Making the Case for Skeletal Myopathy as the Major Limitation of Exercise Capacity in Heart Failure

Middlekauff, Holly R.

doi:10.1161/circheartfailure.109.903773

Cited by 148 publications

(134 citation statements)

References 82 publications

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“…Although not addressed by our study, potential causes for the skeletal muscle abnormalities we observed include neuroendocrine activation, sympathetic overdrive, oxidative stress, inflammation, abnormal Ca 2ϩ cycling and excitation-contraction coupling, and deconditioning (49). Chronic elevations in sympathetic neural activity and decreased nitric oxide bioavailability result in increased vasoconstriction and reduced skeletal muscle blood flow.…”

Section: Discussionmentioning

confidence: 79%

“…However, our results are believable given what is known from many reports regarding skeletal muscle fiber composition and capillarity in patients with HFREF and other populations. Specifically, several investigators have reported that HFREF patients have decreased type I fibers compared with HC subjects (12,39,42,45,64,66,67) and that this is related to peak V O 2 (49). Moreover, several investigators Values are means Ϯ SD or numbers of patients/subjects per group (n) with percentages.…”

Section: Discussionmentioning

confidence: 99%

“…It is known that aging results in alterations in skeletal muscle, including a reduction in the relative number of type II fibers (40) and in capillary density (9), and that these are associated with a decline in physical performance (51). Furthermore, it is well established that patients with HF with reduced ejection fraction (HFREF) have multiple skeletal muscle abnormalities (12,39,42,43,45,58,64,66,72), including a reduced percentage of type I (oxidative) fibers and a decreased number of capillaries per fiber, and that these contribute significantly to their severe exercise intolerance (49,64,65). However, despite the high prevalence of HFPEF and the impact of exercise intolerance as its key chronic symptom, there is no information available regarding skeletal muscle phenotype and its relationship to peak V O 2 in HFPEF.…”

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confidence: 99%

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Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction

Kitzman

Nicklas

Kraus

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

272

229

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Kitzman DW, Nicklas B, Kraus WE, Lyles MF, Eggebeen J, Morgan TM, Haykowsky M. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol 306: H1364-H1370, 2014. First published March 21, 2014 doi:10.1152/ajpheart.00004.2014.-Heart failure (HF) with preserved ejection fraction (HFPEF) is the most common form of HF in older persons. The primary chronic symptom in HFPEF is severe exercise intolerance, and its pathophysiology is poorly understood. To determine whether skeletal muscle abnormalities contribute to their severely reduced peak exercise O2 consumption (V O2), we examined 22 older HFPEF patients (70 Ϯ 7 yr) compared with 43 age-matched healthy control (HC) subjects using needle biopsy of the vastus lateralis muscle and cardiopulmonary exercise testing to assess muscle fiber type distribution and capillarity and peak V O2. In HFPEF versus HC patients, peak V O2 (14.7 Ϯ 2.1 vs. 22.9 Ϯ 6.6 ml·kg Ϫ1 · min Ϫ1 , P Ͻ 0.001) and 6-min walk distance (454 Ϯ 72 vs. 573 Ϯ 71 m, P Ͻ 0.001) were reduced. In HFPEF versus HC patients, the percentage of type I fibers (39.0 Ϯ 11.4% vs. 53.7 Ϯ 12.4%, P Ͻ 0.001), type I-to-type II fiber ratio (0.72 Ϯ 0.39 vs. 1.36 Ϯ 0.85, P ϭ 0.001), and capillary-to-fiber ratio (1.35 Ϯ 0.32 vs. 2.53 Ϯ 1.37, P ϭ 0.006) were reduced, whereas the percentage of type II fibers was greater (61 Ϯ 11.4% vs. 46.3 Ϯ 12.4%, P Ͻ 0.001). In univariate analyses, the percentage of type I fibers (r ϭ 0.39, P ϭ 0.003), type I-to-type II fiber ratio (r ϭ 0.33, P ϭ 0.02), and capillary-to-fiber ratio (r ϭ 0.59, P Ͻ 0.0001) were positively related to peak V O2. In multivariate analyses, type I fibers and the capillary-to-fiber ratio remained significantly related to peak V O2. We conclude that older HFPEF patients have significant abnormalities in skeletal muscle, characterized by a shift in muscle fiber type distribution with reduced type I oxidative muscle fibers and a reduced capillary-to-fiber ratio, and these may contribute to their severe exercise intolerance. This suggests potential new therapeutic targets in this difficult to treat disorder. heart failure; exercise; aging APPROXIMATELY 50% OF HEART FAILURE (HF) patients living in the community have preserved left ventricular (LV) ejection fraction (HFPEF) (33,52,68). HFPEF is nearly exclusively a disorder of older persons and is most common in women. The primary symptom in patients with chronic HFPEF is severe exercise intolerance, measured objectively as decreased peak exercise O 2 uptake (peak V O 2 ) (2,3,5,26,30,34,35,41), and this is associated with a reduced quality of life. Despite its importance, the pathophysiology of exercise intolerance in HFPEF is not well understood.Several lines of evidence suggest that in older HFPEF patients, noncardiac factors may contribute to reduced peak V O 2 and may be major contributors to the improvement in peak V O 2 after endurance exercise training (2,5,23,24,26,36,47,54). It is known that aging results in alter...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction

Kitzman

Nicklas

Kraus

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

272

229

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“…Since skeletal muscle morphology and metabolism are altered in HF 66) , roles played by activation of the EPR in patients with HF have attracted research attention. Reportedly, isolated activation of muscle metaboreflex by postexercise circulatory occlusion of the exercising limb resulted in less elevation of muscle SNA 60) and less renal vasoconstriction 61,62) in HF patients than in healthy subjects.…”

Section: Contribution Of Rat Studies To Understanding Mechanisms Undementioning

confidence: 99%

Exercise pressor reflex in health and diseases: Animal studies

Koba

2015

JPFSM

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A reflex originating in exercising skeletal muscle contributes to sympathoexcitation during exercise. This muscle-based reflex is termed the exercise pressor reflex (EPR). In this review, mechanisms underlying activation of the EPR are examined based on findings mainly obtained from cat studies. Specifically, roles played by chemical and mechanical stimuli due to contraction in increasing discharges of muscle afferent fibers are discussed. Roles metabolic byproducts play in stimulating and sensitizing muscle afferents are also examined. Central cardiovascular sites involved in activation of the EPR are investigated. In this review, moreover, mechanisms by which the EPR function becomes abnormal in heart failure and hypertension are discussed on the basis of experimental data mainly provided by rat studies. In heart failure, the muscle metaboreflex is attenuated while the mechanoreflex is enhanced. In hypertension, both the muscle metabo-and mechano-reflexes are enhanced. Peripheral factors leading to EPR dysfunction in these pathological conditions are examined.

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“…A number of studies have demonstrated a significant relationship between exercise tolerance and skeletal muscle abnormalities. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Subsequently, the discrepancy between exercise tolerance and resting left ventricular ejection fraction in CHF has been shown. 3,4 Why are resting indices of cardiac function not related to exercise tolerance?…”

Section: Exercise Intolerance and Central Hemodynamic Functionmentioning

confidence: 99%

Exercise Intolerance in Chronic Heart Failure

Okita

Kinugawa

Tsutsui

2013

Circ J

106

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Chronic heart failure (CHF) is characterized as a clinical disorder displaying exercise intolerance; patients typically complain of early muscular fatigue. Previously, it was thought to be simply a failure of perfusion to the exercising musculature and consequent early onset of intramuscular acidosis in CHF. However, improved hemodynamics by cardiotonic agents did not lead to an increase in exercise tolerance. Later studies have shown that intrinsic skeletal muscle abnormalities exist in patients with CHF and could induce the early anaerobic metabolism that limits exercise tolerance. We review the clinical importance of skeletal muscle abnormalities in patients with CHF. Considering the significance of peripheral muscle abnormalities and their development might help physicians and researchers better understand the mechanisms of well-established exercise training and pharmacological therapies that have been shown to improve the prognosis for CHF, and thus develop potential novel therapies. (Circ J 2013; 77: 293 -300)

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Making the Case for Skeletal Myopathy as the Major Limitation of Exercise Capacity in Heart Failure

Cited by 148 publications

References 82 publications

Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction

Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction

Exercise pressor reflex in health and diseases: Animal studies

Exercise Intolerance in Chronic Heart Failure

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