Exercise Performance In Patients Research Articles

Expression of the Irisin Precursor FNDC5 in Skeletal Muscle Correlates With Aerobic Exercise Performance in Patients With Heart Failure

Exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression has been shown to increase the expression of the fibronectin type III domain containing 5 (FNDC5) gene and thereby its product, irisin, in mice. Given that exercise intolerance is a hallmark characteristic of heart failure (HF), and because PGC-1α and irisin promote exercise benefits in animals, we hypothesized that expression of these genes relates to aerobic performance in patients with HF. Systolic HF (left ventricular ejection fraction ≤40%) patients underwent cardiopulmonary exercise testing to evaluate aerobic performance. High versus low aerobic performance was assessed using oxygen consumption (peak Vo(2) [>14 versus ≤14 mL O(2)·kg(-1)·min(-1)]) and ventilatory efficiency (VE/Vco(2) slope [<34 versus ≥34]). Muscle biopsies of the vastus lateralis and real-time polymerase chain reaction were used to quantify muscle gene expression. Twenty-four patients were studied. FNDC5 (5.7±3.5 versus 3.1±1.2, P<0.05) and PGC-1α (9.9±5.9 versus 4.5±1.9, P<0.01) gene expressions were greater in the high-peak Vo(2) group; correlation between FNDC5 and PGC-1α was significant (r=0.56, P<0.05) only in the high-peak Vo(2) group. Similarly, FNDC5 and PGC-1α gene expression was greater in the high-performance group based on lower VE/Vco(2) slopes (5.8±3.6 versus 3.3±1.4, P<0.05 and 9.7±6 versus 5.3±3.4, P<0.05); FNDC5 also correlated with PGC-1α (r=0.55, P<0.05) only in the low VE/Vco(2) slope group. This is the first study to show that FNDC5 expression relates to functional capacity in a human HF population. Lower FNDC5 expression may underlie reduced aerobic performance in HF patients.

Maximal exercise performance in patients with postcancer fatigue

The aim of this study is to examine whether physical fitness of severely fatigued and non-fatigued cancer survivors, as measured by maximal exercise performance, is different between both groups and, if so, whether this difference can be explained by differences in physical activity, self-efficacy regarding the exercise test, and/or social support. Severely fatigued (n = 20) and sex- and age-matched non-fatigued (n = 20) disease-free cancer survivors, who completed treatment for a malignant, solid tumor at least 1 year earlier, participated in this case-control study. Maximal oxygen consumption was measured during an incremental cycling exercise test. Physical activity was assessed via actigraphy. Self-efficacy regarding the test and social support were assessed via questionnaires to study its relationship with physical fitness. Maximal oxygen consumption was significantly lower in fatigued compared to non-fatigued participants. Actual physical activity, self-efficacy regarding the test, and negative interactions of social support were significantly different between both groups. However, after inclusion of these three variables in linear regression analyses, the difference in physical fitness between fatigued and non-fatigued cancer survivors persisted. Maximal oxygen consumption, a measure for physical fitness, was reduced in severely fatigued compared to non-fatigued cancer survivors. The inferior maximal exercise performance cannot fully be explained by differences in physical activity, self-efficacy, or social support between both groups. Other currently still unknown factors, such as a disturbance in the cardiopulmonary circuit, may play a role.

Addition of tiotropium to formoterol improves inspiratory muscle strength after exercise in COPD

The addition of tiotropium bromide (TIO) to formoterol fumarate (FOR) improves exercise performance in patients with chronic obstructive pulmonary disease (COPD). In this study, we test the hypothesis that the addition of TIO to FOR may improve respiratory muscle performance and oxygen uptake kinetics after exercise in patients with COPD. Thirty eight patients with COPD were randomized to a 2 week treatment with FOR 12μg twice a day plus TIO 18μg once a day (FOR+TIO) or FOR 12μg twice a day plus placebo (FOR+PLA) once a day, using a double-blind crossover design. Inspiratory muscle. Strength was measured before, immediately after, as well as 2, 5, and 10min during recovery of exercise. Time to limit of tolerance on a constant work load exercise test and oxygen uptake kinetics during recovery were evaluated before and after intervention. Only FOR+TIO improved resting (63±10cm to 84±11 cmH(2)O) and post-exercise (49±7cm to 84±11 cmH(2)O) maximal inspiratory pressure. Time to limit of tolerance on the constant work load test was increased by FOR+PLA and by FOR+TIO, but the size of the increment was significantly larger with FOR+TIO (40.7±7.6% vs. 84.5±8.2%; p<0.05). Only FOR+TIO improved oxygen uptake kinetics during recovery (69±21 to 60±18s). The improvement in maximal inspiratory pressure (0.78, p<0.001) and in oxygen uptake kinetics (-0.91, p<0.001) correlated with the change in time to the limit of tolerance. The addition of TIO to FOR improves inspiratory muscle strength and oxygen uptake kinetics after exercise in COPD patients.

Short‐term exercise training improves the cardiovascular response to exercise in the postural orthostatic tachycardia syndrome

Recent studies have suggested the presence of cardiac atrophy as a key component of the pathogenesis of the postural orthostatic tachycardia syndrome (POTS), similar to physical deconditioning. It has also been shown that exercise intolerance is associated with a reduced stroke volume (SV) in POTS, and that the high heart rate (HR) observed at rest and during exercise in these patients is due to this low SV. We tested the hypotheses that (a) circulatory control during exercise is normal in POTS; and (b) that physical ‘reconditioning' with exercise training improves exercise performance in patients with POTS. Nineteen (18 women) POTS patients completed a 3 month training programme. Cardiovascular responses during maximal exercise testing were assessed in the upright position before and after training. Resting left ventricular diastolic function was evaluated by Doppler echocardiography. Results were compared with those of 10 well-matched healthy sedentary controls. A lower SV resulted in a higher HR in POTS at any given oxygen uptake (V(O(2))) during exercise while the cardiac output (Q(c))-V(O(2)) relationship was normal. V(O(2peak)) was lower in POTS than controls (26.1 ± 1.0 (SEM) vs. 36.3 ± 0.9 ml kg-1 min-1; P < 0.001) due to a lower peak SV (65 ± 3 vs. 80 ± 5 ml; P = 0.009). After training in POTS, HR became lower at any given due to increased SV without changes in the – relationship. V(O(2peak)) increased by 11% (P < 0.001) due to increased peak SV (P = 0.021) and was proportional to total blood volume. Peak HR was similar, but HR recovery from exercise was faster after training than before training (P = 0.036 for training and 0.009 for interaction). Resting diastolic function was mostly normal in POTS before training, though diastolic suction was impaired (P = 0.023). There were no changes in any Doppler index after training. These results suggest that short-term exercise training improves physical fitness and cardiovascular responses during exercise in patients with POTS.

The Effects of a “New” Walking Aid on Exercise Performance in Patients With COPD: A Randomized Crossover Trial

Generally, the use of a rollator improves mobility in patients with COPD. Nevertheless, not all patients benefit from its use, and many patients feel embarrassed about using it. Therefore, other walking aids are worthwhile to consider. We compared the direct effects of a "new" ambulation aid (a modern draisine) with the effects of a rollator on 6-min walk distance (6MWD) in patients with COPD. Twenty-one patients with COPD performed two 6-min walk tests (6MWTs) during prerehabilitation assessment (best 6MWD: 369 ± 88 m). Additionally, two extra 6MWTs were performed on two consecutive days in random order: one time with a rollator and one time with a modern draisine. Walking pattern (n = 21) was determined using an accelerometer, and metabolic requirements (n = 10) were assessed using a mobile oxycon. Walking with the modern draisine resulted in a higher 6MWD compared with walking with the rollator (466 ± 189 m vs 383 ± 85 m). Moreover, patients had fewer strides (245 ± 61 vs 300 ± 49) and a greater stride length (1.89 ± 0.73 m vs 1.27 ± 0.14 m) using the modern draisine compared with the rollator (all P ≤ .001). Oxygen uptake, ventilation, heart rate, oxygen saturation, and Borg symptom scores were comparable between both walking aids. Ten percent of the patients felt embarrassed using the modern draisine compared with 19% for the rollator, and a significantly smaller proportion of patients would use the modern draisine in daily life. The mean difference in 6MWD between a modern draisine and a rollator seems clinically relevant, with the same metabolic requirements and symptom Borg scores. Therefore, this "new" ambulation aid could be a good alternative to the rollator to improve functional exercise performance in patients with COPD. The Netherlands National Trial Registry; No.: NTR1542; URL: www.trialregister.nl.

LDL lowering in peripheral arterial disease:are there benefits beyond reducing cardiovascular morbidity and mortality?

Peripheral arterial disease affecting the lower extremities is associated with increased mortality due to cardiovascular events and reduced functional capacity due to claudication. There is abundant evidence to support the role of lipid lowering with statins in preventing cardiovascular events in patients with peripheral arterial disease. Over the last 10 years, multiple studies have been designed to test the theory that LDL C lowering with statins could result in improved exercise performance in patients with peripheral arterial disease. However, this remains an active area of investigation to better understand how the pleiotropic effects of statins could lead to enhanced functional capacity for patients with claudication. Furthermore, new insights into the complex pathophysiology of claudication may help us to understand the potential role of lipid lowering therapy in alleviating exercise induced symptoms.

Enhanced Interleukin-1 Activity Contributes to Exercise Intolerance in Patients with Systolic Heart Failure

BackgroundHeart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects.Methods and ResultsWe developed a model of IL-1β-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1β 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO2) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL·kg–1·min–1 (P = 0.016 vs. baseline) and median ventilator efficiency (VE/VCO2 slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline).ConclusionsThese findings suggest that IL-1β activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1β blockade as a novel strategy for pharmacologic intervention.Trial RegistrationClinicalTrials.gov NCT01300650

Functional and haemodynamic recovery after implantation of continuous‐flow left ventricular assist devices in comparison with pulsatile left ventricular assist devices in patients with end‐stage heart failure

Caused by ageing of the population, better survival from ischaemic heart disease, and improved treatment of chronic heart disease, the incidence of heart failure has increased enormously. Worldwide, left ventricular assist devices (LVADs) are increasingly being used as a bridge or alternative to heart transplantation. In this study, we investigated whether there is difference in functional and haemodynamic recovery after implantation of pulsatile and continuous-flow pumps. We compared laboratory and echocardiographic data and exercise performance in patients with end-stage heart failure, before and 3 months after implantation of pulsatile and continuous-flow LVADs. A significant improvement in all laboratory parameters after implantation of both types of LVADs was seen, as well as a significant decrease in heart rate and LV dimensions, indicating better haemodynamics and cardiac recompensation. This improvement was better for the pulsatile device, probably due to higher plasma levels and higher LV dimensions before implantation. Exercise capacity strongly improved: 3 months after implantation of pulsatile and continuous-flow LVADs, peak VO(2) was 20.2 ± 4.8 vs. 18.3 ± 4.8 mL/kg/min (P = 0.09) (53 ± 12 vs. 49 ± 11% of predicted for age and gender) (P = 0.28). Pulsatile and continuous-flow LVADs result in extensive haemodynamic recovery and exercise performance compatible with daily life activities. Exercise performance with continuous-flow LVADs is equal to that with pulsatile devices. This, in combination with improved survival of the newer devices, allows its use as an alternative to heart transplantation in selected patients.

Aquatic Exercise Is Effective in Improving Exercise Performance in Patients with Heart Failure and Type 2 Diabetes Mellitus

Background. Peak oxygen uptake (VO2peak) and muscle function are more decreased in patients with a combination of chronic heart failure (CHF) and type 2 diabetes mellitus (2DM) compared to patients with only one of the conditions. Further, patients with 2DM have peripheral complications that hamper many types of conventional exercises. Aim. To evaluate the efficacy and applicability of eight-week aquatic exercise in patients with the combination of CHF and 2DM. Methods. Twenty patients (four women) with both CHF and 2DM (age 67.4 ± 7.1, NYHA II-III) were randomly assigned to either aquatic exercise or a control group. The patients exercised for 45 minutes 3 times/week in 33–34°C, swimming pool. Results. The training programme was well tolerated. Work rate (+11.7 ± 6.6 versus −6.4 ± 8.1 watt, P < 0.001) and VO2peak (+2.1 ± 0.8 versus −0.9 ± 1.4 mL·kg−1·min−1, P < 0.001) and walking capacity (P = 0.01) increased significantly in the training group. Muscle function was also significantly improved and Hba1c decreased significantly (P < 0.01) during training, while fasting glucose, insulin, c-peptide, and lipids were unchanged . Training also increased vitality measured by SF-36 significantly (P = 0.05). Conclusion. Aquatic exercise could be used to improve exercise capacity and muscle function in patients with the combination of CHF and 2DM.

Tricuspid valve surgery improves cardiac output and exercise performance in patients with Ebstein's anomaly

BackgroundClinical, hemodynamic and functional effects of tricuspid valve surgery in patients with Ebstein's anomaly are not well understood. MethodsSixteen patients (median age of 27.7years) were examined before and eight months after surgery by means of echocardiography, cardiovascular magnetic resonance (CMR) and cardiopulmonary exercise testing. ResultsPeak work load (1.87 to 2.0W/kg; p=0.026), maximum oxygen uptake (21 to 22ml/kg/min; p=0.034) as well as cardiac output (2.7 to 2.9l/min/m2; p=0.035) increased postoperatively. The reduction of tricuspid regurgitation led to a higher pulmonary stroke volume (29 to 42ml/m2, p=0.005) and augmented the left ventricular (LV) volume (55 to 63ml/min/m2; p=0.001) with a trend to better ejection fraction (61 to 64%; p=0.083). Right ventricular (RV) volume index (124 to 108ml/m2; p=0.034) and ejection fraction (50 to 42%; p=0.036) decreased on CMR. Echocardiographic measurements of RV function also decreased (tricuspid annular plane systolic excursion 2.3 to 1.7; p=0.002; isovolumic acceleration 0.98 to 0.65; p=0.004; and 2-d longitudinal global strain −19.3 to −16.25; p=0.006). ConclusionTricuspid valve surgery improves exercise capacity in patients with Ebstein's anomaly. The reduction of tricuspid regurgitation decreases the volume of the right ventricle and increases pulmonary antegrade flow. As a result LV volume and cardiac output increase. This hemodynamic benefit occurs despite the preload dependent reduction in RV volume and ejection fraction.

Effects of oxygen on exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease

The results of studies on the oxygen response in patients with COPD should provide important clues to the pathophysiology of exertional dyspnoea. We investigated the exercise responses to hyperoxia in relation to dyspnoea profile, as well as cardiopulmonary, acidotic and sympathetic parameters in 35 patients with stable COPD (mean FEV(1) 46% predicted). This was a single-blind trial, in which patients breathed 24% O(2) or compressed air (CA) in random order during two incremental cycle exercise tests. PaO(2) and PaCO(2) were higher (P < 0.0001 and P < 0.05, respectively) at each exercise point while patients were breathing 24% O(2) compared with CA. At a standardized time point near peak exercise, use of O(2) resulted in reduced plasma lactate and plasma noradrenaline concentrations (P < 0.01). Peak minute ventilation/indirect maximum voluntary ventilation was similar while breathing 24% O(2) and CA. At peak exercise, the dyspnoea score, pH and plasma noradrenaline concentrations were similar while breathing 24% O(2) and CA. The dyspnoea-ratio (%) of Δoxygen uptake (peak minus resting oxygen uptake) curve reached a break point that occurred at a similar exercise point while breathing 24% O(2) or CA. Regardless of whether they breathed CA or 24% O(2) , patients with COPD did not develop ventilatory compensation for exertional acidosis, and the pH values measured were similar. Hyperoxia during a standardized exercise protocol did not alter the pattern of exertional dyspnoea in these patients, compared with breathing CA, although hyperoxia resulted in miscellaneous effects.

Exercise Performance Comparison of Bicaval and Biatrial Orthotopic Heart Transplant Recipients

Background The standard biatrial technique for orthotopic heart transplantation uses a large atrial anastomosis to connect the donor and recipient atria. A modified technique involves bicaval and pulmonary venous anastomoses and is believed to preserve the anatomic configuration and physiological function of the atria. Bicaval heart transplantation reduces postoperative valvular regurgitation and is associated with a lower incidence of pacemaker insertion. Objective The aim of this study was to compare postoperative functional capacity and exercise performance in patients with bicaval and biatrial orthotopic heart transplantation. Methods Patients were selected for the study if they did not have any of the following: obstructive coronary artery disease (>50% stenosis), severe mitral or tricuspid regurgitation, signs of rejection (grade ≥1B-1R) on endomyocardial biopsy during the prior year, respiratory impairment, a permanent pacemaker, orthopedic or muscular impediments, or lived more than 150 miles from the medical center. A total of 27 patients qualified. In 15 patients who received a biatrial heart transplant and 12 patients with a bicaval heart transplant, a stationary bicycle exercise test was performed. Ventilatory gas exchange and maximum oxygen consumption measurements were measured. Results Recipient and donor characteristics, including body surface area, donor/recipient weight mismatch, immunosuppressive regimen, and self-reported weekly exercise activity, did not differ between the biatrial and bicaval groups ( P = not significant [NS]). At peak exercise, similar heart rate, workload, oxygen consumption, carbon dioxide production, ventilation, functional capacity, and exercise duration were found between the 2 groups ( P = NS). Patients in the biatrial group were studied later than patients in the bicaval group (6.54 ± 0.71 vs 4.68 ± 0.28 years; P < .001). Conclusion There were no significant differences in the exercise capacity between patients with biatrial versus bicaval techniques for orthotopic heart transplantation. Factors other than the atrial connection (such as cardiac denervation, immunosuppressive drug effect, or physical deconditioning) may be more important determinants of subnormal exercise capacity after heart transplantation. Nevertheless, the reduction in morbidity and postoperative complications and the simplicity in the bicaval technique suggest that bicaval heart transplantation offers advantages when compared with the standard biatrial technique.

A phase II dose-ranging study of the phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication

Phosphodiesterase inhibitors have been shown to improve claudication-limited exercise performance in patients with peripheral artery disease. K-134, a novel phosphodiesterase inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess its safety, tolerability, and effect on treadmill walking time. Patients with peripheral artery disease were randomized to receive placebo (n = 87), K-134 at a dose of 25 mg (n = 42), 50 mg (n = 85), or 100 mg (n = 84), or cilostazol at a dose of 100 mg (n = 89), each twice daily for 26 weeks. Peak walking time (PWT) was assessed using a graded treadmill protocol at baseline and after 14 and 26 weeks of treatment. A Data and Safety Monitoring Board-implemented adaptive design was used that allowed early discontinuation of unsafe or minimally informative K-134 arms. As determined by the prospectively defined adaptive criteria, the 25-mg K-134 arm was discontinued after 42 individuals had been randomized to the arm. During the 26-week treatment period, PWT increased by 23%, 33%, 37%, and 46% in the placebo, 50-mg K-134, 100-mg K-134, and cilostazol arms, respectively (primary analysis placebo vs 100-mg K-134 arm not statistically significant, P = .089). Secondary analyses showed that cilostazol significantly increased PWT after 14 weeks of treatment and that the 100-mg K-134 dose and cilostazol both increased PWT vs placebo after 14 and 26 weeks in those individuals who completed the 26-week trial and were compliant with the study drug, or when the data were analyzed using a mixed-effects model incorporating all time points. K-134 had tolerability and adverse effect profiles similar to that of cilostazol. Both drugs were associated with an increase in withdrawals before study completion due to adverse events compared with placebo. K-134 was generally well tolerated. K-134 at a dose of 100 mg twice daily did not affect PWT according to the primary analysis, but K-134 and cilostazol both increased PWT when analyzed using a mixed-effects model and in the per-protocol population.

Abstract 9800: Clinical Effects of the Phosphodiesterase Inhibitor K-134 in Peripheral Artery Disease and Claudication

Background: In peripheral artery disease (PAD), claudication limits exercise performance, functional status and quality of life. Phosphodiesterase III inhibitors improve claudication-limited exercise performance in patients with PAD. K-134, a novel phosphodiesterase III inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess safety, quality of life and peak walking time (PWT) on a graded treadmill with cilostazol as an active comparator. Design: Patients with PAD were randomized to receive placebo (N = 87), K-134 at a dose of 25 mg (N = 42), 50 mg (N = 85) or 100 mg (N = 84), or cilostazol at a dose of 100 mg (N = 89), each given twice daily for 26 weeks. A Data Safety Monitoring Board (DSMB) implemented adaptive design was used to allow early discontinuation of unsafe or minimally informative K-134 arms. Interim safety assessments at 2 weeks included dosing of study medication at the study site followed by measurements of postural vital signs and symptoms, and at 4 weeks with a treadmill test at peak drug concentration to evaluate for ischemia or arrhythmias. Results: Based on prospectively defined adaptive criteria, the 25 mg K-134 arm was discontinued as the 50 mg and 100 mg doses were adequately tolerated, had no unanticipated safety signals, and were thus most likely to be informative concerning K-134 in the target population. In the intention-to-treat cohorts at 26 weeks PWT increased by 37% in the 100 mg K-134 arm and 23% on placebo (primary analysis p = 0.089). Using a mixed effects analysis in the entire population, 100 mg K-134 and cilostazol were each superior to placebo in improving PWT. In the per protocol population both K-134 100 mg and cilostazol 100 mg increased PWT as compared with placebo at 14 and 26 weeks. K-134 had tolerability and adverse effect profiles similar to that of cilostazol, with gastrointestinal adverse events, headache and dizziness the most common. Both drugs were associated with an increase in withdrawals prior to study completion due to adverse events as compared with placebo. Conclusions: K-134 was generally well tolerated, and at a dose of 100 mg twice daily had a safety profile and effect on treadmill walking performance that was similar to that of cilostazol.

Evaluation of trans sodium crocetinate on safety and exercise performance in patients with peripheral artery disease and intermittent claudication

Trans sodium crocetinate (TSC) is a synthetic carotenoid that improves the diffusion of oxygen in animal models of ischemia/hypoxia. This study evaluated multiple doses of TSC in patients with peripheral artery disease (PAD) and hypothesized that a preliminary dose-response relationship could be identified on peak walking time (PWT). Forty-eight patients with symptomatic PAD and an ankle-brachial index < 0.90 were included, while critical limb ischemia, recent revascularization, and exercise limited by symptoms other than claudication were exclusionary. Patients were randomized to placebo or eight dosing levels of TSC ranging from 0.25 mg/kg to 2.0 mg/kg given intravenously once daily for 5 days. Subjects were tested on a graded treadmill protocol to claudication-limited PWT with the change to Day 5 as primary. A cubic regression was fit to detect a pre-specified inverted U-shaped dose-response relationship (65% power). Patient-reported walking distance from the Walking Impairment Questionnaire was a secondary endpoint. Adverse events were not predominant on any drug dose relative to placebo. Changes in PWT demonstrated a cubic trend for dose (p = 0.07, r = 0.39, r (2) = 0.15) with morphologic signals of benefit at doses above 1.00 mg/kg after both the first and fifth dosing days. Similar improvements occurred with the walking distance score at doses above 1.00 mg/kg. In conclusion, TSC was safe and well tolerated at all doses. Notable signals of benefit were observed at higher doses for both PWT and patient-perceived walking distance. These results support a phase II study to define the optimal dose for longer-term therapy with TSC. Clinical Trial Registration - URL:http://www.clinicaltrials.gov. Unique identifier: NCT00725881.

Impact of Oral Chronic Administration of Sildenafil in Children and Young Adults After the Fontan Operation

Evaluation of: Goldberg DJ, French B, McBride MG et al. Impact of oral sildenafil on exercise performance in children and young adults after the Fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation 123, 1185-1193 (2011). After the Fontan operation, patients often have decreased exercise capacity as a result of an inability to increase cardiac output during exercise. Evidence exists that limitation in ventricular preload, related to pulmonary artery resistance plays an important role. A drug able to decrease pulmonary vascular resistance might increase transpulmonary flow and ventricular preload, therefore improving cardiac output and exercise performance. The article by Goldberg et al. is the first randomized, double-blind, placebo controlled, crossover trial to evaluate the impact of the phosphodiestarase-5 inhibitor sildenafil on exercise performance in patients after they have received the Fontan operation. The study included 28 patients with a mean age of 14.9 years. In this population, 6 weeks of sildenafil administration significantly improved ventilatory efficiency. The authors also noted an increase in exercise capacity during submaximal exercise, after 6 weeks of sildenafil in those patients with single left or mixed ventricular morphology and in those with more advanced heart failure (baseline serum brain natriuretic peptide level >100 pg/ml). The drug was well tolerated with no significant side effects. These findings suggest that sildenafil may play a role in improving exercise performance and exercise-induced breathlessness in children and young adults with single-ventricle physiology after the Fontan operation. Additional data on the possible benefit in terms of long-term clinical outcome and safety of sildenafil in this setting are needed.

Exercise blood pressure response during assisted circulatory support: Comparison of the total artifical heart with a left ventricular assist device during rehabilitation

The total artificial heart (TAH) consists of two implantable pneumatic pumps that replace the heart and operate at a fixed ejection rate and ejection pressure. We evaluated the blood pressure (BP) response to exercise and exercise performance in patients with a TAH compared to those with a with a continuous-flow left ventricular assist device (LVAD). We conducted a single-center, retrospective study of 37 patients who received a TAH and 12 patients implanted with an LVAD. We measured the BP response during exercise, exercise duration and change in tolerated exercise workload over an 8-week period. In patients with a TAH, baseline BP was 120/69 ± 13/13, exercise BP was 118/72 ± 15/10 and post-exercise BP was 120/72 ± 14/12. Mean arterial BP did not change with exercise in patients with a TAH (88 ± 10 vs 88 ± 11; p = 0.8), but increased in those with an LVAD (87 ± 8 vs 95 ± 13; p < 0.001). Although the mean arterial BP (MAP) was negatively correlated with metabolic equivalents (METs) achieved during exercise, the association was not statistically significant (β = -0.1, p = 0.4). MAP correlated positively with METs achieved in patients with LVADs (MAP: β = 0.26, p = 0.04). Despite the abnormal response to exercise, patients with a TAH participated in physical therapy (median: 5 days; interquartile range [IQR] 4 to 7 days) and treadmill exercise (19 days; IQR: 13 to 35 days) early after device implantation, with increased exercise intensity and duration over time. During circulatory support with a TAH, the BP response to exercise was blunted. However, aerobic exercise training early after device implantation was found to be safe and feasible in a supervised setting.

Cardiac determinants of impaired exercise performance in patients with type 2 diabetes mellitus

Cardiac determinants of impaired exercise performance in patients with type 2 diabetes mellitus

Rate responsive pacing using cardiac resynchronization therapy in patients with chronotropic incompetence and chronic heart failure

Chronotropic incompetence (CI) is a common finding in patients with advanced chronic heart failure (CHF) and is associated with a worse functional capacity. Whether rate responsive pacing with cardiac resynchronization therapy (CRT) would acutely improve exercise performance in patients with advanced CHF and severe CI (<70% age-predicted maximum heart rate) is unknown. Patients (n = 13) with CHF, a CRT device, and severe CI were randomized in a double-blind crossover pilot study to either DDD (control) or DDDR (rate responsive) pacing. Six minutes walk test (6MWT) distance, oxygen consumption at anaerobic threshold (VO(2) @ AT), and maximal oxygen consumption (VO(2) max) were measured. One week later, testing was repeated in the alternate pacing mode. Rate responsive pacing commenced with standard settings in only 9 of 13 (69%) patients. In these 9 subjects, 6MWT distance improved acutely from 358.5 ± 40.7 to 376.8 ± 24.5 m with DDDR pacing (P< 0.05). VO(2) max did not improve with DDDR pacing (14.0 ± 3.2 mL/kg/min) compared with DDD pacing (13.9 ± 3.0 mL/kg/min; P= 0.69). VO(2) @ AT tended towards improvement with DDDR pacing (10.8 ± 2.9 mL/kg/min) compared with DDD pacing (9.6 ± 1.8 mL/kg/min; P= 0.29). There was a linear relationship between the increase in heart rate at minute 3 during rate responsive pacing and improvement in VO(2) @ AT (r = 0.83, P< 0.05). When rate responsive pacing using a CRT device is achieved in patients with advanced CHF and severe CI, parameters of aerobic exercise performance improve acutely. Routine exercise testing to ensure successful restoration of heart rate response may be beneficial to optimize CRT settings in this patient population.

Trimetazidine improves exercise performance in patients with peripheral arterial disease

Trimetazidine, an inhibitor of free fatty acids (FFA) oxidation, shifts cardiac and muscle metabolism from FFA to glucose utilization. This effect results in a greater production of high energy phosphates and ultimately into an anti-ischemic effect. Whether the anti-ischemic cardiac effects of trimetazidine (TMZ) can be translated to skeletal muscle in patients with claudication is unknown. We investigated the effectiveness of TMZ on functional performance in patients with peripheral arterial disease (PAD) and claudication. One hundred patients with claudication were enrolled in a parallel, double-blind, 3 months study. Patients were randomized to receive TMZ or matching placebo and were included in a domiciliary exercise program, consisting in daily sessions of aerobic and isotonic exercise for at least five days a week. All patients underwent a treadmill test, evaluating maximal walking distance (MWD), and ankle–brachial index (ABI) at baseline and after 3 months. ABI was similar in the two groups at baseline and did not significantly change at the end of the study in either groups (0.83 + 0.04 vs 0.85 + 0.03, TMZ vs placebo, respectively). MWD improved in all patients with exercise training; however, a greater improvement in MWD was observed with TMZ compared to placebo (23% vs 14%, p < 0.0001). Physical training ameliorates functional performance in PAD. The adjunct of TMZ to exercise induces a greater improvement in MWD, suggesting that the inhibition of FFA oxidation improves functional capacity in patients with PAD and claudication.