Early and Late Histological and Ultrastructural Findings in Resected Infantile Capillary Hemangiomas Following Treatment with Topical Beta-Blocker Timolol Maleate 0.5%

<b><i>Background:</i></b> Infantile capillary hemangiomas (IHs) affect approximately 4-5% of infants. The systemic nonselective β-adrenergic antagonist, propranolol, has become the standard first-line treatment for severe IHs. The topical β-antagonist, timolol maleate, has also demonstrated efficacy and safety in treating superficial and some deep capillary hemangiomas. Despite their therapeutic success and prevalent use, the mechanism of action of β-adrenergic antagonists in the treatment of IHs is not well understood. <b><i>Methods:</i></b> Histopathological and electron microscopic evaluation of two periocular IHs excised at 1 week and 24 months following topical timolol treatment was performed. <b><i>Results:</i></b> Distinct morphological differences were observed between spontaneously regressed and β-antagonist-treated IHs. The former was characterized by diffuse collagen deposition and interstitial fibrosis, while the latter showed organized concentric collagen IV deposition within obliterated vessel lumen, suggestive of waves of endothelial cell apoptosis, leaving behind layers of basement membrane deposits as a stress response. <b><i>Conclusions:</i></b> Based on these observations, we hypothesize that, apart from their well-known cardiac and vasodilatory effects, β-antagonists could induce endothelial cell apoptosis in IH leading to endovascular occlusion and we present supporting evidence to explain why this response might be specific to hypoxic tissue.