Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy–lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy–lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy–lysosomal biogenesis and show trehalose's ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease.

ObjectivesTo examine the topographical correlation between ellipsoid zone loss and telangiectasia in the deep capillary plexus in patients with macular telangiectasia type 2 (MacTel).Methods38 eyes (20 subjects) diagnosed with MacTel were imaged with OCTA between March 2016 and June 2019 in this single center, cross-sectional observational study. The en face OCTA and OCT were evaluated for areas of deep capillary plexus telangiectasia and ellipsoid zone loss, respectively, and their outlines were superimposed to study their overlap (mm2). The primary outcome was percentage of overlap and its relationship to MacTel stage. Secondary outcomes included the relationship between neovascularization and hyperreflective foci as well as correlations between ellipsoid zone loss, deep capillary plexus telangiectasia and visual acuity.ResultsIn nonproliferative MacTel stage, ellipsoid zone loss was localized to margins of telangiectatic areas (mean overlap = 15.2%). In proliferative stages, ellipsoid zone loss showed a higher degree of overlap with telangiectatic areas (mean overlap = 62.8%). Overlap increased with advancing MacTel stages, with an overall average of 45.3%. Overlap correlated highly with ellipsoid zone loss (r = 0.831; p<0.0001). Telangiectasia was present in all 38 eyes (range: 0.08mm2–0.99mm2), while ellipsoid zone loss was absent in 6 (range: 0.00–3.32mm2). Visual acuity correlated most strongly with ellipsoid zone loss (r = 0.569; p = 0.0002), followed by overlap (r = 0.544; p = 0.0004), and finally, telangiectasia (r = 0.404; p<0.0118). Presence of hyperreflective foci on OCT correlated with the presence and intraretinal location of neovascularization.ConclusionsEllipsoid zone loss occurs at the margins of deep capillary plexus telangiectasia in nonproliferative MacTel, with progressively increasing overlap as MacTel advances, peaking in proliferative disease. Deep capillary plexus telangiectasia and its overlap with ellipsoid zone loss are two promising markers of nonproliferative MacTel, while hyper-reflective foci are markers for proliferative MacTel.

To evaluate differences in parafoveal vascular density surrounding arterioles and venules in type 2 macular telangiectasia (MacTel). Methods: Thirty-seven eyes (20 subjects) diagnosed with MacTel and 16 healthy eyes (10 subjects) were imaged with optical coherence tomography angiography between March 2016 and June 2019 in this single-center, observational, cross-sectional study. Arterioles and venules were manually identified, and perivascular density was generated using a custom MATLAB code. The primary outcome measure was the ratio of periarteriolar to perivenular vascular density (arteriovenous [A/V] capillary ratio) in the superficial and deep capillary plexuses across MacTel stages. The main secondary outcome measures were overall parafoveal vascular density (VD), periarteriolar VD, and perivenular VD. Results: In the superficial capillary plexus (SCP), the A/V capillary ratio was significantly higher in MacTel subjects than controls (0.914 vs. 0.892; P = 0.0044). The greatest differences occurred between controls and nonproliferative MacTel subjects without optical coherence tomography evidence of disease (P = 0.0055). A/V capillary ratios progressed in a nonlinear fashion with MacTel severity, increasing from nonproliferative disease (0.912) to intraretinal proliferative disease (0.931), then decreasing in subretinal proliferative disease (0.905). Parafoveal VD in the SCP was lower in MacTel subjects than controls only in subretinal proliferative disease (P = 0.0130). Conclusions: The A/V capillary ratio of the SCP is a quantifiable metric of vascular pathology in MacTel that occurs earlier than decline in parafoveal VD. Elevated A/V capillary ratios in MacTel are consistent with an early, disproportionately perivenular disruption in the SCP. Translational Relevance: Findings inform MacTel pathogenesis through revealing early perivenular capillary loss and offer a new quantitative metric for earliest stage MacTel.

In this cross-sectional observational study, we investigated the relationship between photoreceptor layer disruption and telangiectasia in patients diagnosed with early stage macular telangiectasia type 2 (MacTel). A total of 31 eyes (17 patients) with MacTel were imaged with adaptive optics scanning laser ophthalmoscopy (AOSLO) and optical coherence tomography angiography (OCTA). Confocal AOSLO was used to visualize dark regions of nonwaveguiding outer segments, which we refer to as “photoreceptor lesions”. En-face OCTA images of the deep capillary plexus (DCP) were used in conjunction with confocal AOSLO to evaluate the topographic relationship between areas of capillary telangiectasias and photoreceptor lesions. Among seven eyes with early stage MacTel (stage 0–2 based on OCT), we identified ten photoreceptor lesions, all of which were located within parafoveal quadrants containing DCP telangiectasia on OCTA. Seven of the lesions corresponded to the intact ellipsoid zone on spectral-domain OCT (SD-OCT), and three of these also corresponded to the intact interdigitation zone. This work demonstrates a topographic relationship between AOSLO photoreceptor lesions and DCP telangiectasias, and it also suggests that these lesions with normal SD-OCT appearance may represent areas of photoreceptors at risk for dysfunction. Thus, confocal AOSLO may have a meaningful role in detecting early photoreceptor abnormalities in eyes with MacTel.

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