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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018
54
AFRICA
increase in oxidative stress even before the LV starts to develop
systolic dysfunction, which supports the notion that wall stress is
present throughout the evolution of left ventricular remodelling
in primary MR. This oxidative stress appears to be present as
long as the volume overload persists (Fig. 3).
56
Chronic primary MR triggers an inflammatory
response
Tumour necrosis factor (TNF), interleukin-1 (IL-1) and
interleukin-6 (IL-6) are produced by all nucleated cells, including
cardiac myocytes.
57
Cytokines are responsible for beneficial
adaptation to short-term stresses, such as haemodynamic
overload, within the myocardium. These molecules may play
an important role in protecting the heart from oxidative injury
and there are several lines of evidence supporting their beneficial
role in short-term stress.
58
However, the role of cytokines in
remodelling is complicated and not easily predictable. For
example, TNF can have both a protective and an adverse effect
on the myocardium, depending on which TNF receptors are
activated.
59
Furthermore, prolonged elevation of tissue cytokines
has been found to have deleterious effects on the LV.
60,61
Chronic elevation of cytokines has an effect on left ventricular
remodelling by blunting of
β
-adrenergic signalling
57
and activation
of apoptotic pathways.
62-64
TNF-
α
also increases cardiomyocyte
apoptosis
63,65
by activating p38 MAP kinase and NF
κ
B and by
down-regulating ERK 1/2 MAP kinase.
66
Overexpression of TNF
has also been shown to increase tissue matrix metalloproteinase
(MMP) activity, with the resultant acute loss in myocardial
fibrillar collagen and left ventricular dilatation.
67-69
However,
with continuing TNF overexpression, there is an increase in
tissue inhibitors of metalloproteinase (TIMP-1) expression and
reduction in MMP expression, leading to abnormal increases
in fibrillar collagen,
67,68
suggesting a time-dependent effect of
chronic exposure to elevated myocardial TNF.
Cytokines are elevated in patients with heart failure,
70
in
patients with pressure and volume overload,
71
and in other forms
of heart disease.
72,73
Several lines of evidence suggest that the
myocardial response to TNF
α
is similar regardless of aetiology.
Gene expression analysis by micro-array suggests that there is a
time-dependent inflammatory response to volume overload (Fig.
3).
26,45
Very early after the initiation of volume overload in aorto-
caval fistula rats, there is a marked increase in the expression of
inflammatory pathway genes, followed by relative normalisation
during the chronic ‘compensated’ period of volume overload.
26
This is supported by earlier studies that demonstrate that
myocyte stretch induces TNF
α
secretion from myocytes,
44,74
and
mast cell-deficient rats with volume overload were protected from
TNF
α
-dependent left ventricular remodelling.
69
Furthermore, in
humans with compensated chronic primary MR and normal
LVEF, there is a down-regulation of inflammatory pathways.
56
As the LV becomes dilated and dysfunctional, there is an
increase in inflammatory pathway gene expression,
26
which is
supported by clinical work in patients with severe chronic primary
MR
71,75
and severe rheumatic aortic regurgitation.
76
Overall,
there appears to be a biphasic elevation in the inflammatory
response to mitral regurgitation, with early volume overload
activating the expression of numerous inflammatory pathways,
and decompensation triggering a second inflammatory response
(Fig. 3).
Myocyte loss in chronic primary MR
Apoptosis is activated by several extracellular death signals,
including myocyte stretch,
77
catecholamines
25,78-80
and
inflammatory cytokines,
57
and various intracellular death
signals.
81-85
These death signals
25
activate transcription factors,
86
ultimately resulting in activation of the caspase cascade.
87
Loss
of myocytes will increase the stress on remaining myocytes. This
leads to further increases in ROS,
88
cytokine release,
44
increases
in adrenergic activation,
89
perpetuating loss of myocytes in
a downward-spiraling process. Time-dependent apoptosis of
non-myocyte cells has been described in volume-loaded rats
26
and
there is evidence that chronic primary MR causes a reduction in
contractile elements.
21,82,90
Based on this evidence and evidence
from studies in myocardial remodelling due to other causes,
it is probable that cell loss is an important component in left
ventricular dilatation and dysfunction in chronic primary MR.
ECM changes in chronic primary MR
Myocyte arrangement and myocardial integrity is highly
organised to enable the continuously moving myocardium to
produce coordinated contraction, resulting in stroke volume.
91
The structural integrity is provided by the ECM, which comprises
a basement membrane, proteoglycans and glycosaminoglycans,
and ECM proteins such as type I, III and V collagen, of which
approximately 85% is type I collagen.
7
This collagen framework
serves to maintain cardiac myocyte alignment, without which the
myocytes would ‘slip’, altering the shape and size of the cardiac
chambers.
91
The ECM is a highly dynamic part of the myocardium that
changes depending on the degree and type of mechanical stress,
neurohormonal activation, inflammation and oxidative stress.
These stressors on the ECM result in changes in the expression
and activation of the proteins responsible for ECM turnover and,
ultimately, alterations in collagen deposition and degradation.
MMPs are a heterogeous family of enzymes responsible for
the proteolysis of various protein-based extracellular substances.
They include the collagenases (MMP-1, MMP-8 and MMP-13),
stromelysins (MMP-3 and MMP-10) and the gelatinases (MMP-
2 and MMP-9). They are expressed and secreted into the
extracellular space by a variety of cells, including cardiac
myocytes, cardiac fibroblasts and macrophages.
92
However, the
roles of each MMP and the control of their activity are not
yet clearly elucidated and this is an area of on-going research.
7
Some studies have demonstrated a correlation between MMP
expression and cardiomyopathy phenotypes,
93-95
and others have
demonstrated that serum levels of MMPs have prognostic value
in heart failure.
96,97
TIMPs are low-molecular-weight proteins that bind to the
catalytic domain of active MMPs, preventing substrate binding.
There are four species of TIMPs with overlapping functions
within the myocardium, which are not restricted to MMP
inhibition. Other pleomorphic effects have been described. For
example, TIMP-2 increases collagen production by fibroblasts,
whereas TIMP-3 is responsible for fibroblast apoptosis.
98
Biological and/or mechanical stimuli trigger various signal-
transduction pathways, resulting in the production of MMP
transcription factors and the secretion of these enzymes into the
ECM.
92,99-101
Mechanical stimuli, such as stretch,
102
are transduced
through the ECM, which, via collagen–integrin–cytoskeleton