Discussion
This novel study demonstrates that mastoscytosis patients possess
endothelial impairment in the absence of systemic inflammation and
subclinical atherosclerosis which is excessive in advanced forms and is
related to serum VEGF biomarker. It also determines predictive values of
FMD and VEGF for endothelial dysfunction in mastocytosis patients for
the first time.
It is well known that MCs are found in perivascular area and lymphatic
endothelium (4) and increased MC count and its
mediators can increase oxidative stress by effecting the vessel
endothelium (27). In accordance with this knowledge,
the reason of impaired FMD in patients with mastocytosis in our study
can be related to increased MC accumulation in the vessel walls and
decreased stress response of the brachial artery is due to this
accumulation. In addition, when patients were allocated into
mastocytosis subgroups, FMD was low in all subgroups while the lowest
value was detected in advSM and SSM group. Since MC accumulation in
advSM and SSM is expected to be more than other subgroups(1, 2, 28), our this finding supports the hypothesis
that increased MCs and related mediators may cause impaired FMD in
patients with mastocytosis. Interestingly, FMD was found lower in CM
patients than HCs although it was not statistically significant. Since
CM is limited to the skin, the largest organ of our body, and it
probably hosts increased number of MCs in skin vessels, lower FMD in CM
patients can be expected than HCs (29). Similar to our
study, endothelial dysfunction in mastocytosis was reported in a recent
study of limited number of systemic mastocytosis patients. This study
showed a negative correlation between serum baseline tryptase levels and
FMD (5) which is not found in our study probably due
to the heterogeneity and the large number of the patients involved.
Similarly, in our study FMD inversely correlated with systolic and
diastolic blood pressure in accordance with this knowledge(24, 25).
It has been shown that MCs may affect the improvement and rupture of an
atheroma plaque (30) However, in our study endothelial
dysfunction observed in the patient group was not related to subclinical
atherosclerosis determined with CIMT measurement (21).
Since age, smoking habits, fasting glucose level and lipid profile were
similar in patients with mastocytosis and HCs in our study, the risk
factors for atherosclerosis were considered as similar in both groups.
In a previous study, Unal et al indicated that higher IgE levels in
various allergic diseases can be related to the development of
atherosclerosis but failed to show a correlation between total IgE and
CIMT levels (31). Similarly, in our study we did not
observe such a correlation. Consequently, our study revealed that
impairment of FMD in mastocytosis can occur in the absence of
atherosclerosis and follow-up of these patients may be important
considering the increased risk of developing cardiovascular diseases.
VEGF is mainly secreted by ECs but also secreted by macrophages,
platelets, activated T-cells, leukocytes and tumor cells(32). It leads to decreased vessel tonicity by
increasing calcium/calmodulin, endothelial nitric oxide synthase (eNOS)
activity and prostacyclin in ECs(33) and its serum
level can increase in inflammation due to uncontrolled endothelial
activation (13). Two studies showed that VEGF can be
secreted by atypical MCs seen in mastocytosis when compared to
non-neoplastic MCs (34, 35). In our study the median
VEGF level was significantly higher in patients than HCs , most
prominently in advSM patients. Since MC accumulation in advSM and SSM is
expected to be more than ISM and CM (1, 2, 28), we may
speculate that the increase in VEGF observed in the patients can be
directly related to the atypical MC counts in the patients. Moreover,
the inverse correlation between the two parameters which are probably
related to MC counts, FMD and VEGF, found in our study strengthens our
hypothesis that increased accumulation of MCs can cause endothelial
dysfunction in mastocytosis.
Studies showed that endocan can be used as a marker for endothelial
dysfunction in diabetes, hereditary angioedema (HAE), sleep apnea
syndrome and cardiovascular diseases(11, 36-39)Demirtürk et al. found that endocan can be a marker for endothelial
dysfunction in attack free periods in C1 inhibitor deficient HAE (C1 INH
HAE) patients (11). Others reported that higher serum
endocan levels might reflect endothelial dysfunction in primary
hypertension irrespective of blood pressure results(38). In our study, endocan was evaluated for the
first time in mastocytosis. Although there was no significant difference
in endocan levels between the patients and HCs, there was a negative
correlation between FMD and endocan levels. Since endocan induces VEGF
to bind its receptor and also a prominent decrease in the expressions of
the cytoskeleton-associated proteins occludin and ZO-1, which are
important elements of tight junctions in vascular endothelium(40), we believe that further studies are needed to
investigate endocan in relation to VEGF in mastocytosis. Similar to
endocan we could not find any significant relation with ET-1 and
mastocytosis although it has been shown in endothelial dysfunction in
other diaseases (41). Since there was a negative
correlation with FMD and ET-1 and a positive correlation between ET-1
and endocan levels in our study, larger studies can further elucidate
possible relations in between.
Although previous data showed that inflammatory biomarkers TNF-α and
IL-6 can stimulate the release of ET-1, however TNF-α plays a role in
the development of atherosclerosis (15), IL-6 can
increase in severe mastocytosis (42), and hsCRP as an
independent risk factor of cardiovascular disease can increase in
inflammation and atherosclerosis (39), there were no
differences in any of these inflammatory biomarkers between the patients
and the HCs in our study. Although ESR was not different between the
patients and HCs, it was significantly increased in ISM, advSM and SSM
patients when compared to CM patients, probably due the deepened anemia
observed in these patients. All these findings remind us that
endothelial dysfunction occurs in the absence of systemic inflammation
in mastocytosis.
According to our ROC analysis, we propose that when FMD % level is
< 14.5% and VEGF is >62 pg/mL, endothelial
dysfunction may be evident in mastocytosis patients and further
cardiovascular monitoring may be necessary. Since the AUC values of VEGF
and FMD are not statistically different, either of the test can be
performed to predict according to its availability.
Although our study is a comprehensive study evaluating endothelial
dysfunction in mastocytosis, the heterogenous distribution of patients
in mastocytosis subgroups may negatively affect statistical
significance. As a limitation, patients in the advSM and SSM group
(group-3) were relatively low when compared to other groups however we
believe that this distribution reflects the presentation of the disease
in real life.
In conclusion, our study shows that endothelial function is impaired in
mastocytosis patients which can be easily recognized by FMD and VEGF
analysis early before cardiovascular events are evident in the course of
the disease. Further multicenter studies in different populations with a
high number of patients including molecular analysis are needed to
confirm our findings.