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1.
Hemodynamic and perceptual responses to blood flow-restricted exercise among patients undergoing dialysis.
Clarkson, MJ, Brumby, C, Fraser, SF, McMahon, LP, Bennett, PN, Warmington, SA
American journal of physiology. Renal physiology. 2020;(3):F843-F850
Abstract
End-stage kidney disease is associated with reduced exercise capacity, muscle atrophy, and impaired muscle function. While these may be improved with exercise, single modalities of exercise do not traditionally elicit improvements across all required physiological domains. Blood flow-restricted exercise may improve all of these physiological domains with low intensities traditionally considered insufficient for these adaptions. Investigation of this technique appeals, but is yet to be evaluated, in patients undergoing dialysis. With the use of a progressive crossover design, 10 satellite patients undergoing hemodialysis underwent three exercise conditions over 2 wk: two bouts (10 min) of unrestricted cycling during two consecutive hemodialysis sessions (condition 1), two bouts of cycling with blood flow restriction while off hemodialysis on 2 separate days (condition 2), and two bouts of cycling with blood flow restriction during two hemodialysis sessions (condition 3). Outcomes included hemodynamic responses (heart rate and blood pressure) throughout all sessions, participant-perceived exertion and discomfort on a Borg scale, and evaluation of ultrafiltration rates and dialysis adequacy (Kt/V) obtained post hoc. Hemodynamic responses were consistent regardless of condition. Significant increases in heart rate, systolic blood pressure, and mean arterial blood pressure (P < 0.05) were observed postexercise followed by a reduction in blood pressures during the 60-min recovery (12, 5, and 11 mmHg for systolic, diastolic, and mean arterial pressures, respectively). Blood pressures returned to predialysis ranges following the recovery period. Blood flow restriction did not affect ultrafiltration achieved or Kt/V. Hemodynamic safety and tolerability of blood flow restriction during aerobic exercise on hemodialysis is comparable to standard aerobic exercise.
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2.
A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation.
Camm, AJ, Dorian, P, Hohnloser, SH, Kowey, PR, Tyl, B, Ni, Y, Vandzhura, V, Maison-Blanche, P, de Melis, M, Sanders, P
European heart journal. Cardiovascular pharmacotherapy. 2019;(1):21-28
Abstract
AIMS: Antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current IKur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects. METHODS AND RESULTS A randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1% and 70% after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective IKur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients. The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3% to 10.3% at baseline in the four treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up. CONCLUSIONS DIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective IKur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.
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3.
Methodological framework for heart rate variability analysis during exercise: application to running and cycling stress testing.
Hernando, D, Hernando, A, Casajús, JA, Laguna, P, Garatachea, N, Bailón, R
Medical & biological engineering & computing. 2018;(5):781-794
Abstract
Standard methodologies of heart rate variability analysis and physiological interpretation as a marker of autonomic nervous system condition have been largely published at rest, but not so much during exercise. A methodological framework for heart rate variability (HRV) analysis during exercise is proposed, which deals with the non-stationary nature of HRV during exercise, includes respiratory information, and identifies and corrects spectral components related to cardiolocomotor coupling (CC). This is applied to 23 male subjects who underwent different tests: maximal and submaximal, running and cycling; where the ECG, respiratory frequency and oxygen consumption were simultaneously recorded. High-frequency (HF) power results largely modified from estimations with the standard fixed band to those obtained with the proposed methodology. For medium and high levels of exercise and recovery, HF power results in a 20 to 40% increase. When cycling, HF power increases around 40% with respect to running, while CC power is around 20% stronger in running.
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A Phase 1, Randomized, Placebo- and Active-Controlled Crossover Study to Determine the Effect of Single-Dose Ertugliflozin on QTc Interval in Healthy Volunteers.
Sahasrabudhe, V, Saur, D, Matschke, K, Terra, SG, Hickman, A, Huyghe, I, Shi, H, Cutler, DL
Clinical pharmacology in drug development. 2018;(5):513-523
Abstract
Ertugliflozin, a selective sodium-glucose cotransporter-2 inhibitor, is being developed for the treatment of type 2 diabetes mellitus. This randomized, 6-sequence, 3-period crossover study assessed the effect of ertugliflozin (100 mg; supratherapeutic dose) vs placebo and moxifloxacin (400 mg; positive control) on the QT interval corrected for heart rate (QTc) in 42 male or female healthy subjects. Triplicate electrocardiograms were performed predose and serially over 48 hours postdose in each treatment period. The maximum observed least-squares mean (90% CI) difference in QTc using the Fridericia correction (QTcF) between ertugliflozin and placebo was 2.99 (1.68, 4.30) milliseconds, 24 hours postdose, below the 5-millisecond threshold of potential clinical concern. The upper limits of the 2-sided 90% CI were less than 10 milliseconds at all postdose time points. The lower 90% CIs for the least-squares mean QTcF difference between moxifloxacin and placebo were greater than 5 milliseconds at the preselected time points of 2, 3, and 4 hours postdose, establishing study sensitivity. The majority of adverse events were mild in severity. In healthy volunteers, at a supratherapeutic dose of 100 mg, ertugliflozin was not associated with QTc interval prolongation.
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Effects of a Short-Term Recreational Team Handball-Based Programme on Physical Fitness and Cardiovascular and Metabolic Health of 33-55-Year-Old Men: A Pilot Study.
Póvoas, SCA, Castagna, C, Resende, C, Coelho, EF, Silva, P, Santos, R, Pereira, R, Krustrup, P
BioMed research international. 2018;:4109796
Abstract
Recreational team handball is an intermittent high-intensity exercise mode with physiological demands in the range of those found to enhance health and physical fitness of sedentary adults. We examined the effects of a short-term team handball-based training programme on physical fitness and metabolic and cardiovascular health of sedentary 33-55-year-old former male team handball players. Twenty-four participants were divided into team handball (THG; n=15) and control groups (CG; n=9) and evaluated at baseline and postintervention. During 12 weeks, THG performed 2-3 60-min recreational team handball matches weekly (average: 2.2 ± 0.7), and CG maintained an inactive lifestyle. Average heart rate (HR) during matches was 80 ± 7%HRmax, with peak values of 91 ± 6%HRmax. A time-by-group interaction was shown in aerobic performance (p=0.016), postural balance (p=0.019), maximum oxygen uptake (VO2max) (p=0.023), resting HR (p<0.001), high-density lipoprotein (HDL) cholesterol (p=0.048), and fasting blood glucose (p=0.052) in favor of THG. THG improved aerobic performance (80%, p<0.001), VO2max (14%, p<0.001), and postural balance (27%, p=0.018). Decreases in resting HR (16%, p<0.001) and fasting blood glucose (7%, p=0.015) and increases in HDL cholesterol (11%, p=0.002) were found in THG. Recreational team handball practice shows positive physical fitness and health-related adaptations, with high attendance, which may contribute to the reduction of the risk of developing lifestyle diseases.
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QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization.
Keirns, J, Desai, A, Kowalski, D, Lademacher, C, Mujais, S, Parker, B, Schneidkraut, MJ, Townsend, R, Wojtkowski, T, Yamazaki, T, et al
Clinical pharmacology and therapeutics. 2017;(6):782-790
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Abstract
The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double-blind study in healthy individuals who received isavuconazole (after 2-day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post-hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L-type Ca2+ channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein-bound isavuconazole in vivo. In the phase I study (n = 161), isavuconazole shortened the QT interval in a dose- and plasma concentration-related manner. There were no serious treatment-emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study (n = 257). Isavuconazole was associated with a shortened cardiac QT interval.
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L/T-type calcium channel blocker reduces non-Gaussianity of heart rate variability in chronic kidney disease patients under preceding treatment with ARB.
Fukuda, M, Ogiyama, Y, Sato, R, Miura, T, Fukuta, H, Mizuno, M, Kiyono, K, Yamamoto, Y, Hayano, J, Ohte, N
Journal of the renin-angiotensin-aldosterone system : JRAAS. 2016;(2):1470320316643905
Abstract
INTRODUCTION Increased sympathetic nerve activity has been suggested in patients with chronic kidney disease (CKD). Pathologic sympathetic activity can alter heart rate variability (HRV), and the altered HRV has prognostic importance, so that reducing sympathetic activity may be an important strategy. Novel nonlinear HRVs, including deceleration capacity (DC), have greater predictive power for mortality. We have recently proposed an increase in a non-Gaussianity index of HRV, λ(25s), which indicates the probability of volcanic heart rate deviations of departure from each standard deviation level, as a marker of sympathetic cardiac overdrive. L/T-type calcium channel blocker (L/T-CCB), azelnidipine, decreases sympathetic nerve activity in experimental and clinical studies. METHODS In 43 hypertensive patients with CKD under treatment with an angiotensin receptor blocker (ARB), we investigated whether 8-week add-on L/T-CCB treatment could restore HRV. RESULTS Means of all normal-to-normal intervals over 24 h (p<0.0001) and DC (p=0.002) increased, and λ(25s) (p=0.001) decreased regardless of gender, age, renal function or blood pressure, while no significant changes were observed in the other HRVs. CONCLUSIONS Reduction of λ(25s) is useful to assess the effect of sympathoinhibitory treatment. Further studies are needed to investigate if the restoration of HRV is directly associated with the improvement of prognosis in patients with CKD.
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Effect of axitinib on the QT interval in healthy volunteers.
Ruiz-Garcia, A, Houk, BE, Pithavala, YK, Toh, M, Sarapa, N, Tortorici, MA
Cancer chemotherapy and pharmacology. 2015;(3):619-28
Abstract
PURPOSE Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization. METHODS The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily). RESULTS Axitinib and ketoconazole had opposite effects on heart rate: Axitinib lowered it, ketoconazole raised it. The final analysis showed a flat relationship between QTc and axitinib concentration (slope -0.0314 ms·mL/ng) for axitinib alone. Mean highest placebo-matched change from baseline in QTc was -3.0 [90 % confidence interval (CI) -5.4, -0.6] ms. At supratherapeutic axitinib exposures achieved with potent cytochrome P450 3A4/5 inhibition by ketoconazole, the model predicted mean QTc change of 6.5 (90 % CI 4.4-8.5) ms. The slope population mean estimate was -0.331 (95 % CI -0.860, 0.198) ms·mL/µg for ketoconazole alone and 0.0725 (0.0445-0.1005) ms·mL/ng for axitinib in the presence of ketoconazole. The results were then compared with those obtained based on more widely used Fridericia's, Bazett's, and study-specific correction methods. CONCLUSIONS Since axitinib plasma concentrations observed in this study exceeded the range of concentrations observed in patients with RCC at the highest approved clinical dose (10 mg twice daily), axitinib was not associated with clinically significant QTc prolongation in target populations.
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Cardiovascular response to short-term fasting in menstrual phases in young women: an observational study.
Ohara, K, Okita, Y, Kouda, K, Mase, T, Miyawaki, C, Nakamura, H
BMC women's health. 2015;:67
Abstract
BACKGROUND Menstrual cycle-related symptoms are an important health issue for many women, and some may affect cardiac autonomic regulation. In the present study, we evaluated the cardiovascular and physiological stress response to 12-h short-term fasting in the menstrual phases of healthy young women. METHODS We performed a randomized crossover study. Subjects were seven female university students (age: 22.3 ± 1.0 years). The experiments comprised four sessions: meal intake in the follicular phase, meal intake in the luteal phase, fasting in the follicular phase, and fasting in the luteal phase. All subjects participated in a total of four experimental sessions during two successive phases (follicular and luteal phase in the same menstrual cycle, or luteal phase and follicular phase in the next menstrual cycle) according to a randomized crossover design. R-R intervals were continuously recorded before and after meals, and power spectral analysis of heart rate variability was performed. Other physiological data were obtained before and 20, 40, 60, and 80 min after meal intake or after the corresponding time point of meal intake (fasting in the follicular or luteal phase). RESULTS Heart rate decreased during fasting in the follicular and luteal phases. High frequency power increased during fasting in the follicular and luteal phases. In addition, salivary cortisol concentrations decreased during fasting in the luteal phase. CONCLUSIONS In the present study, short-term fasting resulted in higher parasympathetic activity and lower cortisol levels in the luteal phase in these young women. These results indicate a possibility to produce an anti-stress effect in the luteal phase, which may reduce menstrual symptoms.
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The effects of caffeine on heart rate variability in newborns with apnea of prematurity.
Ulanovsky, I, Haleluya, NS, Blazer, S, Weissman, A
Journal of perinatology : official journal of the California Perinatal Association. 2014;(8):620-3
Abstract
OBJECTIVE Apnea of prematurity is a common complication in premature newborns and caffeine is a widespread medication used to treat this complication. Caffeine may have adverse effects on the cardiovascular and central nervous system, yet its effects on the autonomic nervous system modulation of heart rate have not been studied in premature newborns, which was the objective of our study. STUDY DESIGN We prospectively studied 21 premature newborns who were treated with caffeine. We analyzed heart rate variability by power spectral density and by dynamic nonlinear analyses methods. RESULT There were no changes in heart rate, blood pressure or the autonomic nervous system tone following administration of caffeine, nor were the nonlinear dynamical properties of the system altered by caffeine. CONCLUSION Caffeine does not have detrimental effects on heart rate variability, heart rate or blood pressure in conventional doses given to premature newborns.