ResearchPad - arteries https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Collagen methionine sulfoxide and glucuronidine/LW-1 are markers of coronary artery disease in long-term survivors with type 1 diabetes. The Dialong study]]> https://www.researchpad.co/article/elastic_article_13877 Type 1 diabetes is a risk factor for coronary heart disease. The underlying mechanism behind the accelerated atherosclerosis formation is not fully understood but may be related to the formation of oxidation products and advanced glycation end-products (AGEs). We aimed to examine the associations between the collagen oxidation product methionine sulfoxide; the collagen AGEs methylglyoxal hydroimidazolone (MG-H1), glucosepane, pentosidine, glucuronidine/LW-1; and serum receptors for AGE (RAGE) with measures of coronary artery disease in patients with long-term type 1 diabetes.MethodsIn this cross-sectional study, 99 participants with type 1 diabetes of ≥ 45-year duration and 63 controls without diabetes had either established coronary heart disease (CHD) or underwent Computed Tomography Coronary Angiography (CTCA) measuring total, calcified and soft/mixed plaque volume. Skin collagen methionine sulfoxide and AGEs were measured by liquid chromatography-mass spectrometry and serum sRAGE/esRAGE by ELISA.ResultsIn the diabetes group, low levels of methionine sulfoxide (adjusted for age, sex and mean HbA1c) were associated with normal coronary arteries, OR 0.48 (95% CI 0.27–0.88). Glucuronidine/LW-1 was associated with established CHD, OR 2.0 (1.16–3.49). MG-H1 and glucuronidine/LW-1 correlated with calcified plaque volume (r = 0.23–0.28, p<0.05), while pentosidine correlated with soft/mixed plaque volume (r = 0.29, p = 0.008), also in the adjusted analysis.ConclusionsLow levels of collagen-bound methionine sulfoxide were associated with normal coronary arteries while glucuronidine/LW-1 was positively associated with established CHD in long-term type 1 diabetes, suggesting a role for metabolic and oxidative stress in the formation of atherosclerosis in diabetes. ]]> <![CDATA[The adipokine vaspin is associated with decreased coronary in-stent restenosis <i>in vivo</i> and inhibits migration of human coronary smooth muscle cells <i>in vitro</i>]]> https://www.researchpad.co/article/elastic_article_7692 Percutaneous coronary intervention represents the most important treatment modality of coronary artery stenosis. In-stent restenosis (ISR) is still a limitation for the long-term outcome despite the introduction of drug eluting stents. It has been shown that adipokines directly influence vessel wall homeostasis by influencing the function of endothelial cells and arterial smooth muscle cells. Visceral adipose tissue-derived serpin vaspin was recently identified as a member of serine protease inhibitor family and serveral studies could demonstrate a relation to metabolic diseases. The aim of this study was to investigate a role of vaspin in the development of in-stent restenosis in vivo and on migration of smooth muscle cells and endothelial cells in vitro.MethodsWe studied 85 patients with stable coronary artery disease who underwent elective and successful PCI with implatation of drug eluting stents. Blood samples were taken directly before PCI. Vaspin plasma levels were measured by specific ELISA. ISR was evaluated eight months later by coronary angiography. Human coronary artery smooth muscle cells (HCASMC) and human umbilical vein endothelial cells (HUVEC) migration was analyzed by an in-vitro migration assay with different concentrations (0.004ng/mL up to 40ng/mL) of vaspin as well as by an scratch assay. For proliferation an impedance measurement with specialiced E-Plates was performed.ResultsDuring the follow up period, 14 patients developed ISR. Patients with ISR had significantly lower vaspin plasma levels compared to patients without ISR (0.213 ng/ml vs 0.382 ng/ml; p = 0.001). In patients with plasma vaspin levels above 1.35 ng/ml we could not observe any restenosis. There was also a significant correlation of plasma vaspin levels and late lumen loss in the stented coronary segments. Further we could demonstrate that vaspin nearly abolishes serum induced migration of HCASMC (100% vs. 9%; p<0.001) in a biphasic manner but not migration of HUVEC. Proliferation of HCASMC and HUVEC was not modulated by vaspin treatment.ConclusionWe were able to show that the adipokine vaspin selectively inhibits human coronary SMC migration in vitro and has no effect on HUVEC migration. Vaspin had no effect on proliferation of HUVEC which is an important process of the healing of the stented vessel. In addition, the occurrence of ISR after PCI with implantation of drug eluting stents was significantly associated with low vaspin plasma levels before intervention. Determination of vaspin plasma levels before PCI might be helpful in the identification of patients with high risk for development of ISR after stent implantation. In addition, the selective effects of vaspin on smooth muscle cell migration could potentially be used to reduce ISR without inhibition of re-endothelialization of the stented segment. ]]> <![CDATA[Constitutive hydrogen inhalation prevents vascular remodeling via reduction of oxidative stress]]> https://www.researchpad.co/article/Ne1330967-900e-43ee-b1f2-140543b0d511

Molecular hydrogen is thought to have an inhibitory effect on oxidative stress, thereby attenuating the onset and progression of various diseases including cardiovascular disease; however, few reports have assessed the preventive effect of constitutive inhalation of hydrogen gas on of vascular remodeling. Here, we investigated the effect of constitutive inhalation of hydrogen gas on vascular neointima formation using a cuff-induced vascular injury mouse model. After constitutive inhalation of compressed hydrogen gas (O2 21%, N2 77.7%, hydrogen 1.3%) or compressed air only (O2 21%, N2 79%) by C57BL/6 mice for 2 weeks from 8 weeks of age in a closed chamber, inflammatory cuff injury was induced by polyethylene cuff placement around the femoral artery under anesthesia, and hydrogen gas administration was continued until sampling of the femoral artery. Neointima formation, accompanied by an increase in cell proliferation, was significantly attenuated in the hydrogen group compared with the control group. NADPH oxidase NOX1 downregulation in response to cuff injury was shown in the hydrogen group, but the expression levels of NADPH oxidase subunits, p40phox and p47phox, did not differ significantly between the hydrogen and control groups. Although the increase in superoxide anion production did not significantly differ between the hydrogen and control groups, DNA damage was decreased as a result of reduction of reactive oxygen species such as hydroxyl radical (⋅OH) and peroxynitrite (ONOO-) in the hydrogen group. These results demonstrate that constitutive inhalation of hydrogen gas attenuates vascular remodeling partly via reduction of oxidative stress, suggesting that constitutive inhalation of hydrogen gas at a safe concentration in the living environment could be an effective strategy for prevention of vascular diseases such as atherosclerosis.

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<![CDATA[Nocturnal hypercapnia with daytime normocapnia in patients with advanced pulmonary arterial hypertension awaiting lung transplantation]]> https://www.researchpad.co/article/Nacc6463a-eb28-4f4a-acf0-c81fc9df01f4

Background

Pulmonary arterial hypertension (PAH) is frequently complicated by sleep disordered breathing (SDB), and previous studies have largely focused on hypoxemic SDB. Even though nocturnal hypercapnia was shown to exacerbate pulmonary hypertension, the clinical significance of nocturnal hypercapnia among PAH patients has been scarcely investigated.

Method

Seventeen patients with PAH were identified from 246 consecutive patients referred to Kyoto University Hospital for the evaluation of lung transplant registration from January 2010 to December 2017. Included in this study were 13 patients whose nocturnal transcutaneous carbon dioxide partial pressure (PtcCO2) monitoring data were available. Nocturnal hypercapnia was diagnosed according to the guidelines of the American Academy of Sleep Medicine. Associations of nocturnal PtcCO2 measurements with clinical features, the findings of right heart catheterization and pulmonary function parameters were evaluated.

Results

Nocturnal hypercapnia was diagnosed in six patients (46.2%), while no patient had daytime hypercapnia. Of note, nocturnal hypercapnia was found for 5 out of 6 patients with idiopathic PAH (83.3%). Mean nocturnal PtcCO2 levels correlated negatively with the percentage of predicted total lung capacity (TLC), and positively with cardiac output and cardiac index.

Conclusion

Nocturnal hypercapnia was prevalent among advanced PAH patients who were waiting for lung transplantation, and associated with %TLC. Nocturnal hypercapnia was associated with the increase in cardiac output, which might potentially worsen pulmonary hypertension especially during sleep. Further studies are needed to investigate hemodynamics during sleep and to clarify whether nocturnal hypercapnia can be a therapeutic target for PAH patients.

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<![CDATA[A novel visual ranking system based on arterial spin labeling perfusion imaging for evaluating perfusion disturbance in patients with ischemic stroke]]> https://www.researchpad.co/article/N32085c18-73a0-407b-8668-9d011597efb2

We developed a visual ranking system by combining the parenchymal perfusion deficits (PPD) and hyperintense vessel signals (HVS) on arterial spin labeling (ASL) imaging. This study aimed to assess the performance of this ranking system by correlating with subtypes classified based on dynamic susceptibility contrast (DSC) imaging for evaluating the perfusion disturbance observed in patients with ischemic stroke. 32 patients with acute or subacute infarcts detected by DSC imaging were reviewed. Each patient’s brain was divided into 12 areas. ASL ranks were defined by the presence (+) or absence (-) of PPD/HVS as follows; I:–/–, II:–/+, III: +/+, and IV: +/–. DSC imaging findings were categorized based on cerebral blood flow (CBF) and time to peak (TTP) as normal (normal CBF/TTP), mismatched (normal CBF/delayed TTP), and matched (decreased CBF/delayed TTP). Two reviewers rated perfusion abnormalities in the total of 384 areas. The four ASL ranks correlated well with the DSC subtypes (Spearman’s r = 0.82). The performance of ASL ranking system was excellent as indicated by the area under the curve value of 0.94 using either matched or mismatched DSC subtype as the gold standard and 0.97 using only the matched DSC subtype as the gold standard. The two methods were in good-to-excellent agreement (maximum κ-values, 0.86). Inter-observer agreement was excellent (κ-value, 0.98). Although the number of patients was small and the number of dropouts was high, our proposed, ASL-based visual ranking system represented by PPD and HVS provides good, graded estimates of perfusion disturbance that agree well with those obtained by DSC perfusion imaging.

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<![CDATA[Exploring magnetohydrodynamic voltage distributions in the human body: Preliminary results]]> https://www.researchpad.co/article/5c89777ed5eed0c4847d2e42

Background

The aim of this study was to noninvasively measure regional contributions of vasculature in the human body using magnetohydrodynamic voltages (VMHD) obtained from electrocardiogram (ECG) recordings performed inside MRI’s static magnetic field (B0). Integrating the regional VMHD over the Swave-Twave segment of the cardiac cycle (Vsegment) provides a non-invasive method for measuring regional blood volumes, which can be rapidly obtained during MRI without incurring additional cost.

Methods

VMHD was extracted from 12-lead ECG traces acquired during gradual introduction into a 3T MRI. Regional contributions were computed utilizing weights based on B0’s strength at specified distances from isocenter. Vsegment mapping was performed in six subjects and validated against MR angiograms (MRA).

Results

Fluctuations in Vsegment, which presented as positive trace deflections, were found to be associated with aortic-arch flow in the thoracic cavity, the main branches of the abdominal aorta, and the bifurcation of the common iliac artery. The largest fluctuation corresponded to the location where the aortic arch was approximately orthogonal to B0. The smallest fluctuations corresponded to areas of vasculature that were parallel to B0. Significant correlations (specifically, Spearman’s ranked correlation coefficients of 0.96 and 0.97 for abdominal and thoracic cavities, respectively) were found between the MRA and Vsegment maps (p < 0.001).

Conclusions

A novel non-invasive method to extract regional blood volumes from ECGs was developed and shown to be a rapid means to quantify peripheral and abdominal blood volumes.

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<![CDATA[High-resolution contrast-enhanced vessel wall imaging in patients with suspected cerebral vasculitis: Prospective comparison of whole-brain 3D T1 SPACE versus 2D T1 black blood MRI at 3 Tesla]]> https://www.researchpad.co/article/5c8c1948d5eed0c484b4d33a

Purpose

Vessel wall imaging (VWI) using T1 dark blood MRI can depict inflammation of intracranial arteries in patients with cerebral vasculitis. Recently, 3D VWI sequences were introduced at 3 Tesla. We aimed to compare 2D and 3D VWI for detection of intracranial vessel wall enhancement (VWE) in patients suspected of cerebral vasculitis.

Methods

44 MRI scans of 39 patients were assessed that included bi-planar 2D T1 and whole-brain 3D T1 SPACE dark blood VWI pre and post contrast. Visibility and VWE were analyzed in 31 pre-specified intracranial artery segments. Additionally, leptomeningeal and parenchymal contrast enhancement was assessed.

Results

Overall, more arterial segments were visualized with 3D VWI (p<0.0001). Detection of VWE showed fair agreement between 2D and 3D VWI (κ = 0.583). On segmental level, more VWE was detected in intradural ICA by 2D VWI (p<0.001) and in VA V4 segment by 3D VWI (p<0.05). 3D VWI showed more leptomeningeal (p<0.05) and parenchymal (p<0.01) contrast enhancement. In patients with positive diagnosis of cerebral vasculitis, sensitivity was of 67% (2D and 3D VWI) and specificity was 44% (2D VWI) and 48% (3D VWI); more VWE was seen in arteries distal to VA and ICA compared to non-vasculitic patients.

Conclusion

2D and 3D VWI differed in the ability to detect VWE. Whole brain coverage with better evaluability of VAs and distal intracranial artery segments, and depiction of more parenchymal and leptomeningeal enhancement make 3D VWI more favorable. As VWE in arteries distal to VA and ICA may be used for discrimination of vasculitic and non-vasculitic patients, future increase in spatial resolution of 3D VWI sequences may be beneficial.

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<![CDATA[Hypoglycemia does not affect the progression of preclinical atherosclerosis in subjects with type 2 diabetes]]> https://www.researchpad.co/article/5c8823c0d5eed0c484638f5b

Introduction

Intensive treatment aimed at achieving optimal metabolic control to prevent the development of chronic diabetic complications is often associated with an increased rate of hypoglycemic events. Hypoglycemia is believed to be responsible for acute fatal and nonfatal cardiovascular events likely as a consequence of the activation of pro-inflammatory and pro-atherothrombotic pathways. Hypoglycemia has been reported to influence the development of preclinical atherosclerosis. The present study was designed to prospectively evaluate whether hypoglycemia influences the function and the morphology of the arteries in subjects with type 2 diabetes without complications and uncontrolled diabetes.

Material and methods

Seventy-six subjects underwent a noninvasive evaluation of carotid wall thickness and brachial artery function at baseline and after one year of treatment with the intent of obtaining optimal glycemic control. At the end of the observation time, subjects were divided in two groups: with hypoglycemia (H-group) or without hypoglycemia (C-group).

Results

Baseline characteristic were comparable between groups. HbA1c significantly decreased in both groups, and fasting plasma glucose was only significant in the H-group. Subjects with hypoglycemia showed a significant reduction of carotid wall thickness after one-year of treatment (H-groups: right baseline 834±141 vs. 1-year 770±132 μ p<0.05; C-group: 757±162 vs. 767±135 μ p = ns). Endothelial function remained unchanged during the study for both groups.

Discussion

The present findings demonstrate that hypoglycemia does not affect endothelial function. Furthermore, subjects who experience more hypoglycemia show significant reduction of carotid wall thickness. Optimal metabolic control should be pursued as soon as possible.

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<![CDATA[An anatomical study on lumbar arteries related to the extrapedicular approach applied during lumbar PVP (PKP)]]> https://www.researchpad.co/article/5c8823e7d5eed0c48463929f

To observe the regional anatomy of the lumbar artery (LA) associated with the extrapedicular approach applied during percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP), we collected 78 samples of abdominal computed tomography angiography imaging data. We measured the nearest distance from the center of the vertebral body puncture point to the LA (distance VBPP-LA, DVBPP-LA). According to the DVBPP-LA, four zones, Zone I, Zone II, Zone III and Zone IV, were identified. LAs that passed through these zones were called Type I, Type II, Type III and Type IV LAs, respectively. A portion of the lumbar vertebrae had an intersegmental branch that originated from the upper segmental LA and extended longitudinally across the lateral wall of the pedicle; it was called Type V LA. Compared with the DVBPP-LA in L1, L2, L3 and L4, the overall difference and between-group differences were significant (P < 0.05). In L1, L2, L3, L4 and L5, there were 8, 4, 4, 0 and 1 Type I LAs, respectively. There were no Type V LAs in L1 and L2, but there were 2, 16 and 26 Type V LAs in L3, L4 and L5, respectively. In L1-L5, the numbers of Type I LA plus Type V LA were 8, 4, 6, 16 and 27, and the presence ratios were 5.1%, 2.6%, 5.6%, 10.3% and 17.3%, respectively. In L4 and L5, the male presence ratios of Type I LA plus Type V LA were 7.1% and 10.7%, respectively, and the female presence ratios were 13.9% and 25.0%, respectively. Thus, extrapedicular PVP (PKP) in lumbar vertebrae had a risk of LA injury and was not suggested for use in L4 and L5, especially in female patients.

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<![CDATA[Apolipoprotein B correlates with intra-plaque necrotic core volume in stable coronary artery disease]]> https://www.researchpad.co/article/5c75ac91d5eed0c484d08a4e

Objective

To determine the relationship between plaque composition and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (Apo-B), and Apo-A1 using virtual-histology intravascular ultrasound (VH-IVUS).

Methods

We assessed plaque composition in patients with stable coronary artery disease (SCD) admitted to our hospital for percutaneous coronary intervention (PCI) between November 1, 2012, and March 10, 2015. Before PCI, fibrous (FI), fibrofatty (FF), necrotic core (NC), and dense calcium (DC) regions were evaluated using VH-IVUS, and the contributions of each to the culprit lesion volume were recorded. Plasma LDL-C, HDL-C, Apo-B, and Apo-A1 levels were assessed before PCI. The relationship between the regions on VH-IVUS and plasma lipid levels was assessed. Patients were categorized into low Apo-B (LAB) and high Apo-B (HAB) groups, based on the overall cohort median Apo-B level.

Results

We enrolled 115 patients (median Apo-B, 91 mg/dL, male n = 88) with 57 and 58 patients in the LAB (Apo-B ≤ 90 mg/dL) and HAB (Apo-B ≥ 91 mg/dL) groups, respectively. Vessel, plaque, and %NC volumes were significantly greater in the HAB group than in the LAB group. The %FI, %FF, and %DC volumes were similar in both groups. In all 115 patients, the %NC volume correlated with LDL-C (r = 0.2353, P = 0.0114) and Apo-B (r = 0.2487, P = 0.0074) but not with HDL-C and Apo A-1. The high-sensitivity C-reactive protein level tended to be higher in the HAB group than in the LAB group. Multiple regression analysis showed that being male, Apo-A1, and Apo-B were significant predictors of %NC volume extent.

Conclusions

Elevated Apo-B level was related to the %NC in target coronary artery lesions in SCD patients, suggesting a role of Apo-B as a biomarker of unstable plaque in this population.

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<![CDATA[Elevated levels of autoantibodies against EXD2 and PHAX in the sera of patients with chronic thromboembolic pulmonary hypertension]]> https://www.researchpad.co/article/5c6dca33d5eed0c48452a8b5

While circulating autoantibodies have been detected in patients with several cardiovascular diseases, such studies have not been performed for chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Here we investigated the production of certain auto-antibodies in CTEPH patients. Initial screening was performed in 5 CTEPH patients and 5 healthy donors (HDs) using a ProtoArray Human Protein Microarray v5.1 containing 9,375 human proteins, and we selected 34 antigens recognized by IgG antibodies more strongly in the sera of CTEPH patients than in the sera of HDs. In subsequent second/third analyses, we validated the auto-antibody level using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) in 96 CTEPH patients and 96 HDs as follows: At the second screening, we used 63 crude peptides derived from those selected 34 antigens and found that the serum levels of autoantibodies for 4 peptides seemed higher in CTEPH patients than in HDs. In third analysis, we used the purified peptides of those selected in second screening and found that serum antibodies against peptides derived from exonuclease 3'-5' domain-containing 2 (EXD2) and phosphorylated adaptor for RNA export (PHAX) were significantly higher in CTEPH patients than in HDs. The serum antibody levels to these antigens were also elevated in PAH patients. The titers against EXD2 peptide decreased after surgical treatment in CTEPH patients. These autoantibodies may be useful as biomarkers of CTEPH and PAH, and further investigations may provide novel insight into the etiology.

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<![CDATA[Subclinical atherosclerosis in psoriasis. Usefulness of femoral artery ultrasound for the diagnosis, and analysis of its relationship with insulin resistance]]> https://www.researchpad.co/article/5c6730cfd5eed0c484f38183

Background

Psoriasis is associated with an increased risk of cardiovascular disease (CVD) at younger ages that is not identifiable by traditional risk factors. Screening for subclinical atherosclerosis with ultrasound has only been investigated in carotid arteries. Femoral artery ultrasound has never been considered for this purpose. The link between psoriasis and accelerated atherosclerosis has not yet been established.

Objective

To study the usefulness of femoral artery ultrasound for the detection of subclinical atherosclerosis in psoriasis. We also investigated its possible relationship with changes in insulin resistance.

Methods

We conducted a cross-sectional study in 140 participants, 70 patients with moderate-to-severe psoriasis and 70 healthy controls, matched 1:1 for age, sex, and BMI. Femoral and carotid atherosclerotic plaques were evaluated by ultrasonography. Insulin resistance was assessed by the homeostasis model assessment method (HOMA-IR).

Results

Femoral atherosclerotic plaque prevalence was significantly higher in patients with psoriasis (44.64%) than in controls (19.07%) (p<0.005), but no significant difference was found in carotid plaque prevalence (p<0.3). Femoral plaques were significantly more prevalent than carotid plaques (21.42%) among patients with psoriasis (p<0.001). In the regression analysis, insulin resistance was the most influential determinant of atherosclerosis in psoriasis and C-reactive protein the most significant predictor of insulin resistance.

Conclusions

Ultrasound screening for femoral atherosclerotic plaques improves the detection of subclinical atherosclerosis in patients with psoriasis, whereas the study of carotid arteries is not sufficiently accurate. Insulin resistance appears to play a greater role in the development of atherosclerosis in these patients in comparison to other classical CVD risk factors.

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<![CDATA[The association of CHA2DS2-VASc score and carotid plaque in patients with non-valvular atrial fibrillation]]> https://www.researchpad.co/article/5c673079d5eed0c484f37bb6

Objective

The aim of this study was to assess the association between CHA2DS2-VASc score and carotid plaques in patients with non-valvular atrial fibrillation (NVAF).

Methods

We conducted a retrospective study including 3,435 NVAF patients who underwent carotid ultrasound examinations from January 2015 to December 2017.We collected the clinical data on the medical records system. Chi-square trend test was used to analyze trends between the prevalence of carotid plaques with an increasing CHA2DS2-VASc score. Univariate and multivariate logistic regression was also used to assess the association between carotid plaques and CHA2DS2-VASc scores. The area under the receiver operating characteristic (ROC) curve (AUC) was used to determine the optimal cutoff points of different CHA2DS2-VASc scores in NVAF patients.

Results

NVAF patients with carotid plaques had higher CHA2DS2-VASc scores compared with patients who did not have carotid plaques (3.01±1.36 vs. 2.55±1.28, P < 0.05). In all participants, male participants and female participants, the prevalence of carotid plaques increased significantly as the CHA2DS2-VASc score increased (P for trend < 0.001). Multivariate logistic regression analysis demonstrated that for each 1-point increase in the CHA2DS2-VASc score, there was an associated 37% increase in the prevalence of carotid plaques. ROC curve analysis revealed that a CHA2DS2-VASc score ≥ 2 in male patients (sensitivity, 44.67%; specificity, 75.64%; AUC, 0.639) or ≥ 3 in female patients (sensitivity, 47.24%; specificity, 72.40%; AUC, 0.634) were associated with carotid plaques.

Conclusion

The prevalence of carotid plaques in patients with NVAF was associated with the CHA2DS2-VASc score.

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<![CDATA[Role of BRCA1-associated protein (BRAP) variant in childhood pulmonary arterial hypertension]]> https://www.researchpad.co/article/5c5ca2b0d5eed0c48441e8b1

Although mutations in several genes have been reported in pulmonary arterial hypertension (PAH), most of PAH cases do not carry these mutations. This study aimed to identify a novel cause of PAH. To determine the disease-causing variants, direct sequencing and multiplex ligation-dependent probe amplification were performed to analyze 18 families with multiple affected family members with PAH. In one of the 18 families with PAH, no disease-causing variants were found in any of BMPR2, ACVRL1, ENG, SMAD1/4/8, BMPR1B, NOTCH3, CAV1, or KCNK3. In this family, a female proband and her paternal aunt developed PAH in their childhood. Whole-exome next-generation sequencing was performed in the 2 PAH patients and the proband’s healthy mother, and a BRCA1-associated protein (BRAP) gene variant, p.Arg554Leu, was identified in the 2 family members with PAH, but not in the proband’s mother without PAH. Functional analyses were performed using human pulmonary arterial smooth muscle cells (hPASMCs). Knockdown of BRAP via small interfering RNA in hPASMCs induced p53 signaling pathway activation and decreased cell proliferation. Overexpression of either wild-type BRAP or p.Arg554Leu-BRAP cDNA constructs caused cell death confounding these studies, however we observed higher levels of p53 signaling inactivation and hPASMC proliferation in cells expressing p.Arg554Leu-BRAP compared to wild-type BRAP. In addition, p.Arg554Leu-BRAP induced decreased apoptosis of hPASMCs compared with wild-type BRAP. In conclusion, we have identified a novel variant of BRAP in a Japanese family with PAH and our results suggest it could have a gain-of-function. This study sheds light on new mechanism of PAH pathogenesis.

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<![CDATA[VPAC1 receptors play a dominant role in PACAP-induced vasorelaxation in female mice]]> https://www.researchpad.co/article/5c79afecd5eed0c4841e3a63

Background

PACAP and VIP are closely related neuropeptides with wide distribution and potent effect in the vasculature. We previously reported vasomotor activity in peripheral vasculature of male wild type (WT) and PACAP-deficient (KO) mice. However, female vascular responses are still unexplored. We hypothesized that PACAP-like activity is maintained in female PACAP KO mice and the mechanism through which it is regulated differs from that of male PACAP KO animals.

Methods

We investigated the vasomotor effects of VIP and PACAP isoforms and their selective blockers in WT and PACAP KO female mice in carotid and femoral arteries. The expression and level of different PACAP receptors in the vessels were measured by RT-PCR and Western blot.

Results

In both carotid and femoral arteries of WT mice, PACAP1-38, PACAP1-27 or VIP induced relaxation, without pronounced differences between them. Reduced relaxation was recorded only in the carotid arteries of KO mice as compared to their WT controls. The specific VPAC1R antagonist completely blocked the PACAP/VIP-induced relaxation in both arteries of all mice, while PAC1R antagonist affected relaxation only in their femoral arteries.

Conclusion

In female WT mice, VPAC1 receptors appear to play a dominant role in PACAP-induced vasorelaxation both in carotid and in femoral arteries. In the PACAP KO group PAC1R activation exerts vasorelaxation in the femoral arteries but in carotid arteries there is no significant effect of the activation of this receptor. In the background of this regional difference, decreased PAC1R and increased VPAC1R availability in the carotid arteries was found.

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<![CDATA[Reproducibility and validity of a novel invasive method of assessing peripheral microvascular vasomotor function]]> https://www.researchpad.co/article/5c57e6ddd5eed0c484ef3ffe

In healthy arteries, blood flow is regulated by microvascular tone assessed by changes in blood flow volume and vascular resistance to endothelium-dependent and -independent vasodilators. We developed a novel method of using intravascular ultrasound (IVUS) and a Doppler flow wire to measure changes in blood flow volume and vascular resistance of the profunda arterial bed. We assessed the variability over 6 months in measuring microvascular endothelium-dependent dilation to acetylcholine and endothelium-independent dilation to adenosine in 20 subjects who were part of a larger study of Gulf War Illness without obstructive peripheral artery disease. Vasomotor function was assessed by Infusions of control (dextrose), acetylcholine (10-6M), adenosine (50μg), and nitroglycerin (25μg/ml). 400 IVUS and 240 flow velocity images were measured a mean 6 (SD = 2) months apart blind to measurement and infusion stage. The mean (SD) baseline profunda flow was 227 (172) ml/min and vascular resistance 4.6 x 104 (2.4 x 104) dynes-s/cm5. The intraclass correlation coefficients for 6-month variability for vascular function were excellent (range 0.827–0.995). Bland-Altman analyses showed mean differences of less than 2% for microvascular endothelium-dependent function (flow volume and resistance) and less than 1% for macrovascular endothelium-dependent function with acceptable limits of agreement. In 49 subjects assessing concurrent validity of the technique against atherosclerosis risk factors, we observed greater impairment in microvascular endothelium-dependent function per year of age (flow volume = -1.4% (p = 0.018), vascular resistance = 1.5% (p = 0.015)) and current smoking (flow volume = -36.7% (p = .006), vascular resistance = 50.0% (p<0.001)). This novel method of assessing microvascular vasomotor function had acceptable measurement reproducibility and validity.

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<![CDATA[Elevated pulmonary arterial pressure in Zucker diabetic fatty rats]]> https://www.researchpad.co/article/5c58d612d5eed0c484031535

Diabetes is a very strong predictor of chronic systemic vascular diseases and acute cardiovascular events. Recently, associations between metabolic disorders and pulmonary hypertension have also been reported in both humans and animal models. In order to get some further insight into the relationship of pulmonary hypertension with obesity, insulin resistance and hyperglycemia, herein we have used the Zucker diabetic fatty rats (ZDF/clr-lepr fa) at 20 weeks fed a standard diet and compared to their lean Zucker littermates (ZL). ZDF rats were obese, had elevated plasma glucose levels and insulin resistance, i.e. a clinically relevant model of type 2 diabetes. They presented elevated systolic, diastolic and mean pulmonary arterial pressures and a parallel increase in the Fulton index. Systemic arterial pressures were also increased but the left ventricle plus septum weight was similar in both groups and the heart rate was reduced. Wall media thickening was observed in the small pulmonary arteries from the ZDF rats. Isolated pulmonary arteries mounted in a wire myograph showed similar vasoconstrictor responses to phenylephrine and 5-HT and similar responses to the endothelium-dependent vasodilator acetylcholine. However, the iNOS inhibitor 1400W enhanced the vasoconstrictor responses in ZDF but not in ZL rats. The protein expression of eNOS and iNOS was not significantly different in the lungs of the two groups. The lung expression of Bmpr2 mRNA was downregulated. However, the mRNA expression of Kcna5, Kcnk3, Kcnq1, Kcnq4 or Kcnq5, which encode for the potassium channels Kv1.5, TASK-1, Kv7.1, Kv7.4 and Kv7.5, respectively, was similar in ZL and ZDF rats. In conclusion, ZDF rats show increased pulmonary arterial pressure, right ventricular hypertrophy, pulmonary arterial medial thickening and downregulated lung Bmpr2 despite leptin resistance. These changes were mild but are consistent with the view that diabetes is a risk factor for pulmonary hypertension.

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<![CDATA[Usefulness of uterine artery Doppler velocimetry as a predictor for hypertensive disorders in pregnancy in women with prehypertension before 20 weeks gestation]]> https://www.researchpad.co/article/5c5b52d4d5eed0c4842bd0ce

Hypertensive disorders of pregnancy (HDP) is major complication of maternal-fetal outcomes in obstetric field. Although HDP is mainly defined by high blood pressure, the information about the relationship between prehypertension (preHTN, 120-139mmHg and 80-89mmHg) and HDP development is limited. The objective of this study is to determine the usefulness of preHTN before 20 weeks gestation and uterine artery (UtA) Doppler velocimetry as a predictor of HDP. A total of 2039 singleton pregnant women who had received continuous prenatal care were included in this study. The participants were classified into 2 groups based on the highest blood pressure (BP) under 20 gestational weeks as defined by the Joint National Committee 7: Normotensive (n = 1816) and preHTN pregnant women (n = 223). All preHTN pregnant women were assessed using UtA Doppler velocimetry, and the numbers of preHTN assessments were recorded. The risk of HDP was assessed in the PreHTN groups through patient history and Doppler velocimetry. Compared to normotensive patients, a total of 223 preHTN patients had a higher risk of preeclampsia (OR: 2.3; CI: 1.2–4.3), gestational hypertension (OR: 3.3; CI: 2.0–5.4) and any HDP (OR: 3.0; CI: 2.0–4.5). In the preHTN group, 134 (60.1%) patients had preHTN measured at least twice and 89 (39.9%) patients had preHTN. The results showed that two or more preHTN measurements have high sensitivity for predicting HDP (OR: 1.9; CI: 1.0–3.1; sensitivity: 83.8%; specificity: 47.2%). Additionally, the combination of abnormal UtA Doppler velocimetry results and at least two preHTN measurements showed a high accuracy in predicting HDP (OR: 2.9; CI: 1.1–4.1; sensitivity: 67.6%; specificity: 98.4%). In conclusion, close BP monitoring and recording of every preHTN event are important for pregnant women with preHTN history, and UtA Doppler examination in those women during the 2nd trimester can be a further aid in determining the risk of HDP.

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<![CDATA[An optimized low-pressure tourniquet murine hind limb ischemia reperfusion model: Inducing acute ischemia reperfusion injury in C57BL/6 wild type mice]]> https://www.researchpad.co/article/5c536bb5d5eed0c484a49072

Acute ischemia reperfusion injury in skeletal muscle remains an important issue in several fields of regenerative medicine. Thus, a valid model is essential to gain deeper insights into pathophysiological relations and evaluate possible treatment options. While the vascular anatomy of mice regularly prevents sufficient vessel occlusion by invasive methods, there is a multitude of existing models to induce ischemia reperfusion injury without surgical procedures. Since there is no consensus on which model to prefer, this study aims to develop and evaluate a novel, optimized low-pressure tourniquet model. C57BL/6 mice underwent an ischemic procedure by either tourniquet or invasive artery clamping. A sham group served as control. With exception of the sham group, mice underwent 2 hours of ischemia followed by 4 hours of reperfusion. Groups were compared using microcirculatory and spectroscopic measurements, distinctions in tissue edema, histological and immunohistochemical analyses. Both procedures led to a significant decrease in tissue blood flow (- 97% vs. - 86%) and oxygenation (- 87% vs. - 75%) with a superiority of the low-pressure tourniquet. Tissue edema in the tourniquet cohort was significantly increased (+ 59%), while the increase in the clamping cohort was non-significant (+ 7%). Haematoxylin Eosin staining showed significantly more impaired muscle fibers in the tourniquet group (+ 77 p.p. vs. + 11 p.p.) and increased neutrophil infiltration/ROI (+ 51 vs. + 8). Immunofluorescence demonstrated an equal increase of p38 in both groups (7-fold vs. 8-fold), while the increase in apoptotic markers (Caspase-3, 3-Nitrotyrosine, 4-Hydroxynonenal) was significantly higher in the tourniquet group. The low-pressure tourniquet has been proven to produce reproducible and thus reliable ischemia reperfusion injury. In addition, significantly less force was needed than previously stated. It is therefore an important instrument for studying the pathophysiology of ischemia reperfusion injury and for the development of prophylactic as well as therapeutic interventions.

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<![CDATA[Liver regeneration therapy through the hepatic artery-infusion of cultured bone marrow cells in a canine liver fibrosis model]]> https://www.researchpad.co/article/5c521890d5eed0c484798f50

Background

We previously reported regenerative therapies for decompensated cirrhosis based on peripheral venous drip infusion using non-cultured whole bone marrow (BM) cells, or the less invasive cultured BM-derived mesenchymal stem cells (BMSCs). Here, we assessed the efficacy and safety of hepatic arterial infusion using cultured autologous BMSCs, comparing it with peripheral infusion, using our established canine liver fibrosis model.

Methods

Canine BM cells were harvested and cultured, and the resultant BMSCs were returned to carbon tetrachloride (CCl4)-induced liver cirrhosis model canines via either a peripheral vein (Vein group) or hepatic artery (Artery group). A variety of assays were performed before and 4, 8, and 12 weeks after BMSC infusion, and liver fibrosis and indocyanine green (ICG) half-life (t1/2) were compared to those in a control group that received CCl4 but not BMSCs. The safety of this approach was evaluated by contrast-enhanced computed tomography (CT) and serial blood examinations after infusion.

Results

Four weeks after infusing BMSCs, a significant improvement was observed in the Vein group (n = 8) compared to outcome in the Control group (n = 10), along with a decrease in ICG t1/2. In the Artery group (n = 4), ICG t1/2 was significantly shorter than that in the Vein group at 8 weeks (Δt1/2: −3.8 ± 1.7 min vs. +0.4 ± 2.4 min; p < 0.01) and 12 weeks (Δt1/2: −4.2 ± 1.7 min vs. +0.4 ± 2.7 min; p < 0.01) after BMSC administration. Post-infusion contrast-enhanced CT showed no liver infarction, and blood tests showed no elevations in either serum lactate dehydrogenase concentrations or hypercoagulability.

Conclusions

We confirmed the efficacy and safety of the hepatic arterial infusion of cultured autologous BMSCs using a canine model, thereby providing non-clinical proof-of-concept.

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