circulation2010-10-19

(Circulation. 2010;122:1553-1561.)
© 2010 American Heart Association, Inc.
Abstract 1 of 8
Arrhythmia/Electrophysiology
Complication Rates Associated With Pacemaker or Implantable Cardioverter-Defibrillator Generator Replacements and Upgrade Procedures
Results From the REPLACE Registry
Jeanne E. Poole, MD; Marye J. Gleva, MD; Theofanie Mela, MD; Mina K. Chung, MD; Daniel Z. Uslan, MD; Richard Borge, MD; Venkateshwar Gottipaty, MD, PhD; Timothy Shinn, MD; Dan Dan, MD; Leon A. Feldman, MD; Hanscy Seide, MD; Stuart A. Winston, DO; John J. Gallagher, MD; Jonathan J. Langberg, MD; Kevin Mitchell, RN, BS; Richard Holcomb, PhD; for the REPLACE Registry Investigators
From the University of Washington, Seattle (J.E.P.); Washington University in St Louis, School of Medicine, St Louis, Mo (M.J.G.); Massachusetts General Hospital, Boston (T.M.); Cleveland Clinic, Cleveland, Ohio (M.K.C.); University of California Los Angeles (D.Z.U.); Abington Medical Specialists, Abington, Pa (R.B.); South Carolina Heart Center, Columbia (V.K.); Michigan Heart, Ypsilanti (T.S., S.A.W.); Piedmont Heart Institute, Atlanta, Ga (D.D.); Desert Cardiology, Rancho Mirage, Calif (L.A.F.); Halifax Medical Center, Daytona Beach, Fla (H.S.); Spartanburg Regional, Spartanburg, SC (J.J.G.); Emory University, Atlanta, Ga (J.J.L.); BIOTRONIK, Inc, Lake Oswego, Ore (K.M.); and Private practice, Minneapolis, Minn (R.H.).
Correspondence to Jeanne E. Poole, MD, University of Washington, Division of Cardiology, 1959 NE Pacific Street, Box 356422, Seattle, WA 98198-6422. E-mail jpoole@u.washington.edu
Background— Prospective studies defining the risk associated with pacemaker or implantable cardioverter-defibrillator replacement surgeries do not exist. These procedures are generally considered low risk despite results from recent retrospective series reporting higher rates.
Methods and Results— We prospectively assessed predefined procedure-related complication rates associated with elective pacemaker or implantable cardioverter-defibrillator generator replacements over 6 months of follow-up. Two groups were studied: those without (cohort 1) and those with (cohort 2) a planned transvenous lead addition for replacement or upgrade to a device capable of additional therapies. Complications were adjudicated by an independent events committee. Seventy-two US academic and private practice centers participated. Major complications occurred in 4.0% (95% confidence interval, 2.9 to 5.4) of 1031 cohort 1 patients and 15.3% (95% confidence interval, 12.7 to 18.1) of 713 cohort 2 patients. In both cohorts, major complications were higher with implantable cardioverter-defibrillator compared with pacemaker generator replacements. Complications were highest in patients who had an upgrade to or a revised cardiac resynchronization therapy device (18.7%; 95% confidence interval, 15.1 to 22.6). No periprocedural deaths occurred in either cohort, although 8 later procedure-related deaths occurred in cohort 2. The 6-month infection rates were 1.4% (95% confidence interval, 0.7 to 2.3) and 1.1% (95% confidence interval, 0.5 to 2.2) for cohorts 1 and 2, respectively.
Conclusions— Pacemaker and implantable cardioverter-defibrillator generator replacements are associated with a notable complication risk, particularly those with lead additions. These data support careful decision making before device replacement, when managing device advisories, and when considering upgrades to more complex systems.
Abstract 2 of 8
Exercise Physiology
Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy
Khalid Abozguia, PhD, MRCP*; Perry Elliott, MD, FRCP*; William McKenna, MD, FRCP; Thanh Trung Phan, PhD, MRCP; Ganesh Nallur-Shivu, MRCP; Ibrar Ahmed, MRCP; Abdul R. Maher, MRCP; Kulvinder Kaur, PhD; Jenny Taylor, PhD; Anke Henning, PhD; Houman Ashrafian, DPhil, MRCP; Hugh Watkins, PhD, FRCP; Michael Frenneaux, MD, FRCP
From the College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK (K.A., T.T.P., G.N.-S., I.A., A.R.M., M.F.); The Heart Hospital, University College London Hospitals, London, UK (P.E., W.M.); Wellcome Trust Centre for Human Genetics (K.K., J.T., H.W.) and Department of Cardiovascular Medicine (H.A., H.W.), University of Oxford, Oxford, UK; Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland (A.H.); and School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK (M.F.).
Correspondence to Professor Michael Frenneaux, Regius Professor of Medicine, School of Medicine and Dentistry, University of Aberdeen, Polwarth Bldg, Aberdeen, AB25 2ZD, UK. E-mail m.p.frenneaux@abdn.ac.uk
Background— Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity.
Methods and Results— Forty-six consecutive patients with symptomatic exercise limitation (peak O2 <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55±0.26 years) were randomized to perhexiline 100 mg (n=24) or placebo (n=22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by 31P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak o2, symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6±1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27±0.02 to 1.73±0.02 versus 1.29±0.01 to 1.23±0.01; P=0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11±0.008 to –0.01±0.005 versus 0.15±0.007 to 0.11±0.008 second; P=0.03). These changes were accompanied by an improvement in primary end point (peak O2) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL • kg–1 • min–1; P=0.003) and New York Heart Association class (P<0.001) (all P values ANCOVA, perhexiline versus placebo).
Conclusions— In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy.
Abstract 3 of 8
Health Services and Outcomes Research
Outcomes After Acute Myocardial Infarction in South Asian, Chinese, and White Patients
Nadia A. Khan, MD, MSc; Maja Grubisic, MSc; Brenda Hemmelgarn, MD, PhD; Karen Humphries, PhD; Kathryn M. King, PhD; Hude Quan, PhD
From the Department of Medicine (N.A.K.), Center for Health Evaluation and Outcomes Sciences (M.G.), and Division of Cardiology (K.H.), University of British Columbia, Vancouver, British Columbia, and Division of Nephrology (B.H.) and Department of Community Health Sciences (K.M.K., H.Q.), University of Calgary, Calgary, Alberta, Canada.
Correspondence to Nadia Khan, MD, MSc, CHEOS, University of British Columbia, Vancouver, Canada. E-mail nakhan@shaw.ca
Background— Cardiac mortality rates vary substantially between countries and ethnic groups. It is unclear, however, whether South Asian, Chinese, and white populations have a variable prognosis after acute myocardial infarction (AMI). To clarify this association, we compared mortality, use of revascularization procedures, and risk of recurrent AMI and hospitalization for heart failure between these ethnic groups in a universal-access healthcare system.
Methods and Results— We used a population cohort study design using hospital administrative data linked to cardiac procedure registries from British Columbia and the Calgary Health Region Area in Alberta (1994 to 2003) to identify AMI cases. Patient ethnicity was categorized using validated surname algorithms. There were 2190 South Asian, 946 Chinese, and 38479 white patients with AMI identified. There was no significant difference in use of revascularization procedures between ethnic groups at 30 d and 1 year. Short-term (30-day) mortality was higher among Chinese relative to white patients (odds ratio, 1.23; 95% confidence interval, 1.02 to 1.48). There was no significant difference in 30-day mortality between South Asian and white patients. South Asian patients had a 35% lower relative risk of long-term mortality compared with white patients (hazard ratio, 0.65; 95% confidence interval, 0.57 to 0.72). There was no significant difference in long-term mortality between Chinese and white patients. Among AMI survivors, Chinese patients had a lower risk of recurrent AMI, whereas there was no difference between South Asian and white patients.
Conclusion— The ethnic groups studied have striking differences in outcomes after AMI, with South Asian patients having significantly lower long-term mortality after AMI.
Abstract 4 of 8
Imaging
In Vivo Therapeutic Gas Delivery for Neuroprotection With Echogenic Liposomes
George L. Britton, BS; Hyunggun Kim, PhD; Patrick H. Kee, MD, PhD; Jaroslaw Aronowski, PhD; Christy K. Holland, PhD; David D. McPherson, MD; Shao-Ling Huang, MD, PhD
From the Division of Cardiology, Department of Internal Medicine (G.L.B., H.K., P.H.K., D.D.M., S.H.), and Department of Neurology (J.A.), University of Texas Health Science Center at Houston; and Department of Internal Medicine, Division of Cardiovascular Diseases, and Department of Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio (C.K.H.).
Correspondence to Shao-Ling Huang, MD, PhD, Division of Cardiology, Department of Internal Medicine, University of Texas Medical Science Center at Houston, 6431 Fannin St, MSB 1.246, Houston, TX 77030. E-mail Shaoling.Huang@uth.tmc.edu
Background— Ischemia-related neurological injury is a primary cause of stroke disability. Studies have demonstrated that xenon (Xe) may have potential as an effective and nontoxic neuroprotectant. Xe delivery is, however, hampered by lack of suitable administration methods. We have developed a pressurization-freeze method to encapsulate Xe into echogenic liposomes (Xe-ELIP) and have modulated local gas release with transvascular ultrasound exposure.
Methods and Results— Fifteen microliters of Xe were encapsulated into each 1 mg of liposomes (70% Xe and 30% argon). Xe delivery from Xe-ELIP into cells and consequent neuroprotective effects were evaluated with oxygen/glucose-deprived and control neuronal cells in vitro. Xe-ELIP were administered into Sprague-Dawley rats intravenously or intra-arterially after right middle cerebral artery occlusion. One-megahertz low-amplitude (0.18 MPa) continuous wave ultrasound directed onto the internal carotid artery triggered Xe release from circulating Xe-ELIP. Effects of Xe delivery on ischemia-induced neurological injury and disability were evaluated. Xe-ELIP delivery to oxygen/glucose-deprived neuronal cells improved cell viability in vitro and resulted in a 48% infarct volume decrease in vivo. Intravenous Xe-ELIP administration in combination with the ultrasound directed onto the carotid artery enhanced local Xe release from circulating Xe-ELIP and demonstrated 75% infarct volume reduction. This was comparable to the effect after intra-arterial administration. Behavioral tests on limb placement and grid and beam walking correlated with infarct reduction.
Conclusions— This novel methodology may provide a noninvasive strategy for ultrasound-enhanced local therapeutic gas delivery for cerebral ischemia–related injury while minimizing systemic side effects.
Abstract 5 of 8
Molecular Cardiology
Conditional Overexpression of Neuronal Nitric Oxide Synthase Is Cardioprotective in Ischemia/Reperfusion
Natalie Burkard, MSc; Tatjana Williams, PhD; Martin Czolbe, MSc; Nadja Blömer, MSc; Franziska Panther, MD; Martin Link; Daniela Fraccarollo, PhD; Julian D. Widder, MD; Kai Hu, MD; Hong Han, MD; Ulrich Hofmann, MD; Stefan Frantz, MD; Peter Nordbeck, MD; Jan Bulla, PhD; Kai Schuh, PhD; Oliver Ritter, MD
From the Department of Medicine I (N.B., T.W., M.C., N.B., F.P., M.L., D.F., J.D.W., K.H., H.H., U.H., S.F., P.N., O.R.) and Institute of Physiology (K.S.), University of Wuerzburg, Wuerzburg, Germany, and LMNO, Université de Caen, CNRS UMR 6139, France (J.B.).
Correspondence to Oliver Ritter, MD, Department of Medicine I, University of Wuerzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, Germany. E-mail Ritter_O@klinik.uni-wuerzburg.de
Background— We previously demonstrated that conditional overexpression of neuronal nitric oxide synthase (nNOS) inhibited L-type Ca2+ channels and decreased myocardial contractility. However, nNOS has multiple targets within the cardiac myocyte. We now hypothesize that nNOS overexpression is cardioprotective after ischemia/reperfusion because of inhibition of mitochondrial function and a reduction in reactive oxygen species generation.
Methods and Results— Ischemia/reperfusion injury in wild-type mice resulted in nNOS accumulation in the mitochondria. Similarly, transgenic nNOS overexpression caused nNOS abundance in mitochondria. nNOS translocation into the mitochondria was dependent on heat shock protein 90. Ischemia/reperfusion experiments in isolated hearts showed a cardioprotective effect of nNOS overexpression. Infarct size in vivo was also significantly reduced. nNOS overexpression also caused a significant increase in mitochondrial nitrite levels accompanied by a decrease of cytochrome c oxidase activity. Accordingly, O2 consumption in isolated heart muscle strips was decreased in nNOS-overexpressing nNOS+/ MHC-tTA+ mice already under resting conditions. Additionally, we found that the reactive oxygen species concentration was significantly decreased in hearts of nNOS-overexpressing nNOS+/ MHC-tTA+ mice compared with noninduced nNOS+/ MHC-tTA+ animals.
Conclusion— We demonstrated that conditional transgenic overexpression of nNOS resulted in myocardial protection after ischemia/reperfusion injury. Besides a reduction in reactive oxygen species generation, this might be caused by nitrite-mediated inhibition of mitochondrial function, which reduced myocardial oxygen consumption already under baseline conditions.
Abstract 6 of 8
Pediatric Cardiology
Pediatric Metabolic Syndrome Predicts Adulthood Metabolic Syndrome, Subclinical Atherosclerosis, and Type 2 Diabetes Mellitus but Is No Better Than Body Mass Index Alone
The Bogalusa Heart Study and the Cardiovascular Risk in Young Finns Study
Costan G. Magnussen, PhD; Juha Koskinen, BM; Wei Chen, MD, PhD; Russell Thomson, PhD; Michael D. Schmidt, PhD; Sathanur R. Srinivasan, PhD; Mika Kivimäki, PhD; Noora Mattsson, MD; Mika Kähönen, MD, PhD; Tomi Laitinen, MD, PhD; Leena Taittonen, MD, PhD; Tapani Rönnemaa, MD, PhD; Jorma S.A. Viikari, MD, PhD; Gerald S. Berenson, MD; Markus Juonala, MD, PhD; Olli T. Raitakari, MD, PhD
From the Research Center of Applied and Preventive Cardiovascular Medicine (C.G.M., J.K., N.M., M.J., O.T.R.) and the Departments of Medicine (T.R., J.S.A.V., M.J.) and Clinical Physiology (N.M., O.T.R.), University of Turku and Turku University Central Hospital, Turku, Finland; Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia (C.G.M., R.T., M.D.S.); Murdoch Children's Research Institute, Melbourne, Victoria, Australia (C.G.M.); Department of Epidemiology, Tulane Center for Cardiovascular Health, Tulane University School of Public Health and Tropical Medicine, New Orleans, La (W.C., S.R.S., G.S.B.); Department of Kinesiology, University of Georgia, Athens (M.D.S.); Department of Epidemiology and Public Health, University College London, London, UK (M. Kivimäki); Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland (M. Kähönen); Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (T.L.); Department of Pediatrics, Vaasa Central Hospital, Vaasa, Finland (L.T.); and Department of Pediatrics, University of Oulu, Oulu, Finland (L.T.).
Correspondence to Costan G. Magnussen, PhD, Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. E-mail cosmag@utu.fi
Background— The clinical utility of identifying pediatric metabolic syndrome (MetS) is controversial. This study sought to determine the status of pediatric MetS as a risk factor for adult subclinical atherosclerosis (carotid intima-media thickness [cIMT]) and type 2 diabetes mellitus (T2DM) and compare and contrast this prediction with its individual components.
Methods and Results— Using data from the population-based, prospective, observational Bogalusa Heart and Cardiovascular Risk in Young Finns studies, we examined the utility of 4 categorical definitions of youth MetS and their components in predicting adult high cIMT and T2DM among 1781 participants aged 9 to 18 years at baseline (1984 to 1988) who were then examined 14 to 27 years later (2001–2007) when aged 24 to 41 years. Youth with MetS were at 2 to 3 times the risk of having high cIMT and T2DM as adults compared with those free of MetS at youth. Risk estimates with the use of high body mass index were similar to those of MetS phenotypes in predicting adult outcomes. Comparisons of area under the receiver operating characteristic curve and net reclassification index suggested that prediction of adult MetS, high cIMT, and T2DM in adulthood with the use of youth MetS was either equivalent or inferior to classification based on high body mass index or overweight and obesity.
Conclusions— Youth with MetS are at increased risk of meaningful adult outcomes; however, the simplicity of screening for high BMI or overweight and obesity in the pediatric setting offers a simpler, equally accurate alternative to identifying youth at risk of developing adult MetS, high cIMT, or T2DM.
Abstract 7 of 8
Vascular Medicine
Enhanced External Counterpulsation Improves Peripheral Artery Flow-Mediated Dilation in Patients With Chronic Angina
A Randomized Sham-Controlled Study
Randy W. Braith, PhD; C. Richard Conti, MD; Wilmer W. Nichols, PhD; Calvin Y. Choi, MD; Matheen A. Khuddus, MD; Darren T. Beck, MS; Darren P. Casey, PhD
From the Department of Applied Physiology and Kinesiology, College of Health and Human Performance (R.W.B., D.T.B.), and Division of Cardiovascular Medicine, College of Medicine, (R.W.B., C.R.C., W.W.N., C.Y.C., M.A.K.), University of Florida, Gainesville; and Department of Anesthesiology, Mayo Clinic, Rochester, Minn (D.P.C.).
Correspondence to Randy W. Braith, PhD, Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611. E-mail rbraith@hhp.ufl.edu
Background— Mechanisms responsible for anti-ischemic benefits of enhanced external counterpulsation (EECP) remain unknown. This was the first randomized sham-controlled study to investigate the extracardiac effects of EECP on peripheral artery flow-mediated dilation.
Methods and Results— Forty-two symptomatic patients with coronary artery disease were randomized (2:1 ratio) to thirty-five 1-hour sessions of either EECP (n=28) or sham EECP (n=14). Flow-mediated dilation of the brachial and femoral arteries was performed with the use of ultrasound. Plasma levels of nitrate and nitrite, 6-keto-prostaglandin F1 , endothelin-1, asymmetrical dimethylarginine, tumor necrosis factor- , monocyte chemoattractant protein-1, soluble vascular cell adhesion molecule, high-sensitivity C-reactive protein, and 8-isoprostane were measured. EECP increased brachial (+51% versus +2%) and femoral (+30% versus +3%) artery flow-mediated dilation, the nitric oxide turnover/production markers nitrate and nitrite (+36% versus +2%), and 6-keto-prostaglandin F1 (+71% versus +1%), whereas it decreased endothelin-1 (–25% versus +5%) and the nitric oxide synthase inhibitor asymmetrical dimethylarginine (–28% versus +0.2%) in treatment versus sham groups, respectively (all P<0.05). EECP decreased the proinflammatory cytokines tumor necrosis factor- (–16% versus +12%), monocyte chemoattractant protein-1 (–13% versus +0.2%), soluble vascular cell adhesion molecule-1 (–6% versus +1%), high-sensitivity C-reactive protein (–32% versus +5%), and the lipid peroxidation marker 8-isoprostane (–21% versus +1.3%) in treatment versus sham groups, respectively (all P<0.05). EECP reduced angina classification (–62% versus 0%; P<0.001) in treatment versus sham groups, respectively.
Conclusions— Our findings provide novel mechanistic evidence that EECP has a beneficial effect on peripheral artery flow-mediated dilation and endothelial-derived vasoactive agents in patients with symptomatic coronary artery disease.
Abstract 8 of 8
Vascular Medicine
Chemokine Receptor 7 Knockout Attenuates Atherosclerotic Plaque Development
Maren Luchtefeld, PhD; Christina Grothusen, MD; Andreas Gagalick, MD; Kumaravelu Jagavelu, PhD; Harald Schuett, MD; Uwe J.F. Tietge, MD, PhD; Oliver Pabst, PhD; Karsten Grote, PhD; Helmut Drexler, MD ; Reinhold Förster, MD; Bernhard Schieffer, MD
From the Department of Cardiology and Angiology (M.L., C.B., A.G., H.S., K.G., H.D., B.S.) and Institute of Immunology (O.P., R.F.), Hannover Medical School, Hannover, Germany; Gastrointestinal Research Unit, Mayo Clinic, Rochester, Minn (K.J.); and Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (U.J.F.T.).
Correspondence to Bernhard Schieffer, MD, Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany. E-mail Schieffer.Bernhard@MH-Hannover.de
Background— Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the transition from innate to adaptive immune activation by coordinating the migration to and positioning of antigen-presenting dendritic cells and T cells in secondary lymphoid organs. More recently, it was shown that CCR7 is also responsible for T-cell migration into inflamed tissues and T-cell egress from these tissues via the afferent lymph. Thus, we investigated the influence of a systemic CCR7 deficiency on atherogenesis in atherosclerosis-prone low-density lipoprotein receptor (ldlr) knockout mice.
Methods and Results— CCR7 deficiency resulted in reduced atherosclerotic plaque development. CCR7–/– T cells showed impaired entry and exit behavior from atherosclerotic lesions. Oxidized low-density lipoprotein, a key molecule for atherogenesis with antigenic features, was used to pulse dendritic cells and to expand T cells ex vivo. Adoptive transfer of C57BL/6 wild-type T cells but not ccr7–/–-derived T cells primed with oxidized low-density lipoprotein–pulsed dendritic cells resulted in a reconstitution of atherogenesis in ccr7–/–/ldlr–/– mice.
Conclusion— These results demonstrate that both CCR7-dependent T-cell priming in secondary lymphoid organs and CCR7-dependent recirculation of T cells between secondary lymphoid organs and inflamed tissue are crucially involved in atherosclerotic plaque development.