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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018 AFRICA 55
connections, are connected to and activate a number of intra-
myocyte signal-transduction pathways involved in ECM
remodelling.31,46,103-106 Local ROS, endothelin-1, angiotensin II
and catecholamines, via α- and β-receptors, are also responsible
for increases in MMP expression.52,89,107,108
Cytokines, such as TNF α and IL-1, have been found to
increase MMP expression,67,102 promoting matrix degradation
and ventricular dilatation.7 On the other hand, MMP-9
production can be suppressed by TGF-β-activated NFκB
binding in some experiments,109 whereas its expression was
up-regulated by angiotensin II-activated NFκB in other
experiments.110 Angiotensin II107 and aldosterone both increase
ECM remodelling, mainly through TGF-β,111 although the effects
of this protein are multiple and often opposing, depending on
circumstances.112
TGF- β stimulation induces maturation of fibroblasts to
myofibroblasts and enhances ECM protein synthesis via
induction of TIMP expression and inhibition of certain MMP
expression.111 However, this is dependent on the load on the
myocardium and there is clear evidence that volume overload
results in reduction in TGF-β level and loss of interstitial
collagen,113 whereas pressure overload increases TGF-β.114 The
result is increased detection of markers of collagen types I and
III turnover in the serum,115 pathological decreases in interstitial
collagen15,116,117 and left ventricular dilatation.
In response to different haemodynamic overloads (pressure
versus volume), the ECM undergoes different patterns of
remodelling.27 Volume overload produces a distinctive loss
of collagen fibrils surrounding individual myocytes,15,116,118
with the resultant wall thinning and ventricular dilatation
changing the geometrical shape of the LV, whereas excess
matrix deposition is observed in pressure overload.119,120 Despite
similar fibrotic molecular pathways and cellular effectors, the
pathophysiological mechanisms leading to fibrotic remodelling
are different, depending on the load on the heart.7 For example,
ACE inhibitors reduce remodelling and collagen accumulation in
pressure overload,121 but not in chronic MR.15,122 Furthermore, the
expression of integrins, which are important in ECM–myocyte
connectivity and ECM remodelling, are reduced in MR113 but
increased in pressure overload.123 Similarly, profibrotic TGF-β
expression was increased in mice with pressure overload114 but
was decreased in dogs with experimental MR,113 and expression
of PAI-1 was increased in a swine model of early pressure
overload124 but decreased in chronic MR.113
There appears to be a time-dependent increase and decrease in
MMP activity during the evolution of left ventricular remodelling
in response to primary MR (Fig. 3).26,117 Myocardial mast cells
have been found to be instrumental in increases in MMP activity
in early volume overload,69,117,125,126 and are increased in number
in response to volume overload-induced increases in myocardial
TNFα .45 In animal models there is an early rise in myocardial
MMP levels after the volume-loaded state is created but this
seems to normalise after the acute phase.127,128
MMP gene expression in dogs with isolated MR has
confirmed that, at four months, there was down-regulation of
a number of non-collagen genes important in ECM structure,
down-regulation of pro-fibrotic connective tissue growth factor
and plasminogen activator, and down-regulation of numerous
genes in the TGF-β pathway.113 However, MMP-1 and MMP-9
gene expression was still markedly increased in these dogs with
compensated MR compared with controls.113 As the LV started
to dilate in dogs with chronic myxomatous mitral valve disease,
MMP-9 levels decreased.129
Over time, there are characteristic changes in the MMP/TIMP
ratio, enabling the ventricle to initially increase compliance in the
acute and compensated phases of MR. However, at some point
(the ‘transition’ point) there is excessive degradation of the
ECM, leading to the decompensated and dilated LV. 27,130 What
controls the steady deterioration in the myocardium in response
to volume overload is not clear and appears to be complex.
In the early stages of volume overload, there are decreases in
ECM deposition (which contrasts with the picture in pressure
overload),113 but late in the progression of the dilating volume-
loaded heart, an increase in perivascular collagen deposition has
been noted, 26,126 which may reduce ventricular compliance and
promote systolic dysfunction.27
Chronic primary MR activates the neuro-
hormonal system: implications for beta-blocker
therapy
Patients with chronic primary MR demonstrate LV systolic
dysfunction even before a reduction in LVEF occurs.131,132 As
with heart failure due to any other cause, chronic MR results
in activation of the neurohormonal system and inflammatory
cascade at both systemic and local levels. 133-135 Withneurohormonal
activation, myocardial angiotensin II plays an important role in
the regulation of cell proliferation, apoptosis, inflammation and
production of mediators of remodelling such as platelet-derived
growth factor and MMPs.136 Persistent angiotensin receptor-1
activation by angiotensin II not only results in the generation of
ROS but also alterations in protein synthesis via tyrosine kinase
receptor activation and MAP kinase signalling.137 Furthermore,
angiotensin II-activated ROS act as second messengers that also
have effects on inflammation and cell growth.138 Angiotensin II
also acts on the sympathetic nerve endings in the myocardium to
facilitate catecholamine release. 139,140
Long-term increases in myocardial angiotensin II levels
increase local TGF-β , with the resultant increases in activation
of genes involved in ECM production via nuclear translocation
of NFκB.110,141 Unlike the pressure-overloaded heart where there
is progressive fibrosis,142 the increase in myocardial angiotensin
II in volume overload results in an increase in ECM turnover
with loss of interstitial ECM. 143 Despite the clear link between
angiotensin and remodelling in heart failure, to date there
has been little clinical evidence to support the role of medical
therapy directed against angiotensin in subjects with chronic
organic MR.15,144-146 This may be explained by the fact that ACE
inhibitors reduce the breakdown of bradykinin, which has been
implicated in the initial increase in MMP activity and collagen
breakdown seen in volume overload. 143
Three types of β-adrenergic receptors (β-ARs) are known to
exist in the myocardium: β1, β2 and β 3, with an approximate ratio
of 80:17:3.147 β1 and β2 are important in the regulation of myocyte
excitation–contraction coupling.80 β 1-AR is the predominant
receptor subtype expressed in the heart and, like other β -ARs, its
stimulation results in G-protein-coupled activation of the adenyl
cyclase–cAMP–protein kinase A (PKA) signalling cascade.
This leads to activation of a number of subcellular pathways
important in cardiomyocyte contractile function, including