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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018
58
AFRICA
beta-blockade in MR, however, other studies do not support
this.
108,146,197,200,201
The reasons for the discrepancies in these findings
are unclear but some explanations can be proposed.
Firstly, the studies have been performed in different
experimental models and at different stages in the evolution
of MR-related left ventricular remodelling. Many of the
experiments performed thus far have been in animal models
with controlled formation of volume overload showing that early
introduction of beta-blocker therapy
89,90,118
may be beneficial, and
this is supported to some extent by the work of Ahmed
et al
.
199
in
humans. However, there appears to be a time-dependent pattern
during remodelling of the LV in chronic primary MR.
Early after the development of MR there is a marked
increase in inflammatory and neurohormonal response to the
acute volume overload.
26,113
A period of compensation and a
relatively normal inflammatory response appears to follow
until the late decompensated stage is reached, when adverse
pathway activation seems to increase.
26
Depending on when in
this evolution of left ventricular remodelling the studies to date
have been performed, there may be discrepancies in the findings
with regard to the impact of beta-blockade on left ventricular
remodelling. Beta-blockade may have more impressive effects
if used early in the evolution of volume overload-related left
ventricular remodelling but it may be less effective later on.
Secondly, various beta-adrenergic agents have been tested
under different circumstances. Compared to the impressive
beneficial results in heart failure patients with the mixed
adrenergic blocker, carvedilol,
158,202
Pu
et al
.
201
demonstrated
Table 1. Studies of beta-blocker therapy and left ventricular function in primary MR
Authors
Year Subject Cause of MR
Number treated
with BB Type of study Control
Type of BB
Duration
of BB Outcome measures
Favours BB
Tsutsui
et al
.
89
1994 Dog Experimental
chordal rupture
n
=
6
Case
controlled
n
=
6
Atenolol 50
mg daily
3 months Cardiocyte contrac-
tility, myofibrillar
density
+
Nemoto
et al
.
144
2002 Dog Experimental
chordal rupture
n
=
11
Longitudinal NA
Atenolol
100 mg
daily
3 months Haemodynamics, LV
function
+
Tallaj
et al
.
117
2003 Dog Experimental
chordal rupture
2 weeks
MR+BB:
n
=
6
4 weeks
MR+BB:
n
=
8
Case
controlled
Normal:
n
=
8
2 weeks
MR:
n
=
8
4 weeks
MR:
n
=
6
Metoprolol
succinate
100 mg
daily
4 weeks RAAS activation +
Hankes
et al
.
88
2006 Dog Experimental
chordal rupture
4 weeks of
MR+BB
=
8
Case
controlled
Normal
=
6
Untreated
MR
=
6
Metoprolol
succinate
100 mg
daily
4 weeks NE release into
cardiac interstitium
+
Oh
et al
.
145
2007 Human 71% degenera-
tive
n
=
134
Retrospective
cohort
NA
Not ascer-
tained
1–88
months
Echo LVEF
–
Pat
et al
.
199
2008 Dog Experimental
chordal rupture
n
=
11
Case
controlled
n
=
10
Metoprolol
succinate
100 mg
twice daily
4 months LV remodelling
by MRI and echo;
cardiomyocyte
function
Improved cardiomyocyte
function and BB recep-
tiveness but failure to
attenuate remodelling
Sabri
et al
.
107
2008 Dog Experimental
chordal rupture
n
=
6
Case
controlled
Normal
=
6
Untreated
MR
=
6
Metoprolol
succinate
100 mg
daily
4 weeks LV remodelling by
echo; interstitial
collagen quantifica-
tion; FAK signalling
(integrin signalling)
BB reduced FAK tyro-
sine phosphorylation but
no change in remodeling
parameters; BB reduced
epicardial collagen loss
but not endocardial
collagen loss
Varadara-
jan
et al
.
197
2008 Human LVEF
>
55% +
‘severe MR’
n
=
218
Retrospective
observational
cohort study
n
=
614
Not stated 8 years Mortality
+
Stewart
et al
.
195
2008 Human MVP
n
=
25
Double-blind
cross-over
study
NA
Metoprolol
to a maxi-
mum 190
mg daily
14 days MRI
EF
LVEDV
LVESV
LV ‘work’ (CO)
–
–
–
+
Ahmed
et al
.
198
2012 Human MVP
n
=
19
RCT
n
=
19
Toprol XL
25–100 mg
daily
MRI LVEF
MRI LVESV
LV longitudinal
strain rate
+
–
–
Pu
et al
.
200
2013 Rat
Experimental
leaflet disrup-
tion
n
=
43
‘Long-term’
BB in 19
RCT
n
=
44
Carvedilol
(1 200 ppm)
36 weeks Echo only
LV dimensions
LVESV and mass
index
FS and EF
Survival probability
–
Trappanese
et al
.
179
2015 Dog Experimental
chordal rupture
n
=
8
(MR + BB)
Case
controlled
Normal
=
10
Untreated
MR
=
8
Metoprolol
succinate
100 mg
daily
4 weeks Activation of
β
3AR/
NO-cGMP signalling
β
3
-AR expression
+
+
BB
=
beta-blocker; MVP
=
mitral valve prolapse; RCT
=
randomised controlled trial; MR
=
mitral regurgitation; NE
=
norepinephrine; + indicates that the study favoured
BB therapy in primary MR; – indicates that the study did not favour BB therapy in primary MR; LV
=
left ventricle; LVEF
=
left ventricular ejection fraction; LVEDV
=
left ventricular end-diastolic volume; LVESV
=
left ventricular end-systolic volume; CO
=
cardiac output; RAAS
=
renin–angiotensin–aldosterone system; echo
=
echocar-
diogram; MRI
=
magnetic resonance imaging; ppm = parts per million.