MARRIAGE: A Randomized Trial of Moxonidine Versus Ramipril or in Combination With Ramipril in Overweight Patients With Hypertension and Impaired Fasting Glucose or Diabetes Mellitus. Impact on Blood Pressure, Heart Rate and Metabolic Parameters.

BACKGROUND: Moxonidine, an imidazoline I1 receptor agonist, is an effective antihypertensive drug that was shown to improve insulin sensitivity. RAAS-blockers are recommended as first-line therapy in patients with diabetes, alone or in combination with a calcium-channel antagonist or a diuretic. AIMS: This study compared the effects of moxonidine and ramipril on blood pressure (BP) and glucose metabolism in overweight patients with mild-to-moderate hypertension and impaired fasting glucose or type 2 diabetes. METHODS: Treatment-naïve patients for hypertension and dysglycemia were randomized to 12 weeks of double-blind moxonidine 0.4 mg or ramipril 5 mg once-daily treatment. At 12 weeks, for a further 12 weeks non-responders received combination of mox/ram, while responders continued blinded treatment. RESULTS: Moxonidine and ramipril were equivalent in lowering SiDBP and SiSBP at the end of the first 12 weeks. The responder rate was approximately 50% in both groups, with a mean SiDBP and SiSBP decrease of 10 and 15 mm Hg in the responders, respectively. The normalization rate (SiDBP < 85 mm Hg) was non significantly different between treatments groups. Moxonidine reduced heart rate (HR) (average -3.5 bpm, p = 0.017) during monotherapy, and when added to ramipril. HbA1c decreased significantly at Week 12 in both groups. Neither drug affected glucose or insulin response to the oral glucose tolerance test. In non-responders, moxonidine/ramipril combination further reduced BP without compromising metabolic parameters. CONCLUSION: Moxonidine 0.4 mg and ramipril 5 mg were equally effective on BP lowering and were well tolerated and mostly metabolically neutral either as monotherapies or in combination. HR was lowered on moxonidine treatment.

Effects of vatinoxan in rats sedated with a combination of medetomidine, midazolam and fentanyl.

BACKGROUND: Alpha2-adrenoceptor agonists (α2-agonists) are widely used in animals as sedatives and for pre-anaesthetic medication. Medetomidine has often been given subcutaneously (SC) to rats, although its absorption rate is slow and the individual variation in serum drug concentrations is high via this route. In addition, α2-agonists have various effects on metabolic and endocrine functions such as hypoinsulinaemia, hyperglycaemia and diuresis. Vatinoxan is a peripherally acting α2-adrenoceptor antagonist that, as a hydrophilic molecule, does not cross the blood-brain barrier in significant quantities and thus alleviates peripheral cardiovascular effects and adverse metabolic effects of α2-agonists. Aim of this study was to evaluate the effects of vatinoxan on sedation, blood glucose concentration, voiding and heart and respiratory rates and arterial oxygen saturation in rats sedated with subcutaneous medetomidine, midazolam and fentanyl. RESULTS: Onset of sedation and loss of righting reflex occurred significantly faster with vatinoxan [5.35 ± 1.08 (mean ± SD) versus 12.97 ± 6.18 min and 6.53 ± 2.18 versus 14.47 ± 7.28 min, respectively]. No significant differences were detected in heart and respiratory rates and arterial oxygen saturation between treatments. Blood glucose concentration (18.3 ± 3.6 versus 11.8 ± 1.2 mmol/L) and spontaneous urinary voiding [35.9 (15.1-41.6), range (median) versus 0.9 (0-8.0) mL /kg/min] were significantly higher without vatinoxan. CONCLUSIONS: Acceleration of induction of sedation, alleviation of hyperglycaemia and prevention of profuse diuresis by vatinoxan may be beneficial when sedating rats for clinical and experimental purposes with subcutaneous medetomidine, midazolam and fentanyl.

Analysis of cardiohemodynamic and electrophysiological effects of morphine along with its toxicokinetic profile using the halothane-anesthetized dogs.

Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through IKr inhibition in vivo, but its potential to develop torsade de pointes will be small.

Design and Stability Analysis of an Adaptive Neuro-Fuzzy Inference System (ANFIS)-Based Pacemaker Controller in MATLAB Simulink.

We present the design and stability analysis of an adaptive neuro-fuzzy inference system (ANFIS)-based controller of a pacemaker in MATLAB Simulink. ANFIS uses learning and speed properties of fuzzy and neural networks. Based on body states and preprogrammed situations of patients (age and sex, etc.), heart rate and amplitude of pacing pulse are changed. Output signal that is fed backed from heart is compared to the reference fuzzy bases ANFIS signals. After designing ANFIS based controller, the stability of the proposed system has been tested in both the time (step response) and trequency (Bode diagram and Nichols chart) domains. In our previous study, the step response analyzed and compared with other works. For frequency domain, all the possible frequency analysis methods have been tested but because of nonlinear properties of ANFIS, after linearization, just the Bode diagram achieved good results. The step response results in time domain is compared with previous work's results including optimum heart pulse rate for each particular patient. In the frequency domain, the Bode diagram stability analysis showed gain and phase margin as follows: GM (dB) = 42.1 and PM (deg) = 100.

Heart rate and heart rate variability in horses undergoing hot and cold shoeing.

Heart rate variability (HRV) is a frequently used indicator of autonomic responses to various stimuli in horses. This study aimed to investigate HRV variables in horses undergoing cold (n = 25) or hot (n = 26) shoeing. Multiple HRV variables were measured and compared between horses undergoing cold and hot shoeing, including the time domain, frequency domain, and nonlinear variables pre-shoeing, during shoeing, and at 30-minute intervals for 120 minutes post-shoeing. The shoeing method interacted with time to change the HRV variables standard deviation of RR intervals (SDNN), root mean square of successive RR interval differences (RMSSD), very-low-frequency band, low-frequency band (LF), the LF to high-frequency band ratio, respiratory rate, total power, standard deviation perpendicular to the line of identity (SD1), and standard deviation along the line of identity (SD2). SDNN, RMSSD, and total power only increased 30 minutes after hot shoeing (all p < 0.05). Triangular interpolation of normal-to-normal intervals (TINN) and the HRV triangular index increased during and up to 120 minutes after hot shoeing (p < 0.05-0.001). TINN increased only during cold shoeing (p < 0.05). LF increased 30 and 60 minutes after hot shoeing (both p < 0.05). SD1 and SD2 also increased 30 minutes after hot shoeing (both p < 0.05). SDNN, TINN, HRV triangular index, LF, total power, and SD2 were higher in hot-shoed than cold-shoed horses throughout the 120 minutes post-shoeing. Differences in HRV were found, indicating increased sympathovagal activity in hot shoed horses compared to cold shoed horses.

Nine treatments of 1000 mL therapeutic phlebotomy in a subject with polycythemia: A case report.

Large-volume therapeutic phlebotomy is the mainstay of hemochromatosis treatment and offers an opportunity to investigate the hemodynamic changes during acute hypovolemia. An otherwise healthy 64-year-old male with hemochromatosis participated. On nine separate visits, 1000 mL therapeutic phlebotomy was performed. On one occasion, pre- and post-phlebotomy orthostatic challenge with 27° reverse Trendelenburg position was administered. Mean arterial pressure, heart rate, and stroke volume were measured continuously during the procedures. The patient's tolerance to the interventions was continuously evaluated. The procedures were well tolerated by the patient. Mean arterial pressure was maintained during hemorrhage and following phlebotomy in both supine and reverse Trendelenburg positions, primarily through an increase in heart rate and systemic vascular resistance. The present study found that 1000 mL therapeutic phlebotomy in a patient with hemochromatosis may be acceptably and safely used to model hemorrhage. The approach demonstrates high clinical applicability and ethically robustness in comparison with volunteer studies.

The effects of auditory stimulation on heart rate variability in healthy individuals with normal hearing and with hearing loss: a systematic review and meta-analysis.

PURPOSE: To analyze the effects of auditory stimulation on heart rate variability (HRV) indices in healthy individuals with normal hearing and with hearing loss, regardless of type and/or grade, by means of a systematic review. RESEARCH STRATEGIES: This is a systematic review with a meta-analysis that addresses the following question: in healthy individuals with normal hearing and/or with hearing loss, what are the effects of auditory stimulation on HRV indices in comparison to silence? We consulted the Cochrane Library, Embase, LILACS, PubMed, Web of Science, and Scopus databases and the gray literature (Google Scholar, OpenGrey, and ProQuest). SELECTION CRITERIA: There were no restrictions as to period or language of publication. DATA ANALYSIS: We identified 451 records, an additional 261 in the gray literature, and five studies in a search through the references, resulting in a total of 717 records, with 171 duplicate records. After screening the titles and abstracts of 546 studies, we excluded 490 and considered 56 studies in full to assess their eligibility. RESULTS: Nine of these studies were included in the systematic review, eight of which were suitable for the meta-analysis. CONCLUSION: It is suggested that auditory stimulation may influence the RMSSD, pNN50, SDNN, RRTri and SD2 indices of HRV in healthy adults with normal hearing.

The relationship between heart rate variability and glucose clearance in healthy men and women.

Heart rate variability (HRV) is a non-invasive indicator of the activity of the autonomic nervous system, which regulates many physiological functions including metabolism. The purpose of this study was to quantify the relationship between resting markers of HRV and oral glucose tolerance test (OGTT) response. Eighteen healthy individuals (10 males, 8 females, (23.8±2.9 years) underwent a 10-minute resting HRV recording. The final five minutes were evaluated via Kubios HRV Standard for: root mean square of successive differences (RMSSD), standard deviation of normal-to-normal sinus beats (SDNN), high frequency (HF), and low frequency (LF). A standard 2-hour OGTT was then administered. Glucose was measured via finger stick before, 30-minutes post, 1-hour post, and 2-hours post OGTT. Pearson correlations demonstrated that RMSSD, SDNN, HF and LF were strongly correlated to fasting blood glucose (FBG) for the group (p<0.05) but not for glucose area under the curve (AUC). When analyzed by sex, only males demonstrated significant correlations between AUC and RMSSD, SDNN, and LF (p<0.05). An independent samples t-test revealed no sex differences for FBG, AUC, RMSSD, SDNN, HF and LF. These findings provide new and interesting insights into the relationship of autonomic activity and glucose uptake, highlighting sex-based relationships.

Lateral Shuffle-Induced Fatigue Effects on Ankle Proprioception and Countermovement Jump Performance.

To determine how lateral shuffling/lateral shuffle (LS) -induced fatigue affects ankle proprioception and countermovement jump (CMJ) performance. Eighteen male college athletes performed 6 modes of a repeated LS protocol with 2 distances (2.5 and 5 m) and 3 speeds (1.6, 1.8, and 2.0 m/s). After LS, ankle inversion proprioception (AIP) was measured using the active movement extent discrimination apparatus (AMEDA). CMJ, blood lactate (BLa), heart rate (HR) and rating of perceived exertion (RPE) were measured before and after LS. The number of changes of direction (CODs) in each protocol was recorded. LS-induced fatigue was evident in BLa, HR and RPE (all p < 0.05), increasing with shorter shuffle distance and faster speed. RM-ANOVA showed a significant distance main effect on both AIP (p < 0.01) and CMJ (p < 0.05), but the speed main effect was only significant for CMJ (p ≤ 0.001), not AIP (p = 0.87). CMJ performance was correlated with BLa, HR and RPE (r values range from -0.62 to -0.32, all p ≤ 0.001). AIP was only correlated with CODs (r = -0.251, p < 0.01). These results suggested that in LS, shorter distance, regardless of speed, was associated with worse AIP, whereas subsequent CMJ performance was affected by both LS distance and speed. Hence, AIP performance was not related to physiological fatigue, but CMJ performance was. Results imply that LS affects processing proprioceptive input and producing muscular output differently, and that these two aspects of neuromuscular control are affected by physiological fatigue to varying degrees. These findings have implications for injury prevention and performance enhancement.

Effects of conditioning on the left ventricular function of young purebred Arabian horses.

The effects of conditioning on cardiac function in young horses is still unknown. For this reason, this study evaluated the left ventricular (LV) function of young horses by echocardiography after six weeks of conditioning. Fourteen untrained young purebred Arabian horses were evaluated at rest and after a stress test (ST) before and after a six-week conditioning program. There was an increase in V4 (p < 0.001) after conditioning, as well as a reduction in both heart rate (HR) at rest and peak HR during the ST (p < 0.001). There was also a reduction in internal diameter, along with an increase in interventricular septal, free wall and mean thicknesses and LV mass (p < 0.05). After the ST, the conditioned animals showed higher values of velocity time integral, stroke volume, systolic and cardiac indices, ejection (ET) and deceleration times (DT), end-diastolic volume, time to onset of radial myocardial velocity during early diastole and time to peak of transmitral flow velocity, in addition to reduced pre-ejection period (PEP), PEP/ET ratio and mean velocity of circumferential fiber shortening (p < 0.05). The conditioning protocol promoted physiological adaptations that indicate an improvement in the animals' aerobic capacity associated with an enhanced left ventricular function.

Ingestible pills reveal gastric correlates of emotions.

Although it is generally held that gastrointestinal (GI) signals are related to emotions, direct evidence for such a link is currently lacking. One of the reasons why the internal milieu of the GI system is poorly investigated is because visceral organs are difficult to access and monitor. To directly measure the influence of endoluminal markers of GI activity on the emotional experience, we asked a group of healthy male participants to ingest a pill that measured pH, pressure, and temperature of their GI tract while they watched video clips that consistently induced disgust, fear, happiness, sadness, or a control neutral state. In addition to the objective physiological markers of GI activity, subjective ratings of perceived emotions and visceral (i.e. gastric, respiratory and cardiac) sensations were recorded, as well as changes in heart rate (HR), heart rate variability (HRV) and spontaneous eyes blinks as non-gastric behavioral and autonomic markers of the emotional experience. We found that when participants observed fearful and disgusting video clips, they reported to perceive not only cardiac and respiratory sensations but also gastric sensations, such as nausea. Moreover, we found that there was a clear relation between the physiology of the stomach and the perceived emotions. Specifically, when disgusting video clips were displayed, the more acidic the pH, the more participants reported feelings of disgust and fear; the less acidic the pH, the more they reported happiness. Complementing the results found in the deep gastric realm, we found that disgusting stimuli induced a significant increase in HRV compared to the neutral scenarios, and together with fearful video clips a decrease in HR. Our findings suggest that gastric signals contribute to unique emotional states and that ingestible pills may open new avenues for exploring the deep-body physiology of emotions.

The EC50 of propofol with different doses of dexmedetomidine during gastrointestinal endoscopy: A double-blind, placebo-controlled trial.

PURPOSE: The goal of this study was to evaluate the dose-response relationship between dexmedetomidine and propofol in sedating patients and to determine the optimal dosage of dexmedetomidine during gastrointestinal endoscopy. METHODS: One hundred fifty patients were divided into 5 groups, each receiving a loading dose of dexmedetomidine (0.4, 0.6, 0.8, 1.0 µg/kg) or saline, with propofol for sedation. The median effective concentration (EC50) of propofol was calculated using the modified Dixon up-and-down approach. Adverse effects, vital signs, procedure, and recovery times were recorded. RESULTS: The EC50 of propofol in groups NS, D0.4, D0.6, D0.8, and D1.0 were 3.02, 2.44, 1.97, 1.85, and 1.83 µg/mL, respectively. Heart rate in the dexmedetomidine groups decreased more than the NS group (P < .001). The mean arterial pressure (MAP) in the NS group experienced a decline compared to groups D0.8 and D1.0 when the plasma concentration and effect-site concentration reached equilibrium. Additionally, the respiratory rate was found to be lower in groups NS, D0.4, D0.6, and D0.8 (P < .05). Recovery time in groups D0.8 and D1.0 was longer than the NS group (P < .05). Bruggemann comfort scales score was higher in group D1.0 (P < .05). No significant difference was found in the incidences of hypotension and bradycardia, and the dose of ephedrine and atropine. Respiratory depression was significantly reduced in groups D0.8 and D1.0 compared to the NS group. CONCLUSION: A single dose of 0.6 to 0.8 µg/kg of dexmedetomidine should be recommended in combination with propofol for gastrointestinal endoscopy. And the EC50 of propofol is 1.97 to 1.85 µg/mL.

Continuous heart monitoring to evaluate treatment effects in pulmonary hypertension.

BACKGROUND: The treatment of pulmonary hypertension (PH) has improved rapidly in recent decades. There is increasing evidence to support the role of early intervention and treatment in affecting clinical outcomes in PH. OBJECTIVES: To assess treatment effects before and after the escalation of specific PH treatments using continuous heart monitoring with a Reveal LINQ loop recorder. METHODS: Patients were compared before and after treatment escalation. Treatment escalation was defined as an additional pulmonary arterial hypertension (PAH) drug, pulmonary endarterectomy, percutaneous balloon angioplasty or bilateral lung transplantation. Specifically, changes in heart rate variability (HRV), heart rate (HR) and physical activity were assessed. RESULTS: In this prospective study, 41 patients (27 with PAH and 14 with chronic thromboembolic pulmonary hypertension (CTEPH)) were enrolled. Among them, 15 (36.6%) patients underwent PH treatment escalation. Prior to escalation, patients were monitored for a median of 100 (range: 68-100) days and after therapy escalation for a median duration of 165 (range: 89-308) days. In the escalation group, there was a significant increase in HRV, physical activity indexed by daytime HR and a significant decrease in nighttime HR assessed at baseline and after treatment escalation in both the PAH and CTEPH groups. This was paralleled by significant improvements in WHO functional class, 6-min walking distance and N-terminal pro-b-type natriuretic peptide. CONCLUSIONS: This is the first study to demonstrate an association between specific PH therapies and changes in HRV, HR nighttime and physical activity. This indicates the potential of continuous monitoring in the evaluation of treatment effects in PH.

Pacemaker Channels and the Chronotropic Response in Health and Disease.

Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease-including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating ß-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate-sensitive hyperpolarization-activated current (If) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate-dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.

Practical cooling interventions for preventing heat strain in indoor factory workers in Thailand.

BACKGROUND: Occupational heat stress, exacerbated by factors such as climate change and insufficient cooling solutions, endangers the health and productivity of workers, especially in low-resource workplaces. OBJECTIVE: To evaluate the effectiveness of two cooling strategies in reducing physiological strain and productivity of piece-rate workers over a 9-h work shift in a southern Thailand sawmill. METHODS: In a crossover randomized control trial design, 12 (33 ± 7 y; 1.58 ± 0.05 m; 51 ± 9 kg; n = 5 females) medically screened sawmill workers were randomly allocated into three groups comprising an established phase change material vest (VEST), an on-site combination cooling oasis (OASIS) (i.e., hydration, cold towels, fans, water dousing), and no cooling (CON) across 3 consecutive workdays. Physiological strain was measured via core temperature telemetry and heart rate monitoring. Productivity was determined by counting the number of pallets of wood sorted, stacked, and stowed each day. RESULTS: Relative to CON, OASIS lowered core temperature by 0.25°C [95% confidence interval = 0.24, 0.25] and heart rate by 7 bpm [6, 9] bpm, compared to 0.17°C [0.17, 0.18] and 10 [9,12] bpm reductions with VEST. It was inconclusive whether productivity was statistically lower in OASIS compared to CON (mean difference [MD] = 2.5 [-0.2, 5.2]), and was not statistically different between VEST and CON (MD = 1.4 [-1.3, 4.1]). CONCLUSIONS: Both OASIS and VEST were effective in reducing physiological strain compared to no cooling. Their effect on productivity requires further investigation, as even small differences between interventions could lead to meaningful disparities in piece-rate worker earnings over time.

Dynamics of indicators of functional state and physical development of students in the process of high-intensity interval training.

OBJECTIVE: Aim: To investigate the effect of high-intensity interval training (HIIT) based on the CrossFit system on the level of students' functional state and physical development. PATIENTS AND METHODS: Materials and Methods: The research involved 36 male students who were engaged in HIIT during their studies. Indicators of students' functional state and physical development after 1 and 3 years of HIIT were studied. The functional state was assessed by indicators of the cardiovascular and respiratory systems, and physical development - by physical education tests. RESULTS: Results: It has been found that HIIT has a positive effect on the indicators of the functional state of the cardiovascular and respiratory systems of the body and the physical development of students. After three years of HIIT sessions, students significantly improved their heart rate, vital capacity of the lungs, Stange test, Genchi test, duration of recovery heart rate, as well as the level of development of speed qualities, strength qualities, endurance and flexibility. CONCLUSION: Conclusions: It has been established that the sports-oriented form of organization of physical education training sessions with the use of HIIT based on the CrossFit system is quite effective in improving the indicators of the functional state and physical development of students. A high level of these indicators will help to improve students' health, improve their well-being, and increase the effectiveness of their educational and, in the future, professional activities.

Novel predictive approaches for drug-induced convulsions in non-human primates using machine learning and heart rate variability analysis.

Drug-induced convulsions are a major challenge to drug development because of the lack of reliable biomarkers. Using machine learning, our previous research indicated the potential use of an index derived from heart rate variability (HRV) analysis in non-human primates as a biomarker for convulsions induced by GABAA receptor antagonists. The present study aimed to explore the application of this methodology to other convulsants and evaluate its specificity by testing non-convulsants that affect the autonomic nervous system. Telemetry-implanted males were administered various convulsants (4-aminopyridine, bupropion, kainic acid, and ranolazine) at different doses. Electrocardiogram data gathered during the pre-dose period were employed as training data, and the convulsive potential was evaluated using HRV and multivariate statistical process control. Our findings show that the Q-statistic-derived convulsive index for 4-aminopyridine increased at doses lower than that of the convulsive dose. Increases were also observed for kainic acid and ranolazine at convulsive doses, whereas bupropion did not change the index up to the highest dose (1/3 of the convulsive dose). When the same analysis was applied to non-convulsants (atropine, atenolol, and clonidine), an increase in the index was noted. Thus, the index elevation appeared to correlate with or even predict alterations in autonomic nerve activity indices, implying that this method might be regarded as a sensitive index to fluctuations within the autonomic nervous system. Despite potential false positives, this methodology offers valuable insights into predicting drug-induced convulsions when the pharmacological profile is used to carefully choose a compound.

Concentration-QTc modeling of sitravatinib in patients with advanced solid malignancies.

Sitravatinib (MGCD516) is an orally available, small molecule, tyrosine kinase inhibitor that has been evaluated in patients with advanced solid tumors. Concentration-corrected QT interval (QTc; C-QTc) modeling was undertaken, using 767 matched concentration-ECG observations from 187 patients across two clinical studies in patients with advanced solid malignancies, across a dose range of 10-200 mg, via a linear mixed-effects (LME) model. The effect on heart rate (HR)-corrected QT interval via Fridericia's correction method (QTcF) at the steady-state maximum concentration (Cmax,ss) for the sitravatinib proposed therapeutic dosing regimen (100 mg malate once daily [q.d.]) without and with relevant intrinsic and extrinsic factors were predicted. No significant changes in HR from baseline were observed. Hysteresis between sitravatinib plasma concentration and change in QTcF from baseline (ΔQTcF) was not observed. There was no significant relationship between sitravatinib plasma concentration and ΔQTcF. The final C-QTc model predicted a mean (90% confidence interval [CI]) ΔQTcF of 3.92 (1.95-5.89) ms and 2.94 (0.23-6.10) ms at the proposed therapeutic dosing regimen in patients with normal organ function (best case scenario) and patients with hepatic impairment (worst-case scenario), respectively. The upper bounds of the 90% CIs were below the regulatory threshold of concern of 10 ms. The results of the described C-QTc analysis, along with corroborating results from nonclinical safety pharmacology studies, indicate that sitravatinib has a low risk of QTc interval prolongation at the proposed therapeutic dose of 100 mg malate q.d.

Effect of body mass index on exercise capacity following pediatric heart transplantation.

BACKGROUND: Obesity and impaired exercise tolerance following heart transplantation increase the risk of post-transplant morbidity and mortality. The aim of this study was to evaluate the effect of body mass index on markers of exercise capacity in pediatric heart transplant recipients and compare this effect with a healthy pediatric cohort. METHODS: A retrospective analysis of cardiopulmonary exercise test data between 2004 and 2022 was performed. All patients exercised on a treadmill using the Bruce protocol. Inclusion criteria included patients aged 6-21 years, history of heart transplantation (transplant cohort) or no cardiac diagnosis (control cohort) at the time of testing, and a maximal effort test. Patients were further stratified within these two cohorts as underweight, normal, overweight, and obese based on body mass index groups. Two-way analyses of variance were performed with diagnosis and body mass index category as the independent variables. RESULTS: A total of 250 exercise tests following heart transplant and 1963 exercise tests of healthy patients were included. Heart transplant patients across all body mass index groups had higher resting heart rate and lower maximal heart rate, heart rate recovery at 1 min, exercise duration, and peak aerobic capacity (VO2peak). Heart transplant patients in the normal and overweight body mass index categories had higher VO2peak and exercise duration when compared to underweight and obese patients. CONCLUSION: Underweight status and obesity are strongly associated with lower VO2peak and exercise duration in heart transplant patients. Normal and overweight heart transplant patients had the best markers of exercise capacity.

Life's Essential 8 Cardiovascular Health Score and Cardiorespiratory Fitness in the Community.

BACKGROUND: The relation of cardiorespiratory fitness (CRF) to lifestyle behaviors and factors linked with cardiovascular health remains unclear. We aimed to understand how the American Heart Association's Life's Essential 8 (LE8) score (and its changes over time) relate to CRF and complementary exercise measures in community-dwelling adults. METHODS AND RESULTS: Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise testing for direct quantification of peak oxygen uptake (V̇O2). A 100-point LE8 score was constructed as the average across 8 factors: diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure. We related total LE8 score, score components, and change in LE8 score over 8 years with peak V̇O2 (log-transformed) and complementary CRF measures. In age- and sex-adjusted linear models (N=1838, age 54±9 years, 54% women, LE8 score 76±12), a higher LE8 score was associated favorably with peak V̇O2, ventilatory efficiency, resting heart rate, and blood pressure response to exercise (all P<0.0001). A clinically meaningful 5-point higher LE8 score was associated with a 6.0% greater peak V̇O2 (≈1.4 mL/kg per minute at sample mean). All LE8 components were significantly associated with peak V̇O2 in models adjusted for age and sex, but blood lipids, diet, and sleep health were no longer statistically significant after adjustment for all LE8 components. Over an ≈8-year interval, a 5-unit increase in LE8 score was associated with a 3.7% higher peak V̇O2 (P<0.0001). CONCLUSIONS: Higher LE8 score and improvement in LE8 over time was associated with greater CRF, highlighting the importance of the LE8 factors in maintaining CRF.