Effects of exercise training on neurovascular control and skeletal myopathy in systolic heart failure

Neurohormonal excitation and dyspnea are the hallmarks of heart failure (HF) and have long been associated with poor prognosis in HF patients. Sympathetic nerve activity (SNA) and ventilatory equivalent of carbon dioxide (VE/VO2) are elevated in moderate HF patients and increased even further in severe HF patients. The increase in SNA in HF patients is present regardless of age, sex, and etiology of systolic dysfunction. Neurohormonal activation is the major mediator of the peripheral vasoconstriction characteristic of HF patients. In addition, reduction in peripheral blood flow increases muscle inflammation, oxidative stress, and protein degradation, which is the essence of the skeletal myopathy and exercise intolerance in HF. Here we discuss the beneficial effects of exercise training on resting SNA in patients with systolic HF and its central and peripheral mechanisms of control. Furthermore, we discuss the exercise-mediated improvement in peripheral vasoconstriction in patients with HF. We will also focus on the effects of exercise training on ventilatory responses. Finally, we review the effects of exercise training on features of the skeletal myopathy in HF. In summary, exercise training plays an important role in HF, working synergistically with pharmacological therapies to ameliorate these abnormalities in clinical practice.

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Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure

Physiological Genomics ◽

10.1152/physiolgenomics.00188.2006 ◽

2007 ◽

Vol 29 (3) ◽

pp. 246-252 ◽

Cited By ~ 60

Author(s):

Natale P. L. Rolim ◽

Alessandra Medeiros ◽

Kaleizu T. Rosa ◽

Katt C. Mattos ◽

Maria C. Irigoyen ◽

...

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Cardiac Myocyte ◽

Systolic Function ◽

Systolic Dysfunction ◽

Exercise Intolerance ◽

Computer Assisted ◽

Wild Type ◽

Beneficial Effects ◽

Ventricular Fibrosis

The molecular basis of the beneficial effects associated with exercise training (ET) on overall ventricular function (VF) in heart failure (HF) remains unclear. We investigated potential Ca2+ handling abnormalities and whether ET would improve VF of mice lacking α2A- and α2C-adrenoceptors (α2A/α2CARKO) that have sympathetic hyperactivity-induced HF. A cohort of male wild-type (WT) and congenic α2A/α2CARKO mice in a C57BL/J genetic background (5–7 mo of age) was randomly assigned into untrained and trained groups. VF was assessed by two-dimensional guided M-mode echocardiography. Cardiac myocyte width and ventricular fibrosis were evaluated with a computer-assisted morphometric system. Sarcoplasmic reticulum Ca2+ ATPase (SERCA2), phospholamban (PLN), phospho-Ser16-PLN, phospho-Thr17-PLN, phosphatase 1 (PP1), and Na+-Ca2+ exchanger (NCX) were analyzed by Western blotting. ET consisted of 8-wk running sessions of 60 min, 5 days/wk. α2A/α2CARKO mice displayed exercise intolerance, systolic dysfunction, increased cardiac myocyte width, and ventricular fibrosis paralleled by decreased SERCA2 and increased NCX expression levels. ET in α2A/α2CARKO mice improved exercise tolerance and systolic function. ET slightly reduced cardiac myocyte width, but unchanged ventricular fibrosis in α2A/α2CARKO mice. ET significantly increased the expression of SERCA2 (20%) and phospho-Ser16-PLN (63%), phospho-Thr17-PLN (211%) in α2A/α2CARKO mice. Furthermore, ET restored NCX and PP1 expression in α2A/α2CARKO to untrained WT mice levels. Thus, we provide evidence that Ca2+ handling is impaired in this HF model and that overall VF improved upon ET, which was associated to changes in the net balance of cardiac Ca2+ handling proteins.

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Exercise Training for Heart Failure Patients with and without Systolic Dysfunction: An Evidence-Based Analysis of How Patients Benefit

Cardiology Research and Practice ◽

10.4061/2011/837238 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Neil Smart

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Systolic Function ◽

Controlled Trial ◽

Systolic Dysfunction ◽

Systolic Heart Failure ◽

Evidence Based ◽

Heart Failure Patients ◽

Age Related ◽

Clinical Benefits

Significant benefits can be derived by heart failure patients from exercise training. This paper provides an evidence-based assessment of expected clinical benefits of exercise training for heart failure patients. Meta-analyses and randomized, controlled trials of exercise training in heart failure patients were reviewed from a search of PubMed, Cochrane Controlled Trial Registry (CCTR), CINAHL, and EMBASE. Exercise training improves functional capacity, quality of life, hospitalization, and systolic and diastolic function in heart failure patients. Heart failure patients with preserved systolic function (HFnEF) participating in exercise training studies are more likely to be women and are 5–7 years older than their systolic heart failure (CHF) counterparts. All patients exhibit low functional capacities, although in HFnEF patients this may be age related, therefore subtle differences in exercise prescriptions are required. Published works report that exercise training is beneficial for heart failure patients with and without systolic dysfunction.

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Aerobic Exercise and Pharmacological Therapies for Skeletal Myopathy in Heart Failure: Similarities and Differences

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/4374671 ◽

2016 ◽

Vol 2016 ◽

pp. 1-16 ◽

Cited By ~ 11

Author(s):

Aline V. Bacurau ◽

Telma F. Cunha ◽

Rodrigo W. Souza ◽

Vanessa A. Voltarelli ◽

Daniele Gabriel-Costa ◽

...

Keyword(s):

Heart Failure ◽

Aerobic Exercise ◽

Pharmacological Therapy ◽

Aerobic Exercise Training ◽

Exercise Intolerance ◽

Therapeutic Approaches ◽

Beneficial Effects ◽

Skeletal Myopathy ◽

Ambulatory Patients

Skeletal myopathy has been identified as a major comorbidity of heart failure (HF) affecting up to 20% of ambulatory patients leading to shortness of breath, early fatigue, and exercise intolerance. Neurohumoral blockade, through the inhibition of renin angiotensin aldosterone system (RAS) andβ-adrenergic receptor blockade (β-blockers), is a mandatory pharmacological therapy of HF since it reduces symptoms, mortality, and sudden death. However, the effect of these drugs on skeletal myopathy needs to be clarified, since exercise intolerance remains in HF patients optimized withβ-blockers and inhibitors of RAS. Aerobic exercise training (AET) is efficient in counteracting skeletal myopathy and in improving functional capacity and quality of life. Indeed, AET has beneficial effects on failing heart itself despite being of less magnitude compared with neurohumoral blockade. In this way, AET should be implemented in the care standards, together with pharmacological therapies. Since both neurohumoral inhibition and AET have a direct and/or indirect impact on skeletal muscle, this review aims to provide an overview of the isolated effects of these therapeutic approaches in counteracting skeletal myopathy in HF. The similarities and dissimilarities of neurohumoral inhibition and AET therapies are also discussed to identify potential advantageous effects of these combined therapies for treating HF.

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Exercise training for systolic heart failure: Cochrane systematic review and meta-analysis

European Journal of Heart Failure ◽

10.1093/eurjhf/hfq056 ◽

2010 ◽

Vol 12 (7) ◽

pp. 706-715 ◽

Cited By ~ 186

Author(s):

Edward J. Davies ◽

Tiffany Moxham ◽

Karen Rees ◽

Sally Singh ◽

Andrew J.S. Coats ◽

...

Keyword(s):

Heart Failure ◽

Systematic Review ◽

Exercise Training ◽

Meta Analysis ◽

Systolic Heart Failure ◽

Cochrane Systematic Review

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Exercise training normalizes elevated firing rate of hypothalamic presympathetic neurons in heart failure rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00225.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. R110-R120 ◽

Cited By ~ 2

Author(s):

Yiming Shen ◽

Jin Bong Park ◽

So Yeong Lee ◽

Seong Kyu Han ◽

Pan Dong Ryu

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Firing Rate ◽

Gaba Release ◽

Neuronal Firing ◽

Ventrolateral Medulla ◽

Patch Clamp Technique ◽

Electrophysiological Properties ◽

Beneficial Effects ◽

Underlying Mechanisms

Exercise training (ExT) normalizes elevated sympathetic nerve activity in heart failure (HF), but the underlying mechanisms are not well understood. In this study, we examined the effects of 3 wk of ExT on the electrical activity of the hypothalamic presympathetic neurons in the brain slice of HF rats. HF rats were prepared by ligating the left descending coronary artery. The electrophysiological properties of paraventricular nucleus neurons projecting to the rostral ventrolateral medulla (PVN-RVLM) were examined using the slice patch-clamp technique. The neuronal firing rate was elevated in HF rats, and ExT induced a reduction in the firing rate ( P < 0.01). This ExT-induced decrease in the firing rate was associated with an increased frequency of spontaneous and miniature inhibitory postsynaptic current (IPSCs; P < 0.05). There was no significant change in excitatory postsynaptic current. Replacing Ca2+ with Mg2+ in the recording solution reduced the elevated IPSC frequency in HF rats with ExT ( P < 0.01) but not in those without ExT, indicating an increase in the probability of GABA release. In contrast, ExT did not restore the reduced GABAA receptor-mediated tonic inhibitory current in HF rats. A GABAA receptor blocker (bicuculline, 20 μM) increased the firing rate in HF rats with ExT ( P < 0.01) but not in those without ExT. Collectively, these results show that ExT normalized the elevated firing activity by increasing synaptic GABA release in PVN-RVLM neurons in HF rats. Our findings provide a brain mechanism underlying the beneficial effects of ExT in HF, which may shed light on the pathophysiology of other diseases accompanied by sympathetic hyperactivation.

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Role of Diastole in Left Ventricular Function, II: Diagnosis and Treatment

American Journal of Critical Care ◽

10.4037/ajcc2004.13.6.453 ◽

2004 ◽

Vol 13 (6) ◽

pp. 453-466 ◽

Cited By ~ 18

Author(s):

Shannan K. Hamlin ◽

Penelope S. Villars ◽

Joseph T. Kanusky ◽

Andrew D. Shaw

Keyword(s):

Heart Failure ◽

Diastolic Dysfunction ◽

Left Atrial ◽

Diastolic Heart Failure ◽

Systolic Heart Failure ◽

Clinical Signs ◽

Left Ventricular ◽

Exercise Intolerance ◽

Radiographic Findings ◽

Ventricular Compliance

Left ventricular diastolic dysfunction plays an important role in congestive heart failure. Although once thought to be lower, the mortality of diastolic heart failure may be as high as that of systolic heart failure. Diastolic heart failure is a clinical syndrome characterized by signs and symptoms of heart failure with preserved ejection fraction (0.50) and abnormal diastolic function. One of the earliest indications of diastolic heart failure is exercise intolerance followed by fatigue and, possibly, chest pain. Other clinical signs may include distended neck veins, atrial arrhythmias, and the presence of third and fourth heart sounds. Diastolic dysfunction is difficult to differentiate from systolic dysfunction on the basis of history, physical examination, and electrocardiographic and chest radiographic findings. Therefore, objective diagnostic testing with cardiac catheterization, Doppler echocardiography, and possibly measurement of serum levels of B-type natriuretic peptide is often required. Three stages of diastolic dysfunction are recognized. Stage I is characterized by reduced left ventricular filling in early diastole with normal left ventricular and left atrial pressures and normal compliance. Stage II or pseudonormalization is characterized by a normal Doppler echocardiographic transmitral flow pattern because of an opposing increase in left atrial pressures. This normalization pattern is a concern because marked diastolic dysfunction can easily be missed. Stage III, the final, most severe stage, is characterized by severe restrictive diastolic filling with a marked decrease in left ventricular compliance. Pharmacological therapy is tailored to the cause and type of diastolic dysfunction.

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A Rat Model of Pressure Overload Induced Moderate Remodeling and Systolic Dysfunction as Opposed to Overt Systolic Heart Failure

Journal of Visualized Experiments ◽

10.3791/60954 ◽

2020 ◽

Author(s):

Antoine H. Chaanine ◽

L. Gabriel Navar ◽

Patrice Delafontaine

Keyword(s):

Heart Failure ◽

Rat Model ◽

Systolic Dysfunction ◽

Systolic Heart Failure ◽

Pressure Overload

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P2625Pathophysiology of diaphragm involvement in systolic heart failure: insights from diaphragm ultrasound and phrenic nerve stimulation studies

European Heart Journal ◽

10.1093/eurheartj/ehz748.0948 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

J Spiesshoefer ◽

I T Tuleta ◽

A G Giannoni ◽

M B Boentert

Keyword(s):

Heart Failure ◽

Phrenic Nerve ◽

Systolic Heart Failure ◽

Exercise Intolerance ◽

Design Data ◽

Diaphragm Function ◽

Phrenic Nerves ◽

And Gender ◽

The Right ◽

Conductive Properties

Abstract Background Diaphragm ultrasound allows for assessment of both diaphragm excursion and thickness. Cervical and cortical magnetic stimulation (CEMS and COMS) with recording of the diaphragmatic compound motor action potential (CMAP) is diagnostically useful to evaluate the conductive properties of the inspiratory pathway. Systolic heart failure (HF) is characterized by a loss of systolic pump function. Diaphragm weakness in HF has been reported to potentially contribute to exercise intolerance Methods 14 patients with systolic HF (11 men, 3 women; 64±12 years, NYHA 2±0.9, LVEF 36.1±5.6%) and 12 healthy controls matched for age and gender (4 men, 8 women; 56±8 years) underwent spirometric lung function testing and assessment of diaphragm excursion (during tidal breathing, TB, voluntary sniff, VS and deep breathing, DB) and thickness of the right hemidiaphragm by ultrasound. COMS and CEMS of the phrenic nerves with simultaneous bilateral recording of the diaphragm CMAP using surface electrodes was performed in 9 patients. Results Compared to controls, HF patients showed reduced forced vital capacity (75.46±18.05% vs. 107.62±17.13%, p<0.05). Diaphragm excursion amplitude was significantly reduced in HF patients (4.29±1.35 cm vs. 7.34±2.10 cm, p<0.05). Diaphragm contractility was impaired too, as reflected by the diaphragm thickening ratio (DTR; 2.01±0.46 vs. 2.53±0.74, p<0.05). Diaphragm CMAP following COMS and CEMS of the phrenic nerves revealed normal latencies in HF patients compared to controls (COMS Latency; 19.05±2.37 msec vs. 18.97±3.59 msec, p= n. s.). Conclusions Diaphragm involvement in systolic HF is reflected by reduced FVC and impaired ultrasound parameters of diaphragm function. Diaphragmatic pathology is likely to be myopathic because magnetic phrenic nerve conduction studies show no abnormalities. Diaphragm ultrasound may be useful as a diagnostic tool for assessment of diaphragm function in systolic HF. Acknowledgement/Funding This study was supported by Sanofi-Genzyme, Neu-Isenburg, Germany. The funders had no role in study design, data collection and analysis, preparation.

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