Past and Present of Total Artificial Heart Therapy: A Success Story

Background – Heart Failure, the Predicament

Heart failure (HF) continues to be a plight to modern-day humans, affecting almost 23 million people worldwide [1]. In 2004, HF claimed more lives in the U.S. than lung cancer, breast cancer, prostate cancer, and HIV/AIDS combined [2]. It is estimated that 1 in every 5 people will develop HF in their lifetime, a risk notoriously known to increases with age [3]. Furthermore, 5% of patients with HF are end-stage patients, or the so-called “stage D heart failure”, characterized by refractoriness to medical therapy [4]. Considering the progressive nature of the disease, more and more patients in the less severe stages will eventually end up in the D category. These are sobering facts considering the limited treatment options for such patients, for whom heart transplantation has long been considered the optimal salvation [5,6]. However, the paucity of available donors, much less the dysfunction of almost 60% of donated hearts, is a major hurdle impeding attempts to save the lives of these patients by means of transplantation [7,8]. Furthermore, waiting for a heart is a survival battle that almost 45% of patients lose [9]. Mechanically supporting the failing heart with ventricular pumps has emerged as an endeavor to preserve patients’ lives as long as possible until a donor heart is available, a term referred to as “bridge to transplantation” (BTT) [10].

Device for Heart or Devise a Heart

Ventricular assist devices (VAD) were sought and utilized as early as the mid-1960s, until they were FDA-approved in the mid-1990s [9]. Indeed, VAD did prolong life, and early studies have shown a doubling in the 1-year survival rate (from 25% to 51%) in end-stage HF patients [11]. With advances in VAD technology, by 2011, 85% of patients survived the first year with VAD as BTT [12,13]. Many models of VADs are available nowadays in the market, with either continuous or pulsatile flow. Continuous flow VADs are the most commonly used, those include HeartMate II, HeartWare, among others [9–12]. On the other hand pulsatile VADs with pneumatic pumps are more commonly employed for the pediatric populations e.g. Berlin Heart. However, a subset of patients require biventricular support, placing them in a critical state with narrow options, considering their aptness for biventricular pump implantations, which do not guarantee promising survival rates (56% for 6 months) [14]. Adding to the dilemma, late right heart failure was also shown to develop in a subset of patients on continuous-flow VAD, a phenomenon that severely compromise their survival even after transplantation [15,16]. Furthermore, those patients are added to another category of patients, for whom VAD is not even an option, including patients with severe ventricular anatomical damage, intractable arrhythmias, massive ventricular thrombus, or restrictive cardiomyopathy [17]. The only hope for such patients, until a donor heart is found, is the complete substitution of their ventricles with a fully functioning mechanical pump – a “totally artificial heart” (TAH).

Historical Beats

“Ancient Egyptian Mummy has Artificial Heart”, such an astonishing title was from an article published in March 17th, 1992 in Weekly World News, a Canadian newspaper. The article tells a surprising story from 1986 when a team of archeologists reported the discovery of a totally artificial heart in a 5000-year-old mummy of a little boy, which was carefully stitched into the chest and resembles to a great extent the ones available nowadays. As shocking as this might sound, it is, however, not the only such discovery. A second mummy was later discovered by a team of German, Belgian, and Egyptian archeologists excavating in the Valley of Kings. This time, it was of a 35–40-year-old woman, which had a nicely implanted artificial heart. According to pathologists who studied the mummy, it was implanted shortly before the woman’s death, and it had supported her circulation for several weeks, before a defective valve started to leak!

If we now go “back to the future”, the idea of creating a TAH has never stopped luring scientists and physicians. In 1975, Akutsu and Kolff implanted their first TAH in an animal model 10 years before the first human heart transplantation by Barnard in 1967 [18,19]. The first human TAH implantation usually refers to that of Barney Clark in 1982, who received the Jarvik 7, a TAH developed at Kolff’s lab and named after its designer, Dr. Robert Jarvik [20]. However, history has recorded 2 TAH implantation attempts that preceded the Jarvik 7 experiment, starting almost 13 years earlier [21,22]. The Argentinian Domingo Liotta, along with Denton Cooley, reported successful implantation of a Dacron, pneumatically-controlled, double-ventricle cardiac prosthesis that was prototyped earlier in 1961. The 47-year old recipient survived for 64 hours under TAH’s support until he received a donor heart [21–23]. However, the patient died shortly after transplantation from Pseudomonas pneumonia [22]. Twelve years later, in 1981, Dr. Cooley implanted his second TAH, this time using a pneumatic Akutsu TAH made of polyurethane, which supported the 36-year-old patient for 55 hours, of which the last 16 hours were under support of extracorporeal membrane oxygenation (ECMO), which was utilized along with TAH due to deteriorated blood gas values [24]. Nevertheless, bridging to transplantation was reached, and the patient survived for 7 days post-allograft before he died of multiple organ failure and infection [24].

Jarvik 7 – the Invention

The first human TAH to receive international conspicuity was the Jarvik 7, owing to its relatively longer post-implantation survival record and the initially claimed intention for destination therapy (DT), unlike the aforementioned attempts, aimed primarily at BTT [20]. The Jarvik 7 is a pneumatically-powered TAH, composed of 2 separate spherical polyurethane chambers, each representing a ventricle, with a 70-ml filling volume, and containing single-leaflet inflow (27 mm) and outflow (25 mm) valves, which are attached to the heart’s natural atria by Dacron cuffs. Inside each chamber is a 4-layered polyurethane diaphragmatic membrane attached to the interior of the chamber: 1 seamless blood-contacting diaphragm, 2 intermediate diaphragms, and an air diaphragm, which creates a cavity. Air is pulsed in this cavity, forcing the membranes into a disk-shaped volume displacement mechanism, which pushes the blood to the outlet valve, creating systole. Air is then sucked back leading to deflation of the air sac, which allows for passive filling of the blood-contacting compartment of the chamber, creating diastole. The air-driven system powers the pump through reinforced polyurethane drivelines that enter the TAH through the patient’s left side and are externally connected to a console, roughly the size of a household refrigerator, to which the patient is tethered. The console is connected to sources of compressed air, vacuum, and electricity, and is responsible for controlling the airflow, maintaining the heart rate (40–120 beats per minute), and monitoring the device function via pneumotachometers and a portable computer [19,25,26]. The Jarvik 7 can generate a cardiac output of 6–8 lm−1 [25].

Jarvik 7 – the Experiment

The first Jarvik 7 receiver, Barney Clark, suffered from end-stage HF secondary to a non-ischemic idiopathic cardiomyopathy and was deemed as unsuitable candidate for heart transplantation [25]. The 61-year old dentist, however, agreed to undergo the procedure out of his own wish to make a contribution to medical science, a generous intention that merits praise [26]. Implanted by Dr. William DeVries at the University of Utah, the Jarvik 7 functioned quiet well, achieving a decent cardiac output and relieving the congestion. Later on, however, Dr. Clark developed many complications, including pulmonary insufficiency, acute renal failure, a generalized seizure (of uncertain cause), and hemorrhagic complications of anticoagulation. On the 92nd postoperative day, the patient had diarrhea and vomiting, leading to aspiration pneumonia and sepsis. Progressive renal failure later ensued, and the patient died on the 112th day [20]. Interestingly, however, autopsy revealed that the device was intact and thrombus-free [20]. The outcome from this initial case was deemed promising and encouraged further implantations. Three more patients in the USA and 1 patient in Sweden were implanted with the Jarvik 7 as a permanent replacement to their hearts in 1984 and 1985. The second recipient survived 620 days, achieving the first survival record, although debilitated by a stroke [26]. Furthermore, the Jarvik 7 continued to show exceptional success in bridging patients to cardiac transplantation, after which some lived for up to 14 years of normal life [26].

CardioWest & SynCardia – the Descendants

The Jarvik 7 launched a new era of TAH implantation, and by 1991, a sum of 226 patients had received pneumatic TAHs at 39 centers worldwide, of which 5 patients were implanted for permanent support, and 4 patients even received a second TAH [27]. By that time, transfer of rights of the producing company had taken place, and the device was renamed and marketed as CardioWest [26]. The CardioWest heart is identical to the small size Jarvik 7 heart developed for use in women and smaller men in the mid-1980s, except for the smaller air driveline tubes, and an up-to-date laptop computer replacing the portable Compaq computer originally used (26). To date, more than 1300 patients have used the Jarvik 7/CardioWest [28]. According to a 10-year clinical study by Copeland et al., CardioWest produced a 79% success rate for BTT with excellent overall survival, including post-transplantation (70% at 1 year, 50% at 5 years, and 45% at 8 years) [26,29]. In 2004, the FDA granted their approval, making CardioWest the first, and the only, fully approved TAH in the USA [26]. By that time, the company had changed its ownership again, and the device was later renamed and marketed under “SynCardia”. The prime upgrades associated with the introduction of SynCardia focus mainly on enhancing patient mobility. A portable pneumatic driver was introduced early on, allowing for patient discharge from the hospital after stabilization on the implanted TAH. The portable driver is the size of a briefcase, which can be dragged [26,30]. SynCardia broke the record again in a case reported in 2011, where it supported the patient for 2 years and 4 months of normal life as BTT, during which the patient was highly mobile by virtue of a modified version of the Berlin Heart Excor portable driver [32]. Furthermore, SynCardia recently introduced a wearable and even more flexible portable driver called Freedom®, which was FDA approved in 2014 [30].

TAH in the Pediatric Population

Cardiomyopathies in children are the leading reason for end-stage heart failure. In some cases children can respond to the conservative therapy; however, due to the aggressive course of the disease, the clinical state of many children can rapidly deteriorate, making circulatory support an inevitable option until a donor heart is found. Children on transplantation waiting lists usually have the highest mortality risks. In order to improve the clinical situation, TAH can be a valuable therapeutic option, especially in such cases where mechanical circulatory support devices are contraindicated (e.g., due to multifocal thrombi or biventricular failure). Furthermore, TAH can be superior to VAD, which show a higher complication profile, such as left ventricular clots, valvular problems, right heart failure, and arrhythmias [31]. However, the major limitation to be considered with regard to implantation of these devices in the pediatric population is the minimum body surface area (≥1.7 m2), which is imperative for proper fitting and functioning of the implanted TAH. SynCardia has recently introduced a new 50cc-TAH, which received a Humanitarian Device Designation for pediatric bridge to transplant. The pediatric TAH version from SynCardia was successfully reported to be used in a pediatric patient with BSA less than 1.7 m2. By virtue of CT technology and 3D modeling, patient-specific device fit analysis was made possible, leading to a successful implantation [31].

Surgical Implantation

The major surgical implantation steps can be summarized in the following [17,25]:

For further information on surgical implantation techniques for the pneumatic TAHs, as well as associated challenging scenarios, the reader is referred to the report by Torregrossa et al. [17].

Pneumatic TAHs – Pros and Cons

The revolutionary success achieved by SynCardia, CardioWest, and before them, the Jarvik 7, is mainly attributed to the following [25,26]:

However, pneumatic TAHs bear some major drawbacks inherent to their design. First, the incessant noise generated by the pneumatic driver, which can be disturbing to the patient, as well as his companions. The second major disadvantage of the pneumatic TAHs is that they are not fully implanted within the body, and the patient is tethered to the powering console. Dragged, carried, or worn, the console accompanies the patient in every single activity, minimizing his mobility and comfort. Furthermore, the exit sites of the air tubes are a potential source of infection. Two recent studies reported driveline infections in up to 14% of patients [25]. Mediastinitis was reported in up to 5% of patients [25]. The risk of device infection increases with long-term support. A recent study by Torregrosa et al. in 2014 on 47 patients on SynCardia support for longer than 1 year has reported 27% driveline infections [33]. Lastly, the size and weight of the device is not expected to fit in smaller patients, mostly women and adolescents, and might create misfitting problems. Fitting criteria for the CardioWest-Implantation was set as the following [25]:

The clinical experience with pneumatic TAHs has accumulated over the years and multiple studies were launched in different parts of the world, which were able to report the major complications upon TAH implantation (listed below) [25,33–35]:

Abiocor

The unprecedented success accomplished by the Jarvik 7 progeny of pneumatic TAHs was probably satisfactory for BTT, much less if no other option is available for the critically ill patient, such as VAD. Although pneumatic TAHs have been, in a few cases, implanted with the intention for DT, one can clearly see they were not designed for this purpose. The need for a durable and totally implantable TAH is urgent, especially to overcome the paucity of donated hearts and the drawbacks of mechanical circulator support devices. Attempts to create a totally implantable electromechanical heart have been sought in late 1980s and early 1990s, utilizing an extra-corporeally-controlled electrohydraulic system [35,36]. The AbioCor IRH (Abiomed, Danvers, MA, USA) is the culmination of these efforts. This TAH has implantable as well as external components [25,37].

Implantable components are:

The external components include:

Clinical Experience

In 2001, the FDA approved a human feasibility study of the Abiocor IRH [40]. Since Abiocor is intended as a permanent surrogate for the failing heart, candidacy criteria for recipients has to be met before they are considered for implantation. The selection criteria are governed by a prognostic model called AbioScore, which is a mortality prediction model to define patients with 30-day mortality risks greater than 70%. Various laboratory and clinical parameters are included in the AbioScore criteria [40]. Patients with more than 30% 1-month survival are excluded. Importantly, fitting of the device has to be tested prior to implantation decision. The Abiofit™ software, introduced by Abiomed, the developing company, utilizes computed tomography (CT) as well as magnetic resonance imaging (MRI) pictures to virtually implant the device in the chest of the potential candidate and ensure its proper fit [37]. Fourteen patients were implanted with Abiocor between 2001 and 2004 [25]. Two patients died at surgery due to bleeding or aprotinin reaction [40]. The 12 surviving patients lived up to 512 days on Abiocor support, of which 4 patients were ambulatory after the operation and 2 were discharged from the hospital [25,40]. However, multiple complications were reported, which later led to death of the surviving 12 patients. Nine recipients experienced cerebrovascular accidents (CVA), of which 3 had transient ischemic attacks [41]. CVA led to 6 deaths among the recipients. Furthermore, non-device-related infections were reported in 11 patients, and sepsis was reported in 2 patients, of which 1 followed a massive abdominal bleeding episode [41]. Additionally, 2 deaths were reported due to device malfunction; the first due to the membrane wearing out at 17 months, while the second was due to motor-bearing failure at 4.8 months [25,41]. Moreover, there were 3 deaths due to multiple organ failure [40]. Importantly, device thrombosis was a major observation upon autopsy, with 4 patients bearing thrombus on atrial struts [25,40]. Nevertheless, humanitarian device exemption (HDE) approval was granted for Abiocor by the FDA in 2006 [41].

Abiocor – Pros and Cons

Abiocor’s major advantages over available pneumatic TAHs are:

However, Abiocor shows a number of drawbacks:

Novel TAHs – Pending

Since thrombosis and hemocompatibility were major challenges in the previously developed TAHs, a new generation of bio-prosthetic TAHs has emerged. Carmat (Carmat, Velizy, France) is a recently developed electrohydraulic TAH, which incorporates bio-prosthetic valves as well as bio-membranes forming the ventricular cavities [42,43]. The ventricles are enclosed in a flexible external bag with silicon fluid that is pushed to the bio-membranes by 2 miniaturized pumps, leading to blood ejection. The novel biocompatible materials have shown promising results in vitro, portending a reduction of anti-coagulation therapy and thrombosis-associated complications [42]. In December 2013, Carmat was first implanted, supporting the recipient for 75 days [28].

Furthermore, recent studies, aiming to maximize TAH’s biocompatibility are investigating the use of decellularized pericardium to line TAH surfaces [44].

In an attempt to simplify the device mechanics and reduce its size, a novel TAH was recently introduced [45]. RheinHeart is an electromechanical TAH developed in Aachen, and is undergoing pre-clinical validations. Two flexible blood chambers represent each ventricle and in between is a motorized linear drive which thrusts 2 pusher plates on the flexible membranes in an alternating pattern squeezing out the blood from 1 chamber while relaxing the other [45]. The device was tested both in vitro and in vivo in a calf animal model.

Conclusions

TAH is an emerging therapeutic tool for end-stage HF. Stuck in the dilemma of scarce hearts for transplantation, the progressive nature of the disease, and the refractoriness of some cases to other forms of mechanical support, TAH therapy is the last resort to prolong patient survival until a donor heart is found. However, some patients are not candidates for transplantation; therefore, TAH can be implanted as a DT. Modern attempts to create a TAH have been sought for almost half a century. TAH technology has since grown tremendously, improving implantation outcome. Promising results have been achieved with pneumatic TAHs as BTT, but they are not complication-free. On the other hand, totally implantable TAHs, intentionally designed for DT, have a long way to go if they are to permanently replace the natural heart. Issues such as size, powering energy, durability, biocompatibility, and anti-coagulation management remain challenging. Bioengineering and molecular research offer promising alternatives to optimize TAH’s hemodynamics and achieve a high degree of functional and physiological mimicry of the natural heart. Research on TAH remains an open avenue for creative minds, portending a bright future.