Implications of Chronic Heart Failure On Peripheral Vasculature and Skeletal Muscle Before and After Exercise Training

Heart Fail Rev (2008) 13:2137 DOI 10.
1007/s10741-007-9056-8
Implications of chronic heart failure on peripheral vasculature and skeletal muscle before and after exercise training
Brian D. Duscha P. Christian Schulze Jennifer L. Robbins Daniel E. Forman
Published online: 23 October 2007 Springer Science+Business Media, LLC 2007
Abstract The pathophysiology of chronic heart failure (CHF) is typically conceptualized in terms of cardiac dysfunction. However, alterations in peripheral blood ow and intrinsic skeletal muscle properties are also now recognized as mechanisms for exercise intolerance that can be modied by therapeutic exercise. This overview focuses on blood delivery, oxygen extraction and utilization that result from heart failure. Related features of inammation, changes in skeletal muscle signaling pathways, and vulnerability to skeletal muscle atrophy are discussed. Specic focus is given to the ways in which perfusion and skeletal muscle properties affect exercise intolerance and how peripheral
B. D. Duscha J. L. Robbins Duke University Medical Center, Box 3022, Durham NC 27710, USA B. D. Duscha e-mail: Dusch001@mc.duke.edu J. L. Robbins e-mail: j.robbins@duke.edu P. C. Schulze Division of Cardiology, New York Presbyterian Hospital, Columbia University Medical Center, 622 West 168th Street, PH 3-347, New York, NY 10032, USA e-mail: Pcs2121@columbia.edu D. E. Forman (&) Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA e-mail: deforman@partners.org D. E. Forman Veterans Administration Medical Center (VAMC) of Boston, Boston, MA, USA D. E. Forman Harvard Medical School, Boston, MA, USA
improvements following exercise training increase aerobic capacity. We also identify gaps in the literature that may constitute priorities for further investigation. Keywords Vascular Skeletal muscle Capillary density Muscle ber Mitochondria Inammation Apoptosis Ubiquitin ligase Exercise training
Introduction Pathophysiology of systolic chronic heart failure (CHF) entails an initial injury to the heart that results in decreased left ventricular (LV) function and progressive declines in cardiac output. Eventually, pump function is inadequate to supply sufcient blood perfusion for systemic metabolic needs. Clinical consequences can include dyspnea, fatigue, and exercise intolerance. However, over two decades of research have demonstrated that exercise intolerance in CHF is very complex and also extends to systems and abnormalities beyond the heart. Among its systemic effects, CHF has detrimental impact on local blood ow and skeletal muscle oxidative metabolism. In particular, skeletal muscle is a major determinant of exercise intolerance and subsequent disability. Decreased oxygen delivery (abnormal peripheral blood ow/muscle perfusion) and changes in extraction/utilization by muscle affect exercise tolerance. Exercise training induces adaptations that have proved benecial for increasing functional capacity and improvements in skeletal muscle that have been implicated in explaining much of these benets. This article will focus on the known alterations to peripheral blood ow and skeletal muscle in patients with CHF. In addition, it will describe how exercise training
123
22
Heart Fail Rev (2008) 13:2137
interventions have improved skeletal muscle and functional capacity. Throughout this article an attempt will be made to identify gaps in the literature and suggest future directions for investigation.
3.
Interplay between cardiac output, hemodynamics, skeletal muscle, and exercise tolerance The Fick equation states that maximal oxygen consumption can be calculated as the product of cardiac output (stroke volume heart rate) multiplied by A-VO2 difference (the capacity of peripheral tissue to utilize oxygen). It makes clear that functional capacity depends both on central cardiac performance as well as on peripherally mediated oxygen utilization. However, potential to increase cardiac output is inherently limited by heart failure [1], that is, hearts of CHF patients tend to be maximally dilated even at baseline, such that it is less likely that functional gains can be achieved by additional myocyte growth adaptations to increase stroke volume through principles of the Starling mechanism. Likewise, CHF patients have limited chronotropic and inotropic reserves, with inherently reduced capacity for functional gains to be achieved by increasing heart rate and/or contractility. Therefore, for CHF patients on maximal medical therapy, peripheral adaptations that increase A-VO2 differences through exercise training are the mechanisms best suited to enhance functional capacity and clinical performance in spite of the constraints of disease. A large body of literature has contributed to an evolution of insights regarding central versus peripheral mechanisms underlying functional capacity and symptoms among CHF patients. Key principles include the following: (1) there is little correlation with resting central hemodynamic indices and peak oxygen consumption in CHF; (2) acutely improving blood delivery does not lead to improved exercise tolerance in CHF; and (3) deconditioning does not completely explain differences in exercise capacity. Major examples include the following: 1. Studies in which measurements of low LV ejection fraction and increased pulmonary wedge pressures do not relate to exercise intolerance in CHF. The analyses also show that resting LV hemodynamic indices (such as LV end diastolic dimension, mean velocity of circumferential ber shortening, and ratio of preejection period to LV ejection time) are unrelated to exercise capacity or symptom status in CHF [24]. Studies in which acute use of inotropes and vasodilators do not translate into increases in exercise tolerance, despite improving leg blood ow (LBF) and cardiac output. Following these pharmacologic
4.
5.
therapeutic agents, CHF patients still experience early onset of lactate accumulation and early anaerobic metabolism [57]. Studies showing that exercise training improves lactate threshold, but without signicantly improving cardiac output in CHF [8]. 31 P-MRI studies showing early anaerobic metabolism in CHF both in the presence of normal LBF and after occluding skeletal muscle blood ow [912]. Studies demonstrating intrinsic abnormalities in skeletal muscles in CHF patients, compared to aerobically matched sedentary normal controls [13] as well as to other diseased populations with normal ventricular function and disuse atrophy [14]. Furthermore, animal models suggest CHF results in changes in skeletal muscle gene expression at the pre-translational level that cannot be accounted for by inactivity [15].
LBF during exercise When exercising, skeletal muscle demands greater blood and oxygen supply than at rest. In healthy normal adults, up to 85% of the total blood ow is directed toward active skeletal muscle in working limbs [16], with ow to leg muscles usually receiving the greatest increases in ow. Arterioles dilate and cardiac output augments to increase peripheral ow. Usually arteriolar vasodilation and capillary volume can readily facilitate and accommodate the high volume of blood that is needed to sustain working muscle. However, at high workloads, the hearts capacity to supply blood and oxygen is eventually exceeded. Sympathetically mediated vasoconstriction maintains vascular tone and preserves hemodynamic equilibrium even at high workloads, tempering any exercise-induced vasodilating effects [17]. In contrast, vasoconstriction is increased among CHF patients relative to normal at rest and with exertion, contributing to reductions in LBF, and thereby lessoning submaximal and maximal work capacities [1821] (Fig. 1). Overall, LBF falls due to the combined effects of low cardiac output, increased leg vascular resistance, and abnormal arteriolar constriction [19, 22, 23]. Increased vasoconstriction stems, in part, from the effects of heightened sympathetic output in CHF. This is compounded by the impaired release of several vasoactive substances from the endothelium that additionally encumber vasodilatory responses. Normally, endothelial cells along the lumen of large conduit arteries secrete nitric oxide (NO), a potent vasodilator, in response to mechanical shear stress. However, chronic reductions in peripheral blood ow secondary to decreased LV function
2.
123
Heart Fail Rev (2008) 13:2137 Fig. 1 Resting and exercise single leg blood ow, leg vascular resistance, leg arteriovenous oxygen difference, single leg VO2, femoral venous oxygen content and femoral venous oxygen saturation in patients with chronic heart failure (n = 30) (O) and normal subjects (n = 12) (d); *p \ 0.05, p \ 0.01 patients versus normal subjects. Dashed lines indicate inter-group comparisons of maximal data (Reprinted with permission from reference 19)
23
impair the release of endothelial NO that normally occurs via this mechanism [2426]. Vascular smooth muscle responsiveness to NO is also reduced in patients with CHF, further undercutting NO-mediated vasodilation [27, 28]. In addition, prostaglandins may inhibit agonistmediated NO vasodilation in the periphery [29]. Two powerful vasoconstrictors, angiotensin II and endothelin1, are elevated in patients with CHF, which further contribute to the abnormal regulation of vascular tone [3032]. Among the many studies that have demonstrated the signicance of vascular physiology in CHF, some of the most compelling data have come from studies comparing one-legged versus two-legged exercise. Compared to twolegged exercise, one-legged exercise in patients with CHF demonstrates higher LBF, lower leg vascular resistance, and lower central A-VO2 at both submaximal and peak exercise. However, regardless of whether one- or twolegged exercise is performed, mean arterial pressure (MAP) is preferentially preserved at the expense of leg
hypoperfusion [20, 22]. Another key insight relates to the fact that even with relatively higher LBF during one-legged exercise, lactate accumulation is unaltered [19, 33]. In aggregate, these studies highlight the complexity of exercise intolerance and the intricate interplay between central and peripheral mechanisms.
Beyond LBF: intrinsic skeletal muscle limits exercise Patients with CHF compensate for reduced LVF with an increased A-VO2, such that resting and sub-maximal exercise oxygen consumption are similar to that of normals. Despite this increase in A-VO2, CHF patients have increased lactate production, even during sub-maximal exercise [6, 18, 19, 34] (Fig. 1). Early blood lactate production is a function of intramuscular acidosis and not reduced lactate clearance [9, 10]. This nding suggests that intrinsic skeletal muscle abnormalities are responsible for early anaerobic metabolism.
123
24
Interestingly, acute usage of peripheral vasodilators or ACE inhibitors lead to immediate improvements in peripheral vessel dilation and LBF without an immediate increase in peak VO2 [6]. It is hypothesized that 2 3 months of increased LBF (due to pharmacological therapy) may be necessary to induce changes in intrinsic skeletal muscle [35]. This would explain why peak VO2 increases only after several months of the greater LV function achieved with medical therapy [35, 36]. Similarly, it seems likely that prolonged decreases of LV function cause skeletal muscle abnormalities. Nonetheless, it is also possible that these skeletal muscle changes may be independent of LV function. Perhaps the most convincing work was done by Wilson et al. [12] who identied CHF patients with normal LBF during exercise but reduced leg oxygen consumption and early lactate production. While a separate study by Wilson et al. [7] demonstrated immediate improvement in LBF using dobutamine, concomitant improvements in lactate response at a given workload were not similarly elicited. Other investigators [9, 11] have also demonstrated abnormal skeletal muscle metabolism under ischemic conditions, unrelated to LBF.
Capillary density and intra-muscle oxygen dynamics Microcirculation of skeletal muscle constitutes another important dimension of vascular ow dynamics pertinent to CHF, especially since it is a critical juncture between vascular ow dynamics and intrinsic properties of skeletal muscle that affects exercise performance. The primary function of the capillary bed in skeletal muscle is to supply oxygen to muscle bers. In the same way that contractile protein composition and mitochondrial mass are important factors in skeletal muscle physiology, relative vascular density is higher in oxidative, fatigue-resistant muscles compared with glycolytic muscle. A key benet of exercise training is that it induces increased capillary density, which constitutes a primary mechanism by which skeletal muscle can adapt to achieve higher A-VO2 differences and related functional enhancements. For this article we identied seven studies that evaluated capillary density in CHF patients compared to healthy controls. The comparisons reveal signicant variance between analyses. When capillary density was measured as the ratio of capillaries per muscle ber, six of the seven studies reported reduced capillary density (ranging from 17% to 32%) in the skeletal muscle of CHF patients [33, 3741]. Within this group of studies, only one used endothelial cell specic staining (versus a total basement membrane stain). This was also the study that showed the highest difference of capillary density (32%) [37] in CHF
versus normals, and was the only study that demonstrated that capillary density in CHF correlated to exercise performance (peak VO2 and exercise time). In contrast, when capillarity density was analyzed as capillaries per area (mm2), only one of six studies showed reduced capillary density in CHF patients compared to normal controls. One study even showed an increase in capillary density in CHF patients [42]. The discrepancies between studies attest to the importance of ber size when completing capillary density assessments. In general, when measuring capillary density as capillaries per ber, CHF patients have lower capillary density than normal healthy adults. Moreover, when analyzing capillary and functional capacity across a continuum of tness levels or when combining healthy controls and CHF patients, it is possible to demonstrate that capillary density relates to peak VO2. However, when analyzing only CHF patients, it has been difcult to reproduce this relationship between capillary density and functional capacity. Given this ambiguity, it seems that the interplay between capillarity and performance may parallel the issues that pertained to LBF and skeletal muscle metabolism in CHF. Regardless of whether or not microcirculation increases, oxygen uptake may initially lag based upon the capacity of skeletal muscle to extract and utilize the oxygen it receives (i.e., due to decreased oxidative machinery such as mitochondria and enzymes). Consistently, blood drawn from the vasculature draining working muscles during exercise has been demonstrated to show less than 1 ml of O2/100 ml of blood in patients with both cardiovascular disease [43] and heart failure [19], a relationship that cannot acutely change to achieve greater A-VO2 differences. It is possible that increases and decreases in capillary density may be regulated by the muscles need to extract and utilize oxygen. This concept is demonstrated among normal adults by Andersen [44] in work which showed that as muscle blood ow increases linearly with exercise workload, the vascular bed can readily accommodate higher ow, but oxygen utilization becomes limited by mitochondrial enzymes. Likewise, Saltin et al. [45] assert that increases in capillary volume is not induced by a drive to accommodate larger blood ow, but rather to optimize the surface area required for the exchange of oxygen, substrate, and metabolites. Future research on oxygen ux from the red blood cells in the capillary to the muscle is necessary to understand the relationship between microcirculation and skeletal muscle oxidative metabolism. This line of investigations would help to determine the functional importance of capillary density in the skeletal muscle of CHF, with focused attention on ber types, ber atrophy, oxygen diffusion, and timeline relationships to other intrinsic oxidative markers before and after interventions and as CHF severity progresses.
123
25
Many believe that endothelial health may play a key role in complex interrelationships between capillarity, oxygen delivery, and clinical benets. A number of growth factors have been implicated as mediators for the growth and proliferation of endothelial cells (angiogenesis). The growth factor receiving the most attention has been vascular endothelial growth factor (VEGF). Despite this interest, the impact VEGF has on skeletal muscle and functional capacity is poorly understood. Most studies have been limited to animal models or to the myocardium, with few focusing on human skeletal muscle or exercise interventions. Animal models have shown that VEGF mRNA and protein expression is increased in skeletal muscle that is more oxidative versus glycolytic and muscle that is subjected to increases in contractile activity [46, 47]. Vascular endothelial growth factor unquestionably plays a role in angiogenesis. Therefore, it would seem logical to think that the amount of skeletal muscle VEGF can predict capillary density values but, in fact, no clear relationship has been proven. Gustafsson [48] showed that after 8 weeks of one-legged knee extension training that both VEGF at the mRNA and protein levels were increased approximately two times in CHF patients. Unfortunately, capillary density was not measured in this study. It is possible that hypoxia [49], induced by exercise, creates a stimulus for VEGF expression. The difculty of studying VEGF is further complicated by the fact that it has multiple isoforms and receptors. The VEGF receptor VEGFR1 is a soluble form that is believed to have a higher afnity for VEGF than VEGFR2. In addition, VEGFR1 and VEGFR2 are part of different signaling pathways that play separate downstream roles in the regulation of angiogenesis, apoptosis, and NO. How VEGF and potentially other growth factors are affected by CHF, how responsive VEGF is to exercise training, and how VEGF affects other oxidative skeletal muscle characteristics (capillary density and oxidative enzymes) and functional capacity remain compelling areas of research.
oxidative metabolism and to increased muscle weakening and fatigability that are at least partially reversible by exercise training. While the predominant shifts in skeletal muscle were initially discovered by muscle biopsy, conrming data have been collected using 31P magnetic resonance spectroscopy (MRS). MRS studies have shown abnormal phosphocreatine (PCr) and ATP metabolism leading to early anaerobic metabolism during exercise [5356] and recovery from exercise [57]. Furthermore, MRS showed that oxidative metabolism was improved following exercise training [53, 58, 59].
Relative change of ber types Overall, it is well accepted that CHF patients have a lower percentage of oxidative skeletal muscle compared to normal controls and that these alterations are partially responsible for the observed exercise intolerance and fatigue. Studies report 1020% decreases in oxidative type I bers in CHF patients with increases in glycolytic type IIb bers compared to normals [33, 38, 40, 42, 60]. These shifts have been correlated to peak VO2 [42] and leg fatigue during isokinetic knee extension [38]. Related studies conrm these relationships by demonstrating reduced myosin heavy chain (MHC) type I isoforms with reduced peak oxygen consumption and lower functional class in CHF [61, 62]. Furthermore, a series of studies indicate that many aspects of CHF skeletal muscle abnormalities can adapt to aerobic exercise training with restoration of more normal intrinsic properties (Table 1). Interestingly, Sullivan [62] also demonstrated that three of nine CHF subjects had no MHC type I, an abnormal discovery for any population, suggesting that there are fundamental differences in gene expression with CHF pathophysiology. Vescovo [14] also demonstrated MHC alterations specic to CHF when compared to disuse atrophy following patients who have suffered a stroke. The latter two examples point toward a disease-specic pathology or a molecular mechanism unique to CHF.
Intrinsic skeletal muscle abnormalities and reduced oxidative capacity in CHF Although the characteristics of skeletal muscle represent a continuum across tness levels [17, 5052], numerous studies report a phenotypical shift from oxidative (red) type I ber type to more glycolytic (white) type II skeletal muscle ber types in CHF, with these changes rooted in disease pathology and not merely due to exercise deconditioning [13, 14]. This pattern of change appears to affect all characteristics of skeletal muscle including enzymes, mitochondria, capillary density, and the propensity to atrophy. These intrinsic changes correlate to decreased
Enzymes Although glycolytic enzymes appear to be unchanged (or slightly increased) in CHF, oxidative enzymes are decreased [13, 33, 37, 38, 40, 42, 63, 64]. Historically, studies have measured enzymes of the Krebs Cycle and boxidation. Specically, mitochondrial enzymes (citrate synthase and succinate dehydrogenase) and enzymes involved in b-oxidation of fatty acids (3-hydroxyl CoA dehydrogenase) have been shown to be decreased [33].
123
26
Table 1 Aerobic training trials for systolic CHF patients demonstrating benecial skeletal muscle adaptations Training mode Bike Bike 70% 20 min/day 5060% 30 min/ 3 days a week Training did not alter myosin heavy chain distribution Training led to a 27% increase in cytochrome c oxidase (COX) activity. Changes in iNOS (; by 52%) expression and protein content were inversely related to changes in COX-activity Local expression of IGF-I increased signicantly after exercise training by 81% while IGF-I receptor expression was reduced by 33% Local skeletal muscle TNF-a, IL-1-b, IL-6, and iNOS were reduced with training Capillary density and muscle enzyme activity did not signicantly change with training in men or women. Myosin heavy chain increased in men, but not in women A trend toward increased thickness for all three ber types post training. A trend toward a decrease in type I and an increase in type IIB ber area Training increased citrate synthase activity by 46% and increased both protein (92%) and mRNA (99%) levels of VEGF. No changes in ber typing, LDH or PFK PFK activity rose slightly post training. Training had no effect on percentage of distribution of slow-twitch and fast-twitch muscle or on the capillary density around these bers Women with HF had more type I bers and lower CSA of type I and II bers than controls. Exercise training increased CSA while the relative number of type I bers decreased 40% 30 min/3 days a week 70% 4060 min/day Skeletal muscle showed a signicant increase in the capillary/ber ratio, but were not correlated with any clinical ndings Enhanced oxidative enzyme surface density (41% : in cytochrome c oxidase (+) mitochondria which were related to changes in peak VO2, 43% : in mitochondria cristae, and a 92% : in mitochondrial inner border membrane) and an increase in type I bers (4%) and a decrease in type II bers (4%). Bike Dynamic knee extensions Two legged knee extensors 6575% 15 min/ 3 days a week 6575% 15 min/ 3 days a week Training increased activity of citrate synthase by 44% and lactate dehydrogenase by 23% in women Skeletal muscle citrate synthase activity was increased by 28% with training. PFK remained unchanged Training Rx Intrinsic skeletal muscle ndings
123
3 months 6 months 6 months Bike 70% 20 min/day 6 months 1424 weeks Bike, TM, rowing, or arm ergometers 12 weeks Bike 80% 30 min/5 days a week 50% 1618 min/leg/ 3 days a week 5060% 30 min/ 3 days a week 6080% 40 min/3 days a week Bike 70% 20 min/day 8 weeks One-legged knee extension Bike 3 months 8 weeks Dynamic knee extensions 6575% 15 min/ 3 days a week 8 weeks Bike 6 months 8 weeks 8weeks
Study
Subject number (Ex/Cntl) Duration
Harjola et al. [152]
8/9
Gielen et al. [76]
10/10
Hambrecht et al. [153]
9/9
Gielen et al. [126]
10/10
Keteyian et al. [122]
15
Larsen et al. [60]
15
Gustafsson et al. [48]
Kiilavuori et al. [154]
12/15
Tyni-Lenne et al. [120] 16
Scarpelli et al. [155]
9/9
Tyni-Lenne et al. [118] 16
Gordon et al. [127]
13
27
Capillary per ber ratio increased by 47%. Citrate synthase was increased by 77%, HAD increased by 53%, and LDH did not change with training.
Citrate synthase increased by 23% in the one legged training group and by 35% in the two legged training group while PFK remained unchanged in either group
Training increased capillary density slightly (5%) but was reduced per ber (9%). Fiber typing was unchanged with training. High correlation between changes in volume density of mitochondria and changes in peak oxygen consumption and lactate threshold
Changes in cytochrome c oxidase (+) mitochondria (: 41%) were linked to improvement in peak oxygen consumption at ventilatory threshold. Total volume density of mitochondria increased by 19%
Intrinsic skeletal muscle ndings
Furthermore, Sullivan et al. [65] found inverse relationships between oxidative enzyme activity and blood lactate accumulation during sub-maximal exercise. Interestingly, in this study CHF patients had less PCr depletion and lactate accumulation at peak exercise than normals, raising the possibility that intrinsic skeletal muscle abnormalities may be responsible for early anaerobic metabolism. Drexler et al. [40] also demonstrated a close relationship between cytochrome c oxidase, mitochondrial volume density or cristae surface density and peak VO2. To further strengthen a rationale that oxidative enzymes play an important role in exercise capacity, others have also demonstrated relationships between citrate synthase and peak VO2 [38, 66].
Mitochondria In healthy individuals, the most important determinant in maximal oxygen consumption is the delivery system (cardiac output) [67], whereas sub-maximal indices rely on skeletal muscle (mitochondria content and other oxidative machinery) [68]. However, in CHF, due to a compromised delivery system, characteristics of skeletal muscle become relatively more important. Mitochondria generate most of a cells ATP and therefore play an intricate role in skeletal muscle energy metabolism. Surprisingly, we identied only one study that directly measured mitochondria compared to a healthy control group. This study by Drexler et al. [40] demonstrates that oxygen consumption correlates to reduced mitochondrial volume and surface area. Most CHF studies have chosen to measure mitochondrial enzymes as a surrogate of mitochondria versus direct histochemical analysis. A decline in mitochondrial number and size indicates a reduced oxidative capacity of the muscle and has been offered as an explanation for the rapid fatigue that occurs in patients with CHF. Among the factors contributing to the mitochondrial defects seen in the skeletal muscle of CHF patients are increased production of toxic mitochondrial reactive oxygen species and alterations in mtDNA number or mutations. Toxic intracellular levels of NO produced by iNOS may also impair oxidative phosphorylation [69].
One legged and two legged 35% and 6575% knee extensors 15 min/3 days a week
6575% 45 min/ 3 days a week
70% 4060 min/day
One legged dynamic knee extension
Training mode
Subject number (Ex/Cntl) Duration
6 months
Bike
8 weeks
14/7 (2 train groups)
8 weeks
12/10
Belardinelli et al. [124] 18/9
5/6
8 weeks
Bike
40% 30 min/3 days a week
Training Rx
Magnusson et al. [125]
Gordon et al. [156]
Table 1 continued
Increased inammation and CHF The extensive effects of CHF on skeletal muscle, capillarity, and other constitutive aspects of local architecture and function have led to consideration of underlying factors that may change fundamental molecular signaling patterns. CHF entails predominant changes in inammation and
Study
123
28
growth regulating peptides that may factor into these critical processes. Specically, CHF stimulates an imbalance of catabolic over anabolic molecules [70]. TNF-a, IL-1b, and iNOS [71] all increase and contribute to skeletal muscle derangements. TNF-a induces catabolic metabolism, reduced skeletal muscle contractility, and ultimately muscle atrophy. IL-1b suppresses expression of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) and phospholamban [72]. Other factors like sphingosine and iNOS have also been proposed as potential mediators of the negative inotropic actions [73]. NF-jB is a transcription factor that regulates the expression of proinammatory cytokines especially in combination of oxidative stress. Muscle activity and ischemia likely add to this process [74, 75]. Intracellular accumulation of NO generated by iNOS may produce toxic levels of NO high enough to inhibit key enzymes of the oxidative phosphorylation either directly through posttranslational protein modication by NO (-S-nitrosylation) or indirectly through formation of reactive NO metabolites [76]. Therefore, elevated iNOS is linked to diminished citrate synthase and other indices of oxidative metabolism. Furthermore, inammation catalyzes proteolytic pathways, such that apoptosis, ubiquitin proteasome proteolysis, and other key avenues toward muscle atrophy are accelerated.
Effects of inammation and reduced IGF-1 on skeletal muscle Dysregulation of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) signaling is a key consideration in the pathophysiology of CHF. Catabolic syndromes in chronic inammation, sepsis, or cancer show an altered state of the GH/IGF-1 axis due in part to peripheral IGF-1 deciency and also because of an impaired IGF-1 response to GH [77, 78]. Elevated levels of GH with inappropriately normal serum levels of IGF-1 have been described in cardiac cachexia [79]. This has been attributed in part to increased serum levels and the local expression of proinammatory cytokines such as IL-1b and TNF-a [80]. Consistently, low levels of systemic IGF-1 are associated with decreased leg muscle cross-sectional area (CSA) and strength [81]. It is especially notable that a signicant proportion of IGF-1 is produced locally by muscle bers and then acts as a paracrine, rather than endocrine, regulator of skeletal muscle hypertrophy or atrophy. It was recently demonstrated that the local expression of IGF-1 is considerably reduced in skeletal muscle of non-cachectic patients with severe CHF as compared to controls,
even while serum levels of IGF-1, GH, and their binding proteins remained unchanged [82]. In contrast, IGF-1 receptor expression increases, indicating a possible feedback mechanism between local IGF-1 concentrations and receptor density. In a subgroup with low body mass index (\25 kg/m2), IGF-1 decreased, whereas GH increased signicantly, consistent with the development of a peripheral GH resistance [82]. This study also showed that the local expression of IGF-1 is closely correlated with muscle CSA such that local IGF-1 deciency seems likely to increase muscle atrophy in CHF. In a related animal study, Schulze et al. [83] demonstrated reduced local expression of IGF-1 in skeletal muscle of animals with CHF accompanied by increased expression of the IGF-1 receptor in the presence of normal serum levels of IGF-1. Also, signicant local expression of both IL-1b and TNFa were considerably increased in skeletal muscle [83] and single muscle ber CSA was decreased [8385]. Overall, these studies suggest that in spite of normal serum levels of IGF-1 and proinammatory cytokines, local expression of IGF-I in skeletal muscle is substantially reduced in CHF. Skeletal muscle changes seem most likely amidst a local cytokine-based catabolic process that is a critical aspect of CHF pathophysiology. Intriguingly, deletion of TNF-a in an animal model of muscular dystrophy prevents the deterioration of muscle structure and function [86], suggesting that modications to the inammatory substrate may be a key aspect of efcient therapeutic manipulations. However, it is unknown whether this affects local expression and secretion of anabolic growth factors such as IGF-1.
Effects of inammation on vasculature The impact of cytokines and inammation have also been studied in respect to vascular architecture and performance. Experimental evidence suggests that TNF-a impairs the stability of eNOS mRNA, downregulates eNOS expression, and may later lead to an increased rate of endothelialcell apoptosis [87, 88]. Furthermore, cytokine activity has been demonstrated to diminish superoxide dismutase [89], leading to accumulations of free radicals such as superoxide anion, which in turn shorten the half-life of NO [90] and associated propensity for disease instability. Chronic reductions in peripheral blood ow may increase cytokines and cytokine activation. Reduced NO exacerbates the process, with reduced ow as well as reduced cytokine modifying capacity, in a vicious cycle of disease escalation.
123
29
Muscle proteolysis and skeletal muscle atrophy in CHF Muscle mass and strength Many studies have shown that patients with CHF have decreased muscle mass and reduced total muscle CSA compared with healthy normal subjects [9194]. However, the relationship of these factors with the deteriorations in strength and exercise tolerance observed in patients with CHF remains controversial. Although overall muscle strength appears to be decreased in patients with CHF, most groups have found a preservation of maximal force per unit area of muscle [92, 95]. Therefore, total muscle mass appears to affect exercise capacity [39, 94, 96]. Such ndings serve as strong rationale for exercise and adjunct therapies that might build muscle mass, that is, strength training. Theoretically, it is also possible that there are salient clinical differences that distinguish muscle loss in one patient from another, that is, skeletal muscle changes may be very different in cachectic versus non-cachectic patients. However, these implications have not been clearly delineated. Furthermore, even when the lean mass is comparable between CHF patients and healthy subjects, CHF patients continue to exhibit an inferior tolerance to exercise [65, 96]. This relative difference is attributable to other aspects of muscle pathology among CHF patients. Intrinsic differences in ber types, oxidative enzymes, mitochondria, contractile proteins, and capillary density [33, 40, 42, 62, 97] all contribute to qualitative differences.
release. The high iNOS expression present in CHF seems especially conducive to skeletal muscle apoptosis of skeletal myocytes [69, 100, 101]. IGF-1 can modify susceptibility to apoptosis, both with downregulation of IL-1b-mediated NO formation and fasmediated apoptosis [102]. IGF-1 also increases expression of BCL-2 involving a PI3-kinase/Akt/CREB signaling cascade [103] that serves to modulate pro-apoptotic stimuli.
Ubiquitin-proteasome-mediated proteolysis Muscle protein breakdown also results from other cellular systems. In particular, the ATP-dependent ubiquitin-proteasome system has been implicated as an important contributor to protein breakdown and skeletal muscle atrophy in CHF. The role of ubiquitin-proteasome-mediated proteolysis has been well substantiated in other diseases. Muscle atrophy in diabetes mellitus [104], cancer [105], renal failure [106], starvation [107, 108], sepsis [109], and CHF [110] has been associated with an enhanced activation of the ubiquitin-proteasome system. Specic ubiquitin-conjugating enzymes (E3-ligases) target proteins for degradation by the proteasome. Two E3ligases, atrogin-1 (also called MFbx-1) and MURF-1 (muscle ring nger protein-1), are highly induced in muscle atrophy of different origin. Gomes et al. reported increased expression of atrogin-1, a muscle-specic E3-ligase, following starvation [107, 108]. Through a comparable analysis of genes in atrophying muscle caused by different mechanisms, Bodine et al. [111] identied the atrogin-1 and MURF-1. Furthermore, animals with targeted deletion of atrogin-1 or MURF-1 exhibit less muscle atrophy in response to denervation and hind limb suspension [111]. Schulze et al. [110] demonstrated the key role of ubiquitin-mediated proteolysis for skeletal muscle atrophy in a CHF animal model as well as the crucial regulatory role of local IGF-1 in skeletal muscle tissue. Muscle ber CSA was signicantly reduced 12 weeks after myocardial infarction and related development of chronic LV dysfunction. Furthermore, increased amounts of ubiquitinated protein conjugates were demonstrated in extracts from atrophying skeletal muscle, ndings consistent with activation of the ubiquitin-proteasome pathway in the setting of chronic LV dysfunction. This analysis demonstrates that atrogin-1 was strongly induced in several different hind limb muscles. It also shows that increased IGF-1 suppressed atrogin-1 expression and reduced proteolysis and atrophy. Of additional note, infusion of the proinammatory cytokine IL-1b induces the expression of atrogin-1 and TNF-a increases the ubiquitin-conjugating capacity
Apoptosis Activation of apoptosis is one mechanism wherein muscle bulk diminishes with CHF. Apoptosis is tantamount to cell suicide in which progressive loss of muscle-ber nuclei contributes to progressive atrophy. Growth hormone resistance as well as ambient inammation (particularly TNF-a, IL-1, and IL-6 in combination with the transcription activator NF-kB) are known catalysts to this progressive cell loss [98]. Adams showed that apoptosis was detected in skeletal muscle in 50% of patients with CHF as compared to no apoptosis in normal healthy controls [69]. Consistently, Vescovo showed oxygen consumption was negatively correlated with the number of terminal deoxynuceotidyltransferase-mediated UTP endlabeling-positive nuclei (a measure of apoptosis) and skeletal muscle ber CSA in CHF [99]. Several key signaling patterns appear to regulate apoptosis. Inducible NO synthase has been implicated to be both pro-apoptotic depending on the dosage and timing of its
123
30
myocytes, reinforcing the hypothesis that cytokines constitute key mediators of muscular atrophy [112].
Signaling pathways that link different pathophysiologic stimuli Enhanced activation of the PI3K/Akt molecular signaling pathway, downstream from IGF-1, is a key constitutive step in regulating skeletal muscle atrophy in CHF. Unchecked, the PI3K/Akt signaling triggers apoptosis, but Akt phosphorylation inhibits apoptosis as well as the expression of atrogin-1 and MuRF-1 that otherwise promotes ubiquitin-proteasome-mediated proteolysis [113]. While direct inhibitors of PI3K/Akt phosphorylation have not been identied in atrophying muscle, such phosphorylation is in fact inhibited during muscle atrophy [114]. Likewise, phosphorylated Akt has been demonstrated in IGF-1-induced muscle hypertrophy [113, 114]. Phosphorylation of PI3K/Akt also occurs downstream of the badrenergic receptor through the second messenger cAMP. Since expression of b-adrenergic receptors is suppressed in CHF, this suggests another vulnerability of CHF patients to atrophy mediated by the PI3K/Akt pathway, although this has not been veried in skeletal muscle. Studies also show that exogenous administration of IGF1 regulating growth hormone in a rat CHF model countered decline in skeletal muscle function, structure, and morphology [115], particularly by phosphorylating Akt to thereby inhibit FOXO and atrogin-1, that is, IGF-1 stimulates AKT phosphorylation which then moderates ubiquitin-proteasome-mediated proteolysis. Foxo transcription factors have also been identied as a potential mechanism underlying enhanced proteolysis and muscle atrophy [113, 114]. In mammals, the forkhead transcription factors include Foxo1 (FKHR), Foxo3 (FKHRL1), and Foxo4 (AFX) [114]. Increased expression of Foxo1 occurs during muscle atrophy [116] but phosphorylation of Foxo1, 3 and 4 by PI3K/Akt leads to nuclear exclusion inhibiting their transcriptional activity [113, 114]. IGF-1 also leads to robust phosphorylation of Foxo4 and mitigates muscle wasting. Notably, Foxo4 is the most abundant forkhead transcription factor in skeletal muscle [117].
studies examining skeletal muscle characteristics in CHF, fewer than 20% of total subjects have been women. The Tyni-Lenne group at the Karolinska Institute were the rst to explore skeletal muscle between men and women CHF patients both at baseline and after 8 months of knee extensor endurance training [118120]. This series of investigations showed similar citrate synthase activity between men and women at both baseline and after training. However, with exercise training, women improved peak VO2 greater than did men. These analyses also revealed that female CHF patients had normal type I ber distribution but decreased CSA in types I and II compared to normals. Exercise training with a cycle ergometer corrected the baseline atrophy to within normal ranges. Duscha et al. [121] reproduced the nding that citrate synthase was no different between men and women with CHF and that MHC type I was lower but not statistically different in CHF versus normal women. This study extended the eld by also showing no difference in capillary density between men and women with CHF. However, when men and women with CHF were compared to normal controls, the men with CHF had less capillary density versus healthy men, but the women with CHF had increased capillary density versus normal women. In the only other training study that directly compared skeletal muscle between the genders in CHF, Keteyian [122] found a robust increase in MHC I in men and a concordant increase in peak VO2. However, women with CHF had no training effects, that is, an outcome that was discordant with Tyni-Lenne, who found that with training, women had a relatively greater improvement in oxygen consumption. Overall, this limited body of literature comparing peripheral manifestations of CHF in men and women suggests that women with CHF have slightly more oxidative capacity in their skeletal muscle than do men with CHF, possibly indicating that CHF produces less impact on skeletal muscle in women than in men. However, the potential for skeletal muscle to favorably adapt to exercise training, and its relation to improved functional capacity in the context of gender differences, remains a keen topic of research interest.
Overview of exercise training studies Gender differences and skeletal muscle in CHF Men and women CHF patients have been shown to be different in respect to underlying pathophysiology and therapeutic responses, especially with respect to skeletal muscle pathophysiology. However, prior to 1995, few CHF studies included adequate women for meaningful assessments. Careful review of the literature reveals that of the While this review remains focused on peripheral aspects of CHF, and corresponding peripheral benets of exercise, benets of exercise on central cardiac function are also relevant. As detailed by other authors elsewhere in this issue, cardiac output may improve with exercise training, increasing blood supply to support skeletal muscle work demands.
123
31
Although a number of small exercise training studies have examined the adaptations of skeletal muscle to exercise training, these studies have been difcult to interpret for a variety of reasons. To date, there has been no large (highest number of any one study is 16 CHF patients) randomized control study adequately powered and designed to detect changes across multiple markers of oxidative capacity in skeletal muscle. This gap in the literature is especially appreciated when one considers that the ability to detect and relate physiologic differences before and after an intervention is difcult even with robust subject numbers and large changes. Furthermore, CHF has a continuum of functional classications, making it difcult to differentiate how severity of disease impacts skeletal muscle adaptability within each category. Few studies have compared men versus women. Last, the dose of exercise (training range and duration) and mode (cycle, walking, knee-extensor) is all slightly different between studies. For these reasons there have been a number of inconsistencies, conicting data, and null ndings.
responses to exercise training. Three showed increased capillary density and two did not (Table 1). It may be concluded that improvements in aerobic capacity do not necessarily elicit or result from increases in aerobic ber types. Therefore, the fundamental decreases in oxidative bers that occur with CHF (compared to healthy controls) are not completely reversible with exercise training. Furthermore, improved oxidative capacity is more likely linked to oxygen utilization that is determined by changes in intrinsic properties of skeletal muscle.
Exercise as a means to modify ambient tissue inammation A broader benet of exercise training relates to its potential to modify underlying tissue inammation that otherwise deranges muscle function, and which also underlies impaired NO stimulation and efcacy, as well as proclivity to muscle atrophy. Gielen et al. [126] showed benets of aerobic training to reduce TNF-a, IL-1B, IL-6, and iNOS in skeletal muscle of CHF patients. Importantly, these effects in skeletal muscle were independent of serum levels. Accumulating evidence suggests that exercise enhancements to endothelial function may promote these anti-inammatory benets. Physical training has been shown to improve cardiac output during exercise with related increases in endothelial shear stress and associated NO stimulation. Not only does NO decrease peripheral resistance in working muscle, with favorable redistribution of blood ow [24, 128], but it also induces anti-inammatory effects. Diminished free radicals and inammatory cytokines (i.e., TNF-a) have been demonstrated [129, 130]. While increases in NO bioactivity may dissipate within weeks of training cessation, studies of healthy subjects indicate that if exercise is maintained, the short-term functional adaptation catalyzes NO-dependent structural changes, leading to more enduring arterial remodeling and structural normalization of the endothelium [131]. Similarly, as exercise achieves favorable anti-inammatory benets in the skeletal muscle, the implications are broad. Secondary molecular signaling effects are likely, favorably affecting skeletal muscle molecular signaling patterns that otherwise result in atrophy and metabolic declines.
Effects of aerobic exercise training on intrinsic skeletal muscle properties Table 1 summarizes the 17 studies we found that included both an aerobic exercise intervention and skeletal muscle biopsies before and after exercise training. This table primarily highlights intrinsic oxidative characteristics. Despite heterogeneous designs and methods, some consistent ndings do emerge; in particular, studies show that exercise training increases oxidative enzyme activity in CHF patients. Changes in mitochondria structure correlated with improvements in peak VO2 and lactate threshold [123, 124]. Other studies demonstrate increases in citrate synthase (2545%) [48, 118, 125127]. Furthermore, increases in mitochondrial enzymes have been correlated to mitochondrial structure and function [25]. Nonetheless, data pertaining to ber types before and after exercise training have been much more ambiguous. Of the 17 aerobic exercise studies assessed, only 7 measured changes in ber type or MHC, and of these, 5 out of 7 demonstrated no change and only 2 of the 7 show increased type I bers. Furthermore, in one of the two studies that indicated an elevation in type I bers, it was only a modest 4% increase. Some studies show shifts from IIb to IIa ber type but, in general, the plasticity of ber shifting as a result of exercise training was underwhelming. Overall, these data indicate that ber type does not shift readily toward more oxidative forms with exercise training. Similarly, data pertaining to capillary density before and after exercise training have not shown obvious differences. Of the 17 trials assessed, only 5 included capillary density
Effects of exercise on underlying molecular signaling pathways IGF-1 and exercise Muscular stretch is a potent stimulator of IGF-1. McKoy et al. [132] reported that 4 days of muscle stretch
123
32
signicantly induced IGF-mRNA starting as early as 12 h after the stimulus. Exercise training as a natural form of stretch exposure has similar effects on skeletal muscle IGF1 expression. In a model of treadmill exercise in young rats, Eliakim et al. [133] described a signicant increase in skeletal muscle IGF-1 protein levels after 6 days with no change in systemic IGF-1 serum concentrations. Similarly, a greater than a two times increase in local IGF-1 expression after 6 months of exercise training was found in patients with stable CHF [134, 135]. In two other studies involving non-CHF populations, one showed increased IGF-1 immunoreactive cells in skeletal muscle biopsies obtained after 1 week of terrain marching [136]. The second showed a six times increase in local IGF-1 expression after a combined intervention of nutritional supplementation and resistance training [137]. Therefore, the local IGF-I-deciency responds to long-term exercise, indicating that the catabolic state in the skeletal muscle of CHF patients is at least partially reversible by adequate rehabilitation [134]. Furthermore, Singhs study raises consideration of resistance training as potentially a more potent and efcient means to achieve changes in growth peptides and anti-inammatory benets.
Rationale for different training modalities The preponderance of exercise training studies for CHF have utilized aerobic training modalities; however, many now look to strength training as a synergistic exercise modality. Whereas rationale for aerobic training in cardiac patients was originally premised on expectations for improved inotropic and chronotropic capacities, outcomes have mostly demonstrated clinical improvements after exercise training that are attributable to augmented skeletal muscle oxidative metabolism. Many hypothesize that resistance training may more efciently induce skeletal muscle molecular signaling patterns that achieve clinical benets. Notably, resistance training is the exercise modality that has the most potential to increase muscle mass, suggesting it may more successfully respond to the muscle loss and weakening of CHF. In an animal study, Baldwin [138] describes differences in how specic exercise modalities impact muscle plasticity. This study shows myosin heavy chain gene expression is regulated by mechanical stimuli and transcriptional events vary depending on the exercise utilized. Despite the promise of resistance training in CHF, there is some controversy concerning its effect on peak VO2. While some studies have shown an increase in peak VO2 following weight training [139141], others have failed to reproduce these ndings in either CAD [142] or CHF [143] populations. Many report that resistance training improves
other clinical measures such as sub-maximal ventilation and lactate threshold as well as total exercise time [66, 141, 143]. A related analysis by Williams [141] showed that increased mitochondrial ATP production was signicantly related to improvements in peak VO2. This nding suggests that resistance training can have benecial effects similar to that of aerobic training on the skeletal muscle of CHF. In other analyses, multiple investigators assert rationale for exercise regimens that combine aerobic and strength training as an approach that is particularly likely to enhance function. Maiorana et al. [144] showed 18.4% improved exercise time and 13.4% improved peak VO2 after a 12-week aerobic plus circuit weight-training program in CHF patients. Delagardelle et al. [145] and Selig [146] also showed signicant increases in peak VO2 using a combination of resistance and aerobic training. Furthermore, Delagardelle [147] demonstrated that a combined program of endurance and strength training was superior to a program of endurance training alone for the improvement of peak VO2. Investigators have begun to analyze skeletal muscle histology and biochemistry as a result of resistance training. Pu et al. [66] showed increased muscle ber area (9.5% for type 1 and 13.6% for type II muscle bers) as well as improved oxidative capacity (35% increase citrate synthase activity). Magnusson [125] showed 9% increased CSA of the quadriceps femoris muscle. Related analyses are only beginning to focus on the underlying biochemistry, histology [148], and associated muscle signaling cascades. Specic benets of resistance training on IGF-1, myostatin, and several other key mediators are pathways and dynamic areas of investigation pertinent to heart failure as well as to aging and other chronic disease states that are associated with muscle loss and weakening [149, 150]. As these investigations evolve, many related issues regarding the interplay between skeletal muscle and sustaining blood supply need to be explored. While studies demonstrate that resistance training improves skeletal muscle histology, biochemistry, and muscle mass, it remains unknown if there is adequate cardiac output to employ and sustain these added benets. In summary, further research is necessary to evaluate the value of resistance training in CHF. Future challenges include optimizing exercise prescription without compromising LV function as warned by the American Heart Associations position stand on resistance exercise training in individuals with cardiovascular disease [151].
Conclusion As insights regarding heart failure have evolved, the overall complexity of disease has become more evident.
123
33 congestive heart failure. Evidence for abnormalities unrelated to blood ow. Circulation 78:320326 Wilson JR, Mancini DM, Dunkman WB (1993) Exertional fatigue due to skeletal muscle dysfunction in patients with heart failure. Circulation 87:470475 Duscha BD, Annex BH, Green HJ, Pippen AM, Kraus WE (2002) Deconditioning fails to explain peripheral skeletal muscle alterations in men with chronic heart failure. J Am Coll Cardiol 39:11701174 Vescovo G, Serani F, Facchin L, Tenderini P, Carraro U, Dalla Libera L, Catani C, Ambrosio GB (1996) Specic changes in skeletal muscle myosin heavy chain composition in cardiac failure: differences compared with disuse atrophy as assessed on microbiopsies by high resolution electrophoresis. Heart 76:337343 Simonini A, Long CS, Dudley GA, Yue P, McElhinny J, Massie BM (1996) Heart failure in rats causes changes in skeletal muscle morphology and gene expression that are not explained by reduced activity. Circ Res 79:128136 Knight DR, Poole DC, Schaffartzik W, Guy HJ, Prediletto R, Hogan MC, Wagner PD (1992) Relationship between body and leg VO2 during maximal cycle ergometry. J Appl Physiol 73: 11141121 Saltin B, Henriksson J, Nygaard E, Andersen P, Jansson E (1977) Fiber types and metabolic potentials of skeletal muscles in sedentary man and endurance runners. Ann NY Acad Sci 301:329 Wilson JR, Martin JL, Schwartz D, Ferraro N (1984) Exercise intolerance in patients with chronic heart failure: role of impaired nutritive ow to skeletal muscle. Circulation 69: 10791087 Sullivan MJ, Knight JD, Higginbotham MB, Cobb FR (1989) Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood ow is reduced with maintenance of arterial perfusion pressure. Circulation 80:769781 LeJemtel TH, Maskin CS, Lucido D, Chadwick BJ (1986) Failure to augment maximal limb blood ow in response to oneleg versus two-leg exercise in patients with severe heart failure. Circulation 74:245251 Zelis R, Longhurst J, Capone RJ, Mason DT (1974) A comparison of regional blood ow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 50:137143 Sullivan MJ, Cobb FR (1991) Dynamic regulation of leg vasomotor tone in patients with chronic heart failure. J Appl Physiol 71:10701075 Zelis R, Mason DT, Braunwald E (1968) A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 47:960970 Hornig B, Maier V, Drexler H (1996) Physical training improves endothelial function in patients with chronic heart failure. Circulation 93:210214 Hambrecht R, Niebauer J, Fiehn E, Kalberer B, Offner B, Hauer K, Riede U, Schlierf G, Kubler W, Schuler G (1995) Physical training in patients with stable chronic heart failure: effects on cardiorespiratory tness and ultrastructural abnormalities of leg muscles. J Am Coll Cardiol 25:12391249 Rubanyi GM, Romero JC, Vanhoutte PM (1986) Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 250:H1145H1149 Katz SD, Biasucci L, Sabba C, Strom JA, Jondeau G, Galvao M, Solomon S, Nikolic SD, Forman R, LeJemtel TH (1992) Impaired endothelium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol 19:918925
Consistently, it has become clear that peripheral mechanisms of disease, particularly those pertaining to tissue perfusion and skeletal muscle oxidative metabolism, generate key impact on disease progression, and also create potential for novel therapeutic interventions. Certainly, exercise training has been demonstrated to improve many of the vascular and skeletal muscle features that have been associated with CHF. Ongoing research points to the complex interplay between vascular and skeletal muscle performance as the search continues for optimal therapeutic strategies. Eventually, it seems likely that specic types of exercise, possibly a combination of aerobic and resistance modalities, will be identied that target specic peripheral endpoints and how they impact functional outcomes.
12.
13.
14.
15.
16.
References
1. Pina IL, Apstein CS, Balady GJ, Belardinelli R, Chaitman BR, Duscha BD, Fletcher BJ, Fleg JL, Myers JN, Sullivan MJ (2003) Exercise and heart failure: a statement from the American Heart Association Committee on exercise, rehabilitation, and prevention. Circulation 107:12101225 2. Higginbotham MB, Morris KG, Conn EH, Coleman RE, Cobb FR (1983) Determinants of variable exercise performance among patients with severe left ventricular dysfunction. Am J Cardiol 51:5260 3. Szlachcic J, Massie BM, Kramer BL, Topic N, Tubau J (1985) Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardiol 55:10371042 4. Franciosa JA, Park M, Levine TB (1981) Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol 47:3339 5. Maskin CS, Forman R, Sonnenblick EH, Frishman WH, LeJemtel TH (1983) Failure of dobutamine to increase exercise capacity despite hemodynamic improvement in severe chronic heart failure. Am J Cardiol 51:177182 6. Wilson JR, Martin JL, Ferraro N, Weber KT (1983) Effect of hydralazine on perfusion and metabolism in the leg during upright bicycle exercise in patients with heart failure. Circulation 68:425432 7. Wilson JR, Martin JL, Ferraro N (1984) Impaired skeletal muscle nutritive ow during exercise in patients with congestive heart failure: role of cardiac pump dysfunction as determined by the effect of dobutamine. Am J Cardiol 53:13081315 8. Sullivan MJ, Higginbotham MB, Cobb FR (1988) Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 77:552559 9. Wiener DH, Fink LI, Maris J, Jones RA, Chance B, Wilson JR (1986) Abnormal skeletal muscle bioenergetics during exercise in patients with heart failure: role of reduced muscle blood ow. Circulation 73:11271136 10. Massie B, Conway M, Yonge R, Frostick S, Ledingham J, Sleight P, Radda G, Rajagopalan B (1987) Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood ow. Circulation 76:10091019 11. Massie BM, Conway M, Rajagopalan B, Yonge R, Frostick S, Ledingham J, Sleight P, Radda G (1988) Skeletal muscle metabolism during exercise under ischemic conditions in
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
123
34 28. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM (1991) Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 84:15891596 29. Katz SD (1995) The role of endothelium-derived vasoactive substances in the pathophysiology of exercise intolerance in patients with congestive heart failure. Prog Cardiovasc Dis 38:2350 30. Drexler H, Hornig B (1999) Endothelial dysfunction in human disease. J Mol Cell Cardiol 31:5160 31. Kiowski W, Luscher TF, Linder L, Buhler FR (1991) Endothelin-1-induced vasoconstriction in humans. Reversal by calcium channel blockade but not by nitrovasodilators or endothelium-derived relaxing factor. Circulation 83:469475 32. Haynes WG, Webb DJ (1998) Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens 16:10811098 33. Sullivan MJ, Green HJ, Cobb FR (1990) Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 81:518527 34. Weber KT, Janicki JS (1985) Lactate production during maximal and submaximal exercise in patients with chronic heart failure. J Am Coll Cardiol 6:717724 35. Jeserich M, Munzel T, Pape L, Fischer C, Drexler H, Just H (1995) Absence of vascular tolerance in conductance vessels after 48 hours of intravenous nitroglycerin in patients with coronary artery disease. J Am Coll Cardiol 26:5056 36. Drexler H, Banhardt U, Meinertz T, Wollschlager H, Lehmann M, Just H (1989) Contrasting peripheral short-term and longterm effects of converting enzyme inhibition in patients with congestive heart failure. A double-blind, placebo-controlled trial. Circulation 79:491502 37. Duscha BD, Kraus WE, Keteyian SJ, Sullivan MJ, Green HJ, Schachat FH, Pippen AM, Brawner CA, Blank JM, Annex BH (1999) Capillary density of skeletal muscle: a contributing mechanism for exercise intolerance in class II-III chronic heart failure independent of other peripheral alterations. J Am Coll Cardiol 33:19561963 38. Magnusson G, Kaijser L, Rong H, Isberg B, Sylven C, Saltin B (1996) Exercise capacity in heart failure patients: relative importance of heart and skeletal muscle. Clin Physiol 16: 183195 39. Williams AD, Selig S, Hare DL, Hayes A, Krum H, Patterson J, Geerling RH, Toia D, Carey MF (2004) Reduced exercise tolerance in CHF may be related to factors other than impaired skeletal muscle oxidative capacity. J Card Fail 10:141148 40. Drexler H, Riede U, Munzel T, Konig H, Funke E, Just H (1992) Alterations of skeletal muscle in chronic heart failure. Circulation 85:17511759 41. Schaufelberger M, Eriksson BO, Grimby G, Held P, Swedberg K (1995) Skeletal muscle ber composition and capillarization in patients with chronic heart failure: relation to exercise capacity and central hemodynamics. J Card Fail 1:267272 42. Mancini DM, Coyle E, Coggan A, Beltz J, Ferraro N, Montain S, Wilson JR (1989) Contribution of intrinsic skeletal muscle changes to 31P NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. Circulation 80:13381346 43. Koike A, Wasserman K, Taniguchi K, Hiroe M, Marumo F (1994) Critical capillary oxygen partial pressure and lactate threshold in patients with cardiovascular disease. J Am Coll Cardiol 23:16441650 44. Andersen P, Saltin B (1985) Maximal perfusion of skeletal muscle in man. J Physiol 366:233249 45. Saltin B, Kiens B, Savard G, Pedersen PK (1986) Role of hemoglobin and capillarization for oxygen delivery and extraction in muscular exercise. Acta Physiol Scand Suppl 556:2132
Heart Fail Rev (2008) 13:2137 46. Annex BH, Torgan CE, Lin P, Taylor DA, Thompson MA, Peters KG, Kraus WE (1998) Induction and maintenance of increased VEGF protein by chronic motor nerve stimulation in skeletal muscle. Am J Physiol 274:H860H867 47. Folkman J (1995) Seminars in medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 333:17571763 48. Gustafsson T, Bodin K, Sylven C, Gordon A, Tyni-Lenne R, Jansson E (2001) Increased expression of VEGF following exercise training in patients with heart failure. Eur J Clin Invest 31:362366 49. Namiki A, Brogi E, Kearney M, Kim EA, Wu T, Coufnhal T, Varticovski L, Isner JM (1995) Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chem 270:3118931195 50. Houston ME, Bentzen H, Larsen H (1979) Interrelationships between skeletal muscle adaptations and performance as studied by detraining and retraining. Acta Physiol Scand 105:163170 51. Hoppeler H, Luthi P, Claassen H, Weibel ER, Howald H (1973) The ultrastructure of the normal human skeletal muscle. A morphometric analysis on untrained men, women and welltrained orienteers. Pugers Arch 344:217232 52. Kiessling KH, Pilstrom L, Bylund AC, Saltin B, Piehl K (1974) Enzyme activities and morphometry in skeletal muscle of middle-aged men after training. Scand J Clin Lab Invest 33: 6369 53. Kemp GJ, Thompson CH, Stratton JR, Brunotte F, Conway M, Adamopoulos S, Arnolda L, Radda GK, Rajagopalan B (1996) Abnormalities in exercising skeletal muscle in congestive heart failure can be explained in terms of decreased mitochondrial ATP synthesis, reduced metabolic efciency, and increased glycogenolysis. Heart 76:3541 54. Okita K, Yonezawa K, Nishijima H, Hanada A, Nagai T, Murakami T, Kitabatake A (2001) Muscle high-energy metabolites and metabolic capacity in patients with heart failure. Med Sci Sports Exerc 33:442448 55. Chati Z, Zannad F, Robin-Lherbier B, Escanye JM, Jeandel C, Robert J, Aliot E (1994) Contribution of specic skeletal muscle metabolic abnormalities to limitation of exercise capacity in patients with chronic heart failure: a phosphorus 31 nuclear magnetic resonance study. Am Heart J 128:781792 56. Mancini DM, Wilson JR, Bolinger L, Li H, Kendrick K, Chance B, Leigh JS (1994) In vivo magnetic resonance spectroscopy measurement of deoxymyoglobin during exercise in patients with heart failure. Demonstration of abnormal muscle metabolism despite adequate oxygenation. Circulation 90:500508 57. Toussaint JF, Koelling TM, Schmidt CJ, Kwong KK, LaRaia PJ, Kantor HL (1998) Local relation between oxidative metabolism and perfusion in leg muscles of patients with heart failure studied by magnetic resonance imaging and spectroscopy. J Heart Lung Transplant 17:892900 58. Ohtsubo M, Yonezawa K, Nishijima H, Okita K, Hanada A, Kohya T, Murakami T, Kitabatake A (1997) Metabolic abnormality of calf skeletal muscle is improved by localised muscle training without changes in blood ow in chronic heart failure. Heart 78:437443 59. Adamopoulos S, Coats AJ, Brunotte F, Arnolda L, Meyer T, Thompson CH, Dunn JF, Stratton J, Kemp GJ, Radda GK et al (1993) Physical training improves skeletal muscle metabolism in patients with chronic heart failure. J Am Coll Cardiol 21: 11011106 60. Larsen AI, Lindal S, Aukrust P, Toft I, Aarsland T, Dickstein K (2002) Effect of exercise training on skeletal muscle bre characteristics in men with chronic heart failure. Correlation between skeletal muscle alterations, cytokines and exercise capacity. Int J Cardiol 83:2532
123
Heart Fail Rev (2008) 13:2137 61. Vescovo G, Serani F, Dalla Libera L, Leprotti C, Facchin L, Tenderini P, Ambrosio GB (1998) Skeletal muscle myosin heavy chains in heart failure: correlation between magnitude of the isozyme shift, exercise capacity, and gas exchange measurements. Am Heart J 135:130137 62. Sullivan MJ, Duscha BD, Klitgaard H, Kraus WE, Cobb FR, Saltin B (1997) Altered expression of myosin heavy chain in human skeletal muscle in chronic heart failure. Med Sci Sports Exerc 29:860866 63. Schaufelberger M, Andersson G, Eriksson BO, Grimby G, Held P, Swedberg K (1996) Skeletal muscle changes in patients with chronic heart failure before and after treatment with enalapril. Eur Heart J 17:16781685 64. Ralston MA, Merola AJ, Leier CV (1991) Depressed aerobic enzyme activity of skeletal muscle in severe chronic heart failure. J Lab Clin Med 117:370372 65. Sullivan MJ, Green HJ, Cobb FR (1991) Altered skeletal muscle metabolic response to exercise in chronic heart failure. Relation to skeletal muscle aerobic enzyme activity. Circulation 84:15971607 66. Pu CT, Johnson MT, Forman DE, Hausdorff JM, Roubenoff R, Foldvari M, Fielding RA, Singh MA (2001) Randomized trial of progressive resistance training to counteract the myopathy of chronic heart failure. J Appl Physiol 90:23412350 67. Saltin B, Rowell LB (1980) Functional adaptations to physical activity and inactivity. Fed Proc 39:15061513 68. Holloszy JO, Coyle EF (1984) Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol 56:831838 69. Adams V, Jiang H, Yu J, Mobius-Winkler S, Fiehn E, Linke A, Weigl C, Schuler G, Hambrecht R (1999) Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance. J Am Coll Cardiol 33:959965 70. Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, Poole-Wilson PA, Coats AJ (1997) Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 96:526534 71. Levine B, Kalman J, Mayer L, Fillit HM, Packer M (1990) Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323:236241 72. Adams V, Nehrhoff B, Spate U, Linke A, Schulze PC, Baur A, Gielen S, Hambrecht R, Schuler G (2002) Induction of iNOS expression in skeletal muscle by IL-1beta and NFkappaB activation: an in vitro and in vivo study. Cardiovasc Res 54: 95104 73. Oral H, Dorn GW 2nd, Mann DL (1997) Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J Biol Chem 272:48364842 74. Adams V, Spate U, Krankel N, Schulze PC, Linke A, Schuler G, Hambrecht R (2003) Nuclear factor-kappa B activation in skeletal muscle of patients with chronic heart failure: correlation with the expression of inducible nitric oxide synthase. Eur J Cardiovasc Prev Rehabil 10:273277 75. Cai D, Frantz JD, Tawa NE Jr, Melendez PA, Oh BC, Lidov HG, Hasselgren PO, Frontera WR, Lee J, Glass DJ, Shoelson SE (2004) IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119:285298 76. Gielen S, Adams V, Linke A, Erbs S, Mobius-Winkler S, Schubert A, Schuler G, Hambrecht R (2005) Exercise training in chronic heart failure: correlation between reduced local inammation and improved oxidative capacity in the skeletal muscle. Eur J Cardiovasc Prev Rehabil 12:393400 77. Ng EH, Rock CS, Lazarus DD, Stiaino-Coico L, Moldawer LL, Lowry SF (1992) Insulin-like growth factor I preserves host lean tissue mass in cancer cachexia. Am J Physiol 262:R426R431
35 78. Douglas RG, Gluckman PD, Breier BH, McCall JL, Parry B, Shaw JH (1991) Effects of recombinant IGF-I on protein and glucose metabolism in rTNF-infused lambs. Am J Physiol 261:E606E612 79. Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, Poole-Wilson PA, Coats AJ (1997) Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 96:526534 80. Levine B, Kalman J, Mayer L, Fillit HM, Packer MP (1990) Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323:236241 81. Niebauer J, Paum CD, Clark AL, Strasburger CJ, Hooper J, Poole-Wilson PA, Coats AJ, Anker SD (1998) Decient insulinlike growth factor I in chronic heart failure predicts altered body composition, anabolic deciency, cytokine and neurohormonal activation. J Am Coll Cardiol 32:393397 82. Hambrecht R, Schulze PC, Gielen S, Linke A, Mobius-Winkler S, Yu J, Kratzsch JJ, Baldauf G, Busse MW, Schubert A, Adams V, Schuler G (2002) Reduction of insulin-like growth factor-I expression in the skeletal muscle of noncachectic patients with chronic heart failure. J Am Coll Cardiol 39:11751181 83. Schulze PC, Gielen S, Adams V, Linke A, Mobius-Winkler S, Erbs S, Kratzsch J, Hambrecht R, Schuler G (2003) Muscular levels of proinammatory cytokines correlate with a reduced expression of insulin-like growth factor-I in chronic heart failure. Basic Res Cardiol 98:267274 84. Vescovo G, Ambrosio GB, Dalla Libera L (2001) Apoptosis and changes in contractile protein pattern in the skeletal muscle in heart failure. Acta Physiol Scand 171:305310 85. Dalla LL, Sabbadini R, Renken C, Ravara B, Sandri M, Betto R, Angelini A, Vescovo G (2001) Apoptosis in the skeletal muscle of rats with heart failure is associated with increased serum levels of TNF-alpha and sphingosine. J Mol Cell Cardiol 33:18711878 86. Gosselin LE, Barkley JE, Spencer MJ, McCormick KM, Farkas GA (2003) Ventilatory dysfunction in mdx mice: impact of tumor necrosis factor-alpha deletion. Muscle Nerve 28:336343 87. Ferrari R, Bachetti T, Agnoletti L, Comini L, Curello S (1998) Endothelial function and dysfunction in heart failure. Eur Heart J 19(Suppl G):G41G47 88. Agnoletti L, Curello S, Bachetti T, Malacarne F, Gaia G, Comini L, Volterrani M, Bonetti P, Parrinello G, Cadei M, Grigolato PG, Ferrari R (1999) Serum from patients with severe heart failure downregulates eNOS and is proapoptotic: role of tumor necrosis factor-alpha. Circulation 100:19831991 89. Powers SK, Criswell D, Lawler J, Martin D, Lieu FK, Ji LL, Herb RA (1993) Rigorous exercise training increases superoxide dismutase activity in ventricular myocardium. Am J Physiol 265:H2094H2098 90. McMurray J, McLay J, Chopra M, Bridges A, Belch JJ (1990) Evidence for enhanced free radical activity in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 65:12611262 91. Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, Wilson JR (1992) Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 85:13641373 92. Minotti JR, Pillay P, Oka R, Wells L, Christoph I, Massie BM (1993) Skeletal muscle size: relationship to muscle function in heart failure. J Appl Physiol 75:373381 93. Massie BM, Simonini A, Sahgal P, Wells L, Dudley GA (1996) Relation of systemic and local muscle exercise capacity to skeletal muscle characteristics in men with congestive heart failure. J Am Coll Cardiol 27:140145 94. Harrington D, Anker SD, Chua TP, Webb-Peploe KM, Ponikowski PP, Poole-Wilson PA, Coats AJ (1997) Skeletal muscle
123
36 function and its relation to exercise tolerance in chronic heart failure. J Am Coll Cardiol 30:17581764 Buller NP, Jones D, Poole-Wilson PA (1991) Direct measurement of skeletal muscle fatigue in patients with chronic heart failure. Br Heart J 65:2024 Lang CC, Chomsky DB, Rayos G, Yeoh TK, Wilson JR (1997) Skeletal muscle mass and exercise performance in stable ambulatory patients with heart failure. J Appl Physiol 82: 257261 Lipkin DP, Jones DA, Round JM, Poole-Wilson PA (1988) Abnormalities of skeletal muscle in patients with chronic heart failure. Int J Cardiol 18:187195 Libera LD, Vescovo G (2004) Muscle wastage in chronic heart failure, between apoptosis, catabolism and altered anabolism: a chimaeric view of inammation? Curr Opin Clin Nutr Metab Care 7:435441 Vescovo G, Volterrani M, Zennaro R, Sandri M, Ceconi C, Lorusso R, Ferrari R, Ambrosio GB, Dalla Libera L (2000) Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes. Heart 84: 431437 Adams V, Yu J, Mobius-Winkler S, Linke A, Weigl C, Hilbrich L, Schuler G, Hambrecht R (1997) Increased inducible nitric oxide synthase in skeletal muscle biopsies from patients with chronic heart failure. Biochem Mol Med 61:152160 Messmer UK, Brune B (1996) Nitric oxide (NO) in apoptotic versus necrotic RAW 264.7 macrophage cell death: the role of NO-donor exposure, NAD+ content, and p53 accumulation. Arch Biochem Biophys 327:110 Schulze PC, Spate U (2005) Insulin-like growth factor-1 and muscle wasting in chronic heart failure. Int J Biochem Cell Biol 37:20232035 Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P (2005) Muscle-specic expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Invest 115:451458 Liu Z, Miers WR, Wei L, Barrett EJ (2000) The ubiquitinproteasome proteolytic pathway in heart vs skeletal muscle: effects of acute diabetes. Biochem Biophys Res Commun 276:12551260 Costelli P, Tullio RD, Baccino FM, Melloni E (2001) Activation of Ca(2+)-dependent proteolysis in skeletal muscle and heart in cancer cachexia. Br J Cancer 84:946950 Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL, Spiegelman BM (2006) PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specic gene transcription. Proc Natl Acad Sci USA 103:1626016265 Jagoe RT, Lecker SH, Gomes M, Goldberg AL (2002) Patterns of gene expression in atrophying skeletal muscles: response to food deprivation. Faseb J 16:16971712 Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL (2001) Atrogin-1, a muscle-specic F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci USA 98:1444014445 Tiao G, Fagan JM, Samuels N, James JH, Hudson K, Lieberman M, Fischer JE, Hasselgren PO (1994) Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle. J Clin Invest 94:22552264 Schulze PC, Fang J, Kassik KA, Gannon J, Cupesi M, MacGillivray C, Lee RT, Rosenthal N (2005) Transgenic overexpression of locally acting insulin-like growth factor-1 inhibits ubiquitin-mediated muscle atrophy in chronic left-ventricular dysfunction. Circ Res 97:418426 Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD,
Heart Fail Rev (2008) 13:2137 Glass DJ (2001) Identication of ubiquitin ligases required for skeletal muscle atrophy. Science 294:17041708 Spate U, Schulze PC (2004) Proinammatory cytokines and skeletal muscle. Curr Opin Clin Nutr Metab Care 7:265269 Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ (2004) The IGF1/PI3K/Akt pathway prevents expression of muscle atrophyinduced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14:395403 Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiafno S, Lecker SH, Goldberg AL (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117: 399412 Dalla Libera L, Ravara B, Volterrani M, Gobbo V, Della Barbera M, Angelini A, Betto DD, Germinario E, Vescovo G (2004) Benecial effects of GH/IGF-1 on skeletal muscle atrophy and function in experimental heart failure. Am J Physiol Cell Physiol 286:C138C144 Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE, Goldberg AL (2004) Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. Faseb J 18:3951 Furuyama T, Nakazawa T, Nakano I, Mori N (2000) Identication of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem J 349:629634 Tyni-Lenne R, Gordon A, Jansson E, Bermann G, Sylven C (1997) Skeletal muscle endurance training improves peripheral oxidative capacity, exercise tolerance, and health-related quality of life in women with chronic congestive heart failure secondary to either ischemic cardiomyopathy or idiopathic dilated cardiomyopathy. Am J Cardiol 80:10251029 Tyni-Lenne R, Gordon A, Europe E, Jansson E, Sylven C (1998) Exercise-based rehabilitation improves skeletal muscle capacity, exercise tolerance, and quality of life in both women and men with chronic heart failure. J Card Fail 4:917 Tyni-Lenne R, Jansson E, Sylven C (1999) Female-related skeletal muscle phenotype in patients with moderate chronic heart failure before and after dynamic exercise training. Cardiovasc Res 42:99103 Duscha BD, Annex BH, Keteyian SJ, Green HJ, Sullivan MJ, Samsa GP, Brawner CA, Schachat FH, Kraus WE (2001) Differences in skeletal muscle between men and women with chronic heart failure. J Appl Physiol 90:280286 Keteyian SJ, Duscha BD, Brawner CA, Green HJ, Marks CR, Schachat FH, Annex BH, Kraus WE (2003) Differential effects of exercise training in men and women with chronic heart failure. Am Heart J 145:912918 Hambrecht R, Fiehn E, Yu J, Niebauer J, Weigl C, Hilbrich L, Adams V, Riede U, Schuler G (1997) Effects of endurance training on mitochondrial ultrastructure and ber type distribution in skeletal muscle of patients with stable chronic heart failure. J Am Coll Cardiol 29:10671073 Belardinelli R, Georgiou D, Scocco V, Barstow TJ, Purcaro A (1995) Low intensity exercise training in patients with chronic heart failure. J Am Coll Cardiol 26:975982 Magnusson G, Gordon A, Kaijser L, Sylven C, Isberg B, Karpakka J, Saltin B (1996) High intensity knee extensor training, in patients with chronic heart failure. Major skeletal muscle improvement. Eur Heart J 17:10481055 Gielen S, Adams V, Mobius-Winkler S, Linke A, Erbs S, Yu J, Kempf W, Schubert A, Schuler G, Hambrecht R (2003) Antiinammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure. J Am Coll Cardiol 42: 861868
95.
112. 113.
96.
97.
114.
98.
115.
99.
116.
100.
117.
101.
118.
102.
103.
119.
104.
120.
105.
121.
106.
122.
107.
123.
108.
109.
124.
125.
110.
126.
111.
123
Heart Fail Rev (2008) 13:2137 127. Gordon A, Tyni-Lenne R, Jansson E, Kaijser L, TheodorssonNorheim E, Sylven C (1997) Improved ventilation and decreased sympathetic stress in chronic heart failure patients following local endurance training with leg muscles. J Card Fail 3:312 128. Hambrecht R, Fiehn E, Weigl C, Gielen S, Hamann C, Kaiser R, Yu J, Adams V, Niebauer J, Schuler G (1998) Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 98:27092715 129. Adamopoulos S, Parissis J, Karatzas D, Kroupis C, Georgiadis M, Karavolias G, Paraskevaidis J, Koniavitou K, Coats AJ, Kremastinos DT (2002) Physical training modulates proinammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure. J Am Coll Cardiol 39: 653663 130. Varin R, Mulder P, Richard V, Tamion F, Devaux C, Henry JP, Lallemand F, Lerebours G, Thuillez C (1999) Exercise improves ow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant stress. Circulation 99:29512957 131. Green DJ, Maiorana A, ODriscoll G, Taylor R (2004) Effect of exercise training on endothelium-derived nitric oxide function in humans. J Physiol 561:125 132. McKoy G, Ashley W, Mander J, Yang SY, Williams N, Russell B, Goldspink G (1999) Expression of insulin growth factor-1 splice variants and structural genes in rabbit skeletal muscle induced by stretch and stimulation. J Physiol 516.2:583592 133. Eliakim A, Moromisato M, Moromisato D, Brasel JA, Roberts C, Cooper DM (1997) Increase in muscle IGF-I protein but not IGF-I mRNA after 5 days of endurance training in young rats. Am J Physiol 273:R1557R1561 134. Schulze PC, Linke A, Gielen S, Moebius-Winkler S, Schoene N, Erbs S, Adams V, Hambrecht R (2001) Effects of exercise training on the local expression of insulin-like growth factor-I in the skeletal muscle of patients with chronic heart failure. Eur Heart J 22:503 135. Schulze PC, Gielen S, Schuler G, Hambrecht R (2002) Chronic heart failure and skeletal muscle catabolism: effects of exercise training. Int J Cardiol 85:141149 136. Hellsten Y, Hansson HA, Johnson L, Frandsen U, Sjodin B (1996) Increased expression of xanthine oxidase and insulin-like growth factor I (IGF-I) immunoreactivity in skeletal muscle after strenuous exercise in humans. Acta Physiol Scand 157: 191197 137. Singh MA, Ding W, Manfredi TJ, Solares GS, ONeill EF, Clements KM, Ryan ND, Kehayias JJ, Fielding RA, Evans WJ (1999) Insulin-like growth factor I in skeletal muscle after weight-lifting exercise in frail elders. Am J Physiol 277: E135E143 138. Baldwin KM, Haddad F (2001) Effects of different activity and inactivity paradigms on myosin heavy chain gene expression in striated muscle. J Appl Physiol 90:345357 139. Forman D, Hunt B, Santoro C, Bairos L, Levesque S, Roubenoff R, Cosmas A, Manfredi T (2000) Progressive resistance training safely improves aerobic metabolism clinical function, and underlying mitochodrial morphometry in elderly heart failure patients. Circulation 102:II:678 (3280) 140. Grosse T, Kreulich K, Naegele H (2001) Peripheral muscular strength training in patients with severe heart failure. Dtsch Z Sportmed 52:1114 141. Williams AD, Carey MF, Selig S, Hayes A, Krum H, Patterson J, Toia D, Hare DL (2007) Circuit resistance training in chronic heart failure improves skeletal muscle mitochondrial ATP production ratea randomized controlled trial. J Card Fail 13: 7985
37 142. Hickson RC, Rosenkoetter MA, Brown MM (1980) Strength training effects on aerobic power and short-term endurance. Med Sci Sports Exerc 12:336339 143. Hare DL, Ryan TM, Selig SE, Pellizzer AM, Wrigley TV, Krum H (1999) Resistance exercise training increases muscle strength, endurance, and blood ow in patients with chronic heart failure. Am J Cardiol 83:16741677, A7 144. Maiorana A, ODriscoll G, Cheetham C, Collis J, Goodman C, Rankin S, Taylor R, Green D (2000) Combined aerobic and resistance exercise training improves functional capacity and strength in CHF. J Appl Physiol 88:15651570 145. Delagardelle C, Feiereisen P, Krecke R, Essamri B, Beissel J (1999) Objective effects of a 6 months endurance and strength training program in outpatients with congestive heart failure. Med Sci Sports Exerc 31:11021107 146. Selig SE, Carey MF, Menzies DG, Patterson J, Geerling RH, Williams AD, Bamroongsuk V, Toia D, Krum H, Hare DL (2004) Moderate-intensity resistance exercise training in patients with chronic heart failure improves strength, endurance, heart rate variability, and forearm blood ow. J Card Fail 10: 2130 147. Delagardelle C, Feiereisen P, Autier P, Shita R, Krecke R, Beissel J (2002) Strength/endurance training versus endurance training in congestive heart failure. Med Sci Sports Exerc 34:18681872 148. Santoro C, Cosmas A, Forman D, Morghan A, Bairos L, Levesque S, Roubenoff R, Hennessey J, Lamont L, Manfredi T (2002) Exercise training alters skeletal muscle mitochondrial morphometry in heart failure patients. J Cardiovasc Risk 9: 377381 149. Walker KS, Kambadur R, Sharma M, Smith HK (2004) Resistance training alters plasma myostatin but not IGF-1 in healthy men. Med Sci Sports Exerc 36:787793 150. Adamo ML, Farrar RP (2006) Resistance training, and IGF involvement in the maintenance of muscle mass during the aging process. Ageing Res Rev 5:310331 151. Pollock ML, Franklin BA, Balady GJ, Chaitman BL, Fleg JL, Fletcher B, Limacher M, Pina IL, Stein RA, Williams M, Bazzarre T (2000) AHA Science Advisory. Resistance exercise in individuals with and without cardiovascular disease: benets, rationale, safety, and prescription: an advisory from the Committee on Exercise, Rehabilitation, and Prevention, Council on Clinical Cardiology, American Heart Association; Position paper endorsed by the American College of Sports Medicine. Circulation 101:828833 152. Harjola VP, Kiilavuori K, Virkamaki A (2006) The effect of moderate exercise training on skeletal muscle myosin heavy chain distribution in chronic heart failure. Int J Cardiol 109: 335338 153. Hambrecht R, Schulze PC, Gielen S, Linke A, Mobius-Winkler S, Erbs S, Kratzsch J, Schubert A, Adams V, Schuler G (2005) Effects of exercise training on insulin-like growth factor-I expression in the skeletal muscle of non-cachectic patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil 12: 401406 154. Kiilavuori K, Naveri H, Salmi T, Harkonen M (2000) The effect of physical training on skeletal muscle in patients with chronic heart failure. Eur J Heart Fail 2:5363 155. Scarpelli M, Belardinelli R, Tulli D, Provinciali L (1999) Quantitative analysis of changes occurring in muscle vastus lateralis in patients with heart failure after low-intensity training. Anal Quant Cytol Histol 21:374380 156. Gordon A, Tyni-Lenne R, Persson H, Kaijser L, Hultman E, Sylven C (1996) Markedly improved skeletal muscle function with local muscle training in patients with chronic heart failure. Clin Cardiol 19:568574
123

Implications of Chronic Heart Failure On Peripheral Vasculature and Skeletal Muscle Before and After Exercise Training

Hochgeladen von

Dokumentinformationen

Originalbeschreibung:

Originaltitel

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Implications of Chronic Heart Failure On Peripheral Vasculature and Skeletal Muscle Before and After Exercise Training

Hochgeladen von

Copyright:

Verfügbare Formate

Heart Fail Rev (2008) 13:2137 DOI 10.

Published online: 23 October 2007 Springer Science+Business Media, LLC 2007

Heart Fail Rev (2008) 13:2137

Heart Fail Rev (2008) 13:2137

Heart Fail Rev (2008) 13:2137

Subject number (Ex/Cntl) Duration

Harjola et al. [152]

Gielen et al. [76]

Hambrecht et al. [153]

Gielen et al. [126]

Keteyian et al. [122]

Larsen et al. [60]

Gustafsson et al. [48]

Kiilavuori et al. [154]

Tyni-Lenne et al. [120] 16

Scarpelli et al. [155]

Hambrecht et al. [123]

Tyni-Lenne et al. [118] 16

Heart Fail Rev (2008) 13:2137

Gordon et al. [127]

Heart Fail Rev (2008) 13:2137

Intrinsic skeletal muscle ndings

6575% 45 min/ 3 days a week

70% 4060 min/day

One legged dynamic knee extension

Subject number (Ex/Cntl) Duration

14/7 (2 train groups)

Belardinelli et al. [124] 18/9

40% 30 min/3 days a week

Magnusson et al. [125]

Gordon et al. [156]

Hambrecht et al. [25]

Heart Fail Rev (2008) 13:2137

Heart Fail Rev (2008) 13:2137

Heart Fail Rev (2008) 13:2137

Heart Fail Rev (2008) 13:2137

Heart Fail Rev (2008) 13:2137

Heart Fail Rev (2008) 13:2137

Das könnte Ihnen auch gefallen