Utility and optimal dose of nicorandil for physiological assessment of the femoropopliteal artery.

BACKGROUND: Nicorandil is widely used as a vasodilator for the physiological assessment of coronary arteries because of its usefulness and safety; however, there are no data on its use in peripheral arteries. AIMS: To identify the utility of nicorandil and its appropriate dose for the physiological assessment on the femoropopliteal artery. METHODS: We retrospectively enrolled patients from three institutes in which physiological assessment was carried out with various doses of nicorandil before treatment. Twenty-four femoropopliteal artery stenotic lesions from 22 patients were included. The nicorandil doses used were 2, 4, and 6 mg. Twenty-two lesions were also assessed using 30 mg of papaverine. The pressure gradient (PG) and peripheral fractional flow reserve (pFFR) were calculated based on the mean and systolic pressure levels. We examined the correlation of each parameter with the peak systolic velocity ratio (PSVR) based on the duplex ultrasound images using Spearman's rank correlation coefficient. Systemic blood pressure was assessed for safety. RESULTS: The correlations were higher for mean pressure-based parameters than for systolic pressure-based parameters. As the nicorandil dose increased, the correlations among PG, pFFR, and PSVR also increased (mean pressure-based PG: 2 mg, r = 0.360; 4 mg, r = 0.498; 6 mg, r = 0.694, mean pressure-based pFFR: 2 mg, r = -0.479; 4 mg, r = -0.469; 6 mg, r = -0.641). The blood pressure after the administration of 6 mg of nicorandil was low, and the median systemic mean pressure was 65 mmHg. CONCLUSION: A 4 mg dose of nicorandil is effective and safe for the mean pressure-based physiological assessment of lesions in the femoropopliteal artery.

Tissue responses to everolimus-eluting stents implanted in severely calcified lesions following atherectomy.

Histopathological examination has revealed that stents on severely calcified plaques were associated with delayed vascular healing. Although atherectomy devices can increase the number of malapposed struts, tissue responses to implanted drug eluting stents in atherectomy patients remain largely unknown. This retrospective observational study included 30 patients who underwent atherectomy and everolimus-eluting stent (EES) deployment for severely calcified coronary lesions (biodegradable polymer EES (BP-EES), n = 15; durable polymer EES (DP-EES), n = 15). Optical coherence tomography was carried out at baseline and follow-up, and struts with acute stent malapposition (ASM) were categorized as struts on modified calcium (mod-Ca), non-modified calcium (non-mod-Ca), or non-calcium (non-Ca). Adequate vascular healing, defined as ASM resolution with neointimal coverage, was compared between the BP-EES and DP-EES groups. Multivariate linear regression analysis using a generalized estimated equation revealed that BP-EES use was associated with significantly better adequate vascular healing compared with DP-EES (odds ratio [OR]: 3.691, 95% confidence interval [CI] 1.175-11.592, P = 0.025). adequate vascular healing was associated with the underlying plaque morphology (mod-Ca vs non-mod-Ca: OR 2.833, 95% CI 1.491-5.384, P = 0.001; non-Ca vs non-mod-Ca: OR 1.248, 95% CI 0.440-3.543, P = 0.677). This study demonstrates that drug-eluting stent selection and calcium modification are possible factors affecting vascular healing of malapposed struts in severely calcified lesions.

Quantification of pulmonary perfusion using LSIM-CT correlates with pulmonary hemodynamics in patients with CTEPD.

Background: Lung subtraction iodine mapping (LSIM)-CT is a clinically useful technique that can visualize pulmonary mal-perfusion in patients with chronic thromboembolic pulmonary disease (CTEPD). However, little is known about the associations of LSIM images with hemodynamic parameters of patients with CTEPD. This study investigates a parameter of LSIM images associated with mean pulmonary arterial pressure (mPAP) and validates the association between pulmonary vascular resistance, right atrial pressure, cardiac index, and exercise capacity in patients with CTEPD. Methods: This single-center, prospective, observational study involved 30 patients diagnosed with CTEPD using lung perfusion scintigraphy. To examine the correlation of decreased pulmonary perfusion area (DPA) with mPAP, areas with 0-10, 0-15, 0-20, and 0-30 HU in lung subtraction images were adopted in statistical analysis. The DPA to total lung volume ratio (DPA ratio, %) was calculated as the ratio of each DPA volume to the total lung volume. To assess the correlation between DPA ratios of 0-10, 0-15, 0-20, and 0-30 HU and mPAP, Spearman's rank correlation coefficient was used. Results: The DPA ratio of 0-10 HU had the most preferable correlation with mPAP than DPA ratios of 0-15, 0-20, and 0-30 HU (ρ = 0.440, P = 0.015). The DPA ratio of 0-10 HU significantly correlates with pulmonary vascular resistance (ρ = 0.445, P = 0.015). The receiver operating characteristic curve analysis indicated that the best cutoff value of the DPA ratio of 0-10 HU for the prediction of an mPAP of ≥30 mmHg was 8.5% (AUC, 0.773; 95% CI, 0.572-0.974; sensitivity, 83.3%; specificity, 75.0%). Multivariate linear regression analysis, which was adjusted for the main pulmonary arterial to ascending aortic diameter ratio and right ventricular to left ventricular diameter ratio, indicated that the DPA ratio of 0-10 HU was independently and significantly associated with mPAP (B = 89.7; 95% CI, 46.3-133.1, P < 0.001). Conclusion: The DPA ratio calculated using LSIM-CT is possibly useful for estimating the hemodynamic status in patients with CTEPD.

Thrombus or tumor?

Key clinical message: Contrast defects in veins are often diagnosed as benign thrombi, but depending on the patient's background it is necessary to differentiate between tumor thrombi. It is difficult to differentiate between these using contrast-enhanced CT alone, but with angioscopy it is easy to visually distinguish between a benign and tumor thrombi. Abstract: Contrast-enhanced computer tomography (CT) performed on a male patient being treated for de-differentiated chondrosarcoma revealed contrast defects in the pulmonary artery and right femoral vein, and a diagnosis of pulmonary artery thromboembolism and venous thromboembolism was made, and oral anticoagulant therapy was started. However, a follow-up CT showed that the contrast defect had extended to the inferior vena cava. Observation using an angioscope revealed that it was not a benign thrombi but a tumor.

Vaso reactivity test using inhaled nitric oxide for pulmonary arterial hypertension accompanied by severe interstitial lung disease attributed to systemic sclerosis: A case report.

A 70-year-old man with severe interstitial pneumonia attributed to limited cutaneous systemic sclerosis was referred to our institution because of worsening dyspnea. High-resolution computed tomography did not show considerable progression compared with previous images, whereas transthoracic echocardiography showed severe right ventricular dysfunction. Oxygen saturation was decreased to 84% at room air. A blood test showed an increase in the plasma brain natriuretic peptide level (289.4 pg/mL). Right heart catheterization (RHC) showed a remarkably high mean pulmonary arterial pressure (mPAP) of 48 mmHg at room air. A vaso reactivity test using inhaled nitric oxide showed improvement of mPAP, pulmonary vascular resistance (PVR), and partial pressure of arterial oxygen. These findings suggested that the patient responded to pulmonary hypertension (PH)-targeted drugs. We then prescribed tadalafil 10 mg and inhaled iloprost 5 µg six times daily. Three weeks after initiating PH-targeted drugs, RHC indicated hemodynamic improvement similar to hemodynamic changes in the vaso reactivity test (mPAP: 28 mmHg; PVR: 4.2 W.U.). He was discharged with improved symptoms. Inhaled nitric oxide during RHC might be helpful to consider the treatment strategy when patients have PH comorbid systemic sclerosis and severe interstitial lung disease. .

Angioscopic Ulcerated Plaques in the Femoropopliteal Artery Associated with Impaired Infrapopliteal Runoff.

PURPOSE: To determine the correlation between upstream atherosclerosis in the femoropopliteal arteries, assessed using angioscopy, and impaired infrapopliteal runoff. MATERIALS AND METHODS: Thirty-one patients with peripheral arterial disease who underwent endovascular therapy and angioscopy were prospectively included. Yellow plaque color scores were semiquantitatively determined as 0, 1, 2, or 3. Irregular plaques with rough surfaces, similar to gastric ulcers, were defined as ulcerated plaques (UPs). Angioscopic data were correlated with angiographic runoff scores (ARS). RESULTS: UPs were detected in 74.2% of enrolled diseased legs using angioscopy. Mural thrombi were more commonly observed in the femoropopliteal artery in patients with UPs than in those without UPs (91.3% vs 37.5%, respectively; P = .006) and were frequently found on the UPs (21/23 patients with UPs). Univariate and multivariate linear regression analyses revealed that the presence of UPs was positively and independently associated with a poor ARS and that oral anticoagulant use was independently associated with a preferable ARS (standardized ß = 0.462, P = .004 and standardized ß = -0.411, P = .009, respectively, in the multivariate analysis). CONCLUSIONS: UPs, associated with mural thrombi and diagnosed by angioscopic examination, were demonstrated to be one of the factors associated with poor infrapopliteal runoff.

Relationship of high-intensity plaques on T1-weighted magnetic resonance imaging with coronary intraplaque hemorrhage: A directional coronary atherectomy study.

Background: Although intraplaque hemorrhage (IPH) has been identified as a key feature of rupture-prone plaques, noninvasive imaging-based features for its detection in coronary artery have not been clearly established. The aim of this study was to investigate the relationship of the ratio between the signal intensities of coronary plaque and cardiac muscle (PMR) on non-contrast T1-weighted imaging (T1WI) in magnetic resonance with IPH in the directional coronary atherectomy (DCA) specimens. Methods: Fifteen lesions from 15 patients, who underwent DCA and T1WI, were prospectively enrolled. The snap-frozen samples obtained by DCA were used for immunohistochemical staining against a protein specific to erythrocyte membranes (glycophorin A) and macrophages. The percentage of glycophorin A and macrophages was graded using a scale from 0 to 4, with higher scores indicating higher percentages. Results: PMR showed a strong positive correlation with glycophorin A scores (ρ = 0.772, p < 0.001), whreas, there was a weak correlation between the PMR and macrophage scores (ρ = 0.626, p < 0.05). The receiver-operating characteristic curve analysis showed that the optimal PMR cutoff value for predicting glycophorin A scores ≥grade 2 (glycophorin A-positive area ≥5% of the plaque) was 1.2 (area under the curve; 0.91, 95% confidence interval; 0.73-1.00), and this PMR value had a sensitivity of 8/9 (89%), specificity of 6/6 (100%), positive predictive value of 8/8 (100%), and negative predictive value of 6/7 (86%). Conclusions: In patients with ischemic heart disease, a high PMR on T1WI is a predictor of coronary IPH as assessed by DCA specimens.

Successful treatment for a patient with chronic thromboembolic pulmonary hypertension comorbid with essential thrombocythemia with the JAK2 V617F mutation by balloon pulmonary angioplasty.

A-71-year-old woman was diagnosed as chronic thromboembolic pulmonary hypertension (CTEPH) accompanied by essential thrombocythemia (ET) with JAK2 V617F mutation. Blood test showed remarkable increase of platelet counts (132.9 × 10^4/µL) and elevated plasma BNP level (125.1pg/mL). Right heart catheterization (RHC) revealed remarkably high mean pulmonary arterial pressure (mPAP) of 43 mmHg. We gave her riociguat of 7.5mg, oral anticoagulants, oxygen inhalation for CTEPH, and anagrelide for ET. We performed 4 sessions of balloon pulmonary angioplasty (BPA) in 9 months RHC revealed successful hemodynamic improvement (mPAP = 21 mmHg) after final BPA procedure without riociguat. At six month later after final BPA procedure, RHC showed steadily improvement of mPAP (21 mmHg) without riociguat and oxygen inhalation. She lives well without oxygen inhalation and PH targeted therapy. This is the first report of successful treatment for a patient with CTEPH comorbid with ET with JAK2 V617F mutation by BPA.

Association between debulking area of rotational atherectomy and platform revolution speed-Frequency domain optical coherence tomography analysis.

OBJECTIVES: In this study, we sought to investigate the association between revolution speed of rotational atherectomy (RA) and debulking area assessed by frequency domain-optical coherence tomography (FD-OCT). BACKGROUND: The number of patients with severe calcified coronary artery disease requiring treatment with calcium ablation, such as RA, is increasing. However, there is little evidence available regarding the association between debulking area and revolution speed during RA. METHODS: We retrospectively investigated 30 consecutive severely calcified coronary lesions in 29 patients who underwent RA under FD-OCT guidance. The association between preset revolution speed of RA and burr size-corrected debulking area of the calcified lesion was evaluated using a multivariable regression model with nonlinear restricted-cubic-spline, which can help assess nonlinear associations between variables. RESULTS: The median age of study participants was 73 years (quartile 65-78); 82.8% were male. The median burr size was 1.5 mm (1.5-1.75); median total duration of ablation was 120 s (100-180). FD-OCT revealed that the post-procedural minimum lumen area increased significantly from 1.64 mm2 (1.40-2.09) to 2.45 mm2 (2.11-2.98) (p < .001). In addition, the burr size-corrected debulking area increased significantly as the preset revolution speed decreased (p = .018), especially when the revolution speed was less than 150,000 rpm. This result implies that additional lumen gain will be obtained by decreasing rpm when the burr speed is set at <150,000 rpm. CONCLUSIONS: FD-OCT demonstrated that RA with lower revolution speed, below 150,000 rpm, has the potential to achieve greater calcium debulking effect in patients with severe calcified coronary lesions.

Neointimal coverage after second generation drug-eluting stent implantation has a relationship with pre-existing atherosclerotic lesion characteristics.

The relationship between preexisting atherosclerotic lesion characteristics and neointimal thickness after second-generation drug-eluting stent (DES) placement is still unknown. Thus, we evaluated that relationship using optical coherence tomography (OCT).A single-center, retrospective, observational study was conducted. Patients with stable angina or asymptomatic myocardial ischemia who received percutaneous coronary intervention for a de novo lesion using a second-generation DES under frequency domain OCT guidance and underwent follow-up coronary angiography (CAG) and OCT between December 2010 and December 2015 were included. The relationship between the neointimal thickness on the stent strut and the plaque characteristics was retrospectively evaluated using OCT immediately after stent implantation and at the time of follow-up CAG.We analyzed 3459 struts from 20 stents in 15 patients. The mean follow-up period was 264 days. In the follow-up study, no angiographic in-stent restenosis was found. Of the 3459 struts, 3315 (95.8%) were covered with neointima. The median neointimal thicknesses of the stent struts on calcified, fibrous, and lipid-rich lesions were 20 µm (interquartile range [IQR], 10-50 µm), 70 µm (40-140 µm; P < .001), and 90 µm (50-170 µm; P < .001), respectively. These differences were observed regardless of the type of second-generation DES used.Most of the stent struts were covered with neointima. The neointimal thickness after the second-generation DES implantation had a close relationship with the preexisting atherosclerotic lesion characteristics. In this study, we found differences in arterial healing processes due to underlying plaque; therefore, evaluating the lesion characteristics by OCT may predict the risk for future restenosis and thrombosis.

Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor.

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B-cell lymphoma cells harboring gain-of-function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL-AF9, MLL-AF4, and AML1-ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications.

Percutaneous Carbon Dioxide Treatment Using a Gas Mist Generator Attenuates the Development of Right Ventricular Dysfunction in Monocrotaline-induced Pulmonary Hypertensive Rats.

BACKGROUND: Highly concentrated carbon dioxide (GO2) is useful for treating ischemic diseases. Therefore, we investigated whether treatment with a few micrometers of CO2 molecules, atomized by two fluid nozzles (CO2 mist), could attenuate the development of right ventricular (RV) dysfunction in pulmonary hypertensive rats. METHODS: Six-week-old male Wistar rats were divided into three groups: one that received injected saline; a second that received subcutaneous monocrotaline (MCT; 60 mg/kg) without treatment (PH-UT) group; and a third that received MCT with CO2 mist treatment (PH-CM) after MCT administration. The lower body of each rat was encased in a polyethylene bag, filled with the designated gaseous agent via a gas mist generator, for 30 minutes daily. Hemodynamics and cardiac function were measured at 28 days after beginning MCT administration. Protein levels were measured by western blotting. RESULTS: Rats that received MCT without treatment began to die within 3-4 weeks of the initial administration. However, treatment with CO2 mist extended the survival period of rats in that group. At 28 days after MCT administration, the hemodynamic status, such as the blood pressure and heart rate, involved with left ventricular function, of rats in the PH-UT group were similar to those of rats in the PH-CM group. However, MCT-induced RV weight and RV dysfunction were significantly attenuated by treatment with CO2 mist. Both RV phosphorylated endothelial nitric oxide synthase and heat shock protein 72 levels increased significantly in the PH-CM group, compared to the PH-UT group. CONCLUSIONS: Percutaneous CO2 mist therapy may alleviate RV dysfunction in patients with pulmonary hypertension.

Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists.

To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.

Percutaneous carbon dioxide mist treatment has protective effects in experimental myocardial infarction.

Percutaneous treatment with carbon dioxide (CO2) mist, CO2 gas dissolved in water, contributes to improved cardiac function after myocardial infarction (MI). In this study, we investigated the effects of repeated pretreatment with CO2 mist on cardiac dysfunction after MI. The CO2 mist was generated by a dry mist production unit. The whole body of rats below the axilla was wrapped in a polyethylene bag, which was sealed and filled with the CO2 mist in the draft cabinet for 30 min daily for 7 days. MI was induced by ligation of the coronary artery in untreated (UT), CO2 gas-pretreated (CG), and CO2 mist-pretreated (CM) rats. The infarct size and the increase in oxidative stress due to MI were significantly smaller in the CM rats than in the UT rats. Furthermore, the expression of inflammation-related genes, such as monocyte chemoattractant protein-1, and fibrosis-related genes, such as transforming growth factor-ß1, was significantly suppressed in the CM rats. The CM rats had a better left ventricular ejection fraction than the UT rats 7 days after MI. These parameters in the CG rats were the same as in the UT group. Thus, CO2 mist preparative treatment may be potentially useful for the reduction of MI.

Percutaneous carbon dioxide treatment using a gas mist generator enhances the collateral blood flow in the ischemic hindlimb.

AIM: Highly concentrated carbon dioxide (CO2) is thought to be useful for ischemic diseases. We investigated whether treatment with a few micrometers of CO2 molecules atomized via two fluidnozzles (CO2 mist) exerts an angiogenic effect in a mouse ischemic hindlimb model. METHODS: Mice with unilateral hindlimb ischemia were divided into untreated (UT), 100% CO2 gas alone-treated (CG), mixed air (O2; 20%, N2; 80%) mist-treated (AM) and 100% CO2 mist-treated (CM) groups. The lower body of the mice was encased in a polyethylene bag filled with each gaseous agent using a gas mist generator for 10 minutes daily. RESULTS: According to a laser Doppler analysis, the ischemic hindlimb blood flow was persistently higher after the seventh day of induction of ischemia in the CM group than in the UT group. The capillary density was also greater in the CM group on day 28 compared with that observed in the UT group. In addition, the parameters in the AM and CG groups were similar to those obtained in the UT group. The observed effects were abolished by the administration of an inhibitor of nitric oxide synthase (NOS). The vascular endothelial growth factor mRNA expression and protein levels and the phosphorylated endothelial NOS level were increased in the CM group compared with that observed in the UT group. A proteomic analysis using liquid chromatography-tandem mass spectrometry identified novel protein candidates regulated by CO2 mist. CONCLUSION: Percutaneous CO2 mist therapy may be useful for treating ischemia-induced angiogenesis.

Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction.

BACKGROUND: Remote ischemic conditioning (RIC) by repeated treatment of transient limb ischemia is a clinically applicable method for protecting the heart against injury at the time of reperfusion. In this study, we investigated the effects of repeated RIC on cardiac dysfunction after myocardial infarction (MI). METHODS AND RESULTS: At 4weeks after MI, rats were separated into the untreated (UT) group or the RIC-treated group. RIC treatment was performed by 5cycles of 5min of bilateral hindlimb ischemia and 5min of reperfusion once a day for 4weeks. Despite comparable MI size, left ventricular (LV) ejection fraction (LVEF) was significantly improved in the RIC group compared with the UT group. Furthermore, the LVEF in the RIC group was improved, although not significantly, after treatment. RIC treatment also prevented the deterioration of LV diastolic function. MI-induced LV interstitial fibrosis in the boundary region and oxidant stress were significantly attenuated by RIC treatment. MicroRNA-29a (miR-29a), a key regulator of tissue fibrosis, was highly expressed in the exosomes and the marginal area of the RIC group. Even in the differentiated C2C12-derived exosomes, miR-29a expression was significantly increased under hypoxic condition. As well as miR-29a, insulin-like growth factor 1 receptor (IGF-1R) was highly expressed both in the exosomes and remote non-infarcted myocardium of the RIC group. IGF-1R expression was also increased in the C2C12-derived exosomes under hypoxic conditions. CONCLUSIONS: Repeated RIC reduces adverse LV remodeling and oxidative stress by MI. Exosome-mediated intercellular communication may contribute to the beneficial effect of RIC treatment.