Mast cells in atherosclerotic plaques are associated with neovascularisation and future CV events
Mast cells in human carotid atherosclerotic plaques are associated with intraplaque microvessel density and the occurrence of future cardiovascular events.
Willems S, Vink A, Bot I, et al.
Eur Heart J. 2013 Jun 11. [Epub ahead of print]
BackgroundAcute clinical manifestations of atherosclerosis are often the result of plaque rupture followed by intraluminal thrombus formation. Unstable plaques prone to rupture are characterised by a large lipid core, a thin fibrous cap, intraplaque neovascularisation and a large inflammatory infiltrate composed of macrophages, T-cells and mast cells (MCs) . MCs contain cytoplasmic secretory granules, which are exocytosed upon activation. Such activated MCs are abundant at sites of atheromatous erosion or rupture in patients who have died of myocardial infarction .
Recent evidence from animal experiments indicated that MCs are actively involved in the initiation and progression and destabilisation of atherosclerotic disease [3-7]. MCs may render the plaques unstable by inducing neovascularisation . Autopsy studies have revealed that MCs accumulate in neovessel-rich areas of atherosclerotic plaques [9-12]. In addition, MCs near the newly formed vessels contained basis fibroblast growth factor, a potent pro-angiogenic factor . Thus, MCs may accelerate plaque progression to an unstable form by stimulating microvessel formation in the atherosclerotic plaque.
Intraplaque neovascularisation and intraplaque haemorrhage (IPH) in the carotid have been shown to be predictive for CV events elsewhere in the body . This study therefore aimed to improve the understanding of how intraplaque neovascularisation renders atherosclerotic plaques prone to trigger atherothrombotic events, by examining the association of local MC numbers with local plaque characteristics, in human samples.
- Different plaque phenotypes were associated with increasing numbers of MCs per plaque section, to wit fibrous (79 [37-165]), fibroatheromatous (124 [64-237}) and atheromatous (139 [59-243]) plaques.
- The presence of IPH was associated with higher MC numbers (130 (65-241) than plaques without IPH (70 (37-137), P=0.001).
- MC content correlated positively with plaque area covered in macrophages (r=0.156, P=0.011) and with the number of neutrophils (R=0.0380, P<0.001).
- Microvessel density correlated significantly with total MC numbers (r=0.416, P<0.001). Weaker, but significant correlations with microvessel density were also seen for neutrophils and macrophages.
- Plaques with high microvessel density were characterised by high MC numbers, while no strong difference in microvessel density was seen between macrophage-rich vs. –poor areas, when controlled for MC number.
- Patients who had symptoms such as amaurosis fugax, transient ischemic attack, and stroke, when entering the study, had significantly more MCs in their plaques than asymptomatic patients (3.34 (1.75-5,87) vs 2.12 (1.23-4.23) MC/mm2, P=0.016).
- 164 patients who did not have any future CV events, had a median 2.83 (1.48-5.45) MC/mm2, while 89 patients who underwent secondary CV events had higher MC/mm2, with highest median numbers seen for (non-)fatal myocardial infarction (3.68 [1.41-6.80]).
- An optimal cut-off value of 2.75 MC/mm2 was revealed to predict future cardiovascular events. A value >2.75 MC/mm2 was associated with more CV events during follow-up (58 (41%) vs. 31 (28%), HR: 1.62, 95%CI: 1.05-2.51, P=0.029).
ConclusionThis study shows that MCs are abundant in atherosclerotic lesions and associate with microvessel density in atherosclerotic plaques. An overall inflammatory environment appears to be responsible for the formation of neovessels in the plaque, but MCs may be particularly important for plaque neovascularisation, which could be linked to plaque vulnerability. Intraplaque MC numbers associate with future CV events, thus these findings strengthen the hypothesis that the presence of MCs in advanced carotid plaques increases the risk of secondary CV manifestations. Further research is necessary to explore the possible therapeutic benefit of MC stabilising agents to prevent clinical manifestations.
Editorial comment This study shows that the presence of mast cells correlates with microvascular density, which is a predictor of haemorrhage, and mast cell numbers are significantly higher in symptomatic carotid disease, as compared to asymptomatic disease. An outstanding question is how this all happens and why: are mast cells the real culprit for plaque angiogenesis and haemorrhage? The investigators studied several inflammatory markers, only one of which (tryptase) was found to be elevated and correlated with mast cells, which is also the case in patients with an allergic reaction. It is clear the mast cells are extremely active cells and play a role in immunological reactions, and we are beginning to understand the interaction between mast cells and T-cell subtypes, also in atherosclerosis. But their specific role in atherosclerosis remains to be determined.
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