NatIonal Danish endocarditis stUdieS - Design and objectives of the NIDUS registry.

AIMS: The NatIonal Danish endocarditis stUdieS (NIDUS) registry aims to investigate the mechanisms contributing to the increasing incidence of infective endocarditis (IE) and to discover risk factors associated to the course, treatment and clinical outcomes of the disease. METHODS: The NIDUS registry was created to investigate a nationwide unselected group of patients hospitalized for IE. The National Danish healthcare registries have been queried for validated IE diagnosis codes (International Classification of Disease, 10th edition [ICD-10]: DI33, DI38, and DI398). Subsequently, a team of 28 healthcare professionals, including experts in endocarditis, will systematically review and evaluate all identified patient records using the modified Duke Criteria and the 2015 European Society of Cardiology modified diagnostic criteria. The registry will contain all cases with definite or possible IE found in primary data sources in Denmark between January 1, 2016, and December 31, 2021. We will gather individual patient data, such as clinical, microbiological, and echocardiographic characteristics, treatment regimens, and clinical outcomes. A digital data collection form will be used to the gathering of data. A sample of approximately 4,300 individual patients will be evaluated using primary data sources. CONCLUSIONS AND PERSPECTIVES: The NIDUS registry will be the first comprehensive nationwide IE registry, contributing critical knowledge about the course, treatment, and clinical outcomes of the disease. Additionally, it will significantly aid in identifying areas in which future research is needed.

Surgery in patients with infective endocarditis and prognostic importance of patient frailty.

PURPOSE: Surgery is required in 20-50% of patients with infective endocarditis (IE). Frailty increases surgical risk; however, the prognostic implications of frailty in patients undergoing IE-related surgery remain poorly understood. We aimed to assess the association between frailty and all-cause mortality or rehospitalization after discharge (≥ 14 days). METHODS: We identified all IE patients who underwent surgery during admission (2010-2020) in Denmark. The Hospital Frailty Risk Score was used to categorize patients into two frailty risk groups, patients with low frailty scores (< 5 points) and frail patients (≥ 5 points). We analyzed time hospitalized after discharge and all-cause mortality from the date of surgery with a one-year follow-up. Statistical analyses utilized the Kaplan-Meier estimator, Aalen-Johansen estimator, and the Cox regression model. RESULTS: We identified 1282 patients who underwent surgery during admission, of whom 967 (75.4%) had low frailty scores, and 315 (24.6%) were frail. Frail patients were characterized by advanced age, a lower proportion of males, and a higher burden of comorbidities. Frail patients were more hospitalized (> 14 days) in the first post-discharge year (19.1% vs.12.3%) compared to patients with low frailty scores. Additionally, frail patients had higher rates of all-cause mortality including in-hospital deaths (27% vs. 15%) and rehospitalizations (43.5% vs 26.1%) compared to patients with low frailty scores. This was also evident in the adjusted analysis (hazard ratio 1.36 [CI 95% 1.09-1.71]). CONCLUSION: Frailty was associated with an ≈40% increased rate of rehospitalization (≥ 14 days) or death. Further studies are needed to assess the effectiveness of surgery with a focus on frailty to improve prognostic outcomes in these patients.

Recurrence of bacteremia and infective endocarditis according to bacterial species of index endocarditis episode.

PURPOSE: In patients surviving infective endocarditis (IE) recurrence of bacteremia or IE is feared. However, knowledge is sparse on the incidence and risk factors for the recurrence of bacteremia or IE. METHODS: Using Danish nationwide registries (2010-2020), we identified patients with first-time IE which were categorized by bacterial species (Staphylococcus aureus, Enterococcus spp., Streptococcus spp., coagulase-negative staphylococci [CoNS], 'Other' microbiological etiology). Recurrence of bacteremia (including IE episodes) or IE with the same bacterial species was estimated at 12 months and 5 years, considering death as a competing risk. Cox regression models were used to compute adjusted hazard ratios of the recurrence of bacteremia or IE. RESULTS: We identified 4086 patients with IE; 1374 (33.6%) with S. aureus, 813 (19.9%) with Enterococcus spp., 1366 (33.4%) with Streptococcus spp., 284 (7.0%) with CoNS, and 249 (6.1%) with 'Other'. The overall 12-month incidence of recurrent bacteremia with the same bacterial species was 4.8% and 2.6% with an accompanying IE diagnosis, while this was 7.7% and 4.0%, respectively, with 5 years of follow-up. S. aureus, Enterococcus spp., CoNS, chronic renal failure, and liver disease were associated with an increased rate of recurrent bacteremia or IE with the same bacterial species. CONCLUSION: Recurrent bacteremia with the same bacterial species within 12 months, occurred in almost 5% and 2.6% for recurrent IE. S. aureus, Enterococcus spp., and CoNS were associated with recurrent infections with the same bacterial species.

Early surgery to prevent embolic events in patients with infective endocarditis: a comprehensive review.

BACKGROUND: Infective endocarditis (IE) is a dangerous and lethal illness with high mortality rates. One of the main indications for surgery according to the guidelines is prevention of embolic events. However, uncertainty remains concerning the timing of surgery and the effect of early surgery in combination with antibiotic therapy versus antibiotic therapy alone in IE patients with a vegetation size > 10 mm. METHODS: We conducted a comprehensive review by searching the PubMed, MEDLINE, and EMbase databases. Titles and abstracts were screened, and studies of interest were selected for full-text assessment. Studies were selected for review if they met the criteria of comparing surgical treatment + antibiotic therapy to antibiotic therapy alone in patients with vegetations > 10 mm. RESULTS: We found 1,503 studies through our database search; nine of these were eligible for review, with a total number of 3,565 patients. Median age was 66 years (range: 17-80) and the median percentage of male patients was 65.6% (range: 61.8 - 71.4%). There was one randomised controlled trial, one prospective study, and seven retrospective studies. Seven studies found surgery + antibiotic therapy to be associated with better outcomes in patients with IE and vegetations > 10 mm, one of them being the randomised trial [hazard ratio = 0.10; 95% confidence interval 0.01-0.82]. Two studies found surgery + antibiotic therapy was associated with poorer outcomes compared with antibiotic therapy alone. CONCLUSION: Overall, data vary in quality due to low numbers and selection bias. Evidence is conflicting, yet suggest that surgery + antibiotic therapy is associated with better outcomes in patients with IE and vegetations > 10 mm for prevention of emboli. Properly powered randomised trials are warranted.

Bacteremia and infective endocarditis following left-sided heart valve surgery.

BACKGROUND AND AIMS: In patients undergoing heart valve surgery, subsequent bacteremia and infective endocarditis are feared events. Data on the incidence and bacterial microbiological etiology following left-sided heart valve surgery are sparse. METHODS: Between 2010-2021, all patients undergoing left-sided valve surgery were identified using Danish nationwide registries. Incidence and type bacteremia within one-year post-surgery was analyzed. Secondary outcome of interest was infective endocarditis. Cumulative incidence curves were stratified for bacterial species and for subgroups of interest: type of valve surgery, age, and sex. RESULTS: A total of 14 935 patients were included, of which 69% were male and the median age was 70.4 years (25th-75th percentile 62.4-76.2 years). The one-year cumulative incidence of bacteremia was 6.1% (95% CI 5.7-6.5%), and the most frequent bacteremia was coagulase-negative staphylococci (27%). More than half of the bacteremia with coagulase-negative staphylococci occurred within 30 days of follow-up. Patients developing bacteremia had a significantly higher Charlson comorbidity score at baseline, more often underwent CABG concomitant to valve surgery, and more often had surgery on both valves. The one-year cumulative incidence of infective endocarditis was 1.5% (95% CI 1.3-1.7), of which 23% were caused by Enterococci, and 22% were blood culture negative. The median time from surgery to infective endocarditis was 109 days. CONCLUSIONS: Bacteremia and infective endocarditis following left-sided heart valve surgery occurred in 6.1% and 1.5% of patients, respectively. The most frequent bacteremia was coagulase-negative staphylococci, and more than half of these occurred within 30 days of surgery. Optimization of prophylactic strategies are warranted.

Detection of infective endocarditis with [64Cu]Cu-DOTATATE positron emission tomography/computed tomography: a case series.

Background: Infective endocarditis (IE) is a serious and fatal condition, with prosthetic valve endocarditis representing the worst prognosis. The recommended nuclear imaging modality 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) has limitations. In this case series, we present two patients with IE scanned with a novel PET tracer [64Cu]Cu-DOTATATE ([64Cu]Cu-[1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetra acetic acid]-d-Phe1, Tyr3-octreotate). Case summary: An 84-year-old female patient (Patient 1) with a biological mitral valve prosthesis (MVP) was admitted acutely from the outpatient clinic. Transoesophageal echocardiography showed vegetations on the MVP. The patient underwent [64Cu]Cu-DOTATATE PET/CT, which showed uptake at the site of infection. The patient underwent surgical valve replacement. The post-operative period was without significant complications, and the patient was discharged home. In another case, a 72-year-old male patient (Patient 2) with a medical history of mild mitral valve stenosis, aortic valve stenosis, and gastrointestinal stromal tumour was admitted to the hospital for back and abdominal pain and subfebrile episodes. Transoesophageal echocardiography showed large vegetations in the native aortic valve. The patient underwent [64Cu]Cu-DOTATATE PET/CT, which showed no uptake at the site of the suspected infection. The patient underwent surgical valve replacement. The post-operative period was characterized by Candida albicans sternitis, and after prolonged hospitalization, the patient died of respiratory failure as a complication of sepsis. Discussion: In conclusion, this is the first case series presenting two patients with definite IE (modified Duke criteria), who were scanned with the novel [64Cu]Cu-DOTATATE PET/CT. Patient 1, with endocarditis in the MVP, showed an uptake of the tracer, while Patient 2, with native aortic valve endocarditis, did not show any uptake.

Increased Subclinical Coronary Artery Pathology in Type 2 Diabetes With Albuminuria.

Diabetes affects the kidneys, and the presence of albuminuria reflects widespread vascular damage and is a risk factor for cardiovascular disease (CVD). Still, the pathophysiological association between albuminuria and CVD remains incompletely understood. Recent advances in noninvasive imaging enable functional assessment of coronary artery pathology and present an opportunity to explore the association between albuminuria and CVD. In this cross-sectional study, we evaluated the presence of subclinical coronary artery pathology in people with type 2 diabetes, free of overt CVD. Using multimodal imaging, we assessed the coronary microcalcification activity (18F-sodium fluoride positron emission tomography/computed tomography [PET/CT], plaque inflammation [64Cu-DOTATATE PET/CT], and myocardial flow reserve [82Rb PET/CT]). The study population consisted of 90 participants, stratified by albuminuria; 60 had historic or current albuminuria (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g]), and 30 had normoalbuminuria (UACR <30 mg/g). We demonstrated that any albuminuria (historic or current) was associated with a more severe phenotype, in particular, higher levels of microcalcifications and impaired myocardial microvascular function; however, coronary inflammation activity was similar in people with and without albuminuria. Our findings establish a potential underlying mechanism connecting cardiovascular and kidney diseases and could indicate the initial stages of the cardiorenal syndrome.

Genome-Wide Association Study of Accessory Atrioventricular Pathways.

Importance: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. Objective: To investigate the genetics of APs and affiliated arrhythmias. Design, Setting, and Participants: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024. Exposures: Sequence variants. Main Outcomes and Measures: Genome-wide significant association of sequence variants with APs. Results: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response. Conclusions and Relevance: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

Temporal trends in the incidence of infective endocarditis in patients with a prosthetic heart valve.

OBJECTIVE: The incidence of infective endocarditis (IE) is increasing, as is the insertion of prosthetic heart valves. We aimed to examine nationwide temporal trends in the incidence of IE in patients with a prosthetic heart valve in Denmark from 1999 to 2018. METHODS: Using the Danish nationwide registries, we identified patients who underwent heart valve implantation (for other reasons than IE) between 1999 and 2018. Crude incidence rates of IE per 1000 person-years (PY) were computed in 2-year intervals. IE incidences were compared using sex-adjusted and age-adjusted incidence rate ratios (IRR) using Poisson regression across calendar periods (1999-2003, 2004-2008, 2009-2013, and 2014-2018). RESULTS: We identified 26 604 patients with first-time prosthetic valve implantation (median age 71.7 years (IQR 62.7-78.0), 63% males). The median follow-up time was 5.4 years (IQR 2.4-9.6). Patients in the time period 2014-2018 were older (median age of 73.9 years (66.2:80.3)), and with a higher burden of comorbidities compared with the time period 1999-2003 (median age of 67.9 years (58.3:74.5)) at the time of implantation. A total of 1442 (5.4%) patients developed IE. The lowest IE incidence rate was 5.4/1000 PY (95% CI 3.9 to 7.4) in 2001-2002, and the highest incidence rate was 10.0/1000 PY (95% CI 8.8 to 11.1) in 2017-2018 with an unadjusted increase during the study period (p=0.003). We found an adjusted IRR of 1.04 (95% CI 1.02 to 1.06) (p<0.0007) per two calendar-years increments. Age-adjusted IRR for men were 1.04 (95% CI 1.01 to 1.07) (p=0.002) per two calendar years increment, and for women 1.03 (95% CI 0.99 to 1.07) (p=0.12), with p=0.32 for interaction. CONCLUSION: In Denmark, the incidence of IE increased during the last 20 years in patients with prosthetic heart valves.

Temporal trends of mortality in patients with infective endocarditis: a nationwide study.

AIMS: Little is known about the mortality for patients with infective endocarditis (IE) on a nationwide scale, and previous studies have been conducted in selected cohorts from tertiary centers. We aimed to investigate temporal trends in mortality using nationwide Danish registries. METHODS AND RESULTS: We identified patients with first-time IE between 1999-2018, and they were grouped by calendar periods (1999-2003, 2004-2008, 2009-2013, 2014-2018). One-year mortality was estimated using Kaplan-Meier estimates. For calendar periods, odds ratios (ORs) and hazard ratios (HRs) were computed using multivariable adjusted logistic regression and Cox proportional Hazards analyses for in-hospital and one-year mortality, respectively. We identified 8804 patients with IE. Age and proportions of men were: 66.7 (25th-75th percentile: 53.4-76.7) years and 59.9% in 1999-2003 and 72.8 (25th-75th percentile: 63.4-80.3) and 65.8% in 2014-2018. In-hospital mortality was 1999-2003: 24.5%, 2004-2008: 22.8%, 2009-2013: 18.8%, and 2014-2018: 18.3%. Relative to 1999-2003, adjusted likelihoods of in-hospital mortality were: OR = 0.81 (95% CI: 0.69-0.96) in 2004-2008, OR = 0.59 (95% CI: 0.50-0.69) in 2009-2013, and OR = 0.51 (95% CI: 0.43-0.60) in 2014-2018. By calendar periods, crude risks of one-year mortality were: 34.4% (95% CI: 32.0-36.8%), 33.5% (95% CI: 31.5-35.6%), 32.1% (95% CI: 30.2-34.0%), and 33.1% (95% CI: 31.3-34.8%). Relative to 1999-2003, adjusted rates of one-year mortality were: HR = 0.88 (95% CI 0.79-0.99) in 2004-2008, HR = 0.76 (95% CI: 0.68-0.86) in 2009-2013, and HR = 0.72 (95% CI: 0.64-0.81) in 2014-2018. CONCLUSION: In this nationwide study of patients with first-time IE between 1999-2018, both short- and long-term survival has improved over time when accounting for changes in patient characteristics. ONE-SENTENCE SUMMARY: When accounting for patient characteristics, both short- and long-term mortality have improved in patients with first-time infective endocarditis.

Genome-wide association study identifies locus at chromosome 2q32.1 associated with syncope and collapse.

AIMS: Syncope is a common condition associated with frequent hospitalization or visits to the emergency department. Family aggregation and twin studies have shown that syncope has a heritable component. We investigated whether common genetic variants predispose to syncope and collapse. METHODS AND RESULTS: We used genome-wide association data on syncope on 408 961 individuals with European ancestry from the UK Biobank study. In a replication study, we used the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86 189), to investigate the risk of incident syncope stratified by genotype carrier status. We report on a genome-wide significant locus located on chromosome 2q32.1 [odds ratio = 1.13, 95% confidence interval (CI) 1.10-1.17, P = 5.8 × 10-15], with lead single nucleotide polymorphism rs12465214 in proximity to the gene zinc finger protein 804a (ZNF804A). This association was also shown in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (1.30, 95% CI 1.15-1.46, P = 1.68 × 10-5) of incident syncope. Quantitative polymerase chain reaction analysis showed ZNF804A to be expressed most abundantly in brain tissue. CONCLUSION: We identified a genome-wide significant locus (rs12465214) associated with syncope and collapse. The association was replicated in an independent cohort. This is the first genome-wide association study to associate a locus with syncope and collapse.