Progress in Pediatric Cardiology 24 (2007) 5971www.elsevier.com/locate/ppedcard

Review

Nutrition in pediatric cardiomyopathy

Tracie L. Miller , Daniela Neri, Jason Extein, Gabriel Somarriba, Nancy Strickman-Stein

Division of Pediatric Clinical Research, Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, FL, United States

Abstract

Pediatric cardiomyopathies are heterogeneous groups of serious disorders of the heart muscle and are responsible for significant morbidity andmortality among children who have the disease. While enormous improvements have been made in the treatment and survival of children withcongenital heart disease, parallel strides have not been made in the outcomes for cardiomyopathies. Thus, ancillary therapies, such as nutrition andnutritional interventions, that may not cure but may potentially improve cardiac function and quality of life, are imperative to consider in childrenwith all types of cardiomyopathy. Growth failure is one of the most significant clinical problems of children with cardiomyopathy with nearly one-third of children with this disorder manifesting some degree of growth failure during the course of their illness. Optimal intake of macronutrientscan help improve cardiac function. In addition, several specific nutrients have been shown to correct myocardial abnormalities that often occurwith cardiomyopathy and heart failure. In particular, antioxidants that can protect against free radical damage that often occurs in heart failure andnutrients that augment myocardial energy production are important therapies that have been explored more in adults with cardiomyopathy than inthe pediatric population. Future research directions should pay particular attention to the effect of overall nutrition and specific nutritionaltherapies on clinical outcomes and quality of life in children with pediatric cardiomyopathy. 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Pediatric cardiomyopathy; Nutrition; Ancillary therapy

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602. Nutritional status of children with cardiomyopathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603. The effect of nutrients on cardiac endpoints in heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

3.1. Macronutrients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613.2. Micronutrients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663.3. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

3.3.1. Vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663.3.2. Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673.3.3. Taurine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673.3.4. Co-enzyme Q10 (ubiquinone). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673.3.5. Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

3.4. Nutrients that affect myocardial energy production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673.4.1. Thiamine (vitamin B1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673.4.2. L-Carnitine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673.4.3. Creatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Supported by NIH NHLBI grant RO1 HL53392 and the Children's Cardiomyopathy Foundation, Inc. Corresponding author. Division of Pediatric Clinical Research, Department of Pediatrics (D820), Miller School of Medicine at the University of Miami, Batchelor

Children's Research Institute, PO Box 016820, Miami, FL 33101, United States. Tel.: +1 305 243 1423; fax: +1 305 243 8475.E-mail address: tracie.miller@miami.edu (T.L. Miller).

1058-9813/$ - see front matter 2007 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.ppedcard.2007.08.007

mailto:tracie.miller@miami.eduhttp://dx.doi.org/10.1016/j.ppedcard.2007.08.007

60 T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

3.5. Other nutrients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683.5.1. Vitamin D/calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683.5.2. Folate/vitamin B12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683.5.3. Magnesium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683.5.4. Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683.5.5. Selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

1. Introduction

Pediatric cardiomyopathies are heterogeneous groups ofserious disorders of the heart muscle and are responsible forsignificant morbidity and mortality among children who havethe disease. The incidence of pediatric cardiomyopathy isapproximately between 1.13 and 1.24 cases per 100,000 children18 years of age and younger, with the highest incidence amongchildren less than one year of age [13]. The incidence tends tobe higher among African American and Hispanic children in theUS [2]. Despite its overall low incidence, cardiomyopathiesresult in some of the worst pediatric cardiology outcomes and areresponsible for nearly one-half of all pediatric heart transplants[4]. Nearly one-third of all children diagnosed with pediatriccardiomyopathy prior to one year of age will die within one yearof diagnosis [5], and 40% receive heart transplants within twoyears. Among those who live beyond the first year, the five-yearsurvival is nearly 85% [6]. Despite these overall dismal statistics,the clinical course and outcomes of cardiomyopathy vary amongpatients, from complete recovery to death, even among thosewith similar functional types of cardiomyopathy.

The World Health Organization classifies cardiomyopathiesinto four distinct functional categories: 1) dilated cardiomyopa-thy, where the heart muscle fibers stretch, causing a chamber ofthe heart to enlarge, thus weakening the heart's ability to pumpblood; 2) hypertrophic cardiomyopathy, a functional type ofcardiomyopathy that occurs among older children and adults [7]where the growth or arrangement of muscle fibers is abnormal,leading to a thickening of the heart walls and reduction in size ofthe pumping chamber that may obstruct the blood flow; 3)restrictive cardiomyopathy, where the walls of the ventriclesstiffen and lose their flexibility and 4) arrythmogenic rightventricular cardiomyopathy where there is replacement ofmyocytes in the right ventricle with fatty, fibrous tissue [8]. Ithas been found that mutations in genes that encode cell junctionproteins can cause arrythmogenic right ventricular cardiomyop-athy [9]. Distinctions between these cardiomyopathies are criticalbecause differences in etiologies and outcomes vary by thefunctional type of cardiomyopathy. In general, the cause of PCMremains primarily unknown, yet genetic causes are likely to be afactor in most pediatric patients with recent studies demonstratinga large familial component [2,3]. Thus, as more becomes knownof the causes and natural history of pediatric cardiomyopathy,there will be a greater ability to determine etiology-specifictherapeutics that will positively impact outcomes.

While enormous improvements have been made in thetreatment and survival of children with congenital heart disease,

parallel strides have not been made in the outcomes forcardiomyopathies. Heart transplantation remains the standard ofcare for children with progressive disease. The percentage ofchildren with cardiomyopathy who received a heart transplanthas not declined over the past 10 years and cardiomyopathyremains the leading cause of transplantation for children overone year of age [10]. Nearly 40% of children who present withsymptomatic cardiomyopathy receive a heart transplant or die[11,12]. Furthermore, the time to transplant or death for childrenwith cardiomyopathy has not improved during the past 35 years,and the most economically advanced nations have no betteroutcomes than developing nations [10]. Cardiomyopathies havean associated cost of nearly $200 million/year in adults andchildren in the United States alone [13]. Improvements intechnology and medicine have contributed to an improvedsurvival for children having heart transplants, however, it hasnot resulted in either a normal life span, or an improved qualityof life. Recent medical research indicates that new treatmentsmay soon be available. It has been suggested that advancementsin stem cell research may be beneficial to children withcardiomyopathies [14]. Thus, ancillary therapies, such asnutrition and optimizing nutritional interventions, that maynot cure but may potentially improve cardiac function andquality of life are imperative to consider in children with alltypes of cardiomyopathy.

2. Nutritional status of children with cardiomyopathy

Growth problems are common in many pediatric illnesses[1519]. Normal growth in children is considered an importantclinical indicator of health. Chronic illness in children leads to animbalance of energy where there is more energy expendedsecondary to the disease and less devoted to normal metabolicprocesses (i.e. growth). Growth failure can be due to a variety offactors and it is often multifactorial. Increased energy expendi-ture secondary to chronic disease processes (hyperthyroidism,congestive heart failure, chronic infections, to name a few),gastrointestinal malabsorption, chronically low and suboptimaldietary intake, or psychosocial problems are the 4 most commonand cited causes of poor growth in the child with chronic disease.The etiology of malnutrition in children with chronic illness islikely due to a combination of 2 or more of these factors.

Not only is growth an indicator of active and poorly controlleddisease, but there is emerging evidence that progressive declinesin nutritional status are linked closely and independently withdeteriorating organ functions, morbidity and mortality in avariety of disorders [20,21]. The best example of this is the first

61T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

discovery of pneumoncystis carinii pneumonia in otherwisehealthy, but severely malnourished children in developingnations [22]. Investigators have shown that improving nutritionalstatus in malnourished and chronically ill children relates toimproved survival and decreased utilization of health careresources through lower hospitalization rates [23]. In anotherstudy evaluating cardiac outcomes in chronically ill children[24], nutritional status was a strong and independent predictor ofmortality and cardiac function. Thus, better nutritional status ofthe child (or adult) is related to the optimal functioning of theheart and other organ systems and eventual clinical outcomes[25,26].

Growth failure is one of the most significant clinicalproblems of children with cardiomyopathy with nearly one-third of children with this disorder manifesting some degree ofgrowth failure during the course of their illness. In a recentinternational study in Brazil [25], Azevedo determined thatweight z-score was positively and independently correlated withsurvival in a chart review of 165 children with idiopathic dilatedcardiomyopathy between 1979 and 2003. However, short of thisrestrospective chart review, there is a dearth of information onnutritional correlates to cardiac outcomes and function inchildren with cardiomyopathy. We have shown previously thatin other models of chronic illness in children (humanimmunodeficiency virus infection), that cardiac muscle massdoes not always waste in proportion to skeletal muscle [27].This suggests that neurohormonal influences may affect cardiacstatus to a greater extent than skeletal muscle. The underlyingcause of growth failure is usually due to persistent congestiveheart failure as a result of an overall poor response to medicaltreatment. Significant cardiac dysfunction in these children canresult in increased metabolic demands, decreased food intakeand malabsorption of important nutrients. Growth failure ormalnutrition in children can lead to problems in virtually everyorgan system, with many of the effects only partially reversible.Thus cardiomyopathy may lead to growth problems, but growthproblems can lead to further complications that may directly orindirectly impact on heart function, leading to a viciousdownward cycle (Fig. 1). These clinical manifestations indicatethat growth patterns may be an important predictor of theoutcomes among CM patients or an important indicator of theseverity of their cardiomyopathy. If this is so, then it becomes

Fig. 1. Vicious downward cycle of malnutrition in pediatric cardiomyopthy.

apparent that clinicians should be vigilant regarding treatmentissues surrounding growth. The relationship between growthpatterns and echocardiographic findings is unknown.

3. The effect of nutrients on cardiac endpoints in heartfailure

Promotion of adequate nutrition begins with early detectionof children at risk for malnutrition. Optimal nutrition is criticalin providing children the means to recover from their illness andto withstand the detrimental metabolic effects of aggressivetherapies. In theory, patients with heart failure who have eitherinsufficient fat mass (BMI b10% for age and sex) or excess fatmass (BMI 85% for age and sex) should have pooreroutcomes than patients with a BMI in the reference range(between 10% and 95%). Although excess body fat mayincrease the risk of developing heart failure, evidence suggeststhat it may be beneficial once heart failure develops. Onemechanism may be that increased body fat provides a metabolicreserve that allows overweight and obese patients to tolerate themetabolic/catabolic stress associated with heart failure pathol-ogy for a longer time [28]. Another potential mechanism isrelated to the hypothesized differences in proinflammatorycytokine activity between underweight and overweight/obeseindividuals with heart failure [29]. In addition to releasingproinflammatory cytokines, adipose tissue is a source of anti-inflammatory cytokines. However, it is not known whether thepotential positive effects of excess body fat in patients withheart failure vary depending on body fat distribution. Ourcurrent recommendations focus on decreasing body fataccumulation due to the known adverse effects and secondarydiseases that may develop from obesity. However, more studiesare needed in order to tease out the complex interaction betweenobesity and active heart failure with particular focus on thepediatric population that has been often difficult to study owingto limited numbers of children available to study.

3.1. Macronutrients

Children with cardiomyopathy, with varying degrees ofcongestive heart failure, need to receive adequate calories tocompensate for their heart failure (that typically increases basalenergy expenditure) as well as to provide additional calories fornormal growth. As mentioned previously, children in heartfailure often do not grow along expected standards for age andsex and poor growth may either contribute to poor cardiacfunction or be one result of it. Optimal caloric intake is usuallyestimated to be approximately 110125% of the estimatedenergy requirement (EER) (Table 1) [30] for age and sex.However, greater or fewer calories may be required dependingon the child's growth as a response to their intake; as normalnutrition is the balance between energy intake and energyutilization. Children who are in congestive heart failure oftenhave increased metabolic rates due to the increased work ofbreathing, eating, or other routine activities of daily living. Theymay also malabsorb critical nutrients as a result of heart failureleading to gut edema. Furthermore, anorexia, due to a variety of

Table 1Important nutrients in cardiomyopathy

Roles Recommended daily intake Dietary sources

Calories Provide energy for all metabolicprocesses and to support growth.

Healthy weight: calorie levels based on theEstimated Energy Requirements (EER) andactivity levels from the Institute of MedicineDietary Reference Intakes (DRI)Macronutrients Report, 2002.

For mild to moderate undernutrition, adlibitum oral feedings are appropriate, andcaregivers should be advised to increasethe caloric intake by increasing thecaloric density of both liquids and solids.

Increased metabolic rate secondaryto recurrent infections, increasedmuscle activity, and need for rapid growth.

Estimate catch-up growth needs in growthfailure: by determining ideal body weight forheight and using by indirect calorimetry orusing calorie levels based on EER for thatweight. Children in heart failure often require10% to 50% more calories due to increasedmetabolic rates.

Once a nutritional problem becomeschronic and the patient presents withsevere growth failure (BMIb5% orweight/heightb5%), or when the oralsupplementation is no longer sufficient,an aggressive nutrition support planincluding gastrostomy or intravenousalimentation needs to be advised.

Protein (g/d) Serves as the major structuralcomponent of all cells in the body, andfunctions as enzymes in membranes, astransport carriers, and some hormones.

Protein requirements are based on an increasein needs. RDA for protein may be increased by50100%

From animal sources completeprotein: meat, poultry, fish, eggs, milk,cheese, and yogurt.

FTT: DRI protein for age x ideal weight forheight (kg) /actual weight

From plants: legumes, grains,nuts, seeds, and vegetables.

RDA/AI

Children13 y: 1348 y: 19

Males913 y: 34N14 y: 52

Females913 y: 34N14 y: 46

Carbohydrate(g/d)

Source of calories to maintain body weight. 55 to 60% of the total calories Starch and sugar are the major types ofcarbohydrates. Grains and vegetables(corn, pasta, potatoes, breads), aresources of starch. Natural sugars arefound in fruits and juices. Sources ofadded sugars are soft drinks, candy,fruit, drinks, and desserts.

Primary energy source for the brain. Children and adults130 g/dAdded sugars should comprise no more than25% of total calories consumed.

Fat (g/d) Energy source and when found in foods, is a sourceof n6 and n3 polyunsaturated fatty acids. Itspresence in the diet increases absorption of fatsoluble vitamins and precursors such as vitamin Aand pro-vitamin A carotenoids.

AMDR Butter, margarine, vegetable oils, wholemilk, visible fat on meat and poultryproducts, invisible fat in fish, shellfish,some plant products such as seeds andnuts, and bakery products.

Children13 y: 304048 y: 2535

Males and femalesN9 y: 2535

n3polyunsaturatedfatty acids(linolenic acid)(g/d)

Possible favorable effect on left ventricular function. Children Oily fish such as sardines, mackerel,herring, trout, tuna, and salmon. Othersources include flaxseed, soy, and canola oil.

13 y: 0.748 y: 0.9

Males913 y: 1.2N14 y: 1.6

Females913 y: 1.0N14 y: 1.1

n6polyunsaturatedfatty acids(linoleic acid)(g/d)

Essential component of structural membranelipids, involved with cell signaling, andprecursor of eicosanoids.

Children Nuts, seeds, and vegetable oils such assoybean, safflower, and corn oil.13 y: 7

48 y: 10Males

913 y: 121418 y: 17

Females913 y: 101418 y: 12

62 T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

Roles Recommended daily intake Dietary sources

Fibers (g/d) Reduces risk of coronary heart disease, assists inmaintaining normal blood glucose levels.

Children13 y: 19

Soluble fibers: oatmeal, legumes, andsome fruits and vegetables with pectin.

48: 25Males

913 y: 311418 y: 38

Females918 y: 26

Water (ml/d) Essential for maintaining vascular volume. Total fluid requirements: All beverages, including water, as well asmoisture in foods (high moisture foodsinclude watermelon, meats, soups, etc.).

110 kg: 100 ml/kg1020 kg: 1000 ml+50 ml/kg for each

kg above 10 kgN20 kg: 1500 ml+20 ml/kg for each

kg above 20 kgWater restriction may be recommendedin advanced stages.

Vitamins andminerals

Antioxidants play an important role in protectingmitochondria and cells from reactiveoxygen intermediates.

Using multiple micronutrientsupplementations has been shown to improveleft ventricular ejection fraction and qualityof life.Deficiency in both macro and micronutrients may

contribute to the wasting process once triggered.Patients are usually receiving loop diuretics whichincrease urinary excretion of micronutrients.

B1 Thiamine(mg/d)

Coenzyme in many physiologic functionsincluding carbohydrate metabolism andmaintenance of myelin necessary for propernerve and muscle function.

Children Fortified cereals, meat; meat and fish; driedbeans, soy foods and peas; whole grains.13 y: 0.4

48 y: 0.5Males

913 y: 0.71418 y: 1.0

Females913 y: 0.71418 y: 0.9

B3 Niacin(mg/d)

Functions in many biological redox reactionsincluding intracellular respiration, fattyacid synthesis and glucose oxidation.

Children Dairy products, meat, poultry, fish,fortified cereals, and peanuts.13 y: 5

48 y: 6Males

913 y: 9N14 y: 12

Niacin decreases blood levels of cholesteroland lipoprotein, which may reduce the riskof atherosclerosis.

Females913 y: 91418 y: 11

B6 (mg/d) Improvement of endothelial function by reducinghomocysteine levels, which is associated withincreased oxidative stress.

Children Fortified cereals, beans, meat, poultry,fish, and some fruits and vegetables.13 y: 0.5

48 y: 0.6Males

913 y: 1.0N14 y: 1.3

Females913 y: 1.01418 y: 1.8

B12 (g/d) Improvement of endothelial function byreducing homocysteine levels.

13 y: 0.9 Fish, meat, poultry, eggs, milk, milkproducts, and fortified breakfast cereals.48 y: 1.2

913 y: 1.8N14 y: 2.4

Folate (g/d) 13 y: 150 Prepared breakfast cereals, beans, andfortified grains.48 y: 200

913 y: 300N14 y: 400

(continued on next page)

Table 1 (continued )

63T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

Table 1 (continued)

Roles Recommended daily intake Dietary sources

Vitamin A (g/d) Important for normal vision, gene expression,reproduction, embryonic development, growthand immune function.

Children Many breakfast cereals, juices, dairyproducts, and other foods are fortifiedwith vitamin A. Many fruits andvegetables, and some supplements,also contain beta-carotene and othervitamin A precursors, which the bodycan turn into vitamin A.

13 y: 30048 y: 400

Males913 y: 600N14 y: 900

Females913 y: 600N14 y: 700

Note: 1 RAE=1 g retinol, 12 g -carotenePro vitamin Acarotenoids

Possible antioxidant activity. Associated withdecreased risk of some cardiovascular events.

Not determinable due to lack ofdata of adverse effects.

Some fruits (papaya, peach, melon), sometubers (squash, yam, sweet potato), yellow/orange vegetables (carrots, peppers), greenleafy vegetables.

Vitamin C (mg/d) Important antioxidant and also helps maintaintissue levels of vitamins A and E, whichalso serve as antioxidants.

Children Citrus fruits or juices, berries, green andred peppers, tomatoes, broccoli, andspinach. Many breakfast cereals are alsofortified with vitamin C.

13 y: 1548 y: 25

Males913 y: 451418 y: 75

Females913 y: 451418 y: 65

Vitamin E (mg/d) Functions primarily as a chain-breakingantioxidant that prevents propagationof lipid peroxidation.

Children Vegetable oils, nuts, green leafyvegetables, and fortified cereals.13 y: 6

48 y: 7Males

913 y: 111418 y: 15

Females913 y: 11N14 y: 15

Vitamin D (g/d) Essential for calcium absorptionfrom the intestine.

Children Fortified foods such as milk andbreakfast cereals.18 y: 5

Males and femalesN9 y: 5

Calcium (mg/d) In addition to bone metabolism, calcium plays arole in muscle contraction.

Children Dairy products are the mains source ofcalcium in the U.S. diet. Other sourcesinclude green vegetables, calcium-settofu, some legumes, canned fish, seed,nuts, and certain fortified food products.

13 y: 50048 y: 800

Males and females918 y: 1300

Zinc (mg/d) Act as a component of antioxidant enzymes. Children Oysters, red meat, poultry, beans, nuts,certain seafood, whole grains, fortifiedbreakfast cereals, and dairy products.

13 y: 348: 5

Males913 y: 8N14 y: 11

Females913 y: 81418 y: 9

Copper (g/d) Component of enzymes in iron metabolism Children Organ meats, seafood, nuts, seeds, wheatbran cereals, whole grain products, cocoaproducts.

13 y: 3401548 y: 440

Males and females913 y: 7001418 y: 890

Magnesium (mg/d) Act as a component of antioxidant enzymes. Maybe involved in skeletal (and cardiac)

Children Green leafy vegetables, some legumes(beans and peas), nuts and seeds, andwhole, unrefined grains.

13 y: 8048: 130

Males913 y: 2401418 y: 410

Females913 y: 2401418 y: 360

64 T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

Roles Recommended daily intake Dietary sources

Selenium (g/d) Antioxidant protection in concert with vitamin E. Children Cereals, meat, eggs, dairy products,human milk, and infant formula, whichare good sources of highly available Seand are of low risk of providing excessamounts of Se.

13 y: 2048: 30

Males and females913 y: 401418 y: 55

Sodium (g/d) Sodium restriction prevents exacerbations of heartfailure and can reduce the dose of diuretic therapy.

Children Processed foods to which sodiumchloride (salt)/benzoate/phosphate havebeen added; salted meats, nuts, cold cuts;margarine; butter; salt added to foods incooking or at the table.

13 y: 1.048: 1.2

Males913 y: 1.51418 y: 1.5

Females918 y: 1.5

Other nutrition supplementsCarnitine Essential for the transport of

long-chain fatty acids from cytoplasminto the sites of -oxidation within themitochondrial matrix.

No DRI or RDA established. Animal products like meat, fish, poultry,and milk.Conditionally essential nutrients.

Taurine Nonessential amino acid that participates incontrolling cellular calcium levels.

Meat and fish.

Creatinephosphate

Primary high-energy phosphate reservoirof the heart and skeletal muscle.

Meat and fish.

Coenzyme Q10 Critically necessary for oxidative energyproduction and cardiac function.

Widespread throughout all food groups.

Role as a rate-limiting carrier for the flowof electrons through complexes I, II and IIIof the mitochondrial respiratory chain.

BMR = Basal Metabolic Rate.EER = Estimated Energy Requirement.FTT = Failure to Thrive.DRI = Dietary Reference Intake.AMDR = Acceptable Macronutrient Distribution Range is the range of intake for a particular energy source that is associated with reduced risk of chronic diseasewhile providing intakes of essential nutrients. Food and Nutrition Board, Institute of Medicine, National Academies of Sciences. Retrieved June 20, 2007 from http://www.nap.edu.

Table 1 (continued )

Fig. 2. Metabolic pathways with increased nutritional requirements in thedecompensating myocyte. Figure reproduced from Sole MJ, Jeejeebhoy KN.Conditioned nutritional requirements and the pathogenesis and treatment ofmyocardial failure. Curr Opin Clin Nutr Metab Care. 2000 Nov;3(6):41724.Permission granted by Lippincott Williams & Wilkins, Inc.

65T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

reasons including a proinflammatory state (cachexia) or delayedgastric emptying secondary to increased edema may be a factorthat contributes to suboptimal dietary intake. Physical activitylevel also has to be accounted for, with physical activity beingindirectly related to the level of congestive heart failure [31].However, physical inactivity may contribute the digression inheart function leading to worsening heart failure.

There is little information regarding the role of dietarymacronutrients in the development or prevention of leftventricular hypertrophy or heart failure in children withcardiomyopathy. Dietary guidelines aimed at prevention ofcardiovascular disease emphasize the importance of consuminga low-fat/high carbohydrate diet; however recent findingssuggest that reducing fat intake and increasing carbohydrateconsumption does not lower the risk of heart disease [32] inadults. Little information is available for children, yet it isbecoming increasingly recognized that the root of adultcardiovascular disease may begin in childhood.

Studies of animal models have shown that a high-fat dietattenuated the hypertension-induced increase in left ventricularmass, cardiomyocyte hypertrophy, left ventricular chambermarkers of cardiac dysfunction, and induction of molecularmarkers of cardiac hypertrophy and dysfunction [3335].

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66 T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

However there are no data from humans to support extendingthis observation into clinical practice. The interactions among fatand carbohydrate intake, salt intake, hypertension, and cardiacsize and function are complex and difficult to decipher in vivo.The reduced left ventricular hypertrophy with a high-fat/low-carbohydrate diet could be because of less insulin stimulation ofcardiomyocyte growth. Dietary intake of carbohydrates, partic-ularly sugars, determines the exposure of the heart to insulin andinsulin-like growth factor. In addition, it is not clear if a low-sugar/high complex carbohydrate/low-fat diet could be just aseffective at preventing left ventricular hypertrophy and contrac-tile dysfunction in hypertension.

Nonpharmacological factors, often nutrition related, caninfluence the course of heart failure. There is general agreementthat a diet high in sodium is potentially harmful in congestiveheart failure, as it may cause fluid overload and potentiallycontribute to acute decompensation. Besides preventing exacer-bations of heart failure, sodium reduction can reduce the dose ofdiuretic therapy. Water restriction may also be important,especially in advanced stages.

3.2. Micronutrients

Although provision of optimal calories and protein is im-portant for growth and optimal cardiac function in children withcardiomyopathy, it is not always sufficient to optimize cardiacfunction. In adults with congestive heart failure, high proteinfeedings and a marked positive energy balance does not alwayscorrect the significant metabolic problems that occur in heartfailure [36]. Thus, specific nutritional deficiencies specific forheart failure may play a role in optimizing or helping correct thefailure. Children with cardiomyopathy and heart failure, similar toadults, may require greater than standard intakes of certainmicronutrients in order to optimize the cardiac function [36,37].Furthermore, serum levels of micronutrients may not necessarilyreflect adequacy of these nutrients at the tissue level. The follow-ing discussion is of micronutrient, mineral and other nutritionaldeficiencies that are known to be problematic in patients withheart failure or may be therapeutic in improving cardiac functionif given to patients as an ancillary intervention. These nutrients areeither broadly categorized as antioxidants or nutrients known toaffect myocardial energy production. However, several of thesenutrients have more than one cellular role (Fig. 2).

3.3. Antioxidants

Free radicals are products of oxygen metabolism and theirrate of production is usually equal to their metabolism undernormal circumstances. In certain clinical situations of stress, theproduction of these free radicals is greater than their normalclearance. At that point, the host's endogenous antioxidantsystem plays a major role to prevent or limit the deleteriouseffects of free radicals and in children with cardiomyopathyspecifically, control further myocardial damage. Endogenousantioxidants include enzymatic antioxidants (e.g., zinc insuperoxide dismutase or selenium in glutathione peroxidase),free radical scavengers (e.g., vitamins A, C or E) and metal

chelators. Sources of antioxidants include the diet or through theuse of specific nutritional supplements. Increased free radicalformation and reduced antioxidant defenses [38,39] found inpatients with heart failure can result from a combination ofinsufficient dietary intake and excessive utilization of specificantioxidants without adequate recycling or replacement.Recognizing and correcting multiple vitamin marginal defi-ciencies may be the key to the treatment of many heart failurepatients. It has been recommended that individuals strive toachieve a higher intake of dietary antioxidants by increasingconsumption of fruits, vegetables, and whole grains.

As a general rule, food and lifestyle factors that trigger theacute phase response should be avoided. This comprises, forexample, excess of carbohydrates or saturated fat, alcohol, andsmoking. Foods that counteract inflammatory processes cangenerally be recommended, for example fatty fish for its contentof omega-3 fatty acids and possible favorable effect on leftventricular function. There are no clinical trials demonstratingthe benefit of omega-3 fatty acid supplementations in patientswith heart failure. However, the omega-3 fatty acids, eicosa-pentanoic acid and docosahexanoic acid, are essential nutrients.Thus, assuring adequate intake is necessary to meet nutritionalrequirements. The American Heart Association recommends 2meals of fish, preferably fatty fish, per week and the use ofvegetable oils high in -linolenic acid such as canola, flaxseed,soybean, and walnut [40].

Injury from free radicals can contribute to coronary arterydisease, myocardial infarction and cardiac dysfunction in someforms of cardiomyopathy in both humans and animals [41]. Freeradicals can have both cytotoxic effects on the myocardium andalso act as negative inotropes [42]. In models of congestive heartfailure, antioxidants are elevated in cardiac hypertrophy and lowerin cardiac failure [43,44]. For example, administration of vitaminE in one experimental model in Syrian Hamsters with end-stagecardiomyopathy showed optimization of alpha-tocopherol levelsand improved glutathione peroxidase activity [45]. However,despite some experimental evidence, few studies have shownsupplementation with antioxidants to have a significant impact ontreatment of heart failure. The following section outlinesexperimental evidence that is available on the effects of specificantioxidants on cardiac conditions in patients with heart failure.Please note the dearth of information regarding their effects onchildren.

3.3.1. Vitamin AVitamin A can be found in 2 forms; preformed vitamin A

(retinol) and carotenoids. Vitamin A is an antioxidant that candecrease oxidative stress. Some experimental animalmodels haveshown that vitamin A, taken as one of several antioxidants,prevents NF-kappaB activation, reduces mitochondrial cyto-chrome c release, decreases caspase activity, attenuates cardio-myocyte secretion of inflammatory cytokines, and improvesmyocardial contractile function [46]. In the neonatal rat heart, 9-cis-retinoic acid, stimulated transcription from the GLUT4glucose transporter promoter (whose expression may be criticalfor the survival of cardiac myocytes in situations of stress) [47].However, its role in the treatment of heart failure is unknown, and

67T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

some clinical studies have found it to have no benefits in treatingheart failure [48].

3.3.2. Vitamin EVitamin E is an antioxidant that can be detected in lower

concentrations in patients with congestive heart failure [49];however there is little evidence that shows the benefits inimproving myocardial function with exogenous supplementa-tion [5054]. There have been few human trials, and onerandomized, placebo controlled study in adults with congestiveheart failure showed no effect on quality of life, norepinephrinelevels and other neurotransmitters [55].

3.3.3. TaurineChildren with heart failure have increased levels of intracel-

lular and mitochondrial calcium that can depress myocardialenergy production and increase oxidative stress. Taurine, anamino acid, helps regulate calcium flux through the cells [56].Taurine is the most abundant free amino acid in cardiac musclecells. Taurine can be synthesized frommethione and cysteine andis not essential. However, the activity of certain enzymes tosynthesize taurine from these other amino acids is low in humans,thus the majority of taurine in the body is derived from foodsincluding seafood and meat [57]. Proinflammatory cytokines canalso decrease tissue taurine levels. With inflammatory conditionsoften accompanying heart failure, taurine supplementation mayplay a role in controlling oxidative stress as well of optimizingmyocardial energy production [58]. For example, one studyshowed that heart tissue ismore susceptible to adriamycin toxicitywhen taurine levels are low [59]. Studies regarding the benefit oftaurine administration in various heart conditions have beenpromising [57,60,61]. However, taurine's potential beneficialeffects in children have had limited attention.

3.3.4. Co-enzyme Q10 (ubiquinone)Co-enzyme Q10 (ubiquinone) is a vitamin-like substance that

is present in all human cells and responsible for energyproduction by facilitating the actions of the mitochondria. It is arate-limiting carrier for the flow of electrons through complexesI, II and III of the mitochondrial respiratory chain and is also anendogenous lipophilic antioxidant. Those organs with thehighest energy requirements, including the heart, have thehighest Co-enzyme Q10 concentrations [6264]. It is a powerfulantioxidant and stabilizes membranes. Ubiquinone is present invarying amounts in all food groups, thus body stores may bepartially supplied by diet. Oral absorption is slow but it isenhanced with lipids. There is a large hepatic first pass effect sothat only 25% of an oral dose is taken up by the myocardium.Adults with congestive heart failure can have lower concentra-tions of Co-enzyme Q10 in their myocardium as determined bybiopsy [65]. Low levels have also been associated with higherrates of mortality [66]. Studies of Co-enzyme Q10 supplemen-tation have been contradictory with some showing improve-ment in functional status, clinical symptoms, andhospitalizations [67,68], while others showing no benefit [6971]. However, a meta-analysis of published reports [72]supported a hemodynamic benefit.

3.3.5. Vitamin CVitamin C is another powerful antioxidant that has a role in

vitamin E metabolism. Vitamin C levels are reduced in heartfailure [73]. Vitamin C may have an important role in modifyingapoptosis [7477]. It also decreases TNF secretion, therebyimproving inflammation [78]. Large doses have been shown toimprove vasomotor function in patients with heart failure bypossibly increasing nitric oxide production [78]. In NHANES I,subjects with a high dietary intake of antioxidants (includingvitamin C) had a significantly lower all-cause mortality and inparticular from coronary heart disease [79]. However, in sub-sequent prospective, randomized clinical trials in high-riskpopulations, vitamin C showed no benefit [80]. Acute vitamin Cadministration restored peripheral endothelial function in patientswith coronary artery disease to normal values, but not in heartfailure, especially in dilated cardiomyopathy. Thus, factors otherthan oxidative stress (e.g., cytokines) can contribute to endothelialdysfunction in patients with heart failure [81]. Compiling theevidence, vitamin C may hold promise in altering peripheralendothelial function, however, few, if any studies have beenperformed in children with cardiomyopathy.

3.4. Nutrients that affect myocardial energy production

3.4.1. Thiamine (vitamin B1)Thiamine is a water-soluble vitamin and is synthesized by

plants and other microorganisms, yet humans cannot synthesizeit themselves. Thiamine is important for carbohydrate metab-olism and a deficiency is found in up to 93% of patients withheart failure [8287]. Loop diuretics, among other factors,including malnutrition and poor overall nutritional status hasbeen linked to thiamine deficiency [8285]. Symptoms forcongestive heart failure are common and can often be reversedwith adequate supplementation [88].

3.4.2. L-CarnitineL-Carnitine, an amino-acid derivative that helps the transport

of long-chain fatty acids from the cytoplasm into the sites of[beta]-oxidation within the mitochondrial matrix. Furthermore,carnitine binds toxic acyl groups and releases free coenzyme A.Subsequently, these acylcarnitines can diffuse freely out of thecell and be eliminated through the urine. Carnitine alsoindirectly activates pyruvate dehydrogenase, the rate-limitingenzyme for glucose oxidation [89,90]; this, in turn, improves thecoupling between glycolysis and glucose oxidation, therebyreducing the lactate and hydrogen burden on the myocyte.L-Carnitine and its derivates play an important role in myocardialenergy production. Carnitine stores can be replenished fromendogenous synthesis from lysine andmethionine, aswell as fromdietary intake. Patients with genetically determined deficiencydevelop both cardiac and skeletal dysfunction, which can beimproved by carnitine administration [91]. Carnitine deficiencycan also be an acquired state in individuals with establishedcongestive heart failure, with levels reported to be depleted by asmuch as 50% [92]. Plasma levels may be as much as 35 timesthose of intracardiac levels, thus plasma levels are not a goodmeasure of tissue concentrations. Patients in congestive heart

68 T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

failure generally exhibit a marked depletion (up to 50%) of bothfree and total carnitine [89. 92]. L-Carnitine supplementation[89,92,93] can result in overall improvement in the cardiac statusand quality of life of both animals and patients with myocardialdysfunction. A multicentered, randomized, placebo-controlled,double-blind clinical trial [94] showed a significant beneficialeffect, including a reduction in adverse cardiac remodeling, whenL-carnitine was taken for 12 months after myocardial infarction.Furthermore, improved 3 year survival was also found in patientsgiven daily doses of L-carnitine [95]. Similar to other nutrients, itis clear that more studies will be needed to determine the potentialbenefits of this nutrient. Furthermore, there continues to be adearth of studies in the pediatric population with heart failure.

3.4.3. CreatineCreatine phosphate is the substrate for phosphate transfer to

ADP to form ATP by the enzymatic activity of creatine kinase.Creatine is synthesized in the liver and spleen from arginine,glycine and methionine. The concentration of creatine in themyocardiocyte is determined by adrenergic drive [96], thus withheart failure, the concentration of creatine in the cell may bediminished [96,97]. Creatine can improve calcium homeostasis[98] and survival of myocytes in culture.

Creatine supplements increases skeletal muscle creatine, andthis may be most beneficial during short-term exercise to improvemuscle strength, endurance and metabolism by reducing lactate[99101]. Thus, creatine supplementationmaynot be as beneficialunder normal situations. There have been few, if any studies oncreatine's effects on heart failure, with notably none in children.

3.5. Other nutrients

3.5.1. Vitamin D/calciumAdequate intake (Table 1) of calcium and vitamin D needs to

be insured, as these nutrients are critical to optimize cardiacfunction. The childhood diet is typically deficient in both ofthese nutrients with intakes of only 50% of the DRI widelyreported. In animal models, rats fed a vitamin D deficient dietdeveloped poor cardiac function that was reversed withsupplementation of vitamin D [102].

3.5.2. Folate/vitamin B12Folate is required to convert homocysteine to methione.

Folate deficiency is frequently detected in patients with heartfailure [103] and often this is coincident with low folate dietaryintake [104]. Vascular endothelial function may be improved byfolate [105]. Similarly, vitamin B12 deficiency is also linked tohigher homocysteine levels. However, studies show that neitherfolate nor vitamin B12 improves intrinsic cardiac function, yetthere may be greater effects on peripheral vasculature [106].

3.5.3. MagnesiumMagnesium deficiency can occur in up to 30% of patients with

heart failure [107109]. Medications, such as loop and thiazidediuretics contribute to urinary magnesium loss. Magnesiumdeficiency is associated with sodium retention and increasedventricular ectopy [110112] with associated reduced cardiac

contractility and increased peripheral vascular resistance[113,114].

3.5.4. ZincZinc is a trace mineral that is required for proper function of

one of the antioxidant enzyme systems and its deficiency isrelated to apoptosis of the myocardiocyte [115]. Severalmedicines including angiotensin converting enzyme inhibitors,angiotensin II antagonists and thiazide diuretics can increaseurinary zinc [116,117]. However, it is unclear if zinc deficiencyis related to or can improve heart failure.

3.5.5. SeleniumSelenium is a trace mineral that can be found in small

amounts in the soil and food. Depending on the region of theworld, foods grown in certain areas may have sufficient or poorconcentrations of selenium owing to soil content. Meat andseafood have the greatest concentrations of selenium. Seleniumdeficiency has been associated with congestive cardiomyopathy(Keshan disease), skeletal myopathy, osteoarthropathy (KashinBeck disease), anemia, immune system alterations, increasedrisk of cancer, cardiovascular disease, hair and nail changes,infertility, and abnormalities in thyroid hormone metabolism inhumans [118]. Selenium's greatest role is its action as a cofactorfor the antioxidant enzyme, glutathione peroxidase whichremoves hydrogen peroxide and the deleterious lipid hydroper-oxides generated by oxygen-derived species. Glutathioneperoxidase deficiency contributes to endothelial dysfunction amajor contributing factor in heart failure [119], in variousconditions such as hyperhomocysteinemia [120]. This suggeststhat homocysteine may be involved in heart failure associatedendothelial dysfunction through a peroxide-dependent oxidativemechanism. Selenium also plays a role in the control of thyroidhormone metabolism [121] by affecting synthesis and activity ofde-iodinases, enzymes converting thyroxin into the biologicallyactive triiodothyronine [122]. Thus, selenium (through its role inselenoenzymes, thyroid hormones, and interactions with homo-cysteine and endothelial function) appears to be a majormediator in several pathways potentially contributing to orpossibly preventing heart failure.

The first case of endemic selenium deficiency was describedin 1935 in Keshan County, in China. Clinical features were acuteand/or chronic episodes of cardiogenic shock and/or congestiveheart failure. Selenium supplementation may stop progression ofthe cardiac disease but is less successful at reversing the existingcardiac damage [123]. The daily recommended intake ofselenium is 2055 g/day, depending on the age of the child.(30) (Table 1). Selenium deficiency in developed nations is moreoften seen in chronically ill, malnourished patients withmalabsorption and in unsupplemented total parenteral nutrition(TPN)-dependent patients [124,125]. Selenium deficiency alsois encountered when nutrient-limited diets are used such aspatients with phenylketonuria [126] and the ketogenic diet.

Assessment of selenium status is difficult because no optimalmethod is known. Dietary assessment is inaccurate, andselenium content depends on where the food was grown (soilcontent), which is usually unknown. Selenium can be measured

69T.L. Miller et al. / Progress in Pediatric Cardiology 24 (2007) 5971

in serum, plasma, whole blood, erythrocytes, urine, and hair.Serum and plasma concentrations correlate well with dietaryintake and absorption and are a good indicator of short-termselenium status. Whole-blood and erythrocyte selenium levelsreflect longer-term status. Activity of glutathione peroxidase is awell-accepted functional assay of selenium sufficiency.

4. Conclusions

Little is understood regarding the role of growth and nutrition inpediatric cardiomyopathy as a predictor of its outcomes. Un-derstanding the link between nutrition and outcomes in pediatriccardiomyopthy would be useful in classifying patients into ap-propriate prognostic categories that will aid in the identification ofpatients who would benefit most from transplant or other types ofmedical treatment. Furthermore, understanding the role of growthand nutrition in predicting outcomes in pediatric cardiomyopathymay also focus attention on early and aggressive nutritionalinterventions for these children that may ultimately prevent ordelay progressive decline in heart function or eventual hearttransplantation. There is evidence that nutrition can also be used asspecific therapy toward optimizing cardiac function by decreasingthe effects of free radicals or augmenting myocardial energyproduction. However, many scientific studies are contradictory inadults with heart failure and there is a disappointingly few studiesamong children with cardiomyopathy. Future efforts should focuson collaborative descriptive and interventional studies that furtherdefine the role of nutrition and nutritional interventions on cardiac-specific endpoints as well as quality of life in children withcardiomyopathy.

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Nutrition in pediatric cardiomyopathyIntroductionNutritional status of children with cardiomyopathyThe effect of nutrients on cardiac endpoints in heart failureMacronutrientsMicronutrientsAntioxidantsVitamin AVitamin ETaurineCo-enzyme Q10 (ubiquinone)Vitamin CNutrients that affect myocardial energy productionThiamine (vitamin B1)l-CarnitineCreatineOther nutrientsVitamin D/calciumFolate/vitamin B12MagnesiumZincSeleniumConclusionsReferences