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Introduction Preclinical assessment for alterations in cardiac ventricular function for drug candidates has not been a focus of ICH S7b guidelines for cardiovascular safety studies, but there is growing interest given that the cardiovascular risk is associated with positive and negative inotropes. Methods From 2003 through 2013, 163 telemetry studies with left-ventricular function analyses were conducted in dogs and monkeys at Bristol Myers Squibb (BMS) in support for drug development programs. The ability of the telemetry system to detect changes in cardiac contractility was verified with positive control agents pimobendan and atenolol. Control data from a subset of studies were analyzed to determine dP/dt reference range values, and minimum detectable mean differences (control vs. treated) for statistical significance. Results Median minimum detectable differences for dogs ranged from 14 to 21% for positive dP/dt and 11 to 21% for negative dP/dt. For monkeys, median minimum detectable differences were 25 and 14% for positive and negative dP/dt, respectively. For BMS programs, 15 drug candidates were identified that produced primary effects on contractility. Changes in contractility that were associated with, and potentially secondary to, drug-related effects on heart rate or systemic blood pressure were observed with an additional 29 drug candidates. Discussion Changes in contractility have been observed in large animals during drug development studies at BMS over the past 10 years. Model sensitivity has been demonstrated and a dP/dt beat-to-beat cloud analysis tool has been developed to help distinguish primary effects from those potentially secondary to systemic hemodynamic changes.

Objectives.The present study examined left ventricular (LV) and myocyte contractile performance and electrophysiologic variables after long-term digoxin treatment in a model of LV failure.Background.A fundamental therapeutic agent for patients with chronic LV dysfunction is the cardiac glycoside digoxin. However, whether digoxin has direct effects on myocyte contractile function and electrophysiologic properties in the setting of chronic LV dysfunction remains unexplored.Methods.Left ventricular and isolated myocyte function and electrophysiologic variables were examined in five control dogs, five dogs after the development of long-term rapid pacing (rapid pacing, 220 beats/min, 4 weeks) and five dogs with rapid pacing given digoxin (0.25 mg/day) during the pacing period (rapid pacing and digoxin).Results.Left ventricular ejection fraction decreased in the dogs with rapid pacing compared with that in control dogs (30 ± 2% vs. 68 ± 3%, p < 0.05) and was higher with digoxin than that in the rapid pacing group (38 ± 3%, p = 0.038). Left ventricular end-diastolic volume increased in the rapid pacing group compared with the control group (84 ± 6 ml vs. 59 ± 7 ml, p < 0.05) and remained increased with digoxin (79 ± 6 ml). Isolated myocyte shortening velocity decreased in the rapid pacing group compared with the control group (37 ± 1 μm/s vs. 59 ± 1 μm/s, p < 0.05) and increased with digoxin compared with rapid pacing (46 ± 1 μm/s, p < 0.05). Action potential maximal upstroke velocity was diminished in the rapid pacing group compared with the control group (135 ± 6 V/s vs. 163 ± 9 V/s, p < 0.05) and increased with digoxin compared with rapid pacing (155 ± 12 V/s, p < 0.05). Action potential duration increased in the rapid pacing group compared with the control group (247 ± 10 vs. 216 ± 6 ms, p < 0.05) and decreased with digoxin compared with rapid pacing (219 ± 12 ms, p < 0.05).Conclusions.In this model of rapid pacing-induced LV failure, digoxin treatment improved LV pump function, enhanced isolated myocyte contractile performance and normalized myocyte action potential characteristics. This study provides unique evidence to suggest that the cellular basis for improved LV pump function with digoxin treatment in the setting of LV failure has a direct and beneficial effect on myocyte contractile function and electrophysiologic measures.