EXPERIMENTAL STUDY
Reverse remodeling and enhancedadrenergic reserve from passive externalsupport in experimental dilated heart failure
W. Federico Saavedra, MD*,
Richard S. Tunin, MS*,
Nazareno Paolocci, MD, PhD*,
Takayuki Mishima, MD ,
George Suzuki, MD,
Charles W. Emala, MD ,
Pervaiz A. Chaudhry, MD,
Petros Anagnostopoulos, MD,
Ramesh C. Gupta, PhD,
Hani N. Sabbah, PhD, FACC and
David A. Kass, MD, FAHA*,*
* Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
Division of Cardiovascular Medicine, Henry Ford Health System, Detroit, Michigan, USA
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
Manuscript received November 2, 2001;
revised manuscript received March 5, 2002,
accepted March 27, 2002.
* Reprint requests and correspondence: Dr. David A. Kass, Halsted 500, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, Maryland 21287, USA.
dkass{at}bme.jhu.edu
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Abstract
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OBJECTIVES: We sought to test the efficacy of a passive elastic containment device to reverse chronic chamber remodeling and adrenergic down-regulation in the failing heart, yet still maintaining preload reserve.
BACKGROUND: Progressive cardiac remodeling due to heart failure is thought to exacerbate underlying myocardial dysfunction. In a pressure–volume analysis, we tested the impact of limiting progressive cardiac dilation by an externally applied passive containment device on both basal and adrenergic-stimulated function in failing canine hearts.
METHODS: Ischemic dilated cardiomyopathy was induced by repeated intracoronary microembolizations in six dogs. The animals were studied before and three to six months after surgical implantation of a thin polyester mesh (cardiac support device [CSD]) that surrounded both cardiac ventricles. Pressure–volume relations were measured by a conductance micromanometer catheter.
RESULTS: Long-term use of the CSD lowered end-diastolic and end-systolic volumes by –19 ± 4% and –22 ± 8%, respectively (both p < 0.0001) and shifted the end-systolic pressure–volume relation to the left (p < 0.01), compatible with reverse remodeling. End-diastolic pressure and chamber diastolic stiffness did not significantly change. The systolic response to dobutamine markedly improved after CSD implantation (55 ± 8% rise in ejection fraction after CSD vs. –10 ± 8% before CSD, p < 0.05), in conjunction with a heightened adenylyl cyclase response to isoproterenol. There was no change in the density or affinity of beta-adrenergic receptors. Diastolic compliance was not adversely affected, and preload-recruitable function was preserved with the CSD, consistent with a lack of constriction.
CONCLUSIONS: Reverse remodeling with reduced systolic wall stress and improved adrenergic signaling can be achieved by passive external support that does not generate diastolic constriction. This approach may prove useful in the treatment of chronic heart failure.
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Abbreviations and Acronyms
| | ATP | | adenosine triphosphate | | cAMP | | cyclic adenosine monophosphate | | CSD | | cardiac support device | | DHA | | 3H-dihydroalprenelol | | ESPVR | | end-systolic pressure–volume relation | | LV | | left ventricle | | LVAD | | left ventricular assist device | | PMSF | | phenylmethylsulfonyl fluoride | | RV | | right ventricle | | SDS | | sodium dodecyl sulfate |
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Chronic cardiac remodeling is a major hallmark of dilated cardiomyopathy and is thought to play a central role in disease progression (1–4). Chamber dilation and wall thinning elevate wall stress, triggering the local release of neurohormones and adversely affecting myocardial molecular biology and physiology (3). Both beta-adrenergic blockade and angiotensin-converting enzyme inhibition enhance heart failure survival and inhibit or reverse remodeling (5–8). Further evidence supporting a pathophysiologic role of remodeling stems from studies of left ventricular assist devices (LVADs). This intervention profoundly unloads the left heart, leading to reverse remodeling (9,10) and improving myocyte and muscle function (11,12), molecular and calcium signaling (11,13,14) and adrenergic responsiveness (15). However, LVAD studies cannot determine the therapeutic effect of limiting chronic remodeling on the working heart, nor can they easily differentiate unloading influences from changes due to systolic assist and neurohormonal de-activation.
The impact of limiting remodeling on heart failure progression has been directly tested by the application of external containment. An example of this approach is cardiomyoplasty (16,17), in which a flat sheet of skeletal muscle is wrapped around the heart and then stimulated to assist systolic contraction. Intriguingly, both clinical (18) and animal studies (19) have identified a passive girdling effect of the wrap as a dominant mechanism responsible for reverse remodeling and improved function. Such observations have led to the development of a passive polymer jacket that surrounds the heart (cardiac support device [CSD]; Acorn Cardiovascular Inc., St. Paul, Minnesota). In recent studies, the CSD has been shown to limit progressive dilation in heart failure (20), enhance fractional shortening and reduce myocyte hypertrophy and interstitial fibrosis (21,22). However, it remains unknown whether this reflects true remodeling or an influence of diastolic constraint, and whether the CSD favorably alters stimulated functional reserve.
Accordingly, the present study tested the following hypotheses: 1) that the CSD induces reverse remodeling, as reflected by a leftward shift in the end-systolic pressure–volume relation (ESPVR); 2) that this is accompanied by enhanced beta-adrenergic signaling; and 3) that both effects are achieved without limiting preload-recruitable reserve or compromising diastolic compliance.
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Methods
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Animal model.
Heart failure was induced in six adult mongrel dogs (25 to 30 kg) by multiple sequential intracoronary embolizations with polystyrene latex microspheres (70 to 100 µm outer diameter). This model includes many features of human cardiac failure at the chamber, myocardial, cellular and molecular levels (23–25). An average of six microembolizations were performed one to three weeks apart in each animal, until the ejection fraction declined to <35%, a level associated with a 20% to 30% increase in chamber volume. The procedure was performed under sterile conditions and general anesthesia (see next paragraph), and the study approved by the Henry Ford Hospital’s Animal Care and Use Committee, in accordance with the guidelines of the National Institutes of Health.
Experimental protocol
After establishing heart failure, the animals underwent cardiac catheterization with a dual-sensor, pressure–volume catheter (SPC 562 Millar Instruments, Houston, Texas) to assess ventricular function. Right and left heart recordings and a contrast ventriculogram were obtained under general anesthesia (0.22 mg/kg oxymorphone; 0.17 mg/kg diazepam; 150 to 250 mg pentobarbital). Left ventricular pressure–volume relations were then measured at rest and during a transient preload reduction induced by inferior vena caval occlusion (NuMed, New York, New York), in accordance with reported protocols (26). Each animal subsequently underwent dobutamine challenge (5 to 10 µg/kg per min), with data recorded at steady-state. Dobutamine was then discontinued and baseline was re-established (after 10 to 15 min), and then the dogs were given four sequential bolus injections of 100 ml of dextran to test for preload reserve. All catheters were then removed, and the insertion sites were closed.
The CSD was implanted after completion of the baseline study. Details of the surgical procedure have been reported (20,21,27). After induction with diazepam (0.2 mg/kg intravenously) and oxymorphone (0.1 mg/kg), the animals were intubated, and anesthesia was maintained with 0.5% to 1% isoflurane and supplemental oxygen. The heart was exposed by a median sternotomy, and the parachute technique was used to implant the CSD, by slipping it over the apex of the heart with the full-length seam at the center of the anterior surface. The CSD was placed around both ventricles and anchored with approximately eight sutures at the atrioventricular groove (Fig. 1). The fit was made so that the material was nonwrinkled, thus providing contact with the epicardium throughout the cycle. There was only a small, early volume change with CSD placement (–2.1%), as determined by echocardiography. The chest was closed, and the animals fully recovered from the operation. Once in use, the CSD becomes encased in a thin fibrous sheath without inflammation or progressive fibrosis (21). Follow-up study was performed three to six months after CSD implantation. The dogs were then sacrificed with a barbiturate overdose, and tissues were obtained for biochemical analyses.
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Figure 1 The cardiac support device wrap placed around the heart. The polyester mesh material is sutured along an anterior wall seam to achieve containment around both the right and left ventricles. The material is snug to the surface to remove surface wrinkling, but not to constrict diastolic filling.
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Adenylyl cyclase activity
Frozen left ventricular (LV) tissue (300 to 400 mg) was thawed in 5 mmol/l Tris (pH 7.4), 0.25 mol/l sucrose, 1 mmol/l MgCl2, 1 mmol/l EDTA and 10 µmol/l phenylmethylsulfonyl fluoride (PMSF) and homogenized for 45 s. The homogenates were filtered and centrifuged at 1,000 g (10 min, 4°C); the supernatant was recovered and centrifuged at 45,000 g (25 min, 4°C); and the pellets were resuspended in 25 ml of 50 mmol/l Tris (pH 7.4), 10 mmol/l MgCl2, 1 mmol/l EDTA and 10 µmol/l PMSF and centrifuged at 45,000 g (25 min, 4°C). After rewashing in the same solution, the pellet was resuspended in 0.5 ml of buffer and analyzed immediately. Triplicate samples were incubated for 10 min at 37°C and contained the indicated effector, along with 10 to 20 µg of membrane protein: 25 mmol/l Tris (pH 7.5), 5 mmol/l MgCl2, 0.5 mmol/l EDTA, 1 mmol/l cyclic adenosine monophosphate (cAMP), 1 mmol/l adenosine triphosphate (ATP), [ -32P]ATP (0.5 to 1.5 µCi/tube, 800 Ci/mmol), 5 µmol/l PMSF, 7 mmol/l creatine phosphate, 50 µn/ml creatine kinase and 0.25 mg/ml bovine serum albumin in a final volume of 100 µl. Adenylyl cyclase activity was measured under basal conditions, with 10 µmol/l guanosine triphosphate (GTP) plus 1 nmol/l to 100 µmol/l isoproterenol or 10 µmol/l forskolin. The reactions were terminated by the addition of 100 µl of buffer: 50 mmol/l HEPES (pH 7.5), 2 mmol/l ATP, 0.5 mmol/l cAMP, 2% sodium dodecyl sulfate (SDS) and 1 µCi/ml 3H-cAMP (37 Ci/mmol). Newly synthesized 32P-cAMP was separated from the precursor [-32P]ATP by sequential column chromatography with Dowex and aluminum oxide, using recovery of 3H-cAMP to monitor the individual column’s efficiency. Eluted radioactivity was quantitated by liquid scintillation.
Beta-adrenergic receptor radioligand binding
Beta-adrenreceptor density was measured using radioligand 3H-dihydroalprenelol (DHA) (New England Nuclear, Boston, Massachusetts), according to published procedures (28). Specific binding to the beta-adrenoceptor population was defined as the difference between the total amount of radioactivity bound in the presence of 3H-DHA alone and the nonspecific binding in the presence of 3H-DHA and 10 µmol/l alprenolol. Receptor density (Bmax) and the equilibrium dissociation constant (Kd) for 3H-DHA binding to membrane preparations were assessed by Scatchard analysis, using the ReceptorFit Saturation Two-Site Software (Lundon Software, Inc., Cleveland Heights, Ohio).
Data analysis
Pressure–dimension data were recorded at steady-state and during inferior vena caval occlusion; the latter was used to derive pressure–volume relations. Details of the hemodynamic analysis have been reported (29). Systolic function was principally indexed by the ESPVR and preload-recruitable stroke work (30). Preload was expressed as the end-diastolic volume, and arterial load as the effective arterial elastance. The volume signal was calibrated to match the absolute ventricular volumes obtained by constrast ventriculography. All hemodynamic signals were digitally recorded at 200 Hz and analyzed using custom software. Hemodynamic variables before and after CSD implantation were compared by the Student paired t test. The differential effects of dobutamine stimulation before versus after CSD placement were analyzed by three-way analysis of variance (ANOVA), with drug, experimental condition and dog as the categorical variables. A different dobutamine response was defined by significance of the cross-term (dobutamine x condition). Adenylate cyclase data were analyzed by two-way ANOVA. Data are reported as the mean value ± SEM.
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Results
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Induction of reverse remodeling in the heart by use of the CSD.
Figure 2A displays examples of pressure–volume loops and relations before and after long-term CSD treatment. Placement of the CSD resulted in a leftward shift in the rest pressure–volume loop (thicker lines), as well as in the ESPVR. The latter observation is consistent with reversal of remodeling. In contrast, the diastolic pressure–volume curve was changed only a little. The leftward ESPVR shift was quantified by the end-systolic volume at a matched end-systolic pressure measured in the physiologic range (110 mm Hg, or V110). The V110 fell from 44.7 ± 5.2 to 33.9 ± 3.9 ml by long-term CSD treatment (p < 0.01). In contrast, the ESPVR slope was not significantly altered (2.5 ± 0.59 before CSD vs. 4.3 ± 2.3 after CSD, p = NS).
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Figure 2 Hemodynamic effects of the cardiac support device (CSD). (A) Left ventricular pressure–volume relations in one animal before and after long-term CSD use. The darker loops for each condition reflect basal conditions, and the thinner loops were measured during transient load reduction. There was a reduction in both end-diastolic and end-systolic chamber volumes, with preservation of cardiac stroke volume (loop width), and the end-systolic pressure–volume relation shifted leftward, consistent with reversal of chamber remodeling. The diastolic pressure–volume boundary was not altered. (B) Summary of hemodynamic variables before and after long-term CSD use. There was a consistent significant decline in chamber volumes (end-diastolic volume [EDV] and end-systolic volume [ESV]), without a change in cardiac output (CO). End-diastolic pressure (EDP) and end-systolic pressure (ESP) were not significantly changed. EF = ejection fraction.
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The diastolic pressure–volume relation was more variably affected, with some animals displaying a leftward shift and others a downward shift, whereas others had no change. Diastolic chamber elastic stiffness (ß), as determined from a monoexponential fit  did not significantly change (0.09 ± 0.03 before CSD vs. 0.11 ± 0.02 ml–1 after CSD, p > 0.4).
Figure 2B provides a summary of the hemodynamic data. Both end-systolic and end-diastolic volumes significantly declined by –22.1 ± 7.6 and –18.7 ± 4.2%, respectively (both p < 0.0001). In contrast, the EF, end-systolic pressure, end-diastolic pressure, cardiac output (Fig. 2B), maximal rate of rise in pressure (2,025 ± 130 vs. 1,765 ± 67 mm Hg/s), isovolumic relaxation (49.9 ± 4.5 vs. 51.7 ± 5.4 ms, using a non-zero decay asymptote) and preload-recruitable stroke work (54.1 ± 11.1 vs. 54.4 ± 9.4 mm Hg) were not altered. It should be noted that LV end-diastolic pressure either declined or remained minimally changed. Consistent with previous reports (21), we found no evidence of functional constraint after CSD implantation. Right and left heart diastolic pressures were not equalized (19 ± 3 mm Hg for LV end-diastolic pressure; 8 ± 1 mm Hg for right ventricular [RV] end-diastolic pressure) after long-term CSD use.
Preload-recruitable systolic reserve
Because the CSD imposed an external containment around the heart, one concern was that the observed reverse remodeling would be accompanied by inhibition of cardiac preload reserve. Administering dextran infusions in the CSD-treated animals tested this hypothesis. As shown in Figure 3, the preload increased the end-diastolic pressure, as anticipated, but this was accompanied by substantial increases in systolic performance. There was no square-root sign in LV pressure–time tracings (Fig. 3A, bottom graph) before or after volume infusion, supporting the lack of constrictive physiology. Cardiac output rose nearly 100%, and both the maximal rates of rise and decline in pressure were significantly enhanced.
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Figure 3 Effects of an early preload increase in the failing heart after cardiac support device (CSD) implantation. (A) Example of pressure–volume relations before and after infusion of 400 ml of dextran. (B) Summary of hemodyanmic variables in relation to incremental volume expansion. For a near 10 mm Hg rise in end-diastolic pressure (EDP), cardiac output (CO) rose by nearly 100%, and there were significant changes in both the maximal and minimal rates of pressure change. Thus, preload-dependent reserve function was not inhibited by CSD placement. dP/dtmx and dP/dtmn = rate of rise in left ventricular pressure, maximal and minimal, respectively. *p < 0.05 versus baseline, e.g. 0 volume expansion.
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Improved beta-adrenergic reserve and the CSD
Figure 4 shows an example of and summary data on beta-adrenergic reserve before and after CSD placement. In the basal heart failure state, early dobutamine infusion elicited a small systolic response, although this was considerably enhanced after long-term CSD treatment. Stroke volume, stroke work, ejection fraction and cardiac output initially tended to decline with dobutamine, yet each variable rose significantly with the same dobutamine dose after CSD placement (all p < 0.01 for interaction effect of dobutamine and CSD status by ANOVA).
To further assess the mechanism(s) of the augmented adrenergic response with long-term CSD treatment, LV myocardial isoproterenol-stimulated adenylate cyclase activity was determined. This response was enhanced (Fig. 5A) in CSD-treated animals, as compared with a parallel group of animals (n = 5) with heart failure induced by the same methods and for a similar duration, but without CSD placement. In contrast, adenylate cyclase activity in response to forskolin was similar between the groups (Fig. 5B), supporting signaling changes proximal to the enzyme itself. Neither the beta-adrenergic receptor density (76 ± 4 vs. 81 ± 5 fmol/mg with the CSD) nor the binding affinity (1.31 ± 0.1 vs. 1.3 ± 0.1 nmol/l) was different between the two groups.
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Figure 5 (A) Isoproterenol-stimulated adenylate cyclase activity in the failing myocardium, with or without cardiac support device (CSD) treatment. The CSD resulted in an enhanced dose response to isoproterenol. The p value is for the CSD effect on the dose response, by two-way analysis of variance. (B) Adenylyl cyclase activity with direct activation by forskolin revealed no difference between the groups, suggesting altered up-stream signaling as the major source for the disparity in part A. CHF = chronic heart failure.
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Discussion
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This study provides direct evidence that application of a purely passive external containment to a chronically failing heart leads to reversal of chamber remodeling, as detected by a leftward ESPVR shift and accompanied by augmented post-receptor sensitivity and responsiveness to beta-adrenergic stimulation. The CSD effect could not be attributed to systolic assistance and, importantly, was achieved in an intact working heart, without causing diastolic constriction that would otherwise inhibit preload reserve.
reversing remodeling: unloading versus containment.
Cessation or reversal of progressive chamber remodeling is an important aim of heart failure therapy (1,3,4,31). Successful pharmacologic approaches have targeted neurohormones, supporting the link between remodeling and angiotensin and catecholamine toxicity. Recent surgical approaches provide a more direct test of the importance of chamber load and structural geometry of the failing heart. The LVAD has been the most widely studied approach, and it can dramatically unload the LV, leading to reverse remodeling (9,32,33). At the cellular level, this results in reversal of many heart failure abnormalities involving gene expression (12,13,34), calcium homeostasis (13,35), hypertrophy (12), energetics (14) and adrenergic signaling (15). This demonstrates remarkable plasticity of the failing heart in response to profound cardiac unloading and systolic assistance. However, such data do not identify an effect of limiting dilation/remodeling, per se, as LVADs also restore cardiac output and markedly reduce neurohormonal activation. Recent comparisons between RV and LV myocardial responses support a load effect from the LVAD (36), but this analysis remains indirect, as RV failure varies among patients, and synergistic influences of neurohormonal deactivation and normalized output on unloading cannot be ruled out.
External containment, such as that provided by the CSD, physically limits cardiac expansion and, in so doing, breaks a positive feedback loop by which progressive dilation and dysfunction are coupled. This strategy of external containment differs from interventions that directly remodel the heart by removing myocardium (37,38) or placing stents to alter its shape and regional load (39). Hints that containment alone might lead to reverse remodeling first came from studies of cardiomyoplasty. Although this method combined an effect of external girdling with systolic assistance from skeletal muscle contraction, clinical data suggest that the former mechanism was particularly potent (18). Passive effects of the wrap were directly tested in an experimental model, where asynchronous, nonburst stimulation was applied to maintain skeletal muscle health, yet not elicit a contraction (19). Intriguingly, reverse remodeling and improved function by this approach were nearly identical to those seen when tetanic systolic cardiomyopathy stimulation was also applied (40), further supporting the notion that containment was a primary mechanism.
The CSD was developed as an artificial material alternative to a passive skeletal muscle wrap. Early reports performed in an ovine model of heart failure induced by rapid pacing found that the CSD limited progressive heart dilation and mitral regurgitation (20). Similar effects were then demonstrated in an ischemic cardiomyopathic model in association with diminished myocyte hypertrophy and fibrosis (21). The present results expand these findings in several major ways. The pressure–volume analysis identified reverse remodeling in the absence of constrictive pathophysiology as hallmarks of the CSD effect. The observed leftward shift in the ESPVR, with little net slope change, is very similar to those experimental and clinical results with cardiomyoplasty (18,41). Also, in concordance with cardiomyoplasty, the CSD did not have a significant net effect on diastolic compliance, although it prevented progressive dilation.
The present data employing the CSD should be compared with time-controlled data from the same model of ischemic dilated cardiomyopathy, but without this device. As previously reported, animals in this latter model display progressive cardiac dilation and a reduced ejection fraction (21)—strikingly different from the results with the CSD. The observation that a purely passive wrap that does not quickly shrink the size of the heart can eventually lead to reverse remodeling is very intriguing. Although the exact mechanism remains unclear, one hypothesis is that the failing heart involves multiple interactive pathways with concomitant changes that can be both adverse and potentially ameliorative. Unchecked, the balance favors adverse factors and results in gradual deterioration. However, simply by limiting one of these important factors—that is, chamber remodeling—the CSD may tip the balance to allow favorable signaling pathways and energy utilization to become effective, and thereby help reverse progressive failure and enhance adrenergic signaling.
Improved adrenergic response
Improved beta-adrenergic signaling observed with the CSD is similar to that reported with LVAD therapy (15). With the CSD, this change occurred despite continued left heart loading and work, and without direct systolic assistance that could reduce the tonic adrenergic tone. Furthermore, the effects were obtained in hearts that were not terminally depressed. Unlike the LVAD, however, there was no change in beta-receptor density (or affinity) with the CSD, despite augmented adenylate cyclase responses to receptor stimulation and functional changes in the whole heart. This may reflect differences between the CSD and LVAD, which is associated with more extreme LV unloading and concomitant systemic changes. The precise mechanism for an enhanced beta-adrenergic response with the CSD remains unknown, but may lie in alterations in beta-adrenergic receptor kinase, G-protein signaling or cyclic guanosine monophosphate metabolism and catabolism.
Containment versus constriction
The major concern regarding external containment devices is whether or not they constrict diastolic filling and, thereby, preload reserve. The pericardium of the failing heart dilates to accommodate myocardial enlargement, but this expansion is generally insufficient to prevent limitations of preload reserve (42). The passive properties of the CSD are less abruptly nonlinear, compared with the pericardium, with a pressure rise of <7 mm Hg for 20% volume expansion, and a rise of 9 mm Hg at 30% expansion. This better enables the material to stretch to accommodate the filling volume. We found that long-term CSD use allowed substantial systolic reserve with early volume expansion. There was no equalization of diastolic pressures between the right and left heart, nor an LV pressure square-root sign characteristic of restrictive (or constrictive) filling either before or after marked volume loading. Recent clinical studies have found no evidence of interference with coronary flow in either native or bypass vessels in humans (43). The passive properties of the mature CSD, with its fibrous in-growth, remain to be determined, and this is likely to be somewhat stiffer than the CSD alone. Nonetheless, the current data suggest that this combination remains sufficiently pliable to accommodate early volume expansion, yet still limit remodeling/expansion.
Study limitations
We did not perform pressure–volume studies in a parallel sham-operated group, but we did repeat studies in each animal. Previous historic control data in the same experimental model have been reported and support progressive dilation in the absence of the CSD. The duration of CSD treatment was somewhat variable, partially due to practical problems of having to transport co-investigators and equipment from one city to another to perform the studies. Nonetheless, we discerned no significant differences due to this time disparity. Furthermore, the magnitude of the initial volume change with CSD placement was somewhat variable, partly due to the lack of precise on-line measures of CSD snugness and volume change.
Conclusions
We have shown that a purely passive external elastic containment device can reverse remodeling in the failing heart and improve beta-adrenergic signaling, while preserving preload reserve. Preliminary clinical studies with the CSD have been recently reported (27), and the approach appears both safe and generally well tolerated. Ongoing randomized clinical trials in the U.S. and Europe aim to assess the efficacy of the CSD in limiting chronic remodeling in human cardiomyopathy. Such studies should provide the first tests, in humans, of the hypothesis that limiting remodeling alone in the intact working heart can improve long-term function and provide a useful therapy for heart failure.
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Footnotes
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This study was supported by the National Heart, Lung and Blood Institute (grant no. 5P50-HL-52307), National Institutes of Health, Bethesda, Maryland, and by a grant from Acorn Cardiovascular Inc., St. Paul, Minnesota.
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Abstract
Methods
0.001 and