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Corresponding author at: Jenjiratchaya Thanapholsart, Division of Applied Technologies for Clinical Care, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, James Clerk Maxwell Building, Waterloo, London, UK.
Division of Applied Technologies for Clinical Care, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, James Clerk Maxwell Building, Waterloo, London, UK
Department of Adult Nursing, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, James Clerk Maxwell Building, Waterloo, London, UK
Cardiology Department, Guy's and St Thomas’ NHS Foundation Trust, London, UKSchool of Biomedical Engineering and Imaging Sciences, King's College London, London, UK
Division of Applied Technologies for Clinical Care, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, James Clerk Maxwell Building, Waterloo, London, UK
Cardiac cachexia is a muscle wasting process that often develops in those with chronic heart failure resulting in weight loss, low levels of physical activity, reduced quality of life, and is associated with a poor prognosis. The pathology of cardiac cachexia is complex with new evidence emerging that implicates several body systems. This review describes the pathophysiology associated with cardiac cachexia and addresses: 1) hormonal changes- neurohormonal abnormalities and metabolic hormone imbalance; 2) mechanisms of muscle wasting in cardiac cachexia, and the integral mechanisms between changed hormones due to cardiac cachexia and muscle wasting processes, and 3) associated abnormalities of gastrointestinal system that contribute to cardiac cachexia. These pleiotropic mechanisms demonstrate the intricate interplay between the affected systems and account for why cardiac cachexia is difficult to manage clinically. This review summarises current pathophysiology of cardiac cachexia and highlights symptoms of cardiac cachexia, implications for clinical practice and research gaps.
There are multiple terms that identify nutritional status or diseases, such as malnutrition, sarcopenia, cachexia and muscle wasting. Malnutrition is the state of unmet nutritional needs leading to reduced fat free mass and body cell mass as a result in declined physical performance and mental ability, including worsening clinical profile from disease while sarcopenia develops with aging (primary sarcopenia) and factors in addition to ageing (secondary sarcopenia), such as organ failure,
However, the definition of sarcopenia remain controversial as it is used for healthy ageing while sarcopenia in chronic disease leads to muscle wasting without the accompanying weight loss.
Cachexia develops in the advanced stages of chronic diseases, primarily in cancer and chronic heart failure (CHF), chronic kidney disease, and chronic obstructive pulmonary disease.
There are variations in reported prevalence of CC in the literature, reflecting a lack of consensus on the CC diagnostic criteria, with some studies applying 5% as a cut-off point of unintentional weight loss in a previous year as a main criteria,
suggested that 6% weight loss within 1 year was the strongest predictor of reduced survival when compared to 5%, 7.5%, 10% and 15% weight loss and therefore 6% weight loss should be used as a cut-off point to identify CC. Indeed, the different treatments provided in SOLVD and V-HeFTII might affect the finding on the cut-off points of weight loss on mortality rates, and the study was under powered to examine the differences between both groups.
Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study.
Hence, although various cut-off points have been suggested, according to cachexia consensus, the former cut-off point of 5% weight loss within 12 months is recommended, and a person having two major and three minor criteria can be diagnosed cachexia (Table 1).
Chronic heart Failure Pathophysiology and Relationship to Cardiac Cachexia
CHF is caused by numerous pathologies due to abnormal structures and/or functions of the heart leading to increased intracardiac pressures and/or insufficient cardiac output at resting stage and/or during exercise
2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
causing poor perfusion to the vital organs including the kidneys, intestine and skeletal muscle. This in turn triggers neurohormonal abnormalities and immunological activation giving rise to an inflammatory process that leads to muscle wasting.
There are several theories on how CC develops and manifests clinically, including poor gastrointestinal absorption, loss of nutrients in gastrointestinal tracts and imbalances of anabolism and catabolism.
The aim is to provide an evidence-based review of the pathology related to CC (in particular in relation to neural and metabolic hormones), how this relates to symptoms experienced by those with CC, and the implication for clinical practice, including the current gaps in research.
The changes of neural and metabolic hormones in chronic heart failure with cardiac cachexia
There are two main categories of hormones that involve in the pathophysiology of CC; 1) neurohormones- renin-aldosterone-angiotensin system (RAAS), glucocorticoid hormones, testosterone (Table 2); 2) metabolic hormones- growth hormone, ghrelin, leptin, adiponectin, myostatin and follistatin. The changes of these hormones and their interactions lead to catabolic and anabolic imbalances that subsequently reduce muscle mass as a result in CC (Figure 1). The effects and levels of each hormone due to CC, including the conflicting findings have been reported in the literature.
Table 2Role of hormones and changes due to cardiac cachexia.
Hormones
General roles
Changes of hormone levels due to cardiac cachexia
Physiological Effects
Conflicting findings
Neural hormones
Renin-Aldosterone-Angiotensin system
1) Regulating blood volume and systemic vascular resistance.
- Overactivation of β2 adrenoreceptor on skeletal muscle fibres due to increased catecholamines in heart failure could reduce anabolic and anti-catabolic stimuli leading to muscle wasting.
Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation.
Increase in serum adiponectin concentration in patients with heart failure and cachexia: relationship with leptin, other cytokines, and B-type natriuretic peptide.
Myostatin serum was reported lower in patients with CC than without and the reason behind this is that myostatin is mostly found in skeletal muscle rather than serum.
There are at least five main pathways of proteolysis: ubiquitin-proteasome pathway (UPP); Ca2+-dependent; lysosomal autophagy; caspase dependent; matrix metalloproteinases
and mitochondrial dysfunction that can contribute to muscles wasting. This muscle wasting in CHF patients significantly impairs physical exercise tolerance
affecting quality of life. It is associated with frailty, and this in turn leads to an increased risk of falls and associated risk of fractures and as a consequence hospitalisation.
The nuclear factor-κB (NF- κB) transcription factor family facilitates the activation of UPP as a major process of muscle catabolism is reported with a recent model highlighting muscle wasting due to cytokines
Exercise training attenuates MuRF-1 expression in the skeletal muscle of patients with chronic heart failure independent of age: the randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging catabolism study.
and high levels of these hormones and cytokines were observed among CHF with CC. Thus, together these mechanisms cause muscle depletion and atrophy seen in CC via activation of UPP, and CHF patients are highly likely to develop muscle loss.
Another important protein degradation pathway is lysosomal autophagy.
Autophagy is a process that preserves protein homeostasis via lysosomal-dependent degradation, that breaks down long-lived protein, preventing accumulation of redundant or defective proteins.
The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia.
It was evident that mitochondrial dysfunction has a negative impact on both myocardium and skeletal muscles in CC. This might be due to decreased mitochondrial oxidative capacity as a result of reduced adenosine triphosphate (ATP)-energy carrier in cell- and increased production of ROS as a consequence of the activation of the inflammatory process.
Indeed, the collagen-causing fibrosis was significantly found in patients with CC compared to those without. Collagen accumulation leads to fibrosis in skeletal muscles resulting in muscle wasting related to exercise intolerance.
Endothelial cells and myocardium are also reported to release inflammatory cytokines, and the myocardial response leads to the hypothesis that hypoxia might lead to increased pro-inflammatory cytokine secretion in CHF, with the failing heart might be the major source of TNF-α.
All these cytokines trigger upregulation of the UPP increasing protein degradation and increased resting energy expenditure in CHF patients contributing to muscle wasting (which is seen in CC) as indicated in the protein degradation pathway section. TNF- α and other types of cytokines; IL-1, IL-6, also reduce appetite through the activation of anorexigenic agents; such as corticotropin-releasing factor, and inhibition of orexigenic neuropeptide-Y in hypothalamus.
suggesting that TNF-α plays a role in inducing cachexia. As well as the effect of TNF-α on the muscles, it also increases gut permeability. In addition to TNF-α, the level of cytokines; IL-6, in the circulation increases significantly in CHF patients, with even greater levels noted in CC patients compared to non-cachectic CHF patients.
In conclusion, immunological activation in CC due to CHF can worsen muscle wasting through the protein degradation pathway and lead to an imbalance of catabolism and anabolism.
Abnormalities of gastrointestinal tract
CHF reduces cardiac output stimulating the SNS which results in a diversion of blood from the gastrointestinal tract to the core circulation. The reduction in systolic blood supply of 58%, 55% and 57% respectively to the celiac trunk, superior mesenteric artery , and inferior mesenteric artery in CC were reported compared to the control group.
These physiological responses in the gastrointestinal tract may be responsible for bacterial translocation leading to endotoxin release and immune activation.
In addition, the release of IgA; activation of immunological defence, was found to be responsible for an increase in juxtamucosal bacterial concentration with bacterial attachment to biofilm.
This bowel wall oedema is found between the intestinal epithelium and mesenteric capillary that increases the gap between capillary wall and enterocyte membrane in all parts of the intestine in heart failure.
The greatest distance between the basal wall of the enterocyte and the capillary wall and highest collagen content of the mucosal wall in small intestines were seen in CC patients compared to CHF patients without CC and healthy control.
2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
These findings support the presence of bowel wall oedema and increased gut permeability resulting in CC due to impaired nutrient absorption, contributing to accelerated catabolic process.
Cardiac-cachectic symptoms and management
Clinically, changes in the gastrointestinal system cause abdominal discomfort
2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
and protein degradation pathway might worsen exercise tolerance among CC patients causing fatigue and muscle depletion.
Implication for clinical practice and future research development
The literature review has highlighted the variance in reported diagnostic cut off points leading to conflicting prevalence and survival rates. This variance has led to a lack of consensus on the severity of CC and treatments. The recent consensus on the cachexia diagnostic criteria
Muscle wasting can be accelerated via SNS activation along with increasing levels of catecholamines and RAAS that are evident in HF and therefore early medication initiation with ACEIs
have the potential to slow down the muscle wasting process.
Parenteral ghrelin administration shows promising results in CC patients with positive effects on lean body mass, muscle strength, improvement of cardiac structure and function, reducing norepinephrine, epinephrine and BNP.
Similarly, in a meta-analysis study of cancer-related cachexia, the oral form of ghrelin agonist; anamorelin, demonstrated statistically significant increases in body lean mass (and total body weight.
Iron deficiency in CHF and CC should be treated with intravenous iron showing significant improvements in exercise tolerance using the 6 minute walk test (p<0.0001).
Although the European Society of Cardiology (ESC) Guidelines recommend ferric carboxymaltose in acute and chronic HF to improve symptoms, physical performance and quality of life in patients with HF and LVEF ≤ 45%,
2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
In the RCT study, bimagrumab; the inhibitor of ActRIIA and ActRIIB, was tested in elderly with sarcopenia which reported bimagrumab significantly increasing lean muscle mass (P<0.001) but no significant changes in physical performance (P > 0.05) when compared to control group.
Bowel wall oedema can cause poor nutrient absorption due to bacterial translocation, and elevating bowel movement (using metoclopramide) or curbing bacteria overgrowth (using lactobacilli) could indirectly decrease bowel wall oedema as a result in improved food absorption.
Undoubtedly, this area of research will continue as we understand more about the gut microbiome.
Testosterone can be used to improve muscle strength and exercise capacity but its associated increase in cardiovascular adverse effects cannot be ignored, especially when orally administered.
The combination of nutritional support and aerobic exercise should be provided as it might be appropriate to manage CC symptoms. This is because dietary support; high calories and protein supplements, help to compensate excessive catabolism and build the muscle
as bowel oedema can be decreased with improved food absorption, and as a consequence a reduction in muscle wastage. Likewise, exercise-based cardiac rehabilitation is recommended in the ESC heart failure Guidelines.
2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
- when compared to the group with exercise alone while another study by Azhar et al. (2020) reports a significant reduction of pulse pressure and heart rates and improved exercise tolerance using whey protein with exercise training compared to whey protein alone and (p < 0.05).
Potential beneficial effects of dietary protein supplementation and exercise on functional capacity in a pilot study of individuals with heart failure with preserved ejection fraction.
This approach of nutritional and physical training support has potential but larger randomised control trial studies are needed.
Fish oil-omega-3 polyunsaturated fatty acids; PUFA-, containing rich protein, rich calories, nutritional supplements and important amino acid have been used in CC patients
There is a need to involve the multidisciplinary team with the cardiologist, physiotherapist, dietician, pharmacologist and cardiac nurse, to provide comprehensive care and treatment to HF patients with CC and has the potential to improve self-management as seen in HF.
Conclusions
This review has demonstrated the complexity of the pathophysiology of CC in relation to heart failure that is primarily driven by neural and metabolic hormonal changes, the activation of inflammatory process due to cytokines, protein degradation and abnormal gastrointestinal systems leading to a multitude of symptoms. The understanding of pathophysiology of CC can play a role in developing beneficial treatments and this review highlights the lack of robust evidence to support any one treatment.
The immediate priority is to improve the assessment and diagnosis of CC as early detection allows for early treatment and optimisation of medications etc as well as promoting a multidisciplinary approach to managing this complex condition. The development of effective evidenced-based CC treatments is urgently needed.
Authors contributions statement
Jenjiratchaya Thanapholsart, Dr Ehsan Khan, Dr Tevfik F. Ismail and Dr Geraldine A. Lee desinged the concept of the work, methodology and the diagram of pathophysiology of CC; Jenjiratchaya Thanapholsart wrote the original draft, drew the orginal diagram, performed data curation and formal analysis. Dr Ehsan Khan, Dr Tevfik F. Ismail and Dr Geraldine A. Lee supervised and substantially reviewed and edited the work and the diagram.
Acknowledgement
Many thanks to the Royal Thai Government for the PhD scholarship.
Sources of Funding
No funding.
Declaration of Competing Interest
There are no conflicts of interest.
References
Cruz-Jentoft AJ
Bahat G
Bauer J
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Sarcopenia: revised European consensus on definition and diagnosis.
Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study.
2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.
Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation.
Increase in serum adiponectin concentration in patients with heart failure and cachexia: relationship with leptin, other cytokines, and B-type natriuretic peptide.
Exercise training attenuates MuRF-1 expression in the skeletal muscle of patients with chronic heart failure independent of age: the randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging catabolism study.
The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia.
Potential beneficial effects of dietary protein supplementation and exercise on functional capacity in a pilot study of individuals with heart failure with preserved ejection fraction.
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