Hanno L Tan

Publications (89)648.52 Total impact

• Article: Ageing and Brugada syndrome: considerations and recommendations.

  Pieter G Postema, Hanno L Tan, Arthur Am Wilde
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  ABSTRACT: Brugada syndrome is an inherited disease associated with an increased risk of lethal ventricular arrhythmias. Such arrhythmias stem from innate disruptions in cardiac electrophysiology. Typically, such arrhythmias occur in the third or fourth decade of life. However, Brugada syndrome may also affect geriatric patients. In this paper, we focus on the ageing patient with Brugada syndrome, and specifically, on the interaction between Brugada syndrome and the more usually acquired clinical problems that may occur with increasing age, such as the use of cardiovascular and non-cardiovascular drugs, or the need for surgery. Such common conditions may also disrupt cardiac electrophysiology, thereby conferring added risk for Brugada syndrome patients. We present some considerations and recommendations that may serve as guidance to address these complexities.
  Journal of Geriatric Cardiology 03/2013; 10(1):75-81.
• Article: Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community.

  Abdennasser Bardai, Ahmad S Amin, Marieke T Blom, Connie R Bezzina, Jocelyn Berdowski, Pim N J Langendijk, Leander Beekman, Christine A Klemens, Patrick C Souverein, Rudolph W Koster, Anthonius de Boer, Hanno L Tan
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  ABSTRACT: AimsNon-cardiac drugs that impair cardiac repolarization (electrocardiographic QT prolongation) are associated with an increased sudden cardiac arrest (SCA) risk. Emerging evidence suggests that non-cardiac drugs that impair cardiac depolarization and excitability (electrocardiographic QRS prolongation) also increase the risk for SCA. Nortriptyline, which blocks the SCN5A-encoded cardiac sodium channel, may exemplify such drugs. We aimed to study whether nortriptyline increases the risk for SCA, and to establish the underlying mechanisms.Methods and resultsWe studied QRS durations during rest/exercise in an index patient who experienced ventricular tachycardia during exercise while using nortriptyline, and compared them with those of 55 controls with/without nortriptyline and 24 controls with Brugada syndrome (BrS) without nortriptyline, who carried an SCN5A mutation. We performed molecular-genetic (exon-trapping) and functional (patch-clamp) experiments to unravel the mechanisms of QRS prolongation by nortriptyline and the SCN5A mutation found in the index patient. We conducted a prospective community-based study among 944 victims of ECG-documented SCA and 4354-matched controls to determine the risk for SCA associated with nortriptyline use. Multiple mechanisms may act in concert to increase the risk for SCA during nortriptyline use. Pharmacological (nortriptyline), genetic (loss-of-function SCN5A mutation), and/or functional (sodium channel inactivation at fast heart rates) factors conspire to reduce the cardiac sodium current and increase the risk for SCA. Nortriptyline use in the community was associated with a 4.5-fold increase in the risk for SCA [adjusted OR: 4.5 (95% CI: 1.1-19.5)], particularly when other sodium channel-blocking factors were present.Conclusions Nortriptyline increases the risk for SCA in the general population, particularly in the presence of genetic and/or non-genetic factors that decrease cardiac excitability by blocking the cardiac sodium channel.
  European Heart Journal 02/2013; · 10.48 Impact Factor
• Article: Electrocardiographic characteristics of patients with chronic obstructive pulmonary disease.

  Miriam J Warnier, Frans H Rutten, Mattijs E Numans, Jan A Kors, Hanno L Tan, Anthonius de Boer, Arno W Hoes, Marie L De Bruin
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  ABSTRACT: Abstract Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease. Electrocardiography (ECG) carries information about cardiac disease and prognosis, but studies comparing ECG characteristics between patients with and without COPD are lacking. We related ECG characteristics of patients with COPD, to ECG characteristics of patients without COPD, and determined whether ECG abnormalities are related to COPD severity. A cross-sectional study was conducted within a cohort of 243 COPD patients, aged 65 years or older. All patients underwent extensive examinations, including resting 12-lead ECG and pulmonary function tests. The reference group (n = 293) was a sample from the general population, also aged 65 or older, without COPD. Abnormal ECGs were more prevalent in COPD patients (50%) than in patients without COPD (36%, p = 0.054). Conduction abnormalities were the most common ECG abnormality in COPD patients (28%) being significantly more prevalent than in patients without COPD (11%, p < 0.001). The mean heart rate was higher in COPD patients (72 bpm (SD 14)) compared to controls (65 bpm (SD 13), p < 0.001), and QTc prolongation was less frequent in COPD patients (9% versus 14%, p = 0.01). The prevalence of ECG abnormalities increased with severity of pulmonary obstruction. ECG abnormalities, especially conduction abnormalities are common in COPD patients, and the prevalence of ECG abnormalities increases with severity of COPD. This underlines the importance of an integrated-care approach for COPD patients, paying attention to early detection of unrecognized coexisting cardiac disorders.
  COPD Journal of Chronic Obstructive Pulmonary Disease 02/2013; 10(1):62-71. · 1.79 Impact Factor
• Article: Organ explant culture of neonatal rat ventricles: a new model to study gene and cell therapy.

  A Dénise den Haan, Marieke W Veldkamp, Diane Bakker, Geert J J Boink, Rob B Janssen, Jacques M T de Bakker, Hanno L Tan
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  ABSTRACT: Testing cardiac gene and cell therapies in vitro requires a tissue substrate that survives for several days in culture while maintaining its physiological properties. The purpose of this study was to test whether culture of intact cardiac tissue of neonatal rat ventricles (organ explant culture) may be used as a model to study gene and cell therapy. We compared (immuno) histology and electrophysiology of organ explant cultures to both freshly isolated neonatal rat ventricular tissue and monolayers. (Immuno) histologic studies showed that organ explant cultures retained their fiber orientation, and that expression patterns of α-actinin, connexin-43, and α-smooth muscle actin did not change during culture. Intracellular voltage recordings showed that spontaneous beating was rare in organ explant cultures (20%) and freshly isolated tissue (17%), but common (82%) in monolayers. Accordingly, resting membrane potential was -83.9±4.4 mV in organ explant cultures, -80.5±3.5 mV in freshly isolated tissue, and -60.9±4.3 mV in monolayers. Conduction velocity, measured by optical mapping, was 18.2±1.0 cm/s in organ explant cultures, 18.0±1.2 cm/s in freshly isolated tissue, and 24.3±0.7 cm/s in monolayers. We found no differences in action potential duration (APD) between organ explant cultures and freshly isolated tissue, while APD of monolayers was prolonged (APD at 70% repolarization 88.8±7.8, 79.1±2.9, and 134.0±4.5 ms, respectively). Organ explant cultures and freshly isolated tissue could be paced up to frequencies within the normal range for neonatal rat (CL 150 ms), while monolayers could not. Successful lentiviral (LV) transduction was shown via Egfp gene transfer. Co-culture of organ explant cultures with spontaneously beating cardiomyocytes increased the occurrence of spontaneous beating activity of organ explant cultures to 86%. We conclude that organ explant cultures of neonatal rat ventricle are structurally and electrophysiologically similar to freshly isolated tissue and a suitable new model to study the effects of gene and cell therapy.
  PLoS ONE 01/2013; 8(3):e59290. · 4.09 Impact Factor
• Article: Acetylsalicylic acid prevents platelet-induced proarrhythmic effects on intracellular Ca(2+) homeostasis in ventricular myocytes.

  Olga M Zakhrabova-Zwiauer, Arie O Verkerk, Jonas S S G de Jong, Auguste Sturk, Rienk Nieuwland, Hanno L Tan
  International journal of cardiology 10/2012; · 7.08 Impact Factor
• Article: Implantable cardioverter-defibrillators have reduced the incidence of resuscitation for out-of-hospital cardiac arrest caused by lethal arrhythmias.

  Michiel Hulleman, Jocelyn Berdowski, Joris R de Groot, Pascal F H M van Dessel, C Jan Willem Borleffs, Marieke T Blom, Abdenasser Bardai, Carel C de Cock, Hanno L Tan, Jan G P Tijssen, Rudolph W Koster
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  ABSTRACT: Over the last decades, a gradual decrease in ventricular fibrillation (VF) as initial recorded rhythm during resuscitation for out-of-hospital cardiac arrest (OHCA) has been noted. We sought to establish the contribution of implantable cardioverter-defibrillator (ICD) therapy to this decline. Using a prospective database of all OHCA resuscitation in the province North Holland in the Netherlands (Amsterdam Resuscitation Studies [ARREST]), we collected data on all patients in whom resuscitation for OHCA was attempted in 2005-2008. VF OHCA incidence (per 100 000 inhabitants per year) was compared with VF OHCA incidence data during 1995-1997, collected in a similar way. We also collected ICD interrogations of all ICD patients from North Holland and identified all appropriate ICD shocks in 2005-2008; we calculated the number of prevented VF OHCA episodes, considering that only part of the appropriate shocks would result in avoided resuscitation. VF OHCA incidence decreased from 21.1/100 000 in 1995-1997 to 17.4/100 000 in 2005-2008 (P<0.001). Non-VF OHCA increased from 12.2/100 000 to 19.4/100 000 (P<0.001). VF as presenting rhythm declined from 63% to 47%. In 2005-2008, 1972 ICD patients received 977 shocks. Of these shocks, 339 were caused by a life-threatening arrhythmia. We estimate that these 339 shocks have prevented 81 (minimum, 39; maximum, 152) cases of VF OHCA, corresponding with 33% (minimum, 16%; maximum, 63%) of the observed decline in VF OHCA incidence. The incidence of VF OHCA decreased over the last 10 years in North Holland. ICD therapy explained a decrease of 1.2/100 000 inhabitants per year, corresponding with 33% of the observed decline in VF OHCA.
  Circulation 08/2012; 126(7):815-21. · 14.74 Impact Factor
• Article: How much does prior myocardial infarction increase risk of sudden cardiac death in the young?

  Jonas S S G de Jong, Hanno L Tan
  Europace 07/2012; · 1.98 Impact Factor
• Article: Electrophysiologic remodeling of the left ventricle in pressure overload-induced right ventricular failure.

  Maxim Hardziyenka, Maria E Campian, Arie O Verkerk, Sulaiman Surie, Antoni C G van Ginneken, Sara Hakim, André C Linnenbank, H A C M Rianne de Bruin-Bon, Leander Beekman, Mart N van der Plas, Carol A Remme, Toon A B van Veen, Paul Bresser, Jacques M T de Bakker, Hanno L Tan
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  ABSTRACT: The purpose of this study was to analyze the electrophysiologic remodeling of the atrophic left ventricle (LV) in right ventricular (RV) failure (RVF) after RV pressure overload. The LV in pressure-induced RVF develops dysfunction, reduction in mass, and altered gene expression, due to atrophic remodeling. LV atrophy is associated with electrophysiologic remodeling. We conducted epicardial mapping in Langendorff-perfused hearts, patch-clamp studies, gene expression studies, and protein level studies of the LV in rats with pressure-induced RVF (monocrotaline [MCT] injection, n = 25; controls with saline injection, n = 18). We also performed epicardial mapping of the LV in patients with RVF after chronic thromboembolic pulmonary hypertension (CTEPH) (RVF, n = 10; no RVF, n = 16). The LV of rats with MCT-induced RVF exhibited electrophysiologic remodeling: longer action potentials (APs) at 90% repolarization and effective refractory periods (ERPs) (60 ± 1 ms vs. 44 ± 1 ms; p < 0.001), and slower longitudinal conduction velocity (62 ± 2 cm/s vs. 70 ± 1 cm/s; p = 0.003). AP/ERP prolongation agreed with reduced Kcnip2 expression, which encodes the repolarizing potassium channel subunit KChIP2 (0.07 ± 0.01 vs. 0.11 ± 0.02; p < 0.05). Conduction slowing was not explained by impaired impulse formation, as AP maximum upstroke velocity, whole-cell sodium current magnitude/properties, and mRNA levels of Scn5a were unaltered. Instead, impulse transmission in RVF was hampered by reduction in cell length (111.6 ± 0.7 μm vs. 122.0 ± 0.4 μm; p = 0.02) and width (21.9 ± 0.2 μm vs. 25.3 ± 0.3 μm; p = 0.002), and impaired cell-to-cell impulse transmission (24% reduction in Connexin-43 levels). The LV of patients with CTEPH with RVF also exhibited ERP prolongation (306 ± 8 ms vs. 268 ± 5 ms; p = 0.001) and conduction slowing (53 ± 3 cm/s vs. 64 ± 3 cm/s; p = 0.005). Pressure-induced RVF is associated with electrophysiologic remodeling of the atrophic LV.
  Journal of the American College of Cardiology 06/2012; 59(24):2193-202. · 14.16 Impact Factor
• Article: T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells.

  Martijn L Bakker, Gerard J J Boink, Bas J Boukens, Arie O Verkerk, Malou van den Boogaard, A Denise den Haan, Willem M H Hoogaars, Henk P Buermans, Jacques M T de Bakker, Jurgen Seppen, Hanno L Tan, Antoon F M Moorman, Peter A C 't Hoen, Vincent M Christoffels
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  ABSTRACT: Treatment of disorders of the sinus node or the atrioventricular node requires insights into the molecular mechanisms of development and homoeostasis of these pacemaker tissues. In the developing heart, transcription factor TBX3 is required for pacemaker and conduction system development. Here, we explore the role of TBX3 in the adult heart and investigate whether TBX3 is able to reprogramme terminally differentiated working cardiomyocytes into pacemaker cells. TBX3 expression was ectopically induced in cardiomyocytes of adult transgenic mice using tamoxifen. Expression analysis revealed an efficient switch from the working myocardial expression profile to that of the pacemaker myocardium. This included suppression of genes encoding gap junction subunits (Cx40, Cx43), the cardiac Na(+) channel (Na(V)1.5; I(Na)), and inwardly rectifying K(+) ion channels (K(ir) genes; I(K1)). Concordantly, we observed conduction slowing in these hearts and reductions in I(Na) and I(K1) in cardiomyocytes isolated from these hearts. The reduction in I(K1) resulted in a more depolarized maximum diastolic potential, thus enabling spontaneous diastolic depolarization. Neither ectopic pacemaker activity nor pacemaker current I(f) was observed. Lentiviral expression of TBX3 in ventricular cardiomyocytes resulted in conduction slowing and development of heterogeneous phenotypes, including depolarized and spontaneously active cardiomyocytes. TBX3 reprogrammes terminally differentiated working cardiomyocytes and induces important pacemaker properties. The ability of TBX3 to reduce intercellular coupling to overcome current-to-load mismatch and the ability to reduce I(K1) density to enable diastolic depolarization are promising TBX3 characteristics that may facilitate biological pacemaker formation strategies.
  Cardiovascular research 03/2012; 94(3):439-49. · 5.80 Impact Factor
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  Available from: PubMed Central

  Article: SCN5A mutations in Brugada syndrome are associated with increased cardiac dimensions and reduced contractility.

  Frans van Hoorn, Maria E Campian, Anje Spijkerboer, Marieke T Blom, R Nils Planken, Albert C van Rossum, Jacques M T de Bakker, Arthur A M Wilde, Maarten Groenink, Hanno L Tan
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  ABSTRACT: The cardiac sodium channel (Na(v)1.5) controls cardiac excitability. Accordingly, SCN5A mutations that result in loss-of-function of Na(v)1.5 are associated with various inherited arrhythmia syndromes that revolve around reduced cardiac excitability, most notably Brugada syndrome (BrS). Experimental studies have indicated that Na(v)1.5 interacts with the cytoskeleton and may also be involved in maintaining structural integrity of the heart. We aimed to determine whether clinical evidence may be obtained that Na(v)1.5 is involved in maintaining cardiac structural integrity. Using cardiac magnetic resonance (CMR) imaging, we compared right ventricular (RV) and left ventricular (LV) dimensions and ejection fractions between 40 BrS patients with SCN5A mutations (SCN5a-mut-positive) and 98 BrS patients without SCN5A mutations (SCN5a-mut-negative). We also studied 18 age/sex-matched healthy volunteers. SCN5a-mut-positive patients had significantly larger end-diastolic and end-systolic RV and LV volumes, and lower LV ejection fractions, than SCN5a-mut-negative patients or volunteers. Loss-of-function SCN5A mutations are associated with dilatation and impairment in contractile function of both ventricles that can be detected by CMR analysis.
  PLoS ONE 01/2012; 7(8):e42037. · 4.09 Impact Factor
• Article: Epilepsy is a risk factor for sudden cardiac arrest in the general population.

  Abdennasser Bardai, Robert J Lamberts, Marieke T Blom, Anne M Spanjaart, Jocelyn Berdowski, Sebastiaan R van der Staal, Henk J Brouwer, Rudolph W Koster, Josemir W Sander, Roland D Thijs, Hanno L Tan
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  ABSTRACT: People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study. This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1-8.0.], p=0.034). The risk for SCA in epilepsy was particularly increased in young and females. Epilepsy in the general population seems to be associated with an increased risk for SCA.
  PLoS ONE 01/2012; 7(8):e42749. · 4.09 Impact Factor
• Source

  Available from: Esther E Creemers

  Article: Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner.

  Ahmad S Amin, John R Giudicessi, Anke J Tijsen, Anne M Spanjaart, Yolan J Reckman, Christine A Klemens, Michael W Tanck, Jamie D Kapplinger, Nynke Hofman, Moritz F Sinner, Martina Müller, Wino J Wijnen, Hanno L Tan, Connie R Bezzina, Esther E Creemers, Arthur A M Wilde, Michael J Ackerman, Yigal M Pinto
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  ABSTRACT: Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1's 3' untranslated region (3'UTR). This study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1's 3'UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1's 3'UTR with the derived SNP variants was lower than the expression of the 3'UTR with the ancestral SNP variants. Our data indicate that 3'UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.
  European Heart Journal 12/2011; 33(6):714-23. · 10.48 Impact Factor
• Article: Impact of onsite or dispatched automated external defibrillator use on survival after out-of-hospital cardiac arrest.

  Jocelyn Berdowski, Marieke T Blom, Abdennasser Bardai, Hanno L Tan, Jan G P Tijssen, Rudolph W Koster
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  ABSTRACT: There have been few studies on the effectiveness of bystander automated external defibrillator (AED) use in out-of-hospital cardiac arrest. The objective of this study was to determine whether actual use of onsite or dispatched AED reduces the time to first shock compared with no AED use and thereby improves survival. We performed a population-based cohort study of 2833 consecutive patients with a nontraumatic out-of-hospital cardiac arrest before emergency medical system arrival between 2006 and 2009. The primary outcome, neurologically intact survival to discharge, was compared by use of multivariable logistic regression analysis. An onsite AED had been applied in 128 of the 2833 cases, a dispatched AED in 478, and no AED in 2227. Onsite AED use reduced the time to first shock from 11 to 4.1 minute. Neurologically intact survival was 49.6% for patients treated with an onsite AED compared with 14.3% without an AED (unadjusted odds ratio, 5.63; 95% confidence interval, 3.91-8.10). The odds ratio remained statistically significant after adjustment for confounding (odds ratio, 2.72; 95% confidence interval, 1.77-4.18). Dispatched AED use reduced the time from call to first shock to 8.5 minutes. Neurologically intact survival was 17.2% for patients treated with a dispatched AED (unadjusted odds ratio, 1.07; 95% confidence interval, 0.82-1.39). Every year, onsite AEDs saved 3.6 lives per 1 million inhabitants; dispatched AEDs saved 1.2 lives. The use of an onsite AED leads to a doubling of neurologically intact survival. In our system, the survival benefit of dispatched AED use was much smaller than that of onsite AED use.
  Circulation 11/2011; 124(20):2225-32. · 14.74 Impact Factor
• Article: Genetic treatment of heart rhythm disorders--where do we stand?

  Pieter G Postema, Hanno L Tan
  Heart rhythm: the official journal of the Heart Rhythm Society 09/2011; 9(2):273-4. · 4.56 Impact Factor
• Article: Right ventricular pacing improves haemodynamics in right ventricular failure from pressure overload: an open observational proof-of-principle study in patients with chronic thromboembolic pulmonary hypertension.

  Maxim Hardziyenka, Sulaiman Surie, Joris R de Groot, H A C M Rianne de Bruin-Bon, Reinoud E Knops, Maurice Remmelink, Ze-Yie Yong, Jan Baan, Berto J Bouma, Paul Bresser, Hanno L Tan
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  ABSTRACT: Right ventricular (RV) failure in patients with chronic thromboembolic pulmonary hypertension (CTEPH), and other types of pulmonary arterial hypertension is associated with right-to-left ventricle (LV) delay in peak myocardial shortening and, consequently, the onset of diastolic relaxation. We aimed to establish whether RV pacing may resynchronize the onsets of RV and LV diastolic relaxation, and improve haemodynamics. Fourteen CTEPH patients (mean age 63.7 ± 12.0 years, 10 women) with large (≥60 ms) RV-to-LV delay in the onset of diastolic relaxation (DIVD, diastolic interventricular delay) were studied. Temporary RV pacing was performed by atrioventricular (A-V) sequential pacing with incremental shortening of A-V delay to advance RV activation. Effects were assessed using tissue Doppler echocardiography and LV pressure-conductance catheter measurements in a subset of patients. Compared with right atrial pacing, RV pacing at optimal A-V delay (average 140 ± 22 ms, range 120-180 ms) resulted in significant DIVD reduction (59 ± 19 to 3 ± 22 ms, P < 0.001), and increase in LV stroke volume as measured by LV outflow tract velocity-time integral (14.9 ± 2.8 to 16.9 ± 3.0 cm, P < 0.001), along with enhanced global RV contractility and LV diastolic filling. Right-to-left ventricle resynchronization of the onset of diastolic relaxation results in stroke volume increase in CTEPH patients. Whether RV pacing may be a novel therapeutic target in RV failure following chronic pressure overload remains to be investigated.
  Europace 07/2011; 13(12):1753-9. · 1.98 Impact Factor
• Source

  Available from: Pallav Bhatnagar

  Article: Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

  Dan E Arking, M Juhani Junttila, Philippe Goyette, Adriana Huertas-Vazquez, Mark Eijgelsheim, Marieke T Blom, Christopher Newton-Cheh, Kyndaron Reinier, Carmen Teodorescu, Audrey Uy-Evanado, [......], Christopher J O'Donnell, Connie R Bezzina, Renu Virmani, Bruno H C H Stricker, Hanno L Tan, Christine M Albert, Aravinda Chakravarti, John D Rioux, Heikki V Huikuri, Sumeet S Chugh
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  ABSTRACT: Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).
  PLoS Genetics 06/2011; 7(6):e1002158. · 8.69 Impact Factor
• Article: Activated human platelet products induce proarrhythmic effects in ventricular myocytes.

  Jonas S S G de Jong, Arie O Verkerk, Marcel M G J van Borren, Olga M Zakhrabova-Zwiauer, Rienk Nieuwland, Joost C M Meijers, Jan-Willem N Akkerman, Arthur A M Wilde, Hanno L Tan, Lukas R C Dekker
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  ABSTRACT: Sudden cardiac death remains one of the most prevalent modes of death and is mainly caused by ventricular fibrillation (VF) in the setting of acute ischemia resulting from coronary thrombi. Animal experiments have shown that platelet activation may increase susceptibility of ischemic myocardium to VF, but the mechanism is unknown. In the present study, we evaluated the effects of activated blood platelet products (ABPPs) on electrophysiological properties and intracellular Ca(2+) (Ca(2+)(i)) homeostasis. Platelets were collected from healthy volunteers. After activation, their secreted ABPPs were added to superfusion solutions. Rabbit ventricular myocytes were freshly isolated, and membrane potentials and Ca(2+)(i) were recorded using patch-clamp methodology and indo-1 fluorescence measurements, respectively. ABPPs prolonged action potential duration and induced early and delayed afterdepolarizations. ABPPs increased L-type Ca(2+) current (I(Ca,L)) density, but left densities of sodium current, inward rectifier K(+) current, transient outward K(+) current, and rapid component of the delayed rectifier K(+) current unchanged. ABPPs did not affect kinetics or (in)activation properties of membrane currents. ABPPs increased systolic Ca(2+)(i), Ca(2+)(i) transient amplitude, and sarcoplasmic reticulum Ca(2+) content. ABPPs did not affect the Na(+)-Ca(2+) exchange current (I(NCX)) in Ca(2+)-buffered conditions. Products secreted from activated human platelets induce changes in I(Ca,L) and Ca(2+)(i), which result in action potential prolongation and the occurrence of early and delayed afterdepolarizations in rabbit myocytes. These changes may trigger and support reentrant arrhythmias in ischemia models of coronary thrombosis.
  Journal of Molecular and Cellular Cardiology 05/2011; 51(3):347-56. · 5.17 Impact Factor
• Article: Familial Brugada syndrome uncovered by hyperkalaemic diabetic ketoacidosis.

  Pieter G Postema, Alexander P J Vlaar, J Hans DeVries, Hanno L Tan
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  ABSTRACT: We describe a case of diabetic ketoacidosis with concomitant hyperkalaemia that uncovered a typical Brugada syndrome electrocardiogram (ECG). Further provocation testing in the patient and his son confirmed familial Brugada syndrome. Diabetic ketoacidosis with hyperkalaemia may uncover an inheritable arrhythmia syndrome that may put the patient and his/her next of kin at risk for a sudden death, irrespective of diabetes mellitus.
  Europace 05/2011; 13(10):1509-10. · 1.98 Impact Factor
• Source

  Available from: Berthe L van Eck-Smit

  Article: Imaging of programmed cell death in arrhythmogenic right ventricle cardiomyopathy/dysplasia.

  Maria E Campian, Hanno L Tan, Astrid F van Moerkerken, Raymond Tukkie, Berthe L F van Eck-Smit, Hein J Verberne
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  ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a myocardial disease that predominantly affects the right ventricle (RV). Its hallmark feature is fibrofatty replacement of the RV myocardium. Apoptosis in ARVC/D has been proposed as an important process that mediates the slow, ongoing loss of heart muscle cells which is followed by ventricular dysfunction. We aimed to establish whether cardiac apoptosis can be assessed noninvasively in patients with ARVC/D. Six patients fulfilling the ARVC/D criteria were studied. Regional myocardial apoptosis was assessed with (99m)Tc-annexin V scintigraphy. Overall, the RV wall showed a higher (99m)Tc-annexin V signal than the left ventricular wall (p = 0.049) and the interventricular septum (p = 0.026). However, significantly increased uptake of (99m)Tc-annexin V in the RV was present in only three of the six ARVC/D patients (p = 0.001, compared to (99m)Tc-annexin V uptake in the RV wall of the other three patients). Our results are suggestive of a chamber-specific apoptotic process. Although the role of apoptosis in ARVC/D is unsolved, the ability to assess apoptosis noninvasively may aid in the diagnostic course. In addition, the ability to detect apoptosis in vivo with (99m)Tc-annexin V scintigraphy might allow individual monitoring of disease progression and response to diverse treatments aimed at counteracting ARVC/D progression.
  European Journal of Nuclear Medicine 05/2011; 38(8):1500-6. · 4.53 Impact Factor
• Article: Incidence, causes, and outcomes of out-of-hospital cardiac arrest in children. A comprehensive, prospective, population-based study in the Netherlands.

  Abdennasser Bardai, Jocelyn Berdowski, Christian van der Werf, Marieke T Blom, Manon Ceelen, Irene M van Langen, Jan G P Tijssen, Arthur A M Wilde, Rudolph W Koster, Hanno L Tan
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  ABSTRACT: This study sought to determine comprehensively the incidence of pediatric out-of-hospital cardiac arrest (OHCA) and its contribution to total pediatric mortality, the causes of pediatric OHCA, and the outcome of resuscitation of pediatric OHCA patients. There is a paucity of complete studies on incidence, causes, and outcomes of pediatric OHCA. In this prospective, population-based study, OHCA victims younger than age 21 years in 1 province of the Netherlands were registered through both emergency medical services and coroners over a period of 4.3 years. Death certificate data on total pediatric mortality, survival status, and neurological outcome at hospital discharge also were obtained. With a total mortality of 923 during the study period and 233 victims of OHCA (including 221 who died and 12 who survived), OHCA caused 24% (221 of 923) of total pediatric mortality. Natural causes of OHCA amounted to 115 (49%) cases, with cardiac causes being most prevalent (n = 90, 39%). The incidence of pediatric OHCA was 9.0 per 100,000 pediatric person-years (95% confidence interval: 7.8 to 10.3), whereas the incidence of pediatric OHCA from cardiac causes was 3.2 (95% confidence interval: 2.5 to 3.9). Of 51 resuscitated patients, 12 (24%) survived; among survivors, 10 (83%) had a neurologically intact outcome. Out-of-hospital cardiac arrest accounts for a significant proportion of pediatric mortality, and cardiac causes are the most prevalent causes of OHCA. The vast majority of OHCA survivors have a neurologically intact outcome.
  Journal of the American College of Cardiology 05/2011; 57(18):1822-8. · 14.16 Impact Factor