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Acute intravenous infusion of the beta-3 adrenergic receptor antagonist APD418 improves left ventricular function in dogs with advanced heart failure: a dose escalation study

Session Rapid Fire 1 - Basic Science

Speaker Hani Sabbah

Congress : Heart Failure 2019

  • Topic : heart failure
  • Sub-topic : Acute Heart Failure: Pharmacotherapy
  • Session type : Rapid Fire Abstracts
  • FP Number : 15

Authors : HN Sabbah (Detroit,US), K Zhang (Detroit,US), J Xu (Detroit,US), RC Gupta (Detroit,US), J Adams (San Diego,US)

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Authors:
HN Sabbah1 , K Zhang1 , J Xu1 , RC Gupta1 , J Adams2 , 1Henry Ford Hospital - Detroit - United States of America , 2Arena Pharmaceuticals, Inc. - San Diego - United States of America ,

Citation:

Background: Unlike ß1 and ß2-adrenergic receptors (ARs), ß3-AR stimulation inhibits cardiac contractility and relaxation through links to inhibitory G proteins. In the failing left ventricular (LV) myocardium, ß3-ARs are upregulated, a maladaptation that can contribute to LV dysfunction. This study examined the effects of acute intravenous (i.v.) infusions of the ß3-AR antagonist APD418 on LV systolic and diastolic function by conducting a dose-escalation study in dogs with chronic heart failure (HF) (LV ejection fraction, EF~35%).

Methods: Studies were performed in 7 dogs with coronary microembolizations-induced HF. After baseline measurements, 0.9% NaCl (vehicle) was administered as a continuous i.v. infusion for 30 min. This was followed by infusions of 3 escalating doses of APD418 (0.696, 1.407 and 2.814 mg/kg) with each dose maintained for 30 min. Heart rate (HR), mean aortic pressure (mAoP), LV end-diastolic (EDV) and end-systolic (ESV) volumes, EF, stroke volume (SV) cardiac output (CO), LV end-diastolic pressure (EDP) and systemic vascular resistance (SVR) as well as the diastolic function measures Ei/Ai and mitral inflow velocity deceleration time (DCT) were measured at end of each 30 min period.

Results: Infusion of APD418 had no effects on HR, mAoP, or EDV but significantly decreased ESV, LVEDP and SVR and significantly increased EF, SV, CO Ei/Ai and DCT in a dose-dependent manner (Table). 

Conclusions: Acute i.v. infusions of APD418 in HF dogs elicit positive inotropic and lusitropic effects along with modest preload and afterload reductions. The findings support the development of APD418 for the in-hospital treatment of patients with exacerbation of chronic HF.

Baseline

Vehicle

APD418

(0.696 mg/kg)

APD418

(1.407 mg/kg)

APD418

(2.814 mg/kg)

LV EDV (ml)

62±1

63±1

62±2

62±2

61±2

LV ESV (ml)

41±1

41±1

38±1*

38±1*

36±1*

LV EF (%)

34±1

35±1

38±1*

39±1*

41±1*

SV (ml)

21±1

22±1

23±1*

24±1*

25±1*

CO (L/min)

1.70±0.08

1.81±0.07

1.94±0.11

2.02±0.08*

2.14±0.08*

HR (beats/min)

81±2

83±1

83±1

84±1*

85±1*

mAoP (mmHg)

74±2

79±3

79±4

79±5

77±4

LVEDP (mmHg)

14±0.6

15±0.6

14±0.8

13±0.8

12±1.0*

SVR (dynes-sec-cm-5)

3525±257

3537±152

3293±205

3118±183*

2895±153*

Ei/Ai

3.1±0.1

2.9±0.3

3.6±0.3*

3.7±0.3*

4.3±0.4*

DCT (msec)

98±6

99±9

119±14

117±11

133±16*

*=p<0.05 vs. Baseline

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