Hiroyoshi Mori

Pathology of Human Coronary and Carotid Artery Atherosclerosis and Vascular Calcification in Diabetes Mellitus

The continuing increase in the prevalence of diabetes mellitus in the general population is predicted to result in a higher incidence of cardiovascular disease. Although the mechanisms of diabetes mellitus-associated progression of atherosclerosis are not fully understood, at clinical and pathological levels, there is an appreciation of increased disease burden and higher levels of arterial calcification in these subjects. Plaques within the coronary arteries of patients with diabetes mellitus generally exhibit larger necrotic cores and significantly greater inflammation consisting mainly of macrophages and T lymphocytes relative to patients without diabetes mellitus. Moreover, there is a higher incidence of healed plaque ruptures and positive remodeling in hearts from subjects with type 1 diabetes mellitus and type 2 diabetes mellitus, suggesting a more active atherogenic process. Lesion calcification in the coronary, carotid, and other arterial beds is also more extensive. Although the role of coronary artery calcification in identifying cardiovascular disease and predicting its outcome is undeniable, our understanding of how key hormonal and physiological alterations associated with diabetes mellitus such as insulin resistance and hyperglycemia influence the process of vascular calcification continues to grow. Important drivers of atherosclerotic calcification in diabetes mellitus include oxidative stress, endothelial dysfunction, alterations in mineral metabolism, increased inflammatory cytokine production, and release of osteoprogenitor cells from the marrow into the circulation. Our review will focus on the pathophysiology of type 1 diabetes mellitus- and type 2 diabetes mellitus-associated vascular disease with particular focus on coronary and carotid atherosclerotic calcification.

Endogenous Pituitary Adenylate Cyclase Activating Polypeptide Is Involved in Suppression of Edema in the Ischemic Brain

Pituitary adenylate cyclase activating polypeptide is a pleiotropic neuropeptide. We previously showed that heterozygous PACAP gene knockout (PACAP(+/-)) mice had larger infarct volumes and worse neurological scores after middle cerebral artery occlusion (MCAO). However, the relationship between endogenous PACAP levels and edema in the ischemic brain has not yet been evaluated. In this study, the formation of edema in the ischemic brain as well as cerebral blood flow was compared between PACAP(+/-) and wild-type (PACAP(+/+)) mice. The amount of brain edema was calculated by subtracting the contralateral volume from the ipsilateral volume 24 h after permanent MCAO. PACAP(+/-) mice showed significantly greater brain edema than PACAP(+/+) mice. To investigate the effects of endogenous PACAP on blood flow during ischemia, cerebral blood flow in the ipsilateral and the contralateral cortices was compared between PACAP(+/-) and PACAP(+/+) mice for 25 min after ischemia. With a two-dimensional laser Doppler perfusion imaging system, the blood flow in the ipsilateral and contralateral cortices was shown to be similar in PACAP(+/-) and PACAP(+/+) mice during ischemia. These results suggest that endogenous PACAP suppresses the formation of edema in the ischemic brain.

Regulation of oxidative stress by pituitary adenylate cyclase-activating polypeptide (PACAP) mediated by PACAP receptor.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional peptide that has been shown to be neuroprotective following a diverse range of cell injuries. Although several mechanisms regulating this effect have been reported, no direct evidence has linked PACAP to the regulation of oxidative stress, despite the fact that oxidative stress is a factor in the injury progression that occurs in most models. In the present study, we investigated the plasma oxidative metabolite and anti-oxidation potential levels of PACAP-deficient mice, as well as those of wild-type animals treated with PACAP38. These were assayed by the determination of Reactive Oxidative Metabolites (d-ROMs) and the Biological Anti-oxidant Potential (BAP) using the Free Radical Electron Evaluator system. We also investigated the direct radical scavenging potency of PACAP38 and the functional role of its receptor in the regulation of oxidative stress by PACAP, by using vasoactive intestinal peptide (VIP) and the PACAP receptor antagonist, PACAP6–38. Although younger PACAP null mice displayed no significant effect, greater d-ROMs and lower BAP values were recorded in older animals than in their wild-type littermates. Intravenous injection of PACAP38 in wild-type mice decreased the plasma d-ROMs and BAP values in a dose-dependent manner. These effects were not reproduced using VIP and were abolished by co-treatment with PACAP38 and the PAC1R antagonist PACAP6-38. Taken together, these results suggest that PACAP plays an important role in the physiological regulation of oxidative stress.

Histopathological Differential Diagnosis of Optical Coherence Tomographic Image Interpretation After Stenting

OBJECTIVESnThe aim of this study was to identify histological features that correlate with terms commonly used toxa0describe optical coherence tomographic (OCT) and optical frequency-domain imaging (OFDI) images of stented vessels, by means of a histopathological validation study using stented human coronary arteries.nnnBACKGROUNDnOCT imaging and OFDI are used to evaluate vascular responses to stent implantation. Descriptive termsxa0such as peristrut low attenuation and heterogeneous have been used to describe neointimal characteristics that may have clinical relevance. However, only limited histopathological correlations are available.nnnMETHODSnUsing the CVPath stent registry, 19 cases were identified in whom implantation duration was >30 days andxa0OCT imaging or OFDI and histological findings were available. Consecutive OCT or OFDI frames (nxa0= 1,063) of stented coronary arteries were categorized according to their predominant imaging features in 1-mm intervals. Coregistration ofxa0OCT or OFDI frames and histopathological cross sections was performed in 111 frames.nnnRESULTSnSeven distinct OCT or OFDI patterns were found: homogenous (45%), layered (15%), high intensity with high attenuation (14%), intraluminal protruding masses (8%), peristrut low attenuation (7%), heterogeneous (2%), and honeycomb (1%). Histopathologically, the homogenous pattern correlated most often with smooth muscle cells within collagenous/proteoglycan matrix and less often with organized thrombus. The layered pattern correlated with healed neointimal rupture or erosion, peristrut neovascularization, or smooth muscle cells within collagen/proteoglycan matrix. High intensity with high attenuation correlated with superficial macrophage accumulation in the majority of cases, but with other histological findings in 30% of cases. The diagnostic accuracy was greater in restenotic lesions. The only OCT or OFDI finding that had a single histological feature was the honeycomb pattern.nnnCONCLUSIONSnThis study suggests a lack of correlation between OCT image patterns and distinct histological tissuexa0characteristics.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Stimulates Proliferation of Reactive Astrocytes In Vitro

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide originally isolated from ovine hypothalamus. Recently, we have shown that the PACAP receptor (PAC1-R) is expressed in reactive astrocytes following an in vivo stub wound brain injury. However, the functional role of PACAP has not yet been clarified. In order to investigate the effect of PACAP on the proliferation of reactive astrocytes, a scratch wound paradigm was applied to astrocytic monolayers. Following injury, there was an increase in PAC1-R and glial fibrillary acidic protein (GFAP) immunoreactivity in the astrocytes surrounding the scratch line. PACAP at concentrations of 10−15 to 10−7u2009M was applied immediately after scratching, and the proliferating astrocytes were visualized by multiple immunofluorescence labeling. The percentage of cells that colabeled for Ki67 (a marker of proliferating cells) and GFAP increased in the 10−11- and 10−13-M PACAP-treated groups. The proliferating astrocytes induced by PACAP treatment mainly occurred in the proximal wound area where many reactive astrocytes were observed. Pretreatment with the PACAP receptor antagonist PACAP6-38 significantly suppressed the PACAP-induced effects. These results strongly suggest that PACAP plays an important role in the proliferation of reactive astrocytes following nerve injury.

Comparison of Particulate Embolization after Femoral Artery Treatment with IN.PACT Admiral versus Lutonix 035 Paclitaxel-Coated Balloons in Healthy Swine

PURPOSEnDifferent carrier excipients unique to individual drug-coated balloons (DCBs) may influence embolic safety characteristics in peripheral vascular territories through embolization of released particulates. A comparator study of IN.PACT Admiral vs Lutonix 035 balloons in healthy swine was therefore performed to assess which balloon produces more downstream emboli.nnnMATERIALS AND METHODSnSingle or overlapping 80-mm IN.PACT and Lutonix 035 DCBs were assessed in the femoral arteries of 21 swine with 28- and 90-day follow-up, with standard balloon angioplasty as a control. Histologic analysis of arterial wall and downstream skeletal muscle and coronary band was performed. This analysis was supported by an analytic measurement of paclitaxel levels.nnnRESULTSnIN.PACT DCBs demonstrated a more pronounced change in medial wall composition, characterized by a paclitaxel-induced loss of medial smooth muscle cells accompanied by increased proteoglycans. The percentage of sections with arterioles exhibiting paclitaxel-associated fibrinoid necrosis in downstream tissues was higher at 90 days with overlapping IN.PACT DBCs compared with Lutonix 035 DCBs (46.2% [interquartile range, 19.2-57.7] vs 0.0% [0.0-11.5]; P = .01), with similar trends noted for 28-day single and overlapping DCBs. Drug analysis in parallel tissues further confirmed higher paclitaxel concentrations in nontarget tissues for IN.PACT than Lutonix 035 balloons for single and overlapping configurations at both time points. Rare embolic crystalline material was observed in downstream tissues, but only for IN.PACT balloons.nnnCONCLUSIONSnThere was more fibrinoid necrosis in tissues treated with IN.PACT DCBs compared with Lutonix DCBs, suggesting increased emboli debris with higher paclitaxel levels.

Kisspeptin-10 induces endothelial cellular senescence and impaired endothelial cell growth

The KPs (kisspeptins) are a family of multifunctional peptides with established roles in cancer metastasis, puberty and vasoconstriction. The effects of KPs on endothelial cells have yet to be determined. The aim of the present study was to investigate the effects of KP-10 on endothelial cell growth and the mechanisms underlying those effects. The administration of recombinant KP-10 into the hindlimbs of rats with ischaemia significantly impaired blood flow recovery, as shown by laser Doppler, and capillary growth, as shown using histology, compared with the controls. HUVECs (human umbilical vein endothelial cells) express the KP receptor and were treated with KP-10 in culture studies. KP-10 inhibited endothelial cell tube formation and proliferation in a significant and dose-dependent manner. The HUVECs treated with KP exhibited the senescent phenotype, as determined using a senescence-associated β-galactosidase assay, cell morphology analysis, and decreased Sirt1 (sirtuin 1) expression and increased p53 expression shown by Western blot analysis. Intriguingly, a pharmacological Rho kinase inhibitor, Y-27632, was found to increase the proliferation of HUVECs and to reduce the number of senescent phenotype cells affected by KP-10. In conclusion, KP-10 suppressed endothelial cells growth both in vivo and in vitro in the present study. The adverse effect of KP on endothelial cells was attributable, at least in part, to the induction of cellular senescence.

The Effect of Cilostazol on Endothelial Function as Assessed by Flow-Mediated Dilation in Patients with Coronary Artery Disease

Aim: The vascular endothelium plays a key role in the pathophysiology of atherosclerosis. Flow-mediated dilation (FMD) is a novel way of assessing endothelial function. Cilostazol is a unique antiplatelet drug that also has the potential to improve endothelial function. The objective of this present study was to investigate the effects of cilosatzol on endothelial function as assessed by FMD. Methods: Fifty-one patients with coronary artery disease (CAD) were assigned to one of two groups: the Cilostazol(+) group (with cilostazol) and Cilostazol(−) group (without cilostazol). In addition to conventional dual antiplatelet therapy with aspirin and clopidogrel/ticlopidine, the Cilostazol(+) group (n = 27) was also given cilostazol (100 mg/day). The Cilostazol(−) group (n = 24) did not receive cilostazol. FMD was assessed at enrollment and after 6–9 months. Results: The FMD of both the Cilostazol(+) and Cilostazol(−) groups remained similar at 5.2 (interquartile range: 3.8–8.5) to 5.4 (interquartile range: 4.2–6.7) (P = 0.29) and 5.0 (interquartile range: 3.6–6.4) to 4.9 (interquartile range: 4.0–7.0) (P = 0.38), respectively. However, the diameters of the baseline and maximal brachial arteries tended to increase in the Cilostazol(−) group (baseline: 4.2 ± 0.7 to 4.4 ± 0.7, P = 0.18; maximal: 4.5 ± 0.7 to 4.6 ± 0.7 P = 0.22), whereas that of the Cilostazol(−) group tended to decrease (baseline: 4.1 ± 0.6 to 3.9 ± 0.5, P = 0.10; maximal: 4.3 ± 0.7 to 4.1 ± 0.5, P = 0.05). The rates of change in the baseline diameter (Cilostazol(+): 3.7 ± 9.8% vs. Cilostazol(−): −3.8 ± 12.2%, P = 0.03) and maximal diameter (Cilostazol(+): +3.1 ± 8.9% vs. Cilostazol(−): −4.4 ± 12.0%, P = 0.02) were significantly different. Conclusion: Although cilostazol didnt affect the FMD, there was a significant difference in the rates of change in baseline and maximal brachial artery diameter. This may have a beneficial effect in patients with cardiovascular disease.

Very Late Pathological Responses to Cobalt–Chromium Everolimus‐Eluting, Stainless Steel Sirolimus‐Eluting, and Cobalt–Chromium Bare Metal Stents in Humans

Background The “very late” clinical outcomes for durable polymer drug‐eluting stents and bare metal stents (BMSs) have been shown to be dissimilar in clinical studies. Conceptually, the long‐term vascular compatibility of BMSs is still regarded to be superior to drug‐eluting stents; however, no pathologic study to date has specifically addressed this issue. We evaluated the very late (≥1 year) pathologic responses to durable polymer drug‐eluting stents (cobalt–chromium [CoCr] everolimus‐eluting stents [EESs] and stainless steel sirolimus‐eluting stents [SS‐SESs]) versus BMSs (CoCr‐BMSs). Methods and Results From the CVPath stent registry, we studied a total of 119 lesions (40 CoCr‐EESs, 44 SS‐SESs, 35 CoCr‐BMSs) from 92 autopsy cases with a duration ranging from 1 to 5 years. Sections of stented coronary segments were pathologically analyzed. Inflammation score and the percentage of struts with giant cells were lowest in CoCr‐EESs (median inflammation score: 0.6; median percentage of struts with giant cells: 3.8%) followed by CoCr‐BMSs (median inflammation score: 1.3 [P<0.01]; median percentage of struts with giant cells: 8.9% [P=0.02]) and SS‐SESs (median inflammation score: 1.7 [P<0.01]; median percentage of struts with giant cells: 15.3% [P<0.01]). Polymer delamination was observed exclusively in SS‐SESs and was associated with increased inflammatory and giant cell reactions. The prevalence of neoatherosclerosis with CoCr‐EESs (50%) was significantly less than with SS‐SESs (77%, P=0.02) but significantly greater than with CoCr‐BMSs (20%, P<0.01). Conclusions CoCr‐EESs, SS‐SESs, and BMSs each demonstrated distinct vascular responses. CoCr‐EESs demonstrated the least inflammation, near‐equivalent healing to BMSs, and lower neointimal formation. These results challenge the belief that BMSs have superior biocompatibility compared with some polymeric coated drug‐eluting stents and may have implications for future stent design.

Malapposition: is it a major cause of stent thrombosis?

This editorial refers to ‘Mechanisms of stent thrombosis analysed by optical coherence tomography: insights from the national PESTO French registry’[†][1], by G. Souteyrand et al . on page 1208. nnStent thrombosis (ST) is a devastating complication associated with a high morbidity and mortality in patients who have undergone percutaneous coronary intervention (PCI) for coronary heart disease (CHD). In-hospital mortalities of patients suffering from ST have been reported to be as high as 7.9% for acute ST (AST; occurring <24 h after PCI) and subacute ST (SAST; occurring within 30 days after PCI), 3.8% for late ST (LST; occurring within the first year after PCI), and 3.6% for very late ST (VLST; occurring 1 year after PCI).1 Recently, longer duration (30 months) of dual antiplatelet therapy (DAPT) has been shown to reduce, but not eliminate, thrombotic events following drug-eluting stent (DES) implantation as compared with the traditional 12 months of therapy.2 While the introduction of newer generation DES with thinner struts, more biocompatible polymers, and lower drug load have reduced ST rates, it still continues to be a significant cause of morbidity.3 From the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) registry of patients undergoing PCI for acute myocardial infarction, the cumulative rates of definite stent thrombosis up to 3 years were 2.0% for bare metal stents (BMS), 2.1% for first-generation DES, and 1.3% for second-generation DES, while cumulative rates of all-cause mortality up to 3 years were 12.8% for BMS, 10.3% for first-generation DES, and 10.6% for second-generation DES.3nnWhile human pathology examinations of patients who suffered ST have helped us understand associations between various morphological and histological findings …nn [1]: #fn-2