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.