The new inotropic agent pren lte 01 was admini te in a canine model of acute ischemic heart failu... more The new inotropic agent pren lte 01 was admini te in a canine model of acute ischemic heart failure d int and in venously patients witn severe chronic heart failure. Experimental heart failure in anesthetized dogs was induced by two vessel coronary artery constriction and intravenous prenalterol (0.005-15 ug/kg/min) was compared to dobutamine (0.001-30 ug/kg/min) and saline. Significant dose-dependent increases in left ventricular dP/dt cardiac output and non-ischemic zone contractile force and significant reductions in systemic vascular resistance were present during infusions of both inotropic agents. High dose dobutamine caused greater increases in mean arterial pressure and pressure rate product with a trend toward greater increases in heart rate.
In order to assess regional myocardial contractile responses to the beta-adrenergic stimulant pre... more In order to assess regional myocardial contractile responses to the beta-adrenergic stimulant prenalterol after recent myocardial infarction, 9 male mongrel dogs underwent left circumflex coronary artery (LCX) occlusion after implantation of miniature subendocardial sonomicrometer crystals in normal, marginally ischemic (border) and central ischemic zones. 90-min LCX occlusion with reperfusion resulted in substantial infarction (mean +/- SEM 24 +/- 3% of total left ventricular area) and characteristic regional functional alterations. In conscious, unsedated animals 72 h after infarction, intravenous prenalterol (30 micrograms/kg) significantly decreased end-diastolic and end-systolic segment length and increased percent systolic shortening in normal and border zones, but did not alter ischemic zone function. Heart rate increased significantly with prenalterol. Regional myocardial function before drug administration correlated closely with response to the inotropic agent. These results indicate that the mechanism by which prenalterol improves cardiac function 72 h after myocardial infarction is stimulation of normal and marginally ischemic myocardium.
Journal of the American College of Cardiology, 1998
phy~lolOglo process for disposing Dells through orderly soil deotruoflon, while no~rosls results ... more phy~lolOglo process for disposing Dells through orderly soil deotruoflon, while no~rosls results from cytolytlo oh~ngos following Doll miss/ WQ nssos.~od their p~ttom aed extonl ~n m~,l~tlple samp~ ~a fre~~ ;~9 p.',ient ,~ M~lhpd~; Apoptosio was doto(;tod by in sih4 er~d labeling and n(l~l~ar cl~mm~ftn ~lalntng and neorosts tmmunohlstochomt~dly using a ooniug=Ued myosin light chain monoclonal ~ntibody, Accompanying tnflsmmalery infil. trains were Id~nttflod by tmmgnop, rexidasa staining of lymphncvle subsets Rosult~ were oompared with clinical doln ~nd re~dlnn hem~toxylin.~esln evaluation of ondomyocnrdh~l btopslns, RP,qUII~: Apoptosta was Identified at tbe perlphoq/of the isel~amlc to0i in 75% of the biopsi¢ls that showod peri(ransplant lachemic mltlry by Iigl~t mtoros~opy, whllo ~mmt!noh(~tochnmloal slolnlng for myosin light ohain leNly nocrests) was obsontod within the cores of ~11 lschomic loci, Apoptottc my. DO/los w~re observed In 90% el the blopsteS which showed aouto rejection and immunohtstochomlcnl staining for myosin light chain was obeowod in 86% el those btopstea Endy myocyto necresls waa dotoctod in 70% Of the bl0psi0S ovakmted without necrosis by reutlne I~lslologle grading (Grade tA • relo¢tlon),
This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotr... more This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotropic agent with calcium-sensitizing properties and activity as a phosphodiesterase inhibitor, in patients with heart failure. One hundred ninety-eight ambulatory patients with symptoms of moderate to severe heart failure despite therapy with digitalis and diuretics with or without a single vasodilator were randomly assigned to receive either placebo (n = 49) or pimobendan (n = 149) in a double-blind fashion for 12 weeks. A dose range of pimobendan was used including 2.5 (n = 49), 5 (n = 51), or 10 mg/day (n = 49). One hundred fifty-eight (80%) patients were taking a converting enzyme inhibitor (CEI) and 28 (14%) patients were taking a non-CEI vasodilator. At end point, the 5-mg dose of pimobendan significantly increase exercise duration compared with placebo (121.6 +/- 19.1 seconds, p less than 0.001), whereas the 10-mg dose produced an increase of borderline significance (81.1 +/- 19.5 seconds, p = 0.05). Peak VO2 was significantly increased by 2.23 +/- 0.58 ml/kg/min in the 5-mg group (p less than 0.01 versus placebo). Furthermore, quality of life measured with the Minnesota Living With Heart Failure Questionnaire improved by 8.5 +/- 2.3 units in the 5-mg group compared with 1.3 +/- 2.2 units in the placebo group (p less than 0.01). There were a total of 23 all-cause hospitalizations in the placebo group, which was significantly greater compared with 33 in the three groups treated with pimobendan (p less than 0.01). There were no significant differences between the placebo and pimobendan groups with respect to changes in ejection fraction and plasma norepinephrine measured at baseline and at the completion of the 12-week study, proarrhythmic effect, or the number of patients with a significant adjustment in background therapy. Eleven patients died, including three (6%) on placebo and eight (5%) on pimobendan (p = NS). Among all adverse events, headache tended to be more common in the pimobendan groups compared with placebo, with the incidence increasing with dose (p less than 0.05). These data demonstrate that pimobendan significantly increases exercise duration, peak VO2, and quality of life in patients with heart failure. Pimobendan appears to be useful adjunctive therapy when added to digitalis, diuretics, and vasodilators.
Neuroendocrine activation is known to occur in patients with congestive heart failure, but there ... more Neuroendocrine activation is known to occur in patients with congestive heart failure, but there is uncertainty as to whether this occurs before or after the presence of overt symptoms. In the Studies of Left Ventricular Dysfunction (SOLVD), a multicenter study of patients with ejection fractions of 35% or less, we compared baseline plasma norepinephrine, plasma renin activity, plasma atrial natriuretic factor, and plasma arginine vasopressin in 56 control subjects, 151 patients with left ventricular dysfunction (no overt heart failure), and 81 patients with overt heart failure before randomization. Median values for plasma norepinephrine (p = 0.0001), plasma atrial natriuretic factor (p less than 0.0001), plasma arginine vasopressin (p = 0.006), and plasma renin activity (p = 0.03) were significantly higher in patients with left ventricular dysfunction than in normal control subjects. Neuroendocrine values were highest in patients with overt heart failure. Plasma renin activity was normal in patients with left ventricular dysfunction without heart failure who were not receiving diuretics and was significantly increased (p less than 0.05) in patients on diuretic therapy. We conclude that neuroendocrine activation occurs in patients with left ventricular dysfunction and no heart failure. Neuroendocrine activation is further increased as overt heart failure ensues and diuretics are added to therapy.
The immediate and longer term variability of selected vasoactive- and volume-regulating neurohorm... more The immediate and longer term variability of selected vasoactive- and volume-regulating neurohormones were measured in patients entering a substudy of the Studies of Left Ventricular Dysfunction--a randomized clinical trial in patients with left ventricular ejection fraction < or = 35%. The variability of these hormones has not been determined in a large cohort of patients. Immediate (short-term) variability was assessed by systematically comparing levels after 15 and 30 minutes of supine rest at the initial visit, and longer term variability was assessed by comparing 30-minute supine rest values at the initial visit with corresponding values taken at 30 minutes after 16 to 24 days of stable therapy. Initial values obtained at the first visit after 30-minute supine rest for all 209 patients were (mean +/- SEM) 512 +/- 21 pg/ml pg/ml for plasma norepinephrine, 1.9 +/- 0.2 ng/ml/hr for plasma renin activity, 3.0 +/- 0.1 pg/ml for plasma arginine vasopressin, and 129 +/- 5.3 pg/ml for plasma atrial natriuretic peptide. All variables were moderately increased relative to established normal values. There was a small but significant decrease from 15- to 30-minute supine posture in all neurohormones, except arginine vasopressin. In the presence of stable background therapy, no significant differences were found between measurements obtained after 30 minutes supine rest at the initial visit and 16 to 24 days later. Spearman correlation coefficients corresponding to immediate and longer term variability were high (range 0.55 to 0.79) (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Normal, marginal, and central ischemic regional myocardial function were evaluated in a canine mo... more Normal, marginal, and central ischemic regional myocardial function were evaluated in a canine model of myocardial infarction during 90 minute left circumflex coronary artery occlusion in 25 anesthetized dogs randomly assigned to intravenous ibuprofen infusion (n = 13,5.36 mg/kg/h beginning 1 hour before occlusion) or vehicle solution as control (n = 12) and in 15 conscious, unsedated dogs 48 and 72 hours after 90 minute circumflex artery occlusion followed by reperfusion (ibuprofen, 5.36 mg/kg/h by intravenous infusion over 7 hours beginning 1 hour before occlusion, n = 7; or vehicle solution infusion as control, n = 8).
Journal of the American College of Cardiology, 1994
ejection fincilm and a" increase in pima tm-ewphria (ti = -0.1.9, p c 0.wlO1), plum0 rain actlvll... more ejection fincilm and a" increase in pima tm-ewphria (ti = -0.1.9, p c 0.wlO1), plum0 rain actlvlly mill = -0.24, p < 0.0001) and a&dne vpwpre& (rho = -0.12, p < 0.003). The only mKqtlcm wtw llrlal natrlttnllc peptkk, rkkh skewed Ike
Hemodynamic and myocardial metabolic parameters in ischemic left ventricular (LV) dysfunction wer... more Hemodynamic and myocardial metabolic parameters in ischemic left ventricular (LV) dysfunction were evaluated in response to the beta-agonist prenalterol. Twenty micrograms/kg intravenous prenalterol increased resting heart rate and cardiac output and decreased LV filling pressure, systemic vascular resistance, and pulmonary artery pressure. Resting coronary blood flow and myocardial oxygen consumption increased but net myocardial lactate and oxygen extraction did not change significantly. During pacing induced tachycardia (121 +/- 4 beats/min), prenalterol improved cardiac index and stroke work index; whereas, LV filling pressure, systemic vascular resistance, and pulmonary artery pressure decreased. Coronary blood flow and myocardial oxygen extraction did not change significantly. Net myocardial lactate extraction during pacing decreased insignificantly; one patient developed overt lactate production. Thus, prenalterol improves cardiovascular function at rest and during pacing-induced tachycardia in ischemic LV failure, but at the cost of higher resting myocardial oxygen consumption. The majority of subjects had no adverse metabolic response.
Angiotensin-converting enzyme (ACE) inhibition with captopril is accepted therapy for the treatme... more Angiotensin-converting enzyme (ACE) inhibition with captopril is accepted therapy for the treatment of symptomatic congestive heart failure. In this trial, we compared the new ACE inhibitor, lisinopril, to captopril during a 12-week randomized double-blind study. One hundred twenty-nine patients with New York Heart Association class II, III, or IV congestive heart failure were randomized to receive either lisinopril 5 mg/day (n = 64) or captopril 37.5 mg/day (n = 65) in 15 centers. Drug doses could be titrated upwards every 4 weeks. The primary measure of drug efficacy was improvement in treadmill exercise time using a modified Naughton protocol. Secondary measures of efficacy and the development of adverse effects were also examined. Lisinopril improved exercise time (following 12 weeks of therapy) more than captopril [from 500 +/- 30 to 682 +/- 34 sec (mean +/- SEM) with lisinopril versus 480 +/- 26 to 600 +/- 35 sec with captopril; difference between groups, p less than 0.05]. Adverse drug effects were unusual and similar in frequency in the two groups, although an increase in blood urea nitrogen was more common with lisinopril than with captopril (p less than 0.05). These results indicate that using the doses and treatment regimens studied, lisinopril is more effective than captopril for the treatment of symptomatic congestive heart failure. Adverse experiences with lisinopril were infrequent and similar in incidence to those observed with captopril.
The new inotropic agent pren lte 01 was admini te in a canine model of acute ischemic heart failu... more The new inotropic agent pren lte 01 was admini te in a canine model of acute ischemic heart failure d int and in venously patients witn severe chronic heart failure. Experimental heart failure in anesthetized dogs was induced by two vessel coronary artery constriction and intravenous prenalterol (0.005-15 ug/kg/min) was compared to dobutamine (0.001-30 ug/kg/min) and saline. Significant dose-dependent increases in left ventricular dP/dt cardiac output and non-ischemic zone contractile force and significant reductions in systemic vascular resistance were present during infusions of both inotropic agents. High dose dobutamine caused greater increases in mean arterial pressure and pressure rate product with a trend toward greater increases in heart rate.
In order to assess regional myocardial contractile responses to the beta-adrenergic stimulant pre... more In order to assess regional myocardial contractile responses to the beta-adrenergic stimulant prenalterol after recent myocardial infarction, 9 male mongrel dogs underwent left circumflex coronary artery (LCX) occlusion after implantation of miniature subendocardial sonomicrometer crystals in normal, marginally ischemic (border) and central ischemic zones. 90-min LCX occlusion with reperfusion resulted in substantial infarction (mean +/- SEM 24 +/- 3% of total left ventricular area) and characteristic regional functional alterations. In conscious, unsedated animals 72 h after infarction, intravenous prenalterol (30 micrograms/kg) significantly decreased end-diastolic and end-systolic segment length and increased percent systolic shortening in normal and border zones, but did not alter ischemic zone function. Heart rate increased significantly with prenalterol. Regional myocardial function before drug administration correlated closely with response to the inotropic agent. These results indicate that the mechanism by which prenalterol improves cardiac function 72 h after myocardial infarction is stimulation of normal and marginally ischemic myocardium.
Journal of the American College of Cardiology, 1998
phy~lolOglo process for disposing Dells through orderly soil deotruoflon, while no~rosls results ... more phy~lolOglo process for disposing Dells through orderly soil deotruoflon, while no~rosls results from cytolytlo oh~ngos following Doll miss/ WQ nssos.~od their p~ttom aed extonl ~n m~,l~tlple samp~ ~a fre~~ ;~9 p.',ient ,~ M~lhpd~; Apoptosio was doto(;tod by in sih4 er~d labeling and n(l~l~ar cl~mm~ftn ~lalntng and neorosts tmmunohlstochomt~dly using a ooniug=Ued myosin light chain monoclonal ~ntibody, Accompanying tnflsmmalery infil. trains were Id~nttflod by tmmgnop, rexidasa staining of lymphncvle subsets Rosult~ were oompared with clinical doln ~nd re~dlnn hem~toxylin.~esln evaluation of ondomyocnrdh~l btopslns, RP,qUII~: Apoptosta was Identified at tbe perlphoq/of the isel~amlc to0i in 75% of the biopsi¢ls that showod peri(ransplant lachemic mltlry by Iigl~t mtoros~opy, whllo ~mmt!noh(~tochnmloal slolnlng for myosin light ohain leNly nocrests) was obsontod within the cores of ~11 lschomic loci, Apoptottc my. DO/los w~re observed In 90% el the blopsteS which showed aouto rejection and immunohtstochomlcnl staining for myosin light chain was obeowod in 86% el those btopstea Endy myocyto necresls waa dotoctod in 70% Of the bl0psi0S ovakmted without necrosis by reutlne I~lslologle grading (Grade tA • relo¢tlon),
This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotr... more This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotropic agent with calcium-sensitizing properties and activity as a phosphodiesterase inhibitor, in patients with heart failure. One hundred ninety-eight ambulatory patients with symptoms of moderate to severe heart failure despite therapy with digitalis and diuretics with or without a single vasodilator were randomly assigned to receive either placebo (n = 49) or pimobendan (n = 149) in a double-blind fashion for 12 weeks. A dose range of pimobendan was used including 2.5 (n = 49), 5 (n = 51), or 10 mg/day (n = 49). One hundred fifty-eight (80%) patients were taking a converting enzyme inhibitor (CEI) and 28 (14%) patients were taking a non-CEI vasodilator. At end point, the 5-mg dose of pimobendan significantly increase exercise duration compared with placebo (121.6 +/- 19.1 seconds, p less than 0.001), whereas the 10-mg dose produced an increase of borderline significance (81.1 +/- 19.5 seconds, p = 0.05). Peak VO2 was significantly increased by 2.23 +/- 0.58 ml/kg/min in the 5-mg group (p less than 0.01 versus placebo). Furthermore, quality of life measured with the Minnesota Living With Heart Failure Questionnaire improved by 8.5 +/- 2.3 units in the 5-mg group compared with 1.3 +/- 2.2 units in the placebo group (p less than 0.01). There were a total of 23 all-cause hospitalizations in the placebo group, which was significantly greater compared with 33 in the three groups treated with pimobendan (p less than 0.01). There were no significant differences between the placebo and pimobendan groups with respect to changes in ejection fraction and plasma norepinephrine measured at baseline and at the completion of the 12-week study, proarrhythmic effect, or the number of patients with a significant adjustment in background therapy. Eleven patients died, including three (6%) on placebo and eight (5%) on pimobendan (p = NS). Among all adverse events, headache tended to be more common in the pimobendan groups compared with placebo, with the incidence increasing with dose (p less than 0.05). These data demonstrate that pimobendan significantly increases exercise duration, peak VO2, and quality of life in patients with heart failure. Pimobendan appears to be useful adjunctive therapy when added to digitalis, diuretics, and vasodilators.
Neuroendocrine activation is known to occur in patients with congestive heart failure, but there ... more Neuroendocrine activation is known to occur in patients with congestive heart failure, but there is uncertainty as to whether this occurs before or after the presence of overt symptoms. In the Studies of Left Ventricular Dysfunction (SOLVD), a multicenter study of patients with ejection fractions of 35% or less, we compared baseline plasma norepinephrine, plasma renin activity, plasma atrial natriuretic factor, and plasma arginine vasopressin in 56 control subjects, 151 patients with left ventricular dysfunction (no overt heart failure), and 81 patients with overt heart failure before randomization. Median values for plasma norepinephrine (p = 0.0001), plasma atrial natriuretic factor (p less than 0.0001), plasma arginine vasopressin (p = 0.006), and plasma renin activity (p = 0.03) were significantly higher in patients with left ventricular dysfunction than in normal control subjects. Neuroendocrine values were highest in patients with overt heart failure. Plasma renin activity was normal in patients with left ventricular dysfunction without heart failure who were not receiving diuretics and was significantly increased (p less than 0.05) in patients on diuretic therapy. We conclude that neuroendocrine activation occurs in patients with left ventricular dysfunction and no heart failure. Neuroendocrine activation is further increased as overt heart failure ensues and diuretics are added to therapy.
The immediate and longer term variability of selected vasoactive- and volume-regulating neurohorm... more The immediate and longer term variability of selected vasoactive- and volume-regulating neurohormones were measured in patients entering a substudy of the Studies of Left Ventricular Dysfunction--a randomized clinical trial in patients with left ventricular ejection fraction &amp;amp;lt; or = 35%. The variability of these hormones has not been determined in a large cohort of patients. Immediate (short-term) variability was assessed by systematically comparing levels after 15 and 30 minutes of supine rest at the initial visit, and longer term variability was assessed by comparing 30-minute supine rest values at the initial visit with corresponding values taken at 30 minutes after 16 to 24 days of stable therapy. Initial values obtained at the first visit after 30-minute supine rest for all 209 patients were (mean +/- SEM) 512 +/- 21 pg/ml pg/ml for plasma norepinephrine, 1.9 +/- 0.2 ng/ml/hr for plasma renin activity, 3.0 +/- 0.1 pg/ml for plasma arginine vasopressin, and 129 +/- 5.3 pg/ml for plasma atrial natriuretic peptide. All variables were moderately increased relative to established normal values. There was a small but significant decrease from 15- to 30-minute supine posture in all neurohormones, except arginine vasopressin. In the presence of stable background therapy, no significant differences were found between measurements obtained after 30 minutes supine rest at the initial visit and 16 to 24 days later. Spearman correlation coefficients corresponding to immediate and longer term variability were high (range 0.55 to 0.79) (p &amp;amp;lt; 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Normal, marginal, and central ischemic regional myocardial function were evaluated in a canine mo... more Normal, marginal, and central ischemic regional myocardial function were evaluated in a canine model of myocardial infarction during 90 minute left circumflex coronary artery occlusion in 25 anesthetized dogs randomly assigned to intravenous ibuprofen infusion (n = 13,5.36 mg/kg/h beginning 1 hour before occlusion) or vehicle solution as control (n = 12) and in 15 conscious, unsedated dogs 48 and 72 hours after 90 minute circumflex artery occlusion followed by reperfusion (ibuprofen, 5.36 mg/kg/h by intravenous infusion over 7 hours beginning 1 hour before occlusion, n = 7; or vehicle solution infusion as control, n = 8).
Journal of the American College of Cardiology, 1994
ejection fincilm and a" increase in pima tm-ewphria (ti = -0.1.9, p c 0.wlO1), plum0 rain actlvll... more ejection fincilm and a" increase in pima tm-ewphria (ti = -0.1.9, p c 0.wlO1), plum0 rain actlvlly mill = -0.24, p < 0.0001) and a&dne vpwpre& (rho = -0.12, p < 0.003). The only mKqtlcm wtw llrlal natrlttnllc peptkk, rkkh skewed Ike
Hemodynamic and myocardial metabolic parameters in ischemic left ventricular (LV) dysfunction wer... more Hemodynamic and myocardial metabolic parameters in ischemic left ventricular (LV) dysfunction were evaluated in response to the beta-agonist prenalterol. Twenty micrograms/kg intravenous prenalterol increased resting heart rate and cardiac output and decreased LV filling pressure, systemic vascular resistance, and pulmonary artery pressure. Resting coronary blood flow and myocardial oxygen consumption increased but net myocardial lactate and oxygen extraction did not change significantly. During pacing induced tachycardia (121 +/- 4 beats/min), prenalterol improved cardiac index and stroke work index; whereas, LV filling pressure, systemic vascular resistance, and pulmonary artery pressure decreased. Coronary blood flow and myocardial oxygen extraction did not change significantly. Net myocardial lactate extraction during pacing decreased insignificantly; one patient developed overt lactate production. Thus, prenalterol improves cardiovascular function at rest and during pacing-induced tachycardia in ischemic LV failure, but at the cost of higher resting myocardial oxygen consumption. The majority of subjects had no adverse metabolic response.
Angiotensin-converting enzyme (ACE) inhibition with captopril is accepted therapy for the treatme... more Angiotensin-converting enzyme (ACE) inhibition with captopril is accepted therapy for the treatment of symptomatic congestive heart failure. In this trial, we compared the new ACE inhibitor, lisinopril, to captopril during a 12-week randomized double-blind study. One hundred twenty-nine patients with New York Heart Association class II, III, or IV congestive heart failure were randomized to receive either lisinopril 5 mg/day (n = 64) or captopril 37.5 mg/day (n = 65) in 15 centers. Drug doses could be titrated upwards every 4 weeks. The primary measure of drug efficacy was improvement in treadmill exercise time using a modified Naughton protocol. Secondary measures of efficacy and the development of adverse effects were also examined. Lisinopril improved exercise time (following 12 weeks of therapy) more than captopril [from 500 +/- 30 to 682 +/- 34 sec (mean +/- SEM) with lisinopril versus 480 +/- 26 to 600 +/- 35 sec with captopril; difference between groups, p less than 0.05]. Adverse drug effects were unusual and similar in frequency in the two groups, although an increase in blood urea nitrogen was more common with lisinopril than with captopril (p less than 0.05). These results indicate that using the doses and treatment regimens studied, lisinopril is more effective than captopril for the treatment of symptomatic congestive heart failure. Adverse experiences with lisinopril were infrequent and similar in incidence to those observed with captopril.
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