64 / 74
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 5, September/October 2018
326
AFRICA
Diabetes mellitus (DM), the other major conventional risk
factor for PAD, has been shown in multiple research studies
to induce a pro-inflammatory state that leads to accelerated
atherosclerosis. The proposed mechanism is that of increased
expression of adhesion molecules, leading to inflammatory cells
crossing the endothelium and forming foam cells, thus initiating
and perpetuating the vicious circle of atherosclerotic plaque
formation.
102
A study on patients with diabetic foot showed markedly
elevated levels of IL-6 and resistin, coupled with reduced
adiponectin plasma levels,
103
suggesting an important anti-
inflammatory and anti-atherosclerotic role for this glucose-
regulating protein. Tuttle
et al.
reported higher levels of
circulating IL-6 and TNF-a in diabetic women, irrespective of
clinically manifested cardiovascular disease.
104
Similar results
were found in a study on Indian subjects with type 2 DM
(which had higher plasma levels of hs-CRP and lower levels of
adiponectin compared to healthy controls),
105
confirming the
pro-inflammatory state that diabetes mellitus induces, one that
transcends gender or age.
Dyslipidaemia has also been related to increased systemic
inflammation in several trials. The Justification for the Use
of Statins in Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER) study showed that in healthy women
with high levels of low-density lipoprotein cholesterol (LDL-C)
(
>
130 mg/dl; 3.37 mmol/l) and a value of hs-CRP above 2 mg/
dl, the overall risk of developing adverse cardiovascular events,
even PAD related, increased greatly.
106
Elevated serum levels of
CRP in women have been related to the presence of diabetes, the
metabolic syndrome and collagen vascular disease,
107
all of these
conditions being known for their predisposition to accelerated
atherosclerosis.
Multiple other associations between lipid components
and inflammatory status have been revealed. For example, in
men with established cardiovascular disease, including PAD,
a clear association between lipoprotein (a), LDL-C, arterial
hypertension and elevated fibrinogen levels has been found,
108
suggesting that the novel biomarkers of atherosclerosis and
inflammation are strongly related to traditional risk factors for
the disease in a pathophysiological continuum that reveals some
gender-specific peculiarities.
Conclusion
Although many of the above biomarkers represent a hallmark of
atherogenesis in both genders [lipoprotein (a), TNF-
α
, sRAGE,
VEGF, CD163/TWEAK, thrombospondin-1, galectin-3], some
tend to correlate positively and strongly with the presence of
PAD in females (CRP, IL-6, ICAM-1, VCAM-1, ROS, leptin,
apolipoprotein CIII, adiponectin, MMP-9), while others, such
as homocysteine, seem to be associated with the disease only in
male individuals. Acknowledging these gender differences could
be useful for the early identification and optimal management of
patients with PAD.
References
1.
Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott
MM,
et al
. Comparison of global estimates of prevalence and risk
factors for peripheral artery disease in 2000 and 2010: a systematic
review and analysis.
Lancet
2013;
382
: 1329–1340. doi: 10.1016/S0140-
6736(13)61249-0.
2.
Allison MA, Ho E, Denenberg JO, Langer RD, Newman AB, Fabsitz
RR,
et al
. Ethnic-specific prevalence of peripheral arterial disease in
the United States.
Am J Prev Med
2007;
32
: 328–333. doi: 10.1016/j.
amepre.2006.12.010.
3.
Gardner AW, Parker DE, Montgomery PS, Sosnowska D, Casanegra
AI, Ungvari Z,
et al
. Gender and racial differences in endothelial
oxidative stress and inflammation in patients with symptomatic periph-
eral artery disease.
J Vasc Surg
2015;
61
: 1249–1257. doi: 10.1016/j.
jvs.2014.02.045.
4.
Kullo IJ, Bailey KR, Kardia SL, Mosley TH, Jr., Boerwinkle E, Turner
ST. Ethnic differences in peripheral arterial disease in the NHLBI
Genetic Epidemiology Network of Arteriopathy (GENOA) study.
Vasc
Med
2003;
8
: 237–242. doi: 10.1191/1358863x03vm511oa.
5.
Allison MA, Criqui MH, McClelland RL, Scott JM, McDermott MM,
Liu K,
et al
. The effect of novel cardiovascular risk factors on the ethnic-
specific odds for peripheral arterial disease in the Multi-Ethnic Study of
Atherosclerosis (MESA).
J Am Coll Cardiol
2006;
48
: 1190–1197. doi:
10.1016/j.jacc.2006.05.049.
6.
Fowkes FG, Aboyans V, Fowkes FJ, McDermott MM, Sampson UK,
Criqui MH. Peripheral artery disease: epidemiology and global perspec-
tives.
Nat Rev Cardiol
2017;
14
: 156–170. doi: 10.1038/nrcardio.2016.179.
7.
Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin
JL,
et al.
ACC/AHA 2005 practice guidelines for the management of
patients with peripheral arterial disease (lower extremity, renal, mesen-
teric, and abdominal aortic): a collaborative report from the American
Association for Vascular Surgery/Society for Vascular Surgery, Society
for Cardiovascular Angiography and Interventions, Society for Vascular
Medicine and Biology, Society of Interventional Radiology, and the
ACC/AHA Task Force on Practice Guidelines (writing committee to
develop guidelines for the management of patients with peripheral arte-
rial disease): endorsed by the American Association of Cardiovascular
and Pulmonary Rehabilitation; National Heart, Lung, and Blood
Institute; Society for Vascular Nursing; TransAtlantic Inter-Society
Consensus; and Vascular Disease Foundation.
Circulation
2006;
113
:
e463–654. doi: 10.1161/CIRCULATIONAHA.106.174526.
8.
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes
FG,
et al.
Inter-Society Consensus for the Management of Peripheral
Arterial Disease (TASC II).
J Vasc Surg
2007;
45
(Suppl S): S5–67. doi:
10.1016/j.jvs.2006.12.037.
9.
Berenson GS, Srinivasan SR, Bao W. Precursors of cardiovascular risk
in young adults from a biracial (black–white) population: the Bogalusa
Heart Study.
Ann NY Acad Sci
1997;
817
: 189–198. doi: 10.1111/j.1749-
6632.1997.tb48206.x.
10. Napoli C, D’Armiento FP, Mancini FP, Postiglione A, Witztum JL,
Palumbo G,
et al
. Fatty streak formation occurs in human fetal aortas
and is greatly enhanced by maternal hypercholesterolemia. Intimal accu-
mulation of low density lipoprotein and its oxidation precede monocyte
recruitment into early atherosclerotic lesions.
J Clin Invest
1997;
100
:
2680–2690. doi: 10.1172/JCI119813.
11. Napoli C, Glass CK, Witztum JL, Deutsch R, D’Armiento FP, Palinski
W. Influence of maternal hypercholesterolaemia during pregnancy on
progression of early atherosclerotic lesions in childhood: Fate of Early
Lesions in Children (FELIC) study.
Lancet
1999;
354
: 1234–1241. doi:
10.1016/S0140-6736(99)02131-5.
12. Teodorescu VJ, Vavra AK, Kibbe MR. Peripheral arterial disease in
women.
J Vasc Surg
2013;
57
: 18S–26S. doi: 10.1016/j.jvs.2012.10.115.
13. Vouyouka AG, Egorova NN, Salloum A, Kleinman L, Marin M, Faries
PL,
et al.
Lessons learned from the analysis of gender effect on risk