The role of submaximal exercise‐induced skeletal muscle remodelling in heart failure with reduced ejection fraction patients

Heart failure is the progressive decline in cardiac function in response to chronic myocardial stress and persistent cardiac remodelling. It is a rising public health epidemic affecting over 31.6 million people worldwide (Bloom et al. 2017). Heart failure can be measured as the capacity of the left ventricle to pump blood; and when this ejection percentage falls below 40% per heart contraction, heart failure with reduced ejection fraction (HFrEF) ensues. A variety of cardiovascular diseases such as acute myocardial infarction, coronary artery disease, valvular heart disease and hypertension contribute to the pathogenesis of HFrEF. Other risk factors including diabetes, smoking and increased age can predispose a person to the development of this condition and exacerbate the severity of its clinical symptoms (Bloom et al. 2017). In fact, 25–30% of hospitalized HFrEF patients die within the first year after discharge, and those living experience several symptoms that greatly decrease their quality of life. This disease can manifest in fatigue, decreased exercise tolerance, fluid retention and dyspnoea, all due to the decline in cardiac function and consequences of compensatory mechanisms (Bloom et al. 2017). It is known that cardiomyocyte apoptosis and myocardial remodelling play a major role in the development of this chronic disease. Both these insults impair left ventricular function, decreasing the functional cardiac output of the heart. In order to compensate for this drop, activation of the sympathetic nervous system and renin–angiotensin–aldosterone system aims to improve function by increasing heart rate and strength of contractions, while causing peripheral vasoconstriction and increasing cardiac preload (Bloom et al. 2017). These compensatory mechanisms advance the decline of the already failing heart. Concomitant with the impairments in the cardiac muscle, the skeletal muscle undergoes alterations in HFrEF (Kinugawa et al. 2015). Diminished skeletal muscle metabolism, mitochondrial dysfunction, oxidative stress, fibre-type conversion and atrophy are all potential changes that can affect the skeletal muscle, causing catabolism and deconditioning, during HFrHF. Exercise has the potential to counter these skeletal muscle changes by inducing angiogenesis, which is the expansion of existing vascular networks, restoring muscle integrity and function (Kinugawa et al. 2015). An article recently published in The Journal of Physiology by Esposito et al. (2018) examined the structural, functional and cellular properties of this skeletal muscle in patients with HFrHF following exercise training. Specifically, the group wanted to determine if exercise can reverse the HFrHF-induced changes in skeletal muscle. To do this, six patients with New York Heart Association functional class II–III HFrEF followed a chronic exercise protocol and were measured for various parameters before and after the training. Knee extensor exercises were employed to provide acute exercise stress at baseline and after training. Pre- and post-training data were compared with each other and with six healthy matched controls who did not undergo the 8-week chronic exercise pre-training. Subjects were well matched between HFrEF and healthy controls based on their biophysical profiles. Body mass was the only parameter that differed between the HFrEF and control groups. The exercise programme implemented in the study was adhered to by 98% of the subjects and resulted in a 15% increase in quadriceps muscle mass. Following training in HFrEF patients, muscle fibre cross-sectional area increased, with a greater percentage area of type I fibres and concomitant reduction in type II fibres. After training, the HFrEF group reached control levels for maximum work rate (WRmax) and peak pulmonary oxygen consumption () on cycle exercise despite being significantly lower pre-training. The same trend was observed for the knee extensor WRmax in the post-training HFrEF group versus control. Before exercise training, HFrEF patients had worse perfusion and in their muscle while also having a 15% higher vascular resistance in their legs when compared to controls. These all improved significantly when comparing post-training findings to pre-training baselines. Leg blood flow and were also no longer statistically different from control levels after training. When assessing levels of angiogenesis in HFrEF and controls, no difference was seen in the capillary-to-fibre ratio. Training in HFrEF patients resulted in a significant increase in the capillary-to-fibre ratio. Interestingly, levels of vascular endothelial growth factor (VEGF) mRNA in the vastus lateralis of a rested leg did not differ between controls and HFrEF, regardless of chronic exercise training. This finding was further explored to show that after an acute exercise stimulus (knee extensor), VEGF mRNA rises significantly above rested levels in control and pre-training patients, but not in those who followed the 8-week exercise protocol. Despite this, capillarity (capillary density) was unchanged by exercise training. Finally, mitochondrial volume density was shown to be 22% lower in HFrEF patients compared to controls. Exercise training returned mitochondrial volume density back to control levels. The work by Esposito et al. provides evidence for structural and functional plasticity of skeletal muscle in HFrEF patients undergoing chronic submaximal exercise training. It involved an in-depth investigation of molecular, cellular and vascular changes in these patients, both pre- and post-submaximal exercise training. Additionally, it highlights the benefits of prolonged, submaximal training programmes in order to promote muscle growth and angiogenesis, and to reduce vascular resistance (Fig. 1). Traditional exercise protocols used in rehabilitation for patients with HFrEF incorporate whole body (cycle) exercise, which puts significant stress on both central and peripheral haemodynamics. While this practice has consistently produced beneficial results, exercise intolerance and poor adherence can limit its effectiveness (Fleg et al. 2015). Reduced exercise tolerance and poor adherence in patients with HF is an independent predictor of hospital readmission (Asrar Ul Haq et al. 2015). Implementation of tolerable submaximal chronic exercise programmes may provide additional non-pharmacological options to manage HF and reduce hospital readmission. This study supports the notion that submaximal chronic exercise training in HFrEF patients is better tolerated and promotes remodelling of muscle and its surrounding vasculature. It demonstrates that submaximal chronic exercise can reduce peripheral vascular resistance and sympathetic nervous system activation. Angiogenesis and mitochondrial volume density were increased by the exercise regimen. While this study contributes to the elucidation of underlying physiological changes following chronic submaximal exercise, it does have some limitations. Additional control groups would have enabled a clearer analysis of the effect of exercise on skeletal muscle structure and function. Healthy controls that receive a similar training regimen to that of the study population would provide a baseline comparison for muscular and vascular changes. A second control using a biopsy of non-trained muscle after the exercise course would provide a better reference for magnitude of change seen in trained muscle. This would also control for systemic changes caused by targeted training. Additionally, a larger sample size would provide greater insight into the muscular and vascular changes observed in HFrEF patients due to greater statistical power. That said, patient recruitment is difficult for a study of this nature. Finally, the potential side effects of the medication taken by some of the HFrEF patients were not controlled for. Rhabdomyolysis is a rare but serious side effect of statin use, which can be exacerbated by physical activity, and should be considered in studies investigating muscle physiology following acute and chronic exercise (Diechmann et al. 2015). It is worth noting that to control for medications may be more of an idealistic notion, as finding patients with the same drug regimens who do not have heart failure themselves would severely limit potential candidates. Future studies derived from the findings of this study could focus on comparing HFrEF patients who undergo submaximal chronic exercise courses to control subjects who also undergo the same training programme. Many of the conclusions from this study focus on exercise training returning skeletal muscle biophysical parameters to control levels. Adding this control group would provide insight as to whether the HFrEF patients are still limited in their muscular function and adaptation compared to controls. Similarly, a project which focuses on submaximal training that progresses to full body exercise programmes would provide insight into whether these patients can tolerate more rigorous exercise if they are prepared adequately. Addressing changes in myocardial tissue before and after exercise would be useful to compare alterations seen in skeletal muscle. Finally, the authors mention applying the concepts from this study to other chronic diseases. Findings from the setting of chronic obstructive pulmonary diseases and chronic renal failure would be interesting as they both have elements of tissue hypoxia in their pathogenesis. As the population ages, the prevalence of heart failure is set to increase. Advances in medicine are prolonging the lifespan of patients with heart failure and as such, a greater focus needs to be put on their quality of life. This pilot study provides evidence for the role of tolerable exercise regimens in the clinical management of HFrEF patients. It shows that submaximal chronic exercise can induce structural and functional changes to skeletal muscle in HFrEF patients, thereby showing that this population retains some of their muscular plasticity. The responsiveness of their mitochondrial biogenesis, capillarity and fibre type remodelling all support this conclusion. The resilience of skeletal muscle in HFrEF suggests that these patients may be able to build muscle in an incremental fashion, thus allowing them to partially regain their autonomy. None declared. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.

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