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

Abstract

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.

Respiratory Muscle Weakness in Patients with Heart Failure: Time to Make It a Standard Clinical Marker and a Need for Novel Therapeutic Interventions?

“…The recent study by Miyagi et al [8] clearly highlights that more data are urgently needed in relation to HFpEF. We have confirmed that rats with HFpEF similarly demonstrate significant impairments to contractile function in isolated diaphragm fibers [15,16], with impaired mitochondrial complex I function appearing as one key mechanism. Importantly, this was attenuated by endurance exercise training [16].…”

Effects of Endurance Training on Detrimental Structural, Cellular, and Functional Alterations in Skeletal Muscles of Heart Failure With Preserved Ejection Fraction

“…secondary prevention). In this study, we used a recently established cardiometabolic obese-driven rat model of HFpEF [3,12,13]. The model closely resembles a typical patient phenotype, where cardiac impairments and exercise intolerance are underpinned by numerous comorbidities including obesity, type II diabetes, hypertension, and kidney dysfunction [14,15].…”

“…Procedures and experiments in this study were approved by the Norwegian Animal Research Authority, in accordance the European Directive 2010/63/EU. A full description of the present study design and animal cohort as well as the methods employed were recently described elsewhere [3]. Briefly, obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats (Charles River, Kingston, US) were used as a model to induce HFpEF, which occurs by 20 weeks of age [3,12,13].…”

“…A full description of the present study design and animal cohort as well as the methods employed were recently described elsewhere [3]. Briefly, obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats (Charles River, Kingston, US) were used as a model to induce HFpEF, which occurs by 20 weeks of age [3,12,13]. Non-invasive echocardiography as well as invasive hemodynamics were used to confirm the presence of HFpEF, where left ventricular diastolic impairments and a preserved ejection fraction were confirmed alongside measures of obesity, hypertension, type II diabetes, and…”

“…This has shifted focus towards possible treatment of "non-cardiac organs", such as the skeletal muscle, endothelial, and pulmonary systems. Recent studies have now established functional and structural impairments are present in skeletal muscle from both patients and animal models of HFpEF [3][4][5][6][7]. Muscle-specific changes include fiber atrophy, adipose infiltration, oxidative to glycolytic fiber type shift, reduced capillary density, and mitochondrial dysfunction, which have also been closely correlated to the main symptom of exercise intolerance [5][6][7][8].…”