Heart failure (HF) is one of the largest unsolved problems in cardiac care today with more than five million patients in the United States alone.1 In 2008, the direct and indirect cost of HF in the United States was estimated to be $34.8 billion.2 According to the American Heart Association, approximately 670,000 new cases of HF are diagnosed annually.1 Current treatment options for HF include pharmacological therapy, cardiac resynchronization therapy (CRT), mechanical circulatory support (MCS), and heart transplantation. Despite improvements in survival with pharmacological therapy and CRT, the prognosis remains poor, with 1 year mortality at 15.0% and 28.0% for New York Heart Association classes III and IV patients, respectively.3 In advanced HF, transplantation offers the best opportunity for long-term survival; however, the number of available donor organs cannot meet the growing demand. The shortage of appropriate donor hearts is worse in other countries, such as Canada (<200 heart donors per year) and Japan (11 heart transplants in 2008).4,5
The large patient population with advanced HF and the limited number of donor organs have stimulated development of MCS devices. Despite years of research and excellent long-term results with MCS, only a small percentage of patients receive MCS therapy annually. Device implantation requires major surgical intervention as well cardiopulmonary bypass (CPB). The invasiveness and complexity of the surgical procedure have associated complications, including bleeding, thromboembolism, stroke, and infection. In addition, CPB increases implantation time, blood loss, and risk of exposure to donor blood products. Currently, the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry reports a 30 day post-left ventricular assist device (LVAD) implant mortality rate of 7%.6
To overcome some of these limitations, the HeartWare miniaturized left ventricular assist device (MVAD) pump with transapical cannulation is being developed, which may enable implantation with less-invasive techniques. The transapical intraventricular device design originated from early CPB strategies published in the 1960s and 1970s to unload the left ventricle (LV) using a single cannula passed through the LV apex as a technique to establish rapid bypass initiation in cardiogenic shock patients.7 In 1992, Yamazaki et al.8 published findings on a transapical axial LVAD, wherein the pump sits at the apex and LV blood is advanced into the aorta via a cannula resting anterograde across the aortic valve. The authors evaluated the device in mock circulatory loops and in a healthy dog model and demonstrated feasibility of pump placement and assessment of flow characteristics. Following design modifications, the authors additionally evaluated a new purged seal system and reported improved hemocompatibility.9 In 2007, Wang et al.,10 in collaboration with Dr. Kolff,7 published findings on a transapical-to-aorta intraventricular LVAD demonstrating feasibility of device placement, pump flow and hemodynamic characteristics, and the absence of significant blood trauma and thrombosis using a healthy sheep model. Notably, both Yamazaki et al.8 and Wang et al.10 demonstrated a pulsatile pump flow pattern as a result of LV contractile contributions to device inflow. The prototype design for the HeartWare MVAD with transapical cannulation has been previously reported.11 Based on early proof-of-concept testing, the MVAD was redesigned to improve anatomic fit, surgical implant and removal procedures, and performance. In this study, we present development and testing of the redesigned MVAD with transapical cannulation in human cadaver and large animal bovine models to demonstrate feasibility.
The HeartWare MVAD Pump is a miniature, full-support, continuous-flow LVAD. Operational speed ranges from 12,000 rpm to 22,000 rpm, and the pump is capable of generating partial and full-support flows. The MVAD Pump is fitted with an outflow cannula that is designed to pass through the aortic valve (transvalvular).11 This allows for intraventricular placement of the pump (via a transapical implant technique) with the outflow cannula passing transvalvular.
The MVAD Pump in this transapical configuration consists of six components: a pedestal, standpipe, pump body, impeller, diffuser, and outflow cannula. The pedestal is sutured to the epicardial surface of the LV via a gimbaled sewing ring, while the standpipe supports the pump body, vane diffuser, and outflow cannula (Figure 1A). The standpipe is a hollow cylinder (3 mm in diameter) that carries the motor cables that drive pump operation via an external controller. The standpipe also provides adjustability to accommodate different long-axis ventricular lengths. The vane diffuser guides flow through the vanes, reducing turbulence and improving hydraulic efficiency. The outflow cannula is a composite of silicone and barium sulfate, which provides radiopacity to allow verification of device placement via echocardiography and fluoroscopy. The cannula tip implements a trilobar diffuser, which provides a radial force component and minimizes movement of the outflow cannula. The tip of the trilobar outflow cannula has been designed for placement immediately distal to the aortic root and proximal to the innominate artery (Figure 1B).
The MVAD Pump uses a platinum alloy impeller, which is suspended in a ceramic tube and is rotated by sequentially energizing stator coils. Impeller position is maintained via a hybrid suspension system based on both passive magnetic and hydrodynamic forces. The primary flow path through the MVAD Pump is through the impeller channels, with a secondary flow path through the radial gap between the impeller and inner pump housing. The hybrid system allows for a wearless design and elimination of support structures.
The first objective of this study was to evaluate anatomic fit and surgical approach. This was demonstrated using an anatomic fit study conducted in human cadavers (n = 4). The second objective was to demonstrate feasibility of MVAD Pump with the integrated outflow cannula in acute (n = 2) and chronic (n = 1) bovine model experiments by evaluating hemodynamic metrics (LV pressure-volume [PV] loops), biocompatibility (blood chemistry, complete blood count [CBC]), flow dynamics (fluoroscopy), transthoracic echocardiography (TTE), and histopathology (aortic valve, myocardium, and end organs).
An anatomic fit study of this MVAD Pump configuration was performed in human cadavers (45–120 kg, n = 4). The MVAD Pump with integrated outflow cannula was implanted via two minimally invasive approaches: subcostal incision (Figure 2, top left) and minithoracotomy (Figure 2, bottom left). Factors including surgical access, ease of use, and surgical tools were evaluated and compared with standard LVAD implantation techniques. The heart (including pump) was then excised from the cadaver to assess device fit and placement across the aortic valve (Figure 2, right).
Acute and Chronic Bovine Experiments
Acute (n = 4) and 30 day chronic (n = 1) bovine model (Jersey calves, 60–80 kg) experiments were conducted to evaluate the hemodynamic efficacy, biocompatibility, hemocompatibility, and the aortic valve response to the outflow cannula. Animals were anesthetized with 1–5% isoflurane and 100% oxygen. A left thoracotomy was performed at the fifth intercostal space to provide access and exposure of the pulmonary artery, LV apex, and descending thoracic aorta. Heparin (100–300 U/kg via intravenous central line) was administered. Eight to twelve pledgeted sutures were placed to secure the gimbal sewing ring to the LV apex. A small incision was made within the confines of the sewing ring, and the modified MVAD Pump was inserted and secured. The pump was deaired through the lumen of a Swan-Ganz catheter, which also provided an arterial pressure waveform facilitating placement of the cannula across the aortic valve. Transthoracic echocardiography and fluoroscopy were also performed to verify pump positioning and placement of the outflow cannula across the aortic valve.
During acute experiments, the animal was instrumented with high-fidelity PV conductance catheters (Millar Instruments, Houston, TX) to measure left atrial pressure, LV pressure and volume, and aortic pressure. Flow probes (Transonic Systems, Ithaca, NY) were placed for the measurement of pulmonary artery, coronary, and aortic flow. Hemodynamic waveforms were recorded at 400 Hz. The animal’s normal hemodynamic condition was tested before pharmacologically inducing the following test conditions: HF (esmolol), hypotension (nitroprusside), hypertension (phenylephrine), and exercise (epinephrine). At each test condition, the pump was run at baseline (0 rpm), partial pump support (16,000 rpm and 19,000 rpm), and full pump support (22,000 rpm). Baseline measurements were repeated between test conditions to ensure state steady baseline was maintained. During chronic experiments, the animal was instrumented with only a pulmonary artery flow probe and an arterial fluid-filled catheter. For both acute and chronic experiments, hemodynamic parameters were analyzed using Hemodynamic Evaluation and Assessment Research Tool (HEART), custom software developed on a MATLAB platform (MathWorks, Natick, MA).12
Echocardiography was performed preoperatively, after pump insertion, and on a weekly basis postoperatively (for chronic studies) to assess cardiac function, blood flow, and device placement. A Phillips iE 33 TTE system (Andover, MA) with S8-3 ultrasound probe was used to obtain M-mode and Doppler echocardiographic recordings. Left ventricular end-diastolic volume, end-systolic volume, ejection fraction, and aortic valve function were recorded. Color Doppler was used to detect and quantify potential aortic regurgitation resulting from placement of the outflow cannula across the aortic valve (0–4+ severity scale). Fluoroscopy was also performed in the chronic animal model using an angiography catheter placed in the LV and aorta for injection of radiopaque dye to evaluate blood flow, coronary perfusion, and anatomic positioning of the modified MVAD Pump during implant and before euthanasia.
Routine blood samples (15 ml) were collected to assess biocompatibility in the chronic bovine model. A baseline sample was collected preimplantation, and then samples were collected on a daily basis during the first postoperative week and on a weekly basis from postoperative day 7 through 30. Blood chemistry, CBC, liver enzymes, activated clotting time, arterial blood gases, platelet function test, and plasma free hemoglobin (PfHb) were measured. Following animal euthanasia, a complete necropsy and histopathologic analyses were performed, including examination of the aortic valve and root. In the aortic leaflets, tissue blocks were sectioned at 5 μm thick and prepared for staining with hematoxylin and eosin for visualization of histopathologic changes under light microscopy. Immunohistochemistry was performed to identify potential damage to endothelial cells (stained with endothelin) and smooth muscle cells (stained with actin). The explanted MVAD Pump with integrated outflow cannula was visually inspected for evidence of thrombus, wear or any other defects.
Two surgical access points were evaluated in our cadaver studies (n = 4). Results demonstrated surgical feasibility via a minimally invasive subcostal or a thoracotomy incision. The cadaver studies showed that both surgical approaches to implant and explant the modified MVAD Pump were feasible but demonstrated the need for re-engineering of the next generation outflow cannula and standpipe to ensure anatomic fit for multiple sized hearts in HF patient population.
Acute Bovine Experiments
The MVAD Pump with integrated outflow cannula across the aortic valve was capable of sufficiently unloading the LV as demonstrated through acute bovine experiments under test conditions of normal and pharmacologically induced HF, hypotension, hypertension, and exercise. Increasing pump speed resulted in reduced ventricular workload as evidenced by decreasing LV pressures and volumes (Figure 3). In addition, there was a leftward shift of LV PV loops and diminishing aortic pressure pulsatility with increasing MVAD Pump support (Figures 4 and 5). Gross necropsy of the calves showed no evidence of embolization in the brain, heart, or end organs.
Chronic Bovine Experiments
Biocompatibility and long-term impact on aortic valve function were assessed in a 30 day chronic bovine model. Echocardiography and fluoroscopy verified the in vivo position of the device and demonstrated the aortic valve leaflets coapt around the pump’s outflow cannula. One animal (n = 1) was electively euthanized during the first postoperative day due to abnormally high PfHb levels and observed hematuria, while the other animal (n = 1) was electively euthanized at study term. In the animal that was terminated prematurely, a small piece of myocardial tissue was found lodged in an impeller flow channel, causing an obstruction. This myocardial tissue debris was likely dislodged during the ventricular coring process. For the animal supported throughout the study period, there was no indication of aortic insufficiency. Complete blood chemistry evaluation of venous blood samples demonstrated that there were no significant changes in measurements of hepatic function (alkaline phosphatase, alanine transaminase) or renal function (creatinine). This suggests that the device had no negative effect on end-organ function. Plasma free hemoglobin, blood urea nitrogen, and creatinine were normal at all measured time points (Table 1). One animal was electively euthanized at study term, and a complete necropsy and histopathologic analyses were performed, including examination of the device, aortic valve, all major abdominal and thoracic organs, and the brain. An independent pathologist (Mass Histology, Boston, MA) examined all end-organ tissues and concluded that there were no notable histopathologic changes. In addition, the explanted pump outflow cannula and impeller were free of thrombus.
A considerable portion of this work was focused on determining the long-term effect of the cannula crossing the aortic valve. Histological analysis of the aortic valve cusps revealed minimal to mild, multifocal subendothelial hyperplasia and minimal neutrophilic inflammation (Figure 6). The observed valvular changes were likely due to repeated physical contact between the aortic cusps and the outflow cannula in this animal model. The explanted weight of this animal was 90 kg. According to Inman et al.,13 the approximate resting cardiac output for this animal model size is 7.3 ± 0.9 L/min. Based on these assumptions, we believe that this animal model is not representative of the conditions the aortic valve would encounter in a patient with HF implanted with the MVAD Pump and likely represents a worst-case scenario.
In this feasibility study, we demonstrated in a human cadaver model (n = 4) that the MVAD Pump with transaortic outflow cannula can provide proper anatomic fit and may be implanted with minimally invasive surgical approaches (subcostal and minithoracotomy). Acute (n = 2) and 30 day chronic (n = 2) bovine experiments demonstrated ventricular volume unloading without device failure, significant aortic valve damage, thrombosis, or hemolysis. Functional and cell morphology changes to the valve leaflets are nonexistent in the literature with regard to the potential long-term impact of an LVAD being placed across the aortic valve. The Impella 2.5 (Abiomed Inc, Danvers, MA) is a short-term partial circulatory support device that is designed to sit across the aortic valve. Studies with a primary end-point of 30 days have shown no aortic valve dysfunction.14–16
Yamazaki et al.8 and Wang et al.10 demonstrated advantages of the transapical approach including a compact and accessible design that requires a less-invasive and off-pump surgical approach, minimal blood loss during device placement, the absence of lengthy grafts and cannulae that minimize surface area of blood contact and that eliminate the need for vessel cannulation/anastamoses, and anterograde blood flow comparable to native circulation. Similarly, the modified MVAD Pump requires a single incision via a subcostal or mini-left thoracotomy. The surgical procedures can be simplified, thereby shortening patient recovery times and improving patient outcomes. Implantation of this MVAD Pump and integrated outflow cannula may be performed without CPB, which will reduce surgery time as well as the complications associated with CPB. Unlike current LVADs, this MVAD Pump configuration also delivers blood flow in the same direction (i.e., antegrade flow) as native ventricular ejection across the aortic valve. This shortens the flow delivery path and also prevents blood stasis associated with retrograde flow from an outflow graft implanted in the aorta.17,18
Potential limitations of the transapical approach include the following: pump resides in the left ventricle, no direct visibility during pump placement instead requires imaging to verify correct placement, and challenges quantifying pump flow.
Future enhancements to this modified MVAD Pump design include a straight standpipe and two cannula lengths (radiopaque) to improve device fit and placement. In addition, a valved access port for a guidewire has been added to the pedestal to enable implant using the Seldinger technique19 (Figure 7).
Heart failure is a major health care burden that is expected to double in incidence in the next decade. To address limitations associated with current VAD technology, HeartWare Inc. (Miami Lakes, FL) has developed the MVAD Pump technology, which due to its small size and axial flow configuration enables multiple cannulation possibilities, including transaortic valve placement. This full-support device can be implanted without CPB via a minimally invasive subcostal or minithoracotomy surgical approach with minimal or no blood loss.
The Phase I program (NIH-SBIR phase I grant 1R43HL103014-01A1) began on April 4, 2011, and was completed on September 30, 2012. The objective of this proposal was to develop a minimally invasive surgical implant procedure and complete feasibility testing of a transapical miniaturized ventricular assist device for the potential treatment of patients with less advanced HF.
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