Henning Bundgaard

Children's Heart Center, Las Vegas, Nevada, United States

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Publications (132)683.71 Total impact

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    ABSTRACT: Background Family history of myocardial infarction (MI) is an independent risk factor for MI. Several genetic variants are associated with increased risk of MI and family history of MI in a first-degree relative doubles MI risk. However, although family history of MI is not a simple dichotomous risk factor, the impact of specific, detailed family histories has not received much attention, despite its high clinical relevance. We examined risk of MI by MIs in first- and second-degree relatives and by number and age of affected relatives. Methods and Findings Using Danish national registers, we established a nationwide cohort of persons born between 1930 and 1992 with identifiable first- or second-degree relatives. Incident MIs in both cohort members and relatives aged ≥20 years were identified. We calculated incidence rate ratios (IRRs) for MI by family history of MI, by Poisson regression. In 4.4 million persons followed for 104 million person-years, we identified 128,384 incident MIs. IRRs with 95% confidence intervals [CIs] for MI by history of MI in 1, 2 or ≥3 first-degree relatives were 1.46 (1.42-1.49), 2.38 (2.22-2.56) and 3.58 (2.66-4.81), respectively. Corresponding estimates for second-degree relatives were 1.17 (1.05-1.30), 1.87 (1.46-2.38) and 2.18 (1.09-4.36). A history of MI in combinations of first- and second-degree relatives increased risks 1.8- to 7-fold in middle-aged persons (36 to 55 years). Estimates were robust to adjustment for diabetes, hypertension, dyslipidemia and use of cardiovascular medications. Conclusion A detailed family history, particularly number of affected first- and second-degree relatives, contributes meaningfully to risk assessment, especially in middle-aged persons. Future studies should test for potential improvement of risk algorithm prediction using detailed family histories.
    PLoS ONE 05/2015; 10(5). DOI:10.1371/journal.pone.0125896
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    ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease primarily caused by mutations in genes coding for sarcomeric proteins. A molecular-genetic etiology can be established in ~60% of cases. Evolutionarily conserved mitochondrial DNA (mtDNA) haplogroups are susceptibility factors for HCM. Several polymorphic mtDNA variants are associated with a variety of late-onset degenerative diseases and affect mitochondrial function. We examined the role of private, non-haplogroup associated, mitochondrial variants in the etiology of HCM. In 87 Danish HCM patients, full mtDNA sequencing revealed 446 variants. After elimination of 312 (69.9%) non-coding and synonymous variants, a further 109 (24.4%) with a global prevalence > 0.1%, three (0.7%) haplogroup associated and 19 (2.0%) variants with a low predicted in silico likelihood of pathogenicity, three variants: MT-TC: m.5772G>A, MT-TF: m.644A>G, and MT-CYB: m.15024G>A, p.C93Y remained. A detailed analysis of these variants indicated that none of them are likely to cause HCM. In conclusion, private mtDNA mutations are frequent, but they are rarely, if ever, associated with HCM.
    PLoS ONE 04/2015; 10(4):e0124540. DOI:10.1371/journal.pone.0124540
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    ABSTRACT: Transcatheter aortic valve implantation (TAVI) is an advancing mode of treatment for inoperable or high-risk patients with aortic stenosis. Prosthetic valve endocarditis (PVE) after TAVI is a serious complication, but only limited data exist on its incidence, outcome, and procedural risk factors. Observational single-center study of 509 consecutive patients treated with a transcatheter implanted self-expandable aortic valve prosthesis (Medtronic CoreValve). We identified 18 patients diagnosed with TAVI-PVE during a median follow-up period of 1.4 years (interquartile range, 0.5-2.5 years; longest follow-up was 6.3 years). TAVI-PVE was most frequent in the first year after implantation (first-year incidence, 3.1% [confidence interval, 1.4%-4.8%]); the overall annualized rate was 2.1% per patient-year (confidence interval, 1.2%-3.3%). Seventeen patients (94%) were treated conservatively and 1 with surgery. Four patients (22%) died from endocarditis or complications to treatment, 2 of those (11%) during initial hospitalization for PVE. An increased risk of TAVI-PVE was seen in patients with low implanted valve position (hazard ratio, 2.8 [1.1-7.2]), moderate or worse postprocedural paravalvular regurgitation (hazard ratio, 4.0 [1.5-11]), implantation of >1 prosthesis (hazard ratio, 5.2 [1.5-18]), and any vascular complication (hazard ratio, 3.8 [1.5-9.8]). TAVI-PVE occurred at a slightly higher rate than reported for surgically implanted valves. Conservative treatment was associated with an acceptable outcome. Suboptimal valve deployment and vascular complications were associated with an increased risk of TAVI-PVE. © 2015 American Heart Association, Inc.
    Circulation Cardiovascular Interventions 04/2015; 8(4). DOI:10.1161/CIRCINTERVENTIONS.114.001939
  • Journal of the American College of Cardiology 03/2015; 65(10):A857. DOI:10.1016/S0735-1097(15)60857-9
  • Journal of the American College of Cardiology 03/2015; 65(10):A978. DOI:10.1016/S0735-1097(15)60978-0
  • ACC 2015; 03/2015
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    ABSTRACT: To assess the degree and progression of cardiac involvement in patients with limb-girdle type 2 (LGMD2) and Becker muscular dystrophies (BMD). A follow-up study of 100 LGMD2 (types A-L) and 30 BMD patients assessed by electrocardiogram (ECG) and echocardiography, supplemented by Holter-monitoring at follow-up. After a median of 8.9years (range 0.4-13.7), twelve patients had died: LGMD2 (n=10, mean age 61±11years), BMD (n=2, age 43 and 45years). Of the remaining 118 patients, 89 completed follow-up: LGMD2 (n=64, age 48±13years) and BMD (n=25, age 40±13years). In BMD, LVEF decreased from 60% (10-62) to 50% (10-64), p=0.02 corresponding to a one percentage drop annually. Among patients with LGMD2, LVEF decreased significantly in patients with LGMD type 2I (n=28) from 59% (15-72) to 55% (20-61), p=0.03, i.e. a 0.4 percentage drop annually, and LVEF≤50% was associated with increased mortality in this subgroup. In LGMD2E, 3/5 patients (60%) at baseline and 4/5 (80%) at follow-up had LVEF≤50%. ECG abnormalities were non-progressive in BMD and in all subgroups of LGMD2. SVT and NSVT were present in both groups: BMD (3/14 (21%) and (2/14 (14%)), LGMD2 (16/51 (31%) and 8/51 (16%)), respectively, all asymptomatic. LVEF decreased significantly in patients with BMD and LGMD2I, and the majority of patients with LGMD2E had left ventricular systolic dysfunction. This study emphasizes the need for tailored regular cardiac assessments according to molecular diagnosis with special focus on BMD and LGMD types 2I and 2E. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International Journal of Cardiology 12/2014; 182C:403-411. DOI:10.1016/j.ijcard.2014.12.090
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    ABSTRACT: No medical treatment has been reliably shown to halt or reverse disease progression in hypertrophic cardiomyopathy, but the results of several pilot studies have suggested beneficial effects of angiotensin II receptor blockers on left ventricular hypertrophy and fibrosis, which are predictive of an adverse outcome. We aimed to assess the effect of the angiotensin II receptor blocker losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. In this single-centre, randomised, double-blind, placebo-controlled trial, adult patients (aged 18 years and older) with obstructive or non-obstructive hypertrophic cardiomyopathy were randomly assigned via computer-based system to losartan (100 mg per day) or placebo for 12 months. Patients and investigators were masked to assigned treatment. The primary endpoint was change in left ventricular mass as assessed by cardiac magnetic resonance imaging (CMR) or CT. Efficacy analyses were done in the modified intention-to-treat population (all patients with data available at the 12-month follow-up). The trial is registered with ClinicalTrials.gov, number NCT01447654. Between Dec 1, 2011, and May 1, 2013, 318 patients were screened. 133 patients (mean age 52 years [SD 13], 35% women) consented and were randomly assigned to placebo (n=69) or losartan (n=64). 124 (93%) patients completed the study and were included in the modified intention-to-treat analysis for the primary endpoint. After 12 months we noted no significant difference in the change in left ventricular mass between the placebo group and the losartan group (mean difference 1 g/m(2), 95% CI -3 to 6; p=0·60). A decrease in systolic blood pressure in the losartan group (from mean 127 mm Hg [SD 12] to 121 mm Hg [14]; p=0·0001) confirmed drug compliance; blood pressure did not decrease in the placebo group. Two (2%) patients, both in the placebo group, died from sudden cardiac death during follow-up. In the losartan group, one (1%) patient had angioedema, one (1%) had deterioration of renal function, and one (1%) had hyperkalaemia. Treatment was well tolerated by patients with left ventricular outflow obstruction at baseline. Our findings challenge the generally held view that angiotensin II receptor blockers reduce cardiac hypertrophy. Treatment with losartan was safe, suggesting that it can be used for other indications in patients with hypertrophic cardiomyopathy, irrespective of obstructive physiology. Additional studies are needed to assess the effect of angiotensin II receptor blockers in preclinical hypertrophic cardiomyopathy-eg, in genotype-positive but phenotype-negative individuals. Capital Region of Denmark, Rigshospitalet Research Fund, Danish Heart Association, Heart Centre Research Foundation, P A Messerschmidt and Wife Foundation, Westerberg Foundation, Beckett Foundation, Soren Segel and Wife Johanne Segel Research Foundation, and A P Møller and Chastine Mc-Kinney Møller Foundation. Copyright © 2014 Elsevier Ltd. All rights reserved.
    The Lancet Diabetes & Endocrinology 12/2014; 3(2). DOI:10.1016/S2213-8587(14)70241-4
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    ABSTRACT: Sudden cardiac death (SCD) is responsible for a large proportion of sudden deaths in young individuals. In forensic medicine, many cases remain unexplained after routine postmortem autopsy and conventional investigations. These cases are called sudden unexplained deaths (SUD). Genetic testing has been suggested useful in forensic medicine, although in general with a significantly lower success rate compared to the clinical setting. The purpose of the study was to estimate the frequency of pathogenic variants in the genes most frequently associated with SCD in SUD cases and compare the frequency to that in patients with inherited cardiac channelopathies. Fifteen forensic SUD cases and 29 patients with channelopathies were investigated. DNA from 34 of the genes most frequently associated with SCD were captured using NimbleGen SeqCap EZ library build and were sequenced with next-generation sequencing (NGS) on an Illumina MiSeq. Likely pathogenic variants were identified in three out of 15 (20 %) forensic SUD cases compared to 12 out of 29 (41 %) patients with channelopathies. The difference was not statistically significant (p = 0.1). Additionally, two larger deletions of entire exons were identified in two of the patients (7 %). The frequency of likely pathogenic variants was >2-fold higher in the clinical setting as compared to SUD cases. However, the demonstration of likely pathogenic variants in three out of 15 forensic SUD cases indicates that NGS investigations will contribute to the clinical investigations. Hence, this has the potential to increase the diagnostic rate significantly in the forensic as well as in the clinical setting.
    International Journal of Legal Medicine 12/2014; DOI:10.1007/s00414-014-1105-y
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    ABSTRACT: Infection with Listeria monocytogenes is rare and mainly seen in immunosuppressed patients. Infection with L. monocytogenes has a mortality rate of 30%. We present a case report of L. monocytogenes bacteraemia and endocarditis in a 70-year-old man with several co-morbidities and following four major surgical procedures. This illustrates the findings and characteristics in one of the 16 patients who died in 2013 and 2014 this summer due to sausage-related L. monocytogenes infection.
    Ugeskrift for laeger 11/2014; 176(48).
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    ABSTRACT: Several cardiac diseases are autosomal dominantly inherited. This includes cardiomyopathies, primary arrhythmias (channelopathies), dyslipidaemias, premature ischaemic heart diseases and diseases of the thoracic aorta. Sudden cardiac death in the young is also often due to one of the inherited cardiac diseases. Clinical and genetic cascade family screening of the relatives to patients with inherited cardiac diseases is now organized in a national network of centres of cardiology, sharing pedigrees, clinical and genetic information. This gives unique opportunities for offering focused prophylaxis in the group of high-risk relatives.
    Ugeskrift for laeger 11/2014; 176(46).
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    ABSTRACT: Sudden cardiac death (SCD) is responsible for a large proportion of non-traumatic, sudden and unexpected deaths in young individuals. Sudden cardiac death is a known manifestation of several inherited cardiac diseases. In post-mortem examinations, about two-thirds of the SCD cases show structural abnormalities at autopsy. The remaining cases stay unexplained after thorough investigations and are referred to as sudden unexplained deaths. A routine forensic investigation of the SCD victims in combination with genetic testing makes it possible to establish a likely diagnosis in some of the deaths previously characterized as unexplained. Additionally, a genetic diagnose in a SCD victim with a structural disease may not only add to the differential diagnosis, but also be of importance for pre-symptomatic family screening. In the case of SCD, the optimal establishment of the cause of death and management of the family call for standardized post-mortem procedures, genetic screening, and family screening. Studies of genetic testing in patients with primary arrhythmia disorders or cardiomyopathies and of victims of SCD presumed to be due to primary arrhythmia disorders or cardiomyopathies, were systematically identified and reviewed. The frequencies of disease-causing mutation were on average between 16 and 48% in the cardiac patient studies, compared with ∼10% in the post-mortem studies. The frequency of pathogenic mutations in heart genes in cardiac patients is up to four-fold higher than that in SCD victims in a forensic setting. Still, genetic investigation of SCD victims is important for the diagnosis and the possible investigation of relatives at risk.
    Europace 10/2014; 17(3). DOI:10.1093/europace/euu210
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    ABSTRACT: Background Myotonic dystrophy type 1 (DM1) is associated with increased cardiac morbidity and mortality. Therefore, assessment of cardiac involvement and risk stratification for sudden cardiac death is crucial. Nevertheless, optimal screening-procedures are not clearly defined. ECG, echocardiography and Holter-monitoring are useful but insufficient. Cardiovascular magnetic resonance (CMR) can provide additional information of which myocardial fibrosis may be relevant.The purpose of this study was to describe the prevalence of myocardial fibrosis in patients with DM1 assessed by CMR, and the association between myocardial fibrosis and abnormal findings on ECG, Holter-monitoring and echocardiography.Methods We selected 30 unrelated patients with DM1: 18 patients (10 men, mean age 51 years) with, and 12 patients (7 men, mean age 41 years) without abnormal findings on ECG and Holter-monitoring.Patients were evaluated with medical history, physical examination, ECG, Holter-monitoring, echocardiography and CMR.ResultsMyocardial fibrosis was found in 12/30 (40%, 9 men). The presence of myocardial fibrosis was associated with the following CMR-parameters: increased left ventricular mass (median (range) 55 g/m2 (43¿83) vs. 46 g/m2 (36¿64), p = 0.02), increased left atrial volume (median (range) 52 ml/m2 (36¿87) vs. 46 ml/m2 (35¿69), p = 0.04) and a trend toward lower LVEF (median (range) 63% (38¿71) vs. 66% (60¿80), p = 0.06). Overall, we found no association between the presence of myocardial fibrosis and abnormal findings on: ECG (p = 0.71), Holter-monitoring (p = 0.27) or echocardiographic measurements of left ventricular volumes, ejection fraction or global longitudinal strain (p = 0.18).Conclusion Patients with DM1 had a high prevalence of myocardial fibrosis which was not predicted by ECG, Holter-monitoring or echocardiography. CMR add additional information to current standard cardiac assessment and may prove to be a clinically valuable tool for risk stratification in DM1.
    Journal of Cardiovascular Magnetic Resonance 08/2014; 16(1):59. DOI:10.1186/PREACCEPT-1991790702125713
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    ABSTRACT: This study evaluates the agreement between echocardiographic and cardiac magnetic resonance (CMR) imaging data, and the impact a discrepancy between the two may have on the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: From the Nordic ARVC Registry, 102 patients with definite ARVC who had undergone both echocardiography and CMR were included (median age 42 ± 16 years, 36% female, 78% probands). Patients were divided into two groups according to CMR-positive or -negative criteria, and the echocardiographic data were compared between the two. There were 72 CMR-positive patients. They had significantly larger RV dimensions and lower fractional area change on echocardiography compared with CMR-negative patients; parasternal long-axis right ventricular outflow tract (RVOT) 37 ± 7 vs. 32 ± 5 mm, parasternal short-axis RVOT 38 ± 7 vs. 32 ± 6 mm, fractional area shortening 31 ± 9 vs. 39 ± 9% (P < 0.003 for all). Only 36 (50%) of the CMR-positive patients fulfilled ARVC criteria by echocardiography, hence the diagnostic performance was low; sensitivity 50% and specificity 70%, positive predictive value 80% and negative predictive value 37%. Individuals with regional wall abnormalities on CMR were more likely to have ventricular arrhythmias (77 vs. 57%, P = 0.047). CONCLUSION: A significant proportion of patients with imaging-positive ARVC by CMR did not fulfil echocardiographic ARVC 2010 criteria. These findings confirm that echocardiographic evaluation of subtle structural changes in the right ventricle may be unreliable, and the diagnostic performance of CMR compared with echocardiography should be reflected in the guidelines.
    European Heart Journal – Cardiovascular Imaging 06/2014; DOI:10.1093/ehjci/jeu109
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    ABSTRACT: Injection drug users (IDUs) account for a considerable number of the hospitalizations for infective endocarditis (IE), but the prevalence of diagnosed and unrecognized IE in IDUs is unknown. The aim of the present study was to assess the prevalence of valvular abnormalities suggestive of IE in IDUs attending a supervised injection facility. We performed transthoracic echocardiographic examinations on-site in the injection facilities. A total of 206 IDUs (mean age 43 ± 9 years, 23% women) with a median injection drug abuse of 18 years (interquartile range 10 to 26) were included. Fourteen IDUs (14 of 206, 7%, 95% confidence interval [CI] 4% to 11%) had a previous history of IE. IDUs with a history of IE were significantly older than IDUs without a history of IE (48 ± 8 vs 42 ± 9 years, respectively, p = 0.03) and had a longer duration of injection drug use (27 [18 to 36] vs 17 years [10 to 25], p = 0.008). In the subgroup of IDUs with a history of IE, 4 subjects (4 of 14, 29%, 95% CI 11% to 55%) had persistent or relapse vegetations. Of the remaining 10 IDUs with a history of IE, 5 (5 of 10, 50%, 95% CI 24% to 76%) had moderate-to-severe regurgitation. In the subgroup of IDUs without a history of IE, vegetations were seen in 9 subjects (9 of 192, 5%, 95% CI 2% to 9%). This group of IDUs with possibly unrecognized IE was older than IDUs without vegetations (48 ± 12 vs 42 ± 9, respectively, p = 0.04). Among the IDUs without a history of IE who did not have vegetations, 30 IDUs (30 of 183, 16%, 95% CI 11% to 22%) had moderate-to-severe regurgitation with or without concomitant thickening of leaflets. Thus, in IDUs without a history of IE, some extent of valvular abnormalities was seen in 20% (39 of 192, 95% CI 15% to 27%) of subjects. None of the IDUs with valvular vegetations had current symptoms consistent with active IE. In conclusion, valvular abnormalities assessed by echocardiography were prevalent in asymptomatic IDUs without a medical history of IE, and vegetations were seen in 5% of subjects.
    The American journal of cardiology 04/2014; 114(1). DOI:10.1016/j.amjcard.2014.04.010
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    ABSTRACT: To quantify the association between myotonic dystrophy (DM) and cardiac disease in a nationwide cohort. We identified a nationwide cohort of 1146 DM patients (period 1977-2011) using the National Patient Registry (NPR) and a subcohort of 485 patients who had undergone genetic testing for DM1. Information on incident cardiac diseases was obtained from the NPR. We estimated standardized incidence ratios (SIRs) of cardiac disease compared with the background population, overall and according to selected diagnostic subgroups (cardiomyopathy, heart failure, conduction disorders, arrhythmias, and device implantation). In the DM cohort, SIR for any cardiac disease was 3.42 [95% confidence interval (CI) 3.01-3.86]; for a cardiac disease belonging to the selected subgroups 6.91 (95% CI: 5.93-8.01) and for other cardiac disease 2.59 (95% CI: 2.03-3.25). For a cardiac disease belonging to the selected subgroups, the risk was particularly high in the first year after DM diagnosis [SIR 15.4 (95% CI: 10.9-21.3)] but remained significantly elevated in subsequent years [SIR 6.07 (95% CI: 5.11-7.16]). The risk was higher in young cohort members [e.g. 20-39 years: SIR 18.1 (95% CI: 12.3-25.8)] compared with older [e.g. 60-79 years: SIR 3.99 (95% CI: 2.98-5.23)] but remained significantly increased in all age categories. Results were similar in separate analyses of the genetically confirmed DM1 patients. Myotonic dystrophy is strongly associated with cardiac disease. The risk is pronounced in the young and remains elevated throughout life, stressing the importance of lifelong cardiac follow-up from time of DM diagnosis.
    European Heart Journal 04/2014; 35(32). DOI:10.1093/eurheartj/ehu157
  • Journal of the American College of Cardiology 04/2014; 63(12):A1272. DOI:10.1016/S0735-1097(14)61272-9
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    ABSTRACT: Patients with myotonic dystrophy type 1 (DM1) have a three-fold higher risk of sudden cardiac death (SCD) than age-matched healthy controls. Despite numerous attempts to define the cardiac phenotype and natural history, existing literature suffers from low power, selection-bias and lack of controls. Thus, the optimal strategy for assessing cardiac involvement in DM1 is unclear. In this large single-centre study, we evaluated 129 unselected DM1 patients (49.6% men), mean (SD) age 44 (14.7) years with family history, physical examination, electrocardiogram (ECG), echocardiography, Holter-monitoring and muscle strength testing. Cardiac involvement was found in 71 patients (55%) and included: 1) Conduction abnormalities: atrio-ventricular block grade I (AVB grade I) (23.6%), AVB grade II (5.6%), right/left bundle branch block (5.5/3.2%) and prolonged QTc (7.2%); 2) arrhythmias: atrial fibrillation/flutter (4.1%), other supraventricular tachyarrhythmia (7.3%) and non-sustained ventricular tachycardia (4.1%); and 3) structural abnormalities: left ventricular systolic dysfunction (20.6%) and reduced global longitudinal strain (21.7%). A normal ECG was not significantly associated with normal findings on Holter-monitoring or echocardiography. Patients with abnormal cardiac findings had weaker muscle strength than those with normal cardiac findings: ankle dorsal flexion (median (range) 4.5 (0-5) vs. 5.0 (2.5-5), p=0.004) and handgrip (median 4.0 (0-5) vs. 4.50 (2-5), p=0.02). The cardiac phenotype of DM1 includes a high prevalence of conduction disorders, arrhythmias and risk factors of SCD. Systematic cardiac screening with ECG, Holter-monitoring and echocardiography is needed in order to make a proper characterization of cardiac involvement in DM1.
    International journal of cardiology 03/2014; 174(1). DOI:10.1016/j.ijcard.2014.03.088
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    ABSTRACT: Several drugs used in the treatment of mental diseases are associated with an increased risk of sudden cardiac death (SCD). A general cause-relationship between the intake of these drugs and SCD is unattainable, but numerous case reports of drug-induced malignant arrhythmia and epidemiological studies, associating the use of specific drugs with SCD, strongly support the presence of an increased risk. Whereas the absolute risk of drug-induced life-threatening arrhythmia may be relatively low, even small increments in risk of SCD may have a major health impact considering that millions of patients are treated with psychotropics. In subgroups of pre-disposed patients, e.g. patients with cardiac diseases or other co-morbidities, the elderly or patients treated with other negatively interacting drugs, the absolute risk of drug-induced arrhythmia may be considerable. On the other hand, several of the major mental disorders are associated with a large risk of suicide if untreated. The observed risk of malignant arrhythmia associated with treatment with psychotropic drugs calls for clinical guidelines integrating the risk of the individual drug and other potentially interacting risk factors. In this review, data from various authorities on the risk of arrhythmia associated with psychotropic medications were weighted and categorized into three risk categories. Additionally, we suggest a clinically applicable algorithm to reduce the risk of malignant arrhythmia in patients to be treated with psychotropic medications. The algorithm integrates the risk categories of the individual drugs and pre-disposing risk factors and suggests a prudent follow-up for patients with an increased risk. We believe this clinically manageable guideline might improve safety in the many and rapidly increasing number of patients on psychotropic drugs.
    European Heart Journal 03/2014; 35(20). DOI:10.1093/eurheartj/ehu100
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    ABSTRACT: Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A. We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2. Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 "unrelated" families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000. The genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.
    BMC Medical Genetics 03/2014; 15(1):31. DOI:10.1186/1471-2350-15-31

Publication Stats

1k Citations
683.71 Total Impact Points

Institutions

  • 2015
    • Children's Heart Center
      Las Vegas, Nevada, United States
  • 2003–2014
    • Copenhagen University Hospital
      København, Capital Region, Denmark
    • University of Cologne
      • Department of Internal Medicine
      Köln, North Rhine-Westphalia, Germany
  • 1995–2014
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 2013
    • University of Copenhagen Herlev Hospital
      Herlev, Capital Region, Denmark
  • 2006–2011
    • Statens Serum Institut
      • Department of Clinical Biochemistry and Immunology
      København, Capital Region, Denmark
  • 2000–2009
    • Royal North Shore Hospital
      Sydney, New South Wales, Australia
  • 2007
    • University of Sydney
      Sydney, New South Wales, Australia
  • 2001–2003
    • Slovak Academy of Sciences
      • Institute for Heart Research
      Presburg, Bratislavský, Slovakia
  • 1996–2003
    • National University (California)
      San Diego, California, United States