- Email: [email protected]
Effect of long-term therapy with valsartan on mitochondrial respiration in dogs with moderate heart failure
The Second Annual Scientific Meeting
•
HFSA
39
145
146
Effect of Long-Term Therapy with Valsartan on Mitochondrial Respiration in Dogs with Moderate Heart Failure Victor G. Sharov, Anastassia Goussev, Mitsuhero Tanimura, Sidney Goldstein, Hani N. Sahbah. Henry Ford Heart and Vascular Institute, Detroit, MI
Carvedilol Induced Reduction in Oxidative Stress is Associated with Improved Ejection Fraction and Smaller Ventricular Volumes in Patients with Heart Failure Tej Sheth, Shanas Mohamed, Susanna Mak, Denis Lehotay, Wally Bartfay, Nicolas Fields, Peter Liu. The Toronto Hospital, University of Toronto
We previously showed that mitochondrial (MIT) oxygen utilization is depressed in failed LV myocardiumof humans and dogs with chronic heart failure (HF). In the present study, we examined whether early, long-term therapy with valsartan, an ATI receptor antagonist, prevents the decline in oxygen utilization by MIT in myoeardium of dogs with moderate HI? produced by multiple sequential intracoronary microembolization. Dogs with LV ejection fraction between 30% and 40% were randomized to 3 months therapy with low dose (LD) valsartan(400 nag Bid, n=5), high dose (HI)) valsartan (800 mg Bid, n=5) or to no treatment at all (Placebo, n=5). Hearts from 5 normal (NL) dogs (n=5) were used as a controls. At the end of therapy, dogs were sacrificed and fresh tissue samples(about 30 mg) were obtained from the LV free wall. MIT respiratoryparameterswere measured in saponin-skinnedfiber bundles using an oxygraphand Clark electrode and respiratory rates quantified in ngatoms of oxygen/mirdmgprotein. MIT state-3 respiration was measured in the presence of 1.7 mM glutamate, 0.7 mM malate and 1 mM ADP (VADp)and surrogate state 4 respiration was measured alter the addition of 0.35 mM atmctiloside (VAT).The respiratory control index (RCI) was calculated as the ratio VADp/VAT.
VAop RCI
i c-ro,I"F "ceb°bv"a't'L°I
42.8+3.6 15.2+2.2"i" 30.1+5.8"i" 30.0+2.4"1" 2.93+0.8 2.02 + 0.2"t 3.56+0.5* 2.44+0.2t' [*=P<0.05 vs HF-placebo;"t=P<0.05 vs NL-control]
WADP and RCI were higher in myoeardium of dogs treated with valsartan
compared to placebo. This finding suggests that the early, long-term therapy with valsartan may prevent or, at the very least, attenuate abnormalities of MIT metabolism and bioenergeties in the failing heart.
Heart failure is characterized by increased oxidative stress. We studied the effect of Carvedilol, a ~-blocking agent with antioxidant properties, in 12 patients with congestive heart failure (10 males, age 54_+14.3 yrs, NYHA 2-3, 10 non-ischemic), to determine the relationship between changes in oxidative stress and ventricular remodeling. All patients had EF<0.35, and were studied at baseline and 3 months following titration on carvedilol. Oxidative stress was measured by mass spectroscopy on peripheral blood in terms of total aldehydes (TAL) and malonydialdehyde (MDA). EF and ventricular volumes were measured by radionuclide angiography (mear~+SD): Baseline 3 Months p value ..LV.Eg.(.%) .......................... .?..?.:.?+.7..::1 ........................... 2-.7.::~,.-+..?.: 5 .............. 9...94 ................ ..ED.y...!m~.s) ........................ .?.1 L_+..1 ?0. ........................... 2.69..+.J..43 ............... 0:.1.2 ................ E § . V L m h ) . ......................... 246=+.!15 ........................... 2 9 2 ~ 1 . ; 7 ...............o:f17 ................
TAL ( r i M ) 94587+139897 49880_+87310 NS Among individual patients, reductions in TAL and MDA (8/12 pts) were associated with increase in ejection fraction (r=-0.65, p=0.02; and r=-0.48, p=0.11 respectively), decreased EDV (r=0.690, p<0.05; and r=0.739, p<0.01) and decreased ESV (r=0.685, p<0.05; r=0,706, p<0.01). Conclusions: Carvedilol reduces oxidative stress in a number of patients with heart failure. This reduction in oxidative stress is associated with significant improvements in EF and reverse remodeling of the left ventricle.
147
148
Outpatient Continuous Intravenous Inotropic Therapy in Patients with End Stage Heart Failure: Palliative or Life-Prolonging? Kathy Crispell, Deirdre Nauman, Tracy Walker, Diana Dutton, Warren Toy, Anne Rosenfeld, Hanyu Ni, Ray Hershberger. Oregon Health Sciences University, Portland, OR
Safety and Efficacy of High Dose ACE-Inhibitor Therapy in Patients with Chronic Heart Failure Casey M. Lawler, Gregory A. Ewald, Edward M. Geltman, Joseph G. Rogers, Washington University, St. Louis, MO
Background. Outpatient continuous intravenous inotropic therapy (OCIIT) use in patients with end stage heart failure has evolved into accepted treatment, an approach suggested to be palliative. Our experience has suggested that OCIIT has been life-prolonging. The purpose of this study was to characterize those patients who were treated with OCIIT and to assess clinical and cost outcomes. Methods. A retrospective chart review of all patients placed on OCIIT from 1/93-7/97 in a university based Heart Failure Treatment Program, associated with a cardiac transplant program. Results. Fifteen patients were identified; all had dobutamine therapy initiated in hospital for decompensated heart failure. At initiation, 60% were NYHA IV, and 40% were late NYHA III; 93% had orthopnea and 86% had PND. All patients were receiving maximal oral medical therapy for heart failure. Most patients had > 1 attempt to wean dobutamine in the hospital with hemodynamic monitoring. All were assessed as unable to survive without inotropic support. Three patients required the addition of milrinone to OCIIT. OCIIT was discontinued in 13 patients for death. Two patients still survive; one on OCIIT 8 months after initiation, and one after valve replacement. Duration of OCIIT averaged 4.2 months (range 1-20 months). Eighty percent of patients were rehospitalized at least once (32 total; 133 total days) with hospital cost estimated at $17,733 per patient. The most common complication was infection related to dmg delivery. Conclusions. Patients with severe, refractory heart failure received OCIIT that extended survival approximately 4 months; additional attention is needed to assess cost effectiveness.
Angiotensin converting enzyme inhibitors (ACEI) improve functional status and survival in patients with congestive heart failure (CHF). However, the optimal dosage of these agents has not been defined. We performed a retrospective analysis of the 138 outpatient referrals to our CHF clinic from 8/95 to 1/97. Fifty-four patients met the inclusion criteria of NYttA Class H-IV, LVEF < 40%, serum creatinine (SCr) < 2.0 mg/dl, and follow-up > 3 months. ACEI were titrated to a target daily dose (TDD) of 400 mg of captopril or equivalent (80 mg enalapril, lisinopril, or quinapril) unless limited by symptoms, hypotension, or increasing SCr. The mean patient age was 54.1 + 10.7 years, 80% were male, and 50% had ischemic cardiomyopathy. The LVEF was < 25% in 85% of patients and 96% were receiving ACEI at initial visit. The mean follow-up period was 11.1 + 6.5 months. Overall the initial and final ACEI doses were 30.0 + 20.9% and 82.1 + 23.7% of the TDD, respectively. Following ACEI titration, the NYHA Class improved from 2.9 + 0.7 to 2.3 + 0.7 (p < 0.001). Thirty-eight patients achieved > 75% TDD (mean = 96.1 +_9.0% TDD) which defined a high dose ACEI group (HI)). The remaining patients achieved a moderate dose (MD) of 50.0 + 10.9% TDD. The mean change in SBP (HI) = 2.1 + 16.7 vs. MD = 9.0 -+ 23.1, p = 0.22) and SCr (HD = 0.1 + 0.4 vs. MD = 0.1 + 0.3, p = 0.75) were not significantly different. Compared to the MD group, a greater number of I-ID patients had > 1 NYHA Class improvement (47.0 vs. 31.5%, p < 0.20). Thus, these data suggest that high dose ACEI therapy in patients with chronic CHF is safe and welltolerated, and provides an incremental benefit in functional status relative to lower doses in some patients.
•
HFSA
39
145
146
Effect of Long-Term Therapy with Valsartan on Mitochondrial Respiration in Dogs with Moderate Heart Failure Victor G. Sharov, Anastassia Goussev, Mitsuhero Tanimura, Sidney Goldstein, Hani N. Sahbah. Henry Ford Heart and Vascular Institute, Detroit, MI
Carvedilol Induced Reduction in Oxidative Stress is Associated with Improved Ejection Fraction and Smaller Ventricular Volumes in Patients with Heart Failure Tej Sheth, Shanas Mohamed, Susanna Mak, Denis Lehotay, Wally Bartfay, Nicolas Fields, Peter Liu. The Toronto Hospital, University of Toronto
We previously showed that mitochondrial (MIT) oxygen utilization is depressed in failed LV myocardiumof humans and dogs with chronic heart failure (HF). In the present study, we examined whether early, long-term therapy with valsartan, an ATI receptor antagonist, prevents the decline in oxygen utilization by MIT in myoeardium of dogs with moderate HI? produced by multiple sequential intracoronary microembolization. Dogs with LV ejection fraction between 30% and 40% were randomized to 3 months therapy with low dose (LD) valsartan(400 nag Bid, n=5), high dose (HI)) valsartan (800 mg Bid, n=5) or to no treatment at all (Placebo, n=5). Hearts from 5 normal (NL) dogs (n=5) were used as a controls. At the end of therapy, dogs were sacrificed and fresh tissue samples(about 30 mg) were obtained from the LV free wall. MIT respiratoryparameterswere measured in saponin-skinnedfiber bundles using an oxygraphand Clark electrode and respiratory rates quantified in ngatoms of oxygen/mirdmgprotein. MIT state-3 respiration was measured in the presence of 1.7 mM glutamate, 0.7 mM malate and 1 mM ADP (VADp)and surrogate state 4 respiration was measured alter the addition of 0.35 mM atmctiloside (VAT).The respiratory control index (RCI) was calculated as the ratio VADp/VAT.
VAop RCI
i c-ro,I"F "ceb°bv"a't'L°I
42.8+3.6 15.2+2.2"i" 30.1+5.8"i" 30.0+2.4"1" 2.93+0.8 2.02 + 0.2"t 3.56+0.5* 2.44+0.2t' [*=P<0.05 vs HF-placebo;"t=P<0.05 vs NL-control]
WADP and RCI were higher in myoeardium of dogs treated with valsartan
compared to placebo. This finding suggests that the early, long-term therapy with valsartan may prevent or, at the very least, attenuate abnormalities of MIT metabolism and bioenergeties in the failing heart.
Heart failure is characterized by increased oxidative stress. We studied the effect of Carvedilol, a ~-blocking agent with antioxidant properties, in 12 patients with congestive heart failure (10 males, age 54_+14.3 yrs, NYHA 2-3, 10 non-ischemic), to determine the relationship between changes in oxidative stress and ventricular remodeling. All patients had EF<0.35, and were studied at baseline and 3 months following titration on carvedilol. Oxidative stress was measured by mass spectroscopy on peripheral blood in terms of total aldehydes (TAL) and malonydialdehyde (MDA). EF and ventricular volumes were measured by radionuclide angiography (mear~+SD): Baseline 3 Months p value ..LV.Eg.(.%) .......................... .?..?.:.?+.7..::1 ........................... 2-.7.::~,.-+..?.: 5 .............. 9...94 ................ ..ED.y...!m~.s) ........................ .?.1 L_+..1 ?0. ........................... 2.69..+.J..43 ............... 0:.1.2 ................ E § . V L m h ) . ......................... 246=+.!15 ........................... 2 9 2 ~ 1 . ; 7 ...............o:f17 ................
TAL ( r i M ) 94587+139897 49880_+87310 NS Among individual patients, reductions in TAL and MDA (8/12 pts) were associated with increase in ejection fraction (r=-0.65, p=0.02; and r=-0.48, p=0.11 respectively), decreased EDV (r=0.690, p<0.05; and r=0.739, p<0.01) and decreased ESV (r=0.685, p<0.05; r=0,706, p<0.01). Conclusions: Carvedilol reduces oxidative stress in a number of patients with heart failure. This reduction in oxidative stress is associated with significant improvements in EF and reverse remodeling of the left ventricle.
147
148
Outpatient Continuous Intravenous Inotropic Therapy in Patients with End Stage Heart Failure: Palliative or Life-Prolonging? Kathy Crispell, Deirdre Nauman, Tracy Walker, Diana Dutton, Warren Toy, Anne Rosenfeld, Hanyu Ni, Ray Hershberger. Oregon Health Sciences University, Portland, OR
Safety and Efficacy of High Dose ACE-Inhibitor Therapy in Patients with Chronic Heart Failure Casey M. Lawler, Gregory A. Ewald, Edward M. Geltman, Joseph G. Rogers, Washington University, St. Louis, MO
Background. Outpatient continuous intravenous inotropic therapy (OCIIT) use in patients with end stage heart failure has evolved into accepted treatment, an approach suggested to be palliative. Our experience has suggested that OCIIT has been life-prolonging. The purpose of this study was to characterize those patients who were treated with OCIIT and to assess clinical and cost outcomes. Methods. A retrospective chart review of all patients placed on OCIIT from 1/93-7/97 in a university based Heart Failure Treatment Program, associated with a cardiac transplant program. Results. Fifteen patients were identified; all had dobutamine therapy initiated in hospital for decompensated heart failure. At initiation, 60% were NYHA IV, and 40% were late NYHA III; 93% had orthopnea and 86% had PND. All patients were receiving maximal oral medical therapy for heart failure. Most patients had > 1 attempt to wean dobutamine in the hospital with hemodynamic monitoring. All were assessed as unable to survive without inotropic support. Three patients required the addition of milrinone to OCIIT. OCIIT was discontinued in 13 patients for death. Two patients still survive; one on OCIIT 8 months after initiation, and one after valve replacement. Duration of OCIIT averaged 4.2 months (range 1-20 months). Eighty percent of patients were rehospitalized at least once (32 total; 133 total days) with hospital cost estimated at $17,733 per patient. The most common complication was infection related to dmg delivery. Conclusions. Patients with severe, refractory heart failure received OCIIT that extended survival approximately 4 months; additional attention is needed to assess cost effectiveness.
Angiotensin converting enzyme inhibitors (ACEI) improve functional status and survival in patients with congestive heart failure (CHF). However, the optimal dosage of these agents has not been defined. We performed a retrospective analysis of the 138 outpatient referrals to our CHF clinic from 8/95 to 1/97. Fifty-four patients met the inclusion criteria of NYttA Class H-IV, LVEF < 40%, serum creatinine (SCr) < 2.0 mg/dl, and follow-up > 3 months. ACEI were titrated to a target daily dose (TDD) of 400 mg of captopril or equivalent (80 mg enalapril, lisinopril, or quinapril) unless limited by symptoms, hypotension, or increasing SCr. The mean patient age was 54.1 + 10.7 years, 80% were male, and 50% had ischemic cardiomyopathy. The LVEF was < 25% in 85% of patients and 96% were receiving ACEI at initial visit. The mean follow-up period was 11.1 + 6.5 months. Overall the initial and final ACEI doses were 30.0 + 20.9% and 82.1 + 23.7% of the TDD, respectively. Following ACEI titration, the NYHA Class improved from 2.9 + 0.7 to 2.3 + 0.7 (p < 0.001). Thirty-eight patients achieved > 75% TDD (mean = 96.1 +_9.0% TDD) which defined a high dose ACEI group (HI)). The remaining patients achieved a moderate dose (MD) of 50.0 + 10.9% TDD. The mean change in SBP (HI) = 2.1 + 16.7 vs. MD = 9.0 -+ 23.1, p = 0.22) and SCr (HD = 0.1 + 0.4 vs. MD = 0.1 + 0.3, p = 0.75) were not significantly different. Compared to the MD group, a greater number of I-ID patients had > 1 NYHA Class improvement (47.0 vs. 31.5%, p < 0.20). Thus, these data suggest that high dose ACEI therapy in patients with chronic CHF is safe and welltolerated, and provides an incremental benefit in functional status relative to lower doses in some patients.