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Multi-centre Crossover Comparison of Carvedilol, Metoprolol Succinate and Bisoprolol in Patients with Chronic Heart Failure
409 MULTI-CENTRE CROSSOVER COMPARISON OF CARVEDILOL, METOPROLOL SUCCINATE AND BISOPROLOL IN PATIENTS WITH CHRONIC HEART FAILURE A. Jabbour 1,2,5 , P.S. Macdonald 1,2,5 , A.M. Keogh 1,2,5 , E. Kotlyar 1 , S. Mellemkjaer 3 , C.F. Coleman 1 , M. Elsik 4 , H. Krum 4 , C.S. Hayward 1,2 1 St
Vincent’s Hospital, Sydney, Australia of New South Wales, Sydney, Australia 3 Aarhus University Hospital, Denmark 4 NHMRC Centre of Clinical Research Excellence in Therapeutics and Monash University/Alfred Hospital, Australia 5 Victor Chang Cardiac Research Institute, Sydney, Australia 2 University
Abstracts
S181
410 NITRIC OXIDE-ACTIVATED GUANYLYL CYCLASE MODULATES NAD(P)H OXIDASE AND OXIDATIVE INHIBITION OF THE NA+ –K+ PUMP IN VENTRICULAR MYOCYTES IN A PHOSPHATASE DEPENDENT MANNER Karin K.M. Chia 1,2 , Elisha Halmilton 2 , Alvaro Garcia 1 , Dennis Wang 1,2 , Chia-Chia Liu 2 , Gemma Figtree 1,2 , Helge Rasmussen 1,2 1 Royal
North Shore Hospital, Sydney, Australia
2 North Shore Heart Research Centre, Kolling Institute for Med-
ical Research, University of Sydney, Australia
Background: Carvedilol (C), metoprolol succinate (M) and bisoprolol (B) are established -blockers for chronic heart failure (CHF), however their comparative effects in patients with obstructive lung disease (OLD) and CHF are incompletely characterised. Methods: Haemodynamic, respiratory and clinical effects of C, M and B were studied in a randomised, triple-crossover design (6-week intervals) in 51 patients on optimal therapy for CHF (35 with concomitant OLD vs. 16 without). Echocardiography, NT-proBNP, central augmented pressure (AugP) from pulse waveform analysis, respiratory function testing (RFT), 6 min walk distance (6MWD) and NYHA class were assessed at each visit. Results: Age 66 ± 1.7, NYHA I:II:III; 6:30:15, LVEF 36.9 ± 1.4% (mean ± SEM). NT-proBNP was significantly lower on C than either M or B (C-1001 ± 182 ng/L; M1371 ± 294; B-1349 ± 281, p < 0.01), and returned to the baseline level on resumption of the initial -blocker. AugP (measure of pulsatile afterload) was lowest on C (C9.9 ± 1.1 mmHg; M-11.5 ± 1.1; B-12.2 ± 1.2, p = 0.02). Heart rate was highest on C (C-66.4 ± 1.8 bpm; M-64.5 ± 2.1; B62.5 ± 1.8, p = 0.03). No difference in systolic or postural BP was observed. In OLD patients, FEV1 was lowest on C and best on B (C-1.85 ± 0.09 L; M-1.94 ± 0.10; B-2.0 ± 0.11, p < 0.001). This change was not significant in patients without OLD. NYHA, 6MWD and LVEF did not change significantly. -Blocker switches were well tolerated. Conclusions: NT-proBNP, a marker of heart failure severity was consistently lower in patients on carvedilol. Lower AugP and FEV1 with carvedilol were consistent with its known drug pharmacology. These results aid in selecting appropriate -blocker treatment in patients with CHF and concomitant lung disease.
Background: The Na+ –K+ pump in cardiac myocytes is inhibited by an oxidative modification, glutathiolation, of its 1 subunit. Glutathiolation and inhibition can be induced by kinase-dependent activation of NADPH oxidase by angiotensin II (AII). Since there is glutathiolation at baseline and since nitric oxide (NO) stimulates the Na+ –K+ pump, we tested the hypothesis that pump stimulation is due to a decrease in oxidant stress and de-glutathiolation of its 1 subunit. This is important for conditions with raised myocyte Na and oxidant stress, e.g. heart failure. Methods and results: Glutathiolation was detected by loading rabbit cardiomyocytes with biotin-tagged glutathione, precipitation of lysate with streptavidin and immunoblotting with 1 subunit antibody. Exposure of myocytes to the synthetic NO-dependent guanylyl cyclase activator, YC-1, decreased glutathiolation. Since NADPH oxidase activation is kinase-dependent, we inhibited protein phosphatase (PP) with okadaic acid (OA). OA in a concentration chosen to inhibit PP2A abolished the effect of YC-1 on glutathiolation. Exposure of myocytes to 100 nM AII to activate NADPH oxidase increased their superoxide-sensitive DHE fluorescence measured with confocal microscopy. YC-1 induced a significant OAsensitive decrease in this fluorescence. To study functional correlates, we measured ouabain-sensitive Na+ –K+ pump current (Ip ) in voltage clamped myocytes exposed to AII. YC-1 induced a OA-sensitive increase in Ip . The OAsensitive increase was reproduced by exposing myocytes to C6 ceramide, an activator of PP2A. Conclusion: Activation of NO-dependent guanylyl cyclase inhibits NAD(P)H oxidase induced glutathiolation of the 1 subunit of the Na+ –K+ pump and stimulates pump activity in a PP2A dependent manner in cardiomyocytes.
doi:10.1016/j.hlc.2009.05.411
doi:10.1016/j.hlc.2009.05.412
ABSTRACTS
Heart, Lung and Circulation 2009;18S:S1–S286
Vincent’s Hospital, Sydney, Australia of New South Wales, Sydney, Australia 3 Aarhus University Hospital, Denmark 4 NHMRC Centre of Clinical Research Excellence in Therapeutics and Monash University/Alfred Hospital, Australia 5 Victor Chang Cardiac Research Institute, Sydney, Australia 2 University
Abstracts
S181
410 NITRIC OXIDE-ACTIVATED GUANYLYL CYCLASE MODULATES NAD(P)H OXIDASE AND OXIDATIVE INHIBITION OF THE NA+ –K+ PUMP IN VENTRICULAR MYOCYTES IN A PHOSPHATASE DEPENDENT MANNER Karin K.M. Chia 1,2 , Elisha Halmilton 2 , Alvaro Garcia 1 , Dennis Wang 1,2 , Chia-Chia Liu 2 , Gemma Figtree 1,2 , Helge Rasmussen 1,2 1 Royal
North Shore Hospital, Sydney, Australia
2 North Shore Heart Research Centre, Kolling Institute for Med-
ical Research, University of Sydney, Australia
Background: Carvedilol (C), metoprolol succinate (M) and bisoprolol (B) are established -blockers for chronic heart failure (CHF), however their comparative effects in patients with obstructive lung disease (OLD) and CHF are incompletely characterised. Methods: Haemodynamic, respiratory and clinical effects of C, M and B were studied in a randomised, triple-crossover design (6-week intervals) in 51 patients on optimal therapy for CHF (35 with concomitant OLD vs. 16 without). Echocardiography, NT-proBNP, central augmented pressure (AugP) from pulse waveform analysis, respiratory function testing (RFT), 6 min walk distance (6MWD) and NYHA class were assessed at each visit. Results: Age 66 ± 1.7, NYHA I:II:III; 6:30:15, LVEF 36.9 ± 1.4% (mean ± SEM). NT-proBNP was significantly lower on C than either M or B (C-1001 ± 182 ng/L; M1371 ± 294; B-1349 ± 281, p < 0.01), and returned to the baseline level on resumption of the initial -blocker. AugP (measure of pulsatile afterload) was lowest on C (C9.9 ± 1.1 mmHg; M-11.5 ± 1.1; B-12.2 ± 1.2, p = 0.02). Heart rate was highest on C (C-66.4 ± 1.8 bpm; M-64.5 ± 2.1; B62.5 ± 1.8, p = 0.03). No difference in systolic or postural BP was observed. In OLD patients, FEV1 was lowest on C and best on B (C-1.85 ± 0.09 L; M-1.94 ± 0.10; B-2.0 ± 0.11, p < 0.001). This change was not significant in patients without OLD. NYHA, 6MWD and LVEF did not change significantly. -Blocker switches were well tolerated. Conclusions: NT-proBNP, a marker of heart failure severity was consistently lower in patients on carvedilol. Lower AugP and FEV1 with carvedilol were consistent with its known drug pharmacology. These results aid in selecting appropriate -blocker treatment in patients with CHF and concomitant lung disease.
Background: The Na+ –K+ pump in cardiac myocytes is inhibited by an oxidative modification, glutathiolation, of its 1 subunit. Glutathiolation and inhibition can be induced by kinase-dependent activation of NADPH oxidase by angiotensin II (AII). Since there is glutathiolation at baseline and since nitric oxide (NO) stimulates the Na+ –K+ pump, we tested the hypothesis that pump stimulation is due to a decrease in oxidant stress and de-glutathiolation of its 1 subunit. This is important for conditions with raised myocyte Na and oxidant stress, e.g. heart failure. Methods and results: Glutathiolation was detected by loading rabbit cardiomyocytes with biotin-tagged glutathione, precipitation of lysate with streptavidin and immunoblotting with 1 subunit antibody. Exposure of myocytes to the synthetic NO-dependent guanylyl cyclase activator, YC-1, decreased glutathiolation. Since NADPH oxidase activation is kinase-dependent, we inhibited protein phosphatase (PP) with okadaic acid (OA). OA in a concentration chosen to inhibit PP2A abolished the effect of YC-1 on glutathiolation. Exposure of myocytes to 100 nM AII to activate NADPH oxidase increased their superoxide-sensitive DHE fluorescence measured with confocal microscopy. YC-1 induced a significant OAsensitive decrease in this fluorescence. To study functional correlates, we measured ouabain-sensitive Na+ –K+ pump current (Ip ) in voltage clamped myocytes exposed to AII. YC-1 induced a OA-sensitive increase in Ip . The OAsensitive increase was reproduced by exposing myocytes to C6 ceramide, an activator of PP2A. Conclusion: Activation of NO-dependent guanylyl cyclase inhibits NAD(P)H oxidase induced glutathiolation of the 1 subunit of the Na+ –K+ pump and stimulates pump activity in a PP2A dependent manner in cardiomyocytes.
doi:10.1016/j.hlc.2009.05.411
doi:10.1016/j.hlc.2009.05.412
ABSTRACTS
Heart, Lung and Circulation 2009;18S:S1–S286