Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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1 Introduction

Over the last half-century, numerous scientific and clinical reports have examined

the relationship between cardiovascular health and physical fitness. The prevailing

findings of these studies have concluded that more active individuals tend to develop

less cardiovascular disease than their less active counterparts [ 1 ]. All types of exer-

cise training have been shown to foster the health and performance of the cardiovas-

cular system. The beneficial effects of exercise can best be explained by the

reduction of cardiovascular risk factors as well as the modification of molecular and

cellular remodelling pathways in the heart [ 2 ]. This review focuses on the beneficial

effects of exercise in cardiac fibrosis as demonstrated in basic research studies.

Attention will be given to the characterisation of the relationship between exercise

and cardiac remodelling, including the molecular and cellular adaptations of the

heart in response to exercise as well as benefits of exercise in preventing or revers-

ing the pathological remodelling of the heart [ 3 ].

Cardiomyocytes, fibroblasts, and vascular cells in the heart are connected by a

complex matrix principally composed of fibrillary collagen. This collagen is instru-

mental in preserving the structural integrity and plasticity of the cardiac tissue. A

cardiac fibroblast is typically described as a cell that synthesizes and secretes pro-

teins that contribute to connective tissue. The heart’s matrix, unlike the highly orga-

nized connective tissue of bone and tendon, is dense, irregular, and composed of

collagens, proteoglycans and glycoproteins. Collagen types I, III, V and VI, as well

as fibronectin, periostin and vimentin are some of the structural molecules that are

synthesized by cardiac fibroblasts [ 19 ]. In the diseased heart, the matrix undergoes

structural and subcellular changes that progressively impair cardiac function. Under

physiological conditions, fibroblasts secrete extracellular procollagen chains that

assemble into cross-linked fibrils in the interstitium. Under pathological conditions,

changes in the matrix environment, increased release of cytokines and growth fac-

tors, as well as increases in mechanical stress dynamically modulate fibroblast

transdifferentiation into myofibroblasts. Higher levels of cross-linking of collagen

ensue, leading to increases in myocardial tensile strength [ 4 ].

Thus, cardiac fibrosis is characterized by the systolic or diastolic dysfunction

that results from the accumulation of extracellular connective tissue proteins in the

heart’s interstitium. Both clinical evidence and experimental studies have suggested

that fibrotic changes in the heart are reversible [ 5 ]. Animal models have shown that

the beneficial cardiac effects of training are related to signaling pathways involved

in hypertrophy and fibrosis. Given our understanding of these signaling pathways,

the selection of the animal model that is most appropriate for the proposed research

project is of crucial importance to the quality and the eventual translational applica-

tions of the research outcomes. From this perspective, this review will focus on

providing better insight into the current state of basic research relating to the benefi-

cial effects of exercise in cardiac fibrosis.

J. Kyselovič and J.J. Leddy