Sarcopenia and cachexia are significant medical problems with a high disease-related burden in cardiovascular illness. Muscle wasting and weight loss are very frequent particularly in chronic heart failure and they relate to poor prognosis. Although clinically largely underestimated, the fields of cachexia and sarcopenia are of great relevance to cardiologists. In cachexia and sarcopenia a significant number of research publications related to basic science questions of muscle wasting and lipolysis were published between 2010 and 2012. Recently, the two processes of muscle wasting and lipolysis were found to be closely linked. Treatment research in pre-clinical models involves studies on a number of different therapeutic entities, including ghrelin, selective androgen receptor modulators (SARMs), as well as drugs targeting myostatin or melanocortin-4. In the human setting, studies using enobosarm (a SARM) and anamorelin (ghrelin) are in phase III. The last 3 years have seen significant efforts to define the field using consensus statements. In the future, these definitions should also be considered for guidelines and treatment trials in cardiovascular medicine. The current review aims to summarize important information and development in the fields of muscle wasting, sarcopenia and cachexia, focusing on findings in cardiovascular research, in order for cardiologists to have a better understanding of the progress in this still insufficiently known field.

Background

Heart failure (HF) patients often depend on driving for access to specialty care. We analyzed a public-use copy of the Cardiovascular Health Study (CHS) data to determine if HF is a risk factor for driving cessation and to identify other risk factors for driving cessation among those with HF.

Methods and results

Of the 5383 community-dwelling drivers ≥65 years (mean age, 73 years, 55% women, 13% African American), 839 had HF: 246 had baseline prevalent HF and 593 developed incident HF before driving cessation during 9 years of follow-up. Incident driving cessation occurred at rates of 3980 and 3709 per 10,000 person-years of follow-up for those with and without HF, respectively (unadjusted hazard ratio {HR} associated with HF as a time-varying variable, 2.13; 95% confidence interval {CI}, 1.83–2.47; p<0.001). This association remained unchanged after multivariable risk adjustment (HR, 1.43; 95% CI, 1.21–1.68; p<0.001). Among the 839 older drivers with HF, independent predictors for incident driving cessation were age ≥75 years (HR, 1.99; 95% CI, 1.44–2.73; p<0.001), female gender (HR, 1.93; 95% CI, 1.37–2.74; p<0.001), difficulty walking half a mile (HR, 1.47; 95% CI, 1.04–2.08; p=0.028), vision problems (HR, 1.47; 95% CI, 1.07–2.02; p=0.018), and stroke as a time-varying covariate (HR, 1.96; 95% CI, 1.38–2.79; p<0.001).

Conclusion

HF is an independent risk factor for incident driving cessation among community-dwelling older drivers. Several patient characteristics predicted driving cessation in older HF patients, which may be targets for interventions to prevent driving cessation among these patients.

Human muscle undergoes constant changes. After about age 50, muscle mass decreases at an annual rate of 1–2 %. Muscle strength declines by 1.5 % between ages 50 and 60 and by 3 % thereafter. The reasons for these changes include denervation of motor units and a net conversion of fast type II muscle fibers into slow type I fibers with resulting loss in muscle power necessary for activities of daily living. In addition, lipids are deposited in the muscle, but these changes do not usually lead to a loss in body weight. Once muscle mass in elderly subjects falls below 2 standard deviations of the mean of a young control cohort and the gait speed falls below 0.8 m/s, a clinical diagnosis of sarcopenia can be reached. Assessment of muscle strength using tests such as the short physical performance battery test, the timed get-up-and-go test, or the stair climb power test may also be helpful in establishing the diagnosis. Serum markers may be useful when sarcopenia presence is suspected and may prompt further investigations. Indeed, sarcopenia is one of the four main reasons for loss of muscle mass. On average, it is estimated that 5–13 % of elderly people aged 60–70 years are affected by sarcopenia. The numbers increase to 11–50 % for those aged 80 or above. Sarcopenia may lead to frailty, but not all patients with sarcopenia are frail—sarcopenia is about twice as common as frailty. Several studies have shown that the risk of falls is significantly elevated in subjects with reduced muscle strength. Treatment of sarcopenia remains challenging, but promising results have been obtained using progressive resistance training, testosterone, estrogens, growth hormone, vitamin D, and angiotensin-converting enzyme inhibitors. Interesting nutritional interventions include high-caloric nutritional supplements and essential amino acids that support muscle fiber synthesis.

Iron is a micronutrient essential for cellular energy and metabolism, necessary for maintaining body homoeostasis. Iron deficiency is an important co-morbidity in patients with heart failure (HF). A major factor in the pathogenesis of anaemia, it is also a separate condition with serious clinical consequences (e.g. impaired exercise capacity) and poor prognosis in HF patients. Experimental evidence suggests that iron therapy in iron-deficient animals may activate molecular pathways that can be cardio-protective. Clinical studies have demonstrated favourable effects of i.v. iron on the functional status, quality of life, and exercise capacity in HF patients. It is hypothesized that i.v. iron supplementation may become a novel therapy in HF patients with iron deficiency.

Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7–8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject.

Aims

The purpose of this study was to evaluate the cost-effectiveness of iron repletion using intravenous (i.v.) ferric carboxymaltose (FCM) in chronic heart failure (CHF) patients with iron deficiency with or without anaemia. Cost-effectiveness was studied from the perspective of the National Health Service in the UK.

Methods and results

A model-based cost-effectiveness analysis was used to compare iron repletion with FCM with no iron treatment. Using data from the FAIR-HF trial and publicly available sources and publications, per patient costs and clinical effectiveness of FCM were estimated compared with placebo. Cost assessment was based on study drug and administration costs, cost of CHF treatment, and hospital length of stay. The incremental cost-effectiveness ratio (ICER) of FCM use was expressed as cost per quality-adjusted life year (QALY) gained, and sensitivity analyses were performed on the base case. The time horizon of the analysis was 24 weeks. Mean QALYs were higher in the FCM arm (difference 0.037 QALYs; bootstrap-based 95% confidence interval 0.017–0.060). The ICER of FCM compared with placebo was €4414 per QALY gained for the FAIR-HF dosing regimen. Sensitivity analyses confirmed the base case result to be robust.

Conclusion

From the UK payers’ perspective, managing iron deficiency in CHF patients using i.v. FCM was cost-effective in this analysis. The base case ICER was clearly below the threshold of €22 200–€33 300/QALY gained (£20 000–£30 000) typically used by the UK National Institute for Health and Clinical Excellence and proved to be robust in sensitivity analysis. Improved symptoms and better quality of life contributed to this result.

Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Anaemia has been associated with adverse outcomes in CKD populations, and the ability to modify this parameter with the use of erythropoiesis-stimulating agents has been a topic of much debate. Data on the effects of anaemia correction on cardiovascular outcomes and survival in CKD have been both discordant and controversial. It is hoped that the ongoing Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT) will help to redress the current clinical gaps and the uncertainty over the optimal management of anaemia in patients with CKD and type 2 diabetes mellitus. Anaemia is also increasingly being recognized as an important comorbid condition in patients with symptomatic heart failure. The ongoing Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HFTM) trial is designed to determine whether the treatment of anaemia improves outcomes in such patients.

Growing awareness that heart failure, renal impairment, and anaemia are frequent co-morbidities which can exacerbate one another in a vicious circle of clinical deterioration has led to the concept of the cardiorenal anaemia syndrome (CRAS). The role of iron deficiency within this complex interplay has been less well examined. Scrutiny of data from the recent FAIR-HF trial raises a new hypothesis: is it time for ‘CRAS’ to be supplemented with new acronyms such as CRIDS (cardiorenal–iron deficiency syndrome) or even CRAIDS (cardiorenal–anaemia–iron deficiency syndrome)? Iron deficiency occurs frequently in heart failure patients with or without anaemia. It not only impairs oxygen transport through reduced erythropoiesis, but adversely affects oxidative metabolism, cellular energetics, and immune mechanisms, and the synthesis and degradation of complex molecules such as DNA. One large observational study in patients with heart failure found iron deficiency to be an independent predictor of death or urgent heart transplantation (hazard ratio 1.58, 95% confidence interval 1.14–2.17, P = 0.005). In the FAIR-HF trial, i.v. iron therapy was associated with significant improvements in physical functioning in iron-deficient patients with heart failure, even in non-anaemic patients in whom haemoglobin levels did not change following i.v. iron administration. Key questions regarding the use of i.v. iron supplementation in the setting of heart failure merit exploration and could readily be answered by appropriately designed clinical trials. It is to be hoped that these important clinical trials are conducted, to permit a more subtle characterization of the patient's pathological condition and interventional requirements.

Body size, particularly large, is a matter of concern among the lay public. Whether this is justified depends upon the state of health and should be judged individually. For patients with established chronic disease, there is sufficient evidence to support the benefits of large body size, i.e., the obesity paradox. This uniform finding is shared over a variety of cardiovascular, pulmonary, and renal diseases and is counterintuitive to the current concepts on ideal body weight. The scientific community has to increase the awareness about differences for optimal body size in health and disease. Simultaneously, clinicians have to be aware about body weight dynamics implications and should interpret the changes in the context of an underlying disease in order to implement the best available management.

Body size, particularly large, is a matter of concern among the lay public. Whether this is justified depends upon the state of health and should be judged individually. For patients with established chronic disease, there is sufficient evidence to support the benefits of large body size, i.e., the obesity paradox. This uniform finding is shared over a variety of cardiovascular, pulmonary, and renal diseases and is counterintuitive to the current concepts on ideal body weight. The scientific community has to increase the awareness about differences for optimal body size in health and disease. Simultaneously, clinicians have to be aware about body weight dynamics implications and should interpret the changes in the context of an underlying disease in order to implement the best available management.

Aim

To determine if the association between hyperuricaemia and poor outcomes in heart failure (HF) varies by chronic kidney disease (CKD).

Methods and results

Of the 2645 systolic HF patients in the Beta-Blocker Evaluation of Survival Trial with data on baseline serum uric acid, 1422 had hyperuricaemia (uric acid ≥6 mg/dL for women and ≥8 mg/dL for men). Propensity scores for hyperuricaemia, estimated for each patient, were used to assemble a matched cohort of 630 pairs of patients with and without hyperuricaemia who were balanced on 75 baseline characteristics. Associations of hyperuricaemia with outcomes during 25 months of median follow-up were examined in all patients and in those with and without CKD (estimated glomerular filtration rate of <60 mL/min/1.73 m2). Hyperuricaemia-associated hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality and HF hospitalization were 1.44 (1.12–1.85, P = 0.005) and 1.27 (1.02–1.58, P = 0.031), respectively. Hazard ratios (95% CIs) for all-cause mortality among those with and without CKD were 0.96 (0.70–1.31, P = 0.792) and 1.40 (1.08–1.82, P = 0.011), respectively (P for interaction, 0.071), and those for HF hospitalization among those with and without CKD were 0.99 (0.74–1.33, P = 0.942) and 1.49 (1.19–1.86, P = 0.001), respectively (P for interaction, 0.033).

Conclusion

Hyperuricaemia has a significant association with poor outcomes in HF patients without CKD but not in those with CKD, suggesting that hyperuricaemia may predict poor outcomes when it is primarily a marker of increased xanthine oxidase activity, but not when it is primarily due to impaired renal excretion of uric acid.

Aims

Obesity is paradoxically associated with survival benefit in patients with chronic heart failure (HF). However, obesity complicates the management of diabetes mellitus (DM), which is common in HF. Yet, little is known about the impact of obesity in HF patients with DM. Therefore, we examined the association between obesity and outcomes in propensity-matched cohorts of HF patient with and without DM.

Methods and results

Of the 7788 participants with chronic mild to moderate HF in the Digitalis Investigation Group trial, 7379 were non-cachectic [body mass index (BMI) ≥20 kg/m2] at baseline. Of these, 2153 (29%) had DM, of whom 798 (37%) were obese (BMI ≥30 kg/m2). Of the 5226 patients without DM, 1162 (22%) were obese. Propensity scores for obesity were used to separately assemble 636 pairs of obese and non-obese patients with DM and 770 pairs of obese and non-obese patients without DM, who were balanced on 32 baseline characteristics. Among matched patients with DM, all-cause mortality occurred in 38 and 39% of obese and non-obese patients, respectively [hazard ratio (HR) when obesity was compared with no obesity 0.99; 95% confidence interval (CI) 0.80–1.22; P = 0.915]. Among matched patients without DM, all-cause mortality occurred in 23 and 27% obese and non-obese patients, respectively (HR associated with obesity 0.77; 95% CI 0.61–0.97; P = 0.025).

Conclusion

In patients with chronic mild to moderate HF and DM, obesity confers no paradoxical survival benefit. Whether intentional weight loss may improve outcomes in these patients needs to be investigated in future prospective studies.

Aims

Patients with chronic heart failure (CHF) show impaired health-related quality of life (HRQoL), an important target for therapeutic intervention. Impaired iron homeostasis may be one mechanism underlying the poor physical condition of CHF patients. This detailed subanalysis of the previously published FAIR-HF study evaluated baseline HRQoL in iron-deficient patients with CHF and the effect of intravenous ferric carboxymaltose (FCM) on HRQoL.

Methods and results

FAIR-HF randomized 459 patients with reduced left ventricular ejection fraction and iron deficiency, with or without anaemia, to FCM or placebo (2:1). Health-related quality of life was assessed at baseline and after 4, 12, and 24 weeks of therapy using the generic EQ-5D questionnaire and disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ). Baseline mean Visual Analogue Scale (VAS) score was 54.3 ± 16.4 and KCCQ overall summary score was 52.4 ± 18.8. Ferric carboxymaltose significantly improved VAS and KCCQ (mean differences from baseline in KCCQ overall, clinical and total symptom scores, P< 0.001 vs. placebo) at all time points. At Week 24, significant improvement vs. placebo was observed in four of the five EQ-5D dimensions: mobility (P= 0.004), self-care (P< 0.001), pain/discomfort (P= 0.006), anxiety/depression (P= 0.012), and usual activity (P= 0.035). Ferric carboxymaltose improved all KCCQ domain mean scores from Week 4 onward (P≤ 0.05), except for self-efficacy and social limitation. Effects were present in both anaemic and non-anaemic patients.

Conclusions

HRQoL is impaired in iron-deficient patients with CHF. Intravenous FCM significantly improved HRQoL after 4 weeks, and throughout the remaining study period. The positive effects of FCM were independent of anaemia status.

Background

Cancer cachexia is characterized by loss of both adipose and skeletal muscle tissue and by an increased production of proinflammatory cytokines. Ursodeoxycholic acid (UDCA), a bile acid used for centuries in the treatment of liver disease, is known to confer anti-inflammatory and anti-apoptotic effects as well as beneficial effects on mitochondrial integrity and cell signaling. We hypothesized that UDCA ameliorates the wasting process in the Yoshida hepatoma tumor model. In addition, we sought to establish if UDCA exerts beneficial effects on survival in this model.

Methods and results

Forty-seven male rats were inoculated intraperitoneally with 108 Yoshida hepatoma AH-130 cells and treated with placebo or one of two different doses of UDCA, 25 or 100 mg/kg daily. Body weight, body composition, and activity indicators were measured over the course of study up to day 16. UDCA treatment had no effect on tumor growth, loss of body weight, and loss of fat mass. Compared with placebo, low-dose UDCA improved tissue loss in the lung (p = 0.022) and tended to reduce tissue loss in brown adipocytes (p = 0.06), gastrocnemius muscle (p = 0.06), extensor digitorum longus muscle (p = 0.09), and soleus muscle (p = 0.07). Compared with placebo, high-dose UDCA tended to reduce the loss of lean body mass (p = 0.06), lung tissue (p = 0.1), white adipose tissue (p = 0.11), and gastrocnemius muscle (p = 0.11). The activity and food intake were not altered in tumor-bearing rats by either dose of UDCA. Both doses tended to decrease the mortality rate in tumor-bearing rats, (hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.17–1.04; p = 0.061 for low-dose UDCA; HR, 0.44; 95% CI, 0.18–1.05; p = 0.065 for high-dose UDCA).

Conclusion

UDCA treatment in the Yoshida hepatoma model showed a trend towards attenuation of tissue loss in animals with progressive weight loss in cancer cachexia. Tumor growth and activity indicators were not altered. Both doses of UDCA tended to reduce the mortality rates in tumor-bearing animals. Larger studies with longer follow-up are required to verify these findings.

Background

Cancer cachexia is characterized by loss of both adipose and skeletal muscle tissue and by an increased production of proinflammatory cytokines. Ursodeoxycholic acid (UDCA), a bile acid used for centuries in the treatment of liver disease, is known to confer anti-inflammatory and anti-apoptotic effects as well as beneficial effects on mitochondrial integrity and cell signaling. We hypothesized that UDCA ameliorates the wasting process in the Yoshida hepatoma tumor model. In addition, we sought to establish if UDCA exerts beneficial effects on survival in this model.

Methods and results

Forty-seven male rats were inoculated intraperitoneally with 108 Yoshida hepatoma AH-130 cells and treated with placebo or one of two different doses of UDCA, 25 or 100 mg/kg daily. Body weight, body composition, and activity indicators were measured over the course of study up to day 16. UDCA treatment had no effect on tumor growth, loss of body weight, and loss of fat mass. Compared with placebo, low-dose UDCA improved tissue loss in the lung (p = 0.022) and tended to reduce tissue loss in brown adipocytes (p = 0.06), gastrocnemius muscle (p = 0.06), extensor digitorum longus muscle (p = 0.09), and soleus muscle (p = 0.07). Compared with placebo, high-dose UDCA tended to reduce the loss of lean body mass (p = 0.06), lung tissue (p = 0.1), white adipose tissue (p = 0.11), and gastrocnemius muscle (p = 0.11). The activity and food intake were not altered in tumor-bearing rats by either dose of UDCA. Both doses tended to decrease the mortality rate in tumor-bearing rats, (hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.17–1.04; p = 0.061 for low-dose UDCA; HR, 0.44; 95% CI, 0.18–1.05; p = 0.065 for high-dose UDCA).

Conclusion

UDCA treatment in the Yoshida hepatoma model showed a trend towards attenuation of tissue loss in animals with progressive weight loss in cancer cachexia. Tumor growth and activity indicators were not altered. Both doses of UDCA tended to reduce the mortality rates in tumor-bearing animals. Larger studies with longer follow-up are required to verify these findings.

Cachexia is an irreversible process that can develop in the course of chronic disease. It is characterized by the remodeling of the metabolic, inflammatory, and endocrine pathways. Insulin, growth hormone (GH), and insulin-like growth factor 1 (IGF-1) are involved in glucose, protein, and fat metabolism, which regulates body composition. In body wasting and cachexia, their signaling is impaired and causes anabolic/catabolic imbalance. Important mechanisms include inflammatory cytokines and neurohormonal activation. Remodeled post-receptor insulin, GH, and IGF-1 pathways constitute a potential target for pharmacological treatment in the setting of body wasting and cachexia. Peroxisome proliferator-activated receptor gamma agonists, drugs inhibiting angiotensin II action (angiotensin II antagonists and inhibitors of angiotensin-converting enzyme), and testosterone, which interfere with post-receptor pathways of insulin, GH, and IGF-1, were investigated as pharmacological intervention targets and various clinically important implications were reported. There are several other potential targets, but their treatment feasibility and applicability is yet to be established.

Cachexia is an irreversible process that can develop in the course of chronic disease. It is characterized by the remodeling of the metabolic, inflammatory, and endocrine pathways. Insulin, growth hormone (GH), and insulin-like growth factor 1 (IGF-1) are involved in glucose, protein, and fat metabolism, which regulates body composition. In body wasting and cachexia, their signaling is impaired and causes anabolic/catabolic imbalance. Important mechanisms include inflammatory cytokines and neurohormonal activation. Remodeled post-receptor insulin, GH, and IGF-1 pathways constitute a potential target for pharmacological treatment in the setting of body wasting and cachexia. Peroxisome proliferator-activated receptor gamma agonists, drugs inhibiting angiotensin II action (angiotensin II antagonists and inhibitors of angiotensin-converting enzyme), and testosterone, which interfere with post-receptor pathways of insulin, GH, and IGF-1, were investigated as pharmacological intervention targets and various clinically important implications were reported. There are several other potential targets, but their treatment feasibility and applicability is yet to be established.

Cardio-renal syndromes (CRS) are defined as disorders of the heart and kidney whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. CRS have been classified into five categories, where types 2 and 4 represent respectively chronic cardio-renal and chronic reno-cardiac syndromes. In these conditions, the chronic disorder of either the heart or kidney has been shown to induce some degree of cachexia. At the same time, cachexia has been proposed as a possible mechanism contributing to the worsening of such pathological organ cross talk. Common pathogenetic mechanisms underlie body wasting in cachectic states of different chronic heart and kidney diseases. In these circumstances, a vicious circle could arise, in which cachexia associated with either heart failure or chronic kidney disease may contribute to further damage of the other organ. In chronic CRS, activation of the immune and neuroendocrine systems contributes to the genesis of cachexia, which in turn can negatively affect the heart and kidney function. In patients with cardiac sustained activation of the immune and neuroendocrine systems and oxidative stress, renal vascular resistance can increase and therefore impair renal perfusion, leading to worsening kidney function. Similarly, in renal cachexia, increased levels of pro-inflammatory cytokines can cause progressive left ventricular systolic dysfunction, myocardial cell death, endothelial dysfunction and increased myocardial fibrosis, with consequent impairment of the chronic reno-cardiac syndrome type 4. Thus, we speculate that the occurrence of different types of chronic CRS could represent a fundamental step in the genesis of cachexia, being renal and cardiac dysfunction closely related to the occurrence of systemic disorders leading to a final common pathway. Therefore, the heart and kidney and cachexia represent a triad causing a vicious circle that increases mortality and morbidity: In such circumstances, we may plausibly talk about cardio-renal cachexia syndrome. Complex interrelations may explain the transition from CRS to cachexia and from cachexia to CRS. Identification of the exact mechanisms occurring in these conditions could potentially help in preventing and treating this deadly combination.

Cardio-renal syndromes (CRS) are defined as disorders of the heart and kidney whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. CRS have been classified into five categories, where types 2 and 4 represent respectively chronic cardio-renal and chronic reno-cardiac syndromes. In these conditions, the chronic disorder of either the heart or kidney has been shown to induce some degree of cachexia. At the same time, cachexia has been proposed as a possible mechanism contributing to the worsening of such pathological organ cross talk. Common pathogenetic mechanisms underlie body wasting in cachectic states of different chronic heart and kidney diseases. In these circumstances, a vicious circle could arise, in which cachexia associated with either heart failure or chronic kidney disease may contribute to further damage of the other organ. In chronic CRS, activation of the immune and neuroendocrine systems contributes to the genesis of cachexia, which in turn can negatively affect the heart and kidney function. In patients with cardiac sustained activation of the immune and neuroendocrine systems and oxidative stress, renal vascular resistance can increase and therefore impair renal perfusion, leading to worsening kidney function. Similarly, in renal cachexia, increased levels of pro-inflammatory cytokines can cause progressive left ventricular systolic dysfunction, myocardial cell death, endothelial dysfunction and increased myocardial fibrosis, with consequent impairment of the chronic reno-cardiac syndrome type 4. Thus, we speculate that the occurrence of different types of chronic CRS could represent a fundamental step in the genesis of cachexia, being renal and cardiac dysfunction closely related to the occurrence of systemic disorders leading to a final common pathway. Therefore, the heart and kidney and cachexia represent a triad causing a vicious circle that increases mortality and morbidity: In such circumstances, we may plausibly talk about cardio-renal cachexia syndrome. Complex interrelations may explain the transition from CRS to cachexia and from cachexia to CRS. Identification of the exact mechanisms occurring in these conditions could potentially help in preventing and treating this deadly combination.