H
eart failure (HF) remains a
worldwide epidemic and con-
tinues to be associated with high
morbidity and mortality.
1,2
Heart
failure is categorized into cases of
reduced ejection fraction (HFrEF)
and HF with preserved ejection
fraction (HFpEF), primarily because
patients with HFrEF seem to benefit
from a variety of neurohormonal
antagonist and device therapies,
whereas most patients with HFpEF
do not. Patients with clinical HF are
divided roughly equally between
HFrEF and HFpEF.
3
There have
been recent pharmacologic advances
in HFrEF; however, there are several
mainstay treatments with a strong
evidence base that are recommended
in the most recent American College
of Cardiology Foundation (ACCF)
and American Heart Association
(AHA) 2013 Guidelines for the
Management of Heart Failure.
4
This article is the second in a series
to describe pharmacologic agents
named in the guidelines that impact
the morbidity and mortality that is
associated with HFrEF. In addition,
practical applications for their use
are described (see Table 1 for sum-
mary of trials for the agents dis-
cussed within this review).
”
-Adrenergic Antagonists
Pharmacology/Pathophysiology
Within the human myocyte, 3 dif-
ferent adrenergic receptors exist:
”
1
,
”
2
,and
!
1
, which are associated
with a positive inotropic response
and cell growth.
5
Y
7
The
”
-adrenergic
receptors are coupled to the enzyme
adenylyl cyclase through G pro-
teins, which convert adenosine tri-
phosphate to cyclic adenosine
monophosphate, which in turn is
a positive inotropic and chrono-
tropic secondary messenger. The
heart has both
”
1
and
”
2
receptors,
with
”
1
as the predominant recep-
tor type. In HFrEF, there is down-
regulation in the
”
1
receptor by
overexposure to catecholamines,
making the
”
2
receptors more equiv-
alent to the
”
1
receptors.
8,9
These
”
2
receptors are present on the adren-
ergic nerve terminals of the myocyte,
where they stimulate an increase in
cardiotoxic norepinephrine release.
Overexpression of
”
2
receptors even-
tually leads to systolic dysfunction
and a cardiomyopathy phenotype.
Overexpression of
!
1
receptor also
occurs in the myocardium, leading
to concentric hypertrophy. There-
fore, continuous increased adren-
ergic drive, which is seen in patients
with HFrEF, has a devastating
impact on the cardiac myocytes via
the
”
and
!
adrenergic receptors.
5
Y
7
By blocking adrenergic receptors
within the myocyte,
”
blockade
can reduce the harmful effects of
excessive and continuous increased
adrenergic drive on the myocar-
dium, which in turn can cause time-
dependent improvements in systolic
function, prevent progression of
remodeling, decrease heart rate and
blood pressure, reduce atrial and
ventricular arrhythmias, and exert
anti-ischemic effects.
5
Y
7
Currently, there are 3 classes of
”
-blockers available for clinical use
(Table 2).
5
Y
7
Introduced in 1968 as
an antianginal agent, propranolol
is considered to be the prototype
nonselective
”
-blocker. Proprano-
lol and timolol are first-generation
”
-blockers as they possess equal
affinities for blocking both the
”
1
and
”
2
receptors with no other ad-
ditional pharmacological proper-
ties. In the 1970s, cardioselective
or second-generation
”
-blockers
entered the market. These agents
selectively antagonized the
”
1
re-
ceptor compared to the
”
2
receptor
without any additional pharmaco-
logical properties. Metoprolol is
approximately 74-fold selective
for the
”
1
receptor versus the
”
2
receptor, with bisoprolol being
119-fold selective. However, this
selectivity can be lost with increas-
ing doses. In the 1980s, the third-
generation
”
-blockers were
marketed, primarily for hyperten-
sion. What separated these agents
from their counterparts were their
additional vasodilatory properties
in addition to
”
blockade. For
example, carvedilol, although only
being 7-fold selective for the
”
1
receptor, is a potent
!
1
blocking
agent with 2- to 3-fold selectivity
for the
”
1
versus
!
1
receptor. In
addition, carvedilol also exerts
antioxidant effects attributable to
stimulation of nitric oxide produc-
tion,aswellashavinganti-
inflammatory and other metabolic
effects such as small reductions in
low-density lipoproteins.
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