AIMS Clinical studies suggest that intake of omega-3 polyunsaturated fatty acids (omega-3 PUFA) may lower the incidence of heart failure. Dietary supplementation with omega-3 PUFA exerts metabolic and anti-inflammatory effects that could prevent left ventricle (LV) pathology; however, it is unclear whether these effects occur at clinically relevant doses and whether there are differences between omega-3 PUFA from fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and vegetable sources [alpha-linolenic acid (ALA)]. METHODS AND RESULTS We assessed the development of LV remodelling and pathology in rats subjected to aortic banding treated with omega-3 PUFA over a dose range that spanned the intake of humans taking omega-3 PUFA supplements. Rats were fed a standard food or diets supplemented with EPA+DHA or ALA at 0.7, 2.3, or 7% of energy intake. Without supplementation, aortic banding increased LV mass and end-systolic and -diastolic volumes. ALA supplementation had little effect on LV remodelling and dysfunction. In contrast, EPA+DHA dose-dependently increased EPA and DHA, decreased arachidonic acid in cardiac membrane phospholipids, and prevented the increase in LV end-diastolic and -systolic volumes. EPA+DHA resulted in a dose-dependent increase in the anti-inflammatory adipokine adiponectin, and there was a strong correlation between the prevention of LV chamber enlargement and plasma levels of adiponectin (r = -0.78). Supplementation with EPA+DHA had anti-aggregatory and anti-inflammatory effects as evidenced by decreases in urinary thromboxane B(2) and serum tumour necrosis factor-alpha. CONCLUSION Dietary supplementation with omega-3 PUFA derived from fish, but not from vegetable sources, increased plasma adiponectin, suppressed inflammation, and prevented cardiac remodelling and dysfunction under pressure overload conditions.

Adenylyl cyclase (AC) is the effective enzyme in the beta‐adrenergic receptor signaling cascade coupled with the G‐protein. AC type 5 knockout mouse (AC5KO) is a new mouse model of longevity with increased median lifespan of ~30%. Caloric restriction (CR) is the most established mechanism of longevity, which occurs through modifications in metabolism. We examined these features in AC5KO mice determining their metabolic rate at rest and during exercise. Male AC5KO mice (n=6) and wild type (WT) mice (n=6) were exercised on a treadmill. Food intake was greater in AC5KO than WT, 3.7±0.1 vs 3.1±0.1g/day (p<0.05), respectively, whereas their body weight (BW) tended to be lower (29±1 vs 33±2g, p<0.05). Oxygen consumption (VO2)and CO2 production (VCO2) were similar in both groups (56±2 vs 51±3ml/kg/min; 43±2 vs 38±3ml/kg/min). AC5KO mice ran significantly longer (834±107 vs 578±42m; p=0.05) and performed more work than WT (38±3 vs 26±2m.kg; p<0.05). RERmax, an indicator of metabolic substrate utilization, decreased in the AC5KO group (0.92±0.02 vs 0.96±0.02; p<0.05). Thus, AC5KO not only results in increased longevity, but also enhanced exercise performance. This occurs in the face of increased food intake, and reduced body weight, suggesting that a common feature of this model of longevity and the CR model is an alteration in metabolism.

Objective Sugar consumption affects insulin release and, in hypertension, may stimulate cardiac signaling mechanisms that accelerate left ventricular hypertrophy and the development of heart failure. We investigated the effects of high-fructose or sucrose diets on ventricular function and mortality in hypertensive Dahl salt-sensitive rats.Methods Rats were fed chows that were either high starch (70% starch, 10% fat by energy), high fat (20% carbohydrates, 60% fat), high fructose (61% fructose, 9% starch, 10% fat), or high sucrose (61% sucrose, 9% starch, 10% fat). Hypertension was induced by adding 6% salt to the chow (n=8-11/group).Results After 8 weeks of treatment, systolic blood pressure and left ventricular mass were similarly increased in all rats that were fed high-salt diets. Hypertension caused a switch in mRNA myosin heavy chain isoform from alpha to beta, and this effect was greater in the high-salt sucrose and fructose groups than in starch and fat groups. The cardiac mRNA for atrial natriuretic factor was also increased in all high-salt groups compared to respective controls, with the increase being significantly greater in the hypertensive sucrose fed group. Mortality was greater in the sucrose group (44%) compared to all the other hypertensive groups (12-18%), as was cardiomyocyte apoptosis. Left ventricular ejection fraction was lower in the high-salt sucrose group, which was due to an increase in end-systolic volume, and not increased end-diastolic volume.Conclusion Diets high in sugar accelerated cardiac systolic dysfunction and mortality in hypertension compared to either a low-carbohydrate/high-fat or high-starch diet.

Background: It is not known how carbohydrate and fat intake affect the development of left ventricular (LV) hypertrophy and contractile dysfunction in response to pressure overload. We hypothesized that a low-carbohydrate/high-fat diet prevents LV hypertrophy and dysfunction compared with high-carbohydrate diets.Methods and Results: Rats were fed high-carbohydrate diets composed of either starch or sucrose, or a low-carbohydrate/high-fat diet, and underwent abdominal aortic banding (AAB) for 2 months. AAB increased LV mass with all diets. LV end-diastolic and systolic volumes and the ratio of the mRNA for myosin heavy chain beta/alpha were increased with both high-carbohydrate diets but not with the low-carbohydrate/ high-fat diet. Circulating levels of insulin and leptin, both stimulants for cardiac growth, were lower, and free fatty acids were higher with the low-carbohydrate/high-fat diet compared with high-carbohydrate diets. Among animals that underwent AAB, LV volumes were positively correlated with insulin and LV mass correlated with leptin.Conclusion: A low-carbohydrate/high-fat diet attenuated pressure overload-induced LV remodeling compared with high-carbohydrate diets. This effect corresponded to lower insulin and leptin concentrations, suggesting they may contribute to the development of LV hypertrophy and dysfunction under conditions of pressure overload.

The need to assess heart failure at an early stage highlights the importance of accurate microarray analysis using small tissue samples. To test our ability to obtain high quality RNA from biopsy-sized cardiac specimens, amplification was performed on RNA from biopsy-sized samples of left ventricle (LV) tissue from one explanted failing human heart and one non-failing heart. Two methods were used: one-cycle (1C) amplification of 1.6 μg of RNA, and two-cycle (2C) amplification of 50 ng of RNA. The resulting cRNA was hybridized to Affymetrix GeneChip® arrays. Over 65% of all differentially expressed genes for failing vs non-failing hearts were concordant between 1C and 2C RNA amplification. Differentially expressed genes between 1C and 2C RNA amplification in our study were highly correlated (R2 = 0.957 and changes in gene expression agreed with prior studies on genes and heart failure; e.g., decreased α-myosin heavy chain and α-tropomyosin, as well as increased expression of insulin-like growth factor). Two cycles of amplification from cardiac biopsies will permit accurate transcription profiling of heart failure at pre-symptomatic stages. Ability to measure gene expression from nanogram amounts of RNA will provide new opportunities to predict progression to symptomatic heart failure, and to identify potential targets for therapy.

Objective: Epidemiological studies suggest that consumption of omega-3 polyunsaturated fatty acids (omega-3 PUFA) decreases the risk of heart failure. We assessed the effects of dietary supplementation with w-3 PUFA from fish oil on the response of the left ventricle (LV) to arterial pressure overload. Methods: Male Wistar rats were fed a standard chow or a omega-3 PUFA-supplemented diet. After 1 week rats underwent abdominal aortic banding or sham surgery (n=9-12/group). LV function was assessed by echocardiography after 8 weeks. In addition, we studied the effect of omega-3 PUFA on the cardioprotective adipocyte-derived hormone adiponectin, which may alter the pro-growth serine-threonine kinase Akt. Results: Banding increased LV mass to a greater extent with the standard chow (31%) than with omega-3 PUFA (18%). LV end diastolic and systolic volumes were increased by 19% and 105% with standard chow, respectively, but were unchanged with omega-3 PUFA. The expression of adiponectin was up-regulated in adipose tissue, and the plasma adiponectin concentration was significantly elevated. Treatment with omega-3 PUFA increased total Akt protein expression in the heart, but decreased the fraction of Akt in the active phosphorylated form, and thus did not alter the amount of active phospho-Akt. Conclusion: Dietary supplementation with omega-3 PUFA attenuated pressure overload-induced LV dysfunction, which was associated with elevated plasma adiponectin. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Consumption of fish oil (enriched in ω-3 polyunsaturated fatty acids (PUFA)) is associated with lower incidence of cardiovascular diseases, however the mechanism is still unknown. Recently, it has been reported that adiponectin, a cytokine released from adipose tissue, has protective effect on the heart under conditions of arterial pressure overload. In this study we tested the hypothesis that PUFA consumption protects against pressure overload-induced left ventricular hypertrophy (LVH) through enhanced adiponectin signaling. Forty-two male adult Wistar rats were randomly divided into groups fed with either standard rodent chow (NC) or chow supplemented with PUFA, and underwent either abdominal aortic constriction (band) or sham surgery. At 8 weeks after surgery, their cardiac function was assessed by echocardiogram, prior to euthanasia and tissue harvest. Left ventricular end-systolic volume (LVESV) and end-diastolic volume (LVEDV) were significantly increased in NC-band group (19% and 203%, vs. NC-sham, respectively; p < 0.05); indicating impaired contractile function, whereas in the PUFA groups both indices remained unchanged. LVH, as illustrated by the LV/body weight ratio, was present in both NC-band and PUFA-band groups (31% and 18% increase vs. respective shams; p < 0.05), however to a much reduced level in the latter (p < 0.05). The PUFA group also had significantly increased level of plasma adiponectin (9.2 ± 0.4 vs. 6.8 ± 0.3 μg/ml), as well as a 3-fold increase in adiponectin mRNA in abdominal adipose tissue (p < 0.05). The myocardial mRNA and protein expression of adiponectin receptor 1 and 2 were not changed. Myocardial Akt content was significantly increased in the PUFA groups, whereas AMPK, a putative metabolic regulator downstream of adiponectin, was not changed. Taken together, our data demonstrate that dietary PUFA induces higher expression and release of adiponectin from abdominal adipose tissue, which improves hypertrophy and protects cardiac function in response to pressure overload, and suggest that PUFA supplementation may be effective in the prevention and treatment of heart failure in hypertension.

Little consideration has been given to macronutrient composition in development of pressure-overload LV hypertrophy and dysfunction. This study assessed the effects of dietary macronutrients on cardiac function in response to pressure overload. Dahl salt-sensitive rats were fed either: high starch/low fat chow (70% carb/10% fat by energy); low carb/high fat (20% carb/60% fat), or high sucrose/low fat chow (70% sucrose/10% fat); with either low or high salt (LS/HS). After 8-week treatment, BP and LV mass increased with HS (p<0.05), but mortality increased only with high sucrose (44%) vs. all other groups (0–18%), (p<0.05). Hypertension (HTN) raised mRNA levels for atrial natriuretic factor (7.9±1.7-fold), which was further elevated in sucrose/HS vs. all other HS (10.5±1.5-fold, p<0.05). Myosin heavy-chain β/α ratio increased in high-starch/HS (4.3±1.4-fold) and sucrose/HS (10.9±3.3-fold), with a further elevation with sucrose/HS vs. all other HS (p<0.05). Ejection fraction decreased and end systolic volume increased with sucrose/HS vs. LS (84±1 to 73±4%; 0.09±0.01 to 0.18±0.02 mL, respectively, p<0.05), but was unaffected in high-starch/HS or high-fat/HS. Cardiomyocyte (CM) apoptosis increased with sucrose/HS (0.14±0.04 to 0.26±0.04 cells per 1000, p<0.05 vs. LS). In conclusion, high-sucrose feeding in pressure overload triggered pathological LV hypertrophy as seen in increased CM apoptosis and contractile dysfunction. In contrast, LV cardiac function was preserved during pressure overload with high-starch or high-fat feeding, suggesting a compensatory hypertrophic response.

Introduction: Transcription profiling can uncover genetic fingerprints for diseases such as cancer and heart failure. However, gene array experiments are limited by the amount of tissue obtained. The ability to assess heart failure at an early stage highlights the importance of accurate microarray analysis using small tissue samples. Hypothesis: After two rounds of amplification, RNA from failing (F) and non-failing (NF) human hearts produces similar gene expression profiles to those obtained using RNA from one-round of amplification. Methods: RNA amplification was performed on total RNA samples obtained from biopsy-sized samples of left ventricle from ventricle from two explanted human hearts, one failing and one non-failing. Two methods were used: one-cycle (1C) RNA amplification of 1.6μg of RNA, and two-cycle (2C) amplification of 50ng of RNA. Each method was performed 3 times for each heart. The amplified RNA was hybridized to individual Affymetrix GeneChip® U133 Plus 2.0 arrays. Gene profiles from F and NF hearts were compared based on amplification protocol. Patient or guardian consent was received. Results: A comparison of gene expression of the F hearts vs NF heart revealed that 90% of the genes which showed the greatest differential expression from 1C RNA amplification were also differentially-expressed by >2-fold using RNA from 2C amplification. In addition, 43-46% of all differentially-expressed genes in the F vs NF hearts using 1C RNA amplification were also differentially-expressed with 2C RNA amplification. No genes were found to be expressed in opposing directions between 1C and 2C RNA amplification. Differential gene expression using 2C amplification in our study agreed with other studies on genes and heart failure, such as; decreased α-myosin heavy chain, decreased Ca2+-transporting ATPase, and increased insulin-like growth factor. Conclusions: Amplification of RNA from cardiac biopsies permits accurate transcription profiling of heart failure at a pre-symptomatic stage. This has the potential to assist researchers in predicting progression to symptomatic heart failure, and to identify pathways that are potential targets for therapy.