Nutritional management of heart disease (Proceedings)

Knowledge about management of heart disease in Veterinary Medicine has grown tremendously in the last two decades. In part, this has been due to widespread availability of ultrasound technology, which has enabled the clinician to diagnose cardiac problems earlier in the course of the disease and more accurately, as well as gain a greater understanding of cardiovascular disease itself. Improved diagnostic capabilities, expanded uses for existing drugs, as well as development of new drugs has increased survival and quality of life for many veterinary patients with heart disease. However, most of our pharmacologic therapy remains symptomatic and supportive, and does little to address the primary disease process itself.

Some of the more exciting advances in cardiovascular therapy in the past two decades have not come from the development of new drugs, but rather from nutritional management of heart disease. Some of these nutritional advances, such as the discovery in the mid-1980s that taurine deficiency was the cause of the majority of cases of feline dilated cardiomyopathy (DCM) at the time, has had a major impact on this disease. Until the mid-1980s, DCM was the most common cardiomyopathy in cats, and despite our best efforts, the majority of feline patients with DCM succumbed to this disease within months of being diagnosed with it. However, the discovery that taurine deficiency was the underlying cause for the majority of DCM in cats, and that taurine supplementation could reverse this disease, changed the outcome of this disease in most cats. Subsequently, increased quantities of taurine were added to cat foods, which resulted in a dramatic decrease in the prevalence of DCM in cats. Today, DCM is quite rare in cats, and hypertrophic cardiomyopathy (HCM) is now the most common cardiomyopathy diagnosed in cats. As you will discover in the course of this seminar, nutritional discoveries continue to improve the prognosis for many veterinary patients with heart disease, and in some cases, completely reverse the disease.

Dietary Sodium

Congestive heart failure (CHF) is associated with decreased cardiac output and tissue perfusion. These decreases lead to sodium and fluid retention by the kidneys, which are compensatory changes that can have detrimental effects on the failing heart. The mechanisms by which sodium and fluid retention occur is related to the interaction of volume receptors (renin-angiotensin-aldosterone system) and osmoreceptors (ADH).

Occasionally low serum sodium concentrations are observed in animals with severecongestive heart failure. Usually, this is a not an absolute sodium deficit, but rather a dilutional phenomenon due to excessive fluid retention. Once fluid retention resolves, serum sodium tends to return to normal. In clinical terms, it is commonly referred to as chronic dilutional hyponatremia. Even though serum sodium concentrations are below normal, dietary sodium-restriction is often of benefit to these patients. In contrast, diets that are not restricted in sodium, or that are supplemented with sodium may actually be detrimental.

It is not known at this time if dietary sodium restriction is warranted in dogs with earlyheart disease prior to developing heart failure. Pending such studies, it is wise to recommend that excess sodium be avoided in these patients. Likewise, it is logical to consider mild sodium restriction in companion animals with mild cardiac disease.

Taurine

Taurine is a β-amino acid in which sulfonic acid replaces the carboxyl group of β-alanine, It is the most abundant free amino acid in the heart. Several mechanisms for taurine's actions on the heart have been proposed:

1. Osmoregulation

• Taurine is a small but highly osmotically active molecule. Changes in cellular osmolality

• induced by changes in intracellular taurine concentrations have been proposed to be a

• protective mechanism in nervous tissue as well as the myocardium.

2. Calcium modulation

• Much of the available evidence supports a theory that taurine's major effects on cellular function

• may be related to modulation of tissue calcium concentrations and availability. It plays a role in

• regulating transcellular fluxes and intracellular availability of calcium and potassium. It also

• protects the heart from calcium overload, and during hypoxic stress, taurine can increase

• calcium intake by the heart. As a result, taurine has a positive inotropic effect on the heart.

3. Inactivation of free radicals

It is a well established fact that cats are at risk for development of taurine deficiency for two reasons. First, they have very limited ability to synthesize taurine from the precursor amino acids, cysteine and methionine. Second, they preferentially use taurine for bile acid conjugation, even when their bodies are depleted of taurine. In the mid-1980's, taurine deficiency was linked to dilated cardiomyopathy (DCM) in cats. Treatment of affected cats with taurine often results in reversal of DCM.

Until recently, dogs were not considered to be at risk for developing taurine deficiency because they can readily synthesize taurine from precursor amino acids cysteine and methionine. However, like cats, dogs preferentially use taurine for bile acid conjugation, and therefore have an obligatory loss of taurine. Recently, taurine deficiency has been linked to a limited number of cases of DCM in dogs (American Cocker Spaniels, Golden Retrievers, and some dogs with urate and cystine urolithiasis). In addition, contrary to what was concluded from previous studies by other investigators, an article was published by Sanderson, et al (AJVR, 2001) that documented that taurine deficiency can be induced in healthy dogs with dietary manipulation alone. In addition, this study showed that taurine deficiency can cause DCM in the dogs, and like the cat, it can be reversed with taurine supplementation.

If DCM develops in American Cocker Spaniels, Golden Retrievers, and some dogs with urate and cystine urolithiasis, it is recommended that treatment include taurine supplementation. It is likely that taurine deficiency will be discovered in more breeds of dogs or more dogs with underlying diseases. Currently, the recommended dose of taurine in dogs has been extrapolated from cats. Studies in taurine deficient dogs with DCM by Sanderson and colleagues at the University of Minnesota and at the University of Georgia have documented that the following doses of taurine normalize taurine levels in dogs. Whether a lower dose of taurine or a decreased frequency of taurine would achieve the same outcome is not known at this time.

Currently recommended dose of taurine for dogs:

• 500 mg of taurine PO TID for dogs weighing ~ 25-30 pounds

• 1000 mg of taurine PO TID for dogs weighing ~50-60 pounds.

Taurine is very cheap and no side effects are known at this time. In takes approximately 3 - 4 months for echocardiographic improved to occur with taurine supplementation in dogs with DCM.

The point is, do not stop taurine supplementation too early

Carnitine

Carnitine has been classified as an amino acid derivative or a vitamin-like substance. Although it has many functions, its primary role is to shuttle long chain fatty acids (LCFA) across the inner mitochondrial membrane. The heart preferentially uses LCFA for energy, and carnitine is important in the transport of LCFA into the mitochondria of heart muscle. Once in the mitochondria, LCFAs undergo β-oxidation (the cleaving of 2-carbon fatty acid units from the LCFA) to generate energy. Carnitine also shuttles toxic metabolites out of mitochondria. Therefore carnitine deficiency can be detrimental to cardiac function.

Types of carnitine deficiency that occur in the dog are:

• Plasma carnitine deficiency is defined as decreased plasma carnitine concentrations

• Systemic carnitine deficiency is defined as decreased plasma and tissue carnitine concentrations.

• Myopathic carnitine deficiency is defined at decreased cardiac muscle carnitine concentrations with normal to increased plasma carnitine concentrations.

• Carnitine Insufficiency is defined as a shortage of free carnitine either due to

• abnormal loss or to excessive use.

Therefore, if plasma is used to screen for carnitine deficiency, detection of low plasma carnitine concentrations is of diagnostic value. However, detection of normal plasma carnitine concentrations does not rule out the possibility that the myopathic form of carnitine deficiency is present, and this last form of carnitine deficiency is estimated to occur in 17-60% of dogs with DCM. Unfortunately, it is not practical to obtain endomyocardial biopsies from every dog with DCM to detect the myopathic form of carnitine deficiency.

Carnitine was first linked to DCM in a family of boxers in 1991. Due to the difficulty in evaluating carnitine concentrations in heart muscle, only a few investigators have documented an association between carnitine deficiency and DCM in the dog. Another difficulty in the study of carnitine deficiency is to determine whether carnitine deficiency caused cardiac dysfunction or occurred as a result of cardiac dysfunction. However, in research at the University of Minnesota-VTH, we have documented that carnitine deficiency existed prior to the onset of DCM in a limited number of cases. In addition, carnitine (sometimes combined with taurine) therapy in some of our patients with DCM has resulted in varying degrees of reversal of cardiac dysfunction.

A limited number of published studies have documented a beneficial effect of carnitine supplementation in certain breeds of dog or dogs with a particular underlying disorder.

Currently, it is recommended that carnitine be included in the treatment of DCM in the following dogs: Boxers, American Cocker Spaniels, and dogs with urate and cystine urolithiasis that develop DCM. It is important to use L-carnitine and not D-carnitine (although this is no longer supposed to be available in the United States) because D-carnitine does not provide the beneficial functions of L-carnitine (D-carnitine competes with L-carnitine for enzymes, and can competitively bind up the enzyme system, rendering a situation in the body where any L-carnitine is unavailable).

The dose of carnitine commonly published in the literature for dogs with DCM is 50-100 mg/kg PO BID to TID. However, based on results from studies at the University of Minnesota, we recommend 50-200 mg/kg PO of carnitine TID. We initially start our patients at the upper end of the dosage range because of the high percentage of dogs with the myopathic form of carnitine deficiency. It is speculated that the myopathic form of carnitine deficiency is due to a membrane transport defect, and therefore giving high concentrations of carnitine may be able to overcome this transport defect. The only side effect we've occasionally noticed in dogs is diarrhea. If diarrhea persists, reduce the dose of carnitine to the highest amount the dog will tolerate.

Like taurine, it takes about 3-4 months of carnitine supplementation for echocardiographic improvement to occur (don't give up too early). Unlike taurine, carnitine is fairly expensive. Obtaining carnitine from a health food store is cost prohibited for most clients. In addition, the Health Food Industry is poorly regulated, so the amount of actual carnitine in a product labeled as carnitine can vary considerably. Therefore, we generally purchase carnitine in bulk. For dosing purposes, the weight of carnitine is roughly 2 grams per teaspoon. Carnitine can be obtained in bulk from one of the following sources:

Based on clinical studies published in the literature, dogs with dilated cardiomyopathy that may benefit from Carnitine and/or Taurine Supplementation are as follow:

Coenzyme Q10 (Ubiquinone)

Coenzyme Q is a lipid soluble substance that inhabits the inside of the inner mitochondrial membrane. It is an integral part of the respiratory chain that generates ATP. It is also an antioxidant. It is currently being used in humans for the treatment of various types of cardiomyopathy (ischemic, dilated and valvular disease). Recently, reports of the use of coenzyme Q for the treatment of DCM in dogs have appeared in the veterinary literature. However, there have been no controlled studies of dogs to show whether it is beneficial in the treatment of DCM. At this time the risks and benefits of coenzyme Q in the dog are also unknown.

N-3 Polyunsaturated Fatty Acids (Pufas)

Fat is an essential component of the diet for the absorption of fat soluble vitamins, as well for essential fatty acid requirements. Fat also improves the palatability of the diet and is a concentrated source of energy.

The essential fatty acids are generally n-6 PUFAs. Nonetheless, although n-3 PUFAs (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) are not essential fatty acids, they can provide beneficial effects when diets are supplemented with n-3 PUFAs. The eicosanoids derived from n-3 PUFAs are less potent inflammatory mediators than those derived from n-6 fatty acids. In addition n-3 fatty acids decrease the production of the cytokines, TNF and IL-1, which contribute to development of cardiac cachexia in some dogs with congestive heart failure. n-3 PUFAs have also been shown to have antiarrhythmic properties.

Dog with congestive heart failure have been shown to have plasma fatty acid abnormalities, including decreased concentrations of EPA and DHA compared to normal dogs, and fish oil supplementation (source of n-3 PUFA's) can normalize these plasma fatty acid abnormalities. Some of the therapeutic cardiac diets for dogs are already supplemented with n-3 fatty acids, and the majority of renal failure diets are as well.

Antioxidants

Reactive oxygen species are normal by-products of oxygen metabolism. Antioxidants are essential to counteract the negative effects associated with reactive oxygen species. Antioxidants can be endogenously synthesized in the body, or they can be provided in the diet (e.g., vitamins C and E, β-carotene, glutathione, carnitine, taurine). Dogs with more severe dilated cardiomyopathy or chronic valvular disease have been shown to have increased oxidative stress and decreased vitamin E levels. As a result, diets supplemented with antioxidants may benefit patients with congestive heart failure.

Arginine

Nitric oxide is an endogenous vascular smooth muscle relaxant. It is synthesized from L-arginine and molecular oxygen, and is catalyzed by the enzyme, nitric oxide synthase (NOS). Three forms of NOS exist; inducible NOS [iNOS], endothelial NOS [eNOS], and neuronal NOS [nNOS]. eNOS and nNOS are constitutive forms and are always produced in low levels. eNOS is required for maintenance of normal vascular tone and as a physiologic messenger. On the other hand, iNOS is inducible by a variety of inflammatory mediators including the cytokines TNF and IL-1, and free radicals. High levels of iNOS are induced as mediators of the inflammatory response and in the host defense mechanism. Circulating nitric oxide is elevated in people, dogs, and cats with CHF. However, while iNOS is up-regulated in patients with CHF producing high circulating levels of nitric oxide, eNOS is actually down-regulated, thereby. Arginine supplementation has been show to improve endothelial dysfunction in people with CHF, with no negative effects on cardiac contractility or other echocardiographic variables.