Tetsunori Ishikawa

Involvement of C-reactive protein obtained by directional coronary atherectomy in plaque instability and developing restenosis in patients with stable or unstable angina pectoris

We investigated whether positive immunohistochemical staining of C-reactive protein (CRP) in initial culprit lesions is related to coronary plaque instability and whether it could affect the outcome of directional coronary atherectomy (DCA). The plasma level of CRP is a reliable marker of the risk of coronary events and restenosis after percutaneous coronary intervention. However, the influence of tissue CRP in atheromatous plaque on plaque vulnerability and restenosis remains unknown. Samples of DCA obtained from 12 patients with stable angina pectoris and 15 patients with unstable angina pectoris were immunohistochemically stained with a monoclonal antibody against CRP. We performed follow-up coronary angiography on 22 of 27 patients to evaluate the presence of restenosis after DCA. Immunoreactivity to CRP was localized to macrophages, smooth muscle cells, and necrotic areas. The ratio of CRP positive cells to total cells was significantly higher in DCA samples from patients with unstable (17.9 +/- 2.0%) than with stable angina (11.0 +/- 2.5%) (p <0.05). Follow-up coronary angiography showed that 12 of 22 patients developed restenosis after DCA. The ratio was also significantly higher in DCA specimens from patients with restenosis (19.3 +/- 2.8%) compared with those without restenosis (11.0 +/- 2.0%) (p <0.05). In addition, the ratio significantly correlated with late luminal loss (r = 0.428, p <0.05) and loss index (r = 0.636, p = 0.0011) after DCA. Immunoreactivity to CRP in coronary atheromatous plaque increases in culprit lesions of unstable angina, and it affects restenosis after DCA. These findings suggest that CRP in atheromatous plaque plays an important role in the pathogenesis of unstable angina and restenosis after coronary intervention.

Podoplanin expression in advanced atherosclerotic lesions of human aortas

Thrombus formation on disrupted atherosclerotic lesion is a key mechanism of cardiovascular events. Podoplanin (Aggrus), expressed on the surface of several tumor cells, is an endogenous ligand for C-type lectin-like receptor 2 (CLEC-2), and is involved in tumor cell-induced platelet aggregation and its malignant potency. Podoplanin, which is also expressed in lymphatic endothelial cells, facilitates blood/lymphatic vessel separation. However, podoplanin expression in atherosclerotic lesion has not been investigated. To clarify podoplanin expression in atherosclerotic lesion and to assess its importance for the onset of cardiovascular events, we examined podoplanin expression in abdominal aortas obtained from 31 autopsy cases. Immunohistochemical analysis indicated that podoplanin was localized to smooth muscle cells and macrophages. Moreover, podoplanin immunoreactivity was increased in advanced atherosclerotic lesions containing necrotic core, many macrophages and smooth muscle cells, compared with early lesions composed of smooth muscle cells and small numbers of macrophages. Furthermore, Western-blot and real time-PCR analyses showed that podoplanin expression was significantly enhanced in advanced atherosclerotic lesions, compared with early lesions. These results suggest that podoplanin contributes to thrombotic property of advanced stages of atherosclerosis and that it might be a novel molecular target for an anti-thrombus drug.

Increased adrenomedullin immunoreactivity and mRNA expression in coronary plaques obtained from patients with unstable angina

Objective: To examine the expression and localisation of adrenomedullin in human coronary atherosclerotic lesions from patients with unstable angina (UAP) and stable angina (SAP), and to study the relation between adrenomedullin expression and plaque instability. Design: A retrospective observational study. Patients: Directional coronary atherectomy samples were obtained from 15 patients with UAP and 12 with SAP. Methods: The localisation of adrenomedullin was examined by immunohistochemistry, and adreno-medullin mRNA expression was measured by quantitative polymerase chain reaction. Results: Adrenomedullin immunoreactivity was preferentially localised in macrophages, intimal smooth muscle cells, and proliferated microvessels. The mean number of adrenomedullin positive cells in five high power fields (× 400) per specimen was higher in patients with UAP than in those with SAP (mean (SEM), 110 (13) v 76 (7); p < 0.05); and the ratio of adrenomedullin positive to total cells was higher in patients with UAP (43.0 (2.2)% v 34.2 (2.0)%; p < 0.01). More adrenomedullin mRNA was expressed in the plaque of patients with UAP than in those with SAP (60.4 (16.9)% v 9.7 (3.3)%; p < 0.01). Conclusions: The findings suggest that adrenomedullin is involved in the development of atherosclerosis and plaque instability in human coronary arteries, in an autocrine or paracrine manner.

Osteoprotegerin is Secreted Into the Coronary Circulation: A Possible Association with the Renin-Angiotensin System and Cardiac Hypertrophy

The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67±10 years old, male 57%, hypertension 73%, coronary artery disease 50%) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7±4.1 vs. 6.7±3.6 pmol/l, p<0.001). The trans-cardiac OPG concentration was significantly (p=0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients subgroup who did not take an ACEI/ARB (n=27), the trans-cardiac OPG level was positively correlated with age (r=0.396, p=0.041) and relative wall thickness of left ventricle (r=0.534, p=0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p=0.004). Moreover, trans-cardiac OPG was significantly (p=0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased (≥116 for males, or ≥ 104 for females, g/m(2)) or not (p=0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system.

18F-Fluorodeoxyglucose Positron Emission Tomography 10 Days Before Onset of Aortic Dissection

Received June 6, 2017; revised manuscript received June 30, 2017; accepted July 13, 2017; released online August 22, 2017 Time for primary review: 7 days Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, Miyazaki (T.T., M.Y., S.S., T.I., K.K.); Department of Radiology, Faculty of Medicine, Fukuoka University, Fukuoka (S.N.), Japan Mailing address: Toshihiro Tsuruda, MD, PhD, Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan. E-mail: ttsuruda@med.miyazakiu.ac.jp ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp 18F-Fluorodeoxyglucose Positron Emission Tomography 10 Days Before Onset of Aortic Dissection

A Baker Cyst Accompanied by Venous Thromboembolism

A 36-year-old woman who had received low-dose estrogen and progesterone therapy to alleviate menstrual cramps was referred to the emergency department of our hospital due to left calf pain with mild edema. The patient‘s laboratory data revealed elevated levels of D-dimer (6.94 μg/mL) and fibrinogen degradation product (FDP) (15.0 μg/mL). Computed tomography demonstrated the presence of a pulmonary thrombotic embolism (PTE) (Picture A) and deep vein thrombosis (DVT) in the left posterior tibial vein (Picture B). The left popliteal vein was also found to be externally compressed by a Baker cyst (BC) (Picture C). These findings were also confirmed by an ultrasound examination (Picture D, E). Symptomatic BC is sometimes associated with pseudothrombophlebitis (1) which is characterized by the absence of thrombus; however, true DVT and PTE were both present in this patient. However, it should be noted that it is difficult to distinguish the contribution of BC-induced vein compression from that of hormone therapy to the occurrence of venous thromboembolism.

SIGNIFICANCE OF CARDIAC TROPONIN T LEVELS IN SUPRAVENTRICULAR TACHYCARDIA

Background: Cardiac troponin T is sensitive and specific markers of myocardial injury and is used routinely for the diagnosis of acute coronary syndrome. Recently, the magunitude of troponin T levels in heart failure patients has been reported to correlate with severity of the disease and with adverse outcomes. They may suggest ongoing myocardial damage. In supraventricular tachycardia, common atrial flutter (AFL) and atrial tachycardia (AT) often produce changes in cardiac function and structure, but atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) do not. To our knowledge, there are no reports about the relationship between the levels of troponin T and the types of supraventricular tachycardia. We examined the clinical usefulness of previously unmeasurable levels of troponin T (hs-TnT) by using highly sensitive assay for the differential diagnosis of supraventricular tachycardia.

Interleukin-10 correlates with oxidized low density lipoprotein in coronary culprit plaques

Inflammation plays an important role in the pathogenesis of atherosclerosis and plaque instability [1,2]. We and others have demonstrated that many pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-18 and interferon-γ are expressed in human atherosclerotic plaques, and the expression levels of most of them are increased at sites of plaque rupture [1–3]. However, the roles of antiinflammatory cytokines and their localization in coronary culprit plaque have not been defined. Oxidized low density lipoprotein (oxLDL) is also involved in the disruption of atherosclerotic plaque [2,4]. Vulnerable plaques contain more significant numbers of ox-LDLpositive macrophages [4], which when stimulated by ox-LDL release many pro-inflammatory cytokines that contribute to plaque instability [2], as well as IL-10, which is an important anti-inflammatory cytokine [1,5]. We therefore immunohistochemically investigated the localiza-