Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs (n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls (n = 8), DOCA/WD-treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model.

Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca-ATPase 2a axis and Na-Ca exchanger function in Ca extrusion. This resulted in reduced sarcoplasmic reticulum Ca content, diastolic Ca overload, systolic dysfunction and impaired contractile force. Furthermore, saxagliptin reduced protein kinase C-mediated delayed rectifier K current that prolonged action potential duration and consequently QTc interval. Importantly, saxagliptin aggravated pre-existing cardiac dysfunction induced by ischemia/reperfusion injury. In conclusion, our novel results provide mechanisms for the off-target deleterious effects of saxagliptin on cardiac function and support the outcome of SAVOR-TIMI 53 trial that linked saxagliptin with the risk of heart failure.

The induction of MH after cardiac resuscitation improves systolic myocardial function without further sympathetic activation. A reduced metabolism during MH outweighs a decreased CO and thereby acts favourably on systemic oxygen supply/demand balance.

An experimental model was established to study circulation in retrograde arterialized venous flaps (RAVF). Venous flaps measuring 7 x 4 cm with a matching venous system were harvested from both forearms of 10 fresh human cadavers. In each trial, both flaps were simultaneously perfused with heparinized human blood driven by a pulsatile circulation model. In each trial there was one flap with retrograde perfusion, and one flap with antegrade perfusion. Clinical assessment, measurement of outflow, and angiographic examination with digitally assisted assessment after 3 h of perfusion showed better results for retrograde perfusion in 8 of the 10 trials. This study indicates that blood circulation in the periphery of arterialized venous flaps can be enhanced by retrograde arterialization.

We conclude that the loss of LV end-diastolic capacitance during MH can be explained at least in part by slowed LV relaxation. MH thereby is an example of incomplete LV relaxation at a spontaneous low heart rate. Caution may be advised, when heart rate is increased in patients treated with MH.