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Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers.
Amore, BM, Cramer, CT, MacDougall, DE, Sasiela, WJ, Emery, MG
Clinical and translational science. 2021;(6):2487-2496
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Abstract
Bempedoic acid is an inhibitor of adenosine triphosphate-citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether-a-go-go-related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgus monkeys. A randomized, double-blind, parallel-design clinical study assessed the effects of steady-state bempedoic acid at a supratherapeutic dose (240 mg/day, 33.3% higher the180 mg/day therapeutic dose), placebo, and moxifloxacin (400 mg) in healthy subjects. In vitro binding potency for bempedoic acid to the hERG potassium channel was weak, with half-maximal inhibition (IC50 ) estimated at greater than 1000 μM (>1670-fold the bempedoic acid 180 mg/day steady-state unbound maximum concentration). In monkeys, individual rate-corrected QT intervals showed no time- or dose-dependent changes up to 100 mg/kg of bempedoic acid. In human subjects, the upper 90% confidence interval (CI) for the difference in QTc interval, corrected using Fridericia's formula (QTcF), between bempedoic acid and placebo was less than 5 msec at all time points. Concentration-QTcF analysis showed that maximum bempedoic acid concentration at steady-state was attained at a median 2.1 h postdose, and the predicted mean change (90% CI) in QTcF at the observed mean bempedoic acid concentration 2 h postdose was -0.5 (-5.0, 4.0) msec. The lower bound of the moxifloxacin 90% CI exceeded 5 msec at prespecified time points, establishing study sensitivity. Steady-state bempedoic acid at a supratherapeutic dose of 240 mg was generally well-tolerated and not associated with QTc prolongation in healthy subjects.
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Nicotine supplementation enhances simulated game performance of archery athletes.
Hung, BL, Chen, LJ, Chen, YY, Ou, JB, Fang, SH
Journal of the International Society of Sports Nutrition. 2021;(1):16
Abstract
BACKGROUND Nicotine is beneficial to mood, arousal and cognition in humans. Due to the importance of cognitive functioning for archery athletes, we investigated the effects of nicotine supplementation on the cognitive abilities, heart rate variability (HRV), and sport performance of professional archers. METHODS Eleven college archers were recruited and given 2 mg of nicotine supplementation (NIC group) and placebo (PLA group) in a crossover design. RESULTS The results showed that at 30 min after the intake of nicotine gum, the "correct rejection" time in the NIC group was significantly lower than that of the PLA group (7.29 ± 0.87 vs. 8.23 ± 0.98 msec, p < 0.05). In addition, the NIC group completed the grooved pegboard test in a shorter time than the PLA group (48.76 ± 3.18 vs. 53.41 ± 4.05 s, p < 0.05), whereas motor reaction times were not different between the two groups. Saliva α-amylase activity was significantly lower after nicotine supplementation (p < 0.01) but increased immediately after the archery test in the NIC group (p < 0.05). In addition, nicotine supplementation significantly decreased HRV and increased the archery score (290.58 ± 10.09 vs. 298.05 ± 8.56, p < 0.01). CONCLUSIONS Nicotine enhances the performance of archery athletes by increasing cognitive function and stimulating the sympathetic adrenergic system.
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Effects of age on blood pressure and heart rate responses to whey protein in younger and older men.
Giezenaar, C, Oberoi, A, Jones, KL, Horowitz, M, Chapman, I, Soenen, S
Journal of the American Geriatrics Society. 2021;(5):1291-1299
Abstract
BACKGROUND Postprandial falls in blood pressure (BP) are more common in older compared to younger individuals. The effects of protein compared to carbohydrates and fat on postprandial BP, and the relation to gastric emptying rates, are poorly studied. OBJECTIVES To determine the effects of a whey protein compared to a control drink on systolic BP (SBP) and diastolic BP (DBP), and heart rate (HR) in healthy younger and older men, and to relate these effects to gastric emptying. DESIGN A pooled analyses of two randomized, double-blind, cross-over studies. SETTING Two acute clinical intervention studies with identical study design. PARTICIPANTS Nineteen older (age: 74 ± 1 years, body mass index: 26 ± 1 kg/m2 ) and 13 younger (23 ± 1 years, 24 ± 1 kg/m2 ) healthy men. INTERVENTION A 70 g/280 kcal whey-protein or control (water with diet cordial, ~2 kcal) drink (450 ml). MEASUREMENTS BP and HR were assessed with an automated device immediately before and at 3-min intervals after drink ingestion (0-180 min). Gastric emptying of the drinks was measured using 3D ultrasonography (0-180 min). RESULTS Older versus younger men exhibited a greater fall in SBP (-23 ± 2 vs -15 ± 2 mmHg, p = 0.001) after whey-protein versus control, as BP did not change after the two drinks in younger men (p > 0.05). The nadir in SBP occurred later in the older than younger men (114 ± 11 vs 62 ± 14 min; p < 0.001), with SBP still apparently declining 180 min after whey-protein ingestion in the older men. The magnitude of the rise in HR was greater (p < 0.05) in the younger than older men. CONCLUSION Following ingestion of 70 g whey protein, healthy older men exhibited a sustained fall in BP, despite an increase in HR, whereas in younger men there was no change in BP. BP may need to be monitored after high protein meals in older people at risk of postprandial hypotension.
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Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome.
Garland, EM, Gamboa, A, Nwazue, VC, Celedonio, JE, Paranjape, SY, Black, BK, Okamoto, LE, Shibao, CA, Biaggioni, I, Robertson, D, et al
Journal of the American College of Cardiology. 2021;(17):2174-2184
Abstract
BACKGROUND High sodium intake is recommended for the treatment of postural tachycardia syndrome (POTS) to counteract the hypovolemia and elevated plasma norepinephrine that contribute to excessive orthostatic tachycardia, but evidence of its efficacy is not available. OBJECTIVES This study tested whether a high sodium (HS) diet reduces orthostatic tachycardia (Δ heart rate) and upright heart rate compared with a low sodium (LS) diet in POTS patients, and secondarily its effect on plasma volume (PV) and plasma norepinephrine. METHODS A total of 14 POTS patients and 13 healthy control subjects (HC), age 23 to 49 years, were enrolled in a crossover study with 6 days of LS (10 mEq sodium/day) or HS (300 mEq sodium/day) diet. Supine and standing heart rate, blood pressure, serum aldosterone, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine were measured. RESULTS In POTS, the HS diet reduced upright heart rate and Δ heart rate compared with the LS diet. Total blood volume and PV increased, and standing norepinephrine decreased with the HS compared with the LS diet. However, upright heart rate, Δ heart rate, and upright norepinephrine remained higher in POTS than in HC on the HS diet (median 117 beats/min [interquartile range: 98 to 121 beats/min], 46 beats/min [interquartile range: 32 to 55 beats/min], and 753 pg/ml [interquartile range: 498 to 919 pg/ml] in POTS vs. 85 beats/min [interquartile range: 77 to 95 beats/min], 19 beats/min [interquartile range: 11 to 32 beats/min], and 387 pg/ml [interquartile range: 312 to 433 pg/ml] in HC, respectively), despite no difference in the measured PV. CONCLUSIONS In POTS patients, high dietary sodium intake compared with low dietary sodium intake increases plasma volume, lowers standing plasma norepinephrine, and decreases Δ heart rate. (Dietary Salt in Postural Tachycardia Syndrome; NCT01547117).
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Snacking on Whole Almonds for Six Weeks Increases Heart Rate Variability during Mental Stress in Healthy Adults: A Randomized Controlled Trial.
Dikariyanto, V, Smith, L, Chowienczyk, PJ, Berry, SE, Hall, WL
Nutrients. 2020;(6)
Abstract
Cardiac autonomic regulation can be indirectly measured by heart rate variability (HRV). Low HRV, which can be induced by mental stress, is a predictor of risk of sudden cardiac death. Few studies have investigated cause-and-effect relationships between diet and HRV. Nut consumption is associated with CVD risk reduction, but the impact on HRV, particularly in response to stress, is unclear. Men and women (30-70 y) with above average risk of developing CVD were randomly assigned in a 6-week randomized, controlled, parallel arm trial to consume either whole almond or isocaloric control snacks (20% of daily estimated energy requirement). Control snacks contained the average nutrient profile of UK snacks. Five-minute periods of supine heart rate (HR) and HRV were measured at resting and during mental stress (Stroop color-word test) at baseline and six weeks. High frequency (HF) power, which reflects parasympathetic regulation of HR, was increased following almonds during the mental stress task relative to control (mean difference between groups 124 ms2; 95% CI 11, 237; p = 0.031, n = 105), but other indices were unaffected. Snacking on whole almonds instead of typical snacks may reduce risk of CVD partly by ameliorating the suppression of HRV during periods of mental stress.
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Heart Rate Variability Behavior during Exercise and Short-Term Recovery Following Energy Drink Consumption in Men and Women.
Clark, NW, Herring, CH, Goldstein, ER, Stout, JR, Wells, AJ, Fukuda, DH
Nutrients. 2020;(8)
Abstract
This study examined the cardiac autonomic responses, as measured by heart rate variability (HRV), during cycling exercise and short-term rest after energy drink consumption. Seventeen participants (seven males and 10 females; age: 22.8 ± 3.5 years; BMI: 24.3 ± 3.3 kg/m2) completed this double-blind, placebo-controlled, counterbalanced crossover design study. Participants received an energy drink formula containing 140 mg of caffeine and a placebo in a randomized order before completing a 10-min steady-state warm up (WUP) and a graded exercise test to exhaustion (GXT) followed by a 15-min short-term rest (STR) period. Heartbeat intervals were recorded using a heart rate monitor. Data were divided into WUP, GXT, and STR phases, and HRV parameters were averaged within each phase. Additionally, root mean square of the standard deviation of R-R intervals (RMSSD) during GXT was analyzed to determine the HRV threshold. Separate two-way (sex (male vs. female) x drink (energy drink vs. placebo)) repeated measures ANOVA were utilized. Significant increases in high frequency (HF) and RMSSD were shown during WUP after energy drink consumption, while interactions between drink and sex were observed for HRV threshold parameters (initial RMSSD and rate of RMSSD decline). No significant differences were noted during STR. Energy drink consumption may influence cardiac autonomic responses during low-intensity exercise, and sex-based differences in response to graded exercise to exhaustion may exist.
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Cardiovascular and metabolic responses to passive hypoxic conditioning in overweight and mildly obese individuals.
Chacaroun, S, Borowik, A, Doutreleau, S, Belaidi, E, Wuyam, B, Tamisier, R, Pépin, JL, Flore, P, Verges, S
American journal of physiology. Regulatory, integrative and comparative physiology. 2020;(2):R211-R222
Abstract
Although severe intermittent hypoxia (IH) is well known to induce deleterious cardiometabolic consequences, moderate IH may induce positive effects in obese individuals. The present study aimed to evaluate the effect of two hypoxic conditioning programs on cardiovascular and metabolic health status of overweight or obese individuals. In this randomized single-blind controlled study, 35 subjects (54 ± 9.3 yr, 31.7 ± 3.5 kg/m2) were randomized into three 8-wk interventions (three 1-h sessions per week): sustained hypoxia (SH), arterial oxygen saturation ([Formula: see text]) = 75%; IH, 5 min [Formula: see text] = 75% - 3 min normoxia; normoxia. Ventilation, heart rate, blood pressure, and tissue oxygenation were measured during the first and last hypoxic conditioning sessions. Vascular function, blood glucose and insulin, lipid profile, nitric oxide metabolites, and oxidative stress were evaluated before and after the interventions. Both SH and IH increased ventilation in hypoxia (+1.8 ± 2.1 and +2.3 ± 3.6 L/min, respectively; P < 0.05) and reduced normoxic diastolic blood pressure (-12 ± 15 and -13 ± 10 mmHg, respectively; P < 0.05), whereas changes in normoxic systolic blood pressure were not significant (+3 ± 9 and -6 ± 13 mmHg, respectively; P > 0.05). IH only reduced heart rate variability (e.g., root-mean-square difference of successive normal R-R intervals in normoxia -21 ± 35%; P < 0.05). Both SH and IH induced no significant change in body mass index, vascular function, blood glucose, insulin and lipid profile, nitric oxide metabolites, or oxidative stress, except for an increase in superoxide dismutase activity following SH. This study indicates that passive hypoxic conditioning in obese individuals induces some positive cardiovascular and respiratory improvements despite no change in anthropometric data and even a reduction in heart rate variability during IH exposure.
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Combined treatment with valsartan and fluvastatin to delay disease progression in nonpermanent atrial fibrillation with hypertension: A clinical trial.
Zhao, Z, Yang, Y, Wang, J, Dong, Z, Niu, X, Liu, E, Liu, T, Li, L, Liang, Y, Li, G
Clinical cardiology. 2020;(12):1592-1600
Abstract
BACKGROUND Atrial fibrillation (AF) is a complex cardiac arrhythmia in clinical practice with increasing incidence. However, the effects of statins on patients with AF are not quite clear. HYPOTHESIS To investigate the protective effect of calcium channel blocker (CCB) and valsartan combined fluvastatin on hypertension (HTN) patients with nonpermanent AF. METHODS In three and a half years, 189 cases of patients diagnosed as HTN combining nonpermanent AF by eight medical centers, were recruited and randomly assigned to four groups with varied treatments: CCB group; CCB + statin group; valsartan group; and valsartan + statin group. The four groups were followed up for 24 months. The 7-day Holter ultrasound echocardiography (UCG) and biochemical indexes were completed at preset time nodes respectively. RESULTS After 24 months of follow-up, 178 patients completed the study. Compared with CCB group, the blood lipid level, inflammatory index, ultrasonic index and electrocardiographic measurement results of CCB + statin group, valsartan group and valsartan + statin group were improved in different degrees and had statistical significance (P < .05 or P < .01). Furthermore, the improvement trend of CCB + statin group and valsartan + statin group was more obvious. CONCLUSIONS The results indicated that valsartan can reduce AF load and recurrence rate, and delay the progression of nonpermanent AF to permanent AF in multiple ways, and the effect of combination of valsartan and fluvastatin is more significant. These results provide a new direction for the integrated upstream control strategy of AF.
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Effect of exercise training for five years on all cause mortality in older adults-the Generation 100 study: randomised controlled trial.
Stensvold, D, Viken, H, Steinshamn, SL, Dalen, H, Støylen, A, Loennechen, JP, Reitlo, LS, Zisko, N, Bækkerud, FH, Tari, AR, et al
BMJ (Clinical research ed.). 2020;:m3485
Abstract
OBJECTIVE To evaluate the effect of five years of supervised exercise training compared with recommendations for physical activity on mortality in older adults (70-77 years). DESIGN Randomised controlled trial. SETTING General population of older adults in Trondheim, Norway. PARTICIPANTS 1567 of 6966 individuals born between 1936 and 1942. INTERVENTION Participants were randomised to two sessions weekly of high intensity interval training at about 90% of peak heart rate (HIIT, n=400), moderate intensity continuous training at about 70% of peak heart rate (MICT, n=387), or to follow the national guidelines for physical activity (n=780; control group); all for five years. MAIN OUTCOME MEASURE All cause mortality. An exploratory hypothesis was that HIIT lowers mortality more than MICT. RESULTS Mean age of the 1567 participants (790 women) was 72.8 (SD 2.1) years. Overall, 87.5% of participants reported to have overall good health, with 80% reporting medium or high physical activity levels at baseline. All cause mortality did not differ between the control group and combined MICT and HIIT group. When MICT and HIIT were analysed separately, with the control group as reference (observed mortality of 4.7%), an absolute risk reduction of 1.7 percentage points was observed after HIIT (hazard ratio 0.63, 95% confidence interval 0.33 to 1.20) and an absolute increased risk of 1.2 percentage points after MICT (1.24, 0.73 to 2.10). When HIIT was compared with MICT as reference group an absolute risk reduction of 2.9 percentage points was observed (0.51, 0.25 to 1.02) for all cause mortality. Control participants chose to perform more of their physical activity as HIIT than the physical activity undertaken by participants in the MICT group. This meant that the controls achieved an exercise dose at an intensity between the MICT and HIIT groups. CONCLUSION This study suggests that combined MICT and HIIT has no effect on all cause mortality compared with recommended physical activity levels. However, we observed a lower all cause mortality trend after HIIT compared with controls and MICT. TRIAL REGISTRATION ClinicalTrials.gov NCT01666340.
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N-acetylcysteine Restored Heart Rate Variability and Prevented Serious Adverse Events in Transfusion-dependent Thalassemia Patients: a Double-blind Single Center Randomized Controlled Trial.
Pattanakuhar, S, Phrommintikul, A, Tantiworawit, A, Srichairattanakool, S, Chattipakorn, SC, Chattipakorn, N
International journal of medical sciences. 2020;(9):1147-1155
Abstract
Regular blood transfusions in transfusion-dependent thalassemia (TDT) patients can lead to iron overload, causing oxidative stress and sympathovagal imbalance, resulting in increased cardiac complications. We hypothesized that administrating of N-acetylcysteine (NAC) prevents serious adverse events including cardiac complications in TDT patients by reducing systemic oxidative stress and balancing cardiac sympathovagal control. This study was double-blind, randomized control trial, investigating in 59 Thai TDT patients. After randomization, the participants were divided into two groups. The control group received standard care of TDT patient plus placebo, whereas the intervention group received 600 mg of NAC orally for six months. Serum 8-isoprostane, TNF-alpha, IL-10, 24-hour ECG monitoring, echocardiograms and the incidence of thalassemia-related complications were collected. At baseline, no significant difference in any parameters between the control and the intervention groups. At the end of intervention, the incidence of serious adverse events (i.e. infection, worsening thalassemia) was significantly higher in the control group when compared with the intervention group (24.1% vs. 3.3%, p=0.019) (Chi-square test; absolute risk reduction=20.8%, number needed to treat=4.8). The control group also had significantly lower time-dependent HRV parameters, compared with the intervention group (p=0.025 and 0.030, independent t-test). Treatment with NAC restored HRV and reduced serious adverse event in TDT patients, however, no difference in cardiac complications could be demonstrated. NAC could prevent serious adverse events in TDT patients. The proposed mechanism might be the balancing of sympathovagal control.