II.9	The Translational Pathway for Mechanical Circulatory Support

A. The Need for Translational Platforms

Despite recent improvements in heart failure therapy, advanced heart failure remains the most common hospital discharge diagnosis for patients 65 years of age and over (1,2).

In past decades, heart transplantation has been the gold standard therapy for advanced heart failure patients (3). However, due to the shortage of donor hearts, the use of mechanical circulatory support (MCS) is rapidly growing (4) and emerging as a versatile therapy in heart failure treatment. MCS involves the surgical implantation of a pump to supplement or replace native blood flow and provide sufficient blood pressure to perfuse end organs. With recent advancements in technology, the treatment for end stage heart failure has entered a new era. The trend is toward smaller and more durable mechanical assist devices that can be applied to various clinical situations, enabling longer-term support. The goal of this chapter is to review achievements in device progress, current device technology, and to consider future directions that may provide better patient care. Finally, the specific components of a translational platform for MCS will be detailed, from assessment criteria, markers and techniques, to preclinical testing.

B. Type of Device

Pulsatile flow devices

Pulsatile pumps are subdivided into pneumatic and electromechanical types, and can be operated in several different modes including a synchronous mode triggered by EKG (similar to an intra-aortic balloon pump [IABP]) and an asynchronous mode.  Pulsatile flow devices operate via blood volume displacement using valves, a reservoir chamber, and a pusher-like mechanism, and can facilitate flow rates of up to 10 L/m. Despite the ascendancy of continuous flow pumps, pulsatile platforms still have an important role in the modern ere. In acute cardiogenic shock, pulsatile flow maximizes both perfusion pressure and unloading of the pulmonary circuit and right heart (9). In general, pulsatile flow devices have a bulky controller and constant mechanical noise. Pulsatile technology also has an exclusive role in the bridge to transplant (BTT) setting when biventricular support or replacement is required either in the form of biventricular assist devices or total artificial heart (TAH).

Continuous flow devices

Continuous flow (CF) devices are typically smaller and operate via a valve- and chamber-less system using an impeller or rotor pump that facilitates an axial-style blood flow. CF pumps often have a ‘noncontact’ bearing design, reducing contact wear on moving parts; this allows for a more silenced operation and greater mechanical durability than pulsatile devices. The transition from pulsatile technology toward continuous flow has been a remarkable shift. However, this breakthrough technology introduced new adverse events such as acquired von Willebrand deficiency, platelet dysfunction, and gastrointestinal bleeding.

Total Artificial Heart Implants in Humans

The earliest use of a total artificial heart occurred in 1969 when Dr. Denton Cooley implanted a TAH prototype in a 47-year old patient with heart failure. The device allowed the patient to survive for three days until a donor heart was transplanted, however the patient died from infection two days following heart transplantation. Nearly 20 years later in 1982, a Jarvik 7 TAH was implanted in a 61-year old patient who survived for 112 days on the device before ultimately dying from device-related multi-organ failure. Then in 2004, following engineering improvements and a successful clinical trial that demonstrated increased survival until transplant compared to medical management, the CardioWest Total Artificial Heart was the first TAH to gain FDA approval to be used in patients as a bridge to transplantation.

For patients with severe refractory cardiac failure for whom a left or biventricular assist device is contraindicated, a total artificial heart (TAH) may be considered. The current model of a TAH is a pulsatile pump device that replaces both ventricles and all four valves of the native heart. Stroke volumes and flow rates of up to 70cc and 9 L/m can be achieved, respectively.

Present TAHs: Currently there are two FDA-approved TAH devices: the pneumatic-driven SynCardia temporary Total Artificial Heart (SynCardia Systems, Tucson, AZ) and the hydraulic AbioCor Total Artificial Heart (ABIOMED Co. Inc., Danvers, MA). The table below shows all Total Artificial Heart Implants in humans since 1969 (Table 1).

C. The History of Mechanical Circulatory Support

At the conclusion of World War II while Europe underwent a period of rebuilding America saw a period of prosperity and medical innovation reminiscent of the industrial revolution. It was in this atmosphere that the field of cardiac surgery evolved from ambitious theory to common practice. Though cardiac surgeries can be traced back to the late 1800s the number of clinical procedures performed before 1945 was extremely low. The successful use of cardiopulmonary bypass during open heart surgery, by Dr. John Gibbon in 1953, enabled many more complex and invasive procedures to be performed. As the use of bypass increased a problem arose. Some patients’ hearts were too weak following surgery to successfully wean from bypass unassisted. Thus the first clinical uses of MCS systems were to aid in postoperative myocardial repair as a bridge to recovery, the first of which performed by Dr. Michael DeBakey in 1966.

As the field of heart transplantation grew the deficiency of donor hearts lead to increased investigations of ventricular assist devices as a bridge to transplant. The combination of relentless innovators and funding from the newly formed NIH and NHLBI lead to several achievements in the field of MCS at the end of the twentieth century. In 1978, a 21-year-old patient was supported for 5 days before receiving a transplant becoming the first successful use of an LVAD as bridge to transplant. In the following decades various companies developed three generations of devices. Each generation solving a problem of its predecessor; that evolution is detailed in the following section. In the same time period TAHs were also approved for BTT. In 1982 following FDA approval, the Jarvik 7 TAH was implanted into a patient that lived 112 days.

The final evolution of MCS was destination therapy. In 2000, results of the REMATCH trial lead to the FDA premarket approval of the Thoratec HeartMate XVE LVAD as destination therapy.

The historical perspective on mechanical circulatory support is summarized in Fig. 1 (10).

First generation

First generation VADs were pulsatile volume displacing devices. The most common first generation devices were: the Thoratec paracorporeal ventricular assist devices (Thoratec Inc.: Pleasanton, Calif, US), the Berlin Heart Excor (Berlin Heart AG, Berlin, Germany), and implantable pumps such as HeartMate XVE (Thoratec Inc.) (Fig. 2) and Novacor (World Heart Corp., Oakland, Calif). These early devices had several shortcomings. Primarily the mechanical contact required to provide the pulsatile flow lead to wear of the device and limited VAD potential for long-term use. Furthermore, these paracorporeal devices require large external machinery and also a large internal space for implant limiting patient mobility and patient selection. Additionally, early devices were plagued with high device failure rates.

Second generation

Second generation devices ameliorated many of challenges of the early VADs. First, the second generation VADs are characterized by continuous flow driven by a rotary motor. These systems no longer required a reservoir chamber or valves, reducing size and increasing reliability. Also, smaller device size allowed for the expansion of a treatable population. One possible complication of the second generation VADs is ventricular collapse due to negative ventricular pressure caused by continuous flow.

Third generation

The third generation of VADs addressed an issue the second was not able to solve: mechanical ware. These devices are also continuous flow but use magnetic and/or hydrodynamic levitation of the impeller; removing all mechanical contact and greatly increasing device durability.

D. New Devices

Percutaneous devices: TandemHeart Pump, Impella System

TandemHeart

The TandemHeart percutaneous ventricular assist device (pVAD) (CardiacAssist, Inc., Pittsburgh, PA) is a useful system in the setting of cardiogenic shock to perfuse organs and achieve hemodynamic stability (88). It is a continuous flow, extracorporeal device consisting of an atrial drainage cannula, a low volume (10cc) hydrodynamic centrifugal pump, and a femoral arterial cannula that can be used percutaneously in patients with severe cardiac dysfunction. This pump can flow up to 8.0 L/min depending on cannulae size and individual patient characteristics. When used with the TandemHeart Transseptal Cannula which is placed in the left atrium via the atrial septum and femoral arterial cannula, the device can provide percutaneous left ventricular support for up to 30 days (11). Although early comparisons between IABP and the TandemHeart pVAD did not demonstrate significant differences in early survival (12), severe refractory cardiogenic shock despite IABP insertion can be reversed by the pVAD (13,87).

Impella System

The Impella family system (ABIOMED, Danvers, MA) consists of a miniaturized impeller pump located within a catheter and can provide left or right ventricular support. The pump electrical connections, motor, sensor, and additional lumen for fluid transfer is located within the implanted catheter. Catheter placement can be inserted surgically at the ascending aorta, or using surgical cut-down or percutaneous access at the axillary or femoral artery through a Dacron graft positioned across the aortic valve to the left ventricle. The Impella 5.0 can flow up to 5 L/m and is indicated for use in patients with cardiogenic shock not responsive to standard therapy. Smaller than the Impella 5.0, the Impella 2.5 has a flow rate of 2.5 L/m and is used mainly for short-term partial left-ventricular support. The Impella 2.5 and IABP demonstrated similar patient outcomes in supporting with symptomatic patients with severe, complex multivessel, or left main disease as well as major adverse events at discharge or 30 day follow up (16).

The Impella RP device can be used for circulatory support following right ventricular (RV) failure in a minimally invasive fashion. The device is deployed from the femoral vein to the pulmonary artery and can be used for up to 14 days. This is a valuable device to assist RV function in a short-term capacity as most patients recover from acute RV failure sufficiently to warrant device explant (17,18).

Small devices: CircuLite, MVAD, Centrimag CircuLite

Full mechanical support with an LVAD is often limited to patients with severe cardiac dysfunction. Smaller devices with less invasive surgical techniques can potentially reduce mortality and recurrent decompensations while on the transplant list (19). The Circulite SYNERGY partial support pump (HeartWare, Framingham, MA) is small (approximately the size of an AA battery) and consists of a micro-electric motor that facilitates axial, centrifugal and orthogonal flow paths through a single stage impeller. The pump design consists of a magnetic hydrodynamically-levitated rotor that operates at 20,000-28,000 rpm and can facilitate flow up to 3 L/m. The inflow cannula is inserted into the left atrium (LA) through a right mini thoracotomy while the outflow graft is anastomosed to the subclavian artery (20). This device is designed to be used for the less sick patient population with NYHA class IIIB or IV heart failure. A clinical trial led by Klotz et al demonstrated improved cardiac index, reductions in pulmonary capillary wedge pressure, and increases in arterial pressure in patients implanted with the Circulite SYNERGY (21). This partial support appears to interrupt the progressive hemodynamic deterioration typical of late-stage heart failure (21,22).

The HeartWare MVAD

The large size of current left ventricular assist devices limits the treatable patient population and contributes to invasive surgical trauma and postoperative complications (88). The trend toward engineering smaller devices that can treat smaller individuals and facilitate less invasive implantation is gaining popularity. The HeartWare (HeartWare, Framingham, MA) MVAD is a miniature, continuous-axial flow, full-support device with a displacement volume of 22ml and a maximum flow up to 10 L/m (Fig. 4). Previous animal studies have demonstrated device success and suggest that the small design of the MVAD may reduce hemolysis and thrombogenicity, eliminate the need of cardiopulmonary bypass, and reduce surgical trauma and postoperative complications due to minimal invasive thoracotomy approach (5,8). Schima et al demonstrated the minimally invasive implantation technique using the HeartWare MVAD, together with a novel inflow cannula, including a new flow-optimized tip, provided excellent results in a chronic sheep model including 100 days of support without any complications (6). McGee et al also reported excellent hemodynamic support with no device malfunctions throughout the chronic animal study (7).

Centrimag

E. Indication of Mechanical Circulatory Support and Clinical trials (DT BTT results)

Currently Bridge to Transplant (BTT) and Destination Therapy (DT) are the indication for MCS. However, with temporary MCS device usage, Bridge to Candidacy and Bridge to Recovery scenarios are considered depending on pre operative patient’s medical, social, and financial state (Table 3) (10).

Some clinical studies have been designed and reported the clinical outcome of MCS therapy (Table 4) (10). INTERMACS profile is a useful risk stratification to guide optimal therapy for heart failure treatment (Table 5) (10,23). Since the number of DT has been increasing over time resulting from the shortage of donor organs, specific requirements for DT coverage exist (Table 6).

Multicenter studies have demonstrated a continued improvement in outcomes with durable MCS. The greatest survival gains are reported in patients implanted under the DT indication with a HeartMate II (Thoratec Corp, Pleasanton, CA), mainly because of the inferior survival in the early DT experience (24). The BTT HeartWare Left Ventricular Assists Device for the Treatment of Advanced Heart Failure (ADVANCE) study compared outcomes in 140 BTT patients undergoing a HeartWare HVAD (HeartWare International Inc, Framingham MA) implant with 499 patients in a contemporaneous control group from INTERMACS who were largely supported with the HeartMate II (25). Survival rates at 1 year were 90.7% in the HVAD group and 90.1% in control group. This led to the U.S. Food and Drug Administration’s approval of the HeartWare HVAD for BTT candidates and an expansion of HVAD indications beyond European borders. As opposed to INTERMACS 3 and 4 who are considered to be the best candidate for MCS, INTERMACS profile 6 or 7 are very rarely considered for LVAD (26). The multi-institutional REVIVE-IT trial has been enrolling patients who fit the “too well” category to determine if early implantation of long-term MCS can result in better outcomes in this patient subset and prevent progression to “sicker” INTERMACS profiles (10,27,28) (Table 5). Recently completed and future studies in MCS are shown in Table 7 (29). Since MCS therapy outcomes are better with INTERMACS 3 or 4 compared to 1 or 2, the trend to initiate patient evaluation for VAD therapy becomes earlier stage of heart failure symptoms (Table 8) (10).

Minimally invasive approach

LVAD placement for an end stage heart failure patient, or a patient who has had multiple previous surgeries, requires multiple blood transfusions and has a relatively high risk to open the chest. To minimize the transfusions and risk of injuring the heart, and to maximize the post implant recovery, the minimally invasive approach is an attractive option. Left minithoracotomy and upper hemisternotomy with or without cardiopulmonary bypass is the most common strategy for this approach. For patients with chronic obstructive lung disease, careful evaluation of the capacity of postoperative pulmonary recovery from a thoracotomy is performed. A baseline pulmonary function test is reviewed for this approach. In order to assess if a patient has good anatomy for a minimally invasive approach, a chest CT scan is a useful modality. In patients with multiple previous proximal coronary artery bypasses, the length of the ascending aorta is assessed, along with the patency of grafts on preoperative angiogram. Also, the distance from the left chest wall to the LV apex and anatomic positioning of the ascending aorta is useful information (30).

Anesthesia

A double lumen intubation is not mandatory for most patients. Before the skin incision, the LV apex position is confirmed by using transesophageal echocardiography (TEE). If it is an off-pump implant, administering 4 g of magnesium and 100 mg of lidocaine is useful to decrease LV arrhythmogenicity and to allow proper placement of the inflow ring. Also, administering 30 mg of adenosine induces a short bradycardiac arrest during off-pump LVAD placement (30). Maltais et al. reported that administering adenosine adds an additional benefit that reduces pulmonary pressure and protects the RV function (31,32).

Minimally invasive on-pump strategy

The HVAD is the preferable device for a minimally invasive type of procedure based on no need for a pump pocket creation. Minimally invasive on-pump strategies involve left anterior minithoracotomy and mini upper hemisternotomy. Schmitto et al. described the method (33). After tunneling of the driveline, a cardiopulmonary bypass was established by venous cannulation into the right femoral vein and arterial cannulation into the ascending aorta via an upper hemisternotomy or right femoral artery. A LV apex sewing ring placement is done under cardiopulmonary bypass. The position of the sewing ring is confirmed by TEE before the placement. The outflow graft is tunneled within the pericardium and anastomosed on-pump end-to-side to the proximal ascending aorta. Some patients have right sided-curvature positioning of the ascending aorta. In these cases a second intercostal incision is utilized to gain access to the aorta for the outflow graft anastomosis (30). This approach is appealing in bridged patients to spare the sternal incision for heart transplantation and with previous coronary artery bypass surgery, where patency of previous grafts is important.

This approach is equally effective for initial surgery patients and re-do patients.

Minimally invasive off-pump strategy

The approach for this procedure is minithoracotomy and upper hemisternotomy or a second intercostal incision. A modified non-fibrillatory technique is used for inflow cannula placement. After setting the permanent pacemaker to a backup rate of 40 beats per minute, a 30mg bolus of adenosine is given to induce a brief bradycardiac asystole. The LV apex is quickly cored and the HVAD is locked to its final position. The outflow graft is tunneled and anastomosed end-to-side to the ascending aorta (30).

Minimally invasive robotic strategy

Utilizing a da Vinci robot system (Intuitive Surgical, Inc, Sunnyvale, Calif) will enable surgeons to avoid redo sternotomy, which can potentially cause post operative RV failure by prolonged cardiopulmonary bypass time, bleeding, excessive transfusions, and inflammation. This approach has the advantages of having a more precise dissection, better visualization of small spaces, as well as sparing a redo sternotomy (34).

With the right lung isolated, 3 small robotic ports were placed in the right chest via the second (left robotic arm), third (camera and working port), and fifth (right robotic arm) intercostal spaces in the anterior axillary line (Fig. 5). Robotic assistance was used to pass the outflow graft through a mediastinal tunnel created anterior to the RV into the right chest for anastomosis with the aorta. A side-biting clamp was placed onto the ascending aorta via a stab incision in the first intercostal space, right of midline with direct visualization to avoid injuring the right internal thoracic artery. CPB was initiated after appropriate activated clotting time–guided heparinization; an apical core was removed from the left ventricle, and the HVAD was secured into position. The outflow cannula was anastomosed to the aorta using robotic instruments with and without a 2-cm right anterior thoracotomy. Once the device was placed, flow through the device was initiated, and an angiocatheter was placed into the outflow graft to de-air through the third intercostal space. The device was covered with a polytetrafluoroethylene (Gore-Tex) mesh to minimize lung adhesions (34).

F. Complications

Bleeding

Bleeding, especially gastrointestinal (GI) bleeding, is a major adverse event of continuous flow LVADs. Significant incidences of GI bleeding occur in destination therapy populations. Fifty seven percent of the patients with bleeding experienced upper GI bleeding, and 35% lower GI bleeding. Previous history of GI bleeding, elevated INR, and low platelet count were independent predictors of GI hemorrhage (35). The mechanisms of GI bleeding are multifactorial. Reduced pulsatility in patients supported with the continuous flow LVAD HeartMate II is associated with an increased risk of nonsurgical bleeding such as GI bleeding, epistaxis, genitourinary, and intracranial bleeding (36). The other mechanisms responsible for these adverse events include acquired von Willebrand disease, GI tract angiodysplasia formation, impaired platelet aggregation, and overuse of anticoagulation therapy (37,38).

Neurological events

Ischemic stroke, hemorrhagic stroke, and transient ischemic attack are relatively common and often severe complications following LVAD placement. According to the INTERMACS annual report, the risk of stroke is 3% at 1 month, 5% at 3 months, 7% at 6 months, 11% at 12 months, 17% at 24 months, and 19% at months post-implant (4,39). Similarly, the HeartMate II DT trial showed rates of ischemic and hemorrhagic stroke as high as 8% and 11%, respectively, in the first 2 years following LVAD placement, with hemorrhagic stroke being the leading cause of death among patients with a continuous flow LVAD (40).

Infection

Patients are at increased risk of bacterial infections following LVAD implantation, occurring at the driveline, pump pocket, or systemically. Driveline infections in the international HVAD trial are reported at 18% at 1 year (41), while the HeartMate II BTT trial and trial registry report rates as high as 14% at 6 months (42,43). In general, the longer the support duration, the higher the likelihood that patients will develop driveline infections (44). Developing any type of infection is associated with decreased survival and quality of life (45). In one cohort, the two-year cumulative survival rate was 67% for patients with infections and 81% in those without (46).

Device malfunction (thrombosis)

Device malfunction is a potentially lethal complication of continuous flow LVAD. It usually necessitates a device replacement procedure or a heart transplant. Causes of device malfunction include thrombus formation with hemolysis and driveline-lead fractures with electrical failure. The highest rate of thrombosis requiring pump exchange was in the international HVAD trial at 8% at 2 years (41). In the HeartMate II patient series, a recent study from three high volume centers including 837 HeartMate II patients, showed an increase in the rate of confirmed pump thrombosis at 3 months post-implant from 2.2% before March 2011 to 8.4% by January 2013 (47). Although the reason for increasing incidents of pump thrombosis in the HeartMate II patients is unknown (48), these recent studies illustrate the dynamic potential for rates of adverse events overtime, possibly reflecting changes in device technology, patient selection, young patients with high BMI, surgical technique outflow graft kinking, acute angulation of inflow cannula (49), and post implantation management such as sub-therapeutic INR. Temporal changes in thrombosis rates were not seen in a recent analysis of HeartWare HVAD (50).

Right ventricular failure

Right ventricular (RV) function is crucial to keep LVAD flow more than adequate. Outcomes of LVAD patients are dependent on right heart function due to the necessity of adequate flow through the pulmonary circuit to the left heart. Hence, RV function assessment prior to LVAD implantation is of utmost importance. Currently there are no standard methods to predict post-LVAD implantation RV failure. In the HeartMate II DT trial, 20% of patients received extended inotropic therapy for persistent right heart failure and 4% required placement of a right ventricular assist device (40). In the ADVANCE: HVAD BTT Trial CAP, 25% of patients developed dependence on inotropic therapy and 3% required a RV assist device (51). The HeartMate II BTT Trial-Registry and an analysis of 484 enrolled patients demonstrated that right heart failure post LVAD implantation is associated with significant poor survival rates and longer hospital stays (42,52). Currently there are no reliable modalities to predict RV failure, which necessitates RVAD support or prolonged inotropic support (Table 9) (10). However, tricuspid repair at the time of LVAD implant, if preoperative tricuspid regurgitation is severe, might promote reverse remodeling of the RV (53).

Cardiac arrhythmias

Cardiac arrhythmias, both ventricular and supraventricular, can develop after LVAD implantation. A study of 184 HMII devices showed an incidence of ventricular arrhythmias up to 32% post-LVAD (54). One study of 61 patients reported pre-LVAD ventricular arrhythmia was a significant risk predictor of post-LVAD ventricular arrhythmia (55). The same study further showed that patients with post-LVAD ventricular arrhythmias had a significantly increased risk of mortality (55). However, another cohort of 61 patients showed post LVAD ventricular arrhythmias had no association with survival or transplantation rates, but did associate arrhythmias with other morbidities, such as greater re-hospitalization rates (56). In addition, patients with post LVAD ventricular arrhythmias had higher rates of appropriate (31%) and inappropriate (15%) defibrillator shocks (56). Supraventricular arrhythmia such as atria flutter impaired ventricular filling, which results in right heart failure. Catheter ablation of medically refractory atrial flutter in LVAD patients might be an effective treatment resulting in immediate and significant improvement in symptoms of right heart failure (57).

LVAD patients with preoperative atrial fibrillation have been shown to have increased thromboembolic events such as stroke, transient ischemic attack, hemolysis or pump thrombosis (58). Refinements in anticoagulation strategies may be required for this patient subset.

Re-hospitalization

Recurrent hospital admissions are another important aspect of post-operative LVAD treatment. This is recognized as a critical and growing problem as LVAD technology gains a wider penetration and greater focus is paid to curbing re-hospitalizations. In addition to all complications previously described, progression of cardiac pathology can lead to unplanned readmission (59). One trial reported readmission rates for LVADs as high as 94% (40) and another reports up to 1.2 readmissions per patient year (41). One study of 71 CF LVAD patients found that most patients are often readmitted within 6 months of discharge, with GI bleeding as the most common cause (60). Another report also demonstrated that the 30-day readmission rate was 26.1% with recurrent heart failure (33.3%) and GI bleeding (22.2%) (61). Interestingly, in a study comparing readmission rates of MCS patients as destination therapy vs. bridge to transplant, cumulative incidence of unplanned readmissions was higher for destination therapy than bridge to transplant patients (9/patient vs. 4/patient at 24 months) (59).

G. Future

LVAD plus stem cell – bridge to regeneration

Myocardium reverse remodeling by LVAD therapy

End stage heart failure is characterized by progressive cardiomyocyte hypertrophy, cellular apoptosis, myocardial fibrosis, and eccentric ventricular remodeling, which leads to severe chamber dilatation. These macro level changes are a result of pathological changes occurring at the microscopic level with dysregulation of calcium metabolism and altered gene expression of myocyte contractile proteins. The LVAD implantation improves circulation by mechanically unloading the failing LV which induces reverse remodeling and may trigger the release of cytokines. It demonstrates cellular, molecular, and genetic changes in cardiomyocytes, which potentially provides a better environment for myocardium recovery. Failing cardiomyocytes replicate DNA without successfully completing mitosis, resulting in increased polyploid cardiomyocytes (62). On the contrary, a recent report demonstrated that the number of polyploid cardiomyocytes decreased, while the number of diploid cardiomyocytes increased, in a group of end-stage HF patients with LVAD therapy (63). LVAD unloading may trigger releasing cytokines and hormones, which promote cardiomyocyte healing and allow for the successful completion of karyokinesis and thus a change form polyploidy to diploid cardiomyocytes (64). Recent evidence also suggests that decompressed LV by LVAD therapy may be augmented by an increase in recruitment of proliferation of regenerative cell types, including mast cells (65), cardiomyocytes, and stem cells (66) rather than inducing polyploidy to diploid cardiomyocytes (64,66). Suzuki et al. also reported that an animal model of mechanical unloading increased the number of stem cells in the myocardium, including Sca-1-positive and c-kit-positive cells (67).

Also, on the cellular level, there is a major change after mechanical unloading. The mechanical unloading induces a large reduction in cell size clinically as well as an animal model (68,69). However, the reduction in cell size does not correlate with functional recovery (68) and large reduction in cell size sometimes relates to dysfunction (70). Nelson et al. showed that the QT interval prolongation, which is a part of the myocardial infarction-related pathological remodeling, was partially halted by iPSC therapy, whereas injected fibroblasts did not (71). The important mechanism of cellular contraction is membrane electric excitation with cellular contraction. The patients who demonstrated cardiac functional recovery during LVAD therapy had a specific pattern of electrophysiological reverse remodeling. It has impact on cardiac function (68). This finding indicates this electrophysiological can be reversible.

LVAD plus stem cell therapy

Combining stems cells and LVAD therapies can provide better results compared to previous stem cell transplantation studies, which showed improved myocardial perfusion in ischemic heart, although efficacy was limited by delivery method, engraftment, and survival (72-74). Nassere et al. found no evidence for enhanced cardiac repair under injection of bone mallow stem cells and pulsatile LVAD, but concluded that other cell therapies should be trialed (75). On the contrary, Anastasiadis et al demonstrated that LVAD support increased the viability and survival of implanted stem cells by unloading LV, improved coronary perfusion, and reduced inflammation (76). They also demonstrated that when human autologous bone mallow cells consisting of EPCs (CD133+), hematopoietic stem cells (CD34+), and mesenchymal stem cells (CD105+) were injected into a severely ischemic myocardium supported with a Jarvik 2000 LVAD, the LVEF improved from 15% preoperatively to 45% after 1 year follow up (77).

There are a couple of unknown questions such as the type of LVAD (centrifugal vs. axial continuous flow) and the degree of LV decompression will effect on myocardial functional recovery.

Clinical trial

A study using allogeneic mesenchymal precursor cells (MPCs) injected during LVAD implantation to assess safety. This study demonstrated that no safety events were observed and successful temporary LVAD weaning (30 minutes) was achieved in 50% of MPC and 20% of control patients at 90 days (P =0.24). There was no significant difference after LVAD wean between MPC and control (24.0% and 22.5% respectively). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support (P =0.69). This study also demonstrated donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months (78).

Currently, there aren’t many clinical trials that show significant improvements for LVAD explant rate and long-term survival. To maximize the efficacy of stem cell therapy, identifying the best cell population, the method of harvesting, delivering the stem cells, the timing of injection, and the best device for recovery needs to be addressed as well as optimal pharmacological therapy (79).

Tetherless power transmission technology “no driveline”

A driveline infection is one of the most devastating complications of continuous flow LVAD. A transcutaneous energy transmission system (TETS) is potentially very useful to minimize a device related infection.

With transcutaneous energy transmission system use, morbidity from device related infections would likely decrease. Because of the potential for less infection, it is useful for any chronically implanted medical device. Although TETS technology was developed nearly 50 years ago and has been tested extensively in laboratory studies, not much clinical experience exists. The principle of TETS is based on the inductive coupling of energy between an external primary coil and an internal secondary coil. An external power oscillator converts a direct current power source into an alternating current at the high frequency for transmission between the coils. The transcutaneous transformer transfers the external power to the internal components by electromagnetic induction. A rectifier/regulator circuit located within the secondary coil converts the AC power to DC power and regulates the power to charge the internal battery or to power the pump motor (80).

TETS technology has been incorporated into numerous TAH and LVAD designs, but only two of these devices have been used clinically to date. The AbioCor TAH (Abiomed, Danvers, MA, USA) and the LionHeart LVAD (Arrow International, Reading, PA, USA). The AbioCor TAH has completed an FDA-approved clinical trial and is currently approved for humanitarian use only in the United States. The trial enrolled 14 patients with endstage biventricular failure who were not candidates for other therapies. Although a final summary of the trial has not been published, reports indicate that there were few technical problems with the device and that the TETS worked well (81,82). The LionHeart 2000 LVAD is a totally implantable system that includes the blood pump, secondary TET coil, a compliance chamber, and a controller unit that also houses a rechargeable battery. The compliance chamber is a circular polymer sac with an attached subcutaneous access port. Pressure within the chamber is intermittently monitored and, as needed (approximately once per month), air is added through the access port to maintain pressure. An external power pack with rechargeable batteries provides power to the primary TET coil. An external monitor communicates by telemetry with the implanted controller. The LionHeart LVAD has been implanted in 23 patients in the Clinical Utility Baseline Study (CUBS). The overall survival rates at one and two years of support were 39% and 22%, respectively, which was worse than that of other similar studies (83,84). Although the device-related infection rate was lower, possibly due to the use of the TETS (85), device failures and neurologic events were responsible for the worsened morbidity and mortality rates (86).

Future of TET use

Although, neither device for clinical studies demonstrated great long-term results, the incidence of infections was reduced significantly. Integrating this technology into continuous flow LVAD potentially decrease device related infections. Another technology related refinement such as implantable battery, needs to last longer, have shorter recharge times, and needs to be reduced in size. The TET coil design could also be improved to increase efficiency and minimize heat loss, which can potentially damage the skin and surrounding tissues. The design of the TET coils (size, shape, and malleability) should accommodate a wide range of patient sizes and allow for a variety of patient activities. , Finally, the safety of the system by determining the potentially harmful effects of exposures to other sources of electromagnetic energy, which can potentially couple to the artificial heart system and drive it by accident, such as a stove that uses induction heating (80).

H. Overview of United States Device Regulation

Introduction:In the United States, the FDA’s Center for Devices and Radiological Health (CDRH) is responsible for regulating companies who manufacture, repackage, relabel, and/or import medical devices. Devices are classified into Class I, II, and III. Most Class I devices are exempt from Premarket Notification 510(k). Most Class II devices require Premarket Notification 510(k). Most Class III devices require Premarket Approval.

Premarket Notification 510(k): The documentation required to get a Premarket Notification 510(k) shows a device is substantially equivalent to one that existed prior to 1976, (before the FDA regulated devices).

Premarket Approval (PMA): PMA’s are required for Class III devices. These devices are high risk and pose a significant risk of illness or injury. Most of the devices in the mechanical support space require PMA approval. The PMA process includes the submission of clinical data collected in a clinical study, to support claims made for the particular device. An Investigational Device Exemption (IDE) allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data required for a PMA.

Humanitarian Device Exemption (HDE): An addition FDA approval path exists if a device is intended to benefit patients by treating or diagnosing a disease or condition that affects fewer than 4000 individuals in the United States per year. If this condition is met, a HDE is submitted to the FDA, which is similar to a PMA application, but is exempt from effectiveness requirements of a PMA.

Summary: There have only been a few devices that have met the PMA requirement over the last 25 years. Lately the temporary support devices that in the past received 510(K) approval, are now required to meet PMA requirements. This will limit incremental innovation to devices that have a PMA.

I. Conclusions

The field of MCS has seen significant progress in the past 40 years. There has been a lot of progresses in mechanical engineering and advancements of surgical techniques which allow us to provide a better quality of life to advanced heart failure patients in a less invasive fashion. Although in its infancy, a hybrid MCS – stem cell therapy can potentially lead a way to new era of treatment for advanced heart failure patients. Furthermore, whole organ engineering is on the horizon and new techniques, such as 3-D bioprinting have opened the way for this to proceed. Ultimately, progress on alternative therapies largely depends on our deeper understanding of the mechanisms of heart failure.

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