Cardiac disease is one of the most common disorders in both dogs and cats, affecting 11% of all dogs and up to 20% of some feline populations (Buchanan 1999, Cote and others 2004, Paige and others 2009). While medical therapy for cardiac disease has improved, with newer and more effective drugs, it is still only palliative with the goals of controlling clinical signs, slowing the progression of disease and improving quality of life. Maintaining good quality of life is particularly important in dogs and cats, for whom owners often prefer quality of life to quantity of life (Oyama and others 2008).
Nutrition is critical for the optimal treatment of animals with cardiac disease and should be an integral part of their medical management. Nutritional goals for animals with cardiac disease include maintaining optimal body condition, avoiding nutritional deficiencies and excesses, and gaining potential benefits from pharmacologic doses of certain nutrients. Omega-3 fatty acids appear to have a role in each of these important goals.
Optimal body condition: the syndrome of cardiac cachexia
Figure 3. A dog with severe heart failure and cardiac cachexia. Careful attention to monitoring bodyweight and muscle condition allows the clinician to detect cachexia at an earlier and more subtle stage, when interventions such as omega-3 fatty acids are more likely to be beneficial
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In health, weight loss is associated primarily with reductions in fat and lean tissue is relatively spared. Cachexia, however, is unusual in that it primarily depletes the metabolically active lean body mass. Cachexia is not unique to heart failure, as it also occurs in cancer, chronic obstructive pulmonary disease, rheumatoid arthritis, chronic kidney disease and other diseases. While there appear to be some subtle differences between cachexia in these varied diseases, loss of lean body mass is a hallmark of all forms of cachexia.
Recent studies have underscored the deleterious effects of cachexia and emphasised the role of bodyweight and body composition in heart failure. While obesity is a risk factor for development of heart disease in people, obesity may actually be associated with a protective effect once heart failure is present – this is known as the obesity paradox. A recent meta-analysis of more than 28,000 people was published on this phenomenon and concluded that, once heart failure was present, obesity and overweight were associated with lower all-cause and cardiovascular mortality and that underweight patients consistently had a higher risk of death (Oreopoulos and others 2008). The benefit of obesity in heart failure appears due to a lack of cachexia, rather than to the obesity per se, given the adverse effects associated with cachexia. Typically, excess weight is comprised of 75% adipose and 25% lean tissue. Therefore, obese people also have more lean body mass and this extra lean body mass may provide a greater reserve during the catabolic state of heart failure. The obesity paradox has also been demonstrated in dogs and cats with naturally occurring heart failure (Slupe and others 2008, unpublished data). These human and canine data emphasise the importance of avoiding weight (and muscle) loss in patients with heart failure.
Cachexia of all types is associated with increased inflammation and heart failure is no exception (Ross and others 1999, Freeman 2009, von Haehling and others 2009). While heart failure is known to be an inflammatory condition, cardiac cachexia is associated with an even greater degree of inflammation than heart failure alone (Anker and others 1997a, Anker and others 1997b, von Haehling and others 2009). Therefore, the anti-inflammatory effects of omega-3 fatty acids have made these compounds of interest in cachexia for many years. The mechanisms of inflammation and the resultant muscle loss that occurs in heart failure is now an area of great interest due to the large number of people with cardiac disease and the important detrimental effects of cachexia. The inflammatory cytokines, especially TNF and IL-1, are primary mediators of cachexia as they inhibit appetite, increase energy metabolism and accelerate the breakdown of muscle protein (catabolism) of lean body mass via the NF-κB pathway, myoD and myogenin downregulation, reduced muscle regeneration and inhibition of muscle differentiation (Moresi and others 2008). It has been known for many years that omega-3 fatty acids reduce protein catabolism by blocking the effects of TNF and IL-1 (Hirschberg and others 1990). Complete blockade of TNF or other inflammatory mediators may have adverse effects but other anti-inflammatory agents, such as certain cardiovascular drugs (e.g. angiotensin converting enzyme inhibitors, beta blockers; Gullestad and others 1999; Tatli and others 2008), antioxidants and omega-3 fatty acids may be more successful in combating cachexia. This may be strictly via anti-inflammatory effects of reducing TNF, IL-1 and inflammatory eicosanoids, but also may involve other mechanisms (Freeman 2009).
Despite a large body of research in other forms of cachexia (e.g. cancer cachexia), little research has been published on the effects of omega-3 fatty acids in heart failure. In a study of dogs with dilated cardiomyopathy (DCM) and heart failure, Freeman and others (1998) showed that omega-3 fatty acid supplementation (25 mg/kg EPA and 18 mg/kg DHA) significantly reduced IL-1 and prostaglandin E2 production, and reduced muscle loss compared with placebo. In addition, there was a significant negative correlation between a reduction in IL-1 and survival time. In people with heart failure, omega-3 fatty acid supplementation (61 mg/kg/day EPA and 33 mg/kg/day DHA) reduced TNF and IL-1, and was associated with an increase in body fat (Mehra and others 2006). Not all human studies of omega-3 fatty acids in other forms of cachexia (e.g. cancer, AIDS) have had positive results (Dewey and others 2007). However, newer research in human cancer patients has begun to successfully combine omega-3 fatty acids for their anti-inflammatory effects with calorie and protein supplementation (to ensure adequate substrates) (Fearon and others 2006, Fearon 2008, Bayram and others 2009). This underscores the importance of ensuring adequate calorie and protein intake in combination with omega-3 fatty acid supplementation in animals with cardiac disease.
Decreased intake of calories is a major problem for any species with heart failure and can be a significant contributor to cardiac cachexia (Freeman and Roubenoff 1994, Freeman and others 1998, Freeman 2009). Anorexia, either a complete or partial loss of appetite, is extremely common in cardiac disease, particularly in dogs with congestive heart failure (CHF), with prevalence between 34 and 84% of dogs and cats with cardiac disease (Mallery and others 1999, Freeman and others 2003, Torin and others 2007). Animals may not develop complete anorexia but instead have reductions in food intake, changes in food preferences or “cyclical” appetite
(i.e. the animal will eat one food well for several days and then refuse it). In cachexia, there is altered neural control of appetite such that normal factors that trigger a person to eat are reduced and satiety factors are elevated (Laviano and others 2008). This imbalance is primarily the result of an elevated inflammatory state, especially the inflammatory cytokines TNF and IL-1 (Laviano and others 2008). While a critical issue for managing anorexia is to optimise medical therapy including dietary modifications, modulation of cytokine production also can help to improve appetite (Freeman and Rush 2010). Omega-3 fatty acid supplementation, by decreasing production of inflammatory cytokines, can improve food intake which may aid in minimising loss of lean body mass in animals with heart failure (Freeman and others 1998).
Dogs with heart failure have been shown to have a relative deficiency of plasma EPA and DHA compared with normal dogs (Freeman and others 1998). One study of dogs with heart failure secondary to DCM showed that 8 weeks of fish oil supplementation normalised these plasma fatty acid abnormalities (Freeman and others 1998). Another canine study showed multiple differences in plasma fatty acids between Boxers and Doberman pinschers (Smith and others 2008). For example, Boxers had higher plasma concentrations of γ-linolenic acid but lower concentrations of arachidonic acid and total omega-6 fatty acids compared with Doberman pinschers (Smith and others 2008).
While more research is needed to delineate the fatty acid changes in various breeds and underlying forms of heart disease in dogs, alterations in plasma fatty acid also may have important implications for the heart. Prenatally, glucose is the main source of energy for cardiomyocytes, but there is a postnatal switch that allows fatty acids to become the major energy source in the adult heart (Stanley and others 2005, Neubauer 2007). When heart failure develops, however, the heart reverts to a fetal metabolic phenotype such that glucose once again becomes the major myocyte fuel, but the capacity for glucose utilisation in heart failure is limited. Thus, a myocardial energy deficit can result (Stanley and others 2005, Neubauer 2007). One promising approach to improving myocardial energy metabolism and mitochondrial function is to use omega-3 fatty acids (Duda and others 2009). Therefore, supplementation of omega-3 fatty acids may benefit energy metabolism via correction of a deficiency or through effects that are more pharmacologic in nature.
“Pharmacologic” effects of omega-3 fatty acids
Arrhythmia Many human studies, including a recent meta-analysis, have shown a benefit of fish consumption in reducing risk of coronary heart disease and death from myocardial infarction (Kromhout and others 1985, Ascherio and others 1995, Daviglus and others 1997, Albert and others 2002, He and others 2004, Iso and others 2006). Intake of omega-3 fatty acids from supplementation, rather than fish intake, has also been studied in a variety of human populations, such as people with implantable defibrillators (Leaf and others 2005, Raitt and others 2005, Brouwer and others 2006, London and others 2007, Brouwer and others 2009) and those with DCM (Nodari and others 2009), with mixed results. For example, a meta-analysis of people with defibrillators showed no benefit of omega-3 fatty acids (Brouwer and others 2009). However, the GISSI-HF Trial of nearly 7000 people with heart failure followed for a median of 3·9 years showed that omega-3 fatty acids (1 g/day) reduced mortality and hospital admission for cardiovascular reasons compared with placebo (Tavazzi and others 2008). Most of the human studies have evaluated effects on ventricular arrhythmias but recent publications also have shown benefits of omega-3 fatty acids on atrial fibrillation (Mozaffarian and others 2004, Calo and others 2005, London and others 2007, Sakabe and others 2007, Virtanen and others 2009). One of these, an induced canine model of atrial tachypacing (Sakabe and others 2007), suggested that omega-3 fatty acids reduced atrial fibrillation. Two epidemiologic studies showed that higher fish intake or circulating omega-3 fatty acid concentrations were associated with a lower incidence of atrial fibrillation (Mozaffarian and others 2004; Virtanen and others 2009). Finally, a randomised, controlled trial of omega-3 fatty acids after coronary artery bypass surgery in 160 people showed a significant reduction in postoperative atrial fibrillation (Calo and others 2005). A large study evaluating the effects of omega-3 fatty acids in people with recurrent atrial fibrillation currently is ongoing (Pratt and others 2009).
Although dogs have sometimes been used in experimentally induced conditions to study the effect of omega-3 fatty acids on arrhythmia, only one study has been published evaluating their effect in dogs with naturally occurring disease. Smith and others (2007) reported the results of a study in Boxers with ventricular arrhythmias which showed a reduction in arrhythmia number after 6 weeks of fish oil supplementation compared with control (sunflower oil). This effect was not found with supplementation of a similar dose of flax oil although the sample size may have been insufficient. As this study was conducted only in Boxers, further research is needed to determine whether these effects are consistent in a larger population of dogs and also in dogs of other breeds. As previously mentioned, Boxers and Doberman pinschers have some differences in plasma fatty acids and may have different relationships between arrhythmias and fatty acid concentrations (Smith and others 2008). Despite positive results, the effects of omega-3 fatty acids on arrhythmias appear to be modest and omega-3 fatty acids should only be viewed as an adjunct to medical therapy for dogs with significant arrhythmias.
Other cardiovascular effects of omega-3 fatty acids Most of the beneficial effects of omega-3 fatty acids in people with heart failure have been presumed to be the result of reduced arrhythmias. However, more recent studies are beginning to delineate additional positive effects. For example, one study showed that fish intake was associated with a reduced incidence of heart failure (Mozaffarian and others 2005a), although a recent large study, while showing similar patterns, was not significant (Levitan and others 2009). Omega-3 fatty acids have been associated with improved survival in some studies of human (Tavazzi and others 2008) and canine (Slupe and others 2008) heart failure. For example, a retrospective study of 108 dogs with heart failure secondary to DCM or chronic valvular disease (CVD) showed a significant effect of omega-3 fatty acids on survival (P=0·009; Slupe and others 2008). These associations may be related to the aforementioned anti-inflammatory effects, prevention of cachexia, improved appetite or anti-arrhythmic effects. However, omega-3 fatty acids also have a number of other effects that may also play a role and warrant further research. For example, omega-3 fatty acids reduce cardiac remodelling and subsequent dysfunction, reduce heart rate and blood pressure, improve endothelial function, and enhances baroreceptor function and heart rate variability (Geleijnse and others 2002, Mozaffarian and others 2005b, Morgan and others 2006, Radaelli and others 2006). Omega-3 fatty acids can alter immune function (Kearns and others 1999, Hall and others 2003, Farabaugh and others 2004, Freeman and Rush 2005) which may contribute to the cardiovascular effects of omega-3 fatty acids. Finally, omega-3 fatty acids reduce platelet aggregation as a result of production of the less potent thromboxane B5 (Bright and others 1994). This latter effect might be particularly useful in cats with cardiac disease at risk for thrombus formation but also is an important effect to consider with the use of omega-3 fatty acids in animals with coagulopathies (see below).
Current American Heart Association recommendations for people are to include 0·5 to 1·8 g/day either as fatty fish or supplements for primary prevention of cardiovascular disease (Kris-Etherton and others 2003). As coronary heart disease is not a concern in veterinary patients, there is less potential for a preventive role for dogs and cats. However, the author believes that there is adequate evidence to warrant the use of omega-3 fatty acids in dogs, and likely cats, with heart failure or certain arrhythmias for secondary prevention. In addition, omega-3 fatty acids may have benefits in earlier stages of cardiac disease (e.g. DCM, CVD, hypertrophic cardiomyopathy (HCM)) due to their numerous positive effects on the cardiovascular system but this requires further research. Despite their promise, many questions about the use of omega-3 fatty acids in animals with cardiac disease remain, such as patient selection, when to initiate omega-3 fatty acids, and whether they have similar benefits in cats. Therefore, further research is required to determine the optimal use of omega-3 fatty acids in animals with cardiac disease.