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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.

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.

BACKGROUND: The aim of the study was to investigate the associated risk of stroke after discharge of infective endocarditis (IE) in patients with stroke during IE admission compared with patients without stroke during IE admission.METHODS: Using Danish nationwide registries, we identified nonsurgically treated patients with IE discharged alive in the period from 1996 to 2016. The study population was grouped into (1) patients with stroke during IE admission and (2) patients without stroke during IE admission. Multivariable adjusted Cox proportional-hazard analysis was used to compare the associated risk of stroke between groups.RESULTS: We identified 4,284 patients with IE, of whom 239 (5.6%) had a stroke during IE admission. We identified differentials in the associated risk of stroke during follow-up between groups (P = .006 for interaction with time). The associated risk of stroke was higher in patients with stroke during IE admission with a 1-year follow-up, HR = 3.21 (95% CI 1.66-6.20), compared with patients without stroke during IE admission. From 1 to 5 years of follow-up, we identified no difference in the associated risk of stroke between groups, HR = 0.91 (95% CI 0.33-2.50).CONCLUSIONS: Patients with nonsurgically treated IE with a stroke during IE admission were at significant higher associated risk of subsequent stroke within the first year of follow-up as compared with patients without a stroke during IE admission. This risk difference was not evident beyond 1 year of discharge. These findings underline the need for identification of causes and mechanisms of recurrent strokes after IE to develop preventive means.

Heart failure with preserved ejection fraction (HFpEF) involves half of hospitalised patients with heart failure (HF), but estimates vary due to unclear diagnostic criteria. We performed a prospective observational study of hospitalised patients admitted with dyspnoea. The aim was to apply contemporary guidelines to diagnose HF due to valvular disease (HFvhd), HF due to reduced ejection fraction (HFrEF), HF due to midrange EF (HFmrEF) and HFpEF in relation to presumed cardiac or non-cardiac dyspnoea. Methods We included consecutive hospitalised patients with presumed HF or dyspnoea and excluded patients with acute coronary syndrome, estimated glomerular filtration rate <30 mL/min/1.73 m or low NT-proBNP (<296 ng/L). Higher age-adjusted NT-proBNP values excluded patients with presumptive non-cardiac dyspnoea. Contemporary criteria for HFpEF and diastolic dysfunction were assessed, and we adjudicated whether acute decompensated HF (ADHF) had been the primary diagnosis. Results Of 707 eligible patients, we included 370 patients of whom 75 had non-cardiac dyspnoea. Of these, 10% (38/370) had no cardiac dysfunction. Cardiac dysfunction consisted of 18.4%, HFvhd, 30.1% HFrEF, 10.2% HFmrEF and 41.3% HFpEF. HFpEF was twice as common in presumptive non-cardiac dyspnoea versus cardiac dyspnoea (71% vs 34%, p<0.0001). However, adjudicated ADHF was the primary diagnosis in 80% of HFrEF, 62% of HFmrEF and just 28% of HFpEF. Conclusion HF according to contemporary criteria applied to 90% of patients admitted with dyspnoea and elevated NT-proBNP irrespective of the presumptive cause of dyspnoea, of whom 10% had HFmrEF and 41% HFpEF. However, significant non-cardiac diagnoses related to 9 out of 10 with HFpEF with pulmonary disease as the predominant adjudicated problem.

AIMS: Stratification of patients at risk of infective endocarditis (IE) remains a cornerstone in guidance of prophylactic strategies of IE. However, little attention has been given to patients considered at moderate risk.METHODS AND RESULTS: Using Danish nationwide registries, we assessed the risk of IE in patients with aortic and mitral valve disorders, a cardiac implantable electronic device (CIED), or hypertrophic cardiomyopathy (HCM) and compared these patient groups with (i) controls from the background population using risk-set matching and (ii) a high-risk population (prosthetic heart valve). Cumulative incidence plots and multivariable adjusted Cox proportional hazard analysis were used to compare risk of IE between risk groups. We identified 83 453 patients with aortic or mitral valve disorder, 50 828 with a CIED, and 3620 with HCM. The cumulative risk of IE after 10 years was 0.9% in valve disorder, 1.3% in CIED, and 0.5% in HCM patients. Compared with the background population, valve disorder, CIED, and HCM carried a higher associated risk of IE, hazard ratio (HR) = 8.75 [95% confidence interval (CI) 6.36-12.02], HR = 6.63 (95% CI 4.41-9.96), and HR = 6.57 (95% CI 2.33-18.56), respectively. All three study groups were associated with a lower risk of IE compared with high-risk patients, HR = 0.27 (95% CI 0.23-0.32) for valve disorder, HR = 0.28 (95% CI 0.23-0.33) for CIED, and HR = 0.13 (95% CI 0.06-0.29) for HCM.CONCLUSIONS: Heart valve disorder, CIED, and patients with HCM were associated with a higher risk of IE compared with the background population but have a lower associated risk of IE compared with high-risk patients.

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.

Aims: Patients undergoing aortic valve replacement (AVR) are at increased risk of infective endocarditis (IE) as are patients with a cardiac implantable electronic device (CIED). However, few data exist on the IE risk after AVR surgery in patients with a CIED.Methods and results: Using the Danish administrative registries, we identified patients undergoing AVR from January 1996 to December 2015. Patients were categorized by CIED and non-CIED and followed up till hospitalization due to IE, death, 10 years after AVR discharge, end of study period (December 2015) or emigration, whichever came first. Using multivariable-adjusted Cox proportional hazard analysis with time-varying exposure, we investigated whether CIED was associated with an increased risk of IE. We included 15 538 patients (median age 71.4 years, 25th-75th percentiles 63.7-77.1, and 65.2% male). There were 890 patients with a CIED; 531 of these received their device during the AVR hospitalization and 14 648 patients with no CIED. The crude incidence rate of IE was 149.4/10 000 person-years in the CIED group and 74.3/10 000 person-years in the non-CIED group. Overall, CIED was associated with an increased risk of IE (hazard ratio 1.66, 95% confidence interval 1.27-2.17). There was no difference in associated IE according to the timing of CIED (P for interaction = 0.21 for CIED implantation before vs. in conjunction with AVR surgery).Conclusion: Patients with a CIED who underwent surgery for AVR were associated with an increased risk of IE compared with patients without a CIED. The association was independent of the timing of CIED implantation (before or in conjunction with AVR surgery).

Aims: Patients with prior infective endocarditis (IE), a prosthetic heart valve, or a cyanotic congenital heart disease (CHD) are considered to be at high risk of IE by guidelines. However, knowledge is sparse on the relative risk of IE between these three groups and compared controls. Methods and results: Using Danish nationwide registries (1996-2015), we identified all patients with prior IE, a prosthetic heart valve, or a complex CHD (defined as tetralogy of Fallot, truncus arteriosus, and transposition of great arteries) as well as matched control populations. Patients were followed up until death, end of study period, IE hospitalization, emigration, or a maximum of 10 years of follow-up, whichever came first. Multivariable adjusted Cox proportional hazard analysis was used to compare the risk of IE between the study groups and the matched controls. We included 25 945 patients: 5096 had prior IE, 19 478 had a prosthetic heart valve, and 1371 had complex CHD. The cumulative risk of IE at 10 years of follow-up was 8.8%, 6.0%, and 1.3% for patients with prior IE, a prosthetic valve, and complex CHD, respectively. Patients with prior IE and a prosthetic valve had a significant increased associated risk of IE compared with the matched controls [hazard ratio (HR) 65.4, 95% confidence interval (CI) 43.1-99.1 and HR 19.1, 95% CI 15.0-24.4), respectively]. No events occurred among the matched controls for the complex CHD group and an HR could not be calculated. Conclusion: All IE high-risk groups carried a higher risk of IE than the matched controls from the general population. These results justify the European and American guidelines in considering these groups at high risk of IE.

Cardiac myocytes express the cholecystokinin gene (CCK) at propeptide level. We recently reported that cardiac CCK expression is acutely regulated by isoprenaline in a porcine model. The regulation of CCK expression after myocardial infarction, in exercise, and in severe heart failure is, however, unknown. Cardiac tissue was obtained from healthy new-born and adolescent farm pigs. Myocardial infarction was induced by coronary artery occlusion in adult minipigs. Healthy male subjects performed a 3-hour exercise test, and patients with severe heart failure referred for right heart catheterization were included. Extracts of porcine cardiac tissue and human plasma were analysed with specific proCCK radioimmunoassays. Cardiac proCCK expression shifted from the right atrium in new-born piglets to include the left atrium in adolescent pigs. Regional proCCK expression in the adolescent pig heart was mainly confined to the atria without different expression in sinus node tissue. In adult minipigs with myocardial infarction, no changes in overall left ventricular function or proCCK expression were observed after 8 weeks. In healthy adults, proCCK in circulation increased markedly during exercise in parallel with pro-B-type natriuretic peptide. Finally, patients with severe heart failure displayed markedly increased proCCK – but not CCK – concentrations in plasma. Taken together, our data shows that regional proCCK expression reflects haemodynamic changes in the mammalian heart. The data supports the notion that cardiac CCK expression resembles that of cardiac natriuretic peptides in atria. The ventricular content of proCCK, however, differs from natriuretic peptides and suggests a distinct secretory pathway in ventricular cardiomyocytes.

Aims: Left ventricular function is a well-established predictor of malignant ventricular arrhythmias, but little is known about the importance of right ventricular (RV) function. The aim of this study was to investigate the importance of RV function for prediction of sudden cardiac death (SCD) or malignant ventricular arrhythmias (VAs) after acute myocardial infarction (MI).Methods and results: A total of 790 patients with acute MI were prospectively included. All patients had 2D strain echocardiography performed to evaluate right ventricular (RV) free wall strain (RVS) and RV mechanical dispersion (MD) defined as the standard deviation of time to peak negative strain in all myocardial segments. The primary composite end point [SCD, admission with VA or appropriate therapy from a primary prophylactic implantable cardioverter-defibrillator (ICD)] was analysed with Cox models. Mean age was 69 ± 12 years, and 74% were male. Thirty-one patients experienced the primary end point during a median follow-up of 898 days (Q1-Q3 704-981). RVS was independently associated with outcome in a multivariable model including age and left ventricular global longitudinal strain; pr 1% change [hazard ratio (HR) 1.08, 95% confidence interval (CI) 1.01-1.15; P = 0.038]. Patients in the lower tertile (poor strain) showed a 10-fold risk of an event compared with the upper tertile (HR 9.8, 95% CI 2.23-42.3; P = 0.002). RV MD was not independently associated with VA/SCD (HR 0.99, 95% CI 0.91-1.09; P = 0.93). RVS proved superior to tricuspid annular plane systolic excursion (TAPSE) (P = 0.03) in the multivariable model.Conclusion: RVS, but not RV MD, was significantly and independently related to SCD/VA in patients with acute MI. Furthermore, RVS was shown to be superior to TAPSE.

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.

Aims: Patients with left-sided heart valve replacement are considered at high-risk of infective endocarditis (IE). However, data on the incidence and risk factors associated with IE are sparse.Methods and results: Through Danish administrative registries, we identified patients who underwent left-sided heart valve replacement from January 1996 to December 2015. Patients were categorized in mitral and aortic valve replacement (MVR and AVR) and followed until: 12 years after valve surgery, end of study, death, emigration, or hospitalization due to IE, whichever came first. Multivariable adjusted Cox proportional hazard analysis was used to investigate which baseline characteristics were associated with IE. A total of 18 041 patients were included. The cumulative IE risk at 10 years follow-up was 5.2% in both MVR and AVR patients. In patients with MVR, male sex [hazard ratio (HR) = 1.68, 95% confidence interval (95% CI) 1.06-2.68], bioprosthetic valve (HR = 1.91, 95% CI 1.08-3.37), and heart failure (HR = 1.69, 95% CI 1.06-2.68) were among factors associated with an increased risk of IE. In AVR patients, male sex (HR = 1.59, 95% CI 1.33-1.89), bioprosthetic valve (HR = 1.70, 95% CI 1.35-2.15), and cardiac implantable electronic device (CIED) (HR = 1.57, 95% CI 1.19-2.06) were among factors associated with an increased risk of IE.Conclusion: Infective endocarditis after left-sided heart valve replacement is not uncommon and occurs in about 1/20 over 10 years. Male, bioprosthetic valve, and heart failure were among factors associated with IE in MVR patients while male, bioprosthetic valve, and CIED were among factors associated with IE in AVR patients.

BACKGROUND: The ability to return to work after infective endocarditis (IE) holds important socioeconomic consequences for both patients and society, yet data on this issue are sparse. We examined return to the workforce and associated factors in IE patients of working age.METHODS: Using Danish nationwide registries, we identified 1,065 patients aged 18-60 years with a first-time diagnosis of IE (1996-2013) who were part of the workforce prior to admission and alive at discharge.RESULTS: One year after discharge, 765 (71.8%) patients had returned to the workforce, 130 (12.2%) were on paid sick leave, 76 (7.1%) received disability pension, 23 (2.2%) were on early retirement, 65 (6.1%) had died, and 6 (0.6%) had emigrated. Factors associated with return to the workforce were identified using multivariable logistic regression. Younger age (18-40 vs 56-60 years; odds ratio, 2.85; 95% CI, 1.71-4.76) and higher level of education (higher educational level vs basic school; 5.47, 2.05-14.6) and income (highest quartile vs lowest; 3.17, 1.85-5.46) were associated with return to the workforce. Longer length of hospital stay (>90 vs 14-30 days; 0.16, 0.07-0.38); stroke during IE admission (0.38, 0.21-0.71); and a history of chronic kidney disease (0.29, 0.11-0.75), chronic obstructive pulmonary disease (0.31, 0.13-0.71), and malignancy (0.39, 0.22-0.69) were associated with a lower likelihood of returning to the workforce.CONCLUSIONS: Seven of 10 patients who were part of the workforce prior to IE and alive at discharge were part of the workforce 1 year later. Younger age, higher socioeconomic status, and absence of major comorbidities were associated with return to the workforce.

BACKGROUND: Infective endocarditis (IE) is a complex disease necessitating extensive clinical guidelines. The guidelines from the American Heart Association (AHA) and the European Society of Cardiology (ESC) have been markedly extended during the last 12 years. We examined the evidence base for these changes.METHODS: IE guidelines published by AHA and ESC were reviewed. We categorized and combined guidelines into 3 time periods: (1) 2004 (AHA) and 2005 (ESC), (2) 2007 (AHA) and 2009 (ESC), and (3) 2015 (AHA) and 2015 (ESC). Number of recommendations, classes of recommendations (I, II, or III), and levels of evidence (LOE) (A, B, or C) were assessed and the changes over time.RESULTS: From period 1 to period 3, we found a statistically significant increase in total number of IE recommendations from 37 to 253 (P<.01), a 6.8-fold increase. There were a significant decrease in LOE A (from 7 [20.0%] in period 1 to 4 [1.6%] in period 3, P<.0001, a 57% decrease), a nonsignificant decrease in LOE B recommendations (from 17 [48.6%] in period 1 to 115 [45.9%] in period 3, P=.29, a 6.8-fold increase), and a significant increase in LOE C recommendations (from 11 [31.4%] in period 1 to 134 [53.0%] in period 3, P=.02, a 12.2-fold increase).CONCLUSIONS: The number of IE guideline recommendations has increased 6- to 7-fold during the last decade without a corresponding increase in evidence. These results highlight the strong need for more clinical studies to improve the level of evidence in IE guidelines.