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Right arrow Mechanical Circulatory Assistance

Ann Thorac Surg 2001;71:S210-S219
© 2001 The Society of Thoracic Surgeons

Etiology of cardiac recovery

Healing the heart with ventricular assist device therapy: mechanisms of cardiac recovery

James B. Young, MDa

a Kaufman Center for Heart Failure, Section of Heart Failure and Cardiac Transplant Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Address reprint requests to Dr Young, The George M. and Linda H. Kaufman Center for Heart Failure, Section of Heart Failure and Cardiac Transplant Medicine, The Cleveland Clinic Foundation, 9500 Euclid Ave, F25, Cleveland, OH 44195
e-mail: youngj{at}ccf.org

Presented at the Fifth International Conference on Circulatory Support Devices for Severe Cardiac Failure, New York, NY, Sept 15–17, 2000.

Abstract

As experience has grown with the use of mechanical circulatory support systems in patients with cardiogenic shock, many anecdotes have been noted where myocardial recovery occurred and devices could be removed with reasonable residual cardiovascular performance and resolution of the shock syndrome. Indeed, when first used, ventricular assist devices were inserted to bridge patients unable to be separated from cardiopulmonary bypass to eventual recovery. Many successes with ventricular support systems have been recorded in individuals with postcardiotomy cardiogenic shock, acute myocarditis, and in the periinfarction period where stunning of potentially viable myocardial tissue contributed to severe heart failure. From an experimental standpoint, recovery of myocyte function and restoration of more normal myocardial geometry and constitution have been noted. There are many explanations for this, but principally, benefit is related to amelioration of circulatory insufficiency with attenuation of perturbed humoral networks and reduction of myocardial wall stress. It is important to understand how ventricular assist device implantation in select advanced heart failure patients might precipitate recovery of depressed myocardial function.

Heart failure has become an extraordinary epidemic with high morbidity and troubling mortality [1]. Therapeutic protocols for heart failure are now designed keeping in mind a patient’s underlying diagnosis, stage of the syndrome, and availability of therapies. Insight into the pathophysiology of heart failure has been critical to designing and completing a spectrum of clinical trials whose results in both acute and chronic heart failure give guidance when planning medical and surgical therapies [2, 3]. Despite tremendous gains made with the polypharmacy of heart failure, many patients still progress to unsatisfactory stages with rather profound hemodynamic distress. Radical therapeutic options, such as cardiac transplantation, have proved miraculous in those individuals appropriately chosen for this surgical intervention. Furthermore, mechanical circulatory sustenance has become a common method of stabilizing patients with profound heart failure such that preservation of global organ function is possible, allowing time for identification of a suitable organ donor. Unfortunately, the limitations of organ donor supply are well known [4], and great pressure is therefore placed on defining alternative strategies to decrease morbidity and mortality. It is not surprising that great effort has been made with chronic, long-term mechanical cardiac support options to achieve this goal [5].

Interestingly, as experience grew with use of mechanical circulatory support systems in patients with cardiogenic shock, anecdotes arose where myocardial recovery occurred, and the device could be removed with reasonable residual cardiovascular performance. It should be remembered, however, that early proponents of mechanical circulatory assistance viewed these devices initially as a "bridge-to-recovery" rather than "bridge-to-heart transplant" or "destination" therapy. Indeed, DeBakey’s first reported cases and successes occurred when rudimentary prototypes were inserted in the early and mid-1960s [6]. At that time, development of pulsatile extracorporeal left ventricular assist devices were being pursued to transiently support patients who were unable to be weaned from cardiopulmonary bypass after cardiotomy and open heart surgery. Many subsequent successes with ventricular support systems have been noted in individuals with cardiogenic shock postcardiotomy and cardiopulmonary bypass, patients with acute myocarditis, and patients in the periinfarction period where stunning of potentially viable myocardial tissue had occurred. Less frequently, patients with more chronic, advanced, "end-stage" heart failure have been noted to have improve cardiac function parameters to a point where removal of the ventricular assist device was possible. These observations fueled excitement and raised a more general question regarding one’s ability to prospectively identify patients who would benefit from ventricular assist device insertion as "bridge-to-cardiac recovery" rather than "bridge-to-cardiac transplantation" or "destination" therapy. A major question is, then: How might ventricular assist device support in chronic, advanced heart failure patients effect myocardial recovery?

Gaining insight into the pathophysiology of heart failure

Several recent reviews of today’s understanding of heart failure point out the fact that this difficulty is a pleiotropic problem with a wide spectrum of anatomic, physiologic, and clinical abnormalities [7–10]. Table 1 summarizes some of the important pathophysiologic mechanisms underlying heart failure. As the cited reviews all point out, heart failure is a milieu or syndrome whereby some index injurious event causes myocardial injury, which results in abnormal mechanical properties that, in conjunction with the injurious process, produces cardiac remodeling. These processes can be sudden or insidious in their development. The underlying disease accounting for heart failure, coupled to cardiac and circulatory responses, is what accounts for the clinical heart failure syndrome presentation. Injurious events can include a variety of well-defined problems, such as acute and chronic myocardial ischemia, exposure to toxins, infectious agents, inflammatory responses to systemic illnesses, cardiac volume and pressure overload, genetic abnormalities, or unknown (idiopathic) causes.


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  		Table 1. Pathophysiology of Heart Failure

 
Alterations in myocyte biology associated with heart failure include attenuation of normal excitation contraction coupling mechanisms with a reversion to myosin heavy chain fetal gene expression and beta-adrenergic receptor desensitization. These and additional changes in cytoskeletal protein production lead to myocyte hypertrophy, myocytolysis, and interstitial fibrosis, setting the stage for cardiac chamber enlargement and myocardial hypertrophy. Systolic dysfunction ensues with interstitial fibrosis, causing a stiffening of the heart and diastolic dysfunction. Programmed cell death, or premature apoptosis, leads to an accelerated loss of functional myocytes. Altered contractility of the heart with chamber geometry remodeling toward a more spherical state causes mitral regurgitation and diminished stroke volume, which leads to perfusion abnormalities in systemic organs. This, then, causes perpetuation of the heart failure milieu by eliciting expression of a variety of neurohumors and mediators of inflammation. Indeed, the growth of myocytes seems primarily related to many growth factors subsequently liberated, including catecholamines, endothelin, growth hormone, tumor necrosis factor, angiotensin-II, and insulin-dependent growth factor. Mechanical stretch is also important and likely directly stimulates cell growth. Myocyte stretch also induces release of intracellular angiotensin-II. This is an extraordinarily important observation because ventricular assist device insertion primarily might effect cardiac recovery by attenuating these stretch-induced responses with ventricular unloading (or "rest"). Fibrosis as part of the remodeling process is promoted by activation of the renin-angiotensin-aldosterone axis as well as through increased endothelin and transforming growth factor-beta (TGF-beta) responses. Regulation of apoptosis, or programmed cell death, is altered via changes in the expression of a variety of genes that, perhaps, are regulated in adverse fashion by increased tumor necrosis factor. Certain counter-regulatory forces are activated as well and include secretion of atrial and B-type natriuretic peptides. Nitric oxide, driven by bradykinin and natriuretic peptides, may have antigrowth properties, holding uncontrolled cell hypertrophy in check. Important also is the role of altered systemic organ perfusion in the pathophysiologic process, because ventricular assist device insertion, in addition to unloading the heart and reducing "stretch," is intended to restore peripheral perfusion. It would be anticipated that neurohumoral responses to low flow states would, thus, be ameliorated by restoration of more normal cardiac output. Whether or not pulsatile flow is necessary to change some of these basic pathophysiologic mechanisms is not yet entirely clear.

Ameliorating heart failure

Therapeutic interventions in heart failure initially focussed on symptom relief with diuretics, inotropes, and vasodilators. These drugs were effective by attenuating processes inherent in the cardio-renal and circulatory model of heart failure. As the importance of remodeling became evident, treatments now focus on both amelioration of symptoms when they are present, but perhaps more important is prevention of disease progression even when patients are entirely asymptomatic but have abnormally remodeled hearts. Treating the so-called neurohormonal model of heart failure relies on use of angiotensin-converting enzyme inhibitors, beta blockers, and possibly emerging agents such as angiotensin receptor blockers, aldosterone antagonists, cytokine inhibitors, neutral endopeptidase actuators, and endothelin antagonists. Obviously, use of ventricular assist device therapies in an attempt to "heal" the heart focuses on amelioration of symptoms as well as prevention of disease progression. No one can doubt the importance of restoring intracardiac pressures and circulatory flows to more normal levels after observing the dramatic improvement that occurs in a cachectic end-stage heart failure patient dying of circulatory insufficiency with hepatic and renal failure after ventricular assist device insertion and cardiovascular system resuscitation. The question at hand is: Will such therapy promote reversal of the heart failure phenotype such that "de-remodeling" or "re-remodeling" occurs and the heart failure syndrome abates with substantive enough recovery to allow separation of the patient from the mechanical support device? Indeed, this philosophy serves as the basis for a variety of antiremodeling strategies, including gene therapies, cardiac myoblast implants, and mechanical surgical interventions such as the Batista and Dor operations, mitral valve repair, and application of the Acorn and Myosplint devices.

Promoting myocardial recovery with ventricular assist devices

In view of the above factors, determining if ventricular assist device support might truly promote healing of the heart is important. It is helpful, then, to critically overview reports describing fortuitous cardiac recovery during ventricular assist device support and studies designed to clinically and experimentally give insight into the effects of this operation on the pathophysiology of heart failure.

Clinical observations
General reports
Excluding the pretransplant era postcardiotomy ventricular assist device successes, a few notable observations of resolution of heart failure with long-term circulatory support are evident. Again, it should be noted that patients receiving mechanical circulatory assist device therapy several decades ago invariably had the machines implanted in an attempt to bridge patients to recovery. Perhaps the first report of a patient receiving a ventricular assist device as a bridge-to-transplant with it ultimately being removed because of satisfactory return of native heart function after longer term support was that of Holman, Bourge, and Kirklin from the University of Alabama at Birmingham in 1991. They detailed use of a heterotopic extracorporeal, pulsatile, ventricular assist device (Thoratec) to support the circulation of a 19-year-old gentleman with profound circulatory impairment until a donor heart became available. Improvement was noted, however, in the patient’s cardiac function, after 4 weeks of circulatory assistance and at the 70-day mark, and the device was removed with the patient developing normal rest and exercise cardiac systolic function [11]. It is, perhaps, extremely important to note that the description of this case suggested that a "flu-like" syndrome preceded the patient’s heart failure. Despite this, histologic examination of biopsy specimens did not suggest inflammatory heart disease was present. Nonetheless, as will be seen, a common theme appears to be the fact that inflammatory conditions of the heart may be reversible. Also, it may be important that the patient did not have coronary heart disease present.

In 1995, Nakatani and associates reported on the use of long-term circulatory support to promote recovery from profound heart failure [12]. These authors used a paracorporeal pneumatic ventricular assist device that they had implanted in 31 patients since 1982. The group observed that 6 patients supported more than 3 weeks were able to be weaned from the ventricular assist system, with 4 doing well, but 2 deteriorating to the point where cardiac transplantation was necessary. Of these 6 patients weaned from the device, 2 had ischemic heart disease, 1 valvular heart disease, and 3 idiopathic cardiomyopathy (2 dilated and 1 hypertrophic-dilated).

Loebe and associates reported in 1997 an extraordinary case of a 36-year-old gentleman with dilated cardiomyopathy who was supported with a left ventricular assist device for more than 2 years. During the support interval, gradual functional recovery occurred, but a suitable donor organ finally came available. In preparation for the transplant operation, the ventricular assist device (a Novacor electrical device) was "switched off" and native ventricular function assumed the total cardiac load. Because cardiac performance was judged acceptable, the left ventricular assist device was explanted and transplantation not performed, with the report noting that the patient continued to improve and was successfully discharged [13]. A subsequent report from this same Berlin surgical group expanded on this initial case report [14]. This more detailed manuscript furthered observations about long-term effects of ventricular unloading on cardiac function, humoral anti-beta-1 adrenoreceptor autoantibodies, and myocardial fibrosis. Seventeen patients with nonischemic dilated cardiomyopathy received either a Novacor or HeartMate intracorporeal pulsatile ventricular assist device. The mean duration of support was 230 days, with 6 patients dying, 4 ultimately transplanted, and 2 supported at the time of their publication. Five patients were noted to have significant recovery and were weaned after 160 to 794 days of support with follow-up post-device removal of 51 to 592 days. Anti-adrenoreceptor antibodies disappeared during mechanical circulatory support and did not increase after weaning. Cardiac function and volume density of fibrosis remained normal in the successfully weaned patients. It should be noted, however, that 9 patients did not have any improvement in ventricular function.

Frazier and Myers reported in 1999 the use of left ventricular assist systems as a bridge to myocardial recovery in their program [15]. Data on 5 patients having devices removed after 46 to 447 days were reported. In 3 patients, the system was removed electively after the patient demonstrated signs of myocardial recovery, and in 2 patients, the device was removed because of pump malfunction. One patient died of cardiac-related causes 10 days after ventricular assist system removal, with the remaining patients noted to be alive and well at 35, 33, 14, and 2 months after system removal. None of the patients had ischemic heart disease as the underlying pathologic difficulty.

Hetzer and Muller provided additional observations on their Berlin patients in 1999 [16]. In this report, they attempted to extend their clinical experience with the "weaning" concept. In 19 patients with ventricular assist devices explanted after support periods of up to 26 months, they demonstrated that 7 had persistently restored cardiac function for more than 8 months and 5 patients for less than 5 months. Five patients with recurrent heart failure after device removal died 4 to 8 months after explantation, 4 patients had to be transplanted, and 2 patients died for reasons unrelated to their cardiac function. These investigators suggested that markers of successful pump removal included decreased ventricular volumes and improved ejection fraction as the pump contribution to circulation was decreased. Nonetheless, the fact that a minority of patients did well in the long term after device removal is concerning and emphasizes the caution needed during consideration of this sailing tack.

Postcardiotomy cardiogenic shock
Clearly, the greatest experience with circulatory assists placed as "bridge-to-recovery" is in patients for whom these devices were initially proposed, those with postcardiotomy cardiogenic shock. The first large case series appeared in 1992, when a "registry" experience was detailed by Pae and associates [17]. This report summarized outcomes in 965 patients voluntarily registered between 1985 and 1990. Approximately 45% of patients were weaned from temporary circulatory assistance, with about 25% being discharged from the hospital. In 90% of patients who were discharged, circulatory support was able to be discontinued in about 7 days. Rates of weaning and discharge favored those patients requiring only univentricular support. Interestingly, with devices used in this fashion, results were equal whether nonpulsatile centrifugal or pulsatile pneumatic devices were employed. Frequent complications were noted, but in patients able to be discharged, 2-year actuarial survival was 82%, with 86% of patients being New York Heart Association functional class I or II. Only 4.5% of the patients were deemed device dependent without contraindications to transplantation. Of these 43 patients, 32 (about 75%) underwent cardiac transplantation with 20 (63%) discharged. Clearly, this multiinstitutional experience demonstrated the ability of a variety of ventricular assist devices to sustain patients during postcardiotomy cardiogenic shock and emphasized the potential for recovery of the myocardium after stunning injury associated with cardiotomy and cardiopulmonary bypass. This observation prompted the adoption of many protocols designed to "bail out" patients failing cardiopulmonary bypass wean or developing early postoperative cardiogenic shock. The practice of inserting ventricular assist devices early on today reflects the reasonable experience with success observed in these patients. One must again emphasize the distinction between this patient population and individuals having more chronic heart failure syndromes with acute decompensation unrelated to acute cardiotomy and cardiopulmonary bypass or a sudden critical ischemic event.

Myocarditis
Another growing experience with ventricular assist devices as "bridge-to-recovery" can be seen in patients with fulminant myocarditis and the acute onset of cardiogenic shock. Many cases of both presumed and well-documented myocarditis have been bridged to recovery. Martin and associates [18] reported an example of a case with myocarditis and profound circulatory failure typical of those patients successfully treated with ventricular assist device insertion. The individual was a 30-year-old woman who presented suddenly with tachycardia, dyspnea, hypotension, oliguria, and a dilated hypocontractile heart in the setting of cardiogenic shock. A pneumatically actuated extracorporeal biventricular assist system was inserted acutely and the patient supported for 17 days with evidence of myocardial function improving. The device was removed with the patient returning to work and 7 months of follow-up reported. Interestingly, commentary about histologic examination of a right ventricular biopsy suggested that the cause of the acute cardiac failure could not be determined. The patient did not, however, have coronary artery disease.

Houel and associates discussed two cases more recently treated with mechanical circulatory support with documented acute lymphocytic myocarditis. One patient had the device explanted on the 12th postoperative day and subsequently improved with 2 months of follow-up noted. A second patient had the device explanted on the 50th postoperative day, and deteriorated rapidly after device removal but fortuitously underwent cardiac transplantation 20 hours after removal of the left ventricular assist device. These authors point out that myocardial recovery in patients undergoing mechanical circulatory support for acute myocarditis remains difficult to predict, but that recovery is quite possible [19].

Most recently, Westaby and colleagues reported a case of a 21-year-old female with acute and fulminant lymphocytic myocarditis who presented with cardiogenic shock and was successfully supported by a nonpulsatile centrifugal implantable system (the AB-180 centrifugal blood pump; Cardiac Assist Technologies Inc., Pittsburgh, PA) for 7 days [20]. After removal of the device, the patient had normal left and right ventricular function at a follow-up of 7 months. This report prompted an intense media response when the story was told by John Dyson in the April 2000 edition of Reader’s Digest. In the scientific report, Westaby summarizes successful mechanical bridge to recovery in an additional 11 acute nonrheumatic myocarditis patients [20]. All patients were alive and well with as much as 3 years of follow-up. This experience adds to the growing literature suggesting some, but certainly not all, patients with acute inflammatory heart disease causing cardiogenic shock can be bridged to recovery. Obviously controversial is how best to diagnose and treat these patients, particularly what additional pharmacotherapeutic strategies should be used.

Recovery of the circulatory system
As suggested, ventricular assist device insertion provides dramatic amelioration of cardiac filling pressures and systemic flow. Several studies have assessed exercise hemodynamics and capacity during long-term follow-up of patients with ventricular assist devices in place. Jaski and colleagues [21] detailed 3 patients requiring implantation of a Thermetics Heart Mate 1000 IP left ventricular assist device (TCI) with 1-month postimplant graded supine bicycle exercise hemodynamics. Significant workloads compatible with activities of daily life were supported by adequate exercise hemodynamics. This observation suggested that amelioration of the heart failure milieu could certainly occur during wait for transplant and imply that many of the circulatory perturbations responsible for perpetuation of the heart failure syndrome would dissipate [22–24].

Reversal of left ventricular remodeling
Left ventricular assist device insertion has been associated with reduction in left ventricular size, improved contractility, and regression of myocyte hypertrophy. Frazier and associates in 1996 [25] looked at 31 patients supported for more than 30 days with the HeartMate system. Chest roentgenogram demonstrated an improvement in cardiothoracic ratio from 0.64 to 0.55, while echocardiography performed with the pump off showed significant decrease in left ventricular end-diastolic dimension (6.81 to 5.35 cm) with a significant improvement in ejection fraction (11% to 22%). Off-pump cardiac index also increased, as did mean aortic pressure, with a significant reduction in pulmonary capillary wedge pressure and pulmonary vascular resistance. These hemodynamic studies were coupled to an analysis of tissue samples taken from the ventricle at the time of ventricular assist device implantation and subsequent transplant. Histologic studies showed marked reduction in myocytolysis.

Levin and associates [26] did an elegant study of idiopathic dilated cardiomyopathy patients supported with prolonged ventricular assist device insertion to correlate improvements in pressure-volume relationships to mechanical sustenance. The end-diastolic pressure-volume relationships of 7 patients were measured ex vivo at the time of cardiac transplantation and compared with findings from three normal human hearts not used for transplantation. Only 3 patients of the 7 undergoing heart transplant underwent ventricular assist device insertion and were supported for approximately 4 months. Compared with normal hearts, the end-diastolic pressure-volume relationship from medically treated patients ultimately undergoing transplantation shifted toward markedly larger volumes, whereas those hearts supported by ventricular assist devices were similar to the normal hearts studied. This observation supported the contention that chronic unloading of the failing ventricle with sufficient magnitude and duration resulted in deremodeling, or reversal of the chamber enlargement associated with heart failure. In a later overview, Burkhoff from this group pointed out that additional data indicated this normalization of the passive pressure-volume relationship were associated with improved contractile response to increased heart rate and to beta-agonist stimulation. In addition to reverse remodeling from the macroscopic perspective, reverse molecular remodeling has also been noted with, as Burkhoff points out, increased expression of several genes involved in calcium metabolism that are downregulated in heart failure [27].

The relationship of left ventricular size and shape improvement to histologic changes occurring during ventricular assist device support were also explored by Nakatani and associates from the Cleveland Clinic Foundation [28]. In this study, intraoperative transesophageal echocardiography at the time of insertion and explantation of the HeartMate left ventricular assist device in 19 patients was correlated with myocardial specimens taken at the time of implantation of the device and again at transplantation. Patients were supported by the device for 3 to 153 days. Left atrial and left ventricular diastolic and systolic diameters decreased immediately after insertion of the left ventricular assist device (from 4.6 to 3.5, 6.3 to 4.1, and 5.9 to 3.6 cm, respectively). Left ventricular wall thickness increased from 1.0 to 1.4 cm for the interventricular septum. Myocardial histologic findings demonstrated a reduction in myocyte damage as estimated by the decreased appearance of wavy band fibers and contraction band necrosis. There was, however, a slight increase in fibrosis but no significant change in myocyte diameter.

Scheinin and associates explored the histopathologic effect of prolonged left ventricular unloading with a left ventricular assist device in 8 males with either ischemic (2 patients) or end-stage dilated (6 patients) cardiomyopathy in 1992 [29]. The average length of support was about 80 days, and apical core specimens from all patients exhibited extensive areas of attenuated myocardial fibers combined with wavy patterns and infarcted areas in the patients with ischemic cardiomyopathy. At the time of heart transplantation, compared with the specimen obtained at the time of ventricular assist device insertion, myocardial tissue demonstrated significant decrease or disappearance of stretched fibers with a slight increase in interstitial replacement fibrosis, as well as an increase in the diameter of the myocardial fibers. These observations also supported the concept that morphologic parameters were normalized with mechanical circulatory support.

McCarthy and associates further reviewed this issue and again noted increase in fibrosis, but otherwise generally improved histologic markers of acute myocyte damage [30]. Dipla in 1998 [31] evaluated myocytes from human explanted hearts and failing hearts (heart failure myocytes) before and after left ventricular assist device support. Studies of myocyte function indicated that the magnitude of contraction was greater, the time to peak contraction was significantly abbreviated, and the time to 50% relaxation reduced in patients supported by the ventricular assist device. Myocytes removed from the ventricular assist device patients had greater contraction than control myocytes at all frequencies of stimulation. The negative force-frequency relationship of assist device-supported myocytes improved, but was not reversed. Responses to beta-adrenergic stimulation were also greater in the ventricular assist device-supported myocytes, confirming observations by Burkhoff. This study supported the concept that mechanical circulatory sustenance improves myocardial contractile properties and increases beta-adrenergic responsiveness.

Zafeiridis and associates [32] also confirmed the fact that myocytes supported with chronic circulatory assist demonstrated reversed remodeling. In 10 patients with failing hearts undergoing ventricular assist device insertion for a mean of 75 days (compared with 6 nonfailing hearts), cardiac myocyte volume, length, width, and thickness were determined. Myocytes taken from myopathic hearts exhibited increased volume, length, width, and length-to-thickness ratio, compared with normal myocytes; however, there were no differences in any parameter between myocytes from ischemic and nonischemic cardiomyopathic hearts. Long-term ventricular assist device support was associated with significant reduction in myocyte volume, cell length, cell width, and length-to-thickness ratio. These changes were associated with reductions in left ventricular dilation and left ventricular mass measured by echocardiography and further support the concept that reverse remodeling is occurring in response to chronic ventricular assist device sustenance. However, a response to this publication by Dr Soloff raises a haunting issue [33]. Soloff argued that the morphologic changes described were more consistent with atrophy of the myocardium than normalization of a severely remodeled heart. This, in conjunction with the increased fibrosis in two studies detailed above, raised great concern that "resting" the heart substantially with chronic circulatory sustenance can lead to potentially detrimental and regressive changes in the heart muscle. This might be analogous to the severe atrophy associated with fractured limbs that have been placed in a cast and immobilized for long periods of time.

Molecular remodeling
Adding support to the hypothesis that chronic ventricular assist device support will effect structural remodeling of the heart are more recent observations indicating that molecular remodeling is also occurring. Milting and colleagues [34] studied the impact that ventricular assist devices had on apoptosis regulation. This group measured transcription of apoptosis-associated genes, Fas Exo6 Del, Fas receptor, and Bel-XL, as markers of recovery. They found that transcription of apoptosis-inhibiting genes was upregulated in patients supported for more than 6 weeks with a ventricular assist device. Fas receptor mRNA remained unaffected by mechanical circulatory support. Their conclusions were that transcriptional upregulation of apoptosis-inhibiting genes could have been induced by desensitization to apoptotic stimuli and might indicate reversed molecular remodeling of the heart during ventricular assist device support.

These initial observations were expanded to include studies clarifying the molecular dynamics of calcium exchange [35]. Belland, of Temple University, has confirmed the fact that patients with advanced heart failure undergoing ventricular assist device insertion have extensive cardiac myocyte apoptosis, and that prolonged left ventricular assist device support and mechanical unloading alter cardiac myocyte apoptosis by decreasing the extent of myocyte apoptosis overall in the ventricle [36].

Effects on neurohumoral and inflammatory perturbation
James and associates in 1995 followed patients serially while on left ventricular assist device support to determine changes in neurohormones [37]. In 13 patients awaiting transplantation who underwent HeartMate implant, venous atrial natriuretic peptide, epinephrine, norepinephrine, plasma renin activity, angiotensin, and arginine vasopressin were measured immediately before pump insertion and then again at pump explantation and heart transplantation. Mean time of support was 86 days. Dramatic changes were noted in most neurohormones, with plasma renin activity decreasing from 57 to 3 nm, angiotensin-II decreasing from 237 to 14 U/L, plasma epinephrine falling from 6,800 to 46 pg/mL, norepinephrine decreasing from 2,953 to 518 pg/mL, and arginine vasopressin decreasing from 6 to 0.8 pg/mL, all changes highly statistically significant. Only atrial natriuretic peptide did not significantly change, moving from 227 to 168 pg/mL. Accompanying these changes were dramatic improvements in cardiac index and central hemodynamics (indeed, they were normalized long term with ventricular assist device support). Delgado and colleagues [38] confirmed these findings, as did Noirhomme and associates [39]. These observations indicate that circulatory support normalizes the peripheral milieu of heart failure to such an extent that the sympathetic and parasympathetic nervous system and neurohumoral expression markers characteristic of heart failure are attenuated.

Inflammatory markers of heart failure also seem to be beneficially effected by chronic support. Goldstein and colleagues [40] characterized the cytokine profile in 14 patients with acute circulatory collapse undergoing left ventricular assist device placement. Interleukin-6 level was elevated in 11 patients, and interleukin-8 in 10 patients, with tumor necrosis factor (TNF) being abnormally elevated in 2. After hemodynamic recovery, a significant attenuation of interleukin-6 and -8 levels was noted, but TNF-alpha did not change significantly.

Torre-Amione and colleagues more recently reported an elegant study of myocyte TNF-alpha production in ventricular assist device supported patients [41]. In this study, myocardial tissue was obtained from normal hearts and from paired samples of 8 patients with nonischemic end-stage cardiomyopathy at the time of left ventricular assist device implantation and removal. Tissue was stained for TNF-alpha and a quantitative analysis performed. TNF content decreased significantly after left ventricular assist device support. The magnitude of changes did not correlate with the length of mechanical circulatory sustenance, but greater reductions in myocardial TNF content were found in those patients successfully weaned off the ventricular assist device obviating need for transplant. This suggests that myocardial expression of genes regulating TNF production are attenuated and further supports the concept that "molecular remodeling" is occurring with ventricular assist device support.

Altering myocardial phenotype
As alluded to, evidence suggests that the myocardial phenotype characteristic of the failing ventricle is altered with prolonged left ventricular assist device therapies. This molecular remodeling appears to track with structural remodeling that has been observed. Further supporting this concept are observations by Altemose and associates regarding tissue immunoreactivity for atrial and brain natriuretic peptide production [42]. This group examined left ventricular size, myocyte morphometry, and myocardial immunoreactivity for atrial and brain natriuretic peptide in 8 patients with advanced idiopathic dilated cardiomyopathy before and after ventricular assist device insertion. Support averaged 42 days. Echocardiographic left ventricular mass decreased from 505 to 297 g during support, whereas myocyte diameter also decreased significantly. Furthermore, ventricular atrial natriuretic peptide immunopositivity and brain natriuretic peptide immunopositivity also decreased significantly and were highly correlated to the reduction in left ventricular mass.

Moravec and associates have also reported reversal of the heart failure phenotype by chronic mechanical unloading and, specifically, that mRNA levels for the sarcoplasmic reticulum calcium ATPase enzyme were 1.5 to 4.5 times greater in the left ventricular tissue removed after unloading by the ventricular assist device as compared with the original apical core tissue from the same patient. This group has also confirmed the fact that mRNA for atrial natriuretic peptide decreased after ventricular assist device sustenance. The decrease in these mRNA activities after mechanical unloading in human hearts suggests again that human heart failure phenotype is reversable, and such changes may result in functional recovery of the heart [43].

Takeishi and associates have also explored the relationship of mechanical assist device support to improved calcium cycling [44]. These investigators specifically examined whether protein kinase-C activation and decreased calcium-cycling protein levels could be reversed by left ventricular assist device support. Left ventricular myocardial specimens were obtained from 7 patients during left ventricular assist device sustenance and subsequent heart transplantation. Changes were found in protein levels of g-alpha-q, phospholipase-C-beta-1, regulators of g-protein signaling, sarcoplasmic reticulum calcium ATPase, phospholamban, and translocation of protein kinase-C isoforms. The paired pre- and post-left ventricular assist device samples revealed that a selective inhibitor of g-alpha-q was significantly decreased, while the status of g-alpha-q phospholipase-C-beta-1 and regulators of g-protein signaling were unchanged after left ventricular assist device implantation. Translocation of protein kinase-C isoforms also remained unchanged. Left ventricular assist device support increased sarcoplasmic reticulum calcium ATPase protein level with phospholamban concentrations unaffected. These authors concluded that altered protein expression and stoichiometry of the major cardiomyocyte calcium cycling proteins, rather than reduced phospholipase-C-beta-1 activation, occurred during ventricular assist device support and may contribute to improved mechanical function.

Improvement in myocardial mitochondrial function after left ventricular assist device support has also been noted [45]. Lee and colleagues isolated mitochondria from myocardial tissue obtained from 13 patients with heart failure without a left ventricular assist device and 7 patients with heart failure treated with ventricular assist systems. Mitochondrial respiratory states were measured, as well as a respiratory control index. The respiratory control index was higher in ventricular assist device patients than in the heart failure-alone population. Similarly, the respiratory control index measured was greater in those mechanically supported. Their conclusions were that cardiomyocyte mitochondrial function is improved by long-term therapy with a left ventricular assist device and that this improvement suggested that cardiomyocyte metabolic dysfunction in heart failure may actually be reversed with left ventricular device support.

Altering the global heart failure milieu
Table 2 summarizes the evidence suggesting that an injured and failing heart can be "healed" with ventricular assist device therapy. Important observations detailed above include the fact that ventricular assist device insertion can reverse cardiac chamber enlargement and normalize end-diastolic pressure-volume relationships. Furthermore, a reduction in left ventricular global mass and regression in myocyte hypertrophy have been noted. There appears to be an enhanced inotropic response to epinephrine with improved cytosolic calcium transients. Also important is the fact that an upregulation of apoptosis inhibiting genes has been demonstrated, as well as improved myocardial mitochondrial function and attenuation of systemic neurohormonal and cytokine perturbations. Perhaps most important is the fact that a more normal myocardial phenotype expression for natriuretic peptides, sarcoplasmic reticular calcium ATPase activity, and TNF has been seen. This suggests that a link exists between structural remodeling and molecular remodeling of the heart.


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  		Table 2. Evidence Suggesting That the Heart Can "Heal" With VAD Therapy

 
Low incidence of success with ventricular assist device "bridge-to-recovery"

Why is it then that more patients are not successfully bridged to recovery with chronic mechanical sustenance? Mancini and colleagues [46] evaluated patients receiving ventricular assist devices as bridge to cardiac transplantation in their program. They prospectively attempted to identify potential explant candidates using an exercise testing protocol. There were 39 consecutive patients studied after insertion of a HeartMate vented electric device with such a protocol. Approximately 3 months after device implantation, a maximal exercise test with hemodynamic monitoring and respiratory gas exchange analysis was performed with the device in an automated mode. The device rate was reduced to 20 bpm. Hemodynamic measurements were recorded as the device rate was decreased, and a repeat exercise test was performed if the patient remained hemodynamically stable. Eighteen of the 39 patients were ultimately studied, with 15 patients exercised with maximal device support. In only 1 patient were hemodynamics felt sufficient to justify device removal. Furthermore, in a review of 111 consecutive ventricular assist device insertions in their program, only 5 successful explant patients were identified. This observation is in distinct contrast to that made with acutely decompensated patients suffering from myocarditis or postcardiotomy cardiogenic shock or acute myocardial infarction with cardiogenic shock, where myocardial recovery rates appear much more common and devices seemingly can be removed successfully more often. Whereas acutely decompensated patients have reasonable likelihood of recovery with support, the finding that few patients with chronic long-standing heart failure will do well after such intervention led Mann and Willerson to speculate that left ventricular assist devices in the chronic failing heart might be a "bridge too far to cross" [47].

Table 3 summarizes the reasons ventricular assist device support is not currently used primarily for "bridge-to-recovery." These include the fact that few device removals have actually occurred in the chronic end-stage heart failure patient, and even fewer seem to have been associated with long-term success after removal in this population. Importantly, however, we also lack insight into markers that will predict meaningful recovery of the chronically injured myocardium. Furthermore, there is an absence of suitable device-weaning protocols. It is also possible that the high systemic infection rates and altered immunologic states associated with ventricular assist device insertion may be counter-regulatory, contributing to heart failure deterioration rather than cardiac "healing." The possibility that myocyte atrophy and myocardial fibrosis might be related to chronic "unloading" (or "casting") of the heart could lead to detrimental hemodynamic effects as devices are being weaned or removed. Finally, we cannot forget that drugs are available that reduce left ventricular size, myocyte hypertrophy, and improve left ventricular function such as angiotensin-converting enzyme inhibitors and beta-blockers. Their role in treating ventricular assist device-supported patients has not been completely characterized. Drugs, however, seem futile in most patients requiring ventricular assist device insertion, and that clearly should be recognized.


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  		Table 3. Reasons VADs Are Not Used Primarily for Recovery

 
Despite the limitations summarized on Table 3, the few successes noted and the scientific rationale behind using ventricular assist devices as tools to heal the heart cannot be ignored. In order to further this approach, several important challenges need to be addressed (Table 4). First, and possibly foremost, better ventricular assist devices are necessary that are simpler, smaller, safer, more reliable, easier to insert, need not be removed, and are less expensive. If this challenge is met, one could argue that these pumps should be inserted much earlier in the course of heart failure than they are now. It may be that by the time chronically ill patients reach the stage of profound circulatory perturbation, and, particularly, collapse, healing the heart is impossible. Small devices that could be inserted intracorporeally but then allowed to clot off and not require removal may be attractive as well. These small devices might also be more conducive to quick change-outs if mechanical dysfunction occurs. Still important is further clarification of myocardial recovery pathophysiology and, in particular, better understanding of whether or not atrophy and myocardial fibrosis is related to ventricular assist device support. We also must determine the best intervention circumstances, including underlying disease states likely to benefit. As pointed out, most successful device removals have been done in patients with periinfarction cardiogenic shock, postcardiotomy cardiogenic shock, cardiogenic shock due to acute myocarditis, and when removed in the more longstanding chronic heart failure patient, those with idiopathic dilated cardiomyopathy. This is not to deny the fact that a few successes have been seen in patients with chronic ischemic heart disease. Also important, clarification of optimal intervention time points is essential, and it is very likely that success will be related to earlier operations. Finally, it is critical to develop weaning protocols and markers of success in patients supported with these devices with an intent to promote heart healing and heart failure recovery rather than bridging to transplantation or allowing the devices to permanently be inserted.


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  		Table 4. VADs as "Bridge-to-Recovery" Needs

 
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