**2. Cachexia in heart failure and cancer**

Cachexia (from the Greek 'kakos' for bad, and 'hexis' for condition) was first described, as a result of chronic disease, in 1860 by the French physician Charles Mauriac, which consider only as muscle disease, close to a metabolic syndrome [25, 33, 34]. Over the years, the term cachexia has been updated and nowadays is considered as a multifactorial syndrome characterized by loss of appetite, body weight (with significant muscle wasting), which may or not extend to adipose tissue. The advancement of cachexia decreases muscle function, worse fatigue, and reduces the quality of life and life expectancy of patients [21, 25, 35]. Also, recent studies demonstrate that cachexia can communicate with multiple organs, such as the heart, adipose tissue, intestine, kidneys, and liver, helping the development and progression of disease [31, 36].

Among the chronic diseases that commonly progress to cachexia, HF and CA have the largest number of affected patients [37]. Anker et al. [38] were the first authors to describe muscle wasting in HF patients, where patients with reduced body weight were diagnosed with cardiac cachexia. In 2012, the European Society of Cardiology (ESC) recognized cachexia as a comorbidity of HF [39] and in 2016 the ESC began to recommend the non-reduction of body weight in HF for obese or overweight patients [40]. In HF, the involuntary loss of body weight is considered an independent factor to reduce physical capacity, and poorer quality of life [38, 41].

The cardiac cachexia prognosis is extremely complex, with annual mortality about 20 to 40%, reaching up to 50% of patients death after 18 months of diagnosis [37, 38]. On the other hand, the cardiac cachexia incidence can range from 10–39%, depending on study design and HF patients prognosis [42, 43]. In the SICA-HF study (studies investigating co-morbidities aggravating HF), investigated cardiac caquexia in 207 HF patients with reduced ejection fraction (HFrEF) and preserved (HFpEF), of these 21% had cachexia independent of ejection fraction [44]. Studies show that cardiac cachexia would be more present in patients with HFrEF, being associated with a 3-fold higher risk of death from all causes compared to those with HFpEF [38]. On the other hand, implications of cardiac cachexia in patients with HFpEF still need further studies [42]. Valentova et al. [42], based on their clinical experience, reported that patients with HFpEF shows cardiac cachexia signs only in advanced stages of HF, possibly acting in a different biological pathway in the development of the disease [45].

Numerous changes between central and peripheral organs were observed in patients with HF [46], followed by abnormalities in skeletal muscle such as capillary rarefaction, type I to II fiber switch, impaired oxidative metabolism, decreased excitation-contraction coupling, and muscle atrophy [47, 48]. In general, cardiac cachexia is responsible for muscle atrophy in the early stages of the disease and may progress to loss of adipose tissue, just in the late stages of the disease [42]. Regarding myocardial impairment in cardiac cachexia, more solid data are needed to help distinguish the structural and functional changes related to cardiac disease from those found in cardiac cachexia. Currently, contradictory data demonstrate cardiomyocytes wasting with or without cardiac impairment [22, 49]. It is necessary to emphasize to achieve correct values of cardiac cachexia it is necessary to exclude edema values from the total body weight, a difficult task for patients with HF that hinders the accurate diagnosis of cardiac cachexia [32].

In CA, depending on the stage and development of the disease, 80% of patients have cachexia, leading to death of 30% of these patients [15, 50]. Fearon et al. [51] classifies CA cachexia into 3 stages: pre-cachexia, cachexia, and refractory cachexia. It is necessary to understand that not all patients will go through the

#### **Figure 1.**

*Common symptoms of cardiac and cancer cachexia.*

three stages. Then, the type and stage of CA can influence the progression of cachexia, as well as systemic inflammation, low food intake. In addition, CA cachexia can reduce tolerance to responses to chemotherapy treatments, worsening the prognosis of patients [50, 52].

Regarding the incidence of CA cachexia, the type of cancer may influence, since patients with gastric or pancreatic CA have over 80% of incidence. On the other hand, patients with lung, prostate, or colon CA have an incidence of 50%, and 40% of patients with advanced breast, head, and neck tumors and some leukemias develop the syndrome [35, 53, 54].

Both cardiac and CA cachexia share symptoms, as described in **Figure 1**, but cardiac cachexia presents a slower and more gradual muscle wasting [55] when compared to CA, with a progressive and rapid muscle wasting, leading to earlier death compared to cachexia from cardiac causes [56]. The international consensus for the diagnosis of cachexia is similar between HF and AC, namely: body weight loss >5% or > 2% in individuals with low BMI (< 20 kg/m<sup>2</sup> ) or loss of skeletal muscle mass in 12 months [31, 51].
