circulation2011-02-01

Abstract 1 of 8
Arrhythmia/Electrophysiology
Longevity of Sprint Fidelis Implantable Cardioverter-Defibrillator Leads and Risk Factors for Failure
Implications for Patient Management
Robert G. Hauser, MD; William H. Maisel, MD, MPH; Paul A. Friedman, MD; Linda M. Kallinen, BS; Andrew S. Mugglin, PhD; Kapil Kumar, MD; David O. Hodge, MS; Thomas B. Morrison, MD; David L. Hayes, MD
From the Minneapolis Heart Institute Foundation, Minneapolis, MN (R.G.H., L.M.K.); Mayo Clinic, Rochester, MN (P.A.F., D.O.H., T.B.M., D.L.H.); Beth Israel Deaconess Medical Center, Boston, MA (W.H.M., K.K.); and University of Minnesota (Biostatistics), Minneapolis (A.M.).
Correspondence to Robert G. Hauser, MD, FACC, FHRS, Minneapolis Heart Institute Foundation, 920 E 28th St, Ste 300, Minneapolis, MN 55407. E-mail rhauser747@aol.com .
Background— Sprint Fidelis (Fidelis) implantable cardioverter-defibrillator leads are prone to fractures that have caused adverse events, primarily inappropriate shocks, and a few reported deaths. More than 100 000 patients have Fidelis leads. No independent multicenter long-term performance information exists for this lead, and single-center studies suggest that certain patients are at increased risk for Fidelis failure. Our aim was to assess the longevity of Fidelis leads and to evaluate clinical variables and adverse events associated with Fidelis failure. The results were compared with like data for Quattro Secure (Quattro) implantable cardioverter-defibrillator leads implanted at our centers.
Methods and Results— This 3-center study included adults 18 years of age who received Fidelis or Quattro leads for the prevention of sudden cardiac death. From November 2001 to January 2009,1023 Fidelis and 1668 Quattro leads were implanted and followed up. The failure rate for Fidelis leads was 2.81%/y compared with 0.43%/y for Quattro leads (P<0.0001). No deaths or injuries occurred as a result of lead failure, but 42% of fractures caused inappropriate shocks. The survival of Fidelis leads at 4 years was 87.0% (95% confidence interval, 83.6 to 90.1) compared with 98.7% (95% confidence interval, 97.9 to 99.4) for Quattro leads (P<0.0001). Multivariate predictors of Fidelis failure were younger age (hazard ratio, 0.98; 95% confidence interval, 0.96 to 0.99), female gender (hazard ratio, 0.61; 95% confidence interval, 0.40 to 1.00), and cardiac disease (P=0.041).
Conclusions— Compared with Quattro leads, the survival of Fidelis leads continues to decline, and Fidelis failure is notably higher in younger patients, women, individuals with hypertrophic cardiomyopathy, and patients with arrhythmogenic right ventricular dysplasia or channelopathies. These findings have significant implications for the management of patients who have Fidelis leads, and they demonstrate the importance of weighing clinical variables in assessments of implantable cardioverter-defibrillator lead performance.
Abstract 2 of 8
Congenital Heart Disease
Characterization and Functionality of Cardiac Progenitor Cells in Congenital Heart Patients
Rachana Mishra, PhD*; Kalpana Vijayan, PhD*; Evan J. Colletti, PhD; Daniel A. Harrington, PhD; Thomas S. Matthiesen, BS; David Simpson, PhD; Saik Kia Goh, BS; Brandon L. Walker, MS; Gra?a Almeida-Porada, MD, PhD; Deli Wang, MD, PhD; Carl L. Backer, MD; Samuel C. Dudley, Jr, MD; Loren E. Wold, PhD; Sunjay Kaushal, MD, PhD
From the Division of Cardiovascular-Thoracic Surgery, Children's Memorial Hospital, Chicago, IL (R.M., K.V., D.A.H., T.S.M., D.S., S.K.G., B.L.W., D.W., C.L.B., S.K.); Northwestern University Feinberg School of Medicine, Chicago, IL (C.L.B., S.K.); Department of Animal Biotechnology, University of Nevada, Reno (E.J.C., G.A.-P), Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago (S.C.D.); and Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH (L.E.W.).
Correspondence to Dr Sunjay Kaushal, Children's Memorial Hospital, Division of Cardiovascular-Thoracic Surgery, 2300 Children's Plaza, mc 22, Chicago, IL 60614. E-mail skaushal@childrensmemorial.org
Background— Human cardiac progenitor cells (hCPCs) may promote myocardial regeneration in adult ischemic myocardium. The regenerative capacity of hCPCs in young patients with nonischemic congenital heart defects for potential use in congenital heart defect repair warrants exploration.
Methods and Results— Human right atrial specimens were obtained during routine congenital cardiac surgery across 3 groups: neonates (age, <30 days), infants (age, 1 month to 2 years), and children (age, >2 to 13 years). C-kit+ hCPCs were 3-fold higher in neonates than in children >2 years of age. hCPC proliferation was greatest during the neonatal period as evidenced by c-kit+ Ki67+ expression but decreased with age. hCPC differentiation capacity was also greatest in neonatal right atrium as evidenced by c-kit+, NKX2–5+, NOTCH1+, and NUMB+ expression. Despite the age-dependent decline in resident hCPCs, we isolated and expanded right atrium–derived CPCs from all patients (n=103) across all ages and diagnoses using the cardiosphere method. Intact cardiospheres contained a mix of heart-derived cell subpopulations that included cardiac progenitor cells expressing c-kit+, Islet-1, and supporting cells. The number of c-kit+–expressing cells was highest in human cardiosphere-derived cells (hCDCs) grown from neonatal and infant right atrium. Furthermore, hCDCs could differentiate into diverse cardiovascular lineages by in vitro differentiation assays. Transplanted hCDCs promoted greater myocardial regeneration and functional improvement in infarcted myocardium than transplanted cardiac fibroblasts.
Conclusions— Resident hCPCs are most abundant in the neonatal period and rapidly decrease over time. hCDCs can be reproducibly isolated and expanded from young human myocardial samples regardless of age or diagnosis. hCPCs are functional and have potential in congenital cardiac repair.
Abstract 3 of 8
Genetics
Genetic Risk Score and Risk of Myocardial Infarction in Hispanics
Lu Qi, MD, PhD; Jiantao Ma, MD; Qibin Qi, PhD; Jaana Hartiala, MS; Hooman Allayee, PhD; Hannia Campos, PhD
From the Department of Nutrition, Harvard School of Public Health, Boston, MA (L.Q., J.M., Q.Q., H.C.); Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (L.Q.); and Department of Preventive Medicine and Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, CA (J.H., H.A.).
Reprint requests to Dr Hannia Campos or Dr Lu Qi, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115. E-mail hcampos@hsph.harvard.edu or nhlqi@channing.harvard.edu
Background— Genome-wide association studies have identified loci associated with coronary heart disease in whites of European ancestry. This study evaluated whether genetic markers previously identified in whites are associated with nonfatal acute myocardial infarction (MI) in Hispanics.
Methods and Results— Cases (n=1989) with a first nonfatal acute MI and population-based controls (n=2096) living in Costa Rica were studied. Fourteen single-nucleotide polymorphisms were genotyped. Seven single-nucleotide polymorphisms at 3 independent loci showed significant associations with MI. The odds ratios for the loci with the strongest associations were 1.16 (95 confidence interval [CI], 1.05 to 1.27) for rs4977574 (CDKN2A/2B), 1.15 (95 CI, 1.03 to 1.29) for rs646776 (CELSR2-PSRC1-SORT1), and 1.22 (95 CI, 1.08 to 1.38) for rs501120 (CXCL12); the corresponding PARs were 6.8, 10.5, and 15.2; respectively. We developed a genetic risk score by summing the number of the top 3 associated risk alleles. The OR for MI per genetic risk score unit was 1.18 (95 CI, 1.11 to 1.25; P=4.83x10–8). Discrimination of MI was significantly improved (P=0.02) when the genetic risk score was added to a model including clinical predictors. However, the increase in the area under the receiver-operating characteristic curve after the genetic risk score was added was moderate, from 0.67 (95 CI, 0.65 to 0.69) to 0.68 (95 CI, 0.66 to 0.70).
Conclusions— These results indicate both the consistency and disparity of genetic effects on risk of MI between Hispanic and white populations. The improvement in the identified genetic markers on discrimination of MI in Hispanics was modest.
Abstract 4 of 8
Heart Failure
Reversal of Severe Heart Failure With a Continuous-Flow Left Ventricular Assist Device and Pharmacological Therapy
A Prospective Study
Emma J. Birks, FRCP, PhD; Robert S. George, BSc, BM, MRCS; Mike Hedger, RN; Toufan Bahrami, FRCS; Penny Wilton, FRACS; Christopher T. Bowles, PhD; Carole Webb, BSc; Robert Bougard, BSc; Mohammed Amrani, FRCS; Magdi H. Yacoub, FRS; Gilles Dreyfus, FRCS; Asghar Khaghani, FRCS
From the Royal Brompton and Harefield NHS Foundation Trust (E.J.B., R.S.G., M.H., T.B., P.W., C.T.B., C.W., R.B., M.A., G.D., A.K.) and Heart Science Centre, Imperial College (E.J.B., R.S.G., C.T.B., M.H.Y.), Harefield, Middlesex, UK, and University of Louisville, Louisville, KY (E.J.B.).
Correspondence to Emma Birks, FRCP, PhD, Professor of Medicine, Medical Director of Heart Failure, Transplantation and Mechanical Support, University of Louisville, 201 Abraham Flexner Way, Ste 1200, Louisville, KY 40222. E-mail e.birks@imperial.ac.uk
Background— We have previously shown that a specific combination of drug therapy and left ventricular assist device unloading results in significant myocardial recovery, sufficient to allow pump removal, in two thirds of patients with dilated cardiomyopathy receiving a Heartmate I pulsatile device. However, this protocol has not been used with nonpulsatile devices.
Methods and Results— We report the results of a prospective study of 20 patients who received a combination of angiotensin-converting enzymes, β-blockers, angiotensin II inhibitors, and aldosterone antagonists followed by the β2-agonist clenbuterol and were regularly tested (echocardiograms, exercise tests, catheterizations) with the pump at low speed. Before left ventricular assist device insertion, patient age was 35.2±12.6 years (16 male patients), patients were on 2.0±0.9 inotropes, 7 (35) had an intra-aortic balloon pump, 2 were hemofiltered, 2 were ventilated, 3 had a prior Levitronix device, and 1 had extracorporeal membrane oxygenation. Cardiac index was 1.39±0.43 L ? min–1 ? m–2, pulmonary capillary wedge pressure was 31.5±5.7 mm Hg, and heart failure history was 3.4±3.5 years. One patient was lost to follow-up and died after 240 days of support. Of the remaining 19 patients, 12 (63.2) were explanted after 286±97 days. Eight had symptomatic heart failure for 6 months and 4 for >6 months (48 to 132 months). Before explantation, at low flow for 15 minutes, ejection fraction was 70±7, left ventricular end-diastolic diameter was 48.6±5.7 mm, left ventricular end-systolic diameter was 32.3±5.7 mm, m O2 was 21.6±4 mL ? kg–1 ? min–1, pulmonary capillary wedge pressure was 5.9±4.6 mm Hg, and cardiac index was 3.6±0.6 L ? min–1 ? m–2. Estimated survival without heart failure recurrence was 83.3 at 1 and 3 years. After a 430.7±337.1-day follow-up, surviving explants had an ejection fraction of 58.1±13.8, left ventricular end-diastolic diameter of 59.0±9.3 mm, left ventricular end-systolic diameter of 42.0±10.7 mm, and m O2 of 22.6±5.3 mL ? kg–1 ? min–1.
Conclusions— Reversal of end-stage heart failure secondary to nonischemic cardiomyopathy can be achieved in a substantial proportion of patients with nonpulsatile flow through the use of a combination of mechanical and pharmacological therapy.
Abstract 5 of 8
Heart Failure
Distinct Effects of Leukocyte and Cardiac Phosphoinositide 3-Kinase Activity in Pressure Overload–Induced Cardiac Failure
Federico Damilano, PhD*; Irene Franco, BSc*; Cinzia Perrino, MD,, PhD; Katrin Schaefer, MD; Ornella Azzolino, BSc; Daniela Carnevale, PhD; Giuseppe Cifelli, BSc; Pierluigi Carullo, BSc; Riccardo Ragona, PhD; Alessandra Ghigo, BSc; Alessia Perino, BSc; Giuseppe Lembo, MD, PhD; Emilio Hirsch, PhD
From the Department of Genetics, Biology, and Biochemistry and Molecular Biotechnology Center, University of Torino, Torino, Italy (F.D., I.F., O.A., A.G., A.P., E.H.); Department of Angio-Cardio-Neurology, IRCCS Neuromed, Pozzilli, Italy (C.P., D.C., G.C., P.C., G.L.); Department of Cardiology and Pulmonology, University of Goettingen, Goettingen, Germany (K.S.); Department of Medical and Surgical Sciences, Radiation Oncology Unit, University of Torino, S. Giovanni Battista Hospital, Torino, Italy (R.R.); and Department of Molecular Medicine, Sapienza University, Rome, Italy (G.L.).
Correspondence to Emilio Hirsch, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy (E-mail emilio.hirsch@unito.it ); or Giuseppe Lembo, Sapienza University of Rome and Department of Angio-Cardio-Neurology, Neuromed Institute IRCCS, Loc Camerelle, 86077 Pozzilli (IS), Italy (E-mail lembo@neuromed.it ).
Background— Signaling from phosphoinositide 3-kinase (PI3K ) is crucial for leukocyte recruitment and inflammation but also contributes to cardiac maladaptive remodeling. To better understand the translational potential of these findings, this study investigates the role of PI3K activity in pressure overload–induced heart failure, addressing the distinct contributions of bone marrow–derived and cardiac cells.
Methods and Results— After transverse aortic constriction, mice knock-in for a catalytically inactive PI3K (PI3K KD) showed reduced fibrosis and normalized cardiac function up to 16 weeks. Accordingly, treatment with a selective PI3K inhibitor prevented transverse aortic constriction–induced fibrosis. To define the cell types involved in this protection, bone marrow chimeras, lacking kinase activity in the immune system or the heart, were studied after transverse aortic constriction. Bone marrow–derived cells from PI3K KD mice were not recruited to wild-type hearts, thus preventing fibrosis and preserving diastolic function. After prolonged pressure overload, chimeras with PI3K KD bone marrow–derived cells showed slower development of left ventricular dilation and higher fractional shortening than controls. Conversely, in the presence of a wild-type immune system, KD hearts displayed bone marrow–derived cell infiltration and fibrosis at early stages but reduced left ventricular dilation and preserved contractile function at later time points.
Conclusions— Together, these data demonstrate that, in response to transverse aortic constriction, PI3K contributes to maladaptive remodeling at multiple levels by modulating both cardiac and immune cell functions.
Abstract 6of 8
Heart Failure
Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction
Daniela Fraccarollo, PhD; Stefan Berger, PhD; Paolo Galuppo, PhD; Susanne Kneitz, PhD; Lutz Hein, MD; Günther Schütz, PhD; Stefan Frantz, MD; Georg Ertl, MD; Johann Bauersachs, MD
From the Klinik fuer Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover (D.F., P.G., J.B.); Medizinische Klinik und Poliklinik I, Universit?tsklinikum, Wuerzburg (D.F., P.G., S.F., G.E.); Klinik fuer Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover (D.F., P.G., J.B.); Deutsches Krebsforschungszentrum, Heidelberg (S.B., G.S.); Institut fuer Virologie and Immunbiologie, Universitaetsklinikum, Wuerzburg (S.K.); and Institut fuer Experimentelle und Klinische Pharmakologie und Toxikologie, Freiburg (L.H.), Germany.
Correspondence to Prof Dr Johann Bauersachs, Klinik fuer Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30175 Hannover, Germany. E-mail bauersachs.johann@mh-hannover.de
Background— Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MRMLCCre) that were generated with a conditional MR allele (MRflox) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter.
Methods and Results— Control (MRflox/flox, MRflox/wt) and MRMLCCre mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MRMLCCre mice. Chronically infarcted MRMLCCre mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O2?– production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MRMLCCre mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor- B and reduced apoptosis early after myocardial infarction.
Conclusion— Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression.
Abstract 7 of 8
Interventional Cardiology
Associations Between Acute Kidney Injury and Cardiovascular and Renal Outcomes After Coronary Angiography
Matthew T. James, MD; William A. Ghali, MD, MPH; Merril L. Knudtson, MD; Pietro Ravani, MD, PhD; Marcello Tonelli, MD, SM; Peter Faris, PhD; Neesh Pannu, MD, MSc; Braden J. Manns, MD, MSc; Scott W. Klarenbach, MD, MSc; Brenda R. Hemmelgarn, MD, PhD, for the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) Investigators
From the Departments of Medicine (M.T.J., M.L.K., P.R., B.J.M., B.R.H.) and Community Health Sciences (M.T.J., W.A.G., M.L.K., P.R., P.F., B.J.M., B.R.H.), University of Calgary, Calgary; Department of Medicine, University of Alberta, Edmonton (M.T., N.P., S.W.K.); and Institute of Health Economics, Edmonton (M.T., B.J.M., S.W.K.), Alberta, Canada.
Correspondence to Dr Matthew T. James, Foothills Medical Centre, 1403 29th St NW, Calgary, Alberta T2N 2T9 Canada. E-mail mjames@ucalgary.ca .
Background— Acute kidney injury (AKI) is associated with early mortality after percutaneous coronary revascularization procedures, but its prognostic relevance to long-term clinical outcomes remains controversial.
Methods and Results— We conducted a retrospective study of 14 782 adults who received coronary angiography in the province of Alberta, Canada, between 2004 and 2006. AKI was identified on the basis of changes in serum creatinine concentration within 7 days of the procedure according to AKI Network criteria. The associations between AKI and long-term outcomes, including mortality, end-stage renal disease, and cardiovascular and renal hospitalizations, were studied with the use of Cox regression of multiple failure times. The adjusted risk of death increased with increasing severity of AKI; compared with no AKI, the adjusted hazard ratio for death was 2.00 (95% confidence interval, 1.69 to 2.36) with stage 1 AKI and 3.72 (95% confidence interval, 2.92 to 4.76) with stage 2 or 3 AKI. The adjusted risk of end-stage renal disease requiring renal replacement therapy also increased according to the severity of AKI (hazard ratio, 4.15 [95% confidence interval, 2.32 to 7.42] and 11.74 [95% confidence interval, 6.38 to 21.59], respectively), as did the risks of subsequent hospitalizations for heart failure and acute renal failure.
Conclusions— These findings inform the controversy surrounding AKI after angiography, demonstrating that it is a significant risk factor for long-term mortality, end-stage renal disease, and hospitalization for cardiovascular and renal events after coronary angiography.
Abstract 8 of 8
Interventional Cardiology
Safety of Percutaneous Left Atrial Appendage Closure
Results From the Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF (PROTECT AF) Clinical Trial and the Continued Access Registry
Vivek Y. Reddy, MD; David Holmes, MD; Shephal K. Doshi, MD; Petr Neuzil, MD, PhD; Saibal Kar, MD
From the Mount Sinai School of Medicine, New York, NY (V.Y.R.); Homolka Hospital, Prague, Czech Republic (V.Y.R., P.N.); St John's Health Center, Santa Monica, CA (V.Y.R., S.K.D.); Mayo Clinic, Rochester, MN (D.H.); and Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA (S.K.).
Correspondence to Vivek Y. Reddy, MD, Helmsley Electrophysiology Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY 10029. E-mail vivek.reddy@mountsinai.org
Background— The Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF (PROTECT AF) randomized trial compared left atrial appendage closure against warfarin in atrial fibrillation (AF) patients with CHADS2 1. Although the study met the primary efficacy end point of being noninferior to warfarin therapy for the prevention of stroke/systemic embolism/cardiovascular death, there was a significantly higher risk of complications, predominantly pericardial effusion and procedural stroke related to air embolism. Here, we report the influence of experience on the safety of percutaneous left atrial appendage closure.
Methods and Results— The study cohort for this analysis included patients in the PROTECT AF trial who underwent attempted device left atrial appendage closure (n=542 patients) and those from a subsequent nonrandomized registry of patients undergoing Watchman implantation (Continued Access Protocol [CAP] Registry; n=460 patients). The safety end point included bleeding- and procedure-related events (pericardial effusion, stroke, device embolization). There was a significant decline in the rate of procedure- or device-related safety events within 7 days of the procedure across the 2 studies, with 7.7% and 3.7% of patients, respectively, experiencing events (P=0.007), and between the first and second halves of PROTECT AF and CAP, with 10.0%, 5.5%, and 3.7% of patients, respectively, experiencing events (P=0.006). The rate of serious pericardial effusion within 7 days of implantation, which had made up >50% of the safety events in PROTECT AF, was lower in the CAP Registry (5.0% versus 2.2%, respectively; P=0.019). There was a similar experience-related improvement in procedure-related stroke (0.9% versus 0%, respectively; P=0.039). Finally, the functional impact of these safety events, as defined by significant disability or death, was statistically superior in the Watchman group compared with the warfarin group in PROTECT AF. This remained true whether significance was defined as a change in the modified Rankin score of 1, 2, or 3 (1.8 versus 4.3 events per 100 patient-years; relative risk, 0.43; 95% confidence interval, 0.24 to 0.82; 1.5 versus 3.7 events per 100 patient-years; relative risk, 0.41; 95% confidence interval, 0.22 to 0.82; and 1.4 versus 3.3 events per 100 patient-years; relative risk, 0.43; 95% confidence interval, 0.22 to 0.88, respectively).
Conclusion— As with all interventional procedures, there is a significant improvement in the safety of Watchman left atrial appendage closure with increased operator experience.