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lysine readers, and histone methylation  - are reviewed in Stratton and McKinsey

(2016) [ 34 ]. It is worth noting that, to date, there are no relevant data regarding the

effects of exercise in cardiac fibrosis occurring via interactions with epigenetic con-

trol mechanisms.

The molecular biology of cardiac remodelling and fibrosis is complicated by the

fact that there exists no single signaling pathway specific to cardiac fibroblasts.

Furthermore, a better understanding of the communication between cardiac fibro-

blasts and cardiomyocytes is further complicated by the complex nature of their

interactions (not only paracrine signals but structural and electrical signals as well).

Inflammatory signals appear to be more important in reparative and ischemic fibro-

ses. These fibroses are associated with significant activation of cytokine and chemo-

kine signaling cascades [ 26 , 27 ]. The renin-angiotensin II-aldosterone system and

fibrogenic growth factors (such as TGF-β and PDGF) appear to be involved in most

fibrotic cardiac conditions regardless of aetiology. For a more thorough review of

the molecular pathogenesis of cardiac fibrosis, please consult Kong et  al. which

describes the cellular effectors and molecular pathways contributing to cardiac

fibrosis along with a detailed review of the various mediators involved in the fibrotic

process: fibrogenic growth factors, matricellular proteins, mast cell-derived prote-

ases, reactive oxygen species, inflammatory cytokines and chemokines, renin-

angiotensin II-aldosterone signaling cascade and endothelin-1 [ 11 ].

The significant and close relationship that exists between cardiomyocytes and

cardiac fibroblasts suggests that it would probably be beneficial to consider both of

these cell populations when designing therapeutic interventions that seek to activate

regenerative processes. Targeted signals that modulate the activity of myofibro-

blasts or that seek to activate the survival pathways of cardiomyocytes should be

developed in combination to promote better cardiac regeneration and avoid the

potential clinical complications of current therapeutic approaches. It is important to

underline that both clinical and experimental evidence support the notion that

changes resulting from cardiac fibrosis may be reversible.

4 The Beneficial Effects of Exercise in Cardiac Fibrosis

Historically, the treatment of heart disease included rest and strict limitations of

physical activity. The past 20 years have seen an almost complete reversal in this

way of thinking. It is now commonplace for moderate to vigorous exercise to be

highly recommended not only for the prevention but also for the treatment of isch-

aemic heart disease. Focusing on myocardial fibrosis may potentially improve

patient care through the targeted diagnosis and treatment of emerging fibrotic path-

ways [ 3 ]. It is therefore of utmost importance to better comprehend the mechanisms

involved in the initial changes, subsequent progression, and eventual resolution of

cardiac fibrosis in order to devise the most effective therapeutic approaches. Animal

models have allowed researchers to make significant inroads in studying the impact

of physical activity on cardiovascular and overall health. In such studies, exercise

14 Cardiac Fibrosis: The Beneficial Effects of Exercise in Cardiac Fibrosis