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

Kitzman, Dalane W.; Haykowsky, Mark J.; Tomczak, Corey R.

doi:10.1161/circheartfailure.117.004281

Cited by 51 publications

(68 citation statements)

References 15 publications

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“…Both HFD and HFHS did not affect Mfn2 protein expression in the heart tissue of obese-insulin resistant rats. Since data from clinical studies showed that Mfn2 protein expression was significantly decreased in the skeletal muscle from patients with HFpEF, leading to severe exercise intolerance, [43,44] future studies need to investigate whether similar finding can be observed in the skeletal muscle of this animal model. The diagram illustrating the proposed mechanism responsible for the effects of HFD and HFHS on cardiometabolic dysfunction is shown in Figure 9.…”

Section: Discussionmentioning

confidence: 96%

High‐Saturated Fat High‐Sugar Diet Accelerates Left‐Ventricular Dysfunction Faster than High‐Saturated Fat Diet Alone via Increasing Oxidative Stress and Apoptosis in Obese‐Insulin Resistant Rats

Apaijai

Arinno

Palee

et al. 2018

Molecular Nutrition Food Res

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Scope It has been hypothesized that a high‐saturated‐fat, high‐sugar diet (HFHS) causes worse cardiometabolic dysfunction than a high‐saturated‐fat diet (HFD) due to severe mitochondrial dysfunction, oxidative stress, and apoptosis in obese insulin‐resistant rats. Methods and Results Rats are divided into three groups to receive normal diet (ND), HFD, or HFHS for 24 weeks. Cardiometabolic parameters are determined at baseline and every 4 weeks until the end of the feeding protocol. At week 24, hearts are removed to determine mitochondrial function and dynamics, apoptosis, and insulin signaling. HFD and HFHS rats develop obese insulin‐resistance at week 8. However, fasting plasma glucose level is increased only in HFHS rats. Myocardial insulin signaling is markedly impaired in HFHS rats compared to other groups. Cardiac autonomic imbalance is observed in both HFD and HFHS rats beginning at week 8. However, cardiac dysfunction is observed earlier (week 8) in HFHS rats, and later at week 12 in HFD rats. Moreover, cardiac and mitochondrial oxidative stress levels, and apoptosis are greater in HFHS rats than HFD rats. Conclusion Both HFD and HFHS cause cardiometabolic dysfunction. HFHS causes more severe metabolic disturbance, oxidative stress, and apoptosis than HFD, which leads to an accelerated LV dysfunction in HFHS rats.

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Section: Discussionmentioning

confidence: 96%

High‐Saturated Fat High‐Sugar Diet Accelerates Left‐Ventricular Dysfunction Faster than High‐Saturated Fat Diet Alone via Increasing Oxidative Stress and Apoptosis in Obese‐Insulin Resistant Rats

Apaijai

Arinno

Palee

et al. 2018

Molecular Nutrition Food Res

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“…Further, improvement in exercise capacity in patients with HFpEF is in itself a potentially approvable phase 3 endpoint, provided any such improvement is not counteracted by adverse clinical effects. Secondly, given the potential effects of neladenoson bialanate on mitochondrial function in both cardiac and skeletal myocytes, an improvement in 6MWD may directly reflect the mode of action of this therapy …”

Section: Discussionmentioning

confidence: 99%

“…In this study, neladenoson bialanate was well tolerated and no second-or third-degree AV block was detected on 48 h ambulatory electrocardiographic monitoring. The Partial Adenosine Receptor Agonist in Heart Failure (PARSiFAL) pilot study was a double-blind, placebo-controlled study of the effects of 7-day treatment with 10 mg or 20 12 In this small study, neladenoson bialanate was also well tolerated-no episodes of second-or third-degree AV block or detrimental effects on heart rate or blood pressure were observed. In addition, no clinically relevant neurological side effects were seen.…”

Section: Clinical Trial Datamentioning

confidence: 99%

“…Secondly, given the potential effects of neladenoson bialanate on mitochondrial function in both cardiac and skeletal myocytes, an improvement in 6MWD may directly reflect the mode of action of this therapy. 20 However, in both PANTHEON and PANACHE, no single surrogate endpoint will be sufficient to make a decision to move forward to a phase 3 trial. In making this decision the totality of data collected will be considered, including the different domains of (i) echocardiographic parameters, (ii) biomarkers, (iii) activity, and (iv) quality of life.…”

Section: Justification Of the Efficacy Variablesmentioning

confidence: 99%

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Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1‐receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction

Voors

Shah

Bax

et al. 2018

European J of Heart Fail

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Despite major advances in the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF), morbidity and mortality associated with the condition remain high, suggesting the need for additional treatment options, particularly haemodynamically neutral treatments that do not alter blood pressure, heart rate, or renal function. HF with preserved ejection fraction (HFpEF) is also associated with high morbidity and mortality and adequate treatment options are limited; thus there is a critical unmet need for the development of novel therapies for HFpEF. Chronic HFrEF and HFpEF are both systemic disorders that affect not only the heart but several other tissues and organs including skeletal muscle, leading to exercise intolerance and dyspnoea. Partial adenosine A1-receptor agonists represent a novel potential therapy for HF regardless of underlying ejection fraction given their minimal effect on heart rate and blood pressure, and preclinical data demonstrate several possible beneficial mechanisms, including improved mitochondrial function and sarcoplasmic reticulum Ca -ATPase (SERCA2a) activity, enhanced energy substrate utilization, reverse ventricular remodelling, and anti-ischemic, cardioprotective properties. However, data on this class of drugs in humans are scarce, and the optimal dose of the partial adenosine A1 receptor, neladenoson bialanate, has not been defined. Here we describe the design and rationale of two randomized, double-blind, placebo-controlled, parallel-group, dose-finding phase 2b trials, PANTHEON (HFrEF) and PANACHE (HFpEF), that will advance our understanding of the potential benefit and optimal dose of neladenoson bialanate and provide critical information for the planning of future phase 3 trials.

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“…[ 12 – 18 ] Furthermore, emerging evidence suggests that non-cardiac factors such as skeletal myopathy and vascular dysfunction also contribute to exercise intolerance in this patient group. [ 4 , 19 – 21 ]…”

mentioning

confidence: 99%

Effects of Exercise Training on Cardiac Function in Heart Failure with Preserved Ejection Fraction

Fukuta

2020

Card Fail Rev

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Nearly half of patients with heart failure in the community have heart failure with preserved ejection fraction (HFpEF). Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance. Left ventricular diastolic dysfunction is associated with the pathophysiology of HFpEF and is an important contributor to exercise intolerance in HFpEF patients. The effects of exercise training on left ventricular diastolic function in HFpEF patients have been examined in several randomised clinical trials. Meta-analysis of the trials indicates that exercise training can provide clinically relevant improvements in exercise capacity without significant change in left ventricular structure or function in HFpEF patients. Further studies are necessary to elucidate the exact mechanisms of exercise intolerance in HFpEF patients and to develop recommendations regarding the most effective type, intensity, frequency, and duration of training in this group.

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

Cited by 51 publications

References 15 publications

High‐Saturated Fat High‐Sugar Diet Accelerates Left‐Ventricular Dysfunction Faster than High‐Saturated Fat Diet Alone via Increasing Oxidative Stress and Apoptosis in Obese‐Insulin Resistant Rats

High‐Saturated Fat High‐Sugar Diet Accelerates Left‐Ventricular Dysfunction Faster than High‐Saturated Fat Diet Alone via Increasing Oxidative Stress and Apoptosis in Obese‐Insulin Resistant Rats

Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1‐receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction

Effects of Exercise Training on Cardiac Function in Heart Failure with Preserved Ejection Fraction

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