5′-AMP Activated Protein Kinase is Involved in the Regulation of Myocardial β-Oxidative Capacity in Mice

5′-adenosine monophosphate-activated protein kinase (AMPK) is considered central in regulation of energy status and substrate utilization within cells. In heart failure the energetic state is compromised and substrate metabolism is altered. We hypothesized that this could be linked to changes in AMPK activity and we therefore investigated mitochondrial oxidative phosphorylation capacity from the oxidation of long- and medium-chain fatty acids (LCFA and MCFA) in cardiomyocytes from young and old mice expressing a dominant negative AMPKα2 (AMPKα2-KD) construct and their wildtype (WT) littermates. We found a 35–45% (P < 0.05) lower mitochondrial capacity for oxidizing MCFA in AMPKα2-KD of both age-groups, compared to WT. This coincided with marked decreases in protein expression (19/29%, P < 0.05) and activity (14/21%, P < 0.05) of 3-hydroxyacyl-CoA-dehydrogenase (HAD), in young and old AMPKα2-KD mice, respectively, compared to WT. Maximal LCFA oxidation capacity was similar in AMPKα2-KD and WT mice independently of age implying that LCFA-transport into the mitochondria was unaffected by loss of AMPK activity or progressing age. Expression of regulatory proteins of glycolysis and glycogen breakdown showed equivocal effects of age and genotype. These results illustrate that AMPK is necessary for normal mitochondrial function in the heart and that decreased AMPK activity may lead to an altered energetic state as a consequence of reduced capacity to oxidize MCFA. We did not identify any clear aging effects on mitochondrial function

Sinoatrial node dysfunction induces cardiac arrhythmias in diabetic mice

BACKGROUND: The aim of this study was to probe cardiac complications, including heart-rate control, in a mouse model of type-2 diabetes. Heart-rate development in diabetic patients is not straight forward: In general, patients with diabetes have faster heart rates compared to non-diabetic individuals, yet diabetic patients are frequently found among patients treated for slow heart rates. Hence, we hypothesized that sinoatrial node (SAN) dysfunction could contribute to our understanding of the mechanism behind this conundrum and the consequences thereof. METHODS: Cardiac hemodynamic and electrophysiological characteristics were investigated in diabetic db/db and control db/+ mice. RESULTS: We found improved contractile function and impaired filling dynamics of the heart in db/db mice, relative to db/+ controls. Electrophysiologically, we observed comparable heart rates in the two mouse groups, but SAN recovery time was prolonged in diabetic mice. Adrenoreceptor stimulation increased heart rate in all mice and elicited cardiac arrhythmias in db/db mice only. The arrhythmias emanated from the SAN and were characterized by large RR fluctuations. Moreover, nerve density was reduced in the SAN region. CONCLUSIONS: Enhanced systolic function and reduced diastolic function indicates early ventricular remodeling in obese and diabetic mice. They have SAN dysfunction, and adrenoreceptor stimulation triggers cardiac arrhythmia originating in the SAN. Thus, dysfunction of the intrinsic cardiac pacemaker and remodeling of the autonomic nervous system may conspire to increase cardiac mortality in diabetic patients

Development of heart failure is independent of K+ channel-interacting protein 2 expression

Abnormal ventricular repolarization in ion channelopathies and heart disease is a major cause of ventricular arrhythmias and sudden cardiac death. K(+) channel-interacting protein 2 (KChIP2) expression is significantly reduced in human heart failure (HF), contributing to a loss of the transient outward K(+) current (I(to)). We aim to investigate the possible significance of a changed KChIP2 expression on the development of HF and proarrhythmia. Transverse aortic constrictions (TAC) and sham operations were performed in wild-type (WT) and KChIP2(−/−) mice. Echocardiography was performed before and every 2 weeks after the operation. Ten weeks post-surgery, surface ECG was recorded and we paced the heart in vivo to induce arrhythmias. Afterwards, tissue from the left ventricle was used for immunoblotting. Time courses of HF development were comparable in TAC-operated WT and KChIP2(−/−) mice. Ventricular protein expression of KChIP2 was reduced by 70% after 10 weeks TAC in WT mice. The amplitudes of the J and T waves were enlarged in KChIP2(−/−) control mice. Ventricular effective refractory period, RR, QRS and QT intervals were longer in mice with HF compared to sham-operated mice of either genotype. Pacing-induced ventricular tachycardia (VT) was observed in 5/10 sham-operated WT mice compared with 2/10 HF WT mice with HF. Interestingly, and contrary to previously published data, sham-operated KChIP2(−/−) mice were resistant to pacing-induced VT resulting in only 1/10 inducible mice. KChIP2(−/−) with HF mice had similar low vulnerability to inducible VT (1/9). Our results suggest that although KChIP2 is downregulated in HF, it is not orchestrating the development of HF. Moreover, KChIP2 affects ventricular repolarization and lowers arrhythmia susceptibility. Hence, downregulation of KChIP2 expression in HF may be antiarrhythmic in mice via reduction of the fast transient outward K(+) current