Hypertrophic cardiomyopathy is a heart disease that is characterized by an enlarged heart muscle. Mutations to sarcomere proteins in the muscle fibers give rise to the disease, and this review aims to compile the mechanisms by which the mutations cause the disease phenotype. β-myosin heavy chain mutants affect the thick filament structure and contraction velocity of the muscle. Mutations to the myosin-binding protein C produces truncated proteins with decreased expression in the cells. Troponin T mutants cause myofibrillar disarray, alters affinity to α-tropomyosin, and are linked to a higher risk of sudden death. Troponin I is an unpredictable mutant that needs to be further researched but is thought to cause regulatory problems. Mutations to α-tropomyosin and the regulatory myosin light chain both affect the Ca2+-affinity of the proteins and leads to contractile problems. Hypercontractility as a result of the mutations seems to be the primary cause of the disease. Hypertrophic cardiomyopathy is linked to sudden death, and factors such as a family history of sudden death, multiple simultaneous mutations, unexplained syncope, non-sustained ventricular tachycardia, abnormal blood pressure response and extreme hypertrophy (>30 mm) heightens the risk of a sudden death. An increased knowledge about the disease will aid in the mission to better the treatments for the affected, but further investigation of pathological pathways needs to be performed.

Профилактика внезапной сердечной смерти спорте является актуальной задачей, решение которой способно значительно улучшить показатели продолжительности и качества жизни спортсменов. Проблема состоит в отсутствии рекомендаций по планированию тренировочного процесса и профилактике возникновения угрожающих жизни состояний при занятиях спортом у лиц с синдромом дисплазии соединительно ткани. Цель исследования – повышение адаптивных возможностей организма и профилактику осложнений у молодых спортсменов с дисплазией соединительной ткани. В соответствии с целью была выдвинута гипотеза, что рациональное дозирование физических нагрузок в ходе тренировочного процесса, с учетом индивидуальных особенностей организма, у молодых спортсменов с синдромом дисплазии соединительной ткани позволит улучшить адаптацию к физическим нагрузкам, а также снизить риск развития осложнений дисплазии соединительной ткани, в том числе внезапной сердечной смерти. / Prevention of sudden cardiac death in sports is an urgent problem of the modern society. It is critically important to improve life expectancies and quality of life of competitive athletes. The main issue is the absence of recommendations for exercise prescription and training schedule in terms of connective tissue dysplasia syndrome. The purpose of the study was to increase the adaptation abilities of an organism and prevention of possible health complications in young athletes with connective tissue dysplasia. It was hypothesized that rational physical loads dozing in accordance to individual capacity of these individuals will result in better adaptation to exercise loads and decrease of the possible risks, including sudden cardiac death.

Thesis (PhD)-- Stellenbosch University, 2014. / ENGLISH ABSTRACT: Ventricular arrhythmias are the most important cause of sudden cardiac death (SCD) among adults living in industrialised nations. Genetic factors have substantial effects in determining population-based risk for SCD and may also account for inter-individual variability in susceptibility. Great progress has been made in identifying genes underlying various Mendelian disorders associated with inherited arrhythmia susceptibility. The most well studied familial arrhythmia syndrome is the congenital long QT syndrome (LQTS) caused by mutations in genes encoding subunits of myocardial ion channels. Not all mutation carriers have equal risk for experiencing the clinical manifestations of disease (i.e. syncope, sudden death). This observation has raised the possibility that additional genetic factors may modify the risk of LQTS manifestations. This study establishes the genetic aetiology of LQTS in South Africa and Denmark through the identification and characterisation of LQTS-causative mutations in five previously identified genes, as well as examining possible novel genetic causes of LQTS in a cohort comprising Danish and British probands. We have functionally characterised several of the mutations identified in this study and examined other cardiac phenotypes that may be explained by variants causing repolarisation disorders. / AFRIKAANSE OPSOMMING: Ventrikulêre aritmie bly die enkele belangrikste oorsaak van skielike hart dood (SCD) onder volwassenes wat in geïndustrialiseerde lande woon. Genetiese faktore het aansienlike gevolge in die bepaling van bevolking-gebaseerde risiko vir SCD en kan ook verantwoordelik wees vir die inter-individuele variasie in vatbaarheid. Groot vordering is gemaak in die identifisering van gene onderliggende verskeie Mendeliese siektes wat verband hou met geërf aritmie vatbaarheid. Die mees goed bestudeerde familie aritmie sindroom is die aangebore lang QT-sindroom (LQTS) wat veroorsaak word deur mutasies in gene kode subeenhede van miokardiale ioonkanale. Nie alle mutasie draers het 'n gelyke risiko vir die ervaring van die kliniese manifestasies van die siekte (dws sinkopee, skielike dood). Hierdie waarneming het die moontlikheid genoem dat genetiese faktore anders as die primêre siekte-verwante mutasie kan die risiko van LQTS manifestasies verander. Hierdie studie stel die genetiese oorsake van LQTS in Suid-Afrika en Denemarke deur die identifisering en karakterisering van LQTS-veroorsakende mutasies in vyf voorheen geïdentifiseer gene, asook die behandeling van moontlike nuwe genetiese oorsake van LQTS in 'n groep wat bestaan uit van die Deense en die Britse probands. Ons het funksioneel gekenmerk verskeie van die mutasies wat in hierdie studie ondersoek en ander kardiovaskulêre fenotipes wat deur variante veroorsaak repolarisasie versteurings verduidelik word. / South African National Research Foundation / Harry and Doris Crossley Foundation / Danish Strategic Research Foundation.

Le diabète de type 2 (DT2) est devenu de plus en plus une maladie métabolique chronique fréquente, associée à de nombreuses complications micro et macro-vasculaires. Les patients diabétiques ont environ deux fois plus de risque de mort subite d'origine cardiaque (MSC) que ceux normaux. Les interventions pharmacologiques (anti-plaquettaires, anti-hypertenseurs, anti-diabétiques et hypolépimiants) nous semblent les candidats les plus efficaces, accessibles et économiques pour prévenir cet événement à long terme, par contre leurs effets sur la MSC n'ont pas été bien connus. Nous visons à estimer leur impact sur la santé publique et à optimiser leur utilisation chez les DT2, grâce à des études d'analyse, de synthèse et de modélisation.Ce travail inclut trois étapes: premièrement, de construire un score de risque permettant de prédire le risque de MSC dans le DT2 en utilisant les bases de données INDANA. Deuxièmement, d'effectuer des méta-analyses/revues systématiques de différentes stratégies thérapeutiques afin d'estimer leurs effets sur le risque de MSC. Enfin, de simuler différentes stratégies sur une population virtuelle réaliste (PVR) des diabétiques français et d'intégrés les résultats obtenus sur cette plate-forme pour estimer le risque de MSC avec et sans traitements. Cette simulation permet d'estimer leurs bénéfices absolus, par le nombre d'événements prévus (Number of Events Prevented, NEP) et le nombre de patients à traiter pour prévenir une MSC (Number Needed to Treat, NNT). Nous avons construit un score incluant 7 facteurs de risque de MSC chez les patients atteints d'hypertension artérielle (+/- diabète) et collecté les meilleures estimations sur l'effet des médicaments. Notre simulation sur la PVR générée a suggéré que chez 10% des patients ayant le risque de MSC prédit le plus haut, la co-prescription de l'inhibiteurs de l'enzyme de conversion-l'aspirine-l'empagliflozine permettait de prévenir une MSC sur 57 individus traités dans les 5 ans. Le chiffre correspondant pour toute la PVR était 135. Nous concluons que cette approche pourrait aider à mieux transposer les résultats des essais cliniques à la pratique ; et à faciliter la décision clinique aux niveaux populationnel et individuel / Type 2 diabetes (T2D) has increasingly become a common metabolic condition, associated with numerous micro and macro-vascular complications. Diabetic patients are at about two-time higher risk of sudden cardiac death (SCD), compared to non-diabetic ones. Pharmacologic intervention (anti-platelet, anti-hypertensive, lipid lowering, and to a lesser extent, anti-diabetic agents) appear to be the most efficient and economic candidate to prevent this event at long term, yet treatment effects have not well addressed. We aimed to optimize their use and estimate their impact on public health via analysis, synthesis and modeling studies.This work engaged three phases: First, to construct a risk score to predict SCD risk in T2D from the INDANA database. Second, to perform the meta-analyses/systematic reviews of different therapeutic strategies in order to estimate their effects on SCD risk. Finally, to simulate therapeutic strategies on a generated French diabetic realistic virtual population (RVP) of T2D, by estimating the occurrence of SCD with and without treatments, thus their absolute benefits, through the Number of Events Prevented (NEP) due to treatment, and the Number of patients Needed to be Treated to prevent one SCD (NNT).We built a 7-risk factor to predict 5-year risk of SCD in patients with hypertension (+/-diabetes) and collected the best evidence on drugs’ effects. Integrating and simulating altogether on a generated French diabetic RVP suggested that for every 57 individuals of the 10% highest predicted SCD risk, the co-prescription of angiotensin converting enzyme inhibitor-aspirin-empagliflozin could prevent one SCD in 5 years. For the whole population, the corresponding number was 135. In perspectives, this approach could help better transposing clinical trial results into practice and facilitating clinical decision at both public health and individual levels

The aim was to investigate associations of fitness and types and levels of physical activity with subsequent risk of cardiovascular disease. Four large-scale longitudinal cohort studies were used. The exposures were different measures related to physical activity and the outcomes were obtained through linkage to the Swedish In-Patient Register. In a cohort of 466 elderly men without pre-existing cardiovascular disease, we found that skeletal muscle morphology was associated with risk of cardiovascular events. A high amount of type I (slow-twitch, oxidative) skeletal muscle fibres was associated with lower risk of cardiovascular events and high amount of type IIx was associated with higher risk of cardiovascular events. This association was only seen among physically active men. Among 39,805 participants in a fundraising event, higher levels of both total and leisure time physical activity were associated with lower risk of heart failure. The associations were strongest for leisure time physical activity. In a cohort of 53,755 participants in the 90 km skiing event Vasaloppet, a higher number of completed races was associated with higher risk of atrial fibrillation and a higher risk of bradyarrhythmias. Further, better relative performance was associated with a higher risk of bradyarrhythmias. Among 1,26 million Swedish 18-year-old men, exercise capacity and muscle strength were independently associated with lower risk of vascular disease. The associations were seen across a range of major vascular disease events (ischemic heart disease, heart failure, stroke and cardiovascular death). Further, high exercise capacity was associated with higher risk of atrial fibrillation and a U-shaped association with bradyarrhythmias was found. Higher muscle strength was associated with lower risk of bradyarrhythmias and lower risk of ventricular arrhythmias. These findings suggest a higher rate of atrial fibrillation with higher levels of physical activity. The higher risk of atrial fibrillation does not appear to lead to a higher risk of stroke. In contrast, we found a strong inverse association of higher exercise capacity and muscle strength with vascular disease. Further, high exercise capacity and muscle strength are related to lower risk of cardiovascular death, including arrhythmia deaths. From a population perspective, the total impact of physical activity on cardiovascular disease is positive.

No description available.

Abstract Sudden cardiac death (SCD) is a major medical and public health concern responsible for 50% of cardiovascular deaths and as much as 15% to 20% of overall mortality. Coronary heart disease is the underlying cause of most of these deaths, and in 50% of such cases, SCD is the first manifestation of the disease. Researchers have investigated numerous noninvasive methods to more accurately identify individuals at high risk of SCD, but most such studies have focused on patients with specific heart disease. The standard 12-lead electrocardiogram (ECG) is a widely available tool to analyze the electrical activity of the heart, but few epidemiological studies have successfully identified specific electrocardiographic risk markers of SCD at the population level. This thesis aims to clarify the prognostic implications of several ECG patterns in the general population. We evaluated the 12-lead ECGs of 10899 middle-aged Finnish subjects (52% male) recorded between 1966 and 1972, and followed the subjects for 30 ±  11 years. The prevalence of a prolonged QRS duration ≥ 110 ms and nonspecific intraventricular conduction delay (IVCD; defined as QRS ≥ 110 ms with no partial or complete bundle branch block) in the population was 1.3% and 0.6%, respectively. Both were significantly associated with an elevated risk of all-cause mortality and cardiovascular mortality. QRS duration ≥ 110 ms doubled the risk of SCD, and IVCD was associated with a three-fold higher risk of SCD. Two percent of the subjects presented with wide frontal QRS-T angle ≥ 100° (the angle between the QRS axis and the T-wave axis in the frontal plane). A wide QRS-T angle was associated with higher overall mortality and more than doubled the risk of SCD, which was mainly due to an abnormal T-wave axis. Inverted T-waves in the right precordial leads (V1–V3) or beyond were present in 0.5% of the population. No increase in mortality or SCD was associated with right precordial T-wave inversions. In contrast, inverted T-waves in other leads than V1–V3 were associated with higher risk of cardiovascular mortality and SCD. Altogether 2.1% of the study participants presented with a prolonged PR interval > 200 ms. No rise in overall mortality, SCD, or hospitalizations due to heart failure, atrial fibrillation, or stroke was observed among these subjects during the follow-up period. In conclusion, of the electrocardiographic parameters studied, prolonged QRS duration, IVCD, and wide QRS-T angle are associated with SCD in the general population, and such changes in an ECG should therefore alert the physician to more closely evaluate and follow the patient. On the other hand, a prolonged PR interval and right precordial T-wave inversions seem to have no prognostic implications in the absence of other features suggestive of underlying heart disease. / Tiivistelmä Sydänperäinen äkkikuolema on yleisin kuolinsyy länsimaissa, missä puolet sydänkuolemista ja 15–20 % kokonaiskuolleisuudesta johtuu äkillisestä sydänpysähdyksestä. Sepelvaltimotauti on yleisin taustalla oleva syy, ja jopa puolessa sepelvaltimotautikuolemista äkkikuolema on taudin ensimmäinen oire. Jo pitkään on yritetty kehittää menetelmiä, joilla voitaisiin tunnistaa suurimmassa äkkikuoleman vaarassa olevat. 12-kanavainen EKG on laajalti käytössä oleva tutkimus, jolla tutkitaan sydämen sähköistä toimintaa, mutta sydänperäistä äkkikuolemaa spesifisti väestössä ennustavia EKG-poikkeavuuksia ei ole juuri pystytty osoittamaan. Tämän väitöskirjatyön tarkoituksena oli tutkia, miten EKG:ssä nähtävät ilmiöt kuten QRS kompleksin kesto, QRS-kompleksin ja T-aallon välinen kulma, kääntyneet T-aallot sekä PR-aika korreloivat ennusteeseen väestötasolla. Tutkimme 10899 suomalaisen keski-ikäisen henkilön (52 % miehiä) EKG:t, jotka oli rekisteröity 1966–1972, ja seurasimme tutkittavia keskimäärin 30 (± 11) vuotta. Leventynyt QRS kompleksi ≥ 110 ms löytyi 1.3 %:lta ja epäspesifi kammionsisäinen johtumishäiriö eli IVCD (QRS ≥ 110 ms ilman osittaista tai täydellistä haarakatkosta) 0.6 %:lta tutkituista. Molemmat muutokset liittyivät lisääntyneeseen kokonaiskuolleisuuteen sekä sydänkuoleman riskiin. QRS kompleksin kesto ≥ 110 ms assosioitui lisäksi kaksinkertaiseen ja IVCD kolminkertaiseen äkkikuolemariskiin. 2 %:lla tutkituista sydänlihaksen depolarisaation suuntaa kuvaavan QRS-kompleksin akselin ja repolarisaatiota kuvaavan T-aallon akselin välinen frontaalitason QRS-T kulma oli leveä ≥ 100°. Näillä henkilöillä kokonaiskuolleisuus oli lisääntynyt, ja sydänperäisen äkkikuoleman riski oli yli kaksinkertainen verrattuna henkilöihin jolla QRS-T kulma oli  < 100°. Oikeanpuoleisissa rintakytkennöissä V1–V3 todettiin negatiiviset T-aallot 0.5 %:lla tutkituista, mutta näillä ei ollut vaikutusta kuolleisuuteen. Sen sijaan henkilöillä, joilla todettiin negatiiviset T-aallot muissa kytkennöissä, oli yli kaksinkertainen sydänkuoleman ja äkillisen sydänpysähdyksen vaara muihin tutkittuihin verrattuna. Osallistujista 2.1 %:lla todettiin pidentynyt PR-aika > 200 ms. Tämä ei kuitenkaan vaikuttanut henkilöiden kuolleisuuteen eikä sydämen vajaatoiminnasta, eteisvärinästä tai aivoverenkiertohäiriöistä johtuvien sairaalahoitojen määrään. Tutkituista EKG:n poikkeavuuksista siis pidentynyt QRS-kompleksin kesto, IVCD ja leveä QRS-T kulma liittyvät selvästi lisääntyneeseen äkillisen sydänpysähdyksen riskiin. Sen sijaan pidentynyt PR-aika tai T-inversiot oikeanpuoleisissa rintakytkennöissä ilman muuta viitettä sydänsairaudesta eivät vaikuta ennusteeseen keski-ikäisessä väestössä.

No description available.

Abstract Despite advances in treatment of cardiovascular diseases, coronary heart disease (CHD) remains the most common cause of death in the Western countries; and its first manifestation is often sudden cardiac death (SCD). The development of CHD is a lifelong process, the pace of which is governed by the burden of several risk factors. The purpose of this study was to investigate the association of levels of cardiorespiratory fitness (CRF), exercise-induced myocardial ischemia and physical activity with the risk of CHD-related death, including SCD events among men with different risk factor profiles. This study is based on the population of the Kuopio Ischaemic Heart Disease Risk Factor Study, which recruited a sample of 2682 men aged 42–60 years. Their CRF was assessed with a maximal exercise test using respiratory gas analysis. Exercise-induced ST segment depression was defined as a ≥1 mm ST segment depression on the electrocardiogram. Anthropometric measurements, blood sample analyzes and questionnaires regarding leisure-time physical activity (LTPA) and smoking were performed at baseline. Men with both low CRF and exercise-induced ST segment depression were at higher risk of death from CHD and SCD than men with high CRF without ST segment depressions. Men with low CRF and low LTPA were at higher risk of SCD than men with low CRF and high LTPA. The amount of LTPA did not alter the incidence on SCD among men with high CRF. These findings were adjusted for age, type 2 diabetes and CHD, smoking, alcohol consumption, body mass index, systolic blood pressure, serum low density lipoprotein cholesterol, and serum C-reactive protein level. These findings emphasize the importance of physical activity and treatment of other modifiable risk factors, especially among the men with low CRF. / Tiivistelmä Sydän- ja verisuonisairauksien ennaltaehkäisystä ja hoidon edistysaskeleista huolimatta sepelvaltimotauti on edelleen kehittyneiden maiden yleisin kuolinsyy, sydänperäisen äkkikuoleman ollessa usein taudin ensimmäinen ilmentymä. Sepelvaltimotaudin syntyminen on pitkäaikainen prosessi, jossa riskitekijät määrittävät suurelta osin taudin etenemisen nopeuden. Tämän tutkimuksen tavoitteena oli selvittää kliinisessä rasituskokeessa todetun aerobisen suorituskyvyn, sydänlihasiskemian sekä fyysisen aktiivisuuden yhteyttä sepelvaltimotautikuolemiin ja sydänperäisiin äkkikuolemiin eri sydän- ja verisuonisairauksien riskitekijäyhdistelmien omaavien miesten keskuudessa. Tämä tutkimus perustuu Kuopio Ischaemic Heart Disease Risk Factor Study- aineistoon, johon kuuluu 2682 42–60 vuotiasta miestä. Tutkittavien aerobista suorituskykyä arvioitiin kliinisessä rasituskokeessa mittaamalla hapenkulutus suoraan hengityskaasuista. Sydänlihasiskemian merkkinä pidettiin rasituksen provosoimaa ≥1 mm ST-välin laskua tutkittavien EKG:ssa. Tutkittavilta kartoitettiin alussa antropometriset mittaukset, verikokeet sekä kyselylomakkeilla selvitettiin mm. vapaa-ajan liikunnan määrää ja tupakointia. Miehet, joilla todettiin huono suorituskyky sekä samanaikainen rasituksen aiheuttama sydänlihasiskemia olivat suuremmassa vaarassa menehtyä sepelvaltimotautiin ja sydänperäiseen äkkikuolemaan verrattuna miehiin, joilla todettiin hyvä suorituskyky eikä rasituksen aiheuttamaa sydänlihasiskemiaa. Miehet joilla todettiin huono suorituskyky, mutta harrastivat enemmän liikuntaa vapaa-ajalla, olivat pienemmässä vaarassa sydänperäiseen äkkikuolemaan kuin huonokuntoiset miehet, jotka harrastivat vähemmän liikuntaa vapaa-ajallaan. Vapaa-ajan liikunnan määrä ei muuttanut sydänperäisen äkkikuoleman esiintyvyyttä hyväkuntoisten miesten keskuudessa. Nämä tulokset vakioitiin iän, tyypin 2-diabeteksen, todetun sepelvaltimotaudin, tupakoinnin, alkoholin kulutuksen, painoindeksin, systolisen verenpaineen, seerumin LDL-kolesterolin ja C-reaktiivisen proteiinin suhteen. Nämä löydökset korostavat liikunnan harrastamisen tärkeyttä muiden riskitekijöiden hoidon ohessa, erityisesti lähtötasoltaan huonokuntoisilla miehillä.

Introduction : La cardiopathie arythmogène du ventricule droit (CAVD) est une pathologie d’origine génétique se traduisant par un remplacement cicatriciel qui affecte de façon prédominante le ventricule droit (VD). Le diagnostic est complexe car il repose sur un ensemble de critères cliniques plutôt que sur un seul test diagnostic. L’atteinte du VD se traduit de façon prédominante par des arythmies ventriculaires qui peuvent parfois conduire à la complication la plus redoutée de cette affection : la mort subite. La prédiction et la prévention de celle-ci sont des enjeux cruciaux de la prise en charge de cette maladie. Objectifs : Ce travail vise à améliorer la prise en charge des patients atteints de CAVD de deux façons distinctes. Premièrement, en tentant de faciliter le diagnostic par la validation des critères diagnostiques en vigueur. Deuxièmement, en améliorant la stratification du risque d’arythmie ventriculaires soutenues et plus spécifiquement celui de la mort subite et des arythmies potentiellement mortelles (tachycardie ventriculaire > 250 bpm, fibrillation ventriculaire) en créant des modèles de prédiction du risque permettant de déterminer le risque individuel de chaque patient. Résultats : Article 1 - Un total de 407 patients consécutifs référés pour une résonnance magnétique cardiaque pour suspicion de CAVD ont été inclus. De ceux-ci, 66 (16%) ont reçu un diagnostic définitif selon le critère de référence établi pour cette étude: le consensus d’un panel d’experts. Globalement, les critères performent bien avec une sensibilité et spécificité à 92%. Cependant, certains critères tels l’ECG haute amplitude (SAECG) et certains critères reliés à l’histoire familiale ne sont pas discriminants. Le retrait de ces critères pourrait réduire le nombre de faux positifs sans pour autant augmenter le nombre de faux négatifs (net reclassification improvement de 4,3%, p=0,019). De plus, la combinaison des critères électrocardiographiques et de la présence d’arythmies ventriculaires a une sensibilité de 100%, ce qui peut faciliter dans certains cas le dépistage en limitant la nécessité de recourir à l’imagerie. Pour les articles 2 et 3, une base de données incluant des patients avec un diagnostic définitif de CAVD a été assemblée à partir de bases de données provenant de six pays (Canada, États-Unis, Pays-Bas, Suède, Norvège, Suisse). Article 2 - Un total de 528 patients sans histoire antérieure d’arythmies ventriculaires soutenues a été inclus pour développer un modèle de prédiction de risque. De ceux-ci, 146 (27,7%) ont subi un événement arythmique durant un suivi médian de 4,8 ans. Des huit prédicteurs initialement identifiés (âge inférieur au diagnostic, sexe masculin, syncope cardiaque récente, nombre de dérivations avec des inversions des ondes T, fardeau d’extrasystoles ventriculaires (ESV) en 24h, tachycardie ventriculaire non-soutenue et fractions d’éjection des ventricules gauche et droit), sept ont été retenus dans le modèle, excluant seulement la fraction d’éjection du ventricule gauche (FEVG). Le modèle peut distinguer adéquatement entre les patients avec et sans événement (C-index de 0,77) avec un optimisme minimal (courbe de calibration de 0,93). L’utilisation de cet algorithme permettrait de réduire l’utilisation de défibrillateurs implantables de 20% par rapport à l’algorithme du consensus le plus largement utilisé. Article 3 - Une cohorte de 864 patients incluant à la fois ceux avec et sans histoire antérieure d’arythmie ventriculaire soutenue a été assemblée. Durant un suivi médian de 5,75 ans, 93 patients ont eu un épisode d’arythmie rapide selon la définition préalablement établie. Des huit facteurs de risque cités ci-haut, seulement quatre ont été retenus dans le modèle : l’âge plus jeune au diagnostic, sexe masculin, fardeau d’ESV en 24h et nombre de dérivations avec des inversions des ondes T. Fait à noter, les événements antérieurs ne se sont pas avérés prédicteurs d’arythmies potentiellement mortelles subséquentes. Le modèle peut distinguer adéquatement entre les patients avec et sans événement (C-index de 0,74) et présente un optimisme minimal avec une courbe de calibration de 0,95. Conclusion : Bien que les critères diagnostiques en vigueur pour la CAVD aient une performance adéquate, ceux-ci peuvent être simplifiés et améliorés par le retrait de certains de ces critères. L’absence de critères électrocardiographiques combinés et d’arythmies ventriculaires peut exclure une CAVD, ce qui peut en simplifier le dépistage. Chez les patients atteints de CAVD, la prédiction du risque et la sélection des patients pour l’implantation d’un défibrillateur peuvent être facilités grâce à deux modèles complémentaires de prédiction du risque permettant de prédire les événements arythmiques soutenus dans le premier et plus spécifiquement les arythmies ventriculaires potentiellement mortelles dans le deuxième. Ces outils sont particulièrement utiles dans une approche de prise de décision partagée. / Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic pathology resulting in a fibro-fatty replacement predominantly affecting the right ventricle. The diagnosis is complex and is based on a set of clinical criteria. Involvement of the right ventricle predominantly results in ventricular arrhythmias which constitutes the most common presentation but can also lead to the most feared consequence: sudden cardiac death. Predicting and preventing this catastrophic outcome are crucial in the management of this disease. Objectives: This work aims to improve the management of patients with ARVC in two distinct ways. First, by attempting to facilitate the diagnosis by validating the currently used diagnostic criteria. Second by improving risk stratification for sustained ventricular arrhythmias and specifically life-threatening ventricular arrhythmias (LTVA defined as ventricular tachycardia > 250 bpm, ventricular fibrillation, and sudden death) by creating risk prediction models to derive individual risk. Results: Manuscript 1: a total of 407 patients referred for cardiac magnetic resonance for suspected ARVC were consecutively enrolled. Of these, 66 (16%) received a definitive diagnosis of ARVC by the determined endpoint: the consensus of an expert panel. Overall, the criteria performed well with a sensitivity and specificity of 92%. However, certain criteria such as the signal averaged electrocardiogram (SAECG) and certain criteria related to family history failed to discriminate. Removing these criteria could reduce false positives without increasing false negatives (net reclassification improvement of 4.3%, P = 0.019). In addition, the electrocardiographic criteria and the presence of arrhythmia had a sensitivity of 100%, which can facilitate screening in some cases by making imaging optional. For manuscripts 2 and 3, a cohort including patients with a definitive diagnosis of ARVC was assembled from databases in 6 countries (Canada, United States, Netherlands, Sweden, Norway, Switzerland). Manuscript 2: a total of 528 patients with no previous history of sustained ventricular arrhythmias were included to develop a risk prediction model. Of these, 146 (27.7%) had an arrhythmic event during a median follow-up of 4.8 years. Of the eight predictors initially identified (younger age at diagnosis, male sex, recent cardiac syncope, the number of leads with T wave inversions on the ECG, burden of extrasystoles in 24 hours, non-sustained ventricular tachycardia and left and right ventricular ejection fraction), seven were retained in the model, excluding only left ventricular ejection fraction. The model adequately distinguished between patients with and without an arrhythmic event (C-index of 0.77) with minimal optimism (calibration slope of 0.93). Using this prediction model would reduce the use of defibrillators by 20% compared with the most commonly used consensus based on a risk factor approach. Manuscript 3: a cohort including both patients with and without a prior history of ventricular arrhythmia of 864 patients was assembled. During a follow-up of 5.75 years, 93 patients had an LTVA as defined above. Of the 8 risk factors cited above, only 4 were retained in the model: younger age at diagnosis, male sex, burden of extrasystoles in 24 hours and number of leads with T-wave inversions. Importantly, previous events are not predictive of these subsequent life-threatening arrhythmias. The model adequately distinguished between patients with and without an event (C-index of 0.74) with minimal optimism (calibration slope of 0.95). Conclusion: Although the current diagnostic criteria for ARVC perform adequately, they can be simplified and improved by removing underperforming individual criteria. The absence of any ECG criteria and ventricular arrhythmias may rule out ARVC, which may simplify screening. In patients with ARVC, risk prediction and patient selection for a defibrillator can be facilitated by two complementary risk prediction models for sustained arrhythmic events or more specifically for LTVA. These tools are particularly useful in a shared decision-making approach for implantable cardioverter defibrillator implantation.