Published online before print April 21, 2008, doi: 10.1161/CIRCULATIONAHA.107.734384
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(Circulation. 2008;117:2262-2269.)
© 2008 American Heart Association, Inc.
Vascular Medicine |
Angiotensin-Converting Enzyme Inhibition Improves Vascular Function in Rheumatoid Arthritis
From the Cardiovascular Centre, Cardiology (A.J.F., I.S., F.H., F.E., D.P., M.H., T.F.L., R.C., G.N., F.R.), and Department of Rheumatology (S.G., A.F., M.N., P.K.), University Hospital Zurich, Zurich; Center for Integrative Human Physiology (S.G., T.F.L., R.C., G.N., F.R.), University of Zurich, Zurich; and Department of Internal Medicine, Division of Angiology and Hypertension (J.N.), University Hospital Lausanne, Lausanne, Switzerland.
Correspondence to Frank Ruschitzka, MD, FESC, FRCP, Cardiology, University Hospital, Rämistrasse 100, 8091 Zurich, Switzerland. E-mail frank.ruschitzka{at}usz.ch
Received August 21, 2007; accepted February 8, 2008.
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Abstract |
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Background— The excess in cardiovascular risk in patients with rheumatoid arthritis provides a strong rationale for early therapeutical interventions. In view of the similarities between atherosclerosis and rheumatoid arthritis and the proven benefit of angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease, it was the aim of the present study to delineate the impact of ramipril on endothelial function as well as on markers of inflammation and oxidative stress in patients with rheumatoid arthritis.
Methods and Results— Eleven patients with rheumatoid arthritis were included in this randomized, double-blind, crossover study to receive ramipril in an uptitration design (2.5 to 10 mg) for 8 weeks followed by placebo, or vice versa, on top of standard antiinflammatory therapy. Endothelial function assessed by flow-mediated dilation of the brachial artery, markers of inflammation and oxidative stress, and disease activity were investigated at baseline and after each treatment period. Endothelial function assessed by flow-mediated dilation increased from 2.85±1.49% to 4.00±1.81% (P=0.017) after 8 weeks of therapy with ramipril but did not change with placebo (from 2.85±1.49% to 2.84±2.47%; P=0.88). Although systolic blood pressure and heart rate remained unaltered, diastolic blood pressure decreased slightly from 78±7 to 74±6 mm Hg (P=0.03). Tumor necrosis factor-
showed a significant inverse correlation with flow-mediated dilation (r=–0.408, P=0.02), and CD40 significantly decreased after ramipril therapy (P=0.049).
Conclusions— Angiotensin-converting enzyme inhibition with 10 mg/d ramipril for 8 weeks on top of current antiinflammatory treatment markedly improved endothelial function in patients with rheumatoid arthritis. This finding suggests that angiotensin-converting enzyme inhibition may provide a novel strategy to prevent cardiovascular events in these patients.
Key Words: angiotensin-converting enzyme inhibitors • arthritis, rheumatoid • endothelium • inflammation
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Introduction |
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The striking similarities between atherosclerotic vascular disease and states of autoimmune inflammation such as rheumatoid arthritis (RA)1 have prompted the hypothesis that inflammatory mechanisms responsible for synovial lesions in patients with RA also might be involved in endothelial cells and may thus facilitate the development of atherosclerotic lesions. This may explain the excess cardiovascular disease and the shortened life expectancy in patients with RA2 and may provide a rationale for therapeutical interventions at an early stage of the disease process before overt cardiovascular disease has developed.
Clinical Perspective p 2269
Particularly, angiotensin-converting enzyme (ACE) inhibitors (ACEIs) have the potential to beneficially affect cardiovascular disease progression in patients with RA; the Heart Outcomes Prevention Evaluation (HOPE) trial and the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) showed the effectiveness of ACEIs such as ramipril and perindopril in reducing mortality and morbidity from cardiovascular events among patients with established disease or at high cardiovascular risk.3,4 Intriguingly, the benefit observed in HOPE and EUROPA was beyond what would have been expected from the blood pressure–lowering effects of the drug. Indeed, by inhibiting angiotensin II or by increasing the concentration of bradykinin, ACE inhibition is associated with a decrease in vascular NADPH activity and reactive oxygen species5; reduced activation of important signaling pathways, including nuclear factor-
B activation6; and an improvement in fibrinolysis7 and endothelial function,8 all of which may reduce the progression of atherosclerosis.
Recently, we provided the first evidence of endothelial dysfunction in RA patients in whom other traditional cardiovascular risk factors were absent.9,10 Endothelial dysfunction has been implicated in the pathogenesis and clinical course of all known cardiovascular diseases and is associated with future risk of adverse cardiovascular events.11–14 As such, the detection of vascular dysfunction at an early stage of the disease process long before symptoms of cardiovascular disease become evident provides a strong rationale for an intervention with a well-established strategy known to beneficially affect outcome in patients at increased cardiovascular risk. Hence, the present study investigated the effect of the ACEI ramipril on vascular function, inflammation, and oxidative stress in RA patients.
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Methods |
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Patients
Thirteen patients with RA (4 of 7 American Rheumatism Association criteria fulfilled) who had normal blood pressure, were not treated for hypertension, and were on a stable background medication for at least 3 months were enrolled. Eleven patients were included in the analysis (4 men, 7 women; all white; mean age, 54.9±11.2 years); 2 patients withdrew consent for personal reasons. Patients were screened at the University Hospital Zurich (Switzerland). Patients with previous myocardial infarction, coronary interventions, or coronary surgery and patients taking statins or ACEIs within the last 6 months were excluded. Further exclusion criteria were low-density lipoprotein >4.9 mmol/L, obesity (body mass index >35 kg/m2), anemia, kidney disease (creatinine >150 µmol/L), insulin-dependent diabetes mellitus, chronic heart failure (New York Heart Association class >I), pregnancy, malignancy, chronic inflammatory disease other than RA, predisposition to angioedema, and smoking. Patients did not take study drugs or receive standard treatment on the day of examination to allow us to obtain results at trough levels. The local ethics committee of the University Hospital Zurich approved the study protocol. All procedures were in accordance with institutional guidelines, and all research was carried out in compliance with the Helsinki Declaration.
Study Protocol
The effect of an 8-week treatment with either ramipril or placebo was studied using a randomized, double-blind, crossover protocol. After written informed consent was given, baseline characteristics, including physical examination, ECG, blood sample, and a noninvasive assessment of endothelial function, were obtained. Arterial blood pressure was measured by sphygmomanometer in the sitting position according to guidelines.15 The patients were then randomly assigned to receive either ramipril 10 mg (uptitration scheme; starting with 2.5 mg/d in the first week, then 5 mg/d in the second week, followed by 2x5 mg/d [10 mg] for the final 6 weeks) followed by placebo or vice versa. The uptitration scheme was chosen to avoid clinical manifest hypotension in these normotensive patients. The target dose (10 mg/d) was according to the maximum dose allowed in Switzerland, which is based primarily on the results of the HOPE study.4 The individual antirheumatic drug therapy was continued unchanged throughout the study. The above-mentioned examinations were repeated after 8 weeks of treatment with the first and 8 weeks of treatment with the second study drug. At weeks 1 and 2 in each treatment period, a safety visit was scheduled.
Assessment of Endothelial Function
Flow-mediated dilation (FMD) was the predefined primary end point of the study.
FMD- and glycerol trinitrate (GTN) (0.4 mg sublingual, Nitrolingual Spray, Pohl-Boskamp, Hohenlockstedt, Germany)–induced vasodilation of the brachial artery was assessed at baseline and after each treatment period by a high-resolution ultrasound vessel wall tracking device with a 10-MHz linear-array transducer (WTS-2, Pie Medical, Bilthoven, the Netherlands) according to guidelines.16,17 Reactive hyperemia reflects endogenous nitric oxide formation, resulting in endothelium-dependent vasodilation, whereas GTN acts as an exogenous nitric oxide donor directly on vascular smooth muscle cells, inducing endothelium-independent vasodilation. FMD of the brachial artery was induced by release of a wrist cuff inflated to 220 mm Hg for 5 minutes. After release, we recorded the arterial diameter every 15 seconds for 2 minutes. After GTN application, we recorded the diameter every 30 seconds for 6 minutes. Arterial flow velocity was obtained by pulsed Doppler signal at 70° to the vessel with the range gate (1.5 mm) in the center of the artery.
Assessment of Inflammatory and Oxidative Stress Markers
Markers of vascular inflammation and oxidative stress represented the predefined secondary end point of the study. Isoprostane was measured from plasma with an 8-isoprostane enzyme immunoassay (Cayman Chemicals, Ann Arbor, Mich). Interleukin (IL) -1β, IL-6, and tumor necrosis- (TNF-) were measured by ELISA using the commercially available Quantikine HS kits (R&D Systems, Abingdon, UK). For bradykinin and sCD40, enzyme immunoassay kits (Bachem, Bubendorf, Switzerland, and Bender MedSystems, Vienna, Austria, respectively) were used. Myeloperoxidase was determined by ELISA using the myeloperoxidase ELISA kit (Immunodiagnostic AG, Bersheim, Germany).
Assessment of Plasma Renin Activity and Aldosterone
Plasma renin activity was measured by trapping generated angiotensin I by high-affinity antibodies and subsequent radioimmunoassay.18 Aldosterone was measured by a direct radioimmunoassay using high-affinity antibodies produced in a New Zealand White rabbit.19
Cell Culture
Human umbilical vein endothelial cells were cultivated in EGM-2 growth medium (both from Lonza, Basel, Switzerland) to a confluence of 80% to 90% under standard conditions (37°C, 5% CO2). Human umbilical vein endothelial cells were prestimulated with the inflammatory cytokines IL-1β (1 ng/mL) and TNF- (10 ng/mL) (R&D Systems) for 1 hour before the addition of ramipril (100 nmol/L). Stimulated but untreated cultures served as controls. After 24 hours, total RNA was extracted and used for differential gene expression analysis by Affymetrix GeneChip technology (Affymetrix, Santa Clara, Calif).
Affymetrix GeneChip
Total RNA was isolated with the RNeasy MiniPrep Kit (Qiagen, Basel, Switzerland), including treatment with RNase-free DNase. Quality and concentration of the RNA were checked first with the Nanodrop ND-1000 Spectrophotometer (Witec AG, Littau, Switzerland) and a second time with the Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, Calif). Double-stranded cDNA was synthesized from 5 µg total RNA with the GeneChip One-Cycle cDNA Synthesis Kit, including labeling with the One-Cycle Target Labeling Assay (both from Invitrogen, Basel, Switzerland). The labeled cRNA was hybridized with the probe sets present on the Human Genome U133 Plus 2.0 Gene Expression Array (Affymetrix) using the Fluidics Station 450 according to standard protocols. The hybridization picture was scanned with a GeneChip Scanner 3000 and further analyzed with the GCOS software.
Data were normalized (measurements <0.01 were set to 0.01, and normalization per chip was set to the 50th percentile) and analyzed with GeneSpring Microarray Analysis Software (Silicon Genetics, Redwood City, Calif). Filters were set on 2-fold regulation; expression levels had to be >2.0; and flags had to be present or marginal in at least 1 of 2 compared samples.
Statistical Analysis
Results are presented as mean±SD. Measurements of FMD- and GTN-induced vasodilation represent the maximal increase in brachial diastolic arterial diameter and are expressed as percentage increase from baseline. For differences in parameters in the ramipril and placebo groups, we used 2-tailed paired Student t test. For correlation between FMD and TNF-, we used Pearson correlation analysis. A value of P
0.05 was considered statistically significant.
The power calculation was based on the hypothesis of the superiority of ramipril, assuming results similar to those in our previous study of RA9: endothelial function improved from 3.2% to 4.1% (SD, 1%). No change was expected in the placebo group. With a significance level of =0.05 and power of 0.8, we calculated a needed sample size of 12 patients to provide a crossover design. Statistical analyses were performed with SPSS 11.0.4 for Mac OS X (SPSS Inc, Chicago, Ill).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Study Cohort
A total of 13 patients were enrolled; however, 2 patients withdrew their informed consent shortly after inclusion. Therefore, 11 patients were included in the analysis; their baseline demographic, laboratory, and clinical characteristics are presented in Tables 1 and 2
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Primary End Point
Effect of Ramipril on Vascular Function
ACE inhibition improved endothelium-dependent vasodilatation after 8 weeks of treatment with ramipril (from 2.85±1.49% to 4.00±1.81%; P=0.017), whereas placebo did not change endothelial function (from 2.85±1.49% to 2.84±2.47%; P=0.88; Figure 1). Endothelium-independent vasodilatation assessed by GTN remained unaltered (from 13.40±5.68% to 12.67±2.44% with ramipril [P=0.67] and to 12.25±3.4% with placebo [P=0.5], respectively). Percentage changes in flow velocity (from resting condition to reactive hyperemia) were similar between groups (baseline visit, 197±58%; after placebo, 230±94%; and after ramipril, 187±68%; P between groups=0.41)
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Secondary End Points
Markers of Oxidative Stress, Inflammation, and the Renin-Angiotensin-Aldosterone System
A significant reduction in CD40 levels occurred after ramipril: CD40 decreased from 84.3±85.6 to 63.1±83.8 pg/mL (P=0.049) after ramipril therapy, whereas the change was not significant after placebo (P=0.29) (Figure 2A). TNF- tended to decrease from 1.74±1.82 to 1.21±1.28 pg/mL (P=0.22) in the ramipril group. Interestingly, a significant inverse correlation of TNF- with FMD was found (r=–0.408, P=0.02; Figure 2B and 2C).
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Other inflammation parameters like high-sensitivity C-reactive protein, IL-1, IL-6, myeloperoxidase, and blood sedimentation rate, as well as the oxidative stress parameter 8-isoprostane, were not influenced by an 8-week treatment of ramipril (Table 3).
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Renin activity significantly increased after ramipril therapy but remained unchanged after placebo (from 1.00±0.86 to 3.37±3.6 ng · mL–1 · h–1 after ramipril [P=0.022] and to 0.94±0.5 ng · mL–1 · h–1 after placebo [P=0.73]), indicating adherence to therapy throughout the study (Figure 2D). The ratio of aldosterone to renin changed from 16.82±10.23 to 52.53±67.26 (P=0.13) and remained unchanged after placebo (23.02±30.62; P=0.44).
Effect of Ramipril on Clinical and Laboratory Parameters
Eight weeks of treatment with ramipril tended to decrease systolic blood pressure and to significantly decrease diastolic blood pressure compared with baseline (from 122.5±7.7 to 119±10.8 mm Hg [P=0.13] and from 77.9±6.7 to 73.6±5.6 mm Hg [P=0.028], respectively; Figure 3). Disease activity score in 28 joints, heart rate, creatinine, potassium, and cholesterol remained unaltered after treatment with ramipril or placebo (Tables 1 and 2
).
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GeneChip Analysis of Human Umbilical Vein Endothelial Cells
The differential gene expression analysis in stimulated and nonstimulated cells revealed plenty of off-target effects of ramipril. For example, leukotriene B4 12-hydroxydehydro-genase was upregulated >2-fold. In addition, ACE inhibition downregulates proinflammatory arachidonate lipoxygenase 3 by >50%. Moreover, the dual-specificity phosphatase 6 is also downregulated, indicating modulation of phosphorylation of the mitogen-activated protein kinase pathway. Finally, in nonstimulated endothelial cells, ramipril induces an 8-fold and a 2.5-fold upregulation of carbonic anhydrase VB-like protein and angiomotin, respectively. However, the data warrant further validation and investigation.
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Discussion |
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In this study, we provide evidence that long-term ACE inhibition with 10 mg ramipril improves endothelial function in the brachial artery of patients with RA.
Endothelial dysfunction plays a pivotal role in the pathogenesis and clinical course of cardiovascular diseases and predicts future risk of adverse cardiovascular events.11–14 Importantly both ACEIs and angiotensin receptor blockers improve endothelial function in patients with atherosclerotic vascular disease.20–24
Similar to patients with classic cardiovascular risk factors, RA patients are characterized by impaired endothelial function compared with normal subjects.9,10,25–27 Because RA patients suffer from premature atherosclerosis and a life expectancy that is reduced up to 10 years because of cardiovascular comorbidities compared with age-related controls,2 any additional gain in maintaining endothelial integrity, as shown in our study, may indicate the potential of a therapeutic intervention such as ACEI in patients with RA.
Our group10 and Tikiz et al28 demonstrated a beneficial effect of simvastatin on endothelial function and inflammatory parameters in RA patients. In contrast, ACE inhibition with quinapril failed to ameliorate endothelial function in the latter study.28 This discrepancy compared with the present study may be related to the rather low dosage of quinapril used by Tikiz et al (10 mg), which may not provide potent ACE inhibition. The dose of ramipril used in the present study, on the other hand, markedly suppresses ACE, as reported previously.29 In addition, it was recently shown in hypertensive patients that ramipril 10 mg, the dose also used in the HOPE trial,4 induced a greater improvement in nitric oxide–dependent vasodilation compared with a lower dose (5 mg).30 Similarly, the Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE) trial showed a more pronounced reduction in intimal-medial thickness progression of the carotid artery with 10 versus 5 mg.31
Whereas ACE inhibition is associated with reduced atherosclerotic vascular events, mainly because it lowers blood pressure, the clinical relevance of its potential pleiotropic effects on oxidative stress and inflammation is still a matter of debate.32 It is of note that angiotensin II upregulates inflammatory TNF- and IL-6 gene expression in different vascular beds, as well as macrophages and cardiac fibroblasts.33 In addition, in animal models of atherosclerosis and vascular injury, ACE inhibition is associated with reduced lesion formation.34,35
In RA patients, increased ACE activity, along with upregulation of proinflammatory cytokines, particularly TNF-, IL-1, and IL-6, has been demonstrated in synovial fluid and tissue and in blood monocytes.36–38 Because these cytokines appear to affect expression of cellular adhesion molecules on endothelial cells, TNF- in particular has been implicated in the initiation of vascular inflammation.39 Indeed, in the present study, plasma levels of CD40, another important modulator in the inflammation pathway40 and a member of the TNF- superfamily, were reduced and the circulating levels of proinflammatory TNF- tended to decrease after ramipril therapy. Interestingly, we also found a significant inverse correlation between TNF- and FMD, thus indicating a key role of TNF- in vascular inflammation and endothelial dysfunction in patients with RA. This is further supported by recent findings that ACE inhibition with quinapril reduces articular TNF- production41 and by beneficial effects of anti–TNF- treatment on endothelial function in RA.9,42,43
It is of note that all patients in this study presented with moderate disease activity; they had to remain clinically stable to allow comparable conditions during the repetitive assessment of the end points at different time points throughout the study. Circulating levels of these cytokines may, however, only partially reflect local vascular changes.
Because high-dose ACE inhibition markedly improved endothelial function with a modest reduction in markers of vascular inflammation or oxidative stress, the benefit provided by ramipril also could be related to the small blood pressure reduction and/or an upregulation of endothelial nitric oxide expression and activity as demonstrated in experimental studies.44
However, because the results of the present study indicate a role of the inflammatory cytokines, particularly TNF-, in vascular dysfunction in patients with RA, the differential gene expression analysis in stimulated and nonstimulated cells revealed plenty of off-target effects of ramipril, some of which conceptually could have contributed to the beneficial effects of the ACE inhibition on vascular function. In particular, leukotriene B4 12-hydroxydehydrogenase was upregulated. Importantly, leukotriene B4 12-hydroxydehydrogenase constitutes an important inactivation pathway for these key lipid mediators involved in inflammation.45 In addition, differential gene expression analysis unexpectedly revealed that ACE inhibition downregulates proinflammatory arachidonate lipoxygenase 3. Moreover, the dual-specificity phosphatase 6 also is downregulated, indicating modulation of phosphorylation of the mitogen-activated protein kinase pathway. In nonstimulated endothelial cells, ramipril induces an upregulation of carbonic anhydrase VB-like protein and angiomotin. Angiomotin, a newly discovered molecule that regulates the migration and tubule formation of endothelial cells, has thus been implicated in the control of angiogenesis.46
Taken together, differential gene expression analysis results demonstrate novel off-target effects of ramipril that, in view of the multiple background therapies of the present study population, are beyond the scope of the present study but warrant further investigation, particularly in RA patients.
Our study has several limitations. Although the study was powered for and successful in its primary end point, it was not powered to detect significant differences in the secondary end points, markers of vascular inflammation and oxidative stress. Although we could demonstrate a significant reduction in CD40 concentration and an inverse correlation between TNF- and FMD, definitive statements based on the results of the secondary end points should be interpreted with caution. The results of our study could be influenced by background treatment such as methotrexate, corticosteroids, and nonsteroid anti-inflammatory drugs. However, only patients with moderate disease activity were included, so all background medications, including nonsteroid anti-inflammatory drugs, were kept stable throughout the entire course of this crossover study.
Triglycerides are slightly but significantly elevated after ramipril therapy compared with placebo therapy. Because triglycerides are known to impair endothelial function,47 the significant beneficial impact of ACE inhibition on endothelial function may even be underestimated in the present study.
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Conclusions |
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Eight weeks of therapy with ramipril on top of standard antiinflammatory treatment significantly improves endothelial function in RA patients. Because cardiovascular disease is considered the leading cause of mortality in RA and is responsible for approximately half the deaths observed in RA, the results of the present study underscore the need for large-scale prospective randomized clinical trials with ACE inhibition in these patients at high cardiovascular risk.
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Acknowledgments |
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We would like to thank Priska Kaiser, Astrid Hirt, Rosy Hug, Sandra Blumhardt, Astrid Jüngel, Diana Frey, and Sylvie Bertholet for excellent technical assistance and patient recruitment.
Sources of Funding
This work was partly supported by the Swiss National Research Foundation (grants 3200B0-100318 and 32000BO-105758), the University Research Priority Program "Integrative Human Physiology" at the University of Zurich (ZIHP), a grant from the Mercator Foundation, Zurich, Switzerland, and an unrestricted educational grant from Sanofi-Aventis.
Disclosures
The study was investigator initiated and investigator driven. The maker of the study drug was not involved in the study design or execution other than supplying the study drug. The study was supported primarily by the Swiss National Foundation. Dr Ruschitzka received an unrestricted research grant from Sanofi-Aventis. Dr Nussberger received a research grant from Sanofi-Aventis and was cowinner of the Sanofi-Aventis Heart Prize 2007. The other authors report no conflicts.
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Footnotes |
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Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
*Drs Flammer and Sudano contributed equally to this article. 
Guest Editor for this article was Edgardo Escobar, MD.
Clinical trial registration information—URL: ClinicalTrials.gov. Unique identifier: NCT00273533.
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