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

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2.6 Physical Exercise Preserves Atherosclerotic Plaque

Stability

Most of the acute coronary syndrome (ACS) occurs because of plaque rupture.

Plaque rupture exposes sub-endothelial to various of thrombogenic factors in the

blood. Thrombus forms immediately after the exposure, leading to acute myocar-

dial infarction or stroke [ 16 , 18 ]. The vulnerability renders plaques to rupture. A

vulnerable atherosclerotic plaque has thin fibrous cap, large lipid core (>50% total

plaque surface), high inflammatory cell burden but low volume of SMCs [ 149 ].

Physical exercise has shown its capacity to slow the progression of atherosclero-

sis via promoting plaque stability and preventing plaque rupture in animal studies

[ 76 , 106 , 150 , 151 ]. ApoE −/− mouse model has been commonly used in athero-

sclerosis studies. Using this model, swimming training was applied to study its

effect on the plaque. After swimming training, it is observed that the plaques are

more stable by thicker fibrous cap, less adventitia inflammation, decreased media

degeneration and inflammatory macrophage plaque content [ 106 ]. Physical exercise

regulates plaque size and its rupturing potential through regulation of matrix con-

tent and matrix regulators [ 151 ]. Physical exercise decreases MMP-2, MMP-3, and

MMP-8 levels as well as IL-6. Besides, collagen, elastin, and TIMP-2 (inhibitor of

MMP-2 and MMP-9) were also found to be increased in parallel with the change of

fibrous cap thickness [ 147 , 151 ]. In other studies, MMPs, TIMP-1 are also found to

be modulated by physical exercise [ 152 ].

Apart from the ability to modifying lipoproteins, macrophages can worsen the

plaque status by producing MMPs, which is known to degrade collagen in plaque

[ 153 ]. Collagen is the basic structure to keep the atherosclerotic plaque well-formed.

Destruction of the collagen would lead to thrombogenic disasters as mentioned

above. Physical exercise could prevent this from happening by modifying macro-

phage function.

Pro-inflammatory enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2)

is a novel marker for plaque inflammation and rupture-prone plaques [ 154 ].

Lp-PLA2 binds to ApoB-containing lipoproteins and degrades oxidized phospho-

lipids in LDL-cholesterol. Elevated level of Lp-PLA2 can be detected within the

necrotic core and macrophages of vulnerable plaques, but not in early stable plaques

[ 154 ]. Furthermore, Lp-PLA2 predicts mortality in MI and post-MI patients [ 155 ].

Physical exercise has negative effects on this new biomarker, however, clinical evi-

dence remains insufficient [ 156 , 157 ]. In one clinical study, patients with dyslipid-

emia have suppressed level of Lp-PLA2 after strict lifestyle modification [ 158 ].

High plasma Hcy concentration is associated with atherosclerotic plaque rupture

and morbidity in type 2 diabetes patients, and is considered as an independent risk

factor for CVD [ 84 – 86 , 159 – 161 ]. It encourages plaque maturation by activating

SMCs and promoting macrophage differentiation. While physical exercise can

potentially reduce the detrimental effects of HHcy on macrophages. It should be

noted that this effect has not be tested in vivo so far.

J. Yang et al.