Papers by Alex Christensen
Circulation
Introduction: Left ventricular non-compaction (LVNC) is characterized by excessive trabeculations... more Introduction: Left ventricular non-compaction (LVNC) is characterized by excessive trabeculations of the left ventricular wall and may be associated with reduced systolic function. It is debated whether LVNC is congenital or may develop later as part of other cardiomyopathies. The clinical importance and heredity of LVNC with normal systolic function is unclear. We aimed to describe the cardiac development in children with LVNC from birth to 2-4 years of age, compared to matched controls. Additionally, we aimed to describe the prevalence of LVNC in first-degree relatives. Methods: A follow-up transthoracic echocardiography was performed in children at 2-4 years of age diagnosed with LVNC at birth (<30 days) in the Copenhagen Baby Heart Study. Cases were matched to controls on mothers age at delivery, parity, and age of child at follow-up. First-degree relatives (parents, siblings and half-siblings) were also included. LVNC was defined as a non-compact to compact ratio of myocardi...
Journal of Molecular and Cellular Cardiology, 2014
The two-pore domain potassium channel, K2P3.1 (TASK-1) modulates background conductance in isolat... more The two-pore domain potassium channel, K2P3.1 (TASK-1) modulates background conductance in isolated human atrial cardiomyocytes and has been proposed as a potential drug target for atrial fibrillation (AF). TASK-1 knockout mice have a predominantly ventricular phenotype however, and effects of TASK-1 inactivation on atrial structure and function have yet to be demonstrated in vivo. The extent to which genetic variation in KCNK3, that encodes TASK-1, might be a determinant of susceptibility to AF is also unknown. To address these questions, we first evaluated the effects of transient knockdown of the zebrafish kcnk3a and kcnk3b genes and cardiac phenotypes were evaluated using videomicroscopy. Combined kcnk3a and kcnk3b knockdown in 72 hour post fertilization embryos resulted in lower heart rate (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), marked increase in atrial diameter (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), and mild increase in end-diastolic ventricular diameter (p=0.01) when compared with control-injected embryos. We next performed genetic screening of KCNK3 in two independent AF cohorts (373 subjects) and identified three novel KCNK3 variants. Two of these variants, present in one proband with familial AF, were located at adjacent nucleotides in the Kozak sequence and reduced expression of an engineered reporter. A third missense variant, V123L, in a patient with lone AF, reduced resting membrane potential and altered pH sensitivity in patch-clamp experiments, with structural modeling predicting instability in the vicinity of the TASK-1 pore. These in vitro data suggest that the double Kozak variants and V123L will have loss-of-function effects on ITASK. Cardiac action potential modeling predicted that reduced ITASK prolongs atrial action potential duration, and that this is potentiated by reciprocal changes in activity of other ion channel currents. Our findings demonstrate the functional importance of ITASK in the atrium and suggest that inactivation of TASK-1 may have diverse effects on atrial size and electrophysiological properties that can contribute to an arrhythmogenic substrate.
Journal of Electrocardiology, 2011
Introduction: Structural right atrial abnormalities have been described in patients with arrhythm... more Introduction: Structural right atrial abnormalities have been described in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). However, little is known about ECG signs of atrial involvement in ARVC as no systematic studies have been conducted. Methods: P-wave triggered signal-averaged orthogonal ECG from 40 ARVC patients (46±15 years, 16 females) was compared with recordings from age-and gender-matched healthy control subjects for assessment of P-wave duration and morphology. P-wave morphology was classified in regard to the P-wave polarity in leads X, Y and Z. Results: P wave duration was longer in patients (135±18 vs. 124±12 ms, p=0,003). Two typical P wave morphologies were identified in the controls: positive in X and Y and negative (45%) or biphasic (55%) in Z. In ARVC pts, typical P waves were seen in only 60% while 15 pts (37%) had atypical P waves positive in all three leads (p<0,0001). The presence of atypical P waves in ARVC group was not associated with the presence of either structural or functional right ventricular abnormality. Conclusions: Patients with ARVC commonly demonstrate deteriorated atrial activation expressed either as prolonged P-wave duration or abnormal P wave morphology. The P wave abnormalities were not secondary to right ventricular dilatation. These findings show that atrial involvement is common in ARVC and may represent yet another manifestation of the disease to be considered for inclusion in ARVC diagnostic work-up.
European Journal of Preventive Cardiology
Background and aims The causal contribution of apolipoprotein B (apoB) particles to coronary arte... more Background and aims The causal contribution of apolipoprotein B (apoB) particles to coronary artery disease (CAD) is established. We examined whether this atherogenic contribution is better reflected by non-high-density lipoprotein cholesterol (non-HDL-C) or apoB particle concentration. Method and results We performed Mendelian randomization (MR) analysis using 235 variants as genetic instruments; testing the relationship between their effects on the exposures, non-HDL-C and apoB, and on the outcome CAD using weighted regression. Variant effect estimates on the exposures came from the UK Biobank (N = 376 336) and on the outcome from a meta-analysis of five CAD datasets (187 451 cases and 793 315 controls). Subsequently, we carried out sensitivity and replication analyses. In univariate MR analysis, both exposures associated with CAD (βnon-HDL-C = 0.40, P = 2.8 × 10−48 and βapoB = 0.38, P = 1.3 × 10−44). Adding effects on non-HDL-C into a model that already included those on apoB sig...
Cardiology, 2010
healthy controls, although at a lower frequency. Evaluation of all reported missense mutations in... more healthy controls, although at a lower frequency. Evaluation of all reported missense mutations in PKP2 showed unclear pathogeneity of several reported mutations. Conclusions: Fifteen percent of Danish ARVC/D patients carried PKP2 mutations. Our finding of reported disease-causing mutations at a low frequency among healthy controls suggests that these variants are disease modifying but not directly disease causing. We recommend conservative interpretation of missense variants in PKP2 , functional characterization and largescale sequencing to clarify normal variation in the gene.
Pediatrics
OBJECTIVES Interpretation of the neonatal electrocardiogram (ECG) is challenging due to the profo... more 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; 0.9...
Ugeskrift for Læger, 2008
INTRODUCTION The aim of this study was to investigate the age, sex, etiology, frequency of implan... more INTRODUCTION The aim of this study was to investigate the age, sex, etiology, frequency of implantable cardioverter-defibrillator (ICD) and previous cardiac arrest among patients discharged from the Department of Cardiology, Rigshospitalet (Copenhagen University Hospital), Denmark, due to ventricular tachyarrhythmias. MATERIALS AND METHODS We conducted a retrospective review of 993 patients discharged from Rigshospitalet over 6 years and 5 months with the diagnostic codes ventricular tachycardia, ventricular fibrillation or premature ventricular contractions. RESULTS The population had an average age of 59 years (ranging 15-95 years) with a majority of males (76%). Among the patients with known etiology ischemic heart disease (60%), dilated cardiomyopathy (6%) and arrhythmogenic right ventricular cardiomyopathy (6%) were the most frequent. A substantial number of the patients (15%) had unknown etiology; 492 (50%) of the patients overall had an ICD implanted, the majority of whom had...
European Heart Journal
Background: Dilated cardiomyopathy (DCM) associated with Lamin A/C gene (LMNA) mutations has a po... more Background: Dilated cardiomyopathy (DCM) associated with Lamin A/C gene (LMNA) mutations has a poor prognosis and rapid evolution to end-stage heart failure and malignant ventricular tachyarrhythmias (mVTAs) with increased risk of sudden cardiac death (SCD). Objectives: The purpose of this research was to study electrical, mechanical, and structural cardiac properties in LMNA mutation positive DCM patients to identify predictors of mVTA / SCD. Methods: We evaluated family members from thirteen pedigrees previously identified to carry LMNA mutations (missense, trV) for ECG and HM abnormalities, SCD / mVTA events. Left ventricular (LV) myocardial function was assessed as ejection fraction and speckle tracking longitudinal strain by echocardiography. Cardiovascular magnetic resonance (CMR) examination consisted of ventricular functional analysis and assessment of LGE for detection of myocardial fibrosis. We included 27 LMNA mutation positive patients (aged 33,4±15,9 years, LVEF 34,1±11,2%, follow-up 35±12 months). Results: Myocardial fibrosis was found exclusively in the interventricular septum in patients with septal ECG criteria in V1-V3 leads (Q or QS, poor R wave progression, QRS fragmentation similar to 'a big epsilon wave'). PR-interval was longer in pts with septal fibrosis compared with those absent (310+ 82 vs 185+ 37 ms, P<0,005). Myocardial function by strain was reduced in basal regions compared with the other LV segments (GLS bas:-14,9% vs.-16,8%; p<0,05) and correlated to PR-interval (Rs= 0,48; p<0,05). The following events were accepted as a primary endpoints: SCD, successful resuscitation, stable VT/VF (HM or device-interrogation), appropriate ICD/CRT-D shock. The above mVTAs were documented in 14 pts (51,9%). As a result of discriminant analysis independent predictors of mVTA were identified: a baseline PR interval (λ=0,77; F=94,6; p=0,0001), unstable fast-VT (≥5 ventricular complexes with HR ≥150 bpm: λ=0,51; F=6,32; p=0,012), and both septal signs: septal ECG criteria and septal fibrosis by LGE-CMR (λ=0,49; F=5,47; p=0,021). By ROC curve analysis of the prognostic value confirmed the significance of unstable fast-VT (sensitivity 79%, specificity 76%; AUC = 0,789; 95% CI: 0,698-0,908; p=0,011) and PR interval (cut-off PR ≥227 ms: sensitivity 75%, specificity 73%; AUC= 0,824; 95% CI: 0,799-0,998; p=0,003). Conclusion: Unstable fast-VT and prolonged PR-interval were the significant predictors of mVTA in LMNA-positive DCM pts. Our findings confirmed the relationship of the cardiac electrical, mechanical, genetic, and structural properties. Myocardial septal fibrosis there is a possible cause reduced septal contractile function and atrioventricular conduction delay as well as mVTA in the DCM pts with LMNA mutations.
Cardiology
A variety of life-threating arrhythmias are caused by mutations in the cardiac voltage-gated sodi... more A variety of life-threating arrhythmias are caused by mutations in the cardiac voltage-gated sodium channel encoded by the SCN5A gene. In this study, we report a novel loss-of-function SCN5A variant, p.Ile1343Val (c.4027A>G), identified in a 42-year-old proband who presented with an unusual ECG with abnormal repolarization with biphasic T-waves in anteroseptal leads, persistent atrial fibrillation (AF), intermittent left bundle branch block (LBBB), and reversible cardiomyopathy. The patient did not meet the diagnostic criteria for Brugada syndrome, long QT syndrome, or any other known SCN5A-associated phenotype. Characterization of the biophysical properties of the variant by in vitro patch clamp experiments revealed a reduced Na+ current with no effect on the inactivation kinetics of the channel. This loss-of-function of Na+ current could explain the intermittent LBBB as well as the AF. In conclusion, we describe a unique combination of electrical and structural abnormalities as...
European Heart Journal - Case Reports
Background Prolongation of the QT interval on the electrocardiogram is clinically important due t... more Background Prolongation of the QT interval on the electrocardiogram is clinically important due to the association with an increased risk of sudden cardiac death. A long QT interval may be genetically determined (congenital long QT syndrome) or be drug-induced long QT syndrome e.g. caused by pharmaceutical drugs and electrolyte imbalances.
New England Journal of Medicine
To the Editor: Several classic cardiac genetic disorders have been identified from specific elect... more To the Editor: Several classic cardiac genetic disorders have been identified from specific electrocardiographic (ECG) patterns. 1-3 Here, we describe five unrelated families, from three different countries, with features that appear to represent a previously unrecognized autosomal dominant syndrome. These families were identified at three tertiary referral centers for patients with known or suspected inherited cardiac disorders (as described in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The index patient of Family A was followed regularly for more than 30 years after his incidental presentation at 36 years of age with an ECG showing deep and persistent, concave-upward ST-segment depression in leads I, II, aVL, aVF, and V2 through V6 (Fig. 1A). The ECG changes remained stable over time (Fig. S1A in the Supplementary Appendix) but worsened during exercise (Fig. S1B in the Supplementary Appendix). The patient remained asymptomatic until atrial fibrillation developed at 55 years of age. Eight
European Heart Journal
Risk prediction and sudden cardiac death syndromes heart disease. Phenotype-guided genetic testin... more Risk prediction and sudden cardiac death syndromes heart disease. Phenotype-guided genetic testing in these patients is considered useful, while the utility of the test in phenotype-negative unexplained cardiac arrest (UCA) remains disputable. Purpose: To evaluate the utility of genetic testing in cardiac arrest survivors with or without evident cardiac phenotype. Methods: We included all UCA survivors sent to our center for genetic testing between January 2014 and October 2017. Initial clinical evaluation included 12-lead ECG, stress test, coronary angiography and echocardiography. After obtained informed consent, DNA was extracted from peripheral blood. Targeted exome sequencing was performed using the TruSight One Sequencing Panel from Illumina. Variants in 190 clinically relevant cardiac genes with a minor allele frequency of <1% were further evaluated. Variant interpretation followed the 2015 guidelines of the American College of Medical Genetics. Results: Fifty-one unrelated cases (age: 33±16 yrs, 80% males) were included. After the initial clinical evaluation, 31 (61%) were considered as phenotypenegative (PhN-UCA) and 20 (39%) exhibited some clinical cardiac phenotype (PhP-UCA). Genetic testing revealed pathogenic or likely pathogenic variants in 18 cases in the overall cohort (35%): 7 out of 31 (23%) in the PhN-UCA group and 11 out of 20 (55%) in the PhP-UCA. In 5 out of 31 (16%) cases of PhN-UCA the identified variant helped to clarify the phenotype while in the group of PhP-UCA in 10 cases out of 18 (56%) the identified variant correlated with the clinical phenotype. Identified pathogenic variants located mainly in catecholaminergic polymorphic ventricular tachycardia (CPVT) or channelopathy-associated genes (67%). Seven out of 18 (39%) patients carried ≥1 additional variant of uncertain clinical significance (VUS). Age ≤35 was associated with a higher likelihood of identifying a putative pathogenic variant (48% vs. 21%, p<0.05). Conclusions: The yield of genetic testing is 2-times higher in PhP-UCA compared to PhN-UCA. The majority of identified mutations were associated with channelopathies, most commonly CPVT. Since 16% of the cases and family members of the PhN-UCA group benefit from genetic testing, it should be generally recommended in all patients with UCA. Funding Acknowledgements: Swiss Heart Foundation P3818 Kinetic changes in a mutant hERG channel (N588K) in in humaninduced pluripotent stem cell-derived cardiomyocytes
European Heart Journal
Aims To explore whether variability in dietary cholesterol and phytosterol absorption impacts the... more Aims To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols. Methods and results We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genet...
EP Europace
Aims International guidelines recommend cardiogenetic screening in families with sudden cardiac d... more Aims International guidelines recommend cardiogenetic screening in families with sudden cardiac death (SCD) if the suspected cause is an inherited cardiac disease. The aim was to assess the diagnostic yield of inherited cardiac diseases in consecutively referred SCD families. Methods and results In this single-centre retrospective study, we consecutively included families referred to our tertiary unit between 2005 and 2018 for screening due to SCD. Following evaluation of premortem medical records and postmortem findings for the proband, the families underwent a guideline-based screening protocol. Relatives were followed and cardiovascular events registered. In total, 304 families with 695 relatives were included. In probands, mean age at death was 39 years (75% males) and in relatives mean age at screening was 35 years (47% males). The proband-diagnosis was established through autopsy findings (n = 89), genetic analyses (n = 7), or based on premortem findings (n = 21). In the remai...
BMC Cardiovascular Disorders
Background Several inherited cardiac diseases may lead to sudden cardiac death (SCD) a devastatin... more Background Several inherited cardiac diseases may lead to sudden cardiac death (SCD) a devastating event in the families. It is crucial to establish a post mortem diagnosis to facilitate relevant work-up and treatment of family members. Sudden unexplained death (SUD) victims constitute roughly one third of all SCD cases in Denmark. Methods This was a single center, retrospective study investigating SUD cases. Victims who died unexplained due to suspected or confirmed cardiac disease were consecutively referred to a third line referral center established in 2005. All autopsy reports were investigated. Victims were divided into two groups: non-diagnostic cardiac findings and normal cardiac findings. None of the included victims had findings consistent with a diagnosis based on existing criteria. Results In total, 99 SUD cases were referred. The mean age of the victims was 37 years (range 0–62 years, 75% males). A total of 14 (14%) victims had a cardiovascular diagnosis pre-mortem. Thi...
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Papers by Alex Christensen