Discussion
This is the first study to evaluate the prevalence and clinical impact of muscle wasting in patients with chronic HF. A total of 19.5% of patients in this mixed cohort with clinically relevant HF presented with clinical features diagnostic of muscle wasting, defined using the criteria suggested to diagnose sarcopenia. These patients exhibit reduced exercise capacity as evidenced by significantly lower muscle strength in both the legs and the arms, reduced LVEF, and worse exercise capacity in treadmill performance as well as in the 6-min corridor and 4-m walk test.
One of the key clinical features of HF is the reduction in exercise capacity that limits patients' activities of daily life. Such reduction in exercise capacity can be clinically assessed using the peak VO2 or exercise time assessment and by the measurement of walking distance in the 6-min walk test. Reduced exercise capacity impacts on the patients' quality of life and prognosis. Preserving muscle mass and function can be viewed as pivotal to the maintenance of exercise capacity and, thus, quality of life.
It is interesting to note that the muscle mass is lost in chronic disease much earlier than, for example, fat tissue. Weight loss has been identified as a major player in unfavourably influencing the prognosis in patients with chronic HF. The types of tissue that cause weight loss have not been identified so far. The decline of muscle mass and muscle strength is part of the pathophysiology of the ageing process. Indeed, the structure of muscles changes in healthy ageing. For example, the character of muscle fibres switches from that of fast type 2 to slow type 1 fibres, and the muscle mass is replaced by adipose tissue. All these changes lead to a decrease in muscle quality. According to data obtained in healthy adults aged 60–70 years, 5–13% are affected by pathologically important muscle wasting. In our study, ~19.5% are affected by muscle wasting, thus, considering the mean age of our patients, many more subjects than expected for ageing alone. One can assume that this chronic process is partly responsible for the greater loss of muscle mass. The fact that no difference was detected between patients with vs. those without muscle loss in terms of the ratio of muscle strength over muscle mass argues that the strength of the individual muscle unit is not altered.
In general, sarcopenic elderly subjects display several features that may contribute to reduced functional capacity and disability, and an increase in hospitalization and healthcare costs. The latter two are particularly influenced by a higher risk of falls. In addition, sarcopenic elderly subjects display an increased mortality rate. Previous studies have highlighted the presence of muscle wasting in subjects with chronic illnesses other than chronic HF. The Third National Health and Nutrition Examination Survey (NHANES III) study, for example, revealed the relation between impaired kidney function and an increase in the prevalence of muscle wasting. Muscle wasting is also common among patients with chronic obstructive pulmonary disease. Furthermore, the Korean Sarcopenic Obesity Study (KSOS) detected sarcopenia/muscle loss in patients with type 2 diabetes mellitus as well as in patients with liver cirrhosis evaluated for liver transplantation.
The pathophysiology of muscle wasting in elderly healthy subjects or in patients with chronic illnesses is less clear. It is suspected that inflammatory processes may lead to metabolic changes. These changes lead to a imbalance between anabolic and catabolic signals. This stimulation of catabolic pathways directly affects the skeletal muscle and induces protein breakdown. Pro-inflammatory cytokines, like IL-6 and TNF-α, intensify catabolism. High levels of these inflammatory mediators activate the ubiquitine-proteasome pathway that degrades proteins. This is one of the pathways potentially involved in muscle wasting. Indeed, patients with chronic illnesses often present with a high-serum level of these pro-inflammatory cytokines, and we also detected significantly elevated serum levels of IL-6 in our cohort of patients.
The mechanisms of muscle wasting and cachexia may be overlapping to some degree. Indeed, patients with muscle wasting may also display features of cachexia. The presence of cachexia implies a loss of body weight, usually defined as a loss of 5% of body weight within 6 months or less in the presence of chronic illness. However, the term cachexia does not imply the loss of a particular type of tissue, and the tissues involved may embrace muscle, fat tissue, or bone. Patients with muscle wasting, on the other hand, lose functional tissue, and the degree of muscle wasting may or may not lead to the development of cachexia as well. Cachexia, in turn, may or may not be associated with functional impairment, although one would usually expect a loss of exercise capacity in these patients as well. With regard to developing novel therapeutic approaches, it may be important to differentiate the two distinct clinical phenomena, because patients may in clinical practice present with muscle wasting only, with cachexia only, or with both at the same time. Patients with either diagnosis may benefit from tailored therapies that emphasize gaining muscle or body weight.
Physical fitness and exercise training have a great impact in preventing the loss of muscle mass. Other arrangements, such as nutritional supplementation of amino acids, hormone substitution, especially testosterone, or vitamin D replacements, are other therapeutic options in affected patients. These possibilities are currently limited to patients outside clinical routine, for example, in patients with terminal disease, as evidence from randomized trials is scarce and no guidance has been implemented in the treatment guidelines. Some limitations, however, should be considered when looking at our data. We did not include a prospectively recruited group of control subjects but rather analysed data from a historical reference group. In addition, the inclusion criteria of SICA-HF are broad. Although we are confident that our data can thus be extrapolated to many patients with clinical signs of HF, it is not clear whether our data can be reproduced in, for example, patients with HFpEF using stricter criteria such as the ones suggested by the European Society of Cardiology. Finally, we did not differentiate patients with and without cachexia at study entry. Muscle wasting is a process that is restricted to the muscle and it does not usually cause weight loss. Thus, patients may present with muscle wasting alone or in combination with cachexia. Future studies need to consider this point.
In conclusion, this single-centre experience from the multinational SICA-HF study shows that muscle wasting is a frequent co-morbidity among patients with chronic HF. Compared with patients without muscle wasting, patients affected by muscle wasting have lower muscle strength, worse exercise capacity in treadmill performance and in walking exercise tests, and reduced LVEF. Larger studies are required to pave the way for developing tailored therapies for this important subgroup of patients.