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Microvascular disease confers additional risk to COVID-19 infection.
Bale BF, Doneen AL, Vigerust DJ
(2020) Med Hypotheses 144: 109999
MeSH Terms: Adult, Aging, COVID-19, Cardiovascular Diseases, Child, Diabetes Mellitus, Disease Susceptibility, Humans, Hydrogen Peroxide, Hypertension, Hypochlorous Acid, Immunity, Innate, Lung, Microcirculation, Microvessels, Neutrophils, Pandemics, Peroxidase, Risk Factors, United States
Show Abstract · Added June 25, 2020
The majority of fatalities thus far in the COVID-19 pandemic have been attributed to pneumonia. As expected, the fatality rate reported in China is higher in people with chronic pulmonary disease (6.3%) and those who have cancer (5.6%). According to the American College of Cardiology Clinical Bulletin "COVID-19 Clinical Guidance for the CV Care Team", there is a significantly higher fatality rate in people who are elderly (8.0% 70-79 years; 14.8% ≥80 years), diabetic (7.3%), hypertensive (6.0%), or have known cardiovascular disease (CVD) (10.5%). We propose a biological reason for the higher mortality risk in these populations that is apparent. We further present a set of pathophysiological reasons for the heightened danger that could lead to therapies for enhanced management and prevention.
Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
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20 MeSH Terms
Perfusion controls muscle glucose uptake by altering the rate of glucose dispersion in vivo.
McClatchey PM, Williams IM, Xu Z, Mignemi NA, Hughey CC, McGuinness OP, Beckman JA, Wasserman DH
(2019) Am J Physiol Endocrinol Metab 317: E1022-E1036
MeSH Terms: 4-Chloro-7-nitrobenzofurazan, Animals, Blood Flow Velocity, Carbon Radioisotopes, Deoxyglucose, Dextrans, Glucose, Hypoglycemic Agents, Insulin, Intravital Microscopy, Mice, Microcirculation, Microspheres, Muscle, Skeletal, Ultrasonography
Show Abstract · Added March 30, 2020
These studies test, using intravital microscopy (IVM), the hypotheses that perfusion effects on insulin-stimulated muscle glucose uptake (MGU) are ) capillary recruitment independent and ) mediated through the dispersion of glucose rather than insulin. For , capillary perfusion was visualized before and after intravenous insulin. No capillary recruitment was observed. For , mice were treated with vasoactive compounds (sodium nitroprusside, hyaluronidase, and lipopolysaccharide), and dispersion of fluorophores approximating insulin size (10-kDa dextran) and glucose (2-NBDG) was measured using IVM. Subsequently, insulin and 2[C]deoxyglucose were injected and muscle phospho-2[C]deoxyglucose (2[C]DG) accumulation was used as an index of MGU. Flow velocity and 2-NBDG dispersion, but not perfused surface area or 10-kDa dextran dispersion, predicted phospho-2[C]DG accumulation. For , microspheres of the same size and number as are used for contrast-enhanced ultrasound (CEU) studies of capillary recruitment were visualized using IVM. Due to their low concentration, microspheres were present in only a small fraction of blood-perfused capillaries. Microsphere-perfused blood volume correlated to flow velocity. These findings suggest that ) flow velocity rather than capillary recruitment controls microvascular contributions to MGU, ) glucose dispersion is more predictive of MGU than dispersion of insulin-sized molecules, and ) CEU measures regional flow velocity rather than capillary recruitment.
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15 MeSH Terms
Endothelial-Dependent Vasomotor Dysfunction in Infants After Cardiopulmonary Bypass.
Krispinsky LT, Stark RJ, Parra DA, Luan L, Bichell DP, Pietsch JB, Lamb FS
(2020) Pediatr Crit Care Med 21: 42-49
MeSH Terms: Acetylcholine, Biomarkers, Cardiac Surgical Procedures, Cardiopulmonary Bypass, Cardiovascular Diseases, Child, Child, Preschool, Cytokines, Endothelium, Vascular, Heart Defects, Congenital, Humans, Infant, Microcirculation, Nitric Oxide, Pilot Projects, Postoperative Complications, Prospective Studies, Severity of Illness Index, Vascular Resistance, Vasodilator Agents, Vasomotor System
Show Abstract · Added July 2, 2019
OBJECTIVES - Cardiopulmonary bypass-induced endothelial dysfunction has been inferred by changes in pulmonary vascular resistance, alterations in circulating biomarkers, and postoperative capillary leak. Endothelial-dependent vasomotor dysfunction of the systemic vasculature has never been quantified in this setting. The objective of the present study was to quantify acute effects of cardiopulmonary bypass on endothelial vasomotor control and attempt to correlate these effects with postoperative cytokines, tissue edema, and clinical outcomes in infants.
DESIGN - Single-center prospective observational cohort pilot study.
SETTING - Pediatric cardiac ICU at a tertiary children's hospital.
PATIENTS - Children less than 1 year old requiring cardiopulmonary bypass for repair of a congenital heart lesion.
INTERVENTION - None.
MEASUREMENTS AND MAIN RESULTS - Laser Doppler perfusion monitoring was coupled with local iontophoresis of acetylcholine (endothelium-dependent vasodilator) or sodium nitroprusside (endothelium-independent vasodilator) to quantify endothelial-dependent vasomotor function in the cutaneous microcirculation. Measurements were obtained preoperatively, 2-4 hours, and 24 hours after separation from cardiopulmonary bypass. Fifteen patients completed all laser Doppler perfusion monitor (Perimed, Järfälla, Sweden) measurements. Comparing prebypass with 2-4 hours postbypass responses, there was a decrease in both peak perfusion (p = 0.0006) and area under the dose-response curve (p = 0.005) following acetylcholine, but no change in responses to sodium nitroprusside. Twenty-four hours after bypass responsiveness to acetylcholine improved, but typically remained depressed from baseline. Conserved endothelial function was associated with higher urine output during the first 48 postoperative hours (R = 0.43; p = 0.008).
CONCLUSIONS - Cutaneous endothelial dysfunction is present in infants immediately following cardiopulmonary bypass and recovers significantly in some patients within 24 hours postoperatively. Confirmation of an association between persistent endothelial-dependent vasomotor dysfunction and decreased urine output could have important clinical implications. Ongoing research will explore the pattern of endothelial-dependent vasomotor dysfunction after cardiopulmonary bypass and its relationship with biochemical markers of inflammation and clinical outcomes.
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21 MeSH Terms
Rapid changes in the microvascular circulation of skeletal muscle impair insulin delivery during sepsis.
Mignemi NA, McClatchey PM, Kilchrist KV, Williams IM, Millis BA, Syring KE, Duvall CL, Wasserman DH, McGuinness OP
(2019) Am J Physiol Endocrinol Metab 316: E1012-E1023
MeSH Terms: Animals, Capillaries, Capillary Permeability, Disease Models, Animal, Echocardiography, Hyperglycemia, Insulin, Insulin Resistance, Lipopolysaccharides, Mice, Microcirculation, Microvessels, Muscle Fibers, Skeletal, Muscle, Skeletal, Sepsis
Show Abstract · Added March 26, 2019
Sepsis costs the healthcare system $23 billion annually and has a mortality rate between 10 and 40%. An early indication of sepsis is the onset of hyperglycemia, which is the result of sepsis-induced insulin resistance in skeletal muscle. Previous investigations have focused on events in the myocyte (e.g., insulin signaling and glucose transport and subsequent metabolism) as the causes for this insulin-resistant state. However, the delivery of insulin to the skeletal muscle is also an important determinant of insulin action. Skeletal muscle microvascular blood flow, which delivers the insulin to the muscle, is known to be decreased during sepsis. Here we test whether the reduced capillary blood flow to skeletal muscle belies the sepsis-induced insulin resistance by reducing insulin delivery to the myocyte. We hypothesize that decreased capillary flow and consequent decrease in insulin delivery is an early event that precedes gross cardiovascular alterations seen with sepsis. This hypothesis was examined in mice treated with either lipopolysaccharide (LPS) or polymicrobial sepsis followed by intravital microscopy of the skeletal muscle microcirculation. We calculated insulin delivery to the myocyte using two independent methods and found that LPS and sepsis rapidly reduce insulin delivery to the skeletal muscle by ~50%; this was driven by decreases in capillary flow velocity and the number of perfused capillaries. Furthermore, the changes in skeletal muscle microcirculation occur before changes in both cardiac output and arterial blood pressure. These data suggest that a rapid reduction in skeletal muscle insulin delivery contributes to the induction of insulin resistance during sepsis.
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15 MeSH Terms
Automated quantification of microvascular perfusion.
McClatchey PM, Mignemi NA, Xu Z, Williams IM, Reusch JEB, McGuinness OP, Wasserman DH
(2018) Microcirculation 25: e12482
MeSH Terms: Animals, Automation, Blood Flow Velocity, Hematocrit, Mice, Microcirculation, Microscopy, Fluorescence, Microscopy, Video, Microvessels, Perfusion, Phenylephrine, Reproducibility of Results, Saline Solution, Software
Show Abstract · Added March 26, 2019
OBJECTIVE - Changes in microvascular perfusion have been reported in many diseases, yet the functional significance of altered perfusion is often difficult to determine. This is partly because commonly used techniques for perfusion measurement often rely on either indirect or by-hand approaches.
METHODS - We developed and validated a fully automated software technique to measure microvascular perfusion in videos acquired by fluorescence microscopy in the mouse gastrocnemius. Acute perfusion responses were recorded following intravenous injections with phenylephrine, SNP, or saline.
RESULTS - Software-measured capillary flow velocity closely correlated with by-hand measured flow velocity (R = 0.91, P < 0.0001). Software estimates of capillary hematocrit also generally agreed with by-hand measurements (R = 0.64, P < 0.0001). Detection limits range from 0 to 2000 μm/s, as compared to an average flow velocity of 326 ± 102 μm/s (mean ± SD) at rest. SNP injection transiently increased capillary flow velocity and hematocrit and made capillary perfusion more steady and homogenous. Phenylephrine injection had the opposite effect in all metrics. Saline injection transiently decreased capillary flow velocity and hematocrit without influencing flow distribution or stability. All perfusion metrics were temporally stable without intervention.
CONCLUSIONS - These results demonstrate a novel and sensitive technique for reproducible, user-independent quantification of microvascular perfusion.
© 2018 John Wiley & Sons Ltd.
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14 MeSH Terms
The Vasculature in Prediabetes.
Wasserman DH, Wang TJ, Brown NJ
(2018) Circ Res 122: 1135-1150
MeSH Terms: Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Vessels, Cardiovascular Diseases, Combined Modality Therapy, Diabetes Mellitus, Type 2, Diet, Reducing, Disease Progression, Endothelium, Vascular, Extracellular Matrix, Fatty Acids, Nonesterified, Fibrinolysis, Glucose, Humans, Hyperglycemia, Hypoglycemic Agents, Inflammation, Insulin Resistance, Life Style, Metabolic Syndrome, Mice, MicroRNAs, Microcirculation, Muscle, Skeletal, Obesity, Prediabetic State, Risk, Weight Loss
Show Abstract · Added March 26, 2019
The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.
© 2018 American Heart Association, Inc.
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28 MeSH Terms
New paradigms in sepsis: from prevention to protection of failing microcirculation.
Hawiger J, Veach RA, Zienkiewicz J
(2015) J Thromb Haemost 13: 1743-56
MeSH Terms: Animals, Genetic Predisposition to Disease, Genome, Bacterial, Genome, Fungal, Genome, Viral, Host-Pathogen Interactions, Humans, Inflammation Mediators, Microcirculation, Microvessels, Phenotype, Risk Factors, Sepsis, Signal Transduction, Treatment Outcome
Show Abstract · Added October 4, 2015
Sepsis, also known as septicemia, is one of the 10 leading causes of death worldwide. The rising tide of sepsis due to bacterial, fungal and viral infections cannot be stemmed by current antimicrobial therapies and supportive measures. New paradigms for the mechanism and resolution of sepsis and consequences for sepsis survivors are emerging. Consistent with Benjamin Franklin's dictum 'an ounce of prevention is worth a pound of cure', sepsis can be prevented by vaccinations against pneumococci and meningococci. Recently, the NIH NHLBI Panel redefined sepsis as 'severe endothelial dysfunction syndrome in response to intravascular and extravascular infections causing reversible or irreversible injury to the microcirculation responsible for multiple organ failure'. Microvascular endothelial injury underlies sepsis-associated hypotension, edema, disseminated intravascular coagulation, acute respiratory distress syndrome and acute kidney injury. Microbial genome products trigger 'genome wars' in sepsis that reprogram the human genome and culminate in a 'genomic storm' in blood and vascular cells. Sepsis can be averted experimentally by endothelial cytoprotection through targeting nuclear signaling that mediates inflammation and deranged metabolism. Endothelial 'rheostats' (e.g. inhibitors of NF-κB, A20 protein, CRADD/RAIDD protein and microRNAs) regulate endothelial signaling. Physiologic 'extinguishers' (e.g. suppressor of cytokine signaling 3) can be replenished through intracellular protein therapy. Lipid mediators (e.g. resolvin D1) hasten sepsis resolution. As sepsis cases rose from 387 330 in 1996 to 1.1 million in 2011, and are estimated to reach 2 million by 2020 in the US, mortality due to sepsis approaches that of heart attacks and exceeds deaths from stroke. More preventive vaccines and therapeutic measures are urgently needed.
© 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.
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Vasodilator-responsive idiopathic pulmonary arterial hypertension: evidence for a new disease?
Brittain EL, Hemnes AR
(2015) Ann Intern Med 162: 148-9
MeSH Terms: Capillaries, Familial Primary Pulmonary Hypertension, Female, Humans, Male, Microcirculation, Vasodilator Agents
Added February 10, 2015
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7 MeSH Terms
Vascular content, tone, integrity, and haemodynamics for guiding fluid therapy: a conceptual approach.
Chawla LS, Ince C, Chappell D, Gan TJ, Kellum JA, Mythen M, Shaw AD, ADQI XII Fluids Workgroup
(2014) Br J Anaesth 113: 748-55
MeSH Terms: Blood Vessels, Delphi Technique, Dialysis, Fluid Therapy, Hemodynamics, Humans, Microcirculation, Perfusion, Regional Blood Flow, Sepsis
Show Abstract · Added October 20, 2015
BACKGROUND - Despite many clinical trials and investigative efforts to determine appropriate therapeutic intervention(s) for shock, this topic remains controversial. The use of i.v. fluid has represented the cornerstone for the treatment of hypoperfusion for two centuries.
METHODS - As a part of International Acute Dialysis Quality Initiative XII Fluids Workgroup meeting, we sought to incorporate recent advances in our understanding of vascular biology into a more comprehensive yet accessible approach to the patient with hypoperfusion. In this workgroup, we attempted to develop a framework that incorporates key aspects of the vasculature into a diagnostic approach.
RESULTS - The four main components of our proposal involve the assessment of the blood flow (BF), vascular content (vC), the vascular barrier (vB), and vascular tone (vT). Any significant perturbation in any of these domains can lead to hypoperfusion at both the macro- and micro-circulatory level. We have termed the BF, vC, vB, and vT diagnostic approach the vascular component (VC) approach.
CONCLUSIONS - The VC approach to hypoperfusion has potential advantages to the current diagnostic system. This approach also has the distinct advantage that it can be used to assess the systemic, regional, and micro-vasculature, thereby harmonizing the approach to clinical vascular diagnostics across these levels. The VC approach will need to be tested prospectively to determine if this system can in fact improve outcomes in patients who suffer from hypoperfusion.
© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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The role of cytochrome P450 epoxygenases in retinal angiogenesis.
Capozzi ME, McCollum GW, Penn JS
(2014) Invest Ophthalmol Vis Sci 55: 4253-60
MeSH Terms: Animals, Animals, Newborn, Aryl Hydrocarbon Hydroxylases, Astrocytes, Cell Proliferation, Cells, Cultured, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System, Disease Models, Animal, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Regulation, Developmental, Humans, Microcirculation, RNA, Messenger, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Retina, Retinal Neovascularization, Vascular Endothelial Growth Factor A
Show Abstract · Added February 19, 2015
PURPOSE - The purpose of this study was to investigate the role(s) of cytochrome P450 epoxygenases (CYPs) and their products, the epoxyeicosatrienoic acids (EETs), in hypoxia-induced VEGF production and pathologic retinal angiogenesis.
METHODS - Human retinal astrocytes, Müller cells, and retinal microvascular endothelial cells (HRMEC) were exposed to hypoxia, and relative CYP2C expression was measured by RT-PCR. Astrocyte and Müller cell VEGF production was measured by ELISA after exposure to hypoxia and treatment with the general CYP inhibitor, SKF-525a. Human retinal microvascular endothelial cells were treated with the CYP product, 11,12-epoxyeicosatrienoic acid [EET], or SKF-525a in the presence or absence of VEGF. Proliferation of HRMEC and tube formation were assayed. Oxygen-induced retinopathy (OIR) was induced in newborn rats. Retinal CYP2C11 and CYP2C23 expression were measured by RT-PCR. The OIR rats received SKF-525a by intravitreal injection and preretinal neovascularization (NV) was quantified. Retinal VEGF protein levels were measured by ELISA.
RESULTS - Human retinal astrocytes were the only cells to exhibit significant induction of CYP2C8 and CYP2C9 mRNA expression by hypoxia. Astrocytes, but not Müller cells, exhibited reduced hypoxia-induced VEGF production when treated with SKF-525a. 11,12-EET induced HRMEC proliferation and tube formation, and SKF-525a inhibited VEGF-induced proliferation. Oxygen-induced retinopathy induced expression of CYP2C23, but had no effect on CYP2C11. SKF-525a inhibited retinal NV and reduced retinal VEGF levels in OIR rats.
CONCLUSIONS - The CYP-derived 11,12-EET may exhibit a proangiogenic biological function in the retina following stimulation by hypoxia in astrocytes. Inhibition of CYP may provide a rational therapy against retinal NV, because it can reduce VEGF production and VEGF-induced angiogenic responses in endothelial cells.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
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23 MeSH Terms