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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. [ABSTRACT FROM AUTHOR]

Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that catalyzes formation of the first double bond in the carbon chain of saturated fatty acids. Four isoforms of SCD have been identified in mice, the most poorly characterized of which is SCD4, which is cardiac-specific. In the present study, we investigated the role of SCD4 in systemic and cardiac metabolism. We used WT and global SCD4 KO mice that were fed standard laboratory chow or a high-fat diet (HFD). SCD4 deficiency reduced body adiposity and decreased hyperinsulinemia and hypercholesterolemia in HFD-fed mice. The loss of SCD4 preserved heart morphology in the HFD condition. Lipid accumulation decreased in the myocardium in SCD4-deficient mice and in HL-1 cardiomyocytes with knocked out Scd4 expression. This was associated with an increase in the rate of lipolysis and, more specifically, adipose triglyceride lipase (ATGL) activity. Possible mechanisms of ATGL activation by SCD4 deficiency include lower protein levels of the ATGL inhibitor G0/G1 switch protein 2 and greater activation by protein kinase A under lipid overload conditions. Moreover, we observed higher intracellular Ca 2+ levels in HL-1 cells with silenced Scd4 expression. This may explain the activation of protein kinase A in response to higher Ca 2+ levels. Additionally, the loss of SCD4 inhibited mitochondrial enlargement, NADH overactivation, and reactive oxygen species overproduction in the heart in HFD-fed mice. In conclusion, SCD4 deficiency activated lipolysis, resulting in a reduction of cardiac steatosis, prevented the induction of left ventricular hypertrophy, and reduced reactive oxygen species levels in the heart in HFD-fed mice., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The incidence of life-threatening ventricular arrhythmias, the most common cause of sudden cardiac death (SCD), depends largely on the arrhythmic substrate that develops in the myocardium during the aging process. There is a large deficit of comparative studies on the development of this substrate in both sexes, with a particular paucity of studies in females. To identify the substrates of arrhythmia, fibrosis, cardiomyocyte hypertrophy, mitochondrial density, oxidative stress, antioxidant defense and intracellular Ca 2+ signaling in isolated cardiomyocytes were measured in the hearts of 3- and 24-month-old female and male rats. Arrhythmia susceptibility was assessed in ex vivo perfused hearts after exposure to isoproterenol (ISO) and hydrogen peroxide (H 2 O 2 ). The number of ventricular premature beats (PVBs), ventricular tachycardia (VT) and ventricular fibrillation (VF) episodes, as well as intrinsic heart rate, QRS and QT duration, were measured in ECG signals recorded from the surfaces of the beating hearts. After ISO administration, VT/VFs were formed only in the hearts of males, mainly older ones. In contrast, H 2 O 2 led to VT/VF formation in the hearts of rats of both sexes but much more frequently in older males. We identified several components of the arrhythmia substrate that develop in the myocardium during the aging process, including high spontaneous ryanodine receptor activity in cardiomyocytes, fibrosis of varying severity in different layers of the myocardium (nonheterogenic fibrosis), and high levels of oxidative stress as measured by nitrated tyrosine levels. All of these elements appeared at a much greater intensity in male individuals during the aging process. On the other hand, in aging females, antioxidant defense at the level of H 2 O 2 detoxification, measured as glutathione peroxidase expression, was weaker than that in males of the same age. We showed that sex has a significant effect on the development of an arrhythmic substrate during aging. This substrate determines the incidence of life-threatening ventricular arrhythmias in the presence of additional stimuli with proarrhythmic potential, such as catecholamine stimulation or oxidative stress, which are constant elements in the pathomechanism of most cardiovascular diseases., (© 2024. The Author(s).)

Hypertrophic cardiomyopathy is the most common cardiovascular disease, which is characterized by structural and functional myocardial abnormalities. It is caused predominantly by autosomal dominant mutations, mainly in genes encoding cardiac sarcomeric proteins, resulting in diverse phenotypical patterns and a heterogenic clinical course. Unconventional myosin VI (MVI) is one of the proteins important for heart function, as it was shown that a point mutation within MYO6 is associated with left ventricular hypertrophy. Previously, we showed that MVI is expressed in the cardiac muscle, where it localizes to the sarcoplasmic reticulum and intercalated discs. Here, we addressed the mechanisms of its involvement in cardiac dysfunction in Snell's waltzer mice (natural MVI knockouts) during heart development. We showed that heart enlargement was already seen in the E14.5 embryos and newborn animals (P0), and was maintained throughout the examined lifespan (up to 12 months). The higher levels of MVI were observed in the hearts of E14.5 embryos and P0 of control heterozygous mice. A search for the mechanisms behind the observed phenotype revealed several changes, accumulation of which resulted in age-progressing heart dysfunction. The main changes that mostly contribute to this functional impairment are the increase in cardiomyocyte proliferation in newborns, disorganization of intercalated discs, and overexpression of SERCA2 in hearts isolated from 12-month-old mice, indicative of functional alterations of sarcoplasmic reticulum. Also, possible aberrations in the heart vascularization, observed in 12-month-old animals could be additional factors responsible for MVI-associated heart dysfunction., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ANNA IZABELA GRABOWSKA reports financial support was provided by National Science Centre Poland. MARIA JOLANTA REDOWICZ reports financial support was provided by National Science Centre Poland., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Disturbances in cardiac lipid metabolism are associated with the development of cardiac hypertrophy and heart failure. Spontaneously hypertensive rats (SHRs), a genetic model of primary hypertension and pathological left ventricular (LV) hypertrophy, have high levels of diacylglycerols in cardiomyocytes early in development. However, the exact effect of lipids and pathways that are involved in their metabolism on the development of cardiac dysfunction in SHRs is unknown. Therefore, we used SHRs and Wistar Kyoto (WKY) rats at 6 and 18 weeks of age to analyze the impact of perturbations of processes that are involved in lipid synthesis and degradation in the development of LV hypertrophy in SHRs with age. Triglyceride levels were higher, whereas free fatty acid (FA) content was lower in the LV in SHRs compared with WKY rats. The expression of de novo FA synthesis proteins was lower in cardiomyocytes in SHRs compared with corresponding WKY controls. The higher expression of genes that are involved in TG synthesis in 6-week-old SHRs may explain the higher TG content in these rats. Adenosine monophosphate-activated protein kinase phosphorylation and peroxisome proliferator-activated receptor α protein content were lower in cardiomyocytes in 18-week-old SHRs, suggesting a lower rate of β-oxidation. The decreased protein content of α/β-hydrolase domain-containing 5, adipose triglyceride lipase (ATGL) activator, and increased content of G0/G1 switch protein 2, ATGL inhibitor, indicating a lower rate of lipolysis in the heart in SHRs. In conclusion, the present study showed that the development of LV hypertrophy and myocardial dysfunction in SHRs is associated with triglyceride accumulation, attributable to a lower rate of lipolysis and β-oxidation in cardiomyocytes., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Cardiac hypertrophy is accompanied by molecular remodeling that affects different cellular pathways, including fatty acid (FA) utilization. In the present study, we show that cardiac lipid metabolism is differentially regulated in response to physiological (endurance training) and pathological [abdominal aortic banding (AAB)] hypertrophic stimuli. Physiological hypertrophy was accompanied by an increased expression of lipogenic genes and the activation of sterol regulatory element-binding protein-1c and Akt signaling. Additionally, FA oxidation pathways regulated by AMP-activated protein kinase (AMPK) and peroxisome proliferator activated receptor-α (PPARα) were induced in trained hearts. Cardiac lipid content was not changed by physiological stimulation, underlining balanced lipid utilization in the trained heart. Moreover, pathological hypertrophy induced the AMPK-regulated oxidative pathway, whereas PPARα and expression of its downstream targets, i.e., acyl-CoA oxidase and carnitine palmitoyltransferase I, were not affected by AAB. In contrast, pathological hypertrophy leads to cardiac triglyceride (TG) and diacylglycerol (DAG) accumulation, although the expression of lipogenic genes and the levels of FA transport proteins (CD36 and FATP) were not changed or reduced compared with the sham group. A possible explanation for this phenomenon is a decrease in lipolysis, as evidenced by the increased content of adipose triglyceride lipase inhibitor G0S2, the increased phosphorylation of hormone-sensitive lipase at Ser(565), and the decreased protein levels of DAG lipase that attenuate TG and DAG contents. The increased TG and DAG accumulation observed in AAB-induced hypertrophy might have lipotoxic effects, thereby predisposing to cardiomyopathy and heart failure in the future.

Polyunsaturated fatty acids omega-3 (PUFA omega-3), in particular eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), are bioactive lipids that positively impact signaling pathways involved in the development of cardiovascular diseases. PUFA omega-3 affect a myriad of molecular pathways, including alteration physical and chemical properties of membrane microdomains, modulation of membrane receptors and channels, regulation of gene expression via nuclear receptors and transcription factors and changes in eicosanoid clasess' profiles and conversion of EPA and DHA to proresolving mediators. This review summarizes our current knowledge regarding the mechanism of cardioprotective action of PUFA omega-3.

Despite aggressive pharmacotherapy, heart failure is still clinical problem. Current therapies improve clinical symptoms and slow progression to heart failure, but overall the prognosis remains poor. Evidence from epidemiological, clinical and experimental studies indicates a beneficial role of the omega-3 polyunsaturated fatty acids (omega-3 PUFA) found in fish oils in the prevention and management of heart failure. Although the mechanisms is still unclear, clinical and animals studies indicate that the benefits of omega-3 PUFA may be attributed to a number of distinct biological effects on lipoprotein metabolism, inflammation response and mitochondrial function. This review summarise the data related to use of omega-3 PUFA supplementation as a potential treatment for heart failure and discussed possible mechanism of action.

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.

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 approximately 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 B(2) 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 supplementation. Fish oil limited LV hypertrophy on the standard diet, and prevented upregulation of fetal genes associated with heart failure (myosin heavy chain-beta 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.

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.

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 omega-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.

Background: Chronic hypertension leads to cardiac hypertrophy, heart failure, and premature death. Little is known about the impact of dietary macronutrient composition on hypertension-induced cardiac hypertrophy and mortality. We investigated the effects of consuming either a high complex carbohydrate diet, a high simple sugar diet, or a high fat diet on cardiac hypertrophy and mortality in hypertensive Dahl salt-sensitive (DSS) rats., Methods: Rats were assigned to four diets: complex carbohydrate (CC; 70% starch, 10% fat, 20% protein by energy), high fat (FAT; 20% carbohydrates, 60% fat, 20% protein), high fructose (FRU; 70% fructose, 10% fat, 20% protein), and "western" (WES; 35% fructose, 45% fat, 20% protein). Hypertension was initiated by adding 6% NaCl (+S) to the chow of half the animals within each diet (n = 10 to 13/group). Tail cuff blood pressure measurements were assessed after 5 and 11 weeks of treatment, and echocardiography were assessed after 12 weeks of treatment., Results: All rats fed a high salt diet had similar levels of hypertension (CC+S 220 +/-2 mm Hg, FAT+S 221 +/- 3 mm Hg, FRU+S 221 +/- 1 mm Hg, WES+S 226 +/- 3 mm Hg). Echocardiography results show that the addition of salt to FRU resulted in increased regional wall thickness that was not observed in other dietary groups. All rats fed a low salt diet (CC, FAT, FRU, WES) and the FAT+S group survived 90 days. On the other hand, there was 90-day mortality in the WES+S group (18% mortality) and the CC+S group (30% mortality). In addition, FRU+S rats started dying after 45 days of salt feeding, and only 15% survived the full 90 days., Conclusions: These results demonstrate that a high fructose diet consumed during hypertension increases mortality and left ventricular (LV) wall thickness compared to either a high fat, high starch, or a "western" diet.

Currently, a high carbohydrate/low fat diet is recommended for patients with hypertension; however, the potentially important role that the composition of dietary fat and carbohydrate plays in hypertension and the development of pathological left ventricular hypertrophy (LVH) has not been well characterized. Recent studies demonstrate that LVH can also be triggered by activation of insulin signaling pathways, altered adipokine levels, or the activity of peroxisome proliferator-activated receptors (PPARs), suggesting that metabolic alterations play a role in the pathophysiology of LVH. Hypertensive patients with high plasma insulin or metabolic syndrome have a greater occurrence of LVH, which could be due to insulin activation of the serine-threonine kinase Akt and its downstream targets in the heart, resulting in cellular hypertrophy. PPARs also activate cardiac gene expression and growth and are stimulated by fatty acids and consumption of a high fat diet. Dietary intake of fats and carbohydrate and the resultant effects of plasma insulin, adipokine, and lipid concentrations may affect cardiomyocyte size and function, particularly in the setting of chronic hypertension. This review discusses potential mechanisms by which dietary carbohydrates and fats ca affect cardiac growth, metabolism, and function, mainly in the context of pressure overload-induced LVH.