Translational Research of the Acute Effects of Negative Emotions on Vascular Endothelial Health: Findings From a Randomized Controlled Study.

BACKGROUND: Provoked anger is associated with an increased risk of cardiovascular disease events. The underlying mechanism linking provoked anger as well as other core negative emotions including anxiety and sadness to cardiovascular disease remain unknown. The study objective was to examine the acute effects of provoked anger, and secondarily, anxiety and sadness on endothelial cell health. METHODS AND RESULTS: Apparently healthy adult participants (n=280) were randomized to an 8-minute anger recall task, a depressed mood recall task, an anxiety recall task, or an emotionally neutral condition. Pre-/post-assessments of endothelial health including endothelium-dependent vasodilation (reactive hyperemia index), circulating endothelial cell-derived microparticles (CD62E+, CD31+/CD42-, and CD31+/Annexin V+) and circulating bone marrow-derived endothelial progenitor cells (CD34+/CD133+/kinase insert domain receptor+ endothelial progenitor cells and CD34+/kinase insert domain receptor+ endothelial progenitor cells) were measured. There was a group×time interaction for the anger versus neutral condition on the change in reactive hyperemia index score from baseline to 40 minutes (P=0.007) with a mean±SD change in reactive hyperemia index score of 0.20±0.67 and 0.50±0.60 in the anger and neutral conditions, respectively. For the change in reactive hyperemia index score, the anxiety versus neutral condition group by time interaction approached but did not reach statistical significance (P=0.054), and the sadness versus neutral condition group by time interaction was not statistically significant (P=0.160). There were no consistent statistically significant group×time interactions for the anger, anxiety, and sadness versus neutral condition on endothelial cell-derived microparticles and endothelial progenitor cells from baseline to 40 minutes. CONCLUSIONS: In this randomized controlled experimental study, a brief provocation of anger adversely affected endothelial cell health by impairing endothelium-dependent vasodilation.

Non-Invasive Monitoring of Microvascular Oxygenation and Reactive Hyperemia using Hybrid, Near-Infrared Diffuse Optical Spectroscopy for Critical Care.

The detection of levels of impairment in microvascular oxygen consumption and reactive hyperemia is vital in critical care. However, there are no practical means for a robust and quantitative evaluation. This paper describes a protocol to evaluate these impairments using a hybrid near-infrared diffuse optical device. The device contains modules for near-infrared time-resolved and diffuse correlation spectroscopies and pulse-oximetry. These modules allow the non-invasive, continuous, and real-time measurement of the absolute, microvascular blood/tissue oxygen saturation (StO2) and the blood flow index (BFI) along with the peripheral arterial oxygen saturation (SpO2). This device uses an integrated, computer-controlled tourniquet system to execute a standardized protocol with optical data acquisition from the brachioradialis muscle. The standardized vascular occlusion test (VOT) takes care of the variations in the occlusion duration and pressure reported in the literature, while the automation minimizes inter-operator differences. The protocol we describe focuses on a 3-min occlusion period but the details described in this paper can readily be adapted to other durations and cuff pressures, as well as other muscles. The inclusion of an extended baseline and post-occlusion recovery period measurement allows the quantification of the baseline values for all the parameters and the blood/tissue deoxygenation rate that corresponds to the metabolic rate of oxygen consumption. Once the cuff is released, we characterize the tissue reoxygenation rate, magnitude, and duration of the hyperemic response in BFI and StO2. These latter parameters correspond to the quantification of the reactive hyperemia, which provides information about the endothelial function. Furthermore, the above-mentioned measurements of the absolute concentration of oxygenated and deoxygenated hemoglobin, BFI, the derived metabolic rate of oxygen consumption, StO2, and SpO2 provide a yet-to-be-explored rich data set that can exhibit disease severity, personalized therapeutics, and management interventions.

Associations of between- and within-day patterns of physical activity accumulation with arterial stiffness and indices of microvascular health-Evidence from The Maastricht study.

While physical activity (PA) is understood to promote vascular health, little is known about whether the daily and weekly patterns of PA accumulation associate with vascular health. Accelerometer-derived (activPAL3) 6- or 7-day stepping was analyzed for 6430 participants in The Maastricht Study (50.4% women; 22.4% Type 2 diabetes mellitus (T2DM)). Multivariable regression models examined associations between stepping metrics (average step count, and time spent slower and faster paced stepping) with arterial stiffness (measured as carotid-femoral pulse wave velocity (cfPWV)), and several indices of microvascular health (heat-induced skin hyperemia, retinal vessel reactivity and diameter), adjusting for confounders and moderators. PA pattern metrics were added to the regression models to identify associations with vascular health beyond that of stepping metrics. Analyses were stratified by T2DM status if an interaction effect was present. Average step count and time spent faster paced stepping was associated with better vascular health, and the association was stronger in those with compared to those without T2DM. In fully adjusted models a higher step count inter-daily stability was associated with a higher (worse) cfPWV in those without T2DM (std ß = 0.04, p = 0.007) and retinal venular diameter in the whole cohort (std ß = 0.07, p = 0.002). A higher within-day variability in faster paced stepping was associated with a lower (worse) heat-induced skin hyperemia in those with T2DM (std ß = -0.31, p = 0.008). Above and beyond PA volume, the daily and weekly patterns in which PA was accumulated were additionally associated with improved macro- and microvascular health, which may have implications for the prevention of vascular disease.

Differential Effect of Aortic Valve Replacement for Severe Aortic Stenosis on Hyperemic and Resting Epicardial Coronary Pressure Indices.

BACKGROUND: Coronary pressure indices to assess coronary artery disease are currently underused in patients with aortic stenosis due to many potential physiological effects that might hinder their interpretation. Studies with varying sample sizes have provided us with conflicting results on the effect of transcatheter aortic valve replacement (TAVR) on these indices. The aim of this meta-analysis was to study immediate and long-term effects of TAVR on fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs). METHODS AND RESULTS: Lesion-specific coronary pressure data were extracted from 6 studies, resulting in 147 lesions for immediate change in FFR analysis and 105 for NHPR analysis. To investigate the long-term changes, 93 lesions for FFR analysis and 68 for NHPR analysis were found. Lesion data were pooled and compared with paired t tests. Immediately after TAVR, FFR decreased significantly (-0.0130±0.0406 SD, P: 0.0002) while NHPR remained stable (0.0003±0.0675, P: 0.9675). Long-term after TAVR, FFR decreased significantly (-0.0230±0.0747, P: 0.0038) while NHPR increased nonsignificantly (0.0166±0.0699, P: 0.0543). When only borderline NHPR lesions were considered, this increase became significant (0.0249±0.0441, P: 0.0015). Sensitivity analysis confirmed our results in borderline lesions. CONCLUSIONS: TAVR resulted in small significant, but opposite, changes in FFR and NHPR. Using the standard cut-offs in patients with severe aortic stenosis, FFR might underestimate the physiological significance of a coronary lesion while NHPRs might overestimate its significance. The described changes only play a clinically relevant role in borderline lesions. Therefore, even in patients with aortic stenosis, an overtly positive or negative physiological assessment can be trusted.

Clinical outcomes of perforator-based propeller flaps versus free flaps in soft tissue reconstruction for lower leg and foot trauma: a retrospective single-centre comparative study.

BACKGROUND: The efficacy and safety of perforator-based propeller flaps (PPF) versus free flaps (FF) in traumatic lower leg and foot reconstructions are debated. PPFs are perceived as simpler due to advantages like avoiding microsurgery, but concerns about complications, such as flap congestion and necrosis, persist. This study aimed to compare outcomes of PPF and FF in trauma-related distal lower extremity soft tissue reconstruction. METHODS: We retrospectively studied 38 flaps in 33 patients who underwent lower leg and foot soft tissue reconstruction due to trauma at our hospital from 2015 until 2022. Flap-related outcomes and complications were compared between the PPF group (18 flaps in 15 patients) and the FF group (20 flaps in 18 patients). These included complete and partial flap necrosis, venous congestion, delayed osteomyelitis, and the coverage failure rate, defined as the need for secondary flaps due to flap necrosis. RESULTS: The coverage failure rate was 22% in the PPF group and 5% in the FF group, with complete necrosis observed in 11% of the PPF group and 5% of the FF group, and partial necrosis in 39% of the PPF group and 10% of the FF group, indicating no significant difference between the two groups. However, venous congestion was significantly higher in 72% of the PPF group compared to 10% of the FF group. Four PPFs and one FF required FF reconstruction due to implant/fracture exposure from necrosis. Additionally, four PPFs developed delayed osteomyelitis post-healing, requiring reconstruction using free vascularized bone graft in three out of four cases. CONCLUSIONS: Flap necrosis in traumatic lower-leg defects can lead to reconstructive failure, exposing implants or fractures and potentially causing catastrophic outcomes like osteomyelitis, jeopardizing limb salvage. Surgeons should be cautious about deeming PPFs as straightforward and microsurgery-free procedures, given the increased complication rates compared to FFs in traumatic reconstruction. DATA ACCESS STATEMENT: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Near-Infrared Spectroscopy During Reactive Hyperemia for the Assessment of Lower Limb Vascular Function.

Vascular diseases of the lower limb contribute substantially to the global burden of cardiovascular disease and comorbidities such as diabetes. Importantly, microvascular dysfunction can occur prior to, or alongside, macrovascular pathology, and both potentially contribute to patient symptoms and disease burden. Here, we describe a non-invasive approach using near-infrared spectroscopy (NIRS) during reactive hyperemia, which provides a standardized assessment of lower limb vascular (dys)function and a potential method to evaluate the efficacy of therapeutic interventions. Unlike alternative methods, such as contrast-enhanced ultrasound, this approach does not require venous access or sophisticated image analysis, and it is inexpensive and less operator-dependent. This description of the NIRS method includes representative results and standard terminology alongside the discussion of measurement considerations, limitations, and alternative methods. Future application of this work will improve standardization of vascular research design, data collection procedures, and harmonized reporting, thereby enhancing translational research outcomes in the areas of lower limb vascular (dys)function, disease, and treatment.

A New Approach to Vascular Screening: Identification of Impaired Vascular Function Using the FMSF Technique.

Arterial blood pressure monitoring plays an important role in preventive medicine, allowing, in selected cases, the identification of vascular dysfunction. In this review, we propose a new non-invasive approach to assessment of the circulatory system, based on its reaction to hypoxia induced by post-occlusive reactive hyperemia (PORH). Three key parameters can be used for vascular screening: the Reactive Hyperemia Response (RHR), which represents the overall reaction of the macro- and microcirculation to transient hypoxia; Hypoxia Sensitivity (HS), which reflects hypoxia-induced activation of myogenic oscillations of the microcirculation; and Normoxia Oscillatory Index (NOI), which characterizes microcirculatory oscillations under normoxia conditions. A method for assessing these parameters, analogous in simplicity to arterial blood pressure measurement, is provided by the Flow Mediated Skin Fluorescence (FMSF) technique. Reference values are proposed based on numerous test measurements.

Dry eye disease pathogenesis and clinical signs: searching for correspondence in the clinical practice.

BACKGROUND: Ocular surface alterations causing dry eye disease (DED) can be described as a vicious circle consisting of different consecutive stages. Among the factors involved, the ocular surface immune-inflammatory response has been established as a key player in the pathogenesis of the vicious circle of DED. Thus, the prompt recognition of the disruption of the immunoregulatory mechanisms is crucial for properly managing the ocular surface alterations. To increase awareness and knowledge of the identification and clinical interpretation of immunological mechanisms of dry eye in clinical practice, we present two clinical cases related to DED patients to provide a practical example of clinical examination application and interpretation of diagnostic parameters in daily practice. Moreover, a literature overview of the available clinical examinations to assess the immunological involvement in DED patients, with a particular focus on the correlation between diagnostic parameters and pathogenesis of clinical signs, is provided with an educational intent. CASE PRESENTATION: The presented clinical experiences suggested that in ocular surface pathologies, knowledge of the immune-inflammatory pathogenetic mechanisms underlying the observed clinical sign is of great help for understanding what is being observed in the patient and, consequently, for the choice of appropriate therapy. Literature evidence suggests that many different clinical examinations can be used to assess inflammation in DED patients, such as the assessment of hyperemia, staining of the ocular surface and measurement of hyperosmolarity and MMP-9 levels. The combination of impression cytology and flow cytometry to assess for markers of inflammation is considered the best technique to quantify the level of inflammation on the ocular surface, even if not always applicable in clinical practice. CONCLUSIONS: Literature evidence and clinical experiences suggest that basic diagnostic approaches (assessment of hyperemia, MMP-9 levels, and staining of the ocular surface with Lissamine green or fluorescein) represent useful tools to assess the inflammatory component of DED in everyday practice, providing a guide to establish the correct therapeutic strategy.

Applications of topical immunomodulators enhance clinical signs of vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC): a meta-analysis.

PURPOSE: This meta-analysis aimed to review the safety and efficacy of topical cyclosporine A (CsA) and topical tacrolimus in allergic eye disease. METHODS: A systematic search identified thirteen studies and a total of 445 patients for inclusion, making this the largest meta-analysis published on the subject. The current review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Thirteen randomized control trials were included in the meta-analysis. Eleven studies used CsA as the treatment, and two used Tacrolimus. In total, 445 participants were included, of whom 76.6% were male. The mean age of participants across the included studies was 14 years. All studies reported clinical signs as evaluated by an examining clinician. Signs were usually assessed by anatomical region, with the most common regions being the conjunctiva and the cornea, and the most common signs assessed were hyperemia and papillae. Three studies accounted for more than 50% of the meta-analysis's weight. Effect size (d) ranged from - 2.37 to - 0.03, negative values favoring immunomodulators. Fixed Effect Meta-Analysis returned an SMD of - 0.81 (95% CI [- 0.98, - 0.65]). However, there was significant heterogeneity (I2 = 61%, Qw = 30.76) in the outcome measure (P = 0.0021); therefore, a random-effect meta-analysis was also completed in which the pooled SMD was - 0.98 (95% CI [- 1.26, - 0.69], τ2 = 0.16). CONCLUSIONS: This study affirms the current scientific community's stance that immunomodulators effectively treat clinical signs, including blepharitis, conjunctival hyperemia, edema, papillae, and corneal damage in severe ocular allergic disease.

High-frequency repetitive transcranial magnetic stimulation promotes ipsilesional functional hyperemia and motor recovery in mice with ischemic stroke.

Neurovascular decoupling plays a significant role in dysfunction following an ischemic stroke. This study aimed to explore the effect of low- and high-frequency repetitive transcranial magnetic stimulation on neurovascular remodeling after ischemic stroke. To achieve this goal, we compared functional hyperemia, cerebral blood flow regulatory factors, and neurochemical transmitters in the peri-infract cortex 21 days after a photothrombotic stroke. Our findings revealed that low- and high-frequency repetitive transcranial magnetic stimulation increased the real-time cerebral blood flow in healthy mice and improved neurobehavioral outcomes after stroke. Furthermore, high-frequency (5-Hz) repetitive transcranial magnetic stimulation revealed stronger functional hyperemia recovery and increased the levels of post-synaptic density 95, neuronal nitric oxide synthase, phosphorylated-endothelial nitric oxide synthase, and vascular endothelial growth factor in the peri-infract cortex compared with low-frequency (1-Hz) repetitive transcranial magnetic stimulation. The magnetic resonance spectroscopy data showed that low- and high-frequency repetitive transcranial magnetic stimulation reduced neuronal injury and maintained excitation/inhibition balance. However, 5-Hz repetitive transcranial magnetic stimulation showed more significant regulation of excitatory and inhibitory neurotransmitters after stroke than 1-Hz repetitive transcranial magnetic stimulation. These results indicated that high-frequency repetitive transcranial magnetic stimulation could more effectively promote neurovascular remodeling after stroke, and specific repetitive transcranial magnetic stimulation frequencies might be used to selectively regulate the neurovascular unit.

Venous congestion in septic shock quantified with point-of-care ultrasound: a pilot prospective multicentre cohort study.

PURPOSE: Venous congestion is a pathophysiologic state that can result in organ dysfunction, particularly acute kidney injury (AKI). We sought to evaluate the feasibility of performing a definitive observational study to determine the impact of venous congestion quantified using point-of-care ultrasound (POCUS) in patients with septic shock. METHODS: We conducted a prospective observational feasibility study at two intensive care units (ICUs). We recruited adult patients with septic shock within 12 hr of ICU admission. Using the validated Venous Excess Ultrasound Score (VEXUS), we quantified venous congestion on day 1 and day 3 of ICU admission. The primary feasibility outcome was successful completion rate of the two VEXUS scores. We performed a survival analysis to quantify the hazard of renal replacement therapy (RRT). RESULTS: We enrolled 75 patients from January 2022 to January 2023. The success rate of completion for VEXUS scans was 94.5% (95% confidence interval [CI], 89.5 to 97.6). Severe venous congestion was present in 19% (14/75) of patients on ICU admission day 1 and in 16% (10/61) of patients on day 3. Venous congestion on ICU admission may be associated with a higher risk of requiring RRT (unadjusted hazard ratio, 3.35; 95% CI, 0.94 to 11.88; P = 0.06). CONCLUSIONS: It is feasible to conduct a definitive observational study exploring the association between venous congestion quantified with POCUS and clinical outcomes in patients with septic shock. We hypothesize that venous congestion may be associated with an increased hazard of receiving RRT.

RéSUMé: OBJECTIF: La congestion veineuse est un état physiopathologique qui peut entraîner un dysfonctionnement des organes, en particulier une insuffisance rénale aiguë (IRA). Nous avons cherché à évaluer la faisabilité de la réalisation d'une étude observationnelle définitive pour déterminer l'impact de la congestion veineuse quantifiée à l'aide de l'échographie ciblée (POCUS) chez des patient·es en choc septique. MéTHODE: Nous avons réalisé une étude de faisabilité observationnelle prospective dans deux unités de soins intensifs (USI). Nous avons recruté des patient·es adultes souffrant d'un choc septique dans les 12 heures suivant leur admission aux soins intensifs. À l'aide du score VEXUS (score d'échographie de l'excès veineux) validé, nous avons quantifié la congestion veineuse au jour 1 et au jour 3 de leur admission aux soins intensifs. Le principal critère de faisabilité était le taux de réussite des deux scores VEXUS. Nous avons réalisé une analyse de survie pour quantifier le risque de thérapie de substitution rénale (TSR). RéSULTATS: Nous avons recruté 75 patient·es de janvier 2022 à janvier 2023. Le taux de réussite des scores VEXUS était de 94,5 % (intervalle de confiance [IC] à 95 %, 89,5 à 97,6). Une congestion veineuse sévère était présente chez 19 % (14/75) des patient·es au jour 1 d'admission aux soins intensifs et chez 16 % (10/61) des patient·es au jour 3. La congestion veineuse lors de l'admission aux soins intensifs peut être associée à un risque plus élevé de nécessiter une TSR (rapport de risque non ajusté, 3,35; IC 95 %, 0,94 à 11,88; P = 0,06). CONCLUSION: Il est possible de mener une étude observationnelle définitive explorant l'association entre la congestion veineuse quantifiée par POCUS et les devenirs cliniques chez les patient·es en choc septique. Nous émettons l'hypothèse que la congestion veineuse peut être associée à un risque accru de recevoir une thérapie de substitution rénale.