Muscle afferent contributions to exercise intolerance in heart failure

An exaggerated exercise pressor reflex (EPR) causes excessive sympatho-excitation and exercise intolerance during physical activity in the chronic heart failure (CHF) state. Muscle afferent sensitization contributes to the genesis of the exaggerated EPR in CHF. However, the cellular mechanisms underlying muscle afferent sensitization in CHF remain unclear. Considering that voltage-gated potassium (Kv) channels critically regulate afferent neuronal excitability, we examined the potential role of Kv channels in mediating the sensitized EPR in male CHF rats. Real time RT-PCR and western blotting experiments demonstrate that both mRNA and protein expressions of multiple Kv channel isoforms (Kv1.4, Kv3.4, Kv4.2 and Kv4.3) were downregulated in lumbar DRGs of CHF rats compared to sham rats. Immunofluorescence data demonstrates significant decreased Kv channel staining in both NF200-positive and IB4-positive lumbar DRG neurons in CHF rats compared to sham rats. Data from patch clamp experiments demonstrate that the total Kv current, especially IA, was dramatically decreased in medium-sized IB4-negative muscle afferent neurons (a subpopulation containing mostly Aδ neurons) from CHF rats compared to sham rats, indicating a potential functional loss of Kv channels in muscle afferent Aδ neurons. In in vivo experiments, adenoviral overexpression of Kv4.3 in lumbar DRGs for one week attenuated the exaggerated EPR induced by muscle static contraction and the mechanoreflex by passive stretch without affecting the blunted cardiovascular response to hindlimb arterial injection of capsaicin in CHF rats. These data suggest that Kv channel dysfunction in DRGs play a critical role in mediating the exaggerated EPR and muscle afferent sensitization in CHF.

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Faculty Opinions recommendation of Fatigability, exercise intolerance, and abnormal skeletal muscle energetics in heart failure.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727807886.793538097 ◽

2017 ◽

Author(s):

Barry Borlaug

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Exercise Intolerance ◽

Muscle Energetics

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Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients

Scientific Reports ◽

10.1038/s41598-021-81736-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Takashi Yokota ◽

Shintaro Kinugawa ◽

Kagami Hirabayashi ◽

Mayumi Yamato ◽

Shingo Takada ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Skeletal Muscle ◽

Energy Metabolism ◽

Aerobic Capacity ◽

Plantar Flexion ◽

Exercise Intolerance ◽

Whole Body ◽

Resonance Spectroscopy ◽

Systemic Oxidative Stress

AbstractOxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

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Soothing the sleeping giant: improving skeletal muscle oxygen kinetics and exercise intolerance in HFpEF

Journal of Applied Physiology ◽

10.1152/japplphysiol.01127.2014 ◽

2015 ◽

Vol 119 (6) ◽

pp. 734-738 ◽

Cited By ~ 14

Author(s):

Satyam Sarma ◽

Benjamin D. Levine

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Oxygen Consumption ◽

Functional Capacity ◽

Oxidative Capacity ◽

Exercise Intolerance ◽

Aerobic Performance ◽

Muscle Oxygen ◽

Oxygen Kinetics ◽

Patients With Heart Failure

Patients with heart failure with preserved ejection fraction (HFpEF) have similar degrees of exercise intolerance and dyspnea as patients with heart failure with reduced EF (HFrEF). The underlying pathophysiology leading to impaired exertional ability in the HFpEF syndrome is not completely understood, and a growing body of evidence suggests “peripheral,” i.e., noncardiac, factors may play an important role. Changes in skeletal muscle function (decreased muscle mass, capillary density, mitochondrial volume, and phosphorylative capacity) are common findings in HFrEF. While cardiac failure and decreased cardiac reserve account for a large proportion of the decline in oxygen consumption in HFrEF, impaired oxygen diffusion and decreased skeletal muscle oxidative capacity can also hinder aerobic performance, functional capacity and oxygen consumption (V̇o2) kinetics. The impact of skeletal muscle dysfunction and abnormal oxidative capacity may be even more pronounced in HFpEF, a disease predominantly affecting the elderly and women, two demographic groups with a high prevalence of sarcopenia. In this review, we 1) describe the basic concepts of skeletal muscle oxygen kinetics and 2) evaluate evidence suggesting limitations in aerobic performance and functional capacity in HFpEF subjects may, in part, be due to alterations in skeletal muscle oxygen delivery and utilization. Improving oxygen kinetics with specific training regimens may improve exercise efficiency and reduce the tremendous burden imposed by skeletal muscle upon the cardiovascular system.

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Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2021.07.014 ◽

2021 ◽

Vol 78 (11) ◽

pp. 1166-1187

Author(s):

Ambarish Pandey ◽

Sanjiv J. Shah ◽

Javed Butler ◽

Dean L. Kellogg ◽

Gregory D. Lewis ◽

...

Keyword(s):

Heart Failure ◽

Older Adults ◽

Ejection Fraction ◽

Exercise Intolerance ◽

Preserved Ejection Fraction

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Radiographic Assessment of Dogs with Congestive Heart Failure

Indian Journal of Animal Research ◽

10.18805/ijar.b-4352 ◽

2021 ◽

Author(s):

N. Saini ◽

S.K. Uppal ◽

A. Anand

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Dilated Cardiomyopathy ◽

Clinical Signs ◽

Abdominal Distension ◽

Cardiac Insufficiency ◽

Exercise Intolerance ◽

Pulmonary Vasculature ◽

Non Invasive ◽

Valvular Diseases

Background: Radiography is widely used for diagnosis of congestive heart failure as it enables non-invasive assessment of cardiac size, shape and pulmonary vasculature. So, the present study was conducted to record the radiographic changes in dogs with congestive heart failure.Methods: Fifty-one dogs with cardiac insufficiency brought to Teaching Veterinary Hospital of GADVASU, showing one of the clinical signs of chronic cough, dyspnea, exercise intolerance, abdominal distension, syncope and cyanosis were selected and were subjected to Lateral and Ventro-dorsal chest radiography. Result: Dilated cardiomyopathy was present in 24 dogs. Radiographically, pulmonary edema, cardiomegaly, vessel congestion were more common in dilated cardiomyopathy (DCM). Valvular diseases were present in 16 dogs and radiographically left atrial (LA) dilatation was present in dogs with valvular diseases. Pericardial effusions were present in 11 dogs showing enlarged globoid heart radiographically.

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Bradykinin Contributes to Sympathetic and Pressor Responses Evoked by Activation of Skeletal Muscle Afferents P2X in Heart Failure

Cellular Physiology and Biochemistry ◽

10.1159/000447906 ◽

2016 ◽

Vol 39 (6) ◽

pp. 2101-2109 ◽

Cited By ~ 5

Author(s):

Jihong Xing ◽

Jianhua Li

Keyword(s):

Heart Failure ◽

Nervous Activity ◽

Muscle Afferents ◽

Receptor Expression ◽

Sympathetic Nervous Activity ◽

Published Data ◽

Drg Neurons ◽

Arterial Blood ◽

Pressor Responses ◽

Muscle Afferent

Background/Aims: Published data suggest that purinergic P2X receptors of muscle afferent nerves contribute to the enhanced sympathetic nervous activity (SNA) and blood pressure (BP) responses during static exercise in heart failure (HF). In this study, we examined engagement of bradykinin (BK) in regulating responses of SNA and BP evoked by P2X stimulation in rats with HF. We further examined cellular mechanisms responsible for BK. We hypothesized that BK potentiates P2X currents of muscle dorsal root ganglion (DRG) neurons, and this effect is greater in HF due to upregulation of BK kinin B2 and P2X3 receptor. As a result, BK amplifies muscle afferents P2X-mediated SNA and BP responses. Methods: Renal SNA and BP responses were recorded in control rats and rats with HF. Western Blot analysis and patch-clamp methods were employed to examine the receptor expression and function of DRG neurons involved in the effects of BK. Results: BK injected into the arterial blood supply of the hindlimb muscles heightened the reflex SNA and BP responses induced by P2X activation with α,β-methylene ATP to a greater degree in HF rats. In addition, HF upregulated the protein expression of kinin B2 and P2X3 in DRG and the prior application of BK increased the magnitude of α,β-methylene ATP-induced currents in muscle DRG neurons from HF rats. Conclusion: BK plays a facilitating role in modulating muscle afferent P2X-engaged reflex sympathetic and pressor responses. In HF, P2X responsivness is augmented due to increases in expression of kinin B2 and P2X3 receptors and P2X current activity.

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Obesity and hemoglobin content impact peak oxygen uptake in human heart failure

European Journal of Preventive Cardiology ◽

10.1177/2047487318802695 ◽

2018 ◽

Vol 25 (18) ◽

pp. 1937-1946 ◽

Cited By ~ 9

Author(s):

Erik H Van Iterson ◽

Chul-Ho Kim ◽

Katelyn Uithoven ◽

Thomas P Olson

Keyword(s):

Heart Failure ◽

Body Mass Index ◽

Oxygen Uptake ◽

Left Ventricular ◽

Exercise Intolerance ◽

Left Ventricular Ejection ◽

Peak Exercise ◽

Ventricular Ejection Fraction ◽

Group 4 ◽

Group 1

Background Exercise intolerance, obesity, and low hemoglobin (hemoglobin<13 and <12 g/dl, men/women, respectively) are common features of heart failure. Despite serving as potent contributors to metabolic dysfunction, the impact of obesity and low hemoglobin on exercise intolerance is unknown. This study tested the hypotheses, compared with non-obese (NO) heart failure with normal hemoglobin, (a) counterparts with low hemoglobin and obesity or non-obesity will demonstrate reduced peak exercise oxygen uptake; (b) obese with normal hemoglobin will demonstrate decreased peak exercise oxygen uptake; (c) compared across stratifications, obese with low hemoglobin will demonstrate the sharpest decrement in peak exercise oxygen uptake. Methods Adults with heart failure ( n = 315; left ventricular ejection fraction≤40%; 77% men) (Group 1: normal hemoglobin and non-obese, n = 137; Group 2: low hemoglobin and non-obese, n = 51; Group 3: normal hemoglobin+obesity, n = 89; Group 4, n = 38: low hemoglobin+obesity; body mass index = 26 ± 3, 26 ± 2, 34 ± 4, 34 ± 4 kg/m2, respectively) completed treadmill cardiopulmonary exercise testing as part of routine clinical management. Peak exercise oxygen uptake was measured via standard metabolic system. Results There were no group-wise differences for heart failure class, gender, left ventricular ejection fraction, and resting cardiopulmonary function. Group 1 demonstrated increased peak exercise oxygen uptake versus Groups 2–4 (20 ± 6 versus 17 ± 6, 17 ± 5, 13 ± 4 ml/kg/min, respectively; all p < 0.001); whereas Group 4 peak exercise oxygen uptake was reduced versus all groups ( p < 0.001). Additionally, both body mass index (R2 = 0.10) and hemoglobin (R2 = 0.12) were significant predictors of peak exercise oxygen uptake in Group 1; which were relationships not mirrored for Groups 2–4. Conclusion These data suggest obesity together with low hemoglobin are potent contributors to impaired peak exercise oxygen uptake and, hence, oxidative metabolic capacity. In diverse populations of heart failure where obesity and/or low hemoglobin are present, it is important to consider these features together when interpreting peak exercise oxygen uptake and underlying exercise limitations.

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