Sanger Heart and Vascular Institute

Charlotte, NC, United States

Sanger Heart and Vascular Institute

Charlotte, NC, United States
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Katz M.G.,Sanger Heart and Vascular Institute | Fargnoli A.S.,Sanger Heart and Vascular Institute | Williams R.D.,Sanger Heart and Vascular Institute | Bridges C.R.,Sanger Heart and Vascular Institute
Therapeutic Delivery | Year: 2014

During the last two decades the fields of molecular and cellular cardiology, and more recently molecular cardiac surgery, have developed rapidly. The concept of delivering cDNA encoding a therapeutic gene to cardiomyocytes using a vector system with substantial cardiac tropism, allowing for long-term expression of a therapeutic protein, has moved from hypothesis to bench to clinical application. However, the clinical results to date are still disappointing. The ideal gene transfer method should be explored in clinically relevant animal models of heart disease to evaluate the relative roles of specific molecular pathways in disease pathogenesis, helping to validate the potential targets for therapeutic intervention. Successful clinical cardiovascular gene therapy also requires the use of nonimmunogenic cardiotropic vectors capable of expressing the requisite amount of therapeutic protein in vivo and in situ. Depending on the desired application either regional or global myocardial gene delivery is required. Cardiac-specific delivery techniques incorporating mapping technologies for regional delivery and highly efficient methodologies for global delivery should improve the precision and specificity of gene transfer to the areas of interest and minimize collateral organ gene expression. © 2014 Future Science Ltd.


Powell B.D.,Sanger Heart and Vascular Institute | Saxon L.A.,University of Southern California | Boehmer J.P.,Penn State Milton rshey Medical Center | Day J.D.,Intermountain Medical Center | And 5 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives This study sought to determine if the risk of mortality associated with inappropriate implantable cardioverter-defibrillator (ICD) shocks is due to the underlying arrhythmia or the shock itself. Background Shocks delivered from ICDs are associated with an increased risk of mortality. It is unknown if all patients who experience inappropriate ICD shocks have an increased risk of death. Methods We evaluated survival outcomes in patients with an ICD and a cardiac resynchronization therapy defibrillator enrolled in the LATITUDE remote monitoring system (Boston Scientific Corp., Natick, Massachusetts) through January 1, 2010. First shock episode rhythms from 3,809 patients who acutely survived the initial shock were adjudicated by 7 electrophysiologists. Patients with a shock were matched to patients without a shock (n = 3,630) by age at implant, implant year, sex, and device type. Results The mean age of the study group was 64 ± 13 years, and 78% were male. Compared with no shock, there was an increased rate of mortality in those who received their first shock for monomorphic ventricular tachycardia (hazard ratio [HR]: 1.65, p < 0.0001), ventricular fibrillation/polymorphic ventricular tachycardia (HR: 2.10, p < 0.0001), and atrial fibrillation/flutter (HR: 1.61, p = 0.003). In contrast, mortality after first shocks due to sinus tachycardia and supraventricular tachycardia (HR: 0.97, p = 0.86) and noise/artifact/oversensing (HR: 0.91, p = 0.76) was comparable to that in patients without a shock. Conclusions Compared with no shock, those who received their first shock for ventricular rhythms and atrial fibrillation had an increased risk of death. There was no significant difference in survival after inappropriate shocks for sinus tachycardia or noise/artifact/oversensing. In this study, the adverse prognosis after first shock appears to be more related to the underlying arrhythmia than to an adverse effect from the shock itself. © 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.


Lobdell K.W.,Sanger Heart and Vascular Institute | Stamou S.,Michigan State University | Sanchez J.A.,University of Connecticut
Surgical Clinics of North America | Year: 2012

Health-acquired infection (HAI) is defined as a localized or systemic condition resulting from an adverse reaction to the presence of infectious agents or its toxins. This article focuses on HAIs that are well studied, common, and costly (direct, indirect, and intangible). The HAIs reviewed are catheter-related bloodstream infection, ventilator-associated pneumonia, surgical site infection, and catheter-associated urinary tract infection. This article excludes discussion of Clostridium difficile infections and vancomycin-resistant Enterococcus. © 2012 Elsevier Inc.


Stone G.W.,Columbia University Medical Center | Witzenbichler B.,Charite Campus Benjamin Franklin | Weisz G.,Columbia University Medical Center | Rinaldi M.J.,Sanger Heart and Vascular Institute | And 13 more authors.
The Lancet | Year: 2013

Background The relation between platelet reactivity and stent thrombosis, major bleeding, and other adverse events after coronary artery implantation of drug-eluting stents has been incompletely characterised. We aimed to determine the relation between platelet reactivity during dual therapy with aspirin and clopidogrel and clinical outcomes after successful coronary drug-eluting stent implantation. Methods ADAPT-DES was a prospective, multicentre registry of patients successfully treated with one or more drugeluting stents and given aspirin and clopidogrel at 10-15 US and European hospitals. We assessed platelet reactivity in those patients after successful percutaneous coronary intervention using VerifyNow point-of-care assays, and assigned different cutoffs to define high platelet reactivity. The primary endpoint was definite or probable stent thrombosis; other endpoints were all-cause mortality, myocardial infarction, and clinically relevant bleeding. We did a propensity-adjusted multivariable analysis to determine the relation between platelet reactivity and subsequent adverse events. This study is registered with ClinicalTrials.gov, number NCT00638794. Findings Between Jan 7, 2008, and Sept 16, 2010, 8665 patients were prospectively enrolled at 11 sites, of which 8583 were eligible. At 1-year follow-up, stent thrombosis had occurred in 70 (0·8%) patients, myocardial infarction in 269 (3·1%), clinically relevant bleeding in 531 (6·2%), and death in 161 (1·9%) patients. High platelet reactivity on clopidogrel was strongly related to stent thrombosis (adjusted HR 2·49 [95% CI 1·43-4·31], p=0·001) and myocardial infarction (adjusted HR 1·42 [1·09-1·86], p=0·01), was inversely related to bleeding (adjusted HR 0·73 [0·61- 0·89], p=0·002), but was not related to mortality (adjusted HR 1·20 [0·85-1·70], p=0·30). High platelet reactivity on aspirin was not significantly associated with stent thrombosis (adjusted HR 1·46 [0·58-3·64], p=0·42), myocardial infarction, or death, but was inversely related to bleeding (adjusted HR 0·65 [0·43-0·99], p=0·04). Interpretation The findings from this study emphasise the counter-balancing effects of haemorrhagic and ischaemic complications after stent implantation, and suggest that safer drugs or tailored strategies for the use of more potent agents must be developed if the benefits of greater platelet inhibition in patients with cardiovascular disease are to be realised.


Glower D.D.,Duke University | Kar S.,Cedars Sinai Medical Center | Trento A.,Cedars Sinai Medical Center | Lim D.S.,University of Virginia | And 11 more authors.
Journal of the American College of Cardiology | Year: 2014

Background The EVEREST II (Endovascular Valve Edge-to-Edge REpair STudy) High-Risk registry and REALISM Continued Access Study High-Risk Arm are prospective registries of patients who received the MitraClip device (Abbott Vascular, Santa Clara, California) for mitral regurgitation (MR) in the United States. Objectives The purpose of this study was to report 12-month outcomes in high-risk patients treated with the percutaneous mitral valve edge-to-edge repair. Methods Patients with grades 3 to 4+ MR and a surgical mortality risk of ≥12%, based on the Society of Thoracic Surgeons risk calculator or the estimate of a surgeon coinvestigator following pre-specified protocol criteria, were enrolled. Results In the studies, 327 of 351 patients completed 12 months of follow-up. Patients were elderly (76 ± 11 years of age), with 70% having functional MR and 60% having prior cardiac surgery. The mitral valve device reduced MR to ≤2+ in 86% of patients at discharge (n = 325; p < 0.0001). Major adverse events at 30 days included death in 4.8%, myocardial infarction in 1.1%, and stroke in 2.6%. At 12 months, MR was ≤2+ in 84% of patients (n = 225; p < 0.0001). From baseline to 12 months, left ventricular (LV) end-diastolic volume improved from 161 ± 56 ml to 143 ± 53 ml (n = 203; p < 0.0001) and LV end-systolic volume improved from 87 ± 47 ml to 79 ± 44 ml (n = 202; p < 0.0001). New York Heart Association functional class improved from 82% in class III/IV at baseline to 83% in class I/II at 12 months (n = 234; p < 0.0001). The 36-item Short Form Health Survey physical and mental quality-of-life scores improved from baseline to 12 months (n = 191; p < 0.0001). Annual hospitalization rate for heart failure fell from 0.79% pre-procedure to 0.41% post-procedure (n = 338; p < 0.0001). Kaplan-Meier survival estimate at 12 months was 77.2%. Conclusions The percutaneous mitral valve device significantly reduced MR, improved clinical symptoms, and decreased LV dimensions at 12 months in this high-surgical-risk cohort. (Endovascular Valve Edge-to-Edge REpair STudy [EVERESTIIRCT]; NCT00209274). © 2014 By The American College of Cardiology Foundation Published By Elsevier Inc.


Stamou S.C.,University of Iowa | Williams M.L.,University of Louisville | Gunn T.M.,University of Iowa | Hagberg R.C.,Hartford Hospital | And 2 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2015

Objective: The purpose of the present study was to evaluate the early clinical outcomes of aortic root surgery in the United States. Methods: The Society of Thoracic Surgeons database was queried to identify all patients who had undergone aortic root replacement from 2004 to early 2010 (n = 13,743). The median age was 58 years (range, 18-96); 3961 were women (29%) and 12,059 were white (88%). The different procedures included placement of a mechanical valve conduit (n = 4718, 34%), stented pericardial (n = 879, 6.4%) or porcine (n = 478, 3.5%) bioprosthesis, stentless root (n = 4309, 31%), homograft (n = 498, 3.6%), and valve sparing root replacement (n = 1918, 14%). Results: The median number of aortic root surgeries per site was 2, and only 5%of sites performed>16 aortic root surgeries annually. An increased trend to use biostented (porcine or pericardial) valves during the study period (7%in 2004 vs 14%in 2009). The operative (raw) mortality was greater among the patients with aortic stenosis (6.2%) who had undergone aortic root replacement, independent of age. Mortality was greater in patients who had undergone concomitant valve or coronary artery bypass grafting or valve surgery (21%). The lowest operative mortality was observed in patients who had undergone aortic valve sparing procedures (1.9%). Conclusions: Most cardiac centers performed aortic root surgery in small volumes. The unadjusted operative mortality was greater for patients>80 years old and those with aortic stenosis, regardless of age. Valve sparing root surgery was associated with the lowest mortality. A trend was seen toward an increased use of stented tissue valves from 2004 to 2009. Copyright © 2015 by The American Association for Thoracic Surgery.


Robicsek F.,Sanger Heart and Vascular Institute | Watts L.T.,Sanger Heart and Vascular Institute
Thoracic Surgery Clinics | Year: 2010

Pectus carinatum or keel chest is a spectrum of progressive inborn anomalies of the anterior chest wall, named after the keel (carina) of ancient Roman ships. It defines a wide spectrum of inborn protrusion anomalies of the sternum and/or the adjacent costal cartilages. Pectus carinatum is often associated with various conditions, notably Marfan disease, homocystinuria, prune belly, Morquio syndrome, osteogenesis imperfecta, Noonan syndrome, and mitral valve prolapse. Treatment of pectus carinatum by nonsurgical methods such as exercise and casting has not been worthwhile, whereas surgical management is simple and successful. © 2010 Elsevier Inc.


Johnson T.V.,Sanger Heart and Vascular Institute | Symanski J.D.,Sanger Heart and Vascular Institute | Patel S.R.,Sanger Heart and Vascular Institute | Rose G.A.,Sanger Heart and Vascular Institute
Journal of the American Society of Echocardiography | Year: 2011

Background: The aim of this study was to demonstrate improvement in the characterization of diastolic function in the routine practice of a clinical echocardiography laboratory after the implementation of a quality improvement initiative. The echocardiographic analysis of left ventricular (LV) diastolic dysfunction is an inherently complex process involving the integration of multiple indices for accurate assessment. Methods: A baseline survey of 50 randomly chosen echocardiographic studies was reviewed for the accuracy of diastolic function assessment. A four-step quality improvement protocol was then initiated: (1) sonographer and physician education; (2) the implementation of data acquisition protocol changes using LV inflow, tissue Doppler velocity of the mitral annulus in early diastole (e′), flow propagation velocity of LV inflow (Vp), and left atrial volume index (LAVI), along with the establishment of uniform criteria for diagnostic interpretation; (3) peer review of performance; and (4) focused interactive case review sessions. Results: At baseline, measurements of LV inflow were most often correct (100% accurate), while measurements of e′ (82% accurate), Vp (12% accurate), and LAVI (12% accurate) and the proper classification of diastolic function (44% accurate) were significantly limited. After the quality improvement initiative, there were significant increases in the accuracy of all recorded measurements, with e′ 92% accurate (a 10% improvement; P <.10), Vp 67% accurate (a 55% improvement; P <.001), LAVI 80% accurate (a 68% improvement, P <.001), and proper characterization of diastolic function 76% accurate (a 32% improvement, P <.001). Conclusions: A multifaceted quality improvement protocol including staff education, systematic support with enhanced infrastructure, and peer review with feedback can be effective for improving the clinical performance of a nonacademic echocardiography laboratory in the characterization of diastolic function. © 2011 by the American Society of Echocardiography.


Katz M.G.,Sanger Heart and Vascular Institute | Fargnoli A.S.,Sanger Heart and Vascular Institute | Bridges C.R.,Sanger Heart and Vascular Institute
Human Gene Therapy | Year: 2013

Heart diseases are major causes of morbidity and mortality in Western society. Gene therapy approaches are becoming promising therapeutic modalities to improve underlying molecular processes affecting failing cardiomyocytes. Numerous cardiac clinical gene therapy trials have yet to demonstrate strong positive results and advantages over current pharmacotherapy. The success of gene therapy depends largely on the creation of a reliable and efficient delivery method. The establishment of such a system is determined by its ability to overcome the existing biological barriers, including cellular uptake and intracellular trafficking as well as modulation of cellular permeability. In this article, we describe a variety of physical and mechanical methods, based on the transient disruption of the cell membrane, which are applied in nonviral gene transfer. In addition, we focus on the use of different physiological techniques and devices and pharmacological agents to enhance endothelial permeability. Development of these methods will undoubtedly help solve major problems facing gene therapy. © Copyright 2013, Mary Ann Liebert, Inc.


Katz M.G.,Sanger Heart and Vascular Institute | Fargnoli A.S.,Sanger Heart and Vascular Institute | Williams R.D.,Sanger Heart and Vascular Institute | Bridges C.R.,Sanger Heart and Vascular Institute
Human Gene Therapy | Year: 2013

Gene therapy is one of the most promising fields for developing new treatments for the advanced stages of ischemic and monogenetic, particularly autosomal or X-linked recessive, cardiomyopathies. The remarkable ongoing efforts in advancing various targets have largely been inspired by the results that have been achieved in several notable gene therapy trials, such as the hemophilia B and Leber's congenital amaurosis. Rate-limiting problems preventing successful clinical application in the cardiac disease area, however, are primarily attributable to inefficient gene transfer, host responses, and the lack of sustainable therapeutic transgene expression. It is arguable that these problems are directly correlated with the choice of vector, dose level, and associated cardiac delivery approach as a whole treatment system. Essentially, a delicate balance exists in maximizing gene transfer required for efficacy while remaining within safety limits. Therefore, the development of safe, effective, and clinically applicable gene delivery techniques for selected nonviral and viral vectors will certainly be invaluable in obtaining future regulatory approvals. The choice of gene transfer vector, dose level, and the delivery system are likely to be critical determinants of therapeutic efficacy. It is here that the interactions between vector uptake and trafficking, delivery route means, and the host's physical limits must be considered synergistically for a successful treatment course. © 2013, Mary Ann Liebert, Inc.

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