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Hypertension (Dallas, Tex. : 1979) Jun 2024Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence...
BACKGROUND
Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk.
METHODS
Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging.
RESULTS
The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (β, -0.67 [95% CI, -1.21 to -0.13]; =0.016), lower stress myocardial blood flow (β, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; =0.001), and higher stress coronary vascular resistance (β, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; =0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (=0.71; <0.001), independent of hemodynamics.
CONCLUSIONS
In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.
Topics: Humans; Female; Pre-Eclampsia; Pregnancy; Adult; Vascular Resistance; Coronary Circulation; Vascular Endothelial Growth Factor Receptor-1; Microcirculation; Positron-Emission Tomography; Placenta Growth Factor; Postpartum Period; Severity of Illness Index; Fractional Flow Reserve, Myocardial; Coronary Vessels; Microvessels
PubMed: 38563161
DOI: 10.1161/HYPERTENSIONAHA.124.22905 -
Anaesthesia Dec 2023Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative...
Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α -agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4-0.8 μg.kg .h ) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24-7.23) to 1.56 (0.84-2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33-7.07) to 1.51 (0.33-2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi-quantitative scale (0-3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1-2 [0-3]) vs. 0 (0-0.3 [0-1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass.
Topics: Animals; Brain; Cardiopulmonary Bypass; Dexmedetomidine; Kidney; Microcirculation; Neuroinflammatory Diseases; Sheep
PubMed: 37880924
DOI: 10.1111/anae.16152 -
Microcirculation (New York, N.Y. : 1994) Aug 2023Recent advances in tissue clearing and high-throughput imaging have enabled the acquisition of extended-volume microvasculature images at a submicron resolution. The...
OBJECTIVE
Recent advances in tissue clearing and high-throughput imaging have enabled the acquisition of extended-volume microvasculature images at a submicron resolution. The objective of this study was to extract information from this type of images by integrating a sequence of 3D image processing steps on Terabyte scale datasets.
METHODS
We acquired coronary microvasculature images throughout an entire short-axis slice of a 3-month-old Wistar-Kyoto rat heart. This dataset covered 13 × 10 × 0.6 mm at a resolution of 0.933 × 0.933 × 1.866 μm and occupied 700 Gigabytes of disk space. We used chunk-based image segmentation, combined with an efficient graph generation technique, to quantify the microvasculature in the large-scale images. Specifically, we focused on the microvasculature with a vessel diameter up to 15 μm.
RESULTS
Morphological data for the complete short-axis ring were extracted within 16 h using this pipeline. From the analyses, we identified that microvessel lengths in the rat coronary microvasculature varied from 6 to 300 μm. However, their distribution was heavily skewed toward shorter lengths, with a mode of 16.5 μm. In contrast, vessel diameters ranged from 3 to 15 μm and had an approximately normal distribution of 6.5 ± 2 μm.
CONCLUSION
The tools and techniques from this study will serve other investigations into the microcirculation, and the wealth of data from this study will enable the analysis of biophysical mechanisms using computer models.
PubMed: 37392132
DOI: 10.1111/micc.12820 -
American Journal of Physiology. Heart... Oct 2023
Topics: Humans; Endotoxemia; Glycocalyx; Sepsis
PubMed: 37594482
DOI: 10.1152/ajpheart.00499.2023 -
Clinical Cancer Research : An Official... Jul 2023Pancreatic ductal adenocarcinoma (PDA) resists immunotherapy of adoptive cell transfer (ACT) and immune checkpoint inhibitors. Understanding the mechanisms underlying...
PURPOSE
Pancreatic ductal adenocarcinoma (PDA) resists immunotherapy of adoptive cell transfer (ACT) and immune checkpoint inhibitors. Understanding the mechanisms underlying this resistance will improve PDA immunotherapy. This study investigated therapeutic effects and underlying mechanisms of anticoagulants on immunotherapy in PDA.
EXPERIMENTAL DESIGN
The antitumor activity of immunotherapy was evaluated in mouse models of desert, excluded, and inflamed tumors. The underlying mechanisms were investigated by analyzing immune cell infiltration by immunofluorescence imaging and tumor microcirculation by interstitial fluid pressure and coagulation status measurement.
RESULTS
Combined use of heparin and ACT inhibited tumor growth and metastasis, whereas neither heparin nor ACT had any therapeutic effect. The combination of heparin and ACT significantly increased the intratumor infiltration of CD8+ T cells and M1 macrophages and reduced the infiltration of immunosuppressive M2 macrophages and FOXP3+/CD4+ regulatory T cells (Treg). Assessments of tumor microenvironment revealed that heparin promoted tumor vascular regression and normalized the remaining blood vessels, facilitating the extravasation and perivascular accumulation of activated CD8+ T cells in tumors. Mechanistically, tumor microvessel hemodynamic properties were significantly improved by heparin, which is consistent with its inhibitory effects on tumor angiogenesis. Similarly, the combination of heparin and anti-PD1 also produced a pronounced antitumor activity, whereas neither heparin nor anti-PD1 treatment had appreciable antitumor activity.
CONCLUSIONS
Combined treatment of heparin and ACT or anti-PD1 produced synergistic antitumor effects, which were at least in part through tumor vascular normalization, hence increased antitumor T-cell responses due to reduced Treg infiltration and increased M1 macrophage polarization. This synergistic combination therapy warrants clinical evaluation. See related commentary by Korc, p. 2348.
Topics: Mice; Animals; Heparin; Anticoagulants; Microcirculation; Pancreatic Neoplasms; Immunotherapy; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed: 36729148
DOI: 10.1158/1078-0432.CCR-22-2757 -
Anesthesiology Aug 2023The administration of epinephrine after severe refractory hypotension, shock, or cardiac arrest restores systemic blood flow and major vessel perfusion but may worsen...
BACKGROUND
The administration of epinephrine after severe refractory hypotension, shock, or cardiac arrest restores systemic blood flow and major vessel perfusion but may worsen cerebral microvascular perfusion and oxygen delivery through vasoconstriction. The authors hypothesized that epinephrine induces significant microvascular constriction in the brain, with increased severity after repetitive dosing and in the aged brain, eventually leading to tissue hypoxia.
METHODS
The authors investigated the effects of intravenous epinephrine administration in healthy young and aged C57Bl/6 mice on cerebral microvascular blood flow and oxygen delivery using multimodal in vivo imaging, including functional photoacoustic microscopy, brain tissue oxygen sensing, and follow-up histologic assessment.
RESULTS
The authors report three main findings. First, after epinephrine administration, microvessels exhibited severe immediate vasoconstriction (57 ± 6% of baseline at 6 min, P < 0.0001, n = 6) that outlasted the concurrent increase in arterial blood pressure, while larger vessels demonstrated an initial increase in flow (108 ± 6% of baseline at 6 min, P = 0.02, n = 6). Second, oxyhemoglobin decreased significantly within cerebral vessels with a more pronounced effect in smaller vessels (microvessels to 69 ± 8% of baseline at 6 min, P < 0.0001, n = 6). Third, oxyhemoglobin desaturation did not indicate brain hypoxia; on the contrary, brain tissue oxygen increased after epinephrine application (from 31 ± 11 mmHg at baseline to 56 ± 12 mmHg, 80% increase, P = 0.01, n = 12). In the aged brains, microvascular constriction was less prominent yet slower to recover compared to young brains, but tissue oxygenation was increased, confirming relative hyperoxia.
CONCLUSIONS
Intravenous application of epinephrine induced marked cerebral microvascular constriction, intravascular hemoglobin desaturation, and paradoxically, an increase in brain tissue oxygen levels, likely due to reduced transit time heterogeneity.
Topics: Mice; Animals; Microcirculation; Oxyhemoglobins; Microscopy; Epinephrine; Oxygen; Cerebrovascular Circulation
PubMed: 37079748
DOI: 10.1097/ALN.0000000000004592 -
Medicinski Glasnik : Official... Feb 2024Aim To study the character of blood circulation in the bone stump at tight and loose closure of the medullary cavity. Methods Two series of experiments on 39 rabbits...
Aim To study the character of blood circulation in the bone stump at tight and loose closure of the medullary cavity. Methods Two series of experiments on 39 rabbits with mid-third femoral amputation and muscular plasty were carried out. In the 1st (experimental) series, the bone scapula was closed by thin cortical autograft taken from the epimetaphyseal area, and then the muscles were sutured, and in the 2nd - the scapula was closed by myoplasty only. Follow-up periods: 1st series - 7, 14, 21 days and 1, 3, 6 months, 2nd series - 1, 3, 6 months. Histological methods with infusion of vessels with ink-gelatin mixture and morphometry was used. Results In the 1st series there was a rapid restoration of the disturbed macro- and microcirculation due to the reserve sources of blood circulation and the development of extravascular ways of microcirculation. In the 2nd series, blood circulation recovery was significantly slower and occurred mainly due to the development of extravascular microcirculatory pathways. Conclusion The study established undeniable usefulness of tight closure of the bone marrow cavity during amputation.
PubMed: 38341643
DOI: 10.17392/1677-23 -
Ultrasound in Medicine & Biology Sep 2023The aim of the work described here was to provide an evidence-based evaluation of contrast-enhanced ultrasonography (CEUS) in acute kidney injury (AKI) and assess... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The aim of the work described here was to provide an evidence-based evaluation of contrast-enhanced ultrasonography (CEUS) in acute kidney injury (AKI) and assess variations in renal microperfusion with CEUS quantitative parameters in patients at a high risk of developing AKI.
METHODS
A meta-analysis and systematic review were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the Embase, MEDLINE, Web of Science and the Cochrane Library databases were used to search the relevant articles systematically (2000-2022). Studies using CEUS to assess renal cortical microcirculation in AKI were included.
RESULTS
Six prospective studies (374 patients) were included. The overall quality of included studies was moderate to high. CEUS measures, maximum intensity (standard mean difference [SMD]: -1.37, 95% confidence interval [CI]: -1.64 to -1.09) and wash-in rate (SMD: -0.77, 95% CI: -1.09 to -0.45) were lower in the AKI+ group than in the AKI- group, and mean transit time (SMD: 0.76, 95% CI: 0.11-1.40) and time to peak (SMD: 1.63, 95% CI: 0.99-2.27) were higher in the AKI+ group. Moreover, maximum intensity and wash-in rate values changed before creatinine changed in the AKI+ group.
CONCLUSION
Patients with AKI had reduced microcirculatory perfusion, prolonged perfusion time and a reduced rising slope in the renal cortex, which occurred before serum creatinine changes. And they could be measured using CEUS, indicating that CEUS could help in the diagnosis of AKI.
Topics: Humans; Prospective Studies; Microcirculation; Acute Kidney Injury; Kidney; Ultrasonography; Contrast Media
PubMed: 37391293
DOI: 10.1016/j.ultrasmedbio.2023.06.002 -
CNS Neuroscience & Therapeutics Feb 2024In the field of stroke thrombectomy, ineffective clinical and angiographic reperfusion after successful recanalization has drawn attention. Partial or complete... (Review)
Review
In the field of stroke thrombectomy, ineffective clinical and angiographic reperfusion after successful recanalization has drawn attention. Partial or complete microcirculatory reperfusion failure after the achievement of full patency of a former obstructed large vessel, known as the "no-reflow phenomenon" or "microvascular obstruction," was first reported in the 1960s and was later detected in both experimental models and patients with stroke. The no-reflow phenomenon (NRP) was reported to result from intraluminal occlusions formed by blood components and extraluminal constriction exerted by the surrounding structures of the vessel wall. More recently, an emerging number of clinical studies have estimated the prevalence of the NRP in stroke patients following reperfusion therapy, ranging from 3.3% to 63% depending on its evaluation methods or study population. Studies also demonstrated its detrimental effects on infarction progress and neurological outcomes. In this review, we discuss the research advances, underlying pathogenesis, diagnostic techniques, and management approaches concerning the no-reflow phenomenon in the stroke population to provide a comprehensive understanding of this phenomenon and offer references for future investigations.
Topics: Humans; No-Reflow Phenomenon; Microcirculation; Stroke; Thrombectomy; Reperfusion; Treatment Outcome
PubMed: 38358074
DOI: 10.1111/cns.14631 -
Journal of the American College of... Feb 2024Diagnosing coronary microvascular dysfunction remains challenging, primarily due to the lack of direct measurements of absolute coronary blood flow (Q) and microvascular... (Review)
Review
Diagnosing coronary microvascular dysfunction remains challenging, primarily due to the lack of direct measurements of absolute coronary blood flow (Q) and microvascular resistance (R). However, there has been recent progress with the development and validation of continuous intracoronary thermodilution, which offers a simplified and validated approach for clinical use. This technique enables direct quantification of Q and R, leading to precise and accurate evaluation of the coronary microcirculation. To ensure consistent and reliable results, it is crucial to follow a standardized protocol when performing continuous intracoronary thermodilution measurements. This document aims to summarize the principles of thermodilution-derived absolute coronary flow measurements and propose a standardized method for conducting these assessments. The proposed standardization serves as a guide to ensure the best practice of the method, enhancing the clinical assessment of the coronary microcirculation.
Topics: Humans; Coronary Circulation; Vascular Resistance; Thermodilution; Hemodynamics; Myocardial Ischemia; Microcirculation; Coronary Vessels
PubMed: 38325996
DOI: 10.1016/j.jacc.2023.12.014