CODA: quantitative 3D reconstruction of large tissues at cellular resolution.

A central challenge in biology is obtaining high-content, high-resolution information while analyzing tissue samples at volumes relevant to disease progression. We address this here with CODA, a method to reconstruct exceptionally large (up to multicentimeter cubed) tissues at subcellular resolution using serially sectioned hematoxylin and eosin-stained tissue sections. Here we demonstrate CODA's ability to reconstruct three-dimensional (3D) distinct microanatomical structures in pancreas, skin, lung and liver tissues. CODA allows creation of readily quantifiable tissue volumes amenable to biological research. As a testbed, we assess the microanatomy of the human pancreas during tumorigenesis within the branching pancreatic ductal system, labeling ten distinct structures to examine heterogeneity and structural transformation during neoplastic progression. We show that pancreatic precancerous lesions develop into distinct 3D morphological phenotypes and that pancreatic cancer tends to spread far from the bulk tumor along collagen fibers that are highly aligned to the 3D curves of ductal, lobular, vascular and neural structures. Thus, CODA establishes a means to transform broadly the structural study of human diseases through exploration of exhaustively labeled 3D microarchitecture.

Plaque erosion masquerading as spontaneous coronary artery dissection: A case of sudden coronary death.

The three most common mechanisms of thrombosis in acute coronary syndrome (ACS) are plaque rupture, plaque erosion and calcified nodule. Plaque erosion occurs over an intact fibrous cap, commonly over pathological intimal thickening (PIT) rather than thin cap fibroatheroma (TCFA), and is more common among younger and female patients.1 A very rare mechanism of ACS is spontaneous coronary artery dissection (SCAD), resulting from the formation of an intramural hematoma and/or intimal disruption.2 We present a case of sudden coronary death with the appearance of SCAD on coronary computed tomography angiography (CCTA).

Intravascular imaging and histological correlates of medial and intimal calcification in peripheral artery disease.

BACKGROUND: In peripheral artery disease, two different types of calcification are frequently observed, i.e., medial and intimal calcification. AIMS: The aim of this study was to determine the ability of intravascular ultrasound (IVUS) imaging and optical frequency domain imaging (OFDI) to detect medial and intimal calcification in human peripheral arteries. METHODS: We performed ex vivo intravascular imaging of cadaveric human peripheral arteries with calcifications. IVUS and OFDI images were co-registered with histology. A total of 12 legs from nine patients were examined, and 438 cross-sectional images were co-registered with histology. RESULTS: OFDI could detect 183 of 231 intimal calcifications by histology, whereas IVUS could detect 194 (OFDI: sensitivity 79%, specificity 86%, area under the curve [AUC] 0.83; IVUS: sensitivity 84%, specificity 85%, AUC 0.85). Of 245 medial calcifications by histology, 160 and 164 were detected by OFDI and IVUS, respectively (OFDI: sensitivity 65%, specificity 85%, AUC 0.75; IVUS: sensitivity 67%, specificity 80%, AUC 0.74). Medial calcification with overlying intimal calcification (overlapped calcification) and an unclear border between intima and media were the main reasons for misdiagnosis. Without those 89 overlapped calcifications, sensitivity in both OFDI and IVUS was improved (OFDI: sensitivity 81%, specificity 85%, AUC 0.83; IVUS: sensitivity 88%, specificity 80%, AUC 0.84). CONCLUSIONS: There are limitations in detecting medial calcification in overlapped intimal calcification and with an unclear border between intima and media by both IVUS and OFDI. It is important to distinguish medial calcification from intimal calcification before proceeding with endovascular therapy since different approaches will be required.

Eruptive Calcified Nodules as a Potential Mechanism of Acute Coronary Thrombosis and Sudden Death.

BACKGROUND: Calcified nodule (CN) has a unique plaque morphology, in which an area of nodular calcification causes disruption of the fibrous cap with overlying luminal thrombus. CN is reported to be the least frequent cause of acute coronary thrombosis, and the pathogenesis of CN has not been well studied. OBJECTIVES: The purpose of this study is to provide a comprehensive morphologic assessment of the CN in addition to providing an evolutionary perspective as to how CN causes acute coronary thrombosis in patients with acute coronary syndromes. METHODS: A total of 26 consecutive CN lesions from 25 subjects from our autopsy registry were evaluated. Detailed morphometric analysis was performed to understand the plaque characteristics of CN and nodular calcification. RESULTS: The mean age was 70 years, with a high prevalence of diabetes and chronic kidney disease. CNs were equally distributed between men and women, with 61.5% of CNs found in the right coronary artery (n = 16), mainly within its mid-portion (56%). All CNs demonstrated surface nonocclusive luminal thrombus, consisting of multiple nodular fragments of calcification, protruding and disrupting the overlying fibrous cap, with evidence of endothelial cell loss. The degree of circumferential sheet calcification was significantly less in the culprit section (89° [interquartile range: 54° to 177°]) than in the adjacent proximal (206° [interquartile range: 157° to 269°], p = 0.0034) and distal (240° [interquartile range: 178° to 333°], p = 0.0004) sections. Polarized picrosirius red staining showed the presence of necrotic core calcium at culprit sites of CNs, whereas collagen calcium was more prevalent at the proximal and distal regions of CNs. CONCLUSIONS: Our study suggests that fibrous cap disruption in CN with overlying thrombosis is initiated through the fragmentation of necrotic core calcifications, which is flanked-proximally and distally-by hard, collagen-rich calcification in coronary arteries, which are susceptible to mechanical stress.

Vascular responses to coronary calcification following implantation of newer-generation drug-eluting stents in humans: impact on healing.

AIMS: Vascular calcification is routinely encountered in percutaneous coronary intervention (PCI) and severe coronary calcification is a known predictor of in-stent restenosis and stent thrombosis. However, the histopathologic mechanisms behind such events have not been systematically described. METHODS AND RESULTS: From our registry of 1211 stents, a total of 134 newer-generation drug-eluting stents (DES) (Xience, Resolute-Integrity, PROMUS-Element, and Synergy) with duration of implant ≥30 days were histologically analysed. The extent of calcification of the stented lesions was evaluated radiographically and divided into severe (SC, n = 46) and non-severely calcified lesions (NC, n = 88). The percent-uncovered struts per section {SC vs. NC; median 2.4 [interquartile range (IQR) 0.0-19.0] % vs. 0.0 (IQR 0.0-4.6) %, P = 0.02} and the presence of severe medial tears (MTs) (59% vs. 44%, respectively, P = 0.03) were greater in SC than NC. In addition, SC had a higher prevalence of ≥3 consecutive struts lying directly in contact with surface calcified area (3SC) (52% vs. 8%, respectively, P < 0.0001). Multivariate analysis demonstrated that sections with duration of implantation ≤6 months [odds ratio (OR): 7.7, P < 0.0001], 3SC (OR: 6.5, P < 0.0001), strut malapposition (OR: 5.0, P < 0.0001), and lack of MTs (OR: 2.5, P = 0.0005) were independent predictors of uncovered struts. Prevalence of neoatherosclerosis was significantly lower in SC than that of NC (24% vs. 44%, P = 0.02). CONCLUSION: Severe calcification, especially surface calcified area is an independent predictor of uncovered struts and delayed healing after newer-generation DES implantation. These data expand of knowledge of the vascular responses of stenting of calcified arteries and suggests further understand of how best to deal with calcification in patients undergoing PCI.