Among the many advances in medical therapy, the last decade has certainly witnessed the emergence of mechanical assist therapy from a dream to a tangible reality. Advances in device design, surgical techniques, and post-operative management have clearly and firmly established these devices as a critical option available for the treatment a challenging group of patients with heart failure. This article is a brief synopsis of the current state of mechanical circulatory support for the heart, with a perspective on the current limitations of this technology and the future direction of this exciting and rewarding field.
The need for acute cardiac support beyond cardiopulmonary bypass was clear from the early days of cardiac surgery. Spencer and colleagues reported the first successful clinical use of a temporary device in 1965 after four patients were placed on femoral-femoral cardiopulmonary bypass. Only one patient survived to discharge. Subsequently, in 1966 the first successful use of a left ventricular assist device was reported after a double valve operation. DeBakey used an assist device that was implanted in an extracorporeal location between the left atrium and the axillary artery, marking the first use of an extracorporeal temporary device support system. The patient survived for 10 days on the pump and was eventually discharged.
The excitement surrounding these events prompted the formation of the Artificial Heart Program in 1964 and propelled the National Heart Institute (now the National Heart, Lung, and Blood Institute (NHLBI)) to support and encourage the development of mechanical circulatory support systems. The objectives of this program were to promote the development of a support system that would be used for:
- acute circulatory insufficiency;
- temporary support systems that would work for days to months until recovery occurred;
- permanent heart systems that would support the patient for the remainder of their life; and
- totally implantable artificial hearts.
Based on these primary objectives, a request for proposals were issued by the Device and Technology branch of the NHLBI that eventually laid the foundation for this field to evolve and lead to the development of currently available devices.
Mechanical circulatory support systems can be broadly categorized into two groups relative to duration of support:
- Temporary support for clinical situations in which cardiac recovery is likely and a period of pressure and volume unloading of the heart may prove beneficial.
- Chronic support from days to months that allow physical rehabilitation of patients while awaiting the availability of a suitable heart for transplantation.
Temporary Circulatory Support
Indications for Support and Patient Selection
Temporary circulatory support is generally applied to patients in cardiogenic shock who are unresponsive to high dose inotropic support and other adjunctive treatments such as nitric oxide and intra-aortic balloon pump counter pulsation. The criteria for considering instituting mechanical have previously been published1 and the importance of early decision-making in this process has been clearly established.2 Generally, the vast majority of patients need temporary circulatory support as a complication of one of the following:
- ostcardiotomy shock;
- acute myocardial infarction; and
- acute myocarditis.
The primary goal of acute mechanical support is rapid restoration of the circulation and stabilization of hemodynamics. The routine use of transesophageal echocardiography (TEE) has greatly helped in assessing the etiology of cardiogenic shock by allowing evaluation of ventricular function, regional wall motion abnormalities, and valvular mechanics. In a patient with mechanical complications secondary to myocardial infarction such as acute rupture with tamponade, acute papillary muscle rupture, or postinfarction ventricular septal defect, emergent surgical correction may obviate the need for device support. Similarly, in the postcardiotomy setting with failure to separate from cardiopulmonary bypass,TEE may direct the surgeon to the need for additional revascularization and reparative valve surgery and successful weaning from bypass.
If echocardiography fails to reveal a surgically correctable cause for cardiogenic shock, most surgeons use hemodynamic data to consider the need for mechanical assistance. These criteria include a cardiac index <2.2L/min/m2, systolic blood pressure 90mmHg, mean pulmonary capillary wedge pressure or central venous pressure 20mmHg, and concomitant use of high doses of least two inotropic agents. In clinical situations associated with the above hemodynamic criteria mortality in absence of mechanical support exceeds 80%, and early institution of device support is mandatory for a successful outcome.
Once mechanical assistance has been instituted, the stabilized patient can undergo periodic evaluation to assess native heart recovery, end-organ function, and neurological status. Evaluation for cardiac transplantation is initiated concomitantly. Patients who do not have occult malignancy, severe untreated infection, or neurological deficit are selected for cardiac transplantation if all other criteria are met and there is no sign of cardiac recovery.
In this subgroup, transition to a chronic ventricular assist device until an organ becomes available is generally the strategy with the best survival outcome. In those patients with gradual improvement in myocardial pump function, the devices may be weaned and removed.
Results with Temporary Mechanical Support
Centrifugal pumps and extracorporeal membrane oxygenator (ECMO) are the most commonly used devices for temporary support primarily because of ease of implantation and surgeon familiarity with this technology. The added advantage of ECMO is the existence of an in-line oxygenator which allow for complete cardiac and respiratory support with the option of complete percutaneous cannulation of the femoral vessels. This device is ideal for situations where immediate circulatory support is needed, such as situations that may arise during high risk percutaneous interventions.
In 1992, Pae and associates in a large case series from the registry, summarized outcomes in 965 patients who had been supported with centrifugal pumps.3 In this group, 45% were weaned and 25% survived to discharge from the hospital, with the rates of weaning and discharge favoring those requiring univentricular support. In the group surviving to discharge, two-year actuarial survival was 82% with 86% of patients in NYHA class 1 or 2.
Although patients who survive to discharge generally do well, the disappointingly low initial salvage rates have hardly improved over the last decade. Several pre-existing factors seem to adversely affect outcomes in patients treated for post-cardiotomy shock, including age, re-operation, emergency operations, higher creatinine, and greater LV dysfunction prior to initiation of support.4 Unfortunately, these pre-existing factors are difficult to modify and encompass many of the patients that require cardiac operations. However, there are several other areas of potential improvement. First, it has clearly been shown that early institution of circulatory support is associated with improved outcomes. Second, a network concept relating easy transfer of patients from smaller hospitals (the spokes) to a tertiary care center for bridge to chronic devices or transplantation has been shown to improve results. It should be emphasized that the referring center should have the primary responsibility of full stabilization of the patient, control of bleeding, correction of metabolic and homodynamic abnormalities with delayed transfer within 24 to 48 hours to a tertiary care facility. Finally, there is growing evidence that device type does make a difference in overall outcome. One of the primary problems with ECMO support continues to be the high complications that have been reported by all groups.
Smedira reported infection in 49%, dialysis in 40%, neurological events in 33%, and limb complications in 25% of patients supported by ECMO.5 Peripheral cannulation for ECMO is generally fraught with limb complications secondary to arterial and venous insufficiency unless a side graft is used. Continuous requirement for heparin and the consumptive coagulopathy that is associated with the circuit and the oxygenator sets up a perpetual cycle of bleeding and large transfusion requirements. Furthermore, under the best circumstance ECMO flows achieved are generally in the range of 2.5 to 3.5 literatures/min.6 Low flows, open chest, limb ischemia, and the need for immobilization and ventilation undoubtedly contribute to the large number of infectious complications and multisystem organ failure that has been reported.
In cases of postcardiotomy shock, the majority of myocardial damage is likely to have occurred intra-operatively with poor preservation of the heart during the period of arrest. With advances in myocardial preservation including use of both antegrade and retrograde cardioplegia, this complication can be reduced, but poor distribution of cardioplegia and the unpredictable deleterious effect of ischemia-reperfusion injury can lead to a poorly functioning ventricle even in the most experienced hands. Golding and colleagues found that 69% of patients autopsied after postcardiotomy ventricular support had extensive myocardial injury.7 It seems that it is the erratic nature, extent and distribution of myocardial damage that makes the clinical course of these patients unpredictable. What differentiates patients with irreversible myocardial necrosis from those with viable but stunned myocardium? What length of support is appropriate to make that decision?
Over the last decade, as experience with chronic support devices has increased, the use of these systems has been extended to the treatment of patients with acute circulatory decompensation. The chronic systems allow for extubation, ambulation, and physical rehabilitation of patients. By extending the time for safe support, the period for recovery of myocardial function can be extended. For patients who do not show recovery, they can be bridged to cardiac transplantation if they are deemed to be appropriate candidates. Using this strategy, survival of patients has been improved, with recent reports in the range of 60% to 70%.8 It is likely that, in the future, the use of chronic pulsatile or non-pulsatile devices that allow chronic long-term support will expand for acute circulatory support. As permanent support becomes an option, many of those who can be stabilized but cannot be weaned, will be offered permanent device therapy.
Chronic Support Devices
There has been an impressive increase in the number of centers worldwide that offered chronic ventricular support therapy as bridge to transplantation. In the US there are currently four devices that have a track record as bridge to transplantation: the Heartmate and Novacor devices are available as implantable electrically driven systems for left ventricular assist support; the Thoratec device an extracorporeal (or paracorporeal) device that is designed for support of the left or right ventricle in isolation or combined (biventricular); and the CardioWest device, the only total artificial heart that has been recently approved.
With all of these systems, patients are physically recuperated with reversal of end-organ dysfunction and improvement in New York Heart functional classification. The vision of patients tied down to the hospital after getting a mechanical pump has rapidly vanished as there is now a large out-patient experience with the Heartmate and Novacor devices because both systems are easily portable. The Thoratec and CardioWest devices are in the process of developing or getting approval for consoles that would allow patient discharge from the hospital. With all these systems, reported survival to transplantation is in the range of 60% to 70% with post-transplant survival essentially equivalent to those patients that have received primary cardiac transplantation. Numerous studies have reported similar favorable results in otherwise moribund patients. In parallel, it has also become clear that the best results with device therapy is in fact for patients in whom the decision to implant the device is made early, prior to development of significant end-organ dysfunction. Most complications associated with device implantation are common to all devices and may be largely related to the late decision-making process. First, significant bleeding requiring massive transfusions are uniform in the range of 40% to 50%. Hepatic congestion, pre-existent coagulopathy, and the added insult of cardiopulmonary bypass to a large extent contribute to this problem. Second, stroke related to thromboembolization or primary intracranial hemorrhage is, in part, related to the need for chronic anticoagulation and the fine tuning of this art to balance thrombotic and hemorrhagic complications. Third, infectious complications related to the pump pocket (the location within the body created for the pump), or the percutaneous drivelines that exit the skin and connect the device to the controller, continue to haunt all surgeons with incidence as high as 20% to 30%. Finally, for patients receiving left ventricular support systems, right ventricular dysfunction in setting of high pulmonary vascular resistance, can lead to low pump output which inherently increases the risk of stroke and also may impact complete end-organ recovery.
Although right ventricular dysfunction is common, the majority can be managed medically with inotropic support and inhaled agents that reduce pulmonary vascular resistance.The need for addition of a right ventricular support is reported in 10% of patients with survival to transplantation in this group being reduced to approximately 50%.
Despite these limitations and significant complications, the use of VADs for bridge to transplantation is firmly established and has gained a stronghold in the treatment of end-stage heart failure. Numerous publications relay how, in situations previously associated with 100% mortality, VADs have allowed for successful survival to transplantation. Reports on using VAD support as a bridge to recovery are less supportive of this concept for general applicability. Most studies have clearly demonstrated reverse remodeling of the dilated ventricle to a more favorable position on the Frank-Starling curve after pressure and volume unloading imparted by a VAD. In addition, there has been significant data on favorable morphological and histological changes that accompany VAD support. Unfortunately, these data have not translated into clinical applicability. Some recent data suggest that pharmacologic treatment of the heart with _-agonists will lead to hypertrophy and successful weaning and removal of the device.9 It is also likely that, in the future, adjunctive treatments such as stem cell transplantation will become a reality, allowing myocardial 'repairÔÇÖ during the recovery phase. In addition, better understanding of genomics and proteonomics will likely lead to combined approaches and make VADs as bridge to recovery a clinical reality.
VADs for Permanent Therapy
The success of VADs for bridge to transplantation provided the grounds for extending the indications as permanent therapy to patients who were not transplant candidates. The landmark study, Randomized Evaluation of Mechanical Assistance for The Treatment of Congestive Heart Failure (REMATCH) trial, was the first trial to specifically compare the survival of patients receiving the Heartmate VAD with those treated with optimal medical therapy.10 The rates of survival at one year were 52% in the device group and 25% in the medical therapy group, and the rates at two years were 23% and 8%, respectively. This landmark trial opened the stage for the first-time approval of this device as permanent therapy for non-transplant candidates by the US Food and Drug Administration (FDA).
Widespread application of this technology seems to be reasonable, based on the significant survival advantage offered by VAD therapy. Unfortunately, this trial also was disappointing because of the significantly large number of complications reported. Most notably LVAD mechanical failure accounted for seven deaths in the 68 patients on the VAD and device malfunction occurred in 37% of the patients. Incidence of neurological dysfunction, broadly defined as any neurological abnormality including reversible toxic/metabolic causes, occurred in 42% of patients.
Despite these results, The REMATCH trial has clearly set the stage for evaluation of device therapy for permanent application. The Heartmate LVAD has undergone significant design and engineering modifications to improve longevity of the device and reduce infectious complications. Over the last several years patient management and post-operative care has significantly improved and preliminary data suggests that patients enrolled in the latter two years of the REMATCH trial, have improved survival beyond the 23% originally reported at two years.
The Challenge for the Future
The next few years will continue to be exciting times for treatment of heart failure patients as medical therapy eventually approaches a plateau. With the continued increasing demand for hearts and the significant limited donor availability, the future of device therapy will likely be glorious. Advances in device design and engineering will undoubtedly lead to improved durability. Various axial flow and newer centrifugal pumps are currently in clinical trials throughout the world. Preliminary reports suggest a significant improvement in durability of these devices. In addition, the smaller sizes should allow broader applicability to patients with smaller body size, reduce infections previously related to pump pockets (as they do not require creation of a pump pocket) and eventually lead to enabling technologies that would allow complete implantation within the body without exiting drivelines. It is not inconceivable to envision a day when device therapy replaces cardiac transplantation as the 'gold standardÔÇÖ for treatment of end-stage heart failure. In addition, these new developing technologies, paralleled by better understanding of the cellular and molecular mechanisms of heart failure, may lead to the ultimate therapeutic goal: strategies that would allow repair of damaged myocardium by cellular or molecular engineering of the underlying substrate.