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Improved Hemodynamics With a Novel Miniaturized Intra-aortic Axial Flow Pump in a Porcine Model of Acute Left Ventricular Dysfunction

Raissi Shabari, Farshad*; George, Joggy*; Cuchiara, Michael P.; Langsner, Robert J.; Heuring, Jason J.; Cohn, William E.*; Hertzog, Benjamin A.; Delgado, Reynolds*

doi: 10.1097/MAT.0b013e31828a6e74
Adult Circulatory Support
Free

Currently, long-term mechanical circulatory support (MCS) is limited to large, complex devices that require invasive, high-risk surgical implantation. These devices are mainly used in patients with late stage heart failure (HF). We are developing a novel percutaneous intra-aortic micro-axial fluid entrainment pump intended for long-term MCS in patients with earlier stage HF. This study examined the pump’s hemodynamic effects in a porcine model of acute HF. In three porcine experiments, the pump was deployed in the thoracic aorta by standard cardiac catheterization techniques and was anchored with self-expanding struts. Acute cardiac dysfunction was induced by infusing esmolol continuously. Pump support increased cardiac output (+10.4%), stroke volume (+8.9%), and ejection fraction (+10.8%) while decreasing cardiac stroke work (−10.8%) and afterload (−22.7%). Furthermore, pump support significantly enhanced renal perfusion through sustained increases in both renal artery flow (+36.4%) and pressure (+73.6%). In a porcine model of acute HF, the catheter-based intra-aortic fluid entrainment pump improved hemodynamics and renal perfusion. These results suggest that the pump could improve HF outcomes and patients’ quality of life by resting the heart, promoting reverse remodeling, and augmenting end-organ perfusion. Furthermore, the enhanced renal perfusion may help disrupt the cardiorenal syndrome cycle and improve HF treatment.

From the *Department of Cardiopulmonary Transplantation and Center for Cardiac Support, Texas Heart Institute, Houston, Texas, and Procyrion, Inc, Houston, Texas.

Submitted for consideration October 2012; accepted for publication in revised form January 2013.

Disclosure: Reynolds Delgado is an equity stakeholder in Procyrion Inc. Ben Hertzog, Jace Heuring, and Michael Cuchiara are paid consultants and equity stakeholders in Procyrion Inc. Robert Langsner is a paid consultant for Procyrion Inc.

Reprint Requests: Dr R. Delgado, 6624 Fannin, Suite 2420, Houston, TX 77030. Email: RDelgado@texasheart.org.

Conventional long-term mechanical circulatory support (MCS) devices are large and complex, and the surgical procedures required to implant them are associated with high morbidity and mortality.1 Consequently, long-term MCS is limited to full cardiac support through surgical intervention2 in a New York Heart Association (NYHA) class IV patient population with end-stage heart disease, limited life expectancy, and low odds of recovery.3 Despite these limitations, cardiac recovery sufficient to allow device explantation has been reported in a small percentage of these patients.4

Smaller, less invasive partial circulatory support devices could reduce periprocedural risks and could be used in less sick patients with a greater propensity to recover cardiac function. Previous less invasive partial MCS devices, such as the Cancion System (Orqis Medical, Lake Forest, CA), showed significant and effective unloading of the left ventricle (LV) in short-term nonambulatory trials.5,6 Although 96 hours of Cancion support improved short-term hemodynamics, this improvement was not sustained at 30 days.7,8 Furthermore, the extracorporeal nature of the Cancion System limited the duration of therapy and did not provide enough freedom of movement to maintain quality of life in earlier stage heart failure (HF) patients. Other less invasive devices, such as the Synergy Micropump (Circulite Inc, Saddle Brook, NJ), provide long-term ambulatory partial circulatory support and have been shown to improve cardiac index and pulmonary capillary wedge pressure for up to 81 days. Although the Synergy Micropump is less invasive than traditional full-support MCS devices, implanting this device still requires thoracotomy access, a surgical transseptal puncture, and a subclavian artery anastomosis.9

Because of the invasiveness of even the most recent and advanced MCS devices, circulatory support is only available to a small percentage of HF patients.3,10 To increase the usage and improve the outcomes of circulatory support, long-term MCS devices should be percutaneously implantable in a catheterization laboratory. This could greatly reduce periprocedural and long-term risk. Furthermore, a shift in treatment strategy from full MCS (completely replacing heart function) in end-stage HF to earlier stage partial support interventions that rest and unload the heart would permit the use of smaller, cheaper, and less invasive devices. Compared to full-support devices, these partial support devices may place a lower financial burden on the healthcare system in terms of both device and hospitalization costs.

The intra-aortic MCS system was designed to embody this paradigm shift in circulatory support. The intra-aortic pump is a miniaturized, percutaneous, micro-axial fluid entrainment pump consisting of a small-diameter continuous flow pump mounted within a self-expanding nitinol strut anchoring system (Figure 1). The device is deployed and anchored within the descending aorta through percutaneous transcatheter delivery, and it is connected to a motor controller by a thin, flexible electrical wire (Figures 1 and 2). When the pump is activated, high-velocity jets at its outlet entrain and accelerate native aortic flow, thereby partially unloading the LV and enhancing end-organ perfusion (Figure 2B).

Figure 1

Figure 1

Figure 2

Figure 2

Traditional surgical LV assist devices are connected to the LV apex and are designed to replace heart function by entirely bypassing segments of the native circulation. In contrast, the intra-aortic pump’s location in the descending aorta leaves no components in contact with the heart and places all hardware downstream of the carotid arteries. This placement minimizes periprocedural risk and may reduce stroke risk and myocardial damage. Previous mock flow-loop studies from our group (unpublished data) showed that this device and system configuration accelerated native flow, increased cardiac output (CO), and decreased cardiac workload. This study was aimed to build on these results and validate the intra-aortic pump’s short-term hemodynamic effects in a porcine model of acute HF.

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Materials and Methods

All studies were performed at The Cullen Cardiovascular Research Laboratories at the Texas Heart Institute, and all surgical procedures and animal care in this study complied with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No 86-23, revised 1996). The study was also approved by the Institutional Animal Care and Use Committee at the Texas Heart Institute. To date, we have deployed and operated the intra-aortic pump in seven large animal models. In this study, we examined the intra-aortic pump’s hemodynamic effects in three domestic pigs with acute pharmacologically induced HF.

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Intra-aortic Pump Deployment and Retrieval

Our device consists of an axial-flow fluid entrainment pump and a custom nitinol strut anchoring system (Figure 1; collapsed diameter 7mm). An off-the-shelf Impella 5.0 (Abiomed, Danvers, MA) was used for the motor and pump head. Before deployment, the entire system was advanced in its collapsed state via a 24 Fr catheter from an arterial cut-down insertion site to a location in the descending thoracic aorta superior to the splanchnic arteries (Figure 2, B and C). The sheath was then retracted with an obturator, and the self-expanding strut system was deployed to anchor the pump to the aortic wall (Figure2, B and C). After deployment, the sheath was fully retracted and all deployment catheters were removed, leaving only a small-diameter (<1mm) flexible electrical power wire exiting the vessel. Upon completion of the hemodynamic study, a 24 fr retrieval catheter was advanced along the power wire to re-sheath the pump and retrieve the device.

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Esmolol Infusion and Pump Operation

In the three pigs, acute HF was induced with esmolol HCl, a β1-adrenergic blocking agent. Continuous esmolol infusion (2000mg/h) was used to depress cardiac contractility until the real-time rate of rise in left ventricular pressure (dp/dt) reached 50% of its baseline level. Then, hetastarch (500ml/h) and vasopressin (2 units/h) were administered as needed to keep mean arterial pressure above 60 mmHg. While the device was implanted, heparin was administered (150 IU/kg) as needed to manage activated clotting time > 300 seconds. In each pig, the intra-aortic pump’s hemodynamic effects were assessed in five cycles of 1 minute with the pump off (baseline) and 1 minute with the pump on. In all studies, when activated, the pump was operated in continuous flow mode at 30,000 RPM.

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Data Acquisition and Analysis

The common carotid artery and internal jugular vein were exposed for the insertion of an LV pressure–volume catheter and a Swan–Ganz pulmonary artery catheter (Edwards Lifesciences, Irvine, CA), respectively. The LV pressure and volume were measured with a conductance-sensing pressure–volume (P-V) catheter (Millar Instruments, Houston, TX) to provide continuous P-V loop monitoring of the LV. The renal artery flow and pressure were measured with a 4mm ultrasonic clamp-on flow probe (Transonics, Ithaca, NY) and a RADI PressureWire (St Jude Medical, St Paul, MN). All other pressure measurements were made by using fluid-filled transducers connected to introducer sheath access ports. All hemodynamic data were continuously acquired and imported through Power Labs data acquisition hardware by using Lab Charts software (AD Instruments, Colorado Springs, CO).

The pertinent hemodynamic parameters—maximum dp/dt (the cyclic maximum of the LV pressure’s first derivative), stroke volume (SV; end-diastolic volume minus end-systolic volume), CO (heart rate × SV), stroke work (area of LV P-V loop), arterial elastance (Ea; an indicator of afterload, computed as end-systolic pressure/SV),11 and LV end-diastolic pressure—were calculated by using the P-V Loop software module within Lab Charts. Arterial elastance is a commonly used indicator of systemic vascular resistance (SVR) or afterload. The Ea is equivalent to the SVR when heart rate is constant across conditions and central venous pressure is much less than mean arterial pressure. Because both these conditions were satisfied in this study, Ea was used as our measure of afterload. Mean values for hemodynamic parameters were compared between pump-on and pump-off states by using a two-tailed paired t-test; p < 0.05 was considered to indicate a significant difference.

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Results

Device Implantation, Device Retrieval, and HF Model

The device was successfully inserted, deployed, and retrieved under fluoroscopic guidance in all three pigs with no acute damage to the aortic wall noted from gross morphological observations. The esmolol infusion resulted in stable and repeatable diminished cardiac function as indicated by decreases in CO, LV contractility (max dp/dt), and end-systolic P-V relationships (Figure 3, A and B).

Figure 3

Figure 3

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LV Function and Afterload

Activating the intra-aortic pump significantly decreased LV filling pressures (−6%), LV filling volumes (−6.4%), and cardiac stroke work (−10.8%) compared to pump-off baseline measurements (Figure 3, B–D; p < 0.01). Furthermore, these decreases were accompanied by increases in CO (+10.4%), SV (+8.9%), and ejection fraction (+10.8%) (Figure 4; p < 0.01). Intra-aortic pump support significantly reduced afterload, as indicated by decreases in Ea (−22.7%), compared to baseline (Figure 4; p < 0.01). All of the changes in hemodynamics occurred while preserving the pulsatility and shape of the native LV pressure and volume waveforms (Figure 3, C and D).

Figure 4

Figure 4

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Renal Perfusion

Intra-aortic pump support significantly increased renal perfusion. Immediately after device activation, renal flow increased by 36.4% and renal pressure increased by 73.6% (Figure 5; p < 0.01). The increase in renal pressure was sustained for the entire duration of support, whereas renal flow decreased to 8% above baseline by the end of the support period (Figure 5B).

Figure 5

Figure 5

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Discussion

Large Animal Model

This short-term animal study shows the favorable hemodynamic effects of an intra-aortic micro-axial fluid entrainment pump in a model of acute cardiac dysfunction. Device access, deployment, strut fixation, and pump operation were successful in all animals. Continuous esmolol infusion resulted in stable and repeatable acute cardiac dysfunction. The esmolol infusion is advantageous for preliminary investigations because of its low cost and because it rapidly and easily diminishes cardiac function. However, it cannot produce lasting dysfunction without continuous infusion (esmolol elimination half-life = 9 minutes),12 and it does not generate the elevated filling pressures indicative of chronic HF.13,14 To better evaluate the intra-aortic pump’s effects on the chronically failing heart, future investigations will focus on this device’s short- and long-term efficacy in large animal models that more closely mimic the characteristics of patients with chronic HF (e.g., coronary ligation, coronary microsphere embolization, or cardiotoxic pharmacologic models).

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Hemodynamic Effects

Intra-aortic pump support significantly improved hemodynamics compared to the pump-off baseline. The observed increases in SV, CO, and ejection fraction are similar to the effects of an intra-aortic balloon pump.15 However, unlike these pumps, our system has a design that allows for long-term ambulatory support. Cardiac performance improved (i.e., CO and SV increased), while the overall stroke work decreased, suggesting improved cardiac efficiency.16 These improvements can mostly be attributed to two factors: First, pump activation lowered the pressure at which the aortic valve opens and closes, leading to more complete emptying of the LV at lower diastolic and systolic pressures. Second, the device produced an immediate and significant reduction in afterload. Together, reductions in afterload and stroke work reduce myocardial oxygen demand and ventricular wall stress, resulting in an unloaded heart that operates at a more efficient point on the Starling Curve. This change in operating point has been shown to promote recovery and remodeling.17

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Renal Perfusion

With the increased focus on cardiorenal syndrome and on renal function as a marker for long-term end-organ function,18 it is encouraging to note that the intra-aortic pump markedly augmented renal perfusion. This is probably an effect of increased antegrade arterial flow. Enhanced renal perfusion has two distinct clinical benefits. The first is a direct increase in end-organ perfusion that improves kidney function and health. The second, indirect, benefit is renal and systemic vasodilation that leads to decreased SVR and disruption of the cardiorenal syndrome that exacerbates HF by increasing the workload of the heart.19 More direct testing and validation of renal perfusion-induced effects are needed to fully understand the potential of the intra-aortic pump to disrupt cardiorenal syndrome. The current results, however, support the general conclusion that suprarenal intra-aortic fluid entrainment provides a mechanism for enhancing renal flow and pressure.

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Fluid Entrainment

The mechanism responsible for the intra-aortic pump’s augmentation of hemodynamics is intra-aortic fluid entrainment. Fluid entrainment has been used extensively in mining, refrigeration, in-line mixing, and other industrial applications to promote efficient mixing and mass transfer.20,21 To our knowledge, however, this is the first application of a fluid entrainment pump in an implantable medical device. The intra-aortic fluid entrainment pump is not intended to provide the flow rates necessary for full MCS (i.e., 5–10L/min), but it is perfectly suited for partial support regimens (i.e., 2–3L/min)22 whose therapeutic goal is cardiac resting and promotion of cardiac recovery. The entrainment pump’s low profile makes it especially suitable for minimally invasive, transcatheter deployment and retrieval, and its low power requirement (1–2 watts) maximizes “un-tethered” time from a static power source, making this pump ideal for use in ambulatory patients. This device thus has characteristics capable of meeting many of the critical design challenges that have limited the translation of existing surgical MCS devices to minimally invasive placement procedures that could be performed on patients in earlier stages of HF.

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Potential System Design Advantages

Transfemoral access and suprarenal intra-aortic pump deployment have certain key advantages over traditional MCS configurations. The transcatheter implantation and retrieval procedures are ideally suited to the catheterization laboratory. All device hardware is downstream of the carotid arteries in a high-flow, continually “washed” environment, thus potentially reducing the risk of thromboembolic cerebrovascular events. Furthermore, the device is mounted in series with the heart in the descending aorta and does not occlude or bypass native blood flow. The mechanisms and consequences of failure are, therefore, significantly less severe than those of full-support MCS devices that bypass the native circulation, are configured in parallel with the heart, and have substantial blood-contacting components upstream of the carotid arteries.

Reliable anchoring of the device in the intra-aortic configuration, which the self-expanding strut mechanism ensures, is critical to efficient pump function. It also enables the device to provide long-term support in ambulatory patients by preventing proximal and distal migration from the implantation site. Together, these characteristics reduce the procedural and operational risks associated with circulatory support and further increase the intra-aortic pump’s suitability for use in earlier stages of HF.

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Challenges and Future Directions

This short-term proof-of-concept study was necessary to determine the intra-aortic pump’s systemic hemodynamic effects. Future research will address several limitations of the current approach. One limitation is that inducing acute HF with esmolol infusion does not mimic the physiology of chronic HF and thus lacks neurohormonal parallels with the physiologic alterations seen in patients with chronic HF. In the near future, we plan to investigate the long-term hemodynamic and neurohormonal effects of this device in animals with chronic HF. Long-term studies in chronic HF models will help to identify the effects of intra-aortic partial circulatory support on functional recovery, cardiac reverse remodeling, and disruption of neurohormonal signaling pathways important in treating cardiorenal syndrome. Furthermore, additional studies will focus on addressing safety concerns such as durable long-term transarterial access, retrievability of long-term implanted intravascular strut anchoring systems, characterization of hemolysis levels, presence of acquired Von Willebrand disease, determination of necessary anticoagulation or antiplatelet therapy, and evaluation of steal phenomenon on vessels upstream of the pump (e.g., carotid and coronary arteries).

In conclusion, our results suggest that the intra-aortic pump has beneficial short-term hemodynamic effects. The lower-risk system design has the potential to provide long-term ambulatory MCS to a population of HF patients that is already large and that continues to grow.

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Acknowledgment

Stephen N. Palmer, PhD, ELS, contributed to the editing of the article. Texas Heart Institute Cardiovascular Research Lab personnel, especially Jesse Rios, Steve Parnis, and Aaron Palmer, were incredibly helpful with the planning, preparation, and execution of the animal studies.

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Keywords:

heart failure; mechanical circulatory support; ventricular assist device

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