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Statin Therapy Is Associated with Dose-Related Improvement in LV Remodeling in Non-Ischemic Heart Failure
The 10th Annual Scientific Meeting to conventional pharmacological therapy while simultaneously potentiating renal function. These data need to be confirmed in an adequately powered study. LVEF (%) Statin Non-statin LVESD (mm) Statin Non-statin LVEDD (mm) Statin Non-statin
HFSA
S83
Statin vs. Non-statin, p valuey
Baseline
Follow-up
Mean Change
24 6 10 25 6 11
36 6 12* 30 6 14*
12 6 11 5 6 13
0.002
51 6 10 50 6 10
43 6 10* 48 6 10
e7 6 9 e2 6 10
0.004
60 6 9 59 6 9
55 6 9* 58 6 9
e5 6 8 067
0.003
Data are mean 6 SD. *p ! 0.05 compared to baseline. y Multivariate Analysis.
268 Valsartan Reverses Post-Translational Modifications of ATP Synthase D-Chain during Prolonged Post-Ischemic Reperfusion Grzegorz Sawicki, Bodh I. Jugdutt; Medicine, University, Edmonton, AB, Canada Background: Cardioprotection induced by the angiotensin II type 1 receptor (AT1R) blocker valsartan during reperfused myocardial infarction (RMI) is associated with attenuation of the increase in the metabolic enzyme mitochondrial ATP synthase D-chain (ATP/D). We hypothesized that RMI induces post-translational modifications (PTMs) of ATP/D that are reversed by valsartan. Methods: We applied a pharmaco-proteomics approach to detect regional differences in PTMs of ATP/D in ischemic (IZ) and non-ischemic (NIZ) zones of dog hearts subjected to in vivo RMI (90 min left anterior descending coronary occlusion; 120 min reperfusion) and randomized to placebo or valsartan. We measured hemodynamics and left ventricular (LV) function (2D-Echocardiogram/Doppler) and identified/analyzed ATP/ D using 2D electrophoresis, PD Quest, and in-gel trypsin digestion of protein spots (Fig. A) followed by mass spectrometry, and FindMod tool for finding potential PTMs. Results: Compared to controls, RMI induced ischemic injury and systolic and diastolic dysfunction that were attenuated by valsartan. Compared to the NIZ, RMI increased ATP/D in the IZ (nearly 2-fold) and this was normalized by valsartan (Fig. B). Importantly, RMI increased hydroxylation of ATP/D, S-nitrosylation of cysteine-100, nitration of tyrosine-80 and e225, and hydroxylation of lysine-182 followed by its myristoylation (Fig. C). Valsartan reduced ATP/D hydroxylation, abolished the PTMs including lysine myristoylation in the IZ, and additionally triggered phosphorylation of serine-76 in both the IZ and NIZ. Conclusions: Valsartaninduced cardioprotection is associated with reversal of PTMs of ATP/D during RMI. This new pleiotropic effect of AT1R blockade suggests that PTMs may represent a novel therapeutic target after RMI.
267 Statin Therapy Is Associated with Dose-Related Improvement in LV Remodeling in Non-Ischemic Heart Failure Sunil Matiwala1, Andreia Biolo1, Warren Chuang1, William Chung1, Bindu Akkanti1, Wilson Colucci1, Henry Ooi1; 1Dept of Cardiovascular Medicine, Boston University Medical Center, Boston, MA Introduction: HMG-CoA reductase inhibitors (statins) appear to exert beneficial effects on clinical outcomes in patients with heart failure. In in vitro and animal studies statins inhibit cardiac myocyte hypertrophy and apoptosis, suggesting that improved clinical outcomes may be due to inhibition of pathological remodeling. We performed a retrospective analysis of the relationship between statin use and left ventricular (LV) remodeling in patients with non-ischemic LV systolic dysfunction. Methods and Results: 154 patients with non-ischemic cardiomyopathy and a LV ejection fraction (EF) #45% were selected from the Boston University Medical Center Cardiomyopathy Database: 58 consecutive patients had been started on a statin, and 96 contemporaneous patients not treated with a statin served as a control group. The two groups were similar with regard to age, sex, race and NYHA class. An echocardiogram was performed before and an average of 25 months after the initiation of statin therapy. Over this interval, a significantly greater improvement in EF, endsystolic (LVESD) and end-diastolic diameters (LVEDD) were seen in statin-treated patients compared to the non-statin group. By multivariate analysis controlling for age, gender, creatinine, serum cholesterol, hypertension, diabetes, beta-blocker, ACEI and ARB, interval between echocardiograms and baseline echo parameters, statin use was an independent predictor of favorable change in LVEF, LVESD and LVEDD (Table), with a statin-attributable change of þ7% (3 to 11), e5 mm (e8 to e2) and e4 mm (e6 to e1), respectively (95% CI). The increase in LVEF was greater with statin doses above (19 6 13%) vs. below (10 6 11%) the 50% FDA maximum dose (p ! 0.05). Conclusions: In patients with non-ischemic systolic LV dysfunction, statin use is associated with more favorable LV remodeling and systolic function. This effect is independent of other drug therapies and is greater at higher doses. An anti-remodeling effect of statins may contribute to the beneficial effect of statins on clinical outcomes.
HFSA
S83
Statin vs. Non-statin, p valuey
Baseline
Follow-up
Mean Change
24 6 10 25 6 11
36 6 12* 30 6 14*
12 6 11 5 6 13
0.002
51 6 10 50 6 10
43 6 10* 48 6 10
e7 6 9 e2 6 10
0.004
60 6 9 59 6 9
55 6 9* 58 6 9
e5 6 8 067
0.003
Data are mean 6 SD. *p ! 0.05 compared to baseline. y Multivariate Analysis.
268 Valsartan Reverses Post-Translational Modifications of ATP Synthase D-Chain during Prolonged Post-Ischemic Reperfusion Grzegorz Sawicki, Bodh I. Jugdutt; Medicine, University, Edmonton, AB, Canada Background: Cardioprotection induced by the angiotensin II type 1 receptor (AT1R) blocker valsartan during reperfused myocardial infarction (RMI) is associated with attenuation of the increase in the metabolic enzyme mitochondrial ATP synthase D-chain (ATP/D). We hypothesized that RMI induces post-translational modifications (PTMs) of ATP/D that are reversed by valsartan. Methods: We applied a pharmaco-proteomics approach to detect regional differences in PTMs of ATP/D in ischemic (IZ) and non-ischemic (NIZ) zones of dog hearts subjected to in vivo RMI (90 min left anterior descending coronary occlusion; 120 min reperfusion) and randomized to placebo or valsartan. We measured hemodynamics and left ventricular (LV) function (2D-Echocardiogram/Doppler) and identified/analyzed ATP/ D using 2D electrophoresis, PD Quest, and in-gel trypsin digestion of protein spots (Fig. A) followed by mass spectrometry, and FindMod tool for finding potential PTMs. Results: Compared to controls, RMI induced ischemic injury and systolic and diastolic dysfunction that were attenuated by valsartan. Compared to the NIZ, RMI increased ATP/D in the IZ (nearly 2-fold) and this was normalized by valsartan (Fig. B). Importantly, RMI increased hydroxylation of ATP/D, S-nitrosylation of cysteine-100, nitration of tyrosine-80 and e225, and hydroxylation of lysine-182 followed by its myristoylation (Fig. C). Valsartan reduced ATP/D hydroxylation, abolished the PTMs including lysine myristoylation in the IZ, and additionally triggered phosphorylation of serine-76 in both the IZ and NIZ. Conclusions: Valsartaninduced cardioprotection is associated with reversal of PTMs of ATP/D during RMI. This new pleiotropic effect of AT1R blockade suggests that PTMs may represent a novel therapeutic target after RMI.
267 Statin Therapy Is Associated with Dose-Related Improvement in LV Remodeling in Non-Ischemic Heart Failure Sunil Matiwala1, Andreia Biolo1, Warren Chuang1, William Chung1, Bindu Akkanti1, Wilson Colucci1, Henry Ooi1; 1Dept of Cardiovascular Medicine, Boston University Medical Center, Boston, MA Introduction: HMG-CoA reductase inhibitors (statins) appear to exert beneficial effects on clinical outcomes in patients with heart failure. In in vitro and animal studies statins inhibit cardiac myocyte hypertrophy and apoptosis, suggesting that improved clinical outcomes may be due to inhibition of pathological remodeling. We performed a retrospective analysis of the relationship between statin use and left ventricular (LV) remodeling in patients with non-ischemic LV systolic dysfunction. Methods and Results: 154 patients with non-ischemic cardiomyopathy and a LV ejection fraction (EF) #45% were selected from the Boston University Medical Center Cardiomyopathy Database: 58 consecutive patients had been started on a statin, and 96 contemporaneous patients not treated with a statin served as a control group. The two groups were similar with regard to age, sex, race and NYHA class. An echocardiogram was performed before and an average of 25 months after the initiation of statin therapy. Over this interval, a significantly greater improvement in EF, endsystolic (LVESD) and end-diastolic diameters (LVEDD) were seen in statin-treated patients compared to the non-statin group. By multivariate analysis controlling for age, gender, creatinine, serum cholesterol, hypertension, diabetes, beta-blocker, ACEI and ARB, interval between echocardiograms and baseline echo parameters, statin use was an independent predictor of favorable change in LVEF, LVESD and LVEDD (Table), with a statin-attributable change of þ7% (3 to 11), e5 mm (e8 to e2) and e4 mm (e6 to e1), respectively (95% CI). The increase in LVEF was greater with statin doses above (19 6 13%) vs. below (10 6 11%) the 50% FDA maximum dose (p ! 0.05). Conclusions: In patients with non-ischemic systolic LV dysfunction, statin use is associated with more favorable LV remodeling and systolic function. This effect is independent of other drug therapies and is greater at higher doses. An anti-remodeling effect of statins may contribute to the beneficial effect of statins on clinical outcomes.