Electrophysiological basis of metabolic syndrome-induced cardiac dysfunction

Myocardial contractility is controlled by intracellular Ca2+-cycling with the contribution of sarcoplasmic reticulum (SR). In this study we aimed to investigate the role of altered SR function in defective regulation of intracellular Ca2+ levels in rats with metabolic syndrome (MetS) induced by a 16-week high-sucrose drinking-water diet. Electric-field stimulated transient intracellular Ca2+-changes in MetS-cardiomyocytes exhibited significantly reduced amplitude (30%) and prolonged time courses (2-fold) as well as depressed SR-Ca2+ loading (55%) with increased basal Ca2+ level. Consistent with these data, altered ryanodine receptor (RyR2) function and SERCA2a activity were found in MetS-cardiomyocytes through Ca2+ spark measurements and caffeine application assay in a state in which sodium calcium exchanger was inhibited. Furthermore, tetracaine application-assay results and hyperphosphorylated level of RyR2 also support the “leaky RyR2” hypothesis. Moreover, altered phosphorylation levels of phospholamban (PLN) support the depressed SERCA2a-activity thesis and these alterations in the phosphorylation of Ca2+-handling proteins are correlated with altered protein kinase and phosphatase activity in MetS-cardiomyocytes. In conclusion, MetS-rat heart exhibits altered Ca2+ signaling largely due to altered SR function via changes in RyR2 and SERCA2a activity. These results point up RyR2 and SERCA2a as potential pharmacological targets for restoring intracellular Ca2+-homeostasis and thereby combatting dysfunction in MetS-rat heart.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Onset of Depressed Heart Work is Correlated with the Increased Heart Rate and Shorten QT-Interval in High-Carbohydrate Fed Overweight Rats

Mechanical activity of the heart is adversely affected with metabolic syndrome (MetS) characterized with increased body-mass and marked insulin-resistance. Herein, we examined effects of high-carbohydrate intake on cardiac functional abnormalities via evaluating in situ heart-work, heart-rate and electrocardiograms (ECG) in rats. MetS is induced in Wistar male rats by adding 32% sucrose for 22-24 weeks and confirmed with insulin-resistance, increased body-weight, blood glucose and insulin, systolic and diastolic blood pressures besides significant left ventricular integrity-lost and increased connective-tissue around myofibrils. Analysis of in situ ECG-recordings showed markedly shorten QT-interval and depressed QRP with increased heart-rate. We also observed augmented oxidative stress and decreased antioxidant defense characterized with decreases in serum total thiol-level and attenuated paraoxonase and arylesterase activities. Our data clearly indicate that increased heart-rate and shortened QT-interval concomitant with higher left ventricular developed pressure responses to β-adrenoreceptor stimulation as a result of less cAMP-release could be regarded as natural compensation mechanisms in overweight MetS rats. Since MetS leads further to persistent insulin-resistance and obesity, one should get into consideration these important facts associated with onset of the depressed heart-work, the increased heart-rate and shorten QT-interval in high-carbohydrate intake, which will possible lead to more deleterious effects on mammalian heart.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author