J. R. de Groot

The Risk of Sensibilization and Contact Urticaria upon Topical Application of Fumaric Acid Derivatives

Systemic and sometimes topical therapy with fumaric acid (FA) and its derivatives is used in the treatment of psoriasis. Scattered data show that the topical application of these derivatives elicits side effects. Application of FA and some derivatives on the skin was accompanied by perilesional skin irritation, macular papular rashes and urticarial reactions. In order to determine the irritating and sensitizing properties of FA derivatives we used a cytotoxicity, flank irritation, ear swelling and guinea pig maximization test. The results of the cytotoxicity test demonstrated that dimethylfumarate (DMF) was the most toxic derivative. DMF induced also contact-urticarial reactions in contrast to mono-ethylfumarate (MEF). Challenge experiments with FA, MEF and DMF in MEF- and DMF-sensitized guinea pigs demonstrated that both MEF and DMF are moderate contact sensitizers. In DMF-sensitized animals cross-reactions with MEF were found. As DMF and MEF have cytotoxic, contact-urticarial and/or sensitizing properties, topical application should be avoided.

Postoperative arrhythmias in adults with congenital heart disease: Incidence and risk factors

BACKGROUND Little is known about the clinical impact of arrhythmias after surgery for congenital heart disease (CHD) in adults. Therefore, we investigated the prevalence of in-hospital arrhythmias after CHD surgery and their impact on clinical outcome. METHODS This was a multicenter retrospective study and included adults who underwent congenital cardiac surgery between January 2009 and December 2011. Clinical events were defined as all cause mortality, heart failure (HF) requiring medical treatment, thrombo-embolic event, major infections and permanent pacemaker (PM) implantation. RESULTS Overall, 419 patients were included (mean age 38 ± 14 years, 55% male). Arrhythmias occurred in 134 patients (32%) and included supraventricular tachycardia (SVT, n = 100), bradycardias (n = 47) and ventricular tachycardia (VT, n = 19). In multivariate analysis age ≥40 years at surgery (OR 2.48, 95% Cl 1.40-4.60, P = 0.003), NYHA class ≥ II (OR 2.42, 95% Cl 1.18-4.67, P = 0.009), significant subpulmonary AV-valve regurgitation (OR 2.84, 95% Cl 1.19-6.72, P = 0.018), coronary bypass time (OR 1.35/60 minute increase, 95% Cl 1.06-1.82, P = 0.019) and CK-MB (OR 1.05 per 10 U/L increase, 95% Cl 1.01-1.09, P = 0.021) were associated with in-hospital arrhythmias. Overall, 58 clinical events occurred in 55 patients (13%) and included in the majority of the cases permanent PM implantation (5%), HF (4%) and death (2%). In-hospital arrhythmias were independently associated with clinical events (OR 7.80, 95% CI 2.41-25.54, P = 0.001). CONCLUSION Arrhythmias are highly prevalent after congenital heart surgery in adults and are associated with worse clinical outcome. Older and symptomatic patients with significant valvular heart disease at baseline are at risk of in-hospital arrhythmias.

Aldosterone Pathway Blockade to Prevent Atrial Fibrillation: A Systematic Review and Meta-Analysis

BACKGROUND Despite advances in therapeutic interventions AF remains a progressive and symptomatic disease. Therefore, novel therapeutic interventions targeting the underlying arrhythmogenic substrate for AF is needed. Atrial fibrosis is an important component of the arrhythmogenic substrate of AF and may be initiated by aldosterone binding to the mineralocorticoid receptor. We hypothesized that aldosterone pathway blockade with mineralocorticoid receptor antagonists (MRA) reduces atrial fibrosis, and thus AF. METHODS We searched OVID MEDLINE, OVID EMBASE and the Cochrane Central Register of Controlled Trials from inception to June 10th, 2016 for randomized controlled trials (RCT) and observational studies addressing MRA and providing information on AF occurrence. Two independent reviewers selected and appraised the data. We performed random-effects meta-analyses. Summary odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS We included 14 studies, 5 RCT and 9 observational cohorts, with a cumulative number of 5332 patients (male: 74.9%, age: 65.3years); 2397 (45.0%) received an MRA (spironolactone or eplerenone). During follow-up, 204 (8.5%) patients treated with MRAs, developed AF, compared to 547 (18.6%) patients, without MRA treatment. Meta-analyses showed a significant overall reduction of AF risk in MRA treated patients (OR: 0.48 CI: 0.38-0.60 p<0.001), including a reduction of new-onset AF (OR: 0.52 CI: 0.37-0.74 p<0.001) and recurrent AF (OR: 0.37 CI: 0.24-0.57 p<0.001), but not post-operative AF (POAF) (OR: 0.60 CI: 0.33-1.09 p=0.09). CONCLUSIONS MRAs significantly reduce new-onset AF and recurrent AF, but not POAF. MRA treatment can be considered an additive therapeutic strategy in AF.

Weighing the risks: Thrombotic and bleeding events in adults with atrial arrhythmias and congenital heart disease

INTRODUCTION Atrial arrhythmias are associated to thromboembolism and anticoagulant treatment is installed according to risk profile. This study aimed to assess the rate of thrombotic events and major bleedings in adults with congenital heart disease (CHD) and atrial arrhythmias, as well as to determine the predictive value of specific clinical features and two risk scores for thromboembolism and bleeding. METHODS AND RESULTS In this retrospective study, a total of 229 adult CHD patients with atrial arrhythmias, were included. Incidence and risk factors of thromboembolism were assessed in patients without a mechanical valve (n = 191), whereas bleeding incidence and risk factors were studied in patients receiving vitamin K antagonists (n = 164). In 13 patients without a mechanical valve thrombotic events occurred, the first thrombotic event rate per year being 1.4%. A total of 29 patients on vitamin K antagonists suffered from major bleedings, at an annual first event rate of 4.4%. CHA2DS2-VASc score and HAS-BLED score predicted thromboembolic and bleeding risk best in a dichotomized form. At a cut-off of ≥ 2 for high risk the rate of thrombotic events was 3.0% per year compared to 0.7% for a score of <2 (HR 3.7; 95%-CI 1.2-11.5; p = 0.021). A major bleeding rate of 10.8% per year was found in patients on vitamin K antagonists for HAS-BLED ≥ 2 as opposed to 3.5% with a score of <2 (HR 2.6; 95%-CI: 1.1-6.6; 0.017). CONCLUSION In adult CHD patients, thrombotic events and major bleedings are important complications of atrial arrhythmias and anticoagulant treatment. Assessment of thromboembolic and bleeding risk in this patients group can be performed with dichotomized CHA2DS2-VASc and HAS-BLED scores respectively.

Impact of atrial arrhythmias on outcome in adults with congenital heart disease

BACKGROUND Adults with congenital heart disease (ACHD) are affected by atrial arrhythmias (AA). To elucidate the impact of AA on prognosis, we aimed to determine the impact of AA on death, heart failure and stroke in ACHD patients in a prospective nationwide clinical registry. METHODS All patients aged ≥18years included in the CONCOR registry per October 1st 2015 were analysed. Prior AA was defined as atrial fibrillation, atrial flutter or unspecified AA before inclusion in CONCOR and new-onset AA as a first documented AA during follow-up. The outcomes were death, first stroke and first admission for heart failure (HF). RESULTS The study cohort comprised 14,224 patients (baseline median age 33.6 [IQR 23-47], male 49.5%, AA n=1501, complex defect 10.3%, repaired defect 58.9%). Median follow-up was 6.5years [IQR 3-10]. Adjusting for age, sex, repair status and defect severity, patients with prior AA had higher mortality and more HF admissions, but no increased risk of stroke compared to those without AA (HR=2.11; 95% CI=1.79-2.49; p<0.001, HR=4.06; 95% CI=2.66-6.19; p<0.001 and HR=1.09; 95% CI=0.71-1.68; p=0.698, respectively). New-onset AA during follow-up was significantly associated with stroke (HR=2.04; 95% CI=1.05-3.96; p=0.036). CONCLUSIONS ACHD patients with prior AA have a 2-fold increased risk of death and a 4-fold increased risk of heart failure, but no increased risk for stroke compared to those without AA. Defect severity and age appear to be more important risk factors for stroke than prior AA. Stroke risk is increased only after conversion of new onset AA.

Oral anticoagulant therapy in adults with congenital heart disease and atrial arrhythmias: Implementation of guidelines

BACKGROUND Current guidelines on oral anticoagulation (OAC) in adults with congenital heart disease (ACHD) and atrial arrhythmias (AA) consist of heterogeneous and divergent recommendations with limited level of evidence, possibly leading to diverse OAC management and different outcomes. Therefore, we aimed to evaluate real-world implementation and outcome of three guidelines on OAC management in ACHD patients with AA. METHODS The ESC GUCH 2010, PACES/HRS 2014 and ESC atrial fibrillation (AF) 2016 guidelines were assessed for implementation. ACHD patients with recurrent or sustained non-valvular AA from 5 tertiary centers were identified using a national ACHD registry. After two years of prospective follow-up, thromboembolism, major bleeding and death were assessed. RESULTS In total, 225 adults (mean age 54±15years, 55% male) with various defects (simple 43%; moderate 37%; complex 20%) and AA were included. Following the most strict indication (OAC is recommended in all three guidelines), one should treat a mere 37% of ACHD patients with AA, whereas following the least strict indication (OAC is recommended in any one of the three guidelines), one should treat 98% of patients. The various guidelines were implemented in 54-80% of patients. From all recommendations, Fontan circulation, CHA2DS2-VASc≥1 and AF were independently associated with OAC prescription. Superiority of any guideline in identifying outcome (n=15) could not be demonstrated. CONCLUSIONS The implementation of current guidelines on OAC management in ACHD patients with AA is low, probably due to substantial heterogeneity among guidelines. OAC prescription in daily practice was most consistent in patients with AF and CHA2DS2-VASc≥1 or Fontan circulation.

Myocardial infarction, atrial fibrillation and mortality: timing is everything

In this issue of the Netherlands Heart Journal, Gal et al. provide an analysis of patients included in the On-TIME II study, in which patients undergoing primary percutaneous coronary intervention for ST-elevation MI (STEMI) were randomly assigned to tirofiban or placebo treatment on top of usual medical treatment [7, 8]. The authors confirm the relation between AF and mortality in this setting and report the 30-day mortality in 830 patients without a previous history of AF, stratified by the moment of AF onset: (1) AF occurrence on the day of admission for MI, during which participants were continuously monitored; (2) AF between 24 and 72 h after admission, with continuous monitoring for another 24 h (24–48 h) and a single electrocardiogram (ECG) the following day (48–72 h) and (3) AF > 72 h after admission, when ECGs were performed daily or whenever symptoms occurred. During follow-up, AF was detected in 41 patients on the day of admission, in 14 in the subsequent 48 h and in 18 in the last 27 days. This decreasing prevalence of AF may partially reflect the lower amount of AF monitoring. The incident of new-onset AF was significantly associated with 30-day mortality when AF occurred on the day of admission. Three patients (7.3 %) died in the AF group, versus 17 in the non-AF group (2.2 %, p = 0.036). When AF occurred between 24–72 h after admission, mortality was 14.3 and 1.4 % in the AF group and non-AF group, respectively (p < 0.001). There was no association between AF and mortality when AF was diagnosed > 72h after admission, as no deaths were seen in the new-onset AF patients, but > 1 % of the patients without AF died. The suggestion presented by Gal et al. that earlybut not late-onset AF after MI is associated with increased mortality is interesting. However, the higher mortality in patients with AF < 72 h after admission cannot exclusively be ascribed to the timing of AF onset. First, a daily ECG is clearly less sensitive than continuous rhythm monitoring during the first New-onset atrial fibrillation (AF) occurs commonly following myocardial infarction (MI) with an incidence ranging from 5 to 23 %. Unlike other complications of MI, such as cardiac failure or ventricular arrhythmias, it has long been underappreciated as a cause of adverse outcome [1, 2]. Indeed, several studies demonstrated an independent risk of AF on mortality, whereas others showed no significant independent effect, which may suggest that the simultaneous onset of AF and MI merely reflects the severity of the underlying disease. Interestingly, there are also reports of a beneficial effect of AF following MI on outcome [3–5]. Meta-analyses nevertheless consistently show that both preexisting AF and new-onset AF following MI independently increase the risk of mortality by 40–50 %, but controversy remains whether this altered risk relates to the pre-existence and type of AF, MI presentation or performed intervention [1, 6]. In 2011, a meta-analysis including 43 studies of in total 278,854 patients demonstrated a 46 % excess in mortality in patients with AF after acute MI. A subgroup analysis of nine studies that explicitly defined the new onset of AF showed similar results with an odds ratio (OR) of 1.37 (95 % confidence interval: 1.26–1.49) for mortality [5]. In 2012, a second meta-analysis even reported an OR of 3.38 for patients with new-onset AF. Here, the risk of death was 87 % higher for patients with new-onset AF compared with those with (possible) pre-existing AF, suggesting that the risk of mortality depends on the timing of AF onset.[1]

Do elderly patients benefit from implantable-cardioverter defibrillators?

Sudden cardiac death resulting from lethal ventricular arrhyth-mias forms a major cause of mortality. The implantable cardioverter defibrillator (ICD) has been shown to reduce mortality in patients who survived cardiac arrest, who experienced a previous myocardial infarction and have a diminished left ventricular ejection fraction (LVEF), or who have a dilated cardiomyopathy and an LVEF. This has been demonstrated and verified in several randomised trials, and has subsequently entered the guidelines (1). Consequently, the implantation rate of ICDs has increased exponentially worldwide over the last decade. A case can be made that this conveys an enormous success of medical technology to improve quality and quantity of life. Indeed, it was recently reported that there were fewer cases of ventricular fibrillation encountered during out-of-hospital cardiac arrest between 2005–2008, compared with the time frame 1995–1997, which could be explained in part (33 %) by the increased number of ICD carriers among subjects vulnerable for sudden death.(2) However, ICDs only protect against ventricular arrhythmia-induced cardiac arrest, and the question arises whether some ICD candidates may not have too many life-threatening comorbid conditions to have the chance to experience gain in life expectancy from ICD implantation. Therefore, Goldenberg et al. performed a post hoc analysis of the MADIT 2 trial, and proposed a simple and easily applicable clinical model of five risk factors associated with the usefulness of ICD therapy.(3;4) They showed that a risk score model including: 1) age above 70 years, 2) renal insuf-ficiency (defined as blood urea nitrogen >26 mg/dl), 3) atrial fibrillation, 4) NYHA class >2 and 5) a QRS complex >120 msec on the ECG was able to predict clinical benefit of ICD implantation. In their analysis, ICD implantation was futile in patients with none of these risk factors, as no events urging ICD therapy occurred. The curve of ICD benefit was U shaped, however, and on its right side were patients with 3 or more risk factors. These patients had no benefit from ICD therapy, because they died from other than arrhythmic causes such as advanced heart failure. Hence, optimal benefit from the ICD was gained in the patient group with more than 0 but less than 3 risk factors. It is suggested that within the population of patients conforming to the inclusion criteria of the randomised ICD trials, or conforming to the guidelines, patient selection may potentially be further optimised to select those patients who will really …

A wider scope on the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common chronic arrhythmia, and its incidence and prevalence are expected to double within the forthcoming decades [1–3]. Currently, approximately 250,000 patients have AF in the Netherlands, corresponding to a prevalence of 5.5% in patients older than 55 years [4]. The vast majority of those patients can effectively be treated with pharmacological rate or rhythm control. However, there is a small subset of patients that remains severely symptomatic despite treatment with class 1 or 3 antiarrhythmic drugs. For those patients, an invasive approach can be indicated [5, 6]. Historically, this means either a classic Cox-Maze 3 operation or a catheter isolation of the pulmonary veins. The Maze operation, although associated with impressive success rates in some centres, has been abandoned as standalone procedure because of its surgical complexity and the requirement of cardiopulmonary bypass. Catheter ablation for atrial fibrillation is less invasive and is being performed by an increasing number of operators and centres. The procedure has a lower efficacy, particularly in patients with persistent AF or an enlarged left atrium. Moreover, patients are frequently not free of AF after a single procedure, and more than one procedure might therefore be required. In a recent meta analysis, the single procedure success of catheter ablation for AF was 57%, which rose to 71% after multiple procedures in selected patients [7]. The 5-year freedom of AF rates from Bordeaux, one of the most esteemed AF ablation centres in the world, were 29% after a single procedure (40% after one year), which increased to 63% after up to 7 procedures [8]. The volume of the number of catheter ablations for AF in comparison with the number of patients with AF is limited: approximately 2200 catheter ablations for AF were performed in the Netherlands in 2010 (exact data from two centres missing, S.A.I.P. Trines, personal communication), accounting for less than 1% of the number of patients with AF [4]. Bearing this in mind, a thoracoscopic surgical approach toward pulmonary vein isolation was developed in an effort to combine the efficacy reported with surgical ablation with a less invasive approach. There are several small studies showing the feasibility and safety of thoracoscopic pulmonary vein isolation, and a recent systematic review demonstrates that absence of AF recurrence (without the use of antiarrhythmic drugs) is 79% in paroxysmal AF and 69% in persistent AF after a single procedure in the studies published so far [9]. The number of patients and the number of studies are low, but there also seems to be a tendency toward better outcomes when the procedures are performed in a hybrid fashion, that is, by a surgeon and electrophysiologist together. Data from Maastricht and from our own hospital show that in a mixed population of patients with paroxysmal and persistent AF 83 and 86%, respectively, are free of AF without the use of antiarrhythmic drugs one year after the procedure [9–11]. This suggests that a hybrid procedure, where the ablation lines are controlled for conduction block during the procedure, is associated with less AF recurrence. Thoracoscopic or minimal invasive surgery for AF has not been established in the Guidelines as a ‘reasonable alternative’ for either antiarrhythmic drugs or catheter ablation, which might be due to the limited availability of published evidence. The most recent European Society of Cardiology (ESC) Guidelines for AF award a 2B recommendation for standalone minimally invasive surgery for AF only for patients with a previously failed catheter ablation [5]. The 2007 Heart J. R. de Groot (*) Heart Center, Department of Cardiology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands e-mail: j.r.degroot@amc.uva.nl Neth Heart J (2012) 20:143–145 DOI 10.1007/s12471-012-0266-x

Do we understand the rationale behind driving restrictions in patients with an implantable cardioverter defibrillator

Patients with an implantable cardioverter defibrillator (ICD) have restrictions with regards to driving a motor vehicle. The Dutch Health Counsel initially recommended a 6month driving restriction after ICD implantation for primary or secondary prevention of sudden cardiac death [1]. This was reduced to a 2-month restriction in 2004 [2], and recently even further in patients with a primary ICD indication to 2 weeks [3]. Driving restrictions in ICD patients are essentially based on two studies published in the late 1990s. A survey by Curtis et al. found that 30 (10.5%) of 286 ICD shocks during driving resulted in accidents. However, the estimated injury and fatality rate for ICD patients was significantly lower than in the general population [4]. Jung et al. estimated the risk of harm (RH) to other road users or innocent bystanders posed by a driver implanted with an ICD, using the RH formula created by The Canadian Cardiovascular Society Consensus Conference [5, 6]. With the estimated annual risk of sudden cardiac death or incapacitation (SCI) as most important factor influencing this formula, the annual RH rate remained below the set cutoff value of 0.0005% in private ICD drivers but rose above the cutoff value in commercial drivers with an ICD. Subsequently, several risk of harm estimations have been published to establish evidence-based driving restrictions after ICD implantation or ICD shocks while driving [7]. This has led to a worldwide difference in driving restrictions in ICD patients [8]. As there is a lack of data regarding syncope symptoms in ICD patients while driving, the overall syncope rate in ICD patients has been used instead in most studies and RH calculations [8]. Also, recommendations are mostly based on older reports in a population of ICD patients with heart failure and coronary artery disease. As there are