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Aims Heart failure is associated with altered myocardial substrate metabolism and impaired cardiac energetics. Comorbidities like diabetes may influence the metabolic adaptations during heart failure development. We quantified to what extent changes in substrate preference, lipid accumulation, and energy status predict the longitudinal development of hypertrophy and failure in the non-diabetic and the diabetic heart. Methods and results Transverse aortic constriction (TAC) was performed in non-diabetic (db/+) and diabetic (db/db) mice to induce pressure overload. Magnetic resonance imaging, 31P magnetic resonance spectroscopy (MRS), 1H MRS, and 18F-fluorodeoxyglucose-positron emission tomography (PET) were applied to measure cardiac function, energy status, lipid content, and glucose uptake, respectively. In vivo measurements were complemented with ex vivo techniques of high-resolution respirometry, proteomics, and western blotting to elucidate the underlying molecular pathways. In non-diabetic mice, TAC induced progressive cardiac hypertrophy and dysfunction, which correlated with increased protein kinase D-1 (PKD1) phosphorylation and increased glucose uptake. These changes in glucose utilization preceded a reduction in cardiac energy status. At baseline, compared with non-diabetic mice, diabetic mice showed normal cardiac function, higher lipid content and mitochondrial capacity for fatty acid oxidation, and lower PKD1 phosphorylation, glucose uptake, and energetics. Interestingly, TAC affected cardiac function only mildly in diabetic mice, which was accompanied by normalization of phosphorylated PKD1, glucose uptake, and cardiac energy status. Conclusion The cardiac metabolic adaptations in diabetic mice seem to prevent the heart from failing upon pressure overload, suggesting that restoring the balance between glucose and fatty acid utilization is beneficial for cardiac function. [ABSTRACT FROM AUTHOR]

Aims: Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). β-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease. [ABSTRACT FROM PUBLISHER]

Aims We report three young patients presenting with life-threatening ventricular tachycardia (VT) or ventricular fibrillation (VF) and/or survived sudden cardiac arrest, who were admitted to our institution for further diagnostic evaluation. [ABSTRACT FROM PUBLISHER]

Objective: Left ventricular assist devices (LVAD) are used to ‘bridge’ patients with end-stage heart failure to transplantation. After long-term LVAD support, ventricular function may partially recover, a process called ‘reverse remodeling’. As several kinase-mediated signal transduction pathways have been implicated in the development of cardiac hypertrophy and failure, we examined the activities of the Erks, MEKs, Akt, GSK-3β, p70S6K, JNKs and p38 under LVAD support as well as during single myocyte strain and whole heart stretch. Methods: Western blotting and immunohistochemistry were performed using phospho-specific antibodies in matched samples from ten patients with end-stage heart failure before and after LVAD. Cyclic strain was performed in rat neonatal cardiac myocytes, and tensile stretch applied to Langendorff-perfused mouse hearts via a left ventricular balloon. Results: The activity of Erks and Akt in failing hearts dramatically decreased after LVAD support, while that of GSK-3β increased. There was an endo/epicardial gradient for Erk activity which persisted after LVAD despite the reduction of total Erk activity. TUNEL-positivity and myocyte size decreased after LVAD, but independently of changes in kinase activity. In cardiomyocytes and Langendorff-perfused mouse hearts both strain/stretch and its relief regulated the activities of Erks, Akt, and GSK-3β. Conclusion: Erks and Akt/GSK-3β are highly responsive to myocyte stretch in vitro and in vivo, and may be sensitive molecular parameters of ‘reverse remodeling’ under LVAD support. [Copyright &y& Elsevier]

Background: Myocardial hibernation and stunning are characterized by depressed cardiac function in the presence of reduced or normal coronary blood flow. The underlying biochemical mechanisms are widely unknown and only limited data are available in human hearts. Methods and Results: Left ventricular transmural myocardial biopsies were obtained from normal and dysfunctional segments of patients undergoing coronary bypass surgery. Segments were classified as hibernating (n=10) or stunned (n=9) using contrast ventriculography and echocardiography, single photon emission computed tomography (SPECT), and positron emission tomography (PET). In each patient, biopsies from normal myocardial segments were used as controls (n=19). Compared to control myocardium, levels of cAMP (3′-5′cyclic adenosine monophosphate, in fmol/mg wet weight, means±S.E.M.) were higher in hibernating (673±76 versus 518±47, P<0.05) but unchanged in stunned myocardium (513±73 versus 466±97, P>0.05). Protein expression of phospholamban, sarcoendoplasmic Ca2+-ATPase 2a, calsequestrin, the inhibitory subunit of troponin, as well as the activation of p38 MAP kinase were not different when compared to controls. However, heat shock protein 72 (Hsp72) was increased 55% in stunned (2.89±0.58 versus 1.86±0.32, P<0.05) but not in hibernating myocardium (1.68±0.34 versus 1.67±0.29, P>0.05). Conclusions: The data from the present study suggest different pathophysiological mechanisms for myocardial hibernation and stunning. Alterations in the homeostasis of cAMP might be a compensatory mechanism in myocardial hibernation, whereas expression of Hsp72 appears to be cardioprotective in human myocardial stunning. Future studies should further elucidate these mechanisms and their potential impact on future therapeutic interventions. [Copyright &y& Elsevier]