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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