Induction of Antioxidant Gene Expression in a Mouse Model of Ischemic Cardiomyopathy Is Dependent on Reactive Oxygen Species

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Journal of Cardiac Failure Vol. 11 No. 6 Suppl. 2005

076 Renal Hyporesponsiveness to BNP Overcome with High Dose BNP in Experimental CHF John A. Schirger1, Horng H. Chen1, Lisa C. Costello-Boerrigter1, Guido Boerrigter1, Alessandro Cataliotti1, Ondrej Lisy1, John C. Burnett1; 1Cardiovascular Medicine, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN Introduction: Human Brain Natriuretic Peptide (hBNP) in acute heart failure (CHF) improves symptoms and decreases filling pressures. There is controversy regarding effects of hBNP in CHF on renal function. Recognizing the complexity of neurohumoral activation in the control of renal function in different stages of CHF, the current studies tested the renal response to hBNP in experimental moderate heart failure (MHF) and severe heart failure (SHF). We hypothesized that SHF, characterized by marked activation of the renin angiotensin aldosterone system (RAAS), would be resistant to renal effects of clinical dose (CD) IV hBNP as compared to MHF, characterized by less activation of the RAAS. Further we interrogated the effects of supraclinical doses (SCD) on renal function in experimental SHF. Methods: MHF and SHF (n ⫽ 7 both) were induced by ventricular pacing at 180 and 240 bpm, respectively, for 10 days. After a baseline clearance IV human BNP (hBNP) was infused in all groups at 100 ng/kg/min (approximating CD) for 30 min followed by a 30 min clearance with continued infusion. In SHF this was followed by infusion of 1000ng/kg/min (SCD). Results: MHF and SHF were characterized by decreased mean arterial pressure (MAP) and cardiac output (CO) compared to normal (n ⫽ 7) with linear trends toward further decreases in CO from MHF to SHF. Pulmonary capillary wedge pressure tended to increase vs normal in MHF and increased in SHF. Plasma ANP, BNP and aldosterone, and plasma renin activity (PRA) tended to increase vs normal in MHF and increased with SHF. Glomerular Filtration Rate (GFR), Renal Blood Flow (RBF) and urinary sodium excretion (UNaV) decreased in MHF and SHF compared to normal. CD of IV hBNP increased UNaV, GFR and RBF in normals and in MHF. In response to CD of IV hBNP there was no increase in UNaVor GFR in SHF. However SCD IV hBNP resulted in increased UNaV (1 ⫾ 0.3 to 12 ⫾ 6 uEq/min) with preservation of GFR. These beneficial renal actions to SCD dose hBNP occurred in the absence of further decline in MAP or other adverse hemodynamic or neurohumoral responses. Conclusion: CD IV hBNP increases UNaV, GFR and RBF in normals and MHF. SHF, in contrast, is characterized by renal resistance to these effects. SCD in SHF results in increases in urinary sodium excretion and preservation of GFR without adverse cardiorenal effects. These studies provide insight into what type of neurohumoral environment in CHF favors renal responsiveness.

and interpreting scientific studies for SDB and assessing SDB in association with heart failure status. Long-term trending apnea diagnostics rather than single-night studies are needed to assess change in SDB over time.

078 Induction of Antioxidant Gene Expression in a Mouse Model of Ischemic Cardiomyopathy Is Dependent on Reactive Oxygen Species Saumya Sharma1, Oliver Dewald2, Julia V. Adrogue1, Rebecca Salazar1, Peter Razeghi1, Russell P. Bowler3, James D. Crapo3, Mark L. Entman2, Heinrich Taegtmeyer1; 1Cardiology, The University of Texas Houston Medical School, Houston, TX; 2Cardiovascular Sciences and DeBakey Heart Center, Baylor College of Medicine and the Methodist Hospital, Houston, TX; 3Department of Medicine, National Jewish Medical and Research Center, Denver, CO Ischemia and reperfusion (I/R) are characterized by oxidative stress as well as changes in the antioxidant enzymes of the heart. However, little is known about the transcriptional regulation of myocardial antioxidant enzymes in repetitive I/R and hibernating myocardium. In a mouse model of ischemic cardiomyopathy induced by repetitive I/ R, we postulated that induction of antioxidant gene expression was dependent on reactive oxygen species (ROS). Repetitive closed-chest I/R (15 min) was performed daily in C57/BL6 mice and in mice overexpressing extracellular superoxide dismutase (EC-SOD). Antioxidant enzyme expression was measured at 3, 5, 7, and 28 days of repetitive I/R as well as 15 and 30 days after discontinuation of I/R. Repetitive I/R caused an early and sustained increase in glutathione peroxidase (GPX) transcript levels, while heme-oxygenase-1 (HO-1) expression increased only after 7 days of repetitive I/R. Overexpression of EC-SOD prevented the upregulation of GPX and HO-1 transcript levels by repetitive I/R suggesting that both genes are regulated by ROS. In conclusion, repetitive I/R was associated with an early upregulation of GPX expression as well as a delayed increase of HO-1 transcript levels in the heart. The induction of both antioxidant genes was dependent on ROS suggesting that alterations in redox balance not only mediate tissue injury but also components of “programmed cell survival” in hibernating myocardium.

077 Inter-Night Variability of Sleep Disordered Breathing in an Atrial Overdrive Pacing Study Alaa Shalaby1, Jeffrey Fowler2, Roger Freedman2, Claudius Hansen3, Robert Simpson2, Charles Atwood1, Joerg Neuzner3, Martin Konermann4, Michel CramerBornemann5, Deborah Burton6, Yachuan Pu6, Jonathan Kwok6; 1Cardiology, Pittsburgh VA Healthcare System; 2Pulmonology, Pittsburgh VA Healthcare System; 3 Cardiology, University of Utah; 4Pulmonology, University of Utah; 5Cardiology, Klinikum Kassel; 6Pulmonology, Marienkrankenhaus Kassel; 7Pulmonology, Hennepin County Medical Center; 8CRM, Guidant Corp. Background: Sleep disordered breathing (SDB) adversely affects cardiovascular health. It has been suggested that obstructive apnea may worsen heart failure (HF) status while central apnea may indicate worsening HF status. Therefore, apnea-hypopnea index (AHI) and other polysomnography (PSG) data may be important clinical measures. We assessed SDB variability and the suitability of single-point measurements. Methods: Pacemaker (PM) patients (Guidant PULSAR MAX I/II or INSIGNIA) underwent PSG to screen for SDB with lower rate limit (LRL) set at 50 bpm. We studied 13 PM patients (12M, 1F) who screened positive (AHI ⬎ 15). Within 4 weeks, PSG was repeated with no change in medical treatment received on both nights, including PM LRL. The differences in AHI and SDB measures were compared using t-test between screening (S) and control (P0) studies. Results are displayed as the mean ⫾ standard deviation. Results: Mean LVEF was 52 ⫾ 12% with all patients in NYHA class I/II (n ⫽ 8/5). The time between the studies was 14 ⫾ 7 days. There was no difference in mean heart rate between S and P0 (p ⫽ 0.96, 58 ⫾ 8 vs. 58 ⫾ 10). AHI varied by ⫺4.0 ⫾ 17.2 from S to P0 nights (p ⫽ 0.42). Other SDB measures, including mean oxygen desaturation per SDB event and circulation delay, varied significantly between S and P0 nights for some patients. Conclusion: Individual patient’s AHI values were observed to vary by clinically significant values between two sleep studies without changes in medical therapy. Other aspects of SDB also varied significantly. Inter-night variability should be taken into consideration in designing

079 Effects of ACE Inhibitor Therapy Versus Valsartan on Cellular Markers of Cell Growth, Metabolism and Survival in the Transplanted Human Heart: The Valsartan in Cardiac Transplantation Trial Michel White1, Laure Voisin2, Heather Ross3, Jean-Lucien Rouleau1, Lucette Whittom4, Guy Pelletier1, Normand Racine1, Sylvain Meloche2; 1Cardiology, Montreal Heart Institute, Montreal, QC, Canada; 2Pharmacology, University of Montreal, Montreal, QC, Canada; 3Research Center, The Toronto Hospital, Toronto, ON, Canada; 4 Research Center, Montreal Heart Institute, Montreal, QC, Canada Background: Both angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) therapy provided some beneficial efforts on morbidity and/ or mortality in high-risk patients. The effects of ACE inhibitor therapy vs substitution for an ARB valsartan on cardiac cellular mechanisms have not been investigated in the human heart. Methods: Twenty-six stable long-term cardiac transplant recipients aged 51.8 ⫾ 12 years, 48.4 ⫾ 46.5 months following transplantation were recruited. All subjects were treated with a calcineurin inhibitor and exhibited well controlled hypertension without any evidence of LV hypertrophy on echo. The patients were randomized to continue on ACE inhibitor therapy (n ⫽ 8) vs substitution for valsartan (n ⫽ 18) titrated to 160 mg o.d. Endomyocardial biopsies for the monitoring of rejection plus 2 extra-pieces of 3 to 5 mg were harvested at the time of randomization and after 9 months of therapy. Angiotensin type (AT) I and II receptors, and ANF mRNA were measured by real-time quantitative polymerase chain reaction (PCR). The total expression level and activity of the MAP kinases ERK1/2, JNK and p38, and the protein kinases AKT and mTOR was measured by immunoblotting. Results for selected markers are presented in the table. Conclusions: The substitution of valsartan for ACE inhibitor therapy provides similar effects on cellular mechanisms involved in the regulation of cell growth, metabolism and survival in the transplanted human heart. Accordingly, a similar cardio-protective effect is expected with both ACE inhibitor and valsartan. Table 1 -

AT1

ACEI (n ⫽ 8) BSL 9 months Valsartan (n ⫽ 18) BSL 9 months

0.04 ⫾ 0.03 0.05 ⫾ 0.02 0.03 ⫾ 0.02 0.04 ⫾ 0.02

AT2

ERK-1

mTOR

AKT

0.02 ⫾ 0.02 0.02 ⫾ 0.03 0.01 ⫾ 0.01 0.01 ⫾ 0.01

0.51 ⫾ 0.56 0.70 ⫾ 0.67 0.72 ⫾ 0.91 0.46 ⫾ 0.78

0.70 ⫾ 0.25 0.79 ⫾ 0.41 0.92 ⫾ 0.29 0.95 ⫾ 0.23

0.46 ⫾ 0.25 0.51 ⫾ 0.35 0.47 ⫾ 0.24 0.39 ⫾ 0.21

Data are mean ⫾ SD; P ⫽ NS for all markers.