Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia.

The role of host genetic variation in the development of complicated Staphylococcus aureus bacteremia (SAB) is poorly understood. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 complicated and 84 uncomplicated, frequency matched by age, sex, and bacterial clonal complex [CC]), and then evaluated the most significantly associated genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched for age, sex, and CC) using targeted sequence capture. In the discovery sample, gene-based analysis using the SKAT-O program identified 334 genes associated with complicated SAB at p<3.5 x 10-3. These, along with eight biologically relevant candidate genes were examined in the replication sample. Gene-based analysis of the 342 genes in the replication sample using SKAT-O identified one gene, GLS2, significantly associated with complicated SAB (p = 1.2 x 10-4) after Bonferroni correction. In Firth-bias corrected logistic regression analysis of individual variants, the strongest association across all 10,931 variants in the replication sample was with rs2657878 in GLS2 (p = 5 x 10-4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4 x 10-3) in which the minor allele (associated here with complicated SAB) has been previously associated with lower plasma concentration of glutamine. In a microarray-based gene-expression analysis, individuals with SAB exhibited significantly lower expression levels of GLS2 than healthy controls. Similarly, Gls2 expression is lower in response to S. aureus exposure in mouse RAW 264.7 macrophage cells. Compared to wild-type cells, RAW 264.7 cells with Gls2 silenced by CRISPR-Cas9 genome editing have decreased IL1-ß transcription and increased nitric oxide production after S. aureus exposure. GLS2 is an interesting candidate gene for complicated SAB due to its role in regulating glutamine metabolism, a key factor in leukocyte activation.

Left axis deviation in patients with left bundle branch block is a marker of myocardial disease associated with poor response to cardiac resynchronization therapy.

AIMS: Patients with left axis deviation (LAD) and left bundle branch block (LBBB) show less benefit from cardiac resynchronization therapy (CRT) compared to other LBBB-patients. This study investigates the reasons for this. METHODS: Sixty-eight patients eligible for CRT were included. Patients were divided into groups according to QRS-axis; normal axis (NA), left axis deviation (LAD) and right axis deviation (RAD). Before CRT implantation CMR imaging was performed to evaluate scar tissue. Echocardiography was performed before and after implantation. The electrical substrate was assessed by measuring interlead electrical delays. Response was evaluated after 8 months by left ventricular (LV) remodelling and clinical response. RESULTS: Forty-four (65%) patients were responders in terms of LV remodelling. The presence of LAD was found to be independently associated with a poor LV remodelling non-response OR 0.21 [95% CI 0.06-0.77] (p = 0.02). Patients with axis deviation had more myocardial scar tissue (1.3 ±â€¯0.6 vs. 0.9 ±â€¯0.6, P = 0.04), more severe LV hypertrophy (14 (64%) and 6 (60%) vs. 7 (29%), P = 0.05) and tended to have a shorter interlead electrical delay than patients with NA (79 ±â€¯40 ms vs. 92 ±â€¯48 ms, P = 0.07). A high scar tissue burden was more pronounced in non-responders (1.4 ±â€¯0.6 vs. 1.0 ±â€¯0.5, P = 0.01). CONCLUSIONS: LAD in the presence of LBBB is a predictor of poor outcome after CRT. Patients with LBBB and LAD have more scar tissue, hypertrophy and less activation delay.

Prevalence of infective endocarditis in patients with positive blood cultures: a Danish nationwide study.

AIMS: Increasing attention has been given to the risk of infective endocarditis (IE) in patients with certain blood stream infections (BSIs). Previous studies have been conducted on selected patient cohorts, yet unselected data are sparse. We aimed to investigate the prevalence of IE in BSIs with bacteria typically associated with IE. METHODS AND RESULTS: By crosslinking nationwide registries from 2010 to 2017, we identified patients with BSIs typically associated with IE: Enterococcus faecalis (E. faecalis), Staphylococcus aureus (S. aureus), Streptococcus spp., and coagulase negative staphylococci (CoNS) and examined the concurrent IE prevalence. A trend test was used to examine temporal changes in the prevalence of IE. In total 69 021, distributed with 15 350, 16 726, 19 251, and 17 694 BSIs were identified in the periods of 2010-2011, 2012-2013, 2014-2015, and 2016-2017, respectively. Patients with E. faecalis had the highest prevalence of IE (16.7%) followed by S. aureus (10.1%), Streptococcus spp. (7.3%), and CoNS (1.6%). Throughout the study period, the prevalence of IE among patients with E. faecalis and Streptococcus spp. increased significantly (P = 0.0005 and P = 0.03, respectively). Male patients had a higher prevalence of IE for E. faecalis, Streptococcus spp., and CoNS compared with females. A significant increase in the prevalence of IE was seen for E. faecalis, Streptococcus spp., and CoNS with increasing age. CONCLUSION: For E. faecalis BSI, 1 in 6 had IE, for S. aureus BSI 1 in 10 had IE, and for Streptococcus spp. 1 in 14 had IE. Our results suggest that screening for IE seems reasonable in patients with E. faecalis BSI, S. aureus BSI, or Streptococcus spp. BSI.

Interlead electrical delays and scar tissue: Response to cardiac resynchronization therapy in patients with ischemic cardiomyopathy.

BACKGROUND: The importance of interlead electrical delays (IEDs) in the presence of scar tissue for response to cardiac resynchronization therapy (CRT) in patients with ischemic cardiomyopathy is poorly described. METHODS: Sixty-eight CRT patients with ischemic cardiomyopathy and left bundle branch block were included. IEDs, the time between sensing of native impulse at the RV lead and LV lead, were measured at implantation and after 8 months. Magnetic resonance imaging was used for assessment of scar tissue. Echocardiographic response was defined as ≥ 15% decrease in left ventricular end-systolic volume. New York Heart Association (NYHA) class, Minnesota Living with Heart Failure Questionnaire, and 6-minute walk-test were used to assess clinical response. RESULTS: A total of 44 patients (65 %) were responders to CRT. At implantation, IEDs were significantly longer among responders compared to nonresponders (RV-LV-IED: 87 ms ± 33 ms vs 65 ms ± 47 ms, P < 0.05), most evident in patients with QRS < 150 ms. Responders had less myocardial scar tissue than nonresponders (1 ± 0.5 vs 1.4 ± 0.6, P = 0.01). However, in the multivariate model including QRS duration and scar tissue, IEDs were independently associated with LV remodeling after CRT: odds ratio 3.99 [95% confidence interval 1.02-15.7] (P = 0.04). During the course of treatment, no changes were observed in IEDs among echocardiographic responders. CONCLUSION: RV-LV-IED was an independent marker of response in CRT patients with ischemic cardiomyopathy even in the presence of scar tissue and may be particularly useful in patients with QRS < 150 ms. CRT did not influence this measurement over time.

Infectious endocarditis caused by Escherichia coli.

Although Escherichia coli is among the most common causes of Gram-negative bacteraemia, infectious endocarditis (IE) due to this pathogen is rare. A 67-y-old male without a previous medical history presented with a new mitral regurgitation murmur and persisting E. coli bacteraemia in spite of broad-spectrum intravenous antibiotics. Transthoracic and transoesophageal echocardiography revealed a severe mitral endocarditis. E. coli DNA was identified from the mitral valve and the vegetation, and no other pathogen was found. The case was further complicated by spondylodiscitis and bilateral endophthalmitis. Extra-intestinal pathogenic E. coli (ExPEC) are able to colonize tissue outside the gastrointestinal tract and contain a variety of virulence factors that may enable the pathogens to invade and induce infections in the cardiac endothelia. In these cases echocardiography as the imaging technology is of paramount importance for the correct diagnosis and treatment.

Valve regurgitation in patients surviving endocarditis and the subsequent risk of heart failure.

BACKGROUND: Significant valve regurgitation is common in patients surviving native valve infective endocarditis (IE), however the associated risk of heart failure (HF) subsequent to hospital discharge after IE is sparsely described. METHODS: We linked data from the East Danish Endocarditis Registry with administrative registries from 2002 to 2016 and included patients treated medically for IE who were discharged alive. Left-sided valve regurgitation was assessed by echocardiography at IE discharge and examined for longitudinal risk of HF. Multivariable adjusted Cox analysis was used to assess the associated risk of HF in patients with regurgitation (moderate or severe) compared with patients without regurgitation. RESULTS: We included 192 patients, 87 patients with regurgitation at discharge (30 with aortic regurgitation and 57 with mitral regurgitation) and 105 patients without. The cumulative risk of HF at 5 years of follow-up was 28.7% in patients with regurgitation at IE discharge and 12.4% in patients without regurgitation; the corresponding multivariable adjusted HR was 3.53 (95% CI 1.72 to 7.25). We identified an increased associated risk of HF for patients with aortic regurgitation (HR=2.91, 95% CI 1.14 to 7.43) and mitral regurgitation (HR=3.95, 95% CI 1.80 to 8.67) compared with patients without regurgitation. During follow-up, 21.9% and 5.7% underwent left-sided valve surgery among patients with and without regurgitation. CONCLUSION: In patients surviving IE, treated medically, we observed that severe or moderate left-sided native valve regurgitation was associated with a significantly higher risk of HF compared with patients without regurgitation at IE discharge. Close monitoring of these patients is needed to initiate surgery timely.

Residual vegetation after treatment for left-sided infective endocarditis and subsequent risk of stroke and recurrence of endocarditis.

BACKGROUND: Little is known about the subsequent risk of stroke and recurrence of IE for patients surviving infective endocarditis (IE) with a residual vegetation at discharge. METHODS: Patients were consecutively included in the East Danish Endocarditis Registry from 2002 to 2012. We included patients undergoing medical treatment only during IE admission who were discharged alive. Size of residual vegetation was assessed by echocardiography at discharge and patients were categorized according to median length of residual vegetation. Using multivariable adjusted Cox Proportional hazard analysis, we assessed the associated risk of stroke and recurrence of IE between study groups. RESULTS: Among 915 IE patients, 305 were included after selection criteria were applied, 151 patients without residual vegetation, 73 patients with 1-5 mm residual vegetation, and 81 patients with >5 mm residual vegetation. We identified an increased associated risk of stroke for patients with 1-5 mm and > 5 mm residual vegetation, HR = 0.88 (95% CI: 0.26-2.94) and HR = 2.95 (95% CI:1.18-7.34) compared with patients without residual vegetation. No difference was seen between groups for the associated risk of recurrence of IE, HR = 1.39 (95% CI: 0.91-2.13) and HR = 1.38 (95% CI: 0.91-2.10) for patients with a residual vegetation 1-5 mm and > 5 mm compared with patients without residual vegetation. CONCLUSIONS: Patients surviving IE with a residual vegetation > 5 mm had an increased associated risk of stroke compared with patients without residual vegetation. These findings provide new perspectives on a patient group sparsely describe, suggesting a potential benefit of therapy among patients surviving IE with a residual vegetation > 5 mm.

Two-dimensional global longitudinal strain is superior to left ventricular ejection fraction in prediction of outcome in patients with left-sided infective endocarditis.

BACKGROUND: Impaired cardiac function is the main predictor of poor outcome in infective endocarditis (IE). Global longitudinal strain (GLS) derived from two-dimensional strain echocardiography has proven superior in prediction of long-term outcome as compared to left ventricular ejection fraction (LVEF) in valvular disease and heart failure in general. Whether measurements of cardiac deformation can predict survival in patients with IE has not previously been investigated. METHODS: The study included consecutive patients with Duke definite IE who underwent transthoracic and transesophageal echocardiography within 7 days. Clinical and echocardiographic markers associated with 1-year survival were identified using a Cox-proportional hazards model that included propensity adjustment for surgery. Reclassification statistics including receiver operating characteristic curves and net reclassification improvement were applied to LVEF and GLS, respectively. RESULTS: A cohort of 190 patients met eligibility criteria. LVEF and GLS were both prognostic markers of mortality. Independent markers of 1-year mortality were S. aureus IE (HR:2.02; 95%CI 1.11-5.72, p = .022), diabetes (HR:2.05; 95%CI 1.12-3.75, p = .020), embolic stroke (HR:3.95; 95%CI 1.93-8.10, p < .001) and LVEF<45% (HR: 3.02; 95% CI 1.70-5.38, p < .001), GLS> -15.4% (HR:2.95; 95%CI 1.52-5.72, p < .001). Adding LVEF<45% to a model with known risk factors of IE did not significantly improve risk classification, whereas addition of GLS to the model resulted in significant increase (AUC = 0.763, p < .001). CONCLUSIONS: When treatment was taken into account, LVEF<45% and GLS > -15.4% were both associated with adverse long-term outcome in left-sided IE. GLS >-15.4 % was significantly associated with 1-year mortality in the multivariate analysis. Further, GLS was superior to LVEF in risk prediction and risk discrimination of long-term outcome in patients with left-sided IE.

Long-term causes of death in patients with infective endocarditis who undergo medical therapy only or surgical treatment: a nationwide population-based study.

OBJECTIVES: It is known that patients surviving infective endocarditis have a poor long-term prognosis; however, few studies have addressed the long-term causes of death in patients surviving the initial hospitalization. METHODS: Using Danish administrative registries, we identified patients admitted to a hospital with 1st time infective endocarditis in the period from January 1996 to December 2014, who were alive at the time of discharge. The study population was categorized into (i) patients undergoing medical therapy only and (ii) patients undergoing surgical and medical treatment. We examined the cardiovascular and non-cardiovascular causes of death. Using the Cox analysis, we investigated the associated risk of dying from a specific prespecified cause of death (heart failure, infective endocarditis and stroke) within the surgery group when compared with the medically treated group. RESULTS: We identified 5576 patients: 4220 patients belonged to the medically treated group and 1356 patients to the surgery group. At the 10-year follow-up, the mortality rate was 63.1% and 41.6% in the medically treated group and the surgery group, respectively. Cardiovascular disease was the most frequent cause of death in both groups accounting for 52.5% in the medically treated group and 55.2% in the surgery group. Patients undergoing surgery were associated with a lower risk of dying from heart failure and stroke when compared with medically treated patients [hazard ratio = 0.66 (95% confidence interval: 0.46-0.94) and hazard ratio = 0.59 (95% confidence interval: 0.37-0.96), respectively]. CONCLUSIONS: No major differences were found in the main causes of death between groups. Patients in the surgical group were associated with a lower risk of dying from heart failure and stroke when compared with medically treated patients.

Echocardiographic agreement in the diagnostic evaluation for infective endocarditis.

Echocardiography is essential for the diagnosis and management of infective endocarditis (IE). However, the reproducibility for the echocardiographic assessment of variables relevant to IE is unknown. Objectives of this study were: (1) To define the reproducibility for IE echocardiographic variables and (2) to describe a methodology for assessing quality in an observational cohort containing site-interpreted data. IE reproducibility was assessed on a subset of echocardiograms from subjects enrolled in the International Collaboration on Endocarditis registry. Specific echocardiographic case report forms were used. Intra-observer agreement was assessed from six site readers on ten randomly selected echocardiograms. Inter-observer agreement between sites and an echocardiography core laboratory was assessed on a separate random sample of 110 echocardiograms. Agreement was determined using intraclass correlation (ICC), coverage probability (CP), and limits of agreement for continuous variables and kappa statistics (κweighted) and CP for categorical variables. Intra-observer agreement for LVEF was excellent [ICC = 0.93 ± 0.1 and all pairwise differences for LVEF (CP) were within 10 %]. For IE categorical echocardiographic variables, intra-observer agreement was best for aortic abscess (κweighted = 1.0, CP = 1.0 for all readers). Highest inter-observer agreement for IE categorical echocardiographic variables was obtained for vegetation location (κweighted = 0.95; 95 % CI 0.92-0.99) and lowest agreement was found for vegetation mobility (κweighted = 0.69; 95 % CI 0.62-0.86). Moderate to excellent intra- and inter-observer agreement is observed for echocardiographic variables in the diagnostic assessment of IE. A pragmatic approach for determining echocardiographic data reproducibility in a large, multicentre, site interpreted observational cohort is feasible.

[Linezolid therapy for infectious endocarditis]. / Linezolid som behandling af infektiøs endokarditis.

In Denmark enterococci causes 15 to 20% of all endocarditis (IE) cases. The development of multi-resistant bacterial strains has increased the need for new antibiotics. Linezolid is an alternative to conventional treatment of infections with gram positive cocci. In this case report linezolid was used to treat IE in a patient, who was allergic to penicillin and where conventional treatment caused development of acute renal failure. No side effects were observed and the patient responded well to the treatment.