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infarctions, and due to the limited regenerative capacity of the heart muscle, repre-
sents myocardial healing. In contrast, persistent increases in preload or afterload
attributable to hypertension, metabolic disorders, valvular disease, ischaemic injury
and cardiomyopathies result in chronic diffuse or focal reactive myocardial fibrosis
[ 4 , 7 ]. The dysregulation of distinct pro- and anti- fibrotic factors (i.e. hormones,
growth factors, cytokines, chemokines, proteases and reactive oxygen species) is
responsible for the alteration of the collagen matrix [ 13 ]. The conversion of fibro-
blasts into active myofibroblasts involves the expression of different cellular markers
(see Table 14.1). The conversion of phenotype begins with changes in the subcellular
structure such as the onset of expression of α-smooth muscle actin and the increased
secretion and assembly of extracellular procollagen chains into collagen type I and
type III fibrils that become cross-linked to form the final fibres. The cross-linking of
collagen represents a significant post-translational modification as it results in
increased myocardial tensile strength and increased resistance of collagen fibres to
degradation by matrix metalloproteinases [ 12 , 14 ]. Fibrosis of cardiac tissue disrupts
the myocardial architecture, contributes to myofibrils disarray, and determines
mechanical, electrical, and vasomotor dysfunction, thus promoting the progression of
cardiac diseases to heart failure [ 15 ]. Clinical studies have shown that the severity of
histologically-confirmed myocardial fibrosis is associated with higher long-term mor-
tality in patients with cardiac diseases, particularly those with heart failure. From this
perspective, detecting, preventing, and reversing myocardial fibrosis have emerged as
important novel strategies in the approach to heart failure therapy. Of note, fibrosis
persists in the myocardium of heart failure patients under the current treatment regi-
mens recommended by the official guidelines. Thus, the current treatment of heart
failure patients, although improving clinical symptoms, does not appear to reverse the
underlying fibrosis. In aortic stenosis patients, aortic valve replacements result in
regression of left hypertrophy, providing further evidence that hypertrophy and fibro-
sis appear to be reversible for many cardiovascular diseases [ 4 , 15 – 18 ].
Table 14.1 The relative expression of fibroblast markers in cardiac fibroblast and myofibroblast
Fibroblast marker Adult cardiac fibroblast Myofibroblast
Thymus cell antigen-1/CD90 ++ ++
Vimentin ++ ++
Periostin +/− ++
Discoidin domain receptor 2 + ++
Fibroblast specific protein-1 +/− +++
α-smooth muscle actin +/− +++
Platelet derived growth receptor β ++ ++
Fibroblast activation protein ++ ++
Stem cells antigen-1 ++ ++
ADAM metallopeptidase domain 12 + ++
Lysine 6-oxidase + +++
Wnt-1-induced secreted protein ++ +++Adapted from Refs. [ 8 , 19 ]
J. Kyselovič and J.J. Leddy