The vagus nerve in cardiovascular physiology and pathophysiology: From evolutionary insights to clinical medicine.

The parasympathetic nervous system via the vagus nerve exerts profound influence over the heart. Together with the sympathetic nervous system, the parasympathetic nervous system is responsible for fine-tuned regulation of all aspects of cardiovascular function, including heart rate, rhythm, contractility, and blood pressure. In this review, we highlight vagal efferent and afferent innervation of the heart, with a focus on insights from comparative biology and advances in understanding the molecular and genetic diversity of vagal neurons, as well as interoception, parasympathetic dysfunction in heart disease, and the therapeutic potential of targeting the parasympathetic nervous system in cardiovascular disease.

Lactate infusion elevates cardiac output through increased heart rate and decreased vascular resistance: a randomised, blinded, crossover trial in a healthy porcine model.

BACKGROUND: Lactate is traditionally recognized as a by-product of anaerobic metabolism. However, lactate is a preferred oxidative substrate for stressed myocardium. Exogenous lactate infusion increases cardiac output (CO). The exact mechanism underlying this mechanism has yet to be elucidated. The aim of this study was to investigate the cardiovascular mechanisms underlying the acute haemodynamic effects of exogenous lactate infusion in an experimental model of human-sized pigs. METHODS: In this randomised, blinded crossover study in eight 60-kg-pigs, the pigs received infusions with one molar sodium lactate and a control infusion of tonicity matched hypertonic saline in random order. We measured CO and pulmonary pressures using a pulmonary artery catheter. A pressure-volume admittance catheter in the left ventricle was used to measure contractility, afterload, preload and work-related parameters. RESULTS: Lactate infusion increased circulating lactate levels by 9.9 mmol/L (95% confidence interval (CI) 9.1 to 11.0) and CO by 2.0 L/min (95% CI 1.2 to 2.7). Afterload decreased as arterial elastance fell by  -1.0 mmHg/ml (95% CI  -2.0 to  -0.1) and systemic vascular resistance decreased by  -548 dynes/s/cm5 (95% CI  -261 to  -835). Mixed venous saturation increased by 11 percentage points (95% CI 6 to 16), whereas ejection fraction increased by 16.0 percentage points (95% CI 1.1 to 32.0) and heart rate by 21 bpm (95% CI 8 to 33). No significant changes in contractility nor preload were observed. CONCLUSION: Lactate infusion increased cardiac output by increasing heart rate and lowering afterload. No differences were observed in left ventricular contractility or preload. Lactate holds potential as a treatment in situations with lowered CO and should be investigated in future clinical studies.

Early heart development: examining the dynamics of function-form emergence.

During early embryonic development, the heart undergoes a remarkable and complex transformation, acquiring its iconic four-chamber structure whilst concomitantly contracting to maintain its essential function. The emergence of cardiac form and function involves intricate interplays between molecular, cellular, and biomechanical events, unfolding with precision in both space and time. The dynamic morphological remodelling of the developing heart renders it particularly vulnerable to congenital defects, with heart malformations being the most common type of congenital birth defect (∼35% of all congenital birth defects). This mini-review aims to give an overview of the morphogenetic processes which govern early heart formation as well as the dynamics and mechanisms of early cardiac function. Moreover, we aim to highlight some of the interplay between these two processes and discuss how recent findings and emerging techniques/models offer promising avenues for future exploration. In summary, the developing heart is an exciting model to gain fundamental insight into the dynamic relationship between form and function, which will augment our understanding of cardiac congenital defects and provide a blueprint for potential therapeutic strategies to treat disease.

Test-retest reliability of Doppler ultrasound-based leg blood flow assessments during exercise in patients with chronic obstructive pulmonary disease.

Doppler ultrasound may be used to assess leg blood flow ( Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ ), but the reliability of this method remains unexplored in patients with chronic obstructive pulmonary disease (COPD), where between-subject variability may be larger than healthy due to peripheral vascular changes. This study aimed to investigate the reliability of Doppler ultrasound in quantifying Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ during single-leg knee-extensor exercise (KEE) in COPD patients compared with those obtained from healthy matched controls. In this case-control study, 16 participants with COPD were matched based on sex and age with 16 healthy controls. All participants underwent measurement of Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ using Doppler ultrasound in a KEE set-up at various intensities on two separate visits. Confounding factors on Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ were controlled for, and the ultrasound scans were consistently performed by the same sonographer. During exercise, smallest real difference (SRD) ranged from 367 mL to 583 mL in COPD and 438 mL to 667 mL in the control group. The coefficient of variation (CV) ranged from 7.9% to 14.3% in COPD and 9.4% to 10.4% in the control group. The intraclass correlation coefficient ranged from 0.75 to 0.92 in COPD and 0.67 to 0.84 in the control group. CV was lower in the control group during exercise at 0 W, but apart from that, reliability was not different between groups during exercise. Doppler ultrasound showed nearly equal reliability when evaluating Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ in COPD patients and healthy individuals with a CV below 15% during exercise for both groups. HIGHLIGHTS: What is the central question of this study? What is the between-day reliability of Doppler ultrasound when quantifying leg blood flow during single-leg knee-extensor exercise in COPD patients compared to healthy matched controls? What is the main finding and its importance? This study demonstrates a coefficient of variation ranging from 7.9 to 14.3% during single-leg knee-extensor exercise for between-day reliability when applying Doppler ultrasound to assess leg blood flow in patients with COPD. Furthermore, it offers insights into the peripheral circulatory constraints in COPD, as evidenced by diminished leg blood flow. This study is the first of its kind to evaluate the reliability of Doppler ultrasound in the assessment of the peripheral circulation during exercise in COPD.

Cold stimulation of the oral cavity redistributes blood towards the brain in healthy volunteers.

BACKGROUND: The aim of this study was to analyze cold stimulation-induced changes in cerebral and cardiac hemodynamics. METHODS: Upon ingestion of an ice cube, the changes in resistance index, mean flow velocity and flow index of the middle cerebral arteries (MCA) were assessed using transcranial Doppler sonography. Extracranial duplex sonography was used to measure the mean flow velocity and resistance index of the right internal carotid artery (ICA). The change in mean arterial pressure, heart rate, root mean square of successive differences (RMSSD) and end-tidal carbon dioxide pressure were analyzed additionally. These changes were compared to sham stimulation. RESULTS: Compared with sham stimulation, cooling of the oral cavity resulted in significant changes in cerebral and cardiac hemodynamics. The cold stimulation decreased the resistance index in the MCA (-4.5% ± 5.4%, p < 0.0001) and right ICA (-6.3% ± 15.6%, p = 0.001). This was accompanied by an increase in mean flow velocity (4.1% ± 8.0%, p < 0.0001) and flow index (10.1% ± 43.6%, p = 0.008) in the MCA. The cardiac effects caused an increase in mean arterial pressure (1.8% ± 11.2%, p = 0.017) and RMSSD (55% ± 112%, p = 0.048), while simultaneously decreasing the heart rate (-4.3% ± 9.6%, p = 0.0001). CONCLUSION: Cooling of the oral cavity resulted in substantial changes in cerebral and cardiac hemodynamics resulting in a blood flow diversion to the brain.

Pharmacological and physiological effects of cannabidiol: a dose escalation, placebo washout study protocol.

BACKGROUND: Cannabinoids such as cannabidiol (CBD) exhibit anti-inflammatory properties and have the potential to act as a therapeutic following mild traumatic brain injury. There is limited evidence available on the pharmacological, physiological and psychological effects of escalating CBD dosages in a healthy, male, university athlete population. Furthermore, no dosing regimen for CBD is available with implications of improving physiological function. This study will develop an optimal CBD dose based on the pharmacokinetic data in contact-sport athletes. The physiological and psychological data will be correlated to the pharmacokinetic data to understand the mechanism(s) associated with an escalating CBD dose. METHODS/DESIGN: Forty participants will receive escalating doses of CBD ranging from 5 mg CBD/kg/day to 30 mg CBD/kg/day. The CBD dose is escalated every two weeks in increments of 5 mg CBD/kg/day. Participants will provide blood for pharmacological assessments at each of the 10 visits. Participants will complete a physiological assessment at each of the visits, including assessments of cerebral hemodynamics, blood pressure, electrocardiogram, seismocardiogram, transcranial magnetic stimulation, and salivary analysis for genomic sequencing. Finally, participants will complete a psychological assessment consisting of sleep, anxiety, and pain-related questionnaires. DISCUSSION: This study will develop of an optimal CBD dose based on pharmacological, physiological, and psychological properties for future use during contact sport seasons to understand if CBD can help to reduce the frequency of mild traumatic injuries and enhance recovery. TRIAL REGISTRATION: Clinicaltrials.gov: NCT06204003.

Cardiac Output Changes during Renal Replacement Therapy: A Scoping Review.

INTRODUCTION: Renal replacement therapy (RRT) is associated with hypotension. However, its impact on cardiac output (CO) is less understood. We aimed to describe current knowledge of CO monitoring and changes during RRT. METHODS: We searched MEDLINE, Embase, and Cochrane from January 1, 2000, to January 31, 2023, using Covidence for studies of intermittent hemodialysis (IHD) and continuous RRT (CRRT) with at least three CO measurements during treatment. Two independent reviewers screened citations, and a third resolved disagreements. The findings did not allow meta-analysis and are presented descriptively. RESULTS: We screened 3,285 articles and included 48 (37 during IHD, nine during CRRT, and two during both). Non-invasive devices (electrical conductivity techniques and finger cuff pulse contour) were the most common CO measurement techniques (21 studies). The median baseline cardiac index in IHD studies was 3 L/min/m2 (95% CI, 2.7-3.39). Among the 88 patient cohorts studied, a decrease in CO occurred in 63 (72%). In 16 cohorts, the decrease was severe (>25%). Changes in blood pressure (BP) were not concordant in extent or direction with changes in CO. The decrease in CO correlated weakly with ultrafiltration rate (r = -0.3, p = 0.05) and strongly with changes in systemic vascular resistance (SVR) (r = -0.6, p < 0.001). CONCLUSION: There are limited data on CO changes during RRT. However, a decrease in CO appeared common and was marked in 1 of 5 patient cohorts. Such decreases often occurred without BP changes and were associated with increased SVR.

A Pilot and Feasibility Study of Continuous Cardiac Output and Blood Pressure Monitoring during Intermittent Hemodialysis.

INTRODUCTION: Hypotension is common during intermittent hemodialysis (IHD) and may be due to a decreased cardiac index (CI). However, no study has simultaneously and continuously measured CI and mean arterial pressure (MAP) to understand the prevalence, severity, and duration of CI decreases or relate them to MAP, blood volume (BV), and net ultrafiltration (NUF) rate. METHODS: In a prospective, pilot and feasibility investigation, we studied 10 chronic IHD patients. We used the ClearSight System™ to continuously monitor CI and MAP; the CRIT-LINE®IV monitor to detect BV changes and collected data on NUF rate. RESULTS: Device tolerance and compliance were 100%. All patients experienced at least ≥1 episode of severe CI decrease (>25% from baseline), with a median duration of 24 min (IQR 6-87) and of 68 min [14-106] for moderate decreases (>15% but ≤25% from baseline). Eight patients experienced a low CI state (<2.2 L/min/m2). The lowest CI was 0.9 L/min/m2 with a concomitant MAP of 94 mm Hg. When the fall in CI was severe, MAP increased in 58% of cases and remained stable in 28%. Overall, CI decreased by -0.55 L/min/m2 when BV decrease was moderate versus mild (p < 0.001) and by -0.8 L/min/m2 when NUF rate was high versus low (p < 0.001). CONCLUSION: Continuous CI monitoring is feasible in IHD and shows frequent moderate-severe CI decreases, sometimes to low CI state levels. Such decreases are typically associated with markers of decreased intravascular volume status but not with a decrease in MAP, implying marked vasoconstriction.

Inhaled endotoxin induces a systemic neutrophil response without affecting cardiovascular measures in a randomized cross-over exposure study.

OBJECTIVE: The gram-negative bacterial cell wall component endotoxin (lipopolysaccharide, LPS) is a key component of particulate matter (PM). PM exposure is associated with cardiovascular morbidity and mortality. However, the contribution of individual components of PM to acute and chronic cardiovascular measures is not clear. This study examines whether systemic inflammation induced by LPS inhalation causes acute changes in cardiovascular physiology measures. MATERIALS AND METHODS: In this double blinded, placebo-controlled crossover study, fifteen adult volunteers underwent inhalation exposure to 20,000 EU Clinical Center Reference Endotoxin (CCRE). Peripheral blood and induced sputum neutrophils were obtained at baseline and six hours post-exposure. Blood pressure, measures of left ventricular function (ejection fraction (LVEF) and global longitudinal strain (LVGLS)), and indices of endothelial function (flow mediated dilation (FMD) and velocity time integral during hyperemia (VTIhyp)) were measured before and after treatment. Wilcoxon sign-rank tests and linear mixed models were used for statistical analysis. RESULTS: In comparison with normal saline, LPS inhalation resulted in significant increases in peripheral blood and sputum neutrophils but was not associated with significant alterations in blood pressure, LVGLS, LVEF, FMD, or VTIhyp. DISCUSSION AND CONCLUSIONS: In healthy adults, systemic inflammation after LPS inhalation was not associated with acute changes in cardiovascular physiology. Larger studies are needed to investigate the effects of other PM components on inflammation induced cardiovascular dysfunction.

Within the optimal thermal range, temperature fluctuations with similar means have little effect on offspring phenotypes: A comparison of two approaches that simulate natural nest conditions.

Temperature influences nearly every aspect of organismal function. Because aspects of global change such as urbanization and climate change influence temperature, researchers must consider how altering thermal regimes will impact biodiversity across the planet. To do so, they often measure temperature in natural and/or human-modified habitats, replicate those temperatures in laboratory experiments to understand organismal responses, and make predictions under models of future change. Consequently, accurately representing temperature in the laboratory is an important concern, yet few studies have assessed the consequences of simulating thermal conditions in different ways. We used nest temperatures for two urban-dwelling, invasive lizards (Anolis sagrei and A. cristatellus) to create two egg incubation treatments in the laboratory. Like most studies of thermal developmental plasticity, we created daily repeating thermal fluctuations; however, we used different methods to create temperature treatments that differed in the magnitude and breadth of thermal cycles, and then evaluated the effects of these different approaches on embryo development and hatchling phenotypes. Additionally, we measured embryo heart rate, a proxy for metabolism, across temperature to understand the immediate effects of treatments. We found that treatments had minimal effect on phenotypes likely because temperatures were within the optimal thermal range for each species and were similar in mean temperature. We conclude that slight differences in thermal treatments may be unimportant so long as temperatures are within a range appropriate for development, and we make several recommendations for future studies of developmental plasticity.

The good, the bad and the ugly: the impact of extracellular vesicles on the cardiovascular system.

Cardiovascular diseases (CVDs), which encompass a myriad of pathological conditions that affect the heart and/or the blood vessels, remain the major cause of morbidity and mortality worldwide. By transferring a wide variety of bioactive molecules, including proteins and microRNAs (miRNAs), extracellular vesicles (EVs) are recognized as key players in long-range communication across the cardiovascular system. It has been demonstrated that these highly heterogeneous nanosized vesicles participate both in the maintenance of homeostasis of the heart and vessels, and contribute to the pathophysiology of CVDs, thus emerging as promising tools for diagnosis, prognosis and treatment of multiple CVDs. In this review, we highlight the beneficial roles of EV-mediated communication in regulating vascular homeostasis, and inter-organ crosstalk as a potential mechanism controlling systemic metabolic fitness. In addition, the impact of EV secretion in disease development is described, particularly focusing on cardiac remodelling following ischaemia, atherogenesis and atrial fibrillation progression. Finally, we discuss the potential of endogenous and bioengineered EVs as therapeutic tools for CVDs, as well as the suitability of assessing the molecular signature of circulating EVs as a non-invasive predictive marker of CVD onset and progression. This rapidly expanding field of research has established the role of EVs as key conveyors of both cardioprotective and detrimental signals, which might be of relevance in uncovering novel therapeutic targets and biomarkers of CVDs.

Adjusting for muscle strength and body size attenuates sex differences in the exercise pressor reflex in young adults.

Females typically exhibit lower blood pressure (BP) during exercise than males. However, recent findings indicate that adjusting for maximal strength attenuates sex differences in BP during isometric handgrip (HG) exercise and postexercise ischemia (PEI; metaboreflex isolation). In addition, body size is associated with HG strength but its contribution to sex differences in exercising BP is less appreciated. Therefore, the purpose of this study was to determine whether adjusting for strength and body size would attenuate sex differences in BP during HG and PEI. We obtained beat-to-beat BP in 110 participants (36 females, 74 males) who completed 2 min of isometric HG exercise at 40% of their maximal voluntary contraction followed by 3 min of PEI. In a subset (11 females, 17 males), we collected muscle sympathetic nerve activity (MSNA). Statistical analyses included independent t tests and mixed models (sex × time) with covariate adjustment for 40% HG force, height2, and body surface area. Females exhibited a lower absolute 40% HG force than male participants (Ps < 0.001). Females exhibited lower Δsystolic, Δdiastolic, and Δmean BPs during HG and PEI than males (e.g., PEI, Δsystolic BP, 15 ± 11 vs. 23 ± 14 mmHg; P = 0.004). After covariate adjustment, sex differences in BP responses were attenuated. There were no sex differences in MSNA. In a smaller strength-matched cohort, there was no sex × time interactions for BP responses (e.g., PEI systolic BP, P = 0.539; diastolic BP, P = 0.758). Our data indicate that sex differences in exercising BP responses are attenuated after adjusting for muscle strength and body size.NEW & NOTEWORTHY When compared with young males, females typically exhibit lower blood pressure (BP) during exercise. Adjusting for maximal strength attenuates sex differences in BP during isometric handgrip (HG) exercise and postexercise ischemia (PEI), but the contribution of body size is unknown. Novel findings include adjustments for muscle strength and body size attenuate sex differences in BP reactivity during exercise and PEI, and sex differences in body size contribute to HG strength differences.

Cardiovascular responses to mild perinatal asphyxia in growth-restricted preterm lambs.

Growth-restricted neonates have worse outcomes after perinatal asphyxia, with more severe metabolic acidosis than appropriately grown neonates. The cardiovascular physiology associated with fetal growth restriction (FGR) may alter their response to asphyxia. However, research on asphyxia in FGR is limited. Here we compared cardiovascular hemodynamics in preterm FGR and control lambs during mild perinatal asphyxia. We induced FGR in one twin at 89 days gestation (term 148 days), while the other served as a control. At 126 days gestation, lambs were instrumented to allow arterial blood pressure and regional blood flow recording, and then mild perinatal asphyxia was induced by umbilical cord clamping, and resuscitation followed neonatal guidelines. FGR lambs maintained carotid blood flow (CBF) for 7 min, while control lambs rapidly decreased CBF (P < 0.05). Fewer growth-restricted lambs needed chest compressions for return of spontaneous circulation (ROSC) (17 vs. 83%, P = 0.02). The extent of blood pressure overshoot after ROSC was similar, but it took longer for MAP to return to baseline in FGR lambs (18.83 ± 0.00 vs. 47.67 ± 0.00 min, P = 0.003). Growth-restricted lambs had higher CBF after ROSC (P < 0.05) and displayed CBF overshoot, unlike control lambs (P < 0.03). In conclusion, preterm growth-restricted lambs show resilience during perinatal asphyxia based on prolonged CBF maintenance and reduced need for chest compressions during resuscitation. However, CBF overshoot after ROSC may increase the risk of cerebrovascular injury in FGR.NEW & NOTEWORTHY Preterm growth-restricted lambs maintain carotid blood flow for longer than control lambs during asphyxia and have a lower requirement for chest compressions than control lambs during resuscitation. Preterm growth-restricted, but not control, lambs displayed an overshoot in carotid blood flow following return of spontaneous circulation.

Sex differences in cardiovascular disease and dysregulation in Down syndrome.

This meta-analysis, which consisted of a scoping review and retrospective medical record review, is focused on potential sex differences in cardiovascular diseases in patients with Down syndrome. We limited our review to peer-reviewed, primary articles in the English language, in the PubMed and Web of Science databases from 1965 to 2021. Guidelines for scoping reviews were followed throughout the process. Four categorical domains were identified and searched using additional keywords: 1) congenital heart disease, 2) baseline physiology and risk factors, 3) heart disease and hypertension, and 4) stroke and cerebrovascular disease. Articles were included if they reported male and female distinct data, participants with Down syndrome, and one of our keywords. The retrospective medical record review was completed using 75 participating health care organizations to identify the incidence of congenital and cardiovascular diseases and to quantify cardiovascular risk factors in male and female patients. Female patients with Down syndrome are at higher risk of hypertension, ischemic heart disease, and cerebrovascular disease. The risk of congenital heart disease is higher in males with Down syndrome at all ages included in our analyses. Some of the male-to-female sex differences in cardiovascular disease risk in the general patient population are not present, or reversed in the Down syndrome population. This information should be considered for future investigations and ongoing patient care.NEW & NOTEWORTHY In patients with Down syndrome (DS), CHD is the leading cause of death <20 yr old and cardiovascular disease is a leading cause of death in individuals >20 yr old. Men with DS live longer than women. It is unknown if sex differences are present in cardiovascular disease and dysregulation in DS across the lifespan. We observed higher risk of hypertension, ischemic heart disease, and cerebrovascular disease in females and a higher risk of CHD in males with DS.

Cardiovascular research at the Heart of Clinical Science.

Clinical Science was originally established as the journal Heart in 1909 by Sir Thomas Lewis and Sir James Mackenzie. Heart was an influential journal publishing cardiovascular research and was renamed Clinical Science in 1933 to attract broader research interests. Nevertheless, cardiovascular research contributions remain a foundational part of the journal to this day. This editorial provides historical perspective on the journal's cardiovascular origins and includes data related to cardiovascular publications from the past decade. Clinical Science is committed to publishing leading cardiovascular research from the field and looks forward to receiving your submission.

The O-GlcNAc dichotomy: when does adaptation become pathological?

O-Linked attachment of ß-N-acetylglucosamine (O-GlcNAc) on serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins is a highly dynamic and ubiquitous post-translational modification that impacts the function, activity, subcellular localization, and stability of target proteins. Physiologically, acute O-GlcNAcylation serves primarily to modulate cellular signaling and transcription regulatory pathways in response to nutrients and stress. To date, thousands of proteins have been revealed to be O-GlcNAcylated and this number continues to grow as the technology for the detection of O-GlcNAc improves. The attachment of a single O-GlcNAc is catalyzed by the enzyme O-GlcNAc transferase (OGT), and their removal is catalyzed by O-GlcNAcase (OGA). O-GlcNAcylation is regulated by the metabolism of glucose via the hexosamine biosynthesis pathway, and the metabolic abnormalities associated with pathophysiological conditions are all associated with increased flux through this pathway and elevate O-GlcNAc levels. While chronic O-GlcNAcylation is well associated with cardiovascular dysfunction, only until recently, and with genetically modified animals, has O-GlcNAcylation as a contributing mechanism of cardiovascular disease emerged. This review will address and critically evaluate the current literature on the role of O-GlcNAcylation in vascular physiology, with a view that this pathway can offer novel targets for the treatment and prevention of cardiovascular diseases.

Krüppel-like factor (KLF)5: An emerging foe of cardiovascular health.

Krüppel-like factors (KLFs) are DNA-binding transcriptional factors, which regulate various pathways that pertain to development, metabolism and other cellular mechanisms. KLF5 was first cloned in 1993 and by 1999, it was reported as the intestinal-enriched KLF. Beyond findings that have associated KLF5 with normal development and cancer, it has been associated with various types of cardiovascular (CV) complications and regulation of metabolic pathways in the liver, heart, adipose tissue and skeletal muscle. Specifically, increased KLF5 expression has been linked with cardiomyopathy in diabetes, end-stage heart failure, and as well as in vascular atherosclerotic lesions. In this review article, we summarize research findings about transcriptional, post-transcriptional and post-translational regulation of KLF5, as well as the role of KLF5 in the biology of cells and organs that affect cardiovascular health either directly or indirectly. Finally, we propose KLF5 inhibition as an emerging approach for cardiovascular therapeutics.

Oral and intravenous glucose administration elicit opposing microvascular blood flow responses in skeletal muscle of healthy people: role of incretins.

Insulin infusion increases skeletal muscle microvascular blood flow (MBF) in healthy people but is impaired during insulin resistance. However, we have shown that eliciting insulin secretion via oral glucose loading in healthy people impairs muscle MBF, whilst others have demonstrated intravenous glucose infusion stimulates MBF. We aimed to show that the route of glucose administration (oral versus intravenous) influences muscle MBF, and explore potential gut-derived hormones that may explain these divergent responses. Ten healthy individuals underwent a 120 min oral glucose tolerance test (OGTT; 75 g glucose) and on a subsequent occasion an intravenous glucose tolerance test (IVGTT, bypassing the gut) matched for similar blood glucose excursions. Femoral artery and thigh muscle microvascular (contrast-enhanced ultrasound) haemodynamics were measured at baseline and during the OGTT/IVGTT. Plasma insulin, C-peptide, glucagon, non-esterified fatty acids and a range of gut-derived hormones and incretins (gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1(GLP-1)) were measured at baseline and throughout the OGTT/IVGTT. The IVGTT increased whereas the OGTT impaired MBF (1.3-fold versus 0.5-fold from baseline, respectively, P = 0.0006). The impairment in MBF during the OGTT occurred despite producing 2.8-fold higher plasma insulin concentrations (P = 0.0001). The change in MBF from baseline (ΔMBF) negatively correlated with ΔGIP concentrations (r = -0.665, P < 0.0001). The natural log ratio of incretins GLP-1:GIP was positively associated with ΔMBF (r = 0.658, P < 0.0001), suggesting they have opposing actions on the microvasculature. Postprandial hyperglycaemia per se does not acutely determine opposing microvascular responses between OGTT and IVGTT. Incretins may play a role in modulating skeletal muscle MBF in humans. KEY POINTS: Insulin or mixed nutrient meals stimulate skeletal muscle microvascular blood flow (MBF) to aid in the delivery of nutrients; however, this vascular effect is lost during insulin resistance. Food/drinks containing large glucose loads impair MBF in healthy people; however, this impairment is not observed when glucose is infused intravenously (bypassing the gut). We investigated skeletal muscle MBF responses to a 75 g oral glucose tolerance test and intravenous glucose infusion and aimed to identify potential gut hormones responsible for glucose-mediated changes in MBF. Despite similar blood glucose concentrations, orally ingested glucose impaired, whereas intravenously infused glucose augmented, skeletal muscle MBF. The incretin gastric inhibitory polypeptide was negatively associated with MBF, suggestive of an incretin-mediated MBF response to oral glucose ingestion. This work provides new insight into why diets high in glucose may be detrimental to vascular health and provides new avenues for novel treatment strategies targeting microvascular dysfunction.

Smoking-induced microbial dysbiosis in health and disease.

Smoking is associated with an increased risk of cancer, pulmonary and cardiovascular diseases, but the precise mechanisms by which such risk is mediated remain poorly understood. Additionally, smoking can impact the oral, nasal, oropharyngeal, lung and gut microbiome composition, function, and secreted molecule repertoire. Microbiome changes induced by smoking can bear direct consequences on smoking-related illnesses. Moreover, smoking-associated dysbiosis may modulate weight gain development following smoking cessation. Here, we review the implications of cigarette smoking on microbiome community structure and function. In addition, we highlight the potential impacts of microbial dysbiosis on smoking-related diseases. We discuss challenges in studying host-microbiome interactions in the context of smoking, such as the correlations with smoking-related disease severity versus causation and mechanism. In all, understanding the microbiome's role in the pathophysiology of smoking-related diseases may promote the development of rational therapies for smoking- and smoking cessation-related disorders, as well as assist in smoking abstinence.

The multifaceted actions of the lncRNA H19 in cardiovascular biology and diseases.

Cardiovascular diseases are the leading cause of death and debility worldwide. Various molecular mechanisms have been studied to better understand the development and progression of cardiovascular pathologies with hope to eradicate these diseases. With the advancement of the sequencing technology, it is revealed that the majority of our genome is non-coding. A growing body of literature demonstrates the critical role of long non-coding RNAs (lncRNAs) as epigenetic regulators of gene expression. LncRNAs can regulate cellular biological processes through various distinct molecular mechanisms. The abundance of lncRNAs in the cardiovascular system indicates their significance in cardiovascular physiology and pathology. LncRNA H19, in particular, is a highly evolutionarily conserved lncRNA that is enriched in cardiac and vascular tissue, underlining its importance in maintaining homeostasis of the cardiovascular system. In this review, we discuss the versatile function of H19 in various types of cardiovascular diseases. We highlight the current literature on H19 in the cardiovascular system and demonstrate how dysregulation of H19 induces the development of cardiovascular pathophysiology.