Cardiac cachexia

Chronic heart failure (CHF) remains an important and increasing public health care problem. It is a complex syndrome affecting many body systems. Body wasting (i.e., cardiac cachexia) has long been recognised as a serious complication of CHF. Cardiac cachexia is associated with poor prognosis, independently of functional disease severity, age, and measures of exercise capacity and cardiac function. Patients with cardiac cachexia suffer from a general loss of fat tissue, lean tissue, and bone tissue. Cachectic CHF patients are weaker and fatigue earlier, which is due to both reduced skeletal muscle mass and impaired muscle quality. The pathophysiologic alterations leading to cardiac cachexia remain unclear, but there is increasing evidence that metabolic, neurohormonal and immune abnormalities may play an important role. Cachectic CHF patients show raised plasma levels of epinephrine, norepinephrine, and cortisol, and they show high plasma renin activity and increased plasma aldosterone level. Several studies have also shown that cardiac cachexia is linked to raised plasma levels of tumour necrosis factor alpha and other inflammatory cytokines. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. The available evidence suggests that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder with a poor prognosis. A complex imbalance of different body systems may cause the development of body wasting.     

Recent insights on the molecular mechanisms and therapeutic approaches for cardiac cachexia

Cardiac cachexia (CC) affects a large proportion of patients with chronic heart failure, a major public health issue in western countries. The pathophysiology of CC is complex and multifactorial, resulting from several factors interacting in a complex system with metabolic, immune and neurohormonal consequences, triggered to protect the heart and the circulation from damage. Despite the adverse clinical effects, CC diagnosis is not straightforward and has not specifically been targeted, with therapeutic strategies only comprising interventions with appetite stimulants, and anti-inflammatory substances. Here we review the molecular pathways underlying CC-related muscle wasting aiming to provide clues for the definition of CC-specific biomarkers and for the development of drugs that prevent and/or counteract muscle impairment, which will certainly impact the management of cardiovascular disorders.     

The role of vasopressin in congestive heart failure

Neurohormonal abnormalities contribute to the pathophysiology of congestive heart failure (CHF). Successful approaches to improving the prognosis of patients with CHF are based largely on therapeutic interruption of activated neurohormonal systems. The use of antagonists and inhibitors of the renin-angiotensin-aldosterone and sympathetic nervous systems has significantly improved clinical outcomes in CHF. Excessive secretion of arginine vasopressin (AVP) has the potential for deleterious effects on various physiologic processes in CHF Inhibition of AVP through vasopressin receptor antagonist therapy is a potentially beneficial new therapeutic approach to CHF     

癌性恶病质诊断、评估及治疗进展

癌性恶病质是一类复杂的代谢综合征,包括肌肉消耗、脂肪消耗、非计划的体质量下降、厌食和免疫功能破坏等。恶病质可显著降低肿瘤患者的抗肿瘤治疗疗效,增加治疗毒副反应,加重患者的症状负担,影响患者的生活质量,并最终缩短患者的生存时间。本文将对癌性恶病质的诊断、临床评估以及治疗的研究进展进行综述。     

Metabolic modulation and optimization of energy consumption in heart failure

Chronic heart failure (CHF) is a common and disabling syndrome with a poor prognosis. It is a major and increasing public health problem. Angiotensin-converting enzyme inhibitors, diuretics, and digitalis are the standards treatments for CHF. Other drugs, such as beta-blockers, spironolactone, calcium antagonists, vasodilators, and antiarrhythmic agents are used to counteract the progression of the syndrome or to improve the hemodynamic profile. Despite optimum treatment with neurohumoral antagonists, prognosis of CHF remains poor; the patients complain of persistent reductions in their exercise capacity and quality of life. Fatigue and shortness of breath, two common and disabling symptoms in patient with CHF, are relatively independent from hemodynamic and neuroendocrine changes, although they seem to be related to the impairment of peripheral muscle metabolism and energetic phosphate production. Therefore, CHF is a complex metabolic syndrome in which the metabolism of cardiac and peripheral muscles is impaired and novel therapeutic strategies have been aimed at positive modulation with compounds such as carnitine, trimetazidine, and ranolazine.     

Nutrition in the care of patients with cancer cachexia

Cancer cachexia, a progressive wasting syndrome experienced by approximately 80% of patients, is characterized by loss of adipose tissue and lean body mass. This complex metabolic process reflects both reduced nutrient availability and increased nutritional demand. Though cachexia is most commonly associated with particular tumours, no patient or tumour are excluded. This article provides an overview of cachexia and its pathophysiology and the factors contributing to its development before considering its impact on individuals. Emphasis is placed on the nutritional aspects of its management.     

Congestive heart failure is a systemic illness: a role for minerals and micronutrients

Congestive heart failure (CHF) is a clinical syndrome that features a failing heart together with signs and symptoms arising from renal retention of salt and water, mediated by attendant neurohormonal activation, and which prominently includes the renin-angiotensin-aldosterone system. More than this cardiorenal perspective, CHF is accompanied by a systemic illness whose features include an altered redox state in diverse tissues and blood, an immunostimulatory state with proinflammatory cytokines and activated lymphocytes and monocytes, and a wasting of tissues that includes muscle and bone. Based on experimental studies of aldosteronism and clinical findings in patients with CHF, there is an emerging body of evidence that secondary hyperparathyroidism is a covariant of CHF. The aldosteronism of CHF predisposes patients to secondary hyperparathyroidism because of a chronic increase in Ca(2+) and Mg(2+) losses in urine and feces, with a fall in their serum ionized levels and consequent secretion of parathyroid hormone. Secondary hyperparathyroidism accounts for bone resorption and contributes to a fall in bone strength that can lead to nontraumatic fractures. The long-term use of a loop diuretic with its attendant urinary wasting of Ca(2+) and Mg(2+) further predisposes patients to secondary hyperparathyroidism and attendant bone loss. Aberrations in minerals and micronutrient homeostasis that includes Ca(2+), Mg(2+), vitamin D, zinc and selenium appear to be an integral component of pathophysiologic expressions of CHF that contributes to its systemic and progressive nature. This broader perspective of CHF, which focuses on the importance of secondary hyperparathyroidism and minerals and micronutrients, raises the prospect that dietary supplements could prove remedial in combination with the current standard of care.     

Exercise as a Time-conditioning Effector in Chronic Disease: a Complementary Treatment Strategy

Exercise has been widely believed to be a preventive and therapeuticaid in the treatment of various pathophysiological conditionssuch as cardiovascular disease and cancer. A common problemassociated with such pathologies is cachexia, characterizedby progressive weight loss and depletion of lean and fat bodymass, and is linked to poor prognosis. As this syndrome compriseschanges in many physiological systems, it is tempting to assumethat the modulation of the psychoneuroimmunoendocrine axis couldattenuate or even prevent cachexia progression in cancer patients.Cancer cachexia is characterized by a disruption in the rhythmicsecretion of melatonin, an important time-conditioning effector.This hormone, secreted by the pineal gland, transmits circadianand seasonal information to all organs and cells of the body,synchronizing the organism with the photoperiod. Consideringthat exercise modulates the immune response through at leasttwo different mechanisms—metabolic and neuroendocrine—wepropose that the adoption of a regular exercise program as acomplementary strategy in the treatment of cancer patients,with the exercise bouts regularly performed at the same timeof the day, will ameliorate cachexia symptoms and increase survivaland quality of life.     

Understanding cachexia in patients with cancer

Cancer cachexia is a progressive wasting syndrome characterised by loss of both adipose tissue and lean body mass. It is a complex metabolic process common in patients with cancer and responsible for death. Consideration of this syndrome is important because of its prevalence and its significant effect on morbidity, mortality and nutritional and psychological status.     

Novel therapeutic options for cachexia and sarcopenia

ABSTRACT

Introduction: Cachexia and sarcopenia are conditions phenotypically characterized by muscle loss and represent a factor of poor prognosis, increasing patients’ morbidity and mortality. Cachectic and sarcopenic patients often suffer from low quality of life, presenting lower muscle strength and appetite loss, which makes research on novel treatment strategies to ameliorate clinical response including patient’s symptoms, the objective of scientific interest.

Areas covered: This article covers recent developments in the area of cachexia and sarcopenia treatment and therapeutic interventions, targeting central nervous system involvement, key inflammatory and muscle-specific metabolic pathways.

Expert opinion: A number of promising agents have being evaluated, such as enobosarm, a selected androgen receptor modulator, and anamorelin, a ghrelin agonist which have been recently studied in phase III trials. These and other agents (i.e., infliximab, tocilizumab, MABp1, bimagrumab) have shown significant impact on reversal of skeletal muscle loss, but limited effect on physical function.

In the last few years advancement in the number and type of potential treatments for cachexia and sarcopenia have been obtained and we have now available more data on measurable effects of several drugs on patients’ nutritional and metabolic parameters and outcomes.     

Skeletal muscle and whole body protein turnover in cardiac cachexia: influence of branched-chain amino acid administration

Muscle protein wasting commonly accompanies severe heart failure. The mechanism of this so-called cardiac cachexia has been investigated in eight patients with an average body weight decrement of 19%, whose results have been compared with those from 11 healthy control subjects. Exchanges of tyrosine and 3-methylhistidine across leg tissue were used as specific indicators of net protein balance and myofibrillar protein breakdown, respectively. Whole body protein turnover was measured using a stable isotope labelling technique with L-[1-13C]leucine as tracer. In patients with cardiac cachexia there were greater values, relative to those values in normal control subjects, of leg efflux of tyrosine (-8.1 +/- 0.6 nmol 100 ml leg tissue-1 min-1 vs. -4.2 +/- 0.3 nmol 100 ml-1 min-1 (P less than 0.01) and of 3-methylhistidine (-0.8 +/- 0.1 nmol 100 ml leg tissue-1 min-1 vs. -0.1 +/- 0.02 nmol 100 ml-1 min-1 (P less than 0.005), mean +/- SEM). The results suggest that in patients with cardiac cachexia the state of net negative protein balance across leg tissue is associated with an increased rate of myofibrillar protein breakdown. In cardiac cachexia, neither efflux of tyrosine (-8.4 +/- 0.7 nmol 100 ml leg tissue-1 min-1) nor of 3-methylhistidine (-1.0 +/- 0.2 nmol 100 ml leg tissue-1 min-1) were significantly altered by branched-chain amino acid (BCAA) infusion to plasma concentrations of 1300 +/- 14 mumol ml-1, i.e., four times normal plasma values (282 +/- 11 mumol ml-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

The biochemical basis of metabolism in cancer cachexia.

Cancer cachexia is a syndrome of progressive body wasting characterized by loss of adipose tissue and skeletal muscle mass. It is the most common side effect of malignancy occurring in approximately one-half of untreated cancer patients. The pathophysiology of cancer cachexia is not fully understood; however, studies have shown that cytokines are important in the alteration of carbohydrate, lipid, and protein metabolism. This leads to a shorter survival time and a decreased response to therapy. Cachexia is often found before any signs or symptoms of the cancer. An uncertainty with cachexia is whether nutritional support is feeding the patient or the tumor. Often, cachexia is not responsive to simple nutritional interventions. Furthermore, appetite stimulants, cytokine inhibitors, and Cori cycle inhibitors have been used to treat cancer cachexia.     

Conjugated linoleic acid preserves gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma

Cancer cachexia is a syndrome of weight loss, muscle wasting, fatigue, and anorexia that occurs in patients with advanced or recurrent solid tumor disease. Tumor necrosis factor-alpha (TNFalpha) and prostaglandin E2 (PGE2) have been implicated in the biology of cachexia and serve as possible targets for treatment of this condition. Conjugated linoleic acid (CLA) is a polyunsaturated fatty acid that alters the synthesis of PGE2 and reduces the negative effects of TNF on body weight of healthy mice. We hypothesized that a diet supplemented with .5% CLA might reduce muscle wasting in mice bearing the colon-26 adenocarcinoma, an animal model of cancer cachexia. CLA preserved gastrocnemius muscle mass and reduced TNF receptors in muscle of tumor-bearing mice. These data suggest that CLA may preserve muscle mass by reducing the catabolic effects of TNF on skeletal muscle.     

Tumor-derived IL-6 and trans-signaling among tumor,fat, and muscle mediate pancreatic cancer cachexia

Most patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These phenocopied donor weight loss. Furthermore, muscle wasting correlated with mortality and murine IL-6, and human IL-6 associated with the greatest murine cachexia. In cell culture and mice, PDAC cells elicited adipocyte IL-6 expression and IL-6 plus IL-6 receptor (IL6R) in myocytes and blood. PDAC induced adipocyte lipolysis and muscle steatosis, dysmetabolism, and wasting. Depletion of IL-6 from malignant cells halved adipose wasting and abolished myosteatosis, dysmetabolism, and atrophy. In culture, adipocyte lipolysis required soluble (s)IL6R, while IL-6, sIL6R, or palmitate induced myotube atrophy. PDAC cells activated adipocytes to induce myotube wasting and activated myotubes to induce adipocyte lipolysis. Thus, PDAC cachexia results from tissue crosstalk via a feed-forward, IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6, all targetable mechanisms for treatment of cachexia.     

Eicosapentaenoic Acid

Cancer cachexia affects about half of all cancer patients and is associated with negative effects on functional status and quality of life. This condition is also a major contributor to the morbidity and mortality of patients with advanced malignancy. Although current strategies to improve appetite and lean body mass by administering appetite stimulants, increasing physical activity and using nutritional supplementation have a scientific rationale, randomised studies have continued to demonstrate that a reduction in the loss of lean body mass is difficult to achieve unless the underlying metabolic abnormalities in cancer cachexia are corrected. Initial studies using animal models have demonstrated that nuclear factor-κ B (NF-κB) is upregulated in cancer cachexia, increasing proteolysis and breakdown of myofibrillar proteins, which results in sarcopenia. Laboratory studies have shown that eicosapentaenoic acid (EPA), an n-3 fatty acid, has anticachectic effects and may attenuate protein degradation by preventing NF-κB accumulation in the nucleus. EPA is associated with weight stabilisation, gain in lean body mass, and improvement in quality-of-life markers in weight-losing patients with advanced pancreatic cancer. Although animal studies have demonstrated the molecular basis of the effects of EPA, this has never been validated in human clinical trials. On the basis of the promising results of the laboratory and clinical studies, we hypothesise that selective targeting of proteasome activity by EPA (a polyunsaturated fatty acid) administered to cancer patients, including elderly patients, with cancer cachexia will alter metabolic abnormalities by downregulating NF-κB, modulating immune and inflammatory response and thus preventing the breakdown of myofibrillar proteins. This will result in promotion of anabolism, reduction of weight loss and increase in lean body mass and physical function, thus establishing a case for future, prospective clinical trials.     

The role of cytokines in cancer cachexia

A large number of observations point towards cytokines, polypeptides released mainly by immune cells, as the molecules responsible for the metabolic derangements associated with cancer-bearing states. Indeed, these alterations lead to a pathological state known as cancer cachexia which is, unfortunately, one of the worst effects of malignancy, accounting for nearly a third of cancer deaths. It is characterized by weight loss together with anorexia, weakness, anemia, and asthenia. The complications associated with the appearance of the cachectic syndrome affect both the physiological and biochemical balance of the patient and have effects on the efficiency of the anticancer treatment, resulting in a considerably decreased survival time. At the metabolic level, cachexia is associated with loss of skeletal muscle protein together with a depletion of body lipid stores. The cachectic patient, in addition to having practically no adipose tissue, is basically subject to an important muscle wastage manifested as an excessive nitrogen loss. The metabolic changes are partially mediated by alterations in circulating hormone concentrations (insulin, glucagon, and glucocorticoids in particular) or in their effectiveness. The present study reviews the involvement of different cytokines in the metabolic and physiological alterations associated with tumor burden and cachexia. Among these cytokines, some can be considered as procachectic (such as tumor necrosis factor-alpha), while others having opposite effects can be named as anticachectic cytokines. It is the balance between these two cytokine types that finally seems to have a key role in cancer cachexia.     

Prognostic value of cardiac troponin T in patients with both acute and chronic stable congestive heart failure: comparison with atrial natriuretic peptide, brain natriuretic peptide and plasma norepinephrine

BACKGROUND: The prognostic value of cardiac troponin T (cTn-T) in a mixture of patients with both acute and chronic congestive heart failure (CHF), simultaneously assessed and compared with neurohormonal factors, has not yet been thoroughly evaluated. Thus, we focused on the prognostic value of cTn-T in comparison with atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and plasma norepinephrine (PNE) in this population. METHODS: Prognostic correlates of elevation of cTn-T, ANP, BNP, PNE were analyzed in 63 acute and chronic CHF patients followed up to record worsening CHF and cardiac death. RESULTS: cTn-T (> or =0.03 microg/L) was found in 17.4% (11 of 63) of patients. cTn-T correlated with ANP, BNP, PNE. Acute CHF patients were more positive for cTn-T and BNP. In our cohort, neither cTn-T (> or =0.03 microg/L) nor PNE were associated with increased mortality and worsening HF in CHF patients. After adjustment, BNP was the only independent predictor of cardiac events (RR, 3.23; p=0.01). CONCLUSIONS: BNP emerged as the only independent predictor of cardiac events in a mixture of patients with both acute and chronic CHF, suggesting that it is the analyte that best reflects long-term prognosis in a diverse population enrolled to mirror the "real world" situation.     

Indomethacin and ibuprofen preserve gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma

Skeletal muscle wasting is a prominent feature of cancer cachexia and involves decreased muscle protein synthesis and increased activity of the ubiquitin-proteasome pathway of protein degradation. We report that both indomethacin and ibuprofen improved body weight and weight of the gastrocnemius muscle in tumor-bearing mice. Ibuprofen increased the soluble protein content of the muscle without affecting muscle levels of phosphorylated p70 S6 kinase, a ribosomal kinase involved in protein synthesis. Paradoxically, indomethacin increased levels of ubiquitin-conjugated proteins. Further study is needed to understand the mechanism of action by which indomethacin and ibuprofen preserve body weight and muscle mass in the tumor-bearing mice. The data suggest that ibuprofen may have beneficial effects in the treatment of cancer cachexia.     

Management of cancer cachexia

The diagnosis of cancer has traditionally been associated with malnutrition and wasting. Oncology patients are at risk for nutrition-related problems because of the cancer itself, as well as the treatment prescribed. Clinical manifestations of cachexia include anorexia, weight loss, muscle wasting, and fatigue, resulting in poor performance status. Control of symptoms, such as anorexia, nausea and vomiting, and mucositis is imperative in the management of cancer cachexia. Current pharmacologic therapies, as well as complementary and alternative methods, are presented. The nurse plays a key role in ensuring that the nutritional needs of oncology patients are met.