Publications by authors named "Alex Hørby Christensen"

33 Publications

Gestational Age and Neonatal Electrocardiograms.

Pediatrics 2021 Nov 24. Epub 2021 Nov 24.

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

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

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

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

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

Cardiotoxicity in metastatic melanoma patients treated with BRAF and MEK inhibitors in a real-world setting.

Acta Oncol 2021 Oct 19:1-7. Epub 2021 Oct 19.

Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark.

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,  = 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 investigation.
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http://dx.doi.org/10.1080/0284186X.2021.1992010DOI Listing
October 2021

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

Open Heart 2021 09;8(2)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Europace 2021 Jul 19. Epub 2021 Jul 19.

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

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

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

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

The Evolution of the Neonatal QRS Axis during the First Four Weeks of Life.

Neonatology 2021 10;118(2):155-162. Epub 2021 Mar 10.

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

Background: The QRS axis represents the sum and orientation of the ventricular depolarization. Accurate interpretation of abnormalities in the QRS axis may facilitate early diagnosis of heart disease in newborns. We aimed at describing the evolution of the QRS axis during the first 4 weeks of life and provide reference values from healthy newborns.

Methods: The Copenhagen Baby Heart Study is a prospective general population study that offered cardiac evaluation during the first month of life to all newborns delivered in the Copenhagen area.

Results: Electrocardiograms from 12,317 newborns (52% boys; mean age 12 days) with normal echocardiograms were included. The median QRS axis was 119° at the ages 0-7 days and shifted leftward to 102° at the ages 22-28 days (p < 0.001). We found that girls had a significantly less pronounced right-shifted axis than boys (p < 0.001) and that increasing gestational age (GA) was associated with a more pronounced right-shifted axis (p < 0.05). Infant size did not affect the axis (p > 0.05). Only 0.5% had an axis within the interval 0 to -90° and 1.1% in the interval +240 to +30°.

Conclusions: The QRS axis showed a gradual leftward-shift during the first 4 weeks of life and was affected by sex and GA but unaffected by infant size. Less than 1% of the newborns had a QRS axis between 0 and -90°. This study represents updated reference values, which may facilitate the clinical handling of newborns.
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http://dx.doi.org/10.1159/000513526DOI Listing
August 2021

Precordial ECG Amplitudes in the Days After Birth: Electrocardiographic Changes During Transition from Fetal to Neonatal Circulation.

Pediatr Cardiol 2021 Apr 28;42(4):832-839. Epub 2021 Jan 28.

Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 1, 2730, Herlev, Danmark.

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.
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http://dx.doi.org/10.1007/s00246-021-02547-8DOI Listing
April 2021

Dilated cardiomyopathy caused by truncating titin variants: long-term outcomes, arrhythmias, response to treatment and sex differences.

J Med Genet 2021 12 26;58(12):832-841. Epub 2020 Oct 26.

The Capital Region's Unit for Inherited Cardiac Diseases, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Truncating variants in titin (TTNtv) are the most common cause of dilated cardiomyopathy (DCM). We evaluated the genotype-phenotype correlation in TTNtv-DCM, with a special focus on long-term outcomes, arrhythmias, response to treatment and sex-related presentation.

Methods: Data on patient characteristics and outcomes were collected retrospectively from electronic health records of patients genotyped at two Danish heart transplantation centres.

Results: We included 115 patients (66% men). At diagnosis of DCM, mean age was 46±13 years and left ventricular ejection fraction (LVEF) was 28%±13%. During a median follow-up of 7.9 years, 26% reached a composite outcome of left ventricular assist device implantation, heart transplantation or death. In 20% an arrhythmia preceded the DCM diagnosis. In total, 43% had atrial fibrillation (AF) and 23% had ventricular arrhythmias. Long-term left ventricular reverse remodelling (LVRR; LVEF increase ≥10% points or normalisation) was achieved in 58% and occurred more frequently in women (72% vs 51%, p=0.042).In multivariable proportional hazards analyses, occurrence of LVRR was a strong independent negative predictor of the composite outcome (HR: 0.05 (95% CI 0.02 to 0.14); p<0.001). Female sex independently predicted lower rates of ventricular arrhythmias (HR: 0.33 (95% CI 0.11 to 0.99); p=0.05), while the location of the TTNtv was not associated with cardiovascular outcomes.

Conclusion: DCM caused by TTNtv presented in midlife and was associated with a high burden of AF and ventricular arrhythmias, which often preceded DCM diagnosis. Furthermore, LVRR occurred in a high proportion of patients and was a strong negative predictor of the composite outcome. Female sex was positively associated with occurrence of LVRR and longer event-free survival.
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http://dx.doi.org/10.1136/jmedgenet-2020-107178DOI Listing
December 2021

Defining the normal QT interval in newborns: the natural history and reference values for the first 4 weeks of life.

Europace 2021 02;23(2):278-286

Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 1, DK-2730 Herlev, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1093/europace/euaa143DOI Listing
February 2021

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

Heart Rhythm 2021 02 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

Cardiogenetic screening amongst families of sudden cardiac death victims: Authors' reply.

Europace 2020 11;22(11):1754-1755

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

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http://dx.doi.org/10.1093/europace/euaa183DOI Listing
November 2020

Diagnostic yield and long-term outcome of nonischemic sudden cardiac arrest survivors and their relatives: Results from a tertiary referral center.

Heart Rhythm 2020 10 29;17(10):1679-1686. Epub 2020 Jun 29.

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

Background: Cardiac arrest may be the first manifestation of most inherited cardiac diseases. International guidelines recommend screening of relatives of sudden cardiac arrest (SCA) survivors if an inherited cardiac disorder is suspected.

Objective: The purpose of this study was to assess the prevalence and spectrum of inherited cardiac diseases and the long-term outcome in a consecutive cohort of nonischemic SCA survivors (probands) and their relatives.

Methods: This retrospective study consecutively included probands and their relatives referred to our tertiary center for family screening between 2005 and 2018. All participants underwent a systematic workup and follow-up protocol. Data were retrieved from medical records.

Results: We included 155 probands (age 41.2 ± 15.5 years; 61% male) and 282 relatives (age 35.7 ± 18.8 years; 51% male). Mean follow-up was 7.1 years for probands and 4.4 years for relatives. We identified an inherited cardiac disease in 76 (49%) probands and 42 (15%) relatives. An implantable cardioverter-defibrillator was inserted in 147 (95%) probands and 9 (3%) relatives. During follow-up, 4 (3%) probands and 3 (1%) relatives died, and 37 probands and 2 relatives received appropriate shock therapy. All relatives received genetic counseling, and 18 (6%) relatives started pharmacologic treatment during follow-up.

Conclusion: Systematic workup of nonischemic SCA survivors and their relatives identified an inherited cardiac disease in 49% of referred probands and 15% of their relatives. The favorable long-term prognosis of diagnosed relatives probably not only reflects lower age but also the effects of early diagnosis, treatment, and follow-up. These findings support systematic workup of SCA survivors and their relatives.
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http://dx.doi.org/10.1016/j.hrthm.2020.06.030DOI Listing
October 2020

Diagnostic findings and follow-up outcomes in relatives to young non-autopsied sudden death victims.

Int J Cardiol 2020 Nov 20;318:61-66. Epub 2020 Jun 20.

The Clinic for Inherited Cardiac Diseases, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark.

Background: Guidelines recommend clinical assessment of relatives to young sudden cardiac death (SCD) victims in case the SCD was due to an inherited cardiac disorder. Work-up of relatives is guided by findings in the SCD victim. If post-mortem examinations have not been performed the work-up of relatives is challenged.

Method: In this retrospective study we included families referred to our tertiary referral centre between 2005 and 2018 due to a possible SCD (pSCD) in the family. Autopsy had not been performed in any of the pSCD victims. The relatives underwent cardiac work-up focusing on putative presence of inherited cardiac disorders and genetic analysis in selected cases. A family diagnosis was only established if≥1 relative was diagnosed. The families were categorised as: 1) definite inherited cardiac diagnosis, 2) borderline diagnosis, or 3) undiagnosed.

Results: We assessed 149 relatives (43 ± 16 years, 48% men) from 84 pSCD non-autopsied cases (44 ± 11 years, 79% men). In 11 (13%) families a definite inherited cardiac diagnosis was established, a borderline diagnosis in 8 (10%) families, and 65 (77%) families remained undiagnosed. One third of the diagnosed relatives were offered pharmaco- or device-based therapy. During follow-up for 4.7 ± 3.6 years no relatives from the families with definite diagnoses died. No events were seen in the groups with borderline or no diagnoses.

Conclusion: The diagnostic yield and need for treatment in diagnosed relatives warrant work-up, also of families with non-autopsied pSCD victims. No or reduced follow-up of relatives without signs or symptoms of heart diseases may be safe.
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http://dx.doi.org/10.1016/j.ijcard.2020.06.012DOI Listing
November 2020

Diagnostic yield in victims of sudden cardiac death and their relatives.

Europace 2020 06;22(6):964-971

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

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 remaining 187 families with borderline/no diagnosis in the proband, screening of relatives yielded a diagnosis in 26 additional families. In total, an inherited cardiac disease was identified in 143 out of 304 families (47%). In relatives, 73 (11%) were diagnosed. Arrhythmogenic right ventricular cardiomyopathy (n = 16) was the most common diagnosis. During follow-up (mean 5.5 years), a low rate of serious cardiac events was observed (no SCD events).

Conclusion: Forty-seven percent of SCD families were diagnosed. Eleven percent of the screened relatives received a definite diagnosis and were offered treatment according to guidelines. A low rate of serious cardiovascular events was observed among SCD relatives.
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http://dx.doi.org/10.1093/europace/euaa056DOI Listing
June 2020

Non-diagnostic autopsy findings in sudden unexplained death victims.

BMC Cardiovasc Disord 2020 02 4;20(1):58. Epub 2020 Feb 4.

Department of Cardiology The Heart Center, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2142, 2100, Copenhagen, Denmark.

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. Thirty-seven cases had normal cardiac findings and non-diagnostic cardiac findings were found in 62 cases (63%). The five most common findings included ventricular hypertrophy and/or enlarged heart (n = 35, 35%), coronary atheromatosis (n = 31, 31%), myocardial fibrosis (n = 19, 19%), dilated chambers (n = 7, 7%) and myocardial inflammation (n = 5, 5%).

Conclusion: One third of SUD victims had normal cardiac findings and non-diagnostic cardiac findings were seen in almost two thirds of the SUD victims. These non-diagnostic findings may be precursors or early markers for underlying structural cardiac disorders or may be innocent bystanders in some cases. Further studies and improved post-mortem examination methods are needed for optimization of diagnostics in SUD.
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http://dx.doi.org/10.1186/s12872-020-01361-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001247PMC
February 2020

Screening relatives in arrhythmogenic right ventricular cardiomyopathy: yield of imaging and electrical investigations.

Eur Heart J Cardiovasc Imaging 2020 02;21(2):175-182

The Capital Regions Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Center, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen OE, Denmark.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease and presymptomatic screening of relatives is recommended. In 2010, the Task Force Criteria (TFC2010) introduced specific diagnostic imaging parameters. The aim of the study was to evaluate the diagnostic yield of family screening and the value of different diagnostic modalities.

Methods And Results: Family evaluation, including cardiac magnetic resonance (CMR), is routinely offered to ARVC relatives at our institution. We retrospectively registered baseline characteristics, symptomatology, and results of non-invasive examinations from 2010 to 2016 and assessed the findings according to TFC2010. A total of 286 relatives (150 females; age 12-76 years; 251 first-degree) were included. A total of 103 (36%) individuals reported cardiovascular symptoms. The non-invasive workup showed that 101 (35%) relatives had ≥1 positive parameter on signal-averaged electrocardiogram (ECG), 40 (14%) had abnormal findings on Holter monitoring, 36 (13%) fulfilled an ECG criterion, six (2%) fulfilled CMR criteria, and echocardiographic abnormalities was seen in one (0.3%) relative. In total, 21 (7% overall; 13% among gene-positive subgroup) relatives were diagnosed with ARVC and 78 (27% overall; 49% among gene-positive subgroup) with borderline ARVC based on the combined non-invasive evaluations. Family history and electrical investigations alone diagnosed 20 out of 21 (95%) ARVC cases and 73 out of 78 (94%) borderline cases.

Conclusion: Consecutive evaluation of ARVC relatives diagnosed 7% with definite and 27% with borderline ARVC according to the TFC2010. Screening relatives for electrical abnormalities with 12 lead ECG, signal-averaged ECG, and Holter monitoring was more sensitive than imaging modalities.
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http://dx.doi.org/10.1093/ehjci/jez204DOI Listing
February 2020

Rare non-coding Desmoglein-2 variant contributes to Arrhythmogenic right ventricular cardiomyopathy.

J Mol Cell Cardiol 2019 06 30;131:164-170. Epub 2019 Apr 30.

Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Münster, 48149 Münster, Germany.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to variants in the coding sequence of desmosomal genes. The potential contribution of non-coding desmoglein-2 (DSG2) variants for development of ARVC is undescribed. We sequenced 1450 base pairs upstream of ATG in the DSG2 gene in 65 unrelated patients diagnosed with ARVC (10 borderline cases). Identified variants was evaluated by cosegregation and allele population frequency analysis, in silico tools, immunohistological investigations of myocardial biopsies, gene reporter assays, electrophoretic mobility shift assays (EMSA), and chromatin immunoprecipitation. The genetic analysis identified one novel, rare heterozygous DSG2 upstream variant (-317G > A) in a genetically unexplained ARVC patient. The variant segregated with signs of disease, was absent in publicly available databases, and affected a predicted binding site for activating protein-1 (AP-1). Immunohistochemical analysis of a myocardial biopsy from the -317G > A patient showed a marked reduction in DSG2 protein levels compared to healthy controls. Luciferase reporter gene assays showed promoter activity of the identified DSG2 upstream region and a general reduction in transcriptional activity in the presence of the minor DSG2_A allele (p < .01). Moreover, the DSG2_A allele reduced DSG2 activation by TGF-beta1 and a protein kinase C pathway activator (PMA; all p < .001 vs. DSG2_G). EMSAs showed altered transcription factor binding in presence of the DSG2_A allele. Chromatin immunoprecipitation assays in wild type epithelial cells identified AP-1 components c-FOS and c-JUN at the -317 locus. In conclusion, the non-coding DSG2 promoter variant -317G > A reduces DSG2 transcription in vitro and reduced myocardial DSG2 protein levels were observed in vivo. Our data support a contribution of non-coding DSG2 variants to the pathogenesis of ARVC.
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http://dx.doi.org/10.1016/j.yjmcc.2019.04.029DOI Listing
June 2019

Citalopram and the KCNE1 D85N variant: a case report on the implications of a genetic modifier.

Eur Heart J Case Rep 2018 Dec 26;2(4):yty106. Epub 2018 Sep 26.

Department of Cardiology, Herlev-Gentofte Hospital, University Hospital Copenhagen, Herlev Ringvej 75, Copenhagen, Denmark.

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.

Case Summary: In this report, we describe the case a 54-year-old woman, who presented with syncope. At presentation, the QTc interval was markedly prolonged, and she was admitted for observation under telemetry. The following day the patient had experienced a near syncope during an episode of 18 s of Torsade de Pointes (TdP). At the time of TdP, the potassium level (3.4 mmol/L) was mildly reduced, and the ECG showed a QTc interval of 640 ms. In spite of correction of hypokalaemia and discontinuation of the possibly LQTS-inducing drug citalopram the QTc duration remained intermittently prolonged. A transthoracic echocardiogram and a recent coronary angiogram were normal. The patient received an implantable cardioverter-defibrillator. Subsequent genetic testing identified a heterozygous KCNE1 p.D85N (c.253G>A) variant, a known QT modifier with a population prevalence of 1.3%.

Discussion: We conclude that the combination of a commonly prescribed antidepressant, discrete hypokalaemia, and a common KCNE1 QT modifier may cause severe QTc prolongation and life-threatening arrhythmia.
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http://dx.doi.org/10.1093/ehjcr/yty106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426086PMC
December 2018

A Novel SCN5A Variant Associated with Abnormal Repolarization, Atrial Fibrillation, and Reversible Cardiomyopathy.

Cardiology 2018 10;140(1):8-13. Epub 2018 Apr 10.

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

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 associated with a novel SCN5A variant. Our findings broaden the spectrum of cardiac phenotypes associated with SCN5A channelopathy, underlining the complex clinical manifestations of genetic variations within this gene.
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http://dx.doi.org/10.1159/000487475DOI Listing
September 2019

Functional Promoter Variant in Desmocollin-2 Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy.

Circ Cardiovasc Genet 2016 08;9(4):384-7

From the Department of Cardiology, The Heart Centre (A.H.C., H.B., J.H.S.) and Department of Pathology (C.B.A.), Rigshospitalet, Copenhagen University Hospital, Denmark; The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark (A.H.C., J.H.S.); Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Münster, Germany (B.S., M.B.); and Department of Clinical Medicine, Faculty of Medicine and Health Sciences, University of Copenhagen, Denmark (J.H.S.).

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http://dx.doi.org/10.1161/CIRCGENETICS.116.001455DOI Listing
August 2016

The two-pore domain potassium channel, TWIK-1, has a role in the regulation of heart rate and atrial size.

J Mol Cell Cardiol 2016 08 19;97:24-35. Epub 2016 Apr 19.

Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia; Cardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales, Australia. Electronic address:

The two-pore domain potassium (K(+)) channel TWIK-1 (or K2P1.1) contributes to background K(+) conductance in diverse cell types. TWIK-1, encoded by the KCNK1 gene, is present in the human heart with robust expression in the atria, however its physiological significance is unknown. To evaluate the cardiac effects of TWIK-1 deficiency, we studied zebrafish embryos after knockdown of the two KCNK1 orthologues, kcnk1a and kcnk1b. Knockdown of kcnk1a or kcnk1b individually caused bradycardia and atrial dilation (p<0.001 vs. controls), while ventricular stroke volume was preserved. Combined knockdown of both kcnk1a and kcnk1b resulted in a more severe phenotype, which was partially reversed by co-injection of wild-type human KCNK1 mRNA, but not by a dominant negative variant of human KCNK1 mRNA. To determine whether genetic variants in KCNK1 might cause atrial fibrillation (AF), we sequenced protein-coding regions in two independent cohorts of patients (373 subjects) and identified three non-synonymous variants, p.R171H, p.I198M and p.G236S, that were all located in highly conserved amino acid residues. In transfected mammalian cells, zebrafish and wild-type human TWIK-1 channels had a similar cellular distribution with predominant localization in the endosomal compartment. Two-electrode voltage-clamp experiments using Xenopus oocytes showed that both zebrafish and wild-type human TWIK-1 channels produced K(+) currents that are sensitive to external K(+) concentration as well as acidic pH. There were no effects of the three KCNK1 variants on cellular localization, current amplitude or reversal potential at pH7.4 or pH6. Our data indicate that TWIK-1 has a highly conserved role in cardiac function and is required for normal heart rate and atrial morphology. Despite the functional importance of TWIK-1 in the atrium, genetic variation in KCNK1 is not a common primary cause of human AF.
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http://dx.doi.org/10.1016/j.yjmcc.2016.04.006DOI Listing
August 2016

Plakophilin-2 c.419C>T and risk of heart failure and arrhythmias in the general population.

Eur J Hum Genet 2016 May 12;24(5):732-8. Epub 2015 Aug 12.

Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.

A rare genetic variant in the desmosomal gene plakophilin-2 (PKP2) c.419C>T(p.(S140F)) has repeatedly been identified in patients with dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Whether this is a disease-causing variant remains highly controversial. We tested this hypothesis using three approaches. Initially, in a prospective study of 10 407 individuals from the general population, including 2688 who developed heart failure or arrhythmias during >14 years of follow-up, PKP2 c.419C>T was identified in 98 individuals (0.94%). PKP2 genotype was not associated with electrocardiographic or echocardiographic changes, or with plasma levels of probrain natriuretic peptide (all P≥0.05). In c.419C>T carriers versus non-carriers, multifactorially adjusted hazard ratios were 1.26 (95% confidence interval: 0.77-2.07) for heart failure, 1.40 (0.90-2.17) for arrhythmias, 1.15 (0.78-1.71) for end points combined, and 1.33 (0.98-1.80) for all-cause mortality. The cumulative survival as a function of age and PKP2 genotype was similar among carriers and non-carriers (P=0.14). Second, comparing 517 patients referred for genetic testing with 1918 matched controls, odds ratios as a function of c.419C>T genotype were 2.11 (0.50-8.99) for ARVC, 0.72 (0.16-3.28) for hypertrophic cardiomyopathy (HCM)/DCM, and 1.28 (0.46-3.54) for end points combined. Third, in in vitro studies cellular localization of plakophilin-2, plakoglobin, connexin-43, or N-cadherin were similar in cells transfected with wild-type or mutant plakophilin-2. In conclusion, combining epidemiological data, with data on patients referred for genetic testing for ARVC or HCM/DCM, and data from in vitro studies, PKP2 c.419C>T did not associate with heart failure, arrhythmias, or premature death, with ARVC or HCM/DCM, or with effects in vitro, suggesting that this is not a disease-causing variant.
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http://dx.doi.org/10.1038/ejhg.2015.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930081PMC
May 2016

Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis.

J Mol Cell Cardiol 2014 Feb 27;67:69-76. Epub 2013 Dec 27.

Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia; Cardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.

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<0.001), marked increase in atrial diameter (p<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.
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http://dx.doi.org/10.1016/j.yjmcc.2013.12.014DOI Listing
February 2014

The novel desmin mutant p.A120D impairs filament formation, prevents intercalated disk localization, and causes sudden cardiac death.

Circ Cardiovasc Genet 2013 Dec 7;6(6):615-23. Epub 2013 Nov 7.

Background: The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy. Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known.

Methods And Results: We identified the 2 novel variants DES-p.A120D (c.359C>A) and DES-p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D reveal a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation, whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type.

Conclusions: Because of the functional in vivo and in vitro characterization, DES-p.A120D has to be regarded as a pathogenic mutation and DES-p.H326R as a rare variant with unknown significance. Presumably, the loss of the desmin-p. A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000103DOI Listing
December 2013

Efficacy of carvedilol in pediatric heart failure.

Future Cardiol 2013 Jul;9(4):475-8

Molecular Cardiology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, Australia.

Evaluation of: Huang M, Zhang X, Chen S et al. The effect of carvedilol treatment on chronic heart failure in pediatric patients with dilated cardiomyopathy: a prospective, randomized-controlled study. Pediatr. Cardiol. 34, 680-685 (2013). A role for β-blockers in children with heart failure has not been established. Huang et al. conducted a randomized trial of oral carvedilol in children with dilated cardiomyopathy treated with conventional therapy for a minimum of 1 month. The primary end points were Ross score, echocardiographic parameters, brain natriuretic peptide levels and a composite clinical end point. Of the subjects assessed at 6 months, 41 had received carvedilol (up to 0.8 mg/kg/day) and 37 had not (control group). Carvedilol had favorable effects on Ross score, left ventricular function and brain natriuretic peptide levels. However, improvement was also seen in the control group, although this was not as pronounced. Composite end points were similar in the carvedilol-treated and control groups. Only one serious adverse event was observed. The results suggest a possible beneficial effect of carvedilol when added to conventional therapy, but a number of limitations of study design restrict the conclusions that can be drawn.
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http://dx.doi.org/10.2217/fca.13.36DOI Listing
July 2013

Mutation analysis of the candidate genes -, , and in patients with arrhythmogenic right ventricular cardiomyopathy.

Appl Transl Genom 2012 Dec 1;1:44-46. Epub 2012 Oct 1.

Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), Blegdamsvej 3, 2200 Copenhagen N, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Juliane Maries Vej 20, 2100 Copenhagen O, Denmark; Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen O, Denmark.

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart disease characterized by fibrofatty infiltrations in the myocardium, right and/or left ventricular involvement, and ventricular tachyarrhythmias. Although ten genes have been associated with ARVC, only about 40% of the patients have an identifiable disease-causing mutation. In the present study we aimed at investigating the involvement of the genes -, , and in the pathogenesis of ARVC.

Methods: Sixty-five unrelated patients (55 fulfilling ARVC criteria and 10 borderline cases) were screened for variants in -, , and by direct sequencing and LightScanner melting curve analysis.

Results: A total of 28 sequence variants were identified: seven in , three in , two in , two in , four in , and ten in . Three of the variants were novel. One of the variants was non-synonymous. No disease-causing mutations were identified.

Conclusions: In our limited sized cohort the six studied candidate genes were not associated with ARVC.
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http://dx.doi.org/10.1016/j.atg.2012.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121199PMC
December 2012

[Clinical and genetic findings in arrhythmogenic right ventricular cardiomyopathy].

Ugeskr Laeger 2011 Feb;173(9):637-43

Hjertemedicinsk Afdeling B, Hjertecentret, Rigshospitalet, 2100 København Ø, Denmark.

Arrhythmogenic right ventricular cardiomyopathy is an inherited disease of the cardiomyocyte. The disease is diagnosed as a syndrome based on criteria that include ventricular arrhythmias, electrocardiographic findings, imaging, tissue characteristics and family history. An implantable cardioverter-defibrillator is generally recommended. Novel insight into the molecular genetic background has established that the disease may be associated with mutation in the genes encoding desmosomal proteins. Genetic testing is expected to facilitate the diagnostic workup and treatment of patients and their families.
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February 2011

Screening of three novel candidate genes in arrhythmogenic right ventricular cardiomyopathy.

Genet Test Mol Biomarkers 2011 Apr 22;15(4):267-71. Epub 2011 Jan 22.

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

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been associated with mutations in genes encoding cellular adhesion proteins. However, only about 40% of patients have mutations in known genes. We hypothesized that mutations in the genes encoding β-catenin (CTNNB1), α-T-catenin (CTNNA3), and PERP (PERP)-all important structural proteins located at the intercalated disc-were involved in the pathogenesis of ARVC. We screened 65 unrelated patients (55 fulfilling 1994 Task Force criteria and ten borderline cases) for mutations in CTNNB1, CTNNA3, and PERP by direct sequencing and LightScanner melting curve analysis. Our comprehensive mutation scanning did not identify any disease-causing mutations. Thirty-five sequence variants were found, including one rare nonsynonymous variant of unknown significance (CTNNA3 A689V). Fourteen of the variants were novel. In conclusion, in our cohort of a limited size, no mutations were identified in the three studied candidate genes despite their involvement in formation and maintenance of the intercalated disk. We recommend focus on other components of cardiomyocyte adhesion in future research into the pathogenesis of ARVC.
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http://dx.doi.org/10.1089/gtmb.2010.0151DOI Listing
April 2011

Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders?

Cardiology 2010 3;115(2):148-54. Epub 2009 Dec 3.

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

Objectives: Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported missense mutations may not be pathogenic.

Methods: We screened 53 unrelated patients fulfilling Task Force criteria for ARVC/D for mutations in PKP2 by direct sequencing.

Results: Seven different mutations were identified: two insertion/deletions (E329fsX352, P401fsX406), 1 splice site (2146-2A>T), 1 non-sense (R79X) and 4 missense mutations (Q62K in 2 patients, G489R, G673V) of undeterminable pathogeneity. None of these mutations was present in 650 controls. Five of the mutations were novel. Seven patients carried reported missense mutations (D26N, S140F, V587I); however, these mutations were identified in our 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 large-scale sequencing to clarify normal variation in the gene.
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http://dx.doi.org/10.1159/000263456DOI Listing
March 2010
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