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Effect of the vasopeptidase inhibitor, omapatrilat, on bradykinin metabolism in a model of left ventricular hypertrophy induced by myocardial infarction
The Third Annual Scientific Meeting
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HFSA
61
224
225
ACE Inhibitor Use Is Necessary but Not Sufficient for the Treatment of Symptomatic Systolic Left Ventricular Dysfunction Catherine Chelimsky-Fallick, John S. Golden, Donna J. Mateski, Colleen M. Healey, Sharon R. Josephson, Susan J. Morikawa, Carol A. Offutt, Patricia A.G. Powers, Martha I. Spence; Cardiology, Kaiser Permanente Mid Atlantic States, Rockville, MD
Effect of the Vasopeptidase Inhibitor, Omapatrilat, on Bradykinin Metabolism in a Model of Left Veutricular Hypertrophy Induced by Myocardial Infarction Marie-Josee Dunmulin, I Albert Adam] Hugues Gosselin, 2 Jean-Lucien Rouleau, 2 Daniel Lamontagnel; ~Faculte de Pharmacie, Universite de Montreal, 21nstitut de Cardiologie de Montreal, QC, Canada
Angiotensin converting enzyme inhibitors (ACE-I) increase survival and slow the progression of heart failure (HF) in patients (pts) with left ventricular dysfunction. Nonetheless, many pts on optimal doses of ACE-I suffer HF decompensation requiring hospitalization. We examined the impact of a comprehensive heart failure treatment program (HFTP) on a referral population in which ACE-I use was already high. We enrolled 122 pts into the HFTP. Entry criteria included an ejection fraction <35%, New York Heart Association (NYHA) class III or IV symptoms, and a serum creatinine (Cr) of less than 3.5 mg/dl. 83% were on ACE-I at entry. Diuretics, ACE-I and beta blockers were titrated to achieve optimal dosing and clinical compensation, defined as achieving a stable weight for more than two weeks with best NYHA class possible. Pts enrolled in the HFTP were on a variety of ACE4, but for the purposes of this analysis, ACE-I doses have been expressed in lisinopril equivalents. Hospitalization (hosp) days were assessed for the 6 month periods pre- and post-HFTP enrollment.
Pt population: Mean age was 62-+ 13 years. 49% were African Americans and 43% were diabetic. 50% of pts had an ischemic etiology. Mean follow up (F/U) was 33_+18 weeks.
Results:
ACE-I dose (rag)
NYHA class
CC (%)
Initial Last F/U p value
19+16 30-+i4 .01
3.3+0.4 2.3-+0.7 .01
20 77 .01
Cr (mg/dl)
Hosp Days
Omapatrilat is a novel vasopeptidase inhibitor, a single molecule that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). Its ex vivo effects on exogenous bradykinin (BK) metabolism, after a single passage through the coronary bed, were determined in sham and infarcted hearts at 2, 5, and 36 days post-MI and compared with the effect of an ACE inhibitor at 36 days post-MI. MI was induced in rats by ligation of the left anterior descending coronary artery. These drug doses were previously shown to inhibit completely serum ACE activity. Exogenous BK (10 nM), enalaprilat (130 nM), and omapatrilat (510 nM) were infused into isolated Langendorff rat hearts peffused at 1 mL min 1. Residual BK in the coronary effluent was quantified by ELISA. BK degradation rate (Vm~x/ Km,min-~) was significantly reduced (*P<0.05) in infarcted hearts compared with sham hearts, both at days 2 (2.74 -+ 0.13" vs 3.67 -+ 0.37 rainq) and 5 (2.56 _+ 0.20* vs 3.66 -+ 0.22 rnin J), but not at day 36. Omapatrilat decreased BK degradation rate significantly in the post-MI hearts at 2, 5, and 36 days compared with the untreated infarcted hearts: 2 days
Control Omapatrilat Enalaprilat
5 days
2.74-+0.13 1.62_+0.11"
--
2.56-+0.20 0.99-+0.25*
--
36 days (rain i) 2.85_+0.14 0.78-+0,14" 1.15_+0.14"
Conclusion: Despite high ACE-I use at the time of enrollment, a large proportion of pts were poorly compensated. These pts experienced substantial clinical improvement and a 39% decrease in hospitalization days following HFTP enrollment. A comprehensive HFTP improves outcomes to a degree beyond that which can be explained by increasing ACE-I use alone.
*P< 0.05 vs control groups (without treatment) The effect of omapatrilat on BK metaboIism was also compared with an ACE inhibitor (enalaprilat) in the 36-day infarcted and sham hearts. Without treatment, BK degradation rate was 2.85 -+ 0.14 rain ~ for infarcted hearts and 2.92 + 0.35 min-~ for sham hearts. Enalaprilat and omapatrilat treatment significantly decreased the BK degradation rate for the infarcted hearts. For the sham hearts, omapatrilat treatment significantly reduced BK metabolism to 0.96 _+ 0.36 rain 4 , while the enalaprilat reduction did not reach statistical significance (1.56 ± 0.16 rain4). In conclusion, omapatrilat significantly reduced BK degradation; this reduction was greater than that achieved with enalaprilat. This property may be of clidicaI relevance in hypertension and heart failure.
226
227
Regional Contractile Responses to /3-Adrenergic Stimulation in Patients with End Stage Ischemie Cardiomyopathy Versus Idiopathic Dilated Cardiomyopathy Padma Uppalapati, I Vidya Ponnathpur, ~ Kwame Akosah, 2 Andy Prinz] David Brands] P.K. MohantyI; ~McGuire VAMC/Med Coll of VA, Richmond, VA, 2Gundersen Lutheran Hospital, LaCrosse, WI
Treating Major Depression in Congestive Heart Failure: An Open-Label Trial of Nefazodoue Francois Lesperance, Nancy Frasure-Smith, Michel White, Jean-Lacien Rouleau; Montreal Heart Institute, Montreal, Canada
1.3_+0.5 1.4_+0.5 NS
405 243
Background: Patients with end-stage heart thilure (HF) manifest variable response to /3-adrenergic stimulation. Objective: We sought to determine the differences in hemodynamic and regional contractile responses to dobutamine in patients with ischemic (ICM) and idiopathic dilated cardiomyopathy (IDCM) to characterize/3-adrenergic mediated contractile behavior. Methods: Dobutamine echocardiography was performed with dobutamine infusion (5,10,20mcg/kg/min) in patients with ICM and IDCM referred for heart transplant. We measured the heart rate (HR), blood pressure (BP) and regional wall motion response (wall motion score index; WMSI) to dobutamine in 22 patients (mean age 51-+5.07, LVEF 24_+8%). Patients were divided into 2 groups; Gr 1-IDCM (n=7) and Gr 2-ICM (n= 15). Results: The results are summarized in the graph. There was modest improvement in WMSI in response to dobutamine (at 5mcg/kg/ rain) in both groups. In IDCM, augmented response was maintained up to 20mcg/ kg/min. In contrast, there was a significant worsening in WMSI in ICM in response to 20mcg/kg/min dobutamine (p<0.05), suggesting further regional ischemic dysfunction, despite similar HR and BP response in j - B310mcg/kg/min) s ii z| should be avoided in the inotropic OalJllaurln~(racVKl~,mta) tune-up of severe ischemic heart failure due to its potential to induce further ischemia.
Depression is common in patients with coronary artery disease and has been shown to be an independent predictor of mortality through at least the first 18 months following MI. We reasoned that cardiac patients at highest mortality risk might experience the greatest prognostic improvement from treatment of depression, but also might be most prone to adverse effects of antidepressant medication. We obtained preliminary efficacy and safety data for the antidepressant nefazodone in patients with class II and III congestive heart failure (CHF). A 12-week, open-label~ evaluation of nefazodone treatment of major depression was conducted in 21 CHF patients (19 of ischemic origin) with left ventricular ejection fractions --<40% (LVEF). Five women and 16 men, aged 38 to 77, with a mean LVEF of 28.5%-+6.9 participated. Thirteen were class II and 9 were class III on the New York Heart Association classification. Fifteen (5 class III) patients completed the 12-week trial. Reasons for the 6 dropouts were sexual dysfunction, peripheral edema, visual problems, sedation, worsening of CHF, and non-compliance. The final median daily dosage of nefazodone was 400 mg. Mean Hamilton Depression Scores (clinician rating of depression severity) decreased from 25.8_+6.1 to 8.2-+7.0 (P<.001), and self-report Beck Depression Inventory scores decreased from 29.7-+19.8 to 11.1+6.3 (P<.001). There was no change over the 12 weeks of treatment in weight (77.7_+20.3 to 76.7-+21.1; P=0.16), resting heart rate (70.5_+13.3 to 67.7_+16.5; P=0.25), supine systolic blood pressure (125.5_+16.9 to 123.8-+ 17.8; P=0.68) or supine diastolic BP (73.8~ 13.3 to 70.0-+11.3; P=0.21). There were small drops in standing systolic BP (126.6_+ 17.4 to 118.1 -+ i5.5; P=0.027) and standing diastolic BP (78.4_+ 15.0 to 72.9 + 10.3; P-0.057). In conclusion, nefazodone treatment was associated with a significant improvement in depression and relatively few side effects in this sample of depressed patients with moderate to severe CHF. Randomized controlled trials are needed to confirm efficacy and safety in this high-risk population.
•
HFSA
61
224
225
ACE Inhibitor Use Is Necessary but Not Sufficient for the Treatment of Symptomatic Systolic Left Ventricular Dysfunction Catherine Chelimsky-Fallick, John S. Golden, Donna J. Mateski, Colleen M. Healey, Sharon R. Josephson, Susan J. Morikawa, Carol A. Offutt, Patricia A.G. Powers, Martha I. Spence; Cardiology, Kaiser Permanente Mid Atlantic States, Rockville, MD
Effect of the Vasopeptidase Inhibitor, Omapatrilat, on Bradykinin Metabolism in a Model of Left Veutricular Hypertrophy Induced by Myocardial Infarction Marie-Josee Dunmulin, I Albert Adam] Hugues Gosselin, 2 Jean-Lucien Rouleau, 2 Daniel Lamontagnel; ~Faculte de Pharmacie, Universite de Montreal, 21nstitut de Cardiologie de Montreal, QC, Canada
Angiotensin converting enzyme inhibitors (ACE-I) increase survival and slow the progression of heart failure (HF) in patients (pts) with left ventricular dysfunction. Nonetheless, many pts on optimal doses of ACE-I suffer HF decompensation requiring hospitalization. We examined the impact of a comprehensive heart failure treatment program (HFTP) on a referral population in which ACE-I use was already high. We enrolled 122 pts into the HFTP. Entry criteria included an ejection fraction <35%, New York Heart Association (NYHA) class III or IV symptoms, and a serum creatinine (Cr) of less than 3.5 mg/dl. 83% were on ACE-I at entry. Diuretics, ACE-I and beta blockers were titrated to achieve optimal dosing and clinical compensation, defined as achieving a stable weight for more than two weeks with best NYHA class possible. Pts enrolled in the HFTP were on a variety of ACE4, but for the purposes of this analysis, ACE-I doses have been expressed in lisinopril equivalents. Hospitalization (hosp) days were assessed for the 6 month periods pre- and post-HFTP enrollment.
Pt population: Mean age was 62-+ 13 years. 49% were African Americans and 43% were diabetic. 50% of pts had an ischemic etiology. Mean follow up (F/U) was 33_+18 weeks.
Results:
ACE-I dose (rag)
NYHA class
CC (%)
Initial Last F/U p value
19+16 30-+i4 .01
3.3+0.4 2.3-+0.7 .01
20 77 .01
Cr (mg/dl)
Hosp Days
Omapatrilat is a novel vasopeptidase inhibitor, a single molecule that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). Its ex vivo effects on exogenous bradykinin (BK) metabolism, after a single passage through the coronary bed, were determined in sham and infarcted hearts at 2, 5, and 36 days post-MI and compared with the effect of an ACE inhibitor at 36 days post-MI. MI was induced in rats by ligation of the left anterior descending coronary artery. These drug doses were previously shown to inhibit completely serum ACE activity. Exogenous BK (10 nM), enalaprilat (130 nM), and omapatrilat (510 nM) were infused into isolated Langendorff rat hearts peffused at 1 mL min 1. Residual BK in the coronary effluent was quantified by ELISA. BK degradation rate (Vm~x/ Km,min-~) was significantly reduced (*P<0.05) in infarcted hearts compared with sham hearts, both at days 2 (2.74 -+ 0.13" vs 3.67 -+ 0.37 rainq) and 5 (2.56 _+ 0.20* vs 3.66 -+ 0.22 rnin J), but not at day 36. Omapatrilat decreased BK degradation rate significantly in the post-MI hearts at 2, 5, and 36 days compared with the untreated infarcted hearts: 2 days
Control Omapatrilat Enalaprilat
5 days
2.74-+0.13 1.62_+0.11"
--
2.56-+0.20 0.99-+0.25*
--
36 days (rain i) 2.85_+0.14 0.78-+0,14" 1.15_+0.14"
Conclusion: Despite high ACE-I use at the time of enrollment, a large proportion of pts were poorly compensated. These pts experienced substantial clinical improvement and a 39% decrease in hospitalization days following HFTP enrollment. A comprehensive HFTP improves outcomes to a degree beyond that which can be explained by increasing ACE-I use alone.
*P< 0.05 vs control groups (without treatment) The effect of omapatrilat on BK metaboIism was also compared with an ACE inhibitor (enalaprilat) in the 36-day infarcted and sham hearts. Without treatment, BK degradation rate was 2.85 -+ 0.14 rain ~ for infarcted hearts and 2.92 + 0.35 min-~ for sham hearts. Enalaprilat and omapatrilat treatment significantly decreased the BK degradation rate for the infarcted hearts. For the sham hearts, omapatrilat treatment significantly reduced BK metabolism to 0.96 _+ 0.36 rain 4 , while the enalaprilat reduction did not reach statistical significance (1.56 ± 0.16 rain4). In conclusion, omapatrilat significantly reduced BK degradation; this reduction was greater than that achieved with enalaprilat. This property may be of clidicaI relevance in hypertension and heart failure.
226
227
Regional Contractile Responses to /3-Adrenergic Stimulation in Patients with End Stage Ischemie Cardiomyopathy Versus Idiopathic Dilated Cardiomyopathy Padma Uppalapati, I Vidya Ponnathpur, ~ Kwame Akosah, 2 Andy Prinz] David Brands] P.K. MohantyI; ~McGuire VAMC/Med Coll of VA, Richmond, VA, 2Gundersen Lutheran Hospital, LaCrosse, WI
Treating Major Depression in Congestive Heart Failure: An Open-Label Trial of Nefazodoue Francois Lesperance, Nancy Frasure-Smith, Michel White, Jean-Lacien Rouleau; Montreal Heart Institute, Montreal, Canada
1.3_+0.5 1.4_+0.5 NS
405 243
Background: Patients with end-stage heart thilure (HF) manifest variable response to /3-adrenergic stimulation. Objective: We sought to determine the differences in hemodynamic and regional contractile responses to dobutamine in patients with ischemic (ICM) and idiopathic dilated cardiomyopathy (IDCM) to characterize/3-adrenergic mediated contractile behavior. Methods: Dobutamine echocardiography was performed with dobutamine infusion (5,10,20mcg/kg/min) in patients with ICM and IDCM referred for heart transplant. We measured the heart rate (HR), blood pressure (BP) and regional wall motion response (wall motion score index; WMSI) to dobutamine in 22 patients (mean age 51-+5.07, LVEF 24_+8%). Patients were divided into 2 groups; Gr 1-IDCM (n=7) and Gr 2-ICM (n= 15). Results: The results are summarized in the graph. There was modest improvement in WMSI in response to dobutamine (at 5mcg/kg/ rain) in both groups. In IDCM, augmented response was maintained up to 20mcg/ kg/min. In contrast, there was a significant worsening in WMSI in ICM in response to 20mcg/kg/min dobutamine (p<0.05), suggesting further regional ischemic dysfunction, despite similar HR and BP response in j - B310mcg/kg/min) s ii z| should be avoided in the inotropic OalJllaurln~(racVKl~,mta) tune-up of severe ischemic heart failure due to its potential to induce further ischemia.
Depression is common in patients with coronary artery disease and has been shown to be an independent predictor of mortality through at least the first 18 months following MI. We reasoned that cardiac patients at highest mortality risk might experience the greatest prognostic improvement from treatment of depression, but also might be most prone to adverse effects of antidepressant medication. We obtained preliminary efficacy and safety data for the antidepressant nefazodone in patients with class II and III congestive heart failure (CHF). A 12-week, open-label~ evaluation of nefazodone treatment of major depression was conducted in 21 CHF patients (19 of ischemic origin) with left ventricular ejection fractions --<40% (LVEF). Five women and 16 men, aged 38 to 77, with a mean LVEF of 28.5%-+6.9 participated. Thirteen were class II and 9 were class III on the New York Heart Association classification. Fifteen (5 class III) patients completed the 12-week trial. Reasons for the 6 dropouts were sexual dysfunction, peripheral edema, visual problems, sedation, worsening of CHF, and non-compliance. The final median daily dosage of nefazodone was 400 mg. Mean Hamilton Depression Scores (clinician rating of depression severity) decreased from 25.8_+6.1 to 8.2-+7.0 (P<.001), and self-report Beck Depression Inventory scores decreased from 29.7-+19.8 to 11.1+6.3 (P<.001). There was no change over the 12 weeks of treatment in weight (77.7_+20.3 to 76.7-+21.1; P=0.16), resting heart rate (70.5_+13.3 to 67.7_+16.5; P=0.25), supine systolic blood pressure (125.5_+16.9 to 123.8-+ 17.8; P=0.68) or supine diastolic BP (73.8~ 13.3 to 70.0-+11.3; P=0.21). There were small drops in standing systolic BP (126.6_+ 17.4 to 118.1 -+ i5.5; P=0.027) and standing diastolic BP (78.4_+ 15.0 to 72.9 + 10.3; P-0.057). In conclusion, nefazodone treatment was associated with a significant improvement in depression and relatively few side effects in this sample of depressed patients with moderate to severe CHF. Randomized controlled trials are needed to confirm efficacy and safety in this high-risk population.