Evaluation of the Aging of Styrene-Butadiene-Styrene Modified Asphalt Binder with Different Polymer Additives.

A wide variety of polymer additives have been widely used in recent years. However, the effect of different polymer additives on the durability of asphalt binders has not been investigated thoroughly. To evaluate the aging property of styrene-butadiene-styrene (SBS) asphalt binder with different polymer additives, three polymer modifiers, namely high modulus modifier (HMM), anti-rutting agent (ARA), and high viscosity modifier (HVM), were added to it. First, the Thin Film Over Test (TFOT) and Pressure Aging Vessel (PAV) was performed on the asphalt binders. The rheological properties of the four asphalt binders before and after aging were then checked by the Dynamic Shear Rheometer Test (DSR). The chemical compositions of the asphalt binders were determined by the Fourier Transform Infrared Spectrometer (FTIR) test. Several aging indicators were adopted to reflect the aging degree of the asphalt binders. The results show that when polymer additives are added to the SBS asphalt binder, the complex modulus, storage modulus, loss modulus, and rutting factor substantially increase and the phase angle decreases. All the test parameters become higher after aging. The phase angle of the SBS asphalt binder is the highest at both unaged and aged states, while its other parameters values are the smallest. Moreover, the Carbonyl Aging Indicator (CAI) of SBS with polymer additives becomes lower under both TFOT and PAV conditions, indicating that polymer additives can improve the aging resistance of SBS asphalt, of which HVM modifies the aging resistance best. Complex Modulus Aging Indicator (CMAI) and Storage Modulus Aging Indicator (SMAI) have the best correlation coefficients with CAI, and the two aging indicators can be used to predict the aging degree of polymer modified asphalt binders.

Effect of Different Polymer Modifiers on the Long-Term Rutting and Cracking Resistance of Asphalt Mixtures.

To evaluate the long-term performances of different polymer-modified asphalt mixtures, three modifiers were chosen to modify AC-13 (defined as the asphalt concrete with the aggregate nominal maximum particle size of 13.2 mm); namely, high viscosity modifier (HVM), high modulus modifier (HMM), and anti-rutting agent (ARA). The deformation and cracking resistance of different polymer-modified mixtures were checked at different aging conditions (unaged, short-term aged, and long-term aged for 5, 10, and 15 days respectively). The results of the Hamburg wheel-track test and uniaxial penetration test (UPT) showed that the rutting resistance of all asphalt mixtures changed in a V-shape as the aging progressed. From the unaged stage to the long-term aging stage (5 days), the rutting resistance decreases gradually. While after the long-term aging stage (5 days), the rutting resistance increases gradually. Results from the semicircular bending test (SCB) and the indirect tensile asphalt cracking test (IDEAL-CT) indicated that the cracking resistance of all the mixtures gradually decline with the deepening of the aging degree, indicating that aging weakens the crack resistance of asphalt mixtures. Additionally, test results showed that the rutting resistance of ARA AC-13 (defined as AC-13 containing ARA) is the best, the cracking resistances of ARA AC-13, HMM AC-13 (defined as AC-13 containing HMM) and HVM AC-13 (defined as AC-13 containing HVM) have no significant difference, and different polymer modifiers had different sensitivities to aging due to the polymer content and the type of modifier. The conclusions of this study help to further understand the long-term performance of polymer-modified asphalt mixtures during service life and to help guide the selection of modifiers for mixtures.

Cryoablation for advanced non-small cell lung cancer: a protocol for a systematic review.

INTRODUCTION: National Comprehensive Cancer Network has recommended cryoablation to replace the resection in the treatment of medically operable non-small cell lung cancer (NSCLC). Cryoablation also has been used for the advanced NSCLC in randomised controlled trials. However, they have not been systematically reviewed. Here, we provide a protocol to evaluate the effectiveness and safety of cryoablation in the treatment of advanced NSCLC. METHODS AND ANALYSES: We will search PubMed, Embase, the Cochrane Library, Chinese Biomedical Database, China National Knowledge Infrastructure, Wanfang Database and Chinese Scientific Journal Database without language restrictions from inception until 1 February 2020. Trial registers (International Clinical Trials Registry platform, the US National Institutes of Health Ongoing Trials Register and the ISRCTN registry) and reference lists of retrieved articles will also be searched. Two reviewers will independently extract data on participants, interventions, comparisons, outcomes and assess the methodological quality by the Cochrane risk of bias tool. The strength of evidences will be evaluated according to the Grading of Recommendations Assessment, Development and Evaluation approach. Review Manager V.5.3 software will be used for data analyses. Meta-analyses will be performed if the data are sufficiently homogeneous. The primary outcomes will be objective response rate and overall survival. The secondary outcomes will be adverse effects, health-related quality of life, changes of immune indicators and surrogate outcomes (disease control rate, progression-free survival and survival rate). ETHICS AND DISSEMINATION: Ethics approval is not required, as this study will not involve patients. The results of this study will be submitted to a peer-reviewed journal for publication, to inform both clinical practice and further research. PROSPERO REGISTRATION NUMBER: CRD42019138660.

Comparative outcomes of heart failure among existent classes of anti-diabetic agents: a network meta-analysis of 171,253 participants from 91 randomized controlled trials.

BACKGROUND: The cardiovascular (CV) safety in terms of heart failure among different classes of treatment remains largely unknown. We sought to assess the comparative effect of these agents on heart failure outcomes. METHODS: This study was registered in the International Prospective Register of Systematic Reviews (CRD 42016042063). MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials were searched. For the primary outcomes reported previously, studies between Jan 1, 1980 and June 30, 2016 were screened, and subsequently updated till Jan 24, 2019. We performed network meta-analysis to obtain estimates for the outcomes of heart failure, in particular by rankograms for ranking of heart failure risk as well as by pairwise comparisons among all classes of anti-diabetic medications. RESULTS: A total of 91 trials were included, among which were 171,253 participants and 4163 reported cases of heart failure events. As for rankograms, the surface under the cumulative ranking curves (SUCRA) of sodium-glucose co-transporters 2 and thiazolidinediones were 93.4% and 4.3%, respectively, signifying the lowest and highest risk of heart failure, respectively. As for pairwise comparisons in the network, sodium-glucose co-transporters 2 were significantly superior to insulin (OR: 0.75, 95% CI 0.62-0.91), dipeptidyl peptidase 4 inhibitors (OR: 0.68, 95% CI 0.59-0.78), glucagon-like peptide-1 receptor agonists (OR: 0.65, 95% CI 0.54-0.78), and thiazolidinediones (OR: 0.46, 95% CI 0.27-0.77) in terms of heart failure risk. Furthermore, in an exploratory analysis among subjects with underlying heart failure or at risk of heart failure, the superiority of sodium-glucose co-transporters 2 was still significant. CONCLUSIONS: In terms of heart failure risk, sodium-glucose co-transporters 2 were the most favorable option among all classes of anti-diabetic medications.

Effectiveness of afatinib after ineffectiveness of gefitinib in an advanced lung adenocarcinoma patient with a single EGFR exon 20 S768I mutation: a case report.

Epidermal growth factor receptor-tyrosine kinase inhibitors have improved progression-free survival and overall survival in non-small-cell lung cancer (NSCLC) patients with sensitive mutations. However, response of uncommon mutation to epidermal growth factor receptor-tyrosine kinase inhibitors is still unclear. S768I is one of the uncommon mutations. A female patient with advanced NSCLC with a single S768I mutation achieved effectiveness from afatinib after showing no response to gefitinib. The patient had progression-free survival after taking afatinib for 6 months, and her follow-up is continuing. It suggests that afatinib may be a more effective treatment for NSCLC patients with a single S768I mutation, compared to first-generation tyrosine kinase inhibitors.

Association of Inflammation and Endothelial Dysfunction with Coronary Microvascular Resistance in Patients with Cardiac Syndrome X / Associação de Inflamação e Disfunção Endotelial com Resistência Microvascular Coronariana em Pacientes com Síndrome Cardíaca X

Abstract Background: Although a proportion of CSX patients have impaired brachial artery flow-mediated dilatation (FMD) in response to hyperemia, suggesting that endothelial dysfunction in these patients may be systemic and not just confined to the coronary circulation; the underlying mechanisms triggering endothelial dysfunction in these patients are still incompletely understood. Objectives: To assess the association of the index of Microcirculatory Resistance (IMR) with endothelial dysfunction and inflammation in patients with CSX. Methods: We studied 20 CSX patients and 20 age and gender-matched control subjects. Thermodilution-derived coronary flow reserve (CFR) and IMR were measured using a pressure-temperature sensor-tipped guidewire. Brachial artery FMD was measured using high-resolution, two-dimensional ultrasound images obtained with a Doppler ultrasound device (HDI-ATL 5000, USA) with a 5 MHz to 12 MHz linear-array transducer. Results: Compared with in control subjects, CFR was significantly lower (2.42 ± 0.78 vs. 3.59 ± 0.79, p < 0.001); IMR was higher (32.2 ± 8.0 vs. 19.5 ± 5.5, p < 0.001); the concentration of hs-CRP and FMD was higher (4.75 ± 1.62 vs. 2.75 ± 1.50; 5.24 ± 2.41 vs. 8.57 ± 2.46, p < 0.001) in CSX patients. The Duke treadmill score (DTS) was correlated positively to CFR and FMD (0.489 and 0.661, p < 0.001), it was negative to IMR and hsCRP (-0.761 and -0.087, p < 0.001) in CSX patients. Conclusions: The main finding in this study is that the DTS measured in patients with CSX was associated to hsCRP and FMD. Moreover, the independent effects of exercise tolerance can significantly impair FMD and hsCRP in CSX patients; especially it is particularly important to whom where FMD was associated negatively with IMR.

Resumo Fundamentos: Embora uma proporção de pacientes com SCX tenha dilatação mediada por fluxo da artéria braquial (DMF) prejudicada em resposta à hiperemia, sugerindo que a disfunção endotelial nestes pacientes pode ser sistémica e não limitar-se à circulação coronariana, os mecanismos subjacentes que desencadeiam a disfunção endotelial nestes pacientes ainda não são completamente compreendidos. Objetivos: Avaliar a associação do índice de resistência microcirculatória (IMR) com a disfunção endotelial e a inflamação em pacientes com SCX. Métodos: Estudaram-se 20 pacientes com SCX e 20 sujeitos de controle emparelhados em idade e género. A reserva de fluxo coronariano derivada da termodiluição (RFC) e a IMR forma medidas usando um fio guia com ponta de sensor de temperatura e pressão. A DMF da artéria braquial foi medida utilizando imagens ultrassónicas bidimensionais de alta resolução obtidas com um aparelho de ultrassom Doppler (HDI-ATL 5000, EE.UU.) com transdutor linear de 5 MHz a 12 MHz. Resultados: Em comparação com os sujeitos de controle, a RFC foi significativamente menor (2,42 ± 0,78 vs 3,59 ± 0,79, p < 0,001); o IMR foi maior (32,2 ± 8,0 frente a 19,5 ± 5,5, p < 0,001); a concentração de PCR-as e DMF foi maior (4,75 ± 1,62 frente a 2,75 ± 1,50, 5,24 ± 2,41 diante de 8,57 ± 2,46, p < 0,001) em pacientes com SCX. A escore de Duke (ED) se correlacionou positivamente com RFC e DMF (0,489 e 0,661, p < 0,001), foi negativa para IMR e PCR-as (-0,761 e -0,087, p < 0,001) em pacientes com SCX. Conclusões: O principal achado neste estudo é que o ED medido em pacientes com SCX esteve associado a PCR-as e DMF. Por outra parte, os efeitos independentes da tolerância ao exercício podem piorar significativamente a DMF e a PCR-as em pacientes com SCX especialmente, é particularmente importante que a DMF se associou negativamente com a RIM.

Association of Inflammation and Endothelial Dysfunction with Coronary Microvascular Resistance in Patients with Cardiac Syndrome X.

BACKGROUND: Although a proportion of CSX patients have impaired brachial artery flow-mediated dilatation (FMD) in response to hyperemia, suggesting that endothelial dysfunction in these patients may be systemic and not just confined to the coronary circulation; the underlying mechanisms triggering endothelial dysfunction in these patients are still incompletely understood. OBJECTIVES: To assess the association of the index of Microcirculatory Resistance (IMR) with endothelial dysfunction and inflammation in patients with CSX. METHODS: We studied 20 CSX patients and 20 age and gender-matched control subjects. Thermodilution-derived coronary flow reserve (CFR) and IMR were measured using a pressure-temperature sensor-tipped guidewire. Brachial artery FMD was measured using high-resolution, two-dimensional ultrasound images obtained with a Doppler ultrasound device (HDI-ATL 5000, USA) with a 5 MHz to 12 MHz linear-array transducer. RESULTS: Compared with in control subjects, CFR was significantly lower (2.42 ± 0.78 vs. 3.59 ± 0.79, p < 0.001); IMR was higher (32.2 ± 8.0 vs. 19.5 ± 5.5, p < 0.001); the concentration of hs-CRP and FMD was higher (4.75 ± 1.62 vs. 2.75 ± 1.50; 5.24 ± 2.41 vs. 8.57 ± 2.46, p < 0.001) in CSX patients. The Duke treadmill score (DTS) was correlated positively to CFR and FMD (0.489 and 0.661, p < 0.001), it was negative to IMR and hsCRP (-0.761 and -0.087, p < 0.001) in CSX patients. CONCLUSIONS: The main finding in this study is that the DTS measured in patients with CSX was associated to hsCRP and FMD. Moreover, the independent effects of exercise tolerance can significantly impair FMD and hsCRP in CSX patients; especially it is particularly important to whom where FMD was associated negatively with IMR.

Hydrochlorothiazide modulates ischemic heart failure-induced cardiac remodeling via inhibiting angiotensin II type 1 receptor pathway in rats.

AIMS: Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)-ß/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects. METHODS: Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham-operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II. RESULTS: After eight-week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF-ß and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II-induced TGF-ß1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts. CONCLUSIONS: Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects.

TLR4/NF-κB/Ceramide signaling contributes to Ox-LDL-induced calcification of human vascular smooth muscle cells.

Vascular calcification is a major feature of advanced atherosclerosis and highly associated with cardiovascular diseases. Oxidized low density lipoprotein (Ox-LDL) has been recognized as a critical risk factor for atherosclerosis and osteogenic differentiation of vascular smooth muscle cells (VSMCs). Previous studies have demonstrated that toll like receptor 4 (TLR4) is highly expressed in atherosclerotic lesions and participates in the progression of atherosclerosis. However, the role of TLR4 in vascular calcification remains unknown. In this study, we investigated whether TLR4 modulates vascular calcification induced by Ox-LDL. TLR4 expression was up-regulated in cultured human VSMCs treated with Ox-LDL. Knockdown of TLR4 by small interfering RNA (siRNA) significantly reduced Ox-LDL-induced calcification, detected by alizarin red staining and calcium content assay. TLR4 siRNA also decreased the mRNA expression of bone-related proteins including Msx2, osterix, BMP2 and KLF4, but increased the expression of VSMC contractile proteins including SMA and SM22α in VSMCs. In addition, Ox-LDL stimulated nuclear translocation of nuclear factor kappa B (NK-κB) p65. These effects of Ox-LDL on VSMCs were reversed by TLR4 siRNA. Furthermore, NK-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), attenuated Ox-LDL-induced VSMC calcification, which was rescued by C2-ceramide treatment. In conclusion, these findings suggest that TLR4 regulates VSMC calcification induced by Ox-LDL through activation of NK-κB, highlighting the critical role of TLR4/NK-κB signaling in vascular calcification.

Curcumin attenuates osteogenic differentiation and calcification of rat vascular smooth muscle cells.

Vascular calcification has been considered as a biological process resembling bone formation involving osteogenic differentiation. It is a major risk factor for cardiovascular morbidity and mortality. Previous studies have shown the protective effects of curcumin on cardiovascular diseases. However, whether curcumin has effects on osteogenic differentiation and calcification of vascular smooth muscle cells (VSMCs) has not been reported. In the present study, we used an in vitro model of VSMC calcification to investigate the role of curcumin in the progression of rat VSMC calcification. Curcumin treatment significantly reduced calcification of VSMCs in a dose-dependent manner, detected by alizarin red staining and calcium content assay. Similarly, ALP activity and expression of bone-related molecules including Runx2, BMP2, and Osterix were also decreased in VSMCs treated with curcumin. In addition, flow cytometry analysis and caspase-3 activity assay revealed that curcumin treatment significantly suppressed apoptosis of VSMCs, which plays an important role during vascular calcification. Furthermore, we found that pro-apoptotic molecules including p-JNK and Bax were up-regulated in VSMCs treated with calcifying medium, but they were reduced in VSMCs after curcumin treatment. However, curcumin treatment has no effect on expression of NF-κB p65. Taken together, these findings suggest that curcumin attenuates apoptosis and calcification of VSMCs, presumably via inhibition of JNK/Bax signaling pathway.

Vessel heterogeneity of TIMI frame count and its relation to P-wave dispersion in patients with coronary slow flow.

BACKGROUND: The vessel heterogeneity of thrombolysis in myocardial infarction (TIMI) frame count (TFC) in patients with coronary slow flow (CSF) remains to be further evaluated, and the correlation between TFC heterogeneity and P-wave dispersion (PWD) has not been elucidated. We aim to investigate the vessel heterogeneity of TFC in coronary arteries, and its relation to PWD in patients with CSF and otherwise normal coronary arteries. METHODS: We studied 72 patients with angiographically documented CSF and 66 age- and gender-matched control subjects. The coefficient of variation (CV) and mean TFC of the three vessels were calculated. P-wave duration and PWD were measured on the standard electrocardiograms (ECGs). RESULTS: The mean TFC and CV were both significantly higher in CSF patients than in controls (P<0.001 for both comparisons). The maximum P-wave duration (Pmax) and PWD were found to be significantly higher in CSF patients than in controls (P<0.001 for both comparisons). In patients with CSF, both Pmax and PWD were mildly correlated to mean TFC (r=0.318, P=0.009; and r=0.307, P=0.010), and were more significantly correlated to CV (r=0.506, P<0.001; and r=0.579, P<0.001). CONCLUSIONS: These data demonstrate that variability of TFC in three coronary arteries is increased in CSF patients, and that the vessel heterogeneity in coronary flow might be intimately associated with PWD.

Continuous angiotensin-(1-7) infusion improves myocardial calcium transient and calcium transient alternans in ischemia-induced cardiac dysfunction rats.

The aim of this study was to evaluate the impact of Ang-(1-7) on calcium transient (CaT) in cardiomyocytes during the pathogenesis of heart failure. Cardiac dysfunction was induced by ligation of left anterior descending coronary artery in adult SD rats. Randomly selected rats were ligated and continuously infused with Ang-(1-7) [HF + Ang-(1-7) group] or saline (HF + saline group) via osmotic minipumps. After 28 days, hemodynamic parameters, the CaT, and the heart rate threshold of CaT alternans (CaT-Alt) were measured. Continuous Ang-(1-7) treatment could attenuate the impairment of cardiac function following LAD ligation. The amplitudes (F/F0) and 50%/90% recovery time of CaT were significantly different among HF + saline, HF + Ang-(1-7) and Sham-operated group. Compared to the Sham-operated group, the HF + saline group showed decreased CaT amplitude, and a prolonged 50%/90% CaT recovery time; Ang-(1-7) significantly improved these abnormalities. Compared with Sham-operated group, heart rate thresholds of CaT-Alt significantly reduced in HF + saline group, and Ang-(1-7) partly restored it. These findings indicate that Ang-(1-7) attenuates the CaT disturbance and increases the heart rate threshold of CaT-Alt during the pathogenesis of ischemic heart failure.

Thermodilutional Confirmation of Coronary Microvascular Dysfunction in Patients With Recurrent Angina After Successful Percutaneous Coronary Intervention.

BACKGROUND: Recurrent angina (RA) after percutaneous coronary intervention (PCI) remains a challenging problem that confronts cardiologists in routine clinical practice. In patients without epicardial coronary causes, RA is commonly speculated as resulting from coronary microvascular dysfunction. The aim of this study was to investigate the coronary microvascular function in patients with RA late after successful PCI and without epicardial stenosis at the time of repeat angiography. METHODS: We studied 39 consecutive patients with RA in whom PCI was successfully performed 6 to 12 months previously because of angina and single-vessel disease and without restenosis and disease progression at the time of repeat angiography. Twelve subjects without RA were recruited as the control group. Thermodilution-derived coronary flow reserve (CFR) and index of microvascular resistance (IMR) were measured using a pressure-temperature sensor-tipped coronary wire. The exercise treadmill test was performed according to the Bruce protocol. RESULTS: Patients with RA showed significantly higher IMR and lower CFR than control subjects, in the target arteries and in the reference vessels (P < 0.05). The hyperemic IMR was more remarkably increased in the target arteries than in the reference vessels (29.3 ± 11.7 vs 24.4 ± 9.7; P = 0.008). The hyperemic IMR was increased and the CFR was impaired more significantly in patients with a positive exercise treadmill test (P < 0.05). CONCLUSIONS: Using an intracoronary thermodilution method, to our knowledge, we have for the first time confirmed that, in patients who underwent successful coronary stenting and without epicardial stenosis at repeat angiography late after PCI, coronary microvascular dysfunction was responsible for the RA.

Zinc Regulates Lipid Metabolism and MMPs Expression in Lipid Disturbance Rabbits.

Lipid disturbance induced by high-fat diet is a worldwide problem, and it can induce inflammation and oxidative stress in vivo. Zinc is considered as an antioxidant, anti-inflammatory agent. Since matrix metalloprotease 2 (MMP2) and matrix metalloprotease 9 (MMP9)'s expressions are changed under many pathological conditions, we would like to know how zinc affects lipid metabolism and MMP2, MMP9's expressions in the lipid disturbance rabbits. Twenty-four male New Zealand white rabbits were randomly divided into four groups. Each group had six rabbits, and they were fed with regular diet, high-fat diet, high-fat diet+zinc, and regular diet+zinc separately for 12 weeks. High-fat diet induced lipid disturbance significantly which raised the level of aspartate aminotransferase (p<0.01) and alanine transaminase (p<0.05) in the high-fat diet group, but zinc supplement reversed this phenomenon (p<0.05). Zinc did not reduce total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p>0.05), but it lowered triglyceride (TG) and raised high-density lipoprotein cholesterol (HDL-C) (p<0.01). Zinc also reduced high-sensitivity C-reactive protein (hs-CRP) (p<0.01) and interleukin-6 (IL-6)'s expressions (p<0.05). Zinc reduced the epicardial adipose tissue and alleviated the hepatic steatosis. Zinc suppressed MMP2 and MMP9's expressions in vivo, but it did not alleviate the aorta fatty streak's severity in the lipid disturbance rabbits. Zinc protected the liver, reduced TG, hs-CRP, and IL-6 and raised HDL-C in the lipid disturbance rabbits. Zinc suppressed MMP2 and MMP9's expressions in vivo, but it did not alleviate the severity of aorta fatty streak induced by the high-fat diet.

Thermodilution-derived coronary microvascular resistance and flow reserve in patients with cardiac syndrome X.

BACKGROUND: Although increased coronary microvascular resistance (CMR), resulting in coronary microvascular dysfunction, is speculated to be responsible for myocardial ischemia in patients with cardiac syndrome X (CSX), it has never been directly demonstrated, and the correlation between CMR and severity of myocardial ischemia has not been elucidated in this setting. This study aimed to ascertain the increased CMR directly and to explore the relationship between CMR and severity of ischemia in patients with CSX. METHODS AND RESULTS: We studied 18 patients with CSX and 18 age- and sex-matched control subjects. Thermodilution-derived coronary flow reserve and index of microvascular resistance were measured using a pressure-temperature sensor-tipped coronary wire. Exercise treadmill test was performed by the Bruce protocol for calculating Duke treadmill score. Coronary flow reserve was significantly lower (2.37±0.81 versus 3.68±0.72; P<0.001) and index of microvascular resistance was higher (33.1±7.9 versus 18.8±5.6 U; P<0.001) in patients with CSX compared with those in control subjects. The Duke treadmill score was correlated positively to coronary flow reserve (r=0.539; P=0.021) and negatively to index of microvascular resistance (r=-0.742; P<0.001) in patients with CSX. CONCLUSIONS: Using an intracoronary thermodilution method, we for the first time directly demonstrated an increased microvascular resistance in patients with CSX. Furthermore, severity of ischemia was found to be intimately associated with CMR in this setting.

Documentation of impaired coronary blood flow by TIMI frame count method in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with impaired coronary flow and diminished myocardial perfusion. In the present study we aimed to evaluate coronary blood flow by means of Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) in patients with AF in the absence of obstructive coronary artery disease (CAD). METHODS: This prospective study initially enrolled 166 patients with AF and 332 age- and gender-matched control subjects without AF. After diagnostic coronary angiography, TFC was assessed in the participants without obstructive CAD, with 146 in the AF group and 150 in the control group. RESULTS: The TFC for three major coronary arteries and the mean TFC were found to be significantly higher in AF patients compared to control subjects (34.1 ± 10.4 vs. 25.0 ± 10.4, 31.8 ± 9.7 vs. 23.7 ± 9.1, and 32.3 ± 9.5 vs. 24.1 ± 8.4 for each artery and 32.8 ± 9.2 vs. 24.3 ± 8.9 for mean TFC, p<0.001 for all comparisons). The mean TFC was 28.8 ± 7.9 in patients with paroxysmal AF, 33.7 ± 8.7 in those with persistent AF, and 39.0 ± 8.8 in those with long-standing or permanent AF (p<0.01 for all comparisons). After multivariate analysis, we found that the presence of AF remains to be independently associated with mean TFC. In AF group, baseline heart rate, left ventricular ejection fraction, AF duration and left atrium diameter were found to be independently associated with mean TFC. CONCLUSIONS: Patients with atrial fibrillation in the absence of obstructive coronary artery disease have significantly higher TIMI frame counts for all three coronary vessels, indicating impaired coronary blood flow, compared to the control subjects without atrial fibrillation.

Relationship between mean platelet volume and coronary blood flow in patients with atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is associated with impaired coronary flow by means of Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC). Mean platelet volume (MPV) is elevated in patients with AF. In the present study we aimed to investigate the relationship between MPV and TFC in patients with AF in the absence of obstructive coronary artery disease (CAD). METHODS: This observational study enrolled 185 AF patients and 189 control subjects, all with angiographically documented normal coronary arteries. MPV was measured at baseline and mean TFC was assessed after diagnostic coronary angiography. RESULTS: The MPV was 9.95±1.32 in the AF group and 9.02±1.16 in the control group (p<0.001). In AF patients, MPV was significantly correlated with mean TFC (r=0.419, p<0.001), AF duration (r=0.407, p<0.001), AF classification (r=0.378, p<0.001), systemic hypertension (r=0.165, p=0.024), diabetes mellitus (r=0.233, p=0.001), left ventricular ejection fraction (r=-0.347, p<0.001), and baseline use of diuretics (r=0.177, p=0.016). In linear regression analysis, mean TFC, left ventricular ejection fraction and diabetes mellitus were found to be independently associated with MPV (p<0.001, p=0.028 and p=0.045 respectively). CONCLUSION: Mean platelet volume seems to be independently associated with coronary blood flow in patients with atrial fibrillation in the absence of obstructive coronary artery disease.

Interleukin 6 augments mechanical strain-induced C-reactive protein synthesis via the stretch-activated channel-nuclear factor κ B signal pathway.

OBJECTIVES: C-reactive protein (CRP), an inflammation marker, is a strong independent risk factor for cardiovascular disease. Vessels are able to express CRP; however, the molecular mechanism behind this expression is not clear. METHODS: Reverse transcription PCR and ELISA were used to detect messenger RNA and proteins of CRP and nuclear factor κB (NF-κB) activity in vessel rings stretched with different mechanical strains. RESULTS: Interleukin (IL)-6 treatment did not induce CRP expression in vessel rings of white rabbits in the absence of mechanical strain. In contrast, IL-6 augmented CRP expression in vessel rings stretched with mechanical strains of 3 and 5 g (CRP mRNA, IL-6: 11.367±1.68 and 12.78±0.76 vs vehicle: 7.27±0.88 and 8.3±0.91 folds, respectively; CRP, IL-6: 12.79±1.62 and 14.05±2.1 vs vehicle: 7.72±1.04 and 8.16±1.52 folds, respectively; p<0.05 vs 0 g group and vehicle control group; n=5), and this effect was completely blocked by treatment with gadolinium III chloride hexahydrate (GdCl3). Moreover, IL-6 treatment increased NF-κB activity in vessels stretched with a mechanical strain of 3 g, and this effect was blocked by stretch-activated channel inhibitors (streptomycin or GdCl3) and the NF-κB peptide inhibitor SN50, but not by the inactive SN50 analogue SN50M. We also performed similar experiments on human internal mammary arteries and obtained similar results. CONCLUSIONS: These results indicate that the inflammatory cytokine IL-6 alone does not induce CRP synthesis in vessels in the absence of mechanical strain; however, IL-6 augments mechanical strain-induced CRP synthesis in vessels via the stretch-activated channel-NF-κB pathway.

Effect of enhanced external counterpulsation on coronary slow flow and its relation with endothelial function and inflammation: a mid-term follow-up study.

BACKGROUND: Although enhanced external counterpulsation (EECP) showed short-term effects in improving coronary flow in patients with coronary slow flow (CSF), whether such improvement is durable remains uncertain, and the relationships between such improvement and changes in endothelial function as well as inflammatory markers have not been elucidated. OBJECTIVES: The aim of the present study was to investigate the effects of EECP on transthoracic coronary flow, flow-mediated dilatation (FMD), and high-sensitivity C-reactive protein (hsCRP) in patients with CSF. METHODS: Forty-five patients with documented CSF underwent transthoracic Doppler echocardiography (TTDE) for the assessment of coronary diastolic peak flow velocity (DPFV) and coronary flow reserve (CFR), and measurements of FMD and hsCRP; they were then nonrandomly assigned to two groups. Subjects in the control group (n = 24) received only medical therapy, and those in the EECP group (n = 21) were additionally treated with the 36 one-hour sessions of EECP. After 8 weeks of medical/EECP therapy, TTDE, FMD, and hsCRP examinations were repeated, and TTDE was additionally repeated after the 6-month clinical follow-up. RESULTS: In the EECP group, resting DPFV, hyperemic DPFV, and CFR were significantly increased shortly after therapy (p < 0.001) and the improvement was maintained up to the 6-month follow-up, whereas in the control group those variables were not statistically increased. Meanwhile, hsCRP significantly decreased and FMD increased after therapy in the EECP group (p < 0.001). In all subjects, CFR improvement was negatively correlated with hsCRP change and positively correlated with FMD increase (p < 0.001). CONCLUSIONS: EECP may have a durable effect in improving coronary flow in patients with CSF. Such improvement is related to the favorable effects of EECP on vascular inflammation and endothelial function.