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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018 56 AFRICA
calcium channel activation and troponin I phosphorylation. By
contrast, β2-AR signalling has negative effects on adenyl cyclase
activation and the subsequent G-protein-activated ionotropic
response.80 β3-AR appears to be important in protection from
hypertrophic and fibrotic remodelling by preserving NO/cGMP
signalling during cardiac stress.148
The β-adrenergic receptor system plays an important role in
the pathogenesis of myocardial remodelling and heart failure.84
The exact mechanisms are unclear but it has been known for
decades that chronically increased plasma catecholamines
can lead to heart failure.149,150 In dogs with chronic primary
MR, there is activation of the adrenergic system,89,108 and
recent gene array data in chronic primary MR patients with
preserved LVEF demonstrate increased expression of genes
involved in β-adrenergic signalling.56 This indicates that the
adrenergic system is activated during the compensatory phase
of MR and supports the concept that blocking these pathways
may reduce their adverse consequences. However, with
transition to decompensation there is a reduction in adrenergic
responsiveness.
In patients with systolic heart failure (HF), several studies
in the last three decades show that β1-receptor density 151 and
its mRNA152,153 are reduced while β2-receptor density remains
unchanged.154 Similarly, in animals with HF due to chronic
volume overload, β1-AR responsiveness is reduced due to
neurohormonal activation (Fig. 3).47,155 These changes in β1-AR
expression are caused by sustained adrenergic activity, causing
an increase in the expression and activity of GRK 2 (G-protein-
coupled receptor kinase; formerly called β-ARK or β-agonist
receptor kinase), resulting in β1-AR being phosphorylated
and labelled for desensitisation, internalisation and recycling.156
The result is a reduction in the density of β1-ARs and a
reduced propensity for myocyte activation by chronic β 1-receptor
activation, which may protect the myocyte from long-term
catecholamine toxicity.80
Beta-blocker therapy improves β1-AR signal-
ling and clinical outcomes in HF
Chronic β1-AR activation causes a number of detrimental effects,
ultimately resulting in changes in the ECM and cell loss from
necrosis and apoptosis,25 which in turn leads to cardiac dilatation
and failure.157 However, the intracellular pathways responsible
for these final acts are unclear.25 What is clear is that β1-AR
antagonists improve clinical outcomes in patients with systolic
heart failure and improve cardiac function and myocardial
remodelling.158
Mostβ-adrenergic blockers are antagonistic to β-ARs (whether
β-1, β-2 or β -3) by occupying the receptor and preventing signal
transduction via G-protein activation. Importantly, there is
an up-regulation of β1-AR expression and improvements in
receptor sensitivity, resulting in reversal of cardiac remodelling.147
However, the pharmacological and clinical effects of these
agents vary quite considerably. Cardioselective beta-blockers
(metoprolol, bisoprolol and atenolol, for example) have a greater
affinity for β 1-ARs than β2-ARs, whereas carvedilol binds β1-ARs
more than β 2-ARs and has vasodilatory effects, via nitric oxide
and α1-receptor blockade.
There are other important differences between carvedilol
and other beta-blockers. For example, metoprolol upregulates
cardioprotectiveβ3-AR expression, whereas carvedilol does
not.159,160 Carvedilol has antioxidant and antiproliferative
properties161-163 and differs from metoprolol in its effects on
haemodynamics, left ventricular function and β 1-AR
expression.164,165 Carvedilol166 andbisoprolol167 havealsobeenshown
to improve right ventricular (RV) ejection fraction, attenuate RV
dilatation and reduce pulmonary artery hypertension in patients
with ischaemic and non-ischaemic dilated cardiomyopathy.
Although there are no recent confirmatory studies, these
improvements in RV function may be related to reductions in
RV afterload and/or improvements in RV contractility. 166,167 By
contrast, short-term (two-week) metoprolol did not improve RV
function in patients with moderate-to-severe degenerative MR.168
Clinical support for β-adrenergic receptor blocker therapy in
patients with heart failure is well known,158,169,170 with some data
suggesting that patient outcomes are better with carvedilol than
the immediate-release form of metoprolol.171
Several mechanisms for the improvement in outcomes with
β1-receptor blockade have been proposed,84 including anti-
arrhythmic properties;172 improved β-adrenergic signalling
by cardiac β-AR upregulation; 80 free-radical scavenging; 161
improvements in calcium cycling by the sarcoplasmic
reticulum;83,173 bradycardia reducing myocardial work,
mechanical stress, 174 and prolonging diastolic calcium uptake and
cycling by the sarcoplasmic reticulum; inhibition of the renin–
angiotensin–aldosterone system; and there is growing evidence
that β-antagonists, in particular carvedilol,162,163 directly reduce
apoptosis78,175-177 and collagen loss by MMP activation.178
β1-AR blockade in MR counters adverse
adrenergic effects
Since MR leads to a reduction in forward stroke volume,
it is hypothesised that the adrenergic system is activated to
maintain systemic blood pressure and perfusion, and blockade
of the adrenergic system should limit adverse left ventricular
remodelling. There is evidence that chronic primary MR results
in excessive activation of the sympathetic nervous system, with
increases in myocardial catecholamine levels, 89,118,134 similar to
heart failure from other causes.179
Tallajet al.118 demonstrated thatβ-ARblockade with extended-
release metoprolol succinate attenuated angiotensin II-mediated
norepinephrine and epinephrine release in the myocardium of
dogs with ‘subacute’ (two to four weeks’ duration) isolated MR.
Similarly, Hankes et al.89 demonstrated that norepinephrine
release into the cardiac interstitium was significantly higher in
dogs with subacute MR, which was reduced by β1-AR blockade.
In an earlier study by Tsutsui et al.90 in ‘chronic’ (three months)
canine MR, the β1- AR blocker atenolol improved left ventricular
function, which was associated with improvement in contractile
function of isolated cardiocytes and an increase in the number
of contractile elements. This was supported by a similar study by
Nemoto et al.,145 which showed that only when a β1-AR blocker
was added to an ACE inhibitor did forward stroke volume and
cardiac contractility return to normal. Recently, Trappanese et
al .180 demonstrated an improvement in β 3-AR expression and
β3-NO-cGMP coupling with chronic therapy with metoprolol
in dogs with primary MR. Since β3-AR is cardioprotective, this
may partially explain the potential beneficial effects of β 1-AR
blockade in primary MR.159