Nutrition and cardiac cachexia.

Introduction

Congestive heart failure (CHF) remains the leading cause of acute hospitalization among older individuals (aged 65 years and over) in the USA. It has long been appreciated that advanced CHF may be associated with progressive tissue wasting, unintentional weight loss and a poor prognosis. In the first reported observational study of cachexia on the island of Cos, Hippocrates (460–377 BC) observed that in patients with advanced CHF ‘the flesh is consumed and becomes water, …the abdomen fills with water, the feet and legs swell, the shoulders, clavicles, chest and thighs melt away. …This illness is fatal’. Although this condition has been known to exist for over 2300 years, it has been relatively understudied, and until recently a definition had not been clearly established.

Definition

In the literature, the term cachexia in patients with CHF has been used to refer to a state in which there is loss of body fat to less than 27% for men and 29% for women, together with a body weight of less than 80–90% of ideal weight. Recently it was suggested that clinical cardiac cachexia be defined in CHF patients without signs of other primary cachectic states (e.g. cancer, thyroid disease, or severe liver disease) as weight loss of more than 6% of the previous normal weight over 6 months associated with CHF.

Heart failure itself may be defined as a condition in which an abnormality of cardiac structure or function is responsible for the inability of the heart to fill with or eject blood at a rate commensurate with the requirements of the metabolizing tissues. In most instances of chronic CHF, the progressive decline of cardiac performance is usually secondary to myocardial infarction, ischemic cardiomyopathy or long-standing hypertension. Other risk factors predisposing to heart failure include diabetes mellitus and/or valvular heart disease. In addition to having significant myocardial impairment, CHF itself impacts multiple body systems, with abnormalities observed in the vascular, musculoskeletal, neuroendocrine, renal, gastrointestinal and immune systems. The condition of cardiac cachexia occurs in the setting of chronic CHF, especially when there is right heart failure with tricuspid regurgitation and/or in severe, advanced stages of heart failure.

Epidemiology

Severe CHF has been observed to be associated with progressive weight loss and emaciation in approximately 10–15% of the patients. CHF is a common problem in older persons, and is six times more common among the 65–74 age group than those aged 45–54 years. The prevalence of CHF rises nearly exponentially with age, and from about age 55 years onward it doubles every 10 years in men and every 7 years in women. In the USA it afflicts approximately 1.5–2% of the total population and over 10% of the elderly. In developing countries, the prevalence of CHF is estimated to be much higher and according to recent World Health Organization estimates, there are approximately 23 million people with CHF worldwide.

Natural history

The transition that a patient undergoes from a state of compensated chronic CHF to that of decompensated heart failure with cardiac cachexia is a process that is not well understood. The timeline of CHF development or progression is not uniform. Although neuroendocrine and acute-phase reactant activation are associated with CHF progression and certain circulating proteins such as catecholamines, atrial natriuretic peptide, and/or heat-shock protein levels are elevated in cardiac cachexia, indicators of those who are at increased likelihood for development of cardiac cachexia have not been well identified. The prognostic indicators of outcome in CHF include age, gender, CHF functional class, cardiac ejection fraction, duration of disease, VO2 max, and/or a low serum sodium. However, cardiac cachexia itself is a significant mortality risk in patients with CHF, independent of these other prognostic indicators, and cachexia is usually an ominous sign in CHF patients, with an 18-month mortality of up to 50%. It appears in some cases that once cachexia becomes manifest the downward spiral can take a rapidly progressive and potentially irreversible course.

One recent study characterized changes in physical activity and diet intake after 6 months of follow up in CHF patients who developed cardiac cachexia compared with those patients who did not. It reported no significant difference in the baseline body weight or tumor necrosis factor [alpha] (TNF[alpha]) activity between the two groups. However, a lower mid-arm circumference (<25th name="25">

Pathophysiology

The exact mechanisms of how heart failure causes cardiac cachexia remain incompletely established. Possible contributing factors include

(1) dietary deficiency,
(2) malabsorption,
(3) metabolic dysfunction,
(4) loss of nutrients via urinary and/or gastrointestinal tract, and
(5) imbalance between energy intake and expenditure.

It is thought that chronic CHF, especially in the presence of tricuspid regurgitation, may cause blood to back up from the right side of the heart into the liver and intestines. This passive congestion in turn would cause interstitial edema, hepatomegaly and ascites, which would then lead to decreased gastric volume with feelings of abdominal fullness, early satiety, nausea and decreased appetite. It is also possible that edema of the intestines may not allow for adequate absorption of nutrients from the food ingested.

Heart failure may also force one to have to work harder just to breathe, and may cause the body temperature to rise. Both of these conditions burn calories. This increased energy expenditure could cause the already reduced oral caloric intake, due to symptoms of nausea and decreased appetite, to become insufficient for the body's energy requirements. In persons with severe heart failure, activation of the neuroendocrine factors such as catecholamines and of the proinflammatory cytokines such as TNF and other cytokines can further increase the metabolic rate of the tissues, thus burning more calories. The catabolic state associated with increased resting energy expenditure would then predispose some CHF patients to develop cachexia.

Cytokine and neuroendocrine activation

These systems initially help to compensate for the impaired myocardial function, but later contribute to the disease progression and deterioration. Cachectic CHF patients tend to have increased blood levels of TNF[alpha], interleukins 1 and 6, norepinephrine, epinephrine, cortisol, angiotensin II, renin and aldosterone. Growth hormone is often elevated but insulin-like growth factor 1 is usually inappropriately low in cachectic patients. The effects of the proinflammatory cytokines such as TNF[alpha] and interleukins 1 and 6 include proteolysis, apoptosis, muscle wasting and weight loss. The angiotensin II and aldosterone could also contribute to muscle wasting, apoptosis and fibrosis, and may also suppress insulin-like growth factor 1, which is the anabolic hormone that inhibits apoptosis. It is significantly correlated with muscle mass, and its local expression in muscle is very low in CHF patients with cachexia.

Muscle wasting and loss of muscle protein

Fatigue and muscle weakness are two of the most common complaints in CHF patients, and muscle atrophy is present in approximately two-thirds of patients with CHF. The exact stimulus for activation of protein degradation in cachexia is still being investigated. In other catabolic states or in cancer cachexia, ubiquitin levels in skeletal muscle have been reported to be increased. It is therefore possible that the muscle wasting associated with cardiac cachexia may also be due in part to increased protein degradation, likely from activation of the ubiquitin–proteasome proteolytic pathways. Future studies will shed light on this possibility.

The gastrointestinal system in heart failure and cardiac cachexia

The regulation of bowel perfusion is an important determinant of bowel health. The small and large intestines are highly vascularized, and receive their blood supply via the superior and inferior mesenteric arteries. The splanchnic circulation receives 25% of the cardiac output, therefore the gut is the most intensively perfused organ at rest. The gut mucosa is the metabolically active part of the gut, and receives over 50% of the total resting organ blood flow. Impaired bowel perfusion could cause mucosal ischemia, acidosis edema and increased permeability, or a ‘leaky gut’. Cardiac causes of impaired bowel perfusion include low cardiac output and cardiac ischemia. Mucosal injury can also result from ischemia in one of the extremities, which can occur commonly in CHF patients, especially those with diabetes and/or peripheral artery disease. In addition, gut mucosal ischemia and edema can reciprocally cause multiple-organ system failure and increased mortality.

Therapeutic options

Improvement of bowel perfusion with agents such as inhibitors of angiotensin-converting enzyme could help to stabilize systemic hemodynamics and can also minimize or prevent mucosal injury. Bowel-wall ischemia and edema in CHF can result in bacterial translocation, endotoxemia and immune activation. Therapeutic reduction of bacterial translocation might be achieved by increasing gut motility (e.g. reglan) or treating bacterial overgrowth (e.g. lactobacilli). Endotoxin, which forms part of the outer cell membrane of Gram-negative bacteria, may have a role in the development of atherosclerosis, and it may also exacerbate the inflammatory response in cardiac patients. It has been shown that in CHF patients with peripheral edema the endotoxin levels are elevated, but they may become normalized after intensive diuretic therapy. Lipoproteins such as cholesterol can bind to endotoxins and can potentially ameliorate some of the toxic effects of endotoxins. This could partly explain why it has been observed that low serum cholesterol is an independent prognostic factor for a poor outcome in CHF.

Although mild to moderate exercise may be well tolerated and may reduce inflammation and potentially retard or even partly reverse muscle wasting, moderately severe exercise might be detrimental in CHF patients with cardiac cachexia. It has been shown that vigorous exercise can reduce splanchnic blood flow transiently by diverting blood flow away from the gastrointestinal tract, and thereby cause gut ischemia, especially in CHF patients. Influence of heart failure on the gastrointestinal system also includes protein loss from the gut (protein-losing enteropathy) and anorexia, especially in patients with right heart failure.

Future directions and therapeutic options for the gut in patients with cardiac cachexia would include improving splanchnic blood flow, reducing bacterial translocation and endotoxemia, reducing circulating endotoxin, anticytokine therapy, and focusing on treating CHF, including reducing peripheral edema.

Fluid and electrolyte management

Careful attention must be paid to ensure that the treatment of peripheral edema does not result in salt depletion, electrolyte imbalance and/or dehydration. While it would be prudent to avoid excessive intake of overly salty food, one must also guard against hyponatremia as well as hypokalemia from the sodium-depleting diuretics, especially in elderly patients, because of the age-related impairment in salt retention by the kidneys. In addition, it would be important to ensure that there are adequate amounts of potassium, calcium and magnesium as well as other micronutrients in the diet. The supplemental inclusion of one multiple vitamin with minerals each day would be helpful, as would an increased intake of fresh fruits and vegetables, which contain many of the needed micronutrients.

Nutritional and lifestyle remedies

Dietary interventions can be helpful for treating CHF patients with cardiac cachexia. Consultations regarding nutrition, lifestyle and inflammation should be given. Those factors that are proinflammatory (i.e. raise C-reactive protein) should be avoided: for example, sugars, saturated fats, excess alcohol, smoking, sedentary lifestyle, and periodontal or gum disease. Trans fats found in partially hydrogenated oils (e.g. margarine, vegetable shortening) should also be avoided. Those factors that are anti-inflammatory (i.e. reduce C-reactive protein) should be recommended: for example, oily fish and fish oil supplements, olive, walnut or flaxseed oil, fruits and vegetables, garlic, ginger and turmeric (curcumin),sunflower seeds, eggs, herring, nuts or zinc tablets, pineapple or bromelain supplements, grape juice or red wine (small amounts), antioxidant supplements (e.g. vitamins C and E), S-adenosyl-methionine, [alpha]-lipoic acid, coenzyme Q10, mild to moderate exercise, abdominal fat reduction, stress reduction and teeth flossing. Green Tea (one of the strongest natural anti-oxidants) may also be helpful. Omega-3 fatty acid supplements should be used, especially because they have a synergistic effect with drugs for treating conditions such as hypertension, atherosclerosis, restenosis, stroke and CHF.

Other potential therapies may include agents that inhibit TNF[alpha] (such as pentoxyfylline), reduce C-reactive protein (such as statins), and bind endotoxin (such as lipoproteins). In addition, mental and flexibility exercises, such as yoga and/or meditation, may be recommended. Physical activity is associated with lower fasting insulin levels. Regular moderate exercise may promote an increase of plasma high-density lipoprotein.

Lipid mobilization by natriuretic peptides

The cardiac natriuretic peptides (atrial and brain natriuretic peptides) are known to regulate salt and water excretion by the kidneys, thereby playing an important role in blood-pressure control and volume homeostasis. Interestingly, overweight CHF patients have a better prognosis than underweight patients, and they also have lower atrial and brain natriuretic peptide levels compared with underweight patients. Recently it was reported that natriuretic peptides may also be involved in fat-cell metabolism. The cardiac natriuretic peptides control lipid mobilization and lipid oxidation by increasing intracellular cGMP and lipolysis. They also reduce leptin production, increase circulating free fatty acids and increase insulin resistance.

Conclusion

Anthropomorphic predictors of cardiac cachexia may include low baseline physical activity and very low mid-arm circumference. Low energy intake and increased total energy expenditure and TNF[alpha] levels were not as accurate in predicting the development of cardiac cachexia in patients with CHF.

In counseling CHF patients with cardiac cachexia, especially elderly patients, it is important to include the family and community resources. Older patients can (and do) make the needed dietary and lifestyle changes if counseled appropriately. They also need to appreciate the importance of activity (both physical and mental) as a significant part of their treatment plan. Even if the activity level is mild at the beginning, the need to start moving is paramount. Of equal importance is social involvement and psychological well-being. It should also be noted that laughter can burn up to 50 calories per 15 min. Micronutrient and vitamin supplements (including one multiple vitamin with minerals and/or vitamins B, C and E in low doses) should also be recommended, especially in patients with malabsorption secondary to CHF. Finally, the cornerstone in the prevention of cardiac cachexia is early diagnosis and treatment of heart disease and the prevention of its progression to CHF.