I. The trail blazed and the pathway ahead
As the field of Mechanical Circulatory Support (MCS) reaches into its sixth decade beyond first laboratory experimentation, it behooves us to reflect on the historical, pioneering advances on which the future will be leveraged. Such reflection is most valuable when it inspires the thoughtful to blaze new trials.
Much has been accomplished. The field is tantalizingly close to the holy grail of delivering amazing technologies for (1) extending life with (2) quality and (3) safety with (4) easier-to-use therapies applied at the (5) optimum time in (6) properly selected heart failure patients while (7) achieving cost-effectiveness .
And, yet, much remains. The good news is that the pace of progress is accelerating. Hopefully, we are in the final decade of pioneering.
Survival with durable MCS devices is finally approaching that of heart transplantation. The vision of suitable quality of life is within sight.
However, we are still in the early stages of assuring safety , which has been limited by adverse events (AEs). This problem continues to compromise patients with morbidity and mortality , to burden caretakers with the rigors of management, and to strain our healthcare systems with excessive costs . All of that inhibits expansion into earlier stages of heart failure.
Despite the marvels of engineering underlying today’s blood pumps, their interface and interactions with their hosts remain to be perfected. The single most important opportunity to reduce AEs is through preventing sublethal blood damage. Advances in the science of hemocompatibility , as applied to device design and testing, have opened the door for a next generation of devices that will overcome factors that contribute to bleeding, thrombosis, strokes, infection, and inflammation. Other device-host interfaces to be addressed include those that deliver improved durability, enhanced functionality, expanded indications for use, quality of life, and ease of use.
Fortunately, we have learned that it is not only technology, but also management and patient factors, that impacts outcomes in the MCS field. While we continue to await perfected technology , the field will continue to see improvements through advances in management , of both pumps and patients, and through advances in optimizing patients and their selection. That will best be facilitated by organization and integration of MCS field-wide efforts.
Indeed, the future is promising. Our mission now is to deliver on the goals so long envisioned.
II. The future is leveraging the past
There is much to be learned by understanding historical roots. In the words of Winston Churchill, “those who fail to learn from history are doomed to repeat it.”
Early Goals of Life, and then Life Outside the Hospital
The pioneering, clinical experience with durable, implantable blood pumps began in earnest in the late 1980s. In that early era, it was a remarkable breakthrough to offer hope of life to patients declining while awaiting heart transplantation and then, ultimately, offer hope for quality of life .
The first device to complete a controlled, clinical trial culminating in US Food and Drug Administration (FDA) approval in 1994 for bridging to transplantation was the HeartMate IP (Thermo CardioSystems, Boston, MA), an implantable, pulsatile left ventricular assist device (LVAD) powered pneumatically by a 90-pound external console. Patients received a survival benefit but remained hospital bound. A portable, 25-pound, pneumatic driver subsequently offered patients greater mobility and early experience with discharge. Electrically powered blood pumps, emerging with the next-generation HeartMate series, the VE and XVE LVADs, were the next to receive FDA approval. This opened the era of outpatient LVAD support and improved quality of life with patients engaging in light recreation and with some returning to their occupations.
That first-generation implantable technology was limited by durability , with mechanical bearing and tissue valve failures occurring on average at 1.5 years. Infections were problematic, especially with the early, large, rigid percutaneous leads. However, an advantage of that technology that has yet to be reproduced is freedom from anticoagulation more than aspirin.
Exploring Long-Term Life with ‘Destination Therapy’
A decade later, in the late 1990s, the field began the transition to long-term implantation, introducing the era of so-called destination therapy (DT), moving beyond bridging to transplantation. The National Institutes of Health (NIH)-supported Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial became the setting for the first randomized controlled trial of LVAD therapy with the HeartMate XVE compared to optimum medical management over a 2-year period of observation.
Patients receiving an LVAD lived longer, demonstrating a survival benefit greater than any other heart failure therapy previously studied. The hoped-for improvement in quality of life appeared believable. However, mortality (23% survival at 2 years) and morbidity (especially with pump failures and infections) were still considerable, well behind outcomes with heart transplantation. That was not too surprising considering that the population studied had the most advanced level of heart failure ever studied up to that time.
The REMATCH trial served as an early catalyst to the field, opening the door to the long sought-after goal of life-long therapy. Data from that trial were used to secure Medicare approvals for reimbursement at levels that permitted cautious growth of the field. And, clinical teams began forming, with the important, high-profile entry of heart failure cardiologists joining the efforts of the heart surgeons whose leadership had been instrumental during the early startup stages of the MCS field.
The Pathway to Improvement
The pioneering efforts of the late 1980s through the 1990s were leveraged into an era of progressive improvement throughout the decade of the 2000s. Blood pump therapy had to improve substantially to begin approaching heart transplantation, the ‘gold-standard’ for end-stage heart failure at that time. It would have to follow the precedent observed with heart transplantation in which humble beginnings during the initial pioneering stages gave way to progressively improving outcomes.
Three areas of improvement would be necessary:
- 1.
Technology , including a new-generation of blood pumps;
- 2.
Management , of both the patients and devices; and
- 3.
Patient selection , based on new insight into patient risk factors.
The course to be followed for outcomes improvement, throughout that next era and into the future, is illustrated in Fig. 22.1 . The survival outcomes for the pioneering phase of MCS, represented by the 2-year survival curve with LVADs observed during the REMATCH trial, are superimposed on the 17-year survival curve for heart transplantation in the current era. Improving outcomes with MCS would be driven by the three factors most responsible: technology, management, and patient selection.
TECHNOLOGY Breakthroughs
It once was considered dogma that continuous-flow pumps with rotors spinning at high speeds would not be suitable for blood, given expectations of unacceptable hemolysis. This myth was dispelled with the arrival of the Hemopump, after which a whole new generation of implantable blood pumps incorporating rotary blood pump designs, axial or centrifugal, was introduced. These pumps afforded smaller size, elimination of noise and vibration, improved durability, and easier implantation than the previous, pioneering generation of large, pulsing, displacement pumps.
The decade of the 2000s witnessed expanding use of these rotary pumps. Following clinical trials, incorporating randomization against a previous-generation, approved pump, the HeartMate II axial flow LVAD (Thoratec, Pleasanton, CA) received FDA approval in 2008 for bridging to transplantation and 2010 for long-term DT. The HeartWare HVAD centrifugal pump (HeartWare, Boston, MA) received FDA approvals for the same indications in 2012 and 2017.
MANAGEMENT Improvements and Guidelines
How patients and devices are managed markedly affects outcomes. Good management can offset some technological imperfections. The 2010 decade saw the rise of efforts to establish consensus around management issues, the publication of guidelines, and the application of best practices.
PATIENT Selection and Risk Mitigation
Early in the history of the MCS field, patients implanted with devices were extremely high-risk patients, literally on death’s door. Moving to earlier-stage patients would be expected to improve outcomes through lower exposure to perioperative risk. If pushed prematurely, however, the benefits of device therapy could be outweighed by the risks associated with good, but less-than-perfect, technology. The search for appropriate ‘equipoise’ balancing risk versus benefit at a given time with a given technology, has been a subject of considerable discussion.
The US national Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) has afforded guidance with patient risk factor characterization and relevant outcomes data. Fig. 22.2 illustrates the breakdown of New York Heart Association (NYHA) class IV patients into six categories from highest severity of illness (IM 1) to lowest (IM 6), followed by NYHA class III (IM 7). The INTERMACS data confirm a lower likelihood of survival in the higher-acuity categories (lower IM levels), indicating the importance of careful patient selection. Preoperative optimization to reduce risk has been recognized as essential.
The Era of Improving Survival
A review of survival with LVADs throughout multiple clinical trials starting with the REMATCH trial demonstrates progressive improvement, now approaching that of heart transplantation, at least within the first 3 to 5 years. This is illustrated in Fig. 22.3 , demonstrating progressive improvement in survival from early clinical trials to more recent ones.
Real-world experiences have supported this trend. Individual center and small group experiences have excelled, approaching equivalence to survival with heart transplantation.
III. The future is optimizing the present
How the challenges of preceding decades have been addressed, and what remains to be improved, serves as guidance for future directions in MCS. If remaining challenges represent opportunity, there is plenty of opportunity available.
RECOGNIZING the OPPORTUNITIES
The most important prospect in the near-term to improve the MCS field is to address the ominous challenge of adverse events (AEs). Data from the INTERMACS illustrates this and serves as a wake-up call. By 12 months after implantation with current-generation ventricular assist devices (VADs), 70% of patients will have experienced one major AE, whether it be bleeding, stroke, device thrombosis/malfunction, infection, or death. This is illustrated in Fig. 22.4 , which graphically displays the sobering magnitude of the AE challenge and summarizes the estimated rates of occurrence of the most troublesome AEs. The cumulative impact of the AEs year after year is considered the most significant impediment to responsible growth of the MCS field, whether that be through limiting the number of patients served or slowing expansion into earlier-stage heart failure.
In addition to the substantial clinical impact of AEs, the economic challenge created by the AEs is enormous. Underlying this is the high frequency of re-hospitalizations. The costs of device replacement, rehospitalizations, diagnostic workups, and therapeutic interventions quickly add up. While the initial implantation costs remain high, it is the long-term costs that represent the greatest challenge. While there are encouraging trends with the most recent clinical experience, this opportunity for improving cost-effectiveness through improving AEs cannot be ignored.
MAPPING the Pathway to OPTIMIZATION
As was noted throughout the history of the MCS field, ongoing improvements with technology, management, and patient selection will be fundamental to overcoming the challenges. While requests abound for better technology, it is clear that outcomes can be improved even with existing technology by improving management and patient selection.
Insight into this is garnered from observations of large differences in outcomes, varying from center to center even with the same devices. For example, wide differences in rates of pump thrombosis have been noted even with the same LVAD. Stroke rates have varied considerably between centers and across eras even with the same device.
Evidence exists to support the idea that improvements in thrombosis with HeartMate II LVADs can be achieved as a result of minimizing variation in management by standardization around best practices, either evidence based or through consensus. Improvements in stroke rates with HVAD LVADs have been noted with better management of blood pressure. Certainly, patient factors contribute varying degrees of risk for the occurrence of AEs—either through a state of compromise and deterioration induced by progressive heart failure—or through inherent biologic or genetically induced conditions that may predispose a particular patient to specific risks.
Optimizing TECHNOLOGY
A wish list of technological improvements is presented in Fig. 22.5 . These improvements are broadly categorized into those for safety, for performance, and for utility. Safety is the highest priority given that the greatest challenge in MCS is the AE issue.
Improving HEMOCOMPATIBILITY
Hemocompatibility, a subset of biocompatibility, is the term used to describe the avoidance of damage to blood elements. The device-associated AEs of bleeding, thrombosis, and stroke are largely related to hemocompatibility.
Early goals for achieving hemocompatibility were focused on preventing major hemolysis due to shear-mediated damage to red blood cells. Given the relative freedom from significant hemolysis in current pumps, attention has turned to other blood elements, including the von Willebrand factor (vWF), platelets, and white blood cells (WBCs). Damage to the vWF has been associated with clinical bleeding, notably mucosal bleeding, particularly gastrointestinal (GI). Platelet damage and activation have been associated with thrombosis. Damage to WBCs can trigger inflammatory responses and impact defenses against infection.
The recent arrival of a blood pump designed intentionally to improve hemocompatibility has been met with enthusiasm, as evidenced by robust participation in the largest randomized trial ever in the MCS space. The HeartMate 3 LVAD (Abbott, Lake Bluff, IL, USA) is a centrifugal pump employing (a) magnetics to levitate its rotor instead of two other preceding designs: (b) miniature mechanical bearings lubricated by blood or (c) hydrodynamic bearings using inclined planes fabricated into the rotor edges to lift the rotor away from the pump body, suspending it on a thin, blood fluid film created when the rotor turns above a minimum speed, analogous to hydroplaning or skiing across the surface of water. By employing magnetics to continuously suspend the rotor, even when stopped, the gaps between the rotor and housing can be wider, resulting in lower shear forces between the rotor and housing. The HeartMate 3 also employs intermittent, intrinsic speed oscillation to avoid areas of stagnation. In theory, these device improvements could lead to lower rates of bleeding, thrombosis, and stroke.
An overall improvement in hemocompatibility-related AEs with the HeartMate 3 in comparison to the HeartMate II has been reported. Pump thrombosis has been markedly improved, now occurring rarely. However, stroke rates are still higher than ideal, although there are early indications of the potential for improvement. And bleeding remains a frequent, vexing problem. Further improvements in outcomes will depend upon device engineering advances supplemented by changes in clinical management.
The emerging science of hemocompatibility applied to device design
Fortunately, additional improvement with the hemocompatibility of pumps, especially regarding bleeding, appears plausible. This ray of optimism is rooted in the evolving science of hemocompatibility as outlined in Fig. 22.6 .
Fundamental to this endeavor has been the characterization of biomarkers that signal the mal-effects of MCS pumps on an array of blood components, including vWF, platelets, and WBCs, resulting in their damage and/or activation. These biomarkers signal alterations that have associations with clinical AEs, including bleeding, thrombosis, and strokes, as well as inflammation and infection.
Advances in biomarker testing have enabled in vitro side-by-side comparisons of one device configuration against another in the laboratory. In vivo testing in animals allows for preclinical evaluation and clinical testing in patients will continue to refine our understanding of the relationships between the preclinical testing and clinical outcomes.
Research into how these biomarkers are affected under various pump operating conditions will enable further evolution of computation fluid dynamic modeling predictive of blood element damage. The influence of (1) shear forces, (2) flow perturbations, and (3) time of exposure to those conditions on damage to the different components of blood will be better understood. Such tools will enable optimizing pumps for hemocompatibility during the earliest phases of design.
Advances in material science will be increasingly important for identifying metallics, polymers, and ceramics, as well as surface textures, most compatible with blood. Enhanced manufacturing methodologies aid in assuring hemocompatibility, especially important as blood pumps are miniaturized further.
As this field of endeavor matures, it will enable the emergence of devices designed to improve hemocompatibility. The timeframe in which a device can move from concept to clinical reality can hopefully be shortened. And, this new wave of advanced, preclinical testing should have predictive value, raising the level of confidence about how a device will perform in humans even before reaching clinical experience.
Improving BIOCOMPATIBILITY
Biocompatibility involves the degree to which a foreign device is viewed as unobtrusive, relatively inert, and compatible with its host. Achieving biocompatibility is fundamental to avoiding Adverse Events resulting from disturbances originating at the interfaces of an implanted, synthetic device with adjacent tissues.
Especially important is the pump inlet cannula as it interfaces with the surrounding tissues, that being the left ventricle in the case of an LVAD. There is good reason to believe that this interface is a source for thrombus formation contributing to pump thrombosis, strokes, and thromboembolic events either by ingestion or by embolization through the pump or embolization directly out of the left ventricle.
Further understanding of this phenomenon is important as efforts are made to prevent this problem. Solutions may include better cannula designs with more biocompatible surfaces promoting a better interface of the device with surrounding tissue, perhaps with full incorporation within the surrounding tissue.
Blood flow dynamics through the LV to a pump inlet at the LV apex may predispose the region to stasis and thrombosis. Here, too, better cannula designs may be helpful. So might pump operating conditions designed to promote intermittent washout of the regions at risk.
Synthetic vascular grafts and conduits may contribute to thrombosis and thromboembolism. The redesign of these conduits may be part of a future strategy with pump designs, including their elimination with endovascular pumps that reside fully contained within the walls of the cardiovascular pathways.
Eliminating the need for ANTICOAGULATION
The goal of operating a blood pump with little to no anticoagulation has only ever been achieved with one implantable blood pump design, the first-generation HeartMate LVAD IP/VE/XVE series. Aspirin was the only anticoagulation required. This was enabled by the use of nonmechanical tissue valves, carefully engineered blood flow pathways, and notably, textured surfaces promoting a biocompatible, neointimal lining on the blood contacting surfaces and at the myocardial tissue interface.
Whether blood pumps will traverse a journey ‘back to the future’ and revisit this standard has yet to be determined. It should, however, be maintained as a goal, to be pursued through advances with the science of hemocompatibility as applied to device design.
Reducing INFECTION
MCS device infections remain problematic, involving percutaneous lead exit sites, deep infections of the percutaneous leads, or the pumps themselves. They are a leading cause of readmission and are an unfortunate cause of long-term death. New approaches are needed.
The MCS field has been looking forward to transcutaneous energy transmission systems, or TETS, as a long-awaited solution to percutaneous lead infections . Early clinical experience with an LVAD that incorporated TETS (LionHeart, Arrow International) exposed the field to tantalizing images of tether-free life without percutaneous leads. However, those limited experiences faded with the exodus of those systems from clinical use.
Enthusiasm for MCS devices employing TETS in lieu of percutaneous leads has been rekindled. Developers of the two VADs most in clinical use today (HeartMate 3 and HVAD) will be incorporating TETS into their own systems. Independent developers are working on TET systems with potential universal applicability and adaptation for use with different devices.
Progress is needed to overcome barriers to the development and adoption of TETS. Some of the challenges are (1) technical with engineering design and development; (2) clinical with the additional complexities of implantation and the bulk of implanted components, along with infection risk of additional implanted hardware and component replacement, including periodic reoperations to replace batteries; (3) related to human factors and ergonomics; (4) business development related; and (5) financial, given development costs and expected increases in system pricing.
A less elegant, but yet worthy, approach to reducing the burden of percutaneous lead infections has been in practice with the Jarvik technology. The internal cable for that LVAD is exteriorized at a connector configured with a skull-mounted pedestal that serves as the interface to a flexible, small-diameter external cable attached to the controller and batteries. Two enabling features are a well-incorporated skin-subcutaneous interface and stabilization to reduce traction-related trauma at the exit site. In the future, alternative locations for such skin-button connector approaches should improve implantability, ease of access, and cosmesis. With an implanted battery and controller electronics, it would be possible to enjoy periods of uncoupled, tether-free mobility, adding quality of life while reducing infections.
Like all implanted foreign bodies, MCS devices have an inherent vulnerability to s urface infections at the interface of the synthetic materials with surrounding host tissues. In the future, MCS devices may be able to incorporate features to reduce external infections, perhaps (1) with surfaces promoting tissue ingrowth, (2) by using materials with greater infection resistance or (3) the capacity to release antimicrobial materials, and (4) by adopting surface topologies to reduce dead-space pockets in which wound seromas accumulate, serving as culture medium for infections.
A unique vulnerability of MCS devices to infections is related to hemocompatibility, given that blood trauma to white blood cells (WBCs) could alter immune defenses to infections . Far less attention has been given to this aspect of hemocompatibility than to bleeding, thrombosis, and strokes. Much has yet to be learned about shear and flow-related effects on WBCs. Minimizing shear-induced damage and/or activation of white cells should be considered as a goal for next-generation devices.
Extending Device DURABILITY
The incidence of primary mechanical failure with current blood pumps has improved markedly since first-generation technology that was compromised by 50% pump failure rates at only 1.5 years. The elimination of mechanical bearings and reduction of the many moving parts to a single, rotating rotor has helped. Other causes of pump system failure , however, remain problematic and must be improved to allow freedom from pump replacement to extend beyond 5 to 7 years or more.
Percutaneous lead failures occur too frequently, generally the result of use-related trauma. Improved lead designs would make them more durable—perhaps achieved by more flexible, smaller-diameter leads and improved resistance to bend- or cut-related damage.
No matter how well designed, as long as there are percutaneous leads, there will be failures necessitating replacement. Lead failures in exteriorized sections can be managed by splicing in new lead segments externally. However, at the present time, lead failures within internal, implanted sections require pump replacement along with the lead.
Complete lead replacement without replacing the pump , as is currently required, should be made available by incorporating implantable connectors on a pump at the site where the lead is attached to the pump, or in near proximity. This approach awaits further development and adoption, having only ever been achieved with one LVAD (WorldHeart’s Levacor), which is no longer available.
Electronic controller and peripheral component (e.g., batteries, chargers etc.) failures remain troublesome and expensive even though less impactful than pump or lead failures. As many as one-third of the electronic controllers fail each year. More robust designs will be needed anticipating the rigors of routine use, and even abuse. Improved preclinical testing methods should be sought that will better simulate the real-world “torture-testing” by patients to better predict readiness of the devices to meet such challenges.
Expanding FUNCTIONALITY
The implantable MCS field today is dominated by LVAD’s providing full-flow, univentricular LV support in patients with late-stage, mostly NYHA class IV, systolic heart failure. As safer technologies with lower adverse event profiles emerge, the freedom to move to earlier-stage patients will gain traction. Likewise, attention will be turned to enhanced performance afforded by e xpanded functionalities.
Right Heart Support
Obviously missing from the MCS armamentarium is dedicated right heart support. This is despite an increasingly recognized need to address the morbidity and mortality invoked by RV failure post-LVAD and by late RV dysfunction. Without dedicated implantable RV assist device (RVADs), the MCS field has explored off-label and off-specification use of implantable LVADs deployed as RVADs.
Right heart support is needed post-LVAD implantation more often than is indicated by the current use of RVADs. The single greatest cause of perioperative mortality following LVAD implantation is multiorgan failure (MOF) resulting from organ and tissue hypoperfusion. MOF is really a surrogate for RV failure, given that the only reason that a full-flow LVAD (normally capable of delivering 7–8 + liters per minute) cannot maintain adequate organ perfusion is because there is not enough blood pumped through the right heart to maintain adequate filling of the LVAD.
The perioperative burden of RV dysfunction is underappreciated. Patients with RV dysfunction require prolonged inotrope use and have a greater likelihood of experiencing bleeding, sustained inflammatory responses, prolonged intubation, and long lengths of stay in expensive intensive care units (ICUs).
Acute RV support technology is available but limited by having to reoperate to remove surgically placed devices or by restricted patient mobility due to femoral cannulation with percutaneous technology (Abiomed Impella RP). A dual-lumen cannula (Protek Duo, Tandem Heart/LivaNova) placed in the right internal jugular vein is available for use with an external pump drawing blood from the right atrium and returning it to the pulmonary artery. It allows for ambulatory mobilization and percutaneous removal, but patients must remain hospitalized.
It should be considered a high priority for developers to deliver RVADs designed for both early mobilization and percutaneous removal, offering intermediate duration right heart support for up to a 30-day use, knowing that the greatest need will be for the first 1–2 weeks postoperatively. Besides improved clinical outcomes, cost-effectiveness should be possible given expected reductions in hospital costs due to reductions in costly ICU care and long hospital lengths of stay.
Bi-ventricular Support
The MCS field awaits chronic, long-term biventricular support devices on par with advanced LVAD technology. While the pneumatic total artificial heart (TAH; Syncardia) still serves a useful role with patients, it is based on decades-old technology, with significant limitations of utility and quality of life.
Fortunately, newer technology is reaching early clinical use with a pulsatile, electric TAH (Carmat, Paris). Continuous-flow technology, designed for biventricular support as a TAH-equivalent, is also in development (e.g., Bivacor). For those patients who start with an LVAD but develop late RV failure, durable RVADs are needed that are integrated with LVAD systems providing combination LVAD + RVAD support without requiring two controllers and separate leads.
Smart Controllers
Today’s continuous-flow LVADs are the culmination of highly intelligent pump engineering. On the other hand, with regard to physiologic engineering, they fall short, essentially devoid of intelligence. This has ramifications for safety, for performance, and for quality of life.
These pumps function at a single set speed as essentially ‘dumb devices’ with no active auto-regulation capability. That one speed setting is established by clinical studies ramping speed up and down while imaging the LV with echocardiography to find a condition at which the risk of LV collapse with LVAD flow interruption will be minimized in balance with the need to avoid LV overload and distention. Only a limited margin of error is allowed—and, if exceeded, patients will be exposed to undue risks should they become dehydrated or volume overloaded or develop extremes of hypo- or hypertension.
Today’s continuous-flow rotary pumps operating at fixed speeds have an extremely limited capacity to increase output in response to increasing preload pressure, as occurs with the increased hemodynamic demands of exercise. Any increase in pump output is solely an innate, passive response related to the behavioral properties of continuously flowing pumps in which pump flow at a given speed is affected by preload pressure and afterload pressure. Flow through these pumps increases modestly in response to increasing preload, mimicking a very muted Starling-curve-like physiologic response. However, that physiologic-like response can be countered, or even defeated, by high afterload pressures which impede flows through these pumps.
To achieve autoregulation, future generations of continuous-flow pump systems will have to incorporate sensors to provide physiologic and hemodynamic information, preload pressure, for example, by which smart controllers will modulate pump speed and other settings.
Alternatively, the field could ‘return to the future’ redeploying modernized versions of the original MCS pulsatile pumps using volume displacement pumping mechanisms. Such pumps are able to electronically detect, or sense, varying filling conditions as preload and respond with appropriate speed changes.
In the meantime, until pumps behave more physiologically, smarter controllers will have to leverage whatever pump performance information is available electronically. Advanced analyses of the data available in pump system logs are gaining traction for identifying patterns that can be correlated to clinical events. It is hoped that such information may guide preemptive intervention to prevent AEs or to improve pump performance.
Pulsatility
Interest is recurring in reexploring the utility of physiologically meaningful pulsatility. To achieve that, either a new generation of volume displacement pumps or adding the ability to ramp up, then ramp down, the speed of continuous-flow pumps to produce pulsatile output is required. The degree and character of pulsatility that is physiologically useful have yet to be determined.
Advocates for pulsatility suggest that it may be important for preserving the microscopic architecture of blood vessels and vascular endothelial cell linings. Others believe its absence plays some role in mucosal bleeding. However, given generally favorable outcomes observed clinically with long-term exposure to diminished pulsation and with some of the challenging tradeoffs that are obligatory to generating pulsatility, more analysis will be necessary before justifying pulsatility as a standard for next-generation devices.
Extending INDICATIONS
The greatest usage of MCS devices has been in patients with systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), nearing end-stage, mostly in NYHA class IV, primarily in one of two groups, bridge to transplantation (BTT) or long-term DT. Given increasingly blurred lines of distinction between BTT and DT, these end-point categories are changing in favor of duration of support, either short-term (< 6 months) or long-term (> 6 months).
In the future, there will be a shift in the systolic heart failure population from near-end-stage patients to those with earlier-stage heart failure, extending into NYHA class III/IIIB—as it becomes justified to do so based on improving MCS outcomes. Two other populations are expected to receive increasing attention in the future: candidates for cardiac recovery and patients with diastolic heart failure (heart failure with preserved ejection fraction [HFpEF]).
Recovery
The phenomenon of ventricular reverse remodeling in patients with chronic heart failure has been met with considerable enthusiasm but has yet to be established as a meaningful and predictable target for therapeutic intervention. Important examples have illustrated the potential for cardiac recovery—sometimes spontaneously as with acute myocarditis, sometimes facilitated by drugs or cardiac resynchronization pacing.
Numerous approaches have been proposed to augment cardiac recovery, but none have been as hopeful as the use of VADs to provide chronic mechanical unloading. The amazing experience described by the Harefield group reporting 60%–70% recovery rates with either a pulsatile or continuous-flow LVAD supplemented with clenbuterol stimulated the field to pursue this. Such encouraging rates of recovery have been difficult to reproduce—at least until the recent multicenter study, the RESTAGE-HF, reporting findings of a 50% rate of recovery to LVAD explantation.
LVADs as tools to augment recovery may be at the early stage of a new era with new opportunities. The beauty of mechanical unloading is that it stabilizes a patient with decompensated heart failure and creates a durable and sustainable myocardial recovery test-bed in which many different interventions facilitating recovery may be explored—whether pharmacologic, biologic, cellular, genetic, or bioengineered.
The door should be wide open for the development of MCS devices tailored to support cardiac recovery. Well-engineered devices with sensing capabilities will be able to provide diagnostic information about the stage of recovery and the hemodynamic/physiologic conditions for supporting recovery. Next-generation pumps with smart controllers will enable optimum unloading during an initial period of ventricular shape restoration, followed by controlled loading for enhanced retraining while avoiding degenerative apoptosis. Greater success with LVAD-supported recovery will set the stage for even further advances as the science of reverse remodeling matures at the cellular, extracellular, metabolic and genomic levels.
Heart failure with preserved ejection fraction
The large, and growing, population of patients with HFpEF (alternatively referred to as diastolic heart failure) experiences a burden of heart failure as great as those with HFrEF (systolic heart failure). Unfortunately, there are no proven, effective treatment options.
Traditional LVADs with LV apical cannulation have seen only limited use in the HFpEF population. LV cannulation with hypertrophic hearts, as seen with HFpEF, is challenging and generally avoided, given the small LV cavity size and associated risk of obstruction to inflow.
On the other hand, HFpEF patients consistently have enlarged left atria (LA). Thus, a pump designed for HFpEF patients would preferentially employ LA uptake, based on anatomic considerations alone.
Besides the anatomic advantages, there are physiologic benefits of LA to aortic pumping in HFpEF. During exercise, patients with HFpEF markedly increase LA pressures. When the LA pressures become extreme (three to four times normal), patients can no longer exercise. With active pumping from the LA to the aorta, the LA pressure can be decompressed to a level low enough to accommodate exercise while the pump contributes net forward blood flow from the heart to the body. Plus, the LV can still function to support exercise when LA pressures are maintained high enough to allow effective LV filling and ejection from the stiff, poorly compliant LV (as is the case with HFpEF)—but at LA pressures low enough to permit exercise.
Thus a partial-flow pump with output in the 2–4 liter per minute range should be sufficient given that it is working in parallel to supplement a functional LV with preserved systolic ejection capacity. This has been demonstrated by modeling encouraged by clinical experience with the Circulite device, a miniaturized pump with an uptake in the LA and arterial return to the subclavian artery. With expectations of improved pump safety along with less invasive implantation, possibly even with percutaneous delivery, use in earlier-stage heart failure may be warranted. Advanced controller features will be needed to accommodate the unique HFpEF (patho)physiology.
Enhancing QUALITY OF LIFE
The phrase ‘forgettable technology’ has been used to describe an ideal state for the coexistence of patients with their MCS devices. Today, it is a dream beyond foreseeable reach—but the vision of “forgettable technology” should not be forgotten.
Every effort must be made to reduce the burden of MCS therapy for patients. It is one type of achievement to make implantation ‘less invasive’; it is a different accomplishment to make the daily experience ‘less intrusive’. Smaller incisions may sound attractive at the time of implantation—but that attraction soon disappears when patients are obliged to carry an unwieldy bulk of peripherals, every day, for the rest of their lives.
Hardware components to be targeted for improving quality of life include: (1) percutaneous lead elimination or alternatives for periodic untethering; (2) controller size, ergonomics, and user interface, including visuals and alarms; (3) battery size and duration; and (4) external cables and connectors with consideration for wireless interconnectivity, for example, Bluetooth.
Functional features to be addressed for improving quality of life include autoresponsive controllers enabling greater exercise tolerance.
Facilitating IMPLANTATION
Adoption and responsible dissemination of a new therapy are wholly dependent on standardization, reproducibility, and ease of use. Being able to move beyond the pioneering experimental phase and assure successful transfer into the ‘real world’ depends on that.
For MCS implantation, that means making the surgical process less burdensome, reducing complexity, and reducing risk. Much of the responsibility for that is left in the hands of surgeons who develop, adapt, and optimize surgical techniques.
Device developers can take it a step further by providing well-designed surgical tools to simplify implantation. That could include tools designed to support ‘keyhole’ surgery through small incisions. Tools that could make it possible to decrease or eliminate cardiopulmonary bypass could include devices that allow for bloodless insertion of uptake cannulas or for connecting outflow grafts to blood vessels with auto-anastamotic devices and readily accessible imaging tools to help with selecting best anatomic locations to avoid risks related to blind insertion, such as dislodging thrombi or calcified plaques.
Enthusiasm is developing for percutaneous , endovascular deployment of chronic, implantable MCS devices. This approach will have to be reserved for patient populations in which miniaturized, partial-flow devices will be effective. The development of such devices for long-term implantation will necessitate overcoming the engineering challenges of down-scaling while still maintaining manufacturability, performance, durability, and hemocompatibility. Further, the challenges of percutaneous delivery, internal stabilization, endovascular connections, lead exteriorization, etc., will require new, creative developmental effort.
Easing Device USE
Remote Monitoring and Management
The burden for caretakers of managing an increasing number of MCS outpatients at home is substantial and will become onerous with escalating growth of the field. Remote monitoring of pump systems has been demonstrated (e.g., Reliant Heart) and may serve to ease the burden of care. Data security and patient confidentiality must be assured. Adapting existing remote monitoring platforms already in widespread use today such as those for pacemakers and diabetic therapy may be helpful (e.g., Abbott’s Merlin.net and Medtronic’s CareLink networks).
Remote management of pump systems could further ease the burden of care. However, extensive effort will be necessary given the challenges of engineering, information transfer, and regulatory requirements. Automated algorithms for closed-loop responses should reduce the manual burden but will face extensive development and regulatory challenges.
While such capabilities will enable remote care and make it less burdensome, it will not eliminate the need for readily available and responsive clinical teams to engage and intervene as necessary. Efficiency will be important, enabled by high-reliability information and technology.
OPTIMIZING MANAGEMENT
Ongoing advances with management are extremely important to the future of MCS. As essential as improvements in technology are, the future depends on making best use of whatever technology is available at any point in time. Furthermore, innovative management will even circumvent limitations with technology, until further perfected, as has been demonstrated repeatedly since the inception of the MCS field. Clinical teams and care providers will have numerous opportunities to optimize management, whether it be surgical, medical, or lifelong.
Optimizing SURGICAL Management
Enthusiasm for less invasive surgery to implant MCS devices is expected to increase. This trend follows what has been happening with conventional cardiovascular surgery. The less invasive surgical approach most often involves a left thoracotomy for LVAD implantation combined with an upper hemi-sternotomy (or right paramedian approach) for aortic graft anastomosis.
The nonsternotomy approach is sometimes required when the risks associated with a reoperative sternotomy are considered prohibitive. Avoiding a median sternotomy is believed by some as useful with the BTT indication, sparing the median sternotomy for the subsequent transplantation procedure. Other proposed advantages of the non-sternotomy approach may include less bleeding, faster recovery, and better preservation of right heart function. On the other hand, a sternotomy approach is sometimes necessary, for example, when concurrent cardiac surgical procedures such as valve repair or replacement are indicated.
Further advances with minimally invasive implantation tools will be beneficial for less invasive approaches. Until the techniques are well refined and readily reproducible, enabled by expertise and easier-to-use hardware, it seems prudent to exercise caution with widespread dissemination of procedures that can quickly become extraordinarily complicated.
Another approach to the “less is more” concept is what might be referred to as less intrusive surgery . The reduction or elimination of cardiopulmonary bypass time may offer advantages avoiding the potential mal-effects of inflammation and bleeding. This too will be enabled by the development of surgical tools to minimize blood loss and facilitate control.
The presumed advantages of less invasive or less intrusive approaches should be validated by more extensive clinical studies allowing for carefully controlled comparison to traditional, conventional approaches. Among the outcome variables for consideration would be surgical complications, impact on right heart function, impact of loss of access for concomitant surgical procedures, recovery time, pain, impact of surgeon experience and enabling technology, etc.
Another area for optimizing surgical management is to intensify efforts to improve surgical outcomes . This is well exemplified by a wide-open opportunity for surgeons to play a major role in reducing the incidence of strokes that are seen at implantation or in the weeks to early months thereafter.
The neurologic outcomes within the MOMENTUM (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3) Trial of the HeartMate 3 include an amazingly low stroke rate beyond 6 months of 0.04 per patient-year. Assuming such outcomes can be carried into real-world practice, it would be considered a remarkable advance for LVAD therapy. The greatest opportunity for further improvement in neurologic outcomes occurs within the first 6 months after implantation, wherein the stroke rate is 0.15 per patient-year, with 50% of those occurring in the immediate perioperative period, within the first 30 days after the operation.
So, how can surgical management make meaningful contributions to reducing stroke rates? The answer may lie with implementing intensive efforts to mitigate risks for perioperative strokes while encouraging field-wide adoption of surgical best practices incorporating neuroprotective guidelines . Fig. 22.7 provides a list of risk factors that may exist during the implantation of an LVAD.
