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2 Cardiac Remodelling and Fibrosis
Cardiomyocytes, fibroblasts, and vascular cells in the heart are connected by an
elaborate matrix composed mostly of fibrillary collagen which is instrumental in
preserving the plasticity and structural integrity of the heart. Cardiac fibroblasts,
which are the most abundant cells in the mammalian heart, have a dynamic but bal-
anced interaction with cardiomyocytes. Historically, the most recognized role of
fibroblasts has been their contribution to secretion, maintenance and remodelling of
the extracellular matrix. However, fibroblasts have been proposed to participate in
many other aspects of myocardial function and dysfunction. For example, the
mechanical and electrical contributions of myofibroblasts to the heart before and
after injury could be critical [ 8 ].
All aspects of these homeostatic interactions are affected in any cardiac injury.Under pathophysiological conditions, the heart’s matrix displays significant restruc-
turing and subcellular modification that result in progressively decreased cardiac
function. It is now accepted that alterations of the cardiac extracellular matrix and
cardiac remodelling play a major role in the development and evolution of cardiac
diseases leading to heart failure [ 6 ]. Fibrosis is a commonly observed pathological
feature of most chronic inflammatory diseases. It normally involves three overlap-
ping inflammatory phases: proliferation, granulation, and maturation. Each of these
phases involves the participation of cardiac fibroblasts. The process is characterised
by the accumulation of excessive extracellular matrix components, whereby
increased synthesis predominates over unchanged or decreased degradation of col-
lagens resulting in excessive, diffuse collagen accumulation in the interstitial and
perivascular tissues [ 4 ]. Fibrotic remodelling of the heart involves several cell types
that participate either directly by producing matrix proteins (fibroblasts), or indi-
rectly by secreting mediators of fibrogenic activity. Part of the secretome that trig-
gers and maintains fibrosis includes myocytes, myofibroblasts, and macrophages/
leucocytes/mast cells [ 4 , 11 , 12 ]. This dysregulation of collagen turnover takes
place mainly in phenotypically transformed fibroblasts, termed myofibroblasts. In
advanced disease, the fibrotic process eventually leads to severe organ dysfunction
and death.
In the initial pathophysiology, a significant increase in the release of pro-inflammatory cytokines can be detected from injured cardiac fibroblasts. These
cytokines are involved in a feed-forward loop that results in accelerated prolifera-
tion, re-expression and upregulation of many of the markers initially expressed
within the embryonic and homeostatic stages (see Table 14.1). Eventually, the trans-
formation culminates with the differentiation of fibroblasts into highly proliferative
migratory activated myofibroblasts [ 6 , 8 ].
Myofibroblasts are not only derived from cardiac fibroblasts but can also origi-nate from epithelial cells, endothelial cells, bone marrow-derived cells (fibrocytes),
pericytes, and smooth muscle cells [ 9 , 10 ]. Myofibroblasts have been shown to have
important structural, paracrine, and electrical interactions with cardiomyocytes in
both development and disease. Acute focal fibrotic scarring follows myocardial
14 Cardiac Fibrosis: The Beneficial Effects of Exercise in Cardiac Fibrosis