Peripheral vascular remodeling in chronic heart failure: clinical relevance and new conceptualization of its mechanisms.

Increased peripheral vascular tone is a critical factor in the deterioration of clinical stage and symptoms in chronic congestive heart failure (CHF) because of increased cardiac afterload and decreased nutritive skeletal muscle blood flow. Endothelial function as represented by nitric oxide (NO) production shows significant attenuation with the progression of clinical severity of CHF as determined by New York Heart Association class and exercise capacity parameters. This endothelial dysfunction emerges in the early stages of CHF. In the advanced stage of the condition, both endothelium-dependent and endothelium-independent dilator mechanisms are impaired in limb resistance vessels. This occurs because vascular endothelial function, especially NO production, is an important factor in the regulation of vasodilatory function, as well as making an important contribution to vascular structure. Furthermore, although such vasodilatory circulating factors as natriuretic polypeptides and newly discovered adrenomedullin are increased in heart failure, the vasodilatory potency of these polypeptide hormones in the limb vascular bed is significantly blunted. These observations suggest that peripheral circulatory failure in CHF is caused not only by simple arterial muscle constriction, but also by structural and functional changes, including receptor and postreceptor levels in the vasculature. This vascular remodeling may be an important mechanism underlying vasodilatory failure in both limb conduit and intraskeletal muscle vessels and may contribute significantly to left ventricular dysfunction and exercise intolerance in patients with heart failure.     

Effects of phosphodiesterase inhibition on skeletal muscle vasculature

The pathophysiology of the syndrome of congestive heart failure (CHF) includes 2 major components that closely interact. The first one is a reduction in ventricular performance, which is manifested initially during exercise and is later present at rest. The second one involves abnormalities of the peripheral circulation and organs, which become gradually more prominent and lead ultimately to symptoms. The exercise capacity of patients with chronic CHF is limited not only by an inadequate increase in cardiac output and an excessive increase in ventricular filling pressure, but also by a fixed vasodilatory response to exercise. Although the role of increased activity of the sympathetic and renin-angiotensin-aldosterone systems in the derangements of the peripheral circulation has been extensively investigated, the structural abnormalities of the arterial wall have received little emphasis in patients with CHF. Chronic reduction of the cardiac output may lead to endothelium-dependent reduction in arterial diameter and vasomotor response, which may in turn increase systemic vascular resistance and further reduce cardiac output. Therapeutic agents should be characterized by their acute and chronic effects not only on ventricular performance, but also on the peripheral circulation. More specifically, when one is concerned with the effect of a therapeutic intervention on exercise capacity, evaluation of its direct and indirect effects on the skeletal muscle vasculature is particularly important. Accordingly, the effects of phosphodiesterase inhibition on vascular smooth muscle tone and skeletal muscle vasculature are reviewed. In addition, the potential of phosphodiesterase inhibition to reverse structural abnormalities of the arterial wall is discussed.     

Belastung und Belastbarkeit bei chronischer Herzinsuffizienz

BACKGROUND: Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF. During the last years several different peripheral factors as determinants of exercise intolerance have been defined, i.e. abnormalities in ventilation, reduced endothelium-dependent vasodilatation of peripheral conduit and resistance vessels, and altered skeletal muscle metabolism. Skeletal muscle alterations are characterized by a reduced oxidative capacity, a catabolic state with reduced local IGF-I expression and muscle atrophy, chronic inflammation with local expression of the inducible isoform of nitric oxide synthase (iNOS) and an accelerated rate of programmed cell death (apoptosis). EFFECTS OF PHYSICAL EXERCISE: Physical exercise training has evolved as an important therapeutic approach to influence these non-cardiac causes of exercise intolerance. After the first studies documenting the effect of aerobic training on the peripheral causes of exercise intolerance in CHF the question was asked: Should we treat the heart or the periphery to improve exercise intolerance in CHF? Today, we have come closer to the answer: It is now clear that these two systems are not mutually exclusive. Exercise training in CHF has been shown to improve skeletal muscle metabolism and function, to avert muscle catabolism, to reduce neurohumoral overactivation, to reverse endothelial dysfunction and to contribute to the prevention of pathologic left ventricular remodeling. After 6 months of regular exercise training oxidative capacity of the working skeletal muscle increases by approximately 40%. Regular exercise training leads to a significant improvement of endothelium-dependent vasodilatory capacity of peripheral resistance vessels, thereby reducting peripheral resistance in particular during exercise. These beneficial training effects result in a small, but significant improvement of stroke volume and reduction in cardiomegaly. CONCLUSION: Although several questions regarding patient selection, optimal training protocol and training intensity remain unanswered, exercise training can been seen as an established adjunct to pharmacotherapy in CHF. We may soon reach the conclusion that by treating the periphery with exercise programs we are in fact treating the heart, as well. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 ml/kg.min. For patients in stable CHF on optimal cardiac medication a combination of in-hospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potentials as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.     

Serial measurements of peripheral vascular reactivity and exercise capacity in congestive heart failure and after heart transplantation

BACKGROUND: The regulation of nutritive blood flow to skeletal muscles during exercise seems to make an important contribution to exercise capacity. In congestive heart failure (CHF) this regulation seems to be impaired, with attenuated peripheral vasodilatory capacity. The results regarding improvement of peripheral vasoreactivity after heart transplantation (HTx) are conflicting, and the contribution of impaired peripheral vasoreactivity to the observed reduced exercise capacity among heart transplant recipients (HTR) has not been well elucidated. We therefore assessed the reversibility of impaired vasoreactivity in forearm and calf after HTx with relationship to exercise capacity. METHODS AND RESULTS: The vasoreactivity of both forearm and calf was studied with venous occlusion plethysmography and related to exercise capacity in 64 patients with CHF and in 22 controls. Of these patients, 29 patients underwent HTx, and the same measurements were performed 10 days, 6 months and 1 year after HTx, and in a group of 15 HTR who had undergone HTx several years ago. Our main findings were (1) impaired resting blood flow in patients with CHF improved after HTx and even surpassed levels of controls; (2) peak forearm blood flow remained attenuated early after HTx, but normalized during the first year postoperatively; (3) both forearm and calf minimal resistance remained elevated after HTx; (4) vascular reactivity displays regional variations in forearm and calf both during CHF and after HTx; and (5) peripheral vascular reactivity relate to exercise performance in both patients with CHF and HTR, but the relationship seemed more pronounced in CHF. CONCLUSION: With impaired vasoreactivity related to limited exercise capacity in CHF, improvement is evident after HTx, but both forearm and calf minimal resistance remains elevated. These findings suggest increased vasoconstrictor drive to both exercising and non-exercising muscles, possibly contributing to persistent physical limitation after HTx.     

Aging and heart failure--similar syndromes of exercise intolerance? Implications for exercise-based interventions

A classic hallmark of chronic heart failure (CHF) is exercise intolerance; however, the extent of exercise limitation is not correlated with the degree of left ventricular dysfunction. Over the past 2 decades it has become more and more evident that peripheral factors, such as skeletal muscle dysfunction, ventilatory abnormalities, and endothelial dysfunction, contribute the greater part to the limitation of exercise capacity. The molecular and pathophysiological changes observed in these organ systems are not always specific to the underlying CHF but rather represent a common pathway that is activated in several chronic disease processes, including severe chronic obstructive pulmonary disease, cancer, and in the normal aging process. A major contributing factor for skeletal muscle catabolism (i.e. elevated cytokine expression in the skeletal muscle) can be found in both normal healthy aging and in heart failure patients. It is reasonable to assume that the overlap of aging and CHF-associated changes in the skeletal muscle partially explains the disabling consequences of the CHF syndrome among elderly patients (nearly 80% of all patients hospitalized for CHF are >65 years old). Peripheral alterations in CHF are often not adequately treated in routine clinical care since standard pharmacological therapy is still focused on the cardiac function and neurohormonal alteration. Exercise training is a guideline-oriented adjuvant therapy with well-documented beneficial effects on exercise tolerance, skeletal muscle function, endothelial function, and respiration. In this review, the effects of exercise in aging and in CHF are compared and the parallel mechanisms are explored.     

Unraveling new mechanisms of exercise intolerance in chronic heart failure. Role of exercise training

Despite remarkable progress in the therapeutic approach of patients with chronic heart failure (CHF), exercise intolerance remains one of the hallmarks of the disease. During the past two decades, evidence has accumulated to underscore the key role of both endothelial dysfunction and skeletal muscle wasting in the process that gradually leads to physical incapacity. Whereas reverse ventricular remodeling has been attributed to aerobic exercise training, the vast majority of studies conducted in this specific patient population emphasize the reversal of peripheral abnormalities. In this review, we provide a general overview on underlying pathophysiological mechanisms. In addition, emphasis is put on recently identified pathways, which contribute to a deeper understanding of the main causes of exercise tolerance and the potential for reversal through exercise training. Recently, deficient bone marrow-related endothelial repair mechanisms have received considerable attention. Both acute exercise bouts, as well as exercise training, affect the mobilization of endothelial progenitor cells and their function. The observed changes following exercise training are believed to significantly contribute to improvement of peripheral endothelial function, as well as exercise capacity. With regard to skeletal muscle dysfunction and energy deprivation, adiponectin has been suggested to play a significant role. The demonstration of local skeletal muscle adiponectin resistance may provide an interesting and new link between the insulin resistant state and skeletal muscle wasting in CHF patients.     

Physical training as an adjunct therapy in patients with congestive heart failure: Patient selection, training protocols, results, and future directions

Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF: reduced endothelium-dependent vasodilation and altered skeletal muscle metabolism. Physical exercise training has evolved as an important therapeutic approach to influence these noncardiac causes of exercise intolerance. It has been shown to enhance the oxidative capacity of the working skeletal muscle, to attenuate ergoreflex activity, to correct endothelial dysfunction, and to improve ventilation. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 mL/kg.min^-1. Uncertainty remains concerning optimal patient selection, training protocol, and long-term effects on cardiac function. For patients experiencing stable CHF while on optimal cardiac medication, a combination of inhospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potential as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.     

Direct and indirect assessment of skeletal muscle blood flow in chronic congestive heart failure

In patients with chronic congestive heart failure (CHF), skeletal muscle blood flow can be measured directly by the continuous thermodilution technique and by the xenon133 clearance method. The continuous thermodilution technique requires retrograde catheterization of the femoral vein and, thus, cannot be repeated conveniently in patients during evaluation of pharmacologic interventions. The xenon133 clearance, which requires only an intramuscular injection, allows repeated determination of skeletal muscle blood flow. In patients with severe CHF, a fixed capacity of the skeletal muscle vasculature to dilate appears to limit maximal exercise performance. Moreover, the changes in peak skeletal muscle blood flow noted during long-term administration of captopril, an angiotensin-converting enzyme inhibitor, appears to correlate with the changes in aerobic capacity. In patients with CHF, resting supine deep femoral vein oxygen content can be used as an indirect measurement of resting skeletal muscle blood flow. The absence of a steady state complicates the determination of peak skeletal muscle blood flow reached during graded bicycle or treadmill exercise in patients with chronic CHF. Indirect assessments of skeletal muscle blood flow and metabolism during exercise performed at submaximal work loads are currently developed in patients with chronic CHF.     

Skeletal muscle abnormalities in chronic heart failure patients: relation to exercise capacity and therapeutic implications

Recent studies suggest that changes in the periphery, like those occurring in the skeletal muscles of patients with chronic heart failure, might play an important role in the origin of symptoms and exercise intolerance in this condition. Biochemical and histologic changes in the skeletal muscles of chronic heart failure patients relate with the degree of exercise intolerance better than hemodynamics parameters. A reduction in skeletal muscle mass represents another important determinant of exercise intolerance in chronic heart failure patients. The relationship between skeletal muscle changes and exercise intolerance suggests the possibility of modifying the peripheral changes in order to improve functional capacity in chronic heart failure patients. Recent studies have shown that the administration of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can improve the properties of the skeletal muscles. Similarly, exercise training allows improvement in peak oxygen consumption, which parallels important biochemical and histologic changes in the skeletal muscles.     

Physical exercise in older patients with chronic heart failure

Maximal exercise capacity undergoes a steady decline after the age of 30 by approximately 10 % per decade. As a consequence of this development older people > 65 years of age suffer from the exercise limitation caused by age-associated cardiac, vascular and skeletal muscle changes. These physiologic alterations make older people especially vulnerable for the cardiovascular and peripheral alterations associated with chronic heart failure (CHF). These changes are not phenomenologically different from age-associated changes. Physical activity plays an important role for regaining a considerable part of vasomotor function, skeletal muscle contractility, and cardiac reserve. Up to now there are no prospective trials comparing the effects of physical training between older and younger patients with CHF. However, smaller observational studies indicate that elderly patients benefit equally well from training interventions with regard to functional improvements in proportion to their lower baseline values. In an aging population training aims at maintaining skeletal muscle force and muscle mass as well as locomotor coordination. Ultimately, the goal is to reduce the substantial morbidity among elderly CHF patients which constitute 79 % of all hospital admissions for heart failure.     

Skeletal Muscle Abnormalities in Chronic Heart Failure

Skeletal muscle abnormalities are well-established in patients with heart failure from an early stage in the progression of the disease and contribute to their symptoms and the limitation of physical activity. Heart failure–induced skeletal muscle pathology includes morphologic, histologic, and enzymatic changes along with derangements in skeletal muscle metabolism and autonomic function. These alterations influence both peripheral and ventilatory muscles, are present at rest, and deteriorate during exercise and their occurrence depends upon the severity and the duration of CHF syndrome. Future studies will be needed to elucidate the origin of skeletal “myopathy” and its reversibility, which is associated with improvement in exercise capacity, observed after physical training programs.     

Effects of congestive heart failure on Ca2+ handling in skeletal muscle during fatigue

Skeletal muscle weakness and decreased exercise capacity are major symptoms reported by patients with congestive heart failure (CHF). Intriguingly, these skeletal muscle symptoms do not correlate with the decreased heart function. This suggests that CHF leads to maladaptive changes in skeletal muscles, and as reported most markedly in slow-twitch muscles. We used rats at 6 weeks after infarction to measure expression of key proteins involved in SR Ca(2+) release and uptake in slow-twitch soleus muscles. We also measured force and myoplasmic free [Ca(2+)] ([Ca(2+)](i)) in intact single fibers of soleus muscles. CHF rats showed clear signs of severe cardiac dysfunction with marked increases in heart weight and left ventricular end-diastolic pressure compared with sham operated rats (Sham). There were small, but significant, changes in the content of proteins involved in cellular Ca(2+) handling in CHF muscles: slight increases in SR Ca(2+) release channels (ie, the ryanodine receptors) and in SR Ca(2+)-ATPase. Tetanic force and [Ca(2+)](i) were not significantly different between CHF and Sham soleus fibers under resting conditions. However, during the stimulation period there was a decrease in tetanic force without changes in [Ca(2+)](i) in CHF fibers that was not observed in Sham fibers. The fatigue-induced changes recovered rapidly. We conclude that CHF soleus fibers fatigue more rapidly than Sham fibers because of a reversible fatigue-induced decrease in myofibrillar function.     

Reduced vascular compliance is associated with impaired endothelium-dependent dilatation in the brachial artery of patients with congestive heart failure

BACKGROUND: Alterations in elastic properties and vascular structure of conduit vessels are important detrimental factors contributing to increased cardiac load and reduced tissue perfusion in patients with congestive heart failure (CHF). It has been demonstrated that endothelial function in the peripheral vasculature is impaired in this disorder, which may induce abnormal vascular elastic properties and remodeling. However, it remains unknown whether changes in vascular structure or mechanical properties are related to endothelial dysfunction in conduit arteries of patients with CHF. METHODS AND RESULTS: Twenty-five CHF patients with nonischemic heart disease and 20 sex/age-matched controls were enrolled. Brachial artery diameter, intima-media thickness (IMT), and vascular stiffness as represented by distensibility and compliance were determined using a high-frequency linear transducer attached to a high-quality ultrasound system. In addition, flow-mediated dilatation (FMD) after 5-minute forearm occlusion and sublingual nitroglycerin-induced dilatation (NTG) were measured in the brachial artery. Brachial arterial diameter was similar between CHF and controls; however, IMT and wall/lumen ratio were significantly greater in CHF patients than in controls (IMT, 0.37+/-0.01 versus 0.31+/-0.01 mm; wall/lumen, 18.7+/-0.8 versus 15.1+/-0.8%: both P<.01). In addition, vascular stiffness parameters were lower in CHF than in controls (distensibility; 1.09+/-0.14 versus 1.60+/-0.15%/kPa, P<.01: compliance; 0.17+/-0.02 versus 0.26+/-0.02 mm(2) kPa, P<.05). FMD and TNG were significantly reduced in CHF (both P<.001). Although stiffness parameters in CHF were not significantly correlated with vascular structure (ie, IMT, wall/lumen) or clinical parameters (ie, age, lipids, glucose, blood pressure), elastic parameters were significantly correlated with FMD (distensibility; r=0.579, P<.005: compliance; r=0.433, P<.05), but not with NTG. CONCLUSION: The present study found that, in limb muscle conduit artery in patients with CHF, there are hypertrophic remodeling and endothelial dysfunction-associated alterations in vascular wall elastic properties.     

Vasoconstrictive response in the vascular beds of the non-exercising forearm during leg exercise in patients with mild chronic heart failure.

BACKGROUND: Reduced exercise capacity may be related to decreased redistribution of blood flow from the non-exercising tissues to the exercising skeletal muscle in patients with mild chronic heart failure (CHF). METHODS AND RESULTS: In the present study 14 patients with mild CHF and 10 healthy subjects (N) underwent symptom-limited multistage-ergometer exercise, during which forearm vascular resistance (FVR), cardiac index (CI), systemic vascular resistance index (SVRI), and oxygen uptake (VO(2)) were measured non-invasively using the plethysmograph, impedance, and respiratory gas analysis methods, respectively. The VO(2) and CI at peak exercise were lower (p<0.01 each), and SVRI and FVR at both rest and peak exercise were higher in the CHF group than in N. However, both the percent increase in FVR and percent decrease in SVRI from the resting state to peak exercise were lower in CHF than N, and both of them correlated with not only peak VO(2), but also the corresponding resting value of FVR and SVRI (p<0.01 each). CONCLUSIONS: Redistribution of blood flow from the non-exercising tissues to the working skeletal muscles, which may participate in exercise capacity, can be blunted in CHF. The decreased vasoconstrictive response in the non-exercising tissues is intimately related to the increased resting vascular tone in CHF.     

Aging-induced adaptations of microvascular reactivity

Control of blood flow to skeletal muscle depends on the vasomotor tone present in the resistance vasculature. Although muscle blood flow has been shown to decline with advancing age, our knowledge of how alterations of reactivity of the resistance vasculature contribute to reduced delivery or altered distribution of blood in the aged is limited. Recent work has demonstrated that age alters the reactivity of resistance arteries and arterioles from skeletal muscle, and that impairment of both vasodilator and vasoconstrictor responses occurs with advancing age. The alterations in cellular mechanisms that contribute to age-related impairment of vasoreactive responses encompass both the vascular endothelium and smooth muscle, and differ in muscles of varying function and fiber type. Current research suggests that some degree of age-induced endothelial dysfunction occurs in resistance arteries and arterioles from most skeletal muscle; however, the severity of endothelial impairment appears greater in resistance arteries and arterioles from highly oxidative locomotory muscles. Age-related impairment of vasoconstrictor responses to metabolites and endogenous constrictor agents has also been documented. These age-related reductions in vasoreactivity that occur in the skeletal muscle resistance vasculature may contribute to inadequate delivery or distribution of blood flow during exercise and ultimately be a factor in loss of exercise capacity that occurs with advancing age.     

Effects of nitric oxide inhibition on basal forearm blood flow in patients with nonischemic chronic heart failure

Summary Increased peripheral vascular tone in patients with chronic heart failure (CHF) is an important factor which contributes to increased cardiac afterload and reduced exercise capacity, and consequent further deterioration in CHF. The role of endogenous nitric oxide (NO) in the regulation of basal vascular tone in CHF is controversial. This study has investigated (1) whether basal NO bioavailability is reduced in the peripheral vasculature of patients with nonischemic CHF in the absence of confounding factors influencing endothelial function, and (2) if a difference is found, what clinical characteristics are related to the decreased NO-dependent vasodilation. Basal forearm blood flow (FBF) of 12 patients with CHF and 14 healthy volunteers was measured before and after administration ofN ^G-monomethyl-l-arginine (l-NMMA) by venous occlusion plethysmography. Afterl-NMMA administration, basal FBF in both healthy subjects and patients with CHF decreased significantly, with the decrease in CHF patients being less than that in healthy volunteers (–0.7 ± 0.2 vs –1.5 ± 0.2ml/min per 100ml tissue,P < 0.01). When both groups were considered together, basal FBF was closely related to the decrease in FBF afterl-NMMA administration (r = –0.83.P < 0.001). When CHF patients were divided into two groups according to NYHA class, thel-NMMA-induced decrease in FBF in moderate CHF (NYHA III;n = 7) was significantly less than that in mild CHF (NYHA II;n = 5) (–0.36 ± 0.13 vs –1.16 ± 0.72ml/min per 100ml tissue,P < 0.05). In conclusion, basal bioavailability of NO in the peripheral vascular bed in nonischemic CHF is impaired, with an increase in basal vascular tone and with progression of this disorder. This suggests that impaired basal NO bioactivity may make an important contribution to the elevated peripheral vascular tone and expression of symptoms seen in CHF.     

New aspects for the role of physical training in the management of patients with chronic heart failure

Recent experimental and clinical data have shown that physical training is an important therapeutic intervention in the management of patients with chronic heart failure (CHF), improving central hemodynamics and attenuating peripheral abnormalities (endothelial dysfunction and skeletal myopathy) characterizing the progression of the syndrome. Additionally, physical training seems to beneficially modulate peripheral immune responses of CHF expressed by elevated circulating proinflammatory cytokines, soluble cellular adhesion molecules and soluble apoptosis signaling molecules, resulting in improvement in exercise capacity of CHF patients. This article summarizes current knowledge about the beneficial role of physical training in CHF, as well as about traditional and novel mechanisms contributing to the physical training-induced improvement in clinical performance of CHF patients.     

Cardiac and skeletal muscle energy metabolism in heart failure: beneficial effects of voluntary activity

OBJECTIVE: Mitochondrial function and metabolic profile of slow and fast skeletal muscles and cardiac muscle are altered in chronic heart failure (CHF), suggesting a generalized metabolic myopathy in this disease. The aim of this study was to investigate the potential beneficial effects of voluntary activity on cardiac and skeletal muscle energetics in heart failure. METHODS: Heart failure was induced in rats by aortic stenosis. Four months after surgery, part of sham and CHF animals were randomly assigned to activity cages equipped with running wheels for 8 weeks or kept sedentary. Mitochondrial capacity and regulation were measured using saponin skinned fibers in left ventricle, slow and fast skeletal muscles, and metabolic and myosin profiles were established. RESULTS: Despite four times lower performances of CHF rats, alterations in metabolic and myosin parameters (oxidative capacity, mitochondrial enzymes, cytosolic and mitochondrial creatine kinase, myosin heavy chains) observed in all muscles of CHF animals were almost fully restored in soleus muscle though unchanged in heart and fast skeletal muscles. CONCLUSIONS: These results show the powerful beneficial effect of physical activity specifically on active slow oxidative skeletal muscle in CHF, without the worsening of cardiac muscle metabolism.