Making the Case for Skeletal Muscle Myopathy and Its Contribution to Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Introduction: Visceral adipose tissue (AT) promotes inflammation and adverse metabolic changes that mediate disease progression in heart failure with preserved ejection fraction (HFpEF). Exercise intolerance is a hallmark of HFpEF, but little is known about its relation to the extent and distribution of AT. We characterized regional AT distribution in HFpEF patients and controls and analyzed associations with comorbidities and exercise tolerance. Methods: MRI was performed to quantify epicardial, liver, abdominal and thigh skeletal muscle AT. We assessed NYHA class, 6-minute walk distance (6MWD), and global well-being score (GWBS). Multivariable linear and logistic regression models were used, adjusted for age, sex, and body surface area. Results: We studied 55 HFpEF patients (41 women, mean age 67) and 33 controls (21 women, mean age 57). Epicardial AT (4.6 vs 3.2mm, p = 0.03), thigh intermuscular fat (11.0 vs 5.0cm 2 , p < 0.01) and liver fat fraction (FF) (6.4% vs 4.1%, p = 0.04) were higher in HFpEF patients than controls. Women with HFpEF had higher abdominal (443.9 vs 297.3 cm 2 , p = 0.03) and thigh (228.6 vs 112.3 cm 2 , p < 0.001) subcutaneous AT than men. Higher thigh intermuscular fat was associated with higher blood pressure (β [SE] 14.1 [3.3], p < 0.001) and diabetes (β [SE] 2.6 [1.1], p = 0.02), and liver FF was associated with chronic kidney disease (β [SE] 1.6 [0.6], p = 0.01). Higher thigh intramuscular fat was associated with both higher NYHA class and shorter 6MWD, and higher thigh intermuscular AT FF was associated with higher NYHA class ( Table ). Higher epicardial AT and liver FF were associated with lower GWBS. Conclusions: HFpEF patients have increased epicardial, liver, and skeletal muscle fat compared to controls out of proportion to their body size, and adiposity was associated with worse exercise intolerance in HFpEF. These results provide the basis for further investigation into regional AT distribution in relation to HFpEF symptoms and pathophysiology.

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Skeletal Muscle Composition and Its Relation to Exercise Intolerance in Older Patients With Heart Failure and Preserved Ejection Fraction

The American Journal of Cardiology ◽

10.1016/j.amjcard.2013.12.031 ◽

2014 ◽

Vol 113 (7) ◽

pp. 1211-1216 ◽

Cited By ~ 102

Author(s):

Mark J. Haykowsky ◽

Erik J. Kouba ◽

Peter H. Brubaker ◽

Barbara J. Nicklas ◽

Joel Eggebeen ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Ejection Fraction ◽

Older Patients ◽

Exercise Intolerance ◽

Preserved Ejection Fraction ◽

Muscle Composition ◽

Patients With Heart Failure

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Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction

Journal of Applied Physiology ◽

10.1152/japplphysiol.00049.2015 ◽

2015 ◽

Vol 119 (6) ◽

pp. 739-744 ◽

Cited By ~ 87

Author(s):

Mark J. Haykowsky ◽

Corey R. Tomczak ◽

Jessica M. Scott ◽

D. Ian Paterson ◽

Dalane W. Kitzman

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Ejection Fraction ◽

Muscle Blood Flow ◽

Exercise Intolerance ◽

Healthy Controls ◽

Preserved Ejection Fraction ◽

Skeletal Muscle Function ◽

Skeletal Morphology ◽

Patients With Heart Failure

This mini-review summarizes the literature regarding the mechanisms of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction (HFREF and HFPEF, respectively). Evidence to date suggests that the reduced peak pulmonary oxygen uptake (pulm V̇o2) in patients with HFREF compared with healthy controls is due to both central (reduced convective O2 transport) and peripheral factors (impaired skeletal muscle blood flow, decreased diffusive O2 transport coupled with abnormal skeletal morphology, and metabolism). Although central and peripheral impairments also limit peak pulm V̇o2 in HFPEF patients compared with healthy controls, emerging data suggest that the latter may play a relatively greater role in limiting exercise performance in these patients. Unlike HFREF, currently there is limited evidence-based therapies that improve exercise capacity in HFPEF patients, therefore future studies are required to determine whether interventions targeted to improve peripheral vascular and skeletal muscle function result in favorable improvements in peak pulm and leg V̇o2 and their determinants in HFPEF patients.

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Skeletal myopathy in a rat model of postmenopausal heart failure with preserved ejection fraction

Journal of Applied Physiology ◽

10.1152/japplphysiol.00170.2021 ◽

2021 ◽

Author(s):

Rachel C. Kelley ◽

Lauren Betancourt ◽

Andrea M. Noriega ◽

Suzanne C. Brinson ◽

Nuria Curbello-Bermudez ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Ejection Fraction ◽

Strain Difference ◽

Exercise Intolerance ◽

Preserved Ejection Fraction ◽

Cross Sectional ◽

Skeletal Myopathy ◽

Key Features ◽

Wistar Kyoto

Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of all patients with heart failure and frequently affects postmenopausal women. The HFpEF condition is phenotype-specific, with skeletal myopathy that is crucial for disease development and progression. However, most of the current preclinical models of HFpEF have not addressed the postmenopausal phenotype. We sought to advance a rodent model of postmenopausal HFpEF and examine skeletal muscle abnormalities therein. Female, ovariectomized, spontaneously hypertensive rats (SHR) were fed a high fat, high sucrose diet to induce HFpEF. Controls were female sham-operated Wistar-Kyoto rats on a lean diet. In a complementary, longer-term cohort, controls were female sham-operated SHRs on a lean diet to evaluate the effect of strain difference in the model. Our model developed key features of HFpEF that included increased body weight, glucose intolerance, hypertension, cardiac hypertrophy, diastolic dysfunction, exercise intolerance, and elevated plasma cytokines. In limb skeletal muscle, HFpEF decreased specific force by 15-30% (p < 0.05) and maximal mitochondrial respiration by 40-55% (p < 0.05), increased oxidized glutathione by ~2-fold (p < 0.05), and tended to increase mitochondrial H2O2 emission (p = 0.10). Muscle fiber cross-sectional area, markers of mitochondrial content, and indices of capillarity were not different between control and HFpEF in our short-term cohort. Overall, our model of postmenopausal HFpEF recapitulates several key features of the disease. This new model reveals contractile and mitochondrial dysfunction and redox imbalance that are potential contributors to abnormal metabolism, exercise intolerance, and diminished quality of life in patients with postmenopausal HFpEF.

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Abstract 16734: Oral Nitrite Supplementation Improves Skeletal Muscle Mitochondrial Respiration and Cardiorespiratory Fitness in Older Adults With Heart Failure With Preserved Ejection Fraction

Circulation ◽

10.1161/circ.142.suppl_3.16734 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Rohan Shah ◽

Paul Coen ◽

Mark T Gladwin ◽

Daniel E Forman

Keyword(s):

Heart Failure ◽

Older Adults ◽

Skeletal Muscle ◽

Steady State ◽

Ejection Fraction ◽

Cardiorespiratory Fitness ◽

Mitochondrial Respiration ◽

Perceived Exertion ◽

Exercise Intolerance ◽

Preserved Ejection Fraction

Introduction: Prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, especially among older adults. HFpEF is commonly associated with exercise intolerance and skeletal muscle weakening which likely contribute to functional decline. We studied the utility of nitrite (NO 2 ) supplementation with the aim to augment skeletal muscle mitochondrial respiration. Hypothesis: NO 2 administered via oral supplements would be associated with improved mitochondrial respiration. Whereas prior studies with other oral and inhaled nitrate and NO 2 therapy in HFpEF patients have been inconsistent, we used novel NO 2 capsules that we hypothesized would achieve higher serum levels of nitrite and nitrate, and greater cellular and clinical benefits. Methods: A randomized, placebo-controlled pilot trial to study the utility of oral sodium (Na) NO 2 over 4 weeks in an older population (≥70 years) was done. Participants received 20 or 40 mg Na-NO 2 supplements 3 times daily based on their hemodynamic responses. Pre- and post-NO 2 intervention participants underwent biopsies of the vastus lateralis muscle with associated assessments of mitochondrial respiration in permeabilized fibers and also completed cardiopulmonary exercise test. Results: 15 participants were randomized and 13 completed the interventions (n=6 on NO 2 , n=7 on placebo, 69% men, mean age 75.7 years, range 70-91). Post-intervention serum NO 2 level increased (+0.61±0.67 μmol on NO 2, +0.25±0.15 on placebo). Ex-vivo analysis of mitochondrial respiration showed increased O 2 consumption in muscle (+27.1±27.4 pmol/(s*mg) on NO 2 , -11.7±11.3 on placebo). Rated perceived exertion during steady-state walking decreased (-1.2±2.0 on NO 2, +0.2±1.6 on placebo). Peak oxygen uptake (VO 2 ) increased (+1.4±5.2 ml/kg/min on NO2, -3.4±5.2 on placebo). Conclusion: Our study demonstrated efficacy and potential clinical utility of oral NO 2 supplementation in older HFpEF patients with an internally consistent physiologic composite of improved skeletal muscle mitochondrial respiration in association with improved cardiorespiratory fitness and diminished perceived exertion during steady-state walking. Clinical implications are auspicious and further research is indicated.

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