title: Dose-related hemodynamic and electrocardiographic effects of the calcium promoter BAY y 5959 in the presence or absence of congestive heart failure.
abstract: OBJECTIVE
  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.affiliation: Division of Cardiology, University of Louvain, Brussels, Belgium. rousseau@card.ucl.ac.be
authors.forename: M F
authors.initials: MF
authors.lastname: Rousseau
authors.forename: P E
authors.initials: PE
authors.lastname: Massart
authors.forename: C
authors.initials: C
authors.lastname: van Eyll
authors.forename: J
authors.initials: J
authors.lastname: Etienne
authors.forename: S
authors.initials: S
authors.lastname: Ahn
authors.forename: H G
authors.initials: HG
authors.lastname: Schaefer
authors.forename: W
authors.initials: W
authors.lastname: Mueck
authors.forename: M
authors.initials: M
authors.lastname: Bornemann
authors.forename: H
authors.initials: H
authors.lastname: Pouleur
mesh_terms: D002120:Calcium Channel Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016022:Case-Control Studies; D004095:Dihydropyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D013268:Stimulation, Chemical; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology
chemical_list: C109289:BAY y 5959; D002120:Calcium Channel Agonists; D002316:Cardiotonic Agents; D004095:Dihydropyridines