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(Circulation. 2001;104:881.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Mechanical Unloading Restores ß-Adrenergic Responsiveness and Reverses Receptor Downregulation in the Failing Human Heart

Monique L. Ogletree-Hughes, PhD; Linda B. Stull, PhD; Wendy E. Sweet, MS; Nicholas G. Smedira, MD; Patrick M. McCarthy, MD; Christine Schomisch Moravec, PhD

From the Center for Anesthesiology Research (M.L.O.-H., L.B.S., W.E.S., C.S.M.) and the Department of Thoracic and Cardiovascular Surgery (N.G.S., P.M.M.), The Cleveland Clinic Foundation, Cleveland, Ohio.

Correspondence to Christine S. Moravec, PhD, The Cleveland Clinic Foundation, 9500 Euclid Ave, FF40, Cleveland, Ohio 44195. E-mail moravec{at}ccf.org

	Abstract

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Background—— Mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in clinically documented reversal of chamber dilation and improvement of cardiac function. We tested the hypothesis that LVAD support normalizes the ability of cardiac muscle to respond to sympathetic nervous system stimulation by reversing the downregulation of ß-adrenergic receptors.

Methods and Results—— Human LV tissue was obtained from nonfailing hearts of unmatched organ donors and failing hearts at the time of transplantation, with or without LVAD. Baseline contractile parameters and inotropic response to a ß-adrenergic agonist were measured in isolated trabecular muscles. ß-Adrenergic receptor density was quantified by radioligand binding. Results showed a significant increase in the response to ß-adrenergic stimulation after LVAD (developed tension increased by 0.76±0.09 g/mm² in nonfailing, 0.38±0.07 in failing, and 0.68±0.10 in failing+LVAD; P<0.01), accompanied by an increased density of ß-adrenergic receptors (58.7±9.6 fmol/mg protein in nonfailing, 26.2±3.8 in failing, and 63.0±8.3 in failing+LVAD; P<0.05). These changes were unrelated to the duration of support.

Conclusions—— Data demonstrate that mechanically supporting the failing human heart with an LVAD can reverse the downregulation of ß-adrenergic receptors and restore the ability of cardiac muscle to respond to inotropic stimulation by the sympathetic nervous system. This indicates that functional impairment of cardiac muscle in human heart failure is reversible.

Key Words: heart failure • heart-assist device • receptors, adrenergic, beta • myocardial contraction

	Introduction

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Left ventricular assist devices (LVADs) are used to hemodynamically support heart failure patients awaiting transplantation. Studies from our group and others have demonstrated that mechanically unloading the heart with an LVAD can decrease heart size,^1,2 improve cardiac function,^3,4 decrease plasma neurohormones^5,6 and cytokines,⁷ and decrease ventricular expression of atrial natriuretic peptide⁸ and tumor necrosis factor-.⁹ It has been suggested that mechanical unloading provides enough improvement to make cardiac transplantation unnecessary in some patients,¹⁰ although others have disagreed with this contention.¹¹ Recent studies comparing tissue removed at LVAD implantation to the heart at transplantation have suggested that LVAD support improves the structure and function of cardiac myocytes, leading to decreased cell size,^12,13 increased contractility of cells^13,14 and muscles,¹⁵ improved function of intracellular organelles,^15,16 and altered gene expression.^15,17,18

An important compensatory mechanism for maintaining adequate tissue perfusion during functional impairment of the heart is augmentation of cardiac output by the sympathetic nervous system. Inability to respond to ß-adrenergic stimulation is a hallmark of the failing human heart.^19,20 Isolated muscles and myocytes from failing human hearts show a decreased inotropic response to ß-adrenergic agonists^21–23 and downregulation of ß-adrenergic receptors,^19–21 as well as uncoupling of the receptors from the downstream signaling pathway.^21,23

We tested the hypothesis that mechanically unloading the failing human heart with an LVAD can reverse the inability to respond to ß-adrenergic stimulation and the downregulation of ß-adrenergic receptors. A previous study by Dipla and colleagues¹⁴ demonstrated recovery of the inotropic response to isoproterenol in myocytes from LVAD-supported human hearts. In this study, we examined the inotropic responsiveness of LV trabecular muscles from LVAD-supported human hearts to isoproterenol and measured ß-adrenergic receptors in the same hearts. Data demonstrate recovery of both the ß-adrenergic inotropic response and ß-adrenergic receptor density after LVAD. This implies that the inability of the failing human heart to respond to the sympathetic nervous system is not irreversible.

	Methods

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Nonfailing human hearts were obtained from 15 organ donors whose hearts were unsuitable for transplantation but who had no history of cardiac disease. Failing human hearts were obtained from 23 transplant patients who had not been supported with an LVAD and 19 transplant patients who had been supported with an LVAD. All hearts were transported to the laboratory in cold cardioplegia, as previously described.^24,25

Once in the laboratory, tissue was placed in room-temperature Krebs-Henseleit buffer (composition [mmol/L]: NaCl 100.0, KCl 4.0, MgSO₄ 1.5, NaHCO₃ 20.0, NaH₂PO₄ 1.5, NaC₂H₃O₂ 20.0, glucose 10.0, ascorbic acid 0.1, and CaCl₂ 2.5, and insulin 5.0 IU/L) for dissection. Remaining tissue was frozen in liquid nitrogen. Protocols for tissue procurement were approved by the Institutional Review Board.

Isometric muscle contraction studies were performed according to established methods,^24,25 at 37°C, stimulation rate 1.0 Hz, duration 5 ms, and voltage 20% above threshold. Muscle length was adjusted until resting tension (RT) reached 0.5 to 1.0 g, and stimulation was initiated. Muscle length was adjusted in 0.1-mm increments until L_max (length associated with maximal developed tension [DT]) was reached, and function was allowed to stabilize for 45 to 60 minutes. Recorded contractile parameters included RT, DT, time to peak tension (TPT), time to half-relaxation (THR), maximal rate of tension rise (+dT/dt), and maximal rate of tension fall (-dT/dt).

A single dose of 1 µmol/L isoproterenol was used to assess ß-adrenergic responsiveness. The effects of isoproterenol on all isometric contractile parameters were recorded. There was no significant rundown of muscle function over the time course of these studies. Muscle cross-sectional area was calculated and used to normalize RT, DT, +dT/dt, and -dT/dt values. Muscles with cross-sectional area <0.2 mm² or >1.1 mm² or baseline DT <0.30 g/mm² were eliminated from the study.

Comparisons were made between nonfailing and failing hearts to define changes related to heart failure. Comparisons were then made between nonfailing hearts and failing hearts with an LVAD to detect changes in the direction of normal that were related to the LVAD.

ß-Adrenergic receptor density was quantified by radioligand binding with a modification of Bristow’s method.¹⁹ LV tissue from 8 nonfailing hearts, 8 failing hearts without LVAD, and 17 failing hearts with LVAD was homogenized in HEM buffer (composition [mmol/L]: HEPES 10.0 [pH 7.4], EGTA 5.0, MgCl₂ 12.5) with sucrose (250.0 mmol/L) and protease inhibitors. Membranes were washed with 0.5 mol/L KCl to remove myofilaments and centrifuged at 40 000g. The pellet was resuspended in HEM buffer with NaCl (100.0 mmol/L) and washed. Membranes were stored in HEM buffer plus 10% glycerol at -80°C until used for radioligand binding within 4 weeks of membrane preparation. Protein concentration was measured by the Lowry method. Seven increasing concentrations of ¹²⁵I-labeled cyanopindolol (3 to 240 pmol/L) were added to the membranes (protein concentration equal to 10% of the measured K_d) for the binding assay. Nonspecific binding was measured by competitive binding with 10^-4 mol/L propranolol. All reactions were run in triplicate. The mixture was incubated with shaking for 60 minutes at 37°C. Membranes were filtered onto glass fiber filter paper (Whatman, GF-C, Brandel Instruments) and washed 5 times with binding buffer (composition [mmol/L]: HEPES 50.0 [pH 7.4], EGTA 2.5, and MgCl₂ 12.5, and 0.1% BSA). Bound radioactivity was counted on a Micromedic Gamma Counter. Receptor density and dissociation constants were calculated from Scatchard plots. In separate experiments, we confirmed that there was no difference in the density or K_d of ß-adrenergic receptors measured in trabecular muscles versus LV free wall of the same heart.

Results are reported as mean±SEM. Data from multiple muscles per heart were averaged. Baseline contractile parameters, response to isoproterenol, and ß-adrenergic receptor densities and dissociation constants were compared by 1-way ANOVA followed by Student-Newman-Keuls post hoc testing. Relationships between duration of LVAD support and the inotropic response or receptor density were tested with Spearman correlations. Differences between groups were accepted as statistically significant if P<0.05.

	Results

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Table 1 summarizes information on patients from whom tissue was obtained. Table 2 presents information on each patient who had an LVAD, including the duration of support. Any patient who was taking ß-adrenergic blockers was eliminated from the study.

View this table: [in this window] [in a new window]   Table 1. Patient Information for Nonfailing and Failing Human Hearts

View this table: [in this window] [in a new window]   Table 2. Patient Information for Failing Hearts With an LVAD

Average contractile performance at baseline is presented in Table 3. Contractility was measured in 32 muscles from 10 nonfailing hearts, 55 muscles from 15 failing hearts without LVAD, and 41 muscles from 12 failing hearts with LVAD. There were no differences in muscle cross-sectional area or in any of the contractile parameters between groups.

View this table: [in this window] [in a new window]   Table 3. Comparison of Baseline Contractile Parameters at 37°C and 1.0 Hz

The inotropic response to isoproterenol was measured in 16 muscles from 9 nonfailing hearts, 38 muscles from 11 failing hearts without LVAD, and 27 muscles from 10 failing hearts with LVAD. The increase in DT produced by ß-adrenergic stimulation was significantly reduced in muscles from failing hearts without LVAD compared with muscles from nonfailing hearts (P<0.01; Figure 1). Muscles taken from failing hearts after LVAD support, however, showed inotropic responsiveness that was not significantly different from that of nonfailing muscles (Figure 1).

View larger version (23K): [in this window] [in a new window]   Figure 1. Response of muscles to 1 µmol/L isoproterenol. A, Change in RT; B, change in DT. Muscles from nonfailing hearts (NF), failing hearts without LVAD (Failing), and failing hearts with LVAD (Failing+LVAD). Data are shown as change from baseline (mean±SEM). **P<0.01 vs NF. n=No. of muscles/No. of hearts.

In response to isoproterenol, muscles from nonfailing hearts demonstrated the characteristic decreases in RT (Figure 1A), TPT, and THR and increases in +dT/dt and -dT/dt (Figure 2A through 2D). In muscles taken from failing hearts without LVAD, there was a blunting of the +dT/dt and -dT/dt responses to isoproterenol, which had recovered in hearts with LVAD (Figure 2C and 2D; P<0.05). The TPT response to isoproterenol appeared to be diminished in failing hearts without LVAD (Figure 2A), but this was not statistically significant. The THR (Figure 2B) and RT responses did not differ in the 3 groups of muscles.

View larger version (34K): [in this window] [in a new window]   Figure 2. Response of muscles to 1 µmol/L isoproterenol. Muscles from nonfailing hearts (NF), failing hearts without LVAD (Failing), and failing hearts with LVAD (Failing+LVAD). A, TPT; B, THR; C, +dT/dt; and D, -dT/dt. Data are shown as change from baseline contraction (mean±SEM). *P<0.05 vs NF. n=No. of muscles/No. of hearts.

Figure 3A and 3B show a typical saturation binding experiment (A) and Scatchard analysis (B) for 1 failing heart with LVAD. Figure 3C summarizes the quantification of receptor density, which was decreased in failing hearts without LVAD compared with nonfailing hearts (P<0.05). In LVAD-supported failing hearts, however, ß-adrenergic receptor density was not different from that in nonfailing hearts. There was no difference in the K_d among the groups, with an average of 15.6±2.2 pmol/L in nonfailing hearts, 15.5±1.6 pmol/L in failing hearts without LVAD, and 22.6±2.6 pmol/L in LVAD-supported hearts.

View larger version (18K): [in this window] [in a new window]   Figure 3. ß-Adrenergic receptor measurements. Saturation binding (A) and Scatchard analysis (B) from 1 failing heart with LVAD. C, Receptor density of nonfailing hearts (NF), failing hearts without LVAD (Failing), and failing hearts with LVAD (Failing+LVAD). *P<0.05 vs NF. CYP indicates cyanopindolol.

Figure 4 shows the response to isoproterenol (A) and the ß-adrenergic receptor density (B) in failing patients without LVAD, divided into those who were receiving ß-agonist therapy at the time of transplantation and those who were not. There was no significant difference between these 2 groups of patients.

View larger version (15K): [in this window] [in a new window]   Figure 4. Inotropic response to isoproterenol (A) and ß-adrenergic receptor density (B) in failing patients without LVAD. Patients were subdivided into those who were receiving ß-agonist therapy at time of transplantation and those who were not.

Figure 5 shows the relationships, on a heart-by-heart basis, between duration of LVAD support and the inotropic response to isoproterenol (A) or the receptor density (B). Panel C illustrates the relationship between receptor density and inotropic response. Duration of mechanical support does not completely predict either the response to inotropic stimulation or the density of ß-adrenergic receptors in the patients studied. Receptor density alone also does not predict the magnitude of the inotropic response.

View larger version (21K): [in this window] [in a new window]   Figure 5. Relationship between (A) duration of LVAD and response to isoproterenol; (B) duration of LVAD and receptor density; and (C) receptor density and response to isoproterenol. Numbers next to each point indicate patient number and correspond to numbers in Table 2.

	Discussion

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We compared cardiac muscle contractility at baseline and after inotropic stimulation by isoproterenol, as well as the density of ß-adrenergic receptors, in nonfailing human hearts and failing human hearts with or without LVAD. We observed no decrement in contractile function of isolated trabecular muscles from patients with heart failure compared with muscles from nonfailing hearts at 37°C and 1.0 Hz stimulation. The absolute DT of our muscles was similar in magnitude to that reported previously by us^24,25 and by others.²⁶ Early studies of failing human muscles reported decreased DT²⁷ or prolonged TPT and THR.²³ More recently, studies performed at physiological temperatures and stimulation rates showed no change in DT²⁸ or a decrease only at elevated stimulation frequencies.²⁹ LVAD treatment of the failing heart had no effect on any of the contractile parameters at L_max (Table 3).

Although muscles taken from failing human hearts do not consistently demonstrate reduced contractility, there is widespread agreement that the ß-adrenergic response is depressed.^19–23 Trabecular muscles and myocytes show a diminished ability to increase contraction in response to ß-adrenergic agonists.^21–23 The density of ß-adrenergic receptors is decreased, and alterations in downstream signaling have been documented.^21,23 We have shown that unloading the failing human heart with an LVAD can reverse this phenotype. Muscles taken from LVAD hearts produced an inotropic response to isoproterenol that was similar to that measured in nonfailing muscles and significantly better than that observed in muscles from failing hearts without LVAD. This confirms the report by Dipla and coworkers,¹⁴ who demonstrated that ß-adrenergic responsiveness of isolated myocytes could be recovered with LVAD support. We examined the relationship between duration of support and recovery of the inotropic response (Figure 4A). Although patients supported for a longer time had greater recovery of the inotropic response, this relationship was not linear or statistically significant, suggesting that factors in addition to duration contribute to variability in recovery of the inotropic response.

We also measured ß-adrenergic receptor density in the same hearts. In hearts with LVAD support, the density of ß-adrenergic receptors was comparable to that in nonfailing hearts (Figure 3C). Analysis of the relationship between duration and receptor density (Figure 4B) suggested that there was no correlation. In fact, receptor density was actually highest in a heart supported for only 49 days and was considerably lower in hearts supported for significantly longer. We also examined the relationship between receptor density and the inotropic response to isoproterenol (Figure 4C). This relationship was not significant in this population of patients, suggesting that portions of the signaling pathway (downstream of the receptor or involved in the more basic mechanisms of excitation-contraction coupling) play a greater role in dictating the response to inotropic stimulation and should be evaluated for recovery after mechanical support. Given the recent demonstration of the role of ryanodine receptor hyperphosphorylation in the diminished ß-adrenergic response of the failing heart and its recovery after LVAD,³⁰ it is clear that ß-adrenergic receptors are only the first in a long line of signaling molecules whose potential to recover should be examined.

Although we have shown that mechanical unloading may result in recovery of the ß-adrenergic response, our data do not address the mechanism for this change. One possibility is that normalization of plasma neurohormones, which has been shown in LVAD patients,^5,6 results in reversal of ß-adrenergic receptor downregulation. In addition, LVAD support has also been shown to cause a decrease in both plasma⁷ and cardiac⁹ cytokine levels, which could also contribute to the improved response. Several studies have demonstrated that tumor necrosis factor- decreases the ß-adrenergic response in animal cardiac muscle.³¹ It must also be noted, however, that LVAD implantation in most patients is accompanied by a change in the medical regimen. Patients who had previously been supported with ß-adrenergic agonists such as dobutamine may not require this type of inotropic support on the LVAD. To address the question of whether withdrawal of ß-agonist therapy could explain the increased response to ß-adrenergic stimulation, we divided our population of failing patients without LVAD support into 2 groups: those who were receiving ß-agonist therapy at the time of transplantation and those who were not. Data presented in Figure 4 clearly indicate that a lack of ß-agonist therapy does not necessarily result in an improved inotropic response to isoproterenol or an increase in ß-adrenergic receptor density. This lends support to our contention that recovery of the ß-adrenergic response in LVAD patients is related to mechanical unloading and not caused simply by the withdrawal of inotropic support.

In summary, we have shown that LVAD support of the failing human heart results in recovery of the ability of cardiac muscle to respond to sympathetic nervous system stimulation and increased density of ß-adrenergic receptors. Reversal of the inotropic response and receptor density may be related to either mechanical unloading of the heart or decreased circulating neurohormones. On the basis of analyses of the relationship between LVAD duration and the recovery of inotropic responsiveness or receptor density, we propose that factors other than duration predict the extent of recovery and that further investigation must examine the reversal of downstream elements of the ß-adrenergic signaling pathway in these patients. Nevertheless, this study demonstrates that downregulation of ß-adrenergic receptors, which has long been a hallmark of the failing human heart, is not an irreversible phenomenon and supports the contention that the failing human heart retains the capacity for recovery.

	Acknowledgments

 
Dr Ogletree-Hughes was supported by a National Research Service Award (1-F31-HL-90052-01A1) and is currently supported by an American Heart Association (AHA) postdoctoral fellowship (Ohio Valley Affiliate No. 0020389B). Dr Moravec is an Established Investigator of the AHA. The authors acknowledge the assistance of the cardiac transplantation teams, pathology residents, and Dr Norman B. Ratliff for help in procuring failing human heart tissue for research. We thank Life Banc of Northeastern Ohio for nonfailing human heart tissue.

Received March 27, 2001; revision received June 20, 2001; accepted June 21, 2001.

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