Publications by authors named "Henning Bundgaard"

245 Publications

Humoral response to two doses of BNT162b2 vaccination in people with HIV.

J Intern Med 2021 Nov 28. Epub 2021 Nov 28.

Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: People with HIV (PWH) are at increased risk of severe COVID-19. We aimed to determine humoral responses in PWH and controls who received two doses of BNT162b2.

Methods: In 269 PWH and 538 age matched controls, we measured IgG and neutralizing antibodies specific for the receptor-binding domain of SARS-CoV-2 at baseline, three weeks and two months after first dose of BNT162b2.

Results: IgG antibodies increased from baseline to three weeks and from three weeks to two months in both groups, but the concentrations of IgG antibodies were lower in PWH than controls at three weeks and two months (p = 0.025 and p<0.001), respectively. The IgG titers in PWH with a humoral response at two months were 77.9% (95% CI: 62.5-97.0%, age and sex-adjusted p = 0.027) of controls.

Conclusion: Reduced IgG antibody response to vaccination with BNT162b2 was found in PWH, and increased awareness of breakthrough infections in PWH is needed. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/joim.13419DOI Listing
November 2021

Lung Ultrasound Findings Associated With COVID-19 ARDS, ICU Admission, and All-Cause Mortality.

Respir Care 2021 Nov 23. Epub 2021 Nov 23.

Cardiovascular Non-Invasive Imaging Research Laboratory, Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: As lung ultrasound (LUS) has emerged as a diagnostic tool in patients with COVID-19, we sought to investigate the association between LUS findings and the composite in-hospital outcome of ARDS incidence, ICU admission, and all-cause mortality.

Methods: In this prospective, multi-center, observational study, adults with laboratory-confirmed SARS-CoV-2 infection were enrolled from non-ICU in-patient units. Subjects underwent an LUS evaluating a total of 8 zones. Images were analyzed off-line, blinded to clinical variables and outcomes. A LUS score was developed to integrate LUS findings: ≥ 3 B-lines corresponded to a score of 1, confluent B-lines to a score of 2, and subpleural or lobar consolidation to a score of 3. The total LUS score ranged from 0-24 per subject.

Results: Among 215 enrolled subjects, 168 with LUS data and no current signs of ARDS or ICU admission (mean age 59 y, 56% male) were included. One hundred thirty-six (81%) subjects had pathologic LUS findings in ≥ 1 zone (≥ 3 B-lines, confluent B-lines, or consolidations). Markers of disease severity at baseline were higher in subjects with the composite outcome ( 31, 18%), including higher median C-reactive protein (90 mg/L vs 55, < .001) and procalcitonin levels (0.35 μg/L vs 0.13, = .033) and higher supplemental oxygen requirements (median 4 L/min vs 2, = .001). However, LUS findings and score did not differ significantly between subjects with the composite outcome and those without, and were not associated with outcomes in unadjusted and adjusted logistic regression analyses.

Conclusions: Pathologic findings on LUS were common a median of 3 d after admission in this cohort of non-ICU hospitalized subjects with COVID-19 and did not differ among subjects who experienced the composite outcome of incident ARDS, ICU admission, and all-cause mortality compared to subjects who did not. These findings should be confirmed in future investigations. The study is registered at Clinicaltrials.gov (NCT04377035).
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http://dx.doi.org/10.4187/respcare.09108DOI Listing
November 2021

Gestational Age and Neonatal Electrocardiograms.

Pediatrics 2021 Nov 24. Epub 2021 Nov 24.

Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: Interpretation of the neonatal electrocardiogram (ECG) is challenging due to the profound changes of the cardiovascular system in this period. We aimed to investigate the impact of gestational age (GA) on the neonatal ECG and create GA-specific reference values.

Methods: The Copenhagen Baby Heart Study is a prospective general population study that offered cardiac evaluation of neonates. ECGs and echocardiograms were obtained and systematically analyzed. GA, weight, height, and other baseline variables were registered.

Results: We included 16 462 neonates (52% boys) with normal echocardiograms. The median postnatal age was 11 days (range 0 to 30), and the median GA was 281 days (range 238 to 301). Analyzing the ECG parameters as a function of GA, we found an effect of GA on almost all investigated ECG parameters. The largest percentual effect of GA was on heart rate (HR; 147 vs 139 beats per minute), the QRS axis (103° vs 116°), and maximum R-wave amplitude in V1 (R-V1; 0.97 vs 1.19 mV) for GA ≤35 vs ≥42 weeks, respectively. Boys had longer PR and QRS intervals and a more right-shifted QRS axis within multiple GA intervals (all P < .01). The effect of GA generally persisted after multifactorial adjustment.

Conclusions: GA was associated with significant differences in multiple neonatal ECG parameters. The association generally persisted after multifactorial adjustment, indicating a direct effect of GA on the developing neonatal cardiac conduction system. For HR, the QRS axis, and R-V1, the use of GA-specific reference values may optimize clinical handling of neonates.
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http://dx.doi.org/10.1542/peds.2021-050942DOI Listing
November 2021

Effect of Loss-of-Function Genetic Variants in on Glycemic Traits, Neurocognitive Impairment, and Hepatobiliary Function.

Diabetes Care 2021 Nov 10. Epub 2021 Nov 10.

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Objective: To evaluate the association between predicted loss-of-function (pLoF) variants and glycemic traits, hepatobiliary function, and neurocognitive traits.

Research Design And Methods: We identified carriers of pLoF variants in UK Biobank exome sequencing data. We assessed the aggregate effects of these variants on lipid and lipoprotein traits, which served as a positive control. Association of pLoF carrier status and glycemic traits, hepatobiliary function, and neurocognitive traits was then evaluated as a measure for adverse effects.

Results: We identified 374 individuals with 41 pLoF variants. As expected, we found that pLoF carriers had significantly lower LDL cholesterol C levels ( = 7.4 × 10) and apolipoprotein B levels ( = 7.6 × 10) than did noncarriers. However, we found no significant associations between pLoF carrier status and glycemic traits, hepatobiliary function, and neurocognitive traits ( > 0.05).

Conclusions: Our results do not support adverse effects of pLoF variants on glycemic traits, hepatobiliary function, or neurocognitive traits.
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http://dx.doi.org/10.2337/dc21-0955DOI Listing
November 2021

Coagulation parameters in the newborn and infant - the Copenhagen Baby Heart and COMPARE studies.

Clin Chem Lab Med 2021 Nov 9. Epub 2021 Nov 9.

Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.

Objectives: The coagulation system is not fully developed at birth and matures during the first months of infancy, complicating clinical decision making within hemostasis. This study evaluates coagulation parameters at birth and two months after birth, and tests whether cord blood can be used as a proxy for neonatal venous blood measurements.

Methods: The Copenhagen Baby Heart Study (CBHS) and the COMPARE study comprise 13,237 cord blood samples and 444 parallel neonatal venous blood samples, with a two month follow-up in 362 children.

Results: Because coagulation parameters differed according to gestational age (GA), all analyses were stratified by GA. For neonatal venous blood, reference intervals for activated partial thromboplastin time (APTT) and prothrombin time (PT) were 28-43 s and 33-61% for GA 37-39 and 24-38 s and 30-65% for GA 40-42. Reference intervals for international normalized ratio (INR) and thrombocyte count were 1.1-1.7 and 194-409 × 10/L for GA 37-39 and 1.2-1.8 and 188-433 × 10/L for GA 40-42. Correlation coefficients between umbilical cord and neonatal venous blood for APTT, PT, INR, and thrombocyte count were 0.68, 0.72, 0.69, and 0.77 respectively, and the distributions of the parameters did not differ between the two types of blood (all p-values>0.05).

Conclusions: This study describes new GA dependent reference intervals for common coagulation parameters in newborns and suggests that cord blood may serve as a proxy for neonatal venous blood for these traits. Such data will likely improve clinical decision making within hemostasis among newborn and infant children.
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http://dx.doi.org/10.1515/cclm-2021-0967DOI Listing
November 2021

Functional Effects of Receptor-Binding Domain Mutations of SARS-CoV-2 B.1.351 and P.1 Variants.

Front Immunol 2021 7;12:757197. Epub 2021 Oct 7.

Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

The recent identification and rise to dominance of the P.1 and B.1.351 SARS-CoV-2 variants have brought international concern because they may confer fitness advantages. The same three positions in the receptor-binding domain (RBD) are affected in both variants, but where the 417 substitution differs, the E484K/N501Y have co-evolved by convergent evolution. Here we characterize the functional and immune evasive consequences of the P.1 and B.1.351 RBD mutations. E484K and N501Y result in gain-of-function with two different outcomes: The N501Y confers a ten-fold affinity increase towards ACE-2, but a modest antibody evasion potential of plasma from convalescent or vaccinated individuals, whereas the E484K displays a significant antibody evasion capacity without a major impact on affinity. On the other hand, the two different 417 substitutions severely impair the RBD/ACE-2 affinity, but in the combined P.1 and B.1.351 RBD variants, this effect is partly counterbalanced by the effect of the E484K and N501Y. Our results suggest that the combination of these three mutations is a two-step forward and one step back in terms of viral fitness.
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http://dx.doi.org/10.3389/fimmu.2021.757197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529273PMC
November 2021

Risk Factors for Being Seronegative following SARS-CoV-2 Infection in a Large Cohort of Health Care Workers in Denmark.

Microbiol Spectr 2021 10 20;9(2):e0090421. Epub 2021 Oct 20.

Department of Clinical Research, Nordsjaellands Hospital, Hilleroed, Denmark.

Most individuals seroconvert after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but being seronegative is observed in 1 to 9%. We aimed to investigate the risk factors associated with being seronegative following PCR-confirmed SARS-CoV-2 infection. In a prospective cohort study, we screened health care workers (HCW) in the Capital Region of Denmark for SARS-CoV-2 antibodies. We performed three rounds of screening from April to October 2020 using an enzyme-linked immunosorbent assay (ELISA) method targeting SARS-CoV-2 total antibodies. Data on all participants' PCR for SARS-CoV-2 RNA were captured from national registries. The Kaplan-Meier method and Cox proportional hazards models were applied to investigate the probability of being seronegative and the related risk factors, respectively. Of 36,583 HCW, 866 (2.4%) had a positive PCR before or during the study period. The median (interquartile range [IQR]) age of 866 HCW was 42 (31 to 53) years, and 666 (77%) were female. After a median of 132 (range, 35 to 180) days, 21 (2.4%) of 866 were seronegative. In a multivariable model, independent risk factors for being seronegative were self-reported asymptomatic or mild infection hazard ratio (HR) of 6.6 (95% confidence interval [CI], 2.6 to 17; < 0.001) and body mass index (BMI) of ≥30, HR 3.1 (95% CI, 1.1 to 8.8; = 0.039). Only a few (2.4%) HCW were not seropositive. Asymptomatic or mild infection as well as a BMI above 30 were associated with being seronegative. Since the presence of antibodies against SARS-CoV-2 reduces the risk of reinfection, efforts to protect HCW with risk factors for being seronegative may be needed in future COVID-19 surges. Most individuals seroconvert after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but negative serology is observed in 1 to 9%. We found that asymptomatic or mild infection as well as a BMI above 30 were associated with being seronegative. Since the presence of antibodies against SARS-CoV-2 reduces the risk of reinfection, efforts to protect HCW with risk factors for being seronegative may be needed in future COVID-19 surges.
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http://dx.doi.org/10.1128/Spectrum.00904-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528102PMC
October 2021

Severity of congenital long QT syndrome disease manifestation and risk of depression, anxiety, and mortality: a nationwide study.

Europace 2021 Oct 15. Epub 2021 Oct 15.

Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Aims: We examined if a congenital long QT syndrome (cLQTS) diagnosis and severity of cLQTS disease manifestation was associated with increased risk of depression, anxiety, and all-cause mortality.

Methods And Results: All patients with known cLQTS in Denmark were identified using nationwide registries and specialized inherited cardiac disease clinics (1994-2016) and followed for up to 3 years after their cLQTS diagnosis. Risk factors for depression, anxiety, and all-cause mortality were determined using multivariable Cox proportional-hazards regression. An age- and sex-matched control population was identified (matching 1:4). Overall, 589 patients with cLQTS were identified of which 119/589 (20.2%) developed depression or anxiety during follow-up compared with 302/2356 (12.8%) from the control population (P < 0.001). Severity of cLQTS disease manifestation was identified for 324/589 (55%) of patients with cLQTS; 162 were asymptomatic, 119 had ventricular tachycardia (VT)/syncope, and 43 had aborted sudden cardiac death (aSCD). In multivariable models, patients with aSCD, VT/syncope, or unspecified cLQTS disease manifestation had a higher risk of developing depression or anxiety compared with the control population (hazard ratio [HR]=2.4, 95% confidence interval [CI]: 1.1-5.1; HR = 1.9, 95% CI: 1.2-3.0; HR = 1.6, 95% CI: 1.1-2.3, respectively). Asymptomatic patients had similar risk of developing depression or anxiety as the control population (HR = 1.2, 95% CI: 0.8-1.9). During follow-up, 10/589 (1.7%) patients with cLQTS died compared with 27/2356 (1.1%) from the control population (P = 0.5). Furthermore, 4/10 who died had developed depression or anxiety.

Conclusion: A severe cLQTS disease manifestation was associated with a greater risk of depression or anxiety. All-cause mortality for patients with cLQTS was low.
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http://dx.doi.org/10.1093/europace/euab252DOI Listing
October 2021

Lipoprotein(a) Levels at Birth and in Early Childhood - The COMPARE Study.

J Clin Endocrinol Metab 2021 Oct 7. Epub 2021 Oct 7.

Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte Hospital.

Background And Objective: High lipoprotein(a) is a genetically determined causal risk factor for cardiovascular disease and 20% of the adult population has high levels (i.e. >42 mg/dL, >88 nmol/L). We investigated whether early life lipoprotein(a) levels measured in cord blood may serve as a proxy for neonatal venous blood levels, whether lipoprotein(a) birth levels (i.e. cord or venous) predict levels later in life, and whether early life and parental levels correlate.

Methods: The COMPARE study is a prospective cohort study of newborns (N=450) from Copenhagen, Denmark including blood sampling of parents. Plasma lipoprotein(a) was measured in cord blood (N=402), neonatal venous blood (N=356), and at 2 (N=320) and 15 months follow-up (N=148) of infants, and in parents (N=705).

Results: Mean lipoprotein(a) levels were 2.2(95%CI:1.9-2.5), 2.4(2.0-2.7), 4.1(3.4-4.9), and 14.6(11.4-17.9) mg/dL in cord, neonatal venous, and 2- and 15-months venous samples, respectively. Lipoprotein(a) levels in cord blood correlated strongly with neonatal venous blood levels (R2=0.95, p<0.001) and neonatal levels correlated moderately with 2- and 15-months levels (R2=0.68 and 0.67, both p<0.001). Birth levels ≥90th percentile predicted lipoprotein(a) >42 mg/dL at 15 months with positive predictive values of 89% and 85% for neonatal venous and cord blood. Neonatal and infant levels correlated weakly with parental levels, most pronounced at 15 months (R2=0.22, p<0.001).

Conclusions: Lipoprotein(a) levels are low in early life, cord blood may serve as a proxy for neonatal venous blood, and birth levels ≥90th percentile can identify newborns at risk of developing high levels.
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http://dx.doi.org/10.1210/clinem/dgab734DOI Listing
October 2021

Severity of anaemia and association with all-cause mortality in patients with medically managed left-sided endocarditis.

Heart 2021 Oct 5. Epub 2021 Oct 5.

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objective: To assess the prevalence and severity of anaemia in patients with left-sided infective endocarditis (IE) and association with mortality.

Methods: In the Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis trial, 400 patients with IE were randomised to conventional or partial oral antibiotic treatment after stabilisation of infection, showing non-inferiority. Haemoglobin (Hgb) levels were measured at randomisation. Primary outcomes were all-cause mortality after 6 months and 3 years. Patients who underwent valve surgery were excluded due to competing reasons for anaemia.

Results: Out of 400 patients with IE, 248 (mean age 70.6 years (SD 11.1), 62 women (25.0%)) were medically managed; 37 (14.9%) patients had no anaemia, 139 (56.1%) had mild anaemia (Hgb <8.1 mmol/L in men and Hgb <7.5 mmol/L in women and Hgb ≥6.2 mmol/L) and 72 (29.0%) had moderate to severe anaemia (Hgb <6.2 mmol/L). Mortality rates in patients with no anaemia, mild anaemia and moderate to severe anaemia were 2.7%, 3.6% and 15.3% at 6-month follow-up and 13.5%, 20.1% and 34.7% at 3-year follow-up, respectively. Moderate to severe anaemia was associated with higher mortality after 6 months (HR 4.81, 95% CI 1.78 to 13.0, p=0.002) and after 3 years (HR 2.14, 95% CI 1.27 to 3.60, p=0.004) and remained significant after multivariable adjustment.

Conclusion: Moderate to severe anaemia was present in 29% of patients with medically treated IE after stabilisation of infection and was independently associated with higher mortality within the following 3 years. Further investigations are warranted to determine whether intensified treatment of anaemia in patients with IE might improve outcome.
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http://dx.doi.org/10.1136/heartjnl-2021-319637DOI Listing
October 2021

Novel human in vitro vegetation simulation model for infective endocarditis.

APMIS 2021 Nov 18;129(11):653-662. Epub 2021 Oct 18.

Department of Clinical Microbiology, Rigshospitalet, Copenhagen N, Denmark.

Infective endocarditis (IE) is a heart valve infection with high mortality rates. IE results from epithelial lesions, inducing sterile healing vegetations consisting of platelets, leucocytes, and fibrin that are susceptible for colonization by temporary bacteremia. Clinical testing of new treatments for IE is difficult and fast models sparse. The present study aimed at establishing an in vitro vegetation simulation IE model for fast screening of novel treatment strategies. A healing promoting platelet and leucocyte-rich fibrin patch was used to establish an IE organoid-like model by colonization with IE-associated bacterial isolates Staphylococcus aureus, Streptococcus spp (S. mitis group), and Enterococcus faecalis. The patch was subsequently exposed to tobramycin, ciprofloxacin, or penicillin. Bacterial colonization was evaluated by microscopy and quantitative bacteriology. We achieved stable bacterial colonization on the patch, comparable to clinical IE vegetations. Microscopy revealed uneven, biofilm-like colonization of the patch. The surface-associated bacteria displayed increased tolerance to antibiotics compared to planktonic bacteria. The present study succeeded in establishing an IE simulation model with the relevant pathogens S. aureus, S. mitis group, and E. faecalis. The findings indicate that the IE model mirrors the natural IE process and has the potential for fast screening of treatment candidates.
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http://dx.doi.org/10.1111/apm.13182DOI Listing
November 2021

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Nat Med 2021 10 23;27(10):1818-1824. Epub 2021 Sep 23.

Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.
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http://dx.doi.org/10.1038/s41591-021-01505-4DOI Listing
October 2021

Seroprevalence of SARS-CoV-2 antibodies and reduced risk of reinfection through 6 months: a Danish observational cohort study of 44 000 healthcare workers.

Clin Microbiol Infect 2021 Sep 17. Epub 2021 Sep 17.

Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Objectives: Antibodies to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are a key factor in protecting against coronavirus disease 2019 (COVID-19). We examined longitudinal changes in seroprevalence in healthcare workers (HCWs) in Copenhagen and the protective effect of antibodies against SARS-CoV-2.

Methods: In this prospective study, screening for antibodies against SARS-CoV-2 (ELISA) was offered to HCWs three times over 6 months. HCW characteristics were obtained by questionnaires. The study was registered at ClinicalTrials.gov, NCT04346186.

Results: From April to October 2020 we screened 44 698 HCWs, of whom 2811 were seropositive at least once. The seroprevalence increased from 4.0% (1501/37 452) to 7.4% (2022/27 457) during the period (p < 0.001) and was significantly higher than in non-HCWs. Frontline HCWs had a significantly increased risk of seropositivity compared to non-frontline HCWs, with risk ratios (RRs) at the three rounds of 1.49 (95%CI 1.34-1.65, p < 0.001), 1.52 (1.39-1.68, p < 0.001) and 1.50 (1.38-1.64, p < 0.001). The seroprevalence was 1.42- to 2.25-fold higher (p < 0.001) in HCWs from dedicated COVID-19 wards than in other frontline HCWs. Seropositive HCWs had an RR of 0.35 (0.15-0.85, p 0.012) of reinfection during the following 6 months, and 2115 out of 2248 (95%) of those who were seropositive during rounds one or two remained seropositive after 4-6 months. The 133 of 2248 participants (5.0%) who seroreverted were slightly older and reported fewer symptoms than other seropositive participants.

Conclusions: HCWs remained at increased risk of infection with SARS-CoV-2 during the 6-month period. Seropositivity against SARS-CoV-2 persisted for at least 6 months in the vast majority of HCWs and was associated with a significantly lower risk of reinfection.
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http://dx.doi.org/10.1016/j.cmi.2021.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447554PMC
September 2021

Effect of moderate potassium-elevating treatment in long QT syndrome: the TriQarr Potassium Study.

Open Heart 2021 09;8(2)

Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Background: In long QT syndrome (LQTS), beta blockers prevent arrhythmias. As a supplement, means to increase potassium has been suggested. We set to investigate the effect of moderate potassium elevation on cardiac repolarisation.

Methods: Patients with LQTS with a disease-causing or variant were included. In addition to usual beta-blocker treatment, patients were prescribed (1) 50 mg spironolactone () or (2) 100 mg spironolactone and 3 g potassium chloride per day (). Electrocardiographic measures were obtained at baseline and after 7 days of treatment.

Results: Twenty patients were enrolled (10 low dose and 10 high dose+). One patient was excluded due to severe influenza-like symptoms, and 5 of 19 patients completing the study had mild side effects. Plasma potassium in low dose did not increase in response to treatment (4.26±0.22 to 4.05±0.19 mmol/L, p=0.07). Also, no change was observed in resting QTcF (QT interval corrected using Fridericia's formula) before versus after treatment (478±7 vs 479±7 ms, p=0.9). In high dose+, potassium increased significantly from 4.08±0.29 to 4.48±0.54 mmol/L (p=0.001). However, no difference in QTcF was observed comparing before (472±8 ms) versus after (469±8 ms) (p=0.66) high dose treatment. No patients developed hyperkalaemia.

Conclusion: In patients with LQTS, high dose treatment increased plasma potassium by 0.4 mmol/L without cases of hyperkalaemia. However, the potassium increase did not shorten the QT interval and several patients had side effects. Considering the QT interval as a proxy for arrhythmic risk, our data do not support that potassium-elevating treatment has a role as antiarrhythmic prophylaxis in patients with LQTS with normal-range potassium levels.

Trial Registration Number: NCT03291145.
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http://dx.doi.org/10.1136/openhrt-2021-001670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449979PMC
September 2021

Recovery of cardiac function following COVID-19 - ECHOVID-19: a prospective longitudinal cohort study.

Eur J Heart Fail 2021 Sep 12. Epub 2021 Sep 12.

Department of Cardiology, Herlev & Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Aims: The degree of cardiovascular sequelae following COVID-19 remains unknown. The aim of this study was to investigate whether cardiac function recovers following COVID-19.

Methods And Results: A consecutive sample of patients hospitalized with COVID-19 was prospectively included in this longitudinal study. All patients underwent an echocardiographic examination during hospitalization and 2 months later. All participants were successfully matched 1:1 with COVID-19-free controls by age and sex. A total of 91 patients were included (mean age 63 ± 12 years, 59% male). A median of 77 days (interquartile range: 72-92) passed between the two examinations. Right ventricular (RV) function improved following resolution of COVID-19: tricuspid annular plane systolic excursion (TAPSE) (2.28 ± 0.40 cm vs. 2.11 ± 0.38 cm, P < 0.001) and RV longitudinal strain (RVLS) (25.3 ± 5.5% vs. 19.9 ± 5.8%, P < 0.001). In contrast, left ventricular (LV) systolic function assessed by global longitudinal strain (GLS) did not significantly improve (17.4 ± 2.9% vs. 17.6 ± 3.3%, P = 0.6). N-terminal pro-B-type natriuretic peptide decreased between the two examinations [177.6 (80.3-408.0) ng/L vs. 11.7 (5.7-24.0) ng/L, P < 0.001]. None of the participants had elevated troponins at follow-up compared to 18 (27.7%) during hospitalization. Recovered COVID-19 patients had significantly lower GLS (17.4 ± 2.9% vs. 18.8 ± 2.9%, P < 0.001 and adjusted P = 0.004), TAPSE (2.28 ± 0.40 cm vs. 2.67 ± 0.44 cm, P < 0.001 and adjusted P < 0.001), and RVLS (25.3 ± 5.5% vs. 26.6 ± 5.8%, P = 0.50 and adjusted P < 0.001) compared to matched controls.

Conclusion: Acute COVID-19 affected negatively RV function and cardiac biomarkers but recovered following resolution of COVID-19. In contrast, the observed reduced LV function during acute COVID-19 did not improve post-COVID-19. Compared to the matched controls, both LV and RV function remained impaired.
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http://dx.doi.org/10.1002/ejhf.2347DOI Listing
September 2021

Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure.

J Med Genet 2021 Aug 16. Epub 2021 Aug 16.

Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course.

Methods: The Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed.

Results: We evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: in 41%, in 13%, in 7% and in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with // than ARVC (27% vs 4%, p<0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among than // carriers: HR 0.25 (0.10-0.68, p<0.01) for atrial fibrillation/flutter, HR 0.67 (0.44-1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42-0.95, p<0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with // carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01).

Conclusion: In this large cohort of ARVC families with long-term follow-up, we found genotype to be more arrhythmic than /2/ or gene-negative carrier status, whereas reduced LVEF was mostly seen among /2/ carriers. Male sex was associated with a more severe phenotype.
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http://dx.doi.org/10.1136/jmedgenet-2021-107911DOI Listing
August 2021

Effectiveness of Adding a Mask Recommendation to Other Public Health Measures.

Ann Intern Med 2021 08;174(8):1194-1195

Herlev & Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

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http://dx.doi.org/10.7326/L21-0401DOI Listing
August 2021

Cardiac Involvement in Women With Pathogenic Dystrophin Gene Variants.

Front Neurol 2021 27;12:707838. Epub 2021 Jul 27.

Department of Neurology, Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

To determine the frequency and extent of cardiac involvement in female carriers of pathogenic variants in , 53 women were examined through an observational, cross-sectional study. Genetically verified female carriers of pathogenic variants were examined by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement, echocardiography, 24-h Holter monitoring, ECG, and blood concentrations of skeletal and cardiac muscle biomarkers. Fifty-three female carriers of pathogenic variants (mean age 49.6 years, 33 associated with DMD, and 20 with BMD) were included in the study. Sixty-two percent had cardiac dysfunction on echocardiography. On CMR, 49% had myocardial fibrosis, 35% had dilated left ventricles, and 10% had left ventricular hypertrophy. ECGs were abnormal in 72%, and abnormal Holter monitoring was found in 43%. Age did not correlate with myocardial fibrosis or cardiac dysfunction. Myocardial fibrosis was more frequent in carriers of pathogenic variants associated with DMD vs. BMD (61 vs. 28%, = 0.02). This study shows that cardiac involvement, affecting both structure and function of the heart, is found in over 2/3 of women with a pathogenic variant. The study supports early cardiac screening, including ECG, Holter, and cardiac imaging, in this group of carriers, so that symptoms related to pathogenic variants in can be recognized, and relevant treatment can be initiated. Longitudinal studies are needed to assess morbidity and mortality related to single, pathogenic variants in women.
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http://dx.doi.org/10.3389/fneur.2021.707838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353322PMC
July 2021

Association of Variants Near the Bradykinin Receptor B Gene With Angioedema in Patients Taking ACE Inhibitors.

J Am Coll Cardiol 2021 Aug;78(7):696-709

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients.

Objectives: The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema.

Methods: A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model.

Results: The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI: -0.83 to -0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI: -0.46 to -0.05; P = 0.013) blood pressure.

Conclusions: In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B gene were associated with increased risk for ACE inhibitor-related angioedema.
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http://dx.doi.org/10.1016/j.jacc.2021.05.054DOI Listing
August 2021

Genome-wide association study identifies 18 novel loci associated with left atrial volume and function.

Eur Heart J 2021 Jul 29. Epub 2021 Jul 29.

Laboratory for Molecular Cardiology, Department of Cardiology, Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Henrik Harpestrengs Vej 4C, 2100 Copenhagen, Denmark.

Aims : Left atrial (LA) volume and function impose significant impact on cardiovascular pathogenesis if compromised. We aimed at investigating the genetic architecture of LA volume and function using cardiac magnetic resonance imaging data.

Methods And Results : We used the UK Biobank, which is a large prospective population study with available phenotypic and genetic data. On a subset of 35 658 European individuals, we performed genome-wide association studies on five volumetric and functional LA variables, generated using a machine learning algorithm. In total, we identified 18 novel genetic loci, mapped to genes with known roles in cardiomyopathy (e.g. MYO18B, TTN, DSP, ANKRD1) and arrhythmia (e.g. TTN, CASQ2, MYO18B, C9orf3). We observed high genetic correlation between LA volume and function and stroke, which was most pronounced for LA passive emptying fraction (rg = 0.40, P = 4 × 10-6). To investigate whether the genetic risk of atrial fibrillation (AF) is associated with LA traits that precede overt AF, we produced a polygenetic risk score for AF. We found that polygenetic risk for AF is associated with increased LA volume and decreased LA function in participants without AF [LAmax 0.25 (mL/m2)/standard deviation (SD), 95% confidence interval (CI) (0.15; 0.36), P = 5.13 × 10-6; LAmin 0.21 (mL/m2)/SD, 95% CI (0.15; 0.28), P = 1.86 × 10-10; LA active emptying fraction -0.35%/SD, 95% CI (-0.43; -0.26), P = 3.14 × 10-14].

Conclusion : We report on 18 genetic loci associated with LA volume and function and show evidence for several plausible candidate genes important for LA structure.
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http://dx.doi.org/10.1093/eurheartj/ehab466DOI Listing
July 2021

Complications of implantable cardioverter-defibrillator treatment in arrhythmogenic right ventricular cardiomyopathy.

Europace 2021 Jul 19. Epub 2021 Jul 19.

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Aims: Treatment with implantable cardioverter-defibrillators (ICD) is a cornerstone for prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at describing the complications associated with ICD treatment in a multinational cohort with long-term follow-up.

Methods And Results: The Nordic ARVC registry was established in 2010 and encompasses a large multinational cohort of ARVC patients, including their clinical characteristics, treatment, and events during follow-up. We included 299 patients (66% males, median age 41 years). During a median follow-up of 10.6 years, 124 (41%) patients experienced appropriate ICD shock therapy, 28 (9%) experienced inappropriate shocks, 82 (27%) had a complication requiring surgery (mainly lead-related, n = 75), and 99 (33%) patients experienced the combined endpoint of either an inappropriate shock or a surgical complication. The crude rate of first inappropriate shock was 3.4% during the first year after implantation but decreased after the first year and plateaued over time. Contrary, the risk of a complication requiring surgery was 5.5% the first year and remained high throughout the study period. The combined risk of any complication was 7.9% the first year. In multivariate cox regression, presence of atrial fibrillation/flutter was a risk factor for inappropriate shock (P < 0.05), whereas sex, age at implant, and device type were not (all P > 0.05).

Conclusion: Forty-one percent of ARVC patients treated with ICD experienced potentially life-saving ICD therapy during long-term follow-up. A third of the patients experienced a complication during follow-up with lead-related complications constituting the vast majority.
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http://dx.doi.org/10.1093/europace/euab112DOI Listing
July 2021

Anti-biofilm Approach in Infective Endocarditis Exposes New Treatment Strategies for Improved Outcome.

Front Cell Dev Biol 2021 18;9:643335. Epub 2021 Jun 18.

Department of Clinical Microbiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Infective endocarditis (IE) is a life-threatening infective disease with increasing incidence worldwide. From early on, in the antibiotic era, it was recognized that high-dose and long-term antibiotic therapy was correlated to improved outcome. In addition, for several of the common microbial IE etiologies, the use of combination antibiotic therapy further improves outcome. IE vegetations on affected heart valves from patients and experimental animal models resemble biofilm infections. Besides the recalcitrant nature of IE, the microorganisms often present in an aggregated form, and gradients of bacterial activity in the vegetations can be observed. Even after appropriate antibiotic therapy, such microbial formations can often be identified in surgically removed, infected heart valves. Therefore, persistent or recurrent cases of IE, after apparent initial infection control, can be related to biofilm formation in the heart valve vegetations. On this background, the present review will describe potentially novel non-antibiotic, antimicrobial approaches in IE, with special focus on anti-thrombotic strategies and hyperbaric oxygen therapy targeting the biofilm formation of the infected heart valves caused by . The format is translational from preclinical models to actual clinical treatment strategies.
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http://dx.doi.org/10.3389/fcell.2021.643335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249808PMC
June 2021

Danish citizens' preferences for at-home oropharyngeal/nasal SARS-CoV-2 specimen collection.

Int J Infect Dis 2021 Aug 1;109:195-198. Epub 2021 Jul 1.

Department of Cardiology, The Heart Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Introduction: Diagnostic confirmation of SARS-CoV-2 by self-collection of specimens is a reliable method compared with healthcare worker collected samples. Citizens' preferences for collection methods are unknown, but at-home collection could have several advantages.

Methods: This study investigated the preference for guided at-home self-collection versus at-hospital specimen collection by healthcare workers.

Results: Among the 3709 participants, at-home swab collection was the preferred setting for 2362 (63.7%) compared with 1347 (36.3%) reporting a preference for an at-hospital swabbing procedure.

Conclusion: A high preference for guided at-home self-collection of oropharyngeal/nasal SARS-CoV-2 specimens exists and could be a future norm beyond COVID-19.
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http://dx.doi.org/10.1016/j.ijid.2021.06.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245307PMC
August 2021

Lung ultrasound findings in hospitalized COVID-19 patients in relation to venous thromboembolic events: the ECHOVID-19 study.

J Ultrasound 2021 Jul 2. Epub 2021 Jul 2.

Cardiovascular Non-Invasive Imaging Research Laboratory, Department of Cardiology, Herlev & Gentofte Hospital, University of Copenhagen, Niels Andersens vej 65, 2900, Hellerup, Denmark.

Purpose: Several studies have reported thromboembolic events to be common in severe COVID-19 cases. We sought to investigate the relationship between lung ultrasound (LUS) findings in hospitalized COVID-19 patients and the development of venous thromboembolic events (VTE).

Methods: A total of 203 adults were included from a COVID-19 ward in this prospective multi-center study (mean age 68.6 years, 56.7% men). All patients underwent 8-zone LUS, and all ultrasound images were analyzed off-line blinded. Several LUS findings were investigated (total number of B-lines, B-line score, and LUS-scores).

Results: Median time from admission to LUS examination was 4 days (IQR: 2, 8). The median number of B-lines was 12 (IQR: 8, 18), and 44 (21.7%) had a positive B-line score. During hospitalization, 17 patients developed VTE (4 deep-vein thrombosis, 15 pulmonary embolism), 12 following and 5 prior to LUS. In fully adjusted multivariable Cox models (excluding participants with VTE prior to LUS), all LUS parameters were significantly associated with VTE (total number of B-lines: HR = 1.14, 95% CI (1.03, 1.26) per 1 B-line increase), positive B-line score: HR = 9.79, 95% CI (1.87, 51.35), and LUS-score: HR = 1.51, 95% CI (1.10, 2.07), per 1-point increase). The B-line score and LUS-score remained significantly associated with VTE in sensitivity analyses.

Conclusion: In hospitalized COVID-19 patients, pathological LUS findings were common, and the total number of B-lines, B-line score, and LUS-score were all associated with VTE. These findings indicate that the LUS examination may be useful in risk stratification and the clinical management of COVID-19. These findings should be considered hypothesis generating. CLINICALTRIALS.

Gov Id: NCT04377035.
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http://dx.doi.org/10.1007/s40477-021-00605-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249836PMC
July 2021

Comprehensive cardiac rehabilitation for patients following infective endocarditis: results of the randomized CopenHeartIE trial.

Eur J Cardiovasc Nurs 2021 Jun 5. Epub 2021 Jun 5.

The Heart Centre, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen O 2100, Denmark.

Aims: Infective endocarditis is a complex and highly mortal disease requiring lengthy treatment. Physical and mental deconditioning is common. Nonetheless, rehabilitation is virtually unexplored in this population. The aim of this trial was therefore to investigate the effects of cardiac rehabilitation in patients following endocarditis.

Methods And Results: In a randomized trial, adults with left-sided or cardiac device endocarditis were randomized 1:1 to 12 weeks of physical exercise training and five psycho-educational consultations (cardiac rehabilitation) vs. usual care without rehabilitation (control). Primary outcome was mental health measured by SF-36 Mental Component Summary (MCS) at 6 months. Secondary outcome was physical capacity measured by peak oxygen uptake (VO2) at 4 months. Exploratory outcomes were investigated. Low inclusion rate resulted in trial termination before reaching the target sample size. A total of 117 participants (mean age: 60 years, 81% male) were randomized to cardiac rehabilitation (n = 58) or to control (n = 59). Mental health and physical capacity at baseline were generally poor (MCS: 38.9-42.2 points, VO2 peak: 16.1-16.6 mL/kg/min). Cardiac rehabilitation compared with control showed no effect on mental health (MCS: 44.6 points vs. 48.8 points, P = 0.41) or physical capacity (VO2 peak: 19.9 mL/kg/min vs. 18.0 mL/kg/min, P = 0.09). Effects favouring the intervention were identified in exploratory outcomes including general fatigue (P = 0.005), and physical capacity as maximal power (W) (P = 0.005). Adherence to the intervention was 28%.

Conclusions: Results indicate no effect of cardiac rehabilitation in patients following endocarditis; however, lack of statistical power and poor adherence render findings inconclusive. Valuable insight into patients' capabilities and safety was gained, and further investigations into rehabilitation needs and modes of delivery in this high-need population should be a future priority.
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http://dx.doi.org/10.1093/eurjcn/zvab047DOI Listing
June 2021
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