Laser Doppler Flow Research Articles

Evaluation of pulpal blood flow during orthodontic space closure: Prospective clinical trial

Orthodontic tooth movement (OTM) is a biological process that can affect the vascularization of the dental pulp. The forces exerted on the teeth may increase periapical pressure that could compress the arterioles, which in turn affects pulpal blood flow (PBF). The study aimed to investigate how OTM affects PBF during orthodontic space closure. A total of 22 adolescent participants who required orthodontic space closure in mandibular posterior sectors were enrolled in a prospective clinical study. The same sliding mechanics, wires, and active elements were used. Patients were observed before OTM, after leveling before space closure, and at the 4th, 7th, 21st, and 28th during active space closure. PBF was measured with laser Doppler (LD) flowmetry. Dental models were obtained with an intraoral scanner. The LD flow values decreased significantly during the observation period (2-way repeated measures analysis of variance, P<0.001). There was a significant difference in LD flow between tooth categories (2-way repeated measures analysis of variance, P<0.001). During space closure, the most pronounced LD flow reduction was observed in single-rooted teeth closest to the residual space. A higher speed of OTM was associated with a greater decrease in LD flow on day 4 of OTM (Pearson correlation, P= 0.0299). Orthodontic space closure reduced PBF; it was lowest in the early stages of space closure and showed a tendency to increase during the first month. Anterior teeth closer to the interdental space that experiences more OTM and teeth that move faster during initial OTM had a higher risk of reduced blood flow.

New insight into the aortic microcirculation in coronary disease - intraoperative laser Doppler flow measurement and vasa vasorum imaging.

New insight into the aortic microcirculation in coronary disease - intraoperative laser Doppler flow measurement and vasa vasorum imaging.

Dental Pulp Vascular Response to Early Stages of Caries

ObjectivesDuring caries progression, dental pulp is increasingly pathologically affected. Since the accurate assessment of pulp is of vital importance in clinical decision-making, this study aimed to evaluate pulpal condition in the early stages of caries via laser Doppler (LD) flowmetry and histologic analysis and determine their agreement. MethodsFourteen patients with severe dental crowding were included. Prior to extractions and orthodontic treatment, dental pulp condition of 52 premolars was evaluated via LD flowmetry. Teeth were assessed for the presence of caries and lesions were graded according to the International Caries Detection and Assessment System (ICDAS). After extractions, teeth were split and histologically stained for endothelial cells with anti–von Willebrand factor and Movat pentachrome for collagen. Volume densities of vessels (Vvasc) and collagen were calculated. ResultsThere was a significant negative correlation between LD flow and Vvasc of the dental pulp with ICDAS grade. Pulpal LD flow and Vvasc in teeth with the initial lesion were increased, decreasing with progressing stages of caries. A significant positive correlation between the the pulpal LD flow and Vvasc, and a negative correlation of LD flow with collagen fibre density were noted. ConclusionsCaries affects the physiology of the dental pulp, initially with increasing vascularity, and decreasing vascularity at later stges of caries progression. Collagen contents increase with grades of ICDAS. LD flow shows good agreement with the histologic constitution of the dental pulp. Use of clinical measurements of pulpal LD flow could provide a good noninvasive indication of pulpal vascular state and its health.

An Experimental Phototherapy Device for Studying the Effects of Blue Light on Patients with Raynaud's Phenomenon.

Raynaud's phenomenon (RP) is a condition that causes decreased blood flow to areas perfused by small blood vessels (e.g., fingers, toes). In severe cases, ulceration, gangrene, and loss of fingers may occur. Most treatments focus on inducing vasorelaxation in affected areas by the way of pharmaceuticals. Recently, animal studies have shown that vasorelaxation can be induced by non-coherent blue light (wavelength ~ 430-460nm) through the actions of melanopsin, a photoreceptive opsin protein encoded by the OPN4 gene. To study this effect in humans, a reliable phototherapy device (PTD) is needed. We outline the construction of a PTD to be used in studying blue light effects on Raynaud's patients. Our design addresses user safety, calibration, electromagnetic compatibility/interference (EMC/EMI), and techniques for measuring physiological responses (temperature sensors, laser Doppler flow sensors, infrared thermal imaging of the hands). We tested our device to ensure (1) safe operating conditions, (2) predictable, user-controlled irradiance output levels, (3) an ability for measuring physiological responses, and (4) features necessary to enable a double-blinded crossover study for a clinical trial. We also include in the Methods an approved research protocol utilizing our device that may serve as a starting point for clinical study. We introduced a reliable PTD for studying the effects of blue light therapy for patients suffering from Raynaud's phenomenon and showed that our device is safe and reliable and includes the required measurement vectors for tracking treatment effects throughout the duration of a clinical study.

L-Borneol promotes skin flap survival by regulating HIF-1α/NF-κB pathway

Ethnopharmacological relevanceThe clinical application of skin flaps in surgical reconstruction is frequently impeded by the occurrence of distant necrosis. L-Borneol exhibits myogenic properties in traditional Chinese medicine and is used in clinical settings to promote wound healing and conditions such as stroke. Nevertheless, the precise mechanism by which borneol exerts its protective effects on skin flap survival remains unclear. Aim of the studyTo explore the potential of L-borneol to promote skin flap survival and elucidate the underlying mechanisms. Materials and methodsThirty-six male Sprague–Dawley rats were randomly divided into three groups: a high-dose (200 mg/kg L-borneol per day), a low-dose (50 mg/kg/day), and control group (same volume of solvent). In each rat, a modified rectangular McFarlane flap model measuring 3 × 9 cm was constructed. Daily intragastric administration of L-borneol or solvent was performed. The flap was divided into three square sections of equal size, namely Zone I (the proximal zone), Zone II (the intermediate zone), and Zone III (the distal zone). The survival rate was quantified, and the histological state of each flap was evaluated on the seventh day following the surgical procedure. The assessment of angiogenesis was conducted using lead oxide/gelatin angiography, whereas the evaluation of blood flow in the free flap was performed using laser Doppler flow imaging. Superoxide dismutase activity was detected using the water-soluble tetrazolium salt-8 method. The quantities of vascular endothelial growth factor, interleukin (IL)-1β, IL-6, and tumour necrosis factor-α were determined using immunohistochemistry. The levels of nuclear transcription factor-κB, hypoxia-inducible factor-1, B-cell lymphoma-2 (BCL-2), and BCL-2-associated X (BAX) were determined by Western blotting technique. ResultsFlap survival rate significantly improved and neutrophil recruitment and release were enhanced after treatment with the compound. Angiogenesis was promoted. L-borneol protected against oxidative stress by increasing superoxide dismutase activity and decreasing malondialdehyde content. It downregulated the hypoxia-inducible factor nuclear transcription factor-κB pathway, leading to the inhibition of several inflammatory factors. Simultaneously, it facilitated the expression of vascular endothelial growth factor and BCL-2. ConclusionThe study shows that L-borneol may promote skin flap survival by inhibiting HIF-1α/NF-κB pathway.

Pulp Diagnosis: Current guidelines, shortcomings, and future developments

Statement of the problem: Accurate diagnosis of the inflammatory condition of the dental pulp is at the core of endodontics and is essential in selecting the most appropriate treatment option. Available pulpal sensibility tests are useful adjuncts in the formulation of a pulpal diagnosis. However, these tests are associated with a degree of uncertainty and have known limitations. Purpose of the review: The aim of this review manuscript is to analyse current diagnostic systems, discuss their use and limitations as well as highlight future areas of development. Methods: A search strategy was conducted in the MEDLINE Ovid and Embasse databases and the Cochrane Library. No time limit was applied. The search results were limited to those in the English language. Discussion: Sensibility tests, including thermal and electrical stimuli, measure the condition of the neurovascular supply of the tooth, thus providing only a proxy measure of the health of the pulp. In comparison, vitality tests, including pulse oximetry and laser Doppler flow provide a more objective and quantitative measure of the condition of the pulp. However, these latter tools are not accessible clinically. Sensibility testing remains our current gold standard of providing information relating to the health of the pulp and combined with history, examination, and radiographic tests, allows the formulation of a diagnosis to guide treatment. Future trends promise more objective measures of the state of the dental pulp, but further, evidence-based research and non-cost-limiting equipment need to be produced. Conclusions: There is currently no pulpal diagnostic test that is ideal. Despite the limitations outlined, these tools remain essential in the endo diagnostic arsenal. Understanding the accuracy and limitations of current gold standard pulp tests will aid practitioners in accurately diagnosing the degree of pulpitis, thereby facilitating the selection of the most appropriate and effective treatment for dental pulp.

Adjunctive technologies in postoperative free-flap monitoring: a systematic review

Patent microvascular anastomoses are essential for successful free tissue transfer. Early accurate detection of microvascular compromise is required for flap salvage. Adjunctive monitoring techniques, in addition to clinical examination, are increasingly used to detect flap compromise. This systematic review synthesized and appraised the literature to determine the efficacy of different postoperative monitoring technologies. Rates of flap takeback, salvage, failure, and mean time to detection of microvascular compromise were extracted, synthesized, and reviewed. Twenty-two studies were included, comprising 6370 flaps. One thousand three hundred and ninety-five flaps were monitored with Cook Swartz Doppler (21.83%), 1417 flaps with tissue oximetry (22.24%), 291 with laser Doppler (4.56%), 175 with duplex echography (2.74%), 210 with indocyanine green (ICG) fluorescence (3.30%), 196 with Synovis flow coupler (3.07%), and 81 (1.27%) with light spectroscopy. The overall true positive rate for microvascular compromise in taken back flaps was 70.18%. Cook Swartz Doppler (n=1391) had a true positive rate of 80.17% and 83.63% salvage rate and was associated with an overall 2.60% rate of flap failure. Tissue oximetry (n=1417) had a true positive rate of 74.76% and a salvage rate of 88.62%. Laser Doppler, duplex echography, light spectroscopy, and Synovis flow coupler demonstrated true positive rates between 69.4% and 100% with salvage rates between 64% and 100%. Cook Swartz Doppler and tissue oximetry are associated with prompt identification of microvascular compromise and return to theatre. Alternative modalities, including near-infrared spectroscopy, laser Doppler, and duplex echography, show promise. Further well-designed randomised controlled trials (RCTs) appraising head-to-head efficacy are required to comparatively assess adjunctive technologies.

Effect of first epinephrine administration time on cerebral perfusion pressure and cortical cerebral blood flow in a porcine cardiac arrest model

ObjectiveThe optimal time for epinephrine administration and its effects on cerebral blood flow (CBF) and microcirculation remain controversial. This study aimed to assess the effect of the first administration of epinephrine on cerebral perfusion pressure (CePP) and cortical CBF in porcine cardiac arrest model. MethodsAfter 4 min of untreated ventricular fibrillation, eight of 24 swine were randomly assigned to the early, intermediate, and late groups. In each group, epinephrine was administered intravenously at 5, 10, and 15 min after cardiac arrest induction. CePP was calculated as the difference between the mean arterial pressure and intracranial pressure. Cortical CBF was measured using a laser Doppler flow probe. The outcomes were CePP and cortical CBF measured continuously during cardiopulmonary resuscitation (CPR). Mean CePP and cortical CBF were compared using analysis of variance and a linear mixed model. ResultsThe mean CePP was significantly different between the groups at 6–11 min after cardiac arrest induction. The mean CePP in the early group was significantly higher than that in the intermediate group at 8–10 min and that in the late group at 6–9 min and 10–11 min. The mean cortical CBF was significantly different between the groups at 9–11 min. The mean cortical CBF was significantly higher in the early group than in the intermediate and late group at 9–10 min. ConclusionEarly administration of epinephrine was associated with improved CePP and cortical CBF compared to intermediate or late administration during the early period of CPR.

Activation of aldehyde dehydrogenase-2 improves ischemic random skin flap survival in rats.

Random skin flaps have many applications in plastic and reconstructive surgeries. However, distal flap necrosis restricts wider clinical utility. Mitophagy, a vital form of autophagy for damaged mitochondria, is excessively activated in flap ischemia/reperfusion (I/R) injury, thus inducing cell death. Aldehyde dehydrogenase-2 (ALDH2), an allosteric tetrameric enzyme, plays an important role in regulating mitophagy. We explored whether ALDH2 activated by N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1) could reduce the risk of ischemic random skin flap necrosis, and the possible mechanism of action. Modified McFarlane flap models were established in 36 male Sprague-Dawley rats assigned randomly to three groups: a low-dose Alda-1 group (10 mg/kg/day), a high-dose Alda-1 group (20 mg/kg/day) and a control group. The percentage surviving skin flap area, neutrophil density and microvessel density (MVD) were evaluated on day 7. Oxidative stress was quantitated by measuring the superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Blood perfusion and skin flap angiogenesis were assessed via laser Doppler flow imaging and lead oxide-gelatin angiography, respectively. The expression levels of inflammatory cytokines (IL-1β, IL-6, and TNF-α), vascular endothelial growth factor (VEGF), ALDH2, PTEN-induced kinase 1 (PINK1), and E3 ubiquitin ligase (Parkin) were immunohistochemically detected. Indicators of mitophagy such as Beclin-1, p62, and microtubule-associated protein light chain 3 (LC3) were evaluated by immunofluorescence. Alda-1 significantly enhanced the survival area of random skin flaps. The SOD activity increased and the MDA level decreased, suggesting that Alda-1 reduced oxidative stress. ALDH2 was upregulated, and mitophagy-related proteins (PINK1, Parkin, Beclin-1, p62, and LC3) were downregulated, indicating that ALDH2 inhibited mitophagy through the PINK1/Parkin signaling pathway. Treatment with Alda-1 reduced neutrophil infiltration and expressions of inflammatory cytokines. Alda-1 significantly upregulated VEGF expression, increased the MVD, promoted angiogenesis, and enhanced blood perfusion. ALDH2 activation can effectively enhance random skin flap viability via inhibiting PINK1/Parkin-dependent mitophagy. Moreover, enhancement of ALDH2 activity also exerts anti-inflammatory and angiogenic properties.

Roxadustat promotes hypoxia-inducible factor-1α/vascular endothelial growth factor signalling to enhance random skin flap survival in rats.

Random skin flaps have limited clinical application as a broad surgical reconstruction treatment because of distal necrosis. The prolyl hydroxylase domain-containing protein inhibitor roxadustat (RXD) enhances angiogenesis and reduces oxidative stress and inflammation. This study explored the function of RXD in the survival of random skin flaps. Thirty-six male Sprague-Dawley rats were randomly divided into low-dose RXD group (L-RXD group, 10 mg/kg/2 day), high-dose RXD group (H-RXD group, 25 mg/kg/2 day), and control group (1 mL of solvent, 1:9 DMSO:corn oil). The proportion of surviving flaps was determined on day 7 after surgery. Angiogenesis was assessed by lead oxide/gelatin angiography, and microcirculation blood perfusion was evaluated by laser Doppler flow imaging. Specimens in zone II were obtained, and the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured as indicators of oxidative stress. Histopathological status was evaluated with haematoxylin and eosin staining. The levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and the inflammatory factors interleukin (IL)-1β, IL-6, and tumour necrosis factor-α (TNF-α) were detected by immunohistochemistry. RXD promoted flap survival and microcirculatory blood perfusion. Angiogenesis was detected distinctly in the experimental group. SOD activity increased and the MDA level decreased in the experimental group. Immunohistochemistry indicated that the expression levels of HIF-1α and VEGF were increased while the levels of IL-6, IL-1β, and TNF-α were decreased after RXD injection. RXD promoted random flap survival by reinforcing vascular hyperplasia and decreasing inflammation and ischaemia-reperfusion injury.

Abstract 424: Arachidonic Acid Synergizes With Aspirin In Cardioprotection Following Acute Myocardial Infarction

Introduction: Membrane-released arachidonic acid (AA) is metabolized via cyclooxygenase pathway to form prostanoids, including thromboxane, prostacyclin and prostaglandin E2. Aspirin suppresses platelet synthesis of thromboxane, rendering its first-line use for anti-thrombosis in patients with acute myocardial ischemia. We report that endogenous PGE2 protects against myocardial ischemia-reperfusion (MI/R) injury (Nat Commun. 2019;10(1):1888). The impact of AA administration while suppressing thromboxane on MI/R injury is unknown. Methods and Results: C57BL/6J mice were treated intravenously with vehicle, AA, aspirin, or their combination and then subjected to 30min coronary artery ligation and 24hr reperfusion. Cardiac function was assessed by ultrasonography and infraction size quantified by TTC staining. Cardiac microcirculation was assessed by laser doppler flow and vasomotor reactivity determined with isolated coronary arteries. Single treatment with AA at an optimized dose of 0.1mg/Kg, or combined with aspirin at a dose of 10mg/Kg that allowed sufficient suppressing of platelet activation over 24hr, decreased infarct size and improved heart function. Impressively, combination of AA with aspirin provided additional cardioprotection compared with either single treatment. While aspirin, not AA, ameliorated microvascular obstruction following MI/R injury, co-administration of AA and aspirin further increased coronary microcirculatory blood perfusion with improved vascular permeability compared with aspirin alone. MI/R impaired endothelium-dependent dilatation of coronary arteries, and the dual treatment, not AA or ASA alone, increased coronary artery relaxation. Cardiac infiltrated neutrophils and platelet-neutrophil aggregates were also reduced by the combination treatment, consistent with a suppressed leukocyte-ECs adhesion as assessed in vitro. Conclusions: AA and aspirin synergistically protect against MI/R injury and this is attributable to suppressed neutrophil inflammation and improved microvascular obstruction. AA might be used as an adjunct therapy to aspirin in patients with acute myocardial infarction.

The Iatrogenic Injury Potential of Self-adherent, Elastic Bandages in Finger Injuries.

The use of a self-adherent, elastic bandage is a practical way to dress finger injuries. Multiple reports describe iatrogenic injuries from elastic bandages, ranging from skin necrosis to finger gangrene, necessitating amputations. This study investigated whether elastic bandages can compromise digital perfusion by occluding arterial blood flow in healthy volunteers and evaluated the utility of pulse oximetry as a monitoring tool for digital perfusion. A technique for safe bandage application is proposed. A commercially available elastic bandage was wrapped around the index finger of 20 healthy volunteers at varying degrees of stretch. Digital perfusion measurements were carried out using photoelectric pulse transduction, laser Doppler flowmetry, and pulse oximetry. Intracompartmental pressure measurements were recorded using a separate in vitro experimental model. Elastic bandages applied at maximum stretch did not change digital brachial index or pulse oximetry values, suggesting arterial blood flow was preserved distal to the bandage. Intracompartmental pressure measurements at maximum stretch remained below the systolic digital pressure. In contrast, superficial dermal perfusion fell to 32% of normal as measured by laser Doppler flow, at 100% bandage stretch. This study suggests a risk for iatrogenic injury when using elastic bandages for finger dressings. While arterial inflow was never compromised, pressures were high enough to occlude superficial venous outflow, which may begin at 20% bandage stretch. Pulse oximetry failed to detect changes distal to applied dressings, and we do not recommend it to detect digital vascular compromise in this setting.

Neutrophil extracellular traps as a unique target in the treatment of chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of chemotherapy and remains a huge clinical challenge. Here, we explore the role of microcirculation hypoxia induced by neutrophil extracellular traps (NETs) in the development of CIPN and look for potential treatment. The expression of NETs in plasma and dorsal root ganglion (DRG) are examined by ELISA, IHC, IF and Western blotting. IVIS Spectrum imaging and Laser Doppler Flow Metry are applied to explore the microcirculation hypoxia induced by NETs in the development of CIPN. Stroke Homing peptide (SHp)-guided deoxyribonuclease 1 (DNase1) is used to degrade NETs. The level of NETs in patients received chemotherapy increases significantly. And NETs accumulate in the DRG and limbs in CIPN mice. It leads to disturbed microcirculation and ischemic status in limbs and sciatic nerves treated with oxaliplatin (L-OHP). Furthermore, targeting NETs with DNase1 significantly reduces the chemotherapy-induced mechanical hyperalgesia. The pharmacological or genetic inhibition on myeloperoxidase (MPO) or peptidyl arginine deiminase-4 (PAD4) dramatically improves microcirculation disturbance caused by L-OHP and prevents the development of CIPN in mice. In addition to uncovering the role of NETs as a key element in the development of CIPN, our finding provides a potential therapeutic strategy that targeted degradation of NETs by SHp-guided DNase1 could be an effective treatment for CIPN. This study was funded by the National Natural Science Foundation of China81870870, 81971047, 81773798, 82271252; Natural Science Foundation of Jiangsu ProvinceBK20191253; Major Project of "Science and Technology Innovation Fund" of Nanjing Medical University2017NJMUCX004; Key R&D Program (Social Development) Project of Jiangsu ProvinceBE2019732; Nanjing Special Fund for Health Science and Technology DevelopmentYKK19170.

Coupled fluid-structure simulations and experiments of DBD plasma actuator for damping of plate vibrations

In the present work, an experimental and numerical study has been performed to evaluate the suitability of the dielectric barrier discharge plasma actuators to reduce free vibrations of plates. Two configurations composed of two different plexiglass plates and identical actuators were manufactured. Experimental campaigns, in terms of laser doppler anemometer velocity measurements, flow visualization and proper orthogonal decomposition were carried out to characterize the plasma actuator and to validate the numerical models. The plasma-induced virtual body force for the numerical analysis has been calibrated based on the experimental body force and the induced flow field. Then numerical studies of the plasma effect on the flow around an oscillating plate was performed. An experimental modal analysis has been also performed to understand the vibration characteristics of the plate and to support the numerical study. A reduced-order model of the system, based on the harmonic oscillator, was developed to properly design an open loop controller (system natural frequency, amplitude and timing of the attenuation force). Eventually, the work demonstrates that the control strategy based on the plasma actuation is effective in reducing the plate vibrations. However, a deeper study and a more sophisticated control strategy would be required to significantly mitigate the flutter oscillations of airfoils in real applications.

Embracing Heterogeneity in The Multicenter Stroke Preclinical Assessment Network (SPAN) Trial.

The Stroke Preclinical Assessment Network (SPAN) is a multicenter preclinical trial platform using rodent models of transient focal cerebral ischemia to address translational failure in experimental stroke. In addition to centralized randomization and blinding and large samples, SPAN aimed to introduce heterogeneity to simulate the heterogeneity embodied in clinical trials for robust conclusions. Here, we report the heterogeneity introduced by allowing the 6 SPAN laboratories to vary most of the biological and experimental model variables and the impact of this heterogeneity on middle cerebral artery occlusion (MCAo) performance. We included the modified intention-to-treat population of the control mouse cohort of the first SPAN trial (n=421) and examined the biological and procedural independent variables and their covariance. We then determined their impact on the dependent variables cerebral blood flow drop during MCAo, time to achieve MCAo, and total anesthesia duration using multivariable analyses. We found heterogeneity in biological and procedural independent variables introduced mainly by the site. Consequently, all dependent variables also showed heterogeneity among the sites. Multivariable analyses with the site as a random effect variable revealed filament choice as an independent predictor of cerebral blood flow drop after MCAo. Comorbidity, sex, use of laser Doppler flow to monitor cerebral blood flow, days after trial onset, and maintaining anesthesia throughout the MCAo emerged as independent predictors of time to MCAo. Total anesthesia duration was predicted by most independent variables. We present with high granularity the heterogeneity introduced by the biological and model selections by the testing sites in the first trial of cerebroprotection in rodent transient filament MCAo by SPAN. Rather than trying to homogenize all variables across all sites, we embraced the heterogeneity to better approximate clinical trials. Awareness of the heterogeneity, its sources, and how it impacts the study performance may further improve the study design and statistical modeling for future multicenter preclinical trials.

Glucagon-like peptide-2 protects the gastric mucosa via regulating blood flow and metabolites.

Refractory peptic ulcers lead to perforation and hemorrhage, which are fatal. However, these remain a therapeutic challenge. Gastric mucosal blood flow is crucial in maintaining gastric mucosal health. It's reported that Glucagon-like peptide-2 (GLP-2), a gastrointestinal hormone, stimulated intestinal blood flow. However, the direct role of GLP-2 in gastric mucosal blood flow and metabolites remain unclear. Here, we speculated that GLP-2 might protect the gastric mucosa by increasing gastric mucosal blood flow and regulating metabolites. This study was conducted to evaluate the role of GLP-2 in gastric mucosal lesions and its underlying mechanism. We analyzed endogenous GLP-2 during gastric mucosal injury in the serum. Rats were randomly divided into two groups, with 36 rats in each group as follows: (1) normal control group (NC1); (2) ethanol model group (EC1); rats in EC1 and NC1 groups were intragastrically administered ethanol (1 ml/200 g body weight) and distilled water (1 ml/200 g body weight). The serum was collected 10 min before intragastric administration and 15, 30, 60, 90, and 120 min after intragastric administration. Furthermore, additional male Sprague-Dawley rats were randomly divided into three groups, with six rats in each group as follows: (1) normal control group (NC); (2) ethanol model group (EC); (3) 10 μg/200 g body weight GLP-2 group (GLP-2). Rats in the NC and EC groups were intraperitoneally injected with saline. Those in the GLP-2 group were intraperitoneally injected with GLP-2. Thirty minutes later, rats in the EC and GLP-2 groups were intragastrically administered ethanol (1 ml/200 g body weight), and rats in the NC group were intragastrically administered distilled water (1 ml/200 g body weight). After the intragastric administration of ethanol for 1 h, the animals were anesthetized and gastric mucosal blood flow was measured. Serum were collected for ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) metabolomics. There were no significant change in endogenous GLP-2 during gastric mucosal injury (P<0.05). Pretreatment with GLP-2 significantly reduced ethanol-induced gastric mucosal lesions by improving the gastric mucosal blood flow, as examined using a laser Doppler flow meter, Guth Scale, hematoxylin-eosin staining, and two-photon microscopy. UPLC-MS/MS analyses showed that GLP-2 also maintained a steady state of linoleic acid metabolism. Taken together, GLP-2 protects the gastric mucosa against ethanol-induced lesions by improving gastric mucosa blood flow and affecting linoleic acid metabolism.

Laser Doppler flow for the hemodynamic differentiation of tachycardia.

Implantable cardioverter defibrillators (ICDs) offer effective therapy for the prevention of sudden cardiac death (SCD) due to ventricular arrhythmias. However, inappropriate shocks have detrimental effects on survival and quality of life. The addition of hemodynamic monitoring may be useful in discriminating clinically important ventricular arrhythmias. In this study, we assess the ability of laser Doppler flowmetry to assess the hemodynamic effect of paced atrial and ventricular arrhythmias using mean arterial blood pressure as the reference. In this acute human study in patients undergoing an elective electrophysiological study, laser Doppler flowmetry, arterial blood pressure, and surface ECG were acquired during high-rate atrial and ventricular pacing to simulate supraventricular and ventricular tachycardias. Arterial blood pressure and laser Doppler flow signals correlated well during atrial and ventricular pacing (rho = 0.694, p<.001). The hemodynamic impairment detected by both methods was greater during ventricular pacing than atrial pacing (-1.0% vs. 19.0%, p<.001). Laser Doppler flowmetry performed better than rate alone to identify hemodynamic impairments. In this acute study, laser Doppler flowmetry tissue perfusion served as a good surrogate measure for arterial pressure, which could be incorporated into future ICDs.

Prediction Model for Contractile Function of Circulatory Death Donor Hearts Based on Microvascular Flow Shifts During Ex Situ Hypothermic Cardioplegic Machine Perfusion.

Background Hearts procured from circulatory death donors (DCD) are predominantly maintained by machine perfusion (MP) with normothermic donor blood. Currently, DCD heart function is evaluated by lactate and visual inspection. We have shown that MP with the cardioplegic, crystalloid Custodiol-N solution is superior to blood perfusion to maintain porcine DCD hearts. However, no method has been developed yet to predict the contractility of DCD hearts after cardioplegic MP. We hypothesize that the shift of microvascular flow during continuous MP with a cardioplegic preservation solution predicts the contractility of DCD hearts. Methods and Results In a pig model, DCD hearts were harvested and maintained by MP with hypothermic, oxygenated Custodiol-N for 4 hours while myocardial microvascular flow was measured by Laser Doppler Flow (LDF) technology. Subsequently, hearts were perfused with blood for 2 hours, and left ventricular contractility was measured after 30 and 120 minutes. Various novel parameters which represent the LDF shift were computed. We used 2 combined LDF shift parameters to identify bivariate prediction models. Using the new prediction models based on LDF shifts, highest r2 for end-systolic pressure was 0.77 (P=0.027), for maximal slope of pressure increment was 0.73 (P=0.037), and for maximal slope of pressure decrement was 0.75 (P=0.032) after 30 minutes of reperfusion. After 120 minutes of reperfusion, highest r2 for end-systolic pressure was 0.81 (P=0.016), for maximal slope of pressure increment was 0.90 (P=0.004), and for maximal slope of pressure decrement was 0.58 (P=0.115). Identical prediction models were identified for maximal slope of pressure increment and for maximal slope of pressure decrement at both time points. Lactate remained constant and therefore was unsuitable for prediction. Conclusions Contractility of DCD hearts after continuous MP with a cardioplegic preservation solution can be predicted by the shift of LDF during MP.

Characterization of the mesenteric circulatory physiology during hemorrhagic shock in a swine model

This study aimed to characterize blood flow through the mesenteric circulation during hemorrhage and resuscitation in a large animal model. Five male swine (50-70 kg) underwent anesthesia and placement of flow probes and pressure catheters around and within the superior mesenteric artery, portal vein, and inferior vena cava. A laser doppler flow probe was placed on the intestine to measure end-organ perfusion. Animals were then exsanguinated to a systolic blood pressure of <50mmHg with 60-minutes of shock followed by resuscitation for 120-minutes. Animals were placed into hemorrhagic shock (lactate peak 5.9 ± 2.1 mmol/L vs baseline: 3.4 ± 0.7 mmol/L) with lower pressures and flows during shock and restoration to baseline following resuscitation: SMA (70 vs 36 vs 75 mmHg, p<0.001; 856 vs 371 vs 762 mL/min, p<0.001), portal vein (9 vs 8 vs 10mmHg, p<0.001; 200 vs 52 vs 141 mL/min, p<0.001), IVC (12 vs 7 vs 10 mmHg, p<0.001; 209 vs 27 vs 163 mL/min, p<0.001), and mean arterial pressure (MAP) (67 vs 36 vs 69 mmHg, p<0.001). LDF fell during hemorrhage (1.38 vs 0.38 blood perfusion units (BPU), p<0.001) and did not return to baseline during resuscitation (0.70 BPU, p<0.001). The intestine achieved only 51% of baseline LDF perfusion after resuscitation despite return of mesenteric hemodynamics. Despite macrovascular physiologic restoration after hemorrhagic shock, end organ perfusion did not adequately recover following resuscitation to baseline MAP. Continuous physiologic insult to the mesentery is likely ongoing after systemic hemodynamic restoration.

Targeting PDE4B (Phosphodiesterase-4 Subtype B) for Cardioprotection in Acute Myocardial Infarction via Neutrophils and Microcirculation.

Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury. Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries. Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow-derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide-dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside. PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.