Diastolic dysfunction of the cardiac allograft and maximal exercise capacity

BACKGROUND: Peak oxygen uptake (peak Vo(2)) is an established integrative measurement of maximal exercise capacity in cardiovascular disease. After heart transplantation (HTx) peak Vo(2) remains reduced despite normal systolic left ventricular function, which highlights the relevance of diastolic function. In this study we aim to characterize the predictive significance of cardiac allograft diastolic function for peak Vo(2). METHODS: Peak Vo(2) was measured using a ramp protocol on a bicycle ergometer. Left ventricular (LV) diastolic function was assessed with tissue Doppler imaging sizing the velocity of the early (Ea) and late (Aa) apical movement of the mitral annulus, and conventional Doppler measuring early (E) and late (A) diastolic transmitral flow propagation. Correlation coefficients were calculated and linear regression models fitted. RESULTS: The post-transplant time interval of the 39 HTxs ranged from 0.4 to 20.1 years. The mean age of the recipients was 55 +/- 14 years and body mass index (BMI) was 25.4 +/- 3.9 kg/m(2). Mean LV ejection fraction was 62 +/- 4%, mean LV mass index 108 +/- 22 g/m(2) and mean peak Vo(2) 20.1 +/- 6.3 ml/kg/min. Peak Vo(2) was reduced in patients with more severe diastolic dysfunction (pseudonormal or restrictive transmitral inflow pattern), or when E/Ea was > or =10. Peak Vo(2) correlated with recipient age (r = -0.643, p < 0.001), peak heart rate (r = 0.616, p < 0.001) and BMI (r = -0.417, p = 0.008). Of all echocardiographic measurements, Ea (r = 0.561, p < 0.001) and Ea/Aa (r = 0.495, p = 0.002) correlated best. Multivariate analysis identified age, heart rate, BMI and Ea/Aa as independent predictors of peak Vo(2). CONCLUSIONS: Diastolic dysfunction is relevant for the limitation of maximal exercise capacity after HTx.

The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis.

OBJECTIVES This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc). BACKGROUND Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts. METHODS Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 +/- 15 years, mean QTc 428 +/- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45). RESULTS Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons. CONCLUSIONS Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that approximately 65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.

Exercise for osteoarthritis of the hip.

BACKGROUND Current international treatment guidelines recommending therapeutic exercise for people with symptomatic hip osteoarthritis (OA) report are based on limited evidence. OBJECTIVES To determine whether land-based therapeutic exercise is beneficial for people with hip OA in terms of reduced joint pain and improved physical function and quality of life. SEARCH METHODS We searched five databases from inception up to February 2013. SELECTION CRITERIA All randomised controlled trials (RCTs) recruiting people with hip OA and comparing some form of land-based therapeutic exercise (as opposed to exercises conducted in water) with a non-exercise group. DATA COLLECTION AND ANALYSIS Four review authors independently selected studies for inclusion. We resolved disagreements through consensus. Two review authors independently extracted data, assessed risk of bias and the quality of the body of evidence for each outcome using the GRADE approach. We conducted analyses on continuous outcomes (pain, physical function and quality of life) and dichotomous outcomes (proportion of study withdrawals). MAIN RESULTS We considered that seven of the 10 included RCTs had a low risk of bias. However, the results may be vulnerable to performance and detection bias as none of the RCTs were able to blind participants to treatment allocation and, while most RCTs reported blinded outcome assessment, pain, physical function and quality of life were participant self reported. One of the 10 RCTs was only reported as a conference abstract and did not provide sufficient data for the evaluation of bias risk.High-quality evidence from nine trials (549 participants) indicated that exercise reduced pain (standardised mean difference (SMD) -0.38, 95% confidence interval (CI) -0.55 to -0.20) and improved physical function (SMD -0.38, 95% CI -0.54 to -0.05) immediately after treatment. Pain and physical function were estimated to be 29 points on a 0- to 100-point scale (0 was no pain or loss of physical function) in the control group; exercise reduced pain by an equivalent of 8 points (95% CI 4 to 11 points; number needed to treat for an additional beneficial outcome (NNTB) 6) and improved physical function by an equivalent of 7 points (95% CI 1 to 12 points; NNTB 6). Only three small studies (183 participants) evaluated quality of life, with overall low quality evidence, with no benefit of exercise demonstrated (SMD -0.07, 95% CI -0.23 to 0.36). Quality of life was estimated to be 50 points on a norm-based mean (standard deviation (SD)) score of 50 (10) in the general population in the control group; exercise improved quality of life by 0 points. Moderate-quality evidence from seven trials (715 participants) indicated an increased likelihood of withdrawal from the exercise allocation (event rate 6%) compared with the control group (event rate 3%), but this difference was not significant (risk difference 1%; 95% CI -1% to 4%). Of the five studies reporting adverse events, each study reported only one or two events and all were related to increased pain attributed to the exercise programme.The reduction in pain was sustained at least three to six months after ceasing monitored treatment (five RCTs, 391 participants): pain (SMD -0.38, 95% CI -0.58 to -0.18). Pain was estimated to be 29 points on a 0- to 100-point scale (0 was no pain) in the control group, the improvement in pain translated to a sustained reduction in pain intensity of 8 points (95% CI 4 to 12 points) compared with the control group (0 to 100 scale). The improvement in physical function was also sustained (five RCTs, 367 participants): physical function (SMD -0.37, 95% CI -0.57 to -0.16). Physical function was estimated to be 24 points on a 0- to 100-point scale (0 was no loss of physical function) in the control group, the improvement translated to a mean of 7 points (95% CI 4 to 13) compared with the control group.Only five of the 10 RCTs exclusively recruited people with symptomatic hip OA (419 participants). There was no significant difference in pain or physical function outcomes compared with five studies recruiting participants with hip or knee OA (130 participants). AUTHORS' CONCLUSIONS Pooling the results of these 10 RCTs demonstrated that land-based therapeutic exercise programmes can reduce pain and improve physical function among people with symptomatic hip OA.

Effects of exercise with oxygen prebreathe for decompression risk reduction

Astronauts performing extravehicular activities (EVA) are at risk for occupational hazards due to a hypobaric environment, in particular Decompression Sickness (DCS). DCS results from nitrogen gas bubble formation in body tissues and venous blood. Denitrogenation achieved through lengthy staged decompression protocols has been the mainstay of prevention of DCS in space. Due to the greater number and duration of EVAs scheduled for construction and maintenance of the International Space Station, more efficient alternatives to accomplish missions without compromising astronaut safety are desirable. ^ This multi-center, multi-phase study (NASA-Prebreathe Reduction Protocol study, or PRP) was designed to identify a shorter denitrogenation protocol that can be implemented before an EVA, based on the combination of adynamia and exercise enhanced oxygen prebreathe. Human volunteers recruited at three sites (Texas, North Carolina and Canada) underwent three different combinations (“PRP phases”) of intense and light exercise prior to decompression in an altitude chamber. The outcome variables were detection of venous gas embolism (VGE) by precordial Doppler ultrasound, and clinical manifestations of DCS. Independent variables included age, gender, body mass index, oxygen consumption peak, peak heart rate, and PRP phase. Data analysis was performed both by pooling results from all study sites, and by examining each site separately. ^ Ten percent of the subjects developed DCS and 20% showed evidence of high grade VGE. No cases of DCS occurred in one particular PRP phase with use of the combination of dual-cycle ergometry (10 minutes at 75% of VO2 peak) plus 24 minutes of light EVA exercise (p = 0.04). No significant effects were found for the remaining independent variables on the occurrence of DCS. High grade VGE showed a strong correlation with subsequent development of DCS (sensitivity, 88.2%; specificity, 87.2%). In the presence of high grade VGE, the relative risk for DCS ranged from 7.52 to 35.0. ^ In summary, a good safety level can be achieved with exercise-enhanced oxygen denitrogenation that can be generalized to the astronaut population. Exercise is beneficial in preventing DCS if a specific schedule is followed, with an individualized VO2 prescription that provides a safety level that can then be applied to space operations. Furthermore, VGE Doppler detection is a useful clinical tool for prediction of altitude DCS. Because of the small number of high grade VGE episodes, the identification of a high probability DCS situation based on the presence of high grade VGE seems justified in astronauts. ^

Maximal exercise hemodynamics and risk of mortality in apparently healthy men and women

The use of exercise electrocardiography (ECG) to detect latent coronary heart disease (CHD) is discouraged in apparently healthy populations because of low sensitivity. These recommendations however, are based on the efficacy of evaluation of ischemia (ST segment changes) with little regard for other measures of cardiac function that are available during exertion. The purpose of this investigation was to determine the association of maximal exercise hemodynamic responses with risk of mortality due to all-causes, cardiovascular disease (CVD), and coronary heart disease (CHD) in apparently healthy individuals. Study participants were 20,387 men (mean age = 42.2 years) and 6,234 women (mean age = 41.9 years) patients of a preventive medicine center in Dallas, TX examined between 1971 and 1989. During an average of 8.1 years of follow-up, there were 348 deaths in men and 66 deaths in women. In men, age-adjusted all-cause death rates (per 10,000 person years) across quartiles of maximal systolic blood pressure (SBP) (low to high) were: 18.2, 16.2, 23.8, and 24.6 (p for trend $<$0.001). Corresponding rates for maximal heart rate were: 28.9, 15.9, 18.4, and 15.1 (p trend $<$0.001). After adjustment for confounding variables including age, resting systolic pressure, serum cholesterol and glucose, body mass index, smoking status, physical fitness and family history of CVD, risks (and 95% confidence interval (CI)) of all-cause mortality for quartiles of maximal SBP, relative to the lowest quartile, were: 0.96 (0.70-1.33), 1.36 (1.01-1.85), and 1.37 (0.98-1.92) for quartiles 2-4 respectively. Similar risks for maximal heart rate were: 0.61 (0.44-0.85), 0.69 (0.51-0.93), and 0.60 (0.41-0.87). No associations were noted between maximal exercise rate-pressure product mortality. Similar results were seen for risk of CVD and CHD death. In women, similar trends in age-adjusted all-cause and CVD death rates across maximal SBP and heart rate categories were observed. Sensitivity of the exercise test in predicting mortality was enhanced when ECG results were evaluated together with maximal exercise SBP or heart rate with a concomitant decrease in specificity. Positive predictive values were not improved. The efficacy of the exercise test in predicting mortality in apparently healthy men and women was not enhanced by using maximal exercise hemodynamic responses. These results suggest that an exaggerated systolic blood pressure or an attenuated heart rate response to maximal exercise are risk factors for mortality in apparently healthy individuals. ^

Automated wordlength optimization framework for multi-source statistical interval-based analysis of nonlinear systems with control-flow structures

El uso de aritmética de punto fijo es una opción de diseño muy extendida en sistemas con fuertes restricciones de área, consumo o rendimiento. Para producir implementaciones donde los costes se minimicen sin impactar negativamente en la precisión de los resultados debemos llevar a cabo una asignación cuidadosa de anchuras de palabra. Encontrar la combinación óptima de anchuras de palabra en coma fija para un sistema dado es un problema combinatorio NP-hard al que los diseñadores dedican entre el 25 y el 50 % del ciclo de diseño. Las plataformas hardware reconfigurables, como son las FPGAs, también se benefician de las ventajas que ofrece la aritmética de coma fija, ya que éstas compensan las frecuencias de reloj más bajas y el uso más ineficiente del hardware que hacen estas plataformas respecto a los ASICs. A medida que las FPGAs se popularizan para su uso en computación científica los diseños aumentan de tamaño y complejidad hasta llegar al punto en que no pueden ser manejados eficientemente por las técnicas actuales de modelado de señal y ruido de cuantificación y de optimización de anchura de palabra. En esta Tesis Doctoral exploramos distintos aspectos del problema de la cuantificación y presentamos nuevas metodologías para cada uno de ellos: Las técnicas basadas en extensiones de intervalos han permitido obtener modelos de propagación de señal y ruido de cuantificación muy precisos en sistemas con operaciones no lineales. Nosotros llevamos esta aproximación un paso más allá introduciendo elementos de Multi-Element Generalized Polynomial Chaos (ME-gPC) y combinándolos con una técnica moderna basada en Modified Affine Arithmetic (MAA) estadístico para así modelar sistemas que contienen estructuras de control de flujo. Nuestra metodología genera los distintos caminos de ejecución automáticamente, determina las regiones del dominio de entrada que ejercitarán cada uno de ellos y extrae los momentos estadísticos del sistema a partir de dichas soluciones parciales. Utilizamos esta técnica para estimar tanto el rango dinámico como el ruido de redondeo en sistemas con las ya mencionadas estructuras de control de flujo y mostramos la precisión de nuestra aproximación, que en determinados casos de uso con operadores no lineales llega a tener tan solo una desviación del 0.04% con respecto a los valores de referencia obtenidos mediante simulación. Un inconveniente conocido de las técnicas basadas en extensiones de intervalos es la explosión combinacional de términos a medida que el tamaño de los sistemas a estudiar crece, lo cual conlleva problemas de escalabilidad. Para afrontar este problema presen tamos una técnica de inyección de ruidos agrupados que hace grupos con las señales del sistema, introduce las fuentes de ruido para cada uno de los grupos por separado y finalmente combina los resultados de cada uno de ellos. De esta forma, el número de fuentes de ruido queda controlado en cada momento y, debido a ello, la explosión combinatoria se minimiza. También presentamos un algoritmo de particionado multi-vía destinado a minimizar la desviación de los resultados a causa de la pérdida de correlación entre términos de ruido con el objetivo de mantener los resultados tan precisos como sea posible. La presente Tesis Doctoral también aborda el desarrollo de metodologías de optimización de anchura de palabra basadas en simulaciones de Monte-Cario que se ejecuten en tiempos razonables. Para ello presentamos dos nuevas técnicas que exploran la reducción del tiempo de ejecución desde distintos ángulos: En primer lugar, el método interpolativo aplica un interpolador sencillo pero preciso para estimar la sensibilidad de cada señal, y que es usado después durante la etapa de optimización. En segundo lugar, el método incremental gira en torno al hecho de que, aunque es estrictamente necesario mantener un intervalo de confianza dado para los resultados finales de nuestra búsqueda, podemos emplear niveles de confianza más relajados, lo cual deriva en un menor número de pruebas por simulación, en las etapas iniciales de la búsqueda, cuando todavía estamos lejos de las soluciones optimizadas. Mediante estas dos aproximaciones demostramos que podemos acelerar el tiempo de ejecución de los algoritmos clásicos de búsqueda voraz en factores de hasta x240 para problemas de tamaño pequeño/mediano. Finalmente, este libro presenta HOPLITE, una infraestructura de cuantificación automatizada, flexible y modular que incluye la implementación de las técnicas anteriores y se proporciona de forma pública. Su objetivo es ofrecer a desabolladores e investigadores un entorno común para prototipar y verificar nuevas metodologías de cuantificación de forma sencilla. Describimos el flujo de trabajo, justificamos las decisiones de diseño tomadas, explicamos su API pública y hacemos una demostración paso a paso de su funcionamiento. Además mostramos, a través de un ejemplo sencillo, la forma en que conectar nuevas extensiones a la herramienta con las interfaces ya existentes para poder así expandir y mejorar las capacidades de HOPLITE. ABSTRACT Using fixed-point arithmetic is one of the most common design choices for systems where area, power or throughput are heavily constrained. In order to produce implementations where the cost is minimized without negatively impacting the accuracy of the results, a careful assignment of word-lengths is required. The problem of finding the optimal combination of fixed-point word-lengths for a given system is a combinatorial NP-hard problem to which developers devote between 25 and 50% of the design-cycle time. Reconfigurable hardware platforms such as FPGAs also benefit of the advantages of fixed-point arithmetic, as it compensates for the slower clock frequencies and less efficient area utilization of the hardware platform with respect to ASICs. As FPGAs become commonly used for scientific computation, designs constantly grow larger and more complex, up to the point where they cannot be handled efficiently by current signal and quantization noise modelling and word-length optimization methodologies. In this Ph.D. Thesis we explore different aspects of the quantization problem and we present new methodologies for each of them: The techniques based on extensions of intervals have allowed to obtain accurate models of the signal and quantization noise propagation in systems with non-linear operations. We take this approach a step further by introducing elements of MultiElement Generalized Polynomial Chaos (ME-gPC) and combining them with an stateof- the-art Statistical Modified Affine Arithmetic (MAA) based methodology in order to model systems that contain control-flow structures. Our methodology produces the different execution paths automatically, determines the regions of the input domain that will exercise them, and extracts the system statistical moments from the partial results. We use this technique to estimate both the dynamic range and the round-off noise in systems with the aforementioned control-flow structures. We show the good accuracy of our approach, which in some case studies with non-linear operators shows a 0.04 % deviation respect to the simulation-based reference values. A known drawback of the techniques based on extensions of intervals is the combinatorial explosion of terms as the size of the targeted systems grows, which leads to scalability problems. To address this issue we present a clustered noise injection technique that groups the signals in the system, introduces the noise terms in each group independently and then combines the results at the end. In this way, the number of noise sources in the system at a given time is controlled and, because of this, the combinato rial explosion is minimized. We also present a multi-way partitioning algorithm aimed at minimizing the deviation of the results due to the loss of correlation between noise terms, in order to keep the results as accurate as possible. This Ph.D. Thesis also covers the development of methodologies for word-length optimization based on Monte-Carlo simulations in reasonable times. We do so by presenting two novel techniques that explore the reduction of the execution times approaching the problem in two different ways: First, the interpolative method applies a simple but precise interpolator to estimate the sensitivity of each signal, which is later used to guide the optimization effort. Second, the incremental method revolves on the fact that, although we strictly need to guarantee a certain confidence level in the simulations for the final results of the optimization process, we can do it with more relaxed levels, which in turn implies using a considerably smaller amount of samples, in the initial stages of the process, when we are still far from the optimized solution. Through these two approaches we demonstrate that the execution time of classical greedy techniques can be accelerated by factors of up to ×240 for small/medium sized problems. Finally, this book introduces HOPLITE, an automated, flexible and modular framework for quantization that includes the implementation of the previous techniques and is provided for public access. The aim is to offer a common ground for developers and researches for prototyping and verifying new techniques for system modelling and word-length optimization easily. We describe its work flow, justifying the taken design decisions, explain its public API and we do a step-by-step demonstration of its execution. We also show, through an example, the way new extensions to the flow should be connected to the existing interfaces in order to expand and improve the capabilities of HOPLITE.

The adaptive response of humans to exercise: Impact of exercise intensity, fibre-type specific responses and molecular patterns of response

In an attempt to improve the current understanding of the adaptive response to exercise in humans, this dissertation performed a series of studies designed to examine the impact of training intensity and mode on aerobic capacity and performance, fibre-type specific adaptations to training, and individual patterns of response across molecular, morphological and genetic factors. Project #1 determined that training intensity, session dose, baseline VO2max and total training volume do not influence the magnitude of change in VO2max by performing a meta-regression, and meta-analysis of 28 different studies. The intensity of training had no effect on the magnitude of increase in maximal oxygen uptake in young healthy participants, but similar adaptations were achieved with lower training doses following high intensity training. Project # 2 determined the acute molecular response, and training-induced adaptations in aerobic performance, aerobic capacity and muscle phenotype following high-intensity interval training (HIT) or endurance exercise (END). The acute molecular response (fibre recruitment and signal activation) and training-induced adaptations in aerobic capacity, aerobic performance, and muscle phenotype were similar following HIT and END. Project # 3 examined the impact of baseline muscle morphology and molecular characteristics on the training response, and if muscle adaptations are coordinated. The muscle phenotype of individuals who experience the largest improvements (high responders) were lower before training for some muscle characteristics and molecular adaptations were coordinated within individual participants. Project # 4 examined the impact of 2 different intensities of HIT on the expression of nuclear and mitochondrial encoded genes targeted by PGC-1α. A systematic upregulation of nuclear and mitochondrial encoded genes was not present in the early recovery period following acute HIT, but the expression of mitochondrial genes were coordinated at an individual level. Collectively, results from the current dissertation contribute to our understanding of the molecular mechanisms influencing skeletal muscle and whole-body adaptive responses to acute exercise and training in humans.

Temporal aspects of the VO2 response at the power output associated with VO2peak in well trained cyclists: Implications for interval training prescription

The power output achieved at peak oxygen consumption (VO2 peak) and the time this power can be maintained (i.e., Tmax) have been used in prescribing high-intensity interval training. In this context, the present study examined temporal aspects of the VO2 response to exercise at the cycling power that output well trained cyclists achieve their VO2 peak (i.e., Pmax). Following a progressive exercise test to determine VO2 peak, 43 well trained male cyclists (M age = 25 years, SD = 6; M mass = 75 kg SD = 7; M VO2 peak = 64.8 ml(.)kg(1.)min(-1), SD = 5.2) performed two Tmax tests 1 week apart.1. Values expressed for each participant are means and standard deviations of these two tests. Participants achieved a mean VO2 peak during the Tmax test after 176 s (SD = 40; = 74% of Tmax, SD = 12) and maintained it for 66 s (SD = 39; M = 26% of Tmax, SD = 12). Additionally they obtained mean 95 % of VO2 peak after 147 s (SD = 31; M = 62 % of Tmax, SD = 8) and maintained it for 95 s (SD = 38; M = 38 % of Tmax, SD = 8). These results suggest that 60-70% of Tmax is an appropriate exercise duration for a population of well trained cyclists to attain VO2 peak during exercise at Pmax. However due to intraparticipant variability in the temporal aspects of the VO2 response to exercise at Pmax, future research is needed to examine whether individual high-intensity interval training programs for well trained endurance athletes might best be prescribed according to an athlete's individual VO2 response to exercise at Pmax.

Muscle metabolism during sprint exercise in man: Influence of sprint training

In order to examine the influence of sprint training on metabolism and exercise performance during sprint exercise, 16 recreationally-active, untrained, men (TO2peak= 3.8+/-0.1 1.min(-1)) were randomly assigned to either a training (n=8) or control group (n=8). Each subject performed a 30-sec cycle sprint and a test to measure VO2peak before and after eight weeks of sprint training. The training group completed a series of sprints three times per week which progressed from three 30-sec cycle sprints in weeks 1 and 2, to six 30-sec sprints in weeks 7 and 8. Three mins of passive recovery separated each sprint throughout the training period. Muscle samples were obtained at rest and immediately following the pre- and post-training sprints and analysed for high energy phosphagens, glycogen and lactate; the activities of both phosphofructokinase (PFK) and citrate synthase (CS) were also measured and muscle fibre types were quantified, Training resulted in a 7.1% increase in mean power output (p

Exercise training for patients with heart failure: A systematic review of factors that improve mortality and morbidity

PURPOSE: To determine the efficacy of exercise training and its effects on outcomes in patients with heart failure. METHODS: MEDLINE, Medscape, and the Cochrane Controlled Trials Registry were searched for trials of exercise training in heart failure patients. Data relating to training protocol, exercise capacity, and outcome measures were extracted and reviewed. RESULTS: A total of 81 studies were identified: 30 randomized controlled trials, five nonrandomized controlled trials, nine randomized crossover trials, and 37 longitudinal cohort studies. Exercise training was performed in 2387 patients. The average increment in peak oxygen consumption was 17% in 57 studies that measured oxygen consumption directly, 17% in 40 studies of aerobic training, 9% in three studies that only used strength training, 15% in 13 studies of combined aerobic and strength training, and 16% in the one study on inspiratory training. There were no reports of deaths that were directly related to exercise during more than 60,000 patient-hours of exercise training. During the training and follow-up periods of the randomized controlled trials, there were 56 combined (deaths or adverse events) events in the exercise groups and 75 combined events in the control groups (odds ratio [OR] = 0.98; 95% confidence interval [Cl]: 0.61 to 1.32; P = 0.60). During this same period, 26 exercising and 41 nonexercising subjects died (OR = 0.71; 95% CT: 0.37 to 1.02; P = 0.06). CONCLUSION: Exercise training is safe and effective in patients with heart failure. The risk of adverse events may be reduced, but further studies are required to determine whether there is any mortality benefit. (C) 2004 by Excerpta Medica Inc.

Leukocyte subset responses during exercise under heat stress with carbohydrate or water intake

Purpose: This study investigated leukocyte subset responses to moderate-intensity exercise under heat stress, with water (W) or carbohydrate (CHO) drink ingestion. Methods: In repeated trials, 13 soldiers consumed either a W or CHO drink during 3 h of walking at 4.4 km center dot h(-1) with a 5% gradient (15 min rest per hour) under heat stress (35 C and 55% relative humidity). The soldiers wore combat uniforms and carried water bottles and dummy rifles and ammunition, altogether weighing about 11.5 +/- 1.0 kg. Results: Plasma glucose concentration was significantly higher with CHO than W ingestion during exercise (p < 0.01). There were no significant differences between W and CHO conditions in exercise performance, plasma cortisol concentration, heart rate, or core temperature. CHO ingestion significantly moderated the increases in leukocyte (83% in W, 28% in CHO; p < 0.001), monocyte (60% in W, 34% in CHO; p < 0.05), and granulocyte counts (120% in W, 30% in CHO; p < 0.001), but not in lymphocyte count (41% in W, 25% in CHO). Conclusions: The increases in leukocyte and subset counts during moderate-intensity exercise under heat stress may be comparable to those observed during intense exercise in cool conditions. The response of immune cell counts is blunted by CHO intake during moderate-intensity exercise in the heat, and may not occur through the cortisol pathway.

The roles of exercise-induced immune system disturbances in the pathology of heat stroke - The dual pathway model of heat stroke

Heat stroke is a life-threatening condition that can be fatal if not appropriately managed. Although heat stroke has been recognised as a medical condition for centuries, a universally accepted definition of heat stroke is lacking and the pathology of heat stroke is not fully understood. Information derived from autopsy reports and the clinical presentation of patients with heat stroke indicates that hyperthermia, septicaemia, central nervous system impairment and cardiovascular failure play important roles in the pathology of heat stroke. The current models of heat stroke advocate that heat stroke is triggered by hyperthermia but is driven by endotoxaemia. Endotoxaemia triggers the systemic inflammatory response, which can lead to systemic coagulation and haemorrhage, necrosis, cell death and multi-organ failure. However, the current heat stroke models cannot fully explain the discrepancies in high core temperature (Tc) as a trigger of heat stroke within and between individuals. Research on the concept of critical Tc: as a limitation to endurance exercise implies that a high Tc may function as a signal to trigger the protective mechanisms against heat stroke. Athletes undergoing a period of intense training are subjected to a variety of immune and gastrointestinal (GI) disturbances. The immune disturbances include the suppression of immune cells and their functions, suppression of cell-mediated immunity, translocation of lipopolysaccharide (LPS), suppression of anti-LPS antibodies, increased macrophage activity due to muscle tissue damage, and increased concentration of circulating inflammatory and pyrogenic cytokines. Common symptoms of exercise-induced GI disturbances include diarrhoea, vomiting, gastrointestinal bleeding, and cramps, which may increase gut-related LPS translocation. This article discusses the current evidence that supports the argument that these exercise-induced immune and GI disturbances may contribute to the development of endotoxaemia and heat stroke. When endotoxaemia can be tolerated or prevented, continuing exercise and heat exposure will elevate Tc to a higher level (> 42 degrees C), where heat stroke may occur through the direct thermal effects of heat on organ tissues and cells. We also discuss the evidence suggesting that heat stroke may occur through endotoxaemia (heat sepsis), the primary pathway of heat stroke, or hyperthermia, the secondary pathway of heat stroke. The existence of these two pathways of heat stroke and the contribution of exercise-induced immune and GI disturbances in the primary pathway of heat stroke are illustrated in the dual pathway model of heat stroke. This model of heat stroke suggests that prolonged intense exercise suppresses anti-LPS mechanisms, and promotes inflammatory and pyrogenic activities in the pathway of heat stroke.

Monitoring changes in thioredoxin and over-oxidised peroxiredoxin in response to exercise in humans

Introduction. Peroxiredoxin (PRDX) and thioredoxin (TRX) are antioxidant proteins that control cellular signalling and redox balance, although their response to exercise is unknown. This study aimed to assess key aspects of the PRDX-TRX redox cycle in response to three different modes of exercise. Methods. Healthy males (n = 10, mean ± SD: 22 ± 3 yrs) undertook three exercise trials on separate days: two steady-state cycling trials at moderate (60% VO2MAX; 27 min, MOD) and high (80% VO2MAX; 20 min, HIGH) intensities, and a low-volume high-intensity interval training trial (10 × 1 min 90% VO2MAX, LV-HIIT). Peripheral blood mononuclear cells were assessed for TRX-1 and over-oxidised PRDX (isoforms I-IV) protein expression before, during, and 30 min following exercise (post + 30). The activities of TRX reductase (TRX-R) and the nuclear factor kappa B (NF-κB) p65 subunit were also assessed. Results. TRX-1 increased during exercise in all trials (MOD, + 84.5%; HIGH, + 64.1%; LV-HIIT, + 205.7%; p < 05), whereas over-oxidised PRDX increased during HIGH only (MOD, - 28.7%; HIGH, + 202.9%; LV-HIIT, - 22.7%; p < .05). TRX-R and NF-κB p65 activity increased during exercise in all trials, with the greatest response in TRX-R activity seen in HIGH (p < 0.05). Discussion. All trials stimulated a transient increase in TRX-1 protein expression during exercise. Only HIGH induced a transient over-oxidation of PRDX, alongside the greatest change in TRX-R activity. Future studies are needed to clarify the significance of heightened peroxide exposure during continuous high-intensity exercise and the mechanisms of PRDX-regulatory control.

The dual effect of normobaric hypoxia on heart rate variability and substrate partitioning following interval cycling

Recent studies have shown the importance of the beat-by-beat changes in heart rate influenced by the autonomic nervous system (ANS), or heart rate variability (HRV). The purpose of this study was to examine the lasting effects of hypoxic exercise on HRV, and its influences on substrate usage. Results from this study could lead an increased understanding on this topic. Eight active healthy males (age: 31±11 years; height: 180±7 cm; weight: 83±8 kg; VO₂max (maximal oxygen consumption): 4.4±0.6 L•min⁻¹) underwent normoxic and hypoxic (FᵢO₂= 0.15) conditions during high-intensity interval (HIIT) cycling (70%-high interval, 35%-rest interval). Cycling intensity was determined by a peak power output cycling test. Each experimental session consisted of a basal metabolic rate determination, up to 45-minutes of HIIT cycling, and three 30-minute post-exercise metabolic rate measurements (spanning 3 hours and 15 minutes after exercise). During exercise, RPE was higher (p<0.01) and LAC (lactate) increased (p=0.001) at each point of time in hypoxia, with no change in normoxia. After hypoxic exercise, the SNS/PNS ratio (overall ANS activity) was significantly higher (p<0.01) and significantly decreased through time in both conditions (p<0.01). In addition, a significant interaction between time and conditions (p<0.02) showed a decrease in LAC concentration through time post-hypoxic exercise. The findings showed that a single bout of hypoxic exercise alters ANS activity post-exercise along with shifting substrate partitioning from glycolytic to lipolytic energy production. The significant decrease in LAC concentration post-hypoxic exercise supports the notion that hypoxic HIIT induces a greater muscle glycogen depletion leading to increased fat oxidation to sustain glycogenesis and gluconeogenesis to maintain blood glucose level during recovery.