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1 Hydrogen Peroxide, an Endogenous Endothelium-Derived Hyperpolarizing Factor, Plays an Important Role in Coronary Autoregulation In Vivo Toyotaka Yada, MD; Hiroaki Shimokawa, MD; Osamu Hiramatsu, PhD; Tatsuya Kajita, MD; Fumiyuki Shigeto, MD; Masami Goto, MD; Yasuo Ogasawara, PhD; Fumihiko Kajiya, MD, PhD BackgroundRecent studies in vitro have demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans. The aim of this study was to evaluate our hypothesis that endothelium-derived H2O2 is an EDHF in vivo and plays an important role in coronary autoregulation. Methods and ResultsTo test this hypothesis, we evaluated vasodilator responses of canine (n41) subepicardial small coronary arteries (100 m) and arterioles (100 m) with an intravital microscope in response to acetylcholine and to a stepwise reduction in coronary perfusion pressure (from 100 to 30 mm Hg) before and after inhibition of NO synthesis with NG-monomethyl-L-arginine (L-NMMA). After L-NMMA, the coronary vasodilator responses were Downloaded from http://circ.ahajournals.org/ by guest on September 10, 2016 attenuated primarily in small arteries, whereas combined infusion of L-NMMA plus catalase (an enzyme that selectively dismutates H2O2 into water and oxygen) or tetraethylammonium (TEA, an inhibitor of large-conductance KCa channels) attenuated the vasodilator responses of coronary arteries of both sizes. Residual arteriolar dilation after L-NMMA plus catalase or TEA was largely attenuated by 8-sulfophenyltheophylline, an adenosine receptor inhibitor. ConclusionsThese results suggest that H2O2 is an endogenous EDHF in vivo and plays an important role in coronary autoregulation in cooperation with NO and adenosine. (Circulation. 2003;107:1040-1045.) Key Words: endothelium-derived factors microcirculation ischemia nitric oxide adenosine C oronary autoregulation is an important physiological compensatory mechanism that permits the myocardium to relax when coronary perfusion pressure is decreased.1 through gap junctions between endothelial cells and vascular smooth muscle cells.11 Recently, Matoba et al12,13 established that endothelium- Nitric oxide (NO) and adenosine are known to be involved in derived hydrogen peroxide (H2O2) is a primary EDHF in mice ischemic autoregulation during low perfusion pressure.1,2 and humans. Indeed, H2O2 is known to activate calcium-ac- Vascular endothelial cells play an important role in mod- tivated K channels (KCa)14 and to cause hyperpolarizations of ulating vascular tone by releasing at least 3 vasodilator vascular smooth muscle cells. Blockade of KCa channels factors, including NO, prostacyclin (PGI2), and endothelium- inhibits the adenosine-induced coronary vasodilation.15 How- derived hyperpolarizing factor (EDHF).3,4 NO synthase in- ever, it remains to be examined whether H2O2 is an EDHF in hibitors largely suppress acetylcholine (ACh)-induced dila- the coronary circulation in vivo, and if so, whether H2O2 tion of human5 and canine6 epicardial coronary arterioles in contributes to autoregulation as a compensatory mechanism vivo, indicating that EDHF may not be involved in the for NO and adenosine. The aim of the present study was to ACh-induced vasodilation of large coronary arteries in vivo. elucidate those important issues in dogs. The results demon- Conversely, in the coronary microcirculation, inhibition of strated that H2O2 is a primary EDHF in vivo and plays an NO synthase does not abolish ACh-induced vasodilation in important role in coronary autoregulation. dogs.7 Residual dilation to ACh after inhibition of NO synthase and cyclooxygenase has been attributed to EDHF. However, the nature of EDHF has been controversial since Methods the first report on its existence.3,4 The natures of EDHF that Animal Preparation have been proposed include cytochrome P-450 metabolites,8,9 This study conformed to the Guideline on Animal Experiments of endothelium-derived K,10 and electrical communications Kawasaki Medical School and the Guide for the Care and Use of Received September 10, 2002; revision received November 5, 2002; accepted November 6, 2002. From the Departments of Medical Engineering and Systems Cardiology, Kawasaki Medical School, Kurashiki (T.Y., O.H., T.K., F.S., M.G., Y.O.); Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka (H.S.); and Cardiovascular Physiology, Okayama University Graduate School of Medicine and Dentistry, Okayama (F.K.), Japan. Correspondence to Toyotaka Yada, MD, PhD, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan (e-mail [email protected]); reprint requests to Fumihiko Kajiya, MD, PhD, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikatacho, Okayama, 700-8558, Japan. 2003 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000050145.25589.65 1040
2 Yada et al H2O2 and Coronary Autoregulation 1041 Laboratory Animals published by the US National Institutes of Health. Mongrel dogs (n41, 10 to 25 kg) of either sex were anesthetized with morphine (3 mg/kg IM) and sodium pentobarbital (25 mg/kg IV). After intubation, each animal was ventilated with a high- frequency jet ventilator (model VS600, IDC) with room air supple- mented by 100% oxygen. Aortic pressure and left ventricular pressure were measured with an 8F pigtail double manometer catheter (SPC-784A, Millar). Heart rate was kept constant at 100 bpm by right ventricular pacing after atrioventricular node blocking by 40% formaldehyde.16 Needle-Probe Intravital Microscope Briefly, the needle probe (4.5 mm in diameter) contains a gradient index lens surrounded by light guide fibers and a double-lumen Figure 1. Role of H2O2, an endogenous EDHF, in endothelium- sheath. A doughnut-shaped balloon on the tip avoids direct compres- dependent vasodilation of canine coronary microvessels in vivo. sion of the vessels by the needle tip.16 L-NMMA (in presence of ibuprofen) attenuated vasodilator responses to ACh primarily in small arteries (left), whereas Measurements of Arteriolar Diameters L-NMMA followed by catalase attenuated vasodilation of both small arteries and arterioles (right). Number of vessels per ani- We placed the needle probe gently on the subepicardial microvessel. mal used was 10/4 (small arteries) and 9/5 (arterioles). *P0.05, When a clear vascular image was obtained, the end-diastolic vascular **P0.01 vs control; #P0.05 vs L-NMMA. Downloaded from http://circ.ahajournals.org/ by guest on September 10, 2016 images were taken at a rate of 30 pictures per second.16 Coronary Sinus Cannulation ibuprofen. Coronary perfusion pressure was slowly reduced (1 A Sones catheter was inserted into the right external jugular vein and minute) to the next lower level. advanced into the coronary sinus. Blood samples drawn from the (3) To determine the nature of EDHF and the mechanism of coronary sinus catheter were analyzed for plasma adenosine EDHF-mediated vasodilation, additional experiments were per- concentration.17 formed in coronary subepicardial arterioles with a CCD intravital microscope. The inhibitors TEA and catalase were used. In addi- tional experiments, feedback vasodilator responses during coronary Lactate Measurements autoregulation were examined before and after catalase, and after Arterial and coronary venous lactate samples were drawn into catalase followed by L-NMMA compared with L-NMMA followed syringes. Lactate concentration was measured with a YSI 2300 Stat by catalase. Plus model lactate analyzer.17 Myocardial percent lactate extraction (4) To evaluate the compensatory effects of adenosine, coronary was calculated as (arterialvenous)/arterial values100 (%). venous blood samples were drawn. To evaluate the interaction among EDHF, NO, and adenosine, we also evaluated vasodilator Plasma Adenosine Measurements responses after TEA or catalase with L-NMMA followed by aden- The samples were then concentrated by evaporation and resuspended osine receptor blockade (8-sulfophenyltheophylline, 8-SPT, 25 g in 50 L of high-performance liquid chromatography buffer.18 The kg1 min1 IC for 5 minutes).22 adenosine in each sample was separated on a Shimadzu LC10 All drugs were obtained from Sigma Chemical Co. high-performance liquid chromatograph with a C-18 column using an ion-pairing buffer solution of tetrabutylammonium hydrogen Statistical Analysis sulfate and potassium phosphate with an acetonitrile gradient. Results are expressed as meanSEM. Vascular and coronary blood flow responses were analyzed by 2-way ANOVA followed by Application of System for Controlled Perfusion of Scheffs post hoc test. Students t test was used for both paired and Coronary Arteries unpaired comparisons. The criterion for statistical significance was a To manipulate coronary arterial pressure, the heart was perfused with value of P0.05. blood from the left femoral artery.19 An in-line flow probe (Tran- sonic 4-Fr, connected to a T206 Transonic flowmeter) just proximal Results to the Gregg cannula in the left main coronary artery was used to measure phasic coronary blood flow. Coronary perfusion pressure Role of EDHF in Endothelium-Dependent was measured in the first diagonal branch of the left anterior Vasodilation of Coronary Microvessels In Vivo descending coronary artery. The vasodilator responses of small coronary arteries (100 m) to ACh were significantly attenuated by L-NMMA (in Experimental Protocols After the surgical procedure and instrumentation, at least 30 minutes the presence of ibuprofen) and were further attenuated by were allowed for stabilization while hemodynamic variables were catalase (Figure 1, left) or TEA. By contrast, the vasodilator monitored. The following protocols were examined. responses of arterioles (100 m) were relatively resistant to (1) ACh (1.0 g/kg IC for 2 minutes)-induced, EDHF-mediated L-NMMA (in the presence of ibuprofen) but were markedly coronary vasodilation was evaluated before and after inhibition of attenuated by catalase (Figure 1, right) or TEA. We con- NO synthase (NG-monomethyl-L-arginine [L-NMMA], 2 mol/min for 20 minutes)20 with cyclooxygenase blockade (ibuprofen, 12.5 firmed that the inhibitory effects of catalase were comparable mg/kg IV, an inhibitor of the synthesis of vasodilator prostaglandins to those of TEA (data not shown). to evaluate the role of EDHF and NO alone without PGI2) and catalase (40 000 U/kg IV and 240 000 U kg1 min1 IC for 10 Hemodynamics and Blood Gases During minutes, an enzyme that selectively dismutates H2O2 into water and Decreasing Coronary Perfusion Pressure oxygen)21 or tetraethylammonium (TEA, 10 g kg1 min1 IC for 10 minutes, an inhibitor of large-conductance KCa channels).22 In each experimental condition, mean aortic pressure at (2) Coronary perfusion pressure was changed in a stepwise baseline was constant and comparable (control, manner from 100 to 30 mm Hg before and after L-NMMA plus 727 mm Hg; L-NMMA, 748 mm Hg; and L-NMMA
3 1042 Circulation February 25, 2003 Figure 2. Transmural coronary blood flow during decreasing Figure 4. Inhibitory effect of catalase or TEA during coronary perfusion pressure. Coronary blood flow was reduced signifi- autoregulation. Both inhibitors caused a comparable extent of cantly at 50 and 30 mm Hg of perfusion pressure in all 3 condi- inhibition of arteriolar vasodilation (B and C) vs L-NMMA alone tions. Number of animals used was 7. **P0.01 vs 100 mm Hg. (A). Arteriolar vasodilation was comparable after L-NMMA fol- lowed by catalase (C) and after catalase followed by L-NMMA Downloaded from http://circ.ahajournals.org/ by guest on September 10, 2016 (D). Number of vessels per animal used was 12/6 for L-NMMA followed by catalase, 726 mm Hg). PO2, PCO2, and pH were followed by catalase, 11/8 for L-NMMA followed by TEA, and maintained within the physiological range (pH, 7.35 to 7.45; 8/3 for catalase followed by L-NMMA. *P0.05, **P0.01 vs 70 mm Hg of coronary perfusion pressure. PCO2, 25 to 40 mm Hg; PO2, 70 mm Hg) throughout the experiments. Transmural coronary blood flow at 70 mm Hg of perfusion pressure was comparable among the 3 conditions 4C) and after catalase followed by L-NMMA (Figure 4D) (Figure 2). However, the flow was significantly reduced to a irrespective of the order of drug administration. The arteriolar comparable extent at 50 and 30 mm Hg of perfusion pressure responses at 30 mm Hg of coronary perfusion pressure were in all 3 conditions (Figure 2). significantly reduced after L-NMMA, catalase, or TEA alone and were further decreased after L-NMMA followed by Role of EDHF in Coronary Autoregulation catalase, catalase followed by L-NMMA, or TEA followed Under control conditions, coronary autoregulatory vasodila- by L-NMMA with decreased myocardial lactate extraction tor responses to decreasing perfusion pressure were noted in (Figure 5 and the Table). arterioles but not in small arteries (Figure 3, left). In coronary arterioles, the autoregulatory vasodilator responses were sig- Compensatory Effects of Adenosine in nificantly attenuated by L-NMMA (in the presence of ibu- Coronary Autoregulation profen) and were further attenuated by catalase (Figure 3, Coronary venous adenosine concentrations were increased in right). Compared with the responses after L-NMMA alone response to decreasing coronary perfusion pressure after (Figure 4A), L-NMMA followed by TEA (Figure 4B) or L-NMMA alone (Figure 6A), L-NMMA followed by catalase catalase (Figure 4C) caused a comparable extent of inhibition (Figure 6A), catalase followed by L-NMMA (Figure 6B), and on the responses of arterioles. The arteriolar responses were TEA followed by L-NMMA (Figure 6C) but were not further also comparable after L-NMMA followed by catalase (Figure increased after catalase or TEA alone (Figure 6, B and C). The blockade of adenosine receptor with 8-SPT suppressed the residual EDHF-mediated arteriolar dilation after L-NMMA followed by catalase at 30 mm Hg of coronary perfusion pressure with decreased myocardial lactate extrac- tion (Figure 7A, Table). Coronary venous adenosine concen- trations were increased in response to decreasing perfusion pressure after L-NMMA but were not further increased after L-NMMA followed by catalase (Figure 7B) or TEA. This was also the case with L-NMMA followed by TEA and 8-SPT (data not shown). Discussion The major findings of the present study are that (1) H2O2 is a Figure 3. Coronary microvascular responses during coronary primary EDHF in the canine coronary circulation in vivo and autoregulation. Under control conditions (n7), autoregulatory vasodilator responses to decreasing coronary perfusion pres- (2) H2O2 plays an important role in coronary autoregulation as sure were noted in arterioles (right, 12 vessels) but not in small a compensatory mechanism for NO and adenosine. To the arteries (left, 9 vessels). Arteriolar vasodilation was attenuated best of our knowledge, this is the first report that demon- significantly by L-NMMA (in presence of ibuprofen) and was fur- ther attenuated by catalase. **P0.01 vs control; ##P0.01 vs strates the importance of H2O2 as an endogenous EDHF that L-NMMA. plays an important role in coronary autoregulation in vivo.
4 Yada et al H2O2 and Coronary Autoregulation 1043 Figure 5. Coronary arteriolar responses during low perfusion pressure as a func- tion of vessel size. Arteriolar responses at 30 mm Hg of coronary perfusion pres- sure were significantly reduced after L-NMMA (A), catalase (B), or TEA (C) alone and were further decreased after L-NMMA followed by catalase (A), cata- lase followed by L-NMMA (B), or TEA followed by L-NMMA (C). Number of vessels per animal used was 12/6 (A), 8/3 (B), and 7/4 (C). **P0.01 vs control; ##P0.01 vs L-NMMA, catalase, or TEA. Critique of Experimental Model and Methodology vasodilation in dogs in vivo.25 However, miconazole inhibits On the basis of the previous reports, we chose adequate 20 22 intermediate-conductance KCa channels and thus directly doses of L-NMMA, catalase, TEA, and 8-SPT to inhibit NO, inhibits hyperpolarization of vascular smooth muscle.26 Fur- Downloaded from http://circ.ahajournals.org/ by guest on September 10, 2016 H2O2, KCa, and adenosine, respectively. The methodological thermore, inhibitors of cytochrome P-450 metabolites had no validity of the present study was confirmed previously.16 inhibitory effect on the EDHF-mediated vasodilation in mice or humans in vitro.12,13 Indeed, in the present study, EDHF- H2O2 as an Endogenous EDHF in the Coronary mediated vasodilation of coronary arterioles was markedly Circulation In Vivo inhibited by catalase, indicating that H2O2 is a primary EDHF Recently, Matoba et al12,13 showed that H2O2 is a primary in the canine coronary circulation in vivo. EDHF in mesenteric arteries of mice and humans. Indeed, H2O2 is a reasonable candidate for endogenous EDHF, Compensatory Feedback Mechanism Among because it is produced by endothelial cells and causes EDHF, NO, and Adenosine vascular smooth muscle relaxation through activation of KCa It is well known that coronary artery tone is regulated by the channels.12 It is conceivable that H2O2 is produced from interactions among several vasodilators, including NO, aden- superoxide anions that are derived from several sources in osine, and EDHF.27,28 These relaxing factors may play a endothelial cells, including endothelial nitric oxide synthase, crucial role in causing vasodilation of coronary microvessels cyclooxygenase, lipoxygenase, cytochrome P-450 enzymes, in a cooperative manner. In the present study, the arteriolar and NAD(P)H oxidases.12 In the present study, inhibition of vasodilation during coronary autoregulation was not com- NO synthesis did not affect ACh-induced vasodilation of pletely inhibited by L-NMMA plus ibuprofen or by catalase, coronary arterioles, whereas catalase markedly attenuated the and the residual arteriolar dilation was further inhibited after vasodilation in vivo (Figure 1). Furthermore, catalase inhib- administration of all 3 inhibitors. These results indicate the ited residual arteriolar dilation after inhibition of NO synthase negative feedback interaction between NO and EDHF during during coronary autoregulation, indicating that H2O2 func- coronary autoregulation in vivo. The compensatory effect of tions as a primary EDHF in canine coronary microvessels in adenosine may also be important. Stepp et al1 suggested that vivo. Furthermore, in the present study, EDHF/H2O2- adenosine plays an important role in the transition to ischemia mediated vasodilation was greater in arterioles than in small at a coronary perfusion pressure of 50 mm Hg after KATP arteries, supporting the notion that the importance of EDHF channel blockade with glibenclamide. In the present study, increases as vessel size decreases.2325 coronary venous adenosine concentrations were increased at A previous study using miconazole suggested a possible a perfusion pressure of 50 mm Hg within the vasoactive role of cytochrome P-450 metabolites in EDHF-mediated range for endogenous adenosine, as previously reported.29 Myocardial Lactate Extraction Rate (%) at 30 mm Hg of Coronary Perfusion Pressure Control Protocol n Response First Inhibitor Second Inhibitor Third Inhibitor 1 11 304 L-NMMA 234* L-NMMATEA 144* 2 4 361 TEA 301* TEAL-NMMA 204* 3 6 335 L-NMMA 215* L-NMMAcatalase 123* 4 3 341 Catalase 221* CatalaseL-NMMA 151* 5 4 331 L-NMMA 231* L-NMMATEA 131* L-NMMATEA8SPT 27* 6 4 312 L-NMMA 171* L-NMMAcatalase 121* L-NMMAcatalase8SPT 22* Results are expressed as meanSEM. *P0.05 vs control; P0.05 vs L-NMMA; P0.05 vs TEA; P0.05 vs catalase; P0.05 vs L-NMMA plus TEA; P0.05 vs L-NMMA plus catalase.
5 1044 Circulation February 25, 2003 Figure 6. Coronary venous adenosine concentrations and coronary autoregula- tion. Coronary venous adenosine con- centrations were increased in response to decreasing coronary perfusion pres- sure after L-NMMA alone (A), L-NMMA followed by catalase (A), catalase fol- lowed by L-NMMA (B), and TEA followed by L-NMMA (C) but were not further increased after catalase or TEA alone (B and C) compared with control. Number of animals used was 6 (A), 3 (B), and 4 (C). **P0.01 vs control; ##P0.01 vs catalase, TEA, or L-NMMA followed by catalase. The residual arteriolar dilation (5%) after combined admin- onary vasodilation. The present results demonstrate that istration of ibuprofen, L-NMMA, and TEA or catalase was EDHF/H2O2 contributes substantially to the vasodilation dur- Downloaded from http://circ.ahajournals.org/ by guest on September 10, 2016 completely blocked by 8-SPT, indicating that an increased ing coronary autoregulation in vivo. Regarding the mecha- concentration of adenosine compensated for the loss of action nism involved in the KCa channel opening during coronary of NO and EDHF. It remains to be examined why the autoregulation, cellular acidosis32 and increase in intracellular adenosine concentrations did not increase further after admin- Ca2 concentration after ischemia33 have been postulated to istration of L-NMMA followed by TEA compared with open KCa channels as a compensatory mechanism after L-NMMA alone. Cabell et al15 reported that TEA inhibited inhibition of NO synthesis. We have previously demonstrated adenosine-induced vasodilation of canine subepicardial cor- that subendocardial arteriolar dilation during reactive hyper- onary arteries in vitro. Furthermore, Gao and Vanhoutte30 emia is more sensitive to L-NMMA than subepicardial reported that H2O2 relaxed canine bronchial smooth muscle arteriolar dilation.27 These findings indicate that the perfusion and elevated cAMP concentrations. Chaytor et al31 reported of the subendocardium is more dependent on NO than that of that EDHF-mediated relaxation to ACh was associated with the subepicardium. EDHF/H2O2 may compensate coronary an increase in smooth muscle cAMP concentrations. These blood flow, especially in the endocardium, in myocardial findings suggest that a cAMP-mediated pathway is involved, ischemia during coronary autoregulation. at least in part, in the autoregulatory coronary vasodilation through large-conductance KCa channels. Clinical Implications and Conclusions The synthesis and action of endothelium-derived NO are Role of EDHF in Myocardial Ischemia During impaired under various pathological conditions, such as Coronary Autoregulation hypertension and hyperlipidemia.34 Previous studies sug- KCa channels contribute substantially to the coronary vasodi- gested that hypertension causes a compensatory increase in lation in myocardial ischemia.22 However, it remains to be the activity of potassium channels.35 Cosentino et al36 re- examined whether EDHF contributes to autoregulatory cor- ported that in a transgenic mouse model of hyperphenylala- ninemia, reduction in arterial tetrahydrobiopterin, a cofactor of endothelial NO synthase, was accompanied by a decrease in endothelial NO production, whereas H2O2 production was increased. In the present study, NO and EDHF/H2O2 appar- ently compensated each other to cause coronary autoregula- tory vasodilation in vivo. These results may represent a negative feedback interaction between the 2 relaxing factors. In conclusion, we were able to demonstrate that H2O2 is a primary EDHF in the canine coronary circulation in vivo and plays an important role in coronary autoregulation as a compensatory feedback mechanism for NO and adenosine. Figure 7. Comparison of coronary arteriolar responses and These findings may have important clinical implications, venous adenosine concentrations during coronary autoregula- because hyperpolarizing mechanisms contribute substantially tion after L-NMMA and catalase with 8-SPT. Residual EDHF- mediated arteriolar dilation after L-NMMA plus catalase was to endothelium-dependent vasodilation in myocardial abolished by 8-SPT at 30 mm Hg of perfusion pressure (A). Cor- ischemia. onary venous adenosine concentrations were not increased fur- ther in response to decreasing perfusion pressure after L-NMMA followed by catalase (B) with 8-SPT vs control. Number of ves- Acknowledgments sels per animal used was 10/4 (A and B). *P0.05, **P0.01 vs This work was supported in part by grants 12558114 and 14657178 control; #P0.05, ##P0.01 vs L-NMMA; P0.01 vs L-NMMA from the Japanese Ministry of Education, Culture, Sports, Science, followed by catalase. and Technology, Tokyo, Japan.
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7 Hydrogen Peroxide, an Endogenous Endothelium-Derived Hyperpolarizing Factor, Plays an Important Role in Coronary Autoregulation In Vivo Toyotaka Yada, Hiroaki Shimokawa, Osamu Hiramatsu, Tatsuya Kajita, Fumiyuki Shigeto, Masami Goto, Yasuo Ogasawara and Fumihiko Kajiya Downloaded from http://circ.ahajournals.org/ by guest on September 10, 2016 Circulation. 2003;107:1040-1045; originally published online February 3, 2003; doi: 10.1161/01.CIR.0000050145.25589.65 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 2003 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/107/7/1040 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/Load More