Mechanical Device–Based Methods of Managing and Treating Heart Failure
http://www.100md.com
《循环学杂志》
the Division of Cardiology, Columbia University Medical School, New York (D.M., D.B.)
IMPULSE Dynamics, Orangeburg (D.B.), NY.
Abstract
Despite advances in pharmacological treatments aimed at neurohormonal blockade for heart failure in the setting of left ventricular pump dysfunction, there is still a growing number of patients with advanced symptoms who suffer significant morbidity and mortality. Mechanical stresses and chronic neurohormonal activation conspire to propagate maladaptive ventricular remodeling responsible for the insidious nature of this disease. Recent studies suggest that further pharmacological neurohormonal blockade may not be safe or effective, which has driven development of devices for this patient population. Furthermore, such devices may target fundamental pathophysiological abnormalities that are largely hemodynamic and mechanical in nature that are not addressed by available pharmacological agents. The profound reverse remodeling routinely associated with left ventricular assist device use, reviewed in detail, further validates device-based approaches and should inspire research to find ways to make this recovery more complete and permanent. Accordingly, this review focuses on the multitude of mechanical device–based approaches currently being investigated to manage and treat this population. From devices for monitoring patient status to anticipate congestive heart failure exacerbations and preemptively adjust therapy to devices to support preterminal patients with end-stage disease, it is recognized that these device-based approaches will assume an increasingly important role in treating the growing number of patients with advanced heart failure.
Key Words: heart failure ; transplantation ; disease management
Introduction
There have been several important advances in pharmacological treatments for heart failure resulting from decreased ventricular pump function that have significantly reduced mortality—namely ACE inhibitors,1 ;-blockers,2,3 and aldosterone inhibitors.4 Nevertheless, the progression from asymptomatic left ventricular dysfunction to symptomatic heart failure is still common. The number of hospitalizations for heart failure exacerbations continues to increase, and most patients will ultimately die of complications related to heart failure.5 There is a need for treatments that prolong life and enhance exercise tolerance.
Many of the major advances achieved over the past 2 decades came with the recognition that the progression of heart failure is due to neurohormonal activation and abnormal mechanical stresses on the myocardium (increased preload and afterload; Figure 1). This vicious cycle of progressive pump enlargement and dysfunction is collectively referred to as ventricular remodeling. The structural and functional aspects of remodeling can be illustrated on a ventricular pressure-volume diagram (Figure 2A). With sustained neurohormonal activation and its consequences, the pressure-volume relations gradually shift toward larger volumes so that ejection fraction is reduced with marked myocardial hypertrophy. The goal of many heart failure treatments is to prevent, slow, or reverse this process (Figure 2B). Randomized studies have shown that pharmacological blockade of the key neurohormonal pathways interrupts the vicious cycle, retards progression, and improves survival (Figure 1, blue). However, results of several recent trials suggest that attempts to block additional neurohormonal pathways may be detrimental.6 This finding has led to the concept that we may have reached the limit to which neurohormonal and cytokine mechanisms can be blocked in heart failure patients.7
Accordingly, there have been intensive efforts to develop and test device-based therapies for patients with both acute and chronic heart failure. For example, cardiac resynchronization therapy8 has been approved by the US Food and Drug Administration (FDA) for NYHA class III and IV chronic heart failure (CHF) patients with abnormal electric conduction, and recent clinical trials support broader use of implantable cardiac defibrillators in patients with ventricular dysfunction.9,10 Such devices have significantly affected the treatment of CHF patients. Other experimental forms of therapy such as myogenesis (eg, stem cell, myoblasts)11 and other electrical therapies such as cardiac contractility modulating nonexcitatory electrical impulses12 and less invasive defibrillators are under active investigation. These classes of devices are the topic of a recent review in this series. The focus of the present review is on mechanical devices to treat various stages of heart failure that are currently available or are under development. Not included for the sake of brevity, but still noteworthy, are classes of devices under development to aid in comprehensive disease management programs and chronic hemodynamic monitoring systems aimed at prevention and early detection of heart failure exacerbations to reduce hospitalizations and increase longevity.
Surgical Approaches to Treatment of CHF
Surgical reshaping of the dilated heart, a topic of significant research in recent years, is relevant to the topic of device-based heart failure treatments. One class of procedures that has received significant attention is generically referred to as ventricular reduction surgery. The concept behind these procedures is to reduce the increased radius of curvature present in a dilated heart, which increases systolic myocardial wall stress via Laplace’s law. A reduction in radius of curvature would decrease wall stress, in principle allowing for reverse remodeling. The technique for reducing radius of curvature conceptually involves excluding a portion of the ventricular wall and reconstructing a smaller (preferably more normally elliptical) chamber. The surgical procedure differs in technique and physiological effect, depending on the properties of the muscle removed. The Batista operation13 was intended to treat patients with idiopathic cardiomyopathy, so the muscle removed was functional but weak. However, it was prospectively predicted14 and later proven that this approach worsened overall pump function (as indexed by the relation between filling pressure and cardiac output) and did not generally provide benefit to patients.15 This procedure is no longer practiced.
In ischemic cardiomyopathy, myocardium affected by infarctions can heal in different ways, generating either an akinetic scar or a dyskinetic scar (ie, aneurysm). Ventricular reduction surgery in this setting therefore removes noncontractile material. The effects of these ventricular reduction surgeries on ventricular pressure-volume relations has not been studied, and clinical studies of these procedures are generally confined to reports of nonrandomized registries. Removal of dyskinetic scar (aneurysmorophy) is clinically accepted and reported to be associated with satisfactory outcomes.16 The effects of removing akinetic scar (often referred to as the Dor procedure17 or surgical anterior ventricular restoration [SAVR]18) are less clear. The same theoretical modeling that correctly predicted detrimental effects of the Batista operation predicts that aneurysmorophy significantly improves pump function (which matches most of the data in the literature) and predicts that pump function will not be significantly improved by SAVR (Figure 3).19 The SAVR operation is now being studied prospectively as part of the NIH-sponsored Surgical Treatment of Ischemic Heart Failure (STICH) trial (http://www.stichtrial.org/disclaimer/index.cfm). Without firm scientific evidence that proves the benefits of such surgery, many physicians are reluctant to refer patients.
One limitation of these surgeries that could potentially confound the study is the lack of a uniform method of performing the procedure. Thus, the amount of tissue removed and the ultimate size and geometry of the reconstructed chamber are more or less at the discretion of the surgeon, with no firm guidelines. Two devices under development provide a model (CHF Technologies and Chase Medical) that is inserted into the chamber to provide a guide for both resizing and reshaping the left ventricle. These devices are being studied independently outside the STICH trial.
Another method proposed to decrease wall stress and to induce reverse remodeling is by passive ventricular restraint devices (ACORN Cardiovascular Inc; Paracor Medical, Inc; Myocor Inc). This concept evolved from an earlier investigational approach called cardiomyoplasty20 that tested the concept that the latisimus dorsi muscle could be freed, wrapped around the heart, and stimulated to contract in synchrony with the native heart, providing a boost to ventricular performance. However, it was discovered that after a relatively short time, continual stimulation of the skeletal muscle caused fatigue so that the graft no longer contracted with each stimulation.21,22 Rather, the skeletal muscle ultimately became a passive wrap around the heart. Although the overall clinical trial failed to show benefit, some patients appeared to benefit, and there was a reduction in heart size with some improvement in function. This led to the concept that the same effect could be readily achieved with a passive material appropriately tailored and fit snug to the heart.23 Studies in animals in which CHF was induced by repeated coronary artery microembolization have indeed shown reverse remodeling, including a leftward shift back toward normal of the end-systolic pressure-volume relationship (Figure 4), improved pump function and reversal of the fetal gene program associated with heart failure, which is interpreted as being a beneficial consequence of reduced wall stress.23 Importantly, despite the fact that the heart is wrapped to slightly decrease volume acutely, there is no induction of a restrictive physiology. A recently completed multicenter, randomized study of this technology with 300 patients has suggested that this approach improves NYHA functional class and reduces the requirement for subsequent major cardiac procedures such as cardiac transplantation and ventricular assist device insertion. Another device intended to perform similarly is constructed of nitinol, which may more readily permit placement of the device via port access.
Still another form of ventricular reshaping involves use of transventricular struts to bring opposite sides of the dilated left ventricle toward each other to reshape the ventricular circumference from 1 large circle to 2 circles, each with a smaller radius of curvature (in a kind of figure 8 configuration; Myocor, Inc).24 This device is currently under investigation for its potential use in treating heart failure and as a means of less invasively reducing the severity of mitral regurgitation.
For all these forms of surgical heart failure treatments, mitral valve repair or replacement is an important yet potentially confounding factor during clinical trials. Although mitral repair is typically effective at eliminating or reducing the regurgitant volume, it remains controversial as to whether and when to perform such surgery as a sole treatment in patients with low ejection fraction.25 Accordingly, numerous catheter-based devices are being developed to perform mitral valve repair percutaneously to reduce risk and allow it to be performed as a sole therapy to treat symptoms of heart failure.26,27 It is proposed that availability of such devices will allow treatment of more patients, including those at high risk, with reduced procedural morbidity and mortality.
Devices to Treat Acutely Decompensated Heart Failure
As patients deteriorate into more severe decompensation and cardiac output and blood pressure decline, patients become increasingly resistant to high doses of diuretics, and fluid overload ensues. Reduced renal perfusion resulting from relative hypotension and renal artery constriction are contributing factors. Because diuretics reduce glomerular filtration rate, their use, although necessary to treat symptoms, may contribute to further diuretic refractoriness. Accordingly, devices aimed at improving renal perfusion, directly dealing with fluid overload, and/or attempting to improve systemic perfusion have been developed.
One such strategy is local renal artery vasodilator drug delivery.28 Local renal vasodilator therapy can potentially improve renal blood flow and glomerular filtration rate while acting synergistically with diuretics to effect a diuresis with fewer effects on arterial blood pressure than the same drugs delivered systemically. Devices are currently under development for such local drug delivery that would allow testing of this strategy (Flowmedica, Inc).
A direct means of dealing with fluid overload in patients who have inadequate response to diuretic therapy is aquapheresis with a specialized system that provides efficient salt and water removal by a new form of ultrafiltration (Aquadex System 100, CHF Solutions).29 This system uses peripheral or central venous access and requires a low volume of extracorporeal blood to prime the system (33 cm3) compared with standard hemofiltration devices. This system removes isotonic salt and water at rates between 100 and 500 cm3/h without clinically significant changes in serum electrolytes, heart rate, or blood pressure. Because of the relative simplicity of operation, this system can be administered in inpatient settings and outpatient care centers. Four clinical trials of this system have indicated the ease, safety, and efficacy of this strategy to remove fluid. The UNLOAD trial, a prospective, randomized, multicenter, 200-patient trial, is currently underway and is testing the short-term efficacy with respect to fluid and symptoms and 30- to 90-day clinical impact of aquapheresis compared with usual diuretic strategies.
Another novel investigational approach for treating patients with acute heart failure exacerbations who are dependent on or resistant to intravenous inotropic agents involves continuous aortic flow augmentation.30 The Cancion system (Orqis Medical) consists of an extracorporeal, magnetically levitated centrifugal pump that withdraws blood from the femoral artery and returns it to the descending thoracic aorta in a continuous, nonpulsatile manner at rates between 1.1 and 1.5 L/min. Studies in experimental animals with CHF and results of preliminary clinical studies in patients with heart failure exacerbations demonstrate that this continuous flow loop results in increased cardiac output, improved renal function (decreased creatinine) and diuresis, and reduced pulmonary capillary wedge pressure. The suggested mechanisms of action include direct ventricular afterload reduction, stimulation of nitric oxide production (resulting from increased aortic shear stress) that leads to vasodilation, and increased renal perfusion. Randomized, controlled studies are currently underway.
Catheter-Based Pumps for Acute Cardiogenic Shock
As a result of either the progression to end-stage heart failure in patients with longstanding cardiomyopathy or severe ventricular dysfunction in the setting of acute myocardial infarction, cardiogenic shock (inadequate blood pressure and cardiac output to meet the metabolic needs of the body) occurs in many patients surviving to hospital admission. Medical treatment with intravenous inotropes, followed by use of the intra-aortic balloon pumping (IABP), is considered the first line of treatment for such patients.31 However, these strategies are frequently not effective. Several devices are under development for treating such patients.
Approved for short-term (6 hours) hemodynamic support is the TandemHeart percutaneous ventricular assist device (CardiacAssist). This device consists of an extracorporeal centrifugal (continuous flow) pump that withdraws blood from the left atrium via a cannula introduced transseptally via the femoral vein. Blood is then pumped (at up to 3.5 L/min) by a centrifugal pump through cannulas in 1 or both femoral arteries.32 Preliminary results showed that this device can improve hemodynamics in patients with cardiogenic shock. Studies also showed a reduction in serum lactate levels, an indication of improved tissue oxygenation and thus reversal of the cardiogenic shock state. In a more recent study, patients with cardiogenic shock resulting from acute myocardial infarction failing medical treatment were randomized to treatment with either an IABP or the TandemHeart assist device.33 The IABP had almost no effect on hemodynamics, but the TandemHeart device significantly increased cardiac output and blood pressure while significantly decreasing pulmonary capillary wedge pressure. However, mortality was comparable in both groups.
Other devices are being developed to provide acute hemodynamic support. They include 2 axial flow pumps (Impella CardioSystem AG,34 A-Med System, based on a prior system called the Hemopump35). These systems have helical propellers at the tip of catheters that are positioned retrograde across the aortic valve. Motors rotate the propellers, which draw blood from the left ventricle through the distal end of the catheter and discharge it into the aorta. These catheters can be inserted percutaneously via a femoral artery or surgically into the proximal aorta. Like the TandemHeart, these devices unload the left ventricle, thus reducing oxygen demand while improving systemic perfusion (Figure 5). Studies are underway to assess the safety and efficacy of these devices in a variety of settings in which IABPs are now used, including cardiogenic shock.
Devices for Chronic Decompensated CHF
Because of the limited availability of donor organs and the urgency for cardiac support in the setting of severe hemodynamic decompensation, ventricular assist devices capable of completely supporting the circulation are taking on an increasingly important role in heart failure therapy.
Several FDA-approved devices provide short-term circulatory support for postcardiotomy failure or bridge to transplantation. Those who might benefit from device placement for acute cardiac failure include patients unable to be weaned from cardiopulmonary bypass, those experiencing acute myocardial infarction with cardiogenic shock, patients with myocarditis, and patients who deteriorate while awaiting transplantation. In the last group, assist devices can be especially helpful before transplantation by providing a period for recovery of heart failure–related end-organ impairment, thus reducing the risk of transplantation.36,37
Following the results of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, use of left ventricular assist devices (LVADs) as destination therapy is now approved for some patients ineligible for transplantation.38 Use of the HeartMate vented electric device was shown to improve survival over a 2-year period in this population. Although this landmark study ushered in the era of destination therapy, adverse effects related to infection, stroke, bleeding, device failure, and other factors all call for technological advances to improve outcomes.
Many devices are available to provide temporary support, either as a bridge to another treatment or until recovery of heart function. Selecting the appropriate device is dependent on a number of considerations, including the anticipated duration of patient support, the need for right-sided support, and the patient’s size (Table 3).
Extracorporeal Devices
Centrifugal pumps are commonly used to propel blood for standard cardiopulmonary bypass,40 and systems based on these pumps are available for short-term support of critically ill patients. Left- and/or right-sided support can be obtained with these systems. If necessary, an oxygenator may be spliced into the circuit to allow extracorporeal membrane oxygenation. Cardiovascular support with extracorporeal membrane oxygenation in adults, however, has yielded poor results.
The Abiomed BVS 5000 consists of 2 extracorporeal pneumatic, pulsatile pumps that can be used for univentricular or biventricular postcardiotomy support but also is used as a bridge to transplantation. The self-regulating device can achieve flows of up to 6 L/min with adequate preload and is typically used for periods up to 7 days. Because it is easy to insert and operate, the Abiomed BVS has been particularly important in community hospitals where the device can be placed and the patient subsequently transferred to a specialized center. Data from the voluntary worldwide Abiomed BVS 5000 database revealed 1513 implants (most for biventricular support), of which 63% were for postcardiotomy failure.41
The Thoratec VAD is a polyurethane-lined pneumatically driven pusher plate device that can also be used for left- and/or right-sided support. The device has a stroke volume of 65 mL and can achieve flows up to 7 L/min. The main advantages of this device include its versatility for biventricular support and the ability to use it in small patients. Data from the Thoratec database indicate a bridge-to-transplantation success rate of 60% in 729 patients, with support durations as long as 515 days.42 It has also been reported that among 183 patients with postcardiotomy failure treated with the Thoratec VAD, 69 (38%) were ultimately weaned from the device.
Intracorporeal Devices
The HeartMate LVAD is approved in 2 forms: the implantable pneumatic (IP) and the vented electric. Both use pusher plate technology with a polyurethane diaphragm to propel blood in a pulsatile fashion at rates up to 10 L/min and provide only left ventricular support. Each device has a sintered titanium housing that promotes rapid adherence of blood elements and development of a pseudointima.43 Because of this innovation and the use of xenograft valves, anticoagulation can be avoided with a low thromboembolic rate (2.7%).44 The other advantage of this device is the fact that patients can freely ambulate and can be discharged from the hospital. Except for swimming, patients may resume almost all other activities. The challenges associated with the device include the requirement that the patient have a body surface area 1.5 mol/L2, and because the driveline is percutaneous, there is a relatively high risk of infectious complications, with as many as 48% of patients experiencing some type of infection.45 Data from the worldwide registry as of October 1999 accounted for 1934 implants from 160 different centers used to bridge to transplantation.46 Of patients surviving the first 30 days of support, 84% survived to either transplantation or explantation of the device. Patients who ultimately receive transplants do as well as non-LVAD United Network for Organ Sharing (UNOS) status 2 patients and better than non-LVAD UNOS status 1 patients.
The Novacor left ventricular assist system is another device that is FDA approved as a bridge to transplantation.46 This system is an electric dual-pusher-plate system with a polyurethane lining and 2 porcine valves with flows up to 10 L/min. Like the HeartMate, it can be used only for left-sided support and in patients weighing >60 kg. The device has a percutaneous lead that serves as both a vent and an electrical connection. The blood contacting surface of the system requires anticoagulation, which needs to be started soon after implantation if bleeding is relatively well controlled. Patients are able to ambulate and participate in many activities. Despite anticoagulation, the incidence of thrombotic stroke remains relatively high. Like all other devices with a percutaneous line, there is a significant risk for infection. The advantages of this system are the excellent mechanical reliability (few device failures) and successful outpatient experience. Results from the US multicenter trial of 129 patients satisfying all criteria for inclusion demonstrated a transplantation rate of 77%, despite a 30% systemic infection rate and a 26% embolic stroke rate. The global experience has demonstrated support times as long as 4 years. This device is currently under evaluation for destination therapy.
The Arrow Lionheart-2000 is an experimental LVAD that can pump up to 8 L/min. Unlike other LVADs, however, this device is totally implanted. The battery, controller, and a gas compliance chamber are implanted with no lines crossing the skin. The pump is powered via continuous transcutaneous energy transfer that maintains charge on the battery. The battery can operate the device for 1 hour when not being charged, but only 20 to 30 minutes daily is recommended. The device was designed for destination therapy. A 260-patient study in Europe, the CUBS trial, demonstrated reliability of the device over an average of 1 year, with survival and adverse events similar to those reported in the REMATCH trial. Additional testing is underway.
Total Artificial Hearts
Currently, 2 devices are being developed as total artificial hearts. The AbioCor Artificial Heart is a total artificial heart that is implanted in the orthotopic position. It is driven by an internal motor using hydraulically coupled chambers so that, while the left side is ejecting, the right side is filling. The device is completely implantable and has an internal battery and a transcutaneous energy transfer system that permits recharging the battery or running the device with an external coil. Several patients have received the device, and reports of initial experiences have appeared.47
The Cardiowest Total Artificial heart was recently approved by the FDA as a bridge to transplantation in patients in need of biventricular support.48 This is a biventricular, pneumatic, pulsatile pump that totally replaces the native ventricles and all 4 cardiac valves. Like the AbioCor, it is implanted in the orthotopic position. Eighty-one patients treated with this device had a rate of survival to transplantation of 79%. This device is currently powered by a large console that precludes hospital discharge and thus widespread applicability. Development of a smaller console that will allow greater patient mobility is underway.
New Devices
The newest generation of devices includes axial flow and centrifugal pumps. Many devices include magnetically levitated rotating propellers or plates that eliminate a failure mode related to wear on bearings. These pumps are smaller than the devices discussed above but generally have flow rates >5 L/min. Flow is nonpulsatile with all these devices. Potential advantages of these devices include their durability, small size, simpler mechanics, quiet function, and lack of valves (Table 3).49
The smaller size of these pumps is expected to facilitate placement and explantation, with some pumps being placed by lateral thoracotomy incision without the need for cardiopulmonary bypass. The small size should also permit use in smaller patients. Because they have fewer moving parts and points of friction, it is expected that, once perfected, they will have improved longevity. Unfortunately, if device failure occurs, there are few options other than replacement.
Ventricular Assist Devices as a Bridge to Recovery
Early in the course of LVAD use as a bridge to transplantation, it became evident that some patients exhibit substantial recovery of ventricular function.50,51 This prompted explantation of some devices in lieu of transplantation, so-called bridge to recovery therapy.52–54 However, outcomes after these early experiences were poor, with many patients progressing rapidly back to heart failure or dying of heart failure–related complications.50,52 Therefore, LVADs are not generally used with the intention of bridging patients to recovery except in relatively rare, potentially reversible situations (eg, postcardiotomy failure and fulminant myocarditis). However, many insights have been obtained into the mechanisms of remodeling through studies of hearts supported by LVADs.55–66
LVADs provide profound unloading of the left ventricle, although the right ventricle remains hemodynamically loaded (Figure 6A).55 LVADs normalize the circulating neurohormal and cytokine levels66 which would be expected to affect right and left ventricles equally. The effects of LVAD support on the left ventricle include (but are not limited to) near normalization of the passive left ventricular pressure-volume relations (Figure 6B and 6C),55,60 regression of left ventricular free wall mass and cellular hypertrophy (Figure 6D), normalization of the force-frequency relationship (Figure 7A), normalization of ;-adrenergic responsiveness (Figure 7B), normalized phosphorylation of the calcium release channel (ryanodine receptor),62 normalized expression of key genes encoding for proteins involved in calcium cycling,60 and normalized tissue levels of norepinephrine (unpublished). These observations are collectively referred to as reverse remodeling.55 However, in the right ventricle (Figure 6C and 7B),60 only normalization of ;-adrenergic responsiveness, calcium release channel phosphorylation, and tissue norepinephrine levels are observed.67 These observations indicate that some aspects of reverse remodeling are regulated primarily by hemodynamic stress, whereas other aspects are regulated by neurohormonal milieu.60
Although most characteristics improve toward normal during LVAD support, this trend is not ubiquitous. Interstitial fibrosis and total, cross-linked, and type I and III collagen contents are all increased beyond the already abnormal levels found in the heart failure state.61,68 The implications and mechanisms of these changes are under investigation.
Summary and Conclusions
A broad range of devices (many investigational) for treating patients with heart failure have been reviewed. Such devices, along with other classes of devices reviewed elsewhere, attempt to address aspects of the vicious cycle of heart failure not treated or incompletely treated by already available pharmacological therapies (Figure 1). We suggest that some of the fundamental abnormalities not addressed by available pharmacological agents are largely hemodynamic and mechanical in nature (Figure 1) and may most readily lend themselves to device-based solutions. The emphasis in the present medical device era is on less invasive treatments made possible by technological and engineering advances. The profound reverse remodeling routinely associated with LVAD use further validates device-based approaches and should inspire research to find ways to make this recovery more complete and permanent.
Because this field is moving so quickly, it is likely that by the time this review appears in press, new information about several of the devices discussed will already be available, some of the approaches may already have been abandoned, and new approaches will have appeared. It is therefore hoped that the enduring message of this review relates to fundamental concepts learned over the recent decades about why and what types of device-based approaches are likely to play an increasing role in the management of patients with heart failure in the future.
Acknowledgments
Disclosure
Dr Burkhoff is employed by Impulse Dynamics, which is investigating an electrical-based treatment for CHF that is not related to the subject of this article. Dr Burkhoff also has an ownership interest in Abiomed and has served as a consultant to Acorn and Cardiac Assist.
References
Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991; 325: 303–310.
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996; 334: 1349–1355.
Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001; 344: 1651–1658.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999; 353: 2001–2007.
Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, Van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004; 109: 1594–1602.
Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345: 1667–1675.
Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346: 1845–1853.
Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002; 346: 877–883.
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004; 350: 2140–2150.
Lee MS, Makkar RR. Stem-cell transplantation in myocardial infarction: a status report. Ann Intern Med. 2004; 140: 729–737.
Stix G, Borggrefe M, Wolpert C, Hindricks G, Kottkamp H, Bocker D, Wichter T, Mika Y, Ben Haim S, Burkhoff D, Wolzt M, Schmidinger H. Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure. Eur Heart J. 2004; 25: 650–655.
Batista RJV, Santos JL, Takeshita N, Bocchino L, Lima PN, Cunha MA. Partial left ventriculectomy to improve left ventricular function in end-stage heart disease. J Card Surg. 1996; 11: 96–97.
Dickstein ML, Spotnitz HM, Rose EA, Burkhoff D. Heart reduction surgery: an analysis of the impact on cardiac function. J Thorac Cardiovasc Surg. 1997; 113: 1032–1040.
Franco-Cereceda A, McCarthy PM, Blackstone EH, Hoercher KJ, White JA, Young JB, Starling RC. Partial left ventriculectomy for dilated cardiomyopathy: is this an alternative to transplantation; J Thorac Cardiovasc Surg. 2001; 121: 879–893.
Mickleborough LL, Carson S, Ivanov J. Repair of dyskinetic or akinetic left ventricular aneurysm: results obtained with a modified linear closure. J Thorac Cardiovasc Surg. 2001; 121: 675–682.
Dor V, Sbatier M, DiDonato M, Montiglio F, Toso A, Maioli M. Efficacy of endoventricular patchplasty in large post-infarction akinetic scar and severe left ventricular dysfunction: comparison with a series of large dyskinetic scars. J Thorac Cardiovasc Surg. 1998; 116: 50–59.
Athanasuleas CL, Stanley AW Jr, Buckberg GD, Dor V, DiDonato M, Blackstone EH. Surgical anterior ventricular endocardial restoration (SAVER) in the dilated remodeled ventricle after anterior myocardial infarction: RESTORE Group: Reconstructive Endoventricular Surgery, Returning Torsion Original Radius Elliptical Shape to the LV. J Am Coll Cardiol. 2001; 37: 1199–1209.
Artrip JH, Oz M, Burkhoff D. Left ventricular volume reduction surgery for heart failure: a physiologic perspective. J Thoracic Cardiovasc Surgery. 2001; 122: 775–782.
Patel HJ, Lankford EB, Polidori DJ, Pilla JJ, Plappert T, John Sutton MS, Acker MA. Dynamic cardiomyoplasty: its chronic and acute effects on the failing heart. J Thorac Cardiovasc Surg. 1997; 114: 169–178.
Kass DA, Baughman KL, Pak PH, Cho PW, Levin HR, Gardner TJ, Halperin HR, Tsitlik JE, Acker MA. Reverse remodeling from cardiomyoplasty in human heart failure: external constraint versus active assist. Circulation. 1995; 91: 2314–2318.
Cho PW, Levin HR, Curtis WE, Tsitlik JE, DiNatale JM, Kass DA, Gardner TJ, Kunel RW, Acker MA. Pressure-volume analysis of changes in cardiac function in chronic cardiomyoplasty. Ann Thorac Surg. 1993; 56: 38–45.
Saavedra WF, Tunin RS, Paolocci N, Mishima T, Suzuki G, Emala CW, Chaudhry PA, Anagnostopoulos P, Gupta RC, Sabbah HN, Kass DA. Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure. J Am Coll Cardiol. 2002; 39: 2069–2076.
Takagaki M, McCarthy PM, Dessoffy R, Ochiai Y, Doi K, Howard MW, Qin J, Yang H, Shiota CT, Connor J, Fukamachi K. Device based left ventricular shape change: validation of conductance technology in shape changed hearts. ASAIO J. 2002; 48: 268–271.
Bolling SF. Mitral reconstruction in cardiomyopathy. J Heart Valve Dis. 2002; 11 (suppl 1): S26–S31.
Condado JA, Velez-Gimon M. Catheter-based approach to mitral regurgitation. J Interv Cardiol. 2003; 16: 523–534.
Block PC. Percutaneous mitral valve repair for mitral regurgitation. J Interv Cardiol. 2003; 16: 93–96.
Suehiro K, Shimizu J, Yi GH, Gu A, Wang J, Keren G, Burkhoff D. Selective renal vasodilation and active renal artery perfusion improve renal function in dogs with acute heart failure. J Pharmacol Exp Ther. 2001; 298: 1154–1160.
Jaski BE, Ha J, Denys BG, Lamba S, Trupp RJ, Abraham WT. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail. 2003; 9: 227–231.
Haithcock BE, Morita H, Fanous NH, Suzuki G, Sabbah HN. Hemodynamic unloading of the failing left ventricle using an arterial-to-arterial extracorporeal flow circuit. Ann Thorac Surg. 2004; 77: 158–163.
Hochman JS. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. Circulation. 2003; 107: 2998–3002.
Thiele H, Lauer B, Hambrecht R, Boudriot E, Cohen HA, Schuler G. Reversal of cardiogenic shock by percutaneous left atrial-to-femoral arterial bypass assistance. Circulation. 2001; 104: 2917–2922.
Thiele H, Sick P, Boudriot E, Diederich KW, Hambrecht R, Niebaur J, Schuler G. Randomized comparison of intraaortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J. 2005; 26: 1276–1283.
Jurmann MJ, Siniawski H, Erb M, Drews T, Hetzer R. Initial experience with miniature axial flow ventricular assist devices for postcardiotomy heart failure. Ann Thorac Surg. 2004; 77: 1642–1647.
Sweeney MS. The Hemopump in 1997: a clinical, political, and marketing evolution. Ann Thorac Surg. 1999; 68: 761–763.
Frazier OH, Rose EA, McCarthy PM, Burton NA, Tector A, Levin HR, Kayne HL, Poirier VL, Dasse KA. Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist device. Ann Surg. 1995; 222: 327–326.
Ashton RC, Goldstein DJ, Rose EA, Weinberg AD, Levin HR, Oz MC. Duration of left ventricular assist device support affects transplant survival. J Heart Lung Transplant. 1996; 15: 1151–1157.
Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, Long JW, Ascheim DD, Tierney AR, Levitan RG, Watson JT, Meier P, Ronan NS, Shapiro PA, Lazar RM, Miller LW, Gupta L, Frazier OH, Desvigne-Nickens P, Oz MC, Poirier VL. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med. 2001; 345: 1435–1443.
Oz MC, Rose EA, Levin HR. Selection criteria for placement of left ventricular assist devices. Am Heart J. 1995; 129: 173–177.
Curtis JJ. Centrifugal mechanical assist for postcardiotomy ventricular failure. Semin Thorac Cardiovasc Surg. 1994; 6: 140–146.
Registry. ABVW. Courtesy of Abiomed Inc; 1999.
Registry. TVSW. Courtesy of Thoratec Inc; 2000.
Spanier TB, Chen JM, Oz MC, Stern DM, Rose EA, Schmidt AM. Time-dependent cellular population of textured-surface left ventricular assist devices contributes to the development of a biphasic systemic procoagulant response. J Thorac Cardiovasc Surg. 1999; 118: 404–413.
Slater JP, Rose EA, Levin HR, Frazier OH, Roberts JK, Weinberg AD, Oz MC. Low thromboembolic risk without anticoagulation using advanced-design left ventricular assist devices. Ann Thorac Surg. 1996; 62: 1321–1327.
Argenziano M, Catanese KA, Moazami N, Gardocki MT, Weinberg AD, Clavenna MW, Rose EA, Scully BE, Levin HR, Oz MC. The influence of infection on survival and successful transplantation in patients with left ventricular assist devices. J Heart Lung Transplant. 1997; 16: 822–831.
Ramasamy N, Vargo R, Kormos R, Portner R. The Novacor left ventricular assist system. In: Goldstein D, Oz MC, eds. Cardiac Assist Devices. Armonk, NY: Futura Publishing; 2000: 323–339.
Dowling RD, Gray LA Jr, Etoch SW, Laks H, Marelli D, Samuels L, Entwistle J, Couper G, Vlahakes GJ, Frazier OH. Initial experience with the AbioCor implantable replacement heart system. J Thorac Cardiovasc Surg. 2004; 127: 131–141.
Copeland JG, Smith RG, Arabia FA, Nolan PE, Sethi GK, Tsau PH, McClellan D, Slepian MJ. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med. 2004; 351: 859–867.
Kaplon RJ, Oz MC, Kwiatkowski PA, Levin HR, Shah AS, Jarvik RK, Rose EA. Miniature axial flow pump for ventricular assistance in children and small adults. J Thorac Cardiovasc Surg. 1996; 111: 13–18.
Levin HR, Oz M, Catanese K, Rose EA, Burkhoff D. Transient normalization of systolic and diastolic function after LVAD support in a patient with dilated cardiomyopathy. J Heart Lung Transplant. 1996; 15: 840–842.
Frazier OH. First use of an untethered, vented electric left ventricular assist device for long-term support. Circulation. 1994; 89: 2908–2914.
Mancini DM, Beniaminovitz A, Levin H, Catanese K, Flannery M, DiTullio M, Savin S, Cordisco ME, Rose E, Oz M. Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. Circulation. 1998; 98: 2383–2389.
Muller J, Wallukat G, Weng YG, Dandel M, Spiegelsberger S, Semrau S, Brandes K, Theodoridis V, Loebe M, Meyer R, Hetzer R. Weaning from mechanical cardiac support in patients with idiopathic dilated cardiomyopathy. Circulation. 1997; 96: 542–549.
Mann DL, Willerson JT. Left ventricular assist devices and the failing heart: a bridge to recovery, a permanent assist device, or a bridge too far; Circulation. 1998; 98: 2367–2369.
Levin HR, Oz MC, Chen JM, Packer MP, Rose EA, Burkhoff D. Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading. Circulation. 1995; 91: 2717–2720.
Nakatani S, McCarthy PM, Kottke-Marchant K, Harasaki H, James KB, Savage RM, Thomas JD. Left ventricular echocardiographic and histologic changes: impact of chronic unloading by an implantable ventricular assist device. J Am Coll Cardiol. 1996; 15: 894–901.
Torre-Amione G, Stetson SJ, Youker KA, Durand JB, Radovancevic B, Delgado RM, Frazier OH, Entman ML, Noon GP. Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support: a potential mechanism for cardiac recovery. Circulation. 1999; 100: 1189–1193.
Dipla K, Mattiello JA, Jeevanandam V, Houser SR, Margulies KB. Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure. Circulation. 1998; 97: 2316–2322.
Heerdt PM, Holmes JW, Cai B, Barbone A, Madigan JD, Reiken S, Lee DL, Oz MC, Marks AR, Burkhoff D. Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation. 2000; 102: 2713–2719.
Barbone A, Holmes JW, Heerdt PM, Thé AH, Naka Y, Joshi N, Daines M, Marks AR, Oz MC, Burkhoff D. Comparison of right and left ventricular responses to left ventricular assist device support in patients with severe heart failure: a primary role of mechanical unloading underlying reverse remodeling. Circulation. 2001; 104: 670–675.
Madigan JD, Barbone A, Choudhri AF, Morales DLS, Cai B, Oz MC, Burkhoff D. Time course of reverse remodeling of the left ventricle during support with a left ventricular assist device. J Thorac Cardiovasc Surg. 2001; 121: 902–908.
Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000; 101: 365–376.
Ogletree-Hughes ML, Stull LB, Sweet WE, Smedira NG, McCarthy PM, Moravec CS. Mechanical unloading restores ;-adrenergic responsiveness and reverses receptor downregulation in the failing human heart. Circulation. 2001; 104: 881–886.
Ogletree-Hughes ML, Smedira NG, McCarthy PM, Moravec CS. Mechanical unloading causes recovery of calcium cycling in the failing human heart. J Heart Lung Transplant. 2001; 20: 210.
James KB, McCarthy PM, Thomas JD, Vargo R, Hobbs RE, Sapp S, Bravo E. Effect of the implantable left ventricular assist device on neuroendocrine activation in heart failure. Circulation. 1995; 92 (suppl II): II-191–II-195.
McCarthy PM, Savage RM, Fraser CD, Vargo R, James KB, Goormastic M, Hobbs RE. Hemodynamic and physiologic changes during support with an implantable left ventricular assist device. J Thorac Cardiovasc Surg. 1995; 109: 409–417.
Klotz S, Barbone A, Reiken S, Holmes JW, Naka Y, Oz MC, Marks AR, Burkhoff D. Left ventricular assist device support normalizes left and right ventricular beta-adrenergic pathway properties. J Am Coll Cardiol. 2005; 45: 668–676.
Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, Rosenblum W, Kormos RL, Feldman AM. Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation. 2001; 104: 1147–1152.
Reesink KD, Dekker AL, Van Ommen V, Soemers C, Geskes GG, van der Veen FH, Maessen JG. Miniature intracardiac assist device provides more effective cardiac unloading and circulatory support during severe left heart failure than intraaortic balloon pumping. Chest. 2004; 126: 896–902.(Donna Mancini, MD; Daniel)
IMPULSE Dynamics, Orangeburg (D.B.), NY.
Abstract
Despite advances in pharmacological treatments aimed at neurohormonal blockade for heart failure in the setting of left ventricular pump dysfunction, there is still a growing number of patients with advanced symptoms who suffer significant morbidity and mortality. Mechanical stresses and chronic neurohormonal activation conspire to propagate maladaptive ventricular remodeling responsible for the insidious nature of this disease. Recent studies suggest that further pharmacological neurohormonal blockade may not be safe or effective, which has driven development of devices for this patient population. Furthermore, such devices may target fundamental pathophysiological abnormalities that are largely hemodynamic and mechanical in nature that are not addressed by available pharmacological agents. The profound reverse remodeling routinely associated with left ventricular assist device use, reviewed in detail, further validates device-based approaches and should inspire research to find ways to make this recovery more complete and permanent. Accordingly, this review focuses on the multitude of mechanical device–based approaches currently being investigated to manage and treat this population. From devices for monitoring patient status to anticipate congestive heart failure exacerbations and preemptively adjust therapy to devices to support preterminal patients with end-stage disease, it is recognized that these device-based approaches will assume an increasingly important role in treating the growing number of patients with advanced heart failure.
Key Words: heart failure ; transplantation ; disease management
Introduction
There have been several important advances in pharmacological treatments for heart failure resulting from decreased ventricular pump function that have significantly reduced mortality—namely ACE inhibitors,1 ;-blockers,2,3 and aldosterone inhibitors.4 Nevertheless, the progression from asymptomatic left ventricular dysfunction to symptomatic heart failure is still common. The number of hospitalizations for heart failure exacerbations continues to increase, and most patients will ultimately die of complications related to heart failure.5 There is a need for treatments that prolong life and enhance exercise tolerance.
Many of the major advances achieved over the past 2 decades came with the recognition that the progression of heart failure is due to neurohormonal activation and abnormal mechanical stresses on the myocardium (increased preload and afterload; Figure 1). This vicious cycle of progressive pump enlargement and dysfunction is collectively referred to as ventricular remodeling. The structural and functional aspects of remodeling can be illustrated on a ventricular pressure-volume diagram (Figure 2A). With sustained neurohormonal activation and its consequences, the pressure-volume relations gradually shift toward larger volumes so that ejection fraction is reduced with marked myocardial hypertrophy. The goal of many heart failure treatments is to prevent, slow, or reverse this process (Figure 2B). Randomized studies have shown that pharmacological blockade of the key neurohormonal pathways interrupts the vicious cycle, retards progression, and improves survival (Figure 1, blue). However, results of several recent trials suggest that attempts to block additional neurohormonal pathways may be detrimental.6 This finding has led to the concept that we may have reached the limit to which neurohormonal and cytokine mechanisms can be blocked in heart failure patients.7
Accordingly, there have been intensive efforts to develop and test device-based therapies for patients with both acute and chronic heart failure. For example, cardiac resynchronization therapy8 has been approved by the US Food and Drug Administration (FDA) for NYHA class III and IV chronic heart failure (CHF) patients with abnormal electric conduction, and recent clinical trials support broader use of implantable cardiac defibrillators in patients with ventricular dysfunction.9,10 Such devices have significantly affected the treatment of CHF patients. Other experimental forms of therapy such as myogenesis (eg, stem cell, myoblasts)11 and other electrical therapies such as cardiac contractility modulating nonexcitatory electrical impulses12 and less invasive defibrillators are under active investigation. These classes of devices are the topic of a recent review in this series. The focus of the present review is on mechanical devices to treat various stages of heart failure that are currently available or are under development. Not included for the sake of brevity, but still noteworthy, are classes of devices under development to aid in comprehensive disease management programs and chronic hemodynamic monitoring systems aimed at prevention and early detection of heart failure exacerbations to reduce hospitalizations and increase longevity.
Surgical Approaches to Treatment of CHF
Surgical reshaping of the dilated heart, a topic of significant research in recent years, is relevant to the topic of device-based heart failure treatments. One class of procedures that has received significant attention is generically referred to as ventricular reduction surgery. The concept behind these procedures is to reduce the increased radius of curvature present in a dilated heart, which increases systolic myocardial wall stress via Laplace’s law. A reduction in radius of curvature would decrease wall stress, in principle allowing for reverse remodeling. The technique for reducing radius of curvature conceptually involves excluding a portion of the ventricular wall and reconstructing a smaller (preferably more normally elliptical) chamber. The surgical procedure differs in technique and physiological effect, depending on the properties of the muscle removed. The Batista operation13 was intended to treat patients with idiopathic cardiomyopathy, so the muscle removed was functional but weak. However, it was prospectively predicted14 and later proven that this approach worsened overall pump function (as indexed by the relation between filling pressure and cardiac output) and did not generally provide benefit to patients.15 This procedure is no longer practiced.
In ischemic cardiomyopathy, myocardium affected by infarctions can heal in different ways, generating either an akinetic scar or a dyskinetic scar (ie, aneurysm). Ventricular reduction surgery in this setting therefore removes noncontractile material. The effects of these ventricular reduction surgeries on ventricular pressure-volume relations has not been studied, and clinical studies of these procedures are generally confined to reports of nonrandomized registries. Removal of dyskinetic scar (aneurysmorophy) is clinically accepted and reported to be associated with satisfactory outcomes.16 The effects of removing akinetic scar (often referred to as the Dor procedure17 or surgical anterior ventricular restoration [SAVR]18) are less clear. The same theoretical modeling that correctly predicted detrimental effects of the Batista operation predicts that aneurysmorophy significantly improves pump function (which matches most of the data in the literature) and predicts that pump function will not be significantly improved by SAVR (Figure 3).19 The SAVR operation is now being studied prospectively as part of the NIH-sponsored Surgical Treatment of Ischemic Heart Failure (STICH) trial (http://www.stichtrial.org/disclaimer/index.cfm). Without firm scientific evidence that proves the benefits of such surgery, many physicians are reluctant to refer patients.
One limitation of these surgeries that could potentially confound the study is the lack of a uniform method of performing the procedure. Thus, the amount of tissue removed and the ultimate size and geometry of the reconstructed chamber are more or less at the discretion of the surgeon, with no firm guidelines. Two devices under development provide a model (CHF Technologies and Chase Medical) that is inserted into the chamber to provide a guide for both resizing and reshaping the left ventricle. These devices are being studied independently outside the STICH trial.
Another method proposed to decrease wall stress and to induce reverse remodeling is by passive ventricular restraint devices (ACORN Cardiovascular Inc; Paracor Medical, Inc; Myocor Inc). This concept evolved from an earlier investigational approach called cardiomyoplasty20 that tested the concept that the latisimus dorsi muscle could be freed, wrapped around the heart, and stimulated to contract in synchrony with the native heart, providing a boost to ventricular performance. However, it was discovered that after a relatively short time, continual stimulation of the skeletal muscle caused fatigue so that the graft no longer contracted with each stimulation.21,22 Rather, the skeletal muscle ultimately became a passive wrap around the heart. Although the overall clinical trial failed to show benefit, some patients appeared to benefit, and there was a reduction in heart size with some improvement in function. This led to the concept that the same effect could be readily achieved with a passive material appropriately tailored and fit snug to the heart.23 Studies in animals in which CHF was induced by repeated coronary artery microembolization have indeed shown reverse remodeling, including a leftward shift back toward normal of the end-systolic pressure-volume relationship (Figure 4), improved pump function and reversal of the fetal gene program associated with heart failure, which is interpreted as being a beneficial consequence of reduced wall stress.23 Importantly, despite the fact that the heart is wrapped to slightly decrease volume acutely, there is no induction of a restrictive physiology. A recently completed multicenter, randomized study of this technology with 300 patients has suggested that this approach improves NYHA functional class and reduces the requirement for subsequent major cardiac procedures such as cardiac transplantation and ventricular assist device insertion. Another device intended to perform similarly is constructed of nitinol, which may more readily permit placement of the device via port access.
Still another form of ventricular reshaping involves use of transventricular struts to bring opposite sides of the dilated left ventricle toward each other to reshape the ventricular circumference from 1 large circle to 2 circles, each with a smaller radius of curvature (in a kind of figure 8 configuration; Myocor, Inc).24 This device is currently under investigation for its potential use in treating heart failure and as a means of less invasively reducing the severity of mitral regurgitation.
For all these forms of surgical heart failure treatments, mitral valve repair or replacement is an important yet potentially confounding factor during clinical trials. Although mitral repair is typically effective at eliminating or reducing the regurgitant volume, it remains controversial as to whether and when to perform such surgery as a sole treatment in patients with low ejection fraction.25 Accordingly, numerous catheter-based devices are being developed to perform mitral valve repair percutaneously to reduce risk and allow it to be performed as a sole therapy to treat symptoms of heart failure.26,27 It is proposed that availability of such devices will allow treatment of more patients, including those at high risk, with reduced procedural morbidity and mortality.
Devices to Treat Acutely Decompensated Heart Failure
As patients deteriorate into more severe decompensation and cardiac output and blood pressure decline, patients become increasingly resistant to high doses of diuretics, and fluid overload ensues. Reduced renal perfusion resulting from relative hypotension and renal artery constriction are contributing factors. Because diuretics reduce glomerular filtration rate, their use, although necessary to treat symptoms, may contribute to further diuretic refractoriness. Accordingly, devices aimed at improving renal perfusion, directly dealing with fluid overload, and/or attempting to improve systemic perfusion have been developed.
One such strategy is local renal artery vasodilator drug delivery.28 Local renal vasodilator therapy can potentially improve renal blood flow and glomerular filtration rate while acting synergistically with diuretics to effect a diuresis with fewer effects on arterial blood pressure than the same drugs delivered systemically. Devices are currently under development for such local drug delivery that would allow testing of this strategy (Flowmedica, Inc).
A direct means of dealing with fluid overload in patients who have inadequate response to diuretic therapy is aquapheresis with a specialized system that provides efficient salt and water removal by a new form of ultrafiltration (Aquadex System 100, CHF Solutions).29 This system uses peripheral or central venous access and requires a low volume of extracorporeal blood to prime the system (33 cm3) compared with standard hemofiltration devices. This system removes isotonic salt and water at rates between 100 and 500 cm3/h without clinically significant changes in serum electrolytes, heart rate, or blood pressure. Because of the relative simplicity of operation, this system can be administered in inpatient settings and outpatient care centers. Four clinical trials of this system have indicated the ease, safety, and efficacy of this strategy to remove fluid. The UNLOAD trial, a prospective, randomized, multicenter, 200-patient trial, is currently underway and is testing the short-term efficacy with respect to fluid and symptoms and 30- to 90-day clinical impact of aquapheresis compared with usual diuretic strategies.
Another novel investigational approach for treating patients with acute heart failure exacerbations who are dependent on or resistant to intravenous inotropic agents involves continuous aortic flow augmentation.30 The Cancion system (Orqis Medical) consists of an extracorporeal, magnetically levitated centrifugal pump that withdraws blood from the femoral artery and returns it to the descending thoracic aorta in a continuous, nonpulsatile manner at rates between 1.1 and 1.5 L/min. Studies in experimental animals with CHF and results of preliminary clinical studies in patients with heart failure exacerbations demonstrate that this continuous flow loop results in increased cardiac output, improved renal function (decreased creatinine) and diuresis, and reduced pulmonary capillary wedge pressure. The suggested mechanisms of action include direct ventricular afterload reduction, stimulation of nitric oxide production (resulting from increased aortic shear stress) that leads to vasodilation, and increased renal perfusion. Randomized, controlled studies are currently underway.
Catheter-Based Pumps for Acute Cardiogenic Shock
As a result of either the progression to end-stage heart failure in patients with longstanding cardiomyopathy or severe ventricular dysfunction in the setting of acute myocardial infarction, cardiogenic shock (inadequate blood pressure and cardiac output to meet the metabolic needs of the body) occurs in many patients surviving to hospital admission. Medical treatment with intravenous inotropes, followed by use of the intra-aortic balloon pumping (IABP), is considered the first line of treatment for such patients.31 However, these strategies are frequently not effective. Several devices are under development for treating such patients.
Approved for short-term (6 hours) hemodynamic support is the TandemHeart percutaneous ventricular assist device (CardiacAssist). This device consists of an extracorporeal centrifugal (continuous flow) pump that withdraws blood from the left atrium via a cannula introduced transseptally via the femoral vein. Blood is then pumped (at up to 3.5 L/min) by a centrifugal pump through cannulas in 1 or both femoral arteries.32 Preliminary results showed that this device can improve hemodynamics in patients with cardiogenic shock. Studies also showed a reduction in serum lactate levels, an indication of improved tissue oxygenation and thus reversal of the cardiogenic shock state. In a more recent study, patients with cardiogenic shock resulting from acute myocardial infarction failing medical treatment were randomized to treatment with either an IABP or the TandemHeart assist device.33 The IABP had almost no effect on hemodynamics, but the TandemHeart device significantly increased cardiac output and blood pressure while significantly decreasing pulmonary capillary wedge pressure. However, mortality was comparable in both groups.
Other devices are being developed to provide acute hemodynamic support. They include 2 axial flow pumps (Impella CardioSystem AG,34 A-Med System, based on a prior system called the Hemopump35). These systems have helical propellers at the tip of catheters that are positioned retrograde across the aortic valve. Motors rotate the propellers, which draw blood from the left ventricle through the distal end of the catheter and discharge it into the aorta. These catheters can be inserted percutaneously via a femoral artery or surgically into the proximal aorta. Like the TandemHeart, these devices unload the left ventricle, thus reducing oxygen demand while improving systemic perfusion (Figure 5). Studies are underway to assess the safety and efficacy of these devices in a variety of settings in which IABPs are now used, including cardiogenic shock.
Devices for Chronic Decompensated CHF
Because of the limited availability of donor organs and the urgency for cardiac support in the setting of severe hemodynamic decompensation, ventricular assist devices capable of completely supporting the circulation are taking on an increasingly important role in heart failure therapy.
Several FDA-approved devices provide short-term circulatory support for postcardiotomy failure or bridge to transplantation. Those who might benefit from device placement for acute cardiac failure include patients unable to be weaned from cardiopulmonary bypass, those experiencing acute myocardial infarction with cardiogenic shock, patients with myocarditis, and patients who deteriorate while awaiting transplantation. In the last group, assist devices can be especially helpful before transplantation by providing a period for recovery of heart failure–related end-organ impairment, thus reducing the risk of transplantation.36,37
Following the results of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, use of left ventricular assist devices (LVADs) as destination therapy is now approved for some patients ineligible for transplantation.38 Use of the HeartMate vented electric device was shown to improve survival over a 2-year period in this population. Although this landmark study ushered in the era of destination therapy, adverse effects related to infection, stroke, bleeding, device failure, and other factors all call for technological advances to improve outcomes.
Many devices are available to provide temporary support, either as a bridge to another treatment or until recovery of heart function. Selecting the appropriate device is dependent on a number of considerations, including the anticipated duration of patient support, the need for right-sided support, and the patient’s size (Table 3).
Extracorporeal Devices
Centrifugal pumps are commonly used to propel blood for standard cardiopulmonary bypass,40 and systems based on these pumps are available for short-term support of critically ill patients. Left- and/or right-sided support can be obtained with these systems. If necessary, an oxygenator may be spliced into the circuit to allow extracorporeal membrane oxygenation. Cardiovascular support with extracorporeal membrane oxygenation in adults, however, has yielded poor results.
The Abiomed BVS 5000 consists of 2 extracorporeal pneumatic, pulsatile pumps that can be used for univentricular or biventricular postcardiotomy support but also is used as a bridge to transplantation. The self-regulating device can achieve flows of up to 6 L/min with adequate preload and is typically used for periods up to 7 days. Because it is easy to insert and operate, the Abiomed BVS has been particularly important in community hospitals where the device can be placed and the patient subsequently transferred to a specialized center. Data from the voluntary worldwide Abiomed BVS 5000 database revealed 1513 implants (most for biventricular support), of which 63% were for postcardiotomy failure.41
The Thoratec VAD is a polyurethane-lined pneumatically driven pusher plate device that can also be used for left- and/or right-sided support. The device has a stroke volume of 65 mL and can achieve flows up to 7 L/min. The main advantages of this device include its versatility for biventricular support and the ability to use it in small patients. Data from the Thoratec database indicate a bridge-to-transplantation success rate of 60% in 729 patients, with support durations as long as 515 days.42 It has also been reported that among 183 patients with postcardiotomy failure treated with the Thoratec VAD, 69 (38%) were ultimately weaned from the device.
Intracorporeal Devices
The HeartMate LVAD is approved in 2 forms: the implantable pneumatic (IP) and the vented electric. Both use pusher plate technology with a polyurethane diaphragm to propel blood in a pulsatile fashion at rates up to 10 L/min and provide only left ventricular support. Each device has a sintered titanium housing that promotes rapid adherence of blood elements and development of a pseudointima.43 Because of this innovation and the use of xenograft valves, anticoagulation can be avoided with a low thromboembolic rate (2.7%).44 The other advantage of this device is the fact that patients can freely ambulate and can be discharged from the hospital. Except for swimming, patients may resume almost all other activities. The challenges associated with the device include the requirement that the patient have a body surface area 1.5 mol/L2, and because the driveline is percutaneous, there is a relatively high risk of infectious complications, with as many as 48% of patients experiencing some type of infection.45 Data from the worldwide registry as of October 1999 accounted for 1934 implants from 160 different centers used to bridge to transplantation.46 Of patients surviving the first 30 days of support, 84% survived to either transplantation or explantation of the device. Patients who ultimately receive transplants do as well as non-LVAD United Network for Organ Sharing (UNOS) status 2 patients and better than non-LVAD UNOS status 1 patients.
The Novacor left ventricular assist system is another device that is FDA approved as a bridge to transplantation.46 This system is an electric dual-pusher-plate system with a polyurethane lining and 2 porcine valves with flows up to 10 L/min. Like the HeartMate, it can be used only for left-sided support and in patients weighing >60 kg. The device has a percutaneous lead that serves as both a vent and an electrical connection. The blood contacting surface of the system requires anticoagulation, which needs to be started soon after implantation if bleeding is relatively well controlled. Patients are able to ambulate and participate in many activities. Despite anticoagulation, the incidence of thrombotic stroke remains relatively high. Like all other devices with a percutaneous line, there is a significant risk for infection. The advantages of this system are the excellent mechanical reliability (few device failures) and successful outpatient experience. Results from the US multicenter trial of 129 patients satisfying all criteria for inclusion demonstrated a transplantation rate of 77%, despite a 30% systemic infection rate and a 26% embolic stroke rate. The global experience has demonstrated support times as long as 4 years. This device is currently under evaluation for destination therapy.
The Arrow Lionheart-2000 is an experimental LVAD that can pump up to 8 L/min. Unlike other LVADs, however, this device is totally implanted. The battery, controller, and a gas compliance chamber are implanted with no lines crossing the skin. The pump is powered via continuous transcutaneous energy transfer that maintains charge on the battery. The battery can operate the device for 1 hour when not being charged, but only 20 to 30 minutes daily is recommended. The device was designed for destination therapy. A 260-patient study in Europe, the CUBS trial, demonstrated reliability of the device over an average of 1 year, with survival and adverse events similar to those reported in the REMATCH trial. Additional testing is underway.
Total Artificial Hearts
Currently, 2 devices are being developed as total artificial hearts. The AbioCor Artificial Heart is a total artificial heart that is implanted in the orthotopic position. It is driven by an internal motor using hydraulically coupled chambers so that, while the left side is ejecting, the right side is filling. The device is completely implantable and has an internal battery and a transcutaneous energy transfer system that permits recharging the battery or running the device with an external coil. Several patients have received the device, and reports of initial experiences have appeared.47
The Cardiowest Total Artificial heart was recently approved by the FDA as a bridge to transplantation in patients in need of biventricular support.48 This is a biventricular, pneumatic, pulsatile pump that totally replaces the native ventricles and all 4 cardiac valves. Like the AbioCor, it is implanted in the orthotopic position. Eighty-one patients treated with this device had a rate of survival to transplantation of 79%. This device is currently powered by a large console that precludes hospital discharge and thus widespread applicability. Development of a smaller console that will allow greater patient mobility is underway.
New Devices
The newest generation of devices includes axial flow and centrifugal pumps. Many devices include magnetically levitated rotating propellers or plates that eliminate a failure mode related to wear on bearings. These pumps are smaller than the devices discussed above but generally have flow rates >5 L/min. Flow is nonpulsatile with all these devices. Potential advantages of these devices include their durability, small size, simpler mechanics, quiet function, and lack of valves (Table 3).49
The smaller size of these pumps is expected to facilitate placement and explantation, with some pumps being placed by lateral thoracotomy incision without the need for cardiopulmonary bypass. The small size should also permit use in smaller patients. Because they have fewer moving parts and points of friction, it is expected that, once perfected, they will have improved longevity. Unfortunately, if device failure occurs, there are few options other than replacement.
Ventricular Assist Devices as a Bridge to Recovery
Early in the course of LVAD use as a bridge to transplantation, it became evident that some patients exhibit substantial recovery of ventricular function.50,51 This prompted explantation of some devices in lieu of transplantation, so-called bridge to recovery therapy.52–54 However, outcomes after these early experiences were poor, with many patients progressing rapidly back to heart failure or dying of heart failure–related complications.50,52 Therefore, LVADs are not generally used with the intention of bridging patients to recovery except in relatively rare, potentially reversible situations (eg, postcardiotomy failure and fulminant myocarditis). However, many insights have been obtained into the mechanisms of remodeling through studies of hearts supported by LVADs.55–66
LVADs provide profound unloading of the left ventricle, although the right ventricle remains hemodynamically loaded (Figure 6A).55 LVADs normalize the circulating neurohormal and cytokine levels66 which would be expected to affect right and left ventricles equally. The effects of LVAD support on the left ventricle include (but are not limited to) near normalization of the passive left ventricular pressure-volume relations (Figure 6B and 6C),55,60 regression of left ventricular free wall mass and cellular hypertrophy (Figure 6D), normalization of the force-frequency relationship (Figure 7A), normalization of ;-adrenergic responsiveness (Figure 7B), normalized phosphorylation of the calcium release channel (ryanodine receptor),62 normalized expression of key genes encoding for proteins involved in calcium cycling,60 and normalized tissue levels of norepinephrine (unpublished). These observations are collectively referred to as reverse remodeling.55 However, in the right ventricle (Figure 6C and 7B),60 only normalization of ;-adrenergic responsiveness, calcium release channel phosphorylation, and tissue norepinephrine levels are observed.67 These observations indicate that some aspects of reverse remodeling are regulated primarily by hemodynamic stress, whereas other aspects are regulated by neurohormonal milieu.60
Although most characteristics improve toward normal during LVAD support, this trend is not ubiquitous. Interstitial fibrosis and total, cross-linked, and type I and III collagen contents are all increased beyond the already abnormal levels found in the heart failure state.61,68 The implications and mechanisms of these changes are under investigation.
Summary and Conclusions
A broad range of devices (many investigational) for treating patients with heart failure have been reviewed. Such devices, along with other classes of devices reviewed elsewhere, attempt to address aspects of the vicious cycle of heart failure not treated or incompletely treated by already available pharmacological therapies (Figure 1). We suggest that some of the fundamental abnormalities not addressed by available pharmacological agents are largely hemodynamic and mechanical in nature (Figure 1) and may most readily lend themselves to device-based solutions. The emphasis in the present medical device era is on less invasive treatments made possible by technological and engineering advances. The profound reverse remodeling routinely associated with LVAD use further validates device-based approaches and should inspire research to find ways to make this recovery more complete and permanent.
Because this field is moving so quickly, it is likely that by the time this review appears in press, new information about several of the devices discussed will already be available, some of the approaches may already have been abandoned, and new approaches will have appeared. It is therefore hoped that the enduring message of this review relates to fundamental concepts learned over the recent decades about why and what types of device-based approaches are likely to play an increasing role in the management of patients with heart failure in the future.
Acknowledgments
Disclosure
Dr Burkhoff is employed by Impulse Dynamics, which is investigating an electrical-based treatment for CHF that is not related to the subject of this article. Dr Burkhoff also has an ownership interest in Abiomed and has served as a consultant to Acorn and Cardiac Assist.
References
Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991; 325: 303–310.
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996; 334: 1349–1355.
Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001; 344: 1651–1658.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999; 353: 2001–2007.
Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, Van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004; 109: 1594–1602.
Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345: 1667–1675.
Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346: 1845–1853.
Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002; 346: 877–883.
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004; 350: 2140–2150.
Lee MS, Makkar RR. Stem-cell transplantation in myocardial infarction: a status report. Ann Intern Med. 2004; 140: 729–737.
Stix G, Borggrefe M, Wolpert C, Hindricks G, Kottkamp H, Bocker D, Wichter T, Mika Y, Ben Haim S, Burkhoff D, Wolzt M, Schmidinger H. Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure. Eur Heart J. 2004; 25: 650–655.
Batista RJV, Santos JL, Takeshita N, Bocchino L, Lima PN, Cunha MA. Partial left ventriculectomy to improve left ventricular function in end-stage heart disease. J Card Surg. 1996; 11: 96–97.
Dickstein ML, Spotnitz HM, Rose EA, Burkhoff D. Heart reduction surgery: an analysis of the impact on cardiac function. J Thorac Cardiovasc Surg. 1997; 113: 1032–1040.
Franco-Cereceda A, McCarthy PM, Blackstone EH, Hoercher KJ, White JA, Young JB, Starling RC. Partial left ventriculectomy for dilated cardiomyopathy: is this an alternative to transplantation; J Thorac Cardiovasc Surg. 2001; 121: 879–893.
Mickleborough LL, Carson S, Ivanov J. Repair of dyskinetic or akinetic left ventricular aneurysm: results obtained with a modified linear closure. J Thorac Cardiovasc Surg. 2001; 121: 675–682.
Dor V, Sbatier M, DiDonato M, Montiglio F, Toso A, Maioli M. Efficacy of endoventricular patchplasty in large post-infarction akinetic scar and severe left ventricular dysfunction: comparison with a series of large dyskinetic scars. J Thorac Cardiovasc Surg. 1998; 116: 50–59.
Athanasuleas CL, Stanley AW Jr, Buckberg GD, Dor V, DiDonato M, Blackstone EH. Surgical anterior ventricular endocardial restoration (SAVER) in the dilated remodeled ventricle after anterior myocardial infarction: RESTORE Group: Reconstructive Endoventricular Surgery, Returning Torsion Original Radius Elliptical Shape to the LV. J Am Coll Cardiol. 2001; 37: 1199–1209.
Artrip JH, Oz M, Burkhoff D. Left ventricular volume reduction surgery for heart failure: a physiologic perspective. J Thoracic Cardiovasc Surgery. 2001; 122: 775–782.
Patel HJ, Lankford EB, Polidori DJ, Pilla JJ, Plappert T, John Sutton MS, Acker MA. Dynamic cardiomyoplasty: its chronic and acute effects on the failing heart. J Thorac Cardiovasc Surg. 1997; 114: 169–178.
Kass DA, Baughman KL, Pak PH, Cho PW, Levin HR, Gardner TJ, Halperin HR, Tsitlik JE, Acker MA. Reverse remodeling from cardiomyoplasty in human heart failure: external constraint versus active assist. Circulation. 1995; 91: 2314–2318.
Cho PW, Levin HR, Curtis WE, Tsitlik JE, DiNatale JM, Kass DA, Gardner TJ, Kunel RW, Acker MA. Pressure-volume analysis of changes in cardiac function in chronic cardiomyoplasty. Ann Thorac Surg. 1993; 56: 38–45.
Saavedra WF, Tunin RS, Paolocci N, Mishima T, Suzuki G, Emala CW, Chaudhry PA, Anagnostopoulos P, Gupta RC, Sabbah HN, Kass DA. Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure. J Am Coll Cardiol. 2002; 39: 2069–2076.
Takagaki M, McCarthy PM, Dessoffy R, Ochiai Y, Doi K, Howard MW, Qin J, Yang H, Shiota CT, Connor J, Fukamachi K. Device based left ventricular shape change: validation of conductance technology in shape changed hearts. ASAIO J. 2002; 48: 268–271.
Bolling SF. Mitral reconstruction in cardiomyopathy. J Heart Valve Dis. 2002; 11 (suppl 1): S26–S31.
Condado JA, Velez-Gimon M. Catheter-based approach to mitral regurgitation. J Interv Cardiol. 2003; 16: 523–534.
Block PC. Percutaneous mitral valve repair for mitral regurgitation. J Interv Cardiol. 2003; 16: 93–96.
Suehiro K, Shimizu J, Yi GH, Gu A, Wang J, Keren G, Burkhoff D. Selective renal vasodilation and active renal artery perfusion improve renal function in dogs with acute heart failure. J Pharmacol Exp Ther. 2001; 298: 1154–1160.
Jaski BE, Ha J, Denys BG, Lamba S, Trupp RJ, Abraham WT. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail. 2003; 9: 227–231.
Haithcock BE, Morita H, Fanous NH, Suzuki G, Sabbah HN. Hemodynamic unloading of the failing left ventricle using an arterial-to-arterial extracorporeal flow circuit. Ann Thorac Surg. 2004; 77: 158–163.
Hochman JS. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. Circulation. 2003; 107: 2998–3002.
Thiele H, Lauer B, Hambrecht R, Boudriot E, Cohen HA, Schuler G. Reversal of cardiogenic shock by percutaneous left atrial-to-femoral arterial bypass assistance. Circulation. 2001; 104: 2917–2922.
Thiele H, Sick P, Boudriot E, Diederich KW, Hambrecht R, Niebaur J, Schuler G. Randomized comparison of intraaortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J. 2005; 26: 1276–1283.
Jurmann MJ, Siniawski H, Erb M, Drews T, Hetzer R. Initial experience with miniature axial flow ventricular assist devices for postcardiotomy heart failure. Ann Thorac Surg. 2004; 77: 1642–1647.
Sweeney MS. The Hemopump in 1997: a clinical, political, and marketing evolution. Ann Thorac Surg. 1999; 68: 761–763.
Frazier OH, Rose EA, McCarthy PM, Burton NA, Tector A, Levin HR, Kayne HL, Poirier VL, Dasse KA. Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist device. Ann Surg. 1995; 222: 327–326.
Ashton RC, Goldstein DJ, Rose EA, Weinberg AD, Levin HR, Oz MC. Duration of left ventricular assist device support affects transplant survival. J Heart Lung Transplant. 1996; 15: 1151–1157.
Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, Long JW, Ascheim DD, Tierney AR, Levitan RG, Watson JT, Meier P, Ronan NS, Shapiro PA, Lazar RM, Miller LW, Gupta L, Frazier OH, Desvigne-Nickens P, Oz MC, Poirier VL. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med. 2001; 345: 1435–1443.
Oz MC, Rose EA, Levin HR. Selection criteria for placement of left ventricular assist devices. Am Heart J. 1995; 129: 173–177.
Curtis JJ. Centrifugal mechanical assist for postcardiotomy ventricular failure. Semin Thorac Cardiovasc Surg. 1994; 6: 140–146.
Registry. ABVW. Courtesy of Abiomed Inc; 1999.
Registry. TVSW. Courtesy of Thoratec Inc; 2000.
Spanier TB, Chen JM, Oz MC, Stern DM, Rose EA, Schmidt AM. Time-dependent cellular population of textured-surface left ventricular assist devices contributes to the development of a biphasic systemic procoagulant response. J Thorac Cardiovasc Surg. 1999; 118: 404–413.
Slater JP, Rose EA, Levin HR, Frazier OH, Roberts JK, Weinberg AD, Oz MC. Low thromboembolic risk without anticoagulation using advanced-design left ventricular assist devices. Ann Thorac Surg. 1996; 62: 1321–1327.
Argenziano M, Catanese KA, Moazami N, Gardocki MT, Weinberg AD, Clavenna MW, Rose EA, Scully BE, Levin HR, Oz MC. The influence of infection on survival and successful transplantation in patients with left ventricular assist devices. J Heart Lung Transplant. 1997; 16: 822–831.
Ramasamy N, Vargo R, Kormos R, Portner R. The Novacor left ventricular assist system. In: Goldstein D, Oz MC, eds. Cardiac Assist Devices. Armonk, NY: Futura Publishing; 2000: 323–339.
Dowling RD, Gray LA Jr, Etoch SW, Laks H, Marelli D, Samuels L, Entwistle J, Couper G, Vlahakes GJ, Frazier OH. Initial experience with the AbioCor implantable replacement heart system. J Thorac Cardiovasc Surg. 2004; 127: 131–141.
Copeland JG, Smith RG, Arabia FA, Nolan PE, Sethi GK, Tsau PH, McClellan D, Slepian MJ. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med. 2004; 351: 859–867.
Kaplon RJ, Oz MC, Kwiatkowski PA, Levin HR, Shah AS, Jarvik RK, Rose EA. Miniature axial flow pump for ventricular assistance in children and small adults. J Thorac Cardiovasc Surg. 1996; 111: 13–18.
Levin HR, Oz M, Catanese K, Rose EA, Burkhoff D. Transient normalization of systolic and diastolic function after LVAD support in a patient with dilated cardiomyopathy. J Heart Lung Transplant. 1996; 15: 840–842.
Frazier OH. First use of an untethered, vented electric left ventricular assist device for long-term support. Circulation. 1994; 89: 2908–2914.
Mancini DM, Beniaminovitz A, Levin H, Catanese K, Flannery M, DiTullio M, Savin S, Cordisco ME, Rose E, Oz M. Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. Circulation. 1998; 98: 2383–2389.
Muller J, Wallukat G, Weng YG, Dandel M, Spiegelsberger S, Semrau S, Brandes K, Theodoridis V, Loebe M, Meyer R, Hetzer R. Weaning from mechanical cardiac support in patients with idiopathic dilated cardiomyopathy. Circulation. 1997; 96: 542–549.
Mann DL, Willerson JT. Left ventricular assist devices and the failing heart: a bridge to recovery, a permanent assist device, or a bridge too far; Circulation. 1998; 98: 2367–2369.
Levin HR, Oz MC, Chen JM, Packer MP, Rose EA, Burkhoff D. Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading. Circulation. 1995; 91: 2717–2720.
Nakatani S, McCarthy PM, Kottke-Marchant K, Harasaki H, James KB, Savage RM, Thomas JD. Left ventricular echocardiographic and histologic changes: impact of chronic unloading by an implantable ventricular assist device. J Am Coll Cardiol. 1996; 15: 894–901.
Torre-Amione G, Stetson SJ, Youker KA, Durand JB, Radovancevic B, Delgado RM, Frazier OH, Entman ML, Noon GP. Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support: a potential mechanism for cardiac recovery. Circulation. 1999; 100: 1189–1193.
Dipla K, Mattiello JA, Jeevanandam V, Houser SR, Margulies KB. Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure. Circulation. 1998; 97: 2316–2322.
Heerdt PM, Holmes JW, Cai B, Barbone A, Madigan JD, Reiken S, Lee DL, Oz MC, Marks AR, Burkhoff D. Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation. 2000; 102: 2713–2719.
Barbone A, Holmes JW, Heerdt PM, Thé AH, Naka Y, Joshi N, Daines M, Marks AR, Oz MC, Burkhoff D. Comparison of right and left ventricular responses to left ventricular assist device support in patients with severe heart failure: a primary role of mechanical unloading underlying reverse remodeling. Circulation. 2001; 104: 670–675.
Madigan JD, Barbone A, Choudhri AF, Morales DLS, Cai B, Oz MC, Burkhoff D. Time course of reverse remodeling of the left ventricle during support with a left ventricular assist device. J Thorac Cardiovasc Surg. 2001; 121: 902–908.
Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000; 101: 365–376.
Ogletree-Hughes ML, Stull LB, Sweet WE, Smedira NG, McCarthy PM, Moravec CS. Mechanical unloading restores ;-adrenergic responsiveness and reverses receptor downregulation in the failing human heart. Circulation. 2001; 104: 881–886.
Ogletree-Hughes ML, Smedira NG, McCarthy PM, Moravec CS. Mechanical unloading causes recovery of calcium cycling in the failing human heart. J Heart Lung Transplant. 2001; 20: 210.
James KB, McCarthy PM, Thomas JD, Vargo R, Hobbs RE, Sapp S, Bravo E. Effect of the implantable left ventricular assist device on neuroendocrine activation in heart failure. Circulation. 1995; 92 (suppl II): II-191–II-195.
McCarthy PM, Savage RM, Fraser CD, Vargo R, James KB, Goormastic M, Hobbs RE. Hemodynamic and physiologic changes during support with an implantable left ventricular assist device. J Thorac Cardiovasc Surg. 1995; 109: 409–417.
Klotz S, Barbone A, Reiken S, Holmes JW, Naka Y, Oz MC, Marks AR, Burkhoff D. Left ventricular assist device support normalizes left and right ventricular beta-adrenergic pathway properties. J Am Coll Cardiol. 2005; 45: 668–676.
Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, Rosenblum W, Kormos RL, Feldman AM. Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation. 2001; 104: 1147–1152.
Reesink KD, Dekker AL, Van Ommen V, Soemers C, Geskes GG, van der Veen FH, Maessen JG. Miniature intracardiac assist device provides more effective cardiac unloading and circulatory support during severe left heart failure than intraaortic balloon pumping. Chest. 2004; 126: 896–902.(Donna Mancini, MD; Daniel)