP implantation percutaneously versus surgical cutdown procedure.

Dr Brozzi confirmed that in his practice all patients undergoing bariatric

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A-CURE 7th Annual Symposium surgery have also been non-elective inpatients. However, he clarified that we are still at the early stages of this approach.

reduce the ischaemic burden. This patient successfully survived surgery and was discharged 4 days later without the need for anticoagulation but with bicarbonate-based purge solution during Impella. During surgery, the patient experienced a non-sustained ventricular tachycardia and hypertension but did not require any significant escalation of care as a result of the protective nature of preparation prior to surgery with Impella.

Dr Gopalan explained that in his centre they have performed Impella support in outpatients who required elective bariatric surgery but who are considered high-risk with LVEF <25%. He presented the case example of a 60-year-old man who had non-revascularisable CAD with low ejection fraction and a BMI of 41 kg/m2 who could not undergo transplant due to his high BMI. After outpatient discussion, the patient was brought actively into hospital for preparation 2 days prior to undergoing high-risk bariatric surgery. He was found to have low cardiac output with a cardiac index of 1.8. The patient was supported with inotropes before an elective placement of Impella 5.5 via axillary insertion for LV unloading and to 1.

Abraham J, Blumer V, Burkhoff D, et al. Heart failurerelated cardiogenic shock: pathophysiology, evaluation and management considerations: review of heart failure-related cardiogenic shock. J Card Fail 2021;27:1126–40. https://doi. org/10.1016/j.cardfail.2021.08.010; PMID: 34625131 2. Beavers CJ, DiDomenico RJ, Dunn SP, et al. Optimizing anticoagulation for patients receiving Impella support. Pharmacotherapy 2021;41:932–42. https://doi.org/10.1002/ phar.2629; PMID: 34597429.

Dr Anderson wrapped up the discussion by thanking the panellists and stating the importance of collecting the data and collectively analysing it to potentially expand the indications of Impella for non-cardiac surgery. He looks forward to hearing about these data and the application of acute LV unloading in non-cardiac procedures at next year’s A-CURE symposium.

3. Hernandez AF, Whellan DJ, Stroud S, et l. Outcomes in heart failure patients after major noncardiac surgery. J Am Coll Cardiol 2004;44:1446–53. https://doi.org/10.1016/j. jacc.2004.06.059. PMID: 15464326. 4. Haaga JR. Cardiology Fundamentals and Practice. Vol. 1, 2nd edn. St. Louis, MO: Mosby Year Book Publishers, 1991. 5. Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet 2014;383:999–

1008. https://doi.org/10.1016%2FS0140-6736(13)61752-3; PMID: 24084292. 6. Romero Funes D, Gutierrez Blanco D, Botero-Fonnegra C, et al. Bariatric surgery decreases the number of future hospital admissions for diastolic heart failure in subjects with severe obesity: a retrospective analysis of the US National Inpatient Sample database. Surg Obes Relat Dis 2022;18:1–8. https://doi.org/10.1016/j.soard.2021.09.009; PMID: 34756668.

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