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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 5, September/October 2018
318
AFRICA
collagen and elastin, leading to accelerated atherosclerosis,
usually detected by the measurement of carotid intima–media
thickness.
12–15
One meta-analysis of observational studies
undertaken by a Canadian group concluded that the CVD
mortality rate was increased by approximately 50% in RA
patients compared with the general population,
16
with neoplastic
disease and respiratory disease, particularly pneumonia, being
other significant contributors.
4
Notwithstanding traditional risk factors for CVD common
among RA patients in developed countries (smoking, obesity,
type 2 diabetes mellitus, dyslipidaemia and others), those
specifically associated with RA include the presence of extra-
articular manifestations and erosions, as well as prolonged
disease duration with accompanying systemic inflammation
and endothelial dysfunction.
12-18
Given that increased risks for
the development of myocardial infarction, heart failure/sudden
death and stroke in patients with RA have been estimated to be
two- to three-fold, two-fold and 1.7-fold, respectively,
19
it is hardly
surprising that the European League Against Rheumatism
advocates ‘that early detection and pre-emptive treatment of
high-risk (RA) patients is of great importance in reducing the
excess risk of CVD in RA’.
20
In this context, RA-related CV
screening in the developed world setting is considered to be a
cost-effective strategy.
21
The current methods used to assess cardiovascular risk do
not accommodate long-term exposure to inflammation and
tend to underestimate the risk. Different scoring mechanisms
are used and under-estimations of risk as large as two-fold
have been observed with the Framingham Risk Score (FRS)
when applied to RA patients.
22
The European League Against
Rheumatism (EULAR) working group has suggested that the
Systematic Coronary Risk Evaluation (SCORE) scoring system
risk value be multiplied by 1.5 in RA patients who show at least
two of the following: (1) RA disease of more than 10 years,
(2) positive RF, (3) positive ACPA, and (4) presence of extra-
articular manifestations.
23
It is, however, possible that even with
the modified SCORE, a large number of RA patients still may
not be identified and are at high risk for CVD.
24
In addition to ultrasound measurement of carotid intima–
media thickness
13
and high-resolution ultrasound measurement
of flow-mediated vasodilation in the branchial artery (measures
arterial response to hypoxia) to evaluate endothelial function
as a ‘surrogate marker of subclinical atherosclerosis’,
25
several
systemic biomarkers of inflammation and cardiac dysfunction
have also been reported to predict CVD risk and mortality in RA
patients. Currently, the most promising of these is N-terminal
pro-brain natriuretic peptide (NT-proBNP), a well-recognised,
sensitive predictor of future CVD and mortality in general
healthy populations, as well as in RA patients, according to the
limited studies undertaken to date.
26-28
Measurement of cardiac
troponin T may also have predictive potential in RA,
28
but
interpretation of data is complicated by the influence of age and/
or the presence of other co-morbidities.
Pathogenesis of CVD in RA
Chronic, low-grade systemic inflammation leading to prolonged
endothelial activation and an accompanying pro-thrombotic/
pro-coagulant state is believed to be the major contributor to
the increased risk of CVD in RA.
19
Some of the most prominent
proposed immunopathogenic processes underpinning these
events are summarised as follows:
•
increased systemic levels, presumably synovium-derived, of
the endothelial-activating cytokines interleukin (IL)-1
β
, IL-6,
tumour necrosis factor (TNF)-
α
and interferon (IFN)-
γ
19,29-31
•
binding and activation of neutrophils, monocytes and plate-
lets to cytokine-activated, pro-adhesive vascular endothelium,
potentiated by the neutrophil and monocyte chemokines,
CXCL8 (IL-8) and CCL2, respectively
19,29,30
•
systemic activation of platelets, not only via interaction
with cytokine-sensitised vascular endothelium and proximal
neutrophils/monocytes, which may trigger further platelet
activation via protease-activated receptors (PARs) 1 and 4,
but also by exposure to ACPA
32
•
activation of vascular endothelium PAR-1 by adherent
neutrophils/monocytes, thereby exacerbating systemic inflam-
mation and endothelial dysfunction
33
•
creation of a pro-inflammatory milieu conducive to the forma-
tion of pro-atherogenic oxidised low-density lipoprotein
29
•
intra-vascular formation of neutrophil extracellular traps
(NETs) via exposure of these cells to activated platelets
34
•
NETs, in turn, contribute to the intravascular, pro-inflamma-
tory/pro-thrombotic/pro-coagulant environment via expres-
sion of endothelium-activating proteases
33
and histones,
35
as
well as the expression and presentation of functional tissue
factor.
36
Although partially controlled by endogenous anti-inflammatory
mechanisms,
30
this chronic, low-grade activation and dysfunction
of vascular endothelium, triggered and sustained by synovial-
derived mediators of inflammation, is likely to underpin the
pro-atherogenic, pro-thrombotic changes that favour accelerated
development of CVD in patients with untreated RA.
Smoking, smokeless tobacco use, RA and CVD
Smoking is a well-recognised risk factor for the development of
both RA and CVD, and in a recent study from the US, smoking
was found to be an independent predictor, albeit somewhat
weaker than age (
p
<
0.05 vs
p
<
0.001, respectively), of the
presence of atherosclerotic plaques in patients with RA.
37
As
with RA, these atherothrombotic effects of smoking are also
associated with ‘multiple pathological effects in the endothelium’,
as well as activation of platelets and the coagulation cascade.
38
However, less attention has been focused on the possible
pro-atherogenic effects of usage of smokeless tobacco products,
which is common among black South African females, with
a recorded prevalence of 48% among RA participants in
the Gauteng Rheumatoid Evaluation and Assessment Trial
(GREAT).
39
Indeed, on the African continent, only Botswana
and Mauritania have a higher prevalence of smokeless tobacco
use than South Africa.
40
In a recently reported analysis of the
global burden of disease, usage of smokeless tobacco products
was estimated to account for 4.7 million disability-adjusted life
years lost and 204 309 deaths, based on data from the benchmark
52-country INTERHEART study,
40
the risk being statistically
significant with an adjusted odds ratio of 1.57.
41
In this context, it is noteworthy that blood levels of the
nicotine metabolite, cotinine, in South African female users
of inhaled snuff products were found to be comparable with
those of active smokers.
39
In the past, nicotine has been a