- Email: [email protected]
Usefulness of New-Onset Atrial Fibrillation, as a Strong Predictor of Heart Failure and Death in Patients With Native Left-Sided Infective Endocarditis
Accepted Manuscript Usefulness of New-onset Atrial Fibrillation, as a Strong Predictor of Heart Failure and Death in Patients with Native Left-Sided Infective Endocarditis Carlos Ferrera, MD, Isidre Vilacosta, MD, PhD, Cristina Fernández, MD, PhD, Javier López, MD, PhD, Cristina Sarriá, MD, PhD, Carmen Olmos, MD, PhD, David Vivas, MD, PhD, Carmen Sáez, MD, Cristina Sánchez-Enrique, MD, Carlos Ortiz-Bautista, MD, José Alberto San Román, MD, PhD PII:
S0002-9149(15)02248-1
DOI:
10.1016/j.amjcard.2015.11.012
Reference:
AJC 21524
To appear in:
The American Journal of Cardiology
Received Date: 14 September 2015 Revised Date:
4 November 2015
Accepted Date: 9 November 2015
Please cite this article as: Ferrera C, Vilacosta I, Fernández C, López J, Sarriá C, Olmos C, Vivas D, Sáez C, Sánchez-Enrique C, Ortiz-Bautista C, San Román JA, Usefulness of New-onset Atrial Fibrillation, as a Strong Predictor of Heart Failure and Death in Patients with Native Left-Sided Infective Endocarditis, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.11.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Usefulness of New-onset Atrial Fibrillation, as a Strong Predictor of Heart Failure and Death in Patients with Native Left-Sided Infective Endocarditis
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Running title: Atrial fibrillation in Infective Endocarditis
Carlos Ferrera MDa, Isidre Vilacosta MD, PhDa, Cristina Fernández MD,
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PhDa, Javier López MD, PhDb, Cristina Sarriá MD, PhDc, Carmen Olmos MD, PhDa, David Vivas MD, PhDa, Carmen Sáez MDc, Cristina SánchezEnrique MDa, Carlos Ortiz-Bautista MDb, José Alberto San Román MD,
a
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PhDb
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Instituto Cardiovascular, Hospital Clínico San Carlos, Madrid. Address: C/Profesor Martín Lagos S/N, 28040, Madrid, Spain; bInstituto de Ciencias del Corazón (ICICOR), Hospital Universitario de Valladolid. Address: Av. Ramón y Cajal, S/N, Valladolid, Spain; and cServicio de Medicina Interna, Hospital Universitario de la Princesa. Address: C/ Diego Leon, 62, 28006 Madrid, Spain.
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Corresponding author: Carlos Ferrera. Address for correspondence: Instituto Cardiovascular, Hospital Clínico San Carlos. Madrid. C/Profesor Martín Lagos S/N, 28040, Madrid, Spain.Tel.: +34913303149, Fax: +34913303290. Email: [email protected]
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Abstract Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults and has been
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independently related to increased morbidity and mortality. AF is a frequent arrhythmia in infective endocarditis (IE). Nevertheless, there are no data on how AF affects the
clinical outcome of patients with endocarditis. Our purpose was to investigate patient characteristics, microbiology, echocardiographic findings, in-hospital course, and
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prognosis of patients with IE who develop new-onset AF (NAF), and compare them
with those who remained in sinus rhythm (SR) or had previous AF. From 1997 to 2014,
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507 consecutive patients with native left-sided IE were prospectively recruited at three tertiary care centers. We distinguished three groups according to the type of baseline heart rhythm during hospitalization and previous history of AF: NAF-Group (n=52), patients with no prior history of AF and who were diagnosed as having NAF during
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hospitalization; SR-Group (n=380), patients who remained in SR; and PAF-Group (n=75), patients with previous AF. Patients with NAF were older than those who remained in SR (68.3 vs 59.6 years, p<0.001). At admission, heart failure was more
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common in NAF-Group (53% vs 34.3%, p<0.001), whereas stroke (p=0.427) was equally frequent in all groups. During hospitalization, embolic events occurred similarly
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(p=0.411). In the multivariable analysis, NAF was independently associated with heart failure (OR 3.56, p<0.01) and mortality (OR 1.91, p=0.04). In conclusion, the occurrence of NAF in patients with IE was strongly associated with heart failure, and higher in-hospital mortality independently from other relevant clinical variables. Keywords: atrial fibrillation; infective endocarditis; prognosis
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INTRODUCTION Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults and has
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been independently related to increased morbidity and mortality1. It is also well known the association between new-onset AF (NAF) and mortality in patients hospitalized with severe sepsis2,3 or heart failure4. Systemic inflammation and hemodynamic disorders
have been involved in the origin and perpetuation of AF in these clinical scenarios1,4-6.
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Infective endocarditis (IE) is a severe infectious disease producing a great systemic inflammatory reaction and local valve destruction leading to severe hemodynamic
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changes7. Not surprisingly, AF is common in IE, sometimes co-existing with heart failure and systemic embolism8-10. Nevertheless, there are no data on how AF affects the clinical outcome of patients with IE. We hypothesized that patients with IE and NAF have a worse clinical outcome than those who remain in sinus rhythm. Patients with
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NAF might be particularly prone to congestive heart failure and thrombo-embolic events (Figure 1). The purpose of this study was to investigate patient characteristics, microbiology, and echocardiographic findings of patients with IE and NAF. We further
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aim to compare the in-hospital course and prognosis of patients who develop de novo AF with that of those who remained in sinus rhythm or had previous AF.
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METHODS
This study was conducted at three tertiary care centers with surgical facilities,
which have been working together on IE with the use of standardized protocols. To ensure consecutive enrolment, all patients who underwent echocardiography to rule out IE were clinically followed until a diagnosis was established. Only definite cases of leftsided IE were included. Duke criteria were applied until 200211, and modified Duke 3
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criteria thereafter12. Right-sided episodes were excluded due to their different epidemiology, clinical characteristics and prognosis. From 1997 to 2014, 926 consecutive patients with left-sided IE were
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prospectively recruited on an on-going multipurpose database, 110 (11.9%) of them were excluded from the analysis due to inability to assess the baseline heart rhythm
during hospitalization. Patients with prosthetic valve endocarditis were also excluded
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from the study (309 patients). The remaining 507 patients with native left-sided IE formed our final study population
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This registry complies with the Declaration of Helsinki and was approved by the local ethical committee. All participants gave written informed consent. The proportion of missing data was less than 10% in all analyzed variables. For purposes of analysis and comparison, we distinguished three groups according to the type of baseline heart
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rhythm during hospitalization and previous history of AF: NAF-Group (n=52), patients with no prior history of AF and who were diagnosed as having NAF during hospitalization; SR-Group (n=380), patients without history of previous AF, who
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remained in sinus rhythm and that did not suffer AF during hospitalization; and PAFGroup (n=75) included patients with previous AF (permanent, paroxysmal or
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persistent). Those patients who developed post-operative AF after surgery for IE were not considered as NAF. All patients underwent transthoracic (TTE) and transesophageal
echocardiography (TEE). A set of three blood cultures was obtained at admission, and three additional blood cultures 48-72h later, If blood cultures were negative after 72h, specific serologic tests were done for Chlamydia, Brucella, Q fever, Legionella, Mycoplasma, and Bartonella. 4
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Nosocomial and community-acquired IE were defined according to the literature (7). Acute onset IE was applied when the time between the appearance of symptoms and hospital admission was less than 15 days13,14. Previous valvulopathy was defined as
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any kind of valvular heart disease and congenital valvular disease. Anemia was defined as a hemoglobin concentration below 9g/dl; renal insufficiency was established when
the serum creatinine concentration was higher than 2mg/dl. Heart failure was diagnosed
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according to Framingham criteria15. Under the term of immunosuppression were
included patients with HIV and those who were on steroids or other immunosuppressive therapy. Persistent signs of infection and septic shock were defined as previously
derived from imaging procedures.
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described7,10. The diagnosis of systemic embolism was based on clinical signs and data
NAF was defined when AF was registered in a 12-lead electrocardiogram done during hospitalization in a patient with previously documented sinus rhythm and no
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previous history of AF. Paroxysmal, persistent, and permanent AF were defined according to the guidelines1.
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The echocardiographic criteria used for definition and measurement of vegetations, abscesses, pseudoaneurysms and fistulas have been described
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elsewhere16,17. Left atrial dimension was measured in M-mode and 2-D transthoracic echocardiography following the recommendations of the American Society of Echocardiography18.
Surgery was defined as early if done before antibiotic treatment was completed,
and was performed when any of the following occurred: refractory heart failure, recurrent embolism with persistent vegetations in the echocardiogram, persistent signs of infection, and fungal endocarditis. When a patient meeting surgical criteria did not 5
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undergo surgery, the reason was either because of patient rejection, unacceptably highsurgical risk or when the patient was too frail. Continuous variables are reported as a mean value and standard deviation or
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median and interquartile range in cases of non-normality. Continuous variables were
compared between the groups with a 2-tailed Student’s t-test or Mann-Whitney U-test when necessary. Categorical variables are expressed as a frequency and a percentage
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and were compared with the χ2 test and Fisher’s exact test when appropriate. In case of multiple categories, ANOVA or Kruskal-Wallis test were used.
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Two multivariable logistic regression analyses were performed, one for prediction of mortality and another for detection of independent factors for heart failure. We included in the model the variables previously known to be associated to these events and those considered clinically relevant. When a variable statistically significant
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in the univariable analysis was not included in the multivariable analysis, the reason was collinearity or absence of change in the effect of atrial fibrillation. In addition, interactions between variables included in the model were assessed in the model. The
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adjusted odds ratios (OR) with 95% confidence intervals (CI) for each variable have been calculated. All test were two-tailed and differences were considered statistically
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significant at p-values<0.05. Statistical analysis was performed with PASW Statistics V 17.0 (SPSS Inc. Chicago, IL, USA).
RESULTS
Demographic characteristics, comorbidities, and clinical presentation comparisons between groups are summarized in Table 1. Patients with NAF were older than those who remained in sinus rhythm. Concerning comorbidities, chronic renal 6
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failure and chronic obstructive pulmonary disease (COPD) were more common in NAFGroup than in SR-Group. At admission, heart failure and their radiological manifestations were more common in NAF-Group, whereas stroke and systemic
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embolism were equally present in all groups. Interestingly, blood levels of acute phase reactants at admission (C-reactive protein) were higher among patients with NAF (Table 1).
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The microorganisms found in patients with NAF were not significantly different than those isolated in SR-Group and PAF-Group (Table 2).
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Echocardiographic data are shown in Table 3. As expected, left atrial dimension was higher in patients with NAF than in those who remained in sinus rhythm. Vegetations were equally present among groups (Table 3). Vegetation size was similar in all groups. As regard to the presence of moderate to severe valvular insufficiency, no
rhythm (Table 3).
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differences were found between patients with NAF and those who remained in sinus
Heart failure was significantly more frequent in patients with NAF (Table 4). In
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this group, 27 patients (53%) were already in heart failure at admission. Among patients with heart failure, moderate to severe valvular insufficiency was more frequently
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encountered in patients with sinus rhythm than in those with AF irrespective of the type (NAF or previous AF) (NAF-Group: 34 (85%), SR-Group: 193 (93.7%), PAF-Group: 42 (82.4%); p=0.020). According to these results, patients with heart failure and NAF underwent surgery less frequently than those with heart failure and sinus rhythm (NAFGroup: 20 (48.8%), SR-Group: 146 (68.5%), PAF-Group: 33 (62.3%); p=0.048).
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Overall, stroke and systemic embolism occurred in 157 patients (31%) in this series. These complications were not more common in patients with AF irrespective of the type (NAF or previous AF).
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The need for surgery and time from admission to surgery was similar in all
groups (NAF-Group: 13.5 days, SR-Group: 16 days, PAF-Group: 14 days; p=0.726).
There were 146 deaths (28.8%). Death was much more common in NAF-Group
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than in SR-Group (p=0.001), and a greater mortality in NAF-Group vs PAF-Group
(p=0.044) was also detected (Table 4). No differences were observed regarding causes
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of death between the different groups. We noticed that patients with NAF and heart failure had a higher mortality than those who despite having developed heart failure, remained in sinus rhythm (Figure 2).
To determine potential variables independently associated to the presence of
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heart failure at admission and during hospitalization, a multivariable logistic regression analysis was performed. We included in the model variables that were considered clinically relevant and those that were significant in the univariable analysis: age,
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S.aureus, vegetation detection, periannular complications, acute renal failure, septic shock, surgery, moderate to severe valvular insufficiency, and NAF. Prognostic factors
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of heart failure are shown in Figure 3. NAF was found to have strong adjusted association with heart failure (OR 3.56, 95% CI: 1.52-8.26). We performed a multivariable analysis to determine the variables that were
independently associated with mortality during the clinical course of the disease. We included in the model the following variables: age, S.aureus, vegetation detection, periannular complications, heart failure, acute renal failure, septic shock, surgery, moderate to severe valvular insufficiency, stroke and NAF. Prognostic factors of 8
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mortality are shown in Table 5. NAF (OR 1.91, 95% CI: 1.01-4.11) remained independently associated with increased in-hospital mortality after adjusting for other variables.
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Interaction between NAF and patients’ treatment (surgery or medical therapy)
was assessed. Mortality was higher in NAF-Group than in SR-Group independently of the need of surgery (p of interaction 0.764). In addition, interaction between NAF and
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the variables included in the model was also evaluated, in order to determine the potential contribution of these interactions in the association between NAF and
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mortality. All the assessed interactions resulted statistically non-significant.
DISCUSSION
This study is the first to examine the impact of NAF in patients with left-sided IE. We showed that NAF is common in patients hospitalized with IE (10.3%), and that
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it is associated with higher in-hospital mortality. Our findings also show that NAF has a strong adjusted association with heart failure during active IE. This investigation focused on patients that being in sinus rhythm prior to IE fell
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into AF during the course of the disease. The main aim was to compare these patients with those that remained in sinus rhythm. Regarding demographic and comorbidity
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conditions, patients with NAF were older, left atrial dimension was bigger, and they had more frequently chronic renal failure and COPD. With aging, the extent of atrial fibrosis increases19. Fibrosis results from increased collagen deposit and is considered an
important factor in the development and maintenance of the arrhythmia20,21. Chronic
renal failure is a common comorbidity among AF patients22. It is well known that chronic renal failure favors tissue fibrosis and hypertension, and therefore the onset and establishment of AF. 9
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Although AF is associated with increased risks of major cardiovascular events such as stroke, heart failure, and death23, the event rates of these competing outcomes in IE have not been analyzed. In the herein series, the rate of stroke and systemic
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embolism was not higher in episodes with NAF. Our results support the concept that in IE, other factors like presence, mobility, and size of vegetations as well as specific microorganisms have a greater role in the pathogenesis of this complication24.
Interestingly, in a recent study to predict embolism in IE, AF was not statistically
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associated with embolic events25.
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Heart failure is a more frequent complication of AF than stroke26. Acute AF may lead to overt heart failure, the symptoms of which often improve after AF termination27. In IE, heart failure may be secondary to rapid AF, and severe valvular insufficiency among other factors. Understanding the mechanism for developing heart failure in patients with IE is an important goal. In our series, NAF was found to be strongly
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associated to heart failure. Loss of atrio-ventricular synchrony, rapid an irregular ventricular response, and lack of atrial contraction reduce diastolic filling and cardiac output. In this scenario, atrial and pulmonary capillary pressures increase perpetuating
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heart failure and AF. In IE, severe valvular insufficiency secondary to valvular destruction by the infection may also contribute to heart failure. Interestingly, moderate
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to severe valvular insufficiency was not more common in episodes with NAF. As heart failure is the most frequent complication of IE, and represents the most
common indication for surgery7, it is particularly relevant to stand out that in our series the proportion of patients who developed heart failure was higher in episodes with AF (NAF and previous), however these two groups had a lower rate of moderate to severe valvular insufficiency. These facts suggest that heart failure in some patients with left10
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sided IE and AF could be solved by heart rate or rhythm control instead of with valvular surgery. In our series, surgery was performed more frequently in patients with heart failure and sinus rhythm than in those with heart failure and AF (p=0.048).
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Data from a variety of studies have shown that AF is associated with greater
mortality1-4,23. Furthermore, the risk of death is higher in critically ill patients, such as
those with sepsis3. In this series, NAF in patients with left-sided IE was associated with
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a higher in-hospital mortality. Possibly, increased mortality is due to the negative
impact of NAF on cardiac function. However, it is also possible that the cause of NAF
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is also the reason for the increase in mortality. In the latter case, NAF would be a marker instead of a mediator of mortality.
This study has several limitations that should be considered when interpreting the results. It is part of a multiproposal prospective collection of data with a large
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number of cases, but it has potentially referral bias because all the participants are tertiary care centers. Strategies for identifying AF are highly specific, but insensitive so, we likely underestimated the burden of NAF. In addition, we could not exclude the
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possibility that patients with NAF may have had undetected (previous AF) present before IE hospitalization. Although we hypothesized that patients with NAF are at
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increased risk for heart failure, the temporality between AF and heart failure could not be clearly established. Information regarding specific management of AF at admission and during hospitalization was not available.
ACKNOWLEDGMENT There is no sponsor or funding source involved in the study design; collection,
analysis, and interpretation of data; writing the report; and in the decision to submit the article for publication. 11
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CONFLICT OF INTEREST
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None declared.
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FIGURE LEGENDS Figure 1. Main hypothesis of the study – Patients with IE who develop AF might be
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prone to heart failure and embolic events and therefore higher mortality. AF: atrial fibrillation; Em: embolism; HF: heart failure; IE: infective endocarditis
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Figure 2. Mortality risk in patients with heart failure according to the heart
rhythm – Patients with new-onset AF and heart failure had a higher mortality than
atrial fibrillation; SR: sinus rhythm.
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those who remained in sinus rhythm. NAF: new onset atrial fibrillation; PAF: previous
Figure 3. Multivariable analysis to predict heart failure – Diagram showing the
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results (OR and CI) of the multivariable analysis to predict heart failure. New onset atrial fibrillation was found to be independently associated with heart failure (OR 3.56; 95% CI: 1.52-8.26).
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NAF: new onset atrial fibrillation
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Table 1. Demographic and main clinical characteristics, electrocardiographic, radiological and laboratory findings at admission in 507 patients with native left-sided infective endocarditis
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p
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PAF (n= 75) 68.9 (12.1) 44 (59%)c 44 (59%) 59 (80%) 23 (31%) 11 (15%) 20 (27%) 7 (9.3%) 11 (15%)
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Age (years) Male Community-acquired IE Previous valvulopathy Anemia Chronic renal failure Diabetes Alcoholism Chronic obstructive pulmonary disease 6 (12%) Malignant neoplasia 4 (8%) Immunosuppression 12.5 (7-57) Symptoms to admission (days) 26 (50%) Acute onset (<15days) 32 (63%) Fever at admittance 27 (53%) Heart failure 16 (31%) Acute renal failure 6 (12%) Septic shock 5 (10%) Chest pain 5 (10%) Abdominal pain 4 (8%) Splenomegaly 11 (21%) Confusional syndrome 2 (4%) Coma Stroke 1 (2%) Hemorrhagic 7 (14%) Ischemic 9 (17%) Systemic embolism 4 (8%) Hematuria 5 (10%) Arthritis/ Spondylodiscitis 11 (24.4%) Anticoagulation 2 (4%) Second and third degree AV block Left bundle-branch block 3 (6%) 37 (71%) Cardiomegaly 22 (43%) Pleural effusion 17.9 C-reactive protein (6.9-115.3) (mg/dl)* 11 (2.2) Hemoglobin (g/dl)
SR (n=380) 59.6 (16.2) 259 (68.2%) 297 (78.6%) 154 (43.6%) 76 (20.2%) 34 (9%) 67 (17.8%) 41 (10.9%) 20 (5.3%)
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NAF (n=52) 68.3 (10.2) 36 (69%) 33 (64%) 27 (54%) 12 (23%) 10 (19%) 15 (29%) 6 (12%) 7 (14%)
<0.001a,c 0.260 0.002a,c <0.001b,c 0.135c 0.047a 0.057a 0.903 0.005a,c
43 (11.4%) 31 (8.2%) 20.5 (7-60)
11 (15%) 8 (11%) 20 (7-35)
0.721 0.776 0.497
145 (38.7%) 281 (75.5%) 129 (34.3%) 73 (19.5%) 17 (4.6%) 38 (10.2%) 43 (11.6%) 39 (10.5%) 52 (13.9%) 11 (2.9%)
33 (44%) 53 (72%) 38 (51%) 13 (17%) 7 (9%) 7 (9%) 6 (8%) 4 (5%)c 12 (16%) 2 (3%)
0.241 0.138 0.003a,c 0.131a 0.108a 0.968 0.631 0.063 0.376 0.923 0.427
13 (3.5%) 47 (12.5%) 85 (22.5%) 14 (3.7%) 66 (17.7%)
2 (3%) 4 (5%) 11 (15%) 1 (1%) 6 (8%)
0.248 0.181 0.052c
23 (6.2%) 8 (2.1%)
53 (71%) 1 (1%)
<0.001b,c 0.646
10 (2.7%) 160 (42.4%) 83 (22.1%) 14.3 (4.867.8) 11.1 (2.1)
7 (10%) 50 (69%) 19 (26.4%) 6.9 (2.9-14.8)
0.017c <0.001a,c 0.005a,b 0.026a,b,c
11 (2)
0.955
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228x103 196x103 215x103 0.114 3 3 (141x10 ) (99x103)c (124x10 ) AV block= atrioventricular block; NAF: new-onset atrial fibrillation; PAF: previous atrial fibrillation; SR: sinus rhythm a Statistically significant differences between NAF-group and SR-group (p<0.05). b Statistically significant differences between NAF-group and PAF-group (p<0.05). c Statistically significant differences between SR-group and PAF-group (p<0.05). * Upper normal limit for C-reactive protein 0.5mg/dl.
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Platelets
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Table 2. Microbiological profile in 507 patients with native leftsided infective endocarditis
NAF (n=52)
SR-Group (n=380)
PAF-Group (n= 75)
p
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2 (4%) 23 (6.1%) 3 (4%)c 0.654 Streptococcus bovis 5 (10%) 69 (18.3%) 6 (8%) Streptococcus viridans 0.036c 4 (8%) 32 (8.5%) 5 (7%) 0.864 Other estreptococci 6 (11.5%) 33 (8.8%) 8 (11%) 0.738 Enterococci 7 (14%) 66 (17.5%) 13 (17%) 0.766 Staphylococcus aureus 10 (19%) 45 (11.9%) 13 (17%) 0.202 Coagulase negative staphylococci 1 (2%) 11 (2.9%) 2 (3%) 0.918 Gram negative bacilli 0 (0%) 4 (1.1%) 2 (3%) 0.355 Fungi 0 (0%) 4 (1.1 %) 0 (0%) 0.507 HACEK Group 0 (0%) 3 (0.8%) 1 (1%) 0.707 Anaerobes 3 (6%) 20 (5.3%) 7 (9%) 0.403 Polymicrobial 2 (4%) 13 (3.4%) 4 (5%) 0.736 Others 12 (23.1%) 54 (14.3%) 11 (15%) 0.255 Negative cultures NAF: new-onset atrial fibrillation; PAF: previous atrial fibrillation; SR: sinus rhythm a Statistically significant differences between NAF-group and SR-group (p<0.05). b Statistically significant differences between NAF-group and PAF-group (p<0.05). c Statistically significant differences between SR-group and PAF-group (p<0.05).
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Table 3. Echocardiographic findings NAF (n=52)
SR (n=380)
PAF (n= 75)
p
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Location of the infection 29 (56%) 216 (56.8%) 39 (52%) 0.742 Aortic native valve 30 (58%) 227 (59.7%) 45 (60%) 0.958 Mitral native valve 43.3 (6.8) 52.4 (14.3) <0.001a,c Left atrial dimension (mm) 48 (8.5)a Vegetations 332 (90%) 61 (84%) 48 (98%) Detection by 0.035b echocardiography 12 (9.4-18.3) 12.7 (9-18.5) 12 (7-18·4) 0.805 Vegetation size (mm) 40 (82%) 314 (85.1%) 55 (75%) 0.118c Moderate-severe valvular regurgitation 14 (29%) 92 (24.9%) 15 (21%) 0.582 Periannular complications 9 (16%) 46 (12.5%) 14 (19%) 0.275 Abscess 9 (18%) 61 (16.5%) 6 (8%)c 0.168 Pseudoaneurysm 1 (2%) 9 (2.4%) 1 (1%) 0.849 Fistula NAF: new-onset atrial fibrillation; PAF: previous atrial fibrillation; SR: sinus rhythm Values are n (%), except for vegetation size that is presented as median. Location of the infection includes native and prosthetic valves. a Statistically significant differences between NAF-group and SR-group (p<0.05). b Statistically significant differences between NAF-group and PAF-group (p<0.05). c Statistically significant differences between SR-group and PAF-group (p<0.05).
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Table 4. Clinical events during in-hospital evolution in 507 patients with native left-sided infective endocarditis (including events at admission) NAF (n=52) 41 (79%) 7 (14%) 15 (29%) 28 (54%)
SR (n=380) 219 (58.4%) 50 (13.3%) 123 (32.8%) 178 (47.3%)
PAF (n= 75) 53 (71%) 5 (7%) 19 (25%) 45 (60%)
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Heart failure 0.005a 0.373 CNS embolism 0.411 Systemic embolism 0.113c Acute renal insufficiency 13 (25%) 58 (15.7%) 17 (23%) 0.122 Septic shock 26 (50%) 219 (57.6%) 40 (53%) 0.502 Cardiac surgery 24 (48%) 95 (25.6%) 27 (37%) Death 0.002a,c CNS=central nervous system; NAF: new-onset atrial fibrillation; PAF: previous atrial fibrillation; SR: sinus rhythm Values are n (%). Bold values are significant. a Statistically significant differences between NAF-group and SR-group (p<0.05). b Statistically significant differences between NAF-group and PAF-group (p<0.05). c Statistically significant differences between SR-group and PAF-group (p<0.05).
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Table 5. Multivariable analysis to predict mortality
0.99-1.04 0.22-0.67
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1.02 0.38
p <0.001 <0.001 <0.001 0.039 0.072 0.026 0.040 0.110 0.222
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95% CI 4.86-17.16 1.72-6.11 1.79-5.20 1.04-3.82 0.94-4.21 1.08-3.53 1.01-4.11 0.83-6.32 0.76-3.23
0.056 <0.001
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OR 9.04 3.20 3.10 1.99 1.99 1.95 1.91 2.29 1.57
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Variables Septic shock Heart failure Renal failure S. aureus Stroke Periannular complications New-onset AF Vegetation detection Moderate to severe valvular insufficiency Age Surgery
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S0002-9149(15)02248-1
DOI:
10.1016/j.amjcard.2015.11.012
Reference:
AJC 21524
To appear in:
The American Journal of Cardiology
Received Date: 14 September 2015 Revised Date:
4 November 2015
Accepted Date: 9 November 2015
Please cite this article as: Ferrera C, Vilacosta I, Fernández C, López J, Sarriá C, Olmos C, Vivas D, Sáez C, Sánchez-Enrique C, Ortiz-Bautista C, San Román JA, Usefulness of New-onset Atrial Fibrillation, as a Strong Predictor of Heart Failure and Death in Patients with Native Left-Sided Infective Endocarditis, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.11.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Usefulness of New-onset Atrial Fibrillation, as a Strong Predictor of Heart Failure and Death in Patients with Native Left-Sided Infective Endocarditis
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Running title: Atrial fibrillation in Infective Endocarditis
Carlos Ferrera MDa, Isidre Vilacosta MD, PhDa, Cristina Fernández MD,
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PhDa, Javier López MD, PhDb, Cristina Sarriá MD, PhDc, Carmen Olmos MD, PhDa, David Vivas MD, PhDa, Carmen Sáez MDc, Cristina SánchezEnrique MDa, Carlos Ortiz-Bautista MDb, José Alberto San Román MD,
a
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PhDb
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Instituto Cardiovascular, Hospital Clínico San Carlos, Madrid. Address: C/Profesor Martín Lagos S/N, 28040, Madrid, Spain; bInstituto de Ciencias del Corazón (ICICOR), Hospital Universitario de Valladolid. Address: Av. Ramón y Cajal, S/N, Valladolid, Spain; and cServicio de Medicina Interna, Hospital Universitario de la Princesa. Address: C/ Diego Leon, 62, 28006 Madrid, Spain.
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Corresponding author: Carlos Ferrera. Address for correspondence: Instituto Cardiovascular, Hospital Clínico San Carlos. Madrid. C/Profesor Martín Lagos S/N, 28040, Madrid, Spain.Tel.: +34913303149, Fax: +34913303290. Email: [email protected]
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Abstract Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults and has been
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independently related to increased morbidity and mortality. AF is a frequent arrhythmia in infective endocarditis (IE). Nevertheless, there are no data on how AF affects the
clinical outcome of patients with endocarditis. Our purpose was to investigate patient characteristics, microbiology, echocardiographic findings, in-hospital course, and
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prognosis of patients with IE who develop new-onset AF (NAF), and compare them
with those who remained in sinus rhythm (SR) or had previous AF. From 1997 to 2014,
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507 consecutive patients with native left-sided IE were prospectively recruited at three tertiary care centers. We distinguished three groups according to the type of baseline heart rhythm during hospitalization and previous history of AF: NAF-Group (n=52), patients with no prior history of AF and who were diagnosed as having NAF during
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hospitalization; SR-Group (n=380), patients who remained in SR; and PAF-Group (n=75), patients with previous AF. Patients with NAF were older than those who remained in SR (68.3 vs 59.6 years, p<0.001). At admission, heart failure was more
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common in NAF-Group (53% vs 34.3%, p<0.001), whereas stroke (p=0.427) was equally frequent in all groups. During hospitalization, embolic events occurred similarly
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(p=0.411). In the multivariable analysis, NAF was independently associated with heart failure (OR 3.56, p<0.01) and mortality (OR 1.91, p=0.04). In conclusion, the occurrence of NAF in patients with IE was strongly associated with heart failure, and higher in-hospital mortality independently from other relevant clinical variables. Keywords: atrial fibrillation; infective endocarditis; prognosis
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INTRODUCTION Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults and has
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been independently related to increased morbidity and mortality1. It is also well known the association between new-onset AF (NAF) and mortality in patients hospitalized with severe sepsis2,3 or heart failure4. Systemic inflammation and hemodynamic disorders
have been involved in the origin and perpetuation of AF in these clinical scenarios1,4-6.
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Infective endocarditis (IE) is a severe infectious disease producing a great systemic inflammatory reaction and local valve destruction leading to severe hemodynamic
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changes7. Not surprisingly, AF is common in IE, sometimes co-existing with heart failure and systemic embolism8-10. Nevertheless, there are no data on how AF affects the clinical outcome of patients with IE. We hypothesized that patients with IE and NAF have a worse clinical outcome than those who remain in sinus rhythm. Patients with
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NAF might be particularly prone to congestive heart failure and thrombo-embolic events (Figure 1). The purpose of this study was to investigate patient characteristics, microbiology, and echocardiographic findings of patients with IE and NAF. We further
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aim to compare the in-hospital course and prognosis of patients who develop de novo AF with that of those who remained in sinus rhythm or had previous AF.
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METHODS
This study was conducted at three tertiary care centers with surgical facilities,
which have been working together on IE with the use of standardized protocols. To ensure consecutive enrolment, all patients who underwent echocardiography to rule out IE were clinically followed until a diagnosis was established. Only definite cases of leftsided IE were included. Duke criteria were applied until 200211, and modified Duke 3
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criteria thereafter12. Right-sided episodes were excluded due to their different epidemiology, clinical characteristics and prognosis. From 1997 to 2014, 926 consecutive patients with left-sided IE were
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prospectively recruited on an on-going multipurpose database, 110 (11.9%) of them were excluded from the analysis due to inability to assess the baseline heart rhythm
during hospitalization. Patients with prosthetic valve endocarditis were also excluded
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from the study (309 patients). The remaining 507 patients with native left-sided IE formed our final study population
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This registry complies with the Declaration of Helsinki and was approved by the local ethical committee. All participants gave written informed consent. The proportion of missing data was less than 10% in all analyzed variables. For purposes of analysis and comparison, we distinguished three groups according to the type of baseline heart
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rhythm during hospitalization and previous history of AF: NAF-Group (n=52), patients with no prior history of AF and who were diagnosed as having NAF during hospitalization; SR-Group (n=380), patients without history of previous AF, who
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remained in sinus rhythm and that did not suffer AF during hospitalization; and PAFGroup (n=75) included patients with previous AF (permanent, paroxysmal or
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persistent). Those patients who developed post-operative AF after surgery for IE were not considered as NAF. All patients underwent transthoracic (TTE) and transesophageal
echocardiography (TEE). A set of three blood cultures was obtained at admission, and three additional blood cultures 48-72h later, If blood cultures were negative after 72h, specific serologic tests were done for Chlamydia, Brucella, Q fever, Legionella, Mycoplasma, and Bartonella. 4
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Nosocomial and community-acquired IE were defined according to the literature (7). Acute onset IE was applied when the time between the appearance of symptoms and hospital admission was less than 15 days13,14. Previous valvulopathy was defined as
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any kind of valvular heart disease and congenital valvular disease. Anemia was defined as a hemoglobin concentration below 9g/dl; renal insufficiency was established when
the serum creatinine concentration was higher than 2mg/dl. Heart failure was diagnosed
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according to Framingham criteria15. Under the term of immunosuppression were
included patients with HIV and those who were on steroids or other immunosuppressive therapy. Persistent signs of infection and septic shock were defined as previously
derived from imaging procedures.
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described7,10. The diagnosis of systemic embolism was based on clinical signs and data
NAF was defined when AF was registered in a 12-lead electrocardiogram done during hospitalization in a patient with previously documented sinus rhythm and no
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previous history of AF. Paroxysmal, persistent, and permanent AF were defined according to the guidelines1.
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The echocardiographic criteria used for definition and measurement of vegetations, abscesses, pseudoaneurysms and fistulas have been described
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elsewhere16,17. Left atrial dimension was measured in M-mode and 2-D transthoracic echocardiography following the recommendations of the American Society of Echocardiography18.
Surgery was defined as early if done before antibiotic treatment was completed,
and was performed when any of the following occurred: refractory heart failure, recurrent embolism with persistent vegetations in the echocardiogram, persistent signs of infection, and fungal endocarditis. When a patient meeting surgical criteria did not 5
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undergo surgery, the reason was either because of patient rejection, unacceptably highsurgical risk or when the patient was too frail. Continuous variables are reported as a mean value and standard deviation or
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median and interquartile range in cases of non-normality. Continuous variables were
compared between the groups with a 2-tailed Student’s t-test or Mann-Whitney U-test when necessary. Categorical variables are expressed as a frequency and a percentage
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and were compared with the χ2 test and Fisher’s exact test when appropriate. In case of multiple categories, ANOVA or Kruskal-Wallis test were used.
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Two multivariable logistic regression analyses were performed, one for prediction of mortality and another for detection of independent factors for heart failure. We included in the model the variables previously known to be associated to these events and those considered clinically relevant. When a variable statistically significant
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in the univariable analysis was not included in the multivariable analysis, the reason was collinearity or absence of change in the effect of atrial fibrillation. In addition, interactions between variables included in the model were assessed in the model. The
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adjusted odds ratios (OR) with 95% confidence intervals (CI) for each variable have been calculated. All test were two-tailed and differences were considered statistically
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significant at p-values<0.05. Statistical analysis was performed with PASW Statistics V 17.0 (SPSS Inc. Chicago, IL, USA).
RESULTS
Demographic characteristics, comorbidities, and clinical presentation comparisons between groups are summarized in Table 1. Patients with NAF were older than those who remained in sinus rhythm. Concerning comorbidities, chronic renal 6
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failure and chronic obstructive pulmonary disease (COPD) were more common in NAFGroup than in SR-Group. At admission, heart failure and their radiological manifestations were more common in NAF-Group, whereas stroke and systemic
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embolism were equally present in all groups. Interestingly, blood levels of acute phase reactants at admission (C-reactive protein) were higher among patients with NAF (Table 1).
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The microorganisms found in patients with NAF were not significantly different than those isolated in SR-Group and PAF-Group (Table 2).
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Echocardiographic data are shown in Table 3. As expected, left atrial dimension was higher in patients with NAF than in those who remained in sinus rhythm. Vegetations were equally present among groups (Table 3). Vegetation size was similar in all groups. As regard to the presence of moderate to severe valvular insufficiency, no
rhythm (Table 3).
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differences were found between patients with NAF and those who remained in sinus
Heart failure was significantly more frequent in patients with NAF (Table 4). In
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this group, 27 patients (53%) were already in heart failure at admission. Among patients with heart failure, moderate to severe valvular insufficiency was more frequently
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encountered in patients with sinus rhythm than in those with AF irrespective of the type (NAF or previous AF) (NAF-Group: 34 (85%), SR-Group: 193 (93.7%), PAF-Group: 42 (82.4%); p=0.020). According to these results, patients with heart failure and NAF underwent surgery less frequently than those with heart failure and sinus rhythm (NAFGroup: 20 (48.8%), SR-Group: 146 (68.5%), PAF-Group: 33 (62.3%); p=0.048).
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Overall, stroke and systemic embolism occurred in 157 patients (31%) in this series. These complications were not more common in patients with AF irrespective of the type (NAF or previous AF).
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The need for surgery and time from admission to surgery was similar in all
groups (NAF-Group: 13.5 days, SR-Group: 16 days, PAF-Group: 14 days; p=0.726).
There were 146 deaths (28.8%). Death was much more common in NAF-Group
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than in SR-Group (p=0.001), and a greater mortality in NAF-Group vs PAF-Group
(p=0.044) was also detected (Table 4). No differences were observed regarding causes
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of death between the different groups. We noticed that patients with NAF and heart failure had a higher mortality than those who despite having developed heart failure, remained in sinus rhythm (Figure 2).
To determine potential variables independently associated to the presence of
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heart failure at admission and during hospitalization, a multivariable logistic regression analysis was performed. We included in the model variables that were considered clinically relevant and those that were significant in the univariable analysis: age,
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S.aureus, vegetation detection, periannular complications, acute renal failure, septic shock, surgery, moderate to severe valvular insufficiency, and NAF. Prognostic factors
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of heart failure are shown in Figure 3. NAF was found to have strong adjusted association with heart failure (OR 3.56, 95% CI: 1.52-8.26). We performed a multivariable analysis to determine the variables that were
independently associated with mortality during the clinical course of the disease. We included in the model the following variables: age, S.aureus, vegetation detection, periannular complications, heart failure, acute renal failure, septic shock, surgery, moderate to severe valvular insufficiency, stroke and NAF. Prognostic factors of 8
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mortality are shown in Table 5. NAF (OR 1.91, 95% CI: 1.01-4.11) remained independently associated with increased in-hospital mortality after adjusting for other variables.
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Interaction between NAF and patients’ treatment (surgery or medical therapy)
was assessed. Mortality was higher in NAF-Group than in SR-Group independently of the need of surgery (p of interaction 0.764). In addition, interaction between NAF and
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the variables included in the model was also evaluated, in order to determine the potential contribution of these interactions in the association between NAF and
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mortality. All the assessed interactions resulted statistically non-significant.
DISCUSSION
This study is the first to examine the impact of NAF in patients with left-sided IE. We showed that NAF is common in patients hospitalized with IE (10.3%), and that
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it is associated with higher in-hospital mortality. Our findings also show that NAF has a strong adjusted association with heart failure during active IE. This investigation focused on patients that being in sinus rhythm prior to IE fell
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into AF during the course of the disease. The main aim was to compare these patients with those that remained in sinus rhythm. Regarding demographic and comorbidity
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conditions, patients with NAF were older, left atrial dimension was bigger, and they had more frequently chronic renal failure and COPD. With aging, the extent of atrial fibrosis increases19. Fibrosis results from increased collagen deposit and is considered an
important factor in the development and maintenance of the arrhythmia20,21. Chronic
renal failure is a common comorbidity among AF patients22. It is well known that chronic renal failure favors tissue fibrosis and hypertension, and therefore the onset and establishment of AF. 9
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Although AF is associated with increased risks of major cardiovascular events such as stroke, heart failure, and death23, the event rates of these competing outcomes in IE have not been analyzed. In the herein series, the rate of stroke and systemic
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embolism was not higher in episodes with NAF. Our results support the concept that in IE, other factors like presence, mobility, and size of vegetations as well as specific microorganisms have a greater role in the pathogenesis of this complication24.
Interestingly, in a recent study to predict embolism in IE, AF was not statistically
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associated with embolic events25.
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Heart failure is a more frequent complication of AF than stroke26. Acute AF may lead to overt heart failure, the symptoms of which often improve after AF termination27. In IE, heart failure may be secondary to rapid AF, and severe valvular insufficiency among other factors. Understanding the mechanism for developing heart failure in patients with IE is an important goal. In our series, NAF was found to be strongly
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associated to heart failure. Loss of atrio-ventricular synchrony, rapid an irregular ventricular response, and lack of atrial contraction reduce diastolic filling and cardiac output. In this scenario, atrial and pulmonary capillary pressures increase perpetuating
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heart failure and AF. In IE, severe valvular insufficiency secondary to valvular destruction by the infection may also contribute to heart failure. Interestingly, moderate
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to severe valvular insufficiency was not more common in episodes with NAF. As heart failure is the most frequent complication of IE, and represents the most
common indication for surgery7, it is particularly relevant to stand out that in our series the proportion of patients who developed heart failure was higher in episodes with AF (NAF and previous), however these two groups had a lower rate of moderate to severe valvular insufficiency. These facts suggest that heart failure in some patients with left10
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sided IE and AF could be solved by heart rate or rhythm control instead of with valvular surgery. In our series, surgery was performed more frequently in patients with heart failure and sinus rhythm than in those with heart failure and AF (p=0.048).
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Data from a variety of studies have shown that AF is associated with greater
mortality1-4,23. Furthermore, the risk of death is higher in critically ill patients, such as
those with sepsis3. In this series, NAF in patients with left-sided IE was associated with
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a higher in-hospital mortality. Possibly, increased mortality is due to the negative
impact of NAF on cardiac function. However, it is also possible that the cause of NAF
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is also the reason for the increase in mortality. In the latter case, NAF would be a marker instead of a mediator of mortality.
This study has several limitations that should be considered when interpreting the results. It is part of a multiproposal prospective collection of data with a large
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number of cases, but it has potentially referral bias because all the participants are tertiary care centers. Strategies for identifying AF are highly specific, but insensitive so, we likely underestimated the burden of NAF. In addition, we could not exclude the
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possibility that patients with NAF may have had undetected (previous AF) present before IE hospitalization. Although we hypothesized that patients with NAF are at
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increased risk for heart failure, the temporality between AF and heart failure could not be clearly established. Information regarding specific management of AF at admission and during hospitalization was not available.
ACKNOWLEDGMENT There is no sponsor or funding source involved in the study design; collection,
analysis, and interpretation of data; writing the report; and in the decision to submit the article for publication. 11
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CONFLICT OF INTEREST
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None declared.
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6. Acebedo M, Corbalan R, Braun S, Pereira J, Navarrete C, Gonzalez I. C-reactive protein and atrial fibrillation: “evidence for the presence of inflammation in the perpetuation of the arrhythmia”. Int J Cardiol 2006;108:326-331.
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N, Ruimy R, Leport C, Wolff M, Duval X; ECHO-IMAGE Study Group. Determinants of cerebral lesions in endocarditis on systematic cerebral magnetic resonance imaging: a prospective study. Stroke 2013;44:3056-3062.
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11. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis:
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Ronderos R, González Pinto A, Jesús Rollán M, Graupner C, Batlle E, Lahulla F, Stoermann W, Portis M, Fernández-Avilés F. Clinical course, microbiologic profile, and diagnosis of periannular complications in prosthetic valve endocarditis. Am J Cardiol 1999;83:1075-1079.
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18. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT, St John Sutton M, Stewart W. Recommendations for chamber quantification.
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19. Burstein B, Nattel S. Atrial fibrosis: mechanism and clinical relevance in atrial fibrillation. J Am Coll Cardiol 2008;51:802-809.
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institution of antibiotic therapy for infective endocarditis. J Am Coll Cardiol 2002;39:1489-1495. 25. Hubert S, Thuny F, Resseguier N, Giorgi R, Tribouilloy C, Le Dolley Y, Casalta
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FIGURE LEGENDS Figure 1. Main hypothesis of the study – Patients with IE who develop AF might be
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prone to heart failure and embolic events and therefore higher mortality. AF: atrial fibrillation; Em: embolism; HF: heart failure; IE: infective endocarditis
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Figure 2. Mortality risk in patients with heart failure according to the heart
rhythm – Patients with new-onset AF and heart failure had a higher mortality than
atrial fibrillation; SR: sinus rhythm.
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those who remained in sinus rhythm. NAF: new onset atrial fibrillation; PAF: previous
Figure 3. Multivariable analysis to predict heart failure – Diagram showing the
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results (OR and CI) of the multivariable analysis to predict heart failure. New onset atrial fibrillation was found to be independently associated with heart failure (OR 3.56; 95% CI: 1.52-8.26).
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Table 1. Demographic and main clinical characteristics, electrocardiographic, radiological and laboratory findings at admission in 507 patients with native left-sided infective endocarditis
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PAF (n= 75) 68.9 (12.1) 44 (59%)c 44 (59%) 59 (80%) 23 (31%) 11 (15%) 20 (27%) 7 (9.3%) 11 (15%)
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Age (years) Male Community-acquired IE Previous valvulopathy Anemia Chronic renal failure Diabetes Alcoholism Chronic obstructive pulmonary disease 6 (12%) Malignant neoplasia 4 (8%) Immunosuppression 12.5 (7-57) Symptoms to admission (days) 26 (50%) Acute onset (<15days) 32 (63%) Fever at admittance 27 (53%) Heart failure 16 (31%) Acute renal failure 6 (12%) Septic shock 5 (10%) Chest pain 5 (10%) Abdominal pain 4 (8%) Splenomegaly 11 (21%) Confusional syndrome 2 (4%) Coma Stroke 1 (2%) Hemorrhagic 7 (14%) Ischemic 9 (17%) Systemic embolism 4 (8%) Hematuria 5 (10%) Arthritis/ Spondylodiscitis 11 (24.4%) Anticoagulation 2 (4%) Second and third degree AV block Left bundle-branch block 3 (6%) 37 (71%) Cardiomegaly 22 (43%) Pleural effusion 17.9 C-reactive protein (6.9-115.3) (mg/dl)* 11 (2.2) Hemoglobin (g/dl)
SR (n=380) 59.6 (16.2) 259 (68.2%) 297 (78.6%) 154 (43.6%) 76 (20.2%) 34 (9%) 67 (17.8%) 41 (10.9%) 20 (5.3%)
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NAF (n=52) 68.3 (10.2) 36 (69%) 33 (64%) 27 (54%) 12 (23%) 10 (19%) 15 (29%) 6 (12%) 7 (14%)
<0.001a,c 0.260 0.002a,c <0.001b,c 0.135c 0.047a 0.057a 0.903 0.005a,c
43 (11.4%) 31 (8.2%) 20.5 (7-60)
11 (15%) 8 (11%) 20 (7-35)
0.721 0.776 0.497
145 (38.7%) 281 (75.5%) 129 (34.3%) 73 (19.5%) 17 (4.6%) 38 (10.2%) 43 (11.6%) 39 (10.5%) 52 (13.9%) 11 (2.9%)
33 (44%) 53 (72%) 38 (51%) 13 (17%) 7 (9%) 7 (9%) 6 (8%) 4 (5%)c 12 (16%) 2 (3%)
0.241 0.138 0.003a,c 0.131a 0.108a 0.968 0.631 0.063 0.376 0.923 0.427
13 (3.5%) 47 (12.5%) 85 (22.5%) 14 (3.7%) 66 (17.7%)
2 (3%) 4 (5%) 11 (15%) 1 (1%) 6 (8%)
0.248 0.181 0.052c
23 (6.2%) 8 (2.1%)
53 (71%) 1 (1%)
<0.001b,c 0.646
10 (2.7%) 160 (42.4%) 83 (22.1%) 14.3 (4.867.8) 11.1 (2.1)
7 (10%) 50 (69%) 19 (26.4%) 6.9 (2.9-14.8)
0.017c <0.001a,c 0.005a,b 0.026a,b,c
11 (2)
0.955
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228x103 196x103 215x103 0.114 3 3 (141x10 ) (99x103)c (124x10 ) AV block= atrioventricular block; NAF: new-onset atrial fibrillation; PAF: previous atrial fibrillation; SR: sinus rhythm a Statistically significant differences between NAF-group and SR-group (p<0.05). b Statistically significant differences between NAF-group and PAF-group (p<0.05). c Statistically significant differences between SR-group and PAF-group (p<0.05). * Upper normal limit for C-reactive protein 0.5mg/dl.
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Table 2. Microbiological profile in 507 patients with native leftsided infective endocarditis
NAF (n=52)
SR-Group (n=380)
PAF-Group (n= 75)
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2 (4%) 23 (6.1%) 3 (4%)c 0.654 Streptococcus bovis 5 (10%) 69 (18.3%) 6 (8%) Streptococcus viridans 0.036c 4 (8%) 32 (8.5%) 5 (7%) 0.864 Other estreptococci 6 (11.5%) 33 (8.8%) 8 (11%) 0.738 Enterococci 7 (14%) 66 (17.5%) 13 (17%) 0.766 Staphylococcus aureus 10 (19%) 45 (11.9%) 13 (17%) 0.202 Coagulase negative staphylococci 1 (2%) 11 (2.9%) 2 (3%) 0.918 Gram negative bacilli 0 (0%) 4 (1.1%) 2 (3%) 0.355 Fungi 0 (0%) 4 (1.1 %) 0 (0%) 0.507 HACEK Group 0 (0%) 3 (0.8%) 1 (1%) 0.707 Anaerobes 3 (6%) 20 (5.3%) 7 (9%) 0.403 Polymicrobial 2 (4%) 13 (3.4%) 4 (5%) 0.736 Others 12 (23.1%) 54 (14.3%) 11 (15%) 0.255 Negative cultures NAF: new-onset atrial fibrillation; PAF: previous atrial fibrillation; SR: sinus rhythm a Statistically significant differences between NAF-group and SR-group (p<0.05). b Statistically significant differences between NAF-group and PAF-group (p<0.05). c Statistically significant differences between SR-group and PAF-group (p<0.05).
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Table 3. Echocardiographic findings NAF (n=52)
SR (n=380)
PAF (n= 75)
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Location of the infection 29 (56%) 216 (56.8%) 39 (52%) 0.742 Aortic native valve 30 (58%) 227 (59.7%) 45 (60%) 0.958 Mitral native valve 43.3 (6.8) 52.4 (14.3) <0.001a,c Left atrial dimension (mm) 48 (8.5)a Vegetations 332 (90%) 61 (84%) 48 (98%) Detection by 0.035b echocardiography 12 (9.4-18.3) 12.7 (9-18.5) 12 (7-18·4) 0.805 Vegetation size (mm) 40 (82%) 314 (85.1%) 55 (75%) 0.118c Moderate-severe valvular regurgitation 14 (29%) 92 (24.9%) 15 (21%) 0.582 Periannular complications 9 (16%) 46 (12.5%) 14 (19%) 0.275 Abscess 9 (18%) 61 (16.5%) 6 (8%)c 0.168 Pseudoaneurysm 1 (2%) 9 (2.4%) 1 (1%) 0.849 Fistula NAF: new-onset atrial fibrillation; PAF: previous atrial fibrillation; SR: sinus rhythm Values are n (%), except for vegetation size that is presented as median. Location of the infection includes native and prosthetic valves. a Statistically significant differences between NAF-group and SR-group (p<0.05). b Statistically significant differences between NAF-group and PAF-group (p<0.05). c Statistically significant differences between SR-group and PAF-group (p<0.05).
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Table 4. Clinical events during in-hospital evolution in 507 patients with native left-sided infective endocarditis (including events at admission) NAF (n=52) 41 (79%) 7 (14%) 15 (29%) 28 (54%)
SR (n=380) 219 (58.4%) 50 (13.3%) 123 (32.8%) 178 (47.3%)
PAF (n= 75) 53 (71%) 5 (7%) 19 (25%) 45 (60%)
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Heart failure 0.005a 0.373 CNS embolism 0.411 Systemic embolism 0.113c Acute renal insufficiency 13 (25%) 58 (15.7%) 17 (23%) 0.122 Septic shock 26 (50%) 219 (57.6%) 40 (53%) 0.502 Cardiac surgery 24 (48%) 95 (25.6%) 27 (37%) Death 0.002a,c CNS=central nervous system; NAF: new-onset atrial fibrillation; PAF: previous atrial fibrillation; SR: sinus rhythm Values are n (%). Bold values are significant. a Statistically significant differences between NAF-group and SR-group (p<0.05). b Statistically significant differences between NAF-group and PAF-group (p<0.05). c Statistically significant differences between SR-group and PAF-group (p<0.05).
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Table 5. Multivariable analysis to predict mortality
0.99-1.04 0.22-0.67
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p <0.001 <0.001 <0.001 0.039 0.072 0.026 0.040 0.110 0.222
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0.056 <0.001
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OR 9.04 3.20 3.10 1.99 1.99 1.95 1.91 2.29 1.57
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Variables Septic shock Heart failure Renal failure S. aureus Stroke Periannular complications New-onset AF Vegetation detection Moderate to severe valvular insufficiency Age Surgery
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