| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2000;102:1990.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Effects of Dopamine ß-Hydroxylase Inhibition With Nepicastat on the Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Chronic Heart Failure
From the Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Mich (H.N.S., V.G.S., T.M., M.T., S.G.); Case Western Reserve University, Cleveland, Ohio (W.C.S.); the University of Texas, Houston (C.R.B.); and Roche Bioscience, Palo Alto, Calif (S.H.).
Correspondence to Hani N. Sabbah, PhD, Cardiovascular Research, Henry Ford Health System, 2799 W Grand Blvd, Detroit, MI 48202. E-mail hsabbah1{at}hfhs.org
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Inhibition of dopamine ß-hydroxylase (DBH) results in a decrease in norepinephrine synthesis. The present study was a randomized, blinded, placebo-controlled investigation of the long-term effects of therapy with the DBH inhibitor nepicastat (NCT) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with chronic heart failure (HF).
Methods and Results—Moderate HF (LV ejection fraction [LVEF] 30% to 40%) was produced in 30 dogs by intracoronary microembolization. Dogs were randomized to low-dose NCT (0.5 mg/kg twice daily, n=7) (L-NCT), high-dose NCT (2 mg/kg twice daily, n=7) (H-NCT), L-NCT plus enalapril (10 mg twice daily, n=8) (L-NCT+ENA), or placebo (PL, n=8). Transmyocardial (coronary sinus–arterial) plasma norepinephrine (tNEPI), LVEF, end-systolic volume, and end-diastolic volume were measured before and 3 months after initiating therapy. tNEPI levels were higher in PL compared with NL (86±20 versus 13±14 pg/mL, P<0.01). L-NCT alone and L-NCT+ENA reduced tNEPI toward normal (28±4 and 39±17 pg/mL respectively), whereas HD-NCT reduced tNEPI to below normal levels (3±10 pg/mL). In PL dogs, LVEF decreased but was unchanged with L-NCT and increased with L-NCT+ENA. L-NCT and L-NCT+ENA prevented progressive LV remodeling, as evidenced by lack of ongoing increase in end-diastolic volume and end-systolic volume, whereas H-NCT did not
Conclusions—In dogs with HF, therapy with L-NCT prevented progressive LV dysfunction and remodeling. The addition of ENA to L-NCT afforded a greater increase in LV systolic function. NCT at doses that normalize tNEPI may be useful in the treatment of chronic HF.
Key Words: heart failure • drugs • myocytes • norepinephrine
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Blockade of the renin-angiotensin and sympathetic nervous systems in heart failure (HF) elicits beneficial effects that underscore their importance in the pathogenesis of the disease and its progression.1 2 Enhanced sympathetic nervous system activity is manifested by increased plasma norepinephrine, whereas that of the renin-angiotensin system is manifested by increased circulating angiotensin-II. Modulation of these neurohormones with ACE inhibitors and ß-adrenergic receptor blockers results in improvement in the clinical signs and symptoms of HF, a decrease mortality and morbidity,3 4 5 and modulation of ventricular remodeling,6 7 a global and cellular process deemed important in the development of and progression of HF.8
One possible approach aimed at directly countering the adverse effects
of enhanced sympathetic drive in HF is inhibition of the biosynthesis
and release of norepinephrine. This can be achieved by
inhibiting dopamine ß-hydroxylase (DBH), an enzyme that converts
dopamine to norepinephrine within sympathetic nerve
vesicles.9 The reduction in norepinephrine
results in decreased stimulation of ß1- and
ß2-adrenergic receptors and
1 receptors.10 At the same time,
DBH inhibition will increase dopamine levels in the nerve terminal,
which can have a beneficial effect on renal function in HF, and can act
on prejunctional D1 receptors to inhibit
norepinephrine release.10 The recent
development of nepicastat (NCT), a novel and potent DBH
inhibitor with a high degree of selectivity,11
has made it possible to study the efficacy of this therapeutic approach
in HF. The purpose of the present study was to examine the effects
of chronic therapy with NCT on the progression of left
ventricular (LV) dysfunction and remodeling in dogs with
HF. Because ACE inhibition is standard therapy in the treatment of HF,
we also assessed the efficacy of NCT when combined with an ACE
inhibitor.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Model
The canine model of chronic HF used in this study was previously described in detail.12 In this preparation, HF is produced by multiple sequential intracoronary embolizations with polystyrene Latex microspheres (70 to 102 µm in diameter), which results in loss of viable myocardium. Thirty healthy mongrel dogs, weighing between 20 to 25 kg, underwent coronary microembolizations to produce HF. Embolizations were performed 1 to 3 weeks apart and were discontinued when LV ejection fraction, determined angiographically, was between 30% and 40%. Microembolizations were performed during cardiac catheterization under general anesthesia and sterile conditions. Anesthesia consisted of a combination of intravenous injection of oxymorphone (0.22 mg/kg), diazepam (0.17 mg/kg), and sodium pentobarbital (150 to 250 mg) to effect. The study was approved by the Henry Ford Health System Care of Experimental Animals Committee and conformed to the "Position of the American Heart Association on Research Animal Use," adopted by the Association in November 1984.
Study Design and End Points
The study was a randomized, blinded, placebo-controlled trial.
Two weeks after the last embolization, dogs underwent a
prerandomization left and right heart catheterization.
One day later, dogs were randomized to 3 months oral therapy with
low-dose NCT (0.5 mg/kg twice daily, n=7), high-dose NCT (2.0 mg/kg
twice daily, n=7), combined low-dose NCT and enalapril (10 mg twice
daily, n=8), or placebo (n=8). Treatments were based on body weight at
the time of randomization. Hemodynamic, angiographic,
and neurohormonal measurements were made at 2 weeks after the last
embolization and before initiating therapy (pretreatment) and were
repeated after completing 3 months of therapy (posttreatment). The
primary study end points were (1) changes in LV ejection fraction
determined angiographically and (2) changes in global LV remodeling
based on changes in LV end-systolic and
end-diastolic volumes, also determined angiographically.
Secondary end points were (1) changes in transmyocardial
(coronary sinus–arterial) plasma concentrations
and LV tissue levels of norepinephrine and dopamine and (2)
changes in histomorphometric measures of cellular remodeling, namely,
changes of cardiomyocyte hypertrophy,
replacement fibrosis, interstitial fibrosis, capillary
density, and oxygen diffusion distance. Blood and LV tissue samples
were obtained from 7 normal dogs for comparison.
Hemodynamic and Angiographic Measurements
Aortic pressure was measured with catheter-tipped
micromanometers (Millar Instruments). Left
ventriculograms were obtained with the dog placed on its right side and
recorded on 35-mm cinefilm at 30 frames/s. Correction for image
magnification was made with a radiopaque calibrated grid placed at the
level of the LV. LV end-systolic and end-diastolic
volumes were calculated by use of the area-length
method.13 LV ejection fraction was calculated as
previously described.12 The LV end-systolic
sphericity index was calculated from ventriculograms as the ratio of
the major to minor axis.14 As this index approaches unity,
LV shape approaches that of a sphere.
Histomorphometric Measurements
At the end of 3 months of therapy, the heart was removed and
placed in ice-cold cardioplegia solution. Three transverse slices, one
each from the basal, middle, and apical thirds of the LV, 
3 mm
thick, were obtained. Transmural tissue blocks obtained from the free
wall segment of the middle slice were mounted on cork with Tissue-Tek
embedding medium (Miles Inc) and rapidly frozen in isopentane precooled
in liquid nitrogen. Cryostat sections 8 µm thick were
prepared and stained with fluorescein-labeled peanut
agglutinin (Vector Laboratories Inc) and used to delineate the myocyte
border and the interstitial space.15 Sections
were double stained with rhodamine-labeled Griffonia
simplicifolia lectin I to identify capillaries. Ten radially
oriented, scar-free, microscopic fields (magnification x100) were
selected at random from each section and used to measure myocyte
cross-sectional area.15 The surface area occupied by
interstitial space and the surface area occupied by
capillaries were measured from each field by means of computer-based
video densitometry (JAVA, Jandel Scientific). The volume fraction of
interstitial collagen was calculated as the percent total
surface area occupied by interstitial space minus the
percent total area occupied by capillaries. Capillary density was
calculated by means of the index capillary per fiber
ratio.16 The oxygen diffusion distance was measured as
half the distance between two adjoining capillaries.16 The
volume fraction of replacement fibrosis, namely, the proportion of scar
to viable tissue, was calculated from trichrome-stained sections as the
percent total surface area occupied by fibrosis.
Measurements of Norepinephrine and Dopamine
Transmyocardial plasma norepinephrine (tNEPI) and
dopamine (tDOP) concentrations were estimated by obtaining
simultaneous blood samples from the ascending aorta and
coronary sinus during cardiac catheterization.
tNEPI and tDOP were calculated as the difference between the
coronary sinus and arterial samples. Fresh-frozen
tissue obtained from the LV free wall was used to measure tissue levels
of norepinephrine and dopamine. Norepinephrine
and dopamine were assayed in plasma and LV tissue by
high-performance liquid chromatography, as
previously described.11
Data Analysis
For primary end points, tNEPI, tDOP, and sphericity index,
intragroup comparisons between pretreatment and posttreatment measures
were made by means of the Student’s paired t test, with a
value of P<0.05 considered significant. Significance of
treatment effect was examined by comparing the placebo group and each
of the 3 treatment groups on the basis of the change (
) of each
measure calculated as the difference between pretreatment and
posttreatment values. Subsequent pairwise comparisons with placebo were
performed by means of Fisher’s least significant differences test,
with a Bonferroni correction on the pairwise probability value if the
overall probability value was significant (P<0.05). The
Bartlett test for homogeneity of variances was performed before the
ANOVA, and if the Bartlett probability value was P<0.05,
then the corresponding nonparametric analysis
(Kruskal-Wallis test) was performed instead, with subsequent pairwise
comparisons performed on the ranks. The statistical analysis
for tissue levels of norepinephrine, dopamine, and their
ratio and histomorphometric measures was conducted separately. The data
were examined by a 1-way ANOVA, with set at 0.05. If significance
was achieved, pairwise comparisons were performed by means of the
Student-Newman-Keuls test, with a value of P<0.05
considered significant. All data are reported as mean±SEM.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Catecholamine and Dopamine Concentrations in LV Tissue
In placebo dogs, the concentration of dopamine and norepinephrine in the LV tissue was lower compared with normal dogs (P<0.05) (Figure 1
). Treatment with low- and high-dose NCT
resulted in a further decline in norepinephrine level and
an increase in dopamine and dopamine-to-norepinephrine
ratio (Figure 1). Combined therapy of low-dose NCT and enalapril
also resulted in an increase in dopamine and
dopamine-to-norepinephrine ratio but did not significantly
lower the norepinephrine concentration compared with
placebo (Figure 1).
|
Transmyocardial Plasma Levels of Norepinephrine
and Dopamine
Levels of tNEPI and tDOP are depicted in Figure 2. There was a near 6-fold increase in
tNEPI in placebo-treated dogs compared with normal dogs (Figure 2) (P<0.05). tNEPI difference was significantly
reduced with low- and high-dose NCT and with low-dose NCT combined with
enalapril. The reduction was most dramatic with the high dose NCT
(97%) and was significantly lower than in normal. The reduction was
more modest with the low dose NCT (67%) and with combined therapy
(55%) and was not statistically different than in normal dogs. tDOP
increased with all treatments, but the increase was not significant
compared with placebo (Figure 2).
|
Hemodynamic and Angiographic Findings
The pretreatment and posttreatment hemodynamic and
angiographic measures are shown in Table 1. Monotherapy with NCT and
combination of NCT with enalapril had no effects on heart rate or mean
arterial pressure (Table 1). Placebo was associated
with a significant reduction of LV ejection fraction and LV sphericity
index and a significant increase of both LV end-diastolic
and end-systolic volumes. In dogs treated with high-dose NCT,
LV ejection fraction decreased and was accompanied by an increase in LV
end-systolic and end-diastolic volumes, with no
change in the sphericity index. These changes were nearly similar to
placebo. In dogs treated with low-dose NCT, posttreatment values of LV
ejection fraction, end-diastolic volume,
end-systolic volume, and sphericity index were not different
compared with pretreatment (Table 1). In dogs treated with
combined low-dose NCT and enalapril, LV ejection fraction and LV
sphericity index increased significantly after 3 months of therapy,
whereas LV volumes remained essentially unchanged (Table 1).
|
Comparisons of Treatment Effect
The changes between pretreatment and posttreatment LV ejection
fraction and end-systolic and end-diastolic volumes
are shown in Figures 3, 4, and 5.
Intergroup comparisons of change showed that compared with placebo,
low-dose NCT but not high-dose NCT prevented the decline in LV ejection
fraction and the increase in LV end-diastolic and
end-systolic volumes. Similarly, intergroup comparisons of
change showed that combination therapy significantly improved LV
ejection fraction and reduced LV end-systolic and
end-diastolic volumes compared with placebo. In placebo
dogs, the change in LV sphericity index was -0.10±0.03 and was not
different from high-dose NCT (-0.03±0.06) but significantly different
than low-dose NCT (0.04±0.02, P<0.05) and combination
therapy (0.08±0.03, P<0.05).
|
|
|
Histomorphometric Findings
Histomorphometric results are shown in Table 2. Volume fraction of replacement
fibrosis was significantly lower in all treatment groups compared with
placebo and was lowest with combination therapy. Volume fraction of
interstitial fibrosis was significantly higher in placebo
compared with normal dogs. It decreased in all 3 treatment groups when
compared with placebo but was only significant in the low-dose NCT
group and in the combined therapy, with the latter showing the most
reduction. Cardiomyocyte cross-sectional area was significantly larger
in placebo-treated dogs compared with normal dogs. It tended to be
smaller in all 3 treatment groups compared with placebo, but the change
reached significance only in dogs treated with combined low-dose NCT
and enalapril. Capillary density was significantly lower in placebo
dogs compared with normal dogs. It increased in all 3 treatment groups
compared with placebo but reached significance in only the low-dose NCT
group and the combination low-dose and enalapril (Table 2).
Oxygen diffusion distance was significantly longer in placebo dogs
compared with normal dogs. It was significantly shorter in all 3
treatment groups and was shortest in the combined therapy group when
compared with placebo.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This is the first study to assess the effects of DBH inhibition on the progression of LV dysfunction and remodeling in dogs with HF. As expected, inhibition of DBH resulted in a reduction of tNEPI levels with an increase, albeit not significant, of tDOP levels. Low-dose NCT normalized tNEPI, prevented progressive LV dysfunction, and attenuated LV remodeling. In contrast, high-dose NCT, which reduced tNEPI to levels below normal, had no beneficial effects on LV function and global LV remodeling compared with placebo. The addition of enalapril to low-dose NCT attenuated global LV remodeling to an extent similar to that of low-dose NCT alone, but, unlike low-dose NCT alone, the combination therapy significantly increased LV ejection fraction. The observed changes in global LV remodeling were associated with important structural/cellular changes. Low-dose NCT was associated with a lower volume fraction of replacement fibrosis, a lower volume fraction of interstitial fibrosis, reduced cardiomyocyte hypertrophy, increased capillary density, and improved oxygen diffusion distance compared with placebo, findings that favor prevention or attenuation of progressive LV remodeling. The improvements were even more pronounced with combination therapy of low-dose NCT and enalapril. These structural/cellular improvements tended to be present, but to a lesser extent, with high-dose NCT (Table 2
), a treatment regimen that failed to show benefits in
LV function and global remodeling when compared with placebo.
The beneficial effects of NCT on the failing heart are likely due to
the decrease in norepinephrine release from cardiac
sympathetic nerves and subsequently to a lesser stimulation of - and
ß-adrenergic receptors. Placebo-treated dogs had elevated tNEPI
levels and lower cardiac tissue norepinephrine
concentration compared with normal dogs, indicating a high rate of
norepinephrine turnover in cardiac sympathetic nerve
endings. In dogs, NCT produces a concentration-dependent inhibition of
DBH and has negligible affinity for other enzymes and
neurotransmitters11 and has been shown to cause a
dose-dependent decrease in norepinephrine, increase in
dopamine, and an increase in the dopamine/norepinephrine
ratio in the LV.11 Studies performed with radioisotope
spillover techniques concluded that the increase in cardiac
norepinephrine spillover observed in HF was a result of
an increase in norepinephrine release in the setting of
normal neuronal uptake.17 In the present
investigation, HF resulted in increased tNEPI difference, which was
reduced by NCT in a dose-dependent manner. Interestingly, the large
decrease in tNEPI to below normal levels with high-dose NCT did not
improve ventricular function, suggesting that
over-suppression of cardiac sympathetic activity, even in the setting
of HF, can have an adverse effect on the cardiac performance.
This observation offers a potential explanation for the increase in
adverse events seen in the Moxonidine in Congestive Heart Failure Trial
(MOXCON). One possibility is that moxonidine, a selective imidazole
I1-receptor agonist with central sympatholytic
effect, may have been given in too high a dose, which led to excessive
reduction in plasma norepinephrine.18 Also of
interest is the observation that NCT did not reduce heart rate despite
its marked effects on tNEPI. The underlying cause of this finding
remains to be elucidated.
In contrast to ß-adrenergic blockade, which has a rapid
physiological effect on LV function, DBH inhibits
norepinephrine synthesis over a number of days and even
then only attenuates rather than totally abolishes preganglionic and
tyramine-induced cardiovascular
responses.11 Drugs that preferentially inhibit
norepinephrine synthesis, such as NCT, affect the release
of norepinephrine from tissues that have a low storage rate
and a high turnover, which is the case in HF.19 The
reduction of norepinephrine leads to diminished activation
of not only ß1 and ß2
receptors but also 1 receptors. Inactivation
of 1 receptors may have clinical importance in
HF by decreasing ventricular arrhythmias and
potentially the incidence of sudden death. Inhibition of DBH also
increases dopamine production and release, which can promote
urinary sodium excretion by activating dopamine receptors in the renal
tubules.20
In addition to attenuating progressive global LV remodeling, low-dose
NCT reduced replacement fibrosis, a measure of ongoing cell death,
reduced reactive interstitial fibrosis, attenuated myocyte
hypertrophy, and improved oxygen diffusion, alterations
deemed beneficial in the treatment of HF. Enhanced and sustained
norepinephrine release can cause cardiomyocyte
hypertrophy by increasing protein synthesis.21
In a study of LV remodeling produced by repeated DC shock in dogs, the
1-adrenoceptor blocker terazosin attenuated
early LV dilation and hypertrophy.22 The fact
that DBH inhibitors deactivate both
1- and ß-adrenergic pathways may explain the
beneficial effect on cardiomyocyte hypertrophy
observed with NCT therapy in this study. In contrast to low-dose NCT,
high-dose NCT had no effect on global LV remodeling and a lesser effect
on cellular components of LV remodeling despite greater adrenergic
inhibition. Although not fully understood, one can only speculate that
excessive inhibition of adrenergic drive in HF may also adversely
impact cellular remodeling.
Combination of enalapril with low-dose NCT also resulted in attenuation of LV remodeling, along with a significant increase in LV ejection fraction. The increase in ejection fraction was due to a decrease in LV end-systolic volume, suggesting improved contractile performance. Combination therapy also resulted in decreased LV chamber sphericity, increased capillary density, and reduced oxygen diffusion distance; factors important in overall myocardial energetics. The increase in LV ejection fraction, therefore, could be interpreted to be due to improved cardiomyocyte energetics. Angiotensin II is closely linked to myocyte hypertrophy and fibroblast growth23 and therefore inhibiting its formation with an ACE inhibitor is likely to attenuate myocyte hypertrophy and interstitial fibrosis. Angiotensin II also has a direct effect on interstitial fibrosis through its action on fibroblasts.24 In the present study, combination therapy with enalapril elicited additional improvements in all morphological features examined compared with low-dose NCT alone. A limitation of this study, however, is the lack of an enalapril arm only. This would have been useful in determining whether the addition of NCT was beneficial to the underlying effects of the ACE inhibitor or whether the effects of NCT and the ACE inhibitor were additive.
In conclusion, results of the present study indicate that NCT in doses that normalize tNEPI attenuates LV remodeling and prevents progressive LV systolic dysfunction. This beneficial effect of NCT is lost, however, when doses that result in near depletion of tNEPI are used, suggesting that some threshold of sympathoadrenergic drive is necessary even in the setting of HF. Finally, when combined with enalapril, low-dose NCT elicits an improvement in LV ejection fraction that is similar to that seen with ß-blockers in HF when used with ACE inhibitors.4 5 This observation argues in favor of enhanced and sustained sympathoadrenergic drive as a common denominator responsible, in part, for the abnormalities of LV function and LV chamber remodeling that are characteristic of the HF state.
|
Acknowledgments |
|---|
This study was supported in part by research grants from Roche Bioscience and the National Heart, Lung, and Blood Institute (HL-49090-06).
|
Footnotes |
|---|
Guest Editor for this article was Marc A. Pfeffer, MD, PhD, Brigham and Womens Hospital, Boston, Mass.
Received March 17, 2000; revision received May 19, 2000; accepted May 25, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Gavras H, Faxon DP, Berkoben J, et al. Angiotensin converting enzyme inhibition in patients with congestive heart failure. Circulation. 1978;58:770–776:
2.
Francis GS, Benedict C, Johnson DE, et al. Comparison
of neuroendocrine activation in patients with left
ventricular dysfunction with and without congestive heart
failure. Circulation. 1990;82:1724–1729.
3. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med. 1991;325:293–302.[Abstract]
4. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet. 1999;353:9–13.[Medline] [Order article via Infotrieve]
5. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–2007.[Medline] [Order article via Infotrieve]
6.
St. John Sutton M, Pfeffer MAQA, Plappert T, et al.
Quantitative two-dimensional echocardiographic
measurements are major predictors of adverse
cardiovascular events after acute myocardial
infarction: the protective effects of captopril.
Circulation. 1994;89:68–75.
7. Sabbah HN, Shimoyama H, Kono T, et al. Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction. Circulation. 1994;84:2852–2859.
8.
White HD, Norris RM, Brown MA, et al. Left
ventricular end-systolic volume as the major
determinant of survival after recovery from myocardial Infarction.
Circulation. 1987;76:44–51.
9. Goldstein M, Anagnoste M, Lauber B, et al. Inhibition of dopamine ß-hydroxylase by disulfiram. Life Sci. 1964;3:763–767.
10. Lokhadwala MF, Hegde SS. Cardiovascular pharmacology of adrenergic and dopaminergic receptors: therapeutic significance in congestive heart failure. Am J Med. 1991;90:2S–9S.
11. Stanley WC, Li B, Bonhaus DW, et al. Catecholamine modulatory effects of nepicastat (RS-25560–197), a novel, potent and selective inhibitor of dopamine ß-hydroxylase. Br J Pharmacol. 1997;121:1803–1809.[Medline] [Order article via Infotrieve]
12.
Sabbah HN, Stein PD, Kono T, et al. A canine model of
chronic heart failure produced by multiple sequential
intracoronary microembolization. Am J Physiol. 1991;260:H1379–H1384.
13. Dodge HT, Sandler H, Baxley WA, et al. Usefulness and limitation or radiographic methods for determining left ventricular volume. Am J Cardiol. 1995;18:10–24.
14.
Sabbah HN, Kono T, Stein PD, et al. Left
ventricular shape changes during the course of evolving
heart failure. Am J Physiol. 1992;263:H266–H270.
15. Liu YH, Yang XP, Sharov VG, et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin-2 type-1 receptor antagonists in rats with heart failure. J. Clin Invest. 1997;99:1926–1935.[Medline] [Order article via Infotrieve]
16. Rakusan K. Oxygen in Heart Muscle. Springfield, Ill: Charles C. Thomas; 1971:66–71.
17. Meredith IT, Eisenhofer G, Lambert GW, et al. Cardiac sympathetic nervous activity in congestive heart failure. Circulation. 1993;8:136–145.
18. Coats AJS. Heart failure 99: the MOXCON story. Int J Cardiol. 1999;71:109–111.[Medline] [Order article via Infotrieve]
19. Stanley WC, Hegde SS. Dopamine beta-hydroxylase inhibition: a potential therapy for the treatment of congestive heart failure. Heart Failure Rev. 1995;2:195–201.
20. Lokhandwala MF, DeFeo ML, Cavero I. Physiological and pharmacological significance of dopamine receptors in the cardiovascular system. Prog Hypertens. 1988;1:115–144.
21.
Zierhut W, Zimmer HG. Significance of myocardial
infarction and ß-adrenoceptors in
catecholamine-induced cardiac hypertrophy.
Circ Res. 1989;65:1417–1425.
22.
McDonald KM, Garr M, Carlye PF, et al. Relative effects
of -adrenoceptor blockade, converting enzyme
inhibitor therapy, and angiotensin II subtype-1
receptor blockade on ventricular remodeling in the dogs.
Circulation. 1994;90:3034–3046.
23.
Sadoshima J, Izumo S. Molecular characterization of
angiotensin II-induced hypertrophy of cardiac
myocytes and hyperplasia of cardiac fibroblasts. Circ Res. 1993;73:413–423.
24. Eghbali M, Czaja MJ, Zeydel M, et al. Collagen chain RNA in isolated heart cells from young and adult rats. J Mol Cell Cardiol. 1988;20:67–76.
This article has been cited by other articles:
 |
|
 |
|
  S. Rastogi, M. Imai, V. G. Sharov, S. Mishra, and H. N. Sabbah Darbepoetin-{alpha} prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2475 - H2482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rastogi, V. G. Sharov, S. Mishra, R. C. Gupta, B. Blackburn, L. Belardinelli, W. C. Stanley, and H. N. Sabbah Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H2149 - H2155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Zaca, S. Rastogi, M. Imai, M. Wang, V. G. Sharov, A. Jiang, S. Goldstein, and H. N. Sabbah Chronic Monotherapy With Rosuvastatin Prevents Progressive Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure J. Am. Coll. Cardiol., August 7, 2007; 50(6): 551 - 557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. C. Stanley, F. A. Recchia, and G. D. Lopaschuk Myocardial Substrate Metabolism in the Normal and Failing Heart Physiol Rev, July 1, 2005; 85(3): 1093 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Duncker, D. B. Haitsma, D. A. Liem, P. D. Verdouw, and D. Merkus Exercise unmasks autonomic dysfunction in swine with a recent myocardial infarction Cardiovasc Res, March 1, 2005; 65(4): 889 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Chandler, J. Kerner, H. Huang, E. Vazquez, A. Reszko, W. Z. Martini, C. L. Hoppel, M. Imai, S. Rastogi, H. N. Sabbah, et al. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1538 - H1543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Igawa, T. Nozawa, N. Fujii, B.-i. Kato, H. Asanoi, and H. Inoue Long-term treatment with Low-Dose, but not High-Dose, guanethidine improves ventricular function and survival of rats with heart failure after myocardial infarction J. Am. Coll. Cardiol., August 6, 2003; 42(3): 541 - 548. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||