Sarcopenic Obesity and the Pathogenesis of Exercise Intolerance in Heart Failure with Preserved Ejection Fraction

Upadhya, Bharathi; Haykowsky, Mark J.; Eggebeen, Joel; Kitzman, Dalane W.

doi:10.1007/s11897-015-0257-5

Cited by 70 publications

(56 citation statements)

References 120 publications

(114 reference statements)

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“…First, by activating cyclooxygenase‐2 signaling and increasing interleukin‐6 release, LCACs may promote local skeletal muscle inflammation and systemic inflammation, which are both pathophysiological targets in HF 63, 64, 65, 69. Second, LCACs stimulate reactive oxygen species production and promote cellular stress through activation of c‐Jun amino‐terminal kinase, p38 mitogen‐activated protein kinase, and the apoptotic caspase‐3 protein 56, 63.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

Hunter

Kelly

McGarrah

et al. 2016

JAHA

201

137

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BackgroundMetabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF).Methods and ResultsWe identified HFpEF cases, HFrEF controls, and no‐HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No‐HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long‐chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no‐HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance.ConclusionsWe identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.

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Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

Hunter

Kelly

McGarrah

et al. 2016

JAHA

201

137

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“…Limb skeletal muscle abnormalities often occur in patients with HFpEF 13. Dual-energy X-ray absorptiometry has shown that per cent fat of the body and legs is significantly increased in HFpEF compared with healthy controls 13.…”

Section: Sarcopenia Of Each Type Of Skeletal Musclementioning

confidence: 99%

“…Dual-energy X-ray absorptiometry has shown that per cent fat of the body and legs is significantly increased in HFpEF compared with healthy controls 13. However, per cent lean mass of the body and legs is significantly reduced in HFpEF compared with healthy controls 13. Increased fat infiltration in thigh skeletal muscle is associated with reduced functional capacity 13.…”

Section: Sarcopenia Of Each Type Of Skeletal Musclementioning

confidence: 99%

“…However, per cent lean mass of the body and legs is significantly reduced in HFpEF compared with healthy controls 13. Increased fat infiltration in thigh skeletal muscle is associated with reduced functional capacity 13. Therefore, sarcopenic obesity may partly explain skeletal muscle dysfunction and exercise intolerance in patients with HFpEF 13.…”

Section: Sarcopenia Of Each Type Of Skeletal Musclementioning

confidence: 99%

“…Increased fat infiltration in thigh skeletal muscle is associated with reduced functional capacity 13. Therefore, sarcopenic obesity may partly explain skeletal muscle dysfunction and exercise intolerance in patients with HFpEF 13. Ergoreflex may be another determinant of exercise intolerance in patients with HFpEF 18.…”

Section: Sarcopenia Of Each Type Of Skeletal Musclementioning

confidence: 99%

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The challenge of frailty and sarcopenia in heart failure with preserved ejection fraction

Kinugasa

Yamamoto

2016

Heart

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Frailty is a clinical state in which there is an increase in an individual's vulnerability for developing increased dependency and/or mortality when exposed to stressors. Frailty is often accompanied by heart failure with preserved ejection fraction (HFpEF), and frailty is likely to affect its clinical features and outcomes. Frail patients with HFpEF are frequently associated with sarcopenia (ie, muscle loss and weakness), which is a major component of the pathophysiology of frailty. Sarcopenia is a systemic skeletal muscle disease that impairs the function of limb skeletal muscles, as well as respiratory muscles, and this results in further functional decline. In addition, sarcopenia may contribute to cardiovascular remodelling and dysfunction, leading to the development of HFpEF through several metabolic and endocrine abnormalities. Although there is no established strategy for frail patients with HFpEF, a multidisciplinary approach, including various types of muscular training and nutritional intervention, may provide beneficial effects for these patients.

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Heart failure with preserved ejection fraction: New approaches to diagnosis and management

Upadhya

Kitzman

2019

Clinical Cardiology

Self Cite

110

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The majority of older patients who develop heart failure (HF), particularly older women, have a preserved left ventricular ejection fraction (HFpEF). Patients with HFpEF have severe symptoms of exercise intolerance, poor quality‐of‐life, frequent hospitalizations, and increased mortality. The prevalence of HFpEF is increasing and its prognosis is worsening. However, despite its importance, our understanding of the pathophysiology of HFpEF is incomplete, and drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Originally viewed as a disorder due solely to abnormalities in left ventricular (LV) diastolic function, our understanding has evolved such that HFpEF is now understood as a systemic syndrome, involving multiple organ systems, likely triggered by inflammation and with an important contribution of aging, lifestyle factors, genetic predisposition, and multiple‐comorbidities, features that are typical of a geriatric syndrome. HFpEF is usually progressive due to complex mechanisms of systemic and cardiac adaptation that vary over time, particularly with aging. In this review, we examine evolving data regarding HFpEF that may help explain past challenges and provide future directions to care patients with this highly prevalent, heterogeneous clinical syndrome.

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Sarcopenic Obesity and the Pathogenesis of Exercise Intolerance in Heart Failure with Preserved Ejection Fraction

Cited by 70 publications

References 120 publications

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

The challenge of frailty and sarcopenia in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction: New approaches to diagnosis and management

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