Heart failure (HF) is characterized by a pathologic process known as remodeling that involves progressive enlargement (See Chapter 9 ) of the ventricle, reduction in contractility, and an increase in intracardiac pressures. These changes are associated with adverse cellular, structural, and functional changes in the myocardium (see Chapter 9 ). Historically, the remodeling process was considered largely irreversible once HF had been present for a period of time (years). However, patients with chronic advanced HF supported with a left ventricular assist device (LVAD) that provides near-total unloading of the ventricle can show a near-normalization of the structural abnormalities of the myocardium, or “reverse remodeling.” These findings are often associated with significant recovery of the underlying cardiac function, sufficient to allow for removal of the LVAD (myocardial recovery or “remission” of end-stage HF). A cohort of patients now exist who have had their device removed and have had sustained recovery for many years. These patients can return to a normal quality of life, without requiring transplantation, thereby making the precious donor heart available for another needy individual.
Yet, despite significant reversal of structural changes in most patients after a period of mechanical support, only a small percentage of patients have had their LVADs removed. This observation is due to a number of reasons. First, reverse remodeling does not always equate with clinical recovery. Despite favorable cardiac structure, functional improvement may either lag or not occur ( Fig. 19.1 ). Second, while transplant has a defined benefit and well-known natural history, trepidation about recurrence of HF following LVAD removal is prevalent in those who care for these patients. Finally, many institutions do not actively search for myocardial recovery, and as such, it is underevaluated, underpromoted, and underestimated. Conversely, some institutions who have focused on promoting and testing for recovery and removing the pump when patients show significant improvement in underlying cardiac function have shown high rates of recovery. This enthusiasm was ignited following reports showing high rates of recovery and explantation using a prospective attempt combining LVAD support with aggressive adjuvant reverse remodeling drug therapy to concurrently promote recovery, along with regular testing of underlying myocardial function, followed by an additional strategy to sustain recovery. This approach was associated with a 70% recovery rate, with more than 3 years of follow-up. Subsequently, increasingly more institutions are now adopting an aggressive approach of facilitating and testing for recovery and potential LVAD explantation.
This area of myocardial recovery from chronic HF is a relatively new, exciting, and developing field. However, many controversial and challenging questions persist: can chronic HF really reverse? Is there a state of irreversibility? How can clinicians test for recovery? Is the recovery sustainable? What are the markers and predictors of recovery? This chapter addresses these questions and presents the data available on the concept of myocardial recovery with LVAD support.
History of recovery and device explantation
LVADs provide profound pressure and volume unloading of the left ventricle (LV) while restoring systemic blood flow. In 1994, Frazier and colleagues were the first to describe myocardial improvement in a study of 18 patients supported with the pneumatic vented electric HeartMate device (Thoratec Corp., Pleasanton, CA). Of the patients, 12 had nonischemic etiology and six had ischemic etiology of HF. In all cases, the investigators found that LVAD support resulted in a significant reduction in the cardiothoracic ratio (from 0.65 to 0.55, P < 0.003), a decrease in LV end-diastolic dimension (LVEDD; from 7.0 to 5.5 cm, P < 0.05), and a 43% improvement in LV ejection fraction (EF) from baseline by echocardiography. These patients also showed improved hemodynamics, including a reduction in pulmonary capillary wedge pressure (PCWP) and improvement in cardiac index. Histologic examination showed the mean area of attenuated myocytes to be reduced from 60% to 21% from the time of implantation compared to after mechanical circulatory support (MCS). This was the first report suggesting that significant improvement of cardiac structure and function was possible with LVAD support.
Levin and colleagues measured the end-diastolic pressure-volume relationship (EDPVR) at the time of cardiac transplantation in patients treated with medical therapy versus patients bridged with LVAD support. EDPVRs of hearts from medically treated patients were shifted toward markedly larger volumes. In contrast, EDPVRs of hearts from LVAD-supported patients were similar to EDPVRs of normal hearts technically unsuitable for transplantation ( Fig. 19.2 ). This study suggested that chronic hemodynamic unloading of sufficient magnitude and duration can result in reversal of chamber enlargement and normalization of cardiac structure, even in the most advanced stages of HF.
The first report of recovery and subsequent device explantation with LVAD support was in a series of five patients with advanced nonischemic HF (three with idiopathic dilated cardiomyopathy and two with postpartum cardiomyopathy). In three of these patients, the LVAD was removed electively after the patients showed recovery of myocardial function. In the other two patients, it was removed because of device malfunction. One patient died of a noncardiac cause 10 days after LVAD removal, but the other four patients remained alive and well 35, 33, 14, and 2 months after LVAD removal.
Several subsequent reports showed recovery rates between 5% and 10% and impressive transplant-free survival rates near 70%, 5 years after explantation. One of the largest cohorts was derived from the large multicenter Thoratec Registry. In this series, they reported that 22 of 281 (8.1%) patients with nonischemic cardiomyopathy underwent explantation, with 17 of the 22 (70%) patients alive and 16 in New York Heart Association (NYHA) class I and one in class II at latest follow-up. These patients had 86% and 77% transplant-free survival rates at 1 year and 5 years, respectively. Approximately 50% of the patients had proven myocarditis or postpartum cardiomyopathy as the cause of HF, a finding that has been true of several patients who have had recovery with LVAD support.
Another large series was reported by Mancini et al. ( Fig. 19.3 ), who observed in a retrospective review of 111 patients with LVAD support as bridge to transplant (BTT) (46% of whom had dilated cardiomyopathy) that only five (4.5% overall, but 9% of patients with nonischemic etiology) had sufficient myocardial recovery for the device to be explanted. Four of these five patients had nonischemic cardiomyopathy. Only one of the five patients who underwent explantation was alive with maintained LV function after 15 months of follow-up; one patient died of HF 3 months after explantation, one patient had sudden death, and two patients required LVAD reimplantation. These authors argued that significant recovery occurred in only a small percentage of patients and primarily in patients with nonischemic causes of HF. At the time, this study provided skepticism and slowed the belief that recovery was very likely.
A higher success of device removal and more sustained recovery has subsequently been reported by the Berlin group. Their initial report showed that the first five patients who underwent explantation had sustained normal LV function for 51 to 592 days. A subsequent report in 2004 demonstrated that 32 of 131 (24%) patients with nonischemic HF had device explantation associated with a 5-year survival rate of 78.3% ± 8.1%. HF recurred in the first 3 years in 14 of the 31 patients whose devices were explanted, but only two patients died of HF after explantation. The other 12 patients with recurrent HF underwent successful transplantation. The patients whose devices were explanted had 69.4% and 58.2% freedom from recurrence of HF at 3 and 5 years, respectively. Several risk factors were associated with recurrence of HF after explantation, including a pre-explantation EF less than 45%, LVEDD greater than 55 mm, and history of HF greater than 5 years. Among patients who did not have these risk factors, none had HF recurrence during the first 3 years after explantation. By 2008, the Berlin group reported 81 patients weaned from LVADs, biventricular ventricular assist devices, and right ventricular assist devices (VADs) that had been implanted for terminal HF. The investigators analyzed 35 BTT patients older than 14 years who had received an LVAD for nonischemic cardiomyopathy (excluding patients with myocarditis) who were able to undergo device explantation). Of the 35 patients, 30 had the device explanted electively, and in the other five it was precipitated by pump-related complications. There were no established criteria to define recovery. In eight of the electively weaned patients, the LVAD was removed with a subnormal EF (30%–44%) and LVEDD of 56 to 60 mm. However, the overall 5- and 10-year survival rates after LVAD removal (including posttransplant survival for patients with HF recurrence) were 79.1% ± 7.1% and 75.3% ± 7.7%, respectively. At the end of the fifth post-weaning year, these patients had a 61.3% ± 9.0% probability of freedom from HF recurrence. The authors showed that if the patient remained stable 1 year after explantation, the probability of freedom from HF recurrence at the end of 5 and 10 years was 84.2% ± 8.4% and 61.8% ± 11.4%, respectively.
A critical observation from this cumulative series was that patients with long-term weaning stability had a shorter history of HF, were younger, and required a shorter duration of support. One important advance in the approach pursued by the Berlin group was to begin to reduce pump speed and flow to examine native heart function 1 month after implantation, but as with all published reports on recovery up to this point, there was no standardized use of an oral HF drug regimen in these patients and no true off-pump testing (as will be described later).
Until recently, the only prospective serial study was a multicenter study of 67 patients (37 with nonischemic cardiomyopathy and 30 with ischemic cardiomyopathy) who had an LVAD placed for refractory HF carried out by a group of investigators at eight US LVAD centers, called the LVAD Working Group. All patients received a HeartMate XVE device, which minimized the potential confounding effect of various types of support. The patients were to be placed on a regimen of oral HF drugs if tolerated after implantation. However, no target doses of the HF medications were defined, and investigators managed drug selection and dosing by physician preference rather than by protocol. As a result, the maximum doses achieved were highly variable among patients, or the drugs were not given, and no conclusion could be reached regarding the potential benefit of routine use of additional reverse remodeling oral HF drug therapy.
The Thoratec HeartMate XVE could be turned off from automatic pumping and hand pumped four to five times per minute to allow examination of native heart function over time. Not all of the centers in this study were experienced with “pump-off” studies, and they were not performed in all of the patients. Some patients had an echocardiogram at reduced, rather than zero, LVAD support (15 minutes after reducing the LVAD flow to 4 L/min). Patients with an EF greater than 40% at reduced or zero LVAD support underwent dobutamine echocardiography with simultaneous hemodynamic monitoring. Additional testing included cardiopulmonary exercise tests, but these were performed on full pump support in a subset of patients at one site only.
The echocardiograms ( Fig. 19.4 ) showed that there was a fair amount of recovery of native cardiac function after 1 month of support, with EF increasing from a mean of 17% before LVAD implantation to an average of 34% ( P < 0.001), with reduction of LVEDD from 7.1 cm to 5.1 cm ( P < 0.001) and LV mass reduced from 320 g to 194 g ( P < 0.001). Peak VO 2 (peak rate of oxygen consumption) improved on LVAD support (13.7 ± 4.2 mL/kg/min vs. 18.9 ± 5.5 mL/kg/min at 30 vs. 120 days, respectively; P < 0.001). Only six (9%) subjects underwent explantation for myocardial recovery, but there were no protocol-specified explantation criteria.
Possible explanations of the low rate of myocardial recovery
The MCS field has progressed significantly whereby the use of continuous-flow pumps is the norm. Yet, the prospects for recovery remain stagnant nearly two decades later. The general sense that myocardial recovery is more of an anecdote than a true phenomenon has historically been engrained within the annual Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) reports. In each of the yearly publications, competing outcome curves consistently portray the rate of myocardial recovery at 1%–2%. However, missing in these database reports is that few centers prospectively look for evidence of recovery. While one can argue about the pathophysiologic semantics of reverse remodeling, remission of HF, and myocardial recovery, the fundamental issue is that the clinician must look for recovery to find it.
To address this issue further, the University of Utah group studied INTERMACS patients that were a priori designated as bridge to recovery (BTR). Within this cohort, six independent predictors of cardiac recovery were identified: age < 50 years, nonischemic cardiomyopathy, time from cardiac diagnosis < 2 years, absence of an implantable cardioverter defibrillator, serum creatinine level < 1.2 mg/dL, and LVEDD < 6.5 cm. On the basis of these results, the INTERMACS Cardiac Recovery Score was derived. The score ranged from 0 to 9, and three groups with significantly different recovery potential were identified: a low probability group (0–3), an intermediate probability group (4 to 6), and a high probability group (7–9). Using this stratification methodology in the INTERMACS BTR population, evidence of recovery was seen in 0%, 4.9%, and 25.4% for patients in the low, intermediate, and high probability categories, respectively. In those patients not designated as BTR, the recovery rates were lower, but not negligible, in the three groups (low, 0.2%; intermediate, 1.3%; high, 8.1%). When applied to the Utah LVAD population, the score suggested a recovery rate of nearly 40% in the high probability group ( Fig. 19.5 ). These results highlight the importance of prospectively testing for recovery. Summarily, the I-CAR score can potentially identify patients that programs could dedicate time, resources, and therapies to augment the chance for recovery and pump explantation.
Assessment of Myocardial Recovery
In most centers, LVADs are implanted either as a BTT or as destination therapy, and the underlying myocardial function is not retested. Regular evaluation of myocardial function following device implantation is essential during the recovery process. Most of the early weaning protocols did not assess the true native myocardial function because they were based on measurements taken while the device was operating at full support. Echocardiographic studies, cardiopulmonary exercise testing, and right and left heart catheterization methods have now been described that can be performed safely and regularly, with the pump providing negligible or no forward flow, to monitor and detect recovery.
The ultimate goal of removing an LVAD depends upon a safe, accurate, and reproducible method of monitoring myocardial recovery. Patients should be studied during a period of limited or no LVAD support to test the true underlying cardiac function. It is important to perform echocardiographic, functional, and hemodynamic tests before deciding whether to explant the pump. A method was developed at Harefield Hospital for off-pump echocardiographic assessment of patients on the pulsatile HeartMate XVE pump. This protocol required administration of 10,000 units of unfractionated heparin 5 minutes before pump cessation, then acutely stopping the LVAD (while hand pumping for three bursts every 15 seconds to prevent stagnation of blood within the pump) and taking measurements of peripheral hemodynamics (e.g., blood pressure and heart rate) while echocardiographic parameters were obtained both at rest and whenever possible after exercise to test inotropic reserve. Pneumatic hand pumping was stopped while taking hemodynamic and echocardiographic measurements. Hemodynamic assessments were first done at baseline with the device on; then immediately after LVAD discontinuation; and at 5, 10, and 15 minutes after device cessation. Echocardiographic measurements were obtained at baseline and at 5 and 15 minutes after device cessation. If device cessation was tolerated for 15 minutes, a 6-minute walk (6MW) test was performed with repeat measurements afterward to determine the inotropic reserve. Echocardiographic measurements included LV end-systolic diameter (LVESD), LVEDD, and EF, along with a detailed assessment of valvular regurgitation (particularly mitral, which, if significant, could lead to overestimation of LV function and also result in recurrent HF by over reloading after explantation). Simultaneous hemodynamic measurements included systolic and diastolic blood pressure, mean arterial pressure (MAP), and heart rate. During the off-pump periods, patients were closely observed for symptoms such as dizziness, sweating, or palpitations. This series was the first time that these pumps had been turned completely off. Importantly, none of the patients experienced short-term or long-term adverse effects after the testing, and, in particular, no thromboembolic complications were seen. Initial device discontinuation was tolerated in 97.6% of patients.
Inotropic reserve was defined as the change in hemodynamics and echocardiographic parameters after the 6MW test without any infusion with inotropic agents ( Fig. 19.6 ). During these “off-pump” tests in all LVAD conditions, EF was significantly higher in the patients who subsequently recovered compared with the patients who did not. Similarly, the recovered group showed a significant increase in EF after the 6MW compared with the 15-minute off-pump test, suggesting the presence of inotropic reserve, but there was no significant change in EF in the nonrecovered group. Five minutes after device cessation, the LVESD and the LVEDD significantly increased in both groups. However, there was no further increase in ventricular dimensions in the recovered cohort whereas the nonrecovered group had progressive increase in LVEDD. Both the systolic blood pressure and the pulse pressure decreased significantly within 5 minutes after turning the pump off in the nonrecovered group. In contrast, an improvement was noted in systolic blood pressure and pulse pressure in the recovered group as well as a significant increase in EF. These improvements suggest that inotropic reserve was preserved in the recovered group. In the nonrecovered group, there was an increase in heart rate, which appeared to be compensatory for a reduction in MAP ( Fig. 19.6 ).
In this study, the strongest predictors of recovery were stable or increased MAP (60 mm Hg) and pulse pressure measured 15 minutes after pump deactivation or 6MW. An EF ≥ 53% after the 6MW was the strongest predictor of recovery with sensitivity and specificity of 93% and 80%, respectively (receiver operating characteristic curve area = 0.82). Except for the EF, none of the echocardiographic or hemodynamic parameters measured with the device on full support predicted recovery. This study demonstrated the safety and effectiveness of the previous protocol for monitoring myocardial recovery with the pulsatile HeartMate XVE LVAD. While admittedly historic in the era of continuous-flow pumps, this study demonstrated the importance of a standardized approach for searching for myocardial recovery.
In patients supported with a pulsatile-flow device, inflow and outflow valves prevent regurgitation of blood from the aorta to the LV during device deactivation. Hence, LV loading secondary to cessation of a pulsatile pump, such as the HeartMate XVE, reflects a physiologic response that reveals the true underlying function of the native LV. Reducing the speed of continuous-flow devices, such as the HeartMate II LVAD, can result in regurgitant volume flowing from the aorta to the LV, causing excessive loading and making assessment of the native LV function less reliable. With continuous-flow pumps, it is important to identify a speed at which there is no forward or backward flow so that the underlying myocardial function can be safely and effectively assessed. In addition, continuous-flow device patients are anticoagulated with warfarin, so supplemental heparin (5000–10,000 u) is required only if the international normalized ratio (INR) is subtherapeutic.
With regard to continuous-flow pumps, George and colleagues performed a prospective study of flow across the HeartMate II LVAD in patients with idiopathic dilated cardiomyopathy. After ensuring an INR of ≥ 2.0, LV echocardiographic parameters and peripheral hemodynamics were measured serially at three device speed settings: the baseline device speed and 15 minutes after reducing the speed to 6000 rpm, with subsequent reduction to 5000 or 4000 rpm. The LVAD flow pattern was established by positioning a pulsed wave Doppler sample volume at the inflow cannula in the best possible window. Peak velocities in the forward direction (Vmax f ) and the reverse direction (Vmax r ) were assessed ( Fig. 19.7 ). The changing velocities over the flow period in both the forward and the reverse directions were determined by tracing the areas under the Doppler curve from the leading edges of the velocity spectrum to obtain the forward velocity time integral (VTI f ) and reverse velocity time integral (VTI r ). There were no adverse events or symptomatic deterioration when the speed was reduced to 4000 rpm. Reducing the speed to less than 6000 rpm did not have a significant effect on LVEDD, LVESD, fractional shortening, or EF, suggesting that there is no need to reduce the speed of the device to less than 6000 rpm in the assessment of the native LV performance. As the LVAD speed was reduced to 6000 rpm, the blood volume through the inflow cannula decreased significantly, but further reductions in the LVAD speed did not change the inflow cannula blood volume significantly, confirming that speeds less than 6000 rpm were not needed to assess the underlying LV function and that this testing was safe. A summary of proposed low speed echo testing for the HeartMate II is shown in Fig. 19.8 .
Generally, during this testing, the continuous-flow pump is run at a speed that produces just enough forward flow to counteract the backflow (which is around 1 L/min), resulting in as close to no net flow as possible. For the HeartWare pump, the speed at which net neutral flow occurs is 1800 rpm. For the HeartMate 3 pump, the speed at which it is believed net neutral flow would be expected is 4000 rpm ( Fig. 19.9 summarizes the speed at which to run the different pumps to assess recovery with as close to no net flow as possible).
Several investigators have reported more sophisticated echocardiographic parameters to assess recovery potential. Ferrari and colleagues used a minimally invasive method to determine the predictive power of Emax, the slope of the LV end-systolic pressure-volume relationship, and an afterload-independent and preload-independent index of LV contractility. Contractile reserve, also known as inotropic reserve, refers to the objective quantification of LV contractility after either a pharmacologic or physiologic stress and is reduced in patients with ischemic or nonischemic cardiomyopathy. However, different indices have been used to determine contractile reserve. The most frequently used is the absolute change in EF after dobutamine infusion, although there is an inability to distinguish abnormalities in contractility from alterations in preload or afterload. Conventionally, an absolute increase in the EF by 5% during dobutamine infusion compared with resting indicates preservation of contractile reserve with a strong correlation to prognosis.
By recording the hemodynamic response during dobutamine stress echocardiography, Khan and coworkers evaluated 16 patients with increasing doses of dobutamine (from 5 μg/kg/min to 40 μg/kg/min). Hemodynamics and two-dimensional echocardiography were performed at each dose level. Dobutamine stress separated the study population into two groups: patients who had favorable responses to dobutamine (9 of 16) and patients who had unfavorable responses (i.e., experienced hemodynamic deterioration; 7 of 16). Favorable dobutamine responses were characterized by improved cardiac index, improved force-frequency relationship in the LV (dP/dt), improved LVEF, and decreased LVEDD. All nine favorable responders underwent LVAD explantation, and six survived for more than 12 months. Dobutamine stress echocardiography with hemodynamic assessment is also a useful tool in assessing physiologic improvement in myocardial function of patients with LVAD support.
Cardiopulmonary exercise testing with pump settings that provide net neutral flow is also an important component of the recovery testing process of underlying myocardial function. If the INR is greater than 2, then the speed of the device is reduced, and if the INR is less than 2, 5–10,000 units of unfractionated heparin is given 10 minutes before pump speed reduction. During the cardiopulmonary exercise test at reduced pump speed, patients are closely observed for symptoms, and measurements at rest and at peak exercise on a modified Bruce protocol are undertaken. Mancini and colleagues also performed hemodynamic and metabolic measurements both at rest and at peak exercise (cycling) with optimal and reduced LVAD support without reported complications. Although it is important to perform cardiopulmonary exercise testing at net neutral flow speed in LVAD patients, the results are influenced by many other variables, such as the overall condition of the patient. Thus, it is typically used as additional information to help an explantation decision rather than critical information for that decision.
Cardiac power output (CPO) is a novel, central hemodynamic measure that has been suggested to be a direct and possibly the best indicator of overall cardiac function. CPO is calculated as MAP × cardiac output/451, where MAP = [(systolic blood pressure – diastolic blood pressure)/3] + diastolic blood pressure. By incorporating both pressure and flow domains of the cardiovascular system, CPO is an integrative and unique measure of cardiac pumping capability. Resting and peak exercise CPOs have been shown to be powerful predictors of prognosis and mortality in patients with chronic HF and cardiogenic shock. Patients with a peak CPO less than 2 W have a considerably higher mortality rate than do patients with a peak CPO greater than 2 W. Jakovljevic and associates measured CPO in continuous-flow LVAD patients at net neutral flow during cardiopulmonary exercise testing and found CPO to be a useful and predictive marker of recovery.
Patients who tolerate LVAD flow reduction to minimal levels and show echocardiographic signs of recovery should also undergo right ± left heart cardiac catheterization. Important measurements to obtain include right atrial pressure, pulmonary artery pressure, PCWP, LV end-diastolic pressure (LVEDP), and cardiac output (both thermodilution and Fick). It is important to obtain these measurements both with the device on and after 15 minutes at net neutral flow speed. A left ventriculogram after the LVAD has been at low speed for 15 minutes also shows ventricular function well. An outflow graft angiogram may be used to verify device contribution to flow and/or regurgitant volumes at the speed at which the hemodynamics were measured ( Fig. 19.10 ). The most important hemodynamic variables suggesting significant and sustained myocardial recovery with reloading after LVAD removal are stable or improved PCWP and cardiac output following reduction of the pump speed for 15 minutes.
Optimizing myocardial recovery
With an armamentarium of tools to assess recovery, efforts must also be directed at optimizing myocardial recovery. Many patients simply have their devices placed, and therapies are focused on blood pressure control rather than reverse remodeling. The thought process is that the patient has failed advanced HF medical treatment and the machine will provide the output necessary for a patient with lifetime use, or if the patient is bridged to transplant, simply focus on the device rather than the heart. Using the LVAD as a platform to induce myocardial recovery and combining the unloading with other therapies to maximize recovery are likely to lead to a significant increase in the rate of recovery.
Indeed, just the mechanical unloading of the weakened ventricle may be a powerful tool to promote myocardial recovery. To understand the influence of unloading alone, 81 continuous flow (CF)-LVAD patients with echocardiograms performed at reduced pump speed were followed. Within this group, nearly 20% of patients had significant recovery of LV function (EF > 40%). Importantly, most of the improvement in function occurred in the first 6 months after LVAD implantation ( Fig. 19.11 ). Furthermore, these changes occurred both with and without aggressive neurohormonal blockade, with the latter approach being more favorable. Finally, this phenomenon was not just in patients with dilated cardiomyopathies, but also, albeit with lower rates, in those with ischemic disease. These studies are some of the largest to prospectively link mechanical unloading with functional recovery and provides the framework with which to build adjuvant medical strategies to enhance the frequency with which recovery takes place.
Harefield protocol
A strategy was developed at Harefield Hospital that combined LVAD mechanical unloading with specific pharmacologic drugs known to enhance reverse remodeling in an attempt to maximize the incidence of recovery. This regimen consisted of an LVAD speed set for optimal unloading, combined with HF drugs known to enhance reverse remodeling (phase 1), followed by the administration of clenbuterol (phase 2) to improve the durability of recovery in these patients after explantation. The other important part of this protocol was to systematically and regularly test underlying cardiac function in patients throughout the protocol with the pump off, or essentially off, at regular intervals to assess their response to treatment and guide therapy.
Harefield Protocol—Phase 1
The pharmacologic interventions of the first phase were designed to act on component parts of the myocardium, with the aim of reversing pathologic hypertrophy, remodeling, and normalizing cellular metabolic function. Reverse remodeling HF drugs were aggressively initiated immediately after weaning of inotropic support when there is adequate end-organ recovery and titrated to very high doses (targeted doses: lisinopril, 40 mg daily; carvedilol, 25–50 mg twice daily; spironolactone, 25 mg daily; digoxin, 125 μg daily; and losartan, 100 mg daily). Patients had simultaneous increases in angiotensin-converting enzyme inhibitors (ACEIs), beta-1 and beta-2 blockers, and aldosterone inhibitors, followed by the angiotensin II antagonists, although the angiotensin-converting enzyme inhibition is the greatest priority in increasing the therapy.
The rationale of the first phase of this regimen was to combine mechanical unloading with drugs known to enhance reverse remodeling. Patients often did not tolerate large doses of ACEIs, beta blockers, aldosterone antagonists, and angiotensin II inhibitors while in severe HF because of renal failure or hypotension. However, once patients achieved good cardiac output and adequate blood pressure and renal function from LVAD support, they tolerated HF drugs well. ACEI (and angiotensin II inhibition) was a crucial part of this strategy and was used along with the aldosterone antagonist to reduce fibrosis.
The specific benefits of neurohormonal inhibition by using ACEIs with VAD support have been extensively demonstrated. Klotz and colleagues showed that prolonged mechanical hemodynamic unloading increased myocardial tissue levels of angiotensin II with concomitant increases in collagen cross-linking and myocardial stiffness. Elevated serum levels of angiotensin II can be reduced by blocking the renin-angiotensin-aldosterone system with an ACEI. These investigators examined the myocardium of patients before and after LVAD support in patients treated with or without ACEI therapy during LVAD support. After LVAD, tissue angiotensin II levels were significantly reduced in the ACEI group but increased in control subjects. Similarly, cross-linked collagen decreased during LVAD support in the ACEI group, as did LV mass and myocardial stiffness. Myocardial tissue levels of total, soluble, and insoluble cross-linked collagen significantly increased during LVAD support in the control group.
The same group also investigated paired LV myocardial samples obtained from 20 patients before and after LVAD support. Pre-LVAD renin levels were 100 times greater than in normal controls. In patients not receiving ACEIs, LVAD support reversed this. Myocardial aldosterone levels decreased in parallel with cardiac renin in the non-ACEI group. Cardiac norepinephrine increased sevenfold in patients not treated with ACEI, possibly owing to the increase in angiotensin II. ACEI therapy prevented these changes; renin and aldosterone remained high, and no increase in norepinephrine occurred. Thus, while LV unloading lowers myocardial renin and aldosterone, it allows cardiac angiotensin generation to increase, stimulating the sympathetic nervous system, which ACEIs prevent, supporting the rationale for use of ACEI.
Harefield Protocol—Phase 2
It seemed logical that cardiac muscle “atrophy” (observed with isolation and lack of mechanical work) would be a possible consequence of a period of LVAD myocardial unloading and that a lack of preload and mechanical work of the ventricle may partially explain the lack of durability of myocardial recovery observed previously in some other studies. Although the concept of LVAD-induced atrophy has since been disputed, it was hypothesized that to achieve consistent successful device explantation, a period of reverse remodeling and regression of pathologic myocardial hypertrophy should be followed by attempts to produce beneficial “physiological hypertrophy,” with additional beneficial effects at the level of the cardiomyocyte and matrix. Clenbuterol induces a type of myocardial hypertrophy associated with improved systolic and diastolic function, with increased sarcoplasmic reticulum calcium content, histological prevention of fibrosis, normal collagen levels, and enhanced expression of contractile genes. This improved contractility without fibrosis is often referred to as physiological hypertrophy.
In the Harefield protocol, the second stage of pharmacologic therapy was instituted after maximal regression in the LVEDD had been achieved while the LVAD was in place. When the LVEDD was less than 60 mm on low speed testing, the initial nonselective beta blocker carvedilol was switched to a beta-1 selective adrenergic receptor blocker (e.g., bisoprolol or metoprolol), leaving beta-2 receptors unblocked for clenbuterol. Clenbuterol was added to all phase 1 drugs at an initial dose of 40 μg twice daily and then titrated to a target dose of 700 μg three times daily. The dose was adjusted to maintain the resting heart rate at less than 100 beats/min.
The rationale for using clenbuterol, a beta-2 agonist, as the phase 2 pharmacotherapeutic target is multifactorial. Clenbuterol is known to induce physiologic, rather than pathologic, myocardial hypertrophy. This form of hypertrophy is associated with improved systolic and diastolic function, prevention of fibrosis, and enhanced expression of contractile genes. Clenbuterol also has other positive actions on cardiac function. As a selective beta-2-adrenergic receptor agonist, it is a potent synthetic analog to epinephrine; induces insulin-like growth factor 1, through which skeletal muscle hypertrophy is mediated; and reduces adverse signaling patterns mediated through beta-1 receptors, including apoptosis. Because most negative effects of beta stimulation seem to be beta-1 receptor mediated, administration of beta-1 antagonists in conjunction with beta-2 agonists such as clenbuterol seemed safe and appropriate.
Harefield Protocol Prospective Trial—Pulsatile Pump
Using this strategy of combining optimal LVAD unloading with reverse remodeling therapy, followed by clenbuterol administration, two prospective studies were performed at Harefield Hospital in London in patients with nonischemic cardiomyopathy receiving an LVAD. The first prospective study consisted of 20 patients who received a pulsatile HeartMate XVE LVAD as BTT. Patients with myocarditis (proven on histologic examination of the large transmural core of myocardial tissue removed for insertion of the apical cannula) were excluded so as to focus on patients with chronic HF. The average age of the patients was 37.6 ± 13.7 years (range, 15–57 years), and the mean duration of HF was 4.5 ± 4.5 years. All patients had deteriorating NYHA class IV HF despite inotropic support at the time of VAD implantation.
Echocardiography was performed weekly after implantation for the first month and monthly thereafter. After week 4, studies were performed both on- and off-pump (as described above) at 5 minutes and 15 minutes, and after a 6-minute walk (if tolerated), to determine inotropic reserve. When the patients were able to walk 450 m in 6 minutes with the device off, with no deterioration of the echocardiographic measurements, formal cardiopulmonary exercise tests were performed monthly with the device on and off.
Cardiac catheterization was performed before explantation, right-sided and left-sided pressures and cardiac output were measured (with the device on and off for 15 minutes), and a left ventriculogram was obtained with the device off. Explantation was considered if the following criteria were met (measured with the LVAD off for 15 minutes): LVEDD < 60 mm, LVESD < 50 mm, and EF > 45%; a LVEDP (or PCWP) < 12 mm Hg; resting cardiac index > 2.8 L/min/m 2 ; and maximal oxygen consumption (VO 2 max) > 16 mL/kg/min and an increase in minute ventilation (V E ) relative to the production of carbon dioxide (VCO 2 ) (V E /VCO 2 slope) < 34.
Lisinopril, spironolactone, and losartan were restarted after explantation with the same high target doses, but clenbuterol was discontinued. Carvedilol was restarted in place of bisoprolol. Of the 15 patients who received a complete course of the combination therapy, 11 (73%) had sufficient recovery to meet the explantation criteria. For the explanted patients, the mean duration of support was 320 ± 186 (range, 63–603) days. For the explanted patients, the LVEF (with the pump off for 15 minutes) was 64% ± 8% before explantation compared with 12% ± 6% before implantation ( P = 0.001), the LVEDD was 55.9 ± 8.3 mm compared with 75.1 ± 16.3 mm ( P = 0.002), and the LVESD was 39.6 ± 6.5 mm compared with 66.9 ± 16.3 mm ( P = 0.002). Before explantation, the VO 2 max (with the pump off) was 20.7 ± 6.1 mL/kg/min, with a VE/VCO 2 slope of 32.5 ± 7.9. Cardiac catheterization before explantation (with the pump off) showed a PCWP of 9.0 ± 4.1 mm Hg (compared with 23.8 ± 9.7 mm Hg on inotropic therapy before implantation; P = 0.004), cardiac output of 5.4 ± 1.2 L/min, cardiac index of 2.8 ± 0.7 L/min/m 2 , and pulmonary artery oxygen saturation of 66.9% ± 4.8%.
Although the numbers were too small for meaningful analysis, age, LV dimensions, and the duration of HF were not determinants of recovery. Of five patients with an LVEDD of greater than 80 mm, four recovered. The actuarial survival rate 1 year and 4 years after explantation was 90.9% and 81.8%, respectively. One patient died of intractable arrhythmia 24 hours after explantation without evidence of deteriorating ventricular function, and another died of lung carcinoma 27 months after explantation. The minimum period of follow-up after explantation was approximately 4 years (range, 1519–2058 days; mean, 1799 ± 153 days). At a mean follow-up of 59 ± 5 months, EF was 64% ± 12%, LVEDD was 59.4 ± 12.1 mm, LVESD was 42.5 ± 13.2 mm, and mean VO 2 max was 26.3 ± 6.0 mL/kg/min ( Figs. 19.12 and 19.13 ). All surviving patients continued to be in NYHA class I except one, in whom HF recurred and who underwent successful transplantation 33 months after explantation. Among the surviving patients, the cumulative rate of freedom from recurrence of HF 1 year and 4 years after explantation was 100% and 88.9%, respectively ( Fig. 19.14 ).
