circulation2010-08-10

(Circulation. 2010;122:570-578.)
© 2010 American Heart Association, Inc.

Abstract 1 of 7

Epidemiology and Prevention
Correlates of Echocardiographic Indices of Cardiac Remodeling Over the Adult Life Course
Longitudinal Observations From the Framingham Heart Study
Susan Cheng, MD; Vanessa Xanthakis, MS; Lisa M. Sullivan, PhD; Wolfgang Lieb, MD; Joseph Massaro, PhD; Jayashri Aragam, MD; Emelia J. Benjamin, MD, ScM; Ramachandran S. Vasan, MD
From the Framingham Heart Study (S.C., V.X., L.M.S., W.L., J.M., E.J.B., R.S.V.), Framingham, Mass; Division of Cardiovascular Medicine (S.C., J.A.), Department of Medicine, Brigham and Women’s Hospital, Boston, Mass; Clinical Investigator Training Program (S.C.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Biostatistics (V.X., L.M.S., J.M.) and Department of Epidemiology (E.J.B.), Boston University School of Public Health, Boston, Mass; Veterans Administration Hospital (J.A.), West Roxbury, Mass; and Whitaker Cardiovascular Institute (E.J.B., R.S.V.), Preventive Medicine and Cardiology Sections, Boston University School of Medicine, Boston, Mass.
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 15, 2010.
Background— The heart progressively remodels over the life course, yet longitudinal data characterizing such remodeling in the community are limited.
Methods and Results— Using multilevel modeling, we analyzed up to 4 serial echocardiographic observations obtained over a 16-year period in 4062 Framingham Heart Study participants (mean age 45 years, 54% women; 11 485 person-observations). We related left ventricular (LV) wall thickness, LV systolic and diastolic dimensions, and fractional shortening to age, sex, body mass index, blood pressure (including antihypertensive medication use), smoking, and diabetes mellitus (separate analyses for each echocardiographic measure). With advancing age, LV dimensions decreased, whereas fractional shortening and LV wall thickness increased concomitantly. Male sex, body mass index, and blood pressure indices/hypertension treatment were significantly related to both greater LV dimensions and LV wall thickness. The effect of age on cardiac remodeling was influenced by key covariates (P<0.05 for all interactions): Women and individuals with diabetes mellitus experienced greater age-associated increases in LV wall thickness; presence of diabetes or a higher blood pressure was associated with a lesser decrease in LV diastolic dimensions with increasing age; and antihypertensive medication use was a marker of an attenuated increase in fractional shortening with aging.
Conclusions— Cardiac remodeling over the adult life course is characterized by a distinct pattern of increasing LV wall thickness, decreasing LV dimensions, and increasing fractional shortening with advancing age. Overall, female sex, greater blood pressure load, and presence of diabetes mellitus serve to attenuate this remodeling pattern. These observations suggest a mechanism for the preponderance of women with hypertension and individuals with diabetes among patients with diastolic heart failure.

Abstract 2 of 7

Epidemiology and Prevention
Hypertension in Pregnancy and Later Cardiovascular Risk
Common Antecedents?
Pål R. Romundstad, PhD; Elisabeth B. Magnussen, MD; George Davey Smith, MD, DSc; Lars J. Vatten, MD, PhD
From the Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway (P.R.R., E.B.M., L.J.V.); Department of Social Medicine, University of Bristol, Bristol, UK (G.D.S.), and Department of Obstetrics and Gynecology, St. Olavs University Hospital, Trondheim, Norway (E.B.M.).
Correspondence to Pål Richard Romundstad, Department of Public Health, NTNU, N-7489 Trondheim, Norway. E-mail paalr@ntnu.no
Received February 2, 2010; accepted June 2, 2010.
Background— Preeclampsia and gestational hypertension are associated with increased risk for cardiovascular disease later in life. We have assessed whether the effect can be attributed to factors that operate in pregnancy or to prepregnancy risk factors that are shared by both disorders.
Methods and Results— Longitudinal data from 2 consecutive waves of a Norwegian population-based study (the Nord-Trøndelag Health Study [HUNT]) were combined with data from the Medical Birth Registry of Norway. Among 24 865 women who had participated in both HUNT 1 and 2, we indentified 3225 women with a singleton birth between the 2 studies who had standardized measurements of blood pressure, serum lipids, and body mass index. The crude results showed that women who experienced preeclampsia or gestational hypertension in pregnancy had substantially higher levels of body mass index and systolic and diastolic blood pressures and unfavorable lipids compared with other women. However, after adjustment for prepregnancy measurements, the difference in body mass index was attenuated by >65%, and the difference in blood pressure was attenuated by 50%. In relation to high-density lipoprotein cholesterol and triglycerides, differences between the groups were attenuated by 40% and 72%, respectively.
Conclusions— These results suggest that the positive association of preeclampsia and gestational hypertension with postpregnancy cardiovascular risk factors may be due largely to shared prepregnancy risk factors rather than reflecting a direct influence of the hypertensive disorder in pregnancy.

Abstract 3 of 7

Heart Failure
Improving Evidence-Based Care for Heart Failure in Outpatient Cardiology Practices
Primary Results of the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF)
Gregg C. Fonarow, MD; Nancy M. Albert, PhD, RN; Anne B. Curtis, MD; Wendy Gattis Stough, PharmD; Mihai Gheorghiade, MD; J. Thomas Heywood, MD; Mark L. McBride, PhD; Patches Johnson Inge, PhD; Mandeep R. Mehra, MD; Christopher M. O'Connor, MD; Dwight Reynolds, MD; Mary Norine Walsh, MD; Clyde W. Yancy, MD
From the Department of Medicine, Ahmanson–UCLA Cardiomyopathy Center, UCLA Medical Center, Los Angeles, Calif (G.C.F.); Nursing Institute and George M. and Linda H. Kaufman Center for Heart Failure, Cleveland Clinic Foundation, Cleveland, Ohio (N.M.A.); Division of Cardiology, University of South Florida College of Medicine, Tampa (A.B.C.); Department of Clinical Research, Campbell University School of Pharmacy, Research Triangle Park, and Department of Medicine, Duke University Medical Center, Durham, NC (W.G.S.); Division of Cardiology, Northwestern University, Center for Cardiovascular Quality and Outcomes, Chicago, Ill (M.G.); Division of Cardiology, Scripps Clinic, La Jolla, Calif (J.T.H.); Outcome Sciences Inc, Cambridge, Mass (M.L.M., P.J.I.); Division of Cardiology, University of Maryland, Baltimore (M.R.M.); Division of Cardiology, Duke University Medical Center, Durham, NC (C.M.O.); Cardiovascular Section, University of Oklahoma Health Sciences Center, Oklahoma City (D.R.); The Care Group LLC, Indianapolis, Ind (M.N.W.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Tex (C.W.Y.).
Correspondence to Gregg C. Fonarow, MD, Ahmanson–UCLA Cardiomyopathy Center, Ronald Reagan UCLA Medical Center, 10833 LeConte Ave, Room A2–237 CHS, Los Angeles, CA 90095-1679. E-mail gfonarow@mednet.ucla.edu
Received December 23, 2009; accepted June 1, 2010.
Background— A treatment gap exists between heart failure (HF) guidelines and the clinical care of patients. The Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF) prospectively tested a multidimensional practice-specific performance improvement intervention on the use of guideline-recommended therapies for HF in outpatient cardiology practices.
Methods and Results— Performance data were collected in a random sample of HF patients from 167 US outpatient cardiology practices at baseline, longitudinally after intervention at 12 and 24 months, and in single-point-in-time patient cohorts at 6 and 18 months. Participants included 34 810 patients with reduced left ventricular ejection fraction ( 35%) and chronic HF or previous myocardial infarction. To quantify guideline adherence, 7 quality measures were assessed. Interventions included clinical decision support tools, structured improvement strategies, and chart audits with feedback. The performance improvement intervention resulted in significant improvements in 5 of 7 quality measures at the 24-month assessment compared with baseline: β-blocker (92.2% versus 86.0%, +6.2%), aldosterone antagonist (60.3% versus 34.5%, +25.1%), cardiac resynchronization therapy (66.3% versus 37.2%, +29.9%), implantable cardioverter-defibrillator (77.5% versus 50.1%, +27.4%), and HF education (72.1% versus 59.5%, +12.6%) (each P<0.001). There were no statistically significant improvements in angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use or anticoagulation for atrial fibrillation. Sensitivity analyses at the patient level and limited to patients with both baseline and 24-month quality measure data yielded similar results. Improvements in the single-point-in-time cohorts were smaller, and there were no concurrent control practices.
Conclusions— The Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting, a defined and scalable practice-specific performance improvement intervention, was associated with substantial improvements in the use of guideline-recommended therapies in eligible patients with HF in outpatient cardiology practices.

Abstract 4 of 7

Heart Failure
Pathogenesis of Sudden Unexpected Death in a Clinical Trial of Patients With Myocardial Infarction and Left Ventricular Dysfunction, Heart Failure, or Both
Anne-Catherine Pouleur, MD, PhD; Ebrahim Barkoudah, MD; Hajime Uno, PhD; Hicham Skali, MD, MSc; Peter V. Finn, MD; Steven L. Zelenkofske, DO; Yuri N. Belenkov, MD, PhD; Viacheslav Mareev, MD; Eric J. Velazquez, MD; Jean L. Rouleau, MD; Aldo P. Maggioni, MD; Lars Køber, MD; Robert M. Califf, MD; John J.V. McMurray, MD; Marc A. Pfeffer, MD, PhD; Scott D. Solomon, MD, for the VALIANT Investigators
From the Cardiovascular Division, Brigham and Women’s Hospital (A.-C.P., E.B., H.S., P.V.F., M.A.P., S.D.S.), Boston, Mass; Harvard School of Public Health (H.U.), Boston, Mass; Regado Biosciences Inc (S.L.Z.), Basking Ridge, NJ; Cardiology Research Institute (Y.N.B., V.M.), Moscow, Russia; Duke University Medical Center (E.J.V., R.M.C.), Durham, NC; Montreal Heart Institute (J.L.R.), Montreal, Canada; Associazione Nazionale Medici Cardiologi Ospedalieri Research Center (A.P.M.), Florence, Italy; Department of Cardiology, Rigshospitalet (L.K.), Copenhagen, Denmark; and Department of Cardiology, Western Infirmary (J.J.V.M.), Glasgow, United Kingdom.
Correspondence to Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail ssolomon@rics.bwh.harvard.edu
Received January 28, 2010; accepted June 9, 2010.
Background— The frequency of sudden unexpected death is highest in the early post–myocardial infarction (MI) period; nevertheless, 2 recent trials showed no improvement in mortality with early placement of an implantable cardioverter-defibrillator after MI.
Methods and Results— To better understand the pathophysiological events that lead to sudden death after MI, we assessed autopsy records in a series of cases classified as sudden death events in patients from the VALsartan In Acute myocardial infarctioN Trial (VALIANT). Autopsy records were available in 398 cases (14% of deaths). We determined that 105 patients had clinical circumstances consistent with sudden death. On the basis of the autopsy findings, we assessed the probable cause of sudden death and evaluated how these causes varied with time after MI. Of 105 deaths considered sudden on clinical grounds, autopsy suggested the following causes: 3 index MIs in the first 7 days (2.9%); 28 recurrent MIs (26.6%); 13 cardiac ruptures (12.4%); 4 pump failures (3.8%); 2 other cardiovascular causes (stroke or pulmonary embolism; 1.9%); and 1 noncardiovascular cause (1%). Fifty-four cases (51.4%) had no acute specific autopsy evidence other than the index MI and were thus presumed arrhythmic. The percentage of sudden death due to recurrent MI or rupture was highest in the first month after the index MI. By contrast, after 3 months, the percentage of presumed arrhythmic death was higher than recurrent MI or rupture ( 2=23.3, P<0.0001).
Conclusions— Recurrent MI or cardiac rupture accounts for a high proportion of sudden death in the early period after acute MI, whereas arrhythmic death may be more likely subsequently. These findings may help explain the lack of benefit of early implantable cardioverter-defibrillator therapy.

Abstract 5 of 7

Imaging
Cardiac Positron Emission Tomography/Computed Tomography Imaging Accurately Detects Anatomically and Functionally Significant Coronary Artery Disease
S. Kajander, MD; E. Joutsiniemi, MD; M. Saraste, MD; M. Pietilä, MD, PhD; H. Ukkonen, MD, PhD; A. Saraste, MD, PhD; H.T. Sipilä, PhD; M. Teräs, PhD; M. Mäki, MD, PhD; J. Airaksinen, MD, PhD; J. Hartiala, MD, PhD; J. Knuuti, MD, PhD
From the Turku PET Centre (S.K., H.T.S., M.T., J.K.), Department of Medicine (E.J., M.P., H.U., A.S., J.A.), and Department of Clinical Physiology and Nuclear Medicine (M.S., M.M., J.H.), University of Turku, Turku, Finland.
Correspondence to Juhani Knuuti, MD, Turku PET Centre, PO Box 52, FI-20521 Turku, Finland. E-mail juhani.knuuti@utu.fi
Received October 9, 2009; accepted June 1, 2010.
Background— Computed tomography (CT) is increasingly used to detect coronary artery disease, but the evaluation of stenoses is often uncertain. Perfusion imaging has an established role in detecting ischemia and guiding therapy. Hybrid positron emission tomography (PET)/CT allows combination angiography and perfusion imaging in short, quantitative, low-radiation-dose protocols.
Methods and Results— We enrolled 107 patients with an intermediate (30% to 70%) pretest likelihood of coronary artery disease. All patients underwent PET/CT (quantitative PET with 15O-water and CT angiography), and the results were compared with the gold standard, invasive angiography, including measurement of fractional flow reserve when appropriate. Although PET and CT angiography alone both demonstrated 97% negative predictive value, CT angiography alone was suboptimal in assessing the severity of stenosis (positive predictive value, 81%). Perfusion imaging alone could not always separate microvascular disease from epicardial stenoses, but hybrid PET/CT significantly improved this accuracy to 98%. The radiation dose of the combined PET and CT protocols was 9.3 mSv (86 patients) with prospective triggering and 21.8 mSv (21 patients) with spiral CT.
Conclusion— Cardiac hybrid PET/CT imaging allows accurate noninvasive detection of coronary artery disease in a symptomatic population. The method is feasible and can be performed routinely with <10 mSv in most patients.

Abstract 6 of 7

Interventional Cardiology
First Clinical Application of an Actively Reversible Direct Factor IXa Inhibitor as an Anticoagulation Strategy in Patients Undergoing Percutaneous Coronary Intervention
Mauricio G. Cohen, MD; Drew A. Purdy, MD; Joseph S. Rossi, MD, MHS; Liliana R. Grinfeld, MD; Shelley K. Myles, BS; Laura H. Aberle, BSPH; Adam B. Greenbaum, MD; Edward Fry, MD; Mark Y. Chan, MD; Ross M. Tonkens, MD; Steven Zelenkofske, DO; John H. Alexander, MD, MHS; Robert A. Harrington, MD; Christopher P. Rusconi, PhD; Richard C. Becker, MD
From the Cardiovascular Division, University of Miami Miller School of Medicine, Miami, Fla (M.G.C.); Black Hills Cardiology, Rapid City, SD (D.A.P.); Division of Cardiology, University of North Carolina at Chapel Hill (J.S.R.); Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (L.R.G.); Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (S.K.M., L.H.A., M.Y.C., J.H.A., R.A.H., R.C.B.); Henry Ford Heart and Vascular Institute, Detroit, Mich (A.B.G.); The Care Group, Indianapolis, Ind (E.F.); and Regado Biosciences, Inc, Basking Ridge, NJ (R.M.T., S.Z., C.P.R.).
Correspondence to Mauricio G. Cohen, MD, Cardiovascular Division, University of Miami Miller School of Medicine, 1400 NW 12th Ave, Suite 1179, Miami, FL 33136. E-mail mgcohen@med.miami.edu
Received December 1, 2009; accepted June 1, 2010.
Background— The ideal anticoagulant should prevent ischemic complications without increasing the risk of bleeding. Controlled anticoagulation is possible with the REG1 system, an RNA aptamer pair comprising the direct factor IXa inhibitor RB006 and its active control agent RB007.
Methods and Results— This phase 2a study included a roll-in group (n=2) treated with REG1 plus glycoprotein IIb/IIIa inhibitors followed by 2 groups randomized 5:1 to REG1 or unfractionated heparin. In group 1 (n=12), RB006 was partially reversed with RB007 after percutaneous coronary intervention and fully reversed 4 hours later. In group 2 (n=12), RB006 was fully reversed with RB007 immediately after percutaneous coronary intervention. Femoral sheaths were removed after complete reversal. Patients were pretreated with aspirin and clopidogrel. End points included major bleeding within 48 hours; composite of death, myocardial infarction, or urgent target vessel revascularization within 14 days; and pharmacodynamic measures. All cases were successful, with final Thrombolysis in Myocardial Infarction grade 3 flow and no angiographic thrombotic complications. There were 2 ischemic end points in the REG1 group and 1 in the unfractionated heparin group, with 1 major bleed in the unfractionated heparin group. Median activated clotting time values rose from 151 to 236 seconds after RB006. Administration of the partial RB007 dose reversed anticoagulation to an intermediate activated clotting time value of 186 seconds. Complete reversal with RB007 returned the median activated clotting time value to 144 seconds. Both reversal strategies enabled scheduled femoral sheath removal.
Conclusions— This study demonstrates the clinical translation of a novel platform of anticoagulation targeting factor IXa and its active reversal to percutaneous coronary intervention and provides the basis for further investigation.

Abstract 7 of 7

Resuscitation Science
Differences Between Out-of-Hospital Cardiac Arrest in Residential and Public Locations and Implications for Public-Access Defibrillation
Fredrik Folke, MD; Gunnar H. Gislason, MD, PhD; Freddy K. Lippert, MD; Søren L. Nielsen, MD; Peter Weeke, MD; Morten L. Hansen, MD, PhD; Emil L. Fosbøl, MD, PhD; Søren S. Andersen, MD; Søren Rasmussen, MSc, PhD; Tina K. Schramm, MD; Lars Køber, MD, DMSc; Christian Torp-Pedersen, MD, DMSc
From the Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark (F.F., G.H.G., P.W., M.L.H., E.L.F., S.S.A., C.T.-P.); Emergency Medicine and Emergency Medical Services, Capital Region of Denmark (F.K.L.); Mobile Emergency Care Unit of Copenhagen, Capital Region of Denmark (S.L.N.); National Institute of Public Health, Copenhagen, Denmark (S.R.); and Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark (T.K.S., L.K.).
Correspondence to Fredrik Folke, MD, Department of Cardiology, Copenhagen University Hospital, Gentofte, Niels Andersens Vej 65, 2900 Hellerup, Denmark. E-mail FF@heart.dk
Received November 18, 2009; accepted May 20, 2010.
Background— The majority of out-of-hospital cardiac arrests (OHCAs) occur in residential locations, but knowledge about strategic placement of automated external defibrillators in residential areas is lacking. We examined whether residential OHCA areas suitable for placement of automated external defibrillators could be identified on the basis of demographic characteristics and characterized individuals with OHCA in residential locations.
Methods and Results— We studied 4828 OHCAs in Copenhagen between 1994 and 2005. The incidence and characteristics of OHCA were examined in every 100x100-m (109.4x109.4-yd) residential area according to its underlying demographic characteristics. By combining 2 demographic characteristics, it was possible to identify 100x100-m (109.4x109.4-yd) areas with at least 1 arrest every 5.6 years (characterized by >300 persons per area and lowest income) to 1 arrest every 4.3 years (characterized by >300 persons per area, lowest income, low education, and highest age). These areas covered 9.0% and 0.8% of all residential OHCAs, respectively. Individuals with OHCA in residential locations differed from public ones in that the patients were older (70.6 versus 60.6 years; P<0.0001), the ambulance response interval was longer (6.0 versus 5.0 minutes; P<0.0001), arrests occurred more often at night (21.2% versus 11.2%; P<0.0001), the patients had ventricular fibrillation less often (12.8% versus 38.1%; P<0.0001), and the patients had a worse 30-day survival rate (3.2% versus 13.9%; P<0.0001).
Conclusions— On the basis of simple demographic characteristics of a city center, we could identify residential areas suitable for automated external defibrillator placement. Individuals with OHCA in residential locations were more likely to have characteristics associated with poor outcome compared with public arrests.