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Chronic Phosphodiesterase-5 Inhibition Ameliorates Myocardial Contractile Dysfunction in Elderly Canine Model of Hypertensive Heart Disease
The 12th Annual Scientific Meeting Results: In CHF patients, plasma MMP-2 and MMP-9 levels of CS were significantly higher than those of Ao, however, there were no significant differences in MMP-1 or MMP-9 levels between CS and Ao. In NC, any MMPs of CS were not higher than those of Ao. In spironolactone study, left ventricular ejection fraction was significantly increased with spironolactone and furosemide, and plasma BNP level was significantly decreased with spironolactone and furosemide (baseline: 202.5 6 46.0 pg/ ml, spironolactone: 96.3 6 22.5 pg/ml, furosemide: 83.4 6 16.8 pg/ml, p ! 0.05). Plasma MMP-2 (baseline: 10.3 6 1.0 mU/ml, spironolactone: 5.7 6 0.8 mU/ml, furosemide: 10.9 6 1.2 mU/ml, p ! 0.05) and MMP-9 levels (baseline: 2.8 6 0.4 mU/ml, spironolactone: 3.1 6 0.4 mU/ml, furosemide: 1.4 6 0.3 mU/ml, p ! 0.05) were significantly decreased with spironolactone compared with baseline and furosemide, while plasma MMP-1 or MMP-3 levels were not changed. Serum TNF-a level was decreased with spironolactone, not furosemide (baseline: 3.66 6 0.37 pg/ml, spironolactone: 2.22 6 0.38 pg/ml, furosemide: 3.37 6 0.53 pg/ml, p ! 0.05). Conclusions: Failing hearts produced MMP-2 and MMP-9 and spironolactone, not furosemide, decreased plasma MMP-2 and MMP-9 levels as well as TNF-a level in CHF patients.
HFSA
S75
monophosphate (cGMP, pg/mg protein) were measured at tissue harvest. Results: See table. At wk 8, SBP was similar in CON and PDE5-I (Table). EF decreased in CON but was preserved in PDE5-I. Both the mFS-cESS and PkCS-cESS relationships were shifted up (improved contractility) in the PDE5-I group (p ! 0.05 for group effect for both). LV/body weight tended to be lower in PDE5-I (5.2 6 2.7 g/ kg) than CON (5.9 6 0.9 g/kg; p 5 0.13). Myocardial cGMP was increased in PDE5-I (41 6 26 vs. 19 6 7 pg/mg; p ! 0.05). Table 1.
SBP (mmHg) EF (%) cESS (g/cm2) PkCS (%) mFS (%)
CON wk 0
PDE5-I wk 0
N/A 64.3 6 7.9 N/A 16.9 6 2.8 16.5 6 3.1
N/A 67.5 6 6.4 N/A 16.9 6 1.4 18.5 6 4.0
CON wk 8
PDE5-I wk 8
226.1 6 29.6 51.8 6 17.8* 254.6 6 109.8 10.4 6 3.7* 11.6 6 4.6*
233.2 6 29.9 63.0 6 9.8 239.3 6 69.7 14 6 2.4*y 16.7 6 4.0y
yp! 0.05 vs CON at wk 0 or 8; *p! 0.05 vs wk 0 in CON or PDE5-I. Conclusions: Chronic PDE5-I preserved myocardial contractility in this elderly hypertensive canine model. PDE5-I may hold promise as a therapy in HFpEF or high risk hypertension.
237 A Novel Orally Active BNP Possesses Chronic Natriureti Actions, Decreases Mean Arterial Pressure and Activates cGMP in a Model of Acute Hypertension Alessandro Catliotti1, Horng H. Chen1, Guido Boerrigter1, Lisa C. CostelloBoerrigrter1, Fernado L. Martin1, Kenneth D. James1, John C. Burnett1; 1Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN Background: The objective of the current study was to establish the chronic diuretic actions of a novel oral conjugated human BNP (hBNP-054) and to define its blood pressure lowering effects in a model of hypertension (HTN). Methods: First we tested hBNP-054 both acutely and chronically in normal dogs to assess its biological actions as a blood pressure lowering agent and as a natriuretic factor. Secondly, we investigated the effects of acute oral hBNP-054 or vehicle in dogs that received concomitant continuous intravenous infusion of angiotensin II (ANG II). After baseline (BL) determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 mg/kg/min, 1 ml/ min) for 4 hrs to induce HTN. After 30 min of ANG II administration, dogs received oral hBNP-054 (400 mg/kg) or vehicle in a random crossover fashion with a one week interval between dosing. Blood sampling and MAP measurements were repeated 30 min after ANG II and 10, 30, 60, 120, 180 and 240 min after oral administration of hBNP-054 or vehicle. Results: In the chronic study, oral hBNP-054 effectively reduced MAP for 6 days and it induced a significant increase in 24-hr sodium excretion. hBNP was not present in the plasma at BL in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054 with a peak concentration at 30 min of 1060 6 818 pg/ml. After ANG II administration, plasma cGMP was not activated after vehicle, while it was significantly increased after oral hBNP-054 (p ! 0.0001 between two groups). Importantly, MAP was significantly increased after ANG II throughout the study protocol. However, while no changes occurred in MAP after vehicle administration, oral hBNP-054 was followed by a significant reduction in MAP for over 2 hrs (from 138 6 1 after ANG II to 124 6 2 and 130 6 5 mmHg 1 and 2 hrs after oral hBNP-054 respectively; p ! 0.001). Conclusion: For the first time we report that a novel oral hBNP has blood pressure lowering effects over a 6-day period and natriuretic actions when administered chronically. Furthermore, hBNP-054 activates cGMP and significantly reduces MAP in a model of acute HTN.
238 Chronic Phosphodiesterase-5 Inhibition Ameliorates Myocardial Contractile Dysfunction in Elderly Canine Model of Hypertensive Heart Disease Josef Korinek1, Selma F. Mohammed1, Horng H. Chen1, Carolyn S. Lam1, John C. Burnett1, Margaret M. Redfield1; 1Cardiology, Mayo Clinic and Foundation, Rochester, MN Background: Chronic phosphodiesterase-5 inhibitor therapy (PDE5-I) has been shown to preserve LV systolic chamber function and blunt left ventricular hypertrophy (LVH) in murine model of heart failure (HF) (transversal aortic constriction) and to enhance exercise performance (humans) in systolic HF. However, these beneficial effects have not been confirmed in a large animal model of HF with preserved ejection fraction (HFpEF). Further, the effect of PDE5-I on myocardial contractility has not been studied. Hypothesis: Chronic PDE5-I will ameliorate LVH and systolic myocardial or chamber dysfunction in elderly dogs with experimental hypertension. Methods: Elderly dogs (8e12 years; n 5 16) underwent renal wrapping to induce hypertension. Systolic blood pressure (SBP) was measured by implanted aortic catheters. Dogs were randomized to PDE5-I (n 5 8; 40 mg tadalafil po q day) or none (n 5 8, CON). Echo was performed before (wk 0) and after (wk 8) after renal wrapping. Ejection fraction (EF) and midwall fractional shortening (mFS) were measured from M-mode. Peak global circumferential myocardial strain (PkCS, absolute value) was assessed using two dimensional speckle tracking. Myocardial contractility was assessed by mFS-circumferential end systolic wall stress (cESS) relationship and by the PkCS-cESS relationship. LV/body weight and myocardial cyclic guanosine
239 Dipeptidyl Peptidase IV Inhibition with Sitagliptin Augments cGMP-Activating and Hypotensive Properties of B-Type Natriuretic Peptide Guido Boerrigter1, Lisa C. Costello-Boerrigter1, Gail J. Harty1, Lynn K. Harstad1, Syed Ameenuddin1, John C. Burnett1; 1Cardiovascular Research, Mayo Clinic College of Medicine, Rochester, MN Background: B-type natriuretic peptide (BNP 1e32) is a 32-amino acid hormone secreted in response to cardiac overload and has cardiac unloading actions such as natriuresis and vasodilation mediated by its second messenger cyclic guanosine monophosphate (cGMP). Recently, it has been reported that BNP 1e32 is cleaved in vitro to BNP 3e32 by the ubiquitous enzyme dipeptidyl peptidase IV (DPP-IV), which via the breakdown of incretins is also involved in glucose homeostasis. Importantly, BNP 3e32 is not hypotensive and only has a third of the natriuretic effect of BNP 1e32 in healthy canines. Sitagliptin is a novel DPP-IV-inhibitor recently approved for the treatment of type 2 diabetes mellitus. To date the modulating action of sitagliptin on BNP remains undefined. We tested the hypothesis that sitagliptin augments the biological actions of BNP 1e32 in vivo. Methods: In this crossover study six conscious healthy dogs received a 30-minute infusion of canine BNP 1e32 (20 ng/kg/min) both with and without prior oral administration of 100 mg sitagliptin. Blood samples were taken and mean arterial pressure (MAP) was measured before, during, and for ninety minutes after BNP infusion. The areas under the curve (AUC) of plasma BNP, plasma cGMP, and MAP were determined. The AUCs obtained with and without sitagliptin were compared by paired t-test. A p ! 0.05 was considered to indicate statistical significance. Results: Sitagliptin did not affect BNP immunoreactivity (p 5 0.57) during BNP infusion, which however was measured using an assay that cannot differentiate between BNP 1e32 and BNP 3e32. In contrast, sitagliptin significantly augmented the plasma cGMP increase (p 5 0.003) and MAP decrease (p 5 0.02) induced by infusion of BNP. Conclusion: We provide evidence for the first time that BNP 1e32 is a substrate for DPP-IV in vivo and that DPP-IV inhibition with sitagliptin increases the bioactivity of BNP, specifically augmenting cGMP and enhancing the decrease in blood pressure. Further studies are warranted to investigate whether DPP-IV inhibition augments endogenous BNP levels in humans especially if levels are increased by heart failure or hypertension, which could have important therapeutic implications. In addition, given the diagnostic and prognostic value of plasma BNP levels, these findings could also affect the use of BNP as a biomarker in patients on DPP-IV inhibitors.
240 Effect of Aldosterone Antagonists on Shock Frequency with Implantable Cardioverter Defibrillators Jason N. Hoeksema1, Larisa H. Cavallari1, Vicki L. Groo1, Boaz Avitall2, Rosalia C. Gonzalez2; 1Department of Pharmacy Practice, University of Illinois Medical Center at Chicago, Chicago, IL; 2Department of Cardiology, University of Illinois Medical Center at Chicago Introduction: Despite the positive effects of implantable cardioverter defibrillators (ICDs) on mortality, ICD shocks are unpleasant and can lead to significant anxiety over possible future shocks. Aldosterone receptor antagonists (ARAs) have been shown to reduce sudden cardiac death (SCD). Whether ARAs can reduce the frequency of ICD shocks is unknown. We sought to determine whether ARA therapy has an effect on the incidence of (1) shock frequency or antitachycardia pacing or (2) non-sustained ventricular tachycardia (NSVT) in patients with ICDs. Methods: Adult patients with an ICD who were either taking (n 5 44) or not taking (n 5 50) an ARA for $12 months were included. For each patient, data on demographics, medical history, the number of ICD shocks, episodes of antitachycardia pacing,
HFSA
S75
monophosphate (cGMP, pg/mg protein) were measured at tissue harvest. Results: See table. At wk 8, SBP was similar in CON and PDE5-I (Table). EF decreased in CON but was preserved in PDE5-I. Both the mFS-cESS and PkCS-cESS relationships were shifted up (improved contractility) in the PDE5-I group (p ! 0.05 for group effect for both). LV/body weight tended to be lower in PDE5-I (5.2 6 2.7 g/ kg) than CON (5.9 6 0.9 g/kg; p 5 0.13). Myocardial cGMP was increased in PDE5-I (41 6 26 vs. 19 6 7 pg/mg; p ! 0.05). Table 1.
SBP (mmHg) EF (%) cESS (g/cm2) PkCS (%) mFS (%)
CON wk 0
PDE5-I wk 0
N/A 64.3 6 7.9 N/A 16.9 6 2.8 16.5 6 3.1
N/A 67.5 6 6.4 N/A 16.9 6 1.4 18.5 6 4.0
CON wk 8
PDE5-I wk 8
226.1 6 29.6 51.8 6 17.8* 254.6 6 109.8 10.4 6 3.7* 11.6 6 4.6*
233.2 6 29.9 63.0 6 9.8 239.3 6 69.7 14 6 2.4*y 16.7 6 4.0y
yp! 0.05 vs CON at wk 0 or 8; *p! 0.05 vs wk 0 in CON or PDE5-I. Conclusions: Chronic PDE5-I preserved myocardial contractility in this elderly hypertensive canine model. PDE5-I may hold promise as a therapy in HFpEF or high risk hypertension.
237 A Novel Orally Active BNP Possesses Chronic Natriureti Actions, Decreases Mean Arterial Pressure and Activates cGMP in a Model of Acute Hypertension Alessandro Catliotti1, Horng H. Chen1, Guido Boerrigter1, Lisa C. CostelloBoerrigrter1, Fernado L. Martin1, Kenneth D. James1, John C. Burnett1; 1Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN Background: The objective of the current study was to establish the chronic diuretic actions of a novel oral conjugated human BNP (hBNP-054) and to define its blood pressure lowering effects in a model of hypertension (HTN). Methods: First we tested hBNP-054 both acutely and chronically in normal dogs to assess its biological actions as a blood pressure lowering agent and as a natriuretic factor. Secondly, we investigated the effects of acute oral hBNP-054 or vehicle in dogs that received concomitant continuous intravenous infusion of angiotensin II (ANG II). After baseline (BL) determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 mg/kg/min, 1 ml/ min) for 4 hrs to induce HTN. After 30 min of ANG II administration, dogs received oral hBNP-054 (400 mg/kg) or vehicle in a random crossover fashion with a one week interval between dosing. Blood sampling and MAP measurements were repeated 30 min after ANG II and 10, 30, 60, 120, 180 and 240 min after oral administration of hBNP-054 or vehicle. Results: In the chronic study, oral hBNP-054 effectively reduced MAP for 6 days and it induced a significant increase in 24-hr sodium excretion. hBNP was not present in the plasma at BL in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054 with a peak concentration at 30 min of 1060 6 818 pg/ml. After ANG II administration, plasma cGMP was not activated after vehicle, while it was significantly increased after oral hBNP-054 (p ! 0.0001 between two groups). Importantly, MAP was significantly increased after ANG II throughout the study protocol. However, while no changes occurred in MAP after vehicle administration, oral hBNP-054 was followed by a significant reduction in MAP for over 2 hrs (from 138 6 1 after ANG II to 124 6 2 and 130 6 5 mmHg 1 and 2 hrs after oral hBNP-054 respectively; p ! 0.001). Conclusion: For the first time we report that a novel oral hBNP has blood pressure lowering effects over a 6-day period and natriuretic actions when administered chronically. Furthermore, hBNP-054 activates cGMP and significantly reduces MAP in a model of acute HTN.
238 Chronic Phosphodiesterase-5 Inhibition Ameliorates Myocardial Contractile Dysfunction in Elderly Canine Model of Hypertensive Heart Disease Josef Korinek1, Selma F. Mohammed1, Horng H. Chen1, Carolyn S. Lam1, John C. Burnett1, Margaret M. Redfield1; 1Cardiology, Mayo Clinic and Foundation, Rochester, MN Background: Chronic phosphodiesterase-5 inhibitor therapy (PDE5-I) has been shown to preserve LV systolic chamber function and blunt left ventricular hypertrophy (LVH) in murine model of heart failure (HF) (transversal aortic constriction) and to enhance exercise performance (humans) in systolic HF. However, these beneficial effects have not been confirmed in a large animal model of HF with preserved ejection fraction (HFpEF). Further, the effect of PDE5-I on myocardial contractility has not been studied. Hypothesis: Chronic PDE5-I will ameliorate LVH and systolic myocardial or chamber dysfunction in elderly dogs with experimental hypertension. Methods: Elderly dogs (8e12 years; n 5 16) underwent renal wrapping to induce hypertension. Systolic blood pressure (SBP) was measured by implanted aortic catheters. Dogs were randomized to PDE5-I (n 5 8; 40 mg tadalafil po q day) or none (n 5 8, CON). Echo was performed before (wk 0) and after (wk 8) after renal wrapping. Ejection fraction (EF) and midwall fractional shortening (mFS) were measured from M-mode. Peak global circumferential myocardial strain (PkCS, absolute value) was assessed using two dimensional speckle tracking. Myocardial contractility was assessed by mFS-circumferential end systolic wall stress (cESS) relationship and by the PkCS-cESS relationship. LV/body weight and myocardial cyclic guanosine
239 Dipeptidyl Peptidase IV Inhibition with Sitagliptin Augments cGMP-Activating and Hypotensive Properties of B-Type Natriuretic Peptide Guido Boerrigter1, Lisa C. Costello-Boerrigter1, Gail J. Harty1, Lynn K. Harstad1, Syed Ameenuddin1, John C. Burnett1; 1Cardiovascular Research, Mayo Clinic College of Medicine, Rochester, MN Background: B-type natriuretic peptide (BNP 1e32) is a 32-amino acid hormone secreted in response to cardiac overload and has cardiac unloading actions such as natriuresis and vasodilation mediated by its second messenger cyclic guanosine monophosphate (cGMP). Recently, it has been reported that BNP 1e32 is cleaved in vitro to BNP 3e32 by the ubiquitous enzyme dipeptidyl peptidase IV (DPP-IV), which via the breakdown of incretins is also involved in glucose homeostasis. Importantly, BNP 3e32 is not hypotensive and only has a third of the natriuretic effect of BNP 1e32 in healthy canines. Sitagliptin is a novel DPP-IV-inhibitor recently approved for the treatment of type 2 diabetes mellitus. To date the modulating action of sitagliptin on BNP remains undefined. We tested the hypothesis that sitagliptin augments the biological actions of BNP 1e32 in vivo. Methods: In this crossover study six conscious healthy dogs received a 30-minute infusion of canine BNP 1e32 (20 ng/kg/min) both with and without prior oral administration of 100 mg sitagliptin. Blood samples were taken and mean arterial pressure (MAP) was measured before, during, and for ninety minutes after BNP infusion. The areas under the curve (AUC) of plasma BNP, plasma cGMP, and MAP were determined. The AUCs obtained with and without sitagliptin were compared by paired t-test. A p ! 0.05 was considered to indicate statistical significance. Results: Sitagliptin did not affect BNP immunoreactivity (p 5 0.57) during BNP infusion, which however was measured using an assay that cannot differentiate between BNP 1e32 and BNP 3e32. In contrast, sitagliptin significantly augmented the plasma cGMP increase (p 5 0.003) and MAP decrease (p 5 0.02) induced by infusion of BNP. Conclusion: We provide evidence for the first time that BNP 1e32 is a substrate for DPP-IV in vivo and that DPP-IV inhibition with sitagliptin increases the bioactivity of BNP, specifically augmenting cGMP and enhancing the decrease in blood pressure. Further studies are warranted to investigate whether DPP-IV inhibition augments endogenous BNP levels in humans especially if levels are increased by heart failure or hypertension, which could have important therapeutic implications. In addition, given the diagnostic and prognostic value of plasma BNP levels, these findings could also affect the use of BNP as a biomarker in patients on DPP-IV inhibitors.
240 Effect of Aldosterone Antagonists on Shock Frequency with Implantable Cardioverter Defibrillators Jason N. Hoeksema1, Larisa H. Cavallari1, Vicki L. Groo1, Boaz Avitall2, Rosalia C. Gonzalez2; 1Department of Pharmacy Practice, University of Illinois Medical Center at Chicago, Chicago, IL; 2Department of Cardiology, University of Illinois Medical Center at Chicago Introduction: Despite the positive effects of implantable cardioverter defibrillators (ICDs) on mortality, ICD shocks are unpleasant and can lead to significant anxiety over possible future shocks. Aldosterone receptor antagonists (ARAs) have been shown to reduce sudden cardiac death (SCD). Whether ARAs can reduce the frequency of ICD shocks is unknown. We sought to determine whether ARA therapy has an effect on the incidence of (1) shock frequency or antitachycardia pacing or (2) non-sustained ventricular tachycardia (NSVT) in patients with ICDs. Methods: Adult patients with an ICD who were either taking (n 5 44) or not taking (n 5 50) an ARA for $12 months were included. For each patient, data on demographics, medical history, the number of ICD shocks, episodes of antitachycardia pacing,