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Introduction: Myocardial development is still transitioning by the time of birth making the cardiomyocyte vulnerable to maternal and perinatal factors. We aimed at investigating the impact of maternal and perinatal factors on the neonatal electrocardiogram. Methods: In a prospective cohort study, neonates underwent cardiac evaluation with electrocardiograms and echocardiograms (age 0–30 days). Associations between medical and demographic data, pregnancy, and birth-related factors, and electrocardiographic parameters were assessed. Results: A total of 15,928 singletons with normal echocardiograms were included (52% boys). Neonates were divided into groups by accumulated number of maternal/perinatal factors: 0, 1, 2, 3, 4, and ≥5, and between-group differences in electrocardiographic parameters were analysed. We observed an additive effect with a leftward shift of the QRS axis and QT prolongation (all p < 0.01). Comparing extreme groups (0 vs. ≥5 maternal/perinatal factors), we found a 4.3% more left-shifted QRS axis (117 vs. 112°, p < 0.001) and a 0.8% prolonged QTcFridericia (QTcF; 363 vs. 366 ms, p < 0.001); the effect on QTcF was most pronounced in neonates examined in the first week of life (360 vs. 368 ms, p < 0.0001). Conclusion: We observed a cumulative effect of maternal and perinatal factors on neonatal electrocardiographic parameters, including a more left-shifted QRS axis and increased QT duration, although the variation was within normal reference ranges. Our findings add to the knowledge on the neonatal cardiac transition and the cardiac effect of maternal/perinatal factors. Keywords:Cardiac conduction system, Electrocardiography, Neonates, Maternal factors, Perinatal factors, Introduction: Myocardial development is still transitioning by the time of birth making the cardiomyocyte vulnerable to maternal and perinatal factors. We aimed at investigating the impact of maternal and perinatal factors on the neonatal electrocardiogram. Methods: In a prospective cohort study, neonates underwent cardiac evaluation with electrocardiograms and echocardiograms (age 0-30 days). Associations between medical and demographic data, pregnancy, and birth-related factors, and electrocardiographic parameters were assessed. Results: A total of 15,928 singletons with normal echocardiograms were included (52% boys). Neonates were divided into groups by accumulated number of maternal/perinatal factors: 0, 1, 2, 3, 4, and ≥5, and between-group differences in electrocardiographic parameters were analysed. We observed an additive effect with a leftward shift of the QRS axis and QT prolongation (all p < 0.01). Comparing extreme groups (0 vs. ≥5 maternal/perinatal factors), we found a 4.3% more left-shifted QRS axis (117 vs. 112°, p < 0.001) and a 0.8% prolonged QTcFridericia (QTcF; 363 vs. 366 ms, p < 0.001); the effect on QTcF was most pronounced in neonates examined in the first week of life (360 vs. 368 ms, p < 0.0001). Conclusion: We observed a cumulative effect of maternal and perinatal factors on neonatal electrocardiographic parameters, including a more left-shifted QRS axis and increased QT duration, although the variation was within normal reference ranges. Our findings add to the knowledge on the neonatal cardiac transition and the cardiac effect of maternal/perinatal factors.

Pathogenic variants in several genes involved in the function or regulation of smooth muscle cells (SMC) are known to predispose to congenital heart disease and thoracic aortic aneurysm and dissection (TAAD). Variants in MYLK are primarily known to predispose to TAAD, but a growing body of evidence points toward MYLK also playing an essential role in the regulation of SMC contraction outside the aorta. In this case report, we present a patient with co-occurrence of persistent ductus arteriosus (PDA) and thoracic aortic dissection. Genetic analyses revealed a novel splice acceptor variant (c.3986-1G > A) in MYLK, which segregated with disease in the family. RNA-analyses on fibroblasts showed that the variant induced skipping of exon 24, which resulted in an in-frame deletion of 101 amino acids. These findings suggest that MYLK-associated disease could include a broader phenotypic spectrum than isolated TAAD, including PDA and obstructive pulmonary disease. Genetic analyses could be considered in families with TAAD and PDA or obstructive pulmonary disease., Pathogenic variants in several genes involved in the function or regulation of smooth muscle cells (SMC) are known to predispose to congenital heart disease and thoracic aortic aneurysm and dissection (TAAD). Variants in MYLK are primarily known to predispose to TAAD, but a growing body of evidence points toward MYLK also playing an essential role in the regulation of SMC contraction outside the aorta. In this case report, we present a patient with co-occurrence of persistent ductus arteriosus (PDA) and thoracic aortic dissection. Genetic analyses revealed a novel splice acceptor variant (c.3986-1G > A) in MYLK, which segregated with disease in the family. RNA-analyses on fibroblasts showed that the variant induced skipping of exon 24, which resulted in an in-frame deletion of 101 amino acids. These findings suggest that MYLK-associated disease could include a broader phenotypic spectrum than isolated TAAD, including PDA and obstructive pulmonary disease. Genetic analyses could be considered in families with TAAD and PDA or obstructive pulmonary disease.

Ventricular septal defects (VSD) represent the most common congenital heart defect in newborns. We assessed the electrocardiographic characteristics of newborns with VSDs in a general population sample. The Copenhagen Baby Heart Study is a prospective population–based cohort study offering cardiac evaluation of newborns. Echocardiograms and electrocardiograms were obtained within 30 days after birth and systematically analysed. A VSD was identified in 530 newborns (mean age 11 ± 7 days, 42% boys). Newborns with VSDs had a more left-shifted QRS axis (116 ± 34 vs. 120 ± 3°, p = 0.02), and a higher S-wave amplitude in V1 (721 ± 584 vs. 636 ± 549 µV, p = 0.001) than controls. The largest differences were found in newborns with large or perimembraneous VSDs with a higher frequency of left axis deviation, higher S-wave amplitudes in V1, and higher R- and S-wave amplitudes in V6 compared with controls. R-waves in V1 and V6 were significantly associated to left ventricular mass, whereas S-waves in V1 and V6 were dependent on left ventricular end-diastolic diameter on echocardiography. Conclusion: Newborns with VSDs showed significant differences in QRS axis, and R- and S-wave precordial amplitudes compared to matched controls. Perimembranous and large VSDs had the greatest effect on the neonatal ECG., Ventricular septal defects (VSD) represent the most common congenital heart defect in newborns. We assessed the electrocardiographic characteristics of newborns with VSDs in a general population sample. The Copenhagen Baby Heart Study is a prospective population–based cohort study offering cardiac evaluation of newborns. Echocardiograms and electrocardiograms were obtained within 30 days after birth and systematically analysed. A VSD was identified in 530 newborns (mean age 11 ± 7 days, 42% boys). Newborns with VSDs had a more left-shifted QRS axis (116 ± 34 vs. 120 ± 3°, p = 0.02), and a higher S-wave amplitude in V1 (721 ± 584 vs. 636 ± 549 µV, p = 0.001) than controls. The largest differences were found in newborns with large or perimembraneous VSDs with a higher frequency of left axis deviation, higher S-wave amplitudes in V1, and higher R- and S-wave amplitudes in V6 compared with controls. R-waves in V1 and V6 were significantly associated to left ventricular mass, whereas S-waves in V1 and V6 were dependent on left ventricular end-diastolic diameter on echocardiography. Conclusion: Newborns with VSDs showed significant differences in QRS axis, and R- and S-wave precordial amplitudes compared to matched controls. Perimembranous and large VSDs had the greatest effect on the neonatal ECG. What is Known: • Ventricular septal defects in newborns are prevalent and may affect cardiac function and structure. What is New: • The Copenhagen Baby Heart Study is the largest study including a cohort of unselected newborns undergoing postnatal cardiac examination. • We found that newborns with VSD showed significant electrocardiographic differences depending on size and type of VSD compared with healthy newborns.

Aims Wolff–Parkinson–White (WPW) syndrome is a conduction disorder characterized by an accessory electrical pathway between the atria and ventricles, which may predispose to supraventricular tachycardia (SVT) and sudden cardiac death. It can be seen as an isolated finding or associated with structural heart disease. Our aims were to determine the prevalence of a WPW pattern in a large and unselected cohort of neonates and to describe the electro- and echocardiographic characteristics as well as the natural history during early childhood. Methods and results Electrocardiograms and echocardiograms of neonates (aged 0–30 days) from a large, prospective, population-based cohort study were included. Neonates with a WPW pattern were identified and matched 1:4 to controls. Localization of the accessory pathway was assessed by different algorithms. Among 17 489 neonates, we identified 17 (76% boys) with a WPW pattern consistent with a prevalence of 0.1%. One neonate had moderate mitral regurgitation while other echocardiographic parameters were similar between cases and controls (all P > 0.05). The accessory pathways were primarily predicted to be left-sided. At follow-up (available in 14/17 children; mean age 3.2 years) the pre-excitation pattern persisted in only four of the children and none of the children had experienced any episodes of SVT. Conclusion The prevalence of a WPW pattern in our cohort of unselected neonates was 0.1%. The WPW pattern was more frequent in boys and generally not associated with structural heart disease, and the accessory pathways were primarily left-sided. At follow-up, the WPW pattern had disappeared in most of the children suggesting either an intermittent nature or that normalization occurs. Clinical Trial Registration Copenhagen Baby Heart, NCT02753348., AIMS: Wolff-Parkinson-White (WPW) syndrome is a conduction disorder characterized by an accessory electrical pathway between the atria and ventricles, which may predispose to supraventricular tachycardia (SVT) and sudden cardiac death. It can be seen as an isolated finding or associated with structural heart disease. Our aims were to determine the prevalence of a WPW pattern in a large and unselected cohort of neonates and to describe the electro- and echocardiographic characteristics as well as the natural history during early childhood.METHODS AND RESULTS: Electrocardiograms and echocardiograms of neonates (aged 0-30 days) from a large, prospective, population-based cohort study were included. Neonates with a WPW pattern were identified and matched 1:4 to controls. Localization of the accessory pathway was assessed by different algorithms. Among 17 489 neonates, we identified 17 (76% boys) with a WPW pattern consistent with a prevalence of 0.1%. One neonate had moderate mitral regurgitation while other echocardiographic parameters were similar between cases and controls (all P > 0.05). The accessory pathways were primarily predicted to be left-sided. At follow-up (available in 14/17 children; mean age 3.2 years) the pre-excitation pattern persisted in only four of the children and none of the children had experienced any episodes of SVT.CONCLUSION: The prevalence of a WPW pattern in our cohort of unselected neonates was 0.1%. The WPW pattern was more frequent in boys and generally not associated with structural heart disease, and the accessory pathways were primarily left-sided. At follow-up, the WPW pattern had disappeared in most of the children suggesting either an intermittent nature or that normalization occurs.CLINICAL TRIAL REGISTRATION: Copenhagen Baby Heart, NCT02753348.

Multi-frame X-ray images (videos) of the coronary arteries obtained using coronary angiography (CAG) provide detailed information about the anatomy and blood flow in the coronary arteries and play a pivotal role in diagnosing and treating ischemic heart disease. Deep learning has the potential to quickly and accurately quantify narrowings and blockages of the arteries from CAG videos. A CAG consists of videos acquired separately for the left coronary artery and the right coronary artery (LCA and RCA, respectively). The pathology for LCA and RCA is typically only reported for the entire CAG, and not for the individual videos. However, training of stenosis quantification models is difficult when the RCA and LCA information of the videos are unknown. Here, we present a deep learning-based approach for classifying LCA and RCA in CAG videos. Our approach enables linkage of videos with the reported pathological findings. We manually labeled 3545 and 520 videos (approximately seven videos per CAG) to enable training and testing of the models, respectively. We obtained F1 scores of 0.99 on the test set for LCA and RCA classification LCA and RCA classification on the test set. The classification performance was further investigated with extensive experiments across different model architectures (R(2+1)D, X3D, and MVIT), model input sizes, data augmentations, and the number of videos used for training. Our results showed that CAG videos could be accurately curated using deep learning, which is an essential preprocessing step for a downstream application in diagnostics of coronary artery disease.

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: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 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 PKP2 than DSC2/DSG2/DSP 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 DSC2/DSG2/DSP 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 PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.

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.

Background: Combination therapy with BRAF and MEK inhibitors (BRAF/MEKi) has significantly improved the outcome for patients with BRAF-mutated melanoma. A reduction in left ventricular ejection fraction (LVEF) is a known side effect during treatment with BRAF/MEKi. This study aimed to analyze sequential multigated acquisition (MUGA) scans for the evaluation of LVEF and provide real-world data on cardiotoxicity induced by BRAF/MEKi in advanced melanoma. Methods: All patients with advanced melanoma treated with dabrafenib and trametinib at Herlev and Gentofte Hospital, Denmark, between March 2015 and September 2019, were included retrospectively. MUGA scans performed at baseline and every three months during treatment were analyzed. Cardiotoxicity was defined as a decline of ≥10 percentage point (pp) to an LVEF <50% (major cardiotoxicity) or a decline in LVEF of ≥15 pp but remaining >50% (minor cardiotoxicity). Results: A total of 139 patients were included. Forty-six patients (33%) met our criteria for cardiotoxicity; 31 patients (22%) experienced minor cardiotoxicity and 15 patients (11%) experienced major cardiotoxicity. Median time to decline in LVEF was 94 days, and all clinically significant declines in LVEF occurred before evaluation at six months. Reversibility of LVEF was seen in 80% of patients, three patients were not evaluable for reversibility. A low left ventricular peak emptying rate adjusted for heart rate (LVPERadj) at baseline was found a potential risk factor for the development of major cardiotoxicity (RR = 0.159, p = 0.001). Conclusion: A decline in LVEF is common for patients with advanced melanoma treated with BRAF/MEKi but rarely clinically significant. No significant decline in LVEF was observed after evaluation at six months, therefore routine monitoring of LVEF might be stopped after six to nine months of BRAF/MEKi therapy. A low LVPERadj might be a risk factor for the development of cardiotoxicity and is suggested for further inves

Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

Aims: Evaluation of the neonatal QT interval is important to diagnose arrhythmia syndromes and evaluate side effects of drugs. We aimed at describing the natural history of the QT interval duration during the first 4 weeks of life and to provide reference values from a large general population sample. Methods and results: The Copenhagen Baby Heart Study is a prospective general population study that offered cardiac evaluation of newborns. Eight-lead electrocardiograms were obtained and analysed with a computerized algorithm with manual validation. We included 14 164 newborns (52% boys), aged 0-28 days, with normal echocardiograms. The median values (ms, 2-98%ile) for the corrected intervals QTc (Bazett), QTc (Hodges), QTc (Fridericia), and QTc (Framingham) were 419 (373-474), 419 (373-472), 364 (320-414), and 363 (327-405). During the 4 weeks, we observed a small decrease of QTcFramingham, and an increase of QTcHodges (both P < 0.01), while QTcBazett and QTcFridericia did not change (P > 0.05). Applying published QT interval cut-off values resulted in 5-25% of the newborns having QT prolongation. Uncorrected QT intervals decreased linearly with increasing heart rate (HR). Sex and infant size did not affect the QT interval and the gestational age (GA) only showed an effect when comparing the extreme low- vs. high GA groups (≤34 vs. ≥42 weeks, P = 0.021). Conclusion: During the 4 weeks QTcFramingham and QTcHodges showed minor changes, whereas QTcBazett and QTcFridericia were stable. The QT interval was unaffected by sex and infant size and GA only showed an effect in very premature newborns. Reference values for HR-specific uncorrected QT intervals may facilitate a more accurate diagnosis of newborns with abnormal QT intervals.

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.

During the first month of life, the relation between right and left ventricular function is markedly altered. We aimed at describing the electrocardiographic transition from fetal to neonatal circulation by investigating changes in R- and S-wave amplitudes in V1 and V6 during the first 4 weeks of life. This study is part of the prospective, population-based Copenhagen Baby Heart Study offering cardiac evaluation to newborns within 28 days from birth. ECGs were obtained and analyzed using a computerized algorithm. A total of 14,577 newborns (52% boys), median age of 11.0 days, were included. All had normal echocardiograms. Within 28 days from birth, the amplitudes in V1 decreased: R-V1 (1262 µV day0; 947 µV day28, p < 0.001) and S-V1 (1240 µV day0; 473 µV day28, p < 0.001). An increase was observed for R-V6 (825 µV day0; 1196 µV day28, p = 0.002), while S-V6 decreased (830 µV day0; 634 µV day28, p = 0.003). For all amplitudes, interindividual variation was large (up to 20 times). The amplitudes were not affected by sex (p > 0.05), but R-V1, R-V6, and S-V6 positively correlated with newborn weight (p < 0.01). R-V1 and S-V6 showed positive correlation with gestational age (p < 0.05). In conclusion, systematic analyses of ECGs from healthy newborns showed significant decreases in R-V1, S-V1, and S-V6 amplitudes, while R-V6 increased. Interindividual variation was large, making ECGs unlikely as a sensitive tool for diagnosing congenital heart diseases. Our data may serve as updated, digitalized reference values in newborns.