Monika Duda

Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction

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.

ω-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential

Heart failure (HF) is a complex clinical syndrome with multiple aetiologies. Current treatment options can slow the progression to HF, but overall the prognosis remains poor. Clinical studies suggest that high dietary intake of the omega-3 polyunsaturated fatty acids (omega-3PUFA) found in fish oils (eicosapentaenoic and docosahexaenoic acids) may lower the incidence of HF, and that supplementation with pharmacological doses prolongs event-free survival in patients with established HF. The mechanisms for these potential benefits are complex and not well defined. It is well established that fish oil supplementation lowers plasma triglyceride levels, and more recent work demonstrates anti-inflammatory effects, including reduced circulating levels of inflammatory cytokines and arachidonic acid-derived eicosanoids, and elevated plasma adiponectin. In animal studies, fish oil favourably alters cardiac mitochondrial function. All of these effects may work to prevent the development and progression of HF. The omega-3PUFA found in plant sources, alpha-linolenic acid, may also be protective in HF; however, the evidence is not as compelling as for fish oil. This review summarizes the evidence related to use of omega-3PUFA supplementation as a potential treatment for HF and discusses possible mechanisms of action. In general, there is growing evidence that supplementation with omega-3PUFA positively impacts established pathophysiological targets in HF and has potential therapeutic utility for HF patients.

The Cardioprotective Effects of Fish Oil During Pressure Overload Are Blocked by High Fat Intake Role Of Cardiac Phospholipid Remodeling

Supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil may prevent development of heart failure through alterations in cardiac phospholipids that favorably impact inflammation and energy metabolism. A high-fat diet may block these effects in chronically stressed myocardium. Pathological left ventricle (LV) hypertrophy was generated by subjecting rats to pressure overload by constriction of the abdominal aorta. Animals were fed: (1) standard diet (10% of energy from fat), (2) standard diet with EPA+DHA (2.3% of energy intake as EPA+DHA), (3) high fat (60% fat); or (4) high fat with EPA+DHA. Pressure overload increased LV mass by ≈40% in both standard and high-fat diets without fish oil. Supplementation with fish oil increased their incorporation into cardiac phospholipids, and decreased the proinflammatory fatty acid arachidonic acid and urine thromboxane B2 with both the standard and high-fat diet. Linoleic acid and tetralinoloyl cardiolipin (an essential mitochondrial phospholipid) were decreased with pressure overload on standard diet, which was prevented by fish oil. Animals fed high-fat diet had decreased linoleic acid and tetralinoloyl cardiolipin regardless of fish oil supplemention. Fish oil limited LV hypertrophy on the standard diet, and prevented upregulation of fetal genes associated with heart failure (myosin heavy chain-β and atrial natriuetic factor). These beneficial effects of fish oil were absent in animals on the high-fat diet. In conclusion, whereas treatment with EPA+DHA prevented tetralinoloyl cardiolipin depletion, LV hypertrophy, and abnormal genes expression with pressure overload, these effects were absent with a high-fat diet.

Low Carbohydrate/High Fat Diet Attenuates Pressure Overload Induced Ventricular Remodeling and Dysfunction

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.

High-sugar diets increase cardiac dysfunction and mortality in hypertension compared to low-carbohydrate or high-starch diets

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 α to β, 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.

Preserved cardiomyocyte function and altered desmin pattern in transgenic mouse model of dilated cardiomyopathy

Taking advantage of the unique model of slowly developing dilated cardiomyopathy in mice with cardiomyocyte-specific transgenic overexpression of activated Gαq protein (Tgαq*44 mice) we analyzed the contribution of the cardiomyocyte malfunction, fibrosis and cytoskeleton remodeling to the development of heart failure in this model. Left ventricular (LV) in vivo function, myocardial fibrosis, cytoskeletal proteins expression and distribution, Ca(2+) handling and contractile function of isolated cardiomyocytes were evaluated at the stages of the early, compensated, and late, decompensated heart failure in 4-, 12- and 14-month-old Tgαq*44 mice, respectively, and compared to age-matched wild-type FVB mice. In the 4-month-old Tgαq*44 mice significant myocardial fibrosis, moderate myocyte hypertrophy and increased expression of regularly arranged and homogenously distributed desmin accompanied by increased phosphorylation of desmin chaperone protein, αB-crystallin, were found. Cardiomyocyte shortening, Ca(2+) handling and LV function were not altered. At 12 and 14 months of age, Tgαq*44 mice displayed progressive deterioration of the LV function. The contractile performance of isolated myocytes was still preserved, and the amplitude of Ca(2+) transients was even increased probably due to impairment of Na(+)/Ca(2+) exchanger function, while fibrosis was more extensive than in younger mice. Moreover, substantial disarrangement of desmin distribution accompanied by decreasing phosphorylation of αB-crystallin appeared. In Tgαq*44 mice disarrangement of desmin, at least partly related to inadequate phosphorylation of αB-crystallin seems to be importantly involved in the progressive deterioration of contractile heart function.

Low-density lipoprotein reduction by simvastatin is accompanied by angiotensin II type 1 receptor downregulation, reduced oxidative stress, and improved endothelial function in patients with stable coronary artery disease.

ObjectivesWe tested the hypothesis that low-density lipoprotein-cholesterol induces angiotensin II type 1 receptor upregulation that, in turn, accounts for enhanced oxidative stress, and the subsequent endothelial dysfunction in patients with coronary artery disease. MethodsBrachial artery flow-mediated vasodilation, serum 8-iso-prostaglandin F2&agr; (8-isoprostane), and angiotensin II type 1 receptor density on platelets were measured in 19 patients with coronary artery disease, at entry and after 12 weeks of simvastatin therapy, 40 mg/day. ResultsAt entry there was a significant linear correlation between: angiotensin II type 1 receptor density and plasma low-density lipoprotein-cholesterol; plasma 8-isoprostane and angiotensin II type 1 receptor density; and flow-mediated vasodilation and 8-isoprostane. Simvastatin therapy reduced low-density lipoprotein-cholesterol, downregulated angiotensin II type 1 receptor, decreased 8-isoprostane, and improved flow-mediated vasodilation. The slopes of the presimvastatin and the postsimvastatin angiotensin II type 1 receptor/low-density lipoprotein relationships did not significantly differ, indicating that simvastatin caused a downregulation of angiotensin II type 1 receptor that could be predicted by the low-density lipoprotein reduction. In addition, simvastatin-mediated changes in 8-isoprostane could be predicted by angiotensin II type 1 receptor downregulation, and flow-mediated vasodilation improvement by changes in 8-isoprostane. A significant correlation existed between simvastatin-mediated changes in 8-isoprostane and angiotensin II type 1 receptor. ConclusionThe results of this study are consistent with the hypothesis that in coronary artery disease, the impairment of endothelial function is strongly associated with oxidative stress, oxidative stress with cellular angiotensin II type 1 receptor density, and the angiotensin II type 1 receptor density with low-density lipoprotein-cholesterol, suggesting cause–effect relationships between these variables. In support for this notion, these baseline associations were not significantly disturbed by low-density lipoprotein-lowering therapy with simvastatin.

Ivabradine protects against ventricular arrhythmias in acute myocardial infarction in the rat.

Ventricular arrhythmias are an important cause of mortality in the acute myocardial infarction (MI). To elucidate effect of ivabradine, pure heart rate (HR) reducing drug, on ventricular arrhythmias within 24 h after non‐reperfused MI in the rat. ECG was recorded for 24 h after MI in untreated and ivabradine treated rats and episodes of ventricular tachycardia/fibrillation (VT/VF) were identified. Forty‐five minutes and twenty‐four hours after MI epicardial monophasic action potentials (MAPs) were recorded, cardiomyocyte Ca2+ handling was assessed and expression and function of ion channels were studied. Ivabradine reduced average HR by 17%. Combined VT/VF incidence and arrhythmic mortality were higher in MI versus MI + Ivabradine rats. MI resulted in (1) increase of Ca2+ sensitivity of ryanodine receptors 24 h after MI; (2) increase of HCN4 expression in the left ventricle (LV) and funny current (IF) in LV cardiomyocytes 24 h after MI, and (3) dispersion of MAP duration both 45 min and 24 h after MI. Ivabradine partially prevented all these three potential proarrhythmic effects of MI. Ivabradine is antiarrhythmic in the acute MI in the rat. Potential mechanisms include prevention of: diastolic Ca2+‐leak from sarcoplasmic reticulum, upregulation of IF current in LV and dispersion of cardiac repolarization. Ivabradine could be an attractive antiarrhythmic agent in the setting of acute MI. J. Cell. Physiol. 229: 813–823, 2014.

Omega-3 Fatty Acids Do Not Protect Against Arrhythmias in Acute Nonreperfused Myocardial Infarction Despite Some Antiarrhythmic Effects

Ventricular arrhythmias are an important cause of mortality in the acute myocardial infarction (MI). To elucidate the effect of the omega‐3 polyunsaturated fatty acids (PUFAs) on ventricular arrhythmias in acute nonreperfused MI, rats were fed with normal or eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA)‐enriched diet for 3 weeks. Subsequently the rats were subjected to either MI induction or sham operation. ECG was recorded for 6 h after the operation and episodes of ventricular tachycardia/fibrillation (VT/VF) were identified. Six hours after MI epicardial monophasic action potentials (MAPs) were recorded, cardiomyocyte Ca2+ handling was assessed and expression of proteins involved in Ca2+ turnover was studied separately in non‐infarcted left ventricle wall and infarct borderzone. EPA and DHA had no effect on occurrence of post‐MI ventricular arrhythmias or mortality. Nevertheless, DHA but not EPA prevented Ca2+ overload in LV cardiomiocytes and improved rate of Ca2+ transient decay, protecting PMCA and SERCA function. Moreover, both EPA and DHA prevented MI‐induced hyperphosphorylation of ryanodine receptors (RyRs) as well as dispersion of action potential duration (APD) in the left ventricular wall. In conclusion, EPA and DHA have no antiarrhythmic effect in the non‐reperfused myocardial infarction in the rat, although these omega‐3 PUFAs and DHA in particular exhibit several potential antiarrhythmic effects at the subcellular and tissue level, that is, prevent MI‐induced abnormalities in Ca2+ handling and APD dispersion. In this context further studies are needed to see if these potential antiarrhythmic effects could be utilized in the clinical setting. J. Cell. Biochem. 117: 2570–2582, 2016.

Cardiac and renal upregulation of Nox2 and NF‐κB and repression of Nox4 and Nrf2 in season‐ and diabetes‐mediated models of vascular oxidative stress in guinea‐pig and rat

The superoxide‐forming NADPH oxidase homologues, Nox1, Nox2, and Nox5, seem to mediate the pro‐atherosclerotic vascular phenotype. The hydrogen peroxide‐forming Nox4 afforded vascular protection, likely via NF‐E2‐related factor‐2 (Nrf2) activation and/or Nox2 downregulation in transgenic mice. We hypothesized that oxidative stress in the intact vasculature involves, aside from the upregulation of the superoxide‐forming Noxs, the downregulation of the Nox4/Nrf2 pathway. Guinea‐pigs and rats were studied either in winter or in summer, and the streptozotocin diabetic rats in winter. Plasma nitrite, and superoxide production by isolated hearts were measured, while frozen tissues served in biochemical analyses. Summer in both species and diabetes in rats downregulated myocardial Nox4 while reciprocally upregulating Nox2 and Nox5 in guinea‐pigs, and Nox2 in rats. Simultaneously, myocardial Nrf2 activity and the expression of the Nrf2‐directed heme oxygenase‐1 and endothelial NO synthase were reduced while activity of the nuclear factor κB (NF‐κB) and the expression of NF‐κB‐directed inducible NO synthase and the vascular cell adhesion molecule‐1 were increased. Cardiac superoxide production was increased while plasma nitrite was decreased reciprocally. Analogous disregulation of Noxs, Nrf2, and NF‐κB, occurred in diabetic rat kidneys. Given the diversity of the experimental settings and the uniform pattern of the responses, we speculate that: (1) chronic vascular oxidative stress is a nonspecific (model‐, species‐, organ‐independent) response involving the induction of Nox2 (and Nox5 in guinea‐pigs) and the NF‐κB pathway, and the repression of Nox4 and the Nrf2 pathway; and (2) the systems Nox2‐NF‐κB and Nox4‐Nrf2 regulate each other negatively.