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Hemodynamic Effects of Left Atrial or Left Ventricular Cannulation for Acute Circulatory Support in a Bovine Model of Left Heart Injury

Kapur, Navin K.; Paruchuri, Vikram; Pham, Duc Thinh; Reyelt, Lara; Murphy, Barbara; Beale, Corinna; Bogins, Courtney; Wiener, Daniel; Nilson, James; Esposito, Michele; Perkins, Scott; Perides, George; Karas, Richard H.

doi: 10.1097/MAT.0000000000000195
Adult Circulatory Support

Our objective was to examine the hemodynamic effects of a trans-aortic axial flow catheter (Impella CP) in the left ventricle (LV) versus left atrial (LA) to femoral artery bypass using a centrifugal pump (TandemHeart: TH) in a bovine model of acute LV injury. In three male calves, we performed sequential activation of a CP then TH device in each animal. After 60 minutes of left anterior descending artery ligation, a CP was activated at maximal power. The CP was then removed and the TH activated at 5,500 then a maximum of 7,500 rotations per minute (RPM). The CP generated a maximum 3.1 ± 0.2 L/minute (LPM) of flow, whereas the TH at 5,500 and 7,500 RPM generated 3.1 ± 0.4 and 4.4 ± 0.3 LPM. At 3.1 LPM, the CP and TH reduced LV stroke work (LVSW) similarly. The TH reduced stroke volume, whereas the CP did not. The CP reduced end-systolic pressure, whereas the TH did not. At a maximum flow of 4.4 LPM, the TH provided a greater reduction in LVSW than maximal CP activation. This is the first report to compare the hemodynamic effects of trans-aortic LV unloading versus LA-to-femoral artery (FA) bypass.

From The Molecular Cardiology Research Institute and Surgical/Interventional Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, 800 Washington Street, Boston, MA 02339.

Submitted for consideration July 29, 2014; accepted for publication in revised form October 29, 2014.

Cardiac Assist Inc. provided funding for this investigation.

Disclosures: Dr. Kapur receives research funding from Abiomed Inc, Cardiac Assist Inc, Maquet Inc, and Heartware Inc and speaker/consultant honoraria from Abiomed Inc, Maquet Inc, Heartware Inc, and Thoratec Inc. Dr. Pham receives research funding and speaker/consultant honoraria from Heartware Inc.

Correspondence: Navin K. Kapur, MD, Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, Box # 80, Boston, MA 02111.

Over the past 4 decades, acute mechanical circulatory support (MCS) devices have evolved from large, pulsatile systems to miniaturized, percutaneously delivered pumps, which include the intraaortic balloon pump, veno-arterial extracorporeal membrane oxygenation, a catheter-mounted, trans-aortic axial-flow pump (Impella CP; Abiomed Inc., Danvers, MA), and a percutaneous left atrial (LA) to femoral artery centrifugal bypass system (TandemHeart; TH; CardiacAssist Inc. Pittsburgh, PA).1–3 The overall goals of acute MCS systems are to: 1) increase vital organ perfusion, 2) augment coronary perfusion, and 3) reduce ventricular volume and filling pressures, thereby reducing wall stress, stroke work, and myocardial oxygen consumption. Clinical scenarios where these devices are commonly used include: heart failure, cardiogenic shock, mechanical complications after acute myocardial infarction (AMI), high-risk coronary and noncoronary intervention, and for high-risk electrophysiologic ablations.

Both the CP and TH devices are percutaneously delivered, nonsurgical rotodynamic pumps that generate continuous, minimally pulsatile blood flow and reduce native left ventricular (LV) work by transferring kinetic energy from a circulating impeller to the blood stream. A major difference between the two systems is the location of the inflow and outflow cannulas. The Impella CP inflow cannula displaces blood from the LV into the ascending aorta, whereas the TH device delivers blood from the LA into the femoral artery. An unresolved issue in the field of acute mechanical support is whether direct LV unloading provides a greater reduction in LV stroke work (LVSW) compared with LA unloading. Mathematical models have attempted to compare the hemodynamic effect of these devices;4 however, no studies have directly compared the hemodynamic impact of retrograde, trans-aortic LV or LA cannulation using contemporary percutaneous support devices in acute LV injury.

Given the rising use of acute MCS devices, there exists a need for improved understanding of how inflow cannula location may impact LV hemodynamics. In this study, we explore the central hypothesis that inflow cannula location in the LA provides a greater reduction in LVSW compared with trans-aortic LV cannulation in the setting of acute left heart injury.

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Materials and Methods

Studies were conducted in three male bovine calves weighing 75–85 kg. All procedures were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and were approved by Tufts Medical Center and the Institutional Animal Care and Use Committee.

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Experimental Protocol of Myocardial Infarction and Mechanical Circulatory Support

Animals were premedicated with intramuscular ketamine (4.5 mg/kg) and xylazine (0.3 mg/kg). General anesthesia was induced and maintained with isoflurane (1–3%). All animals were intubated and mechanically ventilated (Harvard Apparatus Inc., Holliston, MA.) to control oxygen and isoflurane gas intake, oxygen saturation, and expired CO2 levels. Surface electrocardiography leads, an orogastric tube, peripheral 18 G venous catheters, pulse oximeter, and a rectal thermometer were placed in all animals. Heating pads were used as needed to maintain a core body temperature greater than 99°F. Vascular access sheaths were then deployed into the right internal jugular vein (10 Fr) and left carotid artery (7 Fr). A 5 Fr conductance catheter (CD Leycom, Hengelo, the Netherlands) was placed into the LV via the left carotid artery. Unfractionated heparin boluses with a goal activated clotting time of 300–400 seconds, a continuous lidocaine infusion, and noradrenaline were initiated in all animals. Because of the need for LA cannulation, the CP and TH devices could not be implanted using simultaneous percutaneous approaches. A full sternotomy and pericardiotomy were performed to expose the heart and great vessels, then the 21 Fr trans-septal inflow cannula (TandemHeart; Cardiac Assist Inc. Pittsburgh, PA) was introduced into the LA and secured in place using a purse-string suture and tourniquet. A 17 Fr outflow cannula was deployed into the right femoral artery. The 21 Fr inflow and 17 Fr outflow cannula were connected to the TH pump and clamped. A 14 Fr sheath was placed in the left femoral artery to introduce the CP device. The TH and CP devices were chosen for comparison because they represent the existing options for percutaneously delivered, continuous-flow, LV support in clinical practice without the need for surgical vascular access. To explore the impact of device activation in a clinically relevant model of acute heart injury, the left anterior descending (LAD) artery was ligated after the origin of the first diagonal branch in all three calves. After 60 minutes of LAD ligation, the CP device was inserted via the femoral artery into the LV and immediately activated at a maximum power level of P8 for 30 minutes, which corresponds to 44,000 rotations per minute (RPM) and generated an estimated flow rate of 3.1 ± 0.2 L/minute (LPM) based on power utilization and displayed as a continuous output measure on the CP console. The CP device was then retracted into the descending aorta and turned off. Next, in the same animal, activation of the TH device at 5,500 ± 250 RPMs achieved a matched flow rate of 3.1 ± 0.4 LPM as measured by a flow probe on the outflow cannula. Activation at this level of flow allowed for sequential comparison of the two devices at matched flows in each animal. After 30 minutes, the TH was increased to the maximum 7,500 RPM setting and achieved a flow rate of 4.4 ± 0.3 LPM (Figures 1 and 2). The TH device was then clamped and the animals euthanized with pentobarbital and phenytoin. All three animals survived to protocol completion.

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Conductance Catheter Assessment of Left Ventricular Pressure and Volume

Changes in LV pressure and volume were assessed using a 5 Fr conductance catheter system (Sigma-M; CD Leycom, The Netherlands) deployed via the left carotid into the LV (Figure 1C). Ventricular pressure and volume were measured using a solid-state pressure transducer and dual-field excitation mode, respectively, as previously described.5–7 Measurements were acquired at baseline, after introduction of the CP device at P0 followed by P8, after removal of the CP device, and after activation of the TH device at submaximal flow and maximal flow. In brief, the method measures time-varying electrical conductance across five to seven ventricular blood segments delineated by selected catheter electrodes. Correct positioning of the conductance catheter along the long-axis of the LV was confirmed by fluoroscopy. Time-varying segmental conductance has been shown to reflect segmental LV volumes in prior preclinical and clinical studies.5–7 Parallel conductance was assessed by injecting 20 ml of hypertonic (6%) saline into the right internal jugular vein. Absolute LV volumes were measured by subtracting parallel conductance from total conductance volumes. Native LV stroke volume is calculated as the difference in conductance volumes at dP/dtmax and dP/dtmin. Left ventricular stroke work was calculated as the product of peak LV peak systolic pressure and native stroke volume. Preload recruitable stroke work (PRSW) was calculated as the ratio LVSW and LV end-diastolic volume (LVEDV) using the single-beat method as previously reported.8

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Statistical Analysis

Results are presented as mean ± standard deviation (SD). All data within groups were analyzed by nonparametric two-way repeated measures ANOVA on ranks followed by a Holm–Sidak comparison if warranted. All statistical analyses were performed with SigmaStat version 3.1 (Systat Software, Inc. San Jose, CA). An α level of p < 0.05 was considered to indicate a significant effect or between-group difference.

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Hemodynamics of Matched Flows via the Impella CP and TandemHeart Devices

Left anterior descending occlusion significantly reduced LVSW, PRSW, contractility (dP/dtmax), and LV end-systolic pressure (LVESP) consistent with acute left heart injury (Table 1; Figure 3). Compared with values before LAD occlusion (baseline), maximal activation of the CP reduced LVSW, PRSW, contractility (dP/dtmax), and LVESP (Table 1; Figure 3). Compared with postinfarct values, maximal activation of the CP reduced LVSW and LVESP (Table 1; Figures 3 and 4). Compared with baseline values, activation of the TH at matched flows to the CP (3.1 LPM), reduced native stroke volume, LVSW, PRSW, dP/dtmax, and LVEDV (Table 1; Figure 3). Compared with postinfarct values, the TH at 3.1 LPM reduced native LV stroke volume, LVSW, and LV end-diastolic pressure (LVEDP; Table 1; Figures 3 and 4). Compared with the CP, the TH at 3.1 LPM of flow had a higher LVESP, otherwise all other variables were similar between the two pumps at matched flows.

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Hemodynamics of Maximal TandemHeart Flow versus Maximal CP Flow

To explore whether increased flow through the LA cannula further alters LV hemodynamics, we increased the TH to a maximal RPM setting of 7,500, which generated 4.4 LPM of flow. Compared with baseline values, the TH at 4.4 LPM decreased native stroke volume, LVSW, PRSW, dP/dtmax, LVEDV, LVESP, and LVEDP (Table 1; Figure 3). Compared with postinfarct values, the TH reduced native stroke volume, LVSW, PRSW, and LVEDV (Table 1; Figures 3 and 4). Compared with the CP, the TH at 4.4 LPM had a greater reduction in native stroke volume, LVSW, and PRSW, but had a higher LVESP (Table 1; Figure 3). Compared with the TH at 3.1 LPM of flow, a trend towards lower LVSW and PRSW was observed (p = 0.09 and p = 0.06, respectively) with maximal TH activation.

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This is the first report to directly compare the effects of LA cannulation using the TH device and retrograde, trans-aortic LV using the CP on LV hemodynamics. Our central finding is that at matched flow rates LA or LV positioning of the inflow cannula provide similar degrees of LV unloading in a bovine model of acute left heart injury. Specifically we report that: 1) at matched flows, both trans-aortic LV cannulation using the CP and LA cannulation using the TH reduce LVSW, 2) the TH reduced LV stroke volume, whereas the CP did not, 3) the CP reduced LVESP, whereas the TH did not, and 4) at maximum flow (4.4 LPM), the TH further reduced LV stroke volume and LVSW compared with the CP. These findings suggest that although the magnitude of LVSW reduction is similar at matched flows, LA or LV positioning of the inflow cannula generate distinct profiles of LV unloading. These data further suggest that use of the TH with a 17 Fr arterial outflow cannula generates higher flow and a greater magnitude of LV unloading than the CP. These findings have potentially important implications for clinical decision-making and for the design of future percutaneously delivered circulatory support devices.

Surgically implanted left ventricular assist devices (LVADs) have evolved from large, bulky pulsatile systems to smaller, compact, fully implantable continuous flow pumps that generate minimally pulsatile blood flow when functioning optimally. Several prior studies have examined the hemodynamic impact of LA versus apical LV cannulation using pulsatile pumps and continuous flow pumps.9–13 In parallel to the evolution of surgical LVADs, percutaneously delivered MCS systems have also grown from counter-pulsation balloon systems to centrifugally driven circuits, or catheter-mounted axial-flow pumps. The Impella family of trans-aortic, axial-flow pumps includes two percutaneously delivered sizes, which achieve an estimated 2.5 and 3.5 LPM of flow.14 A third Impella pump can achieve an estimated 5.0 LPM of flow, however requires surgical vascular access through a conduit graft. Unlike LV apical cannulation, trans-aortic delivery may initially increase LVSW until the pump is activated by inducing transient aortic regurgitation.15 Remmelink et al.16 reported decreased LVEDP, but no change in LVSW, LV volumes, or cardiac output with maximal activation of the Impella 2.5 LP device in 11 patients presenting for high-risk coronary intervention. In 2007, Sauren et al.17 reported a 50% reduction in LVSW with a larger Impella prototype device that generated 3.8 LPM of flow in a preclinical model of acute LV injury.

The TH device requires trans-septal puncture for delivery of a 21 Fr inflow cannula into the LA and can provide 3.0 to 5.0 LPM of flow via percutaneous application depending on the size of the outflow (arterial) cannula, which range between 15 Fr and 19 Fr in clinical application.3 By draining the LA, the primary effect of the TH device is reduced LV preload. Prior reports have shown that positioning of the outflow cannula impacts the magnitude of LV unloading. Specifically, LA-to-ascending aortic bypass will increase LVSW, whereas LA-to-descending aortic bypass greatly reduces LVSW. Theoretically by transferring blood volume from the left atrium to the arterial system, the TH device pressurizes the aorta.4 In the ascending aortic position, this increase in afterload limits the magnitude of LV unloading.18 In the descending aorta, the increase in afterload is mitigated by retrograde perfusion of run-off vessels including the mesenteric, renal, and great vessels of the aortic arch, thereby allowing for a reported 66% reduction in LVSW.19

No studies have previously neither examined the hemodynamic effect of the CP device nor directly explored the effect of the CP versus the TH device. To compare these two percutaneously delivered systems in the same animal, an open-chest, surgical approach was required. Maximal activation of the CP generated 3.1 LPM of flow, which corresponded to a 32% and decrease in LVSW compared with postinfarct values. To compare the effect of the TH to maximal CP activation, the TH was set at 5,500 RPMs which generated 3.1 LPM of flow and a corresponding 39% reduction in LVSW compared with postinfarct values. Although both systems reduced LVSW to similar degrees, the primary effect of the CP was a reduction in LVESP, whereas the primary effect of the TH was a reduction in LVEDV. Notably, the TH was associated with a higher LVESP than the CP, which may be related to increased afterload. Maximal activation of the TH at 7,500 RPMs further reduced LVSW and LVEDV with a persistent increase in LVESP compared with the CP. These data indicate that both retrograde, trans-aortic cannulation of the LV (CP device) and LA–FA bypass (TH device) effectively reduce LVSW by reduced LVESP or LVEDV, respectively.

Given the rising use of acute MCS, these data support the use of both the CP and TH to unload the LV. The CP requires a single-arterial access and can be rapidly deployed in emergent situations by most interventional cardiologists. However, the CP cannot be used in the setting of severe aortic regurgitation or LV thrombus. In contrast, the TH requires large bore arterial and venous access and technical expertise in trans-septal puncture, however, can be used in the setting of severe aortic regurgitation and LV thrombus. The TH cannot be used in the setting of LA thrombus. Our findings suggest that although both devices reduce LVSW, maximal activation of the TH provides a superior reduction in LVSW compared with the CP. The cost of this superior degree of unloading, however, must be weighed against the technical challenges and time required to implant the TH. Further studies are required to delineate which patient populations (i.e., AMI, decompensated heart failure, cardiogenic shock, or high risk intervention) may derive benefit from one approach versus the other.

There exist several limitations with this study. First, an open-chested animal model was used thereby limiting our ability to study the hemodynamics of these devices with an intact pericardium. Second, the number of animals studied was small; however, by implanting both devices in the same animal, we were able to generate rarely available comparative data in the same animal. Given the small n numbers, the statistical analysis should be interpreted with caution. Third, we did not study device effects in a chronic model of LV failure with a diseased microcirculation. Future studies involving larger animal numbers and longer duration of LV support are required.

In conclusion, these data show that devices designed to remove blood from the LA or LV can effectively reduce LVSW by primarily reducing LV volume or pressure, respectively. The technical aspects of device deployment including the use of trans-septal puncture, larger bore cannulas, and the need for surgical vascular access to place larger pumps will continue to guide clinical decision making. Findings from this analysis may inform the design of future devices and the development of prospective clinical studies to evaluate the role of acute circulatory support devices.

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circulatory support; heart failure; hemodynamics

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