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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 31, No 2, March/April 2020
62
AFRICA
Endothelial dysfunction is well known to be associated
with atherosclerosis in HIV-negative populations.
31,32
It has also
been described in HIV-positive patients without ACS.
26,33,34
In
our study, HIV+/ACS patients had almost the same degree of
endothelial dysfunction as the control group of ACS patients
without HIV. Although it would appear that endothelial
dysfunction was not more prevalent in the HIV-positive group
with ACS, it must be borne in mind that the latter group had
significantly fewer coronary risk factors such as hypertension,
diabetes, dyslipidaemia and family history of IHD compared
to the HIV-negative patients with ACS, suggesting that
HIV infection itself contributed to endothelial dysfunction.
HIV-positive patients without ACS had the highest brachial
artery vasoreactivity compared to the patients with ACS. This is
an interesting finding but is most likely a reflection of the much
younger age of this group compared to the other two groups.
In HIV-positive patients, endothelial activation may lead
to structural and functional vascular changes. Exposure to
long-term sub-clinical inflammation is related to accelerated
stiffening of large arteries. Peripheral waveform analysis using
PWV has been shown to provide a non-invasive method of
measuring ‘global’ endothelial function.
35
Increasing levels of
arterial stiffness are correlated with higher PWV. The value for
stiff vessels is a PWV > 10 m/s and this value has been found to be
an independent marker of end-organ damage.
36,37
In our study we
found uniformly low values (< 5 m/s) for PWV. This finding, we
believe, is largely an age-related effect. This is supported by Fourie
et al
. who recently reported increasing PWV velocities only after
the age of 50 years in HIV-positive, cART-naïve patients.
16
By studying ACS patients who were HIV positive and
comparing them to ACS patients who were HIV negative, we were
able to assess endothelial activation in both groups of patients.
In developing countries, high levels of endothelial markers
such as IL-6, TNF-
α
, PAI-1 and sCD14 have been reported in
HIV-positive compared with HIV-negative patients.
38-41
Studies of
endothelial function from developing nations have demonstrated
that in recently seroconverted Kenyan women, endothelial
biomarkers (VCAM-1 and ICAM-1) were significantly elevated
in these patients early after HIV infection.
12
In a recent study from South Africa, HIV-positive patients
were found to have higher levels of adhesion molecules compared
to HIV-negative patients, with an odds ratio of 3.9 (2.2–7.0) for
ICAM-1 and 16.2 (7.5–35) for VCAM-1.
42
Furthermore, the
same investigators reported that ICAM-1 and VCAM-1 were
elevated in both treated and cART-naïve patients, with the odds
being greater for the never-treated group.
36
Another study from South Africa, which assessed endothelial
biomarkers in ACS patients who were HIV positive, also found
significantly elevated VCAM-1 levels in HIV-positive patients
with ACS compared to control patients who were either HIV
negative or HIV positive without ACS.
5
Similarly, in our cohort
of HIV+/ACS patients, we found significantly higher levels of
VCAM-1 compared to HIV-negative patients, findings that are
in concert with previous reported results.
VCAM-1 is a member of the immunoglobulin super-family
and is involved in cellular adhesion and transmigration of
leucocytes through endothelial cells, and is thought to a play a
role in the development of atherosclerosis.
34
With the stimulation
of endothelial cells by inflammatory cytokines there is increased
expression of VCAM-1 and this is associated with an increased
predictive value for future cardiovascular events.
43
Therefore
VCAM-1 may be an informative biomarker for predicting the
risk of HIV disease progression, morbidity and mortality.
12
The pro-inflammatory cytokine, IL-6, induces expression of
adhesion molecules such as VCAM-1 and ICAM-1 and may
be seen as an early modulator of leukocyte trafficking in the
vascular wall.
44
However, we did not find significantly elevated
levels of IL-6 in HIV-positive and HIV-negative patients with
ACS. Lack of a significant difference in IL-6 and other markers
of endothelial dysfunction in HIV-infected and non-infected
controls have also been previously reported.
5,36
Non-invasive surrogate tools such as CIMT and coronary
computer tomography angiography indicate an increased
prevalence of sub-clinical atherosclerosis in HIV-positive
compared to HIV-negative patients.
45-47
A meta-analysis of 13
observational studies suggests a trend towards increased CIMT
in HIV-infected patients.
45
As early as childhood, HIV-infected
children receiving cART were found to have increased CIMT,
suggesting that IHD risk may already be heightened in
HIV-infected patients at a young age.
48
CIMT has been shown to decrease with cART and less
CIMT progression was associated with suppressed viral
load at baseline.
49
In our cohort, CIMT measurements were
unexpectedly lower in the HIV+/ACS compared to the HIV-/
ACS patients. The HIV+/no ACS patients also had low CIMT
measurements. One possible explanation for the finding of lower
CIMT in HIV+/ACS patients is the relative lack of traditional
risk factors for atherosclerosis, such as hypertension, diabetes
and low LDL levels in the HIV+/ACS group. It has been shown
that the presence of high cardiovascular risk-factor profiles in
HIV-positive patients is associated with increased CIMT.
50
This study has the following limitations. First, the study is a
single-centre study with a small sample size. Given the nature of
the study, it took almost three years to recruit 20 HIV-positive
patients presenting with ACS to our centre. With the small
sample size we were not able to perform multivariate analyses.
Second, given the type of the clinical presentation of patients
in the study we were unable to completely match case–control
patients for age, gender and cardiovascular risk factors. Although
the HIV+/no ACS group were gender matched, they could not
be matched for age as the majority of HIV+/no ACS patients,
who were cART-naïve, presenting at the HIV clinic were young.
Lastly, HIV+/no ACS patients in the study were newly diagnosed
and therefore the duration of infection was not known.
Conclusion
Endothelial dysfunction as assessed by brachial FMDwas similar
in HIV-positive patients with ACS compared to HIV-negative
patients with ACS. Endothelial biomarkers such as VCAM-1
and ICAM-1 were significantly raised in HIV-positive patients
compared to HIV-negative patients. However, VCAM-1 was
the only endothelial marker that was significantly raised in
HIV-positive patients with ACS compared to HIV-negative
patients with ACS. Our cohort of HIV-positive patients with
ACS had impaired FMD but near-normal CIMT and PWV
measurements. Given that FMD, CIMT and PWV were similar
in HIV-positive and HIV-negative patients with ACS, the use of
endothelial biomarkers may provide a more promising modality
to investigate endothelial activation and subsequent dysfunction.