Reversing dobutamine-induced tachycardia using ivabradine increases stroke volume with neutral effect on cardiac energetics in left ventricular post-ischaemia dysfunction.

AIM: Compensatory tachycardia can potentially be deleterious in acute heart failure. In this study, we tested a therapeutic strategy of combined inotropic support (dobutamine) and selective heart rate (HR) reduction through administration of ivabradine. METHODS: In an open-chest pig model (n = 12) with left ventricular (LV) post-ischaemia dysfunction, cardiac function was assessed by LV pressure catheter and sonometric crystals. Coronary flow and blood samples from the coronary sinus were used to measure myocardial oxygen consumption (MVO2 ). LV energetics was assessed by comparing MVO2 with cardiac work at a wide range of workloads. RESULTS: In the post-ischaemia heart, dobutamine (5 µg kg(-1)  min(-1) ) increased cardiac output (CO) by increasing HR from 102 ± 21 to 131 ± 16 bpm (beats per min; P < 0.05). Adding ivabradine (0.5 mg kg(-1) ) slowed HR back to 100 ± 9 bpm and increased stroke volume from 30 ± 5 to 36 ± 5 mL (P < 0.05) by prolonging diastolic filling time and increasing end-diastolic dimensions. Adding ivabradine had no adverse effects on CO, mean arterial pressure and cardiac efficiency. Similar findings on efficiency and LV function were also seen using an ex vivo working mouse heart protocol. CONCLUSIONS: A combined infusion of dobutamine and ivabradine had a neutral effect on post-ischaemia LV efficiency and increased left ventricular output without an increase in HR.

Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice.

Isolated perfused hearts from type 2 diabetic (db/db) mice show impaired ventricular function, as well as altered cardiac metabolism. Assessment of the relationship between myocardial oxygen consumption (MVO(2)) and ventricular pressure-volume area (PVA) has also demonstrated reduced cardiac efficiency in db/db hearts. We hypothesized that lowering the plasma fatty acid supply and subsequent normalization of altered cardiac metabolism by chronic treatment with a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist will improve cardiac efficiency in db/db hearts. Rosiglitazone (23 mg/kg body weight/day) was administered as a food admixture to db/db mice for five weeks. Ventricular function and PVA were assessed using a miniaturized (1.4 Fr) pressure-volume catheter; MVO(2) was measured using a fibre-optic oxygen sensor. Chronic rosiglitazone treatment of db/db mice normalized plasma glucose and lipid concentrations, restored rates of cardiac glucose and fatty acid oxidation, and improved cardiac efficiency. The improved cardiac efficiency was due to a significant decrease in unloaded MVO(2), while contractile efficiency was unchanged. Rosiglitazone treatment also improved functional recovery after low-flow ischemia. In conclusion, the present study demonstrates that in vivo PPARgamma-treatment restores cardiac efficiency and improves ventricular function in perfused hearts from type 2 diabetic mice.