Muscling Up to Improve Heart Failure Prognosis

This article refers to ‘Comparison of sarcopenia and cachexia in men with chronic heart failure: results from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF)’ by A. Emami et al., published in this issue on pages 1580–1587. Obesity, defined as excess fat mass (FM) that impairs health, is an independent risk factor for several cardiovascular diseases, particularly for heart failure (HF). The relationship between obesity and HF is not as straightforward once HF is diagnosed, especially regarding HF prognosis, where many studies and meta-analyses indicate an obesity paradox.1-3 Increased body weight and body mass index (BMI) typically, in fact, confer protection in the setting of HF. However, overweight and obesity have been often defined using only the BMI, which is a good surrogate of adiposity at the population level,4 but lacks accuracy in detecting body composition abnormalities in specific pathophysiologic conditions, including HF, in which changes in body weight may result from changes in body composition compartments different from FM, such as lean mass (LM), which includes skeletal muscle mass (SMM) and total body water.2, 5 Particularly, increased levels of SMM are associated with improved prognosis in a number of chronic diseases, including HF.2, 5 Due to obvious difficulties related to the direct assessment of SMM, LM is considered its best surrogate, especially appendicular, which includes LM of arms and legs, being a major determinant of cardiorespiratory fitness (CRF), and its role has received intense scrutiny in the last decade, as it can also be used to define sarcopenia and sarcopenic obesity.2, 5 Although a universal definition of sarcopenia has not been established, it is typically defined as a reduction in appendicular LM amount and functionality, with or without weight loss. When sarcopenia is paralleled by an excess FM (i.e. obesity), the definition of sarcopenic obesity can be used, to highlight the further increased cardiometabolic risk resulting from excess FM and reduced LM. Importantly, while sarcopenia and sarcopenic obesity require a LM loss for their definition, a less specific condition in terms of body composition compartment abnormalities associated with poor prognosis in HF is termed cachexia, which is typically associated with unintentional weight loss, including both FM and LM. The role of cachexia and sarcopenia has often been investigated independently, therefore, to date it is unclear whether one of the two is associated with less favourable prognosis, or even CRF. Of note, increased BMI, within the limitations of its use, is typically associated with lower degree of cachexia and greater LM, which have been proposed as potential mechanisms explaining the improved prognosis reported in patients with HF and greater BMI.2, 5 In this issue of the Journal, Emami and colleagues6 performed an elegant cross-sectional analysis in 207 male patients with HF enrolled in the SICA-HF study investigating the role of sarcopenia, cachexia and the combination of the two, on CRF, muscle strength, quality of life (QoL) and other HF metrics. Although limited by the small sample size, lack of female patients, and the majority of patients presenting with HF with a left ventricular ejection fraction ≤40%, the study provided important data to inform potential future therapeutic targets for clinical trials. Particularly, patients with cachexia and/or sarcopenia presented with worse CRF measured as peak oxygen consumption and quadriceps strength compared to those without body composition abnormalities. Interestingly, 6-minute walk test, handgrip strength and questionnaires, measures of functional capacity, muscle strength and QoL were only reduced in patients with sarcopenia, but not in those with cachexia, compared to non-sarcopenic and non-cachectic HF counterparts, perhaps suggesting that the reduced peak oxygen consumption seen in cachectic patients may result from reduced LM in the legs. As expected, when cachexia and sarcopenia coexist (i.e. sarcopenic cachexia), CRF, muscle strength and QoL were further impaired. Interestingly, no major differences were found in regard to systemic low-grade inflammation markers (i.e. high-sensitivity C-reactive protein and interleukin-1), except for interleukin-6, which was increased by about two-fold in sarcopenic non-cachectic HF patients compared to those without sarcopenia and cachexia. Another interesting piece of information provided by the study is the surprisingly high prevalence of body composition abnormalities (>40%) in patients with HF, supporting the concept that perhaps therapeutics aimed at increasing LM or at least aimed at preventing its loss, should be implemented in patients with HF, even before body composition abnormalities occur. While resistance training and aerobic exercise alone are associated with improved CRF, the combination of the two strategies can result in even greater increase in CRF, perhaps by increasing the amount of LM, but also its functionality.7 Fat mass and FM distribution are also major contributors to exercise intolerance and prognosis in HF,2, 5, 8, 9 particularly in HF with preserved ejection fraction, in which the prevalence of obesity is extremely high.2, 5 However, in this study there were not major differences between cachexia and sarcopenia alone compared to non-cachectic and non-sarcopenic patients, further supporting that at least in the investigated population, the reduced LM is perhaps a major driver for reduced CRF. Because the European HF population investigated in the SICA-HF is clearly different from the typical HF population investigated in the US, in which obesity is more prevalent and typically representing the majority of the investigated patients, studies similar to the one presented here are highly encouraged in the US. Furthermore, the study proposed that LM loss, independent of weight loss, is associated with worse CRF and QoL (Figure 1); however, the study did not assess the role of weight loss, and more specifically of unintentional vs. intentional weight loss, the latter typically associated with improved CRF when occurring in the setting of exercise training.10 We could speculate that intentional weight loss obtained with exercise may reduce LM and SMM loss typically associated with unintentional weight loss. Of note, the effects of intentional weight loss on long-term clinical outcomes in HF, as well as most cardiovascular diseases other than atrial fibrillation, remain unknown.1-3, 5, 11, 12 Importantly, non-pharmacologic interventions, such as dietary interventions aimed at increasing the adherence to a Mediterranean dietary pattern or at increasing the consumption of unsaturated fatty acids to improve body composition, independent of body weight changes, are also attractive strategies and recently being investigated in patients with HF.13, 14 Due to the limited sample size, the study by Emami and colleagues6 could not address the effects of sarcopenia and/or cachexia and of specific body composition compartments on clinical outcomes (i.e. HF-related hospitalizations, cardiovascular mortality, all-cause mortality), calling for further larger studies with longer follow-up to better assess the impact of body composition, including the impact of sarcopenia and cachexia, on subsequent prognosis. In conclusion, the effects of body composition abnormalities, particularly a reduction in appendicular LM (i.e. sarcopenia) and unintentional weight loss (i.e. cachexia), are associated with poor CRF, muscle strength and QoL compared to non-sarcopenic non-cachectic patients with HF, with sarcopenia negatively affecting such parameters even more so than does cachexia alone (Figure 1). Interestingly, progressive reductions of BMI occur with cachexia, sarcopenia, and the combination, probably substantially explaining the BMI and HF prognosis paradox. These data suggest, therefore, that sarcopenia is even worse than cachexia and provide support for the premise of muscling up to improve HF prognosis.15 S.C. is supported by the VCU DOIM Pilot Project Grant Program 2017 and by the VCU Pauley Heart Center Pilot Project Grant Program 2017. Conflict of interest: none declared.