Very Late Stent Thrombosis Complicating Immune Thrombocytopenia: Insights From Optical Coherence Tomography and Thrombopathology.

Immune thrombocytopenia (ITP) carries bleeding and thrombotic risks; however, thromboses associated with ITP have not been histologically examined. This report presents optical coherence tomography images of the culprit lesion and histology of coronary aspirates in very late stent thrombosis complicating severe ITP, providing evidence of platelet-rich thrombus formation. (Level of Difficulty: Advanced.).

A likely unavoidable clinical scenario during treatment for venous thromboembolism complicated with severe immune thrombocytopenia: A case report.

Patients with immune thrombocytopenia have increased risks of bleeding and thrombosis. The acute-phase treatment for venous thromboembolism complicated with severe immune thrombocytopenia involves a "platelet dilemma" in therapeutic decision-making.

Questionnaire in patients with aborted sudden cardiac death due to coronary spasm in Japan.

OBJECTIVES: We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm. METHODS: A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter-defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals. RESULTS: The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p < 0.001). Although 16 institutions thought that the spasm provocation tests under the medications had some clinical usefulness of suppressing the next fatal arrhythmias, spasm provocation tests under the medication were performed in just 4 institutions. CONCLUSIONS: In the real world, there was no fundamental strategy for patients with ASCD due to coronary spasm. Each institution has each strategy for these patients. Cardiologists should have the same strategy and the same knowledge about ASCD patients due to coronary spasm in the future.

Nephrotic syndrome and Giant cell arthritis concurrently occurring after percutaneous transluminal angioplasty for renal artery stenosis
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An elderly Japanese woman with bilateral renal artery occlusion who developed massive proteinuria after unilateral percutaneous transluminal renal angioplasty (PTRA) is reported. She had a history of percutaneous coronary intervention and subsequently developed refractory hypertension. She was diagnosed with renovascular hypertension caused by bilateral total occlusion of the renal arteries, and underwent PTRA for the left renal artery. Nephrotic-range proteinuria from the left kidney, confirmed by split urine collection from each kidney under cytoscopic examination, and low-grade fever with positive C-reactive protein became obvious after PTRA. Giant cell arteritis (GCA) was also diagnosed by positive findings on fluorodeoxyglucose-positron emission tomography in the common carotid arteries, subclavian arteries, and aorta, but not in the renal arteries. Administration of corticosteroid and angiotensin-converting enzyme inhibitor decreased the proteinuria (> 9 - 2 g/day). Possible mechanisms for the development of nephrotic-range proteinuria and a hypothesis that GCA became obvious after PTRA are discussed.
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Non-canonical Expression of Cardiac Troponin-T in Neuroendocrine Ethmoid Sinus Carcinoma Following Immune Checkpoint Blockade.

We describe the case of a patient with neuroendocrine ethmoid sinus carcinoma, who exhibited markedly elevated levels of serum cardiac troponin-T and creatine kinase (CK)-MB isoenzyme without any symptom after the administration of nivolumab, immune checkpoint inhibitor. The repeated 12-leads-electrocardiogram did not show any changes in the ST-T segments or arrhythmias. The echocardiogram showed normal ranges of left ventricular contraction in the clinical course. Cardiac magnetic resonance imaging showed minimal myocardial edema and inflammation. Blood clots in the metastatic lesion of bone marrow aspirates exhibited positive staining for cardiac troponin-T and CK-MB in the cytoplasm and nucleoplasm of neoplastic cells. Although we did not perform a second cardiac magnetic resonance imaging and autopsy, we postulate that the attack of the neoplastic cells by the immune checkpoint inhibitor or the secretion from neoplastic cell-derived extracellular vesicles may have exacerbated the increase in concentrations of these molecules in the blood. Our case should warrant consideration a false-positive value of cardiac troponin-T and CK-MB can be obtained in cases with malignancy.

Grading of Left Ventricular Diastolic Dysfunction with Preserved Systolic Function by the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging Recommendations Contributes to Predicting Cardiovascular Events in Hemodialysis Patients.

BACKGROUND: Left ventricular diastolic dysfunction (LVDD) causes heart failure with a preserved left ventricular ejection fraction (LVEF) in the general population. OBJECTIVE: To examine the relationships between the LVDD grades of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) recommendations and several arteriosclerotic parameters and major cardiovascular events (MACE) in hemodialysis patients with preserved LVEF. METHOD: Sixty-three prevalent hemodialysis patients (median age [interquartile range], 69 [64-75] years, 31.7% female) with normal systolic function (LVEF > 50%) were enrolled. LVDD evaluated by echocardiography at baseline was divided into three groups according to ASE/EACVI recommendations (normal diastolic function [ND], n = 24; intermediate, n = 19; diastolic dysfunction [DD], n = 20). All patients underwent analyses of several arteriosclerotic parameters (carotid intima-media thickness [CIMT], plaque score [PS], ankle brachial index [ABI], and brachial-ankle pulse wave velocity [baPWV]). The presence or absence of postdialysis orthostatic hypotension was assessed in each dialysis session. MACE during the 1-year follow-up period was obtained from medical records. Kaplan-Meier and Cox's regression analyses were used to investigate the relationship between LVDD grades and MACE. RESULTS: Postdialysis orthostatic hypotension and PS, but not CIMT, ABI, or baPWV, increased proportionally with LVDD grades. Eleven patients developed MACE, including 2 cardiovascular deaths. The Kaplan-Meier analysis showed that MACE frequently occurred in the DD grade (p = 0.002 by the log-rank test). Cox's regression analysis adjusted for potential confounders (age, sex, diabetes, systolic blood pressure, and body mass index) revealed that the DD grade was associated with MACE when the ND grade was set as a reference. CONCLUSIONS: In maintenance hemodialysis patients with normal ventricular systolic function, a classification of LVDD by the 2016 ASE/EACVI recommendations may be a useful tool for predicting cardiovascular events.

Impact of short-acting loop diuretic doses and cardiac sympathetic nerve abnormalities on outcomes of patients with reduced left ventricular function.

Recent studies reported that high doses of short-acting loop diuretics are associated with poor outcomes in patients with heart failure (HF). Short-acting loop diuretics have been shown to activate the renin-angiotensin system (RAS) and have no favorable effects on cardiac sympathetic nervous system (SNS) activity. The goal of this study is to investigate the relationship between daily doses of furosemide and the outcomes of patients with left ventricular dysfunction (LVD) from the viewpoint of cardiac SNS abnormalities using iodine-123-labeled metaiodobenzylguanidine (l-MIBG) myocardial scintigraphy.We enrolled 137 hospitalized patients (62.5 ±â€Š14.2 years old, 103 men) with LVEF < 45% who underwent l-MIBG myocardial scintigraphy. A delayed heart-to-mediastinum ratio (delayed HMR) was assessed using l-MIBG scintigraphy. Cardiac events were defined as cardiac death or re-hospitalization due to the deterioration of HF. Cox proportional hazard analysis was used to identify predictors of cardiac events.Cardiac events occurred in 57 patients in a follow-up period of 33.1 ±â€Š30 months. In a multivariate Cox proportional hazard analysis, delayed HMR and furosemide doses were identified as independent predictors of cardiac events (P = .0042, P = .033, respectively). Inverse probability of treatment weighting Cox modeling showed that the use of furosemide (≥40 mg /day) was associated with cardiac events with a hazard ratio of 1.96 (P = .003). In the Kaplan-Mayer analysis, the cardiac event-free survival rate was significantly lower in patients treated with high doses of furosemide (≥60 mg/day vs 40-60 mg/day vs <40 mg/day, the Log-rank test P < .0001). In a receiver-operating characteristic (ROC) analysis, the cut-off value for cardiac events was 40 mg/day of furosemide. The cardiac event-free rate was significantly lower in patients with delayed HMR <1.8 (median value) and receiving furosemide ≥40 mg/day than in other patients (the Log-rank test P < .0001). Significant differences in cardiac event rates according to furosemide doses among patients with delayed HMR <1.8 were observed among patients without ß-blocker therapy (P = .001), but not among those with ß-blocker therapy (P = .127).The present results indicate that a relationship exists between higher doses of furosemide and poor outcomes. The prognosis of HF patients with severe cardiac SNS abnormalities receiving high-dose short-acting loop diuretics is poor.

Prognostic Implication of Three-Dimensional Mitral Valve Tenting Geometry in Dilated Cardiomyopathy.

BACKGROUND AND AIM OF THE STUDY: Functional mitral regurgitation (FMR) is a clinically important complication of left ventricular (LV) dysfunction, occurring as a result of geometric deformity in the mitral valve (MV) complex. The study aim was to determine whether tenting parameters derived from real-time three-dimensional echocardiography (RT3DE) can predict the long-term prognosis for patients with dilated cardiomyopathy (DCM). METHODS: Mitral valve tenting morphology, LV volume and function, and papillary muscle positions were monitored using transthoracic RT3DE in 75 subjects (66 with DCM, nine controls). The maximum tenting sites of the leaflet (maxTS) were also mapped from the reconstructed 3D images, to determine if the 3D tenting parameters correlated to long-term outcome. RESULTS: Follow up information was collected from 62 patients with DCM over a mean period of 42 +/- 31 months. Cardiovascular events occurred in 30 patients (48%), including 13 cardiac deaths (21%). The patients were allocated to an Event group (n = 30) or a Non-event group (n = 32). The LV volumes were significantly larger and LV ejection fraction was lower in the Event group compared to the Non-event group. The 3D tenting volumes were significantly larger in the Event group than the Non- event group (p = 0.05). The maxTS were positioned mostly in the middle portion of the anterior mitral leaflet in the Non-event group (maxTS-mid AML), but in the Event group they were mostly found in the MV coaptation region of the leaflet (maxTS-coapt) (p <0.001). Patients with maxTS-coapt had a worse prognosis compared to those with maxTS-mid AML. On multivariate Cox regression analysis, maxTS was the strongest predictor of event-free survival. CONCLUSION: The 3D tenting pattern, assessed with RT3DE, would be an important clinical parameter in predicting long-term prognosis in patients with DCM.

Association between adiponectin production in coronary circulation and future cardiovascular events in patients with coronary artery disease.

Adiponectin has antiatherosclerotic properties and is also produced in the local coronary circulation. We previously reported that significantly less adiponectin was produced in the coronary circulation of patients with than without coronary artery disease (CAD). The goal of this study was to determine whether adiponectin production in the coronary circulation could predict future cardiovascular events in patients with CAD.Forty-eight CAD patients whose left anterior descending coronary arteries required percutaneous coronary intervention (PCI) were enrolled. The amount of adiponectin production in the coronary circulation was defined as the plasma adiponectin level at the great cardiac vein minus that at the orifice of the left coronary artery. All patients were divided by adiponectin production level in the coronary circulation into the adiponectin-positive production group (> 0 µg/ mL) and adiponectin-negative production group (≤ 0 µg/mL). Median follow-up period was 66 months (maximum, 108 months). The primary endpoint was the combined occurrence of major adverse cardiovascular events (MACE), including rehospitalization due to unstable angina, heart failure, nonfatal myocardial infarction, revascularization with PCI or coronary artery bypass grafting, ischemic stroke, and cardiovascular death.Sixteen MACE occurred. The incidence of MACE was significantly higher in the adiponectin-negative production group than in the adiponectin-positive production group (P = 0.02). In multivariate analysis, adiponectin-negative production was a predictor of MACE (P = 0.03). Kaplan-Meier analysis revealed that the MACE-free rate was significantly lower in the adiponectin-negative production group than in the adiponectin-positive production group.Adiponectin production in the coronary circulation with CAD may be associated with MACE.

Reduced fractional shortening of right ventricular outflow tract is associated with adverse outcomes in patients with left ventricular dysfunction.

BACKGROUND: Recent studies suggest the significance of right ventricular (RV) function in the outcome in patients with left ventricular dysfunction (LVSD); however, global assessment of RV remains to be determined by echocardiogram because of its complex geometry. This study aimed to validate RV outflow tract fractional shortening (RVOT-FS) in the evaluation of RV function and its prognostic value in patients with LVSD. METHODS: This study included eighty-one patients (62 ± 17 years, mean ± SD, male 79%) with reduced LV ejection fraction (LVEF) (≤40%). Two-dimensional echocardiogram of the parasternal short axis view was obtained at the level of the aortic root, and RVOT-FS was calculated as the ratio of end-diastole minus end-systole dimension to end-diastole dimension. RESULTS: RVOT-FS ranged from 0.04 to 0.8 (0.3 ± 0.2, mean ± SD), and correlated with LVEF (r = 0.33, p = 0.0028), RV fractional area change (r = 0.37, p = 0.0008) and brain natriuretic peptide level (r = -0.38, p = 0.0005). In Cox multivariate regression analysis, RVOT-FS [hazard ratio (HR) 0.028, 95% confidence interval (CI): 0.002-0.397]; p = 0.008] and New York Heart Association functional class III-IV [HR 2.233, 95% CI: 1.048-4.761]; p = 0.037] were independent factors to predict the events. During a median follow-up period of 319 days (1 to 1862 days), patients with RVOT-FS ≥ 0.2 showed a higher event-free rate than those < 0.2 by Kaplan-Meier analysis (log-rank test, p = 0.0016). CONCLUSIONS: Our data suggest that RVOT-FS is a simple parameter reflecting the severity of both ventricular function in patients with LVSD. In addition, RVOT-FS might be useful to predict adverse outcomes in such a patient population.

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.

Repeated sirolimus-eluting stent implantation to treat sirolimus-eluting stent and bare-metal stent restenosis.

BACKGROUND: In-stent restenosis (ISR) remains a persistent, unresolved issue even in the era of percutaneous coronary intervention (PCI) using drug-eluting stents. The present study compares the clinical and angiographic outcomes of using sirolimus-eluting stents (SES) for re-intervention against ISR that was originally treated with sirolimus-eluting or bare-metal (BMS) stents. METHODS AND RESULTS: This prospective single-center registry investigated 179 ISR lesions in 158 consecutive patients (53 lesions in 49, and 126 in 109 patients originally treated with SES and BMS, respectively), who had undergone re-intervention with SES. The patients were clinically and angiographically followed up at 8 months after re-PCI. The incidence of re-restenosis (29 vs 12%, P<0.01), ischemia-driven target lesion revascularization (TLR; 21 vs 8%, P<0.05) and major adverse cardiac events (MACE; 21 vs 9%, P<0.05) were significantly greater in ISR lesions originally treated with SES than in those originally treated with BMS at 8 months after re-PCI. Moreover, late luminal loss was significantly greater in the group with post-SES restenosis (P<0.05). Even after adjustment, post-SES restenosis was the only independent predictor of re-restenosis and MACE (P<0.05, each). CONCLUSIONS: Although the re-restenosis rate is acceptable, the incidence rates of late restenosis, ischemia-driven TLR and MACE are higher after repeated SES implantation to treat SES, than BMS restenosis. These results might affect the mid-term clinical outcomes of re-intervention with SES.

Adiponectin produced in coronary circulation regulates coronary flow reserve in nondiabetic patients with angiographically normal coronary arteries.

BACKGROUND: Epicardial adipose tissue expresses adiponectin protein, and its expression is significantly lower in patients with severe coronary artery disease (CAD) than in those without CAD. Transcoronary adiponectin levels are significantly decreased in nondiabetic but not in diabetic patients with CAD. Adiponectin is also an important adipocytokine that is linked to insulin resistance and reduces coronary microvascular function. HYPOTHESIS: Adiponectin may play a significant role in the localized coronary circulation. The present study examines the local dynamics of adiponectin in the coronary circulation in nondiabetic individuals with normal coronary arteries and the relationship between adiponectin and coronary microvasculature function. METHODS: We examined 22 consecutive nondiabetic patients whose coronary arteries were angiographically normal. Plasma levels of adiponectin were measured in blood samples that were simultaneously collected from the orifice of the left coronary artery (LCA) and the great cardiac vein (GCV). To evaluate the function of the coronary microcirculation, we measured coronary flow velocity at maximal hyperemia using a Doppler wire. Coronary flow reserve (CFR) was obtained from the ratio of hyperemia to the baseline coronary flow velocity. RESULTS: Plasma adiponectin levels in the GCV (median 6.95 microg/ml) were significantly higher than those in the LCA (median 6.60 microg/ml, p < 0.0005). The difference in plasma adiponectin levels between GCV and LCA significantly correlated with CFR (R = 0.451, p < 0.05). CONCLUSIONS: Adiponectin is locally produced in the coronary circulation. This protein may participate in modulating the coronary circulation of nondiabetic patients with angiographically normal coronary arteries.

Different inflammatory response and oxidative stress in neointimal hyperplasia after balloon angioplasty and stent implantation in cholesterol-fed rabbits.

Inflammatory responses appear to play an important role in the occurrence of restenosis following coronary intervention. However, the contribution of C-reactive protein (CRP) and oxidative stress to restenosis after balloon angioplasty and stent implantation remains unclear. The aim of this study was to examine this issue using hyperlipidemic rabbits. Rabbits were divided into two groups; they were fed with a 0.5% cholesterol diet and with a mixed 0.5% cholesterol and 0.5% probucol diet. Each group of rabbits underwent balloon injury and stent implantation in right and left iliac arteries, respectively. Eight weeks after the intervention, we examined luminal stenosis, neointimal hyperplasia, immunoreactivity for macrophage, CRP and oxidized phosphatidylcholine (oxPC), and also the expression of CRP mRNA. The degrees of neointimal hyperplasia and immunopositive areas (%) for macrophage, CRP, and oxPC in the neointima were significantly higher after stent implantation than after balloon injury, but CRP mRNA was undetectable in either artery. Anti-oxidant probucol reduced angiographic stenosis, neointimal hyperplasia, and macrophage- and oxPC-positive areas much more significantly after stenting. The results demonstrate that the inflammatory response to the development of neointimal hyperplasia differs after balloon injury and stent implantation and that CRP deposition and oxidative stress might be involved more significantly in neointimal development after stent implantation.

Effects of interleukin-6 produced in coronary circulation on production of C-reactive protein and coronary microvascular resistance.

We measured plasma levels of interleukin-6 and C-reactive protein at the orifice of the left coronary artery and at the great cardiac vein in patients who had coronary artery disease and those who had angiographically normal coronary arteries (controls). We also measured coronary microvascular resistance in the control group. We found increased levels of interleukin-6 in the coronary circulation of patients who had coronary artery disease compared with controls. This increase correlated with C-reactive protein production in the coronary circulation and coronary microvascular resistance. These findings suggest that a localized cytokine/inflammatory pathway functions in the coronary circulation and that interleukin-6 is involved in modulating coronary vascular tone.

Relation of CD39 to plaque instability and thrombus formation in directional atherectomy specimens from patients with stable and unstable angina pectoris.

To determine whether the expression of CD39 in coronary atherosclerotic lesions is related to plaque instability and thrombus formation, we assessed directional coronary atherectomy (DCA) specimens from patients with stable and unstable angina pectoris. CD39 immunoreactivity was decreased in culprit lesions in patients with unstable angina pectoris compared with those with stable angina pectoris, and was reduced in DCA specimens with thrombus formation. These results suggest that CD39 expressed in atheromatous plaque plays an important role in preventing acute coronary syndromes.