Corrigendum: Effect of elexacaftor-tezacaftor-ivacaftor on nasal potential difference and lung function in Phe508del rats.

[This corrects the article DOI: 10.3389/fphar.2024.1362325.].

Investigating the relationship between early cardiovascular disease markers and loneliness in young adults.

Loneliness is recognised as a risk factor for cardiovascular disease development. However, it is unclear whether loneliness itself or other closely related mental health symptoms, such as depression and social anxiety, are associated with the development of cardiovascular disease. In the present study, we examined the relationship between loneliness and several early cardiovascular disease markers in young adults, after controlling for depression and social anxiety. Sixty-six young adults (18-35 years old, Mage = 22.70; 75.8% females) completed psychological questionnaires and took part in several physiological tests assessing cardiovascular health (e.g., vascular function). Results revealed higher loneliness was significantly associated with shorter pulse transit time (ß = - 0.70, p = 0.002; shorter pulse transit time is a subclinical marker for arterial stiffness). Additionally, results show that while loneliness and depression were both related to vascular dysfunction in young adults, the underlining physiological mechanisms through which they affect vascular function may be different. Specifically, higher loneliness was associated with increased arterial stiffness, whereas depression was associated with increased endothelial dysfunction (ß = - 0.43, p = 0.04). Our findings indicate that presence of loneliness and depression in young adults may be accompanied by early indicators of poor cardiovascular health, such as arterial stiffness and endothelial dysfunction. Results from the study further support the link between loneliness and cardiovascular disease development.

Effect of elexacaftor-tezacaftor-ivacaftor on nasal potential difference and lung function in Phe508del rats.

Introduction: Phe508del is the most common cystic fibrosis transmembrane conductance regulator (CFTR) gene variant that results in the recessive genetic disorder cystic fibrosis (CF). The recent development of highly effective CFTR modulator therapies has led to significant health improvements in individuals with this mutation. While numerous animal models of CF exist, few have a CFTR mutation that is amenable to the triple combination therapy elexacaftor-tezacaftor-ivacaftor (ETI). Methods: To determine the responsiveness of Phe508del rats to ETI, a baseline nasal potential difference was measured. Subsequently, they received ETI daily for 14 days, after which post-treatment nasal potential difference, lung mechanics (via flexiVent) and lung ventilation (via X-ray Velocimetry) were assessed. Results: Chloride ion transport in nasal airways was restored in Phe508del rats treated with ETI, but neither lung mechanics nor ventilation were significantly altered. Discussion: These findings validate the usefulness of this rat model for future investigations of modulator therapy in CF.

Association of x-ray velocimetry (XV) ventilation analysis compared to spirometry.

Introduction: X-ray Velocimetry (XV) ventilation analysis is a 4-dimensional imaging-based method for quantifying regional ventilation, aiding in the assessment of lung function. We examined the performance characteristics of XV ventilation analysis by examining correlation to spirometry and measurement repeatability. Methods: XV analysis was assessed in 27 patients receiving thoracic radiotherapy for non-lung cancer malignancies. Measurements were obtained pre-treatment and at 4 and 12-months post-treatment. XV metrics such as ventilation defect percent (VDP) and regional ventilation heterogeneity (VH) were compared to spirometry at each time point, using correlation analysis. Repeatability was assessed between multiple runs of the analysis algorithm, as well as between multiple breaths in the same patient. Change in VH and VDP in a case series over 12 months was used to determine effect size and estimate sample sizes for future studies. Results: VDP and VH were found to significantly correlate with FEV1 and FEV1/FVC (range: -0.36 to -0.57; p < 0.05). Repeatability tests demonstrated that VDP and VH had less than 2% variability within runs and less than 8% change in metrics between breaths. Three cases were used to illustrate the advantage of XV over spirometry, where XV indicated a change in lung function that was either undetectable or delayed in detection by spirometry. Case A demonstrated an improvement in XV metrics over time despite stable spirometric values. Case B demonstrated a decline in XV metrics as early as 4-months, although spirometric values did not change until 12-months. Case C demonstrated a decline in XV metrics at 12 months post-treatment while spirometric values remained normal throughout the study. Based on the effect sizes in each case, sample sizes ranging from 10 to 38 patients would provide 90% power for future studies aiming to detect similar changes. Conclusions: The performance and safety of XV analysis make it ideal for both clinical and research applications across most lung indications. Our results support continued research and provide a basis for powering future studies using XV as an endpoint to examine lung health and determine therapeutic efficacy.

Functional imaging for assessing regional lung ventilation in preclinical and clinical research.

Dynamic heterogeneity in lung ventilation is an important measure of pulmonary function and may be characteristic of early pulmonary disease. While standard indices like spirometry, body plethysmography, and blood gases have been utilized to assess lung function, they do not provide adequate information on regional ventilatory distribution nor function assessments of ventilation during the respiratory cycle. Emerging technologies such as xenon CT, volumetric CT, functional MRI and X-ray velocimetry can assess regional ventilation using non-invasive radiographic methods that may complement current methods of assessing lung function. As a supplement to current modalities of pulmonary function assessment, functional lung imaging has the potential to identify respiratory disease phenotypes with distinct natural histories. Moreover, these novel technologies may offer an optimal strategy to evaluate the effectiveness of novel therapies and therapies targeting localized small airways disease in preclinical and clinical research. In this review, we aim to discuss the features of functional lung imaging, as well as its potential application and limitations to adoption in research.

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated ß2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or ß2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting ß2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive ß2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

Evaluating the impact of loneliness and social isolation on health literacy and health-related factors in young adults.

Objectives: In current study, we aim to extend previous research by investigating the unique impact of loneliness on health literacy and health-related factors of young adults, after controlling for social isolation, depressive symptomology, and social anxiety, as well as evaluate how social isolation and loneliness differ in their impact on health literacy, and health-related factors among young adults, after accounting for abovementioned concomitant variables. Methods: Using a cross-sectional study design, 521 young adults completed an online survey in 2020, where they self-reported their loneliness, social isolation, health-related factors, and health literacy data. Results: Increased loneliness was associated with decrease in several health literacy domains (e.g., poorer social support for health, lower appraisal of health information, among others) and increase in some health-related factors (e.g., higher perceived stress, higher negative affect), among young adults, even after controlling for social anxiety, depressive symptomology, and social isolation. Contrastingly, increase in social isolation was associated with changes in some health-related factors - more somatic health complaints, higher alcohol use, poorer cognitive and physical functioning, and lower scores for only one health literacy domain (i.e., social support for health) among young adults, after adjusting for the influence of social anxiety, depressive symptomology, and loneliness. Conclusion: Even after accounting for the influence of several co-occurring social and mental health symptoms, higher loneliness was associated poorer health literacy and health-related factors in young adults. We also found loneliness and social isolation may differ in the mechanisms through which they impact health literacy and health-related factors in young adults.

Impact of loneliness on health-related factors in Australia during the COVID-19 pandemic: A retrospective study.

COVID-19 pandemic and its associated social and physical distancing restrictions may have had a severe impact on health. In the present study, we investigate the changes in physical, social and mental health, as well as the health literacy of Australians subsequent to the onset of COVID-19 pandemic, and examine the influence of loneliness on these health-related factors. Using a retrospective cross-sectional study design, 607 Australian adults completed a self-report online survey which assessed their health-related factors before and after onset of the COVID-19 pandemic (data collected between June 2020 to November 2020). Australians reported statistically significant increase in a number of (poorer) health-related factors (e.g., weight gain, sleeping difficulties, poor somatic health, higher loneliness, more issues navigating the healthcare system) post onset of COVID-19 pandemic. Further, after adjusting for covariates, higher loneliness during pandemic predicted poorer health-related outcomes (e.g., more somatic health complaints, poorer quality of diet, poorer social support for health). The COVID-19 pandemic and its associated social and physical distancing restrictions may have contributed towards poorer health-related factors among Australian adults. Further, increased loneliness during the pandemic may have further worsened physical health and health literacy outcomes among Australians.

MicroRNA-132 may be associated with blood pressure and liver steatosis-preliminary observations in obese individuals.

Recent findings in experimental models have shown that the microRNA miR-132 (mir-132) is an important regulator of liver homeostasis and lipid metabolism. We aimed to assess miR-132 expression in liver and fat tissues of obese individuals and examine its association with blood pressure (BP) and hepatic steatosis. We examined obese individuals undergoing bariatric surgery for weight loss (n = 19). Clinical and demographic information was obtained. Quantitative PCR was performed to determine tissue expression of miR-132 in liver and subcutaneous and visceral fat biopsies obtained during bariatric surgery. Liver biopsies were read by a single liver pathologist and graded for steatosis, inflammation and fibrosis. Participants (aged 39 ± 8.1 years) had a body mass index (BMI) of 42 ± 4.5 kg/m2 and presented with 2.2 ± 1.2 metabolic abnormalities. Supine BP was 127 ± 16/74 ± 11 mmHg. Hepatic and visceral fat expression of miR-132 were correlated (r = 0.59, P = 0.033). There was no correlation between subcutaneous and visceral expression of miR-132 (r = -0.31, P = 0.20). Hepatic and visceral fat miR-132 expression were associated with BMI (r = 0.62 and r = 0.68, P = 0.049 respectively) and degree of liver steatosis (r = 0.60 and r = 0.55, P < 0.05, respectively). Subcutaneous fat miRNA-132 expression was correlated to office systolic BP (r = 0.46, P < 0.05), several aspects of 24 h BP (24 h systolic BP: r = 0.52; day systolic BP: r = 0.59, P < 0.05 for all), plasma triglycerides (r = 0.51, P < 0.01) and liver enzymes (ALT: r = -0.52; AST: r = -0.48, P < 0.05 for all). We found an association between miR-132 and markers of cardiovascular and metabolic disease. Reduction of miR-132 may be a target for the regulation of liver lipid homeostasis and control of obesity-related blood pressure.

Autonomic nervous system function in women with anorexia nervosa.

PURPOSE: Abnormalities in autonomic function have been observed in people with anorexia nervosa. However, the majority of investigations have utilised heart rate variability as the sole assessment of autonomic activity. The current study utilised a variety of methodologies to assess autonomic nervous system function in women with a current diagnosis of anorexia, a past diagnosis of anorexia who were weight-restored, and healthy controls. METHODS: The sample included 37 participants: 10 participants with anorexia, 17 weight-restored participants (minimum body mass index > 18.5 for minimum of 12 months) and 10 controls. Assessments of autonomic function included muscle sympathetic nerve activity (MSNA) using microneurography, heart rate variability, baroreflex sensitivity, blood pressure variability, head-up tilt table test, sudomotor function and assessment of plasma catecholamines. RESULTS: MSNA (bursts/min) was significantly decreased in both anorexia (10.22 ± 6.24) and weight-restored (17.58 ± 1.68) groups, as compared to controls (23.62 ± 1.01, p < 0.001 and p = 0.033, respectively). Participants with anorexia had a significantly lower standard deviation in heart rate, lower blood pressure variability and decreased sudomotor function as compared to controls. Weight-restored participants demonstrated decreased baroreflex sensitivity in response to head-up tilt as compared to controls. CONCLUSION: Women with a current or previous diagnosis of anorexia have significantly decreased sympathetic activity, which may reflect a physiological response to decreased energy intake. During the state of starvation, women with anorexia also displayed decreased sudomotor function. The consequences of a sustained decrease in MSNA are unknown, and future studies should investigate autonomic function in long-term weight-restored participants to determine whether activity returns to normal.

Renal Deafferentation Prevents Progression of Hypertension and Changes to Sympathetic Reflexes in a Rabbit Model of Chronic Kidney Disease.

[Figure: see text].

Renal, Cardiac, and Autonomic Effects of Catheter-Based Renal Denervation in Ovine Heart Failure.

[Figure: see text].

Autonomic Nervous System Function in Anorexia Nervosa: A Systematic Review.

Background: Autonomic nervous system (ANS) dysfunction has been suggested to contribute to the high prevalence of cardiovascular complications in individuals with anorexia nervosa (AN), yet has not been thoroughly investigated. The current review aimed to synthesize the evidence of basal ANS function in individuals with a current diagnosis of AN and those with a previous diagnosis who had achieved weight restoration, as compared to controls. Methods: A systematic review of nine databases was conducted and studies that were published in a peer-review journal, in English, that included at least one assessment of ANS function in individuals with a current or previous diagnosis of AN were selected. Forty-six studies were included with a total of 811 participants with a current diagnosis of AN and 123 participants with a previous diagnosis of AN. Results: ANS function was assessed through heart rate variability (n = 27), orthostatic challenge, blood pressure variability or baroreflex sensitivity (n = 11), adrenergic activity (n = 14), skin conductance level (n = 4), and pupillometry (n = 1). Individuals with AN demonstrated increased parasympathetic activity and decreased sympathetic activity, suggestive of autonomic dysregulation. Following weight restoration, autonomic function trended toward, or was equivalent to, control levels. Discussion: Autonomic dysregulation is indicated through a range of assessments in individuals with AN. Future investigations should utilize a variety of assessments together in order to conclusively establish the nature of autonomic dysfunction in AN, and following extended weight restoration. Moreover, investigation into the co-occurrence of ANS function and cardiovascular risk is required.

Arterial stiffness in underweight and weight-restored anorexia nervosa.

Cardiovascular complications have been demonstrated in patients with anorexia nervosa (AN) in both the state of starvation and during weight restoration, however, the underlying mechanisms remain unclear. The current study aimed to assess arterial stiffness via carotid-femoral pulse wave velocity (cfPWV) in the acute and weight-restored states of AN. The study also aimed to determine the association between psychological distress and cfPWV. The sample included 37 participants; 10 participants with AN, 17 who were weight-restored (AN-WR; minimum body mass index >18.5 for at least 12 months) and 10 healthy controls (HCs). cfPWV via applanation tonometry was conducted to assess arterial stiffness. Psychological distress was assessed using the depression anxiety stress scale (DASS-21) and the state-trait anxiety inventory (STAI). Between-group comparisons were performed to determine differences between groups, a two-stage hierarchical regression model was performed to determine the contribution of physiological and psychological variables on cfPWV and correlation analyses were also performed. Vascular stiffness was significantly increased in the AN and AN-WR groups, relative to HCs. The total DASS score was the only significant predictor of cfPWV across the sample. There were positive associations between cfPWV and depression, anxiety and stress, as assessed by the DASS. Furthermore, cfPWV was positively associated with STAI trait anxiety. Arterial stiffness was increased in individuals in the acute and weight-restored states of AN, demonstrating early signs of the development of arteriosclerotic cardiovascular disease. Increased arterial stiffness was associated with increased psychological distress, which may be a contributing mechanism to the increased cardiovascular risk in AN.

Plasma lipocalin-2/NGAL is stable over 12 weeks and is not modulated by exercise or dieting.

Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18-55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise.

The adrenal medulla in cardiovascular medicine: an untold story.

Unlike noradrenaline, the sympathetic neurotransmitter which overflows to the circulation, adrenaline (ADR) is a secreted hormone, with a low plasma concentration, and plasma concentration for biological action a log order lower than that of noradrenaline. The venous drainage of the left adrenal medulla into the left renal vein does expose this vein to uniquely high plasma ADR concentrations and possible risk of thrombosis at high rates of ADR secretion. There is typically a different timeframe for adrenal medullary and sympathetic nervous system responses: ADR release is short term in contrast with sympathetic activation persisting for years in heart failure and hypertension. The historic view of Walter Cannon, subject to recent review, that the sympathoadrenal system is a unified biological system, was deconstructed further with demonstration of frequent mismatching of adrenal medullary and sympathetic nervous responses. Under gravity stimulation with standing, there is prompt sympathetic activation without ADR release. In many diseases, notably obesity, hypertension, heart failure and depressive illness, an activated sympathetic nervous system and silent adrenal medulla coexist. The therapeutic corollary of this is that ADR blockade is much less commonly needed clinically than pharmacological antagonism of the sympathetic nervous system.

Acute effects of interrupting prolonged sitting on vascular function in type 2 diabetes.

In healthy and overweight/obese adults, interrupting prolonged sitting with activity bouts mitigates impairment in vascular function. However, it is unknown whether these benefits extend to those with type 2 diabetes (T2D), nor whether an optimal frequency of activity interruptions exist. We examined the acute effects on vascular function in T2D of interrupting prolonged sitting with simple resistance activities (SRA) at different frequencies. In a randomized crossover trial, 24 adults with T2D (35-70 yr) completed three 7-h conditions: 1) uninterrupted sitting (SIT), 2) sitting with 3-min bouts of SRA every 30 min (SRA3), and 3) sitting with 6 min bouts of SRA every 60 min (SRA6). Femoral artery flow-mediated dilation (FMD), resting shear rate, blood flow, and endothelin-1 were measured at 0, 1, 3.5, 4.5, and 6.5-7 h. Mean femoral artery FMD over 7 h was significantly higher in SRA3 (4.1 ± 0.3%) compared with SIT (3.7 ± 0.3%, P = 0.04) but not in SRA6. Mean resting femoral shear rate over 7 h was increased significantly for SRA3 (45.3 ± 4.1/s, P < 0.001) and SRA6 (46.2 ± 4.1/s, P < 0.001) relative to SIT (33.1 ± 4.1/s). Endothelin-1 concentrations were not statistically different between conditions. Interrupting sitting with activity breaks every 30 min, but not 60 min, significantly increased mean femoral artery FMD over 7 h, relative to SIT. Our findings suggest that more frequent and shorter breaks may be more beneficial than longer, less frequent breaks for vascular health in those with T2D.NEW & NOTEWORTHY This is the first trial to examine both the effects of interrupting prolonged sitting on vascular function in type 2 diabetes and the effects of the frequency and duration of interruptions. Brief, simple resistance activity bouts every 30 min, but not every 60 min, increased mean femoral artery flow-mediated dilation over 7 h, relative to uninterrupted sitting. With further supporting evidence, these initial findings can have important implications for cardiovascular health in type 2 diabetes.

Plasma Docosahexaenoic Acid and Eicosapentaenoic Acid Concentrations Are Positively Associated with Brown Adipose Tissue Activity in Humans.

Brown adipose tissue (BAT) activation is a possible therapeutic strategy to increase energy expenditure and improve metabolic homeostasis in obesity. Recent studies have revealed novel interactions between BAT and circulating lipid species-in particular, the non-esterified fatty acid (NEFA) and oxylipin lipid classes. This study aimed to identify individual lipid species that may be associated with cold-stimulated BAT activity in humans. A panel of 44 NEFA and 41 oxylipin species were measured using mass-spectrometry-based lipidomics in the plasma of fourteen healthy male participants before and after 90 min of mild cold exposure. Lipid measures were correlated with BAT activity measured via 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), along with norepinephrine (NE) concentration (a surrogate marker of sympathetic activity). The study identified a significant increase in total NEFA concentration following cold exposure that was positively associated with NE concentration change. Individually, 33 NEFA and 11 oxylipin species increased significantly in response to cold exposure. The concentration of the omega-3 NEFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at baseline was significantly associated with BAT activity, and the cold-induced change in 18 NEFA species was significantly associated with BAT activity. No significant associations were identified between BAT activity and oxylipins.

Contribution of the Renal Nerves to Hypertension in a Rabbit Model of Chronic Kidney Disease.

Overactivity of the sympathetic nervous system and high blood pressure are implicated in the development and progression of chronic kidney disease (CKD) and independently predict cardiovascular events in end-stage renal disease. To assess the role of renal nerves, we determined whether renal denervation (RDN) altered the hypertension and sympathoexcitation associated with a rabbit model of CKD. The model involves glomerular layer lesioning and uninephrectomy, resulting in renal function reduced by one-third and diuresis. After 3-week CKD, blood pressure was 13±2 mm Hg higher than at baseline (P<0.001), and compared with sham control rabbits, renal sympathetic nerve activity was 1.2±0.5 normalized units greater (P=0.01). The depressor response to ganglion blockade was also +8.0±3 mm Hg greater, but total norepinephrine spillover was 8.7±3.7 ng/min lower (both P<0.05). RDN CKD rabbits only increased blood pressure by 8.0±1.5 mm Hg. Renal sympathetic activity, the response to ganglion blockade and diuresis were similar to sham denervated rabbits (non-CKD). CKD rabbits had intact renal sympathetic baroreflex gain and range, as well as normal sympathetic responses to airjet stress. However, hypoxia-induced sympathoexcitation was reduced by -9±0.4 normalized units. RDN did not alter the sympathetic response to hypoxia or airjet stress. CKD increased oxidative stress markers Nox5 and MCP-1 (monocyte chemoattractant protein-1) in the kidney, but RDN had no effect on these measures. Thus, RDN is an effective treatment for hypertension in this model of CKD without further impairing renal function or altering the normal sympathetic reflex responses to various environmental stimuli.