Chronic aortic root pressure-loading assessment model

Abstract

Purpose:

Percutaneous placement of transcatheter prosthetic aortic valves without cardiopulmonary bypass (CPB) continues to gain clinical acceptance. However, information on pressure-loading characteristics of the aortic root/annular areas is limited. For this reason, we designed a preclinical model, implanting an aortic root load transducer with a power source/telemetry system for chronic, conscious, loading data acquisition. This research study was conducted to determine whether an animal model could accurately measure in vivo loading.

Methods:

Preoperatively, echocardiography and magnetic resonance imaging were used to determine both aortic annular and sinotubular junction dimensions, as well as ascending aortic length. Six adult sheep were placed on CPB, aortic root and ascending aorta were skeletonized and the origins of both coronary ostia were identified. Cardiac arrest with myocardial protection with cold coronary blood cardioplegia was instituted. A properly sized aortic root load-sensing device, consisting of a transcatheter aortic valve with a ring load transducer was implanted via a left apical ventriculotomy. Verification of position was determined before closure of the ventriculotomy. Each animal was weaned from CPB, and closed in routine fashion with the power source of the device placed in a subcutaneous pocket.

Results:

There were no operative deaths or significant postoperative complications. Serial pressure-load sensing assessments in a conscious state produced reproducible proprietary data.

Conclusions:

This animal model allowed successful serial pressure-load sensing assessment of the aortic root/annular areas, providing a better physiological understanding of these anatomical inter-relationships. This added information could aid in future device designs with potential improved clinical outcomes.

Introduction

Percutaneous implantation of transcatheter prosthetic aortic valves without cardiopulmonary bypass (CPB) has continued to gain clinical acceptance for high-risk patients with aortic stenosis. Historically, the conventional open surgical replacement of a diseased aortic valve has been the gold standard, even in high-surgical-risk patients; however, these high-risk patents can experience severe comorbidities with a slight elevation in mortality with valve replacement [Brennan et al. 2012; Tagliari et al. 2012]. Fortunately, the development of a percutaneous approach without CPB for aortic valve replacement has offered a more ideal option for these high-risk patients [Kesavan et al. 2011; Spargias et al. 2013; Wilbring et al. 2012]. However, this advancement in the less-invasive aortic valve prosthetic implantation without CPB continues to raise questions concerning the pressure-loading characteristics of the aortic root/annular areas. Crystal impregnated annuloplasty rings have provided pressure-load sensing data in both the mitral and tricuspid annular regions; however this has not been documented for the aortic root area due to its anatomy. Currently, biomedical engineers have continued to understand the aortic valve area system through predominantly computer models [Grande et al. 1998].

Geometric asymmetry is present in the native aortic root and aortic valvular architecture. [Grande et al. 1998] To date, actual pressure-loading data centering on the anatomical aortic root sinuses and associated valve leaflet has been limited; and, therefore, a better biomechanical understanding, including retrieved in vivo data of this anatomical region is necessary to provide important hemodynamic and physiological information for developing novel prostheses and/or methods for transcatheter implantation, leading potentially to better clinical outcomes. Therefore, we developed a preclinical chronic animal model to assess aortic root pressure-loading parameters. This paper describes a successful chronic pressure-load sensing model for biomechanical assessment of the aortic valve and aortic root areas.

Material and methods

Preoperative preparations

This novel surgical model was developed at the Medtronic Physiological Research Laboratories (PRL, Medtronic, Inc., Minneapolis, MN). The surgical protocol was approved by PRL’s Institutional Animal Care and Use Committee and all adult sheep received humane care in accordance with the Guide for the Care and Use of Laboratory animals published by the National Institute of Health (National Institutes of Health Publication 85-23, revised 1996). Following a 10-day quarantine period, all animals (male or female) underwent preoperative screening, which included a physical examination, three-lead electrocardiogram (EKG), laboratory assessment and a transesophageal echocardiographic examination, as well as cardiac magnetic resonance imaging to determine aortic annular and sinotubular junction dimensions and the length of the ascending aorta [Kilner and Mohiaddin, 2010; Koos et al. 2012; Shively, 2000] Each animal satisfied protocol entrance criteria, including screening parameters to ensure that the anatomy would accommodate the device, before being enrolled in the protocol. Adult sheep (Polypay species, male or female, n = 6, 50–60 kg in weight) were used in the study. A fentanyl transdermal patch (PirCara Ortho-McNeal Janssen Pharmaceuticals, Inc., Raritan, NJ), 100 µg/h for animals weighing 30-45 kg and 125 µg/h for animals weighing greater than 45 kg. The 125 µg/h dose was applied on an extremity of each animal on the day prior to the surgical procedure. Each animal initially received preinduction medications via a peripheral intravenous line on the day of surgery. Morphine sulfate (1 mg/kg, Baxter Healthcare, Deerfield, IL) was administered as a premedication agent and propofol (4-6 mg/kg, Astra Zeneca Pharmaceuticals, Wilmington, DE) was used for induction. Each animal was intubated and immediately attached to a closed volume-cycle respirator. Isoflurane (1–2%, Halocarbon Products Corporation, River Edge, NJ) and supplemental oxygen, FiO₂ = 1, was used to maintain an appropriate level of general anesthesia, along with a complimentary intravenous anesthetic cocktail of fentanyl, ketamine, and lidocaine [Slatter, 2003]. A gastric tube was placed to decompress the rumen. Methylprednisolone (250 mg, Pharmacia and Upjohn Co., Kalamazoo, MI, USA) was administered intravenously. An initial dose of cefazolin (22 mg/kg) was administered intravenously during the preoperative preparation interval, and further doses were administered every 2 hours intraoperatively and one dose approximately 6–8 hours postoperatively. The animal was transported to the operating room and positioned on the operating table for a left thoracotomy. Electrocardiographic leads were placed. Both esophageal and rectal temperature probes were placed for continuous monitoring of core temperature [Kopcak et al. 2010].

Surgical procedure

All implanted devices were sterilized prior to implantation. Under general anesthesia, succinylcholine bromide (0.05 kg, Abbott Laboratories, North Chicago, IL) was administered. The animal was prepped with ChloraPrep Patient Preoperative Skin Preparation (CareFusion, San Diego, CA) and draped sterilely for both a left neck cut-down and a left thoracotomy. A left neck cutdown was performed and both the left jugular vein and the left common carotid artery were isolated. An arterial sheath (8 Fr) was placed into the left common carotid artery for continuous pressure monitoring and subsequent blood sampling. An introducer was placed into the left jugular vein for fluid replacement. A standard fourth intercostal space left thoracotomy was performed. Due to the rather limited length in the ascending aorta in adult sheep, dual arterial cannulation was utilized. The proximal descending thoracic aorta was isolated and two concentric, diamond-shaped, pledgetted pursestring sutures (Ethicon, Inc., Somerville, NJ) were placed for arterial cannulation. The brachiocephalic arterial trunk was isolated and two concentric, diamond-shaped, pledgetted, pursestring sutures (Ethicon, Inc.) were placed. The aortic arch was isolated. A pursestring suture (Ethicon, Inc.) was placed in the right atrial appendage. A horizontal pledgetted, mattress suture (Ethicon, Inc.) was placed at the apex of the left ventricle. Heparin, 250 units/kg (Pfizer, Inc., New York, NY) was administered to achieve an activated clotting time (ACT) of greater than 480 seconds. Serial ACT measurements were performed during the surgical procedure to confirm adequate anticoagulation. An arterial 5.2 mm metal-tip arterial cannula (Sarns, Inc., Ann Arbor, MI) was inserted into the descending thoracic aorta at the previously placed pursestring sutures and an arterial 5–2 mm metal arterial cannula (Sarns, Inc.) was inserted into the brachiocephalic arterial trunk at the previously placed pursestring sutures. Both arterial cannulas were connected in a “Y” fashion. A single-stage venous cannula (34–36 Fr, Medtronic-DLP Inc., Grand Rapids, MI) was placed into the right atrium at the previously placed pursestring suture for venous drainage [Kopcak et al. 2010].

The CPB circuit was primed with 1500 ml lactated Ringers solution (Abbott Laboratories) and 2000 units of heparin sodium. The CPB circuit was composed of an Affinity® oxygenator (Medtronic, Inc., Minneapolis, MN), a venous reservoir, a Bio-Pump® centrifugal blood pump (Medtronic, Inc.) and a compatible drive console (Medtronic, Inc.). The animal was placed on CPB and cooled to 32°C. A 14 Fr ventricular venting catheter (Medtronic-DLP, Inc.) was inserted into the left ventricle at the previously placed mattress suture [Kopcak et al. 2010].

The main pulmonary arterial trunk was isolated and looped with a Penrose drain for traction purposes. The aortic root and ascending aorta were skeletonized. Both right and left coronary artery origins from the aorta were identified. A pledgetted, horizontal mattress suture (Ethicon, Inc.) was placed into the proximal ascending aorta for the placement of a cardioplegia cannula (Medtronic-DLP, Inc.). Vascular cross clamps were applied, one across the brachiocephalic arterial trunk, proximal to the arterial cannulation site and another clamp applied across the aortic arch, distal to the takeoff of the brachiocephalic arterial trunk. When the cross clamps were applied, cold (4°C) blood cardioplegia (4:1 ratio; crystalloid with 20 mEq potassium; Plegisol, Hospira, Inc., Lake Forest, IL) was instilled into the ascending aorta through the previously placed cardioplegic cannula. Additional dosages of cold blood cardioplegia were instilled at approximately 15–20 minute intervals or when electrical activity was observed [Kopcak et al. 2010].

The left ventricular vent catheter was removed and an apical circular (3 cm diameter) ventriculotomy, using a core cutter, was performed. A left atriotomy was performed to facilitate visualization during the positioning of the cylindrical pressure-load sensing device. A properly sized, cylindrical pressure-load sensing device, housed within a frame was inserted through the left apical ventriculotomy and advanced under fluoroscopy, aided by the left atriotomy. After the pressure-load sensing device was positioned at the annular/sinotubular junction under fluoroscopy, the device was deployed. At the upper portion of the device’s frame, two sutures were placed to secure the device to the ascending aorta. Warming on CPB commenced. The left apical ventriculotomy was closed in a ‘mattress fashion’ using strips of felt. Two wide longitudinal strips of felt were placed epicardially, opposite to each other around the ventriculotomy and secured with a running horizontal suturing technique. A third longitudinal piece of felt was placed over the closed end of the ventriculotomy and secured firmly to the existing felt closure with a running suturing technique.

A left ventricular vent was re-inserted into the left ventricle via the left atriotomy during the closure of the left atriotomy. The aortic cross clamps were removed and when a core temperature of 36°C was reached, pharmaceutical supplementation was instilled into the CPB circuit: lidocaine 30 mg (2%; Vedco, Inc., Saint Joseph, MO); calcium chloride 500 mg (10%, Fujisawa USA, Inc., Deerfield, IL); methylprednisolone 250 mg; sodium bicarbonate 10 mEq (8.4%; Abbott Laboratories); atropine sulfate 1–2 mg; succinylcholine bromide 40 mg). Approximately 5–10 minutes after these pharmaceutical agents were administered, the heart was defibrillated using between 10 and 50 J with epicardial paddles (Lifepak Cardiac Monitor; Medtronic, Inc., Physio-Control, Redmond WA). Following defibrillation, the animal remained on CPB until the core temperature reached 38°C. When hemodynamically stable, the animal was weaned from CPB and decannulated. A left pleural chest tube was placed and the thoracotomy and neck incision were closed in routine fashion [Kopcak et al. 2010]. The wires from the pressure-load sensing device exited through the chest wall and were connected to the device’s power source, which resided in a created subcutaneous pocket.

Postoperative care and assessment

Immediately following the surgical procedure, an echocardiographic examination was performed to confirm device placement. The animal was extubated and transported to a postanesthesia care unit. The left pleural chest tube was removed within the next 24 hours. Serial pressure-load sensing data was obtained over weeks following the surgical procedure. Following the last assessment at postoperative week 8, the animal was euthanized under general anesthesia with Euthasol (Virbac, Fort Worth, TX), 1 ml of standard solution/4.5 kg animal weight, and was transported for postmortem examination.

Results

All animals tolerated and survived the surgical procedure and were extubated without complications. Serial postoperative daily veterinary assessments revealed that each animal was alert, demonstrated appropriate cognitive abilities and normal physiological functions. Weekly, serial pressure-load sensing assessments were performed in the conscious state. These measurements were obtained in all animals and due to the competitive nature for this data, Medtronic, Inc. elected not to publish these confidential, quantitative measurements obtained using this surgical technique/model paper. The data collection methodology and the serial data acquisition have importance; however, the purpose of this paper centers on the creation and success of a very difficult surgical model. The subsequent serial collection of data and its resulting quality are not associated with the surgical procedural outcomes. We believe that this is the first successful attempt at obtaining, chronic, in vivo aortic root pressure-load sensing measurements in an animal model; however, future studies maybe required for data validation.

Discussion

Patients with severe aortic stenosis and found to be high-risk, nonsurgical candidates for prosthetic valve replacement have little therapeutic options until recently. Inoperable critical aortic stenosis was considered untreatable for decades; however, with the development of a transcatheter aortic valve prosthetic approach without CPB, these patients were offered a less-invasive therapy to treat their aortic valve disease [Redberg and Dhruva, 2011]. Preclinical animal investigations and subsequent clinical trials have supported the efficacy of this nonsurgical approach, despite a higher incidence of strokes and major vascular events [Grube et al. 2006; Leon et al. 2010; Sochman et al. 2010]. The proposed minimally invasive implantation of an aortic prosthesis has aided these high-risk patients; however, little has been reported on the biomechanics of the aortic root and aortic valve. Asymmetry of this anatomic region may play a significant role in the performance of an implanted prosthesis. Studies have reported important information pertaining to stress patterns in the aortic valve leaflets [Cataloglu et al. 1977], aortic valve failure mechanisms [Hamid et al. 1986], and insights into optimizing designs of stented bioprosthetic valves. [Hamid et al. 1987]. To further address these issues, Grande and colleagues developed a finite-element model from magnetic-resonance images of human valve–root specimens to evaluate the regional stresses of the valve within the aortic root area [Grande et al. 1998]. They evaluated peak principal stresses for the left, right and noncoronary leaflets, as well as the aortic wall after attaining diastolic pressurization. High measured stresses were found in the noncoronary leaflets, as well as peak stresses at the free margins and belly area near the coaptation surfaces of each leaflet. Stresses measured in the right and noncoronary sinuses were greater than the left sinus and all sinuses demonstrated that the stresses near the annulus were higher than found at the respective sinotubular junctions. Lastly, measured stresses varied across the aortic valve and root area, probably due to their inherent asymmetrical morphology and stress sharing [Grande et al. 1998].

The study data from Grande and colleagues provides important data pertaining to human specimens; however, an actual in vivo animal model assessment is needed for a more pertinent evaluation. Therefore, our successful chronic animal model assesses in vivo pressure-load sensing of this anatomic region. A better understanding of this in vivo geometric and pressure-loading characteristic of the aortic root, aortic valve, aortic annulus and sinuses offers important information in the future designs of prostheses, including transcatheter bioprosthetic valves, and in the implantation procedure of these bioprostheses.