Long-Term Implantable Ventricular Assist Devices (VADs) and Total Artificial Hearts (TAHs)

6.625. Long-Term Implantable Ventricular Assist Devices (VADs) and Total Artificial Hearts (TAHs) A Kumar, Boston Scientific Corporation, Boston, MA, USA P S Khanwilkar, World Heart Corporation, Utah, UT, USA ã 2011 Elsevier Ltd. All rights reserved.

6.625.1. 6.625.1.1. 6.625.1.2. 6.625.2. 6.625.3. 6.625.3.1. 6.625.3.2. 6.625.3.3. 6.625.3.3.1. 6.625.3.3.2. 6.625.4. 6.625.5. 6.625.6. References

Introduction Evolution of VADs and TAHs Anatomical and Physiological Considerations Configuration LVAD Evolution First-Generation LVADs Rotary Axial Pumps Rotary Centrifugal Pumps Rotary centrifugal pumps using hydrodynamic suspension Rotary centrifugal pumps using full magnetic levitation Partial Circulatory Support VADs Total Artificial Heart Conclusions

Abbreviations bpm BTR BTT CAD CFD CPB HDE HF IDE INTREPID trial

6.625.1.

Beats per minute Bridge-to-recovery Bridge-to-transplant Computer-aided design Computational fluid dynamics Cardiopulmonary bypass Humanitarian device exemption Heart failure Investigational device exemption Investigation of nontransplant eligible patients who are inotrope dependent

Introduction

6.625.1.1. Evolution of VADs and TAHs Long-term implantable ventricular assist devices (VADs) and total artificial hearts (TAHs) have been under development since the late ‘60s as therapies for late-stage heart failure (HF), a debilitating and deadly malaise that affects millions worldwide. HF accounts for
7% of death (mortality rate of 1 in 5) from cardiovascular diseases, affects 4.8 million Americans with 500 000 new Americans diagnosed every year and is the leading cause of death in the United States and the rest of the world.1,2 These staggering figures give us an estimate of the magnitude and impact of HF on the society and the motivation for proliferating research and development initiatives from both academia and industry, to address this challenge.3 HF may be caused by coronary atherosclerosis, hypertension, viral or idiopathic cardiomyopathy, or congenital defects. The pathogenesis of chronic HF is a complex process that involves a series of morphological and molecular alterations

LMWH LV MCS NHLBI REMATCH

RV TAH TET VAD

389 389 390 390 392 393 395 396 397 397 399 400 402 402

Low molecular weight heparin Left ventricle Mechanical circulatory support National heart, lung and blood institute Randomized evaluation of mechanical assistance for the treatment of congestive heart failure Right ventricle Total artificial heart Transcutaneous energy transmission Ventricular assist device

of the myocardium (‘remodeling’). Causes such as myocardial infarction, myocarditis, or genetic defects, can initiate cardiac insufficiency. This is followed by several pathophysiological compensatory mechanisms that cause additional stress on the weakening heart, leading to HF, a positive feedback mechanism. A primary component of such a mechanism is the volumetric expansion of the heart in order to provide adequate blood flow, a deficiency that weakens the heart muscle and leads to further volumetric expansion, resulting in a significantly enlarged heart. This is termed congestive HF – as the heart grows to ‘congest’ the chest. Although traditional medical therapy (defibrillator implantation, biventricular pacing) provides a temporary solution to manage and control the seemingly unstoppable progression of HF to end-stage, until now, transplantation has been the only effective treatment for most end-stage HF patients. But a severely limited supply of donor hearts has meant that only about 3000 persons receive transplants each year worldwide while about 15% die waiting for a donor heart.4,5

389

390

Cardiology and Cardiovascular Surgery

This gap and the increasing need for a longer-term solution (an alternate to a heart transplant) was recognized in the 1960s by the US government thanks to early efforts by pioneering clinical researchers that showed the promise for mechanical circulatory support (MCS). The Artificial Heart Program was set up and run by the National Heart, Lung, and Blood Institute (NHLBI) with a goal to fund and foster the development of two types of MCS for long-term implantable use: ventricular assist devices (VADs) and total artificial hearts (TAHs). A Ventricular Assist Device or VAD in short, circulates blood through the host’s circulatory system to compensate for the otherwise poor circulation provided by the recipient’s failing heart which is left intact, while a TAH replaces the natural heart. Since its inception in 1962, by Dr. Domingo Liotta of the Baylor College of Medicine in Houston, the VAD has been used to complement the function of a human heart, either as a ‘bridge-to-transplant’ (BTT) for patients with ailing heart waiting for a natural donor heart or sometimes as a ‘permanent’ implant (the so-called DT indication).6,7 There is a fledgling new indication for VADs called bridge-to-recovery (BTR) in which, after VAD implant and support, native cardiac function of the recipient recovers (‘reverse remodeling’) and removal of the device is possible without subsequent support due to stable restoration of the natural heart pumping function.8 The NHLBI program has spawned the development and growth of a global industry comprised of many VAD/TAH academic institutions and companies not only in the US, but in Europe, Japan, and other locations. There are now several VADs and TAHs that have been approved by regulatory agencies for commercial sale and distribution in these locations, and
10 000 implants with these devices have been performed worldwide to date, with the number increasing significantly every year. Use of LVADs has predominated, with the TAH being used to date in less than a thousand patients. Randomized and controlled clinical trials have shown that VADs provide significant improvement in the quality of life and survival of patients with HF.2,9 Further development continues – several companies are now developing MCS devices to provide short- or long-term support to reduce their size, improve safety and reduce adverse events, and optimize performance and ease-of-use. The use of computer-aided design (CAD) and its application complemented by computational fluid dynamics (CFD) has resulted in the development of some ingenious and novel ‘smart’ devices with potentially superior performance. These next-generation devices are presently being clinically evaluated. This chapter outlines the need for MCS devices and focuses on long-term (multimonth to multiyear) implantable MCS devices, since challenges with these are most relevant from a biomaterials perspective. We provide an overview of generations of VADs that have seen some clinical use, emphasizing so-called left VADs (LVADs). LVADs support the failing left ventricle, which supplies oxygenated blood to the body and does the most work and typically fails more often than the right ventricle. Key devices representative of each generation are described, including a summary of their design configuration, technological innovations, especially biomaterials related, development status, clinical results, and future plans. The intent is to provide a representative overview to promote an understanding of the field and the various technologies, rather than provide an

exhaustive and detailed summary description of every MCS device ever developed. Given their predominant clinical use, long-term implantable LVADs are the primary focus, while TAHs are also described.

6.625.1.2. Anatomical and Physiological Considerations The anatomy of a human heart reveals two sides (left and right), each side having two chambers: an atrium and a ventricle. Each atrium collects incoming blood and helps provide it to the corresponding ventricle which actively pumps it for circulation through the pumping circuit: the right ventricle pumps deoxygenated blood into the lungs, and the left ventricle pumps oxygenated blood into the body, as illustrated in Figure 1. The basic mechanics underlying the functioning of a human heart is such that the ventricles act as unidirectional positive displacement pumps with a pulsatile motion alternating between filling (diastole) and ejection (systole) phases. The blood flow for each phase is regulated by inflow (mitral and tricuspid) and outflow (pulmonary and aorta) valves for the right and left sides, respectively. A normal functional adult heart ejects about 60 cm3 of blood in each stroke and controls cardiac output by primarily varying the heart rate which can range from 40 beats per minute (bpm) at rest to 180 bpm during exercise. Although VADs were designed to assist the right ventricle (RVAD), the left ventricle (LVAD), or both ventricles (BiVAD), this chapter focuses on the LVAD, which is shown schematically implanted in a human in Figure 2(a). Figure 2(b) depicts an implanted TAH. About 15–30% of LVAD implants are reported to need right ventricular support.10 However, this is usually clinically alleviated with short-term measures like nitric oxide or a temporary (multiday) RVAD such as the external Thoratec VAD or the Levitronix CentriMag VAD.11,12 The authors have estimated that the clinical need for mechanical circulatory support can be provided by devices in the proportions of: 80% LVADs, 15% BiVADs, and 5% TAHs. LVADs are designed to support blood circulation when the LV is no longer able to meet the body’s systemic perfusion needs, presuming that the RV normally supports an adequate load, owing to its adaptability to elevated preload and after load changes. An LVAD may be implanted in the upper abdomen, chest, or inside the pericardium either extraventricular or transventricular. The inflow for long-term LVADs is typically from the apex of the left atrium via a cannula to the pump, and the outflow of the pump is connected to the ascending aorta via a graft. Based on various mechanical and physiological performances, an ideal VAD would be expected (1) to provide sufficient cardiac output and complement an ailing heart so as to allow patients to return to their daily activities; (2) to have a low risk of thromboembolism, damage to and activation of blood components, driveline and pump infection, (3) to have a low incidence of malfunction; (4) to be easily implantable and also removable; and lastly (5) to fit well in the human anatomy which usually translates to a small size.

6.625.2.

Configuration

The basic configuration of a pulsatile VAD has three components; (1) an electrically driven electromechanical pump,

Long-Term Implantable Ventricular Assist Devices (VADs) and Total Artificial Hearts (TAHs)

391

Aorta Superior vena cava Pulmonary artery Pulmonary veins Left atrium Right atrium Left ventricle Right ventricle Inferior vena cava Diastole ventricular relaxation and filling

Systole ventricular contraction and ejection

Figure 1 The normal Cardiac Cycle. Source: http://www.xaraxone.com/FeaturedArt/mar04/html/05.htm

Artificial heart left pump

External battery pack Outflowvalve housing

Inflowvalve housing

Energy converter Electronic controller and implanted batteries

Drive line

System controller

Artificial heart right pump

Aorta

Vent adapter and vent filter

Skin line

Prosthetic left ventricle

(a)

Implanted secondary External primary transformer transformer (b)

Figure 2 (a) Left ventricular assist device. (b) Total artificial heart.

(2) an electronic controller, and (3) a power supply. The pump weighs
1.5 pounds typically made of biocompatible titanium with the flexing components made of biocompatible polyurethane. The circumferential acceleration of blood is achieved by controlled electric currents passing through coils contained in the pump housing that apply forces to an electromagnetic actuator that rotates and/or translates. This mechanism in turn squeezes a plastic blood sac to provide systole with the lack of a squeezing action being the diastolic phase of the LVAD’s beat; the direction of blood flow is controlled by a pair of

unidirectional valves embedded in the LVAD, the same types used when a natural heart valve is replaced (e.g., valves from pigs’ hearts or ones made of metal and plastic). A VAD could be classified in numerous ways based on (a) the mechanics of its pump: (1) volume or positive displacement or pulsatile, (2) rotary or continuous flow encompassing axial flow, or centrifugal pumps, (b) pump location (para corporeal, implantable, or extracorporeal): (c) intended clinical use (temporary, bridge-to-decision, recovery, transplant, or destination): (d) support provided (left – LVAD, right – RVAD,

392

Cardiology and Cardiovascular Surgery

or both ventricles – BiVAD): and (e) surgical approaches (percutaneous, subcostal, laparaotomy, sternotomy, thoracotomy). The first classification pulsatile and rotary pumps is how they are described going forward. Table 1 shows the different types of LVADs (pulsatile, and so-called ‘continuous flow’) as well as TAHs and highlights a few representative pulsatile VADs that have played a pioneering role in developing the field. The electronic controller is typically a microprocessor chipbased set of digital and analog electronics component that adjusts functions of the pump, such as pumping speed and provides diagnostic, alarms, alerts, and communications to an external monitor. The power supply for the pump is by two external batteries, via a cable through the abdomen, carried in underarm holsters or a waist pack. A few efforts have been made to transmit electric power across the skin in a transformer-like arrangement; typically, one pair of coils is permanently implanted below the skin and the other is strapped over the skin with the electromagnetic coupling between the two coils allowing power transfer. This transcutaneous energy transmission (TET) technology has seen very limited clinical use and still needs additional improvements prior to further use in the clinical setting.

6.625.3.

LVAD Evolution

The developmental evolution of LVADs dates back to early cardiopulmonary bypass (CPB) machines and experiments in the late 1950s, during which artificial hearts were implanted in dogs. Both TAHs and heart assist devices have achieved significant development and clinical milestones since then. Starting in the 1980s, these advancements in technology and refinements in implantation paved the way for the development of innovative and novel devices, gradually overcoming the shortcomings of earlier versions. LVAD design has made tremendous advances over the last decade, reducing size, increasing durability, and eliminating noise and vibration. The first-generation pulsatile pumps were designed to emulate the natural heart. As a result, they were bulky, large, needed heart valves, consumed much power, and suffered from high noise and vibration. As Table 1 shows, they either suffered from limited life or high complication rates. A new paradigm for long-term blood pumping with MCS was provided by the high-speed rotary Hemopump developed and clinically used in the mid-1980s. This device, despite being commercially unsuccessful, demonstrated that there were no discernible worse outcomes associated with the direct pumping of blood with a rotary pump as compared to a pulsatile pump. This provided the incentive for the development of next-generation rotary pumps to pump blood directly while being immersed in blood. These long-term implantable rotary pumps have also evolved over three generations beyond the first-generation pulsatile pumps. From second-generation pumps (axial flow pumps supported by mechanical bearings) that proved that long-term circulatory support provided by rotary pumps was viable and accepted well by the human body, to third-generation pumps (centrifugal pumps supported by hydrodynamic bearings) to fourth-generation pumps (centrifugal pumps whose rotor is

Table 1 A summary of available cardiac devices highlighting their advantages and disadvantages Thoratec Indications Advantages

Disadvantages

HeartMate Indications Advantages

Disadvantages

Novacor Indications Advantages

Disadvantages

Right, left, or biventricular support Fits in a wide range of patient sizes (body surface area 0.73–2.5 m2) Pump can be changed without invasive surgery Can replace the entire function of the supported ventricle Need for strict anticoagulation with risk of bleeding or thromboembolism Large lines crossing the skin with a high risk of infection Limited patient mobility Not approved for home use Left ventricular support No need for anticoagulation Portability of controller and batteries permits good patient mobility and hospital discharge Can replace the entire function of the supported ventricle Driveline crossing the skin poses a risk of infection Left ventricle support only Does not fit in patients with body surface area 1.5 m2 Left ventricular support Portability of controller and batteries permits good patient mobility and hospital discharge Can replace the entire function of the supported ventricle Need for strict anticoagulation with higher risk of bleeding or thromboembolism Driveline crossing the skin poses a high risk of infection Left ventricle support only Does not fit in patients with body surface area 1.5 m2

Continuous-flow pumps Indications Left ventricular support Advantages Small size permits greater patient mobility Quiet Fit in a wide range of patient body habitus Disadvantages Need anticoagulation; risk of bleeding and thromboembolism unknown May not replace the entire function of the supported ventricle Nonpulsatile flow Still in early clinical trials Total artificial hearts Indications

Advantages Disadvantages

Advanced biventricular dysfunction Pulmonary hypertension? Cardiac tumors? Complete replacement of the heart function Need anticoagulation; risk of bleeding or thromboembolism Due to the size of equipment, they only fit in patients with larger body habitus Still in early clinical trials

Source: DeBakey, M. E. Ann. Thorac. Surg. 2005, 79, S2228–S2231.

Long-Term Implantable Ventricular Assist Devices (VADs) and Total Artificial Hearts (TAHs)

suspended completely using magnetic levitation), VAD technology has developed by leaps and bounds. Because the clinical development cycle time is extensive, today there are second, third, and fourth-generation VADs undergoing clinical trials concurrently. The earliest LVAD was reported in 1961 by Dennis et al. and the strategy was to employ a roller pump to off-load LV by receiving blood from RA and in turn return it to femoral artery.13 Although the device was supposed to have supported 12 patients for 4–17 h, no significant support to recovery was observed. Since then, several researchers and developers had made progress toward VAD and TAH that are fully implantable. In 1963, DeBakey developed the first implantable pulsatile VAD using unidirectional ball valves that bypassed the heart between the left atrium and the descending thoracic aorta.14 The implanted VAD consisted of two coaxial tubes: the blood flowed through an inner biocompatible Dacron tube surrounded by a rigid outer tube. Blood was then pumped by pneumatically increasing the transluminal pressure causing the flexible inner tube to narrow. A second patient, supported for 10 days with an extracorporeal version of this device, became the first patient to be supported to recovery with a VAD. Later in 1969, Cooley et al. performed the first successful BTT using a TAH demonstrating the possibility to support the patient’s circulation until a donor heart became available (Figure 3). Worldwide attention was focused on the University of Utah in 1982 when Barney Clark, received a Jarvik-7 TAH intended for long-term use. Despite an in-hospital stay with numerous complications, this implant was followed by William Schroeder, Murray Haydon, and Jack Burcham who fared a little better. In 1998, two LVAD systems were approved by the FDA and used for bridge-to-transplantation. The HeartMate™ VE pump (Thoratec Laboratories Corp., Pleasanton, CA) and Novacor™ (WorldHeart, Ottawa, Canada) were evaluated in the United States for permanent mechanical circulatory support in the REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) and INTREPID trial (Investigation of nontransplant eligible patients who are inotrope dependent) (Figure 4).7 These early pioneering clinical successes fueled the development of second-generation devices, such as the HeartMate II

393

shown below. The HeartMate II was the first second-generation pump to be approved in 2008 for a BTT indication, a milestone followed by its 2010 approval for DT (Figure 5).

6.625.3.1. First-Generation LVADs Positive/volume displacement pumps mimic the action of the human ventricles to pump blood. These could further be classified based on the mechanism by which they eject blood as pneumatic or electric. The valves incorporated into these VADs may either be bioprosthetic that offers superior biocompatibility, while suffering from poor longevity or of durable, mechanical valve with thrombogenic potential. The most widely used and studied first-generation VADs include HeartMate® I15 (originally developed by Thermo Cardiosystems, Inc., Waltham, MA and acquired by Thoratec Corporation of Pleasanton, CA) and the Novacor® LVAS (originally developed by Novacor Medical of Oakland, CA and later acquired by WorldHeart Corporation of Salt Lake City, Utah by way of Baxter HealthCare and Edwards LifeSciences). The HeartMate I LVAD is available either as implantable pneumatic (IP-portable power unit on a console) that is used as bridge-to-heart transplant or, a more refined vented electric model (XVE), developed after REMATCH trial success that is currently approved for both BTT and DT use in the United States.16,17 Both HeartMate pumps use titanium alloys and Cardioflex® polyurethane with advanced fabrication technology. The device has textured blood-contacting surfaces (textured titanium, textured blood sac) that reduces stroke and thrombus formation and does not require anticoagulant therapy benefiting patients that poorly tolerate these drugs.18,19 A comparative study versus home inotropic infusion therapy reveals that this device certainly improves the quality of life and survival rate of patients (Figure 6).20 The Novacor and the HeartMate™ LVASs are both intracorporeal LVADs. Both incorporate porcine valves and have portable controllers that permit the patient to be discharged from the hospital and to be more ambulatory.15,21 The HeartMate I is estimated to have been implanted in 5000 patients and the Novacor in 1800 patients worldwide.

100

Survival (%)

80 60

LV assisit device

40 20 Medical therapy 0 0

(a)

(b)

Figure 3 (a) Dr. Denton A. Cooley and (b) the total artificial heart used for the first successful bridge-to-transplant.

6

12

18 Months

24

30

Figure 4 An outcome of survival of patients in the randomized evaluation of mechanical assistance for the treatment of congestive heart failure trial. The results reveal an obvious increase in survival of patients with end-stage heart failure. Reproduced with permission from Rose, E.A. et al. Long-term mechanical left ventricular assistance for end-stage heart failure. N. Engl. J. Med., 2001, 345(20), 1435–1443.

394

Cardiology and Cardiovascular Surgery

Aorta External battery pack

From left ventricle

To aorta Left ventricle

Skin entry site

Motor Outlet stator and diffuser

Pump housing

Percutaneous lead

System controller

Continuousflow LVAD

Blood flow Roter

Percutaneous lead (a)

Inlet stator and blood-flow straightener

(b)

Figure 5 (a) Schematic of patient implanted with the HMII and (b) a close-up cross-section of HeartMate II.

(a)

(b)

Figure 6 (a) Thoratec HeartMate I XVE pump. (b) Novacor LVAD blood pump.

The Novacor LVAS had the distinction of supporting a patient for more than 6 years with a single device, and was approved for BTT in the United States, and is CE Marked in Europe as well as approved in Japan. As a historical footnote, it is worthwhile to mention the Arrow LionHeart™ (LionHeart Ventricular Assist System; Arrow International, Reading, PA) whose manufacture and distribution has been discontinued. The LionHeart was a pulsatile LVAD and was notable for its use of transcutaneous wireless power transmitter (TET – transcutaneous energy transfer). In Europe, the CUBS trial (Clinical Utility Baseline Study) evaluated its use as a permanent implant and it obtained the CE Mark. The LionHeart™ received an Investigational Device Exemption

from the US FDA in 2001 and was undergoing Phase I human clinical trials in the United States until it was discontinued in 2006. Since it did not employ a vent tube for exchange of air, unlike its predecessors, and achieved it via an implanted compliance chamber, coupled with its use of a TET for power and data transmission across the skin, it eliminated the need for a percutaneous cable. While this certainly helped address the driveline infection issue, the trade-off was increased volume and number of separate implantable components, and the need to periodically (once every 2 weeks) prime the supple compliance chamber with working gas through an access port (shown in Figure 7), due to its gradual dissipation through the synthetic membrane.

Long-Term Implantable Ventricular Assist Devices (VADs) and Total Artificial Hearts (TAHs)

Outflow

Inflow

Motor controller

395

Compliance chamber

Access port

Blood pump Internal coil

Figure 7 Arrow LionHeart™ (LionHeart Ventricular Assist System; Arrow International, Reading, PA).

The Berlin Heart Group (Berlin Heart AG, Berlin, Germany) produces and sells the EXCOR pulsatile VAD. This external device comes in a variety of sizes selected depending on patient needs, and has been used primarily in adults as a short-term support and more predominantly in newborns and infants with cardiac failure. The EXCOR VAD has received an HDE from the US FDA for this latter niche application. While offering several advantages, the first-generation VAD suffered from serious drawbacks such as bulkiness (pump, driving console), noise, limited life due to mechanical wear and breakdown, high incidence of adverse events, and nonphysiologically high systolic pressure that could result in elevated calcification and hence eventually to valve failure.

6.625.3.2. Rotary Axial Pumps

Figure 8 HeartMate II left ventricular assist device.

The pitfalls of first-generation volume displacement pumps were overcome to some extent with the ‘second-generation’ axial pumps.17,22 Axial pumps were anticipated to be less obtrusive, of low noise and less prone to driveline infections due to reduced driveline diameter, increased flexibility, and less stiffness of the percutaneous cable. Furthermore, these pumps are driven by impellers that operate on a continuous basis using rotary pump technology. With speeds typically up to 12 000–15 000 rpm, these could generate higher flow rates at lower pressure (up to 10 l min1), without the need for a valve.22,23 Initially, concerns were raised about the possibility that such speeds might lead to hemolysis of blood, but soon was discarded when the Hemopump was successfully used in a clinical setting.24 The Hemopump thus set the stage for further evaluation of other types of axial flow pumps.16,17,25–29 Key second-generation pumps include the HeartMate II LVAD23 (Thoratec), the DeBakey- MicroMed VAD® (MicroMed Cardiovascular, Houston, TX), and the Jarvik 2000 (Jarvik Heart, Inc., New York, NY). MicroMed’s device uses an impeller/inducer with six blades and eight magnets, enclosed in a titanium tube and is capable of pumping up to 10 l min1, and is identical to the HeartMate II in many respects. Based on NASA-developed technology, the DeBakey’s compelling features are its size, which is anatomically designed for fit even in the pediatric populace for which it has obtained FDA approval as a BTT, and an implantable ultrasonic flowmeter

to allow better patient monitoring and device speed adjustment.25,27 The DeBakey VAD has been redesigned several times due to thrombotic issues leading to several changes in bloodcontacting coatings. and the latest version is being evaluated under a CE Mark trial in Europe (Figure 8). The Jarvik 2000, also known as the Flowmaker®, has the advantage of requiring no cannulation and potentially decreased thromboembolic events due to its design that is presently being qualified. It is 2.5 cm wide, 5.5 cm long, and weighs 85 g. The pump speed can be tuned by an analog controller on the basis of symptoms and individual requirements offering a unique biofeedback mechanism for the patients. The entire casing is of titanium with the pump suspended on ceramic bearings.26 This device has the distinction of having supported a patient for more than 7 years and is presently in a US BTT clinical trial having received a CE Mark in Europe. The Jarvik 2000 is being adapted and miniaturized for use in the pediatric population (Figure 9). Overall the second-generation VADs offers effective circulatory support and durability, less extensive and invasive surgical procedures hence postoperative complications, and reduction in pocket infections. Based on the above facts demonstrated through controlled clinical trials, HeartMate® II has been approved by FDA as BTT therapy and more recently for DT as well.16 The main disadvantages of these devices are the intense anticoagulation regimens to treat embolic complications,

396

Cardiology and Cardiovascular Surgery

Figure 9 Jarvik 2000 also known as Flowmaker.

Figure 10 BerlinHeart Incor ventricular assist device.

bleeding, and the activation of undesirable blood constituents such as von Willebrand’s factor.30 Since these pumps traditionally rely on mechanical bearings to suspend the rotor spinning at high speeds, the BerlinHeart Incor VAD incorporates an axial flow pump with a fully magnetically levitated suspension. The Incor® LVAD is an impeller device developed by the Berlin Heart Group (Berlin Heart AG, Berlin, Germany).31 The pump is 30 mm in diameter, 12 cm in length, and weighs 200 gms. Blood enters the device through a cannula and passes the inducer and the flow is driven by an impeller that is held in suspension by magnets (both permanent and active electromagnets) and can develop a flow of up to 7 l min1 with motor speeds of 5000–10 000 rpm. The clinical investigation of this device began in 2002 and the results showed a dramatic reduction in infection rate, with a significant increase in thromboembolism.32 A retrospective study revealed that the long inflow cannula in the design yielded better clinical outcomes than a short one (138 patients – short length of inflow cannula and 78 with long inflow cannula) and a lower incidence of embolism.31–33 A 2004–2005 study to evaluate BTT potential of the device revealed its feasibility for long-term use using a combination of LMWH (Heparin) and antiplatelet therapy as an alternative to oral anticoagulants. The study also revealed that, out of 10 patients, 6 patients successfully received transplants and 4 patients died – the last death occurred after 405 days of INCOR implantation. The autopsy indicated the causes of death to be sepsis, intestinal hemorrhage, acute right ventricular failure, and one major stroke.34 A total of 500 patients worldwide have been implanted with the INCOR VAD (Figure 10).

6.625.3.3. Rotary Centrifugal Pumps Centrifugal pumps are regarded as the next stage of evolution of VADs.35 Although similar to axial pumps, in that they are rotary pumps, the rotor of a centrifugal pump is shaped so as to cause the blood to move circumferentially along the outer rim of the pump housing and be ejected. Centrifugal VADs have been found to improve myocardial function and be beneficial to end-organ functioning through pulsatile perfusion.16,31,36 Due to its different pressure-flow characteristics compared to an axial flow pump, a centrifugul pump may be physiologically better suited for adults than an axial flow pump: it provides greater pulsatility in flow, and a more physiologic response to changing preload. The key area of distinction for the centrifugal pumps is how their single moving part, the impeller, is supported. Earlier designs such as the EVAHeart (Pittsburgh, PA) employ solid mechanical bearings, while nextgeneration centrifugal blood pumps either employ the blood itself to suspend the spinning impeller in a hydrodynamic suspension (HeartWare HVAD, VentrAssist’s VentraCor, and the Arrow CorAide). The culmination of centrifugal blood pump technology has resulted in fourth-generation pumps (Terumo DuraHeart, Thoratec HeartMate III, WorldHeart Levacor) whose impellers are completely magnetically levitated inside the pump cavity. These pumps stay suspended with magnetic levitation, providing a smooth, uniform, and unrestricted flow path to blood, and eliminate contact of the spinning rotor with the housing, thereby theoretically eliminating any wear on the impeller blades and mechanical friction resistance.

Long-Term Implantable Ventricular Assist Devices (VADs) and Total Artificial Hearts (TAHs)

6.625.3.3.1. suspension

Rotary centrifugal pumps using hydrodynamic

The VentrAssist™ LVAD (Ventracore, Chatswood, NSW, Australia) was a recently developed third-generation centrifugal blood pump with hydrodynamic suspension.35 Its only moving part, an impeller, consists of four small blades that are embedded with permanent magnets. The combined dynamic interplay of fluid, bearing, and gravitational forces prevents the impeller from contacting the housing. The VentrAssist™ weighs 298 g and is made of titanium. It is
60 mm in diameter and is suitable for use both in children and adults (Figure 11). Recent studies have shown the device’s ability to perform in BTT therapy.24,37,38 The initial pilot study was conducted on four DT and five BTT patients in 2003. Having acquired considerable patient-years of experience (7 years), the safety and efficacy profile displayed no embolic events, minimal sepsis/infections and reportedly remarkable performance even in complex cases.37,39 This pilot study instigated a phase II trial that led to its CE mark approval in the European Union. The overall performance was exceptional with over 70% of patients who achieved early hospital discharge, with better functional status and compliance. To corroborate the survival to transplant or the continued support while the patient was still on transplant wait list, a US multicenter, pilot study to BTT was conducted and the results showed a statistically and clinically significant improvement in the quality of life and functional status, with adverse effects similar to the current LVADs, while certainly being better than pulsatile LVADs.40 The study was terminated early by Data Safety Monitoring Board because its interim analysis criteria for study discontinuation requirement had been fulfilled.40 Further investigation of the device was not feasible owing to the company’s lack of funds and subsequent dissolution. The Arrow CorAide VAD (centrifugal pump, hydrodynamic suspension) was also CE Marked in Europe, but its owner exited the VAD space, and there are no further reports of any future development as both the CorAide and the LionHeart have been mothballed. This attrition leaves the Heartware HVAD as the only clinically used pump in this category.

397

The HVAD™ (Heartware Inc.,) consists of a small continuous flow rotary centrifugal pump with a hydrodynamic bearing design with a unique feature of its size that could be accommodated within the pericardial space near the left ventricle. This design obviates the need for an abdominal dissection. The impeller is suspended via a combination of passive magnetic and active hydrodynamic bearings. This reduces the mechanical strain on the pump and therefore its wear. The integrated design contains two motor stators for singlemotor fault protection to increase reliability. A thin blood film generated by the bearings eliminates physical contact between the housing and the impeller during normal operation.41,42 Since its implantation in March 2006, HVAD™ has undergone clinical evaluations in Europe and Australia and a US BTT trial consisting of 150 patients completed its enrollment in February 2010. After a 6-month follow-up for the last patient enrolled in August 2010, it is anticipated that a BTT PMA submission will occur by year-end 2010, with approval following earliest in mid-late 2011. A DT trial for HVAD with 450 patients randomized 2:1 to the HMI or II has been recently conditionally approved by the FDA (Figure 12).

6.625.3.3.2. Rotary centrifugal pumps using full magnetic levitation The two devices in this category in clinical development are the Duraheart VAD (Terumo Cardiovascular), and the Levacor VAD (WorldHeart Corporation). Both these devices have a similar configuration, including a ‘flat’ inlet to the centrifugal pump that allows the pump to be implanted in the upper abdomen of even small patients. In comparison, the thirdgeneration pumps described above have a traditional inlet to their centrifugal pump, one that is at right angles to the pump body. While this somewhat simplifies the blood flow path design, it is possible it may compromise anatomic fit and position of the third-generation pumps, including that of the inlet cannula. The flat inlet of the fourth-generation pumps described here may avoid this potential problem. The DuraHeart™ VAD comprises an implantable pump with several components to augment its function.43 The ingenuity of the device is attributed to the magnetically levitating centrifugal rotary pump (impeller with 3 positional sensors)

VentrAssist LVAD pump

Magnets and copper coils

Rotor within pump

Figure 11 The VentrAssist™ left ventricular assist device (Ventracore, Chatswood, NSW, Australia).

398

Cardiology and Cardiovascular Surgery

HEARTWARE

HVAD Specs: 145 g Size: Verified accurate data could not be obtained

HVAD The smallest full-output third generation circulatory assist device in development

Figure 12 HVAD Heartware, Inc.

Pump

Inflow conduit

Hospital console Outflow conduit

Battery charger

Controller

Batteries Figure 13 DuraHeart™.

with a thin outflow conduit (Vascutek Gelweave™) that exits the skin and connects to the controller that controls and monitors the system status. The pump comprises an upper housing with the levitation system and the impeller, and bottom housing with an external-drive motor. The device has been fabricated with an active magnetic levitation of the impeller coupled with hydrodynamic bearings to support impeller levitation in case of failure of the magnetic levitation system. This design provides flow rate of 2–8 l min1, with rotor speeds of 1200–2400 rpm. The flow rate can be programmed to vary with physiological changes. DuraHeart™ with its combination of centrifugal pump and magnetic levitation technology was the first such device to reach clinical trial.43 The pump is implanted in an abdominal pocket. The magnetic levitation of the impeller is designed so as to eliminate friction by allowing a wide gap between blood-contacting surface areas, and to enable blood to flow unimpeded, through the pump in a smooth nonturbulent fashion. The DuraHeart™ pump has the dimensions of diameter 72 mm, thickness 45 mm, and weighs
540 g. The displacement volume is 196 ml, that is, 30–50% smaller than the pulsatile pumps. The total horizontal length is
50–60% shorter than that of axial flow LVADs.44 The DuraHeart™ LVAS (Figure 13) is currently being studied in a Pivotal US trial for BTT, a multicenter, nonrandomized study that involves 140 patients. The study is meant to evaluate the safety and efficacy in sustaining patients awaiting transplant and who are more prone to end-stage HF.

The DuraHeart™ LVAS carries a CE Mark and is currently available for sale in European countries.45 Furthermore, the company has completed enrollment for clinical trial in Japan. The Levacor™ VAD was initially developed by MedQuest Products, Inc., a spin-off of the University of Utah’s decadeslong contributions to the MCS field, and is now being commercialized by WorldHeart Corporation (Salt Lake City, UT). The device incorporates an ultracompact, bearingless rotary centrifugal pump that is implanted in the peritoneal space. The rotor which acts as an impeller is completely magnetically levitated, ensuring the lack of contact with the housing under any normally encountered operating condition and thereby virtually minimizing thrombosis, damage to blood components, lack of heat, wear and mechanical damage. The inflow cannula is titanium while the outflow graft consists of 12 mm woven collagen sealed polyester anastomosed to the ascending aorta.46 Its initial clinical evaluation was in Europe in 2006, with anticipated BTT/BTR outcomes in a shorter-term in-hospital setting: after 3 months of support, both patients’ natural hearts recovered. To promote recovery of the natural heart, blood flow provided by the Levacor VAD was slowly reduced while the load on the natural heart was gradually increased. The unique maglev technology allowed the Levacor VAD to provide flow rates as low as 1.3 l min1 for weeks at a time to each patient to promote recovery. Both of these devices were explanted after recovery was deemed to be stable. Now 4 years later, both patients are leading a normal device-free life at home.

Long-Term Implantable Ventricular Assist Devices (VADs) and Total Artificial Hearts (TAHs)

Subsequently, the system underwent further development to enhance its suitability for longer-term applications and outof-hospital use. Pump refinements included: a biocompatible coating on the blood-contacting surfaces to further enhance device performance, hermetic sealing of the motor/electronics cavity, a modular pump lead with implanted connector to permit replacement of the percutaneous lead without pump replacement, and an external connector that allows the distal extension cable to be quickly replaced, without surgery, either prophylactically or in case of damage. Compact, lightweight, and ergonomic controller and battery packs were developed. The controller incorporates a rechargeable reserve battery to support pump operation during exchange of the primary power source. This reduces the number of separate modules to be carried by the recipient, and mitigates the possibility of pump stoppage due to accidental power source disconnection. The controller also provides the ability for the physician to set three different pump speeds, and the patient to then select any of these speeds depending on their condition and activity level. A pivotal US trial evaluating this device for a BTT in 160 patients was initiated in January 2010, with 8 patients implanted in 4 centers through June 2010. the Levacor™ VAD is expected to be evaluated as an alternative to heart transplant and in future probably as a BTR. Potentially, due to its use of the simplest magnetic levitation allowed by physical laws combined with other innovations, the Levacor™

399

VAD could last and provide MCS for many years longer than other blood pumps (Figure 14, Table 2).47

6.625.4.

Partial Circulatory Support VADs

While most devices have focused on providing full and complete support to the circulation, a hypothesis has emerged that, in order to support less-sick HF patients, a much smaller, lessinvasive, more user-friendly device that only has to provide partial circulatory support (from 0 to 2.5–4 l min1) would be needed. Several such devices are in early development (HeartWare MVAD, WorldHeart MiVAD, Orqis Medical Exceleras) and only one (Circulite Synergy) has been clinically evaluated to date. The Synergy® micro-pump (Circulite, Inc., Hackensack, NJ, USA) measures roughly the size of an ‘AA’ battery. The device incorporates a combination of axial, centrifugal, and orthogonal flow paths with a single-stage impeller powered by an integrated brushless micro-electric motor. With the following dimensions: diameter 14 mm, length 49 mm, and weight of only 25 g, Synergy® can pump up to 3 l min1. The pump design features both a combination of magnetically and hydrodynamically levitated and stabilized rotor, that is sealed and a self-washing flow path that is designed to minimize the risk of thrombus formation in or around the rotor. The

Figure 14 Levacor™ ventricular assist device.

Table 2

RCP product comparison

Device

Type

Weight

Size

Comments

Current status

HeartWare™

145 g 540 g

IncorW

CAF

200 g

Approved in Europe BTT trial in progress in the USA Approved in Europe BTT trial in progress in the USA Awaiting Pivotal Trial in the USA as BTT Approved in Europe

SynergyW

HDL, ML

25 g

50 mm diameter, 50 ml DV 72 mm diameter, 45 mm height 180 ml DV 38 mm anteroposterior dimension 30 mm diameter, 120 mm length 80 ml DV 14 mm diameter, 49 mm length

Pericardial placement 2000–3000 rpm Up to 101 min1 1200–2400 rpm 2–81 min1

Levacor™

TG, CCF, HDL, ML TG, CCF, ML, HDL (backup) TG, CCF, ML

Duraheart™

440 g

Flow rate 0–101 min1 6.51 min1 at 100 mmHg and 2500 rpm 5000–10 000 rpm 51 min1 against 100 mmHg 2–31 min1

Safety and performance evaluation in progress in Europe

Abbreviations: BTT, bridge-to-transplantation; CAF, continuous axial flow; CCF, continuous centrifugal flow; DV, displacement volume; HDL, hydrodynamic levitation; ML, magnetic levitation; TG, third generation

400

Cardiology and Cardiovascular Surgery

power console weighs
3.3 pounds and the dual battery pack powers the device for
16–18 h. The controller provides the patient with information on the battery status and also alerts the patient to any change that requires attention. With continued research and innovation, the company also intends to expand the Synergy platform with a fully implantable system with physiological feedback, in the near future. The device also comes with a built-in ‘fail-safe’ mechanism in case of accidental power disconnects, augmented by the patient’s native cardiac flow. CircuLite’s development of Synergy is backed by established proof-of-concept in ongoing clinical studies and 8 years of engineering at the Helmholtz Institute in Aachen, Germany, one of the world’s pioneering centers for blood pump technology development, in collaboration with Katholieke Universiteit in Leuven, Belgium and is specifically designed for long-term use in NYHA Class IIIb/early IV patients (INTERMACS 4–6) (Figure 15).

6.625.5.

Total Artificial Heart

It has been man’s immense quest to find a synthetic replacement for the human heart that could virtually eliminate the need for heart transplant. With the accrued advancements in science and technology over five decades, a TAH in clinical use is now a reality. A TAH is, in design and operation, similar to VADs, but replaces the heart and presents many more challenges than simply to complement the failing ventricle. The challenge lies in positioning both the ventricular pumps in the abdomen. While developing earlier models, the top portions of the natural heart’s atria were left in place when the heart’s components were removed, to facilitate suturing the TAH into position. These portions of the atria provided the natural electric stimuli so that the TAH’s speed could increase during exercise and slow during rest. Despite its earlier start, TAH evolution has not progressed as rapidly as LVADs. The only FDA approved TAHs today are the C7–70 pneumatically driven TAH made by SynCardia Systems Inc. (Tucson, AZ, USA) and the electro-hydraulically driven AbioCor TAH commercialized by Abiomed Corp (Danvers, MA). Some of the earliest pioneering work was done by Cardiowest™ (which was itself a successor to first Kolff Associates and then Symbion, both of Salt Lake City, UT). Nonprofit CardioWest was acquired by for-profit SynCardia Systems Inc.,

and its device, the C7–70 TAH was approved by the FDA in 2009 following a decade of clinical study, for use in BTT for patients with irreversible end-stage biventricular failure. The recent innovation is its conditional approval of the Freedom ™ driver for investigational device exemption (IDE) clinical study and it is the first-ever US portable driver designed to power the SynCardia temporary TAH inside and outside the hospital by the FDA in March 2010. The device driver weighs 13.5 lbs including two onboard batteries, designed to be charged via a standard electrical outlet and a power adaptor. The entire console could be carried in a shoulder bag or backpack. The driver is designed with a ‘dark cockpit,’ meaning the driver only sends an alarm when something requires the user’s attention. The Freedom ™ driver is intended for use as a BTT in clinically stable cardiac transplant-eligible candidates who are implanted with the TAH (Figure 16). The Syncardia TAH costs about $125 000 and about $18 000 a year to maintain.48 Like the thoratec implantable VAD, and SynCardia Temporary Heart System, the Jarvik-7 TAH (named after Dr. Robert Jarvik and developed by the University of Utah and Symbion under the leadership of Dr. Willem Kolff, and later named the Symbion TAH) was also pneumatically driven. This device in its refined form is the present-day Syncardia System; so it is useful to describe it here. It consists of two ventricular pumps joined together and requires a portable console (Big Blue) for power. The ventricle is ellipsoid shaped and is made of polyurethane that has a sac that pushes the blood from the inlet to the outlet valve as it is deflated and inflated by air on the nonblood side of the sac. Air is pulsed through the ventricular air chambers at rates of 40–120 bpm. The artificial heart is fastened to the heart’s natural atrium by cuffs ( Dacron™ felt). The drive-lines are made of reinforced polyurethane tubing. The outlet lines exiting the skin are covered with velour-covered Silastic™ to ensure stability, durability and also encourage tissue growth (minimal scarring). The power console is pretty large and heavy as that of a household refrigerator. In case of emergency or power failure, the system is also backed up by a rechargeable battery and includes on-board compressed air tanks (modified scuba type) for use during transport. Controls in the console regulate pump rate, pumping pressure, and other essential functions.49 Unlike the pneumatically powered devices described above, Abiomed devised an electrohydraulically driven, fully implantable device, the AbioCor® TAH, with transcutaneous energy delivery system (TET). This device is still in investigational use under a humanitarian device exemption (HDE) approved by the FDA. In a limited set of patients, who

Micro-pump

CircuLite W

Figure 15 The Synergy micropump (Circulite, Inc., Hackensack, NJ, USA).

Long-Term Implantable Ventricular Assist Devices (VADs) and Total Artificial Hearts (TAHs)

401

Big Blue driver FreedomTM driver system Caution—The freedomTM driver system is an investigational device, limited by United States law to investigational use.

Caution-For illustration purposes only-not an actual patient.

Figure 16 The only FDA-approved driver for powering the total artificial heart in the United States is the 418-lb hospital driver nicknamed ‘Big Blue’ shown alongside the Freedom™ driver system in a portable backpack for in-home use. Reprinted with permission from SynCardia Systems, Inc.

Carmat-artificial heart

CARMAT-top view

Figure 18 Total artificial heart developed by Carmat SAS. (a)

(b)

Jarvik-7

AbioCor implantable replacement heart

Figure 17 (a): Total artificial heart – Jarvik-7. (b): The AbioCor total artificial heart.

have no other treatment options, the device is reported to have been found safe and beneficial with end-stage HF. Its uniqueness lies in the design of a mechanism that enables both systoles to occur sequentially. The AbioCor® system comprises a TAH, implanted TET, controller, battery, and cables. An energy converter in the replacement heart helps both the pumps keep blood flowing normally. The Energy Converter contains silicone hydraulic fluid in a sealed compartment that is separated from the right and left chambers by flexible membranes. A pump in the energy converter pushes the fluid against the membranes, causing the pumps to empty and fill (Figure 17).50,51 However, both the available TAHs have drawbacks; the former is bulky and obtrusive, while the latter could lead to stroke. A recent TAH under early development by Carmat SAS, the company founded by professor Carpentier and EADS,

Europe’s aerospace and defense giant, promises to overcome these hurdles by utilizing ‘pseudo-skin’ of biosynthetic, microporous materials, and the power source, by implanting a titanium receiver in the skull that would channel energy sent through the skin (noninvasively) from a battery to the heart. The second would work by generating electricity through the skin between two transformers, one inside and one outside the body. The battery is likely to last for between 5 and 16 h, after which it would have to be recharged to prevent the artificial heart stopping. Equipped with ‘smart’ motors and unlike previous artificial hearts, this one detects the body’s activity level (and therefore how much oxygen it requires) and changes its pace accordingly. This new design is likely to be available for clinical use by 2013 (Figure 18).52 While traditional TAH designs in clinical use and under development have focused on positive displacement pumps that inherently provide pulsatility, early work is being done by other researchers to install two rotary pumps back-to-back as ventricular replacements in a TAH configuration. These results are too early but it is a possibility that such a configuration might find greater use than the traditional ‘pulsatile’ devices.

402

Cardiology and Cardiovascular Surgery

6.625.6.

Conclusions

The LVAD has been a remarkable technology that has bridged the void between conventional medical therapy and cardiac transplantation. With increasing number of people diagnosed with heart diseases, and ratio of aging population increasing every year, constraints in donor heart availability, VAD options that aim to support patients with late-stage HF as an alternative to a heart transplant are on the rise. The LVADs have certainly had a positive impact in its role of reducing hospitalization as well as improving the functional status and quality of life of patients. With ongoing research in improving design and performance, the newer LVADs promises to be patient-friendly, durable and minimally invasive to implant or explant, and potentially offer a safety and efficacy profile much superior to earlier-generation devices. The future of LVADs, when complemented with gene therapy could culminate in a permanent ‘dream’ cure, wherein the device takes over the heart’s functions providing the cardiac stem cells with a conducive environment to regenerate [REF]. With emerging technological advances, there certainly is likelihood for a slew of devices that will provide safe and effective therapy to less-severe HF patients. These devices will need to be significantly refined, smaller, and easier-to-use than the marketed ones. In the long-term, it is clear to the authors that the answer to the biological question of HF will need to be answered by biological solutions that involve disciplines such as tissue engineering and genetic engineering.

Acknowledgments The authors would like to acknowledge the contributions of Vivek Srinivasan and Priya Nayar for their diligent work toward the extensive research, sourcing and compilation, and editing of the information needed for this chapter.

References 1. AHA, Our guide to current statistics and the supplement to our Heart & Stroke Facts. In Heart Disease & Stroke Statistics; 2010. 2. Roger, V. L.; Weston, S. A.; Redfield, M. M.; et al. JAMA 2004, 292, 344–350. 3. Douglas, P.; Morgan, C.; Lee, H.; Foster, K. R. IEEE Technol. Soc. Mag. 2004, 23(2), 23–27. 4. Franco, K. L. J. Card. Surg. 2001, 16, 178–192. 5. “Waiting list activity” and “cadaveric transplant”. Transplant Statistics. Scientific Registry of Transplant Recipients, 11/01/2001. 6. Moskowitz, A. J.; Rose, E. A.; Gelijns, A. C. Ann. Thorac. Surg. 2001, 71(Suppl. 3), S195–S198. 7. Rose, E. A.; Moskowitz, A. J.; Packer, M.; et al. Ann. Thorac. Surg. 1999, 67, 723–730. 8. Wohlschlaeger, J.; Schmitz, K. J.; Schmid, C.; et al. Cardiovasc. Res. 2005, 68, 376–386. 9. Frazier, O. H.; Rose, E. A.; Oz, M. C.; et al. J. Thorac. Cardiovasc. Surg. 2001, 122, 1186–1195. 10. Percentage of Patients Who Experience Right Ventricular DysfunctionAfter Implantation of a Left Ventricular Assist Device, http://www.syncardia.com/ Medical-Professionals/lvads-and-rv-dysfunction.html.

11. Dang, N. C.; Topkara, V. K.; Mercando, M.; et al. J. Heart Lung Transplant. 2006, 25(1), 1–6. 12. Bhama, J. K.; Kormos, R. L.; Toyoda, Y.; Teuteberg, J. J.; McCurry, K. R.; Siegenthaler, M. P. J. Heart Lung Transplant. 2009, 28, 971–976. 13. Dennis, C.; Hall, D. P.; Moreno, J. R.; et al. Acta Chir. Scand. 1962, 123, 267–269. 14. DeBakey, M. E. Ann. Thorac. Surg. 2005, 79, S2228–S2231. 15. Goldstein, D. J. In Cardiac Assist Devices; Goldstein, D. J., Oz, M. C., Eds.; Futura: New York, 2000. 16. Frazier, O. H.; Delgado, R. M., III; Kar, B.; et al. Tex. Heart Inst. J. 2004, 31, 157–159. 17. Griffith, B. P.; Kormos, R. L.; Borovetz, H. S.; et al. Ann. Thorac. Surg. 2001, 71, 116–120. 18. Lazar, R. M.; Shapiro, P. A.; Jaski, B. E.; et al. Circulation 2004, 109(20), 2423–2427. 19. Fries, D.; Innerhofer, P.; Streif, W.; et al. Ann. Thorac. Surg. 2003, 76(5), 1593–1597. 20. Aaronson, K.; Eppinger, M.; Write, S.; Pagani, F. D. J. Heart Lung Transplant. 2001, 20(2), 241. 21. Ramasamy, N.; Vargo, R. L.; Kormos, R. L.; Portner, P. M. In Cardiac Assist Devices; Goldstein, D. J., Oz, M. C., Eds.; Futura: New York, 2000. 22. Song, X.; Throckmorton, A. L.; Untaroiu, A.; et al. ASAIO J. 2003, 49, 355–364. 23. Burke, D. J.; Burke, E.; Parsaie, F.; et al. Artif. Organs 2001, 25, 380–385. 24. Wampler, R. K.; Baker, B. A.; Wright, W. M. Cardiology 1994, 84, 194–201. 25. Goldstein, D. J. Circulation 2003, 108, 272–277. 26. Westaby, S.; Banning, A. P.; Jarvik, R.; et al. Lancet 2000, 356, 900–903. 27. Wieselthaler, G. M.; Schima, H.; Hiesmayr, M.; et al. Circulation 2000, 101, 356–359. 28. Miller, L. W.; Pagani, F. D.; Russell, S. D.; et al. N. Engl. J. Med. 2007, 357, 885–896. 29. Feller, E. D.; Sorensen, E. N.; Haddad, M.; et al. Ann. Thorac. Surg. 2007, 83, 1082–1088. 30. Ulrich, G.; Claudia, H.; Friedhelm, B.; et al. Eur. J. Cardiothorac. Surg. 2008, 33, 679–684. 31. Schmid, C.; Tjan, T. D.; Etz, C.; et al. J. Heart Lung Transplant. 2005, 24, 1188–1194. 32. Schmid, C.; et al. J. Heart Lung Transplant. 2008, 27, 253–260. 33. Hetzer, R.; et al. Eur. J. Cardiothorac. Surg. 2004, 25, 964–970. 34. Meuris, B.; Arnout, J.; Vlasselaers, D.; et al. Artif. Organs 2007, 31(5), 402–405. 35. Pagani, F. D. Semin. Thorac. Cardiovasc. Surg. 2008, 20, 255–263. 36. Osorio, J. Nat. Rev. Cardiol. 2010, 7(7), 360. 37. Esmore, D. S.; Kaye, D.; Salamonsen, R.; et al. J. Heart Lung Transplant. 2008, 27, 479–485. 38. Esmore, D.; Kaye, D.; Spratt, P.; et al. J. Heart Lung Transplant. 2008, 27, 579–588. 39. Esmore, D.; et al. Eur. J. Cardiothorac. Surg. 2007, 32, 735–744. 40. Boyle, A. J.; et al. In Presented at the 58th annual meeting of the American College of Cardiology, March 30, 2009. 41. Slaughter, M. S.; et al. Tex. Heart Inst. J. 2009, 36, 12–16. 42. Tuzun, E.; et al. Tex. Heart Inst. J. 2007, 34, 406–411. 43. Nishinaka, T.; et al. Circulation 2006, 70, 1421–1425. 44. Morshuis, M.; El-Banayosy, A.; Arusoglu, L.; et al. Eur. J. Cardiothorac. Surg. 2009, 35, 1020–1028. 45. Nojiri, C. In International Society for Heart and Lung Transplantation 2008 Annual Meeting, Boston, MA, April 12, 2008. 46. Pitsis, A. A.; et al. Hell. J. Cardiol. 2006, 47, 368–376. 47. New Utah-Made Vad Implanted In Idaho Man. April 8, 2010. Available from: http://www.unews.utah.edu/p/?r¼040810-3#Media_Contacts. 48. Ashton, J. Man goes home with “total artificial heart”. CBS Evening News May 21. Available from:http://www.cbsnews.com/stories/2010/05/21/eveningnews/ main6507572.shtml. 49. Arabia, F. A.; Copeland, J. G.; Smith, R. G.; et al. Artif. Organs 2001, 23(2), 204–207. 50. 2010. Available from: http://www.heartreplacement.com/abiocore.html. 51. 2009. Available from: http://www.abiomed.com/products/heart_replacement.cfm. 52. Sage, A. Scientists develop artificial heart that beats like the real thing. cited 2010; Available from:http://www.timesonline.co.uk/tol/life_and_style/health/ article5026788.ece. 53. Nemeh, H. W.; Smedira, N. G. Cleve. Clin. J. Med. 2003, 70(3), 223–233. 54. DiGiorgi, P. L.; Reel, M. S.; Thornton, B.; et al. J. Heart Lung Transplant. 2005, 24, 200–204.