Endothelial Denudation Research Articles

Vasodilating effect of Hypericum revolutum (Vahl) (Clusiaceae) methanol extract in rats


 
 
 
 Purpose: To investigate the vasodilating effect of Hypericum revolutum Vahl (Clusiaceae) in rats.
 Methods: H. revolutum aerial parts were extracted with methanol. The total methanol extract was fractionated with chloroform to yield fraction I. The remaining aqueous solution was chromatographed on Diaion HP-20 using water, 50 % methanol, and methanol to yield three fractions (II- IV). Total methanol extract and fractions I-IV were applied to phenylephrine-pre-contracted (10 μM) rat aortic rings at doses of 1, 3, and 10 μg/mL. Subsequent decreases in aortic tension were recorded by an isometric force transducer to evaluate the vasodilation. Column chromatography was utilized to separate the active components of the bioactive fraction.
 Results: Remarkable decreases in aortic tension (p<0.05) revealed that fraction I (3 and 10 μg/mL) produced a vasodilating effect, whereas fractions III and IV did not possess any substantial effect. Vasodilation induced by fraction I was endothelial-dependent because it was significantly (p<0.05) blocked by endothelial denudation. Phytochemical inspection of fraction I led to the isolation of β- sitosterol (1), 1,7-dihydroxyxanthone (euxanthone) (2), and 2,3,4-tirmethoxy xanthone (3).
 Conclusion: Fraction I of the H. revolutum extract was responsible for its vasodilating effect. This fraction may be used as a possible anti-hypertensive preparation after in vivo testing and successful clinical trials.
 
 
 

A Comorbid Rat Model of Neuroendocrine-Immune System Alterations Under the Impact of Risk Factors for Stroke.

Hypercholesterolemia and carotid atherosclerosis contribute to the etiology of stroke. However, there has been a lack of appropriate comorbid animal models incorporating some of the ubiquitous characteristics that precede strokes. Curcumin is a natural active polyphenolic compound extracted from the rhizoma of Curcuma longa L. which possesses comprehensive bioactivities. The present study aimed to evaluate whether neurobehavioral deficits, neuroendocrine-immune dysregulations and cerebral microcirculation dysfunction, are part of the initial stages of cerebral ischemia in individuals suffering from carotid atherosclerosis resulting from a high cholesterol diet (HCD) and if they could be tested using a comorbid animal model. Furthermore, the utility of this model will be examined following the administration of curcumin. Adult wild-type SD rats were fed a regular diet or HCD and supplemented with either vehicle or curcumin for 4 weeks. Carotid injury was induced by an air-drying endothelial denudation method at the end of the second week. Plasma cholesterol, carotid pathomorphology, neurobehavioral tests, and neuroendocrine-immune parameters were measured. We found higher plasma levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), intima and media (I/M) ratio, but lower high-density lipoprotein-cholesterol (HDL-C), spatial learning and memory capacity impairment, elevated NPY expression in the hypothalamus, increased plasma concentration of leptin, upregulated TNF-α, IL-1β, and CRP in the circulation as well as TNF-α and IL-1β in the cerebral cortex, plus enhanced ICAM-1, VCAM-1, and E-selectin in cerebral microvessels in HCD-fed model rats. All these alterations were ameliorated by curcumin. These results suggest that a comorbid rat model was effectively developed by HCD and carotid injury.

The effect of end-ischaemic normothermic machine perfusion on donor hepatic artery endothelial integrity.

Ex vivo normothermic machine liver perfusion (NMLP) involves artificial cannulation of vessels and generation of flow pressures. This could lead to shear stress-induced endothelial damage, predisposing to vascular complications, or improved preservation of donor artery quality. This study aims to assess the spatial donor hepatic artery (HA) endothelial quality downstream of the cannulation site after end-ischaemic NMLP. Remnant HA segments from the coeliac trunk up to the gastroduodenal artery branching were obtained after NMLP (n = 15) and after static cold storage (SCS) preservation (n = 15). Specimens were fixed in 10% neutral buffered formalin and sectioned at pre-determined anatomical sites downstream of the coeliac trunk. CD31 immunohistostaining was used to assess endothelial integrity by a 5-point ordinal scale (grade 0: intact endothelial lining, grade 5: complete denudation). Endothelial integrity after SCS was used as a control for the state of the endothelium at commencement of NMP. In the SCS specimens, regardless of the anatomical site, near complete endothelial denudation was present throughout the HA (median scores 4.5-5). After NMLP, significantly less endothelial loss in the distal HA was present compared to SCS grafts (NMLP vs. SCS: median grade 3 vs. 4.5; p = 0.042). In NMLP specimens, near complete endothelial denudation was present at the cannulation site in all cases (median grade: 5), with significantly less loss of the endothelial lining the further from the cannulation site (proximal vs. distal, median grade 5 vs. 3; p = 0.005). Loss of endothelial lining throughout the HA after SCS and at the cannulation site after NMLP suggests extensive damage related to surgical handling and preservation injury. Gradual improved endothelial lining along more distal sites of the HA after NMLP indicates potential for re-endothelialisation. The regenerative effect of NMLP on artery quality seems to occur to a greater extent further from the cannulation site. Therefore, arterial cannulation for machine perfusion of liver grafts should ideally be as proximal as possible on the coeliac trunk or aortic patch, while the site of anastomosis should preferentially be attempted distal on the common HA.

Methylglyoxal-induced enhancement of uridine diphosphate-mediated contraction in rat femoral artery was due to activation of p38 MAPK and Syk tyrosine kinase

Although abnormalities of function in femoral artery, including aberrant vascular reactivity to various vasoactive mediators, are common in many chronic disorders including hypertension and diabetes, their inducible and/or progressive factors remain unclear. On the other hand, methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of several chronic disorders. Although our previous studies demonstrated that uridine 5'-diphosphate (UDP)-induced contraction in the femoral artery is increased in hypertensive rat model, the direct relationship between MGO and UDP-mediated contraction is currently unknown in rat femoral artery. We therefore investigated the acute effect of MGO (4.2 × 10−4 M for 60 min) on UDP-induced contraction in the rat femoral artery. MGO amplified the UDP-induced contraction in the Wistar rat femoral artery. This augmented response was not abolished in all conditions, including nitric oxide synthase inhibition by L-NNA (10−4 M), cyclooxygenase inhibition by indomethacin (10−5 M), or endothelial denudation. Moreover, in the endothelium-denuded arteries, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (10−5 M) reduced the UDP-induced contraction in both control and MGO-treated groups, while MGO enhanced the p38 MAPK activation regardless of the UDP presence. Moreover, in the endothelium-denuded arteries, the Syk tyrosine kinase inhibitor piceatannol (10−5 M) reduced the UDP-induced contraction in both control and MGO-treated groups. These results suggest that MGO enhances UDP-induced contraction in rat femoral arteries and that this enhancement may be partly due to increases in the activities of Syk tyrosine kinase and p38 MAPK in femoral arterial smooth muscle.

Spergularia marina: a potential source of a novel calcium channel blocker with antihypertensive and diuretic activities.

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Adventitial Collagen Cross-Linking by Glutaraldehyde Reinforcing Human Saphenous Vein - Implication for Coronary Artery Bypass Grafting.

IntroductionA weak venous wall is one of the major reasons contributing to vein graft failure after coronary artery bypass grafting (CABG). We investigated whether adventitial collagen cross-linking by glutaraldehyde reinforces venous wall, preserving the endothelium of veins during high-pressure distention.MethodsHuman saphenous veins (SVs) were collected from 40 patients undergoing CABG, and adventitia cross-linking was performed with 0.3% glutaraldehyde for five minutes. The cross-linked SVs were accessed by biodegradation assay, immunofluorescent staining, and tensile test. Native SVs and cross-linked SVs from another 20 patients received the 200 mmHg pressure distention for two minutes. Pressure-induced injury of SVs were accessed by immunohistochemistry and electron microscopy.ResultsTime to digestion was 97±13 minutes for native SVs and 720±0 minutes for cross-linked SVs (P<0.05). After adventitial cross-linking, the collagen I fibres of the vein remarkably presented with compact and nonporous arrangement. In the high-stretch region (stretch ratio 1.4-1.8), the Young’s elastic modulus of stress-stretch ratio curve in cross-linked SVs was larger than that in native SVs (13.88 vs. 5.83, P<0.05). The cross-linked SVs had a lower extent of endothelial denudation without fibre fracture during high-pressure distension than native SVs. Comparing with the non-cross-linked SVs, the percentage of endothelial nitric oxide synthase staining length on the endothelium of cross-linked SVs was significantly preserved after high-pressure distension (85.2% vs. 64.7%, P<0.05).ConclusionAdventitial collagen cross-linking by glutaraldehyde reinforced venous wall by increasing stiffness and decreasing extensibility of SVs and mitigated the endothelial damage under high-pressure distension.

Antihypertensive Activity of Sauromatum guttatum Mediated by Vasorelaxation and Myocardial Depressant Effects.

ResumoFundamento:A Sauromatum guttatum (S. guttatum) é utilizado no tratamento de doenças do sangue e supostamente tem atividade espasmolítica através da inibição dos canais de Ca2+.Objetivos:O objetivo deste estudo foi investigar o potencial anti-hipertensivo de S. guttatum em modelo de rato Sprague-Dawley (SD) com hipertensão induzida por dieta com alto teor de sal (HIDATS).Métodos:Ratos SD foram divididos em normotensos, hipertensos e grupos tratados com verapamil e S. guttatum. Extrato bruto de S. guttatum (Sg.B) (100, 150 e 300 mg/kg/dia) e verapamil (5, 10 e 15 mg/kg/dia) foram administrados por via oral junto com NaCl. Anéis aórticos e faixas do átrio direito de ratos normotensos foram utilizados para investigar os mecanismos subjacentes. O nível de significância estatística adotado foi de 5%.Resultados:A pressão arterial média diminuiu nos grupos hipertensos tratados com Sg.B e verapamil de forma dose-dependente (p <0,001). No estudo de reatividade vascular, a acetilcolina induziu relaxamentos com valor CE50 de 0,6 µg/mL (0,3–1,0) em ratos hipertensos tratados com Sg.B (300 mg/kg), sugerindo preservação endotelial. Em aorta isolada de rato normotenso, o Sg.B exibiu vasorrelaxamento com valor de CE50 de 0,15 mg/mL (0,10-0,20), após ablação por desnudamento endotelial ou pré-tratamento com L-NAME e atropina. O tratamento com Sg.B causou relaxamento contra contrações induzidas por K+ alto, como o verapamil. O Sg.B mostrou efeitos inotrópicos (82%) e cronotrópicos (56%) negativos em preparações isoladas atriais de ratos reduzidas com atropina. A avaliação fitoquímica indicou a presença de alcaloides, flavonoides e taninos.Conclusão:O S. guttatum possui efeito vasodilatador através da preservação da função endotelial, liberação de NO mediada pelo receptor muscarínico e inibição do movimento de Ca2+, enquanto o efeito depressor do miocárdio atrial pode estar ligado ao receptor muscarínico. Esses achados fornecem a base farmacológica para o uso do extrato de S. guttatum como um medicamento anti-hipertensivo.

Abstract 13231: Semaphorin3F Reduces Atherosclerosis by Decreasing Endothelial Activation and Barrier Permeability and Smooth Muscle Cell Migration

Coronary artery disease (CAD) remains a leading cause of death worldwide. To identify genes causally linked to CAD, we previously conducted large-scale genetic analyses, and identified an association between genes in the semaphorin pathway and CAD. Expression profiling in human atherosclerosis-relevant cell types and atherosclerotic plaques identified semaphorin3F (SEMA3F) as a possible candidate causally linked to atherosclerosis. Administration of SEMA3F reduced aortic lesion area in western-type diet-fed Ldlr -/- mice (Control: 12.1±1.4; SEMA3F: 8.1±0.8, % lesion area/total aortic sinus area, p=0.02). In contrast, neointimal formation was increased in Sema3f -/- mice with partial carotid artery ligation ( WT : 22.8±2.8; Sema3f -/- : 39.2±4.0; % intimal area/total vessel area, p=0.004). Additionally, SEMA3F administration increased re-endothelialization and reduced restenosis in Ldlr -/- mice that underwent carotid endothelial denudation (Control: 53.3±3.5; SEMA3F: 21.4±3.1; % intimal plaque area/vessel area, p=0.0006). Monocyte adhesion to aortic vascular endothelial cells (VECs) from Sema3f -/- mice was elevated, driven by increased NF-κB activation and increased expression of its target adhesion molecules, VCAM1 and ICAM1, in VECs. Monocyte transmigration through VECs from Sema3f -/- mice was also increased, likely due to increased membrane permeability, assessed by in-vivo intravital two-photon microscopy. The increased membrane permeability was modulated in part by decreased mTOR phosphorylation that in turn suppressed vascular endothelial cadherin protein expression. SEMA3F increased thick actomyosin filaments and elicited larger focal adhesions in VECs, suggesting decreased migration. In line with this, SEMA3F inhibited vascular smooth muscle cell (VSMC) migration and maintained the contractile phenotype of VSMCs, which was mediated by the Rho pathway. SEMA3F is causally atheroprotective in models of atherosclerosis and restenosis, mediated, in part, through the modulation of vascular endothelial cell permeability and adhesion molecule expression, and vascular smooth muscle cell migration and phenotype switching.

Association Between Stent Implantation and Progression of Nontarget Lesions in a Rabbit Model of Atherosclerosis.

Progression of nontarget lesions (NTLs) after percutaneous coronary intervention (PCI) has been reported. However, it remains unknown whether progression of NTLs was causally related to stenting. This study was undertaken to test the hypothesis that stent implantation triggers acute phase response and systemic inflammation which may be associated with progression of NTLs. Thirty New Zealand rabbits receiving endothelial denudation and atherogenic diet were randomly divided into stenting, sham, and control groups. Angiography and intravascular ultrasonography were performed in the stenting and sham groups, and stent implantation performed only in the stenting group. Histopathologic study was conducted and serum levels of APPs (acute phase proteins) measured in all rabbits. Proteomics analysis was performed to screen the potential proteins related to NTLs progression after stent implantation. The serum levels of APPs and inflammatory cytokines were measured in 147 patients undergoing coronary angiography or PCI. Plaque burden in the NTLs was significantly increased 12 weeks after stent implantation in the stenting group versus sham group. Serum levels of APPs and their protein expression in NTLs were significantly increased and responsible for stenting-triggered inflammation. In patients receiving PCI, serum levels of SAA-1 (serum amyloid A protein 1), CRP (C-reactive protein), TNF (tumor necrosis factor)-α, and IL (interleukin)-6 were substantially elevated up to 1 month post-PCI. In a rabbit model of atherosclerosis, stent implantation triggered acute phase response and systemic inflammation, which was associated with increased plaque burden and pathological features of unstable plaque in NTLs. The potential mechanism involved vessel injury-triggered acute phase response manifested as increased serum levels of SAA-1, CRP, and LBP (lipopolysaccharide-binding protein) and their protein expression in NTLs. These findings provided a new insight into the relation between stent implantation and progression of NTLs, and further studies are warranted to clarify the detailed mechanism and clinical significance of these preliminary results. Registration: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900026393. Graphic Abstract: A graphic abstract is available for this article.

Acute Stent-Induced Endothelial Denudation: Biomechanical Predictors of Vascular Injury.

Recent concern for local drug delivery and withdrawal of the first Food and Drug Administration-approved bioresorbable scaffold emphasizes the need to optimize the relationships between stent design and drug release with imposed arterial injury and observed pharmacodynamics. In this study, we examine the hypothesis that vascular injury is predictable from stent design and that the expanding force of stent deployment results in increased circumferential stress in the arterial tissue, which may explain acute injury poststent deployment. Using both numerical simulations and ex vivo experiments on three different stent designs (slotted tube, corrugated ring, and delta wing), arterial injury due to device deployment was examined. Furthermore, using numerical simulations, the consequence of changing stent strut radial thickness on arterial wall shear stress and arterial circumferential stress distributions was examined. Regions with predicted arterial circumferential stress exceeding a threshold of 49.5 kPa compared favorably with observed ex vivo endothelial denudation for the three considered stent designs. In addition, increasing strut thickness was predicted to result in more areas of denudation and larger areas exposed to low wall shear stress. We conclude that the acute arterial injury, observed immediately following stent expansion, is caused by high circumferential hoop stresses in the interstrut region, and denuded area profiles are dependent on unit cell geometric features. Such findings when coupled with where drugs move might explain the drug–device interactions.

Empagliflozin Relaxes Resistance Mesenteric Arteries by Stimulating Multiple Smooth Muscle Cell Voltage-Gated K+ (KV) Channels.

The antidiabetic drug empagliflozin is reported to produce a range of cardiovascular effects, including a reduction in systemic blood pressure. However, whether empagliflozin directly modulates the contractility of resistance-size mesenteric arteries remains unclear. Here, we sought to investigate if empagliflozin could relax resistance-size rat mesenteric arteries and the associated underlying molecular mechanisms. We found that acute empagliflozin application produces a concentration-dependent vasodilation in myogenic, depolarized and phenylephrine (PE)-preconstricted mesenteric arteries. Selective inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 and KV7 abolished empagliflozin-induced vasodilation. In contrast, pharmacological inhibition of large-conductance Ca2+-activated K+ (BKCa) channels and ATP-sensitive (KATP) channels did not abolish vasodilation. Inhibition of the vasodilatory signaling axis involving endothelial nitric oxide (NO), smooth muscle cell soluble guanylyl cyclase (sGC) and protein kinase G (PKG) did not abolish empagliflozin-evoked vasodilation. Inhibition of the endothelium-derived vasodilatory molecule prostacyclin (PGI2) had no effect on the vasodilation. Consistently, empagliflozin-evoked vasodilation remained unaltered by endothelium denudation. Overall, our data suggest that empagliflozin stimulates smooth muscle cell KV channels KV1.5 and KV7, resulting in vasodilation in resistance-size mesenteric arteries. This study demonstrates for the first time a novel mechanism whereby empagliflozin regulates arterial contractility, resulting in vasodilation. Due to known antihypertensive properties, treatment with empagliflozin may complement conventional antihypertensive therapy.

Reduced Relaxant Response to Adenine in the Superior Mesenteric Artery of Spontaneously Hypertensive Rats.

We investigated the vascular response to nucleobase adenine using freshly isolated superior mesenteric arteries of spontaneously hypertensive rats (SHR) and its control, Wistar Kyoto (WKY) rats. Endothelium-dependent and endothelium-independent relaxations were assessed in isolated segments in an organ bath. The releases of the metabolites of thromboxane A2 and prostaglandin I2 were also detected. Adenine induced vasorelaxation in both the endothelium-intact and endothelium-denuded arteries in a concentration-dependent manner. In the SHR group, the adenine-induced relaxation was slightly but significantly reduced in the endothelium-intact rings when compared with that in the WKY group. However, the relaxation in the endothelium-denuded rings were similar between the two groups. The difference in the adenine-mediated relaxation in the superior mesenteric arteries between the SHR and WKY groups was eliminated by endothelial denudation and a nitric oxide (NO) synthase inhibitor. In the absence and presence of adenine, SHR tended to have higher levels of metabolites of thromboxane A2 and prostaglandin I2 compared with WKY. However, adenine did not induce the release of these substances in the arteries in both the SHR and WKY groups. These results suggest that the reduced adenine-mediated relaxation in the superior mesenteric arteries in SHR is due to a lack of contribution from the endothelium-derived NO and not from the release of prostanoids.

Nonbone Marrow CD34+ Cells Are Crucial for Endothelial Repair of Injured Artery.

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Thyroxine Induces Acute Relaxation of Rat Skeletal Muscle Arteries via Integrin αvβ3, ERK1/2 and Integrin-Linked Kinase.

Aim: Hyperthyroidism is associated with a decreased peripheral vascular resistance, which could be caused by the vasodilator genomic or non-genomic effects of thyroid hormones (TH). Non-genomic, or acute, effects develop within several minutes and involve a wide tissue-specific spectrum of molecular pathways poorly studied in vasculature. We aimed to investigate the mechanisms of acute effects of TH on rat skeletal muscle arteries.Methods: Sural arteries from male Wistar rats were used for isometric force recording (wire myography) and phosphorylated protein content measurement (Western blotting).Results: Both triiodothyronine (T3) and thyroxine (T4) reduced contractile response of sural arteries to α1-adrenoceptor agonist methoxamine. The effect of T4 was more prominent than T3 and not affected by iopanoic acid, an inhibitor of deiodinase 2. Endothelium denudation abolished the effect of T3, but not T4. Integrin αvβ3 inhibitor tetrac abolished the effect of T4 in endothelium-denuded arteries. T4 weakened methoxamine-induced elevation of phospho-MLC2 (Ser19) content in arterial samples. The effect of T4 in endothelium-denuded arteries was abolished by inhibiting ERK1/2 activation with U0126 as well as by ILK inhibitor Cpd22 but persisted in the presence of Src- or Rho-kinase inhibitors (PP2 and Y27632, respectively).Conclusion: Acute non-genomic relaxation of sural arteries induced by T3 is endothelium-dependent and that induced by T4 is endothelium-independent. The effect of T4 on α1-adrenergic contraction is stronger compared to T3 and involves the suppression of extracellular matrix signaling via integrin αvβ3, ERK1/2 and ILK with subsequent decrease of MLC2 (Ser19) phosphorylation.

Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure.

Liver sinusoids are lined by liver sinusoidal endothelial cells (LSEC), which represent approximately 15 to 20% of the liver cells, but only 3% of the total liver volume. LSEC have unique functions, such as fluid filtration, blood vessel tone modulation, blood clotting, inflammatory cell recruitment, and metabolite and hormone trafficking. Different subtypes of liver endothelial cells are also known to control liver zonation and hepatocyte function. Here, we have reviewed the origin of LSEC, the different subtypes identified in the liver, as well as their renewal during homeostasis. The liver has the exceptional ability to regenerate from small remnants. The past decades have seen increasing awareness in the role of non-parenchymal cells in liver regeneration despite not being the most represented population. While a lot of knowledge has emerged, clarification is needed regarding the role of LSEC in sensing shear stress and on their participation in the inductive phase of regeneration by priming the hepatocytes and delivering mitogenic factors. It is also unclear if bone marrow-derived LSEC participate in the proliferative phase of liver regeneration. Similarly, data are scarce as to LSEC having a role in the termination phase of the regeneration process. Here, we review what is known about the interaction between LSEC and other liver cells during the different phases of liver regeneration. We next explain extended hepatectomy and small liver transplantation, which lead to “small for size syndrome” (SFSS), a lethal liver failure. SFSS is linked to endothelial denudation, necrosis, and lobular disturbance. Using the knowledge learned from partial hepatectomy studies on LSEC, we expose several techniques that are, or could be, used to avoid the “small for size syndrome” after extended hepatectomy or small liver transplantation.

Roles of MicroRNAs in Peripheral Artery In-Stent Restenosis after Endovascular Treatment.

Endovascular repair including percutaneous transluminal angioplasty (PTA) and stent implantation has become the standard approach for the treatment of peripheral arterial disease; however, restenosis is still the main limited complication for the long-term success of the endovascular repair. Endothelial denudation and regeneration, inflammatory response, and neointimal hyperplasia are major pathological processes occurring during in-stent restenosis (ISR). MicroRNAs exhibit great potential in regulating several vascular biological events in different cell types and have been identified as novel therapeutic targets as well as biomarkers for ISR prevention. This review summarized recent experimental and clinical studies on the role of miRNAs in ISR modification, with the aim of unraveling the underlying mechanism and potential therapeutic strategy of ISR.

B-AB04-03 RADIOFREQUENCY ENERGY APPLICATIONS TO TREAT INCOMPLETE LEFT ATRIAL APPENDAGE CLOSURE IN WATCHMAN PATIENTS WITH PERI- OR POST-PROCEDURAL EVIDENCE OF A SIGNIFICANT RESIDUAL LEAK

Incomplete left atrial appendage closure (LAA) due to significant residual leaks may be observed either acutely and/or chronically after Watchman implantation. Endothelial denudation by means of radiofrequency energy (RF) applications has been proven to prevent recanalization of intracranial aneurysms after coil embolization, thereby favoring complete sealing. In vitro and in vivo experiments have demonstrated that endothelial denudation promotes collagen deposition and tissue retraction. To evaluate the safety and efficacy of RF delivery targeting the atrial side of a significant residual leak in patients with acute and chronic evidence of incomplete percutaneous LAA occlusion. Forty-three patients (mean age: 75±7 yrs; CHA2DS2-VASc: 4.6±1.4; HAS-BLED: 4.0±1.1) with a significant residual LAA leak after Watchman implantation were enrolled. All had transesophageal echocardiographic (TEE) evidence of a leak ≥ 4mm after Watchman deployment and received multiple RFAs targeting the atrial side of the leak. Peri-Watchman ablation was performed under TEE/ICE guidance using a 3.5mm open irrigated-tip ablation catheter. Follow-up TEE was performed approximately 45 days after the procedure. Incomplete LAA occlusion was documented acutely after Watchman deployment in 19 (44.2%) patients, 4 (9.3%) of whom had a Watchman FLX implanted. In the remaining 24 (55.8%) patients, a significant residual leak was documented at the time of a routine follow-up TEE. The median leak size was 5mm (range: 4-7). On average, 18±7 RF applications per patient (mean max contact force: 16±3g, mean power: 44±2W, RF time: 5.1±2.5min) were performed targeting the atrial edge of the leak. Post-RF median leak size was 0 mm [0-2]. No peri-procedural complications were observed. Follow-up TEE revealed complete LAA sealing in 23 (53.5%) cases and a negligible residual leak (1-2mm) in 15 (34.9%). No device dislodgments or thromboses were documented. RF applications targeting the atrial edge of a significant peri-Watchman leak may promote LAA sealing via tissue remodeling, without increasing complications.

Lessons learned from experimental models of cerebrovascular aneurysms to improve endocardial device occlusion of the left atrial appendage.

In patients with atrial fibrillation, left atrial appendage (LAA) occlusion devices represent an alternative to anticoagulation but are associated with residual peridevice leaks (PDLs) and device-related thrombi (DRT). Similarly, cerebrovascular aneurysms can be treated with coil embolization, but pericoil leaks represent a significant limitation. In experimental models of cerebrovascular aneurysms, endothelial denudation achieved independently with (1) embolization with radioactive coils, (2) mechanical removal of the endothelium, or (3) radiofrequency ablation was dramatically effective in preventing or eliminating pericoil leaks.Anatomical, physiological, and blood flow similarities exist between the LAA and saccular aneurysms. Concepts developed in treating aneurysm leaks can be used to treat similar problems in the LAA. Learning from aneurysms, we conceived of a novel technique to denude local endothelium and thus eliminate residual leaks around LAA-occlusion devices. We recently successfully tested this hypothesis in patients with a PDL in a prospective manner in a multicenter study. In this article, we expand on the rationale of the technique developed to close PDLs and potentially also prevent DRTs.

Nitric-Oxide-Mediated Vasodilation of Bioactive Compounds Isolated from Hypericum revolutum in Rat Aorta.

Simple SummaryHypericum revolutum (HR) is reported to produce vasodilating activity in phenylephrine-precontracted aortae, where the chloroform fraction is the most potent. Chemical investigation of this fraction yielded two new compounds, revolutin (1) and hyperevolutin C (2), along with three known metabolites, β-sitosterol (3), euxanthone (4), and 2,3,4-tirmethoxy xanthone (5). Isolated compounds 1, 2, 3, and 5 produce vasodilation activities that are dependent on endothelial nitric oxide release.Vasodilators are an important class in the management of hypertension and related cardiovascular disorders. In this regard, the chloroform fraction of Hypericum revolutum (HR) has been reported to produce vasodilating activity in phenylephrine-precontracted aortae. The current work aims to identify the active metabolites in the chloroform fraction of HR and illustrate the possible mechanism of action. The vasodilation activities were investigated using the isolated artery technique. NO vascular release was assessed by utilizing the NO-sensitive fluorescent probe DAF-FM. Free radical scavenging capacity was assessed utilizing DPPH. Chemical investigation of this fraction yielded two new compounds, revolutin (1) and hyperevolutin C (2), along with three known metabolites, β-sitosterol (3), euxanthone (4), and 2,3,4-tirmethoxy xanthone (5). Compounds 1, 2, 3, and 5 showed significant vasodilation activities that were blocked by either endothelial denudation or L-NAME (nitric oxide synthase inhibitor), pointing towards a role of endothelial nitric oxide in their activities. In confirmation of this role, compounds 1–3 showed a significant release of NO from isolated vessels, as indicated by DAF-FM. On the other hand, only compound 5 showed free radical scavenging activities, as indicated by DPPH. In conclusion, isolated compounds 1, 2, 3, and 5 produce vasodilation activities that are dependent on endothelial nitric oxide release.

High fluid shear stress prevents atherosclerotic plaque formation by promoting endothelium denudation and synthetic phenotype of vascular smooth muscle cells.

Low blood fluid shear stress (SS) promotes vascular remodeling and atherosclerosis; however, the effects of high (H)SS on vascular remodeling and atherogenesis is not fully clarified. The major goal of this study was to investigate the role of HSS in atherosclerotic plaque formation. A perivascular SS modifier was implanted in the right carotid artery of apolipoprotein E (ApoE)−/− mice to induce HSS, whereas the left carotid artery represented undisturbed (U)SS as a control in vivo. In vitro modeling used human umbilical vein endothelial cells and vascular smooth muscle cells exposed to HSS (2.5 Pa) using a parallel-plate flow system. The results demonstrated that there were no plaque formations or endothelial cells in the HSS regions of the carotid artery in ApoE−/− mice. The number of umbilical vein endothelial cells was markedly decreased in a time-dependent manner in HSS. HSS significantly decreased α-smooth muscle actin and increased osteopontin protein expression levels compared with USS in vascular smooth muscle cells (P<0.05). In addition, HSS significantly increased the protein expression levels of collagen α1(XVIII) chain/endostatin and matrix metalloproteinase-8 in vascular smooth muscle cells. These data indicated that HSS may prevent atherosclerotic plaque formation through endothelium denudation and contractile-to-synthetic phenotypic conversion of smooth muscle cells.