Effect of sacubitril/valsartan on inflammation and oxidative stress in doxorubicin-induced heart failure model in rabbits

Our study evaluates the effects of sacubitril/valsartan (SAC/VAL) in the rabbit model of doxorubicin-induced heart failure. Twenty rabbits (5 per group) were administered with doxorubicin (DOX, 1.5 mg kg−1, i.v.) to induce heart failure. Specific biomarkers such as BNP, CnT, CRP and ROMs were determined. The cardiac enzymatic anti-oxidant systems were recorded with their electrographic profiles. HR, SBP, DBP and MAP were restored at 5 or 10 mg kg−1 (p.o.) of SAC/VAL compared to DOX, followed by reduced levels of creatinine and BNP (p < 0.001). Significant improvements (p < 0.05) compared to DOX were also noticed in CAT, SOD and LPO with the same doses of SAC/VAL. Specific biomarkers such as BNP, CnT, CRP and ROMs descended significantly (p < 0.001) with treatment when compared to their baseline values. Our findings implied that SAC/VAL treatment reduced the inflammation and oxidative stress to improve the cardiac function.

The vasculature: a therapeutic target in heart failure?

It is well established that the vasculature plays a crucial role in maintaining oxygen and nutrients supply to the heart. Increasing evidence further suggests that the microcirculation has additional roles in supporting a healthy microenvironment. Heart failure is well known to be associated with changes and functional impairment of the microvasculature. The specific ablation of protective signals in endothelial cells in experimental models is sufficient to induce heart failure. Therefore, restoring a healthy endothelium and microcirculation may be a valuable therapeutic strategy to treat heart failure. This review article will summarize the current understanding of the vascular contribution to heart failure with reduced or preserved ejection fraction. Novel therapeutic approaches including next generation pro-angiogenic therapies and non-coding RNA therapeutics, as well as the targeting of metabolites or metabolic signalling, vascular inflammation and senescence will be discussed.

Investigating the Cardiac effects of New Generation Anti-Diabetic Drug Empagliflozin using Zebrafish Embryo Model

Type 2 diabetes mellitus (T2DM) affects >16% of adults in Qatar. Newly emerging class of antidiabetic drugs focused on SGLT inhibition were observed to reduce CVDs risks in diabetic patients. Up to date, the mechanism contributing to the CV benefits remains unrevealed. Zebrafish embryos were treated with Aristolochic Acid to induce heart failure then treated with Empagliflozin to determine its beneficial effect. Furthermore the expression of SGLT1 & 2 were determined in the hearts of zebrafish. SGLT2 was expressed more then SGLT1 in the heart and whole embryo. Empa significantly improved the zebrafish embryo'scardiachealthafterinductionofheartfailure.

Cardiac Protection of Valsartan on Juvenile Rats with Heart Failure by Inhibiting Activity of CaMKII via Attenuating Phosphorylation

Background. This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods. Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO). Simultaneously, the sham-operated rats were randomly given valsartan (Sham + Val) or placebo (Sham + PBO). After 4 weeks of treatment, Western blot analysis was employed to quantify CaMKII and relative calcium handling proteins (RyR2 and PLN) in all groups. Results. The deteriorated cardiac function was reversed by valsartan treatment. In ventricular muscle cells of group HF + PBO, Thr287 phosphorylation of CaMKII and S2808 phosphorylation of RyR2 and PLN were increased and S16 phosphorylation of PLN was decreased compared to the other groups, while Met281 oxidation was not significantly elevated. In addition, these changes in the expression of calcium handling proteins were ameliorated by valsartan administration. Conclusions. The phosphorylation of Thr286 is associated with the early activation of CaMKII rather than the oxidation of Met281.

Cardiotoxic effects of pavetamine extracted from Pavetta harborii in the rat

Previous studies have shown that crude extracts from Pavetta harborii as well as dried plant material have cardiotoxic effects on rats and sheep that can lead to heart failure. The active component has since been isolated and identified. This substance has been named pavetamine. The aim of this study was to determine whether pavetamine has cardiotoxic effects similar to those seen in previous reports, when administered to rats intraperitoneally. Sprague Dawley rats received two doses, initially 4 mg / kg and then 3 mg / kg pavetamine respectively and were monitored for 35 days before cardiodynamic parameters were measured by inserting a fluid-filled catheter into the left ventricle via the right carotid artery. These values were compared to those of control rats that had received only saline. Pavetamine significantly reduced systolic function and body mass in the treated rats, which indicates that it has the potential to induce heart failure in this animal model.

Comparison of isoproterenol and dobutamine in the induction of cardiac hypertrophy and fibrosis

Isoproterenol (Iso) was a clinical therapeutic that is now used as a research means for the induction of cardiac hypertrophy. Currently, dobutamine (Dob) has replaced Iso as the preferred inotropic β-adrenergic agent to wean patients from cardiopulmonary bypass and to sustain adequate cardiac function during the postoperative period. We sought to compare the cardiac structural and functional effects of long-term administration (7days) of Iso with Dob at a dose of 40μg/mouse/day in 12-week-old C57BL/6 female mice. Cardiac function was determined with transthoracic echo cardiography (ECHO) 24 hours after the last dose. Cardiac wet weights increased 33% and 24% in the Iso and Dob groups compared with controls ( p < 0.05). Dob and Iso significantly increased cardiac fibrosis and decreased cardiac function with chronic administration. Administration also resulted in increased left atrial size, suggesting that both Dob and Iso decreased LV compliance, but did not induce heart failure. In conclusion, chronic administration of Dob may have a detrimental effect on cardiac structure and function.

Effects of induced hyperthyroidism in normal and cardiomyopathic hamsters

Thyroid hormones (TH) enhance cardiac function and reverse gene changes typical of pathological hypertrophy. However, reports in humans, but not animals, indicate that excess TH can cause heart failure. Also, the effects of TH on normal and cardiomyopathic hearts are likely to be different. The goal of this study was to characterize the effects of prolonged hyperthyroidism on cardiac function, chamber and cellular remodeling, and protein expression in both normal and cardiomyopathic hearts. Hyperthyroidism was induced in 3-mo-old normal BIO F1B and dilated cardiomyopathic BIO TO2 hamsters. After TH treatment for 10 days and 2 mo, hemodynamics, echos, myocyte length, histology, and protein expression were assessed. After 10 days and 2 mo, there were no differences between TO2-treated (Tx) and TO2-untreated (Untx) hamsters in chamber diameters or left ventricular function. After 2 mo of treatment, however, F1B-Tx showed evidence of dilated heart failure vs. F1B-Untx. Chamber diameters were increased, and ejection fraction and positive and negative changes in pressure over time were reduced. In F1B-Tx and TO2-Tx hamsters, β-myosin isoform expression was reduced, whereas α-myosin increased significantly in F1B-Tx only. In TO2-Tx hamsters, the percent of viable myocardium was increased, and percent fibronecrosis was reduced vs. TO2-Untx. Myocyte length increased with TH treatment in both hamster strains. We conclude that 1) excess TH can induce heart failure in normal animals as observed in humans, 2) reversal of myosin heavy chain expression does not necessarily improve heart function, and 3) excess TH altered cellular remodeling but did not adversely affect chamber function or dimensions in TO2 hamsters.