Reversal of Cardiac Hypertrophy With a Ketogenic Diet in a Child With Mitochondrial Disease and Hypertrophic Cardiomyopathy.

Mitochondrial diseases are rare metabolic disorders that can cause hypertrophic cardiomyopathy. Herein we describe the case of a 3-year-old girl diagnosed with mitochondrial disease (mutation m.5559A>G in the mitochondrial-tRNATrp gene). Echocardiography showed left ventricular hypertrophy with an enlarged septum (9 mm, z score = 3.26). Antioxidant supplementation associated with a high-fat ketogenic diet was introduced and, as expected, improved neurologic status. In addition, heart parameters improved with normalisation of interventricular septum thickness at 6 years of age (6 mm, z score = 1.05). In this case report, we suggest that a ketogenic diet may improve hypertrophic cardiomyopathy in the context of mitochondrial disease.

A randomized study assessing the effect of diet in cats with hypertrophic cardiomyopathy.

BACKGROUND: Diet might influence progression of hypertrophic cardiomyopathy (HCM). OBJECTIVE: To investigate whether diet composition could alter clinical, biochemical, or echocardiographic variables in cats with HCM. ANIMALS: Twenty-nine cats with HCM (International Small Animal Cardiac Health Council stage 1b) examined at a university teaching hospital. METHODS: Randomized, placebo-controlled trial. After physical examination, echocardiogram, and blood collection, cats were randomized to 1 of 3 diets, which varied in carbohydrate and fat content and ingredients. Measurements were repeated after 6 months. RESULTS: There were no significant differences among the 3 groups at baseline. After 6 months, there were no significant changes in the primary endpoints, left ventricular free wall (Group A, P = .760; Group B, P = .475; Group C, P = .066) or interventricular septal thickness in diastole (Group A, P = .528; Group B, P = .221; Group C, P = .097). Group A had significant increases in BUN (P = .008) and cholesterol (P = .021), while Group B had significant increases in BUN (P = .008), cholesterol (P = .007), and triglycerides (P = .005), and significant decreases in NT-proBNP (P = .013) and hs-troponin I (P = .043). Group C had significant decreases in body weight (P = .021), left atrial dimension (P = .035), interventricular septal thickness in systole (P = .038), and liver enzymes (P = .034-.038). CONCLUSIONS AND CLINICAL IMPORTANCE: These data suggest that diet might influence some clinical, biochemical, and echocardiographic variables in cats with HCM.

Remodeling the cardiac transcriptional landscape with diet.

The perception that soy food products and dietary supplements will have beneficial effects on cardiovascular health has led to a massive consumer market. However, we have previously noted that diet profoundly affects disease progression in a genetic model of hypertrophic cardiomyopathy (HCM). In this model, a soy-based diet negatively impacts cardiac function in male mice. Given the frequent connection between functional changes and transcriptional changes, we investigated the effect of diet (soy- vs. milk-based) on cardiac gene expression and how it is affected by the additional factors of sex and disease. We found that gene expression in the heart is altered more by diet than by sex or an inherited disease. We also found that the healthy male heart may be sensitized to dietary perturbations of gene expression in that it displays a gene expression profile more similar to diseased male and female hearts than to healthy female hearts. These observations may in part account for documented divergence in HCM phenotypes between males and females and between diets.

Drink more, and eat less: advice in obstructive hypertrophic cardiomyopathy.

This report describes a series of symptomatic patients with obstructive hypertrophic cardiomyopathy with significant postprandial hemodynamic changes. This finding was identified by history, clinical examination, and echocardiography in 6 consecutive symptomatic patients referred for the evaluation of ventricular septal reduction therapy. Counseling these patients with dietary changes to include small frequent meals and to increase noncaffeinated fluid intake resulted in reductions in symptoms. In conclusion, severe symptoms in obstructive hypertrophic cardiomyopathy unresponsive to pharmacologic treatment frequently result in referral for definitive septal reduction therapy through surgery or, less frequently, alcohol septal ablation therapy. However, recognition of postprandial exacerbation in symptomatic patients may allow for nonpharmacologic dietary interventions that may obviate the need for more invasive therapies and their associated complications.

Effects of a high saturated fat diet on cardiac hypertrophy and dysfunction in response to pressure overload.

BACKGROUND: Dietary lipid content effects activation of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and may accelerate cardiac hypertrophy and dysfunction in response to pressure overload. This study investigated the effects of a high-fat diet on the development of cardiac hypertrophy. METHODS AND RESULTS: C57BL/6J mice (n = 14-16/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either standard low-fat diet (STD; 10% fat) or a high-fat diet (HFD; 60% fat) for 16 weeks. Sham mice showed no differences between STD and HFD for heart mass or echocardiographic parameters despite greater plasma free fatty acid and leptin concentrations with HFD. TAC increased heart mass and decreased ejection fraction similarly in both groups. Left ventricular end systolic and diastolic diameters with TAC were increased compared with shams on the HFD (P < .05), but were not different from STD TAC mice. High-fat feeding increased expression of PPAR-alpha-regulated genes. The activity of medium chain acyl-coenzyme A dehydrogenase (MCAD), a marker of fatty acid oxidation capacity, was increased in HFD TAC mice compared with STD, consistent with PPAR-alpha activation. CONCLUSIONS: Increased fat intake prevented the fall in MCAD activity and did not exacerbate the hypertrophic response to TAC compared with a low-fat diet.

Nutrition and cardiomyopathy: lessons from spontaneous animal models.

Spontaneously occurring dilated cardiomyopathy in dogs and hypertrophic cardiomyopathy in cats are common diseases and are vastly underutilized as models of human cardiac disease. The goals of nutrition are no longer limited to a low-sodium diet, as research is now showing that nutrients can modulate disease and be an important adjunct to medical therapy. Deficiencies of certain nutrients can contribute to cardiomyopathies, as with taurine, but some nutrients-such as n-3 fatty acids, carnitine, and antioxidants-may have specific pharmacologic benefits. Dogs and cats with spontaneous cardiomyopathies are an exciting and promising model for studying nutritional modulation of cardiac disease.

Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice.

Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. We show here that dietary supplementation with physiologically relevant levels of copper (Cu) reverses preestablished hypertrophic cardiomyopathy caused by pressure overload induced by ascending aortic constriction in a mouse model. The reversal occurs in the continued presence of pressure overload. Sustained pressure overload leads to decreases in cardiac Cu and vascular endothelial growth factor (VEGF) levels along with suppression of myocardial angiogenesis. Cu supplementation replenishes cardiac Cu, increases VEGF, and promotes angiogenesis. Systemic administration of anti-VEGF antibody blunts Cu regression of hypertrophic cardiomyopathy. In cultured human cardiomyocytes, Cu chelation blocks insulin-like growth factor (IGF)-1- or Cu-stimulated VEGF expression, which is relieved by addition of excess Cu. Both IGF-1 and Cu activate hypoxia-inducible factor (HIF)-1alpha and HIF-1alpha gene silencing blocks IGF-1- or Cu-stimulated VEGF expression. HIF-1alpha coimmunoprecipitates with a Cu chaperone for superoxide dismutase-1 (CCS), and gene silencing of CCS, but not superoxide dismutase-1, prevents IGF-1- or Cu-induced HIF-1alpha activation and VEGF expression. Therefore, dietary Cu supplementation improves the condition of hypertrophic cardiomyopathy at least in part through CCS-mediated HIF-1alpha activation of VEGF expression and angiogenesis.

Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only in males.

Mutations in myosin heavy chain (MyHC) can cause hypertrophic cardiomyopathy (HCM) that is characterized by hypertrophy, histopathology, contractile dysfunction, and sudden death. The signaling pathways involved in the pathology of HCM have not been elucidated, and an unresolved question is whether blocking hypertrophic growth in HCM may be maladaptive or beneficial. To address these questions, a mouse model of HCM was crossed with an antihypertrophic mouse model of constitutive activated glycogen synthase kinase-3beta (caGSK-3beta). Active GSK-3beta blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3beta) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca(2+)-ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3beta double transgenic mice exhibited similar cardiac histology, function, and survival to their female HCM littermates. Remarkably, dietary modification from a soy-based diet to a casein-based diet significantly improved survival in HCM/GSK-3beta males. These findings indicate that activation of GSK-3beta is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3beta was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3beta in this HCM model is not therapeutic.

Dietary fish oil attenuates cardiac hypertrophy in lipotoxic cardiomyopathy due to systemic carnitine deficiency.

OBJECTIVE: 1,2-Diacylglycerol (DAG), a lipid second messenger that activates protein kinase C (PKC), is increased with a distinct fatty acid composition in the heart of the juvenile visceral steatosis (JVS) mouse, which develops pathological cardiac hypertrophy with lipid accumulation induced by the perturbation of fatty acid beta-oxidation due to systemic carnitine deficiency. Fish oil (FO) may exert its beneficial effects on the cardiomyopathy in JVS mice by modifying the molecular species composition of myocardial DAG. To test this hypothesis, we investigated the effects of dietary FO on the hypertrophied hearts in JVS mice. METHODS: Both control and JVS mice were fed a FO diet (containing 10% FO) or a standard diet from 4 weeks of age. RESULTS: At 8 weeks of age, the ventricular-to-body weight ratio in JVS mice was 2.7-fold higher than that in controls (9.9 +/- 0.1 vs. 3.7 +/- 0.1 mg/g, P < 0.01) and was reduced by dietary FO (7.7 +/- 0.1 mg/g, P < 0.01 vs. JVS mice). In JVS mice, myocardial DAG levels were elevated by 2.3-fold with a distinct fatty acid composition with increases in C18:1n-7,9 and C18:2n-6 fatty acids compared with controls; dietary FO had no effects on the total DAG levels but significantly altered the fatty acid composition of DAG with reduction of both fatty acid species. Immunoblot analysis showed that dietary FO prevented the membrane translocation of cardiac PKCs alpha, beta2, and epsilon in JVS mice. Dietary FO did not affect the plasma and myocardial total carnitine levels in JVS mice. Furthermore, dietary FO significantly improved the progressive left ventricular dysfunction and survival rate in JVS mice. CONCLUSIONS: Dietary FO may attenuate cardiac hypertrophy with improvements in cardiac function and survival in JVS mice via modification of the molecular species composition of myocardial DAG and the consequent inhibition of PKC redistribution. These results suggest the implication of the molecular species composition of DAG in the pathogenesis of lipotoxic cardiomyopathy due to perturbations of fatty acid beta-oxidation.