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Low-dose fentanyl does not alter muscle sympathetic nerve activity, blood pressure, or tolerance during progressive central hypovolemia.
Huang, M, Watso, JC, Belval, LN, Cimino, FA, Fischer, M, Jarrard, CP, Hendrix, JM, Laborde, CH, Crandall, CG
American journal of physiology. Regulatory, integrative and comparative physiology. 2022;(1):R55-R63
Abstract
Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a presyncopal limited progressive lower body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg·min), which was compared between trials using a paired, two-tailed t test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model [time (LBNP stage) × trial]. LBNP tolerance was not different between trials (fentanyl: 647 ± 386 vs. placebo: 676 ± 295 mmHg·min, P = 0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: P < 0.01, trial: P = 0.29, interaction: P = 0.94) and reductions in mean BP (time: P < 0.01, trial: P = 0.50, interaction: P = 0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.
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The effect of beetroot inorganic nitrate supplementation on cardiovascular risk factors: A systematic review and meta-regression of randomized controlled trials.
Bahrami, LS, Arabi, SM, Feizy, Z, Rezvani, R
Nitric oxide : biology and chemistry. 2021;:8-22
Abstract
OBJECTIVES Inorganic nitrate is one of the most effective compounds in beetroot for improving cardiovascular function due to its conversion to nitric oxide in the body. This review and meta-analysis aimed to investigate the role of beetroot inorganic nitrate supplementation on adults' cardiovascular risk factors. METHODS We conducted a systematic literature review of articles published without time limitation until November 2020 in PubMed, Embase, ISI Web of Science, Scopus, Cochrane Library, and gray literature databases. We included the original randomized clinical trials (RCTs) in which the effect of beetroot inorganic nitrate supplementation on endothelial function, arterial stiffness, and blood pressure was studied. RESULTS 43 studies were included for qualitative synthesis, out of which 27 were eligible for meta-analysis. Beetroot inorganic nitrate supplementation significantly decreased Arterial Stiffness (Pulse Wave Velocity (-0.27 m/s, p = 0.04)) and increased Endothelial function (Flow Mediated Dilation: 0.62%, p = 0.002) but did not change other parameters (p > 0.05). CONCLUSION Beetroot inorganic nitrate supplementation might have a beneficial effect on cardiovascular risk factors. Further high-quality investigations will be needed to provide sufficient evidence.
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Analyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach.
Huang, JY, Cai, S, Huang, Z, Tint, MT, Yuan, WL, Aris, IM, Godfrey, KM, Karnani, N, Lee, YS, Chan, JKY, et al
Nature communications. 2021;(1):5613
Abstract
Assisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (-0.5 SD [95% CI: -0.7, -0.2]), lighter (-0.6 SD [-0.9, -0.3]) and have lower skinfold thicknesses (e.g. -14% [-24%, -3%] suprailiac), and blood pressure (-3 mmHg [-6, -0.5] systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype.
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Venoarterial extracorporeal membrane oxygenation as mechanical circulatory support in adult septic shock: a systematic review and meta-analysis with individual participant data meta-regression analysis.
Ling, RR, Ramanathan, K, Poon, WH, Tan, CS, Brechot, N, Brodie, D, Combes, A, MacLaren, G
Critical care (London, England). 2021;(1):246
Abstract
BACKGROUND While recommended by international societal guidelines in the paediatric population, the use of venoarterial extracorporeal membrane oxygenation (VA ECMO) as mechanical circulatory support for refractory septic shock in adults is controversial. We aimed to characterise the outcomes of adults with septic shock requiring VA ECMO, and identify factors associated with survival. METHODS We searched Pubmed, Embase, Scopus and Cochrane databases from inception until 1st June 2021, and included all relevant publications reporting on > 5 adult patients requiring VA ECMO for septic shock. Study quality and certainty in evidence were assessed using the appropriate Joanna Briggs Institute checklist, and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, respectively. The primary outcome was survival to hospital discharge, and secondary outcomes included intensive care unit length of stay, duration of ECMO support, complications while on ECMO, and sources of sepsis. Random-effects meta-analysis (DerSimonian and Laird) were conducted. DATA SYNTHESIS We included 14 observational studies with 468 patients in the meta-analysis. Pooled survival was 36.4% (95% confidence interval [CI]: 23.6%-50.1%). Survival among patients with left ventricular ejection fraction (LVEF) < 20% (62.0%, 95%-CI: 51.6%-72.0%) was significantly higher than those with LVEF > 35% (32.1%, 95%-CI: 8.69%-60.7%, p = 0.05). Survival reported in studies from Asia (19.5%, 95%-CI: 13.0%-26.8%) was notably lower than those from Europe (61.0%, 95%-CI: 48.4%-73.0%) and North America (45.5%, 95%-CI: 16.7%-75.8%). GRADE assessment indicated high certainty of evidence for pooled survival. CONCLUSIONS When treated with VA ECMO, the majority of patients with septic shock and severe sepsis-induced myocardial depression survive. However, VA ECMO has poor outcomes in adults with septic shock without severe left ventricular depression. VA ECMO may be a viable treatment option in carefully selected adult patients with refractory septic shock.
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14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial.
Walsh, JJ, Neudorf, H, Little, JP
The Journal of clinical endocrinology and metabolism. 2021;(4):e1738-e1754
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Abstract
CONTEXT Postprandial hyperglycemia increases systemic inflammation and is a risk factor for cardiovascular disease. A ketone monoester (KME) drink containing β-hydroxybutyrate (β-OHB) rapidly lowers plasma glucose, which may be a strategy protecting against postprandial hyperglycemia. OBJECTIVE We hypothesized that KME would attenuate 2-hour postprandial glucose, lower systemic inflammation, and improve vascular function in adults with obesity. METHODS In a randomized crossover design, 14 participants with obesity (age = 56 ± 12 years; body mass index = 32.8 ± 7.7 kg/m2) consumed KME (12 g β-OHB) or placebo 15 minutes prior to each meal for 14 days with all meals provided and matched between conditions. Postprandial glycemia was assessed by continuous glucose monitoring. Vascular function and inflammation were assessed before and after treatment periods. RESULTS Postprandial glucose was 8.0% lower in KME versus placebo (g = 0.735; P = 0.011) and 24-hour average glucose reduced by 7.8% (g = 0.686; P = 0.0001). Brachial artery flow-mediated dilation increased from 6.2 ± 1.5% to 8.9 ± 3.3% in KME (g = 1.05; P = 0.0004) with no changes in placebo (condition × time interaction, P = 0.004). There were no changes in plasma cytokines; however, lipopolysaccharide-stimulated monocyte caspase-1 activation was lower following KME supplementation versus placebo (stimulation × condition × time interaction; P = 0.004). The KME supplement was well tolerated by participants and adherence to the supplementation regimen was very high. CONCLUSIONS In adults with obesity, 14 days of premeal KME supplementation improves glucose control, enhances vascular function, and may reduce cellular inflammation. KME supplementation may be a viable, nonpharmacological approach to improving and protecting vascular health in people with heightened cardiometabolic risk.
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Key Enzymes for the Mevalonate Pathway in the Cardiovascular System.
Zhang, C, Jin, DD, Wang, XY, Lou, L, Yang, J
Journal of cardiovascular pharmacology. 2021;(2):142-152
Abstract
Isoprenylation is an important post-transcriptional modification of small GTPases required for their activation and function. Isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate, are indispensable for isoprenylation by serving as donors of a prenyl moiety to small G proteins. In the human body, isoprenoids are mainly generated by the mevalonate pathway (also known as the cholesterol-synthesis pathway). The hydroxymethylglutaryl coenzyme A reductase catalyzes the first rate-limiting steps of the mevalonate pathway, and its inhibitor (statins) are widely used as lipid-lowering agents. In addition, the FPP synthase is also of critical importance for the regulation of the isoprenoids production, for which the inhibitor is mainly used in the treatment of osteoporosis. Synthetic FPP can be further used to generate geranylgeranyl pyrophosphate and cholesterol. Recent studies suggest a role for isoprenoids in the genesis and development of cardiovascular disorders, such as pathological cardiac hypertrophy, fibrosis, endothelial dysfunction, and fibrotic responses of smooth-muscle cells. Furthermore, statins and FPP synthase inhibitors have also been applied for the management of heart failure and other cardiovascular diseases rather than their clinical use for hyperlipidemia or bone diseases. In this review, we focus on the function of several critical enzymes, including hydroxymethylglutaryl coenzyme A reductase, FPP synthase, farnesyltransferase, and geranylgeranyltransferase in the mevalonate pathway which are involved in regulating the generation of isoprenoids and isoprenylation of small GTPases, and their pathophysiological role in the cardiovascular system. Moreover, we summarize recent research into applications of statins and the FPP synthase inhibitors to treat cardiovascular diseases, rather than for their traditional indications respectively.
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Which Microbes Like My Diet and What Does It Mean for My Heart?
Sawicka-Śmiarowska, E, Moniuszko-Malinowska, A, Kamiński, KA
Nutrients. 2021;(11)
Abstract
Cardiovascular diseases are the most common causes of hospitalization, death and disability in Europe. Despite our knowledge of nonmodifiable and modifiable cardiovascular classical risk factors, the morbidity and mortality in this group of diseases remains high, leading to high social and economic costs. Therefore, it is necessary to explore new factors, such as the gut microbiome, that may play a role in many crucial pathological processes related to cardiovascular diseases. Diet is a potentially modifiable cardiovascular risk factor. Fats, proteins, carbohydrates, vitamins and minerals are nutrients that are essential to the proper function of the human body. The style and composition of the human diet has changed over time, evolving from a hunter-gatherer diet to an industrialized and Westernized modern diet that includes processed products. The relationship between the gut microbiome, diet and cardiovascular diseases is complex and still not fully understood. In this review, we discuss, in the context of diet, why particular microbes occur in individuals and how they can influence the host's cardiovascular system in health and disease. We investigate the role of particular microorganisms and changes in the Firmicutes/Bacteroidetes ratio.
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The application of in utero magnetic resonance imaging in the study of the metabolic and cardiovascular consequences of the developmental origins of health and disease.
Giza, SA, Sethi, S, Smith, LM, Empey, MET, Morris, LE, McKenzie, CA
Journal of developmental origins of health and disease. 2021;(2):193-202
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Abstract
Observing fetal development in utero is vital to further the understanding of later-life diseases. Magnetic resonance imaging (MRI) offers a tool for obtaining a wealth of information about fetal growth, development, and programming not previously available using other methods. This review provides an overview of MRI techniques used to investigate the metabolic and cardiovascular consequences of the developmental origins of health and disease (DOHaD) hypothesis. These methods add to the understanding of the developing fetus by examining fetal growth and organ development, adipose tissue and body composition, fetal oximetry, placental microstructure, diffusion, perfusion, flow, and metabolism. MRI assessment of fetal growth, organ development, metabolism, and the amount of fetal adipose tissue could give early indicators of abnormal fetal development. Noninvasive fetal oximetry can accurately measure placental and fetal oxygenation, which improves current knowledge on placental function. Additionally, measuring deficiencies in the placenta's transport of nutrients and oxygen is critical for optimizing treatment. Overall, the detailed structural and functional information provided by MRI is valuable in guiding future investigations of DOHaD.
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Cardiovascular dysautonomia in Achalasia Patients: Blood pressure and heart rate variability alterations.
Rivera, AL, Estañol, B, Macias-Gallardo, JJ, Delgado-Garcia, G, Fossion, R, Frank, A, Torres-Villalobos, GM
PloS one. 2021;(3):e0248106
Abstract
Achalasia is a disease characterized by the inability to relax the esophageal sphincter due to a degeneration of the parasympathetic ganglion cells located in the wall of the thoracic esophagus. Achalasia has been associated with extraesophageal dysmotility, suggesting alterations of the autonomic nervous system (ANS) that extend beyond the esophagus. The purpose of the present contribution is to investigate whether achalasia may be interpreted as the esophageal manifestation of a more generalized disturbance of the ANS which includes alterations of heart rate and/or blood pressure. Therefore simultaneous non-invasive records of the heart inter-beat intervals (IBI) and beat-to-beat systolic blood pressure (SBP) of 14 patients (9 female, 5 male) with achalasia were compared with the records of 34 rigorously screened healthy control subjects (17 female, 17 male) in three different conditions: supine, standing up, and controlled breathing at 0.1 Hz, using a variety of measures in the time and spectral domains. Significant differences in heart rate variability (HRV) and blood pressure variability (BPV) were observed which seem to be due to cardiovagal damage to the heart, i.e., a failure of the ANS, as expected according to our hypothesis. This non-invasive methodology can be employed as an auxiliary clinical protocol to study etiology and evolution of achalasia, and other pathologies that damage ANS.
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Impact of prolonged sitting and physical activity breaks on cognitive performance, perceivable benefits, and cardiometabolic health in overweight/obese adults: The role of meal composition.
Wanders, L, Cuijpers, I, Kessels, RPC, van de Rest, O, Hopman, MTE, Thijssen, DHJ
Clinical nutrition (Edinburgh, Scotland). 2021;(4):2259-2269
Abstract
BACKGROUND & AIMS Physical activity (PA) breaks may effectively attenuate the detrimental impact of prolonged sitting on acute cognitive performance, perceivable benefits (e.g. mood), vascular function, and metabolic health. To date, the impact of meal composition on the effects of sedentary behavior and/or PA breaks on health has been scarcely studied. Therefore, our aim was to investigate whether meal composition alters how sedentary behavior and PA breaks affect these acute health outcomes. METHODS A total of 24 overweight and obese, sedentary adults completed four conditions in randomized order in a cross-over design: [a] high-protein, low-fat breakfast (HPLF) + 4hrs uninterrupted sitting (SIT), [b] HPLF + 4hrs interrupted sitting (ACT; 5-min cycling every 30 min), [c] Western breakfast (WEST; higher in fats/simple sugars, lower in protein/fiber) + SIT, [d] WEST + ACT. WEST and HPLF were isocaloric. Linear mixed models were used to examine changes in cognitive performance (Test of Attentional Performance), perceivable benefits (Likert-scales, Profile of Mood States questionnaire), vascular health (carotid artery reactivity, blood pressure), and metabolic health (post-breakfast glucose, insulin, lipids). RESULTS Independent of meal composition, we did not observe any effect of PA breaks on cognitive performance, vascular health and post-breakfast lipid responses. PA breaks delayed post-breakfast mood and vigor decrements, as well as increases in fatigue and sleepiness (all p < 0.05), but effects were independent of meal composition (p > 0.05). WEST resulted in higher post-breakfast glucose levels compared to HPLF (p < 0.05), while PA breaks did not impact this response (p > 0.05). PA breaks reduced post-breakfast insulin (p < 0.05), which did not differ between meals (p > 0.05). CONCLUSIONS The acute impact of PA breaks and/or prolonged sitting on cognitive performance, perceivable benefits, and vascular and metabolic health was not altered by the composition of a single meal in overweight/obese, sedentary adults. Possibly, breaking up prolonged sitting, rather than meal composition, is a more potent strategy to impact acute health outcomes, such as perceivable benefits and insulin levels.