Comparisons of Nonhyperemic Pressure Ratios: Predicting Functional Results of Coronary Revascularization Using Longitudinal Vessel Interrogation.

OBJECTIVES: The aim of this study was to investigate the accuracy of pre-percutaneous coronary intervention (PCI) predicted nonhyperemic pressure ratios (NHPRs) with actual post-PCI NHPRs and to assess the efficacy of PCI strategy using pre-PCI NHPR pullback. BACKGROUND: Predicting the functional results of PCI is feasible using pre-PCI longitudinal vessel interrogation with the instantaneous wave-free ratio (iFR), a pressure-based, adenosine-free NHPR. However, the reliability of novel NHPRs (resting full-cycle ratio [RFR] and diastolic pressure ratio [dPR]) for this purpose remains uncertain. METHODS: In this prospective, multicenter, randomized controlled trial, vessels were randomly assigned to receive pre-PCI iFR, RFR, or dPR pullback (50 vessels each). The pre-PCI predicted NHPRs were compared with actual NHPRs after contemporary PCI using intravascular imaging. The number and the total length of treated lesions were compared between NHPR pullback-guided and angiography-guided strategies. RESULTS: The predicted NHPRs were strongly correlated with actual NHPRs: iFR, r = 0.83 (95% confidence interval: 0.72 to 0.90; p < 0.001); RFR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001), and dPR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001). The number and the total length of treated lesions were lower with the NHPR pullback strategy than with the angiography-guided strategy, leading to physiological improvement. CONCLUSIONS: Predicting functional PCI results on the basis of pre-procedural RFR and dPR pullbacks yields similar results to iFR. Compared with an angiography-guided strategy, a pullback-guided PCI strategy with any of the 3 NHPRs reduced the number and the total length of treated lesions. (Study to Examine Correlation Between Predictive Value and Post PCI Value of iFR, RFR and dPR; UMIN000033534).

Primary Angiosarcoma in the Right Atrium Diagnosed by a Cardiac Tumor Biopsy Using Intracardiac Echocardiography.

A 47-year-old woman consulted a doctor due to a persistent cough. Computed tomography revealed a 30 mm × 60 mm intracardiac mass in the right atrium. Because of lung metastasis, her respiratory status did not allow a more invasive procedure, such as general anesthesia. Although intracardiac echocardiography (ICE) during percutaneous transcatheter biopsy (PTB) is not covered by medical insurance, we performed PTB under ICE guidance. Pathology and immunohistochemistry revealed primary cardiac angiosarcoma. Primary cardiac angiosarcoma is a rare tumor with a poor prognosis. After seven cycles of chemotherapy, the pulmonary metastasis was clearly improved. The patient is alive 18 months after the first consult, even though the mortality of angiosarcoma is high. ICE during PTB allowed us to choose appropriate chemotherapy and improve her pulmonary metastasis. ICE during PTB reduces the need for a diagnostic open-chest procedure that requires a more invasive approach.

In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study.

AIMS: Although distinct DNA methylation patterns have been reported, its localization and roles remain to be defined in heart failure. We investigated the cellular and subcellular localization of DNA methylation and its pathophysiological significance in human failing hearts. METHODS AND RESULTS: Using left ventricular (LV) endomyocardial biopsy specimens from 75 patients with dilated cardiomyopathy (DCM; age: 58 ± 14 years old, %female: 32%) and 20 patients without heart failure (controls; age: 56 ± 17 years old, %female: 45%), we performed immunohistochemistry and immunoelectron microscopy for methylated DNA, 5-methylcytosine (5-mC). We next investigated possible relations of the incidence of 5-mC-positive (%5-mC+ ) cardiomyocytes with clinicopathological parameters. Immunopositivity for 5-mC was detected in the cardiomyocytes and other cell types. The %5-mC+ cardiomyocytes was significantly greater in DCM hearts than in controls (57 ± 13% in DCM vs. 25 ± 12% in controls, P < 0.0001). The localization of 5-mC immunopositivity in cardiomyocyte nuclei coincided well with that of heterochromatin, as confirmed by immunoelectron microscopy. Substantial DNA methylation was also observed in interstitial non-cardiomyocytes, but the incidences did not differ between control and DCM hearts (39 ± 7.9% in DCM vs. 41 ± 10% in controls, P = 0.4099). In DCM patients, the %5-mC+ cardiomyocytes showed a significant inverse correlation with LV functional parameters such as heart rate (r = 0.2391, P = 0.0388), end-diastolic pressure (r = 0.2397, P = 0.0397), and ejection fraction (r = -0.2917, P = 0.0111) and a positive correlation with LV dilatation (volume index at diastole; r = 0.2442, P = 0.0347; and volume index at systole; r = 0.3136, P = 0.0062) and LV hypertrophy (mass index; r = 0.2287, P = 0.0484)-that is, LV remodelling parameters. No significant correlations between DNA methylation and the histological parameters of the biopsies, including cardiomyocyte hypertrophy, fibrosis, and inflammatory cell infiltration, were noted. CONCLUSIONS: The present study revealed increased nuclear DNA methylation in cardiomyocytes, but not other cell types, from DCM hearts, with predominant localization in the heterochromatin. Its significant relations with LV functional and remodelling parameters imply a pathophysiological significance of DNA methylation in heart failure.

Neovascularization in pericarditis: a possible etiology of hemopericardium.

Hemorrhagic pericardial effusion is life-threatening and mostly occurs during pericarditis; however, its underlying mechanism is unclear. We report a case of pericardial hematoma with obvious hemorrhage. A 56-year-old man without prior chest trauma presenting with exertional dyspnea and abdominal fullness was treated for idiopathic pericarditis. The echocardiogram showed a thickened pericardium with effusion. Imaging showed extravasation and neovascularization. Following ineffective pharmacotherapy, we performed pericardiectomy. The site of bleeding was undetectable. Because parietal pericardiectomy with hematoma evacuation did not improve diastolic function, we removed the epicardium. During the follow-up period, the patient remained almost asymptomatic. We identified neovascularization as the potential source of idiopathic pericardial hemorrhage.

Increased Plasma Adenosine Concentration in the Subacute Phase May Contribute to Attenuation of Left Ventricular Dilation in the Chronic Phase in Patients With Acute Myocardial Infarction.

BACKGROUND: Changes in the plasma adenosine concentration and the effects on left ventricular (LV) function and remodeling in patients with acute myocardial infarction (AMI) remain unclear. Methods and Results: In 58 patients with AMI and 14 subjects without cardiac disease (controls), we measured the plasma adenosine concentration by LC-MS/MS. Blood samples were taken from the antecubital vein on days 0, 1, 7, and 14 after AMI, and from the controls on admission. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. There were no significant differences in the plasma adenosine concentrations among days 0 (211.5±150.2 nmol/L), 1 (192.7±141.3 nmol/L), 7 (218.8±154.1 nmol/L), and the controls (136.0±50.9 nmol/L). The plasma adenosine concentration increased significantly on day 14 (321.1±195.4 nmol/L) after AMI as compared with days 0, 1 and 7. AMI patients with a greater increase in the plasma adenosine concentration in the subacute phase showed an attenuation of LV dilation in the chronic phase. The plasma adenosine concentration in the acute phase did not affect the LV ejection fraction in the chronic phase. CONCLUSIONS: The plasma adenosine concentration significantly increased 14 days after AMI, which may contribute to attenuation of LV dilation in the chronic phase.

Presence of Plaque Neovascularization on Optical Frequency Domain Imaging Predicts Progression of Carotid Artery Stenosis.

BACKGROUND AND PURPOSE: Neovascularization (NV) is regarded to be one of the important features of vulnerable plaque. The purpose of this study was to evaluate associations between the presence of NV, detected using optical frequency domain imaging (OFDI), and ischemic events and the progress of carotid artery stenosis. MATERIALS AND METHODS: Carotid artery plaques were evaluated using an OFDI system before angioplasty. NV was defined as no-signal tubuloluminal structures recognized on at least 3 consecutive images. The total number of NVs was compared between symptomatic and asymptomatic plaques and between progressive and nonprogressive plaques. Carotid plaque was diagnosed as "progressive" when peak systolic velocity increased between serial carotid duplex scans. RESULTS: A total of 36 patients (17 symptomatic, 16 progressive) were included. The percentage of patients with smoking habits was significantly higher with progressive carotid plaque than with nonprogressive carotid plaque (P = 0.003). NV was detected in 34 patients (94%), and the total number of NVs was significantly higher with progressive carotid plaque (10.2 ± 4.8 vs. 3.7 ± 2.8; P < 0.0001). There was no relationship between the number of NVs and ischemic events (symptomatic 6.0 ± 5.1 vs. asymptomatic 7.1 ± 5.0; P = 0.47). In multivariate logistic regression analysis, the number of NVs was an independent predictor of progressive carotid plaque (odds ratio 1.64 per 1 increase [95% confidence interval 1.19-2.64]; P = 0.0005). CONCLUSIONS: NV was more frequently observed in progressive carotid plaques. Evaluation of NV using OFDI may be useful in predicting progressive carotid plaques.

Post-MI treatment with G-CSF and EPO-liposome with SLX repairs infarcted myocardium through EPCs mobilization and activation of prosurvival signals in rabbits.

We investigated whether combination therapy of G-CSF and erythropoietin (EPO)-liposome with Siaryl Lewis X (SLX) is more cardioprotective than G-CSF or EPO-liposome with SLX alone. For the purpose of generating myocardial infarction (MI), rabbits underwent 30 minutes of coronary occlusion and 14 days of reperfusion. We administered saline (control group, i.v.,), G-CSF (G group, 10 µg/kg/day × 5 days, i.c., starting at 24 hours after reperfusion), EPO-liposome with SLX (LE group, i.v., 2500 IU/kg EPO containing liposome with SLX, immediately after reperfusion), and G-CSF + EPO-liposome with SLX (LE + G group) to the rabbits. The MI size was the smallest in the LE+G group (14.7 ± 0.8%), and smaller in the G group (22.4 ± 1.5%) and LE group (18.5 ± 1.1%) than in the control group (27.8 ± 1.5%). Compared with the control group, the cardiac function and remodeling of the G, LE, and LE + G groups were improved, and LE + G group tended to show the best improvement. The number of CD31-positive microvessels was the greatest in the LE + G group, greater in the G and LE groups than in the control group. Higher expressions of phosphorylated (p)-Akt and p-ERK were observed in the ischemic area of the LE and LE + G groups. The number of CD34+/CXCR4+ cells was significantly higher in the G and LE + G groups. The cardiac SDF-1 was more expressed in the G and LE + G groups. In conclusion, Post-MI combination therapy with G-CSF and EPO-liposome with SLX is more cardioprotective than G-CSF or EPO-liposome with SLX alone through EPCs mobilization, neovascularization, and activation of prosurvival signals.

The intestine responds to heart failure by enhanced mitochondrial fusion through glucagon-like peptide-1 signalling.

AIMS: Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone secreted by the intestine. Its receptor (GLP-1R) is expressed in various organs, including the heart. However, the dynamics and function of the GLP-1 signal in heart failure remains unclear. We investigated the impact of the cardio-intestinal association on hypertensive heart failure using miglitol, an α-glucosidase inhibitor known to stimulate intestinal GLP-1 production. METHODS AND RESULTS: Dahl salt-sensitive (DS) rats fed a high-salt diet were assigned to miglitol, exendin (9-39) (GLP-1R blocker) and untreated control groups and treated for 11 weeks. Control DS rats showed marked hypertension and cardiac dysfunction with left ventricular dilatation accompanied by elevated plasma GLP-1 levels and increased cardiac GLP-1R expression as compared with age-matched Dahl salt-resistant (DR) rats. Miglitol further increased plasma GLP-1 levels, suppressed adverse cardiac remodelling, and mitigated cardiac dysfunction. In cardiomyocytes from miglitol-treated DS hearts, mitochondrial size was significantly larger with denser cristae than in cardiomyocytes from control DS hearts. The change in mitochondrial morphology reflected enhanced mitochondrial fusion mediated by protein kinase A activation leading to phosphorylation of dynamin-related protein 1, expression of mitofusin-1 and OPA-1, and increased myocardial adenosine triphosphate (ATP) content. GLP-1R blockade with exendin (9-39) exacerbated cardiac dysfunction and led to fragmented mitochondria with disarrayed cristae in cardiomyocytes and reduction of myocardial ATP content. In cultured cardiomyocytes, GLP-1 increased expression of mitochondrial fusion-related proteins and ATP content. When GLP-1 and exendin (9-39) were administered together, their effects cancelled out. CONCLUSIONS: Increased intestinal GLP-1 secretion is an adaptive response to heart failure that is enhanced by miglitol. This could be an effective strategy for treating heart failure through regulation of mitochondrial dynamics.

Possible mechanism for disposal of degenerative cardiomyocytes in human failing hearts: phagocytosis by a neighbour.

The index case was a 51-year-old woman suffering from doxorubicin cardiomyopathy. In her endomyocardial biopsy specimen, we observed under electron microscopy six scenes in which degenerative cardiomyocytes were engulfed by neighbouring cardiomyocytes. The enclosed cardiomyocytes appeared more degenerative than the enclosing ones in every pair: the myofibrils were more severely damaged. At more degenerative stages, some desmosomes of the intercalated discs on the enclosed cardiomyocyte had disappeared. The membranes between the cardiomyocytes were occasionally disrupted, and there appeared to be sharing of cellular contents between the cells. One pair of such a phagocytosis-like figure was observed in one case with 5-fluorouracil cardiomyopathy (a 68-year-old man) among eight other chemotherapy-induced cardiomyopathies but none among 30 non-drug-induced dilated cardiomyopathies. The findings suggest a mechanism for disposal of degenerative cardiomyocytes in human failing hearts: phagocytosis by a neighbour, although alternative interpretations remain (e.g. giant autophagic vacuoles or two cardiomyocytes with degenerative intercalated discs).

Endogenous Adenosine May Be Related to Left Ventricular Dysfunction, Dilation, and Wall Thinning in Patients With Heart Disease.

BACKGROUND: The role of endogenous adenosine in cardiac patients is still unclear, so we investigated the relationship between the plasma adenosine concentration and left ventricular (LV) function, LV dilation and LV wall thinning in cardiac patients.Methods and Results:In 97 cardiac patients, with angina pectoris, old myocardial infarction, dilated or hypertrophic cardiomyopathy, and valvular heart disease, plasma adenosine concentrations were measured using the LC-MS/MS system, and the LV function, LV end-diastolic dimension (LVDd), LV posterior wall thickness (LVPWth), and interventricular septum thickness (IVSth) were assessed by echocardiography. The plasma adenosine concentration was significantly higher in patients with a LV ejection fraction (EF), an indicator of the LV systolic function, <47% compared with those with LVEF ≥47% (P=0.027). There was no difference between the plasma adenosine concentration and E/e', an indicator of LV diastolic function. The plasma adenosine concentration was significantly higher in patients with LVDd ≥50 mm than in those with LVDd <50 mm (P=0.030). The plasma adenosine concentration was inversely correlated with IVSth (P=0.003) and LVPWth (P=0.0007). The plasma adenosine concentration was significantly higher in patients with IVSth <8 mm than in those with IVSth ≥8 mm (P=0.015), and was significantly higher in patients with LVPWth <8 mm than in those with LVPWth ≥8 mm (P=0.020). CONCLUSIONS: Endogenous adenosine may be related to LV dysfunction, dilation, and wall thinning in cardiac patients.

S1P-S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction.

RATIONALE: Multilineage-differentiating stress enduring (Muse) cells, pluripotent marker stage-specific embryonic antigen-3+ cells, are nontumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow. Their therapeutic efficiency has not been validated in acute myocardial infarction. OBJECTIVE: The main objective of this study is to clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) bone marrow-Muse cells in a rabbit acute myocardial infarction model and their mechanisms of tissue repair. METHODS AND RESULTS: In vivo dynamics of Nano-lantern-labeled Muse cells showed preferential homing of the cells to the postinfarct heart at 3 days and 2 weeks, with ≈14.5% of injected GFP (green fluorescent protein)-Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells was confirmed pharmacologically (S1PR2 [sphingosine monophosphate receptor 2]-specific antagonist JTE-013 coinjection) and genetically (S1PR2-siRNA [small interfering ribonucleic acid]-introduced Muse cells) to be mediated through the S1P (sphingosine monophosphate)-S1PR2 axis. They spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric α-actinin, and connexin-43, and vascular markers. GCaMP3 (GFP-based Ca calmodulin probe)-labeled Muse cells that engrafted into the ischemic region exhibited increased GCaMP3 fluorescence during systole and decreased fluorescence during diastole. Infarct size was reduced by ≈52%, and the ejection fraction was increased by ≈38% compared with vehicle injection at 2 months, ≈2.5 and ≈2.1 times higher, respectively, than that induced by mesenchymal stem cells. These effects were partially attenuated by the administration of GATA4-gene-silenced Muse cells. Muse cell allografts and xenografts efficiently engrafted and recovered functions, and allografts remained in the tissue and sustained functional recovery for up to 6 months without immunosuppression. CONCLUSIONS: Muse cells may provide reparative effects and robust functional recovery and may, thus, provide a novel strategy for the treatment of acute myocardial infarction.

Addition of Tolvaptan Compared With Increased Dose of Furosemide in Heart Failure Patients With Chronic Kidney Disease Under Furosemide Treatment.

Background: Given that residual congestion is a predictor of poor outcome in patients with heart failure (HF), a therapeutic strategy for decongestion is required. Methods and Results: Eighteen HF patients with fluid retention despite oral furosemide >20 mg/day, with chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR], <59 mL/min/1.73 m2) were enrolled. Patients were randomized into 2 groups: a tolvaptan group (tolvaptan, 7.5 mg/day, n=10) and a furosemide group (additional furosemide 20 mg/day, n=8), and followed up for 7 days. The urine volume significantly increased on day 3 in the tolvaptan group but not in the furosemide group. The body weight significantly decreased in the tolvaptan compared with the furosemide group on days 3 and 5. Although there was no difference in serum creatinine or eGFR in the 7 days between the 2 groups, serum cystatin C significantly decreased on day 7 in the tolvaptan group compared with the furosemide group. The residual congestion was more improved in the tolvaptan group than in the furosemide group. Conclusions: Adding tolvaptan but not furosemide significantly increased urine volume, decreased body weight and improved residual congestion without affecting the renal function or electrolytes in patients with HF with CKD under furosemide treatment.

Mobilized Muse Cells After Acute Myocardial Infarction Predict Cardiac Function and Remodeling in the Chronic Phase.

BACKGROUND: Multilineage differentiating stress-enduring (Muse) cells are SSEA3+and CD105+double-positive pluripotent-like stem cells. We aimed to examine the mobilization of Muse cells into peripheral blood after acute myocardial infarction (AMI) and their effects on left ventricular (LV) function and remodeling.Methods and Results:In 79 patients with AMI, 44 patients with coronary artery disease (CAD), and 64 normal subjects (Control), we measured the number of Muse cells in the peripheral blood by fluorescence-activated cell sorting. Muse cells were measured on days 0, 1, 7, 14, and 21 after AMI. Plasma sphingosine-1-phosphate (S1P) levels were measured. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. Muse cell number on day 1 was significantly higher in the AMI (276±137 cells/100 µL) than in the CAD (167±89 cells/100 µL) and Control (164±125 cells/100 µL) groups. Muse cell number peaked on day 1, and had gradually decreased on day 21. Muse cell number positively correlated with plasma S1P levels. Patients with a higher increase in the number of Muse cells in the peripheral blood but not those with a lower increase in number of Muse cells in the acute phase showed improved LV function and remodeling in the chronic phase. CONCLUSIONS: Endogenous Muse cells were mobilized into the peripheral blood after AMI. The number of Muse cells could be a predictor of prognosis in patients with AMI.

Postocclusional Hyperemia for Fractional Flow Reserve After Percutaneous Coronary Intervention.

BACKGROUND: Postocclusional hyperemia caused by balloon occlusion is a potential alternative method of inducing hyperemia for measuring post-percutaneous coronary intervention fractional flow reserve (FFR). The aim of this study was to investigate postocclusional hyperemia as a method of inducing hyperemia. METHODS AND RESULTS: FFR measured by postocclusional hyperemia (FFRoccl) caused by balloon occlusion after percutaneous coronary intervention was compared with FFR measured by drug-induced hyperemia (FFR measured by intravenous ATP; and FFR measured by intracoronary papaverine injection [FFRpap]) in 98 lesions from 98 patients. The hyperemia duration was also measured for FFRoccl and FFRpap. The correlation coefficient between FFRoccl, FFR measured by intravenous ATP (r=0.973; P<0.01), and FFRpap (r=0.975; P<0.01) showed almost identical values to those obtained for the correlation coefficient between FFR measured by intravenous ATP and FFRpap (r=0.967; P<0.01). No clear difference was observed on Bland-Altman analysis. Hyperemia duration was significantly longer with FFRoccl than with FFRpap (70±22 versus 51±25 s; P<0.01). CONCLUSIONS: Strong correlations were found between FFRoccl and FFR measured by intravenous ATP and FFRoccl and FFRpap. Hyperemia caused by FFRoccl was significantly longer than that caused by FFRpap.

Noninvasive Tissue Characterization of Lung Tumors Using Integrated Backscatter Intravascular Ultrasound: An Ex Vivo Comparative Study With Pathological Diagnosis.

BACKGROUND: Endobronchial ultrasonography (EBUS) facilitates a lung cancer diagnosis. However, qualitative tissue characterization of lung tumors is difficult using EBUS. Integrated backscatter (IBS) is an ultrasound technique that calculates the power of the ultrasound signal to characterize tissue components in coronary arteries. We hypothesized that qualitative diagnosis of lung tumors is possible using the IBS technique. The aim of the present study was to elucidate whether the IBS technique can be used in lung tissue diagnoses. METHODS: Thirty-five consecutive patients who underwent surgery for lung cancer were prospectively enrolled. Surgical specimens of the lung and the tumor tissue were obtained, and the IBS values were measured within 48 h after surgery. Histologic images of lung and tumor tissues were compared with IBS values, and the relative interstitial area according to results of Masson's trichrome staining were determined by using an imaging processor. RESULTS: The IBS values in tumor tissue were significantly lower than those in normal lung tissue (-50.9 ± 2.6 dB and -47.6 ± 2.6 dB, respectively; P < .001). The IBS values of adenocarcinomas associated with a good 5-year survival rate were higher than those of non-adenocarcinomas (-48.1 ± 1.6 dB and -52.6 ± 1.4 dB; P < .001). There were significant correlations between the IBS values and the relative interstitial area or micro air area in tumor (r = 0.53 and r = 0.67; P < .01). After combining normal lung tissue and adenocarcinomas with a good prognosis, the sensitivity and specificity for establishing the presence of lung tumors were 84% and 85%. CONCLUSIONS: Qualitative diagnosis of lung tumors was possible, with a sensitivity of 84% and a specificity of 85%, using the ultrasound IBS technique.

Asymptomatic moderate carotid artery stenosis with intraplaque hemorrhage: onset of new ischemic stroke.

BACKGROUND: The degree of stenosis of carotid arteries is recognized as an important risk factor for ischemic stroke. However, high-grade stenosis does not always cause cerebrovascular events, whereas low- to moderate-grade stenosis may often cause strokes. It has been reported that there is an association between carotid intraplaque hemorrhage (IPH) and new brain ischemic events. CASE PRESENTATION: We present three patients with asymptomatic moderate carotid artery stenosis and carotid IPH who underwent both neurological and MRI at baseline and after at least 1 year's follow-up. These patients were admitted to our hospital (after 15-35 months of follow-up) because of neurological deficits. Diffusion-weighted MRI of the brain showed ipsilateral new ischemic lesions due to carotid artery plaques. The patients were treated with carotid artery stenting and discharged uneventfully. CONCLUSIONS: Whether plaques with severe stenosis already had severe stenosis at the onset of events or plaques with moderate stenosis progressed owing to an acute change, such as growth of an IPH, remains unclear, because no carotid imaging was carried out just before the events. This is the first case report which presents neurological symptoms and MRI at both baseline and follow-up in patients with asymptomatic moderate carotid artery stenosis and carotid IPH.

Feasibility of tissue characterization of coronary plaques using 320-detector row computed tomography: comparison with integrated backscatter intravascular ultrasound.

Recently, a new generation of multi-detector row computed tomography (CT) with 320-detector rows (DR) has become available in the clinical settings. The purpose of the present study was to determine the cutoff values of Hounsfield unit (HU) for discrimination of plaque components by comparing HU of coronary plaques with integrated backscatter intravascular ultrasound (IB-IVUS) serving as a gold standard. Seventy-seven coronary atherosclerotic lesions in 77 patients with angina were visualized by both 320-DR CT (Aquilion One, Toshiba, Japan) and IB-IVUS at the same site. To determine the thresholds for discrimination of plaque components, we compared HU with IB values as a gold standard. Optimal thresholds were determined from receiver operating characteristic (ROC) curves analysis. The HU values of lipid pool (n = 115), fibrosis (n = 93), vessel lumen and calcification (n = 73) were 28 ± 19 HU (range -18 to 69 HU), 98 ± 31 HU (44 to 195 HU), 357 ± 65 HU (227 to 534 HU) and 998 ± 236 HU (366 to 1,489 HU), respectively. The thresholds of 56 HU, 210 HU and 490 HU were the most reliable predictors of lipid pool, fibrosis, vessel lumen and calcification, respectively. Lipid volume measured by 320-DR CT was correlated with that measured by IB-IVUS (r = 0.63, p < 0.05), whereas fibrous volume measured by 320-DR CT was not. Lipid volume measured by 320-DR CT was correlated with that measured by IB-IVUS, whereas fibrous volume was not correlated with that measured by IB-IVUS because manual exclusion of the outside of vessel hindered rigorous discrimination between fibrosis and extravascular components.

Intravenous Administration of Endothelial Colony-Forming Cells Overexpressing Integrin ß1 Augments Angiogenesis in Ischemic Legs.

When injected directly into ischemic tissue in patients with peripheral artery disease, the reparative capacity of endothelial progenitor cells (EPCs) appears to be limited by their poor survival. We, therefore, attempted to improve the survival of transplanted EPCs through intravenous injection and gene modification. We anticipated that overexpression of integrin ß1 will enable injected EPCs to home to ischemic tissue, which abundantly express extracellular matrix proteins, the ligands for integrins. In addition, integrin ß1 has an independent angiogenesis-stimulating function. Human endothelial colony-forming cells (ECFCs; late-outgrowth EPCs) were transduced using a lentiviral vector encoding integrin ß1 (ITGB1) or enhanced green fluorescent protein (GFP). We then locally or systemically injected phosphate-buffered saline or the genetically modified ECFCs (GFP-ECFCs or ITGB1-ECFCs; 1 × 10(5) cells each) into NOD/Shi-scid, IL-2Rγnull mice whose right femoral arteries had been occluded 24 hours earlier. Upregulation of extracellular matrix proteins, including fibronectin, was apparent in the ischemic legs. Four weeks later, blood perfusion of the ischemic limb was significantly augmented only in the ITGB1-ECFC group. Scanning electron microscopy of vascular casts revealed increases in the perfused blood vessels in the ischemic legs of mice in the ITGB1-ECFC group and significant increases in the density of both capillaries and arterioles. Transplanted ECFC-derived vessels accounted for 28% ± 4.2% of the vessels in the ITGB1-ECFC group, with no cell fusion. Intravenous administration of ECFCs engineered to home to ischemic tissue appears to efficiently mediate therapeutic angiogenesis in a mouse model of peripheral artery disease. Significance: The intravenous administration of endothelial colony-forming cells (ECFCs) genetically modified to overexpress integrin ß1 effectively stimulated angiogenesis in ischemic mouse hindlimbs. Transplanted ECFCs were observed in the ischemic leg tissue, even at the chronic stage. Moreover, the cells appeared functional, as evidenced by the improved blood flow. The cell type used (ECFCs), the route of administration (intravenous, not directly injected into the affected area), and the use of ligand-receptor interactions (extracellular matrix and integrins) for homing represent substantial advantages over previously reported cell therapies for the treatment of peripheral artery disease.

High-Intensity Signal in Carotid Plaque on Routine 3D-TOF-MRA Is a Risk Factor of Ischemic Stroke.

BACKGROUND: Carotid atherosclerotic disease is recognized as an important risk factor for brain ischemic events. However, high-grade stenosis does not always cause ischemic strokes, whereas moderate-grade stenosis may often cause ischemic strokes. It has been reported that there is an association between carotid intraplaque hemorrhage (IPH) and new cerebral ischemic events. The purpose of this study was to elucidate the relationship between high-intensity signals (HIS) on maximum intensity projection (MIP) images from routine 3-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA) and prior ischemic strokes in the patients with moderate carotid stenosis. MATERIALS AND METHODS: Sixty-one patients with moderate carotid artery stenosis (50-69% stenosis based on North American Symptomatic Carotid Endarterectomy Trial criteria) were included. Carotid IPH was defined as the presence of HIS in carotid plaques on MIP images detected by 3D-TOF-MRA using criteria we previously reported. We analyzed the relationship between the presence of HIS in plaques and prior ischemic strokes defined as ischemic lesions on diffusion-weighted brain images. RESULTS: HIS in carotid plaques were present in 27 (44%) of 61 patients. Prior ipsilateral ischemic strokes occurred more frequently in the HIS-positive group than the HIS-negative group (67 vs. 9%, p < 0.001). Furthermore, there were more smokers in the group with ischemic stroke than without it (62 vs. 25%, p = 0.005). In multivariate logistic regression analysis, HIS in carotid plaque (OR 23.4, 95% CI 4.62-118.3, p < 0.001) and smoking (OR 5.44, 95% CI 1.20-24.6, p = 0.028) were independent determinants of prior ischemic strokes after adjustment for age. CONCLUSIONS: HIS in carotid plaques on 3D-TOF-MRA MIP images are independent determinants of prior ischemic strokes in patients with moderate carotid artery stenosis, and they can potentially provide a reliable risk stratification of patients with moderate carotid artery stenosis.