Abstract
Excessive myocardial oxygen consumption (MVO2) is considered a limitation for catecholamines, termed oxygen cost of contractility. We hypothesize that increased MVO2 induced by dobutamine is not directly related to contractility but linked to intermediary myocardial metabolism. Furthermore, we hypothesize that selective β3 adrenergic receptor (β3AR) antagonism using L-748,337 prevents this. In an open-chest pig model, using general anesthesia, we assessed cardiac energetics, hemodynamics and arterial metabolic substrate levels at baseline, ½ hour and 6 hours after onset of drug infusion. Cardiac efficiency was assessed by relating MVO2 to left ventricular work (PVA; pressure–volume area). Three groups received dobutamine (5 μg/kg/min), dobutamine + L-748,337 (bolus 50 μg/kg), or saline for time-matched controls. Cardiac efficiency was impaired over time with dobutamine infusion, displayed by persistently increased unloaded MVO2 from ½ hour and 47% increase in the slope of the PVA–MVO2 relation after 6 hours. Contractility increased immediately with dobutamine infusion (dP/dt max; 1636 ± 478 vs 2888 ± 818 mmHg/s, P < 0.05) and persisted throughout the protocol (2864 ± 1055 mmHg/s, P < 0.05). Arterial free fatty acid increased gradually (0.22 ± 0.13 vs 0.39 ± 0.30 mM, P < 0.05) with peak levels after 6 hours (1.1 ± 0.4 mM, P < 0.05). By combining dobutamine with L-748,337 the progressive impairment in cardiac efficiency was attenuated. Interestingly, this combined treatment effect occurred despite similar alterations in cardiac inotropy and substrate supply. We conclude that the extent of cardiac inefficiency following adrenergic stimulation is dependent on the duration of drug infusion, and β3AR blockade may attenuate this effect.
Highlights
Dobutamine (Dob) is an inotrope used for treating patients with acute heart failure and cardiogenic shock.[1]
Baseline cardiac volumes varied between the groups, possibly because absolute volumetry is limited by the assumptions of accurate positioning of the sonomicrometric crystals and a perfect ellipsoid shape of the ventricle
As cardiac inefficiency progressed throughout the protocol, this suggests a time dependent myocardial oxygen wastage by sympathomimetic drugs that is not related to the inotropic state of the heart
Summary
Dobutamine (Dob) is an inotrope used for treating patients with acute heart failure and cardiogenic shock.[1] There has been conflicting evidence on the impact on myocardial oxygen consumption (MVO2) using this inotrope. The general understanding is that sympathomimetic drugs lead to myocardial oxygen wastage because of cAMP-induced increase in calcium handling.[2,3,4] Contradictory results have shown that Dob does not induce oxygen wastage at clinically relevant doses.[5] A limitation in that study is that the measurements was carried out shortly after the onset of drug infusion. Several different protocols investigating Dob-induced changes in cardiac energetics have been done using various doses,[6,7,8,9,10,11,12] but with the infusion lasting for a maximum of around 1 hour
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