Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolo... more Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT 1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT 1-ant may block the RAS at the level of the AT 1 receptor and activate the angiotensin II type 2 (AT 2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT 1-ant has a similar effect and whether these effects are partly due to activation of the AT 2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B 2 receptor antagonist icatibant (B 2-ant); or (c) an AT 1ant with and without an AT 2-antagonist (AT 2-ant) or B 2ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT 1-ant. The B 2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT 1-ant was blocked by the AT 2-ant. The decreases in LVEDV and LVESV caused by the AT 1-ant were also partially blocked by the B 2-ant. We concluded that (a) in HF both ACEi and AT 1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT 1-ant is triggered by activation of the AT 2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT 1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT 2 receptor, which in turn may play an important role in the therapeutic effect of the AT 1-ant via kinins and other autacoids.
American Journal of Physiology-Heart and Circulatory Physiology, 1997
Rat models of heart failure (HF) secondary to myocardial infarction (MI) are useful in studying t... more Rat models of heart failure (HF) secondary to myocardial infarction (MI) are useful in studying the progression of cardiac dysfunction and in testing therapeutic approaches. Sprague-Dawley rats are frequently used; however, this model is hampered by high mortality and a marked variability in infarct size and cardiac dysfunction, necessitating large numbers of rats and prolonged follow-up when studying the progression of dysfunction. In the present work, we developed a model of HF utilizing Lewis inbred rats. Ligation of the left anterior descending coronary artery in Lewis rats produced more uniform and larger infarcts (40 +/- 1.7 vs. 28 +/- 2.3%; P < 0.001) and lower mortality (16 vs. 36%; P < 0.001) than in Sprague-Dawley rats. Using this rat model, we further studied the course of left ventricular (LV) dysfunction and enlargement from 1 wk to 6 mo after MI with cineventriculography. LV end-systolic volume and end-diastolic volume were determined with the area-length method....
Background and Aim: Surgical resection of myocardium that acutely reduces left ventricular (LV) v... more Background and Aim: Surgical resection of myocardium that acutely reduces left ventricular (LV) volume in patients with advanced heart failure (HF), the so-called "Batista Operation," remains controversial. We examined the effects of acute LV reduction with the Acorn Cardiac Support Device (CSD) in dogs with HF (LV ejection fraction < 30%). Methods: HF was produced in 15 dogs by intracoronary microembolization. In nine dogs, intravenous dobutamine was administered t o reduce LV end-diastolic dimension (LVEDD) b y 10%-25%0. While on dobutamine infusion, the CSD, a preformed knitted polyester device, was surgically placed around the ventricles, anchored t o the arteriovenous (AV) groove, and tailored anteriorly t o f i t snugly over the ventricles. Dogs were then weaned off dobutamine. Results: On average, the procedure reduced LVEDD by 7 5 1 mm (range 5-12 mm). Of the nine dogs, t w o died before completion of the study and seven survived for the entire period. Six dogs did not undergo device placement and served as controls. All were followed for 3 months prior t o sacrifice. In controls, LV end-diastolic volume increased after 3 months (66 2 5 mL vs 77 5 6 mL; p = 0.007), while in CSD-treated dogs (n = 7). it decreased (80 f 5 m L vs 60 2 3 mL; p = 0.002). In controls, LV ejection fraction (EF) decreased after 3 months I27 2 1% vs 23 2 1%; p = 0.001) but was unchanged in CSD-treated dogs (25 2 1% vs 26 2 1%0; p = 0.66). Compared t o controls, CSD-treated dogs showed improved LV diastolic dysfunction and chamber sphericity, decreased wall stress, and no functional mitral regurgitation (MR). Conclusion: In dogs w i t h advanced HF, acute LV reduction with the Acorn CSD prevents progressive global LV dilatation and ameliorates functional MR.
The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase ... more The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with
Background Peroxisome proliferator-activated receptor + (PPAR+) activators affect the myocardium ... more Background Peroxisome proliferator-activated receptor + (PPAR+) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPAR+ activator, GW347845 (GW), on the progression of heart failure. Methods and results Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n=7), low-dose GW (3 mg/Kg daily, n=7), or no therapy (control, n=7). In control dogs, EF significantly decreased (28±1 vs. 22±1%, p<0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the followup period (64±4 vs. 76±5; p=0.003, 46±3 vs. 59±4 ml, p=0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69±4 vs.81±5 ml, p=0.01), whereas ESV remained statistically unchanged (50±3 vs. 54±3 ml, p=0.10) resulting in modestly increased ejection fraction (27±1 vs. 32±3%, p=0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72±4 vs. 79± 5 ml, p=0.04; 53±3 vs. 62±5 ml, p=0.04) and EF decreased (26±1 vs. 23±1%, p=0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPAR+, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy Conclusions Long-term PPAR+ activation with GW did not prevent progressive LV remodeling in dogs with advanced heart failure. Key words heart failure. remodeling. drugs. hemodynamics Peroxisome proliferator-activated receptor + (PPAR+) is a nuclear receptor that was originally shown to play a crucial role in adipocyte differentiation and insulin sensitivity [1-3]. Therefore, PPAR+ activators are currently extensively used in the treatment of insulin resistance syndromes. Cardiac effects of these agents, however, have not been well studied in the setting of heart failure. PPAR+ is also expressed in the heart but in much lower degree than adipose tissue and skeletal muscle [4]. It has been postulated that PPAR+ activators improve cardiac function through metabolic modulation and regulation of inflammatory responses. These effects have been well
We examined the eects of eprosartan, an AT 1 receptor antagonist, on the progression of left vent... more We examined the eects of eprosartan, an AT 1 receptor antagonist, on the progression of left ventricular (LV) dysfunction and remodelling in dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction, EF 30 to 40%). 2 Dogs were randomized to 3 months of oral therapy with low-dose eprosartan (600 mg once daily, n=8), high-dose eprosartan (1200 mg once daily, n=8), or placebo (n=8). 3 In the placebo group, LV end-diastolic (EDV) and end-systolic (ESV) volumes increased after 3 months (68+7 vs 82+9 ml, P50.004, 43+1 vs 58+7 ml, P50.003, respectively), and EF decreased (37+1 vs 29+1%, P50.001). In dogs treated with low-dose eprosartan, EF, EDV, and ESV remained unchanged over the course of therapy, whereas in dogs treated with high-dose eprosartan, EF increased (38+1 vs 42+1%, P50.004) and ESV decreased (41+1 vs 37+1 ml, P50.006), Eprosartan also decreased interstitial ®brosis and cardiomyocyte hypertrophy. 4 We conclude that eprosartan prevents progressive LV dysfunction and attenuates progressive LV remodelling in dogs with moderate HF and may be useful in treating patients with chronic HF.
Journal of the American College of Cardiology, 1996
Conclusions: I) Receptor-mediated Cot' Endo stimulation modulates LV function in "Ix recipients; ... more Conclusions: I) Receptor-mediated Cot' Endo stimulation modulates LV function in "Ix recipients; 2) Arg augments Cor End0 intiuence on LV function after Tx probably by providing more substrate for Cor Endo production of NO; 3) p.adranergic stimulation with Dob augments Cor Endo influence on LV function probably I~y potentiating the myocardial cerdiodppreesant action of NO.
Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolo... more Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT 1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT 1-ant may block the RAS at the level of the AT 1 receptor and activate the angiotensin II type 2 (AT 2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT 1-ant has a similar effect and whether these effects are partly due to activation of the AT 2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B 2 receptor antagonist icatibant (B 2-ant); or (c) an AT 1ant with and without an AT 2-antagonist (AT 2-ant) or B 2ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT 1-ant. The B 2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT 1-ant was blocked by the AT 2-ant. The decreases in LVEDV and LVESV caused by the AT 1-ant were also partially blocked by the B 2-ant. We concluded that (a) in HF both ACEi and AT 1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT 1-ant is triggered by activation of the AT 2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT 1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT 2 receptor, which in turn may play an important role in the therapeutic effect of the AT 1-ant via kinins and other autacoids.
American Journal of Physiology-Heart and Circulatory Physiology, 1997
Rat models of heart failure (HF) secondary to myocardial infarction (MI) are useful in studying t... more Rat models of heart failure (HF) secondary to myocardial infarction (MI) are useful in studying the progression of cardiac dysfunction and in testing therapeutic approaches. Sprague-Dawley rats are frequently used; however, this model is hampered by high mortality and a marked variability in infarct size and cardiac dysfunction, necessitating large numbers of rats and prolonged follow-up when studying the progression of dysfunction. In the present work, we developed a model of HF utilizing Lewis inbred rats. Ligation of the left anterior descending coronary artery in Lewis rats produced more uniform and larger infarcts (40 +/- 1.7 vs. 28 +/- 2.3%; P < 0.001) and lower mortality (16 vs. 36%; P < 0.001) than in Sprague-Dawley rats. Using this rat model, we further studied the course of left ventricular (LV) dysfunction and enlargement from 1 wk to 6 mo after MI with cineventriculography. LV end-systolic volume and end-diastolic volume were determined with the area-length method....
Background and Aim: Surgical resection of myocardium that acutely reduces left ventricular (LV) v... more Background and Aim: Surgical resection of myocardium that acutely reduces left ventricular (LV) volume in patients with advanced heart failure (HF), the so-called "Batista Operation," remains controversial. We examined the effects of acute LV reduction with the Acorn Cardiac Support Device (CSD) in dogs with HF (LV ejection fraction < 30%). Methods: HF was produced in 15 dogs by intracoronary microembolization. In nine dogs, intravenous dobutamine was administered t o reduce LV end-diastolic dimension (LVEDD) b y 10%-25%0. While on dobutamine infusion, the CSD, a preformed knitted polyester device, was surgically placed around the ventricles, anchored t o the arteriovenous (AV) groove, and tailored anteriorly t o f i t snugly over the ventricles. Dogs were then weaned off dobutamine. Results: On average, the procedure reduced LVEDD by 7 5 1 mm (range 5-12 mm). Of the nine dogs, t w o died before completion of the study and seven survived for the entire period. Six dogs did not undergo device placement and served as controls. All were followed for 3 months prior t o sacrifice. In controls, LV end-diastolic volume increased after 3 months (66 2 5 mL vs 77 5 6 mL; p = 0.007), while in CSD-treated dogs (n = 7). it decreased (80 f 5 m L vs 60 2 3 mL; p = 0.002). In controls, LV ejection fraction (EF) decreased after 3 months I27 2 1% vs 23 2 1%; p = 0.001) but was unchanged in CSD-treated dogs (25 2 1% vs 26 2 1%0; p = 0.66). Compared t o controls, CSD-treated dogs showed improved LV diastolic dysfunction and chamber sphericity, decreased wall stress, and no functional mitral regurgitation (MR). Conclusion: In dogs w i t h advanced HF, acute LV reduction with the Acorn CSD prevents progressive global LV dilatation and ameliorates functional MR.
The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase ... more The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with
Background Peroxisome proliferator-activated receptor + (PPAR+) activators affect the myocardium ... more Background Peroxisome proliferator-activated receptor + (PPAR+) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPAR+ activator, GW347845 (GW), on the progression of heart failure. Methods and results Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n=7), low-dose GW (3 mg/Kg daily, n=7), or no therapy (control, n=7). In control dogs, EF significantly decreased (28±1 vs. 22±1%, p<0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the followup period (64±4 vs. 76±5; p=0.003, 46±3 vs. 59±4 ml, p=0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69±4 vs.81±5 ml, p=0.01), whereas ESV remained statistically unchanged (50±3 vs. 54±3 ml, p=0.10) resulting in modestly increased ejection fraction (27±1 vs. 32±3%, p=0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72±4 vs. 79± 5 ml, p=0.04; 53±3 vs. 62±5 ml, p=0.04) and EF decreased (26±1 vs. 23±1%, p=0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPAR+, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy Conclusions Long-term PPAR+ activation with GW did not prevent progressive LV remodeling in dogs with advanced heart failure. Key words heart failure. remodeling. drugs. hemodynamics Peroxisome proliferator-activated receptor + (PPAR+) is a nuclear receptor that was originally shown to play a crucial role in adipocyte differentiation and insulin sensitivity [1-3]. Therefore, PPAR+ activators are currently extensively used in the treatment of insulin resistance syndromes. Cardiac effects of these agents, however, have not been well studied in the setting of heart failure. PPAR+ is also expressed in the heart but in much lower degree than adipose tissue and skeletal muscle [4]. It has been postulated that PPAR+ activators improve cardiac function through metabolic modulation and regulation of inflammatory responses. These effects have been well
We examined the eects of eprosartan, an AT 1 receptor antagonist, on the progression of left vent... more We examined the eects of eprosartan, an AT 1 receptor antagonist, on the progression of left ventricular (LV) dysfunction and remodelling in dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction, EF 30 to 40%). 2 Dogs were randomized to 3 months of oral therapy with low-dose eprosartan (600 mg once daily, n=8), high-dose eprosartan (1200 mg once daily, n=8), or placebo (n=8). 3 In the placebo group, LV end-diastolic (EDV) and end-systolic (ESV) volumes increased after 3 months (68+7 vs 82+9 ml, P50.004, 43+1 vs 58+7 ml, P50.003, respectively), and EF decreased (37+1 vs 29+1%, P50.001). In dogs treated with low-dose eprosartan, EF, EDV, and ESV remained unchanged over the course of therapy, whereas in dogs treated with high-dose eprosartan, EF increased (38+1 vs 42+1%, P50.004) and ESV decreased (41+1 vs 37+1 ml, P50.006), Eprosartan also decreased interstitial ®brosis and cardiomyocyte hypertrophy. 4 We conclude that eprosartan prevents progressive LV dysfunction and attenuates progressive LV remodelling in dogs with moderate HF and may be useful in treating patients with chronic HF.
Journal of the American College of Cardiology, 1996
Conclusions: I) Receptor-mediated Cot' Endo stimulation modulates LV function in "Ix recipients; ... more Conclusions: I) Receptor-mediated Cot' Endo stimulation modulates LV function in "Ix recipients; 2) Arg augments Cor End0 intiuence on LV function after Tx probably by providing more substrate for Cor Endo production of NO; 3) p.adranergic stimulation with Dob augments Cor Endo influence on LV function probably I~y potentiating the myocardial cerdiodppreesant action of NO.
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