| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2000;101:558.)
© 2000 American Heart Association, Inc.
Cardiovascular Drugs |
ß-Adrenergic Receptor Blockade in Chronic Heart Failure
From the Division of Cardiology, University of Colorado Health Sciences Center, Denver, Colo.
Correspondence to Michael R. Bristow, MD, PhD, Head, Division of Cardiology, University of Colorado Health Sciences Center, 4200 E 9th Ave, Campus Box B139, Denver, CO 80262. E-mail Michael.Bristow{at}UCHSC.edu
Key Words: drugs • heart failure • receptors, adrenergic, beta
 |
Introduction |
|---|
Top
Introduction
Rationale for {beta}-Blocker...The medical treatment of chronic heart failure has undergone a remarkable transition in the past 10 years. The approach has changed from a short-term hemodynamic/pharmacological paradigm to a more long-term, reparative strategy that aims to favorably alter the biological properties of the failing heart.1 This is dramatically illustrated by the recent success in treating mild-to-moderate chronic heart failure with ß-adrenergic blocking agents. This review describes how a treatment that began as a contraindication1 2 3 became an established treatment of chronic heart failure.
|
Rationale for ß-Blocker Therapy in Chronic Heart Failure: Maladaptive Adrenergic Signaling and Altered but Persistent Signal Transduction in the Failing Heart |
|---|
The failing human heart is adrenergically activated,4 5 6 which helps to maintain cardiac performance over the short term by increasing contractility and heart rate. In contrast, in the resting state there is no adrenergic support of normally functioning human left ventricles.6 Multiple lines of evidence7 8 9 indicate that it is the increase in cardiac adrenergic drive rather than an increase in circulating norepinephrine that is both initially supportive and then ultimately damaging to the failing human heart.
As shown in Table 1
, there are 3
adrenergic receptors (ß1,
ß2, and 
1) in human
cardiac myocytes coupled to a positive inotropic response and cell
growth.10 11 12 ß-Adrenergic receptors are coupled via the
"stimulatory" G protein Gs to the effector
enzyme adenylyl cyclase, which converts the substrate MgATP to cAMP.
cAMP is a positively inotropic and chronotropic second messenger and is
strongly growth promoting. In nonfailing human left or right
ventricles, the ß1/ß2
ratio is 70 to 80/30 to 20, but in failing human ventricles, 35% to
40% of the total number of ß-receptors are
ß2 because of selective downregulation in the
ß1 subtype.10 11
1 Receptors are coupled via a different G
protein (Gq) to the effector enzyme phospholipase
C, which, through the second messenger diacyl glycerol,
activates the growth-promoting protein kinase C family. Because
1-receptors are upregulated in the failing
heart, the cardiac myocyte adrenergic receptor profile changes from
predominately (>70% of the total adrenergic receptor population)
ß1 to more of a mixed 2:1:1 ratio in end-stage
heart failure.12 ß2 Receptors are
also present on adrenergic nerve terminals in the heart, where they
facilitate norepinephrine release.13 The
ß3-receptor may also be present in the
human heart as a counterregulatory receptor coupled to the
"inhibitory" G protein
Gi,14 and there is evidence for a
"ß4 " receptor.15
|
Norepinephrine is an exceptionally cardiotoxic substance
that produces cardiac myocyte injury16 in concentrations
found in the failing human heart. Norepinephrine is mildly
(10- to 30-fold compared with the binding affinity to
ß2 receptors)
ß1-receptor selective, and its cytotoxicity
appears to be mediated through ß- rather than -adrenergic
receptors.16 In transgenic mice, cardiac
overexpression of human ß1
receptors17 18 Gs19 or
Gq20 produces an overtly
cardiomyopathic phenotype and ultimately
chamber dilatation and systolic dysfunction. Overexpression of
Gs is also associated with increased markers
of apoptosis,21 which can be produced in adult rat
cardiac myocytes by ß-agonist exposure.22 23 In adult
rat myocytes, the ß1 receptor mediates apoptotic
signaling, whereas the ß2 receptor is antiapoptotic via
coupling to the inhibitor and G protein
(Gi).23 High levels of cardiac overexpression
of the human ß2 receptor eventually result in
depressed systolic function and a cardiomyopathy
phenotype,24 and cardiac expression of a constitutively
activated 1 receptor produces
concentric hypertrophy.25 These data from
model systems incontrovertibly indicate that chronic adrenergic
signaling is a harmful compensatory mechanism in the failing human
heart. The data are extremely convincing for chronic
ß1-receptor signaling and less convincing, but
likely, for chronic ß2- and
1-receptor pathway activation.
In the failing heart, ß-adrenergic signal transduction is reduced secondary to desensitization changes in ß1 and ß2 receptors, the inhibitory G protein (Gi), an enzyme responsible for modulating receptor activity by phosphorylation (ßARK), and even in the expression of the adenylyl cyclase enzyme itself.12 26 In end-stage failing heart, 50% to 60% of the total signal transducing potential is lost, but substantial signaling capacity remains.12 These and other data from model systems27 suggest that the ß-adrenergic receptor pathway desensitization changes present in the failing human heart are adaptive changes, and that a potentially effective therapeutic strategy would be to add to this endogenous antiadrenergic strategy by inhibiting receptor signal transduction.28 29 30
Thus, the continuously increased adrenergic drive present in the
failing human heart delivers adverse biological signals to the cardiac
myocyte via ß1- and likely ß2-
and 1-adrenergic receptors. This is the
fundamental basis for the use of antiadrenergic
agents in the treatment of chronic heart failure.
|
Three Classes of ß-Blockers Available for Clinical Use |
|---|
There are now 3 classes of ß-blockers available for clinical use. Table 2
gives the adrenergic
receptor blocking profiles for selected ß-blocking agents, including
those that have been widely used in heart failure clinical trials.
Propranolol is the prototype nonselective compound,
introduced into clinical practice in 1968 as an antianginal agent.
Propranolol and other "first-generation" compounds,
such as timolol, are nonselective agents with equal affinities for
blocking ß1 and ß2
receptors and no important pharmacological properties other than
ß-blockade.
|
In the 1970s, pharmaceutical companies developed
"cardioselective" or second-generation ß-blockers
that selectively antagonized ß1- compared with
ß2-receptors. This was done in the mistaken
belief10 11 that the human heart could be selectively
ß-blocked, on the basis of data from animal models in which only
ß1-receptor–mediated responses were identified
in the myocardium. It was hoped that a lack of
ß2-receptor blockade would also reduce some of
the perceived peripheral and pulmonary side effects
of ß-blockers, a hypothesis that also was never conclusively proved.
The first truly selective ß1-blocking agent was
practolol,31 which was sufficiently
ß1-selective that it could be used along with
propranolol to demonstrate 3 distinct subtypes
(ß1, ß2, and
ß3) of ß-adrenergic receptors,32
which were ultimately shown to be the products of 3 distinct
genes.33 34 35 Practolol was also the first ß-blocking
agent to be therapeutically administered by the pioneering Goteborg
group to a patient with chronic heart failure.36
Ultimately, practolol was removed from clinical practice because of
immunological adverse effects and was replaced by metoprolol in the
Goteborg studies. As shown in Table 2
, metoprolol is
approximately 75-fold selective for human ß1-
versus ß2-receptors. In the 1980s,
pharmaceutical companies developed even more
ß1-selective compounds, such as bisoprolol,
which is 
120-fold selective (Table 2). As discussed below,
both metoprolol and bisoprolol have been used extensively in heart
failure trials and both have recently been shown to reduce mortality in
phase 3 clinical trials.37 38
In the 1970s and 1980s, another drug development effort aimed at
improving the treatment of hypertension led to the creation of
ß-blockers with vasodilating activity. These "third-generation"
compounds were designed to treat hypertension, and the prototype agent
is labetalol. Labetalol is an -, ß-blocking agent with a higher
affinity for 1- than
ß1- or ß2-
receptors.39 Labetalol has not been systematically
investigated in heart failure populations but has been shown to improve
myocardial function in subjects with hypertensive
cardiomyopathy.40 Another
third-generation compound with limited but favorable
experience41 42 in heart failure trials is nebivolol,
which is a markedly ß1-selective43
compound whose vasodilatory action appears to be due to potentiation of
nitric oxide.44 Two other ß-blockers with vasodilating
activity, carvedilol and bucindolol, have been extensively evaluated in
the treatment of chronic heart failure.
As shown in Table 2, carvedilol is a slightly (7-fold)
ß1-selective agent that becomes nonselective at
higher target doses.45 46 Carvedilol is also a potent
1-blocking agent, with 2- to 3-fold
selectivity for ß1- versus
1-receptors (Table 2).46
This degree of 1-blockade is responsible for
the moderate vasodilator properties of carvedilol.
Bucindolol is a completely nonselective ß-blocking agent with mild
vasodilator properties that were originally thought not to be due to
1-blockade in view of the 60- to 70-fold
difference in binding affinity between human myocardial
ß1- or ß2- and
1-receptors47 48 as deduced from
radioligand competition curves (Table 2). However,
recent data in isolated human saphenous vein preparations indicate that
bucindolol can antagonize 1-mediated
vasoconstrictor responses at concentrations achieved after oral dosing
(R.L. Takett, personal communication, 1999; Table 2), and
1-blockade is the only specific vasodilator
mechanism that has been identified in animal systems.49 50
Thus, it is likely that the weak vasodilator properties of bucindolol
are due to 1-adrenergic receptor blockade. As
with other ß-blocking agents that improve ventricular function in
chronic heart failure, bucindolol has no intrinsic sympathomimetic
activity in human myocardium.47 48 51 52 53 54
Compared with other ß-blocking agents that have been widely used in
chronic heart failure, bucindolol possesses the lowest amount of
"inverse agonism,"55 or the ability of an
antagonist to inactivate active-state
receptors. This seems to correlate with a low incidence of
symptomatic bradycardia with bucindolol, despite the fact
that it reduces average heart rate to the same extent as target doses
of metoprolol and carvedilol.53 55 This same low inverse
agonist profile may contribute to the apparent low amount of myocardial
depression on acute administration of bucindolol.51
Because they (1) block both ß1- and
ß2-adrenergic receptors, (2) reduce cardiac
and/or systemic adrenergic drive,51 52 53 54 55 56 (3) do not
upregulate downregulated ß1-adrenergic
receptors,46 56 and (4) block
1-receptors, the third-generation compounds
carvedilol and bucindolol provide a more comprehensive
antiadrenergic effect than do second-generation,
ß1-selective compounds.57 Limited
data suggest that compared with second-generation compounds,
third-generation compounds produce more beneficial effects on left
ventricular function.47 56 58 However, some
data also demonstrate no difference between a second- and
third-generation compound.59 Both second- and
third-generation compounds improve intrinsic systolic
function,41 60 61 and prevent deterioration in function
and progression in remodeling,62 63 64 65 66 and reverse
remodeling.63 66 As discussed below, from a clinical
standpoint it would appear that both second- and third-generation
compounds reduce hospitalizations and mortality, but quantitative
differences in clinical responses may exist. On the other hand, because
chronic ß1-adrenergic receptor signaling may be
the dominant cardiotoxic pathway in the failing heart,
ß1-selective agents may be as or even more
efficacious than pan-adrenergic receptor blocking
third-generation compounds. The issue of whether second- and
third-generation compounds provide differences in clinical efficacy can
be determined only by direct comparison trials, such as the
Carvedilol or Metroprolol European Trial (COMET), which is
assessing the effects of carvedilol versus metoprolol on all-cause
mortality.
|
Effects on Initiation of Therapy |
|---|
Because the failing heart is dependent on adrenergic support,2 3 6 13 67 the administration of any ß-blocking agent to a subject with overt heart failure from systolic dysfunction will cause some degree of myocardial depression that will be clinically manifest to various degrees. Acute administration of first-generation compounds, such as propranolol, causes a decrease in contractile state.6 This, plus a concomitant increase in systemic vascular resistance,53 67 68 leads to a profound decrease in cardiac output,6 53 57 which results in a drug intolerance rate of >20%.69
On the other hand, second-generation, ß1-selective compounds can be administered in low starting doses to subjects with mild to moderate heart failure and moderate to severe left ventricular dysfunction.70 The reason is that ß1-receptor blockade leaves the ß2-receptor unblocked and capable of supporting myocardial function, either directly71 or through increased norepinephrine overflow mediated by presynaptic ß2-receptors.13 71 Additionally, there is less reflex vasoconstriction with ß1-selective agents because unblocked peripheral vascular ß2-receptors can mediate vasodilatation. The overall effect is that cardiac output and organ perfusion are reduced to a lesser extent than with first-generation compounds.53 57 The drug tolerability rates for the second-generation compound metoprolol in clinical trials, with challenges of 5 or 6.25 mg BID, range from 79% to 100%.53
The third-generation compounds carvedilol, bucindolol, and nebivolol
have the advantage of afterload reduction to counteract the negative
inotropic properties of adrenergic withdrawal.51 53 72 As
a result, in grouped data bucindolol does not lower cardiac
output,51 53 57 and carvedilol may even increase it
slightly.53 72 Because of stereoselective hepatic
metabolism of the S isomer73 and
stereospecificity of the S isomer for binding to ß- but not
-adrenergic receptors,74 on oral administration the
-blocking effects of carvedilol are observed to about the same
degree as the ß-blocking effects.53 72 In contrast, on
intravenous administration, the ß-blocking effects of
carvedilol predominate75 (A. Lahiri, personal
communication, 1998). The prominent vasodilator action of orally
administered carvedilol leads to frequent orthostatic
symptoms on initiation of therapy or uptitration, most of which are
self-limiting or can be managed by smaller diuretic
doses.70 Orthostatic symptoms do not typically
occur with bucindolol because it is only a mild
vasodilator.51 53 57 Carvedilol is tolerated by 92% of
subjects with mild to moderate heart failure challenged with 3.125 to
6.25 mg BID, whereas bucindolol is tolerated by 98% of mild to
moderate heart failure subjects challenged with 6.25 to 12.5 mg
BID.53
The vasodilator properties of third-generation agents allow those compounds with a nonselective profile to be administered with an acceptable tolerability rate, which in effect allows for administration of agents with a more comprehensive antiadrenergic profile.53 57 However, it is unclear whether vasodilation contributes to the long-term benefit of third-generation compounds because after long-term therapy with carvedilol, the reduction in systemic vascular resistance is not different from placebo- or metoprolol-treated control populations.47 56
|
Effects of Long-Term Treatment on Myocardial Function and Chamber Characteristics |
|---|
The myocardial effects of long-term treatment with ß-blocking agents have been recently reviewed in detail.1 53 57 76 The striking generalization about the long-term effects of ß-blockade on myocardial function is that they are diametrically opposite to the short-term negative inotropic effects.1 That is, every placebo-controlled trial conducted for
3 months of treatment has
demonstrated improved systolic function compared with the
short-term negative inotropic effects.1 Somewhat later,
between 4 to 12 months of therapy, regression in myocardial mass and a
normalization in ventricular shape occur, phenomena called
reverse remodeling.1 53 57 63 These time-dependent,
biological effects of ß-blocker therapy are class effects and are
observed after treatment with both second- and third-generation
compounds. Reverse remodeling and the effects on systolic
function are unique to ß-blockade among types of heart failure
therapy. Although inhibitors of the
renin-angiotensin system can attenuate the remodeling
process, they do not typically reverse it and do not produce
improvements in intrinsic systolic function.1 Because these changes in myocardial function and structural geometry amount to a partial reversal of the dilated cardiomyopathy/systolic dysfunction phenotype, they would be expected to produce favorable effects on the natural history of heart failure, which appears to be the case. For example, the third-generation agent carvedilol improves systolic function in a dose-related manner when administered to chronic heart failure subjects over a 6.5-month period, and these effects are associated with an almost mirror image dose-related reduction in mortality.77 Additionally, in studies with the second-generation compound bisoprolol, subjects who demonstrated an improvement in systolic function had a mortality benefit compared with placebo and compared with the small number of subjects whose left ventricular function deteriorated on bisoprolol.62
|
Effects of Long-Term Treatment on Clinical End Points |
|---|
This discussion of the effects of ß-blocking agents on clinical end points will be confined to placebo-controlled trials that enrolled
100 patients with a minimum follow-up of 3 months. The only compound
in clinical development that is not discussed is nebivolol, which has
not yet begun phase 3 trials. All the discussed trials were conducted
since 1985, with background therapy of diuretics, digoxin, and
ACE inhibitors.
Metoprolol
The first placebo-controlled multicenter trial with a ß-blocking
agent was the Metoprolol in Dilated Cardiomyopathy
(MDC) trial,78 planned in 1982 to 1983 and conducted in
European and US centers between 1985 and 1991 (Table 3). This trial compared metoprolol
tartrate to placebo in subjects with symptomatic heart
failure from idiopathic dilated cardiomyopathy. The
trial was powered on an expected 50% reduction by metoprolol in the
combined end point of all-cause mortality and deterioration of the
patient to the point of requiring listing for heart transplantation.
MDC also had numerous prespecified secondary end points, which included
mortality alone, hospitalizations, left ventricular
function, quality of life, and exercise tolerance.78 In
the MDC trial, metoprolol at an average dose of 108 mg/d reduced the
prevalence of the primary end point by 34%, which was not quite
statistically significant (P=0.058).78 The
benefit was entirely due to a reduction by metoprolol in the morbidity
end point (a reduction by metoprolol of 90%), inasmuch as all-cause
mortality actually trended greater in the metoprolol-treated
group.78 In addition, metoprolol compared with placebo
improved left ventricular function, quality of life,
hospitalizations, and exercise tolerance at 12
months.78
|
The results of the MDC trial were viewed as nondefinitive but quite
promising, and they led to a more traditional placebo-controlled
mortality trial (Metoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure [MERIT-HF], Table 3), which began
enrolling subjects in early 1997 and was stopped prematurely for a 34%
reduction in mortality in the metoprolol arm.38 The
MERIT-HF trial enrolled 3991 subjects with ischemic and
nonischemic dilated cardiomyopathies who
had class II through IV heart failure38 ; the metoprolol
preparation used was a continuous release (CR), single-daily-dose
formulation of coated metoprolol succinate pellets.79
Importantly, the average dose of metoprolol achieved in MERIT-HF was
larger than in MDC, 159 versus 108 mg. Most subjects (97%) enrolled in
MERIT-HF were categorized as class II or III heart failure, and on the
basis of the annualized mortality of 11% in the placebo group and the
baseline left ventricular ejection fraction of 28%, this
landmark clinical trial enrolled subjects with mild to moderate heart
failure and moderate to severe systolic dysfunction.
Importantly, in the MERIT-HF trial, mortality resulting from sudden
death or progressive pump failure was reduced.38
Additionally, mortality was reduced across most demographic groups,
including older versus younger subjects, nonischemic versus
ischemic causes, and lower versus higher ejection
fractions.38 However, there was almost no mortality
reduction in the relatively small number of female subjects enrolled
(23% of the total),38 suggesting that sex may influence
the response to ß-blockade in heart failure populations.
The CR preparation used in the MERIT-HF study produces a relatively
constant blood level of metoprolol for 24 hours.79 The
bioavailability of the CR preparation is 70% of the conventional
formulation.77 However, compared with 50 mg BID of the
conventional formulation, 100 mg of the CR preparation produces similar
trough levels and degrees of reduction in exercise heart rate,
indicating bioequivalence of the 2 preparations.79 The
reduced fluctuation in blood levels for the CR compared with the
conventional formulation provides the potential for improved
tolerability of the CR formulation in heart failure patients, but no
direct comparison studies have been performed. In addition, the much
more shallow slope of the CR plasma concentration curve at the end of
the dosing interval would theoretically reduce the potential of
producing a ß-blocker withdrawal effect80 if doses are
missed or dosing intervals are prolonged. Although these differences in
pharmacokinetics could account for a greater efficacy of the CR
preparation in reducing mortality, in the absence of direct comparison
data demonstrating the superiority of the CR formulation, it is
reasonable to assume that twice-daily dosing of the conventional,
tartrate metoprolol preparation is clinically equivalent to the same
daily dose of the CR formulation.
Bucindolol
The third-generation nonselective compound bucindolol was the
first ß-blocking agent shown to improve left ventricular
function in a placebo-controlled trial.51 In that trial,
this nonselective vasodilating compound was well
tolerated,51 in marked contrast to
previous2 3 and subsequent69 experiences with
the nonselective first-generation agent propranolol. The
second multicenter trial performed with a ß-blocking agent was the
bucindolol multicenter trial,81 which was a phase 2
dose-response trial designed to select a dose of bucindolol to be used
in phase 3 trials (Table 3). This trial had primary end points
of left ventricular function and exercise tolerance, with
secondary end points of quality of life and mortality.81
In this multicenter trial conducted in symptomatic
ischemic and nonischemic
cardiomyopathy patients over a 12-week period,
bucindolol produced a dose-related improvement in left
ventricular function and a strong trend toward a reduction
in end-systolic and end-diastolic volumes, along
with a dose-unrelated prevention of deterioration in left
ventricular function.81 Bucindolol did not
affect quality of life or exercise tolerance, although there was a
trend for improved submaximal exercise.81 From the results
of this trial, the high dose (200 mg/d) of bucindolol was selected for
the target dose in subjects weighing >75 kg in the phase 3 bucindolol
trials. The largest of these phase 3 trials, the ß-Blocker Evaluation
of Survival Trial (BEST),82 was recently completed, with
2708 subjects with advanced (class III and IV) heart failure randomized
to placebo or bucindolol (Table 4). In
BEST, bucindolol produced a nonsignificant (P=0.10) 10%
reduction in total mortality, with favorable effects on most secondary
end points (E. Eichhorn, personal communication, 1999). The effect on
mortality in BEST was less than that observed in
MERIT-HF39 or CIBIS-II.37 This suggests that
patients with more advanced heart failure respond less well to
ß-blockade than do subjects with mild-to-moderate heart failure, or
that bucinodolol is less efficacious than metoprolol or bisoprolol.
|
Bisoprolol
The third multicenter trial planned and performed was the Cardiac
Insufficiency Bisoprolol Study (CIBIS-1; Table 3), which was a
placebo-controlled trial of the effects of bisoprolol on mortality in
symptomatic ischemic or nonischemic
cardiomyopathy subjects treated for an average
follow-up of 22.8 months.83 This trial, powered on an
unrealistically high expected event rate in the control group, ended up
with a statistically insignificant 20% mortality
reduction.83 In addition, the benefit in this trial was
confined to subjects with nonischemic
cardiomyopathy who, compared with those receiving
placebo, had a 47% reduction (P=0.01) in
mortality.83 Despite the lack of overall statistical
significance in the CIBIS-I trial, the reduction in mortality was
similar to that accomplished with ACE inhibitors and was
viewed as encouraging. This prompted a follow-up trial,
CIBIS-II,37 with more conservative effect size estimates
and sample size calculations.
The CIBIS-II trial was stopped by the Data and Safety Monitoring
Committee 18 months early because of a 32% reduction
(P<0.001) in all-cause mortality (Table 4) in the
bisoprolol-treated group.37 CIBIS-II enrolled 2647
patients with class III or IV heart failure from ischemic and
nonischemic cardiomyopathies, with a median
follow-up of 1.3 years.37 In addition to the reduction in
mortality, bisoprolol also reduced hospitalizations (by 20%) and
cardiovascular deaths (by 29%). In
CIBIS-II,37 deaths classified as sudden were statistically
reduced (by 44%) in the bisoprolol group, whereas pump failure deaths
were nonsignificantly reduced by 26%. This trend in a greater
reduction in sudden versus pump failure deaths was opposite to that
obtained in CIBIS-I,83 in which bisoprolol reduced pump
failure deaths by 48% and sudden ventricular
tachycardia/fibrillation deaths by 21%. Another difference
between CIBIS-I and CIBIS-II was the effect on ischemic versus
nonischemic cardiomyopathy, which also
demonstrated opposite trends. In CIBIS-I,83 the reduction
in mortality in the nonischemic group was by 47%
(P=0.01), whereas in patients with a history of myocardial
infarction, there was a trend to an increase in mortality (by 11%) in
the bisoprolol group. One possible explanation for the differences
between CIBIS-I and CIBIS-II is the average target doses of bisoprolol
used: 10 mg/d in CIBIS-II37 and 5 mg/d in
CIBIS-I.83
Although CIBIS-II enrolled subjects with class III (>90% of the
total) or IV symptoms, the annualized placebo mortality was only
13.2%.37 This mortality rate is similar to the enalapril
arm of the Studies of Left Ventricular Dysfunction (SOLVD)
treatment trial,84 which comprised 68% class I and II
patients. Additionally, the average blood pressure of subjects enrolled
in CIBIS-II was 130/80 mm Hg, which is higher than the blood
pressures of the SOLVD patients84 or the subjects enrolled
in the US carvedilol trials, in which 50% were class II or
III.85 A relatively large proportion of CIBIS-II subjects
were enrolled in eastern Europe and Russia, where practice patterns,
heart failure origin, or symptom interpretation may not be comparable
to western Europe and the United States. Nevertheless, the results of
CIBIS-II were internally consistent through all major
demographic groups,37 and the impressive results
constitute a landmark clinical trial in the development of ß-blockade
as a treatment for chronic heart failure.
Carvedilol
Carvedilol is currently the only ß-blocker approved for
treatment of chronic heart failure in the United States and most other
countries. There have been 1748 subjects enrolled in 8 randomized,
placebo-controlled phase 2 and 3 clinical trials with
carvedilol.77 85 86 87 88 89 90 91 92 93 In the United States, there were 2
medium-sized phase 3 trials designed to achieve Food and Drug
Administration (FDA) approval for a heart failure indication, the
Multicenter Oral Carvedilol in Heart Failure Assessment
(MOCHA)77 and Prospective Randomized Evaluation of
Carvedilol in Symptoms and Exercise (PRECISE)88 trials
(Table 3). Because of the nature of the submaximal exercise
primary end point, these trials were relatively short, consisting of 6
months of maintenance after an initial 2 to 4 weeks of
uptitration.77 88 Two additional supportive trials were
also conducted as part of the US carvedilol trials program, enrolling
subjects who were "outliers" on baseline submaximal exercise
testing.89 90 The Mild Heart Failure carvedilol study
(Table 3)89 enrolled subjects who exercised >450 m
on the 6-minute walk test, and the Severe Heart Failure carvedilol
trial (Table 3)90 enrolled subjects who exercised
<150 m on the 6-minute walk test, which was used to allocate subjects
to each of the 4 US trials.77 88 89 90 These trials all had
secondary clinical end points consisting of
cardiovascular hospitalizations during the
maintenance phase, symptom and quality of life assessments, and
left ventricular function measured by radionuclide
ventriculography.
The US carvedilol trials were stopped prematurely by the data and safety committee monitoring all 4 trials because of a highly significant (P<0.0001) reduction in mortality by carvedilol, 65% compared with placebo.85 The MOCHA77 and PRECISE88 trials were completed by the time the monitoring committee stopped the entire program, but the mild89 and severe90 trials were stopped prematurely. Neither MOCHA77 nor PRECISE88 demonstrated an improvement in their submaximal exercise primary end points by carvedilol, but MOCHA did demonstrate a highly significant, dose-related reduction in mortality by 73%.77 Both MOCHA77 and PRECISE88 demonstrated a reduction in cardiovascular hospitalizations by carvedilol, and assessments of heart failure symptoms were improved in PRECISE.88 Despite not reaching completion, the mild trial demonstrated a significant improvement in the primary, "combined" end point of total mortality or cardiovascular hospitalizations or increasing heart failure medication.89 In the severe trial, there was no significant effect of carvedilol compared with placebo on the primary end point of the trial (quality of life), but global heart failure assessments improved in the carvedilol-treated patients.90 In all trials conducted in the United States and elsewhere,77 85 86 87 88 89 90 91 92 93 carvedilol improved left ventricular function. In MOCHA,77 the improvement was highly dose related, suggesting that the improvement in survival was related to improved ventricular function. Although carvedilol was generally well tolerated in the randomized subjects in these trials, 8.6% of enrolled subjects could not tolerate carvedilol on initial challenge, and these subjects were not randomized.85
The Australia-New Zealand trial had 2 phases, an initial 6-month
submaximal exercise trial that showed no benefit by carvedilol (ANZ
carvedilol I in Table 3)91 and a longer phase (ANZ
carvedilol II in Table 3) that showed a reduction in the
combined end point of mortality or cardiovascular
hospitalizations.92 Additionally, when the US trials were
analyzed retrospectively for this combined end point, all but
the severe trial showed a reduction compared with
placebo.94
The interpretation of the carvedilol US trials database generated much
comment and discussion,95 96 97 including spirited debate at
2 FDA Cardiorenal Advisory Committee meetings. The main points of
contention were the interpretation of the mortality data and the
failure of 3 of the 4 US trials to meet their primary end points.
Despite the high degree of statistical significance, the mortality data
are not considered conclusive because of the short-term follow-up and
the small total number of deaths,77 85 as well as the fact
that all-cause mortality was not a prespecified primary or secondary
efficacy end point in these trials. Ultimately, carvedilol was approved
in early 1997 by the FDA for the indications of delaying the
progression of the myocardial disease process and lowering the combined
risk of morbidity plus mortality.98 The FDA decision was
based on the facts that the mild heart failure trial89 met
its primary end point of delaying the process of heart failure and that
carvedilol reduced the secondary combined end point of mortality plus
cardiovascular hospitalizations across all 4 US
trials77 88 89 90 and the 1 conducted in Australia and New
Zealand.92 Because the mortality effect of carvedilol and
its efficacy in advanced heart failure have not been established, a
mortality trial with carvedilol in advanced, class III to IV heart
failure, Carvedilol Prospective Randomized Cumulative Survival Trial
(COPERNICUS), is now being conducted (Table 4).
|
General Interpretation of Clinical Results With ß-Blocking Agents |
|---|
The collective interpretation of the placebo-controlled ß-blocker data generalized in subjects with mild-to-moderate heart failure is that the consistently demonstrated favorable effects on ventricular function and remodeling are, as expected,1 57 translated into clinical benefits. The clinical benefits include a decrease in mortality, a reduction in morbidity as assessed by hospitalization rate, and in some but not all trials, improved heart failure symptoms. Moreover, these favorable effects on the natural history of heart failure seem to be exerted across most demographic or descriptive groups, including ischemic versus nonischemic cause of dilated cardiomyopathy,37 38 77 78 85 86 87 88 89 90 91 92 93 99 100 101 older versus younger subjects,37 38 101 diabetic versus nondiabetic subjects,38 102 and lower versus higher initial ejection fractions.38 85 However, more data are needed to assess the effects of ß-blockade in certain demographic groups, particularly women, subjects >75 years of age, and racial subsets. The latter issue may be particularly important. The BEST Trial in patients with advanced heart failure demonstrated a worse outcome in blacks versus nonblacks treated with ß-blockade (E. Eichhorn, personal communication, 1999); however, in the carvedilol trials in the United States, black subjects with mild-to-moderate heart failure responded to carvedilol as well as did nonblack subjects.103
In addition to the favorable effects on myocardial function and structure, the general mechanisms through which ß-blocking agents reduce mortality likely involve their established antiarrhythmic and anti-ischemic properties. In contrast to ACE inhibitors, ß-blocking agents have consistently lowered the sudden death rate in heart failure trials,36 37 75 83 which suggests an antiarrhythmic contribution to mortality reduction. Because of the well-established "secondary prevention" database in ischemic heart disease, it is likely that anti-ischemic properties of ß-blocking agents contribute to mortality reduction in subjects with heart failure from ischemic cardiomyopathy.
On the basis of the comparative effects on left ventricular
function and remodeling1 and the additional
mortality-lowering mechanisms possessed by ß-blocking agents, it is
not surprising that in established mild-to-moderate heart failure,
ß-blocking agents have generally had a quantitatively greater effect
than ACE inhibitors on mortality reduction (Table 5). Table 5 lists all ACE inhibitor
trials conducted in established LV dysfunction (excluding
post-myocardial infarction trials) and symptomatic heart failure, and
ß-blocker trials conducted in mild-to-moderate heart failure. This
comparison yields an identical annualized placebo mortality of 11%
(Table 5). As shown in Table 5, the average reduction in
mortality achieved by 12 months of treatment with an ACE
inhibitor is 16%. Because ß-blocker trials have been
conducted on a background of ACE inhibition, the average reduction in
mortality of 36% shown with ß-blockade is additive with the ACE
inhibitor data. By sequentially combining the average
relative risks, the reduction in mortality by the combination of
treatments is 46% (Table 5), which is obviously major progress
in the treatment of chronic heart failure.
|
|
Pharmacokinetic Issues |
|---|
The strategy for administering all ß-blocking agents in the setting of chronic heart failure is to start at extremely low doses70 and increase the dose gradually, usually at weekly or biweekly intervals. With this strategy, target doses that can substantially (by
20 bpm) decrease exercise heart rate can be
achieved in most patients within 4 to 6 weeks of drug initiation. The
pharmacological half-lives of metoprolol tartrate, carvedilol, and
bucindolol dictate twice-daily dosing, whereas bisoprolol and
metoprolol succinate CR can be given once daily. Carvedilol,
metoprolol, bucindolol, and nebivolol are all highly lipophilic
compounds that are extensively metabolized and cleared by the liver;
bisoprolol is less lipophilic and exhibits mixed hepatic/renal
clearance.106 First-pass hepatic metabolism
occurs with all these agents, so the bioavailability is relatively low,
ranging from 20% to 50%. However, when liver congestion and decreased
liver function are present, such as in advanced heart failure, the
bioavailability increases, and doses of lipophilic ß-blockers produce
relatively greater degrees of ß-blockade. Thus, the doses of
lipophilic ß-blockers may have to be reduced in the presence of liver
dysfunction, whereas the doses of bisoprolol may have to be reduced in
the presence of either liver or renal dysfunction. Pharmacokinetic
interaction with other heart failure medications, including warfarin,
does not typically occur with ß-blocking agents that are used in
heart failure. Carvedilol increases the oral bioavailability of
digoxin, but the increase in digoxin plasma level is small (10% to
15%).107
Lipophilic ß-blocking agents are hepatically metabolized by
cytochrome P450 2D6 (CYP2D6) oxidation. In subjects with
polymorphic variants of CYP2D6 responsible for the debrisoquin
"poor metabolizer" phenotype (present in 2% to 10% of
US populations), the elimination half-life may be prolonged, and plasma
levels and the degree of ß-blockade may be increased.108
In addition, stereoselective metabolism by CYP2D6 occurs
for some but not all lipophilic ß-blockers. Carvedilol undergoes
stereoselective metabolism of the S isomer as described
earlier, which after oral administration leads to plasma concentrations
of the R isomer that are 2- to 3-fold higher than the S
isomer.45 73 106 In the poor metabolizer
phenotype, the clearance of R carvedilol is further reduced
relative to the S isomer.109 This would lead to a
relatively greater degree of - versus ß-blockade in these
individuals compared with subjects who are extensive metabolizers of
debrisoquin. However, it is unclear whether this is of any clinical
significance. Metoprolol also undergoes stereoselective
metabolism by CYP2D6 but in favor of the R
isomer.110 Stereoselective metabolism of
metoprolol results in only a small difference in S/R plasma levels
(1.35-fold higher S/R ratios in extensive debrisoquin metabolizers,
reduced to an S/R ratio of <1 in poor metabolizers).110
However, in poor metabolizers taking metoprolol, the lower S/R ratio
leads to less ß-blockade relative to plasma levels,111
which tends to cancel the effect of the increased plasma levels of both
isomers that is related to the lower oxidation rate. Clinically
important stereoselective metabolism does not occur for
bisoprolol,112 nebivolol,113 or bucindolol
(D. Ward, personal communication, 1999).
|
Who Should Be Treated With a ß-Blocking Agent? |
|---|
Subjects with mild to moderate compensated heart failure from nonischemic or ischemic dilated cardiomyopathies with NYHA class II to III symptoms on standard treatment, including diuretics and ACE inhibitors, who do not have a contraindication to ß-blockade are candidates for treatment with a ß-blocking agent. Subjects who are treated with ß-blocking agents should not have decompensated heart failure because the myocardial depression that accompanies initiation of therapy can be life-threatening in such individuals. At present, the only FDA-approved agent is carvedilol, but metoprolol and bisoprolol are approved for other cardiovascular indications. For now, subjects with advanced class III or IV heart failure should not be routinely treated with ß-blocking agents, but data regarding this patient population will soon be available from the BEST and COPERNICUS trials.
Once heart failure subjects reach a maintenance dose of a ß-blocker, treatment should be maintained indefinitely because of the risk of deterioration on withdrawal.114 If it is necessary to treat a decompensated patient on maintenance ß-blockade with a positive inotropic agent, a phosphodiesterase inhibitor rather than a ß-agonist should be used because the hemodynamic effects of these inhibitors are not antagonized by ß-blockade.115 116
|
Limitations of ß-Blocker Therapy in Chronic Heart Failure |
|---|
Despite their proven efficacy in mild to moderate heart failure in patients with primary or secondary dilated cardiomyopathies, it is important to emphasize that ß-blockers have limitations in their general application in heart failure populations. First and foremost is that many heart failure patients have contraindications to ß-blockade, such as reactive airways disease, sinus node or conduction system disease with bradycardia, and advanced heart failure with hemodynamic decompensation. Another problem is that even in mild to moderate heart failure, initiation of therapy and uptitration of ß-blocking agents can be difficult, requiring both persistence and knowledge of management maneuvers70 that allow target doses to be achieved. A third problem is that for reasons that are not yet clear, some individuals do not respond to ß-blockade in terms of favorable effects on myocardial function, and these individuals may have a worse outcome than patients treated with placebo.62 Some but not all of these problems might be overcome by the development of heart failure–designed "fourth-generation" ß-blockers,57 other effective types of antiadrenergic therapy, or ß-blockers combined with positive inotropic agents.117 The importance of the ß-blocker data set is not that it demonstrates a "cure" for chronic heart failure but rather that it has shown that in some patients, prognosis can be substantially improved by medical therapy. This observation should provide the impetus to develop further types of treatment that improve the biological properties of the failing heart.
In summary, antiadrenergic therapy of chronic heart failure with ß-blocking agents has evolved over a 25-year period from a contraindication to an established treatment for mild to moderate heart failure caused by primary or secondary dilated cardiomyopathies. Whether or not this therapy has value in other heart failure settings will be determined in ongoing and future studies.
|
Acknowledgments |
|---|
I wish to thank Frank Stewart and Laurel Hunter for assistance in manuscript preparation and Doug Robertson for biostatistical support.
|
References |
|---|
1. Eichhorn EJ, Bristow MR. Medical therapy can improve the biologic properties of the chronically failing heart: a new era in the treatment of heart failure. Circulation. 1996;94:2285–2296.
2. Stephen SA. Unwanted effects of propranolol. Am J Cardiol. 1966;18:463–472.[Medline] [Order article via Infotrieve]
3. Epstein SE, Braunwald E. The effect of beta adrenergic blockade on patterns of urinary sodium excretion: studies in normal subjects and in patients with heart disease. Ann Intern Med. 1968;65:20–27.
4. Swedberg K, Viquerat C, Rouleau JL, Roizen M, Atherton B, Parmley WW, Chaterjee K. Comparison of myocardial catecholamine balance in chronic congestive heart failure and in angina pectoris without heart failure. Am J Cardiol. 1984;54:783–786.[Medline] [Order article via Infotrieve]
5.
Hasking GJ, Esler MD, Jennings GL, Burton D, Korner
PI. Norepinephrine spillover to plasma in patients with
chronic congestive heart failure: evidence of increased overall and
cardiorenal sympathetic nervous activity. Circulation. 1986;73:615–621.
6.
Haber HL, Christopher LS, Gimple LW, Bergin JD,
Subbiah ME, Jayaweera AR, Powers ER, Feldman MD. Why do patients with
congestive heart failure tolerate the initiation of ß-blocker
therapy? Circulation. 1993;88:1610–1619.
7. Goldsmith SR, Francis GS, Cohn JN. Norepinephrine infusions in congestive heart failure. Am J Cardiol. 1985;56:802–804.[Medline] [Order article via Infotrieve]
8. Bristow MR, Minobe W, Rasmussen R, Larrabee P, Skerl L, Klein JW, Anderson FL, Murray J, Mestroni L, Karwande SV, Fowler M, Ginsburg R. ß-Adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. J Clin Invest. 1992;89:803–815.
9. Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler D. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol. 1995;26:1257–1263.[Abstract]
10.
Bristow MR, Ginsburg R, Fowler M, Minobe W, Rasmussen
R, Zera P, Menlove R, Shah P, Stinson E.
ß1- and ß2-adrenergic
receptor subpopulations in normal and failing human
ventricular myocardium: coupling of both
receptor subtypes to muscle contraction and selective
ß1-receptor downregulation in heart failure.
Circ Res. 1986;59:297–309.
11. Brodde OE, Schuler S, Kretsch R, Brinkmann M, Borst HG, Hetzer R, Reidemeister JC, Warnecke H, Zerkowski HR. Regional distribution of ß-adrenoceptors in the human heart: coexistence of functional ß1- and ß2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol. 1986;8:1235–1242.[Medline] [Order article via Infotrieve]
12. Bristow MR. Changes in myocardial and vascular receptors in heart failure. J Am Coll Cardiol. 1993;22(suppl A):61A–71A.
13.
Newton GE, Parker JD. Acute effects of
ß1-selective and nonselective ß-adrenergic
receptor blockade on cardiac sympathetic activity in congestive heart
failure. Circulation. 1996;94:353–358.
14. Gauthier C, Tavernier G, Charpentier F, Langin D, LeMarec H. Functional ß3-adrenoceptor in the human heart. J Clin Invest. 1996;98:556–562.[Medline] [Order article via Infotrieve]
15. Kaumann AJ, Molenaar P. Modulation of human cardiac function through 4 beta-adrenergic populations. Naunyn Schmiedebergs Arch Pharmacol. 1997;355:667–681.[Medline] [Order article via Infotrieve]
16.
Mann DL, Kent RL, Parsons B, Cooper G IV. Adrenergic
effects on the biology of the adult mammalian cardiocyte.
Circulation. 1992;85:790–804.
17. Port JD, Weinberger HD, Bisognano JD, Knudson OA, Bohlmeyer TJ, Pende A, Bristow MR. Echocardiographic and histopathological characterization of young and old transgenic mice over-expressing the human ßb1-adrenergic receptor. J Am Coll Cardiol. 1998;31(suppl A):177A. Abstract.
18.
Engelhardt S, Hein L, Wiesman F, Lohse MJ.
Progressive hypertrophy and heart failure in
ß1-adrenergic receptor transgenic mice. Proc Natl
Acad Sci U S A. 1999;96:7059–7064.
19.
Iwase M, Bishop SP, Uechi M, Vatner DE, Shannon RP,
Kudej RK, Wight DC, Wagner TE, Ishikawa Y, Homcy CJ, Vatner SJ. Adverse
effects of chronic endogenous sympathetic drive induced by
cardiac Gsa overexpression. Circ
Res. 1996;78:517–524.
20.
D’Angelo DD, Sakatra Y, Lorenz JN, Boivin GP, Walsh
RA, Liggett SB, Dorin GW II. Transgenic Gq
overexpression induces cardiac contractile failure in mice. Proc
Natl Acad Sci U S A. 1997;94:8121–8126.
21.
Geng YJ, Ishikawa Y, Vatner DE, Wagner TE, Bishop SP,
Vatner SF, Homcy CJ. Overexpression of Gs accelerates
programmed death (apoptosis) of myocardiocytes in
transgenic mice. Circulation. 1996;94(suppl I):I-1640.
Abstract.
22.
Communal C, Singh K, Pimental DR, Colucci WS.
Norepinephrine stimulates apoptosis in adult rat
ventricular myocytes by activation of the
ß-adrenergic receptor. Circulation. 1998;98:1329–1334.
23.
Communal C, Singh K, Sawyer DB, Colucci WS. Opposing
effects of ß1- and ß2-adrenergic receptors
on cardiac myocyte apoptosis: role of a pertussis-toxin sensitive G
protein. Circulation.. 1999;100:2210–2212.
24. Liggett SB, Tepe NM, Lorenz JN, Canning AM, Jantz TD, Yatani A, Dorn GW III. Early and delayed consequences of ß2-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation. In press.
25.
Milano CA, Dolber PC, Rockman HA, Bond RA, Venable
ME, Allen LF, Lefkowitz RJ. Myocardial expression of a constitutively
active 1B-adrenergic receptor in
transgenic mice induces cardiac hypertrophy. Proc
Natl Acad Sci U S A. 1994;91:10109–10113.
26.
Ungerer M, Parruti G, Bohm M, Puzicha M, DeBlasi A,
Erdmann E, Lohse MJ. Expression of ß-arrestins and
ß-adrenergic receptor kinases in the failing human heart. Circ
Res. 1994;74:206–213.
27. Tan LB, Benjamin IJ, Clark WA. ß-adrenergic receptor desensitization may serve a cardioprotective role. Cardiovasc Res. 1992;26:608–614.[Medline] [Order article via Infotrieve]
28. Bristow MR. The adrenergic nervous system in heart failure. N Engl J Med. 1984;311:850–851.[Medline] [Order article via Infotrieve]
29. Bristow MR, Kantrowitz NE, Ginsburg R, Fowler MB. ß-Adrenergic function in heart muscle disease and heart failure. J Mol Cell Cardiol. 1985;17(suppl 2):41–52.
30. Fowler MB, Bristow MR. Rationale for beta-adrenergic blocking drugs in cardiomyopathy. Am J Cardiol. 1985;55:D120–D124.
31. Dunlop D, Shanks RG. Selective blockade of adrenoceptive beta receptors in the heart. Br J Pharmacol Chemother. 1968;32:201–218.[Medline] [Order article via Infotrieve]
32.
Bristow MR, Sherrod TR, Green RD. Analysis of
beta receptor drug interactions in isolated rabbit atrium, aorta,
stomach and trachea. J Pharmacol Exp Ther. 1970;171:52–61.
33.
Kobilka BK, Dixon RAF, Frielle T, Dohlman HG,
Bolanowski MA, Sigal IS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz
RJ. cDNA for the human beta 2-adrenergic receptor: a protein with
multiple membrane-spanning domains and encoded by a gene whose
chromosomal location is shared with that of the receptor for
platelet-derived growth factor. Proc Natl Acad Sci
U S A. 1987;84:46–50.
34.
Frielle T, Collins S, Daniel KW, Caron MG, Lefkowitz
RJ, Kobilka BK. Cloning of the cDNA for the human
ß1-adrenergic receptor. Proc Natl Acad
Sci U S A. 1987;84:7920–7924.
35.
Emorine LJ, Marullo S, Briend-Sutren MM, Patey G,
Tate K, Delavier-Klutchko C, Strosberg AD. Molecular characterization
of the human ß3-adrenergic receptor.
Science. 1989;245:1118–1121.
36.
Waagstein F, Hjalmarson Å, Varnauskas E, Wallentin
I. Effect of chronic beta-adrenergic receptor blockade in congestive
cardiomyopathy. Br Heart J. 1975;37:1022–1036.
37. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13.[Medline] [Order article via Infotrieve]
38. 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;353:2001–2006.[Medline] [Order article via Infotrieve]
39. Richards DA, Prichard BNC. Clinical pharmacology of labetalol. Br J Clin Pharmacol. 1979;8:89S–93S.
40. Johnson LL, Cubbon J, Escala E, Sciacca R, Ramanathan KB, Berger H, Jones RH. Hemodynamic effects of labetalol in patients with combined hypertension and left ventricular failure. J Cardiovasc Pharmacol. 1988;12:350–356.[Medline] [Order article via Infotrieve]
41. Wisenbaugh T, Katz I, Davis J, Essop R, Skoularigis J, Middlemost S, Rothlisberger C, Skudicky D, Sareli P. Long-term (3 month) effects of a new beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy. J Am Coll Cardiol. 1993;21:1094–1100.
42. Uhlir O, Dvorak I, Gregor P, Malek I, Spinarova L, Vojacek J, Van Nueten L. Nebivolol in the treatment of cardiac failure: a double-blind controlled clinical trial. J Card Fail. 1997;3:271–276.[Medline] [Order article via Infotrieve]
43. Van de Water A, Janssens W, Van Neuten J, Xhonneux R, De Cree J, Verhaegen H, Reneman RS, Janssen PAJ. Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective ß1-adrenergic antagonist. J Cardiovasc Pharmacol. 1988;11:552–563.[Medline] [Order article via Infotrieve]
44.
Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CPL-H,
Dupont AG, Van Nueten L, Wooding SJ, Ritter JM. Nebivolol vasodilates
human forearm vasculature: evidence for an
L-arginine/NO-dependent mechanism. J Pharmacol
Exp Ther. 1995;274:1067–1071.
45.
Bristow MR, Abraham WT, Gilbert EM, Yoshikawa T, Port
JD. Relationships between carvedilol stereoisomer plasma concentrations
and ß-receptor occupancies in subjects with chronic heart
failure in the Multicenter Oral Carvedilol Heart Failure Assessment
(MOCHA) trial. Eur Heart J. 1996;17:135. Abstract.
46. Yoshikawa T, Port JD, Asano K, Chidiak P, Bouvier M, Dutcher D, Roden RL, Minobe W, Trammel KD, Bristow MR. Cardiac adrenergic receptor effects of carvedilol. Eur Heart J. 1996;17(suppl B):B8–B16.
47. Bristow MR, Abraham WT, Yoshikawa T, White M, Hattler B, Crisman T, Lowes B, Larrabee P, Gilbert EM. Second and third beta blocking agents in the treatment of chronic heart failure. Cardiovasc Drugs Ther. 1997;11:291–296.
48. Hershberger RE, Wynn JR, Sundberg L, Bristow MR. Mechanism of action of bucindolol in human ventricular myocardium. J Cardiovasc Pharmacol. 1990;15:959–967.[Medline] [Order article via Infotrieve]
49. Deitchman D, Perhach JL, Snyder RW. ß-Adrenoceptor and cardiovascular effects of MJ 13105 (bucindolol) in anesthetized dogs and rats. Eur J Pharmacol. 1980;61:263–277.[Medline] [Order article via Infotrieve]
50.
Rimele TJ, Aarhus LL, Lorenz RR, Rooke TW, Van Houtte
PM. Pharmacology of bucindolol in isolated canine vascular smooth
muscle. J Pharmacol Exp Ther. 1984;231:317–325.
51. Gilbert EM, Anderson JL, Deitchman D, Yanowitz FG, O’Connell JB, Renlund DG, Bartholomew M, Mealey PC, Larrabee P, Bristow MR. Chronic ß-blocker-vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med. 1990;88:223–229.[Medline] [Order article via Infotrieve]
52. Bristow MR, Larrabee P, Minobe W, Roden R, Skerl L, Klein J, Handwerger D, Port JD, Müller-Beckman B. Receptor pharmacology of carvedilol in the human heart. J Cardiovasc Pharmacol. 1992;19(suppl 1):S68–S80.
53. Bristow MR, Roden RL, Lowes BD, Gilbert EM, Eichhorn EJ. The role of third generation ßb-blocking agents in chronic heart failure. Clin Cardiol. 1998;21:I-3–I-13.
54. Sederberg J, Wichman SE, Lindenfeld J, Lowes B, Shakar S, Roden R, Bristow MR. Bucindolol has no intrinsic sympathomimetic activity in nonfailing human ventricular preparations. J Am Coll Cardiol. In press.
55. Lowes BD, Chidiac P, Olsen S, Port JD, Bouvier M, Gilbert EM, Bristow MR. Clinical relevance of inverse agonism and guanine nucleotide modulatable binding properties of ß-adrenergic receptor blocking agents. Circulation. 1994;90(suppl I):I-543. Abstract.
56.
Gilbert EM, Abraham WT, Olsen S, Hattler B, White M,
Mealy P, Larrabee P, Bristow MR. Comparative
hemodynamic, left ventricular functional,
and antiadrenergic effects of chronic treatment
with metoprolol versus carvedilol in the failing heart.
Circulation. 1996;94:2817–2825.
57. Bristow MR. Mechanism of action of beta-blocking agents in heart failure. Am J Cardiol. 1997;80:26L–40L.[Medline] [Order article via Infotrieve]
58. Metra M, Nodari S, Garbellini M, Boldi E, Rosselli F, Zanini R, Dei Cas L. Comparative effects of metoprolol and carvedilol on resting and peak exercise hemodynamics and functional capacity in patients with chronic heart failure. Circulation. 1997;96(suppl I):I-578. Abstract.
59.
Kukin ML, Charney RH, Levy DK, Buchholz-Varley C,
Ocampo ON, Eng C. Prospective, randomized comparison of effect of
long-term treatment with metoprolol or carvedilol on symptoms,
exercise, ejection fraction, and oxidative stress in heart failure.
Circulation. 1999;99:2645–2651.
60.
Eichhorn EJ, Bedotto JB, Malloy CR, Hatfield B,
Deitchman D, Brown M, Willard JE, Grayburn PA. Effect of
beta-adrenergic blockade on myocardial function and energetics in
congestive heart failure: improvements in hemodynamic,
contractile, and diastolic performance with
bucindolol. Circulation. 1990;82:473–483.
61. Eichhorn EJ, Heesch CM, Barnett JH, Alvarez LG, Fass SM, Grayburn PA, Hatfield BA, Marcoux LG, Malloy CR. Effect of metoprolol on myocardial function and energetics in patients with non-ischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 1994;24:1310–1320.
62.
Lechat P, Escolano S, Golmard JL, Lardoux H, Witchitz
S, Henneman JA, Maisch B, Hetzel M, Jaillon P, Boissel J-P, Mallet A.
Prognostic value of bisoprolol-induced hemodynamic
effects in heart failure during the Cardiac Insufficiency Bisoprolol
Study (CIBIS). Circulation. 1997;96:2197–2205.
63. Hall SA, Cigarroa CG, Marcoux L, Risser RC, Grayburn PA, Eichhorn EJ. Time course of improvement in left ventricular function, mass, and geometry in patients with congestive heart failure treated with ß-adrenergic blockade. J Am Coll Cardiol. 1995;25:1154–1161.[Abstract]
64. Quaife RA, Gilbert EM, Christian PE, Datz FL, Mealey PC, Volkman K, Olsen SL, Bristow MR. Effects of carvedilol on systolic and diastolic left ventricular performance in idiopathic dilated cardiomyopathy. Am J Cardiol. 1996;78:779–784.[Medline] [Order article via Infotrieve]
65. Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N, for the Australia-New Zealand Heart Failure Research Collaborative Group. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. J Am Coll Cardiol. 1997;29:1060–1066.[Abstract]
66. Lowes BD, Gill EA, Abraham WT, Larrabee JR, Robertson AD, Bristow MR, Gilbert EM. The effect of carvedilol on left ventricular mass, chamber geometry and mitral regurgitation in chronic heart failure. Am J Cardiol. 1999;83:1201–1205.[Medline] [Order article via Infotrieve]
67. Gaffney TE, Braunwald MD. Importance of the adrenergic nervous system in the support of circulatory function in patients with congestive heart failure. Am J Med. 1963;34:320–324.[Medline] [Order article via Infotrieve]
68. Armstrong PW, Chiong MA, Parker JO. Effects of propranolol on the hemodynamic, coronary sinus blood flow and myocardial metabolic response to atrial pacing. Am J Cardiol. 1977;40:83–89.[Medline] [Order article via Infotrieve]
69. Talwar KK, Bhargava B, Upasani PT, Verma S, Kamlakar T, Chopra P. Hemodynamic predictors of early intolerance and long-term effects of propranolol in dilated cardiomyopathy. J Card Fail. 1996;2:273–277.[Medline] [Order article via Infotrieve]
70. Eichhorn EJ, Bristow MR. Practical guidelines for initiation of beta-adrenergic blockade in patients with chronic heart failure. Am J Cardiol. 1997;79:794–798.[Medline] [Order article via Infotrieve]
71.
Newton GE, Azevedo ER, Parker JD. Inotropic and
sympathetic responses to the intracoronary infusion of a
ß2-receptor agonist: a human in vivo study.
Circulation. 1999;99:2402–2407.
72. Di Lenarda A, Gilbert EM, Olsen SL, Mealey PC, Bristow MR. Acute hemodynamic effects of carvedilol versus metoprolol in idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1991;17:142A. Abstract.
73. Neugebauer G, Akpan W, Kaufmann B, Reiff K. Stereoselective disposition of carvedilol on man after intravenous and oral administration of the racemic compound. Eur J Clin Pharmacol. 1990;38:S108–S111.
74. Ruffolo RR, Gellai M, Hieble JP, Willette RN, Nichols AJ. The pharmacology of carvedilol. Eur J Clin Pharmacol. 1990;38:S82–S88.
75.
Basu S, Senior R, Raval U, van der Does R, Bruckner
T, Lahiri A. Beneficial effects of intravenous and oral
carvedilol treatment in acute myocardial infarction: a
placebo-controlled, randomized trial. Circulation. 1997;96:183–191.
76. Bristow MR, Gilbert EM. Improvement in cardiac myocyte function by biologic effects of medical therapy: a new concept in the treatment of heart failure. Eur Heart J. 1995;16(suppl F):20–31.
77.
Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler
MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young
S, Shusterman N. Carvedilol produces dose-related improvements in left
ventricular function and survival in subjects with chronic
heart failure. Circulation. 1996;94:2807–2816.
78. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Johnson M, Silver MA, Gilbert EM, Hjalmarson Å. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet. 1993;342:1441–1446.[Medline] [Order article via Infotrieve]
79. Sandberg A, Blomqvist I, Jonsson UE, Lundborg P. Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: a comparison with conventional tablets. Eur J Clin Pharmacol. 1988;33(suppl):S9–S14.
80. Reeves RA, Boer WH, DeLeve WH, Leenen FH. Beta-blockade disappearance rate predicts beta-adrenergic hypersensitivity. Clin Pharmacol Ther. 1989;46:279–290.[Medline] [Order article via Infotrieve]
81.
Bristow MR, O’Connell JB, Gilbert EM, French WJ,
Leatherman G, Kantrowitz NE, Orie J, Smucker M, Marshall G, Kelly P,
Deitchman D, Anderson JL, for the Bucindolol Investigators.
Dose-response of chronic ß-blocker treatment in heart failure
from either idiopathic dilated or ischemic
cardiomyopathy. Circulation. 1994;89:1632–1642.
82. The BEST Steering Committee. Design of the Beta-Blocker Evaluation Survival Trial (BEST). Am J Cardiol. 1995;75:1220–1223.[Medline] [Order article via Infotrieve]
83.
CIBIS Investigators and Committees. A randomized
trial of beta-blockade in heart failure: the Cardiac Insufficiency
Bisoprolol Study (CIBIS). Circulation. 1994;90:1765–1773.
84. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.[Abstract]
85.
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB,
Gilbert EM, Shusterman NH. Effect of carvedilol on morbidity and
mortality in patients with chronic heart failure. N Engl
J Med. 1996;334:1349–1355.
86. Olsen SL, Gilbert EM, Renlund DG, Mealey PC, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in heart failure: a double-blind randomized study. J Am Coll Cardiol. 1995;25:1225–1231.
87.
Krum H, Sakner-Bernstein JD, Goldsmith RL, Kukin ML,
Schwartz B, Penn J, Medina N, Yushak M, Horn E, Katz SD, Levin HR,
Neuberg GW, DeLong G, Packer M. Double-blind, placebo-controlled study
of the long-term efficacy of carvedilol in patients with severe chronic
heart failure. Circulation. 1995;92:1499–1506.
88.
Packer M, Colucci WS, Sackner-Bernstein JD, Liang CS,
Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M,
Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH,
Young ST, Lukas MA, Shusterman NH, for the PRECISE Study Group.
Double-blind, placebo-controlled study of the effects of carvedilol in
patients with moderate to severe heart failure: the PRECISE trial.
Circulation. 1996;94:2793–2799.
89.
Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn
JN, Fowler MB, Krueger S, Hershberger RE, Uretsky BF, Bowers JA,
Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA, for the US
Carvedilol Heart Failure Study Group. Carvedilol inhibits clinical
progression in patients with mild symptoms of heart failure.
Circulation. 1996;94:2800–2806.
90. Cohn JN, Fowler MB, Bristow MR, Colucci WS, Gilbert EM, Kinal V, Krueger SK, LeJemtel T, Narahara KA, Packer M, for the Carvedilol Heart Failure Study Group. Effect of carvedilol in severe chronic heart failure. J Am Coll Cardiol. 1996;27:169A. Abstract.
91.
Australia-New Zealand Heart Failure Research
Collaborative Group. Effects of carvedilol, a
vasodilator-ß-blocker, in patients with congestive heart failure
due to ischemic heart disease. Circulation. 1995;92:212–218.
92. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet. 1997;349:375–380.[Medline] [Order article via Infotrieve]
93. Metra M, Nardi M, Giubbini R, Dei Cas L. Effects of short-and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1994;24:1678–1687.
94. Packer M. Effects of ß-blockade on survival of patients with chronic heart failure. Am J Cardiol.. 1997;80:46L–54L.[Medline] [Order article via Infotrieve]
95.
Pfeffer MA, Stevenson LW. ß-adrenergic
blockers and survival in heart failure. N Engl J
Med. 1996;334:1396–1397.
96. Cleland JG, Swedberg K. Carvedilol for heart failure, with care. Lancet. 1996;347:1199–1201.
97.
Chatterjee K. Heart failure therapy in evolution.
Circulation. 1996;94:2689–2693.
98. Coreg finally approved in the US. SCRIP World Pharmaceutical News 2238:17. June 6, 1997.
99. Bristow MR, Colucci WS, Fowler MB, Gilbert EM, Lukas MA, Young ST, Hershberger RE, Adams S, Melman H, Liang C-S. Effect of carvedilol on survival and hospitalization in patients with ischemic or non-ischemic cardiomyopathy. Circulation. 1996;94(suppl I)I-338. Abstract.
100. Fisher ML, Gottlieb SS, Plotnick GD, Greenberg NL, Patten RD, Bennett SK, Hamilton BP. Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol. 1994;23:943–950.
101. Bristow MR, Gilbert EM, Packer M, Colucci WS, Lukas MA, Court M, Fowler MB, Cohn JN. Effects of carvedilol in elderly patients with chronic heart failure. Circulation. 1997;96(suppl I):I-577. Abstract.
102. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger R, Kubo SH, Narahara KA, Robertson AD, Krueger S. Effect of carvedilol on LV function and mortality in diabetic versus non-diabetic patients with ischemic or nonischemic dilated cardiomyopathy. Circulation. 1996;94(suppl I):I-664. Abstract.
103. Yancy C, Fowler MB, Colucci WS, Gilbert EM, Lukas MA. Young ST for the US Carvedilol Heart Failure Study Group: response of black heart failure patients to carvedilol. J Am Coll Cardiol.. 1997;29:284A.
104. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med. 1987;316:1429–1435.[Abstract]
105. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–691.[Abstract]
106. Borchard U. Pharmacokinetics of beta-adrenoceptor blocking agents: clinical significance of hepatic and/or renal clearance. Clin Physiol Biochem. 1990;8(suppl 2):28–34.
107. DeMey C, Brendel E, Enterling D. Carvedilol increases the systemic bioavailability of oral digoxin. Br J Clin Pharmacol. 1990;29:486–490.[Medline] [Order article via Infotrieve]
108. Lennard MS, Tucker GT, Woods HF. The polymorphic oxidation of beta-adrenoceptor antagonists: clinical pharmacokinetic considerations. Clin Pharmacokinet. 1986;11:1–17.[Medline] [Order article via Infotrieve]
109. Zhou HH, Wood AJ. Stereoselective disposition of carvedilol is determined by CYP2D6. Clin Pharmacol Ther. 1995;57:518–524.[Medline] [Order article via Infotrieve]
110. Lennard MS, Tucker GT, Silas JH, Ramsay LE, Woods HF. Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers. Clin Pharmacol Ther. 1983;34:732–737.[Medline] [Order article via Infotrieve]
111. Silas JH, McGoutry JC, Lennard MS, Woods HF. Polymorphic metabolism of metoprolol: clinical studies. Eur J Clin Pharmacol. 1985;28(suppl):85–88.
112. Dutta A, Lanc R, Begg E, Robson R, Sia L, Dukart G, Desjardins R, Yacobi A. Dose proportionality of bisoprolol enantiomers in humans after oral administration of the racemate. J Clin Pharmacol. 1994;34:829–836.[Abstract]
113. Cheymol G, Woestenborghs R, Snoeck E, Ianucci R, LeMoing JP, Naditch L, Levron JC, Poirier JM. Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects. Eur J Pharmacol. 1997;51:493–498.[Medline] [Order article via Infotrieve]
114.
Swedberg K, Hjalmarson Å, Waagstein F, Wallentin I. Adverse
effects of beta-blockade withdrawal in patients with congestive
cardiomyopathy. Br Heart J. 1980;44:134–142.
115. Bohm M, Deutsch HJ, Hartmann D, LaRosee K, Stablein A. Improvement of postreceptor events by metoprolol treatment in patients with chronic heart failure. J Am Coll Cardiol. 1997;30:992–996.[Abstract]
116. Tsvetkova TO, Farber DJ, Abraham WT, Kelly P, Eichhorn E, Gilbert EM, Robertson AD, Lindenfeld J, Wolfel EE, Zisman L, Bristow MR. Comparative hemodynamic effects of milrinone and dobutamine in heart failure patients treated chronically with carvedilol. J Card Fail. 1998;4(suppl 1):36. Abstract.
117.
Shakar SF, Abraham WT, Gilbert EM, Robertson AD, Lowes BD,
Ferguson DA, Bristow MR. Combined oral positive inotropic and
ß-blocker therapy for the treatment of refractory class IV heart
failure. J Am Coll Cardiol. 1998;31:1336–1340.
This article has been cited by other articles:
 |
|
 |
|
  K. Pandya, K. Porter, H. A. Rockman, and O. Smithies Decreased beta-adrenergic responsiveness following hypertrophy occurs only in cardiomyocytes that also re-express beta-myosin heavy chain Eur J Heart Fail, July 1, 2009; 11(7): 648 - 652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Kjekshus, C. Torp-Pedersen, L. Gullestad, L. Kober, T. Edvardsen, I. C. Olsen, I. Sjaastad, E. Qvigstad, T. Skomedal, J.-B. Osnes, et al. Effect of piboserod, a 5-HT4 serotonin receptor antagonist, on left ventricular function in patients with symptomatic heart failure Eur J Heart Fail, June 30, 2009; (2009) hfp087v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. H. Frey, M. Adamzik, E. Kottenberg-Assenmacher, H. Jakob, I. Manthey, M. Broecker-Preuss, L. Bergmann, G. Heusch, W. Siffert, J. Peters, et al. A novel functional haplotype in the human GNAS gene alters G{alpha}s expression, responsiveness to {beta}-adrenoceptor stimulation, and peri-operative cardiac performance Eur. Heart J., June 1, 2009; 30(11): 1402 - 1410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Dixon and F. G. Spinale Large Animal Models of Heart Failure: A Critical Link in the Translation of Basic Science to Clinical Practice Circ Heart Fail, May 1, 2009; 2(3): 262 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-P. Vilardaga, M. Bunemann, T. N. Feinstein, N. Lambert, V. O. Nikolaev, S. Engelhardt, M. J. Lohse, and C. Hoffmann Minireview: GPCR and G Proteins: Drug Efficacy and Activation in Live Cells Mol. Endocrinol., May 1, 2009; 23(5): 590 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Duncker, N. M. Boontje, D. Merkus, A. Versteilen, J. Krysiak, G. Mearini, A. El-Armouche, V. J. de Beer, J. M.J. Lamers, L. Carrier, et al. Prevention of Myofilament Dysfunction by {beta}-Blocker Therapy in Postinfarct Remodeling Circ Heart Fail, May 1, 2009; 2(3): 233 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Laonigro, M. Correale, M. Di Biase, and E. Altomare Alcohol abuse and heart failure Eur J Heart Fail, May 1, 2009; 11(5): 453 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Schmechel, M. Grimm, A. El-Armouche, G. Hoppner, A. P. Schwoerer, H. Ehmke, and T. Eschenhagen Treatment with atorvastatin partially protects the rat heart from harmful catecholamine effects Cardiovasc Res, April 1, 2009; 82(1): 100 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Nicolini and T. Gherli Alternatives to transplantation in the surgical therapy for heart failure Eur. J. Cardiothorac. Surg., February 1, 2009; 35(2): 214 - 228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-Z. Feng, M. Chen, L. S. Weinstein, and J.-P. Jin Removal of the N-terminal Extension of Cardiac Troponin I as a Functional Compensation for Impaired Myocardial {beta}-Adrenergic Signaling J. Biol. Chem., November 28, 2008; 283(48): 33384 - 33393. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I.-M. Kim, D. G. Tilley, J. Chen, N. C. Salazar, E. J. Whalen, J. D. Violin, and H. A. Rockman {beta}-Blockers alprenolol and carvedilol stimulate {beta}-arrestin-mediated EGFR transactivation PNAS, September 23, 2008; 105(38): 14555 - 14560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Koyanagi, L. Y. Wong, K. Inagaki, O. V. Petrauskene, and D. Mochly-Rosen Alteration of gene expression during progression of hypertension-induced cardiac dysfunction in rats Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H220 - H226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. C. Davel, L. E. Fukuda, L. L. De Sa, C. D. Munhoz, C. Scavone, D. Sanz-Rosa, V. Cachofeiro, V. Lahera, and L. V. Rossoni Effects of isoproterenol treatment for 7 days on inflammatory mediators in the rat aorta Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H211 - H219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Masutani, H.-J. Cheng, M. Hyttila-Hopponen, J. Levijoki, A. Heikkila, A. Vuorela, W. C. Little, and C.-P. Cheng Orally Available Levosimendan Dose-Related Positive Inotropic and Lusitropic Effect in Conscious Chronically Instrumented Normal and Heart Failure Dogs J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 236 - 247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Morisco, C. Marrone, J. Galeotti, D. Shao, D. E. Vatner, S. F. Vatner, and J. Sadoshima Endocytosis machinery is required for {beta}1-adrenergic receptor-induced hypertrophy in neonatal rat cardiac myocytes Cardiovasc Res, April 1, 2008; 78(1): 36 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kurzyna and A. Torbicki Neurohormonal modulation in right ventricular failure Eur. Heart J. Suppl., December 1, 2007; 9(suppl_H): H35 - H40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Cole, A. Gawlinski, N. Steers, and J. Kotlerman Animal-Assisted Therapy in Patients Hospitalized With Heart Failure Am. J. Crit. Care., November 1, 2007; 16(6): 575 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Wisler, S. M. DeWire, E. J. Whalen, J. D. Violin, M. T. Drake, S. Ahn, S. K. Shenoy, and R. J. Lefkowitz A unique mechanism of beta-blocker action: Carvedilol stimulates beta-arrestin signaling PNAS, October 16, 2007; 104(42): 16657 - 16662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Okumura, D. E. Vatner, R. Kurotani, Y. Bai, S. Gao, Z. Yuan, K. Iwatsubo, C. Ulucan, J.-i. Kawabe, K. Ghosh, et al. Disruption of Type 5 Adenylyl Cyclase Enhances Desensitization of Cyclic Adenosine Monophosphate Signal and Increases Akt Signal With Chronic Catecholamine Stress Circulation, October 16, 2007; 116(16): 1776 - 1783. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Tutor, P. Penela, and F. Mayor Jr. Anti-{beta}1-adrenergic receptor autoantibodies are potent stimulators of the ERK1/2 pathway in cardiac cells Cardiovasc Res, October 1, 2007; 76(1): 51 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. O. Nikolaev, V. Boivin, S. Stork, C. E. Angermann, G. Ertl, M. J. Lohse, and R. Jahns A Novel Fluorescence Method for the Rapid Detection of Functional {beta}1-Adrenergic Receptor Autoantibodies in Heart Failure J. Am. Coll. Cardiol., July 31, 2007; 50(5): 423 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Rodriguez, B. Mitton, P. Nicolaou, G. Chen, and E. G. Kranias Phosphorylation of human inhibitor-1 at Ser67 and/or Thr75 attenuates stimulatory effects of protein kinase A signaling in cardiac myocytes Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H762 - H769. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ibanez, S. Prat-Gonzalez, W. S. Speidl, G. Vilahur, A. Pinero, G. Cimmino, M. J. Garcia, V. Fuster, J. Sanz, and J. J. Badimon Early Metoprolol Administration Before Coronary Reperfusion Results in Increased Myocardial Salvage: Analysis of Ischemic Myocardium at Risk Using Cardiac Magnetic Resonance Circulation, June 12, 2007; 115(23): 2909 - 2916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Srivastava, B. Chandrasekar, Y. Gu, J. Luo, T. Hamid, B. G. Hill, and S. D. Prabhu Downregulation of CuZn-superoxide dismutase contributes to {beta}-adrenergic receptor-mediated oxidative stress in the heart Cardiovasc Res, June 1, 2007; 74(3): 445 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ly, Y. Kawase, R. Yoneyama, and R. J. Hajjar Gene Therapy in the Treatment of Heart Failure Physiology, April 1, 2007; 22(2): 81 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Yutzey and J. Robbins Principles of Genetic Murine Models for Cardiac Disease Circulation, February 13, 2007; 115(6): 792 - 799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. U. Khand, A. C. Rankin, J. G.F. Cleland, I. Gemmell, E. Clark, and P. W. Macfarlane The assessment of autonomic function in chronic atrial fibrillation: description of a non-invasive technique based on circadian rhythm of atrioventricular nodal functional refractory periods. Europace, November 1, 2006; 8(11): 927 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Matkovich, A. Diwan, J. L. Klanke, D. J. Hammer, Y. Marreez, A. M. Odley, E. W. Brunskill, W. J. Koch, R. J. Schwartz, and G. W. Dorn II Cardiac-Specific Ablation of G-Protein Receptor Kinase 2 Redefines Its Roles in Heart Development and {beta}-Adrenergic Signaling Circ. Res., October 27, 2006; 99(9): 996 - 1003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-J. Du, X.-M. Gao, H. Kiriazis, X.-L. Moore, Z. Ming, Y. Su, A. M. Finch, R. A. Hannan, A. M. Dart, and R. M. Graham Transgenic {alpha}1A-adrenergic activation limits post-infarct ventricular remodeling and dysfunction and improves survival Cardiovasc Res, September 1, 2006; 71(4): 735 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nishii, T. Inomata, H. Niwano, H. Takehana, I. Takeuchi, H. Nakano, H. Shinagawa, T. Naruke, T. Koitabashi, J.-i. Nakahata, et al. {beta}2-Adrenergic Agonists Suppress Rat Autoimmune Myocarditis: Potential Role of {beta}2-Adrenergic Stimulants as New Therapeutic Agents for Myocarditis Circulation, August 29, 2006; 114(9): 936 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hu, X. Jiao, E. Gao, W. J. Koch, S. Sharifi-Azad, Z. Grunwald, X. L. Ma, and J.-Z. Sun Chronic beta-Adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/Reperfusion Injury by Provoking Inducible Nitric-Oxide Synthase-Mediated Nitrative Stress J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 469 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Takahashi, T. Tang, N. C. Lai, D. M. Roth, B. Rebolledo, M. Saito, W. Y.W. Lew, P. Clopton, and H. K. Hammond Increased Cardiac Adenylyl Cyclase Expression Is Associated With Increased Survival After Myocardial Infarction Circulation, August 1, 2006; 114(5): 388 - 396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Mills, H. Kubo, D. M. Harris, R. M. Berretta, V. Piacentino III, and S. R. Houser Phosphorylation of phospholamban at threonine-17 reduces cardiac adrenergic contractile responsiveness in chronic pressure overload-induced hypertrophy Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H61 - H70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Ellery, L Williams, and M Frenneaux Role of resynchronisation therapy and implantable cardioverter defibrillators in heart failure Postgrad. Med. J., January 1, 2006; 82(963): 16 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Molenaar, T. Christ, U. Ravens, and A. Kaumann Carvedilol blocks {beta}2- more than {beta}1-adrenoceptors in human heart Cardiovasc Res, January 1, 2006; 69(1): 128 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Aranda Jr, G. W. Woo, R. S. Schofield, E. M. Handberg, J. A. Hill, A. B. Curtis, S. F. Sears, J. S. Goff, D. F. Pauly, and J. B. Conti Management of Heart Failure After Cardiac Resynchronization Therapy: Integrating Advanced Heart Failure Treatment With Optimal Device Function J. Am. Coll. Cardiol., December 20, 2005; 46(12): 2193 - 2198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-S. Zhang, H.-J. Cheng, K. Onishi, N. Ohte, T. Wannenburg, and C.-P. Cheng Enhanced Inhibition of L-type Ca2+ Current by {beta}3-Adrenergic Stimulation in Failing Rat Heart J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1203 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Bernstein, G. Fajardo, M. Zhao, T. Urashima, J. Powers, G. Berry, and B. K. Kobilka Differential cardioprotective/cardiotoxic effects mediated by {beta}-adrenergic receptor subtypes Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2441 - H2449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Metra, C. Torp-Pedersen, K. Swedberg, J. G.F. Cleland, A. Di Lenarda, M. Komajda, W. J. Remme, B. Lutiger, A. Scherhag, M. A. Lukas, et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial Eur. Heart J., November 1, 2005; 26(21): 2259 - 2268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. R. Paiva, L. S. Matsubara, B. B. Matsubara, M. F. Minicucci, P. S. Azevedo, A. O. Campana, and L. A. M. Zornoff Retinoic Acid Supplementation Attenuates Ventricular Remodeling after Myocardial Infarction in Rats J. Nutr., October 1, 2005; 135(10): 2326 - 2328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-L. Sun, S.-J. Hu, L.-H. Wang, Y. Hu, and J.-Y. Zhou Effect of {beta}-Blockers on Cardiac Function and Calcium Handling Protein in Postinfarction Heart Failure Rats Chest, September 1, 2005; 128(3): 1812 - 1821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Burkhoff and S. A. Ben-Haim Nonexcitatory electrical signals for enhancing ventricular contractility: rationale and initial investigations of an experimental treatment for heart failure Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2550 - H2556. [Full Text] [PDF]
|
|
|
|
|
|
D. L. Mann and M. R. Bristow Mechanisms and Models in Heart Failure: The Biomechanical Model and Beyond Circulation, May 31, 2005; 111(21): 2837 - 2849. [Full Text] [PDF]
|
|
|
|
|
|
E. Qvigstad, T. Brattelid, I. Sjaastad, K. W. Andressen, K. A. Krobert, J. A. Birkeland, O. M. Sejersted, A. J. Kaumann, T. Skomedal, J.-B. Osnes, et al. Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure Cardiovasc Res, March 1, 2005; 65(4): 869 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tachibana, H.-J. Cheng, T. Ukai, A. Igawa, Z.-S. Zhang, W. C. Little, and C.-P. Cheng Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H914 - H922. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. F. McBride and C. M. White Critical Differences Among Beta-Adrenoreceptor Antagonists in Myocardial Failure: Debating the MERIT of COMET J. Clin. Pharmacol., January 1, 2005; 45(1): 6 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Hamlin, P. S. Villars, J. T. Kanusky, and A. D. Shaw Role of Diastole in Left Ventricular Function, II: Diagnosis and Treatment Am. J. Crit. Care., November 1, 2004; 13(6): 453 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.R. Bristow, H. Krause-Steinrauf, R. Nuzzo, C.-S. Liang, J. Lindenfeld, B.D. Lowes, B. Hattler, W.T. Abraham, L. Olson, S. Krueger, et al. Effect of Baseline or Changes in Adrenergic Activity on Clinical Outcomes in the {beta}-Blocker Evaluation of Survival Trial Circulation, September 14, 2004; 110(11): 1437 - 1442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kawai, F. Qin, J. Shite, W. Mao, S. Fukuoka, and C.-s. Liang Importance of antioxidant and antiapoptotic effects of {beta}-receptor blockers in heart failure therapy Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1003 - H1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-a. Koshimizu, G. Tsujimoto, A. Hirasawa, Y. Kitagawa, and A. Tanoue Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human {alpha}1D- and {alpha}1B-adrenergic receptors Cardiovasc Res, September 1, 2004; 63(4): 662 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Okoshi, M. Nakayama, X. Yan, M. P. Okoshi, A. J.T. Schuldt, M. A. Marchionni, and B. H. Lorell Neuregulins Regulate Cardiac Parasympathetic Activity: Muscarinic Modulation of {beta}-Adrenergic Activity in Myocytes From Mice With Neuregulin-1 Gene Deletion Circulation, August 10, 2004; 110(6): 713 - 717. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Ko, P. R. Hebert, C. S. Coffey, J. P. Curtis, J. M. Foody, A. Sedrakyan, and H. M. Krumholz Adverse Effects of {beta}-Blocker Therapy for Patients With Heart Failure: A Quantitative Overview of Randomized Trials Arch Intern Med, July 12, 2004; 164(13): 1389 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zaugg, C. Schulz, J. Wacker, and M. C. Schaub Sympatho-modulatory therapies in perioperative medicine Br. J. Anaesth., July 1, 2004; 93(1): 53 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kindermann, C. Maack, S. Schaller, N. Finkler, K. I. Schmidt, S. Laer, H. Wuttke, H.-J. Schafers, and M. Bohm Carvedilol but Not Metoprolol Reduces {beta}-Adrenergic Responsiveness After Complete Elimination From Plasma In Vivo Circulation, June 29, 2004; 109(25): 3182 - 3190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Salpeter, T. M. Ormiston, and E. E. Salpeter Cardiovascular Effects of {beta}-Agonists in Patients With Asthma and COPD: A Meta-Analysis Chest, June 1, 2004; 125(6): 2309 - 2321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Morimoto, H. Hasegawa, H.-J. Cheng, W. C. Little, and C.-P. Cheng Endogenous {beta}3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2425 - H2433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Odley, H. S. Hahn, R. A. Lynch, Y. Marreez, H. Osinska, J. Robbins, and G. W. Dorn II Regulation of cardiac contractility by Rab4-modulated {beta}2-adrenergic receptor recycling PNAS, May 4, 2004; 101(18): 7082 - 7087. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-J. Blanc, V. Bertault-Valls, M. Fatemi, M. Gilard, P.-Y. Pennec, and Y. Etienne Midterm Benefits of Left Univentricular Pacing in Patients With Congestive Heart Failure Circulation, April 13, 2004; 109(14): 1741 - 1744. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Bauman and R. L. Talbert Pharmacodynamics of{beta}-Blockers in Heart Failure: Lessons from the Carvedilol Or Metoprolol European Trial Journal of Cardiovascular Pharmacology and Therapeutics, April 1, 2004; 9(2): 117 - 128. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Fukuchi, Y. Yasumura, K. Kiso, K. Hayashida, K. Miyatake, and Y. Ishida Gated Myocardial SPECT to Predict Response to {beta}-Blocker Therapy in Patients with Idiopathic Dilated Cardiomyopathy J. Nucl. Med., April 1, 2004; 45(4): 527 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sundell, E. Engblom, J. Koistinen, A. Ylitalo, A. Naum, K. Q. Stolen, R. Kalliokoski, S. G. Nekolla, K. E. J. Airaksinen, J. J. Bax, et al. The effects of cardiac resynchronization therapy on left ventricular function, myocardial energetics, and metabolic reserve in patients with dilated cardiomyopathy and heart failure J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1027 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Engelhardt, L. Hein, V. Dyachenkow, E. G. Kranias, G. Isenberg, and M. J. Lohse Altered Calcium Handling Is Critically Involved in the Cardiotoxic Effects of Chronic {beta}-Adrenergic Stimulation Circulation, March 9, 2004; 109(9): 1154 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Kirstein and P. A. Insel Autonomic Nervous System Pharmacogenomics: A Progress Report Pharmacol. Rev., March 1, 2004; 56(1): 31 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Metra, S. Nodari, and L. Dei Cas Current guidelines in the pharmacological management of chronic heart failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1_suppl): S11 - S16. [Abstract] [PDF]
|
|
|
|
|
|
S. Okuda, M. Yano, M. Doi, T. Oda, T. Tokuhisa, M. Kohno, S. Kobayashi, T. Yamamoto, T. Ohkusa, and M. Matsuzaki Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure Circulation, February 24, 2004; 109(7): 911 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Eisenach, A. M. McGuire, R. M. Schwingler, S. T. Turner, and M. J. Joyner The Arg16/Gly {beta}2-adrenergic receptor polymorphism is associated with altered cardiovascular responses to isometric exercise Physiol Genomics, February 13, 2004; 16(3): 323 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Jortani, S. D. Prabhu, and R. Valdes Jr Strategies for Developing Biomarkers of Heart Failure Clin. Chem., February 1, 2004; 50(2): 265 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Dorn II and J. D. Molkentin Manipulating Cardiac Contractility in Heart Failure: Data From Mice and Men Circulation, January 20, 2004; 109(2): 150 - 158. [Full Text] [PDF]
|
|
|
|
|
|
L. J. Dixon, J. G. Murtagh, S. G. Richardson, and E. W. Chew Reduction in hospitalization rates following cardiac resynchronisation therapy in cardiac failure: experience from a single centre Europace, January 1, 2004; 6(6): 586 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. Singh Survival Advantage with Cardiovascular Drugs: Are they Real? Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2003; 8(4): 249 - 251. [PDF]
|
|
|
|
|
|
E. Omerovic, E. Bollano, B. Soussi, and F. Waagstein Selective {beta}1-blockade attenuates post-infarct remodelling without improvement in myocardial energy metabolism and function in rats with heart failure Eur J Heart Fail, December 1, 2003; 5(6): 725 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Lohse, S. Engelhardt, and T. Eschenhagen What Is the Role of {beta}-Adrenergic Signaling in Heart Failure? Circ. Res., November 14, 2003; 93(10): 896 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. McKelvie, J.-L. Rouleau, M. White, R. Afzal, J. B. Young, A. P. Maggioni, P. Held, and S. Yusuf Comparative impact of enalapril, candesartan or metoprolol alone or in combination on ventricular remodelling in patients with congestive heart failure Eur. Heart J., October 1, 2003; 24(19): 1727 - 1734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mukherjee, S. Baksi, R. A. Dart, S. Gollub, J. Lazar, C. Nair, D. Schroeder, and S. H. Woolf {beta}-Blockers With Vasodilatory Actions Chest, October 1, 2003; 124(4): 1621 - 1621. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Sim, D. Hampton, C. Phillips, S.-N. Lo, S. Vasishta, J. Davies, and M. Penney The use of brain natriuretic peptide as a screening test for left ventricular systolic dysfunction-- cost-effectiveness in relation to open access echocardiography Fam. Pract., October 1, 2003; 20(5): 570 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.N. Singh Increased heart rate as a risk factor for cardiovascular disease Eur. Heart J. Suppl., September 1, 2003; 5(suppl_G): G3 - G9. [Abstract] [PDF]
|
|
|
|
|
|
C.-s. Liang Sympatholysis and cardiac sympathetic nerve function in the treatment of congestive heart failure J. Am. Coll. Cardiol., August 6, 2003; 42(3): 549 - 551. [Full Text] [PDF]
|
|
|
|
 |
|
 D. S.H. Bell Heart Failure: The frequent, forgotten, and often fatal complication of diabetes Diabetes Care, August 1, 2003; 26(8): 2433 - 2441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Maack, M. Bohm, L. Vlaskin, E. Dabew, K. Lorenz, H.-J. Schafers, M. J. Lohse, and S. Engelhardt Partial Agonist Activity of Bucindolol Is Dependent on the Activation State of the Human {beta}1-Adrenergic Receptor Circulation, July 22, 2003; 108(3): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. V. Salukhe, M. Y. Henein, and R. Sutton Pacing in heart failure: patient and pacing mode selection Eur. Heart J., June 1, 2003; 24(11): 977 - 986. [Full Text] [PDF]
|
|
|
|
|
|
D. H. Au, E. M. Udris, V. S. Fan, J. R. Curtis, M. B. McDonell, and S. D. Fihn Risk of Mortality and Heart Failure Exacerbations Associated With Inhaled {beta}-Adrenoceptor Agonists Among Patients With Known Left Ventricular Systolic Dysfunction Chest, June 1, 2003; 123(6): 1964 - 1969. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Bollano, M S. Tang, A Hjalmarson, F Waagstein, and B Andersson Different responses to dobutamine in the presence of carvedilol or metoprolol in patients with chronic heart failure Heart, June 1, 2003; 89(6): 621 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Jessup and S. Brozena Heart Failure N. Engl. J. Med., May 15, 2003; 348(20): 2007 - 2018. [Full Text] [PDF]
|
|
|
|
|
|
S. R. Houser and K. B. Margulies Is Depressed Myocyte Contractility Centrally Involved in Heart Failure? Circ. Res., March 7, 2003; 92(4): 350 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Abbate, G. G. L. Biondi-Zoccai, R. Bussani, A. Dobrina, D. Camilot, F. Feroce, R. Rossiello, F. Baldi, F. Silvestri, L. M. Biasucci, et al. Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure J. Am. Coll. Cardiol., March 5, 2003; 41(5): 753 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bristow Antiadrenergic Therapy of Chronic Heart Failure: Surprises and New Opportunities Circulation, March 4, 2003; 107(8): 1100 - 1102. [Full Text] [PDF]
|
|
|
|
|
|
T. Simon, M. Mary-Krause, C. Funck-Brentano, Ph. Lechat, P. Jaillon, and on behalf of CIBIS II investigators Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II) Eur. Heart J., March 2, 2003; 24(6): 552 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A P Maggioni, G Sinagra, C Opasich, E Geraci, M Gorini, E Gronda, D Lucci, G Tognoni, E Balli, and L Tavazzi Treatment of chronic heart failure with {beta} adrenergic blockade beyond controlled clinical trials: the BRING-UP experience Heart, March 1, 2003; 89(3): 299 - 305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A Turner, K. E Porter, W. H.T Smith, H. L White, S. G Ball, and A. J Balmforth Chronic {beta}2-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism Cardiovasc Res, March 1, 2003; 57(3): 784 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Javaheri Pembrey's Dream: The Time Has Come for a Long-term Trial of Nocturnal Supplemental Nasal Oxygen to Treat Central Sleep Apnea in Congestive Heart Failure Chest, February 1, 2003; 123(2): 322 - 325. [Full Text] [PDF]
|
|
|
|
|
|
A. Palazzuoli, F. Bruni, L. Puccetti, M. Pastorelli, P. Angori, A.L. Pasqui, and A. Auteri Effects of carvedilol on left ventricular remodeling and systolic function in elderly patients with heart failure Eur J Heart Fail, December 1, 2002; 4(6): 765 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Leclercq, S. Walker, C. Linde, J. Clementy, A.J. Marshall, P. Ritter, P. Djiane, P. Mabo, T. Levy, F. Gadler, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation Eur. Heart J., November 2, 2002; 23(22): 1780 - 1787. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Soler-Soler and D. Garcia-Dorado How to best to counteract the enemies? By blocking neurohormonal activation Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G45 - G50. [Abstract] [PDF]
|
|
|
|
 |
|
 M. L. Kukin {beta}-Blockers in Chronic Heart Failure: Considerations for Selecting an Agent Mayo Clin. Proc., November 1, 2002; 77(11): 1199 - 1206. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||