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Out-of-hospital cardiac arrest (OHCA) is a major public health problem that accounts for 50% of all deaths from cardiovascular causes in Western societies. OHCA is usually caused by cardiac arrhythmias (ventricular tachycardia [VT], ventricular fibrillation [VF]). Numerous factors, often interacting, may increase the risk of cardiac arrhythmias ultimately leading to disruptions in cardiac electrophysiology. These factors include co-morbidities (coronary artery disease, congestive heart failure, diabetes mellitus), genetic factors and drug use. A mechanism by which drugs may cause such disruptions is by blocking cardiac ion channels. The observational studies included in this thesis present novel insights into the role of drugs in the occurrence of OHCA. Part 1 of this thesis presents studies aimed to study whether cardiac repolarization blocking drugs increase the risk OHCA. Our findings show that drugs causing QT-prolongation as off-target effect confer higher OHCA risk than drugs that prolong the QT interval by design. Part 2 presents studies aimed to determine whether depolarization blocking (DB) drugs increase the risk of OHCA. Our findings show that use of non-cardiac DB-drugs is associated with increased risk of OHCA compared with no use of any non-cardiac DB-drugs. Part 3 describes a study aimed to determine whether sulfonylurea drugs (SU-drugs) decreases the risk of OHCA. Our findings show that SU-drugs are associated with reduced OHCA risk compared to metformin monotherapy. Lastly, Part 3 presents a study aimed to investigate a possible association of beta-blockers with non-VT/VF during OHCA. Our findings show that non-selective beta-blocker use, but not β1 selective beta-blocker, are associated with non-shockable rhythm in OHCA.

Since men are generally at higher cardiovascular disease (CVD) risk than women, previous research has mainly focussed on men. As a consequence, CVD has been understudied in women, and the causes underlying the differences in CVD risk between men and women are still poorly understood. Additionally, ethnic disparities in CVD risk within populations are well-known, but few studies have investigated whether differences in CVD risk between men and women vary by ethnicity. Thus, the general aim of this thesis was to enhance our understanding of differences in CVD risk between men and women across ethnic groups, and of the sex- and gender-related factors associated with these differences. The studies included in this thesis confirm previous evidence that CVD risk is generally lower in women than in men. However, depending on the type of CVD, the female advantage was relatively small in some ethnic minority groups. Therefore, women from ethnic minority groups, specifically women of South-Asian Surinamese and Turkish origin, may pose an important target group for additional prevention strategies. In addition, our findings indicate that (sociocultural) gender characteristics are relevant for cardiovascular health, mainly in women. Female homemakers may particularly form an additional target group due to their increased risk of CVD. If our findings are confirmed in future research, gender characteristics, specifically related to division of paid and unpaid labour, may pose valuable additional factors for the identification of CVD risk groups, especially for women.

Binnen Europa zijn er grote verschillen in overlevingskansen na een hartstilstand buiten het ziekenhuis. Om een snellere start van de reanimatie en defibrillatie met een AED te bereiken, zijn First Responder (FR) systemen geïntroduceerd in Europa. Zo’n systeem stuurt FRs (politie, brandweer of burgerhulpverleners), via de meldkamer, uit voor een mogelijke reanimatie. Momenteel heeft meer dan 50% van de Europese landen een FR systeem. De aan- of afwezigheid van een FR systeem kan bijdragen aan de verschillen in overlevingskansen tussen verschillende gebieden in Europa. In Europese regio’s met een FR systeem bestaat een hogere kans op terugkeer van de bloedsomloop en overleving als dit wordt vergeleken met Europese regio’s zonder een FR systeem. Naast het hebben van een FR systeem, kunnen bepaalde patiëntkarakteristieken bijdragen aan de overlevingskans na een hartstilstand buiten het ziekenhuis. Zo hebben vrouwen minder kans om gereanimeerd te worden door burgerhulpverleners en een hartstilstand te overleven. Het lagere overlevingspercentage bij vrouwen is grotendeels toe te schrijven aan het feit dat vrouwen ongeveer de helft minder kans hebben op een schokbaar beginritme in vergelijking met mannen. Ook hebben patiënten met veel bijkomende ziekten (comorbiditeiten) een lagere kans om een hartstilstand buiten het ziekenhuis te overleven. De relatieve bijdrage van comorbiditeiten op de overlevingskans van een hartstilstand buiten het ziekenhuis is echter laag. Reanimatiefactoren spelen een veel grotere rol op de overleving. In dit proefschrift zijn de verschillen in FR systemen in verschillende gebieden in Europa en de invloed van bepaalde patiënten karakteristieken (man-vrouw verschil en cumulatieve comorbiditeit) op het overleven van een hartstilstand buiten het ziekenhuis onderzocht.

Cardiac sodium channelopathies, such as long QT syndrome type3 (LQT3), Brugada syndrome (BrS) and cardiac conduction disease (CCD), are heritable diseases associated with mutations in the SCN5A gene and sudden cardiac death. They were classically thought to be a monogenic disease. However, while LQT3 has a strong monogenic component, the genetic architecture of others has recently been questioned. Familial studies in BrS have shown that not all family members carrying the familial mutation develop symptoms. Among mutation carriers, a few develop fatal arrhythmia whereas many develop only ECG abnormalities typical of BrS without major arrhythmic events. Interestingly, certain SCN5A mutations even develop phenotypic overlap of LQT3, BrS and CCD that are attributed to two different mechanisms (i.e. increased sodium current in LQT3 and decreased sodium current in BrS and CCD). Such varied genotype-phenotype relationships in sodium channelopathies indicate their complex mechanism. While environmental factors such as gender have been shown to modify phenotypes in sodium channelopathies, genetic factors may also contribute to phenotypic variability. Recently, genome-wide association studies have uncovered multiple genetic loci that modulate electrocardiographic parameters, which represent intermediate phenotypes in search of genetic factors that impact on rhythm abnormalities. This indicates that common genetic variants may play a role in diseases with complex genetic architecture such as BrS. Therefore, in this thesis, we aimed at dissecting genetic and environmental modifiers of sodium channelopathies. Part I focuses on sodium channelopathies, in particular, genetic modifiers of overlap sodium channelopathy. Part II focuses on genetic and environmental factors in BrS.

Sudden cardiac death (SCD) is a major health problem and accounts for a substantial part of all natural deaths in the Western world. Ventricular arrhythmias, of which ventricular fibrillation (VF) is the most common, underlie most of SCDs in the general population. Therefore, understanding, predicting and preventing VF seems to be the most successful solution to reduce SCD incidence. This thesis focused mainly on ECG-documented potentially lethal ventricular arrhythmias and aimed to distillate their clinical, electrocardiographic and genetic determinants.