Cardiovascular Journal of Africa: Vol 28 No 2 (March/April 2017)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 2, March/April 2017 126 AFRICA
This resulted in 23 biomarkers being considered in the model,
namely triglycerides, low-density lipoprotein (LDL), HDL,
apolipoprotein-B (Apo B), leptin, high-sensitivity C-reactive
protein (hsCRP), interleukin-6 (IL-6), tumour necrosis
factor-α (TNF-α), growth-differentiation factor-15 (GDF-
15), osteoprotegerin (OPG), myeloperoxidase (MPO), B-type
natriuretic peptide (BNP), homocysteine, fibrinogen, troponins,
urinary albumin-to-creatinine ratio (ACR), glycosylated
haemoglobin (HbA1c), insulin-like growth factor-1 (IGF-1),
adiponectin, cortisol, brain-derived neurotrophic factor (BDNF)
and insulin resistance.
In brief, the systematic review of the literature revealed the
pathological effects of various health factors on the pathogenesis
of CHD. This information was combined to form a visual
representation of the pathogenesis of CHD as it is affected by
these health factors. The biomarkers were included in the visual
representation to show functionally measurable aspects of the
pathogenesis.6,7 This visual representation presents an integrated
model of CHD.
This integrated model of CHD schematically illustrates the
complexity of CHD and shows all theoretical pathogenetic
pathways between health factors and CHD. The model has been
previously used to describe the effects of high-carbohydrate
diets on CHD,7 and the possible mechanisms through which
antidepressants9 and moderate alcohol consumption8 may reduce
CHD risk.
In this study the integrated model was used to describe the
integrated effects of exercise on the pathogenesis of CHD.
Furthermore, the effect of exercise on CHD was investigated
by analysing the effect that exercise has been shown to have on
measurable and quantifiable biomarkers.
Statistical analysis
It must be noted that some of the relative risk (RR) values in
this article differ from convention. The need for this comes as a
result of the visual scaling of the traditional RR. Traditionally,
if one plots an RR = 3 and RR = 0.33, respectively, one does not
‘look’ three times worse and the other three times better than
the normal RR = 1. The reason is that the scales for the positive
and negative effects are not numerically similar. A graph of
‘good’ and ‘bad’ RR can therefore be deceptive for the untrained
person, for example a patient.
This article rather uses the method that the conventional
RR = 3 is three times worse than the normal RR = 1, while the
conventional RR = 0.33 means that the patient’s position is three
times better than the normal RR = 1. Therefore, in summary, a
conventional RR = 3 is presented as per normal, as a three-fold
increase in risk and a conventional RR = 0.33 is presented as a
three-fold decrease in risk (1/0.33 = 3).
Results
Integrated model of coronary heart disease
The integrated model of CHD that was developed in previous
studies is presented in Fig. 1. The pathways (pathogenesis of
CHD) within the integrated model can be tracked from where a
chosen health factor influences the relevant tissue, to the end state
of CHD. The pathways are therefore a visual representation of
previously published knowledge. Salient serological biomarkers
(shown in Fig. 1 as ) and pharmacotherapeutics (shown in Fig.
1 as ) that act on the pathways are further indicated in Fig. 1.
The focus of this review is on using the integrated model
to describe the interconnections of moderate exercise on the
pathogenesis of CHD. Therefore a more detailed discussion
of Fig. 1, relevant to exercise, is given in the next section.
This review therefore attempts to quantify the CHD effect of
moderate exercise by the connection of these to an array of
biomarkers that represent increasing or decreasing CHD risk.
Pathogenetic effects of physical exercise
In order to appraise the CHD effects of moderate exercise, the
relevant pathogenetic pathways need to be considered. While
Fig. 1 also indicates other health factors, only the pathways
activated by moderate exercise are summarised in Table 1. It
is however important to note that not all the pathways will be
relevant to every patient and that all the pathways may not be
active simultaneously, or occur in the same patient.
Fig. 1 (pathway: 3a-53-55-hyperglycaemia) shows the
pathways involved in a lack of physical exercise (and decreased
daily energy expenditure) and how this affects carbohydrate
metabolism through changes in muscle glucose transporter
Table 1. Putative effects of moderate exercise and salient CHD
pathogenetic pathways
Pathways, and pathway numbers corresponding to those in
Fig. 1 References
a. 3a-53-↓ blood glucose-55-↓ hyperglycaemia 38, 39
b. 3a-53-↓ blood glucose-54-↓ PI3K:MAPK-69-↓ insulin
resistance-72- ↓ platelet factors-73-↓ hypercoagulability
40–47
c. 3a-53-↓ blood glucose-54-↓ PI3K:MAPK-69-↓ insulin
resistance-72- ↓ ROS
38, 40,
45–48
d. 3a-53-↓ blood glucose-54-28-101-↓ insulin resistance-72-
↑ vasodilation
49
e. 3b-27-↓ cortisol-47-↓ insulin resistance-70-↓ angiotensin
II-89-↓ hypertension-100-↓ ROS-85-↓ COX1/2-85-↓
inflammatory state
29, 30, 38,
45, 48
f. 3b-27-↓ cortisol-47-↓ insulin resistance-70-↓ angiotensin
II-89-↓ SMC proliferation
50
g. 3b-27-↓ cortisol-47-↓ insulin resistance-70-↓ angiotensin
II-89-↑ IGF1-84-↓ SMC proliferation
51–54
h. 3b-27-↓ cortisol-47-↓ insulin resistance-70-↓ angiotensin
II-89-↓ VCAM1/MCP1-73-↓ hypercoagulation
29
i. 3c-↓ visceral adipose tissue-↓ ectopic fat 38, 55, 56
j. 3c-19-↑ adiponectin-38-↓ TNFα /IL6-56-Liver-12-↓
LDL-33-↓ oxLDL-51-↓ hypercholesterolaemia
38, 56, 57
k. 3c-19-↑ adiponectin-39-↓ insulin resistance 58
l. 3c-19-↑ adiponectin-39-↓ SMC proliferation 55
m. 3c-21-↓ TNFα /IL6-56-Liver-12- ↓ LDL-33-↓
oxLDL-51-↓ hypercholesterolaemia
5, 32,
59–62
n. 3c-21-↓ TNFα/IL6-41-↓ P. gingivalis-43- ↓ periodonti-
tis-64-↓ platelet factors-73-↓ hypercoagulability
5, 32,
59–62
o. 3c-18-↓ FFA-37-↓ plasma lipids-34-Liver-12-↓ LDL-33-
↓ oxLDL-51-↓ hypercholesterolaemia
5, 32, 38,
56, 59–62
↑, up regulation/increase; ↓, down regulation/decrease; x-y-z indicates
pathway connecting x to y to z. FFA, free fatty acids; IGF 1, insulin-
like growth factor-1; IL6, interleukin-6; LDL, low-density lipoprotein;
MAPK, mitogen-activated protein (MAP) kinase; MCP 1, monocyte
chemo-attractant protein-1; NO, nitric oxide; oxLDL, oxidised LDL;
P gingivalis, Porphyromonas gingivalis; PI3K, phosphatidylinositol
3-kinase; PI3K:MAPK, ratio of PI3K to MAPK; ROS, reactive oxygen
species; SMC, smooth muscle cell; TNFα, tumour necrosis factor-α ;
VCAM 1, vascular cell adhesion molecule-1.