circulation 2009-11-24

Volume 120, Issue 21; November 24, 2009

Abstract 1 of 8 (Circulation. 2009;120:2040-2045.)
© 2009 American Heart Association, Inc.
Arrhythmia/Electrophysiology
Heart Rate Predicts Outcomes in an Implantable Cardioverter-Defibrillator Population
Mastaneh Ahmadi-Kashani, MD; David J. Kessler, MD; John Day, MD; T. Jared Bunch, MD; Kira Q. Stolen, PhD; Scott Brown, PhD; Salam Sbaity, MD; Brian Olshansky, MD, on behalf of the INTRINSIC RV Study Investigators
From the University of Iowa Hospitals, Iowa City (M.A.-K., S.S., B.O.); Austin Heart PA, Austin, Tex (D.J.K.); Intermountain Medical Center, Murray, Utah (J.D., T.J.B.); Boston Scientific Corporation, St. Paul, Minn (K.S.); and The Integra Group, Brooklyn Park, Minn (S.B.).
Reprint requests to Brian Olshansky, MD, Department of Medicine, University of Iowa Hospitals, 4426a JCP, 200 Hawkins Dr, Iowa City, IA 52242. E-mail brian-olshansky@uiowa.edu
Received January 26, 2009; accepted September 11, 2009.
Background— Elevated heart rate (HR) is associated with adverse cardiovascular events and total mortality in the general population and in individuals with heart disease. Our hypothesis was that mean HR predicts total mortality and heart failure hospitalization in patients undergoing implantable cardioverter-defibrillator (ICD) implantation.
Methods and Results— The Inhibition of Unnecessary RV Pacing With ** Search Hysteresis in ICDs (INTRINSIC RV) trial included 1530 patients undergoing ICD implantation. After implantation of a dual-chamber ICD, patients were followed for a mean of 10.4 months. The mean HR for 1436 patients over the follow-up period was determined from device histograms. Patients were grouped into strata by mean HR, and the relationship between the primary end point and mean HR was analyzed with Mantel-Haenszel ordinal 2 tests. Higher intrinsic (unpaced) HR was associated with greater risk of achieving the primary end point of death or heart failure hospitalization (P<0.001). Of patients with a mean HR <75 bpm, 5.8% died or were hospitalized for heart failure, whereas 20.9% with a mean HR >90 bpm achieved the same end point, a 3.6-fold difference (P<0.0001). In a multivariate model with the use of Cox regression, HR was a significant predictor with a hazard ratio of 1.34 (P=0.0001; 95% confidence interval, 1.19 to 1.50), as were age, New York Heart Association functional class, and percent right ventricular pacing, but it was independent of gender and β-blocker dosing. When considered as continuous or discrete variables grouped by 5-bpm increments, HR remained a significant predictor.
Conclusions— In this ICD population, the mean intrinsic HR was strongly associated with outcomes.

Abstract 2 of 8 (Circulation. 2009;120:2046-2052.)
© 2009 American Heart Association, Inc.
Cardiovascular Surgery
Outcomes of Patients With Acute Type A Aortic Intramural Hematoma
Jae-Kwan Song, MD; Ji Hye Yim, MD; Jung-Min Ahn, MD; Dae-Hee Kim, MD; Joon-Won Kang, MD; Taek Yeon Lee, MD; Jong-Min Song, MD; Suk Jung Choo, MD; Duk-Hyun Kang, MD; Cheol Hyun Chung, MD; Jae Won Lee, MD; Tae-Hwan Lim, MD
From the Divisions of Cardiology (Jae-Kwan Song, J.H.Y., J.A., D.H.K., Jong-Min Song, D.K.), Radiology (J.K., T.L.), and Thoracic Surgery (T.Y.L., S.J.C., C.H.C., J.W.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Correspondence to Jae-Kwan Song, MD, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap-dong Songpa-gu, Seoul, 138-736 South Korea. E-mail jksong@amc.seoul.kr
Received May 12, 2009; accepted September 9, 2009.
Background— The proper treatment option for patients with type A intramural hematoma (IMH), a variant form of classic aortic dissection (AD), remains controversial. We assessed the outcome of our institutional policy of urgent surgery for unstable patients and initial medical treatment for stable patients with surgery in cases with complications.
Methods and Results— Among 357 consecutive patients with type A acute aortic syndrome, 101 (28.3%) had IMH and 256 had AD. Urgent operations were performed in 224 patients with AD (87.5%) and 16 with unstable IMH (15.8%; P<0.001). The remaining 85 stable IMH patients received initial medical treatment, and adverse clinical events developed in 31 patients (36.5%) within 6 months, which included development of AD (n=25), delayed surgery (n=25), or death (n=6). Initial aorta diameter and hematoma thickness were independent predictors for development of these events, and the best cutoff values were 55 and 16 mm, respectively. The overall hospital mortality was lower in IMH patients than in AD patients (7.9% [8/101] versus 17.2% [44/256]; P=0.0296) and was comparable to that of surgically treated AD patients (7.9% versus 10.7% [24/224]; P=0.56). The 1-, 2-, and 3-year survival rates of IMH patients were 87.6±3.6%, 84.9±3.7%, and 83.1±4.1%, respectively. There was no statistical difference of overall survival rates between patients with IMH and surgically treated AD patients (P=0.787).
Conclusions— The clinical outcome of IMH patients receiving treatment by our policy was comparable to that of surgically treated AD patients. However, adverse clinical events were not uncommon with medical treatment alone, and initial aorta diameter and hematoma thickness may identify patients who might benefit from urgent surgery.

Abstract 3 of 8
(Circulation. 2009;120:2053-2061.)
© 2009 American Heart Association, Inc.
Epidemiology and Prevention
Mortality and Vascular Morbidity in Older Adults With Asymptomatic Versus Symptomatic Peripheral Artery Disease
Curt Diehm, MD, PhD; Jens Rainer Allenberg, MD, PhD; David Pittrow, MD, PhD; Matthias Mahn, MD; Gerhart Tepohl, MD; Roman L. Haberl, MD, PhD; Harald Darius, MD, PhD; Ina Burghaus, Dipl-Math; Hans Joachim Trampisch, PhD, for the German Epidemiological Trial on Ankle Brachial Index Study Group
From the Department of Internal Medicine/Vascular Medicine, SRH-Klinikum Karlsbad-Langensteinbach, Karlsbad (C.D.); Department of Vascular Surgery, Ruprecht-Karls University of Heidelberg, Heidelberg (J.R.A.); Department of Clinical Pharmacology, Medical Faculty, Technical University, Dresden (D.P.); Department for Clinical Research, Sanofi-Aventis, Berlin (M.M.); Department of Neurology, Hospital Harlaching, Munich (R.L.H.); Department of Medicine I, Vivantes Neukölln Medical Center, Berlin (H.D.); and Department of Medical Informatics, Biometry and Epidemiology, University of Bochum, Bochum (H.J.T., I.B.), Germany. Dr Tepohl is in private practice in Munich, Germany.
Correspondence to Professor Dr med Curt Diehm, Department of Internal Medicine/Vascular Medicine, SRH-Klinikum Karlsbad-Langensteinbach, Affiliated Teaching Hospital, University of Heidelberg, Guttmannstr 1, D-76307 Karlsbad, Germany. E-mail curt.diehm@kkl.srh.de
Received March 17, 2009; accepted September 9, 2009.
Background— Our aim was to assess the mortality and vascular morbidity risk of elderly individuals with asymptomatic versus symptomatic peripheral artery disease (PAD) in the primary care setting.
Methods and Results— This prospective cohort study included 6880 representative unselected patients 65 years of age with monitored follow-up over 5 years. According to physician diagnosis, 5392 patients had no PAD, 836 had asymptomatic PAD (ankle brachial index <0.9 without symptoms), and 593 had symptomatic PAD (lower-extremity peripheral revascularization, amputation as a result of PAD, or intermittent claudication symptoms regardless of ankle brachial index). The risk of symptomatic compared with asymptomatic PAD patients was significantly increased for the composite of all-cause death or severe vascular event (myocardial infarction, coronary revascularization, stroke, carotid revascularization, or lower-extremity peripheral vascular events; hazard ratio, 1.48; 95% confidence interval, 1.21 to 1.80) but not for all-cause death alone (hazard ratio, 1.13; 95% confidence interval, 0.89 to 1.43), all-cause death/myocardial infarction/stroke (excluding lower-extremity peripheral vascular events and any revascularizations; hazard ratio, 1.18; 95% confidence interval, 0.92 to 1.52), cardiovascular events alone (hazard ratio, 1.20; 95% confidence interval, 0.89 to 1.60), or cerebrovascular events alone (hazard ratio, 1.33; 95% confidence interval, 0.80 to 2.20). Lower ankle brachial index categories were associated with increased risk. PAD was a strong factor for the prediction of the composite end point in an adjusted model.
Conclusions— Asymptomatic PAD diagnosed through routine screening in the offices of primary care physicians carries a high mortality and/or vascular event risk. Notably, the risk of mortality was similar in symptomatic and asymptomatic patients with PAD and was significantly higher than in those without PAD. In the primary care setting, the diagnosis of PAD has important prognostic value.

Abstract 4 of 8 (Circulation. 2009;120:2062-2068.)
© 2009 American Heart Association, Inc.
Genetics
A Common Variant at 9p21 Is Associated With Sudden and Arrhythmic Cardiac Death
Christopher Newton-Cheh, MD, MPH; Nancy R. Cook, ScD; Martin VanDenburgh, BA; Eric B. Rimm, ScD; Paul M. Ridker, MD, MPH; Christine M. Albert, MD, MPH
From the Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (C.N.-C.); Broad Institute of Harvard and MIT, Cambridge, Mass (C.N.-C.); Center for Arrhythmia Prevention (C.M.A.), Division of Preventive Medicine (N.R.C., M.V., P.M.R., C.M.A), Channing Laboratory (E.B.R.), and Cardiovascular Division (C.M.A., P.M.R.), Department of Medicine, Brigham and Women’s Hospital (C.M.A.), Harvard Medical School, Boston, Mass; and Departments of Nutrition (E.B.R.) and Epidemiology (N.R.C., E.B.R.), Harvard School of Public Health, Boston Mass.
Correspondence to Christine M. Albert, MD, MPH, Center for Arrhythmia Prevention, Division of Preventive Medicine, Cardiovascular Division, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02115–1204. E-mail calbert@partners.org
Received February 2, 2009; accepted September 16, 2009.
Background— Although a heritable basis for sudden cardiac death (SCD) is suggested by the impact of family history on SCD risk, common genetic determinants have been difficult to identify. We hypothesized that a common variant at chromosome 9p21 related to myocardial infarction would influence SCD risk.
Methods and Results— This was a prospective, nested, case-control analysis among individuals of European ancestry enrolled in 6 prospective cohort studies. Study subjects were followed up for development of SCD, and genotypes for rs10757274 were determined for 492 sudden and/or arrhythmic deaths and 1460 controls matched for age, sex, cohort, history of cardiovascular disease, and follow-up time. Conditional logistic regression with fixed-effects meta-analysis assuming an additive model was used to test for associations. When individual study results were combined in the meta-analysis, each increasing copy of the G allele at rs10757274 conferred a significantly elevated age-adjusted odds ratio for SCD of 1.21 (95% confidence interval, 1.04 to 1.40; P=0.01). Controlling for cardiovascular and lifestyle risk factors strengthened these relationships (odds ratio, 1.29 per G-allele copy; 95% confidence interval, 1.09 to 1.53; P=0.003). These results were not materially altered in sensitivity analyses limited to definite SCD, in models that further controlled for the development of interim cardiovascular disease, or when the highly correlated variant rs2383207 was tested.
Conclusions— The major allele of a single-nucleotide polymorphism previously associated with increased risk of coronary artery disease events is associated with increased risk of SCD in individuals of European ancestry. Study of the mechanism underlying this association may improve our understanding of lethal cardiovascular disease.

Abstract 5 of 8 (Circulation. 2009;120:2069-2076.)
© 2009 American Heart Association, Inc.
Imaging
Prognostic Significance of Delayed-Enhancement Magnetic Resonance Imaging
Survival of 857 Patients With and Without Left Ventricular Dysfunction
Benjamin Y.C. Cheong, MD; Raja Muthupillai, PhD; James M. Wilson, MD; Angela Sung; Steffen Huber, MD; Samir Amin, BA; MacArthur A. Elayda, MD, PhD; Vei-Vei Lee, MS; Scott D. Flamm, MD
From the Departments of Radiology (B.Y.C.C., R.M., S.H., A.S., S.D.F.), Cardiology (B.Y.C.C., J.M.W., S.D.F.), and Biostatistics and Epidemiology (M.A.E., V.V.L.), the Texas Heart Institute at St. Luke’s Episcopal Hospital, and the Departments of Medicine (B.Y.C.C., S.A.) and Radiology (B.Y.C.C., R.M., S.D.F.), Baylor College of Medicine, Houston, Tex. Dr Flamm is currently at the Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to B.Y.C. Cheong, MD, Department of Diagnostic and Interventional Radiology, St. Luke’s Episcopal Hospital and the Texas Heart Institute, 6720 Bertner Ave, MC 2–270, Houston, TX 77030. E-mail bcheong@sleh.com
Received January 20, 2009; accepted September 11, 2009.
Background— Left ventricular ejection fraction is a powerful independent predictor of survival in cardiac patients, especially those with coronary artery disease. Delayed-enhancement magnetic resonance imaging (DE-MRI) can accurately identify irreversible myocardial injury with high spatial and contrast resolution. To date, relatively limited data are available on the prognostic value of DE-MRI, so we sought to determine whether DE-MRI findings independently predict survival.
Methods and Results— The medical records of 857 consecutive patients who had complete cine and DE-MRI evaluation at a tertiary care center were reviewed regardless of whether the patients had coronary artery disease. The presence and extent of myocardial scar were evaluated qualitatively by a single experienced observer. The primary, composite end point was all-cause mortality or cardiac transplantation. Survival data were obtained from the Social Security Death Index. The median follow-up was 4.4 years; 252 patients (29%) reached one of the end points. Independent predictors of mortality or transplantation included congestive heart failure, ejection fraction, and age (P<0.0001 for each), as well as scar index (hazard ratio, 1.26; 95% confidence interval, 1.02 to 1.55; P=0.033). Similarly, in subsets of patients with or without coronary artery disease, scar index also independently predicted mortality or transplantation (hazard ratio, 1.33; 95% confidence interval, 1.05 to 1.68; P=0.018; and hazard ratio, 5.65; 95% confidence interval, 1.74 to 18.3; P=0.004, respectively). Cox regression analysis showed worse outcome in patients with any DE in addition to depressed left ventricular ejection fraction (<50%).
Conclusion— The degree of DE detected by DE-MRI appears to strongly predict all-cause mortality or cardiac transplantation after adjustment for traditional, well-known prognosticators.

Abstract 6 of 8 (Circulation. 2009;120:2077-2087.)
© 2009 American Heart Association, Inc.
Molecular Cardiology
Enhancement of Myocardial Regeneration Through Genetic Engineering of Cardiac Progenitor Cells Expressing Pim-1 Kinase
Kimberlee M. Fischer, BS; Christopher T. Cottage, MS; Weitao Wu, MS; Shabana Din, BS; Natalie A. Gude, MS; Daniele Avitabile, PhD; Pearl Quijada, BS; Brett L. Collins, BS; Jenna Fransioli, MS; Mark A. Sussman, PhD
From the San Diego State Heart Institute, San Diego State University, San Diego, Calif.
Correspondence to Mark A. Sussman, 5500 Campanile Dr, North Life Sciences 426, San Diego, CA 92182. E-mail sussman@heart.sdsu.edu
Received June 4, 2009; accepted September 18, 2009.
Background— Despite numerous studies demonstrating the efficacy of cellular adoptive transfer for therapeutic myocardial regeneration, problems remain for donated cells with regard to survival, persistence, engraftment, and long-term benefits. This study redresses these concerns by enhancing the regenerative potential of adoptively transferred cardiac progenitor cells (CPCs) via genetic engineering to overexpress Pim-1, a cardioprotective kinase that enhances cell survival and proliferation.
Methods and Results— Intramyocardial injections of CPCs overexpressing Pim-1 were given to infarcted female mice. Animals were monitored over 4, 12, and 32 weeks to assess cardiac function and engraftment of Pim-1 CPCs with echocardiography, in vivo hemodynamics, and confocal imagery. CPCs overexpressing Pim-1 showed increased proliferation and expression of markers consistent with cardiogenic lineage commitment after dexamethasone exposure in vitro. Animals that received CPCs overexpressing Pim-1 also produced greater levels of cellular engraftment, persistence, and functional improvement relative to control CPCs up to 32 weeks after delivery. Salutary effects include reduction of infarct size, greater number of c-kit+ cells, and increased vasculature in the damaged region.
Conclusions— Myocardial repair is significantly enhanced by genetic engineering of CPCs with Pim-1 kinase. Ex vivo gene delivery to enhance cellular survival, proliferation, and regeneration may overcome current limitations of stem cell–based therapeutic approaches.

Abstract 7 of 8
(Circulation. 2009;120:2088-2094.)
© 2009 American Heart Association, Inc.
Vascular Medicine
Human C-Reactive Protein Does Not Promote Atherosclerosis in Transgenic Rabbits
Tomonari Koike, PhD*; Shuji Kitajima, DVM, PhD*; Ying Yu, PhD; Kazutoshi Nishijima, DVM, PhD; Jifeng Zhang, MS; Yukio Ozaki, MD, PhD; Masatoshi Morimoto, DVM, PhD; Teruo Watanabe, MD, PhD; Sucharit Bhakdi, MD, PhD; Yujiro Asada, MD, PhD; Y. Eugene Chen, MD, PhD ; Jianglin Fan, MD, PhD
From the Departments of Molecular Pathology (T.K., Y.Y., J.Z., J.F.) and Clinical and Laboratory Medicine (Y.O.), Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan; Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan (S.K., K.N.); Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor (J.Z., Y.E.C.); Department of Rehabilitation, Kumamoto Health Science University, Kumamoto, Japan (M.M.); Fukuoka Wajiro Hospital, Fukuoka, Japan (T.W.); Institute of Medical Microbiology and Hygiene, Mainz, Germany (S.B.); and First Department of Pathology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan (Y.A.).
Correspondence to Dr Jianglin Fan, Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-City, Yamanashi, 409-3898, Japan. E-mail fan_molpatho@yahoo.co.jp
Received April 12, 2009; accepted September 4, 2009.
Background— Although there is a statistically significant association between modestly raised baseline plasma C-reactive protein (CRP) values and future cardiovascular events, the debate is still unsettled in regard to whether CRP plays a causal role in the pathogenesis of atherosclerosis.
Methods and Results— We generated 2 lines of transgenic (Tg) rabbits expressing human CRP (hCRP). The plasma levels of hCRP in hCRP-Tg-1 and hCRP-Tg-2 rabbits were 0.4±0.13 (n=14) and 57.8±20.6 mg/L (n=12), respectively. In addition, hCRP isolated from Tg rabbit plasma exhibited the ability to activate the rabbit complement. To define the role of hCRP in atherosclerosis, we compared the susceptibility of hCRP-Tg rabbits to cholesterol-rich diet-induced aortic and coronary atherosclerosis with that of non-Tg rabbits. After being fed with a cholesterol-rich diet for 16 weeks, Tg and non-Tg rabbits developed similar hypercholesterolemia and lesion sizes in both aortic and coronary arteries. Immunohistochemical staining and Western blotting revealed that hCRP was indeed present in the lesions but did not affect macrophage accumulation and smooth muscle cell proliferation of the lesions.
Conclusions— Neither high nor low plasma concentrations of hCRP affected aortic or coronary atherosclerosis lesion formation in hCRP-Tg rabbits.

Abstract 8 of 8
(Circulation. 2009;120:2095-2104.)
© 2009 American Heart Association, Inc.
Vascular Medicine
Reconstituted High-Density Lipoprotein Attenuates Platelet Function in Individuals With Type 2 Diabetes Mellitus by Promoting Cholesterol Efflux
Anna C. Calkin, PhD; Brian G. Drew, PhD; Akiko Ono, PhD; Stephen J. Duffy, MBBS, PhD; Michelle V. Gordon, MBBS; Simone M. Schoenwaelder, PhD; Dmitri Sviridov, PhD; Mark E. Cooper, MBBS, PhD; Bronwyn A. Kingwell, PhD; Shaun P. Jackson, MBBS, PhD
From the Diabetes Complications Laboratory (A.C.C., M.V.G., M.E.C.), Metabolic and Vascular Physiology Laboratory (B.G.D., S.J.D., B.A.K.), and Lipoproteins and Atherosclerosis Laboratory (D.S.), Baker IDI Heart and Diabetes Institute, and Australian Centre for Blood Diseases, Monash University (A.C.C., A.O., S.M.S., S.P.J.), Melbourne, Australia.
Correspondence to Dr Anna Calkin, Diabetes Complications Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Australia 8008. E-mail anna.calkin@bakeridi.edu.au
Received April 17, 2009; accepted August 17, 2009.
Background— Individuals with diabetes mellitus have an increased risk of cardiovascular disease and exhibit platelet hyperreactivity, increasing their resistance to antithrombotic therapies such as aspirin and clopidogrel. Reconstituted high-density lipoprotein (rHDL) has short-term beneficial effects on atherosclerotic plaques, but whether it can effectively reduce the reactivity of diabetic platelets is not known.
Methods and Results— Individuals with type 2 diabetes mellitus were infused with placebo or rHDL (CSL-111; 20 mg · kg–1 · h–1) for 4 hours, resulting in an 1.4-fold increase in plasma HDL cholesterol levels. rHDL infusion was associated with a >50% reduction in the ex vivo platelet aggregation response to multiple agonists, an effect that persisted in washed platelets. In vitro studies in platelets from healthy individuals revealed that the inhibitory effects of rHDL on platelet function were time and dose dependent and resulted in a widespread attenuation of platelet function and a 50% reduction in thrombus formation under flow. These effects could be recapitulated, in part, by the isolated phospholipid component of rHDL, which enhanced efflux of cholesterol from platelets and reduced lipid raft assembly. In contrast, the apolipoprotein AI component of rHDL had minimal effect on platelet function, cholesterol efflux, or lipid raft assembly.
Conclusion— These findings suggest that rHDL therapy is highly effective at inhibiting the heightened reactivity of diabetic platelets, partly through reducing the cholesterol content of platelet membranes. These properties, combined with the known short-term beneficial effects of rHDL on atherosclerotic lesions, suggest that rHDL infusions may be an effective approach to reduce atherothrombotic complications in diabetic individuals.