Postprandial cardiac hypertrophy is sustained by mechanics, epigenetic, and metabolic reprogramming in pythons.

Constricting pythons, known for their ability to consume infrequent, massive meals, exhibit rapid and reversible cardiac hypertrophy following feeding. Our primary goal was to investigate how python hearts achieve this adaptive response after feeding. Isolated myofibrils increased force after feeding without changes in sarcomere ultrastructure and without increasing energy cost. Ca2+ transients were prolonged after feeding with no changes in myofibril Ca2+ sensitivity. Feeding reduced titin-based tension, resulting in decreased cardiac tissue stiffness. Feeding also reduced the activity of sirtuins, a metabolically linked class of histone deacetylases, and increased chromatin accessibility. Transcription factor enrichment analysis on transposase-accessible chromatin with sequencing revealed the prominent role of transcription factors Yin Yang1 and NRF1 in postfeeding cardiac adaptation. Gene expression also changed with the enrichment of translation and metabolism. Finally, metabolomics analysis and adenosine triphosphate production demonstrated that cardiac adaptation after feeding not only increased energy demand but also energy production. These findings have broad implications for our understanding of cardiac adaptation across species and hold promise for the development of innovative approaches to address cardiovascular diseases.

Beneficial Effects of Polyphenol-Rich Food Oils in Cardiovascular Health and Disease.

A variety of vegetable and fruit derived food oils are considered beneficial for human health due to their content of functional components including their positive effects in cardiovascular system. In addition to the favorable ratio of unsaturated versus saturated fatty acids, some of these oils include also other health beneficial compounds such as vitamins, minerals, pigments, enzymes and phenolic compounds. Particularly polyphenols have been documented to exert numerous positive effects in cardiovascular system including their anti-hypertensive, anti-atherogenic as well as cardio- and vasculo- protective effects in subjects suffering from various cardiovascular and cardiometabolic diseases, likely via their antioxidant, anti-inflammatory, anti-coagulant, anti-proliferative and anti-diabetic properties. However, it has not been proven so far whether the positive cardiovascular effects of polyphenol-rich food oils are, and to what measure, attributed to their phenolic content. Thus, the current review aims to summarize the main cardiovascular effects of major polyphenol-rich food oils including olive, flaxseed, soybean, sesame and coconut oils, and to uncover the role of their phenolic compounds in these effects.

UGCG modulates heart hypertrophy through B4GalT5-mediated mitochondrial oxidative stress and the ERK signaling pathway.

Mechanical pressure overload and other stimuli often contribute to heart hypertrophy, a significant factor in the induction of heart failure. The UDP-glucose ceramide glycosyltransferase (UGCG) enzyme plays a crucial role in the metabolism of sphingolipids through the production of glucosylceramide. However, its role in heart hypertrophy remains unknown. In this study, UGCG was induced in response to pressure overload in vivo and phenylephrine stimulation in vitro. Additionally, UGCG downregulation ameliorated cardiomyocyte hypertrophy, improved cardiomyocyte mitochondrial oxidative stress, and reduced the ERK signaling pathway. Conversely, UGCG overexpression in cardiomyocytes promoted heart hypertrophy development, aggravated mitochondrial oxidative stress, and stimulated ERK signaling. Furthermore, the interaction between beta-1,4-galactosyltransferase 5 (B4GalT5), which catalyses the synthesis of lactosylceramide, and UGCG was identified, which also functions as a synergistic molecule of UGCG. Notably, limiting the expression of B4GalT5 impaired the capacity of UGCG to promote myocardial hypertrophy, suggesting that B4GalT5 acts as an intermediary for UGCG. Overall, this study highlights the potential of UGCG as a modulator of heart hypertrophy, rendering it a potential target for combating heart hypertrophy.

Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade.

BACKGROUND: This study examined whether BI113823, a novel selective kinin B1 receptor antagonist can reverse established pulmonary arterial hypertension (PAH), prevent right heart failure and death, which is critical for clinical translation. METHODS: Left pneumonectomized male Wistar rats were injected with monocrotaline to induce PAH. Three weeks later, when PAH was well established, the rats received daily treatment of BI113823 or vehicle for 3 weeks. RESULTS: Treatment with BI113823 from day 21 to day 42 after monocrotaline injection reversed established PAH as shown by normalized values of mean pulmonary arterial pressure (mPAP). BI113823 therapy reversed pulmonary vascular remodeling, pulmonary arterial neointimal formation, and heart and lung fibrosis, reduced right ventricular pressure, right heart hypertrophy, improved cardiac output, and prevented right heart failure and death. Treatment with BI113823 reduced TNF-α and IL-1ß, and macrophages recruitment in bronchoalveolar lavage, reduced CD-68 positive macrophages and expression of proliferating cell nuclear antigen (PCNA) in the perivascular areas, and reduced expression of iNOS, B1 receptors, matrix metalloproteinase (MMP)-2 and MMP-9 proteins, and the phosphorylation of ERK1/2 and AKT in lung. Treatment with BI113823 reduced mRNA expression of ANP, BNP, ßMHC, CGTF, collange-I and IV in right heart, compared to vehicle treated controls. In human monocytes cultures, BI113823 reduced LPS-induced TNF-α production, MMP-2 and MMP-9 expression, and reduced TNF-α-induced monocyte migration. CONCLUSIONS: We conclude that BI113823 reverses preexisting severe experimental pulmonary hypertension via inhibition of macrophage infiltration, cytokine production, as well as down regulation of matrix metalloproteinase proteins.

miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density.

MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among others cardiac hypertrophy and atrial fibrillation. The aim of our study was to evaluate the impact of miR-221/222 on cardiac electrical remodeling. Cardiac miR expression was analyzed in a mouse model with altered electrocardiography parameters and severe heart hypertrophy. Next generation sequencing revealed 14 differentially expressed miRs in hypertrophic hearts, with miR-221 and -222 being the strongest regulated miR-cluster. This increase was restricted to cardiomyocytes and not observed in cardiac fibroblasts. Additionally, we evaluated the change of miR-221/222 in vivo in two models of pharmacologically induced heart hypertrophy (angiotensin II, isoprenaline), thereby demonstrating a stimulus-induced increase in miR-221/222 in vivo by angiotensin II but not by isoprenaline. Whole transcriptome analysis by RNA-seq and qRT-PCR validation revealed an enriched number of downregulated mRNAs coding for proteins located in the T-tubule, which are also predicted targets for miR-221/222. Among those, mRNAs were the L-type Ca2+ channel subunits as well as potassium channel subunits. We confirmed that both miRs target the 3'-untranslated regions of Cacna1c and Kcnj5. Furthermore, enhanced expression of these miRs reduced L-type Ca2+ channel and Kcnj5 channel abundance and function, which was analyzed by whole-cell patch clamp recordings or Western blot and flux measurements, respectively. miR-221 and -222 contribute to the regulation of L-type Ca2+ channels as well as Kcnj5 channels and, therefore, potentially contribute to disturbed cardiac excitation generation and propagation. Future studies will have to evaluate the pathophysiological and clinical relevance of aberrant miR-221/222 expression for electrical remodeling.

Fendrr involves in the pathogenesis of cardiac fibrosis via regulating miR-106b/SMAD3 axis.

Cardiovascular diseases (CVDs) is the first cause of death worldwide, generally exhibiting a high morbidity, high disability rate and high mortality especially in the elderly persons (>50 years old). Previously, extensive studies have demonstrated that cardiac fibrosis plays cardinal roles in the pathogenesis of CVDs. However, due to the unclear underlying mechanisms of cardiac fibrosis, its clinical intervention remains very lacking. Long non-coding RNAs (lncRNAs), a class of non-coding RNA but differing from microRNAs, are generally considered as transcripts with a length ranging 200 to 100 nucleotides. Recently, accumulating evidence showed that lncRNAs involve in the pathogenesis of cardiac fibrosis. Fendrr (FOXF1 adjacent non-coding developmental regulatory RNA), is a spliced long non-coding RNA transcribed bi-directionally with FOXF1 on the opposite strand. Fendrr has been demonstrated to be essential for normal development of the heart and body wall in mouse, and shows a good anti-fibrotic activity in pulmonary fibrosis. In this study, we aimed to explore the effects of Fendrr on cardiac fibrosis. Intriguingly, we first observed that lncRNA Fendrr was up-regulated in the heart tissues of transverse aortic constriction (TAC) induced cardiac fibrosis mouse models, determined by RT-QPCR. Loss-function of Fendrr significantly alleviated the cardiac fibrosis phenotypes induced by TAC, indicating that Fendrr is required for the pathogenesis of cardiac fibrosis. In mechanism, we demonstrated experimentally that Fendrr directly targeting miR-106b, by which the lncRNA promotes cardiac fibrosis (indicated by the elevation of Col1a1, Col3a1, CTGF and ACTA2 expression) in a miR-106b mediated manner. Collectively, our findings highlight the axis of Fendrr/miR-106b/Samd3 in the pathogenesis of cardiac fibrosis, which may be a promising target for clinical intervention target of cardiac fibrosis.

A Modified Formulation of Sutaehwan Ameliorates Menopausal Anxiety, Depression and Heart Hypertrophy in the VCD-Induced Menopausal Mouse Model.

Sutaehwan (STH) has been used in Korean medicine for the treatment of abortus habitualis such as fetal restlessness in the uterus. Previously, we reported that a modified formulation of STH, Sutaehwan-Gami, has phytoestrogen-like properties in an ovariectomized menopausal rat model. However, the therapeutic effects of STH and the precise mechanisms by which STH affects various menopausal symptoms remain poorly understood. The current study was designed to explore the effects of a modified form of STH on menopausal anxiety, depression and heart hypertrophy and its mechanisms in 4-vinylcyclohexene diepoxide (VCD)-induced menopausal mouse models. VCD-induced menopausal model mice were fed a modified form of STH, which contained water extract of 3 herbs (called STH_KP17001) at a dose of 100 or 300 mg/kg/d or as a positive control, estradiol at a dose of 0.2 mg/kg/d with standard mouse pellets for 13 weeks. The results show that STH_KP17001 significantly restored the VCD-induced weight reduction of uterine and ovary through the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) in the uterus and ovary. Moreover, STH_KP17001 showed slight proliferative effects and estrogen receptor α phosphorylation in MCF-7 cells. Treatment with STH_KP17001 reversed VCD-induced anxiety and depression through AMP-activated protein kinase (AMPK) activation and brain-derived neurotrophic factor (BDNF) expression in the cerebral cortex, while improving heart hypertrophy through inactivation of inhibitor of kappaB α (IκBα) in the heart. The results indicate that STH_KP17001 improves menopause-induced anxiety, depression and heart hypertrophy, implying its protective role for the management of menopausal symptoms.

Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2α.

BACKGROUND: Vascular occlusion and complex plexiform lesions are hallmarks of the pathology of severe pulmonary arterial hypertension (PAH) in patients. However, the mechanisms of obliterative vascular remodeling remain elusive; hence, current therapies have not targeted the fundamental disease-modifying mechanisms and result in only modest improvement in morbidity and mortality. METHODS AND RESULTS: Mice with Tie2Cre-mediated disruption of Egln1 (encoding prolyl-4 hydroxylase 2 [PHD2]; Egln1(Tie2)) in endothelial cells and hematopoietic cells exhibited spontaneous severe PAH with extensive pulmonary vascular remodeling, including vascular occlusion and plexiform-like lesions, resembling the hallmarks of the pathology of clinical PAH. As seen in patients with idiopathic PAH, Egln1(Tie2) mice exhibited unprecedented right ventricular hypertrophy and failure and progressive mortality. Consistently, PHD2 expression was diminished in lung endothelial cells of obliterated pulmonary vessels in patients with idiopathic PAH. Genetic deletions of both Egln1 and Hif1a or Egln1 and Hif2a identified hypoxia-inducible factor-2α as the critical mediator of the severe PAH seen in Egln1(Tie2) mice. We also observed altered expression of many pulmonary hypertension-causing genes in Egln1(Tie2) lungs, which was normalized in Egln1(Tie2)/Hif2a(Tie2) lungs. PHD2-deficient endothelial cells promoted smooth muscle cell proliferation in part through hypoxia-inducible factor-2α-activated CXCL12 expression. Genetic deletion of Cxcl12 attenuated PAH in Egln1(Tie2) mice. CONCLUSIONS: These studies defined an unexpected role of PHD2 deficiency in the mechanisms of severe PAH and identified the first genetically modified mouse model with obliterative vascular remodeling and pathophysiology recapitulating clinical PAH. Thus, targeting PHD2/hypoxia-inducible factor-2α signaling is a promising strategy to reverse vascular remodeling for treatment of severe PAH.

Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms.

Thrombospondin-4 (TSP-4) is a multidomain calcium-binding protein that has both intracellular and extracellular functions. As an extracellular matrix protein, it is involved in remodeling processes. Previous work showed that, in the cardiovascular system, TSP-4 expression is induced in the heart in response to experimental pressure overload and infarction injury. Intracellularly, it mediates the endoplasmic reticulum stress response in the heart. In this study, we explored the role of TSP-4 in hypertension. For this purpose, wild-type and TSP-4 knockout (Thbs4(-/-)) mice were treated with angiotensin II (ANG II). Hearts from ANG II-treated Thbs4(-/-) mice showed an exaggerated hypertrophic response. Interestingly, aortas from Thbs4(-/-) mice treated with ANG II showed a high incidence of aneurysms. In resistance arteries, ANG II-treated wild-type mice showed impaired endothelial-dependent relaxation. This was not observed in ANG II-treated Thbs4(-/-) mice or in untreated controls. No differences were found in the passive pressure-diameter curves or stress-strain relationships, although ANG II-treated Thbs4(-/-) mice showed a tendency to be less stiff, associated with thicker diameters of the collagen fibers as revealed by electron microscopy. We conclude that TSP-4 plays a role in hypertension, affecting cardiac hypertrophy, aortic aneurysm formation, as well as endothelial-dependent relaxation in resistance arteries.

Melatonin reduces cardiac remodeling and improves survival in rats with isoproterenol-induced heart failure.

Melatonin was previously shown to reduce blood pressure and left ventricular (LV) remodeling in several models of experimental heart damage. This study investigated whether melatonin prevents LV remodeling and improves survival in isoproterenol-induced heart failure. In the first experiment, four groups of 3-month-old male Wistar rats (12 per group) were treated for 2 wk as follows: controls, rats treated with melatonin (10 mg/kg/day) (M), rats treated with isoproterenol (5 mg/kg/day intraperitoneally the second week) (Iso), and rats treated with melatonin (2 wk) and isoproterenol (the second week) in corresponding doses (IsoM). In the second experiment, 30 rats were treated with isoproterenol and 30 rats with isoproterenol plus melatonin for a period of 28 days and their mortality was investigated. Isoproterenol-induced heart failure with hypertrophy of the left and right ventricles (LV, RV), lowered systolic blood pressure (SBP) and elevated pulmonary congestion. Fibrotic rebuilding was accompanied by alterations of tubulin level in the LV and oxidative stress development. Melatonin failed to reduce the weight of the LV or RV; however, it curtailed the weight of the lungs and attenuated the decline in SBP. Moreover, melatonin decreased the level of oxidative stress and of insoluble and total collagen and partly prevented the beta-tubulin alteration in the LV. Most importantly, melatonin reduced mortality and prolonged the average survival time. In conclusion, melatonin exerts cardioprotective effects and improves outcome in a model of isoproterenol-induced heart damage. The antiremodeling effect of melatonin may be of potential benefit in patients with heart failure.

Transesophageal Echocardiography in Healthy Young Adult Male Baboons (Papio hamadryas anubis): Normal Cardiac Anatomy and Function in Subhuman Primates Compared to Humans.

Implantable, viable tissue engineered cardiovascular constructs are rapidly approaching clinical translation. Species typically utilized as preclinical large animal models are food stock ungulates for which cross species biological and genomic differences with humans are great. Multiple authorities have recommended developing subhuman primate models for testing regenerative surgical strategies to mitigate xenotransplant inflammation. However, there is a lack of specific quantitative cardiac imaging comparisons between humans and the genomically similar baboons (Papio hamadryas anubis). This study was undertaken to translate to baboons transesophageal echocardiographic functional and dimensional criteria defined as necessary for defining cardiac anatomy and function in the perioperative setting. Seventeen young, healthy baboons (approximately 30 kg, similar to 5 year old children) were studied to determine whether the requisite 11 views and 52 measurement parameters could be reliably acquired by transesophageal echocardiography (TEE). The obtained measurements were compared to human adult normative literature values and to a large relational database of pediatric "normal heart" echo measurements. Comparisons to humans, when normalized to BSA, revealed a trend in baboons toward larger mitral and aortic valve effective orifice areas and much larger left ventricular muscle mass and wall thickness, but similar pulmonary and tricuspid valves. By modifying probe positioning relative to human techniques, all recommended TEE views except transgastric could be replicated. To supplement, two transthoracic apical views were discovered that in baboons could reliably replace the transgastric TEE view. Thus, all requisite echo views could be obtained for a complete cardiac evaluation in Papio hamadryas anubis to noninvasively quantify cardiac structural anatomy, physiology, and dimensions. Despite similarities between the species, there are subtle and important physiologic and anatomic differences when compared to human.

Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension.

Acid-sensing ion channel 1a (ASIC1a) is a voltage-independent, non-selective cation channel that conducts both Na+ and Ca2+. Activation of ASIC1a elicits plasma membrane depolarization and stimulates intracellular Ca2+-dependent signaling pathways in multiple cell types, including vascular smooth muscle (SM) and endothelial cells (ECs). Previous studies have shown that increases in pulmonary vascular resistance accompanying chronic hypoxia (CH)-induced pulmonary hypertension requires ASIC1a to elicit enhanced pulmonary vasoconstriction and vascular remodeling. Both SM and EC dysfunction drive these processes; however, the involvement of ASIC1a within these different cell types is unknown. Using the Cre-LoxP system to generate cell-type-specific Asic1a knockout mice, we tested the hypothesis that SM-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling, whereas EC-Asic1a opposes the development of CH-induced pulmonary hypertension. The severity of pulmonary hypertension was not altered in mice with specific deletion of EC-Asic1a (TekCre-Asic1a fl/fl). However, similar to global Asic1a knockout (Asic1a -/-) mice, mice with specific deletion of SM-Asic1a (MHCCreER-Asic1a fl/fl) were protected from the development of CH-induced pulmonary hypertension and right heart hypertrophy. Furthermore, pulmonary hypertension was reversed when deletion of SM-Asic1a was initiated in conditional MHCCreER-Asic1a fl/fl mice with established pulmonary hypertension. CH-induced vascular remodeling was also significantly attenuated in pulmonary arteries from MHCCreER-Asic1a fl/fl mice. These findings were additionally supported by decreased CH-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) from Asic1a -/- mice. Together these data demonstrate that SM-, but not EC-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling. Furthermore, these studies provide evidence for the therapeutic potential of ASIC1a inhibition to reverse pulmonary hypertension.

High Exogenous Antioxidant, Restorative Treatment (Heart) for Prevention of the Six Stages of Heart Failure: The Heart Diet.

The exact pathophysiology of heart failure (HF) is not yet known. Western diet, characterized by highly sweetened foods, as well as being rich in fat, fried foods, red meat and processed meat, eggs, and sweet beverages, may cause inflammation, leading to oxidative dysfunction in the cardiac ultra-structure. Oxidative function of the myocardium and how oxidative dysfunction causes physio-pathological remodeling, leading to HF, is not well known. Antioxidants, such as polyphenolics and flavonoids, omega-3 fatty acids, and other micronutrients that are rich in Indo-Mediterranean-type diets, could be protective in sustaining the oxidative functions of the heart. The cardiomyocytes use glucose and fatty acids for the physiological functions depending upon the metabolic requirements of the heart. Apart from toxicity due to glucose, lipotoxicity also adversely affects the cardiomyocytes, which worsen in the presence of deficiency of endogenous antioxidants and deficiency of exogenous antioxidant nutrients in the diet. The high-sugar-and-high-fat-induced production of ceramide, advanced glycation end products (AGE) and triamino-methyl-N-oxide (TMAO) can predispose individuals to oxidative dysfunction and Ca-overloading. The alteration in the biology may start with normal cardiac cell remodeling to biological remodeling due to inflammation. An increase in the fat content of a diet in combination with inducible nitric oxide synthase (NOSi) via N-arginine methyl ester has been found to preserve the ejection fraction in HF. It is proposed that a greater intake of high exogenous antioxidant restorative treatment (HEART) diet, polyphenolics and flavonoids, as well as cessation of red meat intake and egg, can cause improvement in the oxidative function of the heart, by inhibiting oxidative damage to lipids, proteins and DNA in the cell, resulting in beneficial effects in the early stage of the Six Stages of HF. There is an unmet need to conduct cohort studies and randomized, controlled studies to demonstrate the role of the HEART diet in the treatment of HF.

Selenium alleviates heart remodeling through Sirt1/AKT/GSK-3ß pathway.

Selenium, reported as an important medium for maintaining the body's homeostasis, acts to have multiple bioeffects including anti-inflammatory, anti-oxidant and anti-apoptosis effects. However, its role in heart failure still remains unclear. In this study, we explored the effects of selenium on heart failure and its possible mechanism. The heart failure models were induced by aortic banding and isoproterenol. H&E, TUNEL and PSR staining were performed to detect the degree of cardiomyocyte hypertrophy, apoptosis rates and heart fibrosis, respectively. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect different mRNA levels, and western blot was applied to assess the expressions of relative proteins. Immunofluorescence staining was used to evaluate α-SMA density. We first found that treatment of selenium alleviated heart fibrosis and the development of heart failure but not cardiomyocyte cross sectional areas. Besides, selenium improved heart levels of superoxide dismutase2 (SOD2), glutathione peroxidase (Gpx) and glutathione (GSH) and the activity of SOD, accompanied by decreased apoptosis rate. In addition, our in vitro study has shown that selenium reduced mRNA levels of collagen Ⅰ and collagen III, expressions of a-SMA, p-AKT/AKT and p-GSK-3ß/ GSK-3ß, apoptosis rates and reactive oxygen species (ROS) levels in H9C2 cardio-myoblasts treated with TGF-ß1. Moreover, the level of Sirt1 was found to be up-regulated by selenium which effects were weakened after the administration of small interfering RNA (siRNA)-Sirt1 or EX527 (inhibitor of Sirt1). Our current results have demonstrated that the protective effects of selenium on heart hypertrophy is through the regulation of Sirt1 and AKT/GSK-3ß pathway.

Effect of Isolated Obesity on Left Ventricular Function and Structure: A Single-Center Experience.

Background and objectives Obesity can increase cardiac mass and affect cardiac performance independently from other risk factors. Several studies have identified an association in patients who already have comorbidities, however, few studies focused on obesity as an isolated risk factor. This study aimed to assess the associations between isolated obesity and heart morphological and functional characteristics. Methods This was a cross-sectional study that recruited 114 patients referred for echocardiographic study in King Faisal Cardiac Center. Adult patients who had a body mass index (BMI) above 25 kg/m2 were included, while patients with comorbidities such as hypertension, diabetes mellitus, dyslipidemia, or those who use medications for chronic diseases were excluded from this study. Variables of interest that we collected were age, gender, weight, BMI, and those related to morphological and functional changes in the heart including left ventricular mass index (LVMI), LV end-diastolic volume, and left ventricular ejection fraction (LVEF). Results Most of the study participants (63.8%) were class II or class III obesity and about 80% were males. The mean ± SD of LVEF was 55.7% ± 2.8%, while the mean of the left ventricular mass index was 28.5±5.84. The mean of LV end-diastolic volume index (LVEDVI) was slightly higher among males than females (48.8±11.6 versus 46.4±11.7 ml/m2), however, this difference was not statistically significant (p-value= 0.395). There was no correlation between BMI and LVMI in females (R - 0.226, R2 0.05, P-value 0.37), while the LVMI was found to have a negative correlation between BMI and male gender that was significant (R - 0.292, R2 0.09, P-value 0.0052). It was found that there is no correlation between LVEF and BMI for males and females (male= R 0.093, R2 0.032, P-value 0.093; female= R 0.172, R2 0.029, P-value 0.434). With regards to the LVEDVI, there was a negative correlation between higher BMI and male gender that was significant (male= R - 0.396, R2 0.157, P-value 0.0001) while it was not significant in females (R -0.0298, R2 0.0009, P-value 0.893). Conclusions We have found that cardiac function is not affected by isolated obesity. However, indexed cardiac parameters like LVM and LV end diastolic volume were negatively correlated with higher BMI and positively correlated with relative wall thickness (RWT) only in males. This negative correlation might be one of the triggers to the development of obesity-induced cardiomyopathy.

Ivabradine improves survival and attenuates cardiac remodeling in isoproterenol-induced myocardial injury.

This study investigated whether ivabradine, a selective If current inhibitor reducing heart rate (HR), is able to improve survival and prevent left ventricular (LV) remodeling in isoproterenol-induced heart damage. Wistar rats were treated for 6 weeks: controls (n = 10), ivabradine (10 mg/kg/day orally; n = 10), isoproterenol (5 mg/kg/day intraperitoneally; n = 40), and isoproterenol plus ivabradine (n = 40). Isoproterenol increased mortality, induced hypertrophy of both ventricles and LV fibrotic rebuilding, and reduced systolic blood pressure (SBP). Ivabradine significantly increased survival rate (by 120%) and prolonged average survival time (by 20%). Furthermore, ivabradine reduced LV weight and hydroxyproline content in soluble and insoluble collagen fraction, reduced HR and attenuated SBP decline. We conclude that ivabradine improved survival in isoproterenol-damaged hearts.

Differential effect of high-fat, high-sucrose and combined high-fat/high-sucrose diets consumption on fat accumulation, serum leptin and cardiac hypertrophy in rats.

The consumption of high calorie-content diets is the first cause of obesity, probably the main health issue worldwide; however, the experimental evidences for evaluating the differential metabolic modifications of high-sucrose or high-fat diets are scare. We evaluated the metabolic outcomes of the obesity induced by the chronic consumption of high-sucrose (HS), high-fat (HF) or combined diets (HSHF), among the effect on the development of cardiac hypertrophy in Wistar rats. Rats from the HS, HF, and HSHS groups developed moderate obesity. Only the HS group showed increased triglycerides levels after four months. Increased leptin levels were observed in HS and HF groups without changes on cardiac hypertrophy; on the opposing, HSHF group presented hypertrophy without the changes in serum leptin. The three experimental groups showed a decreased expression of leptin receptors ObR-b. In our results, the kind of diet for the induction of obesity is relevant for the outcome of the pathological profile.

Left ventricular phosphorylation patterns of Akt and ERK1/2 after triiodothyronine intracoronary perfusion in isolated hearts and short-term in vivo treatment in Wistar rats.

OBJECTIVES: To determine the effects of triiodothyronine (T3) intracoronary perfusion in isolated hearts and short-term administration in rats on the left ventricular (LV) phosphorylation patterns of Akt and ERK1/2. MATERIALS AND METHODS: Cardiodynamic and hemodynamic parameters were evaluated in Langendorff-perfused hearts. Left ventricles were used for histomorphometric and Western blot analyses. Short-term hyperthyroidism was established by T3 (500 µg.kg-1.d-1; subcutaneous injection) for 1 (T31d), 3 (T33d), and 10 (T310d) days. RESULTS: Isolated hearts receiving T3 perfusion did not modify LV developed pressure, +dP/dtmax, -dP/dtmin, heart rate, and coronary perfusion pressure compared with vehicle-perfused hearts. P-ERK1/2 and p-Akt levels in LV tissues after 5, 15, or 60 min of T3 or vehicle perfusion were similar. Compared with their time-matched controls, isolated hearts of T33d and T310d rats exhibited LV hypertrophy and increased absolute values of +dP/dtmax and -dP/dtmin (i.e., positive inotropic and lusitropic effects). P-ERK1/2 decreased in LV tissues of T31d and T310d but not in those of T33d rats, and p-Akt levels augmented in left ventricles of T33d and stayed unaltered in those of T31d and T310d rats. CONCLUSION: T3 intracoronary perfusion did not alter cardiodynamics and hemodynamics nor influence the activation of Akt and ERK of normal hearts. Accordingly, the rapid non-genomic effects of T3 were not evident. Short-term T3 treatment provoked cardiac hypertrophy coincidental with increased LV function and associated with transient Akt activation and cyclic ERK1/2 inhibition; which implies activation of physiological hypertrophy signaling and deactivation of pathological hypertrophy signaling, respectively.

New Benzofuran N-Acylhydrazone Reduces Cardiovascular Dysfunction in Obese Rats by Blocking TNF-Alpha Synthesis.

INTRODUCTION: Diabetic obese patients are susceptible to the development of cardiovascular disease, including hypertension and cardiac dysfunction culminating in diabetic cardiomyopathy (DC), which represents a life-threatening health problem with increased rates of morbidity and mortality. The aim of the study is to characterize the effects of a new benzofuran N-acylhydrazone compound, LASSBio-2090, on metabolic and cardiovascular alterations in Zucker diabetic fatty (ZDF) rats presenting DC. METHODS: Male non-diabetic lean Zucker rats (ZL) and ZDF rats treated with vehicle (dimethylsulfoxide) or LASSBio-2090 were used in this study. Metabolic parameters, cardiovascular function, left ventricle histology and inflammatory protein expression were analyzed in the experimental groups. RESULTS: LASSBio-2090 administration in ZDF rats reduced glucose levels to 85.0 ± 1.7 mg/dL (p < 0.05). LASSBio-2090 also lowered the cholesterol and triglyceride levels from 177.8 ± 31.2 to 104.8 ± 5.3 mg/dL and from 123.0 ± 11.4 to 90.9 ± 4.8 mg/dL, respectively, in obese diabetic rats (p < 0.05). LASSBio-2090 normalized plasma insulin, insulin sensitivity and endothelial function in aortas from diabetic animals (p < 0.05). It also enhanced systolic and diastolic left-ventricular function and reverted myocardial remodeling by blocking the threefold elevation of TNF-α levels in hearts from ZDF rats. CONCLUSION: LASSBio-2090 alleviates metabolic disturbance and cardiomyopathy in an obese and diabetic rat model, thus representing a novel strategy for the treatment of cardiovascular complications in obesity-associated type 2 diabetes mellitus.

ß-Catenin Regulates Cardiac Energy Metabolism in Sedentary and Trained Mice.

The role of canonical Wnt signaling in metabolic regulation and development of physiological cardiac hypertrophy remains largely unknown. To explore the function of ß-catenin in the regulation of cardiac metabolism and physiological cardiac hypertrophy development, we used mice heterozygous for cardiac-specific ß-catenin knockout that were subjected to a swimming training model. ß-Catenin haploinsufficient mice subjected to endurance training displayed a decreased ß-catenin transcriptional activity, attenuated cardiomyocytes hypertrophic growth, and enhanced activation of AMP-activated protein kinase (AMPK), phosphoinositide-3-kinase-Akt (Pi3K-Akt), and mitogen-activated protein kinase/extracellular signal-regulated kinases 1/2 (MAPK/Erk1/2) signaling pathways compared to trained wild type mice. We further observed an increased level of proteins involved in glucose aerobic metabolism and ß-oxidation along with perturbed activity of mitochondrial oxidative phosphorylation complexes (OXPHOS) in trained ß-catenin haploinsufficient mice. Taken together, Wnt/ß-catenin signaling appears to govern metabolic regulatory programs, sustaining metabolic plasticity in adult hearts during the adaptation to endurance training.