Publications by authors named "Claus Graff"

90 Publications

Sex differences in left ventricular electrical dyssynchrony and outcomes with cardiac resynchronization therapy.

Heart Rhythm O2 2020 Oct 4;1(4):243-249. Epub 2020 Aug 4.

Section of Cardiac Electrophysiology, Duke University School of Medicine, Durham, North Carolina.

Background: Women seem to derive more benefit from cardiac resynchronization therapy (CRT) than men, even after accounting for the higher burden of risk factors for nonresponse often observed in men.

Objective: To assess for sex-specific differences in left ventricular (LV) electrical dyssynchrony as a contributing electrophysiological explanation for the greater degree of CRT benefit among women.

Methods: We compared the extent of baseline LV electrical dyssynchrony, as measured by the QRS area (QRSA), among men and women with left bundle branch block (LBBB) undergoing CRT at Duke University (n = 492, 35% women) overall and in relation to baseline QRS characteristics using independent sample tests and Pearson correlation coefficients. Cox regression analyses were used to relate sex, QRSA, and QRS characteristics to the risk of cardiac transplantation, LV assist device implant, or death.

Results: Although the mean QRS duration (QRSd) did not differ by sex, QRSA was greater for women vs men (113.8 μVs vs 98.2 μVs,  < .001), owing to differences in the QRSd <150 ms subgroup (92.3 ± 28.7 μVs vs 67.6 ± 26.2 μVs, < .001). Among those with nonstrict LBBB, mean QRSd was similar but QRSA was significantly greater among women than men (96.0 ± 25.0 μVs vs 63.6 ± 26.2 μVs, < .001). QRSA was similar among men and women with strict LBBB ( = .533). Female sex was associated with better long-term outcomes in an unadjusted model (hazard ratio 0.623, confidence interval 0.454-0.857, = .004) but sex no longer predicted outcomes after accounting for differences in QRSA.

Conclusions: Our study suggests that sex-specific differences in LV dyssynchrony contribute to greater CRT benefit among women. Standard QRSd and morphology assessments seem to underestimate the extent of LV electrical dyssynchrony among women with LBBB.
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http://dx.doi.org/10.1016/j.hroo.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183970PMC
October 2020

Explaining deep neural networks for knowledge discovery in electrocardiogram analysis.

Sci Rep 2021 May 26;11(1):10949. Epub 2021 May 26.

University of Copenhagen, 2200, Copenhagen N, Denmark.

Deep learning-based tools may annotate and interpret medical data more quickly, consistently, and accurately than medical doctors. However, as medical doctors are ultimately responsible for clinical decision-making, any deep learning-based prediction should be accompanied by an explanation that a human can understand. We present an approach called electrocardiogram gradient class activation map (ECGradCAM), which is used to generate attention maps and explain the reasoning behind deep learning-based decision-making in ECG analysis. Attention maps may be used in the clinic to aid diagnosis, discover new medical knowledge, and identify novel features and characteristics of medical tests. In this paper, we showcase how ECGradCAM attention maps can unmask how a novel deep learning model measures both amplitudes and intervals in 12-lead electrocardiograms, and we show an example of how attention maps may be used to develop novel ECG features.
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http://dx.doi.org/10.1038/s41598-021-90285-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154909PMC
May 2021

Comparing the consistency of electrocardiogram interval measurements by resting ECG versus 12-lead Holter.

Ann Noninvasive Electrocardiol 2021 May 4:e12851. Epub 2021 May 4.

Richmond Research Institute, St George's University of London, London, UK.

In clinical trials, traditionally only a limited number of 12-lead resting electrocardiograms (ECGs) can be recorded and, thus, long intervals may elapse between assessment timepoints and valuable information may be missed during times when patients' cardiac electrical activity is not being monitored. These limitations have led to the increasing use of Holter recorders which provide continuous data registrations while reducing the burden on patients and freeing up time for clinical trial staff to perform other tasks. However, there is a shortage of data comparing the two approaches. In this study, data from a randomized, double-blind, four-period, crossover thorough QT study in 40 healthy subjects were used to compare continuous 12-lead Holter recordings to standard 12-lead resting ECGs which were recorded in parallel. Heart rate and QT interval data were estimated by averaging three consecutive heartbeats. Values exceeding the sample average by more than 5% were tagged as outliers and excluded from the analysis. Visual comparisons of the ECG waveforms of the Holter signal showed a good correlation with resting ECGs at matching timepoints. Resting ECG data revealed sex differences that Holter data did not show. Specifically, women were found to have a longer QTcF of 20 ms, while men had a lower heart rate. We found that continuous recordings provided a more accurate reflection of changes in cardiac electrical activity over 24 hr. However, manual adjudication is still required to ensure the quality and accuracy of ECG data, and that only artifacts are removed thereby avoiding loss of true signals.
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http://dx.doi.org/10.1111/anec.12851DOI Listing
May 2021

A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.

Clin Pharmacol Drug Dev 2021 Jun 3;10(6):572-581. Epub 2021 May 3.

St George's, University of London, London, United Kingdom.

Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.
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http://dx.doi.org/10.1002/cpdd.935DOI Listing
June 2021

Comparison of the three-level and the five-level versions of the EQ-5D.

Eur J Health Econ 2021 Jun 18;22(4):621-628. Epub 2021 Mar 18.

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Inge Lehmanns Vej 7, 2100, Copenhagen, Denmark.

EQ-5D is a generic instrument to measure health-related quality of life. In 2009, a new version, EQ-5D-5L, was introduced as an attempt to reduce ceiling effects and improve sensitivity to small changes over time. The objective of this study was to assess the measurement properties of the EQ-5D-5L instrument compared to the EQ-5D-3L instrument in an elderly general population with a moderate to a high degree of comorbidity. A subgroup of participants in a large clinical trial completed the EQ-5D-3L and the EQ-5D-5L questionnaires. Based on the collected data, we tested for feasibility and ceiling and floor effects. Furthermore, we assessed the redistribution properties of the responses and examined the level of inconsistency, informativity, and convergent validity. A total of 1002 persons diagnosed with hypertension, diabetes, heart failure, and/or previous stroke completed both the EQ-5D-3L and the EQ-5D-5L questionnaires. The overall ceiling effect decreased from 46% with the EQ-5D-3L to 30% with the EQ-5D-5L and absolute and relative informativity were higher for EQ-5D-5L, and there was a stronger correlation between EQ-5D-5L and EQ VAS. The EQ-5D-5L seemed to perform better than the EQ-5D-3L in terms of feasibility, ceiling effect, discriminatory power, and convergent validity. The overall ceiling effect was higher than that found in patient samples in previous studies but lower than the one found in population studies.
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http://dx.doi.org/10.1007/s10198-021-01279-zDOI Listing
June 2021

Associations between left bundle branch block with different PR intervals, QRS durations, heart rates and the risk of heart failure: a register-based cohort study using ECG data from the primary care setting.

Open Heart 2021 02;8(1)

Department of Clinical Epidemiology, Aalborg University Hospital, Aalborg, Denmark.

Aim: Left bundle branch block (LBBB) is associated with an increased risk of heart failure (HF). We assessed the impact of common ECG parameters on this association using large-scale data.

Methods And Results: Using ECGs recorded in a large primary care population from 2001 to 2011, we identified HF-naive patients with a first-time LBBB ECG. We obtained information on sex, age, emigration, medication, diseases and death from Danish registries. We investigated the association between the PR interval, QRS duration, and heart rate and the risk of HF over a 2-year follow-up period using Cox regression analysis.Of 2471 included patients with LBBB, 464 (18.8%) developed HF during follow-up. A significant interaction was found between QRS duration and heart rate (p<0.01), and the analyses were stratified on these parameters. Using a QRS duration <150 ms and a heart rate <70 beats per minute (bpm) as the reference, all groups were statistically significantly associated with the development of HF. Patients with a QRS duration ≥150 ms and heart rate ≥70 bpm had the highest risk of developing HF (HR 3.17 (95% CI 2.41 to 4.18, p0.001). There was no association between the PR interval and HF after adjustment.

Conclusion: Prolonged QRS duration and higher heart rate were associated with increased risk of HF among primary care patients with LBBB, while no association was observed with PR interval. Patients with LBBB with both a prolonged QRS duration (≥150 ms) and higher heart rate (≥70 bpm) have the highest risk of developing HF.
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http://dx.doi.org/10.1136/openhrt-2020-001425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880100PMC
February 2021

Association Between ECG Abnormalities and Fatal Cardiovascular Disease Among Patients With and Without Severe Mental Illness.

J Am Heart Assoc 2021 01 12;10(2):e019416. Epub 2021 Jan 12.

Department of Cardiology Aalborg University Hospital Aalborg Denmark.

Background ECG abnormalities are associated with adverse outcomes in the general population, but their prognostic significance in severe mental illness (SMI) remains unexplored. We investigated associations between no, minor, and major ECG abnormalities and fatal cardiovascular disease (CVD) among patients with SMI compared with controls without mental illness. Methods and Results We cross-linked data from Danish nationwide registries and included primary care patients with digital ECGs from 2001 to 2015. Patients had SMI if they were diagnosed with schizophrenia, bipolar disorder, or severe depression before ECG recording. Controls were required to be without any prior mental illness or psychotropic medication use. Fatal CVD was assessed using hazard ratios (HRs) with 95% CIs and standardized 10-year absolute risks. Of 346 552 patients, 10 028 had SMI (3%; median age, 54 years; male, 45%), and 336 524 were controls (97%; median age, 56 years; male, 48%). We observed an interaction between SMI and ECG abnormalities on fatal CVD (<0.001). Severe mental illness was associated with fatal CVD across no (HR, 2.17; 95% CI, 1.95-2.43), minor (HR, 1.90; 95% CI, 1.49-2.42), and major (HR, 1.40; 95% CI, 1.26-1.55) ECG abnormalities compared with controls. Across age- and sex-specific subgroups, SMI patients with ECG abnormalities but no CVD at baseline had highest standardized 10-year absolute risks of fatal CVD. Conclusions ECG abnormalities conferred a poorer prognosis among patients with SMI compared with controls without mental illness. SMI patients with ECG abnormalities but no CVD represent a high-risk population that may benefit from greater surveillance and risk management.
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http://dx.doi.org/10.1161/JAHA.120.019416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955293PMC
January 2021

Electrocardiographic T-wave morphology and risk of mortality.

Int J Cardiol 2021 04 13;328:199-205. Epub 2020 Dec 13.

Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Electrocardiographic T-wave morphology is used in drug safety studies as an adjunct to the QT interval, but few measurements of T-wave morphology can be interpreted in clinical practice. Morphology combination score (MCS) is a combination of T-wave flatness/peakedness, asymmetry, and notching, enabling easy visual assessment of T-wave morphology. We aimed to test the association between T-wave morphology, quantified by MCS, and mortality.

Methods: We included electrocardiograms recorded in 2001-2011 from 342,294 primary care patients. Using Cox regression, we evaluated the association between MCS, cardiovascular death, and all-cause mortality, adjusting for heart rate, QT, QT-prolonging drugs, diabetes, ischemic heart disease, hypertension, and congestive heart failure.

Results: 270,039 individuals (44% men, median age 55 [inter-quartile range: 42-67 years]) were included and followed for a median of 9.3 years, during which time 13,489 (5.0%) died from cardiovascular causes and 50,481 (18.7%) from any cause. High values of MCS (i.e. asymmetric, flattened, and/or notched T waves) were associated with an adjusted mortality Hazard Ratio of 1.75 (95% CI 1.62-1.89) and 1.61 (1.43-1.92) for women and men, respectively. Low values of MCS (i.e. peaked and symmetric T waves) were associated with a Hazard Ratio of 1.18 (1.08-1.28) and 1.71 (1.48-1.98) for women and men, respectively.

Conclusions: In a large primary care population, we found that T-wave asymmetry, flatness, and notching provided prognostic information on mortality independent of heart rate, QTc, and baseline comorbidities.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.016DOI Listing
April 2021

Echocardiographic abnormalities and predictors of mortality in hospitalized COVID-19 patients: the ECHOVID-19 study.

ESC Heart Fail 2020 10 22. Epub 2020 Oct 22.

Department of Respiratory Medicine and Infectious Diseases, Nordsjaellands Hospital, University of Copenhagen, Copenhagen, Denmark.

Aims: The present study had two aims: (i) compare echocardiographic parameters in COVID-19 patients with matched controls and (2) assess the prognostic value of measures of left (LV) and right ventricular (RV) function in relation to COVID-19 related death.

Methods And Results: In this prospective multicentre cohort study, 214 consecutive hospitalized COVID-19 patients underwent an echocardiographic examination (by pre-determined research protocol). All participants were successfully matched 1:1 with controls from the general population on age, sex, and hypertension. Mean age of the study sample was 69 years, and 55% were male participants. LV and RV systolic function was significantly reduced in COVID-19 cases as assessed by global longitudinal strain (GLS) (16.4% ± 4.3 vs. 18.5% ± 3.0, P < 0.001), tricuspid annular plane systolic excursion (TAPSE) (2.0 ± 0.4 vs. 2.6 ± 0.5, P < 0.001), and RV strain (19.8 ± 5.9 vs. 24.2 ± 6.5, P = 0.004). All parameters remained significantly reduced after adjusting for important cardiac risk factors. During follow-up (median: 40 days), 25 COVID-19 cases died. In multivariable Cox regression reduced TAPSE [hazard ratio (HR) = 1.18, 95% confidence interval (CI) [1.07-1.31], P = 0.002, per 1 mm decrease], RV strain (HR = 1.64, 95%CI[1.02;2.66], P = 0.043, per 1% decrease) and GLS (HR = 1.20, 95%CI[1.07-1.35], P = 0.002, per 1% decrease) were significantly associated with COVID-19-related death. TAPSE and GLS remained significantly associated with the outcome after restricting the analysis to patients without prevalent heart disease.

Conclusions: RV and LV function are significantly impaired in hospitalized COVID-19 patients compared with matched controls. Furthermore, reduced TAPSE and GLS are independently associated with COVID-19-related death.
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http://dx.doi.org/10.1002/ehf2.13044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755011PMC
October 2020

Concomitant changes in ventricular depolarization and repolarization and long-term outcomes of biventricular pacing.

Pacing Clin Electrophysiol 2020 11 26;43(11):1333-1343. Epub 2020 Sep 26.

Division of Cardiology, Duke University Medical Center, Durham, North Carolina.

Background: Biventricular (BiV) pacing increases transmural repolarization heterogeneity due to epicardial to endocardial conduction from the left ventricular (LV) lead. However, limited evidence is available on concomitant changes in ventricular depolarization and repolarization and long-term outcomes of BiV pacing. Therefore, we investigated associations of BiV pacing-induced concomitant changes in ventricular depolarization and repolarization with mortality (i.e., LV assist device, heart transplantation, or all-cause mortality) and sustained ventricular arrhythmia endpoints.

Methods: Consecutive BiV-defibrillator recipients with digital preimplantation and postimplantation electrocardiograms recorded between 2006 and 2015 at Duke University Medical Center were included. We calculated changes in QRS duration and corrected JT (JTc) interval and split them by median values. For simplicity, these variables were named QRS (≤ -12 ms), QRS (> -12 ms), JTc (≤22 ms), and JTc (> 22 ms) and subsequently used to construct four mutually exclusive groups.

Results: We included 528 patients (median age, 68 years; male, 69%). No correlation between changes in QRS duration and JTc interval was observed (P = .295). Compared to QRS /JTc , increased risk of the composite mortality endpoint was associated with QRS /JTc (hazard ratio [HR] = 1.62; 95% confidence interval [CI] = 1.09-2.43), QRS /JTc (HR = 1.86; 95% CI = 1.27-2.71), and QRS /JTc (HR = 2.25; 95% CI = 1.52-3.35). No QRS/JTc group was associated with excess sustained ventricular arrhythmia risk (P = .400).

Conclusion: Among BiV-defibrillator recipients, QRS /JTc was associated with the most favorable long-term survival free of LV assist device, heart transplantation, and sustained ventricular arrhythmias. Our findings suggest that improved electrical resynchronization may be achieved by assessing concomitant changes in ventricular depolarization and repolarization.
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http://dx.doi.org/10.1111/pace.14065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669630PMC
November 2020

Long QT syndrome type 1 and 2 patients respond differently to arrhythmic triggers: The TriQarr in vivo study.

Heart Rhythm 2021 Feb 31;18(2):241-249. Epub 2020 Aug 31.

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

Background: In patients with long QT syndrome (LQTS), swimming and loud noises have been identified as genotype-specific arrhythmic triggers in LQTS type 1 (LQTS1) and LQTS type 2 (LQTS2), respectively.

Objective: The purpose of this study was to compare LQTS group responses to arrhythmic triggers.

Methods: LQTS1 and LQTS2 patients were included. Before and after beta-blocker intake, electrocardiograms were recorded as participants (1) were exposed to a loud noise of ∼100 dB; and (2) had their face immersed into cold water.

Results: Twenty-three patients (9 LQTS1, 14 LQTS2) participated. In response to noise, LQTS groups showed similarly increased heart rate, but LQTS2 patients had corrected QT interval (Fridericia formula) (QTcF) prolonged significantly more than LQTS1 patients (37 ± 8 ms vs 15 ± 6 ms; P = .02). After intake of beta-blocker, QTcF prolongation in LQTS2 patients was significantly blunted and similar to that of LQTS1 patients (P = .90). In response to simulated diving, LQTS groups experienced a heart rate drop of ∼28 bpm, which shortened QTcF similarly in both groups. After intake of beta-blockers, heart rate dropped to 28 ± 2 bpm in LQTS1 patients and 20 ± 3 bpm in LQTS2, resulting in a slower heart rate in LQTS1 compared with LQTS2 (P = .01). In response, QTcF shortened similarly in LQTS1 and LQTS2 patients (57 ± 9 ms vs 36 ± 7 ms; P = .10).

Conclusion: When exposed to noise, LQTS2 patients had QTc prolonged significantly more than did LQTS1 patients. Importantly, beta-blockers reduced noise-induced QTc prolongation in LQTS2 patients, thus demonstrating the protective effect of beta-blockers. In response to simulated diving, LQTS groups responded similarly, but a slower heart rate was observed in LQTS1 patients during simulated diving after beta-blocker intake.
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http://dx.doi.org/10.1016/j.hrthm.2020.08.017DOI Listing
February 2021

Electrocardiography in euthyroid individuals: a Danish general population study.

Minerva Endocrinol 2020 Jul 23. Epub 2020 Jul 23.

Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark -

Background: Thyroid hormones within the euthyroid range have been linked to mortality and differences in heart rate. However, some relations between thyroid hormone concentration and various electrocardiographic measurements remain unassessed. We aimed to investigate the association between thyroid hormone concentrations within the euthyroid range and different electrocardiographic markers in people free of thyroid disease.

Methods: We obtained electrocardiograms (ECG) and blood samples of free T4, total T3, and thyrotropin (TSH) in 20,852 subjects from the general population (the GESUS study). Relations between concentrations of TSH, free T4, and total T3 and heart rate, QTc, QRS duration, PR interval, P-wave duration and T-wave morphology were assessed in a multivariate adjusted linear model stratified by sex.

Results: Roughly half of the 18,046 included participants with thyroid hormone measurements within euthyroid range were men, and the average age was 56 years. Heart rate increased with concentrations of T3 (6.4 bpm/nM, p<0.001 in women and 5.3 bpm/nM, p<0.001 in men) and T4 (3.7 bpm/10pM, p<0.001 in women and 3.1 bpm/10pM, p<0.001 in men). We found no relation between TSH and heart rate. PR interval and QRS duration decreased with higher concentrations of T3 (all p<0.01). QTc increased with higher concentrations of T4 in men (5 ms/10pM), and T waves were flatter, more asymmetric and more often had notches with higher concentrations of T4 (all p≤0.01).

Conclusions: Thyroid hormone concentrations within the euthyroid range in people free of thyroid disease were associated with changes in the electrocardiogram in a general population.
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http://dx.doi.org/10.23736/S0391-1977.20.03170-3DOI Listing
July 2020

Left Atrial Late Gadolinium Enhancement is Associated With Incident Atrial Fibrillation as Detected by Continuous Monitoring With Implantable Loop Recorders.

JACC Cardiovasc Imaging 2020 08 17;13(8):1690-1700. Epub 2020 Jun 17.

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: The authors hypothesized that left atrial (LA) fibrosis was associated with incident atrial fibrillation (AF) as detected by continuous long-term monitoring in an at-risk population.

Background: LA late gadolinium enhancement (LGE) measured with cardiac magnetic resonance is emerging as a marker of atrial fibrosis and has been associated with worse outcomes in AF ablation procedures; however, the prognostic value of LA LGE for incident AF remains unknown.

Methods: Cardiac magnetic resonance, including measurement of left ventricular and LA volumes and function, as well as left ventricular extracellular volume fraction and LA LGE, was acquired in 68 patients aged at least 70 years with risk factors for stroke. All included patients received an implantable loop recorder and were continuously monitored for previously unknown AF. Incident AF was adjudicated by senior cardiologists.

Results: Patients were monitored for AF with an implantable loop recorder during a median of 41 (interquartile range: 7) months. AF episodes lasting ≥6 min were detected in 32 patients (47%), and 16 patients (24%) experienced AF episodes lasting ≥5.5 h. In Cox regression analyses adjusted for sex, age, and comorbidities, we found that LA volumes and function and LA LGE were independently associated with incident AF. For LA LGE, the hazard ratios for time to AF episodes lasting ≥6 min and ≥5.5 h were 1.40 (95% CI: 1.03 to 1.89) per 10 cm increase (p = 0.03) and 1.63 (95% CI: 1.11 to 2.40) per 10 cm increase (p = 0.01), respectively. LA LGE was significantly associated with high burden of AF. The addition of LA LGE to a multivariable risk prediction model for incident AF significantly increased the predictive value.

Conclusions: Extent of LA fibrosis measured by LA LGE was significantly associated with incident AF detected by implantable loop recorder. (Atrial Fibrillation Detected by Continuous ECG Monitoring [LOOP]; NCT02036450).
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http://dx.doi.org/10.1016/j.jcmg.2020.03.024DOI Listing
August 2020

Lead one ratio in left bundle branch block predicts poor cardiac resynchronization therapy response.

Pacing Clin Electrophysiol 2020 05 8;43(5):503-510. Epub 2020 May 8.

Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.

Background: A low electrocardiogram (ECG) lead one ratio (LOR) of the maximum positive/negative QRS amplitudes is associated with lower left ventricular ejection fraction (LVEF) and worse outcomes in left bundle branch block (LBBB); however, the impact of LOR on cardiac resynchronization therapy (CRT) outcomes is unknown. We compared clinical outcomes and echocardiographic changes after CRT implantation by LOR.

Methods: Consecutive CRT-defibrillator recipients with LBBB implanted between 2006 and 2015 at Duke University Medical Center were included (N = 496). Time to heart transplant, left ventricular assist device (LVAD) implantation, or death was compared among patients with LOR <12 vs ≥12 using Cox-proportional hazard models. Changes in LVEF and LV volumes after CRT were compared by LOR.

Results: Baseline ECG LOR <12 was associated with an adjusted hazard ratio (HR) of 1.69 (95% CI: 1.12-2.40, P = .01) for heart transplant, LVAD, or death. Patients with LOR <12 had less reduction of LV end diastolic volume (ΔLVEDV -4 ± 21 vs -13 ± 23%, P = .04) and LV end systolic volume (ΔLVESV -9 ± 27 vs -22 ± 26%, P = .03) after CRT. In patients with QRS duration (QRSd) ≥150 ms, LOR <12 was associated with an adjusted HR of 2.01 (95% CI 1.21-3.35, P = .008) for heart transplant, LVAD, or death, compared with LOR ≥12.

Conclusions: Baseline ECG LOR <12 portends worse outcomes after CRT implantation in patients with LBBB, specifically among those with QRSd ≥150 ms. This ECG ratio may identify patients with a class I indication for CRT implantation at high risk for poor postimplantation outcomes.
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http://dx.doi.org/10.1111/pace.13916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324940PMC
May 2020

Left atrial volume and function assessed by cardiac magnetic resonance imaging are markers of subclinical atrial fibrillation as detected by continuous monitoring.

Europace 2020 05;22(5):724-731

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

Aims: We aimed to investigate whether left atrial (LA) markers from cardiovascular magnetic resonance (CMR) were able to predict atrial fibrillation (AF) in elderly patients with risk factors for stroke.

Methods And Results: At baseline, 203 participants with stroke risk factors but without history of AF underwent advanced CMR and received an implantable loop recorder. During a median of 40 (37-42) months of continuous monitoring, incident AF was detected in 79 patients (39%). With regards to CMR markers, a steep increase in incidence rate of AF was seen with LA maximum volume (LAmax) above 55 mL/m2, LA minimum volume (LAmin) above 30 mL/m2, LA total emptying fraction (LA TEF) below 45%, LA active emptying fraction (LA AEF) below 37%, LA strain S below 25%, LA strain A below 17%, and LA strain rate A above -1.7 s-1. After multivariate adjustment, the above-mentioned CMR markers remained associated with AF incidence: hazard ratio (95% confidence interval) 1.25 (1.06-1.48) and 1.51 (1.22-1.87) per 10 mL/m2 increase of LAmax and LAmin, respectively, 1.49 (1.26-1.76) and 1.46 CI (1.25-1.71) per 5% decrease in LA TEF and LA AEF, respectively, 1.23 (1.05-1.44) and 1.56 (1.18-2.06) per 5% decrease in LA strain S and A, respectively, and 2.06 (1.31-3.23) per s-1 increase in LA strain rate A. In prediction analyses, LA functional indices increased area under the receiver operating characteristic curve significantly.

Conclusion: The risk of AF, including asymptomatic AF, increases significantly with increasing LA volumes and worsening LA function.
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http://dx.doi.org/10.1093/europace/euaa035DOI Listing
May 2020

Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation: Insights From Patients at Risk Monitored Long Term With an Implantable Loop Recorder.

Circulation 2020 05 2;141(19):1510-1522. Epub 2020 Mar 2.

Department of Cardiology, Rigshospitalet (S.Z.D., L.K., J.H.S.).

Background: Stroke is an increasing health problem worldwide. Atrial fibrillation (AF) is a major risk factor for stroke, and the attention given to AF screening is rising, as new monitoring technologies emerge. We aimed to evaluate the performance of a large panel of screening strategies and to assess population characteristics associated with diagnostic yield.

Methods: Individuals with stroke risk factors but without AF were recruited from the general population to undergo screening with an implantable loop recorder. New-onset AF lasting ≥6 minutes was adjudicated by senior cardiologists. After continuous monitoring for >3 years, complete day-to-day heart rhythm data sets were reconstructed for every participant, including exact time of onset and termination of all AF episodes. Random sampling was applied to assess the sensitivity and negative predictive value of screening with various simulated screening strategies compared with the implantable loop recorder. The diagnostic yield across strategies and population subgroups was compared by use of nonparametric tests.

Results: The rhythm data sets comprised 590 participants enduring a total of 659 758 days of continuous monitoring and 20 110 AF episodes. In these data, a single 10-second ECG yielded a sensitivity (and negative predictive value) of 1.5% (66%) for AF detection, increasing to 8.3% (67%) for twice-daily 30-second ECGs during 14 days and to 11% (68%), 13% (68%), 15% (69%), 21% (70%), and 34% (74%) for a single 24-hour, 48-hour, 72-hour, 7-day, or 30-day continuous monitoring, respectively. AF detection further improved when subsequent screenings were performed or when the same monitoring duration was spread over several periods compared with a single period (eg, three 24-hour monitorings versus one 72-hour monitoring; <0.0001 for all comparisons). The sensitivity was consistently higher among participants with age ≥75 years, male sex, CHADS score >2, or NT-proBNP (N-terminal pro-B-type natriuretic peptide) ≥40 pmol/L and among participants with underlying ≥24-hour AF episodes compared with shorter AF (<0.0001 for all screening strategies).

Conclusions: In screening for AF among participants with stroke risk factors, the diagnostic yield increased with duration, dispersion, and number of screenings, although all strategies had low yield compared with the implantable loop recorder. The sensitivity was higher among participants who were older, were male, or had higher NT-proBNP. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02036450.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044407DOI Listing
May 2020

Natural History of Subclinical Atrial Fibrillation Detected by Implanted Loop Recorders.

J Am Coll Cardiol 2019 12;74(22):2771-2781

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: As new heart rhythm monitoring technologies emerge, subclinical atrial fibrillation (AF) signifies a future challenge to health care systems. The pathological characteristics of this condition are largely unknown.

Objectives: This study sought to characterize the natural history of subclinical AF in at-risk patients from the general population.

Methods: The authors studied 590 individuals ≥70 years of age with ≥1 of hypertension, diabetes, previous stroke, or heart failure, without history of AF, undergoing long-term implantable loop recorder monitoring as part of the LOOP (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-risk Individuals) study. Baseline assessments included N-terminal pro-B-type natriuretic peptide (NT-proBNP). All day-to-day heart rhythm and symptom data were extracted from the device. Endpoints included AF burden, AF progression, symptom reports, and heart rate during AF.

Results: A total of 685,445 monitoring days were available for analysis. Adjudicated AF episodes lasting ≥6 min were detected in 205 participants (35%). The AF burden was median 0.13% (interquartile range: 0.03% to 1.05%) of the monitoring time and changed by a factor of 1.31 (95% CI: 1.02 to 1.68) per doubling of NT-proBNP. AF episodes were present 2.7% (interquartile range: 1.0% to 15.7%) of monitoring days after debut. Progression to 24-h episodes was seen in 33 of the AF patients (16%), whereas 46 (22%) had no AF episodes in the last 6 months of monitoring or longer. Symptoms were absent in 185 (90%) at debut, and 178 (87%) never reported AF-related symptoms during follow-up. The averaged heart rate during AF was 96 (interquartile range: 83 to 114) beats/min, 24 (interquartile range: 9 to 41) beats/min faster than daytime sinus rates.

Conclusions: Although previously unknown AF was highly prevalent, the burden was low, and progression was limited. In addition, symptoms were scarce, and the heart rate was only modestly elevated. (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-risk Individuals [LOOP]; NCT02036450).
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http://dx.doi.org/10.1016/j.jacc.2019.09.050DOI Listing
December 2019

Incidence and predictors of atrial fibrillation episodes as detected by implantable loop recorder in patients at risk: From the LOOP study.

Am Heart J 2020 01 20;219:117-127. Epub 2019 Oct 20.

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, Denmark.

Background: Recent studies have suggested a high prevalence of subclinical atrial fibrillation (AF) in various patient populations, and interest in AF screening has increased. However, knowledge about episode duration is scarce, and risk factors for short or long subclinical AF episodes have yet to be recognized. The aim of the study was to assess AF by long-term continuous screening and to investigate predictors of episodes lasting ≥6 minutes, ≥5.5 hours, or ≥24 hours, respectively.

Methods: A total of 597 patients aged ≥70 years and diagnosed with ≥1 of hypertension, diabetes, previous stroke, or heart failure were recruited from the general population to receive implantable loop recorder with remote monitoring. Exclusion criteria included history of AF or cardiac implantable electronic device. AF episodes were adjudicated by senior cardiologists.

Results: During 40 (37; 42) months of continuous monitoring, AF was detected in 209 (35%) of the patients. The cumulative incidences at 3 years were 33.8% (30.2%-37.8%), 16.1% (13.4%-19.4%), and 5.7% (4.1%-7.9%) for AF episodes lasting ≥6 minutes, ≥5.5 hours, and ≥24 hours, respectively. Slower resting sinus rate and higher body mass index, N-terminal prohormone of brain natriuretic peptide, and troponin T at baseline were independently associated with AF detection. Addition of these markers to a model of sex, age, and comorbidities improved prediction of AF episodes ≥24 hours (time-dependent area under the receiver operating characteristic curve 79% vs 65%, P = .037).

Conclusions: A considerable burden of previously unknown AF was detected when long-term monitoring was applied in at-risk patients. Biomarkers were associated with AF incidence and improved prediction of long AF episodes.
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http://dx.doi.org/10.1016/j.ahj.2019.09.009DOI Listing
January 2020

The CardioSynchroGram: A method to visualize and quantify ventricular dyssynchrony.

J Electrocardiol 2019 Nov - Dec;57S:S45-S50. Epub 2019 Oct 20.

CardioTech Research Group, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.

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http://dx.doi.org/10.1016/j.jelectrocard.2019.09.020DOI Listing
May 2021

Long-Term Prognostic Value of Less-Stringent Electrocardiographic Q Waves and Fourth Universal Definition of Myocardial Infarction Q Waves.

Am J Med 2020 05 21;133(5):582-589.e7. Epub 2019 Oct 21.

Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, Denmark.

Background: The Fourth Universal Definition of Myocardial Infarction defines electrocardiographic Q waves as duration ≥30 ms and amplitude ≥1 mm or QS complex in 2 contiguous leads. However, current taskforce criteria may be overly restrictive. Therefore, we investigated the association of isolated, lenient, or strict Q waves with long-term outcome.

Methods: From 2001 to 2015, we included Danish primary care patients with digital electrocardiograms (ECGs) that were evaluated for Q waves. If none occurred, patients had no Q waves. If no other contiguous Q wave occurred, patients had isolated Q waves. If another contiguous Q wave occurred meeting only 1 criterion (≥30 ms and <1 mm or <30 ms and ≥1 mm), patients had lenient Q waves. If another contiguous Q wave occurred, patients had strict Q waves.

Results: Of 365,206 patients, 87,957 had isolated, lenient, or strict Q waves (24%; median age, 61 years; male, 48%), and 277,249 had no Q waves (76%; median age, 53 years; male, 42%). Mortality risk was increased with isolated (all-cause adjusted hazard ratio [aHR], 1.33; 95% confidence interval [CI], 1.29-1.37; cardiovascular-cause aHR, 1.78; 95% CI, 1.70-1.87), lenient (all-cause aHR, 1.41; 95% CI, 1.33-1.50; cardiovascular-cause aHR, 1.78; 95% CI, 1.63-1.94), or strict (all-cause aHR, 1.64; 95% CI, 1.57-1.72; cardiovascular-cause aHR, 2.70; 95% CI, 2.52-2.89) Q waves compared with no Q waves. Highest mortality risk was associated with lenient or strict Q waves in anteroseptal leads.

Conclusions: This large contemporary analysis suggests that less-stringent Q-wave criteria carry prognostic value in predicting adverse outcome among primary care patients.
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http://dx.doi.org/10.1016/j.amjmed.2019.08.056DOI Listing
May 2020

The relationship between serum potassium concentrations and electrocardiographic characteristics in 163,547 individuals from primary care.

J Electrocardiol 2019 Nov - Dec;57:104-111. Epub 2019 Sep 4.

Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Søndre Skovvej 15, 9000 Aalborg, Denmark.

Aims: Potassium disturbances are common and associated with increased morbidity and mortality, even in patients without prior cardiovascular disease. We examined six electrocardiographic (ECG) measures and their association to serum potassium levels.

Methods And Results: From the Copenhagen General Practitioners' Laboratory, we identified 163,547 individuals aged ≥16 years with a first available ECG and a concomitant serum potassium measurement during 2001-2011. Restricted cubic splines curves showed a non-linear relationship between potassium and the Fridericia corrected QT (QTcF) interval, T-wave amplitude, morphology combination score (MCS), PR interval, P-wave amplitude and duration. Therefore, potassium was stratified in two intervals K: 2.0-4.1 mmol/L and 4.2-6.0 mmol/L for further analyses. Within the low potassium range, we observed: QTcF was 12.8 ms longer for each mmol/L decrease in potassium (p < 0.0001); T-wave amplitude was 43.1 μV lower for each mmol/L decrease in potassium (p < 0.0001); and MCS was 0.13 higher per mmol/L decrease in potassium (p < 0.001). Moreover, P-wave duration and PR interval were prolonged by 2.7 and 4.6 ms for each mmol/L decrease in potassium (p < 0.0001), respectively. Within the lowest potassium range (2.0-4.1 mmol/L) P-wave amplitude was 3.5 μV higher for each mmol/L decrease in potassium (p < 0.0001). Within the high potassium range associations with the above-mentioned ECG parameters were much weaker.
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http://dx.doi.org/10.1016/j.jelectrocard.2019.09.005DOI Listing
September 2019

Non-invasively quantified changes in left ventricular activation predict outcomes in patients undergoing cardiac resynchronization therapy.

J Cardiovasc Electrophysiol 2019 11 8;30(11):2475-2483. Epub 2019 Oct 8.

Electrophysiology Section, Duke University Hospital, Durham, North Carolina.

Background: Changes in left ventricular (LV) activation after cardiac resynchronization therapy (CRT) influence survival but are difficult to quantify noninvasively.

Methods And Results: We studied 527 CRT patients to assess whether noninvasive quantification of changes in LV activation, defined by change (Δ) in QRS area (QRSA), can predict outcomes after CRT. The study outcome was time until LV assist device(LVAD), cardiac transplant, or death. The three-dimensional QRSA was measured from clinical 12 lead ECGs which were transformed into vectorcardiograms using the Kors method. QRSA was calculated as (QRSx  + QRSy  + QRSz ) ; ΔQRSA was calculated as post-QRSA minus pre-QRSA, where a negative value represents a reduction in LV activation delay. Kaplan-Meier plots and multivariable Cox proportional hazards models were used to relate ΔQRSA area with outcomes after stratifying the population into quartiles of ΔQRSA. The median baseline QRSA of 93.6 µVs decreased to 59.7 µVs after CRT. Progressive reductions in QRSA with CRT were associated with a lower rate of LVAD, transplant, or death across patient quartiles (P < .001). In Cox regression analyses, ΔQRSA was associated with outcomes independent of QRS morphology and other clinical variables (Q1[greatest decrease] vs Q4[smallest change=reference], HR 0.45, CI, 0.30-0.70, P < .001). There was no interaction between ΔQRSA and QRS morphology.

Conclusions: CRT induced ΔQRSA was associated with clinically meaningful changes in event-free survival. ΔQRSA may be a novel target to guide lead implantation and device optimization.
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http://dx.doi.org/10.1111/jce.14192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818967PMC
November 2019

PR Prolongation predicts inadequate resynchronization with biventricular pacing in left bundle branch block.

Pacing Clin Electrophysiol 2019 11 22;42(11):1477-1485. Epub 2019 Sep 22.

Division of Cardiology, Duke University Medical Center, Durham, North Carolina.

Background: PR interval prolongation is associated with poor outcome after cardiac resynchronization therapy (CRT) among patients with left bundle branch block (LBBB) but the mechanisms are unknown. We investigated clinical outcomes, electrocardiogram (ECG), and echocardiogram changes after CRT by PR interval.

Methods: This is a retrospective study of CRT recipients with a baseline ejection fraction ≤35% and ECG showing sinus rhythm and LBBB. Patients were stratified by baseline PR interval quartile and the primary combined endpoint was time to heart transplantation, left ventricular assist device (LVAD) implantation, or death. ECG, echocardiogram, and clinical variables were compared to identify mechanisms for observed differences in outcomes.

Results: Of 291 eligible patients, the mean age was 65 years, 60% were male, and 19% had prior atrial fibrillation. Patients with PR prolongation (quartile 4, PR > 200 ms) more frequently had a history of atrial fibrillation, coronary artery bypass graft surgery, prior implantable cardioverter defibrillator implantation, and use of amiodarone than patients in PR quartiles 1-3. A PR > 200ms was associated with an adjusted hazard ratio of 1.7 (95% CI: 1.1-2.5) for the primary endpoint. Patients with PR > 200 ms had less reduction in QRS duration and QRS area after CRT while having more increase in QT and QTc intervals than patients with PR ≤ 200 ms. No major differences were observed in echocardiography by baseline PR interval quartiles.

Conclusions: PR prolongation predicts shorter survival free of heart transplantation or LVAD implantation in patients with LBBB. This may be due to inadequate ventricular resynchronization.
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http://dx.doi.org/10.1111/pace.13802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819228PMC
November 2019

Prevalence and risk factors of prolonged QT interval and electrocardiographic abnormalities in persons living with HIV.

AIDS 2019 11;33(14):2205-2210

aDepartment of Infectious Diseases bDepartment of Cardiology cDepartment of Radiology, Rigshospitalt, University of Copenhagen, Copenhagen, Denmark dInstitute for Global Health, UCL., Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), London, United Kingdom eThe Copenhagen General Population Study, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev fFaculty of Health and Medical Sciences, University of Copenhagen gDepartment of Infectious Diseases, Hvidovre Hospital, Copenhagen hDepartment of Health Science and Technology, Aalborg University, Aalborg iCHIP, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Objective: Abnormal ECGs are associated with increased risk of arrhythmias and sudden cardiac death. We aimed to investigate the prevalence and associated risk factors of prolonged QTc and major ECG abnormalities, in persons living with HIV (PLWH) and uninfected controls.

Design: PLWH aged at least 40 years were recruited from the Copenhagen comorbidity in HIV infection (COCOMO) study and matched on sex and age to uninfected controls from the Copenhagen General Population Study.

Methods: ECGs were categorized according to Minnesota Code Manual of ECG Findings definition of major abnormalities. A QT interval corrected for heart rate (QTc) greater than 440 ms in men and greater than 460 ms in women was considered prolonged. Pathologic Q-waves were defined as presence of major Q-wave abnormalities.

Results: ECGs were available for 745 PLWH and 2977 controls. Prolonged QTc was prevalent in 9% of PLWH and 6% of controls, P = 0.052. Pathologic Q-waves were more common in PLWH (6%) than in controls (4%), P = 0.028. There was no difference in prevalence of major ECG abnormalities between PLWH and controls, P = 0.987.In adjusted analyses, HIV was associated with a 3.6 ms (1.8-5.4) longer QTc interval, P < 0.001, and HIV was independently associated with prolonged QTc [adjusted odds ratio: 1.59 (1.14-2.19)], P = 0.005. HIV was borderline associated to pathologic Q-waves after adjusting, P = 0.051.

Conclusion: HIV was associated with higher odds ratio of prolonged QTc after adjustment for cardiovascular risk factors, but analyses were not adjusted for QT-prolonging medication. Although evidence indicated more pathologic Q-waves in PLWH, the risk seemed to be associated mainly with an adverse risk profile.
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http://dx.doi.org/10.1097/QAD.0000000000002327DOI Listing
November 2019

Thyroid dysfunction and electrocardiographic changes in subjects without arrhythmias: a cross-sectional study of primary healthcare subjects from Copenhagen.

BMJ Open 2019 06 21;9(6):e023854. Epub 2019 Jun 21.

Department of Clinical Epidemiology, Aalborg University Hospital, Aalborg, Denmark.

Objective: The objective of the present study was to investigate associations of both overt and subclinical thyroid dysfunction with common ECG parameters in a large primary healthcare population.

Design: Cross-sectional study.

Setting And Participants: The study population comprised of primary healthcare patients in Copenhagen, Denmark, who had a thyroid function test and an ECG recorded within 7 days of each other between 2001 and 2011.

Data Sources: The Danish National Patient Registry was used to collect information regarding baseline characteristics and important comorbidities.

Outcome Measure And Study Groups: Common ECG parameters were determined using Marquette 12SL software and were compared between the study groups. The study population was divided into five groups based on their thyroid status. Euthyroid subjects served as the reference group in all analyses.

Results: A total of 132 707 patients (age 52±17 years; 50% female) were included. Hyperthyroidism was significantly associated with higher heart rate and prolonged QTc interval with significant interaction with age (p<0.009) and sex (p<0.001). These associations were less pronounced for patients with higher age. Subclinical hyperthyroidism was associated with higher heart rate among females, and a similar trend was observed among males. Hypothyroidism was associated with slower heart rate and shorter QTc but only in women. Moreover, longer P-wave duration, longer PR interval and low voltage were observed in patients with both subclinical and overt hypothyroidism. However, the presence of low voltage was less pronounced with higher age (p=0.001).

Conclusion: Both overt and subclinical thyroid disorders were associated with significant changes in important ECG parameters. Age and gender have significant impact on the association of thyroid dysfunction particularly on heart rate and QTc interval.
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http://dx.doi.org/10.1136/bmjopen-2018-023854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596967PMC
June 2019

Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals.

J Am Coll Cardiol 2019 06;73(24):3118-3131

Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

Background: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.

Objectives: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.

Methods: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.

Results: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.

Conclusions: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.
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http://dx.doi.org/10.1016/j.jacc.2019.03.519DOI Listing
June 2019

Electrocardiogram Characteristics and Their Association With Psychotropic Drugs Among Patients With Schizophrenia.

Schizophr Bull 2020 02;46(2):354-362

Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.

Background: There are limited data on electrocardiogram (ECG) characteristics and their association with psychotropic drugs in schizophrenia.

Methods: Using a cross-sectional design, we included Danish primary care patients with first-time digital ECGs from 2001 to 2015. Patients diagnosed with schizophrenia before ECG recording were matched 1:5 on age, sex, and ECG recording year to controls without psychiatric disease. Multivariable logistic regression was used to compute odds ratios (ORs) with 95% confidence intervals (CIs).

Results: We included 4486 patients with schizophrenia matched with 22 430 controls (median age, 47 years; male, 55%). Between groups, the prevalence of abnormal ECGs was similar (54%, P = .536), but patients with schizophrenia demonstrated higher median heart rate (79 vs 69 beats per minute, P < .001) and Fridericia-corrected QT (QTc) interval (416 vs 412 ms, P < .001) than controls. QTc prolongation was also more prevalent among patients with schizophrenia (3.4% vs 1.1%, P < .001), and so were pathological Q waves (5.3% vs 3.9%, P < .001). Patients with schizophrenia less frequently demonstrated left ventricular hypertrophy (6.1% vs 9.6%, P < .001) and atrial fibrillation or flutter (0.7% vs 1.4%, P < .001). Among patients with schizophrenia only, particularly antipsychotics were associated with abnormal ECGs (OR, 1.20; 95% CI, 1.04-1.39).

Conclusions: Patients with schizophrenia demonstrate a different cardiovascular risk profile than matched controls without psychiatric disease, with higher prevalence of elevated heart rate, QTc prolongation, and pathological Q waves, and lower prevalence of left ventricular hypertrophy and atrial fibrillation or flutter. Particularly antipsychotics were associated with abnormal ECGs. This underscores an integrated care approach when ECG abnormalities are detected in this group.
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http://dx.doi.org/10.1093/schbul/sbz064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442389PMC
February 2020

Associations between common ECG abnormalities and out-of-hospital cardiac arrest.

Open Heart 2019;6(1):e000905. Epub 2019 May 21.

Department of Clinical Epidemiology, Aalborg Universitetshospital, Aalborg, Denmark.

Background: Out-of-hospital cardiac arrest (OHCA) is often the first manifestation of unrecognised cardiac disease. ECG abnormalities encountered in primary care settings may be warning signs of OHCA.

Objective: We examined the association between common ECG abnormalities and OHCA in a primary care setting.

Methods: We cross-linked individuals who had an ECG recording between 2001 and 2011 in a primary care setting with the Danish Cardiac Arrest Registry and identified OHCAs of presumed cardiac cause.

Results: A total of 326 227 individuals were included and 2667 (0,8%) suffered an OHCA. In Cox regression analyses, adjusted for age and sex, the following ECG findings were strongly associated with OHCA: ST-depression without concomitant atrial fibrillation (HR 2.79; 95% CI 2.45 to 3.18), left bundle branch block (LBBB; HR 3.44; 95% CI 2.85 to 4.14) and non-specific intraventricular block (NSIB; HR 3.15; 95% CI 2.58 to 3.83). Also associated with OHCA were atrial fibrillation (HR 1.89; 95% CI 1.63 to 2.18), Q-wave (HR 1.75; 95% CI 1.57 to 1.95), Cornell and Sokolow-Lyon criteria for left ventricular hypertrophy (HR 1.56; 95% CI 1.33 to 1.82 and HR 1.27; 95% CI 1.12 to 1.45, respectively), ST-elevation (HR 1.40; 95% CI 1.09 to 1.54) and right bundle branch block (HR 1.29; 95% CI 1.09 to 1.54). The association between ST-depression and OHCA diminished with concomitant atrial fibrillation (HR 1.79; 95% CI 1.42 to 2.24, p < 0.01 for interaction). Among patients suffering from OHCA, without a known cardiac disease at the time of the cardiac arrest, 14.2 % had LBBB, NSIB or ST-depression.

Conclusions: Several common ECG findings obtained from a primary care setting are associated with OHCA.
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http://dx.doi.org/10.1136/openhrt-2018-000905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546195PMC
February 2021