circulaton2010-08-31

(Circulation. 2010;122:861-867.)
© 2010 American Heart Association, Inc.
Abstract 1 of 8
Cardiovascular Surgery
Vascular Reactivity and Flow Characteristics of Radial Artery and Long Saphenous Vein Coronary Bypass Grafts
A 5-Year Follow-Up
Carolyn M. Webb, PhD; Neil E. Moat, MS, FRCS; Chee F. Chong, FRCS; Peter Collins, MD, FRCP
From the Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, and Department of Cardiology, Royal Brompton and Harefield National Health Service Trust, London, UK (C.M.W., P.C.); Department of Cardiac Surgery, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK (N.E.M., C.F.C.); and IRCCS San Raffaele, Rome, Italy (P.C.).
Correspondence to Dr Carolyn Webb, Cardiovascular Sciences, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK. E-mail c.webb@imperial.ac.uk
Received June 15, 2009; accepted June 7, 2010.
Background— Radial artery (RA) aortocoronary bypass grafts anastomosed to a branch of the circumflex coronary artery have significantly better patency rates than saphenous vein (SV) grafts at 5 years, but the physiological characteristics and mechanisms involved are not clearly defined. We compared RA and SV graft vasomotor and flow responses to endothelium-dependent and -independent stimuli 5 years after surgery in a subgroup of patients enrolled in the Radial artery versus Saphenous Vein Patency (RSVP) trial.
Methods and Results— Twenty-seven patients were included in the study (RA, n=15; SV, n=12). Graft blood flow was calculated from flow velocity, measured by intracoronary Doppler, and luminal diameter, measured by quantitative coronary angiography, before and after intragraft infusions of adenosine, acetylcholine, and isosorbide dinitrate. At rest, RA luminal diameters were significantly smaller than SV luminal diameters (P=0.029), blood flow velocity was greater in RA than SV (P=0.008), and volume blood flows were similar. RA but not SV dilated in response to adenosine and isosorbide dinitrate (all P<0.05, RA versus SV, percent change from baseline), and there were no significant differences in the diameter responses to acetylcholine. Volume blood flow responses to adenosine, acetylcholine, and isosorbide dinitrate were comparable.
Conclusions— Five years after surgery, RA coronary bypass conduits grafted to a single coronary territory demonstrated preserved flow-mediated vasodilatation, whereas SV grafts did not. Our results may provide insight into the more favorable patency of RA grafts over SV grafts.
Abstract 2 of 8
Congenital Heart Disease
Arrhythmia Burden in Adults With Surgically Repaired Tetralogy of Fallot
A Multi-Institutional Study
Paul Khairy, MD, PhD; Jamil Aboulhosn, MD; Michelle Z. Gurvitz, MD; Alexander R. Opotowsky, MD; François-Pierre Mongeon, MD; Joseph Kay, MD; Anne Marie Valente, MD; Michael G. Earing, MD; George Lui, MD; Deborah R. Gersony, MD; Stephen Cook, MD; Jennifer Grando Ting, MD; Michelle J. Nickolaus, CRNP; Gary Webb, MD; Michael J. Landzberg, MD; Craig S. Broberg, MD, for the Alliance for Adult Research in Congenital Cardiology (AARCC)
From the Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada (P.K., F.P.M.); University of California, Los Angeles (J.A.); University of Washington, Seattle (M.Z.G.); Boston Adult Congenital Heart Service, Children’s Hospital Boston, Boston, Mass (P.K., A.R.O., A.M.V., M.J.L.); University of Colorado, Denver (J.K.); Medical College of Wisconsin, Milwaukee (M.G.E.); Columbia University Medical Center, New York, NY (G.L., D.R.G.); Ohio State University, Columbus (S.C.); Hershey Medical Center, Pennsylvania State University, Hershey (J.G.T., M.J.N.); The Heart Institute, Cincinnati Children’s Hospital, Cincinnati, Ohio (G.W.); and Oregon Health and Science University, Portland (C.S.B.).
Correspondence to Dr Paul Khairy, Adult Congenital Heart Center, Montreal Heart Institute, 5000 Belanger St E, Montreal, Québec, Canada, H1T 1C8. E-mail paul.khairy@umontreal.ca
Received December 2, 2009; accepted June 3, 2010.
Background— The arrhythmia burden in tetralogy of Fallot, types of arrhythmias encountered, and risk profile may change as the population ages.
Methods and Results— The Alliance for Adult Research in Congenital Cardiology (AARCC) conducted a multicenter cross-sectional study to quantify the arrhythmia burden in tetralogy of Fallot, to characterize age-related trends, and to identify associated factors. A total of 556 patients, 54.0% female, 36.8±12.0 years of age were recruited from 11 centers. Overall, 43.3% had a sustained arrhythmia or arrhythmia intervention. Prevalence of atrial tachyarrhythmias was 20.1%. Factors associated with intraatrial reentrant tachycardia in multivariable analyses were right atrial enlargement (odds ratio [OR], 6.2; 95% confidence interval [CI], 2.8 to 13.6), hypertension (OR, 2.3; 95% CI, 1.1 to 4.6), and number of cardiac surgeries (OR, 1.4; 95% CI, 1.2 to 1.6). Older age (OR, 1.09 per year; 95% CI, 1.05 to 1.12), lower left ventricular ejection fraction (OR, 0.93 per unit; 95% CI, 0.89 to 0.96), left atrial dilation (OR, 3.2; 95% CI, 1.5 to 6.8), and number of cardiac surgeries (OR, 1.5; 95% CI, 1.2 to 1.9) were jointly associated with atrial fibrillation. Ventricular arrhythmias were prevalent in 14.6% and jointly associated with number of cardiac surgeries (OR, 1.3; 95% CI, 1.1 to 1.6), QRS duration (OR, 1.02 per 1 ms; 95% CI, 1.01 to 1.03), and left ventricular diastolic dysfunction (OR, 3.3; 95% CI, 1.5 to 7.1). Prevalence of atrial fibrillation and ventricular arrhythmias markedly increased after 45 years of age.
Conclusions— The arrhythmia burden in adults with tetralogy of Fallot is considerable, with various subtypes characterized by different profiles. Atrial fibrillation and ventricular arrhythmias appear to be influenced more by left- than right-sided heart disease.
Abstract 3 of 8
Coronary Heart Disease
Major Dietary Protein Sources and Risk of Coronary Heart Disease in Women
Adam M. Bernstein, MD, ScD; Qi Sun, MD, ScD; Frank B. Hu, MD, PhD; Meir J. Stampfer, MD, DrPH; JoAnn E. Manson, MD, DrPH; Walter C. Willett, MD, DrPH
From the Departments of Nutrition (A.M.B., Q.S., F.B.H., M.J.S., W.C.W.) and Epidemiology (F.B.H., M.J.S., J.E.M., W.C.W.), Harvard School of Public Health; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (M.J.S.); and Division of Preventive Medicine, Harvard Medical School (J.E.M.), Boston, Mass.
Correspondence to Adam M. Bernstein, MD, ScD, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115. E-mail abernste@hsph.harvard.edu
Received October 14, 2009; accepted June 9, 2010.
Background— With the exception of fish, few major dietary protein sources have been studied in relation to the development of coronary heart disease (CHD). Our objective was to examine the relation between foods that are major dietary protein sources and incident CHD.
Methods and Results— We prospectively followed 84 136 women aged 30 to 55 years in the Nurses’ Health Study with no known cancer, diabetes mellitus, angina, myocardial infarction, stroke, or other cardiovascular disease. Diet was assessed by a standardized and validated questionnaire and updated every 4 years. During 26 years of follow-up, we documented 2210 incident nonfatal infarctions and 952 deaths from CHD. In multivariable analyses including age, smoking, and other risk factors, higher intakes of red meat, red meat excluding processed meat, and high-fat dairy were significantly associated with elevated risk of CHD. Higher intakes of poultry, fish, and nuts were significantly associated with lower risk. In a model controlling statistically for energy intake, 1 serving per day of nuts was associated with a 30% (95% confidence interval, 17% to 42%) lower risk of CHD compared with 1 serving per day of red meat. Similarly, compared with 1 serving per day of red meat, a lower risk was associated with 1 serving per day of low-fat dairy (13%; 95% confidence interval, 6% to 19%), poultry (19%; 95% confidence interval, 3% to 33%), and fish (24%; 95% confidence interval, 6% to 39%).
Conclusions— These data suggest that high red meat intake increases risk of CHD and that CHD risk may be reduced importantly by shifting sources of protein in the US diet.
Abstract 4 of 8
Epidemiology and Prevention
Aortic Root Remodeling Over the Adult Life Course
Longitudinal Data From the Framingham Heart Study
Carolyn S.P. Lam, MBBS, MRCP; Vanessa Xanthakis, MS; Lisa M. Sullivan, PhD; Wolfgang Lieb, MD; Jayashri Aragam, MD; Margaret M. Redfield, MD; Gary F. Mitchell, MD; Emelia J. Benjamin, MD, ScM; Ramachandran S. Vasan, MD
From the Framingham Heart Study, Framingham, Mass (C.S.P.L., W.L., E.J.B., R.S.V.); Department of Biostatistics, Boston University School of Public Health, Boston, Mass (V.X., L.M.S.); Mayo Clinic, Rochester, Minn (C.S.P.L., M.M.R.); Veterans Administration Hospital, West Roxbury, Mass (J.A.); Cardiovascular Engineering Inc, Norwood, Mass (G.F.M.); and Preventive Medicine and Cardiology Sections, Boston University School of Medicine, Boston, Mass (E.J.B., R.S.V.).
Correspondence to Ramachandran S. Vasan, MD, The Framingham Heart Study, 73 Mount Wayte Ave, Suite 2, Framingham, MA 01702–5803. E-mail vasan@bu.edu
Received January 12, 2010; accepted June 13, 2010.
Background— Aortic root remodeling in adulthood is known to be associated with cardiovascular outcomes. However, there is a lack of longitudinal data defining the clinical correlates of aortic root remodeling over the adult life course.
Methods and Results— We used serial routine echocardiograms in participants of the Framingham Heart Study to track aortic root diameter over 16 years in mid to late adulthood and to determine its short-term (4 years; n=6099 observations in 3506 individuals) and long-term (16 years; n=14 628 observations in 4542 individuals) clinical correlates by multilevel modeling. Age, sex, body size, and blood pressure were principal correlates of aortic remodeling in both short- and long-term analyses (all P 0.01). Aortic root diameter increased with age in both men and women but was larger in men at any given age. Each 10-year increase in age was associated with a larger aortic root (by 0.89 mm in men and 0.68 mm in women) after adjustment for body size and blood pressure. A 5-kg/m2 increase in body mass index was associated with a larger aortic root (by 0.78 mm in men and 0.51 mm in women) after adjustment for age and blood pressure. Each 10-mm Hg increase in pulse pressure was related to a smaller aortic root (by 0.19 mm in men and 0.08 mm in women) after adjustment for age and body size.
Conclusions— These longitudinal community-based data show that aortic root remodeling occurs over mid to late adulthood and is principally associated with age, sex, body size, and blood pressure. The underlying basis for these differences and implications for the development of cardiovascular events deserve further study.
Abstract 5 of 8
Heart Failure
Ca2+/Calmodulin-Dependent Kinase II Causes Heart Failure by Accumulation of p53 in Dilated Cardiomyopathy
Haruhiro Toko, MD, PhD; Hidehisa Takahashi, MD, PhD; Yosuke Kayama, MD; Toru Oka, MD, PhD; Tohru Minamino, MD, PhD; Sho Okada, MD, PhD; Sachio Morimoto, PhD; Dong-Yun Zhan, PhD; Fumio Terasaki, MD, PhD; Mark E. Anderson, MD, PhD; Masashi Inoue, MD, PhD; Atsushi Yao, MD, PhD; Ryozo Nagai, MD, PhD; Yasushi Kitaura, MD, PhD; Toshiyuki Sasaguri, MD, PhD; Issei Komuro, MD, PhD
From the Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan (H. Toko, H. Takahashi, Y.K., T.O., T.M., S.O., I.K.); Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan (T.O., I.K.); Department of Clinical Pharmacology, Kyusyu University Graduate School of Medicine, Fukuoka, Japan (S.M., D.Z., T.S.); Department of Internal Medicine III, Osaka Medical College, Takatsuki, Japan (F.T., Y.K.); Department of Internal Medicine, and Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City (M.E.A.); and Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan (M.I., A.Y., R.N.).
Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan. E-mail komuro-tky@umin.ac.jp
Received January 6, 2010; accepted July 2, 2010.
Background— Dilated cardiomyopathy (DCM), characterized by dilatation and dysfunction of the left ventricle, is an important cause of heart failure. Many mutations in various genes, including cytoskeletal protein genes and contractile protein genes, have been identified in DCM patients, but the mechanisms of how such mutations lead to DCM remain unknown.
Methods and Results— We established the mouse model of DCM by expressing a mutated cardiac -actin gene, which has been reported in patients with DCM, in the heart (mActin-Tg). mActin-Tg mice showed gradual dilatation and dysfunction of the left ventricle, resulting in death by heart failure. The number of apoptotic cardiomyocytes and protein levels of p53 were increased in the hearts of mActin-Tg mice. Overexpression of Bcl-2 or downregulation of p53 decreased the number of apoptotic cardiomyocytes and improved cardiac function. This mouse model showed a decrease in myofilament calcium sensitivity and activation of calcium/calmodulin-dependent kinase II (CaMKII ). The inhibition of CaMKII prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function.
Conclusion— CaMKII plays a critical role in the development of heart failure in part by accumulation of p53 and induction of cardiomyocyte apoptosis in the DCM mouse model.
Abstract 6 of 8
Interventional Cardiology
Comparative Evaluation of Left and Right Ventricular Endomyocardial Biopsy
Differences in Complication Rate and Diagnostic Performance
Ali Yilmaz, MD*; Ingrid Kindermann, MD*; Michael Kindermann, MD; Felix Mahfoud, MD; Christian Ukena, MD; Anastasios Athanasiadis, MD; Stephan Hill, MD; Heiko Mahrholdt, MD; Matthias Voehringer, MD; Michael Schieber, MD; Karin Klingel, MD; Reinhard Kandolf, MD; Michael Böhm, MD ; Udo Sechtem, MD
From the Division of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany (A.Y., A.A., S.H., H.M., M.V., M.S., U.S.); the University Hospital of the Saarland, Department of Cardiology, Angiology and Intensive Care Medicine, Homburg/Saar, Germany (I.K., M.K., F.M., C.U., M.B.); and the Department of Molecular Pathology, University of Tübingen, Germany (K.K., R.K.).
Correspondence to Ali Yilmaz, MD, Robert-Bosch-Krankenhaus, Auerbachstrasse 110, 70376 Stuttgart, Germany. E-mail ali.yilmaz@rbk.de
Received November 17, 2009; accepted June 14, 2010.
Background— Endomyocardial biopsy (EMB) represents the gold standard for diagnosing myocarditis and nonischemic cardiomyopathies. This study focuses on the risk of complications and the respective diagnostic performance of left ventricular (LV), right ventricular (RV), or biventricular EMB in patients with suspected myocarditis and/or cardiomyopathy of unknown origin.
Methods and Results— In this 2-center study, 755 patients with clinically suspected myocarditis (n=481) and/or cardiomyopathy of nonischemic origin including those with infiltrative or connective tissue disease (n=274) underwent either selective LV-EMB (n=265; 35.1%), selective RV-EMB (n=133; 17.6%), or biventricular EMB (n=357; 47.3%) after coronary angiography and exclusion of significant coronary artery disease. Cardiovascular magnetic resonance, including late gadolinium enhancement, imaging was performed in 540 patients (71.5%). The major complication rate for LV-EMB was 0.64% and for RV-EMB, 0.82%. Considering postprocedural pericardial effusion that occurred after biventricular EMB, the minor complication rate for LV-EMB varied between 0.64% to 2.89% and for RV-EMB, between 2.24% and 5.10%. Diagnostic EMB results were achieved significantly more often in those patients who underwent biventricular EMBs (79.3%) compared to those who underwent either selective LV-EMB or selective RV-EMB (67.3%; P<0.001). In patients with biventricular EMB, myocarditis was diagnosed in LV-EMB samples in 18.7% and in RV-EMB samples in 7.9% (P=0.002) , and it was diagnosed in both ventricles in 73.4%. There were no differences in the number of positive LV-EMB, RV-EMB, or LV- and RV-EMB findings when related to the site of cardiovascular magnetic resonance–based late gadolinium enhancement.
Conclusions— Both LV-EMB and RV-EMB are safe procedures if performed by experienced interventionalists. The diagnostic yield of EMB may be optimized when samples from both ventricles are available. Preferential biopsy in regions showing late gadolinium enhancement on cardiovascular magnetic resonance does not increase the number of positive diagnoses of myocarditis.
Abstract 7 of 8
Molecular Cardiology
Int6/eIF3e Silencing Promotes Functional Blood Vessel Outgrowth and Enhances Wound Healing by Upregulating Hypoxia-Induced Factor 2 Expression
Li Chen, PhD; Alexander Endler, PhD; Kazuyo Uchida, BS; Shin-ichiro Horiguchi, MD; Yoshihito Morizane, PhD; Osamu Iijima, PhD; Masakazu Toi, MD, PhD; Futoshi Shibasaki, MD, PhD
From the Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan (L.C., A.E., K.U., Y.M., O.I., F.S.); Department of Biology, Medical School, Tongji University, Shanghai, China (A.E.); Department of Pathology, Tokyo Metropolitan Komagome Hospital, Bunkyo-ku, Tokyo, Japan (S.-i.H.); and Breast Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan (M.T.).
Correspondence to Futoshi Shibasaki, MD, PhD, Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. E-mail shibasaki-ft@igakuken.or.jp
Received December 19, 2009; accepted June 18, 2010.
Background— We previously identified INT6/eIF3e as a novel regulator of hypoxia-inducible factor 2 (HIF2 ) activity. Small interfering RNA (siRNA)–Int6 adequately stabilized HIF2 , even under normoxic conditions, and thereby enhanced the expression of several angiogenic factors in vitro, suggesting that siRNA-Int6 may induce angiogenesis in vivo.
Methods and Results— We demonstrated a 6- to 8-fold enhanced formation of normal arteries and veins in the subcutaneous regions of adult mice 5 days after a single siRNA-Int6 application. Subcutaneous fibroblasts were identified as the major source of secreted angiogenic factors that led to the formation of functional vessels during Int6 silencing. Fibroblasts transfected ex vivo with siRNA-Int6 induced potent neoangiogenesis when transplanted into a subcutaneous region of nude mice. Application of siRNA-Int6 promoted neoangiogenesis in the area surrounding the injury in wound healing models, including genetically diabetic mice, thereby accelerating the closure of the injury. HIF2 accumulation caused by siRNA-Int6 was confirmed as the unequivocal cause of the angiogenesis by an in vivo angiogenesis assay. Further analysis of the Int6 silencing–induced neoangiogenesis revealed that a negative feedback regulation of HIF2 stability was caused by HIF2 -induced transcription of Int6 via hypoxia-response elements in its promoter. Thus, siRNA-Int6 temporarily facilitates an accumulation of HIF2 protein, leading to hypoxia-independent transcription of angiogenic factors and concomitant neoangiogenesis.
Conclusions— We suggest that the pathway involving INT6/HIF2 acts as a hypoxia-independent master switch of functional angiogenesis; therefore, siRNA-Int6 application might be of clinical value in treating ischemic diseases such as heart and brain ischemia, skin injury, and diseases involving obstructed vessels.
Abstract 8 of 8
Vascular Medicine
Elevated Levels of Inflammatory Cytokines Predict Survival in Idiopathic and Familial Pulmonary Arterial Hypertension
Elaine Soon, MRCP, M***hir*; Alan M. Holmes, PhD*; Carmen M. Treacy, BSc; Natalie J. Doughty, MSc; Laura Southgate, PhD; Rajiv D. Machado, PhD; Richard C. Trembath, F***; Simon Jennings, PhD; Lucy Barker, PhD; Paul Nicklin, PhD; Christoph Walker, PhD ; David C. Budd, PhD; Joanna Pepke-Zaba, PhD, FRCP; Nicholas W. Morrell, MD, FRCP
From the Department of Medicine, University of Cambridge, Cambridge, UK (E.S., N.W.M.); Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge, UK (E.S., C.M.T., N.J.D., J.P.-Z., N.W.M.); Respiratory Disease Area, Novartis Institutes for Biomedical Research, West Sussex, UK (A.M.H., S.J., L.B., P.N., C.W., D.C.B.); and Department of Medical and Molecular Genetics, King’s College, London, UK (L.S., R.D.M., R.C.T.).
Correspondence to Professor N.W. Morrell, Department of Medicine, University of Cambridge School of Clinical Medicine, Box 157, Addenbrookes’ Hospital, Hills Rd, Cambridge CB2 0QQ, UK. E-mail nwm23@cam.ac.uk
Received December 22, 2009; accepted June 8, 2010.
Background— Inflammation is a feature of pulmonary arterial hypertension (PAH), and increased circulating levels of cytokines are reported in patients with PAH. However, to date, no information exists on the significance of elevated cytokines or their potential as biomarkers. We sought to determine the levels of a range of cytokines in PAH and to examine their impact on survival and relationship to hemodynamic indexes.
Methods and Results— We measured levels of serum cytokines (tumor necrosis factor- , interferon- and interleukin-1β, -2, -4, -5, -6, -8, -10, -12p70, and -13) using ELISAs in idiopathic and heritable PAH patients (n=60). Concurrent clinical data included hemodynamics, 6-minute walk distance, and survival time from sampling to death or transplantation. Healthy volunteers served as control subjects (n=21). PAH patients had significantly higher levels of interleukin-1β, -2, -4, -6, -8, -10, and -12p70 and tumor necrosis factor- compared with healthy control subjects. Kaplan-Meier analysis showed that levels of interleukin-6, 8, 10, and 12p70 predicted survival in patients. For example, 5-year survival with interleukin-6 levels of >9 pg/mL was 30% compared with 63% for patients with levels 9 pg/mL (P=0.008). In this PAH cohort, cytokine levels were superior to traditional markers of prognosis such as 6-minute walk distance and hemodynamics.
Conclusions— This study illustrates dysregulation of a broad range of inflammatory mediators in idiopathic and familial PAH and demonstrates that cytokine levels have a previously unrecognized impact on patient survival. They may prove to be useful biomarkers and provide insight into the contribution of inflammation in PAH.