Durable Continuous-Flow Mechanical Circulatory Support: State of the Art

: Implantable mechanical circulatory support (MCS) systems for ventricular assist device (VAD) therapy have emerged as an important strategy due to a shortage of donor organs for heart transplantation. A growing number of patients are receiving permanent assist devices, while fewer are undergoing heart transplantation (Htx). Continuous-flow (CF) pumps, as devices that can be permanently implanted, show promise for the treatment of both young and old patients with heart failure (HF). Further improvement of these devices will decrease adverse events, enable pulse modulation of continuous blood flow, and improve automatic remote monitoring. Ease of use for patients could also be improved. We herein report on the current state of the art regarding implantable CF pumps for use as MCS systems in the treatment of advanced refractory HF.


Introduction
Given the increasing shortage of donor organs, implantable mechanical circulatory support (MCS) systems for ventricular assist device (VAD) therapy have emerged as an essential element of treatment . These devices are installed permanently in many patients, and fewer are now undergoing heart transplantation (Htx).
During waiting periods for donor availability, the VAD system provides additional support as well as improves the physiology of the heart. Patients supported by VADs can be discharged from intensive care units or hospitals because VADs are mostly intracorporeal and improve quality of life compared with short-term devices. Using VADs as destination therapy (DT) is now an acceptable as well as a feasible therapy for the patients of end-stage heart failure (HF) who cannot qualify for Htx .

The History, Clinical Requirement for, and Technology of VADs
The challenging development of VAD therapy began in 1988 [8,9]. The first continuous-flow pump, which was designated as a Hemopump, was used for circulatory support in patients suffering from cardiogenic shock [8,9]. The Hemopump is a percutaneous catheter-mounted VAD. In contrast to pneumatic systems, the Hemopump pumps blood continuously. The device does not cause hemolysis, despite the high number of revolutions per minute (rpms) of its operating impeller. This finding prompted the MCS scientific community to focus on the adoption of CF-VADs in the second half of the 1980s [8,9]. The advantages of CF-VADs over pulsatile and paracorporeal devices is that they are silent, miniaturized, and reduce trauma during surgery, allowing patients to gain a relatively unrestricted life [6][7][8][9][10][11][12]. The first human insertion of an implantable CF-VAD, the Mi-croMed DeBakey I, was performed in Berlin on November 11, 1998 in a patient with endstage heart failure (HF), who was supported for 47 days until his exitus [8,9].
Advanced medical therapy, last-generation pacemakers, and defibrillators have changed the clinical evolution of HF [9,11,12,[22][23][24]. However, 0.5-5% of patients are refractory to any optimized medical therapy and develop advanced HF. Analyses from the United States of America (USA) suggest that 250,000-300,000 patients under the age of 75 years suffer from advanced systolic HF (defined as New York Heart Association (NYHA class IIIb-IV)) [1,3,22,23]. In Europe, 500,000 patients are likely to be suffering from HF [6,[9][10][11][12]24]. The prognosis for advanced HF is poor; the 1-year mortality rate is >25% for class III-IV outpatients and exceeds 50% for class IV patients. While conservative care is the primary strategy for patients with advanced age and important comorbidities, advanced replacement therapies, such as Htx or a left ventricular assist device (LVAD), are promising options for other cases. Htx is a well-accepted strategy option for many patients, but the lack of donor organs remains a severe limitation. Long-term LVADs have been used for several years in both acute and chronic refractory HF, mostly as a bridge to Htx. Technology improvements, together with the shortage of donors, have recently led to the adoption of LVADs in a much extended range of patients [6][7][8][9][10][11][12]23,24].
Implantable CF-LVADs generate up to 10 L/min of CF, and most patients have no evident arterial pulse peripherally [6][7][8][9][10][11][12]. The HeartMate 3 has software that varies the pump rpms and creates an artificial pulse every 2 s, which facilitates the washing of the blood-contacting surfaces of the system [16,17]. While old-generation pulsatile pumps had a limited durability of around 2 years, CF devices can currently last over 10 years.

Axial Flow
Axial-flow CF-LVADs have an impeller that rotates at speeds between 6000 and 15,000 rpm to circulate blood flow [6][7][8][9][10][11][12]. Due to their miniaturization, the majority of systems are second-generation pumps; however, third-generation technology has also been utilized. The impeller peripheral velocity is higher than that for radial-type devices and leads to relatively high shear force. Additionally, the need for stationary guide vanes and an impeller suspension may facilitate clotting formation in areas of stasis.

Radial Flow
Despite being slightly larger in size than axial-flow systems, radial-flow (centrifugal) pumps are suitable for long-term cardiac assistance due to their lower rotational speed, higher hydraulic efficiency, lack of stationary vanes, and more anatomically suitable shape [6][7][8][9][10][11][12]. Due to their rotor design and increased surface area, these pumps can get third-generation bearing technology for the full suspension of their impeller using hydrodynamic or magnetic forces. This drastically increases the device lifetime.
The most recent American Society for Thoracic Surgery (AATS) and International Society for Heart and Lung Transplantation (ISHLT) guidelines [23] and the 2019 European Association for Cardiothoracic Surgery (EACTS) expert consensus document [24] recommend inflow cannula placement into the left ventricular anterior wall and outflow placement on the lateral ascending aorta tract.
A less invasive outflow line is through the transverse sinus; this is commonly used for BTT [31] and prevents positional changes of the LVAD after sternal closure. Moreover, it enables easier and safer re-entry during Htx.
Outcomes will improve more and more with the development of novel LVAD systems. Recently published results from a study of 50 patients implanted with the Heart-Mate 3, following which CE approval was granted, revealed a 6-month survival rate of 92%. For the first 294 patients randomized to the recent MOMENTUM trial, which compared outcomes between the HeartMate 3 and HeartMate II, the respective 6-month survival rates were 89% and 87% [33,35,36].
In a 2-year study of 366 patients, 190 were assigned to a centrifugal-flow pump group and 176 to an axial-flow pump group [33,35,36]. Two-year survival was 79.5% (n = 151 patients) in the centrifugal-flow pump group and 60.2% (n = 106 patients) in the axial-flow pump group. Reoperation due to pump malfunction was less frequent in the centrifugalflow pump group compared to the axial-flow pump group (1.6% vs. 17.0%; p < 0.001). The rates of death and debilitative stroke were similar between the two groups, but the overall rate of stroke was lower in the centrifugal-flow pump group compared to the axial-flow pump group (10.1% vs. 19.2%; p = 0.02).
Schramm et al. [19] compared 79 HVAD and 79 HeartMate 3 patients and found no difference in survival. However, driveline wound infection was more common in the HeartMate 3 cohort. Mueller et al. [20] matched 100 HVAD and 100 HeartMate 3 patients and found no difference in survival. However, driveline wound infection was again more common in the HeartMate 3 cohort, while the HVAD cohort had a higher rate of cerebral stroke. The incidence of hemocompatibility-related adverse events, however, was significantly higher in the HVAD group (113 points (corresponding to 1.28 events per patientyear) vs. 69 points (corresponding to 0.7 events per patient-year), p < 0.001). Itzhaki Ben Zadok et al. [21] matched 25 HVAD and 26 HeartMate 3 patients and found no difference in survival. However, the risk of stroke and pump thrombosis in the HeartMate 3 group was lower.
A recent EUROMACS propensity score analysis matched 359 HVAD and 359 Heart-Mate 3 patients (personal communication of Dr. Potapov during the 2020 virtual annual EACTS meeting; https://www.eacts.org/resources/eacts-library/) and found no difference in survival [2]. The proportion of patients free from major adverse events after two years was similar between the groups (44.2% vs. 47.9%, p = 0.226). However, overall, HeartMate 3 patients showed poorer health.
Independent of the surgical implantation approach, different risk factors for early mortality after CF-LVADs implantation have been identified, including advanced age, female gender, high body mass index (BMI), INTERMACS level 1-2, renal failure, liver failure, and the need for concomitant cardiac procedures [1][2][3][4][5][6]23,24,36]. Full acknowledgment of these factors, along with optimized pump technologies and improved medical care, will provide a better prognosis for such a delicate patient population in the near future.
In contrast to previously used pulsatile pumps, CF-LVADs have allowed patients to lead quite a normal life and participate in several social activities owing to their quiet operation and lack of a large external drive unit [6][7][8][9][10][11][12].
The deployment of highly trained teams consisting of surgeons, cardiologists, anesthesiologists, perfusionists, and specialized nurses has been vital for reducing complications after CF-LVAD implantation [9,11,12].
The two most innovative systems to avoid cable infections are: (1) the transcutaneous energy transmission (TET) system, which transfers energy via two coils, one under and the other over the skin; and (2) the Jarvik 2000 LVAD (Jarvik Heart Inc., NY), in which a retroauricular titanium pedestal is placed on the skull, thus providing a low infection rate [39,40]. The TET system was used in conjunction with the Arrow LionHeart (Arrow International, PA) as a pulsatile LVAD in an individual who survived for 3.5 years without skin complications [37]. The same concept, even if with different technology, has been applied to the Jarvik 2000 LVAD (Jarvik Heart Inc., NY) associated with the Leviticus-Cardio system (Leviticus-Cardio Ltd., Petach Tikva, Israel) [38] as the first wireless coplanar energy transfer system used in humans.
This once again highlights how critically unwell this cohort is. BiVAD implantation confers double the risk of mortality compared with LVAD alone. Thus, the RHF and associated end-organ dysfunction may be the greatest contributor to the increased mortality.
To conclude, the percutaneous heart pump could be used in the future to minimize trauma from surgical implantation as a fully catheter-based axial-flow system with both transfemoral and transapical applications. These devices are currently under investigation but may ultimately demonstrate the utility of miniaturized CF-LVAD technology for both left and right ventricular support [9,11,12].

Conclusions
Due to the rising population of advanced-stage HF patients and the limited availability of heart donors, durable VADs have become an effective strategy to provide a successful bridge until Htx, comfort cardiac recovery, or assist as DT for those who cannot qualify for Htx.
The innovation in device design such as miniaturized forms, minimally invasive approach for implantation, permanently implantable, enhancement in durability and efficacy of pumps, use of the smart system for monitoring, and the durability of batteries, fully automated devices are either in use or currently being evaluated for promising clinical results.
We have above discussed, in detail, how LVAD therapy developed from a novel idea into a feasible clinical option for an increasing number of patients. Furthermore, CF-LVAD systems are a highly feasible permanent therapeutic option, particularly for elderly patients, and are now being used routinely for treating HF. However, there is a need for smaller CF-LVADs with more durable components. Improved pump design should decrease rates of infection and thrombus formation, increase hemocompatibility, enable pulse modulation of continuous flow, ensure an automatic system monitoring through telemonitoring, and improve ease of use for patients.
The elimination of percutaneous lead and introduction of wireless energy transfer is the forthcoming demand for allowing the patient to pursue activities such as swimming and playing water sports or engage in contact sports, which are not suitable with currently available devices.
Studies on CF-BiVADs are promising [41][42][43][44], and future progress will also accommodate this small but delicate cohort of biventricular failure patients while awaiting definitive transplantation. A dedicated CF-BiVAD device would additionally reduce to a single driveline and controller, thus decreasing infection risk and improving quality of life.
Additionally, in the near future, CF-LVADs that can perform the functions of total artificial hearts are likely to be developed [41][42][43][44].