The β3 Adrenergic Receptor Antagonist L-748,337 Attenuates Dobutamine-Induced Cardiac Inefficiency While Preserving Inotropy in Anesthetized Pigs

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.

‘A bridge over troubled water’: a case report

Background Myocardial bridge (MB) is the most common inborn coronary artery variant, in which a portion of myocardium overlies a major epicardial coronary artery segment. Myocardial bridge has been for long considered a benign condition, although it has been shown to cause effort-related ischaemia. Case summary We present the case of a 17-year-old female patient experiencing chest pain during physical activity. Since her symptoms became unbearable, electrocardiogram and echocardiography were performed together with a coronary computed tomography scan, revealing an MB on proximal-mid left anterior descending artery. In order to unequivocally unmask the ischaemic burden lent by MB, the patient underwent coronary angiography and physiological invasive test: instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) were calculated, both at baseline and after dobutamine infusion (5 µg/kg/min). At baseline, iFR value was borderline (= 0.89), whereas after dobutamine infusion and increase in the heart rate, the patient suffered chest pain. This symptom was associated with a decrease in the iFR value up to 0.77. Consistently, when FFR was performed, a value of 0.92 was observed at baseline, while after inotrope infusion the FFR reached the haemodynamic significance (= 0.79). Therefore, a medical treatment with bisoprolol was started. Discussion Our clinical case shows the importance of a comprehensive non-invasive and invasive assessment of MB in young patients experiencing chest pain, with significant limitation in the daily life. The coronary functional indexes allow to detect the presence of MB-derived ischaemia, thus guiding the decision to undertake a medical/surgical therapy.

Improved Efficiency of Intraventricular Blood Flow Transit Under Cardiac Stress: A 4D Flow Dobutamine CMR Study

Introduction: The effects of heart rate, inotropy, and lusitropy on multidimensional flow patterns and energetics within the human heart remain undefined. Recently, reduced volume and end-diastolic kinetic energy (KE) of the portion of left ventricular (LV) inflow passing directly to outflow, Direct flow (DF), have been shown to reflect inefficient LV pumping and to be a marker of LV dysfunction in heart failure patients. In this study, we hypothesized that increasing heart rate, inotropy, and lusitropy would result in an increased efficiency of intraventricular blood flow transit. Therefore, we sought to investigate LV 4D blood flow patterns and energetics with dobutamine infusion.Methods: 4D flow and morphological cardiovascular magnetic resonance (CMR) data were acquired in twelve healthy subjects: at rest and with dobutamine infusion to achieve a target heart rate ~60% higher than the resting heart rate. A previously validated method was used for flow analysis: pathlines were emitted from the end-diastolic (ED) LV blood volume and traced forward and backward in time to separate four functional LV flow components. For each flow component, KE/mL blood volume at ED was calculated.Results: With dobutamine infusion there was an increase in heart rate (64%, p &lt; 0.001), systolic blood pressure (p = 0.02) and stroke volume (p = 0.01). Of the 4D flow parameters, the most efficient flow component (DF), increased its proportion of EDV (p &lt; 0.001). The EDV proportion of Residual volume, the blood residing in the ventricle over at least two cardiac cycles, decreased (p &lt; 0.001). The KE/mL at ED for all flow components increased (p &lt; 0.001). DF had the largest absolute and relative increase while Residual volume had the smallest absolute and relative increase.Conclusions: This study demonstrates that it is feasible to compare 4D flow patterns within the normal human heart at rest and with stress. At higher heart rate, inotropy and lusitropy, elicited by dobutamine infusion, the efficiency of intraventricular blood flow transit improves, as quantified by an increased relative volume and pre-systolic KE of the most efficient DF component of the LV volume. The change in these markers may allow a novel assessment of LV function and LV dysfunction over a range of stress.

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults

Background To study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry. Methods We conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 μg/kg/min landiolol. Results Dobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20–60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed. Conclusion Landiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects. Trial registration Registration number 2010–023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.

Bezold–Jarisch reflex-mediated asystole during dobutamine stress testing: a case report

Background The Bezold–Jarisch reflex (BJR) is a cardioinhibitory parasympathetic response to activation of ventricular mechanoreceptors, which can result in bradycardia, atrioventricular block, or asystole. This phenomenon has been triggered by acute myocardial ischaemia, intra-arterial nitroglycerine use, natriuretic peptides, and with exceptional rarity, in middle-aged women only, by dobutamine infusion during stress echocardiography. Case summary We present the case of a 61-year-old woman who suffered a 5.1-s sinus pause during her 20 μg/kg/min infusion of dobutamine. Recovery was immediate following termination of dobutamine infusion. Concurrent echocardiography was normal, and subsequent cardiac catheterization and electrophysiologic study were normal. Discussion This is the fifth documented case of a severe BJR causing asystole during dobutamine infusion, which adds to the accumulating evidence supporting the benign nature of the condition.