Skeletal Muscle Alterations Are Exacerbated in Heart Failure With Reduced Compared With Preserved Ejection Fraction

Seiler, Martin; Bowen, T. Scott; Rolim, Natale; Dieterlen, Maja‐Theresa; Werner, Sarah; Hoshi, Tomoya; Fischer, Tina; Mangner, Norman; Linke, Axel; Schuler, Gerhard; Halle, Martin; Wisløff, Ulrik; Adams, Volker

doi:10.1161/circheartfailure.116.003027

Cited by 60 publications

(78 citation statements)

References 44 publications

(51 reference statements)

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“…6,7 While the underlying intracellular mechanisms responsible for diaphragm dysfunction in HFpEF remain poorly explored, our laboratory recently provided initial evidence using a hypertensive rat model of HFpEF. 8,15 Indeed, and consistent with the present study, rats with HFpEF also had a shift towards a type I fiber proportion, an increase in mitochondrial quantitative markers despite impaired qualitative function, and a reduction in maximal contractile function. 8,15 However, our previous animal model used Dahl saltsensitive rats-a model where HFpEF was driven exclusively by hypertension in the absence of the main symptom exercise intolerance.…”

Section: Does Hfpef Induce a Myopathy In The Diaphragm?supporting

confidence: 91%

“…8,15 Indeed, and consistent with the present study, rats with HFpEF also had a shift towards a type I fiber proportion, an increase in mitochondrial quantitative markers despite impaired qualitative function, and a reduction in maximal contractile function. 8,15 However, our previous animal model used Dahl saltsensitive rats-a model where HFpEF was driven exclusively by hypertension in the absence of the main symptom exercise intolerance. 8,15 In the present study, ZSF1 rats were used where multiple comorbidities are developed (eg, obesity, diabetes mellitus, hypertension, chronic kidney disease) as well as exercise intolerance, [9][10][11][12] thus more closely reflecting the HFpEF patient phenotype.…”

Section: Does Hfpef Induce a Myopathy In The Diaphragm?supporting

confidence: 91%

“…However, our previous animal model used Dahl salt‐sensitive rats—a model where HFpEF was driven exclusively by hypertension in the absence of the main symptom exercise intolerance . In the present study, ZSF1 rats were used where multiple comorbidities are developed (eg, obesity, diabetes mellitus, hypertension, chronic kidney disease) as well as exercise intolerance, thus more closely reflecting the HFpEF patient phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…8,15 However, our previous animal model used Dahl saltsensitive rats-a model where HFpEF was driven exclusively by hypertension in the absence of the main symptom exercise intolerance. 8,15 In the present study, ZSF1 rats were used where multiple comorbidities are developed (eg, obesity, diabetes mellitus, hypertension, chronic kidney disease) as well as exercise intolerance, [9][10][11][12] thus more closely reflecting the HFpEF patient phenotype. This may explain, at least in part, why the current obese HFpEF animals demonstrated an %20% type I fiber hypertrophy and no impairment to fatiguing contractions, which is in contrast to our hypertensive HFpEF model where a fiber atrophy of %30% was observed with greater fatigability.…”

Section: Does Hfpef Induce a Myopathy In The Diaphragm?mentioning

confidence: 99%

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Exercise Training Reveals Inflexibility of the Diaphragm in an Animal Model of Patients With Obesity‐Driven Heart Failure With a Preserved Ejection Fraction

Bowen

Brauer

Rolim

et al. 2017

JAHA

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BackgroundRespiratory muscle weakness contributes to exercise intolerance in patients with heart failure with a preserved ejection fraction (HFpEF)—a condition characterized by multiple comorbidities with few proven treatments. We aimed, therefore, to provide novel insight into the underlying diaphragmatic alterations that occur in HFpEF by using an obese cardiometabolic rat model and further assessed whether exercise training performed only after the development of overt HFpEF could reverse impairments.Methods and ResultsObese ZSF1 rats (n=12) were compared with their lean controls (n=8) at 20 weeks, with 3 additional groups of obese ZSF1 rats compared at 28 weeks following 8 weeks of either sedentary behavior (n=13), high‐intensity interval training (n=11), or moderate‐continuous training (n=11). Obese rats developed an obvious HFpEF phenotype at 20 and 28 weeks. In the diaphragm at 20 weeks, HFpEF induced a shift towards an oxidative phenotype and a fiber hypertrophy paralleled by a lower protein expression in MuRF1 and MuRF2, yet mitochondrial and contractile functional impairments were observed. At 28 weeks, neither the exercise training regimen of high‐intensity interval training or moderate‐continuous training reversed any of the diaphragm alterations induced by HFpEF.ConclusionsThis study, using a well‐characterized rat model of HFpEF underpinned by multiple comorbidities and exercise intolerance (ie, one that closely resembles the patient phenotype), provides evidence that diaphragm alterations and dysfunction induced in overt HFpEF are not reversed following 8 weeks of aerobic exercise training. As such, whether alternative therapeutic interventions are required to treat respiratory muscle weakness in HFpEF warrants further investigation.

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Section: Does Hfpef Induce a Myopathy In The Diaphragm?supporting

confidence: 91%

Section: Does Hfpef Induce a Myopathy In The Diaphragm?supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Does Hfpef Induce a Myopathy In The Diaphragm?mentioning

confidence: 99%

See 2 more Smart Citations

Exercise Training Reveals Inflexibility of the Diaphragm in an Animal Model of Patients With Obesity‐Driven Heart Failure With a Preserved Ejection Fraction

Bowen

Brauer

Rolim

et al. 2017

JAHA

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View full text Add to dashboard Cite

show abstract

“…In the heart failure literature, wasting changes in skeletal muscle were described among patients with advanced heart failure . A variety of systemic and humoral mechanisms were presented as possible biological interactions occurring as cross‐talk between skeletal muscle and the diseased heart . In contrast, although our cohort was 65 years of age and older, they did not have clinical heart failure, as evidenced by low BNP levels.…”

Section: Discussionmentioning

confidence: 81%

Associations between Skeletal Muscle and Myocardium in Aging: A Syndrome of “Cardio‐Sarcopenia”?

Keng

Gao

Teo

et al. 2019

J American Geriatrics Society

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Objectives The link between skeletal muscle and heart disease remains intriguing. It is unknown how skeletal muscle may be associated with aspects of myocardial structure and function, particularly in the presence of aging‐related sarcopenia. We hypothesize that among aging adults with sarcopenia, alterations in myocardial structure and/or function may exist, resulting in a syndrome of “cardio‐sarcopenia.” Methods Participants derived from a community cohort study underwent same‐day bioimpedance body composition analysis that measured skeletal muscle in sites such as the trunk, upper limb, and lower limb, and echocardiography for assessment of myocardial structure and function. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia criteria. Results We studied a total of 378 participants, of whom 88 (23.3%) had sarcopenia. Participants with sarcopenia had smaller left ventricular (LV) sizes (lower LV internal diameter end diastole (4.1 ± .7 vs 4.5 ± .6 cm; P < .0001), lower LV internal diameter end systole (2.3 ± .5 vs 2.5 ± .4 cm; P = .010), lower LV posterior wall end diastole (.7 ± .1 vs .8 ± .1 cm; P = .0036), and lower LV posterior wall end systole (1.4 ± .3 vs 1.5 ± .2 cm; P = .0031). Sarcopenic participants also had lower LV mass (106 ± 35 vs 126 ± 53; P = .0014) and lower left atrial (LA) volume (33 ± 13 vs 36 ± 13; P = .033). Adjusting for age and diabetes mellitus, skeletal muscle mass was associated with LV diameter (β = .06; 95% confidence interval [CI] = .03‐.09; P < .0001), LV mass (β = 4.04; 95% CI = 1.78‐6.29; P = .001), LA diameter (β = .05; 95% CI = .01‐.09; P = .007), and LA volume (β = 1.26; 95% CI = .38‐2.13; P = .005). A positive linear correlation was observed between LV mass and handgrip strength (r = .25; P < .0001). Conclusion Among a community sample of older adults with preserved heart function, sarcopenia is associated with reductions in LV and LA sizes. Skeletal muscle mass was independently associated with specific indices of myocardial structure. J Am Geriatr Soc 67:2568–2573, 2019

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Muscular changes in animal models of heart failure with preserved ejection fraction: what comes closest to the patient?

et al. 2020

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Aims Heart failure with preserved ejection fraction (HFpEF) is associated with reduced exercise capacity elicited by skeletal muscle (SM) alterations. Up to now, no clear medical treatment advice for HFpEF is available. Identification of the ideal animal model mimicking the human condition is a critical step in developing and testing treatment strategies. Several HFpEF animals have been described, but the most suitable in terms of comparability with SM alterations in HFpEF patients is unclear. The aim of the present study was to investigate molecular changes in SM of three different animal models and to compare them with alterations of muscle biopsies obtained from human HFpEF patients. Methods and results Skeletal muscle tissue was obtained from HFpEF and control patients and from three different animal models including the respective controls-ZSF1 rat, Dahl salt-sensitive rat, and transverse aortic constriction surgery/deoxycorticosterone mouse. The development of HFpEF was verified by echocardiography. Protein expression and enzyme activity of selected markers were assessed in SM tissue homogenates. Protein expression between SM tissue obtained from HFpEF patients and the ZSF1 rats revealed similarities for protein markers involved in muscle atrophy (MuRF1 expression, protein ubiquitinylation, and LC3) and mitochondrial metabolism (succinate dehydrogenase and malate dehydrogenase activity, porin expression). The other two animal models exhibited far less similarities to the human samples. Conclusions None of the three tested animal models mimics the condition in HFpEF patients completely, but among the animal models tested, the ZSF1 rat (ZSF1-lean vs. ZSF1-obese) shows the highest overlap to the human condition. Therefore, when studying therapeutic interventions to treat HFpEF and especially alterations in the SM, we suggest that the ZSF1 rat is a suitable model.

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Skeletal Muscle Alterations Are Exacerbated in Heart Failure With Reduced Compared With Preserved Ejection Fraction

Cited by 60 publications

References 44 publications

Exercise Training Reveals Inflexibility of the Diaphragm in an Animal Model of Patients With Obesity‐Driven Heart Failure With a Preserved Ejection Fraction

Exercise Training Reveals Inflexibility of the Diaphragm in an Animal Model of Patients With Obesity‐Driven Heart Failure With a Preserved Ejection Fraction

Associations between Skeletal Muscle and Myocardium in Aging: A Syndrome of “Cardio‐Sarcopenia”?

Muscular changes in animal models of heart failure with preserved ejection fraction: what comes closest to the patient?

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