Introdução. Frequência cardíaca (FC) elevada é reconhecida como um fator prognóstico de maior mortalidade na insuficiência cardíaca aguda descompensada (ICAD). Entretanto, pouco se conhece sobre os efeitos da redução da FC na evolução de pacientes com ICAD em ritmo sinusal, não havendo estudo clínico desenhado especificamente para o esclarecimento desta questão até o momento. Objetivos. Avaliar a eficácia e segurança da redução da FC através da inibição da corrente I(f) atrial em pacientes hospitalizados com ICAD em ritmo sinusal. Avaliar os efeitos de curto prazo da redução da FC nos parâmetros hemodinâmicos e de função ventricular por ecocardiografia e sobre os biomarcadores séricos de IC. Métodos. Estudo clínico randomizado, duplo-cego, controlado com placebo, unicêntrico. Os critérios de inclusão foram admissão por ICAD, fração de ejeção do ventrículo esquerdo (FEVE) < 40%, FC >80 bpm, INTERMACS >= 3 e ritmo sinusal. Os participantes do estudo (n=46, 48% feminino, idade média de 48±15 anos) receberam tratamento da ICAD orientado por diretriz e 5 mg de ivabradina (N = 23) ou placebo (N = 23) de 12/12 horas por 1 mês. Os desfechos estudados foram a variação em relação ao basal, aferida no quinto dia de intervenção, das seguintes variáveis: FC, pressão arterial sistêmica; volume sistólico (VS), índice cardíaco (Icar), FEVE, strain longitudinal global do VE (SLG-VE), índice de performance do miocárdio (IPM), relação E/A, tempo de desaceleração da onda E (TD onda E), relação E/e´, excursão sistólica máxima do anel tricúspide lateral (TAPSE), velocidade sistólica máxima do anel tricúspide lateral (s´), variação fracional da área do ventrículo direito (VFA), strain longitudinal global do ventrículo direito (SLG-VD), peptídeo natriurético tipo B (BNP), troponina, proteína C reativa (PCR), creatinina e NGAL (neutrophil gelatinase-associated lipocalin). Os pacientes foram acompanhados durante a internação e após a alta até o sexto mês, ou até a ocorrência de um evento cardiovascular pré-especificado. Resultados. A ivabradina reduziu significativamente a FC em comparação com o placebo (-14 ± 5 vs 0,2 ± 6 bpm, p < 0,001). A redução da FC acompanhou-se de melhora na FEVE (5,5 ± 15 vs -3,0 ± 11%, p = 0,03), no VS do VE (5,8 ± 11 vs -1,8 ± 10 mL, p = 0,02), no SLG-VD (2,0± 2,2 versus 0,3 ± 3,1%, p = 0,007), no TAPSE (1,6 ± 2,4 vs. -0,2 ± 1,7 mm, p = 0,004), na VFA (5,1 ± 7,8 vs -1,4 ± 4,5%, p = 0,001) e na s´ (0,5 ± 1,3 vs. -0.4 ± 1,0 cm/s, p = 0,009). Não houve diferença na pressão arterial sistêmica, Icar, IPM, TD onda E, BNP, troponina, PCR, NGAL e creatinina. Dos 46 pacientes, 24 (52%) apresentaram eventos adversos durante o acompanhamento, com 6 óbitos e 3 transplantes no grupo placebo e 5 óbitos e 2 transplantes no grupo tratado com ivabradina. A FC no quinto dia da intervenção foi um forte preditor de eventos de acordo com o modelo de risco proporcional de Cox (HR 1,08 [IC95% 1,03-1,12], p < 0.001), mesmo quando corrigida pela idade, tempo de diagnóstico de IC e gênero. Conclusão. Os dados sugerem que a inibição da I(f) reduz de forma segura a FC em pacientes admitidos por ICAD em ritmo sinusal, com benefício para a função cardíaca global. Nosso estudo sugere que a FC elevada pode ser considerada um potencial alvo terapêutico em pacientes com ICAD em ritmo sinusal, sendo necessário um estudo multicêntrico sobre o tema / Introduction. Elevated heart rate (HR) is a known prognostic factor of higher mortality in acute decompensated heart failure (ADHF). However, little is known about the effects of HR reduction on the progression of patients with ADHF in sinus rhythm, and there was no clinical study specifically designed to clarify this issue to date. Aims. To evaluate the efficacy and safety of HR reduction through inhibition of the atrial I(f) current in patients hospitalized with ADHF in sinus rhythm. To evaluate the short-term effects of HR reduction on hemodynamic and ventricular function parameters by echocardiography and on serum biomarkers of HF. Methods. Randomized, double-blind, placebo-controlled, single-center clinical trial. Inclusion criteria were ADHF, left ventricle ejection fraction (LVEF) <40%, HR >80 bpm, INTERMACS >= 3 and sinus rhythm. Participants in the study (n = 46, 48% female, mean age 48 ± 15 years) received guideline-guided treatment for ADHF and 5 mg ivabradine (N = 23) or placebo (N = 23) 12/12 hours for 1 month. Outcomes were change from baseline measured on the fifth day of intervention for the following variables: HR, systemic arterial pressure, LV stroke volume (LVSV), cardiac index (CI), LVEF, LV global longitudinal strain (LV-GLS), myocardial performance index (MPI), E/A, E wave deceleration time (E wave DT), E/e\' ratio, tricuspid annular plane systolic excursion (TAPSE), tricuspid annular plane peak-systolic velocity (s´), right ventricle (RV) fractional area change (FAC), RV global longitudinal strain (RV-GLS), B-type natriuretic peptide (BNP), troponin, reactive C protein (RCP), creatinine, and neutrophil gelatinase-associated lipocalin (NGAL). Patients were followed up during hospitalization and after discharge until the sixth month, or until the occurrence of a pre-specified cardiovascular event. Results. Ivabradine significantly reduced HR compared with placebo (-14 ± 5 vs 0.2 ± 6 bpm, p < 0.001). The HR reduction was accompanied by improvement in LVEF (5.5 ± 15 vs -3.0 ± 11%, p = 0.03), LVSV (5.8 ± 11 vs -1.8 ± 10 mL, p = 0.02), RV-GLS (2.0 ± 2.2 versus 0.3 ± 3.1%, p = 0.007), TAPSE (1.6 ± 2.4 vs. -0.2 ± 1,7 mm, p = 0.004), FAC (5.1 ± 7.8 vs -1.4 ± 4.5%, p = 0.001) and s´ (0.5 ± 1.3 vs. -0.4 ± 1.0 cm / s, p = 0.009). There was no difference in systemic arterial pressure, CI, MPI, E wave TD, BNP, troponin, RCP, NGAL and creatinine. Of the 46 patients, 24 (52%) presented events during follow-up, with 6 deaths and 3 transplants in placebo group and 5 deaths and 2 transplants in ivabradine group. HR on the fifth day of the intervention was a strong event predictor according to Cox proportional hazards model (HR 1.08 [95% CI 1.03-1.12], even when corrected for age, time from diagnosis of HF and gender. Conclusion. The data suggest that I(f) inhibition safely reduces HR in patients admitted with ADHF in sinus rhythm, with benefit to global cardiac function. Our study suggests that elevated HR may be considered a potential therapeutic target in patients with ADHF in sinus rhythm, requiring a multicenter study on the subject

Un nouveau règlement (CE) n° 1901/2006 établi par le Parlement européen et le Conseil de l’UE, relatif aux médicaments à usage pédiatrique, vise à améliorer la santé et la qualité de vie des enfants en Europe, en garantissant que les nouveaux médicaments pédiatriques et les médicaments déjà commercialisés seront pleinement adaptés à leurs besoins spécifiques. Ce règlement prévoit de nouvelles obligations pour l'industrie pharmaceutique, assorties de récompenses et d'incitations. Dans ce contexte, un plan d’investigation pédiatrique a été proposé pour l’ivabradine dans plusieurs sous-groupes de la population pédiatrique dans le traitement de l’insuffisance cardiaque chronique. L’ivabradine est une molécule déjà commercialisée chez l’adulte dans la prise en charge de l’angor, et de l’insuffisance cardiaque. Un premier travail a été d’aider au design de cette étude pédiatrique : évaluer la formulation pédiatrique, aider au choix de la dose initiale à administrer chez l’enfant, choisir le protocole de prélèvements et conseiller la méthode de prélèvements. Pour évaluer la formulation pédiatrique, une étude a été conduite pour déterminer la biodisponibilité relative de la formulation pédiatrique par rapport aux comprimés utilisés chez l’adulte. Une biodisponibilité relative similaire a été retrouvée entre les deux formulations. Une approche physiologique (PBPK « Physiollogically based PharmacoKineticsmodel ») a été utilisé pour prédire la dose initiale à administrer et pour proposer un protocole de prélèvements PK. La méthode DBS (Dried blood spot) consistant à collecter à chaque temps de prélèvement une goutte de sang (au pli du coude ou au bout du doigt) a été recommandée. La première dose à administrer chez l’enfant peut être également être déterminée par des modèles de population développés chez l’adulte et adaptés à l’enfant grâce à l’allométrie et à l’ajout de fonctions de maturation. Cette approche a été comparée au PBPK dans le cas de l’ivabradine et des résultats similaires ont été obtenus. Un deuxième travail a été réalisé après que l’étude clinique ait été conduite dans la population pédiatrique. L’étude a été menée chez 116 enfants (74 enfants recevant l’ivabradine, 42 recevant le placebo) âgés de 6 mois à 18 ans et les données ont été analysées. Tout d’abord, une relation a été établie entre les concentrations d’ivabradine plasmatiques et les concentrations d’ivabradine mesurées dans le sang total. Puis, afin de décrire les concentrations d’ivabradine et de son métabolite, un modèle de population prenant en compte l’effet de l’âge et du poids a été développé. En comparant les expositions plasmatiques, une dose par kilogramme plus élevée aurait été nécessaire chez les patients les plus jeunes pour atteindre un niveau d’exposition similaire aux patients plus âgés. Enfin, il a été monté que la relation PK/PD qui avait développé chez l’adulte était conservée dans la population pédiatrique. / New legislation governing the development and authorization of medicines for use in children was introduced in the European Union (EU) in January 2007. This Regulation aims to facilitate the development and accessibility of medicinal products for use in the paediatric population, to ensure that medicinal products used to treat the paediatric population are subject to ethical research of high quality and are appropriately authorised for use in the paediatric population, and to improve the information available on the use of medicinal products in the various paediatric populations. Several rewards and incentives for the development of paediatric medicines for children are available in the European Union (EU). In compliance with the paediatric European regulation, a study will be conducted in paediatric patients with CHF with the objective to determine the efficacious and safe dose of ivabradine, a compound already marketed in adults, and to assess its efficacy and safety in children over 1 year old. A first work was to help design a paediatric study for ivabradine focusing on: the paediatric formulation evaluation, the doses to be administered, the sampling design and the sampling technique. A study was conducted in order to assess the relative bioavailability (Frel) of the paediatric formulation and a similar Frel was observed between the paediatric formulation and the adult marketed tablet. PBPK modelling was used to predict initial doses to be administered in the paediatric study and to select the most appropriate sample time collections. The dried blood spot (DBS) technique was recommended in the clinical trial in children. A secondary objective was to perform a comparison of the prediction of ivabradine pharmacokinetics (PK) in children using a physiologically-based pharmacokinetic (PBPK) approach and allometric scaling of a population pharmacokinetic (PPK) model. Simulations obtained by both the PBPK approach and allometric scaling of a PPK model were compared a posteriori to the paediatric study observations. Both PPK and PBPK approaches allowed an adequate prediction of the PK of ivabradine and its metabolite in children. The second work was done after the study conduction in the paediatric population. The study was performed in 116 children (74 received ivabradine, 42 received the placebo) aged from 6 months to less than 18 years old and data were analysed. The relationship between blood and plasma concentrations was described using linear mixed effect models. In order to describe ivabradine and its metabolite blood concentrations in children, a joint population PK model was developed taking into account weight & age effects on PK parameters. Plasma exposure comparison indicated that higher dose/kg were necessary to achieve a similar exposure between younger and older children. The PK/PD relationship in adult patients is conserved in children.

En étudiant les variations génétiques au sein d'une population, il est possible d'identifier des polymorphismes génétiques qui confèrent une protection naturelle contre la maladie. Si l'on parvient à comprendre le mécanisme moléculaire qui sous-tend cette protection, par exemple en reliant la variation génétique à la perturbation d'une protéine bien précise, il pourrait être possible de développer des thérapies pharmacologiques qui agissent sur la même cible biologique. Cette relation entre les médicaments et les variations génétiques est une des prémisses centrales de la validation génétique de cibles pharmacologiques qui est un facteur de réussite dans le développement de médicaments. Dans cette thèse, nous utiliserons un modèle génétique pour prédire les effets bénéfiques et indésirables de l'ivabradine, un médicament utilisé afin de réduire la fréquence cardiaque. L'ivabradine est un inhibiteur du canal ionique potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4, encodé par le gène HCN4, dont les bénéfices sont hétérogènes chez différentes populations de patients. Ce médicament est efficace pour le traitement de l'angine et de l'insuffisance cardiaque, mais s'est avéré inefficace en prévention secondaire chez des patients coronariens stables sans dysfonction systolique. La caractérisation des effets de l'ivabradine s'est échelonnée sur une période de 6 ans et trois grands essais de phase III ont été menées. Nous étudierons la possibilité d'avoir prédit ou accéléré ce processus à l'aide de modèles génétiques et nous contrasterons les effets spécifiques à l'ivabradine des effets généraux de la réduction de la fréquence cardiaque par une approche de randomisation mendélienne. Deuxièmement, une approche génétique sera utilisée pour évaluer l'effet de l'inhibition de la cholesteryl ester tranfer protein (CETP), une enzyme responsable du transfert des cholestérols estérifiés et des triglycérides entre différentes lipoprotéines ainsi qu'une cible pharmacologique largement étudiée pour le traitement de la maladie coronarienne. Les études génétiques prédisent un bénéfice à l'inhibition de CETP, mais les essais randomisés ont eu des résultats hétérogènes et décevants. Nous utiliserons un modèle génétique d'inhibition de la CETP pour identifier des variables qui peuvent moduler l'effet de l'inhibition de la CETP sur des biomarqueurs et la maladie ischémique. Les biomarqueurs pris en compte comprennent les taux de cholestérol à lipoprotéines de basse et haute densité, mais aussi la capacité du plasma à absorber le cholestérol, une mesure fonctionnelle importante et sous-étudiée. Le sexe et l'indice de masse corporelle se sont avérés être deux variables qui modifient fortement les effets d'une réduction génétiquement prédite de la concentration de CETP sur les paramètres étudiés. Notre modèle prédit un bénéfice plus important de l'inhibition de la CETP pour les femmes et les individus ayant un indice de masse corporelle normal sur le profil lipidique, mais nous n'avons pas pu démontrer une modulation de l'effet sur la maladie ischémique. Cette étude reste importante sur le plan méthodologique, car elle soulève la possibilité d'utiliser des modèles génétiques de cibles pharmacologiques pour prédire l'hétérogénéité dans la réponse au médicament, une lacune des essais randomisés classiques. Enfin, nous avons adopté une approche centrée sur les gènes pour caractériser l'effet de 19 114 protéines humaines sur 1 210 phénotypes de la UK Biobank. Les résultats de cette étude sont accessibles au public (https://exphewas.statgen.org/) et constituent une ressource précieuse pour cerner rapidement les conséquences phénotypiques associées à un locus. Dans le contexte de validation de cibles pharmacologiques, cette plate-forme web peut aider à rapidement identifier les problèmes de sécurité potentiels ou à découvrir des possibilités de repositionnement du médicament. Un exemple d'utilisation de cette plate-forme est présenté où nous identifions le gène de la myotiline comme un nouvel acteur potentiel dans la pathogénèse de la fibrillation auriculaire. / Using population-level data, it is possible to identify genetic polymorphisms that confer natural protection against disease. If the molecular mechanism underlying this protection can be understood, for example by linking variants to the disruption of a particular protein, it may be possible to develop drugs that act on the same biological target. This link between drugs and variants is a central premise of genetic drug target validation. In this work, a genetic model is used to predict the beneficial and adverse effects of ivabradine, a drug used to lower heart rate. Ivabradine is an inhibitor of the ion channel potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4, encoded by the HCN4 gene, with heterogeneous benefits in different patient populations. This drug is effective in the treatment of angina and heart failure but it is ineffective in patients with stable coronary artery disease without systolic dysfunction. Characterization of the effect of ivabradine has occurred over a 6-year period and three large phase III trials have been conducted. We will investigate whether this process could have been streamlined using genetic models and contrast the ivabradine-specific effect with the general effect of heart rate reduction using a Mendelian Randomization approach. Second, a genetic approach is used to study the effect of inhibiting cholesteryl ester tranfer protein (CETP), an enzyme responsible for the transfer of cholestery esters and triglycerides between different lipoproteins and a widely studied drug target for the treatment of coronary artery disease. Genetic studies predict a benefit of CETP inhibition, but randomized trials yielded heterogeneous and disappointing results. We will use a genetic model of CETP inhibition to identify variables that may modulate the effect of CETP inhibition on biomarkers and ischemic disease. The biomarkers we considered included low- and high-density lipoprotein cholesterol levels but also the plasma cholesterol efflux capacity, an important and understudied functional measure of high density lipoproteins. Sex and body mass index strongly modulated the effect of a genetically predicted lower CETP concentration on the lipid profile. Our model predicts a greater benefit of CETP inhibition in women and individuals with normal body mass index on the lipid profile, but these observations did not translate to changes in the effect on cardiovascular outcomes. This study remains methodologically important because it demonstrates the possibility of using genetic models of drug targets to predict heterogeneity in drug response, a shortcoming of conventional randomized trials. Finally, we adopted a gene-centric approach to characterize the effect of 19,114 human protein-coding genes on 1,210 UK Biobank phenotypes. The results of this study are publicly available (https://exphewas.statgen.org/) and provide a valuable resource to rapidly screen the phenotypic consequences associated with a gene. In the context of drug target validation, this platform can help quickly identify potential safety issues or discover drug repurposing opportunities. An example of the use of this platform is presented where we identify the myotilin gene as a potential atrial fibrillation gene.

Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo A significant increase in cardiovascular medication use during pregnancy has occurred in recent years but only limited evidence on its safety profile is available. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. We tested metoprolol, carvedilol, or ivabradine for embryotoxicity and their acute effect on chick embryonic model. We used video microscopy and ultrasound biomicroscopy. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared to controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, 53%, respectively (controls 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of -adrenergic receptors showed a downward tendency during embryonic development but a negative chronotropic effect of tested drugs was increasingly pronounced with embryonic maturity. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death....

Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo A significant increase in cardiovascular medication use during pregnancy has occurred in recent years but only limited evidence on its safety profile is available. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. We tested metoprolol, carvedilol, or ivabradine for embryotoxicity and their acute effect on chick embryonic model. We used video microscopy and ultrasound biomicroscopy. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared to controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, 53%, respectively (controls 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of -adrenergic receptors showed a downward tendency during embryonic development but a negative chronotropic effect of tested drugs was increasingly pronounced with embryonic maturity. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death....