Firing properties of single axons with cardiac rhythmicity in the human cervical vagus nerve.

Microneurographic recordings of the human cervical vagus nerve have revealed the presence of multi-unit neural activity with measurable cardiac rhythmicity. This suggests that the physiology of vagal neurones with cardiovascular regulatory function can be studied using this method. Here, the activity of cardiac rhythmic single units was discriminated from human cervical vagus nerve recordings using template-based waveform matching. The activity of 44 cardiac rhythmic neurones (22 with myelinated axons and 22 with unmyelinated axons) was isolated. By consideration of each unit's firing pattern with respect to the cardiac and respiratory cycles, the functional identification of each unit was attempted. Of note is the observation of seven cardiac rhythmic neurones with myelinated axons whose activity was recruited or enhanced by slow, deep breathing, was maximal during the nadir of respiratory sinus arrhythmia, and showed an expiratory peak. This is characteristic of cardioinhibitory efferent neurones, which are responsible for respiratory sinus arrhythmia. The remaining 15 cardiac rhythmic neurones with myelinated axons were categorised as cardiopulmonary receptors or arterial baroreceptors based on the position of their peak in firing with respect to the R-wave of the cardiac cycle. This latter method is not viable for neurones with unmyelinated axons due to their slow and unknown conduction velocities. With the exception of three neurones whose expiratory modulation implicates them as cardiac-projecting efferent neurones, this population is likely dominated by arterial baroreceptors. In conclusion, the activity of single units with cardiovascular function has been discriminated within the human cervical vagus, enabling their systematic study. KEY POINTS: Recordings of the electrical activity of the vagus nerve have recently been made at the level of the neck in humans. Examination of the gross activity of this nerve reveals subpopulations of neurones whose activity fluctuates in time with the heart's beat, suggesting that the neurones that monitor or modify cardiac function can be studied using this method. Here, the activity of individual cardiac rhythmic neurones was isolated from human vagus nerve recordings using template-based spike sorting. The relationship between this activity and the cardiac and respiratory cycles was used as a means of classifying each neurone. Neuronal firing patterns that are consistent with that of neurones that modify cardiac function, including heart-slowing 'cardioinhibitory' neurones, as well as neurones that inform the brain of cardiovascular status were observed. This approach enables, for the first time, the systematic study of the function of these neurones in humans in both health and disease.

Cardiovascular and hematological responses to a dry dynamic apnea in breath hold divers.

The mammalian dive reflex, characterized by bradycardia and peripheral vasoconstriction, occurs in all mammals, including humans, in response to apnea. However, the dive reflex to a single, maximal, dry, dynamic apnea (DYN) and how it compares to a time-matched exercise control trial (EX) or dry static apnea (SA) has not been studied. We examined the hypotheses that, compared with EX and SA, the magnitude of the 1) cardiovascular response and 2) hematological response to DYN would be greater. Cardiovascular parameters [heart rate (HR), systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressure] were continuously collected in 23 (F = 6 females) moderate and elite freedivers, first during a maximal DYN, then during a time-matched SA and EX on a swimming ergometer in randomized order. Venous blood draws were made before and following each trial. The change in calculated oxygen saturation (DYN: -17 ± 13%, EX: -2 ± 1%, ΔSA: -2 ± 1%; P < 0.05, all comparisons) was greater during DYN compared with EX and SA. During DYN, ΔSBP (DYN: 104 ± 31 mmHg; EX: 38 ± 23 mmHg; and SA: 20 ± 11 mmHg), ΔDBP (DYN: 45 ± 12 mmHg; EX: 14 ± 10 mmHg; and SA: 15 ± 8 mmHg), and ΔMAP (DYN: 65 ± 17 mmHg; EX: 22 ± 13 mmHg; and SA: 16 ± 9 mmHg) were increased compared with EX and SA, while ΔHR was greater during EX (DYN: -24 ± 23 beats/min; EX: 33 ± 13 beats/min; and SA: -1 ± 10 beats/min) than either DYN or SA (P < 0.0001, all comparisons). Females had a greater pressor response to EX (ΔSBP: 59 ± 30 mmHg; ΔDBP: 24 ± 14 mmHg; and ΔMAP: 35 ± 8 mmHg) than males (ΔSBP: 31 ± 15 mmHg; ΔDBP: 11 ± 6 mmHg; and ΔMAP: 18 ± 8 mmHg; P < 0.01, all comparisons). Together, these data indicate that DYN elicits a distinct, exaggerated cardiovascular response compared with EX or SA alone.NEW & NOTEWORTHY This study performed a dry dynamic apnea with sport-specific equipment to closely mimic the physiological demands of competition diving. We found the cardiovascular and hematological responses to dynamic apnea were more robust compared with time-matched exercise and dry static apnea control trials.

The maintenance of core temperature in SCUBA divers: Contributions of anthropometrics, patent foramen ovale, and non-shivering thermogenesis.

OBJECTIVES: To determine the influence of a patent foramen ovale and fibroblast growth factor-21 on core temperature (Tc) responses in SCUBA divers. Additionally, we aimed to quantify the individual and combined influences of wetsuit thickness and anthropometric data on Tc changes during the dives. DESIGN: An experimental study comparing the Tc responses between divers with (n = 17) and without a patent foramen ovale (n = 14). METHODS: A total of 31 divers participated in the study. Tc was measured pre- and post-dive in 17-18 °C sea water using a telemetric pill. Additionally, blood was drawn pre-dive and ~1-2 h post-dive for measurement of fibroblast growth factor-21. RESULTS: There was no influence of a patent foramen ovale on the Tc responses during SCUBA diving in either dive profile (p > 0.05). Additionally, there was no influence of SCUBA diving on fibroblast growth factor-21 concentrations (p > 0.05). The strongest positive and significant associations with the ∆Tc/min were found when multiplying wetsuit thickness in millimeters by body mass (r2 = 0.3147, p = 0.0010), BMI (r2 = 0.3123, p = 0.0011), and body surface area (r2 = 0.2877, p = 0.0019). There was a significant, negative linear relationship between the body surface area to mass ratio and ∆Tc/min (r2 = 0.2812, p = 0.0032). CONCLUSIONS: These data suggest that Tc regulation during recreational SCUBA diving can be facilitated in part by the appropriate choice of wetsuit thickness for a given set of anthropometric characteristics.

Chronic Cannabidiol Administration Mitigates Excessive Daytime Sleepiness and Fatigue in Patients with Primary Hypertension: Insights from a Randomized Crossover Trial.

Background: The chronic effects of cannabidiol (CBD) supplementation on factors that could impact the quality of life (anxiety, sleeping quality, memory, etc.) are poorly explored. Hence, the aim of this study was to establish whether chronic CBD supplementation will improve self-reported outcomes related to quality of life. Methods: In this randomized crossover trial, 64 patients with primary hypertension were assigned to receive CBD (225-450 mg) for 5 weeks followed by 5 weeks of placebo or vice versa, with a 2-week washout in-between the two. Self-reported outcomes were assessed using short form-36 (SF-36), Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), memory complaint questionnaire (MAC-Q), and state-trait anxiety inventory (STAI). Results: Five-week administration of CBD, but not of placebo, resulted in improvement of ESS score (F = 6.738, p = 0.011), as well as fatigue/vitality (ΔCBD = 5.0, p < 0.001) and psychological well-being dimensions of SF-36 (ΔCBD = 7.4, p = 0.039). No overall benefit of CBD on quality of life was noted (p = 0.674). No changes were seen in total scores of MAC-Q, PSQI, or STAI (p = 0.151, p = 0.862, p = 0.702, respectively). No significant correlations were found between plasma CBD concentrations and any of the scores. Conclusions: Chronic CBD administration reduced excessive daytime sleepiness, despite the fact that no change was observed in self-reported quality of sleep. Furthermore, self-reported fatigue and psychological well-being dimensions of quality of life also improved following chronic CBD use.

Selected and shared hematological responses to apnea in elite human free divers and northern elephant seals (Mirounga angustirostris).

Despite elite human free divers achieving incredible feats in competitive free diving, there has yet to be a study that compares consummate divers, (i.e. northern elephant seals) to highly conditioned free divers (i.e., elite competitive free-diving humans). Herein, we compare these two diving models and suggest that hematological traits detected in seals reflect species-specific specializations, while hematological traits shared between the two species are fundamental mammalian characteristics. Arterial blood samples were analyzed in elite human free divers (n = 14) during a single, maximal volitional apnea and in juvenile northern elephant seals (n = 3) during rest-associated apnea. Humans and elephant seals had comparable apnea durations (∼6.5 min) and end-apneic arterial Po2 [humans: 40.4 ± 3.0 mmHg (means ± SE); seals: 27.1 ± 5.9 mmHg; P = 0.2]. Despite similar increases in arterial Pco2 (humans: 33 ± 5%; seals: 16.3 ± 5%; P = 0.2), only humans experienced reductions in pH from baseline (humans: 7.45 ± 0.01; seals: 7.39 ± 0.02) to end apnea (humans: 7.37 ± 0.01; seals: 7.38 ± 0.02; P < 0.0001). Hemoglobin P50 was greater in humans compared to elephant seals (29.9 ± 1.5 and 28.7 ± 0.6 mmHg, respectively; P = 0.046). Elephant seals overall had higher carboxyhemoglobin (COHb) levels (5.9 ± 2.6%) compared to humans (0.8 ± 1.2%; P < 0.0001); however, following apnea, COHb was reduced in seals (baseline: 6.1 ± 0.3%; end apnea: 5.6 ± 0.3%) and was slightly elevated in humans (baseline: 0.7 ± 0.1%; end apnea: 0.9 ± 0.1%; P < 0.0002, both comparisons). Our data indicate that during static apnea, seals have reduced hemoglobin P50, greater pH buffering, and increased COHb levels. The differences in hemoglobin P50 are likely due to the differences in the physiological environment between the two species during apnea, whereas enhanced pH buffering and higher COHb may represent traits selected for in elephant seals.NEW & NOTEWORTHY This study uses similar methods and protocols in elite human free divers and northern elephant seals. Using highly conditioned divers (elite free-diving humans) and highly adapted divers (northern elephant seals), we explored which hematological traits are fundamentally mammalian and which may have been selected for. We found differences in P50, which may be due to different physiological environments between species, while elevated pH buffering and carbon monoxide levels might have been selected for in seals.

Construction and Validation of Newly Adapted Sport-Specific Anaerobic Diving Tests.

Breath-hold diving is explained as an activity that requires enduring muscle asphyxia and acidosis, high anaerobic capacity, and the tactic of the dive. Therefore, this study aimed to construct and validate tests that will mimic anaerobic processes in the specific media of freedivers. The sample of participants included 34 Croatian freedivers (average age: 26.85 ± 4.0 years, competitive age: 3.82 ± 1.92 years, their body height: 180.14 ± 8.93 cm, and their body mass: 76.82 ± 12.41 kg). The sample of variables consists of anthropometric indices, competitive efficiency (maximal length of a dive (DYN)), and specific anaerobic capacities (100 m and 2 min tests). Newly developed tests included the swimming anaerobic sprint test (SAST) and diving anaerobic sprint test (DAST). DAST and SAST variables included the total time of the test (DAST/SAST) and the fastest interval (DASTmax/SASTmax). The results showed good reliability of the tests with high Cronbach alpha coefficients (DAST: 0.98, DASTmax: 0.97, SAST: 0.99, SASTmax: 0.91). Furthermore, pragmatic validity shows a high correlation among all variables and DAST (DYN: -0.70, 100 m: 0.66, 2 min: -0.68). High relation is also found between 100 m (0.96), 2 min (-0.94), and a moderate result for DYN (-0.43) and the SAST test. A factor analysis extracted one significant factor. The factor analysis involved DAST, SAST, DYN, 100 m, and 2 min tests regarding factor 1. After the examination of all variables, the total time of the DAST test showed the best predictive values for the performance of divers. However, both tests could be used for diagnostics and the evaluation of specific condition abilities in freediving.

Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

Do freedivers and spearfishermen differ in local muscle oxygen saturation and anaerobic power?

BACKGROUND: Freediving is defined as an activity where athletes repetitively dive and are exposed to long efforts with limited oxygen consumption. Therefore, anaerobic features are expected to be an important facet of diving performance. This study aimed to investigate differences in anaerobic capacity and local muscle oxygenation in spearfisherman and freedivers. METHODS: The sample of participants included 17 male athletes (nine freedivers, and eight spearfishermen), with an average age of 37.0±8.8 years, training experience of 10.6±9.5 years, body mass of 82.5±9.5 kg and height of 184.2±5.7 cm. Anthropometric characteristics included: body mass, body height, seated height, and body fat percentage. Wingate anaerobic test was conducted, during which local muscle oxygenation was measured with a NIRS device (Moxy monitor). Wingate power outputs were measured (peak power [W/kg] and average power [W/kg]), together with muscle oxygenation variables (baseline oxygen saturation [%], desaturation slope [%/s], minimum oxygen saturation [%], half time recovery [s], and maximum oxygen saturation [%]). RESULTS: The differences were not obtained between freedivers and spearfisherman in power outputs (peak power (9.24±2.08 spearfisherman; 10.68±1.04 freedivers; P=0.14); average power (6.85±0.95 spearfisherman; 7.44±0.60 freedivers; P=0.15) and muscle oxygenation parameters. However, analysis of effect size showed a moderate effect in training experience (0.71), PP (0.89), AP (0.75), Desat slope mVLR (0.66), half time recovery mVLR (0.90). CONCLUSIONS: The non-existence of differences between freedivers and spearfishermen indicates similar training adaptations to the anaerobic demands. However, the results show relatively low anaerobic capacities of our divers that could serve as an incentive for the further development of these mechanisms.

Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies.

A prospective observational study (ClinicalTrial ID: NCT05771415) was conducted to compare placental oxygenation in low-risk, uncomplicated term pregnancies measured by near-infrared spectroscopy (NIRS) in relation to the placental maturity grade determined by ultrasound assessment according to the Grannum scale. We included 34 pregnancies divided into two groups according to placental maturation. For each pregnancy, measurements were taken at the site above the central part of the placenta (test) and at the site outside of the placenta on the lower abdomen (control). Student's t-test was used to compare tissue oxygenation index (TOI) values among the study groups. The normality of distribution was proven by the Kolmogorov‒Smirnov test. In women with low placental maturity grade, the mean TOI value above the placenta was 70.38 ± 3.72, which was lower than the respective value in women with high placental maturity grade (77.99 ± 3.71; p < 0.001). The TOI values above the placenta and the control site were significantly different in both groups (70.38 ± 3.72 vs 67.83 ± 3.21 and 77.99 ± 3.71 vs 69.41 ± 3.93; p < 0.001). The results offer a new perspective on placental function based on specific non-invasive real-time oxygenation measurements. Unfortunately, and because of technical limitations, NIRS cannot yet be implemented as a routine clinical tool.

Effects of CBD supplementation on ambulatory blood pressure and serum urotensin-II concentrations in Caucasian patients with essential hypertension: A sub-analysis of the HYPER-H21-4 trial.

HYPER-H21-4 was a randomized crossover trial that aimed to determine if cannabidiol (CBD), a non-intoxicating constituent of cannabis, has relevant effects on blood pressure and vascular health in patients with essential hypertension. In the present sub-analysis, we aimed to elucidate whether serum urotensin-II concentrations may reflect hemodynamic changes caused by oral supplementation with CBD. The sub-analysis of this randomized crossover study included 51 patients with mild to moderate hypertension that received CBD for five weeks, and placebo for five weeks. After five weeks of oral CBD supplementation, but not placebo, serum urotensin concentrations reduced significantly in comparison to baseline (3.31 ± 1.46 ng/mL vs. 2.08 ± 0.91 ng/mL, P < 0.001). Following the five weeks of CBD supplementation, the magnitude of reduction in 24 h mean arterial pressure (MAP) positively correlated with the extent of change in serum urotensin levels (r = 0.412, P = 0.003); this association was independent of age, sex, BMI and previous antihypertensive treatment (ß ± standard error, 0.023 ± 0.009, P = 0.009). No correlation was present in the placebo condition (r = -0.132, P = 0.357). In summary, potent vasoconstrictor urotensin seems to be implicated in CBD-mediated reduction in blood pressure, although further research is needed to confirm these notions.

Differences in Plasma Cannabidiol Concentrations in Women and Men: A Randomized, Placebo-Controlled, Crossover Study.

The potential therapeutic benefits of cannabidiol (CBD) require further study. Here, we report a triple-blind (participant, investigator, and outcome assessor) placebo-controlled crossover study in which 62 hypertensive volunteers were randomly assigned to receive the recently developed DehydraTECH2.0 CBD formulation or a placebo. This is the first study to have been conducted using the DehydraTECH2.0 CBD formulation over a 12-week study duration. The new formulation's long-term effects on CBD concentrations in plasma and urine, as well as its metabolites 7-hydroxy-CBD and 7-carboxy-CBD, were analyzed. The results of the plasma concentration ratio for CBD/7-OH-CBD in the third timepoint (after 5 weeks of use) were significantly higher than in the second timepoint (after 2.5 weeks of use; p = 0.043). In the same timepoints in the urine, a significantly higher concentration of 7-COOH-CBD was observed p < 0.001. Differences in CBD concentration were found between men and women. Plasma levels of CBD were still detectable 50 days after the last consumption of the CBD preparations. Significantly higher plasma CBD concentrations occurred in females compared to males, which was potentially related to greater adipose tissue. More research is needed to optimize CBD doses to consider the differential therapeutic benefits in men and women.

The Influence of Oral Cannabidiol on 24-h Ambulatory Blood Pressure and Arterial Stiffness in Untreated Hypertension: A Double-Blind, Placebo-Controlled, Cross-Over Pilot Study.

INTRODUCTION: Studies reveal that cannabidiol may acutely reduce blood pressure and arterial stiffness in normotensive humans; however, it remains unknown if this holds true in patients with untreated hypertension. We aimed to extend these findings to examine the influence of the administration of cannabidiol on 24-h ambulatory blood pressure and arterial stiffness in hypertensive individuals. METHODS: Sixteen volunteers (eight females) with untreated hypertension (elevated blood pressure, stage 1, stage 2) were given oral cannabidiol (150 mg every 8 h) or placebo for 24 h in a randomised, placebo-controlled, double-blind, cross-over study. Measures of 24-h ambulatory blood pressure and electrocardiogram (ECG) monitoring and estimates of arterial stiffness and heart rate variability were obtained. Physical activity and sleep were also recorded. RESULTS: Although physical activity, sleep patterns and heart rate variability were comparable between groups, arterial stiffness (~ 0.7 m/s), systolic blood pressure (~ 5 mmHg), and mean arterial pressure (~ 3 mmHg) were all significantly (P < 0.05) lower over 24 h on cannabidiol when compared to the placebo. These reductions were generally larger during sleep. Oral cannabidiol was safe and well tolerated with no development of new sustained arrhythmias. CONCLUSIONS: Our findings indicate that acute dosing of cannabidiol over 24 h can lower blood pressure and arterial stiffness in individuals with untreated hypertension. The clinical implications and safety of longer-term cannabidiol usage in treated and untreated hypertension remains to be established.

Trial of a Novel Oral Cannabinoid Formulation in Patients with Hypertension: A Double-Blind, Placebo-Controlled Pharmacogenetic Study.

Cannabidiol (CBD) is a non-psychoactive cannabinoid, and available evidence suggests potential efficacy in the treatment of many disorders. DehydraTECH™2.0 CBD is a patented capsule formulation that improves the bioabsorption of CBD. We sought to compare the effects of CBD and DehydraTECH™2.0 CBD based on polymorphisms in CYP P450 genes and investigate the effects of a single CBD dose on blood pressure. In a randomized and double-blinded order, 12 females and 12 males with reported hypertension were given either placebo capsules or DehydraTECH™2.0 CBD (300 mg of CBD, each). Blood pressure and heart rate were measured during 3 h, and blood and urine samples were collected. In the first 20 min following the dose, there was a greater reduction in diastolic blood pressure (p = 0.025) and mean arterial pressure MAP (p = 0.056) with DehydraTECH™2.0 CBD, which was probably due to its greater CBD bioavailability. In the CYP2C9*2*3 enzyme, subjects with the poor metabolizer (PM) phenotype had higher plasma CBD concentrations. Both CYP2C19*2 (p = 0.037) and CYP2C19*17 (p = 0.022) were negatively associated with urinary CBD levels (beta = -0.489 for CYP2C19*2 and beta = -0.494 for CYP2C19*17). Further research is required to establish the impact of CYP P450 enzymes and the identification of metabolizer phenotype for the optimization of CBD formulations.

Differential Expression of Vascular-Related MicroRNA in Circulating Endothelial Microvesicles in Adults With Spinal Cord Injury: A Pilot Study.

Background: Spinal cord injury (SCI) is associated with an increased risk and prevalence of cardiopulmonary and cerebrovascular disease-related morbidity and mortality. The factors that initiate, promote, and accelerate vascular diseases and events in SCI are poorly understood. Clinical interest in circulating endothelial cell-derived microvesicles (EMVs) and their microRNA (miRNA) cargo has intensified due to their involvement in endothelial dysfunction, atherosclerosis, and cerebrovascular events. Objectives: The aim of this study was to determine whether a subset of vascular-related miRNAs is differentially expressed in EMVs isolated from adults with SCI. Methods: We assessed eight adults with tetraplegia (7 male/1 female; age: 46±4 years; time since injury: 26±5 years) and eight uninjured (6 male/2 female; age: 39±3 years). Circulating EMVs were isolated, enumerated, and collected from plasma by flow cytometry. The expression of vascular-related miRNAs in EMVs was assessed by RT-PCR. Results: Circulating EMV levels were significantly higher (~130%) in adults with SCI compared with uninjured adults. The expression profile of miRNAs in EMVs from adults with SCI were significantly different than uninjured adults and were pathologic in nature. Expression of miR-126, miR-132, and miR-Let-7a were lower (~100-150%; p < .05), whereas miR-30a, miR-145, miR-155, and miR-216 were higher (~125-450%; p < .05) in EMVs from adults with SCI. Conclusion: This study is the first examination of EMV miRNA cargo in adults with SCI. The cargo signature of vascular-related miRNAs studied reflects a pathogenic EMV phenotype prone to induce inflammation, atherosclerosis, and vascular dysfunction. EMVs and their miRNA cargo represent a novel biomarker of vascular risk and a potential target for intervention to alleviate vascular-related disease after SCI.

Chronic Effects of Oral Cannabidiol Delivery on 24-h Ambulatory Blood Pressure in Patients with Hypertension (HYPER-H21-4): A Randomized, Placebo-Controlled, and Crossover Study.

Background: Recent data indicate that cannabidiol (CBD), a nonintoxicating constituent of cannabis, is involved in several aspects of cardiovascular regulation, including blood pressure (BP). However, the impact of chronic CBD administration on 24-h BP and vascular health has not been previously examined in patients with hypertension. The primary aim of this randomized, triple-blind, placebo-controlled, and crossover study was to examine the influence of chronic CBD on 24-h ambulatory BP and arterial stiffness in hypertensive patients. Methods: Seventy patients with mild or moderate primary hypertension, who were untreated or receiving standard of care therapy, were randomly assigned to receive either 5 weeks of oral CBD or placebo-matched controls. Following a >2-week washout period, patients were crossed over to alternate therapy. The primary outcome of the study was dynamic in 24-h ambulatory BP and was assessed using two-way repeated measure analysis of variance. Results: Administration of CBD reduced average 24 h mean, systolic, and diastolic BP after 2.5 weeks (-3.22±0.90 mmHg [95% confidence interval -1.01 to -5.44 mmHg], -4.76±1.24 mmHg [-1.72 to -7.80 mmHg], and -2.25±0.80 mmHg [-0.30 to -6.01 mmHg], respectively (all p<0.05); however, these values largely remained stable following the uptitration of CBD dosing. There were no changes in liver enzymes or serious adverse events (AEs). There was no significant difference in pulse wave velocity (group×factor interaction: F=1.50, p=0.226) at different time points, regardless of the intervention arm. Conclusions: In conclusion, chronic administration of CBD reduces ambulatory BP in those with untreated and treated hypertension. In addition, lack of serious AEs implies safety and tolerability of the above-noted CBD formulation. ClinicalTrials.gov ID: NCT05346562, Registered April 6th 2022.

CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: A substudy from the HYPER-H21-4 trial.

Data concerning the effects of cannabidiol (CBD) on blood pressure (BP) is controversial. HYPER-H21-4 was a randomized, placebo-controlled, crossover trial which sought to elucidate if 5-week administration of CBD will reduce BP in hypertensive patients. In the substudy of this trial, we aimed to establish the mechanistic background of CBD-induced BP reduction. Specifically, we explored the dynamic of catestatin, a sympathoinhibitory peptide implicated in the pathophysiology of hypertension. In the present analysis, 54 patients with Grade 1 hypertension were included. 5-week administration of CBD but not placebo reduced serum catestatin concentration in comparison to baseline (13.50 [10.85-19.05] vs. 9.65 [6.37-12.26] ng/mL, p < 0.001). Serum catestatin levels at the start of the treatment period demonstrated a negative correlation with the extent of reduction in mean arterial pressure (r = -0.474, p < 0.001). Moreover, the extent of change in catestatin serum levels showed a strong correlation with the extent of mean arterial pressure reduction (r = 0.712, p < 0.001). Overall, the results of the present study imply that the antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.

Knowledge and Attitudes of Cannabidiol in Croatia among Students, Physicians, and Pharmacists.

Due to cannabidiol's health benefits and absence of serious side effects, its use is constantly growing. This is a survey-based cross-sectional study that was conducted to determine Croatian pharmacists', physicians', and students' knowledge and attitudes about cannabidiol (CBD). Two questionnaires were created, one for students and the other for physicians and pharmacists. Our participants (in total 874: 473 students and 401 physicians and pharmacists) generally had positive attitudes towards CBD therapy as approximately 60% of them believe that CBD treatment is generally efficacious. Participants had positive attitudes toward the therapeutic value of CBD, especially pharmacists and pharmacy students (63.8% and 72.2%, respectively). Pharmacists were significantly more convinced that CBD could reduce the use of opioids prescribed for chronic pain (p < 0.05). Only 17.5% of students had read scientific papers about CBD, compared to a significantly higher percentage of physicians and pharmacists (43.0% and 47.8%, respectively) (p < 0.05). This study revealed a gap in knowledge regarding CBD, since 89.3% of pharmacists and physicians, as well as 84.8% of students, believe they need more education about CBD. We conclude that it is important to improve the educational curricula so that medical professionals can recommend CBD use to their patients when needed.

Common carotid artery responses to the cold-pressor test are impaired in individuals with cervical spinal cord injury.

Cervical spinal cord injury (SCI) leads to autonomic cardiovascular dysfunction that underlies the three- to fourfold elevated risk of cardiovascular disease in this population. Reduced common carotid artery (CCA) dilatory responsiveness during the cold-pressor test (CPT) is associated with greater cardiovascular disease risk and progression. The cardiovascular and CCA responses to the CPT may provide insight into cardiovascular autonomic dysfunction and cardiovascular disease risk in individuals with cervical SCI. Here, we used CPT to perturb the autonomic nervous system in 14 individuals with cervical SCI and 12 uninjured controls, while measuring cardiovascular responses and CCA diameter. The CCA diameter responses were 55% impaired in those with SCI compared with uninjured controls (P = 0.019). The CCA flow, velocity, and shear response to CPT were reduced in SCI by 100% (P < 0.001), 113% (P = 0.001), and 125% (P = 0.002), respectively. The association between mean arterial pressure and CCA dilation observed in uninjured individuals (r = 0.54, P = 0.004) was absent in the SCI group (r = 0.22, P = 0.217). Steady-state systolic blood pressure (P = 0.020), heart rate (P = 0.003), and cardiac contractility (P < 0.001) were reduced in those with cervical SCI, whereas total peripheral resistance was increased compared with uninjured controls (P = 0.042). Relative cerebral blood velocity responses to CPT were increased in the SCI group and reduced in controls (middle cerebral artery, P = 0.010; posterior cerebral artery, P = 0.026). The CCA and cardiovascular responsiveness to CPT are impaired in those with cervical SCI.NEW & NOTEWORTHY This is the first study demonstrating that CCA responses during CPT are suppressed in SCI. Specifically, CCA diameter, flow, velocity, and shear rate were reduced. The relationship between changes in MAP and CCA dilatation in response to CPT was absent in individuals with SCI, despite similar cardiovascular activation between SCI and uninjured controls. These findings support the notion of elevated cardiovascular disease risk in SCI and that the cardiovascular responses to environmental stimuli are impaired.

Serum Catestatin Levels Correlate with Ambulatory Blood Pressure and Indices of Arterial Stiffness in Patients with Primary Hypertension.

Accumulating data suggests that catestatin, an eclectic neuroendocrine peptide, is involved in the pathophysiology of primary hypertension (PH). Nevertheless, clinical studies concerning its role in PH are still scarce. Therefore, in the present study, we aimed to explore an association between serum catestatin levels, ambulatory blood pressure (BP) and arterial stiffness in patients with PH and healthy controls. In this single-center study, 72 patients aged 40−70 diagnosed with PH, and 72 healthy controls were included. In patients with PH, serum catestatin concentrations were significantly higher in comparison to the healthy controls (29.70 (19.33−49.48) ng/mL vs. 5.83 (4.21−8.29) ng/mL, p < 0.001). Untreated patients had significantly higher serum catestatin than patients treated with antihypertensive drugs (41.61 (22.85−63.83) ng/mL vs. 24.77 (16.41−40.21) ng/mL, p = 0.005). Multiple linear regression analysis showed that serum catestatin levels retained a significant association with mean arterial pressure (ß ± standard error, 0.8123 ± 0.3037, p < 0.009) after model adjustments for age, sex and body mass index. Finally, catestatin levels positively correlated with pulse wave velocity (r = 0.496, p < 0.001) and central augmentation index (r = 0.441, p < 0.001), but not with peripheral resistance. In summary, increased serum catestatin concentration in PH, predominantly in the untreated subgroup, and its association with ambulatory BP and arterial stiffness address the role of this peptide in PH.