Effect of a specially formulated diet on progression of heart enlargement in dogs with subclinical degenerative mitral valve disease.

BACKGROUND: Previous studies in dogs with degenerative mitral valve disease (DMVD) have identified altered myocardial energy metabolism and oxidation, which might contribute to cardiac hypertrophy. Diets rich in medium chain fatty acids and antioxidants are a potential means of treatment. A previous clinical study found significantly smaller left atrial diameter (LAD) and left atrium-to-aorta diameter ratio (LA : Ao) in dogs with subclinical DMVD fed a specially formulated diet vs control diet for 6 months. HYPOTHESIS/OBJECTIVES: A specially formulated diet will slow or arrest left heart enlargement in dogs with subclinical DMVD over 365 days. ANIMALS: One hundred twenty-seven dogs with unmedicated subclinical DMVD; 101 dogs in the per protocol cohort. METHODS: Randomized double-blinded controlled multicenter clinical trial. RESULTS: The study's primary composite outcome measure was the sum of percentage change in LAD and left ventricular internal dimension at end-diastole (LVIDd) at day 365. In the per protocol cohort, the outcome measure increased by 8.0% (95% confidence interval [CI], 2.9%-13.1%) in dogs receiving the test diet vs 8.8% (95% CI, 5.1%-12.5%) in dogs receiving control diet (P = .79). Neither component of the primary outcome measure was significantly different between groups (LAD, P = .65; LVIDd, P = .92). No difference was found in mitral valve E wave velocity (P = .36) or the proportion of dogs withdrawn from the study because of worsening DMVD and heart enlargement (P = .41). CONCLUSIONS AND CLINICAL IMPORTANCE: Feeding a specially formulated diet for 365 days was not associated with a significantly different rate of change of left heart size in dogs with subclinical DMVD as compared to control.

Supplemental 25-hydroxycholecalciferol Alleviates Inflammation and Cardiac Fibrosis in Hens.

Broiler breeder hens with efficient feed conversion rate under restricted feed intake (R-hens) or allowed unlimited access to feed (Ad-hens) progressed with cardiac functional failure and suffered early sudden death. A supplement of 69 µg 25-hydroxycholecalciferol (25-OH-D3)/kg feed improved heart health and rescued livability in both R- and Ad-hens throughout laying stage (26-60 wks). Improvements occurred through cardiac hypertrophic remodeling, reduced arrhythmias, and pathological cues. Here, we further demonstrated consistently decreased circulating and cardiac IL-6 and IL-1ß levels in conjunction with reduced cardiac chemoattraction and leukocyte infiltration by 25-OH-D3 in Ad-hens and in R-hens at later time points (35 and 47 wks) (p < 0.05). Supplemental 25-OH-D3 also ameliorated cardiac fibrosis, endoplasmic reticulum (ER) stress, and autophagy, mostly in Ad-hens, as both collagen content and expression of COL3A1, as well as CCAAT box binding enhancer homologous protein (CHOP) and activating transcription factor 6 (ATF6), were consistently decreased, and suppression of microtubule-associated protein 1 light Chain 3 beta (LC3B) and Sequestosome 1 (SQSTM1) was rescued at 35 and 47 wks (p < 0.05). Vitamin D receptor-NF-κB signaling was shown to mediate these beneficial effects. The present results demonstrate that ER stress and autophagic processes along the sequence from inflammation to fibrotic changes contribute to pathological cardiac remodeling and functional compromise by Ad-feed intake. 25-OH-D3 is an effective anti-inflammatory and anti-fibrotic supplement to ameliorate cardiac pathogenesis in broiler breeder hens.

CSRP3 mediates polyphenols-induced cardioprotection in hypertension.

Berries contain bioactive polyphenols, whose capacity to prevent cardiovascular diseases has been established recently in animal models as well in human clinical trials. However, cellular processes and molecular targets of berries polyphenols remain to be identified. The capacity of a polyphenol-enriched diet (i.e., blueberries, blackberries, raspberries, strawberry tree fruits and Portuguese crowberries berries mixture) to promote animal survival and protect cardiovascular function from salt-induced hypertension was evaluated in a chronic salt-sensitive Dahl rat model. The daily consumption of berries improved survival of Dahl/salt-sensitive rats submitted to high-salt diet and normalized their body weight, renal function and blood pressure. In addition, a prophylactic effect was observed at the level of cardiac hypertrophy and dysfunction, tissue cohesion and cardiomyocyte hypertrophy. Berries also protected the aorta from fibrosis and modulated the expression of aquaporin-1, a channel involved in endothelial water and nitric oxide permeability. Left ventricle proteomics analysis led to the identification of berries and salt metabolites targets, including cystein and glycin-rich protein 3 (CSRP3), a protein involved in myocyte cytoarchitecture. In neonatal rat ventricular cardiomyocytes, CSRP3 was validated as a target of a berries-derived polyphenol metabolite, 4-methylcatechol sulfate, at micromolar concentrations, mimicking physiological conditions of human plasma circulation. Accordingly, siRNA silencing of CSRP3 and 4-methylcatechol sulfate pretreatment reversed cardiomyocyte hypertrophy and CSRP3 overexpression induced by phenylephrine. Our systemic study clearly supports the modulation of CSRP3 by a polyphenol-rich berries diet as an efficient cardioprotective strategy in hypertension-induced heart failure.

Pathological hypertrophy and cardiac dysfunction are linked to aberrant endogenous unsaturated fatty acid metabolism.

Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue.

Dietary capsaicin ameliorates pressure overload-induced cardiac hypertrophy and fibrosis through the transient receptor potential vanilloid type 1.

BACKGROUND: Dietary capsaicin plays a protective role in hypertension, atherosclerosis, obesity, and hyperlipidemia through activating the transient receptor potential vanilloid type 1 (TRPV1), a nonselective cation channel. This study was designed to investigate the role of capsaicin in cardiac hypertrophy and fibrosis in a pressure overload model. METHODS: TRPV1 knockout (KO) mice and their wild-type (WT) littermates, aged 8 weeks, were randomly divided into sham and aortic banding surgery groups and were fed with chow or chow plus capsaicin for 10 weeks. RESULTS: Dietary capsaicin significantly attenuates pressure overload-induced increase in heart weight index, enlargement of ventricular volume, decrease in cardiac function, and increase in cardiac fibrosis in WT mice. However, these effects of capsaicin were absent in TRPV1 KO mice. Additionally, capsaicin blunted pressure overload-induced upregulation of transforming growth factor ß, connective tissue growth factor, and the phosphorylation of Smad2/3 in WT mice but not in TRPV1 KO mice. Moreover, capsaicin attenuated pressure overload-induced overexpression of metalloproteinase (MMP)-2, MMP-9 and MMP-13 in WT mice but not in TRPV1 KO mice. Capsaicin also attenuated angiotensin II-induced proliferation of cardiac fibroblasts from mice with the TRPV1 channel. CONCLUSIONS: Our results suggest that dietary capsaicin protects against cardiac hypertrophy and fibrosis in pressure overload mice through TRPV1.

Dietary fish oil preserves cardiac function in the hypertrophied rat heart.

Regular fish or fish oil intake is associated with a low incidence of heart failure clinically, and fish oil-induced reduction in cardiac remodelling seen in hypertrophy models may contribute. We investigated whether improved cardiac energy efficiency in non-hypertrophied hearts translates into attenuation of cardiac dysfunction in hypertrophied hearts. Male Wistar rats (n 33) at 8 weeks of age were sham-operated or subjected to abdominal aortic stenosis to produce pressure-overload cardiac hypertrophy. Starting 3 weeks post-operatively to follow initiation of hypertrophy, rats were fed a diet containing 10 % olive oil (control) or 5 % fish oil (ROPUFA® 30 (17 % EPA, 10 % DHA))+5 % olive oil (FO diet). At 15 weeks post-operatively, ventricular haemodynamics and oxygen consumption were evaluated in the blood-perfused, isolated working heart. Resting and maximally stimulated cardiac output and external work were >60 % depressed in hypertrophied control hearts but this was prevented by FO feeding, without attenuating hypertrophy. Cardiac energy efficiency was lower in hypertrophy, but greater in FO hearts for any given cardiac mass. Coronary blood flow, restricted in hypertrophied control hearts, increased with increasing work in hypertrophied FO hearts, revealing a significant coronary vasodilator reserve. Pronounced cardiac dysfunction in hypertrophied hearts across low and high workloads, indicative of heart failure, was attenuated by FO feeding in association with membrane incorporation of n-3 PUFA, principally DHA. Dietary fish oil may offer a new approach to balancing the high oxygen demand and haemodynamic requirements of the failing hypertrophied heart independently of attenuating hypertrophy.

Quercetin-supplemented diets lower blood pressure and attenuate cardiac hypertrophy in rats with aortic constriction.

Quercetin (Q), a flavonoid found in berries and onions, can reduce blood pressure in hypertensive animals and inhibit signal transduction pathways in vitro that regulate cardiac hypertrophy. We hypothesized that quercetin could prevent cardiovascular complications in rats with abdominal aortic constriction (AAC). Rats consumed standard or Q-supplemented chow (1.5 g Q/kg chow) for 7 days before AAC or sham surgery (SHAM, n = 15; AAC, n = 15; SHAMQ, n = 15; AACQ, n = 14). Fourteen days after surgery, plasma and liver Q concentrations were elevated (P < 0.05) and hepatic lipid oxidation was reduced (P < 0.05) in Q-treated versus untreated rats. Carotid arterial blood pressure and cardiac hypertrophy were attenuated (P < 0.05), and cardiac protein kinase C betaII translocation was normalized (P < 0.05) in AACQ versus AAC. Expression of cardiac beta-myosin heavy-chain mRNA was also reduced in AACQ versus AAC (P < 0.05). However, extracellular regulated kinase 1/2 phosphorylation was similar in AAC versus AACQ. The level of aortic endothelial dysfunction (wire myography) was also similar between AAC and AACQ, in spite of reduced aortic thickening in AACQ. Importantly, Q-treated rats did not show any deleterious changes in myocardial function (echocardiography). Our data supports an antihypertensive and antihypertrophic effect of Q in vivo in the absence of changes concerning vascular and myocardial function.