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Comparative effectiveness of torasemide versus furosemide in symptomatic therapy in heart failure patients: Preliminary results from the randomized TORNADO trial.
Balsam, P, Ozierański, K, Marchel, M, Gawałko, M, Niedziela, Ł, Tymińska, A, Sieradzki, B, Sieradzki, M, Fojt, A, Bakuła, E, et al
Cardiology journal. 2019;(6):661-668
Abstract
BACKGROUND Recent reports suggest that torasemide might be more beneficial than furosemide in patients with symptomatic heart failure (HF). The aim was to compare the effects of torasemide and furosemide on clinical outcomes in HF patients. METHODS This study pilot consisted of data from the ongoing multicenter, randomized, unblinded endpoint phase IV TORNADO (NCT01942109) study. HF patients in New York Heart Association (NYHA) II-IV class with a stable dose of furosemide were randomized to treatment with equipotential dose of torasemide (4:1) or continuation of unchanged dose of furosemide. On enrollment and control visit (3 months after enrollment) clinical examination, 6-minute walk test (6MWT) and assessment of fluid retention by ZOE Fluid Status Monitor were performed. The primary endpoint was a composite of improvement of NYHA class, improvement of at least 50 m during 6MWT and decrease in fluid retention of at least 0.5 W after 3-months follow-up. RESULTS The study group included 40 patients (median age 66 years; 77.5% male). During follow-up 7 patients were hospitalized for HF worsening (3 in torasemide and 4 in furosemide-treated patients). The primary endpoint reached 15 (94%) and 14 (58%) patients on torasemide and furosemide, respectively (p = 0.03). CONCLUSIONS In HF patients treated with torasemide fluid overload and symptoms improved more than in the furosemide group. This positive effect occurred already within 3-month observation.
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Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency.
van Veldhuisen, DJ, Ponikowski, P, van der Meer, P, Metra, M, Böhm, M, Doletsky, A, Voors, AA, Macdougall, IC, Anker, SD, Roubert, B, et al
Circulation. 2017;(15):1374-1383
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Abstract
BACKGROUND Iron deficiency is common in patients with heart failure (HF) and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO2], an objective measure of exercise intolerance in HF, has not been examined. METHODS We studied patients with systolic HF (left ventricular ejection fraction ≤45%) and mild to moderate symptoms despite optimal HF medication. Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary end point was the change in peak VO2 from baseline to 24 weeks. Secondary end points included the effect on hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of 0 imputed for 24-week peak VO2. Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data. RESULTS A total of 172 patients with HF were studied and received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well matched; mean age was 64 years, 75% were male, mean left ventricular ejection fraction was 32%, and peak VO2 was 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO2 had decreased in the control group (least square means -1.19±0.389 mL/min/kg) but was maintained on FCM (-0.16±0.387 mL/min/kg; P=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO2 at 24 weeks decreased by -0.63±0.375 mL/min/kg in the control group and by -0.16±0.373 mL/min/kg in the FCM group; P=0.23 between groups). Patients' global assessment and functional class as assessed by the New York Heart Association improved on FCM versus standard of care. CONCLUSIONS Treatment with intravenous FCM in patients with HF and iron deficiency improves iron stores. Although a favorable effect on peak VO2 was observed on FCM, compared with standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01394562.
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High-intensity interval training vs. moderate-intensity continuous exercise training in heart failure with preserved ejection fraction: a pilot study.
Angadi, SS, Mookadam, F, Lee, CD, Tucker, WJ, Haykowsky, MJ, Gaesser, GA
Journal of applied physiology (Bethesda, Md. : 1985). 2015;(6):753-8
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality. Exercise training is an established adjuvant therapy in heart failure; however, the effects of high-intensity interval training (HIIT) in HFpEF are unknown. We compared the effects of HIIT vs. moderate-intensity aerobic continuous training (MI-ACT) on peak oxygen uptake (V̇o₂peak), left ventricular diastolic dysfunction, and endothelial function in patients with HFpEF. Nineteen patients with HFpEF (age 70 ± 8.3 yr) were randomized to either HIIT (4 × 4 min at 85-90% peak heart rate, with 3 min active recovery) or MI-ACT (30 min at 70% peak heart rate). Fifteen patients completed exercise training (HIIT: n = 9; MI-ACT: n = 6). Patients trained 3 days/wk for 4 wk. Before and after training patients underwent a treadmill test for V̇o₂peak determination, 2D-echocardiography for assessment of left ventricular diastolic dysfunction, and brachial artery flow-mediated dilation (FMD) for assessment of endothelial function. HIIT improved V̇o₂peak (pre = 19.2 ± 5.2 ml·kg(-1)·min(-1); post = 21.0 ± 5.2 ml·kg(-1)·min(-1); P = 0.04) and left ventricular diastolic dysfunction grade (pre = 2.1 ± 0.3; post = 1.3 ± 0.7; P = 0.02), but FMD was unchanged (pre = 6.9 ± 3.7%; post = 7.0 ± 4.2%). No changes were observed following MI-ACT. A trend for reduced left atrial volume index was observed following HIIT compared with MI-ACT (-3.3 ± 6.6 vs. +5.8 ± 10.7 ml/m(2); P = 0.06). In HFpEF patients 4 wk of HIIT significantly improved V̇o₂peak and left ventricular diastolic dysfunction. HIIT may provide a more robust stimulus than MI-ACT for early exercise training adaptations in HFpEF.
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Phlebotomy eliminates the maximal cardiac output response to six weeks of exercise training.
Bonne, TC, Doucende, G, Flück, D, Jacobs, RA, Nordsborg, NB, Robach, P, Walther, G, Lundby, C
American journal of physiology. Regulatory, integrative and comparative physiology. 2014;(10):R752-60
Abstract
With this study we tested the hypothesis that 6 wk of endurance training increases maximal cardiac output (Qmax) relatively more by elevating blood volume (BV) than by inducing structural and functional changes within the heart. Nine healthy but untrained volunteers (Vo2max 47 ± 5 ml·min(-1)·kg(-1)) underwent supervised training (60 min; 4 times weekly at 65% Vo2max for 6 wk), and Qmax was determined by inert gas rebreathing during cycle ergometer exercise before and after the training period. After the training period, blood volume (determined in duplicates by CO rebreathing) was reestablished to pretraining values by phlebotomy and Qmax was quantified again. Resting echography revealed no structural heart adaptations as a consequence of the training intervention. After the training period, plasma volume (PV), red blood cell volume (RBCV), and BV increased (P < 0.05) by 147 ± 168 (5 ± 5%), 235 ± 64 (10 ± 3%), and 382 ± 204 ml (7 ± 4%), respectively. Vo2max was augmented (P < 0.05) by 10 ± 7% after the training period and decreased (P < 0.05) by 8 ± 7% with phlebotomy. Concomitantly, Qmax was increased (P < 0.05) from 18.9 ± 2.1 to 20.4 ± 2.3 l/min (9 ± 6%) as a consequence of the training intervention, and after normalization of BV by phlebotomy Qmax returned to pretraining values (18.1 ± 2.5 l/min; 12 ± 5% reversal). Thus the exercise training-induced increase in BV is the main mechanism increasing Qmax after 6 wk of endurance training in previously untrained subjects.
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Two formulations of epoprostenol sodium in the treatment of pulmonary arterial hypertension: EPITOME-1 (epoprostenol for injection in pulmonary arterial hypertension), a phase IV, open-label, randomized study.
Chin, KM, Badesch, DB, Robbins, IM, Tapson, VF, Palevsky, HI, Kim, NH, Kawut, SM, Frost, A, Benton, WW, Lemarie, JC, et al
American heart journal. 2014;(2):218-225.e1
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Abstract
BACKGROUND Epoprostenol sodium with arginine-mannitol excipients (epoprostenol AM; Veletri [Actelion Pharmaceuticals Ltd, Allschwil, Switzerland]) and epoprostenol sodium with glycine-mannitol excipients (epoprostenol GM; Flolan [GlaxoSmithKline, Triangle Park, NC]) are intravenous treatments for pulmonary arterial hypertension (PAH). Epoprostenol AM contains different inactive excipients, resulting in greater stability at room temperature compared with epoprostenol GM. METHODS In this prospective, multicenter, open-label, randomized, phase IV exploratory study, epoprostenol-naïve patients in need of injectable prostanoid therapy were randomized 2:1 to open-label epoprostenol AM or epoprostenol GM. The study period was 28 days, followed by a 30-day safety follow-up. Study aims were to descriptively compare the safety, tolerability, drug metabolite levels, and treatment effects of epoprostenol AM and epoprostenol GM in PAH. Statistical analysis was descriptive only because of the exploratory nature of the study. RESULTS Thirty patients with PAH (18-70 years, 24 women, 20 idiopathic PAH) were randomized to epoprostenol AM (n = 20) or epoprostenol GM (n = 10). Most frequently reported adverse events included jaw pain, headache, nausea, and flushing. Two deaths occurred during the study period, and 1 death occurred during the 30-day safety follow-up period, all in patients receiving epoprostenol AM. All deaths were classified by the treating physician as unrelated to epoprostenol AM. The median (range) change from baseline to day 28 in 6-minute walk distance was 36 m (-127 to 210 m) and 49 m (-44 to 110 m) for the epoprostenol AM and epoprostenol GM groups, respectively. CONCLUSIONS In this randomized clinical study of epoprostenol AM in PAH, use of this novel preparation with greater room temperature stability was well tolerated.
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Exercise-induced brachial artery vasodilation: effects of antioxidants and exercise training in elderly men.
Donato, AJ, Uberoi, A, Bailey, DM, Wray, DW, Richardson, RS
American journal of physiology. Heart and circulatory physiology. 2010;(2):H671-8
Abstract
Aging, vascular function, and exercise are thought to have a common link in oxidative stress. Of the 28 subjects studied (young, 26 +/- 2 yr; old, 71 +/- 6 yr), 12 took part in a study to validate an antioxidant cocktail (AOC: vitamins C, E, and alpha-lipoic acid), while the remaining 8 young and 8 old subjects performed submaximal forearm handgrip exercise with placebo or AOC. Old subjects repeated forearm exercise with placebo or AOC following knee-extensor (KE) exercise training. Brachial arterial diameter and blood velocity (Doppler ultrasound) were measured at rest and during exercise. During handgrip exercise, brachial artery vasodilation in the old subjects was attenuated compared with that in young subjects following placebo (maximum = approximately 3.0 and approximately 6.0%, respectively). In contrast to the previously documented attenuation in exercise-induced brachial artery vasodilation in the young group with AOC, in the old subjects the AOC restored vasodilation (maximum = approximately 7.0%) to match the young. KE training also improved exercise-induced brachial artery vasodilation. However, in the trained state, AOC administration no longer augmented brachial artery vasodilation in the elderly, but rather attenuated it. These data reveal an age-related pro-/antioxidant imbalance that impacts vascular function and show that exercise training is capable of restoring equilibrium such that vascular function is improved and the AOC-mediated reduction in free radicals now negatively impacts brachial artery vasodilation, as seen in the young.
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Core temperature and metabolic responses after carbohydrate intake during exercise at 30 degrees C.
Horswill, CA, Stofan, JR, Lovett, SC, Hannasch, C
Journal of athletic training. 2008;(6):585-91
Abstract
CONTEXT Carbohydrate ingestion has recently been associated with elevated core temperature during exercise in the heat when testing for ergogenic effects. Whether the association holds when metabolic rate is controlled is unclear. Such an effect would have undesirable consequences for the safety of the athlete. OBJECTIVE To examine whether ingesting fluids containing carbohydrate contributed to an accelerated rise in core temperature and greater overall body heat production during 1 hour of exercise at 30 degrees C when the effort was maintained at steady state. DESIGN Crossover design (repeated measures) in randomized order of treatments of drinking fluids with carbohydrate and electrolytes (CHO) or flavored-water placebo with electrolytes (PLA). The beverages were identical except for the carbohydrate content: CHO = 93.7 +/- 11.2 g, PLA = 0 g. SETTING Research laboratory. PATIENTS OR OTHER PARTICIPANTS Nine physically fit, endurance-trained adult males. INTERVENTION(S): Using rectal temperature sensors, we measured core temperature during 30 minutes of rest and 60 minutes of exercise at 65% of maximal oxygen uptake (Vo(2) max) in the heat (30.6 degrees C, 51.8% relative humidity). Participants drank equal volumes (1.6 L) of 2 beverages in aliquots 30 minutes before and every 15 minutes during exercise. Volumes were fixed to approximate sweat rates and minimize dehydration. MAIN OUTCOME MEASURE(S): Rectal temperature and metabolic response (Vo(2), heart rate). RESULTS Peak temperature, rate of temperature increase, and metabolic responses did not differ between beverage treatments. Initial hydration status, sweat rate, and fluid replacement were also not different between trials, as planned. CONCLUSIONS Ingestion of carbohydrate in fluid volumes that minimized dehydration during 1 hour of steady-state exercise at 30 degrees C did not elicit an increase in metabolic rate or core temperature.
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Exercise training in normobaric hypoxia in endurance runners. II. Improvement of mitochondrial properties in skeletal muscle.
Ponsot, E, Dufour, SP, Zoll, J, Doutrelau, S, N'Guessan, B, Geny, B, Hoppeler, H, Lampert, E, Mettauer, B, Ventura-Clapier, R, et al
Journal of applied physiology (Bethesda, Md. : 1985). 2006;(4):1249-57
Abstract
This study investigates whether adaptations of mitochondrial function accompany the improvement of endurance performance capacity observed in well-trained athletes after an intermittent hypoxic training program. Fifteen endurance-trained athletes performed two weekly training sessions on treadmill at the velocity associated with the second ventilatory threshold (VT2) with inspired O2 fraction = 14.5% [hypoxic group (Hyp), n = 8] or with inspired O2 fraction = 21% [normoxic group (Nor), n = 7], integrated into their usual training, for 6 wk. Before and after training, oxygen uptake (VO2) and speed at VT2, maximal VO2 (VO2 max), and time to exhaustion at velocity of VO2 max (minimal speed associated with VO2 max) were measured, and muscle biopsies of vastus lateralis were harvested. Muscle oxidative capacities and sensitivity of mitochondrial respiration to ADP (Km) were evaluated on permeabilized muscle fibers. Time to exhaustion, VO2 at VT2, and VO2 max were significantly improved in Hyp (+42, +8, and +5%, respectively) but not in Nor. No increase in muscle oxidative capacity was obtained with either training protocol. However, mitochondrial regulation shifted to a more oxidative profile in Hyp only as shown by the increased Km for ADP (Nor: before 476 +/- 63, after 524 +/- 62 microM, not significant; Hyp: before 441 +/- 59, after 694 +/- 51 microM, P < 0.05). Thus including hypoxia sessions into the usual training of athletes qualitatively ameliorates mitochondrial function by increasing the respiratory control by creatine, providing a tighter integration between ATP demand and supply.
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Exercise training in normobaric hypoxia in endurance runners. III. Muscular adjustments of selected gene transcripts.
Zoll, J, Ponsot, E, Dufour, S, Doutreleau, S, Ventura-Clapier, R, Vogt, M, Hoppeler, H, Richard, R, Flück, M
Journal of applied physiology (Bethesda, Md. : 1985). 2006;(4):1258-66
Abstract
We hypothesized that specific muscular transcript level adaptations participate in the improvement of endurance performances following intermittent hypoxia training in endurance-trained subjects. Fifteen male high-level, long-distance runners integrated a modified living low-training high program comprising two weekly controlled training sessions performed at the second ventilatory threshold for 6 wk into their normal training schedule. The athletes were randomly assigned to either a normoxic (Nor) (inspired O2 fraction = 20.9%, n = 6) or a hypoxic group exercising under normobaric hypoxia (Hyp) (inspired O2 fraction = 14.5%, n = 9). Oxygen uptake and speed at second ventilatory threshold, maximal oxygen uptake (VO2 max), and time to exhaustion (Tlim) at constant load at VO2 max velocity in normoxia and muscular levels of selected mRNAs in biopsies were determined before and after training. VO2 max (+5%) and Tlim (+35%) increased specifically in the Hyp group. At the molecular level, mRNA concentrations of the hypoxia-inducible factor 1alpha (+104%), glucose transporter-4 (+32%), phosphofructokinase (+32%), peroxisome proliferator-activated receptor gamma coactivator 1alpha (+60%), citrate synthase (+28%), cytochrome oxidase 1 (+74%) and 4 (+36%), carbonic anhydrase-3 (+74%), and manganese superoxide dismutase (+44%) were significantly augmented in muscle after exercise training in Hyp only. Significant correlations were noted between muscular mRNA levels of monocarboxylate transporter-1, carbonic anhydrase-3, glucose transporter-4, and Tlim only in the group of athletes who trained in hypoxia (P < 0.05). Accordingly, the addition of short hypoxic stress to the regular endurance training protocol induces transcriptional adaptations in skeletal muscle of athletic subjects. Expressional adaptations involving redox regulation and glucose uptake are being recognized as a potential molecular pathway, resulting in improved endurance performance in hypoxia-trained subjects.
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Effects of levosimendan on left ventricular functional remodelling and exercise intolerance: a tissue Doppler study.
Kasikcioglu, HA, Unal, S, Tartan, Z, Uyarel, H, Okmen, E, Kasikcioglu, E, Cam, N
The Journal of international medical research. 2005;(4):397-405
Abstract
Levosimendan is a calcium sensitizer that demonstrates enhanced myocardial contractility. There is little information concerning the effect of levosimendan on left ventricular tissue parameters and exercise capacity. We evaluated the effects of a 24-h course of levosimendan therapy on cardiac tissue parameters in 30 patients, aged 48 - 70 years, admitted to our hospital for the management of decompensated heart failure. All patients underwent echocardiographic examination using tissue Doppler imaging (TDI) and a 6-min walk test. Systolic myocardial velocity of the mitral annulus (Sm) was significantly increased in levosimendan-treated patients compared with placebo-treated patients. There was a positive correlation between Sm and exercise capacity. Levosimendan might be expected to increase cardiac contractile force, especially Sm velocity, in parallel with exercise tolerance. The study has also shown that the progress of ventricular function after levosimendan treatment in patients with exercise intolerance could be monitored effectively by Sm velocity measurements using TDI.