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Effects of intravenous nesiritide on renal hemodynamics in patients with congestive heart failure
S88
Journal of Cardiac Failure Vol. 10 No. 4 Suppl. 2004
256
258
Effects of Intravenous Nesiritide on Renal Hemodynamics in Patients with Congestive Heart Failure Uri Elkayam,1 Harpreet Singh,1 Mohammed W. Akhter,1 Naji Bourji,1 Fahed Bitar,1 Salman Khan,1 Ming Liu1; 1Division of Cardiovascular Medicine, University of Southern California, Los Angeles, CA
Long-Term Treatment with the Fatty Acid Oxidation Inhibitor Trimetazidine Improves Systolic Function but Does Not Affect Left Ventricular Dilation in Heart Failure Eric E. Morgan,1 Tracy A. McElfresh,1 Margaret P. Chandler,1 Martin E. Young,3 Brian D. Hoit,1,2 William C. Stanley1; 1Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH; 2Department of Medicine, University Hospitals of Cleveland, Cleveland, OH; 3Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
Objectives: To evaluate the renal circulatory effects of intravenous nesiritide in patients with congestive heart failure (CHF). Background: Nesiritide, recombinant human B-type natriuretic peptide, has been shown to be efficacious in the treatment of decompensated heart failure and to improve renal function. The exact mechanism of nesiritide effect on the kidney and renal circulation in patients with CHF has not been fully investigated. Methods: Thirteen patients with CHF underwent cardiac catheterization and measurements of renal blood flow using quantitative renal artery angiography and intra renal arterial Doppler flow velocity at baseline, after nesiritide bolus injection (2µ/kg) and 15 minutes after initiation of continuous nesiritide infusion (0.01µ/kg/min). Results: Fifteen minutes of continuous nesiritide infusion resulted in 13% reduction in mean right atrial pressure (p ⫽ 0.16), 15% in mean pulmonary artery pressure (p ⬍ 0.005) and 30% in mean pulmonary capillary wedge pressure (p ⬍ 0.005). Changes in renal hemodynamics were as follows: (please see table). Conclusions: Nesiritide exerts a renal vasodilatory effect predominantly on the large conductance vessels. Renal blood flow is increased after bolus nesiritide administration and is maintained during nesiritide continous infusion in spite of a significant decrease in renal perfusion pressure. Changes in renal hemodynamics post nesiritide bolus and during a 15 minutes nesiritide infusion compared to baseline
Baseline Bolus Infusion
Mean Renal Artery Pressure (mmHg)
Renal Artery Diameter (mm)
Average Renal Peak Velocity (m/s)
Renal Blood Flow (ml/min)
99 ⫾ 17 93 ⫾ 15 89 ⫾ 12*
6.24 ⫾ 0.7 6.36 ⫾ 0.8 6.73 ⫾ 0.8**
29 ⫾ 16 32 ⫾ 18 24 ⫾ 16*
269 ⫾ 164 316 ⫾ 213* 262 ⫾ 189†
Introduction: Previous studies suggest that partial inhibition of myocardial fatty acid oxidation improves cardiac function in heart failure. This study tested the hypothesis that chronic treatment with trimetazidine (TMZ), a selective inhibitor of the fatty acid β-oxidation enzyme 3-ketoacyl-CoA thiolase, improves systolic function, reduces left ventricular (LV) dilation and prevents increased expression of atrial natriuretic factor (ANF) in the rat coronary artery ligation model of heart failure. Methods: Male Wistar rats underwent left coronary artery ligation (n ⫽ 18) or sham operation (n ⫽ 9). Eight weeks after surgery, the infarcted rats were randomized into two groups; TMZ treatment (40 mgkg⫺1day⫺1 for 12 weeks)(n ⫽ 6) or control (non-treatment; NT)(n ⫽ 12). Twenty weeks after infarction, rats were anesthetized with isoflurane and studied with 2-D echocardiography. LV area fractional shortening (FSa) was determined from the long axis view, LV end diastolic diameter (EDD) was determined from 2-D guided M-mode tracings obtained from a short axis view at the mid-papillary level, and the myocardial performance index (MPI) was calculated using color-flow directed Doppler of mitral and aortic flow. Hearts were subsequently isolated for measurement of the transcriptional heart failure marker, ANF, by real-time RT-PCR. Results: Coronary artery ligation decreased FSa, and increased EDD, MPI and ANF expression compared to sham controls (Table). TMZ treatment improved FSa, reduced MPI and decreased ANF expression, but did not affect EDD (compared to the untreated infarct group; Table). Conclusion: Chronic treatment with the myocardial fatty acid oxidation inhibitor trimetazidine improves systolic function and reduces expression of ANF, but does not reduce LV dilation in the rat coronary artery ligation model of heart failure. GROUP
*p ⬍ 0.05 vs baseline **p ⬍ 0.0005 vs baseline †p ⫽ 0.02 vs bolus
EDD (cm)
FSa (%)
MPI
Sham (n ⫽ 9) 0.87 ⫾ 0.02 58 ⫾ 2 0.33 ⫾ 0.03 Infarcted NT (n ⫽ 12) 1.10 ⫾ 0.1** 27 ⫾ 2* 0.62 ⫾ 0.04* Infarcted ⫹ TMZ (n ⫽ 6) 1.04 ⫾ 0.07** 37 ⫾ 6*† 0.45 ⫾ 0.03*†
ANF (% of Sham) 100 ⫾ 31 356 ⫾ 49* 160 ⫾ 42†
Data are mean ⫾ SEM, *p ⬍ 0.05 Infarcted vs Sham, **p ⫽ 0.06 Infarcted vs Sham, †p ⬍ 0.05 Infarcted-TMZ vs Infarcted-NT by ANOVA.
257 Acute and Chronic Effect of Subcutaneous Brain Natriuretic Peptide in Experimental Diastolic Heart Failure Donna M. Meyer, Vijaya Munagala, John C. Burnett, Horng H. Chen, Margaret M. Redfield; Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN Background: Nearly 50% of patients with heart failure (HF) have a normal ejection fraction (diastolic HF, DHF). Brain natriuretic peptide (BNP) may be a useful therapy for DHF. Novel delivery systems for chronic subcutaneous (subQ) administration of small peptides such as BNP are emerging and may make chronic BNP therapy an option for patients with DHF. Objective: We investigated the acute and chronic hemodynamic and humoral effects of subQ BNP in an elderly hypertensive canine model characterized by chronic hypertension, ventricular hypertrophy and fibrosis, normal ejection fraction but impaired diastolic function (Stage B DHF). Methods: Chronic hypertension was induced by bilateral renal wrapping in elderly dogs (age 8–13 years; n ⫽ 7) instrumented with a Konigsberg LV transducer and aortic catheter. Six weeks after renal wrapping, dogs were studied in the conscious state. Aortic and LV pressures and humoral function were assessed at baseline (BL) and for 4 hours after subQ BNP (25 ug × 1). Dogs were then treated with subQ BNP (25 ug bid) for 4 weeks (n ⫽ 4 completed). Baseline hemodynamics (at trough BNP levels) and the response to subQ BNP were were reassessed after chronic therapy. Results: The acute response to the first dose of subQ BNP is shown in table. Mean ⫾ sem;*p ⬍ 0.05 vs BL (ANOVA). The hemodynamic and humoral response to subQ BNP was similar after chronic therapy with significant changes in systolic BP, pulse pressure, BNP and cGMP and trends in other parameters. At trough BNP levels, systolic BP (217 ⫾ 17 vs 194 ⫾ 8 mmHg, p ⫽ 0.10) and pulse pressure (87 ⫾ 5 vs 76 ⫾ 5 mmHg, p ⫽ 0.07) tended to be lower after chronic subQ BNP (n ⫽ 4). Conclusions: SubQ BNP activated cGMP, reduced afterload and preload and improved relaxation in a canine model of DHF. With chronic therapy, there was no tolerance and a chronic antihypertensive effect was noted. Chronic subQ BNP may be an effective therapy for hypertension and DHF. Effect of subQ BNP prior to chronic BNP therapy Baseline Systolic BP (mmHg) Pulse Pressure (mmHg) Heart rate (bpm) LV end diastolic P (mmHg) tau (ms) human BNP (pg/ml) cGMP (pmol/ml)
BNP 0.5 Hour
BNP 1 Hour
200 ⫾ 14 168 ⫾ 10* 170 ⫾ 10* 84 ⫾ 4 62 ⫾ 4* 61 ⫾ 3* 102 ⫾ 10 110 ⫾ 7 105 ⫾ 10 14.3 ⫾ 1.9 7.2 ⫾ 1.9* 9.7 ⫾ 1.9* 34.6 ⫾ 2.8 32.1 ⫾ 2.5* 31.6 ⫾ 2.5* 101 ⫾ 84 4768 ⫾ 1171* 2671 ⫾ 1059* 21.5 ⫾ 3.3 64.6 ⫾ 3.8* 65.9 ⫾ 5.9*
BNP 2 Hour
BNP 4 Hour
182 ⫾ 14* 66 ⫾ 6* 107 ⫾ 10 8.9 ⫾ 2.1* 32.6 ⫾ 2.5 653 ⫾ 234* 60.1 ⫾ 4.8*
189 ⫾ 15 71 ⫾ 4* 111 ⫾ 9 7.2 ⫾ 3.2* 31.4 ⫾ 2.1* 109 ⫾ 45 31.8 ⫾ 2.8*
259 The Impact of Serum Digoxin Concentration and Enalapril Therapy in Patients with CHF: The SOLVD Trial Revisited Richard J. Sheppard,1 Sylvie Levesque,2 Simon deDenus,1 Anique Ducharme,1 Martial Bourassa,1 Jean-Claude Tardif,1 Normand Racine,1 Michel White1; 1Clinical Research, Montreal Heart Institute, Montreal, QC, Canada; 2Biostatistics, Montreal Heart Institute, Montreal, QC, Canada Background: Elevated serum digoxin concentrations (SDC) are associated with increased mortality in patients with CHF. The impact of elevated SDC on the efficacy of ACE inhibitors in patients with CHF has not been investigated. We examined the impact of SDC on outcomes and the interaction of enalapril and SDC in patients enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) study at our institution. Methods: There were 391 patients enrolled in SOLVD at the Montreal Heart Institute. Ninety-six patients received digoxin with a documented SDC (age 59 ⫾ 10 years (mean ⫾ SD), LVEF 23 ⫾ 7%, and 86% male). Kaplan Meier curves were generated comparing patients with SDC ⱖ 1 ng/ml (n ⫽ 52), SDC ⬍ 1 ng/ml (n ⫽ 44), and patients not on digoxin (n ⫽ 295). Separate survival analyses were performed for each clinical variable using SDC as a continuous variable in each model. Results: There were no differences in clinical characteristics for patients with SDC ⬍ 1 ng/ml or patients with SDC ⱖ 1 ng/ml. Kaplan-Meier curves comparing patients with SDC ⱖ 1 ng/ml, SDC ⬍ 1 ng/ml and patients not on digoxin are shown in Figure 1. On univariate analysis, for an increase of 0.5 ng/ml in SDC, there was an increased risk of new or worsening CHF with increasing SDC (HR ⫽ 1.46, 95% CI: 1.08–2.00, p ⫽ 0.015). For individual multivariate analyses, increased risk of new or worsening CHF remained similar when we controlled for several factors including age (HR: 1.47 95% CI: 1.09–1.99, p ⫽ 0.013), gender (HR ⫽ 1.47, 95% CI: 1.07– 2.01, p ⫽ 0.017), LVEF (HR⫽1.43 95% CI: 1.06–1.93, p ⫽ 0.020), and creatinine (HR ⫽ 1.44, 95% CI ⫽ 1.04–1.99, p ⫽ 0.030). The SDC did not interact with the use of enalapril/placebo on multivariate analysis (p ⫽ 0.957). Patients with NYHA III, not NYHA I-II, with a higher digoxin level, had an increased risk of new or worsening CHF (HR ⫽ 2.88 CI: 1.56 – 5.31, p ⫽ 0.001). Conclusions: In this small cohort of patients with CHF, elevated SDC is associated with an increased risk of earlier, recurrent CHF. However, the therapeutic benefit with enalapril is not impacted by the SDC.
Journal of Cardiac Failure Vol. 10 No. 4 Suppl. 2004
256
258
Effects of Intravenous Nesiritide on Renal Hemodynamics in Patients with Congestive Heart Failure Uri Elkayam,1 Harpreet Singh,1 Mohammed W. Akhter,1 Naji Bourji,1 Fahed Bitar,1 Salman Khan,1 Ming Liu1; 1Division of Cardiovascular Medicine, University of Southern California, Los Angeles, CA
Long-Term Treatment with the Fatty Acid Oxidation Inhibitor Trimetazidine Improves Systolic Function but Does Not Affect Left Ventricular Dilation in Heart Failure Eric E. Morgan,1 Tracy A. McElfresh,1 Margaret P. Chandler,1 Martin E. Young,3 Brian D. Hoit,1,2 William C. Stanley1; 1Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH; 2Department of Medicine, University Hospitals of Cleveland, Cleveland, OH; 3Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
Objectives: To evaluate the renal circulatory effects of intravenous nesiritide in patients with congestive heart failure (CHF). Background: Nesiritide, recombinant human B-type natriuretic peptide, has been shown to be efficacious in the treatment of decompensated heart failure and to improve renal function. The exact mechanism of nesiritide effect on the kidney and renal circulation in patients with CHF has not been fully investigated. Methods: Thirteen patients with CHF underwent cardiac catheterization and measurements of renal blood flow using quantitative renal artery angiography and intra renal arterial Doppler flow velocity at baseline, after nesiritide bolus injection (2µ/kg) and 15 minutes after initiation of continuous nesiritide infusion (0.01µ/kg/min). Results: Fifteen minutes of continuous nesiritide infusion resulted in 13% reduction in mean right atrial pressure (p ⫽ 0.16), 15% in mean pulmonary artery pressure (p ⬍ 0.005) and 30% in mean pulmonary capillary wedge pressure (p ⬍ 0.005). Changes in renal hemodynamics were as follows: (please see table). Conclusions: Nesiritide exerts a renal vasodilatory effect predominantly on the large conductance vessels. Renal blood flow is increased after bolus nesiritide administration and is maintained during nesiritide continous infusion in spite of a significant decrease in renal perfusion pressure. Changes in renal hemodynamics post nesiritide bolus and during a 15 minutes nesiritide infusion compared to baseline
Baseline Bolus Infusion
Mean Renal Artery Pressure (mmHg)
Renal Artery Diameter (mm)
Average Renal Peak Velocity (m/s)
Renal Blood Flow (ml/min)
99 ⫾ 17 93 ⫾ 15 89 ⫾ 12*
6.24 ⫾ 0.7 6.36 ⫾ 0.8 6.73 ⫾ 0.8**
29 ⫾ 16 32 ⫾ 18 24 ⫾ 16*
269 ⫾ 164 316 ⫾ 213* 262 ⫾ 189†
Introduction: Previous studies suggest that partial inhibition of myocardial fatty acid oxidation improves cardiac function in heart failure. This study tested the hypothesis that chronic treatment with trimetazidine (TMZ), a selective inhibitor of the fatty acid β-oxidation enzyme 3-ketoacyl-CoA thiolase, improves systolic function, reduces left ventricular (LV) dilation and prevents increased expression of atrial natriuretic factor (ANF) in the rat coronary artery ligation model of heart failure. Methods: Male Wistar rats underwent left coronary artery ligation (n ⫽ 18) or sham operation (n ⫽ 9). Eight weeks after surgery, the infarcted rats were randomized into two groups; TMZ treatment (40 mgkg⫺1day⫺1 for 12 weeks)(n ⫽ 6) or control (non-treatment; NT)(n ⫽ 12). Twenty weeks after infarction, rats were anesthetized with isoflurane and studied with 2-D echocardiography. LV area fractional shortening (FSa) was determined from the long axis view, LV end diastolic diameter (EDD) was determined from 2-D guided M-mode tracings obtained from a short axis view at the mid-papillary level, and the myocardial performance index (MPI) was calculated using color-flow directed Doppler of mitral and aortic flow. Hearts were subsequently isolated for measurement of the transcriptional heart failure marker, ANF, by real-time RT-PCR. Results: Coronary artery ligation decreased FSa, and increased EDD, MPI and ANF expression compared to sham controls (Table). TMZ treatment improved FSa, reduced MPI and decreased ANF expression, but did not affect EDD (compared to the untreated infarct group; Table). Conclusion: Chronic treatment with the myocardial fatty acid oxidation inhibitor trimetazidine improves systolic function and reduces expression of ANF, but does not reduce LV dilation in the rat coronary artery ligation model of heart failure. GROUP
*p ⬍ 0.05 vs baseline **p ⬍ 0.0005 vs baseline †p ⫽ 0.02 vs bolus
EDD (cm)
FSa (%)
MPI
Sham (n ⫽ 9) 0.87 ⫾ 0.02 58 ⫾ 2 0.33 ⫾ 0.03 Infarcted NT (n ⫽ 12) 1.10 ⫾ 0.1** 27 ⫾ 2* 0.62 ⫾ 0.04* Infarcted ⫹ TMZ (n ⫽ 6) 1.04 ⫾ 0.07** 37 ⫾ 6*† 0.45 ⫾ 0.03*†
ANF (% of Sham) 100 ⫾ 31 356 ⫾ 49* 160 ⫾ 42†
Data are mean ⫾ SEM, *p ⬍ 0.05 Infarcted vs Sham, **p ⫽ 0.06 Infarcted vs Sham, †p ⬍ 0.05 Infarcted-TMZ vs Infarcted-NT by ANOVA.
257 Acute and Chronic Effect of Subcutaneous Brain Natriuretic Peptide in Experimental Diastolic Heart Failure Donna M. Meyer, Vijaya Munagala, John C. Burnett, Horng H. Chen, Margaret M. Redfield; Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN Background: Nearly 50% of patients with heart failure (HF) have a normal ejection fraction (diastolic HF, DHF). Brain natriuretic peptide (BNP) may be a useful therapy for DHF. Novel delivery systems for chronic subcutaneous (subQ) administration of small peptides such as BNP are emerging and may make chronic BNP therapy an option for patients with DHF. Objective: We investigated the acute and chronic hemodynamic and humoral effects of subQ BNP in an elderly hypertensive canine model characterized by chronic hypertension, ventricular hypertrophy and fibrosis, normal ejection fraction but impaired diastolic function (Stage B DHF). Methods: Chronic hypertension was induced by bilateral renal wrapping in elderly dogs (age 8–13 years; n ⫽ 7) instrumented with a Konigsberg LV transducer and aortic catheter. Six weeks after renal wrapping, dogs were studied in the conscious state. Aortic and LV pressures and humoral function were assessed at baseline (BL) and for 4 hours after subQ BNP (25 ug × 1). Dogs were then treated with subQ BNP (25 ug bid) for 4 weeks (n ⫽ 4 completed). Baseline hemodynamics (at trough BNP levels) and the response to subQ BNP were were reassessed after chronic therapy. Results: The acute response to the first dose of subQ BNP is shown in table. Mean ⫾ sem;*p ⬍ 0.05 vs BL (ANOVA). The hemodynamic and humoral response to subQ BNP was similar after chronic therapy with significant changes in systolic BP, pulse pressure, BNP and cGMP and trends in other parameters. At trough BNP levels, systolic BP (217 ⫾ 17 vs 194 ⫾ 8 mmHg, p ⫽ 0.10) and pulse pressure (87 ⫾ 5 vs 76 ⫾ 5 mmHg, p ⫽ 0.07) tended to be lower after chronic subQ BNP (n ⫽ 4). Conclusions: SubQ BNP activated cGMP, reduced afterload and preload and improved relaxation in a canine model of DHF. With chronic therapy, there was no tolerance and a chronic antihypertensive effect was noted. Chronic subQ BNP may be an effective therapy for hypertension and DHF. Effect of subQ BNP prior to chronic BNP therapy Baseline Systolic BP (mmHg) Pulse Pressure (mmHg) Heart rate (bpm) LV end diastolic P (mmHg) tau (ms) human BNP (pg/ml) cGMP (pmol/ml)
BNP 0.5 Hour
BNP 1 Hour
200 ⫾ 14 168 ⫾ 10* 170 ⫾ 10* 84 ⫾ 4 62 ⫾ 4* 61 ⫾ 3* 102 ⫾ 10 110 ⫾ 7 105 ⫾ 10 14.3 ⫾ 1.9 7.2 ⫾ 1.9* 9.7 ⫾ 1.9* 34.6 ⫾ 2.8 32.1 ⫾ 2.5* 31.6 ⫾ 2.5* 101 ⫾ 84 4768 ⫾ 1171* 2671 ⫾ 1059* 21.5 ⫾ 3.3 64.6 ⫾ 3.8* 65.9 ⫾ 5.9*
BNP 2 Hour
BNP 4 Hour
182 ⫾ 14* 66 ⫾ 6* 107 ⫾ 10 8.9 ⫾ 2.1* 32.6 ⫾ 2.5 653 ⫾ 234* 60.1 ⫾ 4.8*
189 ⫾ 15 71 ⫾ 4* 111 ⫾ 9 7.2 ⫾ 3.2* 31.4 ⫾ 2.1* 109 ⫾ 45 31.8 ⫾ 2.8*
259 The Impact of Serum Digoxin Concentration and Enalapril Therapy in Patients with CHF: The SOLVD Trial Revisited Richard J. Sheppard,1 Sylvie Levesque,2 Simon deDenus,1 Anique Ducharme,1 Martial Bourassa,1 Jean-Claude Tardif,1 Normand Racine,1 Michel White1; 1Clinical Research, Montreal Heart Institute, Montreal, QC, Canada; 2Biostatistics, Montreal Heart Institute, Montreal, QC, Canada Background: Elevated serum digoxin concentrations (SDC) are associated with increased mortality in patients with CHF. The impact of elevated SDC on the efficacy of ACE inhibitors in patients with CHF has not been investigated. We examined the impact of SDC on outcomes and the interaction of enalapril and SDC in patients enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) study at our institution. Methods: There were 391 patients enrolled in SOLVD at the Montreal Heart Institute. Ninety-six patients received digoxin with a documented SDC (age 59 ⫾ 10 years (mean ⫾ SD), LVEF 23 ⫾ 7%, and 86% male). Kaplan Meier curves were generated comparing patients with SDC ⱖ 1 ng/ml (n ⫽ 52), SDC ⬍ 1 ng/ml (n ⫽ 44), and patients not on digoxin (n ⫽ 295). Separate survival analyses were performed for each clinical variable using SDC as a continuous variable in each model. Results: There were no differences in clinical characteristics for patients with SDC ⬍ 1 ng/ml or patients with SDC ⱖ 1 ng/ml. Kaplan-Meier curves comparing patients with SDC ⱖ 1 ng/ml, SDC ⬍ 1 ng/ml and patients not on digoxin are shown in Figure 1. On univariate analysis, for an increase of 0.5 ng/ml in SDC, there was an increased risk of new or worsening CHF with increasing SDC (HR ⫽ 1.46, 95% CI: 1.08–2.00, p ⫽ 0.015). For individual multivariate analyses, increased risk of new or worsening CHF remained similar when we controlled for several factors including age (HR: 1.47 95% CI: 1.09–1.99, p ⫽ 0.013), gender (HR ⫽ 1.47, 95% CI: 1.07– 2.01, p ⫽ 0.017), LVEF (HR⫽1.43 95% CI: 1.06–1.93, p ⫽ 0.020), and creatinine (HR ⫽ 1.44, 95% CI ⫽ 1.04–1.99, p ⫽ 0.030). The SDC did not interact with the use of enalapril/placebo on multivariate analysis (p ⫽ 0.957). Patients with NYHA III, not NYHA I-II, with a higher digoxin level, had an increased risk of new or worsening CHF (HR ⫽ 2.88 CI: 1.56 – 5.31, p ⫽ 0.001). Conclusions: In this small cohort of patients with CHF, elevated SDC is associated with an increased risk of earlier, recurrent CHF. However, the therapeutic benefit with enalapril is not impacted by the SDC.