Altered Heart Research Articles

The Effect of Cold Application to the Lateral Neck Area on Peripheral Vascular Access Pain: A Randomised Controlled Study.

Various types of vagus nerve stimulation are employed in the treatment of a range of conditions, including depression, anxiety, epilepsy, headache, tinnitus, atrial fibrillation, schizophrenia, and musculoskeletal pain. The objective of this study was to apply vagal stimulation to the neck area using standardised cold, and then analyse the level of vascular access discomfort experienced by individuals who underwent venous cannulation from the dorsal side of the hand prior to anaesthesia. A total of 180 patients, aged 18-75, who were scheduled to undergo elective surgery, were categorised into three distinct groups: the Sham group (Group S), the Control group (Group K), and the Cold group (Group M), with each group consisting of 60 individuals. Bilateral cold application to the lateral side of the neck was performed prior to the commencement of vascular access in Group M patients, followed by the subsequent opening of vascular access. The alterations in heart rate among patients was assessed subsequent to the application of cold and following the establishment of vascular access. The participants were instructed to assess their level of vascular access pain on a numerical pain scale (NRS) ranging from 0 to 10. A statistically significant difference (p = 0.035) was seen when comparing the pain ratings of patients during vascular access. The study revealed that the NRS values exhibited a statistically significant decrease in Group M compared to both Group K (p = 0.038) and Group S (p = 0.048). Group M had a higher prevalence of individuals experiencing mild pain compared to other groups, and the difference was statistically significant (p = 0.029). In Group M, the average heart rate following vagal stimulation exhibited a statistically significant decrease compared to the average heart rate observed at the beginning of the study (p < 0.05). Upon comparing the original heart rate measurements with the heart rate values following vascular access, it was observed that there was an elevation in heart rate for both Group S and Group K. Conversely, Group M exhibited a decrease in heart rate after vascular access when compared to the initial heart rate values. In the present investigation, it was discovered that the application of cold to the neck region resulted in a drop in heart rate among the patients, which persisted throughout the process of vascular access. Furthermore, the level of pain experienced by these individuals was reduced during vascular access procedures.

Postnatal Overfeeding during Lactation Induces Endothelial Dysfunction and Cardiac Insulin Resistance in Adult Rats.

Early overnutrition is associated with cardiometabolic alterations in adulthood, likely attributed to reduced insulin sensitivity due to its crucial role in the cardiovascular system. This study aimed to assess the long-term effects of early overnutrition on the development of cardiovascular insulin resistance. An experimental childhood obesity model was established using male Sprague Dawley rats. Rats were organized into litters of 12 pups/mother (L12-Controls) or 3 pups/mother (L3-Overfed) at birth. After weaning, animals from L12 and L3 were housed three per cage and provided ad libitum access to food for 6 months. L3 rats exhibited elevated body weight, along with increased visceral, subcutaneous, and perivascular fat accumulation. However, heart weight at sacrifice was reduced in L3 rats. Furthermore, L3 rats displayed elevated serum levels of glucose, leptin, adiponectin, total lipids, and triglycerides compared to control rats. In the myocardium, overfed rats showed decreased IL-10 mRNA levels and alterations in contractility and heart rate in response to insulin. Similarly, aortic tissue exhibited modified gene expression of TNFα, iNOS, and IL-6. Additionally, L3 aortas exhibited endothelial dysfunction in response to acetylcholine, although insulin-induced relaxation remained unchanged compared to controls. At the molecular level, L3 rats displayed reduced Akt phosphorylation in response to insulin, both in myocardial and aortic tissues, whereas MAPK phosphorylation was elevated solely in the myocardium. Overfeeding during lactation in rats induces endothelial dysfunction and cardiac insulin resistance in adulthood, potentially contributing to the cardiovascular alterations observed in this experimental model.

Δ9-Tetrahydrocannabinol Effects on Respiration and Heart Rate Across Route of Administration in Female and Male Mice.

The physiological impact of cannabinoid receptor agonists is of great public health interest due to their increased use in recreational and therapeutic contexts. However, the body of literature on cannabinoid receptor agonists includes multiple confounding variables that complicate comparisons across studies, including route of administration, timeline across which phenotypes are observed, agonist dose, and sex of the study cohort. In this study, we characterized the impact of sex and route of administration on Δ9-tetrahydrocannabinol (THC)-induced changes in cardiopulmonary phenotypes in mice. Using noninvasive plethysmography and telemetry, we monitored heart rate and respiration in the same cohort of animals across aerosol, oral gavage, subcutaneous, and intraperitoneal administrations of THC (0-30mg/kg THC for oral gavage, subcutaneous, and intraperitoneal, and 0-300mg/ml THC for aerosol). All routes of THC administration altered respiratory minute volume and heart rate, with the direction of effects typically being consistent across dependent measures. THC primarily decreased respiration and heart rate, but females given oral gavage THC showed increased heart rate. Intraperitoneal and subcutaneous THC produced the longest-lasting effects, including THC-induced alterations in physiological parameters for up to 10h, whereas effects of aerosolized THC were short lived. The fastest onset of effects of THC occurred for aerosolized and intraperitoneal THC. Altogether, the work herein establishes the impact of dosing route on THC-induced heart rate and respiratory alteration in male and female mice. This study highlights important differences in the timeline of cardiopulmonary response to THC following the most common preclinical routes of administration.

280 Prevalence of prescribing high anticholinergic scoring medications among over 65-year-old patients in primary care

Abstract Background The effects of anticholinergic drugs are widespread because acetylcholine is involved in regulating various bodily functions, both in the Central Nervous System (CNS) and the Peripheral Nervous System (PNS). By blocking the action of acetylcholine at CNS muscarinic receptors, anticholinergic drugs can lead to cognitive effects such as impaired attention, decreased learning ability, and memory difficulties. Blocking the PNS muscarinic receptors with anticholinergic drugs can lead to side effects such as urinary retention, constipation, and alterations in heart rate. Considering these issues, it is generally advisable to use anticholinergic drugs with caution in the elderly population as an anticholinergic score of 3 or more is associated with increased risk of confusion, falls and death. This audit seeks to determine the prevalence of the higher scoring Anticholinergic drugs (3) among the older population in a city centre GP Practice. Methods The website www.acbcalc.com provides a comprehensive list of medications with an Anticholinergic burden score of 3. Using this list of 48 commonly prescribed medicines, each one was searched on the practice clnical system individually and the number of patients currently prescribed each medicine documented. Results Approximately 5.45% of patients over 65 yrs (N = 2,770) are currently prescribed a medicine with an Anticholinergic score of 3. The most commonly prescribed are Amitriptyline (1.52%), Solifenacin (1.01%), Quetiapine (0.79%), Olanzapine (0.61%). Conclusion While anticholinergic medications can prove useful clinical interventions in certain patients, it is generally accepted that a burden score of 3 or more increases the patient’s risk of confusion, falls and death. Patients who have a high Anticholinergic score should have their medicines optimised through a shared decision making framework regularly, to ensure current therapy is beneficial and alternatives considered. An automated audit tool could be created within the primary care clinical system to score each patient’s anticholinergic burden and thus help target polypharmacy reviews.

Adverse Effect of Metallic Gold and Silver Nanoparticles on Xenopus laevis Embryogenesis.

Exposure to metal nanoparticles is potentially harmful, particularly when occurring during embryogenesis. In this study, we tested the effects of commercial AuNPs and AgNPs, widely used in many fields for their features, on the early development of Xenopus laevis, an anuran amphibian key model species in toxicity testing. Through the Frog Embryo Teratogenesis Assay-Xenopus test (FETAX), we ascertained that both nanoparticles did not influence the survival rate but induced morphological anomalies like modifications of head and branchial arch cartilages, depigmentation of the dorsal area, damage to the intestinal brush border, and heart rate alteration. The expression of genes involved in the early pathways of embryo development was also modified. This study suggests that both types of nanoparticles are toxic though nonlethal, thus indicating that their use requires attention and further study to better clarify their activity in animals and, more importantly, in humans.

Abstract P433: Evidence For An Important Role Of AT1a Receptors In The Renomedullary Interstitial Cells In Basal Blood Pressure Homeostasis And The Development Of Angiotensin Ii-induced Hypertension

The renomedullary interstitial cells (RMICs) are highly specialized lipid-laden interstitial fibroblasts, which form characteristic "ladder-like" structural associations with adjacent microvessels and renal tubules in the kidney medulla. We have previously reported that RMICs express abundant AT 1 (AT 1a ) receptors in vitro and in vivo , but the physiological role of AT 1 (AT 1a ) receptors in RMICs has not been determined. In the present study, we generated and phenotyped for the 1 st time a new mutant mouse model with RMIC-selective deletion of AT 1a receptors in the kidney medulla, RMIC- Agtr1a -/- , using an innovative inducible Tenascin-C-CreER2/Agtr1a f/f approach. Deletion of AT 1a receptors selectively in RMICs did not alter the development and cellular structures in the kidney medulla of RMIC- Agtr1a -/- mice. The heart wt. to body wt. ratio was lower ( P &lt;0.01), whereas the kidney wt. to body wt. ratio was significantly higher ( P &lt;0.01) in RMIC- Agtr1a -/- than wild-type (WT) mice without altering heart rate. Compared with WT mice, basal systolic, diastolic, and mean arterial blood pressure, as measured by the telemetry technique, were significantly lower in adult male RMIC- Agtr1a -/- mice (WT: 122 ± 3 mmHg vs. RMIC- Agtr1a -/- : 103 ± 4 mmHg, P &lt;0.01). The decreases in basal blood pressure in RMIC- Agtr1a -/- mice was associated with significantly lower urine excretion (WT: 1.56 ± 0.15 mL/24 h vs. RMIC- Agtr1a -/- : 0.98 ± 0.13 mL/24 h, P &lt;0.01), urinary sodium (WT: 207.9 ± 7.3 μmol/24 h vs. RMIC- Agtr1a -/- : 145.2 ± 5.4 μmol/24 h, P &lt;0.01), potassium excretion (WT: 221.0 ± 6.7 μmol/24 h vs. RMIC- Agtr1a -/- : 160.8 ± 10.6 μmol/24 h, P &lt;0.01), and markedly decreased urine osmolality in RMIC- Agtr1a -/- mice (WT: 1724 ± 335 mOsm/Kg H 2 O vs. RMIC- Agtr1a -/- : 1128 ± 102 mOsm/Kg H 2 O, P &lt;0.01). Ang II infusion (0.5 mg/kg/day, i.p., 2 weeks) increased blood pressure to 148 ± 5 mmHg in WT mice, as expected, but it increased only to 129 ± 8 mmHg without further altering urine osmolality from controls in RMIC- Agtr1a -/- mice ( P &lt;0.01). In conclusion, the present study provides new evidence for the 1st time for an important role of AT 1a receptors in RMICs in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.

Altered Heart Rate Variability During Rest in Schizophrenia: A State Marker.

Autonomic nervous system (ANS) imbalance has been reported in a number of psychiatric disorders such as depression, schizophrenia, panic disorder, etc. Autonomic dysfunction in schizophrenia has been associated with the symptoms and manifestation of psychosis. Heart rate variability (HRV) as a tool has been widely used to assess ANS activity and the effect of disease on the sympathovagal balance. Therefore, in the present study, HRV derived from electrocardiogram (ECG) lead II at rest was investigated in order to understand the changes in frequency domain measures in patients with schizophrenia and their first-degree relatives compared to healthy controls. Twenty-five patients with schizophrenia, 24 first-degree relatives of patients, and 24 healthy controls (Diagnostic and Statistical Manual of Mental Disorders (DSM)-5; 18-45 years) were included in the study. HRV of the subjects was measured after five minutes of rest. ECG lead II was recorded for five minutes and HRV was analysed in the frequency domain: low frequency (LF), high frequency (HF), total power, and LF/HF ratio. HRV parameters and heart rate were statistically analysed for group comparisons using general linear model multivariate analysis. Patients had significantly higher minimum heart rate and lower HF (normalized units (nu)) compared to their first-degree relatives. A trend was observed in HF (nu) with the lowest in patients followed by healthy controls and first-degree relatives and LF/HF ratio was the highest in patients followed by healthy controls and first-degree relatives, although not statistically significant. No significant difference was found between first-degree relatives and healthy controls. The alteration of HRV in schizophrenia could be attributed to reduction in vagal tone and sympathetic dominance, which in turn could serve as state markers of schizophrenia.

Medication guide for dose adjustment and management of cardiotoxicity and lipid metabolic adverse events of oral antineoplastic therapy.

The management of cardiotoxicity concerning the use of oral antineoplastic agents (OAAs) is a challenge for healthcare professionals. Our objective was to create a comprehensive medication management guide with dose adjustment recommendations on OAAs concerning cardiotoxic and lipid metabolic adverse events (AEs) to assist healthcare professionals when prescribing OAAs. A review of the available information on all dose adjustments necessary to safely prescribe and dispense OAAs concerning cardiotoxicity was conducted. In January 2023, we identified all OAAs authorized by the European Medicines Agency (EMA). For each drug, the latest summary of product characteristics (SPC) approved by the EMA and the tertiary data source Lexicomp® were reviewed. Cardiotoxic AEs were recorded, namely, QT interval prolongation, decrease in left ventricular ejection fraction (LVEF), imbalances in blood pressure (hypertension and hypotension), alterations in heart rate (tachycardia and bradycardia), and thrombosis. Any available dose adjustment recommendations in case of an occurrence of these adverse events were collected. In all, 93 different OAAs had been approved by the EMA and were reviewed. Among them, 51.6% have recognized cardiotoxic AEs and 10.8% can cause alterations in lipid metabolism. A total of 27 (29.0%) OAAs had specific recommendations regarding QT prolongation; 88.9% were listed in the SPC and 59.3% in Lexicomp®. Eight OAAs (9.68%) have reported a decrease in LVEF, and four of these drugs, namely, encorafenib, lorlatinib, ripretinib, and sunitinib, have specific management recommendations. Almost half (49.5%) of currently approved OAAs can potentially alter blood pressure; 34 (36.6%) of them have been reported to cause hypertension and 12 (12.9%) are related to hypotension. Tachycardia and/or bradycardia are associated with 22.6% and 8.6% of the evaluated drugs, respectively. Regarding thrombosis, 30 (32.3%) of the drugs analyzed included the appearance of a thrombus as a possible AE. More than half of the OAAs can produce cardiotoxic effects, with the most frequent being blood pressure alteration and QT interval prolongation with a non-depreciable incidence of LV dysfunction or thrombosis. Before starting the treatment, it is necessary to stratify baseline cardiovascular risk, plan a surveillance schedule, and consider referral to cardio-oncology units.

Abstract P2079: Heart Rate Variability And Chronotropic Incompetence As Prognostic Markers In A Preclinical Model Of HFpEF

The prevalence of heart failure with preserved ejection fraction (HFpEF) in developed countries is increasing alarmingly. This is in part due to an increase in comorbid diseases (obesity, diabetes, hypertension), and risk factors (age, stress, and low physical activity). HFpEF patients often present with chronotropic incompetence (CI) and impaired heart rate variability (HRV), and both CI and decreased HRV are used as prognostic markers of heart disease and sudden cardiac death in clinical studies. In preclinical HFpEF models, however, CI and HRV are not commonly evaluated, and the efficacy of novel compounds is determined primarily through echocardiography results. Thus, there is a need to align efficacy readouts to enhance the translatability of novel compounds from preclinical to clinical stages. Here we sought to determine the utility of CI and HRV in preclinical HFpEF studies in a novel 2-hit HFpEF model; the metabolic syndrome non-alcoholic steatohepatitis mouse with AAV overexpression of renin (MS-NASH+Renin). To collect continuous and conscious electrocardiogram and blood pressure data, C57BL/6 (n=10) and MS-NASH (formerly FATZO, n=32) male mice were implanted with radiotelemeters at 20 weeks and iv injected with either AAV-Vector or AAV-Renin. To assess disease burden, CI and HRV, we acquired and analyzed body weight, electrocardiography, peak VO2, exercise HR, and echocardiography data once a month for 5 months. We found that MS-NASH mice have increased body weight regardless of treatment, and that renin treatment increased blood pressure for both C57BL/6 and MS-NASH mice. Peak VO2, time to exhaustion, distance traveled, and maximum and recovery HR are significantly decreased in MS-NASH mice, indicating CI. HRV is also significantly decreased in MS-NASH mice when compared to C57BL/6. Interestingly, renin treatment did not further decrease treadmill performance or HRV for MS-NASH mice. However, MS-NASH+Renin mice did have decreased functional capacity with preserved ejection fraction and altered heart structure. These results suggest that MS-NASH+Renin is a model for HFpEF, and that CI and HRV are translatable markers for HFpEF. In the future, we will evaluate the use of CI and HRV in preclinical HFpEF drug development studies.

Abstract P2043: Loss Of Full-length Mylk3 Causes Dilated Cardiomyopathy Via A Myl2-independent Mechanism

Introduction: We recently discovered C57BL/6N male mice develop dilated cardiomyopathy (DCM) at 12 months, while the closely related C57BL/6J do not. We identified a variant (Chr8:85365179A&gt;T, c.-5T&gt;A) in myosin light chain kinase 3 ( Mylk3 ) in the B/6N substrain that abolishes translation of the predominant transcript (ENSMUST00000034133). MYLK3 phosphorylates many sarcomere proteins, in particular myosin light chain 2 (MYL2), vital for cardiac development and function. We therefore hypothesise this variant drives the DCM in the B/6N mice. Results: To determine whether the Mylk3 variant alone can cause DCM in mice, we generated two novel isogenic mouse lines. The first carries the Mylk3 c.-5T&gt;A variant on the C57BL/6J background. The second carries the ‘wildtype’ Mylk3 variant on the C57BL/6N background (c.-5A&gt;T, C57BL/6N Mylk3.6J ). While wildtype male C57BL/6J mice developed normally, male littermates expressing the mutant Mylk3 allele (C57BL/6J Mylk3.6N ) show signs of DCM at just 4 weeks old, with increased left ventricular diameter and volume, thinning of the posterior wall and a reduced ejection fraction. In contrast, the C57BL/6N mice develop DCM symptoms, but the C57BL/6N Mylk3.6J mice have smaller left ventricles, thicker left ventricular posterior wall and elevated ejection fraction. We assessed MYL2 phosphorylation by western blot, and contradictory to previous reports, found no difference between any of our mice lines. This may be due to the persistence of a shorter Mylk3 isoform that is unaffected by the variant due to a distinct N-terminus (ENSMUST00000122452; D3Z630). There was no difference between the isoforms in their ability to phosphorylate MYL2 suggesting the shorter isoform could compensate. Phosphoproteomics identified over 500 differentially phosphorylated peptides in 3-day old C57BL/6J and C57BL/6J Mylk3.6N mice. These include many key cardiac transcription factors, such as NFATC2 and FOXK1. Conclusion: We hypothesise that loss of MYLK3 may cause dilated cardiomyopathy in our mice by a MYL2-independent mechanism, possibly by altering vital cardiac transcription causing altered heart development.

0417 Pre-sleep wakefulness in patients with insomnia: heart rate variability during sleep onset

Abstract Introduction Pre-sleep stress or hyperarousal is a known key etiological component in insomnia disorder. However, physiological alterations during the sleep onset period are not well-understood. We aimed to characterize heart rate variability (HRV) in patients with insomnia during sleep onset. Methods Using data from the Sleep Heart Health Study at National Sleep Research Resource, we conducted a secondary analysis exploring HRV during the sleep onset period (defined as the time between lights-off and sleep onset) in patients with insomnia (IS group; n = 68) and comorbid obstructive sleep apnea (IS + OSA group; n = 135), compared with normal sleep controls (NSC group; n = 122). Overall group differences were tested using ANOVA. Post-hoc pairwise comparisons were conducted using the least significant difference (LSD) tests. Results During sleep onset, mean heart rates of the IS group (74.4±15.0 beats/min) and IS+OSA group (72.6±11.5 beats/min) were both significantly higher than the NSC group (69.7±9.4 beats/min, p=0.007 and p=0.044 respectively). Both the IS and IS+OSA groups showed lower heart rate variability compared to the NSC group, with significant differences in both time and frequency domains of HRV analysis including SDNN (p=0.002), RMSSD (p=0.035), pNN20 (p&amp;lt; 0.001), pNN50 (p=0.008), LnLF (p&amp;lt; 0.001), LnHF (p&amp;lt; 0.001). For all these measures, IS+OSA group had lower HRV compared to the IS group, although differences were not significant. When controlling for age, gender and BMI, and compared to the NSC group, IS group had significantly higher heart rates (β=4.8, p=0.008), and the IS+OSA group had significantly lower pNN20 (β=-0.039, p=0.002), pNN50 (β=-0.031, p=0.017) and LnHF (β=0.007, p=0.007). Conclusion Patients with insomnia had lower vagal activity during the sleep onset period, reflected in higher heart rates and lower heart rate variability. Such altered heart rate dynamics may serve as a physiological biomarker for insomnia during bedtime wakefulness, or as a potential tool to evaluate the efficacy of behavioral interventions which target bedtime stress. Support (if any) This research project was made possible by a grant from the American Academy of Sleep Medicine Foundation (PI: Yan Ma). We acknowledge the National Sleep Research Resource as the resource through which the Data/Datasets were obtained.

The usability of daytime and night-time heart rate dynamics as digital biomarkers of depression severity.

Alterations in heart rate (HR) may provide new information about physiological signatures of depression severity. This 2-year study in individuals with a history of recurrent major depressive disorder (MDD) explored the intra-individual variations in HR parameters and their relationship with depression severity. Data from 510 participants (Number of observations of the HR parameters = 6666) were collected from three centres in the Netherlands, Spain, and the UK, as a part of the remote assessment of disease and relapse-MDD study. We analysed the relationship between depression severity, assessed every 2 weeks with the Patient Health Questionnaire-8, with HR parameters in the week before the assessment, such as HR features during all day, resting periods during the day and at night, and activity periods during the day evaluated with a wrist-worn Fitbit device. Linear mixed models were used with random intercepts for participants and countries. Covariates included in the models were age, sex, BMI, smoking and alcohol consumption, antidepressant use and co-morbidities with other medical health conditions. Decreases in HR variation during resting periods during the day were related with an increased severity of depression both in univariate and multivariate analyses. Mean HR during resting at night was higher in participants with more severe depressive symptoms. Our findings demonstrate that alterations in resting HR during all day and night are associated with depression severity. These findings may provide an early warning of worsening depression symptoms which could allow clinicians to take responsive treatment measures promptly.

Cyclophosphamide enfeebles myocardial isometric contraction force via RIP1/RIP3/MLKL/TRPM7-mediated necroptosis

This study explores the negative impact of cyclophosphamide (CP) on cardiac contractility by specifically examining its effect on the active and passive tension of the cardiac muscle in-vitro and revealing the mechanism through which CP induces myocardial insult in-vivo. In young male Sprague-Dawley rats, cardiac toxicity was induced by a single intraperitoneal injection of CP (150 mg/kg body weight). Axial heart tissue slices were electrically stimulated, and the total isometric contraction force was measured at varying pretension levels. Blood and tissue biochemical assays, and histological/ immuno-histological assessments were conducted to evaluate the underlying molecular mechanisms. Statistical analysis shows that there is a significant difference between the drugged and the control groups in terms of the active tension values. Moreover, the pre-tension stress significantly affects both the active and passive tension values. CP altered heart, body, and heart-to-body weight, desolated cardiac muscle architecture, surged cardiac enzymes (CK-MB, LDH, and cTn l), augmented myocardial oxidative stressors (MDA), and weakened myocardial antioxidant status (SOD and GSH). Mechanistically, cyclophosphamide prompted the necroptotic trajectory evidenced by the activation of RIPK1, RIPK3, MLKL and TRPM7, the inhibition of caspase 8 and BCL2 and the upregulation of the protein/mRNA expression of TNF-α and TNFR1. This study identifies necroptosis as a key factor in cyclophosphamide-evoked myocardial contractility impairment, highlighting its potential as a target for alleviating antitumor-related myocardial damage. This innovative approach to investigating the underlying mechanisms of CP-induced cardiac toxicity offers valuable insights into the potential of developing new therapies to mitigate cyclophosphamide’s negative impact.

Intravenous administration of apeling-13 induces a depressor response by releasing an unidentified substance

Apelin and APJ receptor play an important role in the regulating cardiovascular function; however, conflicting results have been reported regarding the effect of apelin on cardiovascular regulation. In this study, blood pressure and heart rate were measured by femoral arterial catheterization; and cardiac contractility was recorded by left ventricular catheterization through the right carotid artery in rats before and after intravenous administration of [pyr1]-apelin-13. The results show that intravenous administration of apelin-13 caused a dramatic reduction in BP but did not significantly alter heart rate and contractility. To study the mechanism of the apelin-induced depressor response, isometric tension was measured in isolated mesenteric arteries using a myograph approach. Surprisingly, treatment of the arteries with [pyr1]-apelin-13 did not cause relaxation of mesenteric arteries preconstricted with norepinephrine; however, treatment with plasma collected from rats that received intravenous administration of [pyr1]-apelin-13 caused pronounced relaxation of isolated arteries. Incubation with the guanylyl cyclase inhibitor, ODQ, blocked NO-induced relaxation, but did not significantly alter the relaxation response to the plasma from apelin-treated rats. Taken together, these findings demonstrate that intravenous injection of apelin causes a significant depressor response that is mediated by a NO-independent mechanism involving an unidentified substance released into the bloodstream leading to vasodilation.

Verapamil improves One-Year C-Peptide Levels in Recent Onset Type-1 Diabetes: A Meta-Analysis.

Meta-analysis studying the role of verapamil in improving C-peptide in people with recent-onset type-1 diabetes (T1DM) has not been conducted to date. We undertook this meta-analysis to address this knowledge gap. Electronic databases were systematically reviewed for RCTs having individuals with T1DM receiving verapamil in the treatment arm and placebo in the control arm over the standard of care. The primary outcome was to evaluate changes in the C-peptide area under the curve (AUC) at a one-year follow-up. Secondary outcomes were to assess alterations in C-peptide AUC, glycated hemoglobin (HbA1c), blood pressure, heart rate, and side effects at different time intervals over a one-year follow-up. From the initially screened 27 articles, data from two RCTs (112 patients) satisfied the inclusion criteria and were analyzed. Compared to placebo, C-peptide AUC in individuals receiving verapamil was not different at three months [MD 0.17 nmol/L (95%CI: -0.05-0.38); P = 0.13; I2 = 86%] but significantly higher at 1-year [MD 0.27 nmol/L (95%CI: 0.19-0.35); P < 0.01; I2 = 12%]. The verapamil arm showed similar changes in HbA1C at three months [MD 0.23% (95%CI: -0.43-0.90); P = 0.49; I2 = 88%] and 1-year [MD 0.18% (95% CI: -0.74 - 1.10); P = 0.70; I2 = 89%] compared to placebo. Occurrence of treatment-emergent adverse events [Risk ratio (RR) 1.90 (95%CI: 0.52-6.91); P = 0.33; I2 = 63%], serious adverse events [RR 1.40 (95%CI: 0.50-3.93); P = 0.53], constipation [RR4.11 (95%CI: 0.93-18.13); P = 0.06; I2 = 0%], headache [RR0.48 (95%CI: 0.16-1.43); P = 0.19; I2 = 0%], severe hypoglycemia [RR 0.87 (95%CI: 0.06 - 13.51); P = 0.92] were comparable across groups. Verapamil was well tolerated, and its use over one year was associated with significant improvements in C-peptide AUC though the HbA1c remained unchanged.

Serotonin (5-HT)-1A receptor activation alters heart rate variability (HRV) in SN 6-OHDA-induced rat model of Parkinson's Disease

Parkinson’s disease (PD) is a multifaceted progressive neurodegenerative disease that includes a broad range of motor and non-motor symptoms (NMS). Autonomic nervous system (ANS) dysfunction is associated with a number of common NMS in PD that exert a profound impact on quality of life and increase the risk of mortality. ANS dysfunction, which likely precedes the onset of motor symptoms, includes changes in heart rate variability (HRV) that reflect pathological adjustments in the balance between sympathetic (SNS) and parasympathetic (PNS; vagal) influences on heart rate control. While the primary neuropathology of PD is related to the loss of dopamine neurons in the nigrostriatal pathway, serotonergic (5-HT) dysfunction also appears to play a role in the development of some motor and NMS and complications in PD. 5-HT is also known to play a critical role in cardiovascular (cardiac) regulation; thus, autonomic dysfunction in PD may be further complicated by 5-HT dysfunction. To begin to address this possibility, we investigated HRV quantified from 5-min segments of continuously recorded ECG activity before and after acute systemic administration of the 5-HT1A receptor agonist 8-OH-DPAT (DPAT) in urethane-anesthetized adult female rats at 2-weeks after unilateral injection of the neurotoxin 6-OHDA (n=11) or vehicle (VEH; n=7) directly into the substantia nigra (SN). HRV measures evaluated included standard deviation (SD) of R-R intervals (SDRR) and root mean square of successive differences in R-R (RMSSD) as time-domain measures; absolute (abs) and normalized (nu) low-frequency (LF: 0.2-0.75 Hz) and high-frequency (HF: 0.75-3.0 Hz) spectral power and the LF/HF ratio as frequency domain measures; and Poincaré plot SD perpendicular to (SD1) and along (SD2) the line of identity and the SD1/SD2 ratio as non-linear measures. For these analyses, SDRR, LF, and SD2 were considered indices of mixed cardiac SNS and PNS activity; RMSSD, HF, and SD1 were considered indices of PNS activity; and LF/HF and SD1/SD2 were considered indices of sympatho-vagal balance. Before DPAT (compared to VEH-injected rats), 6-OHDA-injected rats exhibited slightly but not significantly higher HR and lower SDRR, RMSSD, abs and nu LF power, abs HF power, LF/HF ratio, SD1, and SD2, but the R-R interval, nu HF power, and SD1/SD2 ratio were similar between the groups. Following DPAT administration, both 6-OHDA- and VEH-injected rats exhibited significantly reduced HR by ~15% and increased R-R intervals by 20%. In 6-OHDA-injected rats, DPAT also increased SDRR, RMSSD, abs HF power, SD1, and the SD1/SD2 ratio but significantly reduced nu HF power; similar trends were noted in VEH-injected rats. These data demonstrate that while most HRV measures are minimally altered under baseline conditions, 5-HT1A receptor activation can significantly alter autonomic balance and HRV metrics (especially measures associated with PNS activity) in the SN 6-OHDA-induced lesion rat model of PD. NIH NS101737; Thomas Hartman Center for Parkinson's Disease Research at Stony Brook University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Altered parasympathetic activity during sleep and emotionally arousing wakefulness in frequent nightmare recallers

Nightmare disorder is characterized by dysfunctional emotion regulation and poor subjective sleep quality reflected in pathophysiological features such as abnormal arousal processes and sympathetic influences. Dysfunctional parasympathetic regulation, especially before and during rapid eye movement (REM) phases, is assumed to alter heart rate (HR) and its variability (HRV) of frequent nightmare recallers (NM). We hypothesized that cardiac variability is attenuated in NMs as opposed to healthy controls (CTL) during sleep, pre-sleep wakefulness and under an emotion-evoking picture-rating task. Based on the polysomnographic recordings of 24 NM and 30 CTL participants, we examined HRV during pre-REM, REM, post-REM and slow wave sleep, separately. Additionally, electrocardiographic recordings of resting state before sleep onset and under an emotionally challenging picture-rating task were also analyzed. Applying repeated measures analysis of variance (rmANOVA), a significant difference was found in the HR of NMs and CTLs during nocturnal segments but not during resting wakefulness, suggesting autonomic dysregulation, specifically during sleep in NMs. As opposed to the HR, the HRV values were not significantly different in the rmANOVA in the two groups, implying that the extent of parasympathetic dysregulation on a trait level might depend on the severeness of dysphoric dreaming. Nonetheless, in the group comparisons, the NM group showed increased HR and reduced HRV during the emotion-evoking picture-rating task, which aimed to model the nightmare experience in the daytime, indicating disrupted emotion regulation in NMs under acute distress. In conclusion, trait-like autonomic changes during sleep and state-like autonomic responses to emotion-evoking pictures indicate parasympathetic dysregulation in NMs.

Use of Structured Electronic Health Records Data Elements for the Development of Computable Phenotypes to Identify Potential Adverse Events Associated with Intravenous Immunoglobulin Infusion.

Detection of adverse reactions to drugs and biologic agents is an important component of regulatory approval and post-market safety evaluation. Real-world data, including insurance claims and electronic health records data, are increasingly used for the evaluation of potential safety outcomes; however, there are different types of data elements available within these data resources, impacting the development and performance of computable phenotypes for the identification of adverse events (AEs) associated with a given therapy. To evaluate the utility of different types of data elements to the performance of computable phenotypes for AEs. We used intravenous immunoglobulin (IVIG) as a model therapeutic agent and conducted a single-center, retrospective study of 3897 individuals who had at least one IVIG administration between 1 January 2014 and 31 December 2019. We identified the potential occurrence of four different AEs, including two proximal AEs (anaphylaxis and heart rate alterations) and two distal AEs (thrombosis and hemolysis). We considered three different computable phenotypes: (1) an International Classification of Disease (ICD)-based phenotype; (2) a phenotype-based on EHR-derived contextual information based on structured data elements, including laboratory values, medication administrations, or vital signs; and (3) a compound phenotype that required both an ICD code for the AE in combination with additional EHR-derived structured data elements. We evaluated the performance of each of these computable phenotypes compared with chart review-based identification of AEs, assessing the positive predictive value (PPV), specificity, and estimated sensitivity of each computable phenotype method. Compound computable phenotypes had a high positive predictive value for acute AEs such as anaphylaxis and bradycardia or tachycardia; however, few patients had both ICD codes and the relevant contextual data, which decreased the sensitivity of these computable phenotypes. In contrast, computable phenotypes for distal AEs (i.e., thrombotic events or hemolysis) frequently had ICD codes for these conditions in the absence of an AE due to a prior history of such events, suggesting that patient medical history of AEs negatively impacted the PPV of computable phenotypes based on ICD codes. These data provide evidence for the utility of different structured data elements in computable phenotypes for AEs. Such computable phenotypes can be used across different data sources for the detection of infusion-related adverse events.

Adverse drug reactions in geriatric psychiatry—retrospective cohort study of a 6-year period

ObjectiveTo investigate the frequency and characteristics of adverse drug reactions (ADRs) that occurred on the gerontopsychiatric ward of Hannover Medical School over a 6-year period.DesignRetrospective monocentric cohort study.ResultsSix hundred thirty-four patient cases (mean age 76.6 ± 7.1 years; 67.2% female) were analysed. In total, 92 ADRs in 56 patient cases were registered in the study population. The overall ADR prevalence, the ADR prevalence upon hospital admission, and the ADR prevalence during hospitalisation were 8.8%, 6.3%, and 4.9%, respectively. The most frequent ADRs were extrapyramidal symptoms, alterations in blood pressure or heart rate, and electrolyte disturbances. Of note, two cases of asystole and one case of obstructive airway symptoms related to general anaesthesia in the context of electroconvulsive therapy (ECT) were detected. The presence of coronary heart disease was associated with an increased risk of ADR occurrence (odds ratio (OR) 2.92, 95% confidence interval (CI) 1.37–6.22), while the presence of dementia was associated with a decreased risk of ADR development (OR 0.45, 95% CI 0.23–0.89).ConclusionsType and prevalence of ADRs in the present study were largely in accordance with previous reports. By contrast, we did not observe a relationship between advanced age or female sex and ADR occurrence. We detected a risk signal for cardiopulmonary ADRs related to general anaesthesia in the context of ECT that warrants further investigation. Elderly psychiatric patients should be carefully screened for cardiopulmonary comorbidities before initiation of ECT.

Prediabetes as a risk factor for new-onset atrial fibrillation: the propensity-score matching cohort analyzed using the Cox regression model coupled with the random survival forest

BackgroundThe glycemic continuum often indicates a gradual decline in insulin sensitivity leading to an increase in glucose levels. Although prediabetes is an established risk factor for both macrovascular and microvascular diseases, whether prediabetes is independently associated with the risk of developing atrial fibrillation (AF), particularly the occurrence time, has not been well studied using a high-quality research design in combination with statistical machine-learning algorithms.MethodsUsing data available from electronic medical records collected from the National Taiwan University Hospital, a tertiary medical center in Taiwan, we conducted a retrospective cohort study consisting 174,835 adult patients between 2014 and 2019 to investigate the relationship between prediabetes and AF. To render patients with prediabetes as comparable to those with normal glucose test, a propensity-score matching design was used to select the matched pairs of two groups with a 1:1 ratio. The Kaplan–Meier method was used to compare the cumulative risk of AF between prediabetes and normal glucose test using log-rank test. The multivariable Cox regression model was employed to estimate adjusted hazard ratio (HR) for prediabetes versus normal glucose test by stratifying three levels of glycosylated hemoglobin (HbA1c). The machine-learning algorithm using the random survival forest (RSF) method was further used to identify the importance of clinical factors associated with AF in patients with prediabetes.ResultsA sample of 14,309 pairs of patients with prediabetes and normal glucose test result were selected. The incidence of AF was 11.6 cases per 1000 person-years during a median follow-up period of 47.1 months. The Kaplan–Meier analysis revealed that the risk of AF was significantly higher in patients with prediabetes (log-rank p < 0.001). The multivariable Cox regression model indicated that prediabetes was independently associated with a significant increased risk of AF (HR 1.24, 95% confidence interval 1.11–1.39, p < 0.001), particularly for patients with HbA1c above 5.5%. The RSF method identified elevated N-terminal natriuretic peptide and altered left heart structure as the two most important risk factors for AF among patients with prediabetes.ConclusionsOur study found that prediabetes is independently associated with a higher risk of AF. Furthermore, alterations in left heart structure make a significant contribution to this elevated risk, and these structural changes may begin during the prediabetes stage.