Methods

ICE-PCS. Data for this investigation were obtained from the ICE-PCS, as detailed elsewhere [6, 7]. Established in 1999, this collaboration has enrolled >3000 patients from 61 centers in 28 countries.

All patients with IE from centers that met criteria for participation were included in this study. These criteria included the following: (1) minimum enrollment of 12 patients per year in a center with access to cardiac surgery, (2) patient identification procedures to ensure consecutive enrollment and to minimize ascertainment bias [7], (3) high quality data with query resolution, and (4) institutional review board and/or ethics committee approval or waiver, based on local standards. The ICE-PCS database is maintained at the coordinating center (Duke Clinical Research Institute; Durham, NC) for ICE studies.

Patient selection. Patients were enrolled in ICE-PCS if they met criteria for possible or definite IE, based on modified Duke criteria [8]. In the current investigation, only adult patients with definite NVE and no history of injection drug use were included. Specifically, patients with NVE due to CoNS were required to have either of the following: 2 blood cultures positive for CoNS separated by 12 h, at least 3 blood cultures positive for CoNS, or a valve culture positive for CoNS. Only patients with pure blood cultures positive for CoNS were included. Of the patients with a pacemaker and/or implantable defibrillator, only those who had evidence of valvular infection (rather than solely lead infection) were included.

Data collection. A standard case report form was used at all sites to collect data. The case report form included 275 variables and was developed by ICE according to standard definitions [7]. Specific data domains, the collection process, and query reconciliation have been described previously [6].

Definitions. Long-term immunosuppressive therapy was defined as the administration of recognized immunosuppressive agents (including oral corticosteroids or agents used in solid organ transplantation or for rheumatologic disorders) for >30 days at the time of IE diagnosis. Other chronic illness was defined as chronic comorbidities other than diabetes mellitus and hemodialysis dependence (e.g., coronary artery disease, chronic obstructive pulmonary disease, and cirrhosis). Vascular evidence of IE was defined as conjunctival hemorrhages, vascular embolic events, or Janeway lesions [9]. Immunologic evidence of IE was defined as the presence of Osler nodes or Roth spots [9]. Heart murmurs were defined as present or absent according to the physical examination performed by the investigators at the time of initial evaluation. A stroke was defined as an acute neurological deficit of vascular etiology lasting >24 h. Congestive heart failure was defined according to the New York Heart Association classification system [10].

Health care-associated (HCA) IE was defined as either nosocomial infection or nonnosocomial HCA infection. Nosocomial infection was defined as IE developing in a patient hospitalized for >48 h prior to the onset of IE signs and symptoms. Nonnosocomial HCA infection was defined as IE diagnosed within 48 h of hospital admission in a patient with extensive health care contact, as represented by any of the following: (1) receipt of intravenous therapy, wound care, or specialized nursing care at home within the 30 days before the onset of IE; (2) attendance in a hospital or hemodialysis clinic within the 30 days before the onset of IE; (3) hospitalization in an acute care hospital for ⩾2 days in the 90 days before the onset of IE; or (4) residence in a nursing home or long-term care facility [11]. Community-acquired (CA) IE was defined as IE diagnosed within 48 h after hospital admission in a patient not fulfilling the criteria for HCA infection.

Geographic region. Geographic regions participating in ICE included the following: United States (10 sites), South America (9 sites), Europe (25 sites), Australia and New Zealand (9 sites), Asia and the Middle East (7 sites), and South Africa (1 site).

Speciation, antibiotic susceptibilities, and choice of antibiotic therapy. Speciation and antibiotic susceptibilities for the CoNS isolates were performed at individual ICE sites according to the procedures of the site-specific microbiology laboratories. These results were reported on the standard case report form. Data on antibiotic therapy was decided by the individual ICE site investigator or treating physician.

Statistical analysis. Descriptive statistics are presented as medians with interquartile range for continuous variables and as frequencies with percentages for categorical variables. The Wilcoxon rank-sum test or the χtest was used, as appropriate, for bivariable comparisons, with adjustment for confounding by sites. Multivariable logistic regression analysis was used to determine factors associated with mortality among patients with native valve IE due to CoNS. A generalized estimating equation method was used to account for correlation in outcomes in patients from the same hospital. Variables that were considered for the final model included demographic characteristics, comorbid conditions, surgery, and clinical complications. The variables included in the final adjusted regression model were selected on the basis of a combination of statistical significance (P<.05) and clinical relevance. Final parameter estimates were converted to ORs with corresponding 95% Wald CIs. The c index was used to measure the ability of the model to predict outcome. For all tests, statistical significance was determined at P<.05. All statistical analyses were performed using SAS software, version 8.2 (SAS Institute).

Results

From June 2000 through August 2006, 1635 patients from 61 centers in 28 countries who had no history of injection drug use received a diagnosis of definite NVE and were enrolled in ICE-PCS. Of these patients, 128 (7.8%) had NVE due to CoNS. The median age of patients with NVE due to CoNS was 63 years (interquartile range, 46–72 years), the median age of patients with NVE due to S. aureus was 61 years (interquartile range, 49–74 years; P=.32), and the median age of patients with NVE due to viridans group streptococci (VGS) was 57 years (interquartile range, 41–70 years; P=.19).

Speciation and antimicrobial susceptibilities. CoNS speciation was available for 93 isolates (73%). The majority of these isolates were Staphylococcus epidermidis (74 isolates [80%]), followed by nonepidermidis CoNS (19 [20%]). Antimicrobial susceptibility to methicillin was available for 97 CoNS isolates (76%); of these isolates, 40 (41%) were methicillin resistant.

Clinical features. Prolonged symptom duration (i.e., >1 month) was common in patients with NVE due to CoNS (33 patients [26%]) and in patients with NVE due to VGS (135 [40%]) but was infrequent in patients with NVE due to S. aureus (24 [5.3%]). By contrast, comorbid conditions, invasive procedures, and use of long-term indwelling vascular catheters were similar in patients with NVE due to CoNS and in patients with NVE due to S. aureus and significantly less frequent in patients with NVE due to VGS (P<.01, for all comparisons). Physical examination findings suggestive of vascular and/or immunologic events occurred in a significantly smaller proportion of patients with NVE due to CoNS, compared with patients with NVE due to S. aureus and patients with NVE due to VGS. Similarly, systemic embolization and stroke occurred less frequently among patients with NVE due to CoNS, compared with patients with NVE due to S. aureus (table 1). Congestive heart failure was a frequent complication in patients with NVE due to CoNS (50 patients [39%]) and was the leading indication for surgery among those who underwent surgical therapy (36 [47%] of 76 patients who underwent surgical therapy had congestive heart failure). Furthermore, excluding patients with pacemaker and/or implantable defibrillator removal only, patients with NVE due to CoNS had a higher rate of surgical therapy (76 patients [60%]) than did either patients with NVE due to S. aureus (150 [33%]; P<.01) or patients with NVE due to VGS (149 [44%]; P⩽.01).

Pacemaker- and/or implantable defibrillator-related IE. Among patients with NVE due to CoNS, 19 patients (15%) had a pacemaker and/or implantable defibrillator. As prespecified in the inclusion criteria for the present investigation, all patients with a pacemaker and/or implantable defibrillator had evidence of valvular involvement by echocardiographic examination. Right-sided IE was present in 11 patients, and 7 patients had left-sided IE. One patient had both tricuspid and mitral valve involvement. Nosocomial, nonnosocomial HCA, and CA infection occurred in 32%, 32%, and 37% of patients, respectively. A prolonged duration of symptoms (>1 month) prior to diagnosis occurred in 6 patients (32%). There were 11 patients (58%) who underwent surgical therapy: 7 underwent device removal, 3 underwent surgical therapy (the type of surgical procedure was not specified by the investigator), and 1 underwent mitral valve repair. Although 8 patients did not undergo surgical therapy, 2 of these patients died, and 1 patient was discharged from the hospital to hospice care. The other 5 patients who did not undergo surgical therapy were alive at the time of hospital discharge. The overall mortality among patients with pacemaker- and/or implantable defibrillator-related NVE due to CoNS was 26% (data not shown).

HCA versus CA NVE. The demographic and clinical characteristics of HCA versus CA NVE due to CoNS are summarized in table 2. NVE due to CoNS was acquired in the health care setting in 49% of the patients. These patients had predisposing features, such as receipt of hemodialysis (24 patients [38%]), presence of a long-term indwelling central catheter (13 [21%]), presence of a pacemaker and/or implantable defibrillator (12 [19%]), or a history of recently undergoing an invasive procedure (25 [40%]). In contrast, among patients with NVE due to CoNS who had CA infection, these predisposing risk factors were nearly absent. Methicillin resistance was more common among HCA CoNS isolates than among CA isolates (58% of isolates vs. 22% of isolates; P=.05), and significantly more patients received vancomycin in the HCA NVE group than in the CA NVE group (65% of patients vs. 25% of patients; P<.01). The difference in in-hospital mortality between patients with NVE due to HCA CoNS and patients with NVE due to CA CoNS (29% of patients vs. 22% of patients; P=.49) was not statistically significant (table 2).

Methicillin-resistant (MR) versus methicillin-susceptible CoNS causing NVE. Antibiotic susceptibility data were available for 97 patients (76%). Comparison of patients with NVE due to MR CoNS and patients with NVE due to methicillin-susceptible CoNS is shown in table 3. NVE due to MR CoNS was associated with nosocomial acquisition. Surgical treatment was similar in both groups; however, compared with patients with NVE due to methicillin-susceptible CoNS, patients with NVE due to MR CoNS had a higher rate of persistent bacteremia (8.8% vs. 25%; P=.01) and in-hospital mortality (16% vs. 40%; P=.03).

Factors related to surgical management. Patients who underwent surgical therapy for NVE had a longer duration of symptoms prior to presentation and fewer baseline comorbidities than did patients who received nonsurgical therapy for NVE. In addition, the patients who underwent surgical therapy were more likely to have been transferred from an outside institution. Although not statistically significant, the rate of death was lower among patients who underwent surgical therapy than among patients who received nonsurgical therapy (21% vs. 31%; P=.23) (table 4).

Predictors of mortality. The in-hospital mortality associated with NVE due to CoNS was 25% (32 of 128 patients died), which was similar to the mortality associated with NVE due to S. aureus (27% [124 of 456 patients]; P=.44) and significantly higher than the mortality associated with of NVE due to VGS (7% [24 of 341patients]; P<.01). On multivariable analysis (table 5), persistent bacteremia (OR, 2.65; 95% CI, 1.08–6.51), congestive heart failure (OR, 3.35; 95% CI, 1.57–7.12), and chronic illness (OR, 2.86; 95% CI, 1.34–6.06) were independently associated with mortality: (c index, 0.73). To include infection with MR CoNS as a variable, we repeated the multivariable model (data not shown) using the 97 patients (76% of the total cohort) with antibiotic susceptibility data. In the latter model, the independent predictors of mortality were persistent bacteremia (OR, 3.30; 95% CI, 1.13–9.60), congestive heart failure (OR, 4.86; 95% CI, 2.13–11.0), and infection with MR CoNS (OR, 2.81; 95% CI, 1.41–5.57; c index, 0.77).

Discussion

NVE due to CoNS is uncommon and incompletely understood. Prior studies have been limited by single-center experience [12–16], small sample size, and retrospective design [3, 5]. Using a multinational prospective design to overcome these limitations, we have made several key observations. CoNS have emerged as an important cause of NVE in both community and health care settings. Despite high rates of surgical therapy, NVE due to CoNS is associated with poor outcomes.

In the current multicenter investigation spanning ∼6 years and involving 61 centers in 28 countries, CoNS caused ∼8% of NVE cases not associated with injection drug use. The estimate reported in this investigation is higher than that reported in the older literature [17–19] and is consistent with the increasing prevalence of NVE due to CoNS reported in more-recent studies [2, 5]. Furthermore, health care exposure was a prominent feature of NVE due to CoNS in this investigation. This was demonstrated by the large proportion of patients receiving long-term hemodialysis, with pacemaker and/or implantable defibrillators, and with history of invasive procedures. These features identify patients who are at particular risk of invasive staphylococcal disease and explain, in part, the growing prevalence of NVE due to CoNS among patients with health care contact.

The epidemiology of NVE due to CoNS was similar to that of NVE due to S. aureus. Both NVE due to CoNS and NVE due to S. aureus were associated with a high rate of HCA acquisition and occurred in patients with similar comorbidities. Nevertheless, NVE due to CoNS differed from NVE due to S. aureus in important ways. Patients with NVE due to CoNS had a longer duration of symptoms prior to medical detection than did patients with NVE due to S. aureus. The delayed diagnosis may be secondary to a more indolent course of CoNS infection or failure to recognize initial blood culture results as true positives rather than as contaminants. In addition, patients with NVE due to CoNS were less likely to have vascular or immunologic evidence of IE on physical examination and had fewer embolic events, compared with patients with NVE due to S. aureus. The paradox of fewer embolic events despite a delayed diagnosis could potentially be because of the inherent “stickiness” of CoNS and its propensity to aggregate into biofilms [20], although this is unproven. Lastly, a greater proportion of patients with NVE due to CoNS had a pacemaker and/or implantable defibrillator, compared with patients with NVE due to S. aureus. Although a few studies suggest that pacemaker-related IE may be associated with a relatively low in-hospital mortality [21, 22], the in-hospital mortality associated with pacemaker-related NVE due to CoNS in our investigation was still high (26%). Of note, nearly one-third of patients with a pacemaker were symptomatic for >1 month prior to diagnosis. Taken together, these findings emphasize the importance of maintaining a high clinical suspicion of invasive CoNS infection in specific epidemiologic contexts.

NVE due to CoNS was associated with higher rates of surgical therapy than were either NVE due to S. aureus or NVE due to VGS; however, NVE due to CoNS was not associated with better outcomes. The high rate of surgical therapy associated with NVE due to CoNS is likely related to the high rate of heart failure (>40% of the cohort) and other cardiac complications. On the other hand, the high mortality is at least partly related to pre-existing comorbidities and a delay in diagnosis. Reasons for the high mortality rate associated with NVE due to CoNS are not fully understood; however, we propose that earlier diagnosis is one way to improve outcomes.

It should be noted that one-half of the patients with NVE due to CoNS had CA disease. Unlike patients with HCA infection, patients with CA infection were much less likely to have obvious predisposing risk factors, such as long-term intravascular catheters and a history of invasive procedures. In the absence of extensive health care contact, these patients may possess unique host susceptibility determinants or may have acquired a uniquely invasive strain of CoNS. Although no definitive virulence factors have been identified for CoNS, this is an area of active investigation [23–26].

We found that the overall rate of methicillin resistance among isolates of CoNS causing NVE was 41%, which is lower than the rate of resistance seen in typical prosthetic valve and catheter-related CoNS infections [1]. The low rate of methicillin resistance in this investigation is largely a reflection of the CA infections, because 22% of the CA isolates were MR. This observation is consistent with earlier investigations of NVE due to CoNS that have suggested a high prevalence of community acquisition [3, 5] and low rates of methicillin resistance (14%–22%) [3, 5]. In contrast, the rate of methicillin resistance among HCA NVE isolates in the present study was 58%, which is more consistent with the high rates of resistance typically seen in nosocomial CoNS isolates.

The findings of the current investigation validate the findings that we reported in a smaller series of patients with NVE due to CoNS during the period 1979–1999 [2]. Both studies demonstrate a significant association between NVE due to CoNS and health care acquisition. In addition, these studies demonstrate the invasiveness of this disease, with a high rate of intracardiac abscess, heart failure, and death. In the current investigation, nevertheless, we were able to identify the close relationship of this disease to the use of specific devices (i.e., pacemakers and/or implantable defibrillators and hemodialysis devices) and to the potential role of late diagnosis. As demonstrated by this investigation and others [2–5], CoNS are an increasingly important cause of NVE.

This study has several limitations. The rate of identification of CoNS strains to the species level was low and reflects the reporting practice of individual sites and microbiology laboratories. Thus, the role of different CoNS species, such as Staphylococcus lugdunensis, which is well-known for its virulence, is not appreciated in the current investigation. In addition, microbiology data are limited to individual site contributions and, thus, are subject to sampling bias. The ICE-PCS relies on voluntary participation from different sites; therefore, regional differences are reflective of the sites who participated, and the cohort may not be fully representative of the global spectrum. Because many of the sites that participate in the ICE-PCS have centers that specialize in IE, the data is also subject to referral bias. Finally, our predictive model was restricted to 3 independent variables because of the sample size, and as a result, there may be other predictors that we were not able to identify in our model.

CoNS now cause a significant portion of NVE cases not associated with injection drug use. These cases are associated with a high mortality similar to that seen in NVE due to S. aureus. Health care contact appears to be strongly related to NVE due to CoNS, although other predisposing factors, particularly with respect to CA disease, have yet to be elucidated. A better understanding of the pathogenesis of invasive CoNS infection is needed to improve prevention and treatment strategies.

International Collaboration on Endocarditis Registry Investigators, 2007

Drs. David Gordon and Uma Devi (Flinders Medical Centre, Adelaide, Australia); Dr. Denis Spelman (Alfred Hospital, Amiens, France); Dr. Jan T. M. van der Meer (University of Amsterdam, Amsterdam, The Netherlands); Drs. Carol Kauffman, Suzanne Bradley, and William Armstrong (Ann Arbor Veterans Affairs Medical Center, Ann Arbor, MI); Drs. Efthymia Giannitsioti and Helen Giamarellou (Attikon University General Hospital, Athens, Greece); Dr. Stamatios Lerakis (Emory University, Atlanta, GA); Drs. Ana del Rio, Asuncion Moreno, Carlos A. Mestres, Carlos Paré, Cristina Garcia de la Maria, Elisa De Lazzario, Francesc Marco, Jose M. Gatell, José M. Miró, Manel Almela, Manuel Azqueta, Maria Jesús Jiménez-Expósito, Natividad de Benito, and Noel Perez (Hospital Clinic-Institut d'Investigacions Biomediques, August Pi i Sunyer, University of Barcelona, Barcelona, Spain); Drs. Benito Almirante, Nuria Fernandez-Hidalgo, Pablo Rodriguez de Vera, Pilar Tornos, Vicente Falcó, Xavier Claramonte, and Yolanda Armero (Hospital Universitari Vall d'Hebron, Barcelona, Spain); Nisreen Sidani, Dr. Souha Kanj-Sharara, and Dr. Zeina Kanafani (American University of Beirut Medical Center, Beirut, Lebanon); Drs. Annibale Raglio, Antonio Goglio, Fabrizio Gnecchi, Fredy Suter, Grazia Valsecchi, Marco Rizzi, and Veronica Ravasio (Ospedali Riuniti di Bergamo, Bergamo, Italy); Drs. Bruno Hoen, Catherine Chirouze, Efthymia Giannitsioti, Joel Leroy, Patrick Plesiat, and Yvette Bernard (University Medical Center of Besançon, Besançon, France); Anna Casey, Dr. Peter Lambert, Dr. Richard Watkin, and Dr. Tom Elliott (Queen Elizabeth Hospital, Birmingham, United Kingdom); Drs. Mukesh Patel and William Dismukes (University of Alabama at Birmingham, Birmingham, AL); Drs. Angelo Pan and Giampiero Caros (Spedali Civili-Università di Brescia, Brescia, Italy); Drs. Amel Brahim Mathiron, Christophe Tribouilloy and Thomas Goissen (South Hospital Amiens, Bron Cedex, France); Armelle Delahaye, Dr. Francois Delahaye, and Dr. Francois Vandenesch (Hopital Louis Pradel, Bron Cedex, France); Drs. Carla Vizzotti, Francisco M. Nacinovich, Marcelo Marin, Marcelo Trivi, and Martin Lombardero (Instituto Cardiovascular, Buenos Aires, Argentina); Drs. Claudia Cortes and José Horacio Casabé (Instituto de Cardiología y Cirugía Cardiovascular, Buenos Aires, Argentina); Drs. Javier Altclas and Silvia Kogan (Sanatorio Mitre, Buenos Aires, Argentina); Drs. Liliana Clara and Marisa Sanchez (Hospital Italiano, Buenos Aires, Argentina); Drs. Anita Commerford, Cass Hansa, Eduan Deetlefs, Mpiko Ntsekhe, and Patrick Commerford (Groote Schuur Hospital, Cape Town, South Africa); Drs. Dannah Wray, Lisa L. Steed, Preston Church, and Robert Cantey (Medical University of South Carolina, Charleston, SC); Drs. Arthur Morris, David Holland, David Murdoch, Katherine Graham, Kerry Read, Nigel Raymond, Paul Bridgman, Richard Troughton, Selwyn Lang, and Stephen Chambers (Canterbury Health Laboratories, Christchurch, New Zealand); Drs. Despina Kotsanas and Tony M. Korman (Southern Health, Clayton, Australia); Dr. Gail Peterson, Jon Purcell, and Dr. Paul M. Southern Jr. (University of Texas-Southwestern Medical Center, Dallas, TX); Drs. Manisha Shah and Roger Bedimo (Dallas Veterans Affairs Medical Center, Dallas, TX); Arjun Reddy, Dr. Donald Levine, and Dr. Gaurav Dhar (Wayne State University, Detroit, MI); Alanna Hanlon-Feeney, Dr. Margaret Hannan, and Dr. Sinead Kelly (Mater Hospitals, Dublin, Ireland); Dr. Andrew Wang, Dr. Christopher H. Cabell, Dr. Christopher W. Woods, Dr. Daniel J. Sexton, Dr. Danny Benjamin Jr., Dr. G. Ralph Corey, Dr. Jay R McDonald, Jeff Federspiel, Dr. John J Engemann, Dr. L. Barth Reller, Laura Drew, Dr. L. B. Caram, Dr. Martin Stryjewski, Dr. Susan Morpeth, Dr. Tahaniyat Lalani, Dr. Vance Fowler Jr., and Dr. Vivian Chu (Duke University Medical Center, Durham, NC); Dr. Bahram Mazaheri, Carl Neuerburg, and Dr. Christoph Naber (University Essen, Essen, Germany); Drs. Eugene Athan, Margaret Henry, and Owen Harris (Barwon Health, Geelong, Australia); Dr. Eric Alestig, Dr. Lars Olaison, Lotta Wikstrom, and Dr. Ulrika Snygg-Martin (Sahlgrenska Universitetssjukhuset/Östra, Goteborg, Sweden); Drs. Johnson Francis, K. Venugopal, Lathi Nair, and Vinod Thomas (Medical College Calicut, Kerla, India); Drs. Jaruwan Chaiworramukkun, Orathai Pachirat, Ploenchan Chetchotisakd, and Tewan Suwanich (Khon Kaen University, Khon Kaen, Thailand); Adeeba Kamarulzaman and Dr. Syahidah Syed Tamin (University of Malaya Medical Center, Kuala Lumpur, Malaysia); Drs. Manica Mueller Premru, Mateja Logar, and Tatjana Lejko-Zupanc (Medical Center Ljublijana, Ljublijana, Slovenia); Christina Orezzi and Dr. John Klein (St. Thomas' Hospital, London, United Kingdom); Dr. Emilio Bouza, Dr. Mar Moreno, Dr. Marta Rodríguez-Créixems, Dr. Mercedes Marín, Dr. Miguel Fernández, Dr. Patricia Muñoz, Rocío Fernández, Dr. Victor Ramallo (Hospital General Universitario Gregorio Marañón, Madrid, Spain); Drs. Didier Raoult, Franck Thuny, Gilbert Habib, Jean-Paul Casalta, and Pierre-Edouard Fournier (Faculté de Médecine de Marseille, Marseille, France); Drs. Natalia Chipigina, Ozerecky Kirill, Tatiana Vinogradova, and Vadim P. Kulichenko (Russian Medical State University, Moscow, Russia ); Dr. O. M. Butkevich (Learning Medical Centre of Russian Presidential Affairs Government, Moscow, Russia); Dr. Christine Lion, Dr. Christine Selton-Suty, Dr. Francois Alla, Hélène Coyard, and Dr. Thanh Doco-Lecompte (Centre Hospitalier Universitaire, Nancy-Brabois, Nancy, France); Drs. Diana Iarussi, Emanuele Durante-Mangoni, Marie Françoise Tripodi, and Riccardo Utili (II Università di Napoli, Naples, Italy); Drs. A. Sampath Kumar and Gautam Sharma (All India Institute of Medical Sciences, New Delhi, India); Dr. Stuart A. Dickerman (New York University Medical Center, New York, NY); Alan Street, Dr. Damon Peter Eisen, Dr. Emma Sue McBryde, and Leeanne Grigg (Royal Melbourne Hospital, Parkville, Australia); Dr. Elias Abrutyn (Drexel University College of Medicine, Philadelphia, PA); Drs. Christian Michelet, Pierre Tattevin, and Pierre Yves Donnio (Pontchaillou University, Rennes, France); Dr. Claudio Querido Fortes (Hospital Universitario Clementino Fraga Filho/Univiersidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil); Jameela Edathodu and Dr. Mashael Al-Hegelan (King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia); Drs. Bernat Font, Ignasi Anguera, and Joan Raimon Guma (Hospitál de Sabadell, Sabedell, Spain); Drs. M. Cereceda, Miguel J. Oyonarte, and Rodrigo Montagna Mella (Hospital Clinico Universidad de Chile, Santiago, Chile); Drs. Patricia Garcia and Sandra Braun Jones (Hospital Clínico Pont, Universidad Católica de Chile, Santiago, Chile); Dr. Auristela Isabel de Oliveira Ramos (Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil); Drs. Marcelo Goulart Paiva and Regina Aparecida de Medeiros Tranchesi (Hospital 9 de Julho, São Paulo, Brazil); Lok Ley Woon, Luh-Nah Lum, and Ru-San Tan (National Heart Centre, Singapore, Singapore); Drs. David Rees, Pam Kornecny, Richard Lawrence, and Robyn Dever (St. George Hospital, Sydney, Australia); Drs. Jeffrey Post, Phillip Jones, and Suzanne Ryan (The University of New South Wales, Sydney, Australia); Drs. John Harkness and Michael Feneley (St. Vincent's, Sydney, Australia); Drs. Ethan Rubinstein and Jacob Strahilewitz (Tel Aviv University School of Medicine, Tel Aviv, Israel); Drs. Adina Ionac, Cristian Mornos, and Stefan Dragulescu (Victor Babes University of Medicine and Pharmacy, Timisoar, Romania); Drs. Davide Forno, Enrico Cecchi, Francesco De Rosa, Massimo Imazio, and Rita Trinchero (Maria Vittoria Hospital, Torino, Italy); Drs. Franz Wiesbauer and Rainer Gattringer (Vienna General Hospital, Vienna, Austria ); Drs. Ethan Rubinstein and Greg Deans (University of Manitoba, Winnipeg, Canada); and Drs. Arjana Tambic Andrasevic, Bruno Barsic, Igor Klinar, Josip Vincelj, Suzana Bukovski, and Vladimir Krajinovic (University Hospital for Infectious Diseases, Zagreb, Croatia).