Pathophysiology and Specific Issues of Nutritional Management

4. Pathophysiology and Specific Issues of Nutritional Management

In addition to medications, optimal treatment of dogs with cardiac disease also includes careful attention to the diet. Although sodium restriction is the nutritional modification most often thought of for dogs with cardiac disease (and sometimes is the only nutrient modification thought of), adjustment of a variety of nutrients may be beneficial for these animals. Research is now beginning to show that dietary factors may be able to modulate canine cardiac disease, either by slowing the progression, minimizing the number of medications required, improving quality of life, or in rare cases, actually curing the disease.

In the past, the goal of nutritional management for animals with cardiac disease was purely symptomatic. This was primarily due to the limited number of medications available for treatment, and in that situation, severe sodium restriction was beneficial for reducing fluid accumulation in animals with CHF. Now, with more effective medications available for use in dogs, severe sodium restriction is not critical in most dogs. The emphasis in the nutritional management of dogs with CHF is on providing the optimal number of calories for the individual patient, avoiding nutritional deficiencies and excesses, and gaining potential beneficial effects from pharmacologic doses of certain nutrients.

Optimal Weight Maintenance

Both weight loss and obesity can be problems in animals with cardiac disease, and can adversely affect the dog's health.

Cardiac Cachexia

Dogs with CHF commonly demonstrate weight loss, termed cardiac cachexia (Figure 2). This weight loss in animals with CHF is unlike that seen in a healthy dog that loses weight. In a healthy animal that is receiving insufficient calories to meet requirements (e.g., a starving dog, a dog on a weight reduction diet), fat serves as the primary energy source and this helps to preserve lean body mass. In a dog with injury or illness, including CHF, amino acids from muscle are the primary source of energy, resulting in loss of lean body mass.
Figure 2. Cardiac cachexia in dogs with CHF.

Therefore, a loss of lean body mass is the hallmark of cachexia. There is a spectrum of severity of cachexia and the term does not necessarily equate with an emaciated, end-stage patient (Figure 3 and Figure 4). In the early stages, it can be very subtle and may even occur in obese dogs (i.e., a dog may have excess fat stores but still lose lean body mass). Loss of lean body mass is usually first noted in the epaxial, gluteal, scapular, or temporal muscles. Cardiac cachexia typically does not occur until CHF has developed.

Figure 3. Effects of starvation: differences between a healthy dog and a dog with cardiac disease. There is a dramatic difference between simple starvation, which occurs in a healthy animal and cachexia, the weight loss seen in animals with cardiac disease. A healthy animal will primarily lose fat tissue, whereas cachexia is distinguished by a loss of lean body mass.

Figure 4. Different stages of cachexia.

Cardiac cachexia can occur with any underlying cause of CHF (e.g., DCM, CVD, congenital heart diseases) but most commonly occurs in dogs with DCM, particularly those with right-sided CHF. In one study of dogs with DCM, over 50% of patients had some degree of cachexia (Freeman et al., 1998). Loss of lean body mass has deleterious effects on strength, immune function, and survival, so it is important to recognize cachexia at an early stage to explore opportunities to manage it effectively (Freeman & Roubenoff, 1994).

The loss of lean body mass in cardiac cachexia is a multifactorial process caused by anorexia, increased energy requirements, and metabolic alterations (Freeman & Roubenoff, 1994). The anorexia may be secondary to the fatigue or dyspnea or may be due to medication toxicity or feeding an unpalatable diet. Anorexia is present in 34 - 75% of dogs with cardiac disease (Mallery et al., 1999; Freeman et al., 2003b). Although not yet measured in dogs with CHF, energy requirements up to 30% above normal have been documented in people with CHF (Poehlman et al., 1994).

While these factors play a role in the loss of lean body mass, a major factor in this syndrome is an increased production of inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) (Freeman et al., 1998; Meurs et al., 2002). These inflammatory cytokines are known to directly cause anorexia, to increase energy requirements, and to increase the catabolism of lean body mass. Of particular pertinence to cardiac disease, TNF and IL-1 also cause cardiac myocyte hypertrophy and fibrosis and have negative inotropic effects (Figure 5).

Figure 5. Cardiovascular and nutritional effects of the inflammatory cytokines, tumor necrosis factor (TNF) and interleukin-1 (IL-1).

Nutritional management of dogs with cardiac cachexia consists primarily of providing adequate calories and protein and modulating cytokine production.

Anorexia can be detrimental to the dog with CHF in more than one way. Anorexia can be deleterious because it contributes to the syndrome of cardiac cachexia but, in addition, anorexia is one of the most common factors that contribute to a dog owner's decision of euthanasia. In one study of owners of dogs euthanized for CHF, anorexia was one of the most common contributing factors to the euthanasia decision (Mallery et al., 1999). Anorexia is more common in dogs with CHF compared to asymptomatic dogs, and it also is more common in dogs with DCM compared to dogs with CVD (Freeman et al., 2003b).

One of the most important issues for managing anorexia is to maintain optimal medical control of CHF. An early sign of worsening CHF is a reduction in food intake in a dog that has previously been eating well. Another possible cause of decreased appetite is the side effects of medications. Digoxin toxicity or azotemia secondary to ACE inhibitors or overzealous diuretic use can both cause anorexia. Ensuring a diet that is palatable to the dog while maintaining other nutritional goals is key to minimizing the effects of cachexia in dogs with CHF. Tips that may assist in food intake include feeding small, more frequent meals or warming the food to body temperature (or for some dogs, feeding refrigerated food increases appetite). Gradual introduction of a more palatable diet may be beneficial for some dogs (e.g., switching from a dry food to a canned food, changing to a different brand, or having a veterinary nutritionist formulate a balanced homemade diet). It also may be useful to use flavor enhancers to increase food intake (e.g., yogurt, maple syrup, or honey) (Figure 6).

Figure 6. Keys to nutritional management of anorexia in patients with cardiac disease.

Modulation of cytokine production can also be beneficial for managing cardiac cachexia. Although specific anti-TNF agents have not proven to be beneficial for people with CHF, dietary supplementation may be a safer method of reducing inflammatory cytokines. One method of decreasing the production and effects of cytokines is with n-3 polyunsaturated fatty acid supplementation (see discussion of n-3 fatty acids below). Supplementation of fish oil, which is high in n-3 fatty acids, can decrease cytokine production in dogs with CHF and improve cachexia (Freeman et al., 1998). A reduction of IL-1 has been correlated with survival in dogs with CHF (Freeman et al., 1998).

Optimal medical and nutritional therapy can help to reverse cachexia and improve nutritional status. Nutritional status is difficult to measure objectively in the ill patients but one parameter that can be evaluated is insulin-like growth factor-1 (IGF-1). In people and in dogs, IGF-1 concentrations have been used as an indicator of nutritional status (Clark et al., 1996; Maxwell et al., 1998). Mean IGF-1 concentrations have been shown to be positively correlated with survival, suggesting that maintaining good nutritional status may be able to improve survival (Freeman et al., 1998). In people with CHF, the presence of cachexia has proven to be a poor prognostic indicator (Anker et al., 2003; Davos et al., 2003).

Obesity

Although many dogs, particularly those with more advanced cardiac disease, have weight and muscle loss, some dogs with cardiac disease are overweight or obese (Figure 7). Although cardiac implications of obesity have not been well-studied in dogs and coronary artery disease is not a major concern in dogs, obesity is thought to be deleterious in dogs with cardiac disease because of its documented adverse effects on cardiac output, pulmonary function, neurohumoral activation, blood pressure, and heart rate in people and in experimental animal models (Alexander, 1986). In any obese dog, underlying endocrine diseases such as hypothyroidism and Cushing's disease should be ruled out, but most obese animals simply suffer from excess consumption of calories.

Figure 7. A dog with chronic valvular disease complicated by severe obesity. Obesity may exacerbate the disease. Owners of obese dogs with cardiac disease often report that, when the dog loses weight, it acts less dyspneic and more active.

Weight reduction programs are a difficult and often frustrating endeavor. For information on obesity and weight reduction programs, see Chapter 1. However, one advantage when a dog has cardiac disease is that there is automatically an increased incentive for the owner to commit to a weight reduction plan. Although this may not ensure success, it aids in the first step of successful weight loss.

As with any weight reduction program, it is critical to perform a careful dietary history to determine and control all sources of caloric intake. This diet history is also beneficial in finding other food sources for the dog that may be contributing both calories and sodium. Typically, the pet food is only one source of calories for the pet and as many, or more, calories may be consumed from treats and table food. In one study of dogs with cardiac disease, calorie intake from treats and table food ranged from 0 - 100%, with a median calorie intake from treats of 19% (Freeman et al., 2003b). Therefore, it is important to recommend specific treats that are reduced in both calories and sodium. Fresh non-starchy vegetables (or frozen/canned forms that are labeled as, "no salt added") are excellent low calorie treats for dogs that are obese and have cardiac disease.

If possible, an exercise program will help with the weight reduction program but, for dogs with CHF in which exercise restriction is recommended, this is not possible. For these dogs, the weight reduction program must rely on control of calorie intake.

Preventing Nutrient Excesses

Veterinarians have extrapolated from the human literature since the 1960's in applying nutritional recommendations to dogs with cardiac disease.

Sodium and Chloride

A prime example is sodium restriction. Healthy dogs can easily excrete excess dietary sodium in the urine but, even before clinical signs become apparent in dogs with cardiac disease, there is activation of the renin-angiotensin-aldosterone (RAA) system and abnormal excretion of sodium (Figure 8) (Barger et al., 1955). Based on this pathophysiologic change, sodium restriction has been a mainstay of therapy for dogs with cardiac disease for nearly 50 years. However, very few studies have been conducted on dietary sodium in dogs with cardiac disease. Many questions remain on the specific intake of sodium recommended for dogs with different stages of disease, at what stage sodium restriction should be instituted, and if there are any detrimental effects of sodium restriction.

Figure 8. Pathogenesis of sodium retention in heart disease.

Normal Dogs

Healthy dogs are relatively tolerant toward the sodium content of their diet.

An early study in 1964 showed no significant changes in extracellular water, sodium, or chloride in normal dogs fed a low sodium diet (Pensinger, 1964). This study also showed that healthy dogs were able to maintain sodium and potassium balance on both low and high sodium diets.

Two other studies found that normal dogs fed a low sodium diet had no changes in plasma sodium, chloride, or extracellular fluid volume compared to those fed a high sodium diet (Hamlin et al., 1964; Morris et al., 1976). In 1994, a study examined the effects of a low sodium diet and furosemide in healthy dogs with or without captopril (Roudebush et al., 1994). Although there were no within-group changes in electrolytes in this study, 3 of 6 dogs became hyperkalemic while receiving a low sodium diet plus furosemide and 2 of 6 became hyperkalemic while receiving a low sodium diet plus furosemide and captopril (Roudebush et al., 1994). The effects of the low sodium diet alone were not reported.

In normal dogs, low sodium diets caused an increase in plasma renin activity (PRA) and plasma aldosterone concentration compared to a high sodium diet, although plasma concentrations of ACE, atrial natriuretic peptide (ANP), arginine vasopressin (AVP), and endothelin-1 (ET-1) remained unchanged (Pedersen et al., 1994a, Pedersen et al., 1994b). Normal dogs receiving enalapril while eating a low-sodium diet, however, had an exaggerated increase in PRA and a larger decrease in ACE and ANP compared to a dogs eating a high sodium diet (Koch et al., 1994). These investigators also found an inverse correlation between PRA and sodium content of the diet (Koch et al., 1994).

Dogs with CHF

Dogs with CHF respond differently to dietary sodium restriction. Sodium restriction is one method, along with the use of diuretics and venous vasodilators, to treat excessive increases in preload in patients with CHF. In the 1960's, when few medications were available for treating dogs with CHF, dietary sodium restriction was one of the few methods of reducing fluid accumulation. In this situation, severe sodium restriction clearly was beneficial in reducing signs of congestion.

In one study, dogs with CHF retained sodium on the high sodium diet but did not retain sodium on the low sodium diet (Pensinger, 1964). Untreated dogs with mild, asymptomatic mitral valve insufficiency had a larger increase in PRA and PAC and a lower ACE activity when changed from a high sodium diet to a low sodium diet (Pedersen, 1996). Sodium intake had no effect on endothelin-1, ANP, and AVP (Pedersen, 1996).

A randomized double-blind, placebo-controlled clinical trial of low sodium diets in dogs with CHF secondary to either CVD or DCM demonstrated no significant changes in neurohormones between a low sodium and moderate sodium diet (Rush et al., 2000). Serum sodium and chloride concentrations decreased significantly while dogs were eating the low sodium diet (Rush et al., 2000). Measures of cardiac size decreased significantly on the low sodium diet compared to the moderate sodium diet, especially in dogs with endocardiosis (Rush et al., 2000). The effects of a low sodium diet on survival were not tested.

The biggest gap in the issue of sodium restriction is for dogs with early cardiac disease [Stage I or II: Table 5] (International Small Animal Cardiac Health Council (ISACHC), 2001). Based on the pathogenesis of sodium retention, authors in the 1960's recommended institution of low-sodium diets for dogs when a heart murmur was first detected, even before clinical signs were present (Morris, 1976). Only recently have the benefits and potential problems been questioned. One of the earliest and major compensatory responses in cardiac disease is activation of the renin-angiotensin-aldosterone (RAA) system. Sodium restriction can further activate the RAA system (Pedersen et al., 1994a-1994b; Koch et al., 1994).

Thus, severe sodium restriction in dogs with early cardiac disease could theoretically be detrimental by early and excessive activation of the RAA system. Studies by Pensinger showed that dogs with cardiac disease but without CHF were able to maintain sodium and potassium balance on both low and high sodium diets, similar to normal dogs (Pensinger, 1964) but neurohormone changes were not measured. While any potential detrimental effects of early institution of severe dietary sodium restriction have not been shown, it is clear that all drug therapies shown to improve survival in CHF act by blunting neurohumoral activation. Therefore, severe sodium restriction (i.e., near the AAFCO minimum of 20 mg/100 kcal) is not currently recommended for dogs with ISACHC Stage 1 or 2 cardiac disease. Conversely, high dietary sodium intake in early disease is likely detrimental. Table 5 summarizes the authors' current recommendations, based on available literature and clinical experience.

Most owners are unaware of the sodium content of pet foods and human foods and need very specific instructions regarding appropriate dog foods, acceptable low salt treats, and methods for administering medications (Table 6). Owners also should be counselled on specific foods to avoid such as baby food, pickled foods, bread, pizza, condiments (e.g., ketchup, soy sauce), lunch meats and cold cuts (e.g., ham, corned beef, salami, sausages, bacon, hot dogs), most cheeses, processed foods (e.g., potato mixes, rice mixes, macaroni and cheese), canned vegetables (unless "no salt added"), and snack foods (e.g., potato chips, packaged popcorn, crackers).

Mildly reduced dietary sodium can be achieved with a therapeutic diet designed for animals with early cardiac disease or with certain diets designed for use in older dogs. If using a diet designed for senior dogs, be sure to look at the characteristics of the individual product. There is no legal definition for a senior diet so the levels of calories, protein, sodium, and other nutrients can vary dramatically between different companies' products. Diets designed for animals with renal disease are not recommended for most cardiac patients because of the protein restriction (unless severe renal dysfunction is present).

As CHF becomes more severe, more sodium restriction may allow lower dosages of diuretics to be used to control clinical signs. To achieve severe sodium restriction, it is usually necessary to feed a commercial therapeutic diet designed for cardiac patients. Typically, these diets are severely restricted in both sodium and chloride; levels of other nutrients vary with the individual product.

Dietary chloride levels are often ignored but research suggests that chloride may be important in the optimal management of CHF. Research in people has shown that sodium and chloride administration are necessary for the full expression of hypertension in people (Boegehold & Kotchen, 1989). Chloride administration also appears to decrease plasma renin activity in salt depleted rats (Kotchen et al., 1980; Muller, 1986).

The patient with heart failure has chronic activation of the RAA system, which could be significantly influenced by dietary chloride. In addition, furosemide is known to block chloride transport in the ascending loop of Henle, and hypochloremia (and hyponatremia) can develop in advanced CHF. Therefore, chloride is likely to play an important role in the CHF patient. Unfortunately, little is known about optimal dietary intake for CHF patients and additional research will be required to make specific recommendations.

Potassium

In the past, when digoxin and diuretics were the mainstays of therapy for people and dogs with CHF, hypokalemic was a major consideration. Now, ACE inhibitor therapy has gained widespread use in the management of dogs with CHF and this medication results in renal potassium sparing. Therefore, ACE inhibitors are known to cause increased serum potassium, with some animals developing hyperkalemia (Roudebush et al., 1994; COVE Study Group, 1995; Rush et al., 1998). This can especially be a problem in animals eating commercial cardiac diets since some commercial cardiac diets contain increased potassium concentrations to counteract the theoretical loss due to diuretics.

In addition to the importance of the diets' compatibility with current ACE inhibitor use, other newer cardiac medications may also be used more commonly. Spironolactone, an aldosterone antagonist and a potassium-sparing diuretic is being used with greater frequency in veterinary patient after reports of improved survival in human CHF patients (Pitt et al., 1999). This medication is even more likely than other diuretics to cause hyperkalemia. Finally, many people know about the association between diuretics and hypokalemia either from their own medical condition or that of a friend or relative, and some mistakenly give their dogs with CHF bananas or potassium supplements in an effort to prevent this problem. Routine monitoring of serum potassium is recommended for all patients with CHF, particularly those receiving an ACE inhibitor or spironolactone. If hyperkalemia is present, a diet with a lower potassium content should be selected.

Preventing Nutritional Deficiencies Versus Nutritional Pharmacology

Historically, a variety of nutritional deficiencies have been known to cause cardiac disease in various species. These include thiamine, magnesium, vitamin E, selenium, and taurine. Although nutritional deficiencies are generally uncommon (except in owners feeding unbalanced homemade diets), they may still play a role in some cardiac diseases of dogs. Nutritional deficiencies may also develop secondary to the disease or its treatment. There is also blurring of the lines between the benefits of correcting a nutritional deficiency (e.g. as in a cat with taurine deficiency-induced dilated cardiomyopathy) and the pharmacological effects of a nutrient (e.g. the positive inotropic effects of taurine). In addition, new information is coming out on species and even breed differences in nutrient requirements. Thus, there appears to be much more to providing optimal levels of nutrients than just preventing a deficiency.

Protein and Amino Acids

Protein

In addition to sodium restriction, the dietary recommendations in the 1960's for dogs with CHF were to restrict protein intake to "reduce the metabolic load on congested, aging, and diseased kidneys and liver" (Pensinger, 1964). Restricting protein can actually be detrimental in terms of lean body mass loss and malnutrition. Dogs with CHF should not be protein restricted, unless they have concurrent advanced renal disease. Some of the diets designed for dogs with cardiac disease are low in protein (3.6 - 4.2 g/100 kcal). In addition, some veterinarians recommend protein-restricted renal diets for dogs with cardiac disease because these diets often (but not always) are also moderately sodium restricted.

Unless severe renal dysfunction is present (i.e., serum creatinine >3.0 mg/dL), high-quality protein should be fed to meet canine AAFCO minimums for adult maintenance requirements (5.1 g/100 kcal; Association of American Feed Control Officials (AAFCO), 2005). In one study, daily protein intake of dogs with cardiac disease ranged from 2.3 - 18.8 g/100 kcal so some dogs with cardiac disease are clearly not eating sufficient dietary protein (Freeman et al., 2003b).

Another misconception that impacts cardiac disease is the still widespread belief that dietary protein should be restricted in early renal disease (see Chapter 8). Although the majority of dogs treated with ACE inhibitors do not develop azotemia, some dogs receiving ACE inhibitors can develop azotemia (COVE Study Group, 1995). Azotemia occurs more frequently when ACE inhibitors are used in conjunction with diuretics although, in a small number of dogs, azotemia can develop from ACE inhibitors alone. When concurrent ACE inhibitor and diuretic use causes azotemia, reduction of the furosemide dose is indicated to reduce azotemia. A protein-restricted diet is not necessary in this situation unless medication changes do not correct the problem and the renal disease progresses.

When concurrent ACE inhibitor and diuretic use causes azotemia, reduction of the diuretic dose is indicated to reduce azotemia. A protein restricted diet is not necessary in this situation unless medication changes do not correct the problem and the renal disease progresses.

Taurine

The association between taurine and feline DCM described in the late 1980's prompted investigators to examine the role of taurine in canine DCM (Pion et al., 1987). Unlike cats, dogs are thought to be able to synthesize adequate amounts of taurine endogenously and taurine is not considered to be required in canine diets. Although initial studies showed that most dogs with DCM did not have low plasma taurine concentrations, certain breeds of dogs with DCM (e.g., Cocker Spaniels and Golden Retrievers) did have low taurine concentrations (Kramer et al., 1995). The association between dogs with DCM and low taurine concentrations has been best established in the American Cocker Spaniel (Kramer et al., 1995; Kittleson et al., 1997).

In a study by Backus et al., 12 of 19 Newfoundlands tested had taurine concentrations consistent with taurine deficiency. However, none of these dogs had DCM (Backus et al., 2003). Other commonly reported breeds of dogs with DCM and taurine deficiency include Golden Retriever, Labrador Retriever, Saint Bernard, English Setter (Freeman et al., 2001; Fascetti et al., 2003).

The first question about the relationship between canine DCM and taurine deficiency is whether DCM is caused by dietary deficiency.

In one retrospective study, 20 of 37 dogs with DCM tested for plasma and whole blood taurine concentrations were considered to be taurine-deficient (Freeman et al., 2001). There was no significant difference in mean dietary taurine content (based on manufacturers' information) between taurine deficient and non taurine deficient dogs, nor was there a correlation between dietary content and circulating taurine concentrations (Freeman et al., 2001). Of the taurine deficient dogs, 7 were eating a lamb and rice based diet and seven were eating an ncreased fiber diet.

In a retrospective study, of the taurine deficient dogs, 7 were eating a lamb and rice based diet and 7 were eating an increased fiber diet. (© Psaila).

Twelve dogs with DCM and taurine deficiency were reported to be eating dry diets containing lamb meal, rice, or both as primary ingredients (Fascetti et al., 2003).

Twelve dogs with DCM and taurine deficiency were reported to be eating dry diets containing lamb meal, rice, or both as primary ingredients (Fascetti et al., 2003).

In another study, 131 normal dogs were tested for plasma and whole blood taurine concentrations. In this study, dogs consuming diets containing rice bran or whole grain rice had lower taurine concentrations (Delaney et al., 2003). Thus, it may be the rice bran component of diets that affects taurine concentrations although lamb meal also is known to have decreased amino acid digestibility (Johnson et al., 1998).

Alternatively, dietary protein quality and quantity may also play a role in taurine deficiency. In one study, a group of Beagles fed a low taurine, very low protein diet for 48 months had a decrease in whole blood taurine concentrations and 1 of the 16 dogs developed DCM (Sanderson, 2001).

Finally, some dog breeds may be predisposed to taurine deficiency when fed certain types of diets because of higher requirements or breed-specific metabolic abnormalities.

A second question that still remains is whether taurine supplementation reverses DCM in dogs with concurrent taurine deficiency.

In one small study, 11 Cocker Spaniels supplemented with taurine and carnitine showed improvement in clinical parameters and echocardiographic measurements (Kittleson et al., 1997). Whether the response would be similar with taurine alone remains to be seen. In one small retrospective study that compared dogs with DCM that were taurine deficient and were treated with taurine (plus medical therapy) to dogs that were not taurine deficient, there was no difference in the number that were able to discontinue medications, in the furosemide dosage, in echocardiographic measurements, or survival (Freeman et al., 2001). Another retrospective study of 12 dogs with DCM and taurine deficiency showed a within-group improvement in E-point to septal separation and fractional shortening after taurinesupplementation but there was no comparison group (Fascetti et al., 2003).

Response to therapy may be breed dependent. In a study of a litter of Portugese Water Dogs with DCM, taurine was below the reference range in eight of eight puppies tested, and DCM was diagnosed in eight of the nine puppies (Alroy, 2000). Taurine supplementation was instituted in 6 of the puppies, which significantly increased plasma and whole blood taurine concentrations as well as cardiac function (Alroy, 2000). In a study of Beagles fed a low taurine, very low protein diet for 48 months, the one dog that developed DCM had improvement in fractional shortening after three months of taurine supplementation (Sanderson et al., 2001). Some of the potential benefits of taurine in dogs with DCM may be due to its positive inotropic effects or role in calcium regulation in the myocardium. Beneficial effects of taurine have been shown in animal models with experimentally-induced heart failure and in unblinded human clinical trials (Elizarova et al., 1993, Azuma, 1994).

While it is unlikely that the breeds at high risk for DCM such as the Doberman Pinscher or the Boxer have taurine deficiency, certain breeds (e.g., Cocker Spaniel, Newfoundlands, Golden Retrievers) and atypical breeds (e.g., Scottish Terrier, Border Collie) may have concurrent taurine deficiency. Therefore, in these latter breeds, measuring plasma and whole blood taurine concentrations is recommended. In addition, taurine concentrations should be measured in dogs with DCM that are eating lamb meal and rice, very low protein, or increased fiber diets. Although the extent of the benefit of supplementation is not yet clear, taurine supplementation is recommended until plasma and whole blood taurine concentrations from the patient are available. Even in dogs with taurine deficiency that do respond to taurine supplementation, the response is generally not as dramatic as in taurine deficient cats with DCM. The optimal dose of taurine for correcting a deficiency has not been determined but the currently recommended dose is 500 - 1000 mg q 8 - 12 hours. Taurine can be provided as a supplement although certain diets may contain enough taurine to raise plasma taurine concentrations.

Minimum taurine requirements for dogs have not been established by AAFCO, but the minimum taurine requirement for adult cats is 25 mg/100 kcal for dry food and 50 mg/100 kcal for canned foods (AAFCO, 2005). A diet with a taurine content of 50 mg/100 kcal would provide approximately 1000 mg/day of taurine to a 40 kg dog.

In Cocker Spaniels with DCM, measuring plasma and whole blood taurine concentrations is recommended. (© Renner).

Arginine

Nitric oxide is an endogenous vascular smooth muscle relaxant. It is synthesized from L-arginine and molecular oxygen (Figure 9).

Figure 9. Origin of nitric oxide.

Circulating nitric oxide is elevated in people with CHF, regardless of the underlying cause and in two studies of dogs and cats with heart disease (De Belder et al., 1993; Comini et al., 1999; De Laforcade et al., 2000; Freeman et al., 2003a). However, one study of dogs showed lower nitric oxide concentrations in dogs with untreated CVD (Pedersen et al., 2003). High circulating nitric oxide levels may have an initial beneficial compensatory effect but can be detrimental when this response is prolonged. High levels of nitric oxide can have a negative inotropic effect and can decrease the responsiveness to beta-adrenergic stimulation (Gulick et al., 1989; Yamamoto et al., 1997). There appear to be competing responses occurring in CHF. While iNOS is upregulated in patients with CHF producing high circulating levels of nitric oxide, eNOS is actually downregulated and reduces endothelium-dependent vasodilation (Agnoletti et al., 1999, Katz et al., 2000).

The reduction in eNOS and resulting loss of normal vasodilation have adverse effects in the patient with CHF (Feng et al., 1998). People with CHF have a reduction of peripheral blood flow both at rest and during exercise (Maguire et al., 1998). This abnormality may contribute to exercise intolerance in these patients. Endothelial dysfunction has also been demonstrated in dogs with experimentally-induced CHF and is associated with decreased gene expression of eNOS (Wang et al., 1997).

Based on the findings of endothelial dysfunction in patients with CHF, investigators have begun to study the effects of arginine supplementation in this group. In normal patients, L-arginine supplementation is unlikely to have an effect on nitric oxide production because L-arginine is found in concentrations much higher than the Km values for NOS (Tsikas et al., 2000). But the situation in patients with CHF may be very different and, in fact, L-arginine supplementation has been shown to improve endothelial dysfunction (Kubota et al. a, 1997; Feng et al., 1999; Kanaya et al., 1999; Hambrecht et al., 2000). L-arginine supplementation has been tested in people with CHF in a number of studies (Kubota et al., 1997; Kanaya et al., 1999; Banning & Prendergast, 1999; Bocchi et al., 2000; Hambrecht et al., 2000). These studies have shown increased circulating concentrations of nitric oxide but improved endothelium-dependent vasodilation and cardiac output. These studies also have shown reduced heart rate and systemic vascular resistance, with no negative effects on cardiac contractility or other echocardiographic variables (Kubota et al., 1997; Hambrecht et al., 2000; Bocchi et al., 2000). Although one study of arginine supplementation found no effect on exercise tolerance, another study showed that L-arginine reduced dyspnea in response to increasing CO2 production during exercise in people with severe chronic heart failure (Kanaya et al., 1999; Banning & Prendergast, 1999). Thus, while much research is needed in this area, arginine supplementation may provide beneficial effects in patients with CHF.

Fat

Fat is a source of calories and essential fatty acids and increases the palatability of the diet. However, depending upon the type of fat, it can have significant effects on immune function, the production of inflammatory mediators and even hemodynamics.

n-3 Fatty Acids

Most human and canine diets contain primarily n-6 fatty acids. In n-6 fatty acids (e.g. linoleic acid, γlinolenic acid, and arachidonic acid), the first double-bond is at the position of the 6th carbon from the methyl end. However, n-3 fatty acids [α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)] have the first double-bond at the 3rd carbon from the methyl end. Although this seems like a minor change, it confers very different structure and characteristics to the fatty acid. Plasma membranes normally contain very low concentrations of n-3 fatty acids, but levels can be increased by a food or supplement enriched in n-3 fatty acids.

Dogs with heart failure have lower plasma concentrations of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-6), regardless of the underlying disease (Figure 10) (Freeman et al., 1998; Rush et al., 2000). This alteration in plasma fatty acids has also been found in people with various diseases as well, suggesting that metabolic changes may occur in certain diseases that increase the use of n-3 fatty acids. Therefore, supplementation may improve an absolute or relative n-3 fatty acid "deficiency".

Figure 10. Plasma fatty acid concentrations in dogs with dilated cardiomyopathy (dCM) and heart failure (N=28) compared to healthy control dogs (N=5) (From Freeman et al., 1998).

n-3 fatty acid supplementation also reduces the more inflammatory eicosanoids. n-3 fatty acids are known to reduce the production of the more inflammatory 2- and 4-series eicosanoids (e.g., there is a shift from production of prostaglandin E2 to prostaglandin E3). In a study of dogs with DCM, dogs supplemented with fish oil had a greater reduction in prostaglandin E2 production compared to dogs receiving the placebo (Freeman et al., 1998). This may have benefits in terms of reduced inflammation. n-3 fatty acids also are known to decrease the production of the inflammatory cytokines, TNF and IL-1, which are elevated in CHF (Endres et al., 1989; Meydani et al., 1991; Freeman et al., 1998).

Fish oil supplementation reduced cachexia and, in some, but not all dogs with CHF-induced anorexia, improved food intake (Freeman et al., 1998). Finally, n-3 fatty acids have been shown in a number of rodent, primate, and canine models to reduce arrhythmogenesis (Charnock, 1994; Kang & Leaf, 1996; Bill-man et al., 1999). Many dogs with CVD and most dogs with DCM have arrhythmias. In some dogs with cardiac disease, sudden death due to arrhythmias is the first manifestation of the disease in otherwise asymptomatic dogs. Therefore, n-3 fatty acid supplementation may be beneficial even before CHF develops.

n-3 Fatty Acid Supplementation

There is controversy as to whether dose of n-3 fatty acids or the ratio of n-6: n-3 fatty acids is more important for the beneficial effects of n-3 fatty acids. Some evidence points to the primary importance of the total n-3 dose but it may also be important to avoid a high n-6:n-3 ratio as well. Although an optimal dose has not been determined, the authors currently recommend a dosage of 40 mg/kg EPA and 25 mg/kg DHA for dogs with anorexia or cachexia. Unless the diet is one of a few specially designed therapeutic diets, supplementation will be necessary since other commercial diets will not achieve this n-3 fatty acid dose.

The exact content of EPA and DHA in individual fish oil supplements varies widely. The most common formulation of fish oil, however, is one gram capsules that contain 180 mg EPA and 120 mg DHA. At this concentration, fish oil can be administered at a dose of 1 capsule per 10 pounds of body weight to achieve the authors' recommended EPA and DHA dose. Fish oil with higher concentrations of EPA and DHA can be obtained from medical supply catalogs and may be more feasible for large dogs.

Fish oil supplements should always contain vitamin E as an antioxidant, but other nutrients should not be included to avoid toxicities. Similarly, cod liver oil should not be used because of the possibility for vitamins A and D toxicity. Finally, although flax seed oil contains high levels of α-linolenic acid, this fatty acid must be converted to EPA and DHA for its beneficial effects. Species vary in the ability to make this conversion: dogs have the enzymes to convert it but with limited efficiency. Therefore, flax seed oil is not recommended as an n-3 fatty acid supplement.

Although an optimal dose has not been determined, the authors currently recommend a dosage of 40 mg/kg EPA and 25 mg/kg DHA for dogs with anorexia or cachexia. Unless the diet is one of a few specially designed therapeutic diets, supplementation will be necessary since other commercial diets will not achieve this n-3 fatty acid dose.

Minerals and Vitamins

Potassium

Potassium is an important electrolyte in cardiac patients for a number of reasons. Hypokalemia potentiates arrhythmias, causes muscle weakness, and predisposes patients to digitalis toxicity. In addition, Class I antiarrhythmic drugs, such as procainamide and quinidine, are relatively ineffective in the face of hypokalemia. Hypokalemia was considered to be a common problem in the past when diuretics were the mainstays of therapy. Many of the medications used in dogs with CHF can predispose a patient to hypokalemia, including loop diuretics (e.g., furosemide) and thiazide diuretics (e.g., hydrochlorothiazide). However, with the increased use of ACE inhibitors, hypokalemia is no longer very common in dogs with CHF.

In addition to medication effects, inadequate dietary intake could predispose a dog to hypokalemia. In one study, 49% of dogs with cardiac disease ate less potassium than the AAFCO minimum value (170 mg/100 kcal). Intakes ranged from 37 - 443 mg/100 kcal (Freeman et al., 2003b). This suggests that, based on dietary intake alone, some dogs may be predisposed to hypokalemia (in addition to the risk for hyperkalemia previously discussed) and underscores the importance of monitoring serum potassium in dogs with CHF.

Magnesium

Magnesium is an essential prosthetic group in hundreds of enzymatic reactions involving carbohydrate and fatty acid metabolism, protein and nucleic acid synthesis, the adenylate cyclase system, and cardiac and smooth muscle contractility. Thus, magnesium plays an important role in normal cardiovascular function. It is also clear that alterations in magnesium homeostasis in people and dogs are common, and can have deleterious effects in a variety of cardiovascular conditions including hypertension, coronary artery disease, congestive heart failure, and cardiac arrhythmias (Resnick, 1984; Rayssiguer, 1984; Gottleib et al., 1990; Iseri, 1986; Cobb & Michell, 1992). In addition, numerous drugs used to treat cardiac conditions, including digoxin and loop diuretics are associated with magnesium depletion (Quamme & Dirks, 1994). Therefore, dogs with heart failure receiving these medications have the potential to develop hypomagnesemia. Hypomagnesemia can increase the risk of arrhythmias, decrease cardiac contractility, and can potentiate the adverse effects of cardiac medications.

There have been conflicting reports on the prevalence of hypomagnesemia in dogs with cardiac disease. Reports range from "uncommon" (O'Keefe et al., 1993) to 2/84 (Edwards et al., 1991); fifty percent (Rush, 2000) to two-thirds of Lasix-treated dogs (Cobb & Michell, 1992).

One of the difficulties in diagnosing magnesium deficiency is that only one percent of the total body magnesium is in the extracellular space. Therefore, normal serum magnesium does not necessarily mean there are adequate total body stores. Serial measurements of serum magnesium are currently recommended, especially in dogs with arrhythmias or those receiving large doses of diuretics. If low serum magnesium concentrations do arise and the dog is eating a diet that is low in magnesium, a diet higher in magnesium may be beneficial. Magnesium concentrations vary widely in commercial pet foods. Commercial reduced sodium diets for dogs can contain between 9 - 40 mg magnesium/100 kcal (compared to an AAFCO minimum of 10 mg/100 kcal). If the dog remains hypomagnesemic, oral magnesium supplementation will be required (e.g. magnesium oxide).

Hypokalemia was considered to be a common problem in the past when diuretics were the mainstays of therapy. Many of the medications used in dogs with CHF can predispose a patient to hypokalemia, including loop diuretics (e.g., furosemide) andthiazide diuretics (e.g., hydrochlorothiazide). However, with the increased use of ACE inhibitors, hypokalemia is no longer very common in dogs with CHF.

B vitamins

(Table 7)

Little research has been conducted on the prevalence of B vitamin deficiencies in dogs with cardiac disease. However, there have long been concerns over the risk of B vitamin deficiencies in CHF due to anorexia and urinary loss of water soluble vitamins secondary to diuretic use. This may be less of a problem now that there are more effective medications for treatment of CHF but even in one study from 1991, 91% of people with CHF had low thiamine concentrations (Seligmann et al., 1991). In this study, patients were being treated with furosemide, ACE inhibitors, nitrates, and digoxin (where appropriate).

Low doses of furosemide were shown to cause increased urinary loss of thiamine in healthy people and in rats (Rieck et al., 1999; Lubetsky et al., 1999). Although B vitamin status has not been reported for dogs with CHF, they may have higher dietary B vitamin requirements. Most commercial cardiac diets contain increased levels of water soluble vitamins to offset urinary losses so supplementation usually is not required.

Other Nutrients

Antioxidants

Much attention has been given to antioxidants for their potential role in the prevention and treatment of human cardiac diseases. Reactive oxygen species are a by-product of oxygen metabolism for which the body normally compensates through the production of endogenous antioxidants. An imbalance between oxidant production and antioxidant protection (e.g., oxidative stress), however, could increase the risk for cardiac disease (Figure 11). Antioxidants are produced endogenously but also can be supplied exogenously. The major antioxidants include enzymatic antioxidants (e.g., superoxide dismutase, catalase, glutathione peroxidase) and oxidant quenchers (e.g., vitamin C, vitamin E, glutathione, and β-carotene).

Figure 11. Origin of oxidative stress.

Oxidative stress has been implicated in the development of a number of cardiac diseases. Increased oxidative stress has been demonstrated in people with CHF (Belch et al., 1991; Keith et al., 1998). In dogs with heart failure, regardless of the underlying cause, there are increased levels of biomarkers of oxidative stress and a reduction in certain antioxidants, particularly vitamin E (Freeman et al., 1999; Freeman et al., 2005). These alterations suggest an imbalance between oxidant stress and antioxidant protection in dogs with CHF.

Additional research is required to evaluate the effect, but antioxidant supplementation may hold promise in the future for the therapy of animals with cardiac disease.

L-Carnitine

L-Carnitine is a quaternary amine (Figure 12) whose major role is in long-chain fatty acid metabolism and energy production. Carnitine deficiency syndromes in people have been associated with primary myocardial disease and, based on this and its high concentrations in cardiac muscle, its role in canine DCM also has been of interest.

Figure 12. Carnitine molecule. Discovered in 1905, L-carnitine is synthetized in dogs from lysine and methionine, if vitamin C and pyridoxine (vit B6) are present. It is a quaternary amine that acts as a water soluble vitamin. Carnitine can be synthetized in D or L forms, but L-carnitine is the only one of relevance for dogs with cardiac disease.

L-carnitine deficiency was reported in a family of Boxers in 1991 (Keene et al., 1991). Since that time, L-carnitine supplementation has been used in some dogs with DCM but no blinded prospective studies have been done so a causative role has not been established. In human DCM patients, most studies of L-carnitine have not been well-controlled. However, one randomized, double-blind, placebo-controlled study showed improved three-year survival in human DCM patients receiving 2 mg/day L-carnitine (Rizos, 2000).

One of the difficult aspects of studying L-carnitine in DCM is that one must measure myocardial concentrations since plasma concentrations are often normal even in the face of myocardial deficiency. Therefore, the advancement of knowledge of the role of this nutrient in DCM has been slow. It is not yet clear whether the carnitine deficiency seen in some dogs with DCM is the cause of the disease or merely secondary to the development of CHF. One study of dogs with heart failure induced by rapid pacing showed that myocardial concentrations decreased in normal dogs after the onset of CHF (Pierpont et al., 1993). However, even if L-carnitine deficiency is not the inciting cause of DCM, supplementation may still provide benefits by improving myocardial energy production.

The minimum or optimal dose of L-carnitine necessary to replete a dog with low myocardial carnitine concentrations is not known, but the currently recommended dose is 50 - 100 mg/kg PO q 8 hours.

L-carnitine supplementation has few side effects but it is expensive and this may be a significant deterrent for some owners. The authors offer the option of L-carnitine supplementation to owners of dogs with DCM, especially Boxers and Cocker spaniels, but do not consider it essential. The minimum or optimal dose of L-carnitine necessary to replete a dog with low myocardial carnitine concentrations is not known, but the currently recommended dose is 50 - 100 mg/kg PO q 8 hours.

Coenzyme Q10

Coenzyme Q10 is a cofactor required for energy production and has antioxidant properties. There are a number of mechanisms by which coenzyme Q10 might play a role in cardiac disease. Some investigators have proposed coenzyme Q10 deficiency as a possible cause for DCM but this has not been proven. Even in dogs with experimentally-induced CHF, serum coenzyme Q10 levels were not reduced (Harker-Murray et al., 2000).

The most enthusiasm for coenzyme Q10 has been as a dietary supplement in the treatment of people or dogs with DCM. Coenzyme Q10 supplementation has anecdotally been reported to be beneficial but most of the human studies of coenzyme Q10 supplementation have not been well-controlled and results are conflicting. However, some encouraging results have been found (Langsjoen et al., 1994; Sacher et al., 1997; Munkholm et al., 1999). In one study of dogs with experimentally-induced CHF, coenzyme Q10 supplementation increased serum, but not myocardial, concentrations (Harker-Murray et al., 2000). The bioavailability of coenzyme Q10 varies in different tissues and also depends upon the degree of tissue deficiency in that tissue.

The current recommended dose in canine patients is 30 mg PO BID, although up to 90 mg PO BID has been recommended for large dogs. The purported benefits of supplementation includecorrection of a deficiency, improved myocardial metabolic efficiency, and increased antioxidant protection. Controlled prospective studies will be necessary to accurately judge the efficacy of this supplement.