Key nutrients important in the management of canine myxomatous mitral valve disease and heart failure

Dorothy P. Laflamme Veterinary Nutrition Communications, Floyd, VA

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 DVM, PhD, DACVIM (Nutrition)

Abstract

The most common cause of heart failure in dogs is myxomatous mitral valve disease (MMVD), which accounts for approximately 75% of canine heart disease cases and is especially common in smaller dogs. Although low-sodium diets have been recommended for humans with heart diseases for decades, there is little evidence to support this practice in dogs. In recent years, however, it has become clear that other nutrients are important to heart health. Dogs with heart disease secondary to MMVD experience patterns of metabolic changes that include decreased mitochondrial energy metabolism and ATP availability, with increased oxidative stress and inflammation. These changes occur early in disease and progress with worsening heart disease. Key nutrients that may support normal function and address these changes include omega-3 fatty acids, medium-chain triglycerides, magnesium, antioxidants including vitamin E and taurine, and the amino acids methionine and lysine. The long-chain omega-3 fatty acids provide anti-inflammatory, antithrombotic, and other benefits. Medium-chain fatty acids and ketones derived from medium-chain triglycerides provide an alternative energy source for cardiac mitochondria and help reduce free radical production. Magnesium supports mitochondrial function, normal cardiac rhythm, and provides other benefits. Both vitamin E and taurine counter oxidative stress, and taurine also has direct cardiac benefits. Dogs with MMVD have reduced plasma methionine. Methionine and lysine are important for carnitine production as well as other functions. This article reviews the evidence supporting the functions and benefits of these and other nutrients in MMVD and other cardiac conditions.

Abstract

The most common cause of heart failure in dogs is myxomatous mitral valve disease (MMVD), which accounts for approximately 75% of canine heart disease cases and is especially common in smaller dogs. Although low-sodium diets have been recommended for humans with heart diseases for decades, there is little evidence to support this practice in dogs. In recent years, however, it has become clear that other nutrients are important to heart health. Dogs with heart disease secondary to MMVD experience patterns of metabolic changes that include decreased mitochondrial energy metabolism and ATP availability, with increased oxidative stress and inflammation. These changes occur early in disease and progress with worsening heart disease. Key nutrients that may support normal function and address these changes include omega-3 fatty acids, medium-chain triglycerides, magnesium, antioxidants including vitamin E and taurine, and the amino acids methionine and lysine. The long-chain omega-3 fatty acids provide anti-inflammatory, antithrombotic, and other benefits. Medium-chain fatty acids and ketones derived from medium-chain triglycerides provide an alternative energy source for cardiac mitochondria and help reduce free radical production. Magnesium supports mitochondrial function, normal cardiac rhythm, and provides other benefits. Both vitamin E and taurine counter oxidative stress, and taurine also has direct cardiac benefits. Dogs with MMVD have reduced plasma methionine. Methionine and lysine are important for carnitine production as well as other functions. This article reviews the evidence supporting the functions and benefits of these and other nutrients in MMVD and other cardiac conditions.

Heart disease, depending on its nature, rate of progression, and other factors, may or may not lead to heart failure. Heart failure occurs when heart dysfunction becomes severe enough to cause clinical signs.1 Thus, when heart disease becomes sufficiently severe that the body cannot fully compensate, the result is either congestive heart failure (CHF) or compromised cardiac output that cannot meet the body’s needs either during exercise or at rest. These then cause the typical clinical signs of heart failure, such as reduced appetite, cough, and exercise intolerance. The most common cause of heart failure in dogs is myxomatous mitral valve disease (MMVD), which accounts for approximately 75% of canine heart disease cases seen by veterinary practices in North America.1,2 It is especially common in small- to medium-size (≤ 20-kg) dogs and in older dogs, as prevalence increases with age.3,4 Most dogs with MMVD are clinically asymptomatic for an extended period. However, up to 30% of asymptomatic dogs with MMVD ultimately progress to heart failure or die as a consequence of the disease.58

The 20092 and 20191 American College of Veterinary Internal Medicine consensus statements on canine MMVD divide dogs with MMVD-related heart disease into 4 stages. Stage A includes dogs that are genetically predisposed or otherwise at high risk to develop MMVD, but have no evidence of heart murmur or mitral regurgitation; stage B includes dogs with evidence of structural heart disease (eg, a typical murmur of mitral valve regurgitation) with minor (stage B1) or moderate to severe (stage B2) cardiac remodeling, but that have not developed clinical signs associated with CHF; stage C includes dogs with current or past clinical signs of CHF caused by MMVD; and stage D includes dogs with advanced, end-stage heart failure refractory to standard treatments.1,2

Canine MMVD generally progresses slowly, with a lengthy preclinical period. But, following the development of CHF, the disease advances more rapidly, with a mean survival time of < 12 months.5,9 Thus, it would be of great interest to slow or prevent the progression of MMVD at early preclinical stages to extend longevity and enhance quality of life for affected dogs. As of 2010, there were no treatments recognized to delay the onset of clinical signs of CHF in MMVD dogs.5 Since that time, a multicenter clinical trial identified that pimobendan treatment could delay progression of the disease in dogs with stage B2 MMVD.10 Pimobendan is a calcium sensitizer and phosphodiesterase inhibitor that functions to increase myocardial contractility, and had been shown previously to decrease heart size in dogs with more advanced MMVD.9,10 The study demonstrated a nearly 15-month prolongation of the preclinical period, and 17% longer median survival, in pimobendan-treated dogs compared to placebo-treated dogs. Subsequently, the 2019 American College of Veterinary Internal Medicine consensus statement1 recommends the use of pimobendan in dogs with MMVD stage B2 that meet or exceed certain heart size criteria, but “no treatment” continued to be the recommendation for dogs with stage A or stage B1 MMVD. Since that recommendation was published, evidence has emerged regarding molecular changes in canine MMVD that may respond to nutritional modifications.11,12 The objective of this article is to review the evidence regarding key nutrients associated with metabolic or functional changes in cardiac health across multiple species, as well as other dietary aspects regarding feeding dogs with MMVD.

Molecular Pathophysiology of Canine MMVD

The heart is one of the most metabolically active organs in the body, requiring a continuous supply of ATP for energy. It is estimated that approximately 70% of this ATP is generated from mitochondrial beta-oxidation and oxidative phosphorylation of long-chain fatty acids (LCFAs), with metabolism of glucose, lactate, amino acids, and ketone bodies supplying the rest.13,14 Studies in humans with common acquired forms of heart failure, as well as rodent models, have provided evidence that derangements in fuel and energy metabolism occur in heart disease and contribute to heart failure.15,16 Evidence gathered from transcriptomic and metabolomic studies during the past decade has identified similar important metabolic changes in dogs with MMVD, representing alterations in fat and energy metabolism, antioxidant function, nitric oxide signaling, and extracellular matrix homeostasis pathways.1719 These metabolic changes begin to occur early in heart disease, and many progress concurrent with disease progression.18,19

It is now well recognized that these metabolic changes and myocardial energy deprivation play a causal role in the development of heart failure.12,1921 Among other changes, a shift from LCFAs as the main energy source to other substrates has been documented in the failing heart in both humans and animals.12,14,1921 Although this adaptive mechanism is thought to help maintain heart functions under stress, it ultimately leads to ATP and energy depletion, with subsequent contractile dysfunction and end-stage heart failure.14 Among other evidence of compromised mitochondrial function in MMVD dogs were accumulations in serum ketone bodies, tricarboxylic acid cycle intermediates, and acylcarnitines.12,17,19 These metabolites increased in proportion to the severity of heart disease in both a cross-sectional study and a longitudinal study of dogs with MMVD.18,19 Ketones are used as an alternate energy source by the myocardium directly in proportion to their physiologic concentrations in circulation.13,14 Proteomic and substrate use studies show that the failing heart has a reduced capacity for oxidizing fatty acids, and it shifts to ketone bodies as an alternate fuel.13,20 Although LCFAs yield more ATP per carbon, ketones yield more ATP per unit of oxygen consumed compared to LCFAs, and ketones also diminish oxidative stress by scavenging free radicals.13

Acylcarnitines are intermediates of LCFA transport and oxidation. Circulating acylcarnitines accumulate because of incomplete or inefficient fatty acid oxidation, and are markers of mitochondrial dysfunction.12,18,22 Accumulation of long-chain acylcarnitines may further contribute to heart failure by stimulating reactive oxygen species (ROS) production and releasing circulating inflammatory mediators.18,23 Consistent with this is evidence demonstrating an increase in oxidative stress and inflammation in dogs with MMVD and CHF.1719

Among other interesting observations from metabolite analysis of MMVD dogs was a reduction in circulating deoxycarnitine and the amino acid methionine, and an increase in oxidized glutathione.17,18,24 The increase in oxidized glutathione, which does not have the ability to neutralize ROS, was one of many markers indicating increased oxidative stress in these dogs. Methionine, an essential amino acid for dogs, is a precursor for numerous important metabolites, including S-adenosylmethionine, glutathione, and carnitine. It also serves directly as an antioxidant via methionine sulfoxide.25 Carnitine is a compound derived from the diet or is produced endogenously from the amino acids methionine and lysine. Among its key functions is the transportation of LCFAs across the mitochondrial membranes to facilitate beta-oxidation and, ultimately, ATP production. The heart is unable to produce carnitine directly. Instead, it produces deoxycarnitine, which is then exchanged for carnitine from the bloodstream.12,26 The decrease in deoxycarnitine in dogs with MMVD may indicate an increased risk for myocardial carnitine deficiency. A myocardial deficiency of carnitine also is reported to occur in many dogs with dilated cardiomyopathy (DCM).27,28

Key Nutrients in the Management of Canine MMVD and Heart Disease

Many of the metabolic changes observed in MMVD dogs could potentially be addressed through dietary modifications. The key nutrients identified for this purpose were the anti-inflammatory long-chain omega-3 polyunsaturated fatty acids (n3 PUFAs); medium-chain fatty acids (MCFAs) octanoate and decanoate from medium-chain triglycerides (MCTs) as an alternate cardiac energy source and source of additional ketones; taurine and the carnitine precursor amino acids, methionine and lysine, to support mitochondrial and other metabolic functions; the mineral magnesium to support cardiac mitochondria and other functions; and the additional antioxidant nutrients vitamin E and taurine. Justification for each of these is summarized next.

Omega-3 polyunsaturated fatty acids

The long-chain n3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) help to reduce inflammation associated with heart failure.29,30 Eicosanoids are key mediators of inflammation and are derived from the 20-carbon n6 PUFA (arachidonic acid) or EPA. These mediators are involved in modulating the intensity and duration of inflammatory responses. Metabolism of arachidonic acid by cyclooxygenase and lipoxygenase (LOX) enzymes gives rise to the 2-series prostaglandins (PGs) and thromboxanes, and 4-series leukotrienes (LTB). Although arachidonic acid–derived eicosanoids are generally categorized as proinflammatory mediators, they play an important modulatory role in the immune response through complex interactions with leukocytes; they also have a crucial role in the early phase of inflammation.30 However, in excess, they can contribute to inflammatory disorders and cause damage to host tissues. EPA also acts as a substrate for cyclooxygenase and LOX enzymes, and gives rise to the 3-series PGs and thromboxanes and the 5-series LTBs. The eicosanoids derived from EPA are considered to be less inflammatory, or even anti-inflammatory, compared to eicosanoids derived from arachidonic acid. For example, LTB5, derived from EPA, is 10- to 100-fold less potent as a neutrophil chemotactic agent than LTB4, and PGE3 is a less potent inducer of interleukin 6 (IL-6) production by macrophages than PGE2.30

Not only EPA, but also DHA, can contribute to the anti-inflammatory benefits from n3 PUFAs. DHA can be metabolized to resolvins via LOX-initiated mechanisms. Resolvins are local-acting mediators with potent anti-inflammatory and immunoregulatory properties.30 Another key anti-inflammatory effect of n3 PUFAs is mediated through altered inflammatory gene expression, including via inhibition of transcription factors such as nuclear factor kappa B and peroxisome proliferator-activated receptors.29,30 Downstream effects not only include a reduction in inflammatory mediators, but also reduced cardiac fibrosis and remodeling.29

In addition to their anti-inflammatory effects, n3 PUFAs provide direct cardiovascular benefits. Intake of n3 PUFAs in humans is associated with reduced mortality from cardiovascular diseases.29 Among the mechanisms suggested for this benefit are hypotensive, antithrombotic, and antiarrhythmic effects.29 In dogs, supplementation with n3 PUFAs reduced the inducibility of atrial fibrillation and secondary atrial fibrosis in an experimental model of atrial fibrillation, and reduced ventricular arrhythmias in Boxers with naturally occurring cardiomyopathy.31,32 Four studies have evaluated n3 PUFA supplementation in dogs with naturally occurring heart diseases, with mixed results.3235 As mentioned, Boxers with cardiomyopathy demonstrated a reduction in ventricular arrhythmias with n3 PUFA supplementation.32 Dogs in heart failure supplemented with fish oil as a source of n3 PUFAs showed a reduction in inflammatory mediators as well as improvement in cardiac cachexia, but no improvement in survival.33 Dogs with moderate to severe MMVD (stages B2 and C) supplemented with fish meat as a source of n3 PUFAs showed no clinical benefits and only minor metabolic benefits from the dietary treatment.35 On the other hand, a similar study also in dogs with stages B2 and C MMVD showed multiple benefits from incorporating fish oil into the diet, including a 3-fold decreased risk for arrhythmias and reduced vertebral heart size.34

Medium-chain triglycerides

MCTs, derived from coconut or palm oil, or milk fat, contain fatty acids between 8 and 12 carbons in length. As used in this discussion, the focus is on the 8-carbon (octanoate) and 10-carbon (decanoate) fatty acids because the 12-carbon (dodecanoate) fatty acid has different physiologic and metabolic characteristics. Compared to LCFAs, MCFAs are digested, absorbed, and oxidized more readily, making them useful in various disease conditions.36

In the face of heart disease, the cardiac mitochondria become less efficient at using LCFAs as an energy source and begin to rely on alternate energy sources. Ketone bodies and MCFAs, both derived from MCTs, can provide that energy. The fatty acids from MCTs are rapidly beta-oxidized in the liver and release ketones, especially beta-hydroxybutyrate, into circulation. Dogs fed a diet containing approximately 1.5 g octanoate plus decanoate/100 Kcal metabolizable energy showed a 3- to 4-fold increase in serum beta-hydroxybutyrate.37 In both human and rodent models, the failing heart increases its reliance on ketones as an alternate energy source and as a metabolic stress defense.20,21,38 Ketone supplements improved cardiac function and slowed pathologic remodeling in human heart failure patients and rodent models of heart failure.38,39 Emerging evidence suggests ketone bodies may provide therapeutic benefits to human patients with heart disease, although data are lacking in dogs.40

In addition to ketones, the mammalian heart takes up the free MCFAs, which pass readily into the mitochondria and are metabolized to yield ATP. Unlike typical LCFAs, MCFAs do not rely on membrane transporters for their uptake into cells, or a carnitine shuttle to cross the inner mitochondrial membrane.36,41 Although uptake and oxidation of LCFAs are decreased in heart disease, metabolism of ketones and MCFAs are not compromised. In fact, in various models of heart diseases, feeding MCTs increased fatty acid oxidation, restored energy metabolism, and improved cardiac function.42,43 As with ketones, data on the benefits of MCFAs in canine hearts are lacking.

MCFAs are now recognized to provide additional benefits potentially important for human heart patients. Compared to LCFAs, MCFAs reduce markers of oxidative stress.43,44 One of the ways this occurs is through reduced production of ROS during mitochondrial oxidative phosphorylation.43,45 MCTs also are relatively anti-inflammatory compared to LCFAs.46 In one in vitro study using intestinal cells, octanoate reduced IL-8 secretion by more than 3-fold compared to the LCFA oleic acid.47 Given that IL-8 expression is increased progressively in dogs with advancing MMVD,48 this effect from MCTs may be beneficial in dogs with MMVD. Although research is still underway to understand more fully how MCTs impart their anti-inflammatory effects, it appears that both the MCFAs and the ketone beta-hydroxybutyrate derived from MCTs have important anti-inflammatory effects, as demonstrated in various rodent models, resulting in downregulation of pro-inflammatory cytokines and other mediators, and upregulation of anti-inflammatory cytokines.46,49 Finally, at least in 1 study,44 addition of MCTs to the diet appeared to potentiate benefits attributed to dietary n3 PUFAs, including anti-inflammatory effects.

Mitochondrial support nutrients: taurine, and carnitine precursors

Taurine is a sulfur-containing beta-amino acid that can be produced within the body from the sulfur amino acids methionine and cysteine. In dogs, endogenous production is usually adequate to maintain health, as long as the precursor amino acids are available in sufficient supply. Taurine serves many roles in the body. Perhaps best known is the binding of bile acids within the intestines. Both dogs and cats bind bile acids with taurine, which results in significant quantities of taurine being excreted from the body. Taurine also is involved with numerous metabolic processes, including antioxidation, retinal photoreceptor activity, stabilization of neural membranes, reduction in platelet aggregation, and others, as well as normal myocardial function.50

A deficiency of taurine can cause DCM in both cats and dogs.5052 One potential mechanism for this is the role taurine plays in cardiac energy metabolism and oxidative phosphorylation. Taurine deficiency reduces the functionality of the mitochondrial respiratory chain, leading to decreased ATP production.53

Carnitine is a compound derived from the diet or endogenously from the amino acids methionine and lysine. One key function of carnitine is to transport LCFAs across the mitochondrial membranes to facilitate beta-oxidation and, ultimately, ATP production. Fatty acids can yield up to 90% of the ATP produced in healthy mammalian cardiac mitochondria, so having adequate, active carnitine is critical to normal cardiac function. An association between low myocardial carnitine and DCM in dogs has been reported.27,28,50 In most cases, this myocardial deficiency occurs despite normal blood carnitine concentrations.28 This implies there is not a problem with carnitine synthesis; rather, the problem lies in getting carnitine into the heart muscle. Even the normal heart is unable to produce carnitine directly. Instead, it produces deoxycarnitine, which is then exchanged for carnitine from the bloodstream.12,26 The fact that most dogs with DCM and MMVD have normal plasma carnitine concentrations may explain why only about 5% of dogs with DCM respond positively to L-carnitine supplementation.27

Supplementing the diet with additional methionine and lysine as carnitine precursors appears to be a good option for increasing serum carnitine, and may have an advantage over preformed carnitine. There is growing evidence that trimethyl amine N-oxide (TMAO), a by-product produced from carnitine metabolism via gut bacteria, is associated with increased cardiac morbidity and mortality in people.54,55 Gut microbiota metabolize dietary nutrients such as L-carnitine, choline, phosphatidylcholine, or betaine to produce trimethylamine, which is oxidized to TMAO in the liver and released into circulation. Circulating TMAO concentrations were increased in dogs with stages B2 and C MMVD.18,56 Supplementation with carnitine led to increased plasma TMAO in mice and humans.57,58 Dogs with CHF secondary to MMVD had significantly greater plasma concentrations of both carnitine and TMAO compared to healthy dogs or dogs with asymptomatic MMVD.18,56 However, at this time there are no data on causality versus simple association with disease, nor on the impact of supplementation with carnitine on TMAO production in dogs. Supplementing with the precursor amino acids, especially methionine, appears to be a reasonable approach, especially because dogs with MMVD demonstrate consistently lower plasma levels of methionine, which worsens with stage of disease.17,18

Magnesium

Magnesium serves as a cofactor in hundreds of enzymes in the body, and has a role in glucose and energy metabolism, protein production, ATP synthesis and use, and cardiovascular function.5961 Magnesium modulates vascular smooth muscle tone and endothelial functions to enhance vasodilation, which helps reduce blood pressure.61 Within the heart, magnesium is critical for normal electrolyte transmembrane flux, and thus is required for normal cardiac electrophysiology and function.62,63 Under ischemic conditions, magnesium protects the heart through several mechanisms, including serving as a calcium ion antagonist, protecting ATP and energy-dependent processes, reducing myocardial oxygen demand and consumption, and protecting the myocardium from oxidative damage.61 Magnesium stabilizes cardiac membranes and modulates myocardial excitability to treat or prevent cardiac arrhythmias.61

In humans, multiple studies have indicated a significant association between low magnesium intake or low serum magnesium and cardiovascular diseases or heart failure.60,62,64 Each 0.2-mmol increase in serum magnesium was associated with a 30% lower risk for cardiovascular disease in a meta-analysis of human clinical trials.62 Short-term magnesium restriction induced cardiac arrhythmias, which were corrected by magnesium supplementation.62 In human patients with diabetes, low magnesium is a significant contributor to mitral valve calcification and cardiovascular mortality.65 Mitral valve prolapse is strongly associated with magnesium deficiency in humans, as well as in Cavalier King Charles Spaniels,66,67 although a causal role has not been confirmed.

In addition to direct effects on cardiovascular functions, magnesium plays a role in protection against inflammation and reduction in oxidative stress.59,68 Hypomagnesemia is associated with increases in inflammatory mediators such as IL-1β, tumor necrosis factor-α and C-reactive protein, and with increased production of ROS.59 There is also evidence that magnesium contributes to protection from oxidative stress by scavenging free radicals, increasing production of glutathione and superoxide dismutase, and decreasing nicotinamide adenine dinucleotide phosphate oxidase activity.59 In a rat model of coronary heart disease, magnesium supplementation not only reduced oxidative stress, but also reduced hyperlipidemia and enhanced mitral valve and cardiac function.68

Experimental data from dogs have shown magnesium aids in the control of ventricular arrhythmias and coronary circulation, as well as protection of contractile function after ischemia.6974 Although no data are available in dogs with natural MMVD, the sum of the data in other species suggests a potential role for dietary magnesium in cardiac protection for dogs with MMVD.

Antioxidants: vitamin E and taurine

ROS are unstable molecules with a singlet electron that can initiate a cascade of oxidative damage to cellular lipids, proteins, and even DNA. Although ROS are formed naturally during normal metabolism, the healthy body has abundant antioxidant metabolites that neutralize the ROS. Oxidative stress occurs when ROS exceed the available antioxidants. This can happen in disease, such as heart disease. The mitochondria in diseased hearts become less efficient and produce more ROS.75 Coupled with a shortage of antioxidants, evidenced by the increased level in oxidized glutathione, this can contribute to oxidative stress.17,24

There are numerous antioxidants, including vitamin E, vitamin C, taurine, and many proteins, produced in the body to fight ROS. Taurine not only has antioxidant functions, but also provides direct cardiac benefits. Dietary supplementation can include the antioxidant vitamins, but also precursors to support endogenous production of antioxidant compounds such as glutathione, superoxide dismutase, nitric oxide, and others. In addition, providing alternative energy sources and mitochondrial support can reduce ROS production and decrease oxidative stress.12

Clinical Evidence for Efficacy of Nutrient Blend

Each of the nutrients just described has the possibility to aid cardiac function in MMVD dogs, although supportive evidence specifically in dogs is lacking for some. Rather than evaluate each nutrient separately, a small, controlled clinical trial was performed in dogs with stages B1 and B2 MMVD to assess the efficacy of a combination of the nutrients described. A nutritionally complete and balanced diet containing MCTs, n3 PUFAs from fish oil, magnesium, taurine, vitamin E, and the carnitine precursors methionine and lysine was compared to a similar diet without this blend of nutrients to assess both clinical and metabolomic effects.11 Although MMVD is a slowly progressive condition, within a 6-month period, MMVD dogs fed the control diet demonstrated evolution of cardiac dysfunction. The control dogs showed an average 10% increase in left atrial diameter and a left atrial-to-aortic root ratio, whereas MMVD dogs fed the nutrient blend demonstrated a 3% decrease (improvement) in these parameters. Among the control dogs, 2 of 8 (25%) showed worsened mitral regurgitation by the end of the study, and no control dogs improved. Among those fed the nutrient blend, just 1 of 10 (10%) worsened and 3 (30%) improved. Consistent with these changes, several of the control dogs progressed from stage B1 to stage B2, but none of the MMVD dogs fed the nutrient blend progressed to stage B2.11

Numerous metabolomic differences were noted during the clinical study, reflecting dietary differences.12 However, some key differences related to cardiac and mitochondrial function were also noted. Serum deoxycarnitine is one key example. Although the heart contains more carnitine than other tissues, as mentioned, it is unable to produce carnitine directly. Instead, it produces deoxycarnitine, which is then exchanged for carnitine from the bloodstream.26 The serum concentration of deoxycarnitine is reduced in dogs with MMVD, but was elevated significantly in MMVD dogs fed the nutrient blend.12,17 This indicates that the nutrient blend supports a pathway for the heart to refresh its carnitine supply and promote further mitochondrial fat oxidation.12 Other findings identified numerous serum metabolites suggestive of improved cardiac bioenergetics and fatty acid use by cardiac mitochondria, as well as reduced oxidative stress and reduced markers of inflammation, in MMVD dogs fed the nutrient blend.12

The data from this preliminary study strongly suggest that the key nutrients identified may address metabolic changes observed in dogs with MMVD. A different study76 in MMVD dogs showed reductions in cardiac maximal left-atrial dimension, left-ventricular internal dimension in diastole, and weight-based maximal left-atrial dimension when dogs were fed a diet supplemented with n3 PUFAs, antioxidant vitamins, taurine, carnitine, and arginine, confirming that diet can affect cardiac functions. However, additional research is needed to confirm these findings and to identify the benefits and optimum amounts of the individual nutrients or nutrient blends.

Other Nutrient Considerations for Dogs with MMVD and Heart Failure

Sodium, chloride, and potassium

Sodium is a key extracellular electrolyte and is the most important osmotic agent in blood and extracellular fluid. As such, sodium attracts water molecules, which can increase blood volume. A failing heart is not able to pump enough blood to the body, resulting in a drop in circulating blood volume or pressure, and activation of the renin-angiotensin-aldosterone system (RAAS). This increases sodium and blood volume; but if the volume is more than the heart can handle, it leads to congestion and CHF. When congestion occurs, treatment is targeted at reducing the blood volume.

Sodium restriction has been recommended to human patients with heart failure as a result of its ability to lower blood pressure and prevent hypertension.77 For at least 25 years, a reduced-sodium diet has been suggested for dogs with heart disease.78 However, during that same period, it has been recognized that there is little scientific evidence to support this practice.1,78 In human medicine, sodium restriction to reduce blood pressure has been studied for more than 100 years, yet there remain conflicts in the data and its interpretation.79,80 A fairly recent review of nearly 200 different publications representing randomized, controlled studies in humans, showed that low-sodium intake (< 6 g/d) activates the RAAS, increases insulin resistance, and increases mortality, with minimal effects on blood pressure.79 Low-sodium diets (32 to 62 mg/100 Kcal) fed to dogs with heart failure caused beneficial decreases in heart size, but also induced adverse electrolyte abnormalities and stimulated the RAAS.76,81,82 Restriction of dietary sodium as a means to control hypertension in dogs is controversial because, as in humans, the impact on blood pressure is minimal, and low-sodium intake stimulates the RAAS, which may lead to adverse vascular and cardiac changes.83 Currently, universal sodium restriction in cardiac patients is controversial.77,80,84,85

In addition to the impact on sodium and water balance, aldosterone promotes inflammation and oxidative stress. Although a very high-sodium intake may be harmful, excessive restriction of sodium is confirmed to be detrimental in heart failure, causing an increase in mortality in human patients and upregulating the RAAS in dogs and cats.79,81,82,84,86,87 Studies have confirmed activation of the RAAS in both healthy dogs and dogs with heart disease fed diets containing 22.5 to 62 mg/100 Kcal metabolizable energy.79,81,82 Furthermore, pharmaceutical care in CHF combined with low-sodium intake can result in other electrolyte abnormalities, such as hyperkalemia.81 Avoiding an excessively low-sodium or excessively high-sodium intake (including from treats) seems a reasonable approach, although further research is needed to define “excess.” In the absence of data, published dietary sodium recommendations for dogs with heart disease range from 50 to 100 mg/100 Kcal, depending on the severity of disease.88

Although sodium receives the bulk of the attention, it has been suggested that chloride has a major influence on the RAAS, and may have a greater impact on blood pressure.89 In rats, various studies with nonhalide salts such as sodium citrate or sodium bicarbonate did not affect blood pressure, blood volume, or stroke risk as sodium chloride did.90 However, these alternate salts also affect acid–base balance, which affects blood pressure and cardiovascular risks in both rodents and humans,91,92 thus confounding interpretation of the data. It has been hypothesized that restricting chloride while providing sufficient sodium could avoid stimulation of the RAAS while reducing plasma volume and blood pressure in patients with heart disease,89 but there is currently no evidence to support this premise.

Potassium also interacts with sodium, and it is suggested that the dietary ratio of sodium to potassium is important in controlling blood pressure.93,94 In humans, a low-potassium intake is associated with significant elevations in blood pressure whereas increased dietary potassium reduced blood pressure, stroke risk, and risk for cardiovascular mortality.93 Replacing some sodium chloride with potassium chloride resulted in reductions in blood pressure in both normotensive and hypersensitive humans.95,96 Unfortunately, only limited and conflicting data are available for dogs. IV infusion of potassium chloride reduced blood pressure in a canine model of stress hypertension.97 However, blood pressure was also reduced in the face of potassium deficiency in normotensive and hypertensive dogs.98,99 In the face of CHF, the most common diuretic used (furosemide) promotes excretion of sodium and potassium, and can lead to potassium deficiency. However, the mineralocorticoid antagonist, spironolactone, and angiotensin converting enzyme inhibitors spare potassium, so oversupplementation in this case can contribute to hyperkalemia. Currently, neither restriction nor supplementation of potassium are recommended unless an individual patient shows evidence of excess or deficiency.88 It is clear that further research is needed to define more completely the dietary electrolyte needs for dogs with heart disease.

Body condition in heart disease

Obesity is not typically considered a risk factor for developing heart failure in dogs; however, obesity can compromise cardiopulmonary function in dogs.100,101 Therefore, it may be considered a confounding factor that can worsen clinical signs of heart disease. For dogs with mild heart disease, or those at risk for developing heart failure, maintaining a healthy body weight and body condition score is important. In the face of obesity and existing heart disease, gradual weight loss should be encouraged.

Perhaps of greater concern than obesity is cachexia, as weight loss also is common among dogs with heart disease.102,103 In 1 study, cardiac cachexia—defined as a loss of muscle condition—occurred in about 50% of dogs with advanced heart failure and was associated with shorter survival times.102 Although the exact cause of this phenomenon is not known, it is thought that the inflammatory mediators present in increased amounts in heart disease are a contributing factor. Poor appetite, alterations in nutrient absorption, and altered metabolism all may also contribute.102

The loss of muscle mass may not be detected prior to the development of CHF, yet likely begins much sooner. Muscle condition score assessed regularly may help to identify the loss of muscle mass earlier. Although diet alone cannot prevent cachexia, consuming supplemental protein and calories may help offset or slow the tissue loss associated with cachexia.104 Inadequate intake of either can make cachexia worse, so protein-restricted diets are not recommended for dogs with CHF. In 1 study of dogs with heart failure, the group that gained weight during the study had longer survival compared to other dogs.103 As heart failure progresses, many dogs have reduced appetites, in part due to the effects of medications and in part to the effect of disease. To compensate, feeding a nutrient-dense, highly digestible, and highly palatable diet is recommended. In addition, nutrients that can reduce the inflammation, such as n3 PUFAs, might be helpful.105,106 These may also provide a direct benefit for reducing the loss of muscle mass. In in vitro and human studies, n3 PUFAs, especially EPA, increased endogenous protein synthesis and reduced protein breakdown.107,108 Decreased muscle loss was observed in dogs with CHF receiving n3 PUFA supplements.33 Angiotensin II in rodents leads to skeletal muscle wasting via alterations in insulin-like growth factor 1 signaling, increased apoptosis, and enhanced muscle protein breakdown via the ubiquitin-proteasome system.109 Given that excessive sodium restriction stimulates the RAAS, it appears prudent to avoid excessive sodium restriction in dogs with evidence of cachexia.

Conclusion

Feeding guidelines for dogs with MMVD must take into consideration the stage of the disease, the body condition and age of the pet, as well as any concurrent medical issues. Dogs with asymptomatic MMVD are likely to live for many years, and dietary care may help extend those years. Helping patients achieve and maintain a healthy body condition is important, regardless of any concurrent diseases. Although excess restriction of sodium can be detrimental, it may be prudent to limit intake of very high-sodium foods and treats, especially when dogs develop more advanced heart disease. A nutrient blend containing n3 PUFAs from fish oil, MCTs, supplemental magnesium, vitamin E, taurine, and the amino acids methionine and lysine appears to provide benefits, including slowing of the progression of MMVD beginning in stage B1 MMVD dogs. Many of these nutrients should be beneficial in other forms of heart disease as well.

Acknowledgments

No external funding was used to support the development of this manuscript.

The author is a former employee of Nestlé Purina, and was a paid consultant and participant in the Nestlé Purina cardiac research referenced within this paper.11,12,17

The author appreciates the assistance provided by Drs. Catherine Lenox and Johnny Li in the editing of this manuscript.

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