Infective endocarditis (IE) is a severe condition with risk of recurrence. Oral microorganisms (OM) are frequently implicated as index pathogens, yet patient characteristics, bacteremia with OM and relapse bacteremia after completion of IE treatment remain poorly described among these patients. This descriptive single-center retrospective cohort study included patients hospitalized with possible or definite IE at Copenhagen University Hospital. Patients were stratified by index pathogen into an OM and non-OM group. Baseline characteristics were described, and bacteremia with OM were assessed up to three years after completion of IE treatment using Aalen-Johansen cumulative incidence functions. Also, relapse bacteremia was evaluated in both groups. Of 686 patients, 171 (25

BACKGROUND:Culture-negative infective endocarditis (CNIE) remains a diagnostic and therapeutic challenge. Current evidence on this disease is limited by small sample sizes, lack of granularity, and highly selected data. OBJECTIVES:This study sought to provide a granular characterization of CNIE in the modern diagnostic era from the first nationwide cohort of patients with infective endocarditis (IE). METHODS:This study used data from the nationwide Danish NIDUS (NatIonal Danish endocarditis stUdieS) registry, including all patients hospitalized with first-time left-sided IE (2016-2021). Patients were categorized as having CNIE or culture-positive infective endocarditis (CPIE) on the basis of blood cultures, valve tissue cultures, and polymerase chain reaction analyses. The study described patients' medical history, IE-specific disease features, clinical practice patterns, and treatment regimens. RESULTS:Of 2,875 IE patients, 212 (7.4%) had CNIE. Compared with CPIE, CNIE patients were more likely to have congenital heart disease (9.9% vs 2.9%) and less likely to have previous cancer (9.3% vs 14.7%). At admission, CNIE patients presented less frequently with sepsis (7.1% vs 24.6%) and fever (44.3% vs 61.7%), but they presented more often with embolism (25.9% vs 10.8%) and valvular insufficiency (11.3% vs 7.4%). The median size of vegetations was smaller (8 mm vs 10 mm) for patients with CNIE, whereas rates of prosthetic valve infection (22.2% vs 23.1%) and valve surgery (20.3% vs 21.8%) were similar. Positron emission tomography with computed tomography (PET-CT) was commonly used in both groups (67%-68%), and it was diagnostic in 13.1% of CNIE cases and 10.7% of CPIE cases. Among patients with prosthetic valve CNIE, the diagnostic yield of PET-CT was almost 50%. CONCLUSIONS:Using the first nationwide, unselected IE cohort, this study demonstrated a lower proportion of culture-negative cases than reported in previous studies. Patients with CNIE differed from CPIE in clinical presentation and disease characteristics, notably with less frequent fever and sepsis but higher embolic complication rates. However, culture-negative IE is highly heterogeneous and is better defined by distinct subgroups rather than by a single phenotype.

Infective endocarditis (IE) often presents with non-specific symptoms, which may delay diagnosis and treatment. Previous studies exploring symptom duration have been limited by small cohorts or single-centre studies. We aimed to investigate patient characteristics, microbial aetiology, treatment, and all-cause mortality of patients with IE according to symptom duration prior to diagnosis. We included all patients with first-time IE from the NatIonal Danish Endocarditis StUdies (NIDUS) registry (2016–2021). Patients with left-sided IE and available symptom duration were stratified as short, intermediate, or prolonged (≤ 7, 8–29, or ≥ 30 days). The primary outcome was six-month mortality. Among 2,938 patients with left-sided IE, median symptom duration was 8 days [IQR:4–20], and 17.6

OBJECTIVES:Shared pathophysiologic features of fibrotic diseases, irrespective of anatomical site, have been suggested from epidemiologic, genetic and mechanistic studies. Improvement in diagnostic capabilities and emergence of antifibrotic medications warrants identification of trajectories of fibrotic diseases and earlier identification of patients at risk of organ failure as they may have a fibrotic component. METHODS:We used Danish nationwide health registries to identify all adults with a first-time diagnosis of any of nine major fibrotic diseases from 1998 to 2024. Co-occurrence between fibrotic diseases was assessed using logistic regression, adjusted for sex, birth year, time-at-risk, educational level and ethnicity. Next, we used multivariable Cox proportional hazards models to evaluate the risk of developing an organ failure in all individuals with a fibrotic disease relative to matched controls. RESULTS:We identified 328 344 individuals with at least one fibrotic disease. Median age at first fibrotic diagnosis was 57 years (interquartile range 48-67), with 54% being female. Most fibrotic diseases were associated with an increased odds of co-occurring fibrotic diseases, with the strongest association between carpal tunnel syndrome and trigger finger (odds ratio 6.05, 95% CI 5.94-6.15). Compared with 985 032 controls, individuals with a fibrotic disease had a higher risk of organ failure over a median 10 years of follow-up (hazard ratio: 1.20, 95% CI 1.18-1.22). CONCLUSION:Fibrotic diseases frequently co-occur and are associated with an increased risk of organ failure, which support the concept of a partially shared systemic fibrotic hypothesis, pointing towards the potential of using early onset fibrotic diseases as prognostic markers for system-wide fibrosis susceptibility.

Background:Fetal bradycardia has been reported in neonates with congenital long QT syndrome, but it remains unknown whether there is a general association between fetal heart rate (FHR) and the neonatal QT interval. Objective:We examined whether first- (FHR1) and second-trimester FHR (FHR2) measurements were associated with the neonatal QT interval. Methods:We investigated neonates from a large population-based cohort study with available electrocardiograms and FHR1 measurements. We also investigated a subgroup with FHR2 data. The neonatal corrected QT (QTc) interval was the primary outcome variable. Univariate and multiple regression analyses were also performed. Results:The study cohort included 7998 neonates (48.4% girls) with a median age of 11 days (interquartile range [IQR] 7-14) at electrocardiographic recording. At a median gestation age (GA) of 90 days, we found a median FHR1 of 159 beats per minute (IQR 155-164) and no association with the QTc interval (adjusted difference 0.407 × 10-4; 95% confidence interval -0.656 × 10-4 to 0.147 × 10-3; P > .05). The median FHR2 (available in 2202 neonates; median GA 140 days) was 148 beats per minute (IQR 144-153), and lower FHR2 values were associated with longer QTc intervals (QTc using Fridericia's correction formula 367 vs 362 ms between outer quartiles). This association remained significant after multifactorial adjustment (adjusted difference -0.164 × 10-3; 95% confidence interval -0.880 × 10-4 to -0.110 × 10-4; P < .05). Conclusion:FHR2 is associated with longer neonatal QTc interval, whereas no association was observed between FHR1 and the QTc interval. These findings suggest a GA-dependent association, emphasizing the importance of considering GA when evaluating FHR and neonatal QT intervals.

BACKGROUND:In patients with infective endocarditis on the left side of the heart, the current recommendation of up to 6 weeks of antibiotic therapy is based largely on expert consensus opinion. Whether a clinical response-tailored antibiotic management strategy can shorten treatment duration without compromising safety is unclear. METHODS:In this international, open-label, randomized trial, we assigned adults in stable condition with infective endocarditis caused by Staphylococcus aureus, Enterococcus faecalis, or streptococcus species to receive either response-tailored or standard-duration antibiotic therapy. Before randomization, all the patients received at least the prespecified 2 to 4 weeks of therapy and met criteria for clinical stabilization. After randomization, patients in the tailored-therapy group discontinued antibiotics and those in the standard-therapy group continued standard treatment (total duration, 4 to 6 weeks). The primary efficacy end point was days alive without antibiotic treatment for infective endocarditis or bacteremia within 6 months after randomization (tested for superiority). The primary safety end point was a composite of death from any cause, unplanned cardiac surgery, or symptomatic embolic events within 6 months after randomization (tested for noninferiority; margin, 7.5 percentage points). Relapse of bacteremia or infective endocarditis was a key secondary end point. RESULTS:A total of 508 patients underwent randomization, with 255 assigned to response-tailored therapy and 253 to standard-duration therapy. The median time alive without antibiotic treatment was 183 days (interquartile range, 181 to 183) with tailored therapy and 169 days (interquartile range, 166 to 171) with standard therapy (Hodges-Lehmann estimated difference, 13 days; 95% confidence interval [CI], 12 to 13; P<0.001 for superiority). A primary safety end-point event occurred in 21 patients (8.2%) with tailored therapy and in 27 patients (10.7%) with standard therapy (absolute between-group difference, -2.4 percentage points; 95% CI, -7.7 to 2.7; P<0.001 for noninferiority), indicating noninferiority. Relapse occurred in 13 patients (5.1%) with tailored therapy and in 4 patients (1.6%) with standard therapy (P = 0.04). CONCLUSIONS:Among patients with infective endocarditis on the left side of the heart, the use of a response-tailored antibiotic strategy resulted in a longer time alive without antibiotic therapy than standard-duration therapy and met the criterion for noninferiority with respect to safety but was associated with a higher incidence of relapse of bacteremia or infective endocarditis. (Funded by Sygeforsikringen "danmark" and others; POET II ClinicalTrials.gov number, NCT03851575.).

BACKGROUND:Dental procedures may cause bacteremia, which is considered a risk factor for infective endocarditis (IE). This study sets out to examine whether dental procedures are associated with an increased risk of IE. METHODS:We examined the nationwide time-dependent association between dental procedures and risk of bacteremia and IE among Danes > 18 years on January 1, 2010. Adjusted hazard ratios (HR) for bacteremia and IE were estimated by Cox regression with time-varying exposure (dental visit and three months later). RESULTS:We examined 4,178,514 persons who had dental care (66.9% of residents, median age 44 years [IQR 30-49]). During 9 years of follow-up, 69,928 (1.7%) persons had bacteremia, and 3,754 (0.09%) had IE. Among those with bacteremia or IE in the proximity of dental care (within three months), Streptococci accounted for 16.1% and 26.9%, respectively. The adjusted HRs for bacteremia and IE associated with dental procedures were 0.94 (95% CI 0.92-0.95) and 1.00 (95% CI 0.94-1.08), respectively, compared with non-exposed time. No dose-response relationship for invasive vs non-invasive procedures was found. The IE risk associated with dental care was not different in high-risk patients (prior IE, valve prostheses, or congenital heart disease): HR 0.96 (95% CI 0.83-1.10). CONCLUSION:We did not find an association between dental procedures and bacteremia or IE, and this was irrespective of high-risk cardiac preconditions.

Background: In case of Staphylococcus aureus bacteremia (SAB), complete cardiac implantable electronic device (CIED) removal is advised by the European Heart Rhythm Association. Objectives: The objective of the study was to estimate clinical outcomes after SAB in the Danish CIED carriers. Methods: We conducted a nationwide register-based cohort study including all patients with SAB after CIED implantation between 2000 and 2020. Cumulative incidence of device removal, SAB reinfection, and all-cause mortality were estimated and compared to sex and age-matched non-CIED controls with SAB. Landmark analysis at the time of hospital discharge estimating mortality and reinfection according to CIED removal status in surviving patients was conducted. Results: In total, 1,816 patients with CIED and SAB and 9,080 matched controls were included in the study (median age 77.5 years, 73.0% males). Thirty-day all-cause mortality was 34.0% (95% CI: 31.8%-36.2%) in patients with CIED and 31.0% (95% CI: 30.0%-31.9%) in controls (P = 0.019, adjusted HR: 1.11 [95% CI: 1.02-1.22]). Device removal within 30 days was performed in 286 patients (15.8%). The landmark analysis showed significantly lower 180-days cumulative incidence of SAB reinfection and all-cause mortality in patients undergoing device removal compared to those with retained CIEDs (reinfection: 2.5% vs 5.5%; mortality: 7.8% vs 31.2%). Patients who underwent CIED removal were younger and had less comorbidity compared to those with retained CIEDs. Conclusions: The Danish CIED carriers had slightly higher 30-day all-cause mortality after SAB compared to matched controls. Only a minor selected proportion underwent device removal after SAB diagnosis and, after initial survival, these patients had lower 180-days reinfection rates and mortality compared to patients with retained devices.

Congenital aortic valve regurgitation is seen in approximately 1 in 4,000 live-births globally. This study investigated the prevalence and early impacts of aortic regurgitation in a newborn cohort. Between April 2016 and October 2018, all newborns in the Copenhagen Area were offered systematic transthoracic echocardiography in a prospective, multicenter population-based study. Aortic valve function was categorized as no, trivial (glimpse of regurgitant flow and/or vena contracta < 0.1 cm), or non-trivial aortic regurgitation (vena contracta ≥ 0.1 cm). Newborns with non-trivial regurgitation were matched 1:4 with controls (no regurgitation). Among 25,590 newborns, aortic regurgitation was detected in 329 newborns (52

IntroductionNewborns of mothers with autoimmune systemic connective tissue disease (CTD) have a higher incidence of major congenital heart defects (CHDs) compared to unexposed newborns. Less is known about the association between maternal CTD and less severe cardiac abnormalities in the newborn.MethodsWe analysed prospectively collected echocardiographic data from the Copenhagen Baby Heart Study (CBHS), comparing newborns exposed to maternal CTD with those who were not exposed. Maternal autoimmune CTD diagnoses were identified through the National Patient Register and validated by medical record review. Outcome measures included minor CHDs (atrial and ventricular septal defects, bicuspid aorta valve and patent ductus arteriosus), as well as cardiac dimensions and function.ResultsIn total 25,590 newborns underwent echocardiography in the CBHS, of whom 57 (0.22%) were born to mothers with CTD. When comparing newborns of mothers with overall CTD to non-exposed newborns, we found no differences in structural and functional cardiac parameters. Minor CHDs were more common in newborns born to mothers with Sjögren's disease (n = 3, 33.3%) than in unexposed newborns (n = 1,945, 7.6%, p = 0.03).ConclusionsIn this large population-based study, we did not observe consistent associations between overall maternal CTD and cardiac structure or function in the infant, although minor CHD were more common in newborns exposed to maternal Sjögren's disease. Findings should be interpreted with caution, considering the small sample size of exposed newborns and potential underrepresentation of major CHD due to standard clinical management practices.

Sub-Saharan Africa is experiencing a rapid rise in ischemic heart disease, creating new challenges for regional health systems. As populations grow and urbanize, lifestyle, metabolic, nutritional and environmental factors are reshaping the burden of noncommunicable diseases. Yet health systems, historically oriented toward communicable diseases and maternal health, show variable capacity to prevent, diagnose and treat ischemic heart disease. Despite increasing recognition, systematic assessments of country-level disease burden and healthcare capacity are limited, leaving gaps for evidence-based policy. Here we address this gap by assessing healthcare system readiness across four domains: health system capacities, primary care, secondary and tertiary care, and health system context. We highlight how limitations in workforce, essential medicines, diagnostics and policy intersect with upstream drivers such as obesity, hypertension, diabetes, smoking, dietary transitions, urbanization and environmental stressors. Meeting these challenges will require coordinated investment, equitable resource allocation and integrated prevention strategies.

BACKGROUND AND AIMS:According to ESC guidelines, patients with a cardiac implantable electronic device (CIED) are considered at moderate risk of infective endocarditis (IE), irrespective of CIED type. However, comparative data across CIED types and IE risk groups are limited. We examined IE rates according to CIED type compared with moderate- and high-risk groups. METHODS:Danish nationwide registries were used to identify patients with first-time CIED implantation and reference populations at moderate and high risk of IE (2000-2022), based on ESC guidelines. The high-risk group included patients with a left-sided prosthetic valve. Patients with prior IE or left-sided prosthetic valve were excluded from the CIED group. The primary outcome was incident IE within 10 years. RESULTS:The study included 84,171 CIED recipients, 127,966 moderate-risk patients, and 23,505 high-risk patients. Pacemakers were the most common CIED type (74.9%), followed by ICD (16.6%), CRT-D (4.6%), and CRT-P (3.9%). Pacemaker recipients were the oldest (median 78.2 years) and most frail. The 10-year cumulative incidence of IE was lowest in pacemaker recipients (1.0% [95% CI:0.9-1.1]) and highest in CRT-D recipients (2.2% [95% CI:1.7-2.9]). In adjusted analyses, all CIED types were associated with higher IE rates than the moderate-risk group but lower than the high-risk group. CONCLUSION:In this nationwide cohort, IE risk differed across CIED types, highest in CRT-D and lowest in pacemaker recipients. All CIED types were associated with higher risk than moderate-risk patients but lower risk than high-risk patients, supporting ESC classification. CRT-D recipients may warrant further evaluation of preventive strategies.

BACKGROUND:Patients with phenotypically mild hypertrophic cardiomyopathy (HCM) do not require symptom management, but may be at an earlier stage in the disease course, with potential to benefit from disease-modifying therapies. However, little is known about the natural history and predictors of major adverse cardiovascular events (MACE). OBJECTIVES:Using the Sarcomeric Human Cardiomyopathy Registry, we identified predictors of incident MACE and characterized disease progression in phenotypically mild HCM. METHODS:Phenotypically mild HCM was defined as: having shorter disease duration (<10 years since diagnosis or age ≤30 years), no previous MACE, being NYHA functional class I, and having a left ventricular (LV) maximal wall thickness (MWT) <25 mm. These individuals were followed prospectively for the development of symptoms or MACE: atrial fibrillation (AF), malignant ventricular arrhythmia (MVA) (sudden cardiac death, resuscitated arrest, or appropriate defibrillator therapy), heart failure (HF) (cardiac transplantation, LV assist device implantation, LV ejection fraction <35%, or NYHA functional class III or IV symptoms), stroke, or all-cause mortality. Cox regression identified MACE predictors. Linear and latent class mixed models characterized LV remodeling trajectories and risk clusters. RESULTS:Of 2,500 participants with phenotypically mild HCM (mean age 43 years, 31% women) followed for a mean duration of 7 ± 6 years, 534 (21%) developed MACE, including 289 with AF, 69 with MVA, and 193 with HF. Individuals who progressed from NYHA functional class I to ≥ II symptoms during follow-up (n = 585, 23%) were 2.79 times (95% CI: 2.30-3.39 times) more likely to experience MACE. Age at baseline (HR: 1.24; 95% CI: 1.17-1.32 per 10-year increase), body mass index (HR: 1.10; 95% CI: 1.01-1.21 per 5-kg/m2 increase), left atrial (LA) diameter (HR: 1.16; 95% CI: 1.09-1.25 per 5-mm increase), LV MWT (HR: 1.27; 95% CI: 1.10-1.46 per 5-mm increase), and LV outflow tract (LVOT) gradient (HR: 1.08; 95% CI: 1.05-1.12 per 15-mm Hg increase) associated with higher MACE rates. LV late gadolinium enhancement presence was associated with 36% (95% CI: 5%-76%) higher hazard of MACE. Remodeling trajectories during follow-up predicted risk with each 0.5 mm/year steeper increase in LA diameter associating with doubled AF (HR: 2.24; 95% CI: 1.69-2.97) and HF rates (HR: 2.22; 95% CI: 1.62-3.04) and each 0.5 mm/year steeper LV MWT increase associating with doubled MVA rates (HR: 1.92; 95% CI: 1.38-2.69). Higher sustained values and/or steeper increases in LA diameter, LV MWT, or LVOT gradient associated with the highest MACE rates. CONCLUSIONS:Approximately 21% of patients with phenotypically mild HCM developed MACE over medium-term follow-up. Older age, symptoms development, and increasing LA diameter, LV hypertrophy, or LVOT gradient associated with MACE, particularly in instances of steeper rate of change. These findings can guide management strategies and inform future studies of disease-modifying therapies.

Abstract Background and Aims Aortic root abscess is a severe and diagnostically challenging complication of infective endocarditis (IE). This study aimed to examine differences between IE patients with and without aortic root abscesses in patient characteristics, treatment strategies, and clinical outcomes. Methods We conducted nationwide, unselected, registry-based cohort study using National Danish Endocarditis Studies registry. All patients with aortic valve endocarditis in Denmark from 2016 to 2021 were included. Clinical and microbiological characteristics, treatment, and mortality were compared according to status of aortic root abscess. Mortality was adjusted for clinically relevant covariates. Results The study population included 1902 patients with aortic endocarditis, of whom 316 (17%) had an aortic root abscess. Patients with an abscess versus those without were significantly younger (median 71.5 vs 75.1 years, P-value ≤.001), more often male (76.3% vs. 69.7%, P-value = .02), prosthetic valve (50.0% vs. 30.4%, P-value ≤.001), AV-block (10% vs 1.7%, P-value ≤.001), coagulase-negative staphylococci and streptococci in their blood cultures, and were surgically treated (59.5% vs 16.1%). In multivariable Cox regression, patients with abscesses had significantly higher 1-year mortality rate compared with those without (HR 1.41, 95% CI: 1.13–1.76). When stratifying for surgery, non-operated patients with an abscess had the highest 1-year mortality 55.4%, alongside a high pre-operative risk (median age 79, 38% not self-reliant, more comorbidities including 12% active cancer). Conclusions Aortic root abscess was present in 17% of patients with aortic valve endocarditis and was associated with distinct clinical and microbiological characteristics, a higher frequency of complications, greater prevalence of surgery albeit a higher mortality rate compared with those without an abscess.

Muscle mass is central to physical function and metabolic health 1 , but can decrease with disease, aging 2 and weight loss interventions 3-5 . As such interventions become more widely used, agents that preserve or increase muscle mass are needed. To identify such therapeutic opportunities, we performed genome-wide association meta-analyses (GWAS) of arm, leg, trunk and total lean mass measured by dual-energy X-ray absorptiometry (DXA), a widely used method to estimate muscle mass. We identified 63 loci, including the rare missense variant in MSTN (p.Ile225Thr, rs143242500), which had the largest effect on leg lean mass (β = 0.28 SD [95% CI: 0.19, 0.37], P = 1.9 × 10 -9 ). MSTN encodes myostatin, a negative regulator of skeletal muscle mass and a therapeutic target for muscle wasting disorders 6 . p.Ile225Thr is the first genome-wide significant association in MSTN in humans with functional consequences and could provide further insight into long-term systemic effects of myostatin inhibition.