Dose-related hemodynamic and electrocardiographic effects of the calcium promoter BAY y 5959 in the presence or absence of congestive heart failure.

Abstract

OBJECTIVES:

The aim of this study was to assess the cardiovascular effects of BAY y 5959, a calcium promoter modulating myocardial calcium channels, in the presence or absence of congestive heart failure.

BACKGROUND:

There is still a clinical need for short-term administration of intravenous positive inotropes. BAY y 5959 was developed as a new approach to increase myocardial performance by selectively enhancing calcium influx in the myocytes.

METHODS:

Forty-one patients (21 without and 20 with congestive heart failure) were studied in an open label, dose-ranging study. Hemodynamic variables (including left ventricular [LV] angiography) and plasma samples were obtained at baseline and after 20 min of intravenous infusion of BAY y 5959 at doses ranging from 0.25 to 4.5 microg/kg body weight per min.

RESULTS:

In both study groups, BAY y 5959 produced dose-dependent increases in the indexes of inotropic state, without affecting isovolumetric relaxation rate. The magnitude of the response was comparable in patients with or without heart failure (average 38% increase in maximal first derivative of LV pressure [dP/dt max] at plasma levels of 100 microg/liter). BAY y 5959 also induced mild but statistically significant bradycardia and significantly decreased end-systolic volume while producing a leftward shift of the pressure-volume loop. Mean aortic pressure was unaffected at doses up to 3.0 microg/kg per min, and cardiac index improved in patients with heart failure at doses of 2.0 microg/kg per min (+23%, p < 0.05). However, at a dose of 4.5 microg/kg per min, mean aortic pressure and LV systolic wall stress increased, suggesting systemic vasoconstriction. The QT interval was also prolonged significantly at most doses.

CONCLUSIONS:

BAY y 5959 exhibits positive inotropic effects in patients with and without heart failure. The optimal response--combining bradycardia, reduced preload and improved cardiac output--appeared to be achieved at a dose of approximately 2.0 microg/kg per min. The impact of QT prolongation with regard to potential antiarrhythmic or proarrhythmic effects is unclear at this time.

• Authors: M F Rousseau, P E Massart, C van Eyll, J Etienne, S Ahn, H G Schaefer, W Mueck, M Bornemann, H Pouleur
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 30 Issue 7 Pg. 1751-7 (Dec 1997) ISSN: 0735-1097 [Print] United States
• PMID: 9385903 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BAY y 5959
• Calcium Channel Agonists
• Cardiotonic Agents
• Dihydropyridines

Topics

• Calcium Channel Agonists (administration & dosage, therapeutic use)
• Cardiotonic Agents (administration & dosage, therapeutic use)
• Case-Control Studies
• Dihydropyridines (administration & dosage, therapeutic use)
• Dose-Response Relationship, Drug
• Electrocardiography (drug effects)
• Female
• Heart Failure (drug therapy, physiopathology)
• Hemodynamics (drug effects)
• Humans
• Male
• Middle Aged
• Myocardial Contraction (drug effects)
• Stimulation, Chemical
• Ventricular Dysfunction, Left (drug therapy, physiopathology)