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Background The hexosamine biosynthetic pathway (HBP) is heightened in cardiomyopathies. We aimed at understanding how over-activation of HBP impacts on cardiac electrophysiology, and acts as a trigger or a substrate of cardiac arrhythmias. Methods Overactivation of the HBP by injection of glucosamine (GlcN 270mg/kg) was assessed under basal conditions and during beta-adrenergic stress on the myocardial energetic status (phosphocreatine to ATP ratio) of rats by 31 P nuclear magnetic resonance spectroscopy. Rat hearts were perfused ex vivo to evaluate the effects of the HBP activation (physiologically: glutamine 0.5mM – gln; overactivated: GlcN 1mM) on: cardiac function, MVO 2 , and arrhythmia score (AS) under basal (spontaneous arrhythmias: sAS) and pacing (pAS) conditions. At the cellular level (HL1 cells), HBP overactivation (GlcN) was assessed on conduction velocity characterized by micro-electrode arrays recordings, and properties of voltage gated ionic channels involved in cellular excitability and conduction by patch clamp experiments. Results In vivo GlcN did not modify PCr/ATP of the left ventricle under basal conditions. This ratio was significantly decreased during beta-adrenergic stress, while a similar increased heart rate was reported. When hearts were isolated and perfused ex vivo , GlcN induced a decrease of the heart rate and MVO 2 temporarily, and an increase of the sAS and pAS. Physiological activation of HBP with gln did not impact the ex vivo cardiac function and the sAS, but further increased the probability of atrial arrhythmias during pacing. In HL1 cells, GlcN reduced the rate of spontaneous depolarization, modified the direction and the velocity of the impulse propagation, and altered activation and inactivation properties of the sodium channel. Conclusion Acute HBP activation is associated with an increased vulnerability for arrhythmias and alteration of impulse conduction, suggesting its potential role in the atrial and ventricular arrhythmias. The author hereby declares no conflict of interest [ABSTRACT FROM AUTHOR]

Background Calcium leak from the sarcoplasmic reticulum (SR) favors cardiac sudden death through a calcium overload mechanism. Here we investigate the crosstalk between the calcium overload SR-mediated and the mitochondrial permeability transition pore (mPTP) opening during a ventricular arrhythmic episode. Methods and results a burst pacing protocol was developed to induce ventricular arrhythmia in the perfused rat heart. Surface electrocardiogram, left ventricular pressure, and oxygen consumption were monitored. Epicardial fluorescence was recorded from either a mitochondrial membrane potential dye or an intracellular calcium dye. ECG signals were used to assess both arrhythmia complexity and duration. Hearts were perfused with tacrolimus (FK506) alone or in combination with cyclosporin A (CsA) to promote SR calcium leak or inhibit mPTP, respectively. Prior to arrhythmia induction, FK506 promoted mitochondrial depolarization and intracellular calcium overload in a CsA-sensitive manner. More than 90% of hearts developed complex ventricular arrhythmias in the FK506 group and this was accompanied by a strong mitochondrial membrane depolarization. In contrast, in the FK506 + CsA group, 100% of the hearts spontaneously defibrillate after a few seconds of arrhythmias. In this group, following arrhythmia induction, mitochondrial depolarization amplitude, intracellular calcium overload and heart efficiency depression was decreased in comparison to the FK506 group. Conclusions Here we suggest that the FK506-induced calcium overload promotes mitochondrial calcium accumulation and leads to mPTP opening. We propose that mPTP opening should be considered as an arrhythmogenic substrate. The author hereby declares no conflict of interest [ABSTRACT FROM AUTHOR]

Phosphorus magnetic resonance spectroscopy ( 31 P-MRS) makes a unique and valuable contribution to our understanding of heart energetics, by giving the cardiac energy status from the concentrations of ATP and phosphocreatine (PCr). Changes in PCr/ATP ratio allow detecting energy imbalance that predicts disease and mortality. However, localized MR techniques in vivo are often challenged by tissue contamination and poor signal-to-noise ratio, especially in small animals. Here we purposely aimed at demonstrating good consistency in localized cardiac 31 P-MR spectra obtained from left ventricle of rats in vivo with a surface probe at 9.4T. For that, 3-min MR spectra and short-axis cine-MRI frames were obtained in sinus rhythm during nine consecutive weeks in control and hypertensive rats (SHR) just before the apparition of severe pathology in the later. Then a severe tachycardia was acutely induced by isoproterenol injection (10μg/kg) and the PCr/ATP response kinetically analyzed. Along 9 weeks, we showed highly reproducible, steady and similar PCr/ATP ratios in each group in spite of progressive ventricular hypertrophy in SHR rats. Isoproterenol induced a similar tachycardia in each group (Control: 439bpm ±7, SHR: 411bpm ± 7) but altered responses of the energetics were noted in SHR rats: higher decrease in PCr/ATP ratio (–17.1% ± 0.75 vs. –4.7% ± 0.4, P <0.05) associated with longer recovery time (time constant of exponential fit 23.9 ±10.8 vs. 7.3 ± 1.15min, P <0.05). High signal-to-noise ratio in 3min-MR spectra allowed demonstrating good consistency in follow-up assessments of PCr/ATP in left ventricle of rats in vivo. Thanks to good consistency, small variations in energy status have been detected in response to isoproterenol that revealed a blunted capacity in SHR rats to maintain energy balance. These gains offer exciting possibilities to better investigate primary precursors detection of cardiac pathology in rodent models. [ABSTRACT FROM AUTHOR]