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Translational Pediatrics May 2024The goal of fluid resuscitation and the use of inotropes in septic shock has traditionally focused on improving blood pressure and cardiac output, without considering...
BACKGROUND
The goal of fluid resuscitation and the use of inotropes in septic shock has traditionally focused on improving blood pressure and cardiac output, without considering the microcirculatory changes. Reaching macrocirculatory goals but with persistent microcirculatory abnormalities (hemodynamic incoherence) in septic shock has been associated with greater organ dysfunction and mortality. The objective of this study was to evaluate the microcirculation (flow and capillary density) and endothelial glycocalyx changes associated with the use of milrinone in children with septic shock, as well as their relationship with clinical variables and organ dysfunction.
METHODS
A prospective cohort study from February 2022 to January 2023 at a university hospital (Fundación Cardioinfantil-Instituto de Cardiología). Sublingual video microscopy was used to evaluate capillary density, microvascular flow rates and perfused boundary region (PBR-inverse parameter of glycocalyx thickness-abnormal if >2.0 microns). The primary outcome was the association between microcirculation and endothelial glycocalyx changes related to the use of milrinone.
RESULTS
A total of 140 children with a median age of two years [interquartile range (IQR) 0.58-12.1] were included. About 57.9% (81/140) of the patients received milrinone infusions. Twenty-four hours after receiving milrinone, the patients maintained functional capillary density (P<0.01) and capillary recruitment capacity (P=0.04) with no changes in capillary blood volume versus those who did not receive milrinone. Children under two years old who received milrinone had better 4-6-micron capillary density than older children [odds ratio (OR) 0.33; 95% confidence interval (95% CI): 0.12-0.89; P=0.02] and less endothelial glycocalyx degradation [adjusted OR (aOR) 0.34 95% CI: 0.11-0.99; P=0.04]. These changes persisted despite elevated ferritin (aOR 0.41; 95% CI: 0.18-0.93; P=0.03). Prolonged capillary refill and elevated lactate were correlated with microcirculation changes in both groups. The patients who died had the highest PBR levels (P=0.04).
CONCLUSIONS
Children with septic shock who receive milrinone infusions have microcirculation changes compared with those who do not receive them. The group that received milrinone was found to maintain functional capillary density and capillary recruitment capacity and have less endothelial glycocalyx degradation 24 hours after administration. These changes were present despite the inflammatory response and were more significant in those under two years of age.
PubMed: 38840690
DOI: 10.21037/tp-23-619 -
EuroIntervention : Journal of EuroPCR... Jun 2024It has been suggested that coronary microvascular function decreases with age, irrespective of the presence of epicardial atherosclerosis.
BACKGROUND
It has been suggested that coronary microvascular function decreases with age, irrespective of the presence of epicardial atherosclerosis.
AIMS
Our aim is to quantitatively investigate the effects of age on microvascular function in patients with normal coronary arteries.
METHODS
In 314 patients with angina with no obstructive coronary artery disease (ANOCA), microcirculatory function was tested using the continuous thermodilution method. In 305 patients, the association between age and both resting and hyperaemic myocardial blood flow (Q), microvascular resistance (R), absolute coronary flow reserve (CFR) and microvascular resistance reserve (MRR) was assessed. In addition, patients were divided into 3 groups to test for differences based on age quartiles (≤52 years [24.9%], 53-64 years [49.2%], ≥65 years [25.9%]).
RESULTS
The mean age was 59±9 years with a range from 22 to 79 years. The mean resting Q (Q) was not different in the 3 age groups (88±34 mL/min, 82±29 mL/min, and 86±38 mL/min, R=0.001; p=0.62). A trend towards a decreasing mean hyperaemic Q (Q) was observed with increasing age (223±79 mL/min, 209±84 mL/min, 200±80 mL/min, R=0.010; p=0.083). The mean resting R (R) were 1,204±460 Wood units (WU), 1,260±411 WU, and 1,289±455 WU (p=0.23). The mean hyperaemic R (R) increased significantly with advancing age (429±149 WU, 464±164 WU, 503±162 WU, R=0.026; p=0.005). Consequently, MRR decreased with age (3.2±1.2, 3.1±1.0, 2.9±0.9; p=0.038). This trend was present in both the patients with (n=121) and without (n=184) coronary microvascular dysfunction (CMD).
CONCLUSIONS
There is an age-dependent physiological increase in minimal microvascular resistance and decrease in microvascular function, which is represented by a decreased MRR and is independent of atherosclerosis. The age-dependent decrease in MRR was present in both patients with and without CMD and was most evident in patients with smooth coronary arteries.
Topics: Humans; Middle Aged; Male; Female; Aged; Microcirculation; Coronary Vessels; Adult; Coronary Circulation; Age Factors; Vascular Resistance; Young Adult; Coronary Artery Disease; Angina Pectoris
PubMed: 38840575
DOI: 10.4244/EIJ-D-23-00778 -
Molecular Medicine (Cambridge, Mass.) Jun 2024Advanced glycation end product-modified low-density lipoprotein (AGE-LDL) is related to inflammation and the development of atherosclerosis. Additionally, it has been...
Advanced glycation end product-modified low-density lipoprotein promotes pro-osteogenic reprogramming via RAGE/NF-κB pathway and exaggerates aortic valve calcification in hamsters.
BACKGROUND
Advanced glycation end product-modified low-density lipoprotein (AGE-LDL) is related to inflammation and the development of atherosclerosis. Additionally, it has been demonstrated that receptor for advanced glycation end products (RAGE) has a role in the condition known as calcific aortic valve disease (CAVD). Here, we hypothesized that the AGE-LDL/RAGE axis could also be involved in the pathophysiological mechanism of CAVD.
METHODS
Human aortic valve interstitial cells (HAVICs) were stimulated with AGE-LDL following pre-treatment with or without interleukin 37 (IL-37). Low-density lipoprotein receptor deletion (Ldlr) hamsters were randomly allocated to chow diet (CD) group and high carbohydrate and high fat diet (HCHFD) group.
RESULTS
AGE-LDL levels were significantly elevated in patients with CAVD and in a hamster model of aortic valve calcification. Our in vitro data further demonstrated that AGE-LDL augmented the expression of intercellular cell adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and alkaline phosphatase (ALP) in a dose-dependent manner through NF-κB activation, which was attenuated by nuclear factor kappa-B (NF-κB) inhibitor Bay11-7082. The expression of RAGE was augmented in calcified aortic valves, and knockdown of RAGE in HAVICs attenuated the AGE-LDL-induced inflammatory and osteogenic responses as well as NF-κB activation. IL-37 suppressed inflammatory and osteogenic responses and NF-κB activation in HAVICs. The vivo experiment also demonstrate that supplementation with IL-37 inhibited valvular inflammatory response and thereby suppressed valvular osteogenic activities.
CONCLUSIONS
AGE-LDL promoted inflammatory responses and osteogenic differentiation through RAGE/NF-κB pathway in vitro and aortic valve lesions in vivo. IL-37 suppressed the AGE-LDL-induced inflammatory and osteogenic responses in vitro and attenuated aortic valve lesions in a hamster model of CAVD.
Topics: Animals; Aortic Valve; Glycation End Products, Advanced; NF-kappa B; Humans; Calcinosis; Receptor for Advanced Glycation End Products; Aortic Valve Stenosis; Cricetinae; Osteogenesis; Male; Lipoproteins, LDL; Signal Transduction; Disease Models, Animal; Female; Middle Aged; Glycated Proteins
PubMed: 38840067
DOI: 10.1186/s10020-024-00833-8 -
Scientific Reports Jun 2024The maintenance of intestinal integrity and barrier function under conditions of restricted oxygen availability is crucial to avoid bacterial translocation and local...
The maintenance of intestinal integrity and barrier function under conditions of restricted oxygen availability is crucial to avoid bacterial translocation and local inflammation. Both lead to secondary diseases after hemorrhagic shock and might increase morbidity and mortality after surviving the initial event. Monitoring of the intestinal integrity especially in the early course of critical illness remains challenging. Since microcirculation and mitochondrial respiration are main components of the terminal stretch of tissue oxygenation, the evaluation of microcirculatory and mitochondrial variables could identify tissues at risk during hypoxic challenges, indicate an increase of intestinal injury, and improve our understanding of regional pathophysiology during acute hemorrhage. Furthermore, improving intestinal microcirculation or mitochondrial respiration, e.g. by remote ischemic preconditioning (RIPC) that was reported to exert a sufficient tissue protection in various tissues and was linked to mediators with vasoactive properties could maintain intestinal integrity. In this study, postcapillary oxygen saturation (µHbO), microvascular flow index (MFI) and plasmatic D-lactate concentration revealed to be early markers of intestinal injury in a rodent model of experimental hemorrhagic shock. Mitochondrial function was not impaired in this experimental model of acute hemorrhage. Remote ischemic preconditioning (RIPC) failed to improve intestinal microcirculation and intestinal damage during hemorrhagic shock.
Topics: Animals; Ischemic Preconditioning; Rats; Shock, Hemorrhagic; Microcirculation; Intestines; Male; Biomarkers; Disease Models, Animal; Mitochondria; Intestinal Mucosa; Lactic Acid
PubMed: 38839819
DOI: 10.1038/s41598-024-63293-4 -
Translational Research : the Journal of... Jun 2024Arterial remodeling is a common pathophysiological change in the pathogenesis of cardiovascular diseases in which the phenotypic switch of vascular smooth muscle cells...
BACKGROUND
Arterial remodeling is a common pathophysiological change in the pathogenesis of cardiovascular diseases in which the phenotypic switch of vascular smooth muscle cells (VSMC) plays an important role. Recently, an increasing number of long non-coding RNAs(lncRNAs) have been shown to encode micropeptides that play biological roles and have great clinical transformation potential. However, the role of micropeptides encoded by lncRNAs in arterial remodeling has not been well studied and requires further exploration.
METHODS AND RESULTS
Through bioinformatic analysis and experimental verification, we found that a new lncRNA, the mitochondrial function-related lncRNA (MFRL), encodes a 64-amino acid micropeptide, MFRLP. MFRL and MFRLP play important roles in the phenotypic switch of VSMC. Further experiments showed that MFRLP interacts with mitochondrial cytochrome b to reduce accumulation of reactive oxygen species, suppress mitophagy and inhibit the VSMC switch from contractile to synthetic phenotype.
CONCLUSIONS
LncRNA MFRL encodes the micropeptide MFRLP, which interacts with mitochondrial cytochrome b to inhibit the VSMC switch from contractile to synthetic phenotype and improve arterial remodeling.
PubMed: 38838852
DOI: 10.1016/j.trsl.2024.05.009 -
The New England Journal of Medicine Jun 2024
Topics: Humans; Male; Middle Aged; Blood Vessel Prosthesis Implantation; Coronary Circulation; Coronary Stenosis; Coronary Vessels; Drug-Eluting Stents; Homeostasis; Hyperemia; Microcirculation; Vascular Resistance
PubMed: 38838318
DOI: 10.1056/NEJMc2402216 -
Microcirculation (New York, N.Y. : 1994) Jun 2024Diabetic foot ulcer (DFU) is a severe complication with high mortality. High plantar pressure and poor microcirculation are considered main causes of DFU. The specific...
OBJECTIVE
Diabetic foot ulcer (DFU) is a severe complication with high mortality. High plantar pressure and poor microcirculation are considered main causes of DFU. The specific aims were to provide a novel technique for real-time measurement of plantar skin blood flow (SBF) under walking-like pressure stimulus and delineate the first plantar metatarsal head dynamic microcirculation characteristics because of life-like loading conditions in healthy individuals.
METHODS
Twenty young healthy participants (14 male and 6 female) were recruited. The baseline (i.e., unloaded) SBF of soft tissue under the first metatarsal head were measured using laser Doppler flowmetry (LDF). A custom-made machine was utilized to replicate daily walking pressure exertion for 5 min. The exerted plantar force was adjusted from 10 N (127.3 kPa) to 40 N (509.3 kPa) at an increase of 5 N (63.7 kPa). Real-time SBF was acquired using the LDF. After each pressure exertion, postload SBF was measured for comparative purposes. Statistical analysis was performed using the R software.
RESULTS
All levels of immediate-load and postload SBF increased significantly compared with baseline values. As the exerted load increased, the postload and immediate-load SBF tended to increase until the exerted load reached 35 N (445.6 kPa). However, in immediate-load data, the increasing trend tended to level off as the exerted pressure increased from 15 N (191.0 kPa) to 25 N (318.3 kPa). For postload and immediate-load SBF, they both peaked at 35 N (445.6 kPa). However, when the exerted force exceeds 35 N (445.6 kPa), both the immediate-load and postload SBF values started to decrease.
CONCLUSIONS
Our study offered a novel real-time plantar soft tissue microcirculation measurement technique under dynamic conditions. For the first metatarsal head of healthy people, 20 N (254.6 kPa)-plantar pressure has a fair microcirculation stimulus compared with higher pressure. There might be a pressure threshold at 35 N (445.6 kPa) for the first metatarsal head, and soft tissue microcirculation may decrease when local pressure exceeds it.
PubMed: 38837938
DOI: 10.1111/micc.12860 -
Physiological Reports Jun 2024Superficial, systemic microcirculations, distinct from the pulmonary circulation, supply the mucosae of human nasal and conducting airways. Non-injurious, inflammatory... (Review)
Review
Superficial, systemic microcirculations, distinct from the pulmonary circulation, supply the mucosae of human nasal and conducting airways. Non-injurious, inflammatory challenges of the airway mucosa cause extravasation without overt mucosal oedema. Instead, likely reflecting minimal increases in basolateral hydrostatic pressure, circulating proteins/peptides of all sizes are transmitted paracellularly across the juxtaposed epithelial barrier. Thus, small volumes of extravasated, unfiltered bulk plasma appear on the mucosal surface at nasal and bronchial sites of challenge. Importantly, the plasma-exuding mucosa maintains barrier integrity against penetrability of inhaled molecules. Thus, one-way epithelial penetrability, strict localization, and well-controlled magnitude and duration are basic characteristics of the plasma exudation response in human intact airways. In vivo experiments in human-like airways demonstrate that local plasma exudation is also induced by non-sanguineous removal of epithelium over an intact basement membrane. This humoral response results in a protective, repair-promoting barrier kept together by a fibrin-fibronectin net. Plasma exudation stops once the provisional barrier is substituted by a new cellular cover consisting of speedily migrating repair cells, which may emanate from all types of epithelial cells bordering the denuded patch. Exuded plasma on the surface of human airways reflects physiological microvascular-epithelial cooperation in first line mucosal defense at sites of intact and regenerating epithelium.
Topics: Humans; Blood Proteins; Regeneration; Respiratory Mucosa
PubMed: 38837627
DOI: 10.14814/phy2.16096 -
Microcirculation (New York, N.Y. : 1994) Jun 2024The sympathetic-parasympathetic (or axo-axonal) interaction mechanism mediated that neurogenic relaxation, which was dependent on norepinephrine (NE) releases from...
OBJECTIVE
The sympathetic-parasympathetic (or axo-axonal) interaction mechanism mediated that neurogenic relaxation, which was dependent on norepinephrine (NE) releases from sympathetic nerve terminal and acts on β-adrenoceptor of parasympathetic nerve terminal, has been reported. As NE is a weak β-adrenoceptor agonist, there is a possibility that synaptic NE is converted to epinephrine by phenylethanolamine-N-methyltransferase (PNMT) and then acts on the β-adrenoceptors to induce neurogenic vasodilation.
METHODS
Blood vessel myography technique was used to measure relaxation and contraction responses of isolated basilar arterial rings of rats.
RESULTS
Nicotine-induced relaxation was sensitive to propranolol, guanethidine (an adrenergic neuronal blocker), and N-nitro-l-arginine. Nicotine- and exogenous NE-induced vasorelaxation was partially inhibited by LY-78335 (a PNMT inhibitor), and transmural nerve stimulation depolarized the nitrergic nerve terminal directly and was not inhibited by LY-78335; it then induced the release of nitric oxide (NO). Epinephrine-induced vasorelaxation was not affected by LY-78335. However, these vasorelaxations were completely inhibited by atenolol (a β-adrenoceptor antagonist) combined with ICI-118,551 (a β-adrenoceptor antagonist).
CONCLUSIONS
These results suggest that NE may be methylated by PNMT to form epinephrine and cause the release of NO and vasodilation. These results provide further evidence supporting the physiological significance of the axo-axonal interaction mechanism in regulating brainstem vascular tone.
PubMed: 38837563
DOI: 10.1111/micc.12858 -
Journal of Materials Chemistry. B Jun 2024Boron neutron capture therapy (BNCT) is an emerging approach for treating malignant tumors with binary targeting. However, its clinical application has been hampered by...
Boron neutron capture therapy (BNCT) is an emerging approach for treating malignant tumors with binary targeting. However, its clinical application has been hampered by insufficient B accumulation in tumors and low B concentration ratios of tumor-to-blood (T/B) and tumor-to-normal tissue (T/N). Herein, we developed fluorinated BPA derivatives with different fluorine groups as boron delivery agents for enabling sufficient B accumulation in tumors and enhancing T/B and T/N ratios. Our findings demonstrated that fluorinated BPA derivatives had good biological safety. Furthermore, fluorinated BPA derivatives showed improved B accumulation in tumors and enhanced T/B and T/N ratios compared to the clinical boron drug fructose-BPA (f-BPA). In particular, in B16-F10 tumor-bearing mice, fluorinated BPA derivatives met the requirements for clinical BNCT even at half of the clinical dose. Thus, fluorinated BPA derivatives are potentially effective boron delivery agents for clinical BNCT in melanoma.
Topics: Animals; Mice; Boron Neutron Capture Therapy; Benzhydryl Compounds; Halogenation; Phenols; Humans; Mice, Inbred C57BL; Boron Compounds; Melanoma, Experimental; Molecular Structure
PubMed: 38836578
DOI: 10.1039/d4tb00846d