Succinate is one of the intermediate in the Krebs cycle, which in recent years has been shown to interfere with other cellular events, some of which may affect cardiac ischemic tolerance. The aim of this project was to clarify its cardioprotective role in rat hearts subjected to acute ischemia-reperfusion. The myocardial resistance to acute ischemia (infarct size and incidence and severity of ischemic and reperfusion arrhythmias) was analyzed using the Langendorff method of isolated perfused heart at a constant flow with acute succinate administration. Local ischemia was induced by ligation of left anterior descending coronary artery. Acute administration of 1 mM succinate before 60 minutes of ischemia or before reperfusion only had a beneficial effect on reducing the infarct size by 25-30 % compared to the control group. At the same time, it had an adverse effect on the incidence and severity of ischemic and reperfusion arrhythmias. Key words: Succinate, heart, rat, heart-attack, ventricular arrhythmias

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No / We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats. We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate. Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations.

Introdução: As extrassístoles ventriculares e supraventriculares (EV e ESSV) são frequentes e muitas vezes sintomáticas. O íon magnésio (Mg) desempenha um papel importante na fisiologia do potencial de ação transmembrana celular e do ritmo cardíaco. Objetivo: Avaliar se a administração do Pidolato de Magnésio (PMg) em pacientes com EV e ESSV é superior ao placebo (P) na melhora dos sintomas e densidade das extrassístoles(DES). Métodos: Estudo duplo-cego, randomizado, com 90 pacientes sintomáticos consecutivos, com mais de 240/EV ou ESSV ao Holter de 24 horas e selecionados para receber P ou PMg. Para avaliar a melhora da sintomatologia, foi feito um questionário categórico e específico de sintomas relacionado às extrassístoles. Foi considerada significante uma redução de mais de 70% na DES por hora após o tratamento. A dose do PMg foi de 3,0g/dia por 30 dias, equivalente a 260mg do elemento Mg. Nenhum paciente tinha cardiopatia estrutural ou insuficiência renal. Resultados: Dos 90 pacientes estudados, 49 eram do sexo feminino (54,4%). A faixa etária variou de 16 a 70 anos. No grupo PMg, 77,8% dos pacientes tiveram redução maior que 70%, 6,7% deles entre 50% a 70% e, somente 13,3% dos pacientes com redução menor que 50% na DES . No grupo P, 44,4% dos pacientes tiveram melhora de apenas 30% na frequência de extrassístoles (p<0,001). A melhora dos sintomas foi alcançada em 91,1% dos pacientes do grupo PMg, comparada com somente 15,6% do grupo P(p<0,001). Conclusão: A suplementação de Mg por via oral reduziu a DES, resultando em melhora dos sintomas. Estudos clínicos e moleculares são necessários para avaliar o Mg intracelular e orientar quanto às necessidades diárias deste íon, evidenciar as prováveis deficiências e esclarecer melhor como prevenir e tratar pacientes com extrassístoles sintomáticas e sem cardiopatia estrutural. / Introduction: Premature ventricular and supraventricular complexes (PVC and PsVC) are frequent and often symptomatic. The magnesium (Mg) ion plays a role in the physiology of cell membranes and cardiac rhythm. Objective: We evaluated whether the administration of Mg Pidolate (MgP) in patients with PVC and PsVC is superior to placebo (P) in improving symptoms and arrhythmia frequency. Methods: Randomized double-blind study with 90 consecutive symptomatic patients with more than 240 PVC or PsVC on 24-hour Holter monitoring who were selected to receive placebo or MgP. To evaluate symptom improvement, a categorical and a specific questionnaire for symptoms related to PVC and PsVC was made. Improvement in premature complex density (PCD) per hour was considered significant if percentage reduction was >=70% after treatment. The dose of MgP was 3.0 g/day for 30 days, equivalent to 260mg of Mg element. None of the patients had structural heart disease or renal failure. Results: Of the 90 patients, 49 were female (54,4%). Ages ranged from 16 to 70 years old. In the MgP group, 77.8% of patients had a PCD reduction >70%, 6,7% of them from 50% to 70%, and only 13.3% <50%. In the P group, 44,4% showed slight improvement, <30%, in the premature complexes frequency (p<0.001). Symptom improvement was achieved in 91.1% of patients in the MgP group, compared with only 15.6% in the P group (p<0.001). Conclusions: Oral Mg supplementation decreases PCD, resulting in symptom improvement. Clinical and molecular studies are needed to evaluate intracellular Mg and develop better targets for the daily needs of this ion, show probable deficiencies, and explain how to prevent and better treat patients with symptomatic premature ventricular, and supraventricular complexes and no apparent heart disease.

La fibrose cardiaque fait le lit des arythmies cardiaques, qu’elles soient atriales ou ventriculaires. L’IRM est devenue un outil non invasif indispensable pour diagnostiquer la présence de fibrose au niveau cardiaque, mais offre également des informations pronostiques, ainsi que pour le suivi des patients atteints de fibrillation auriculaire (FA), notamment persistante. La technique de référence reste le rehaussement tardif après injection de gadolinium, permettant de révéler des régions localisées de fibrose. Notre travail a consisté en la mise au point d’une technique non invasive (par la mesure du T2 avec IRM à haut champ à 11,75 T) afin de quantifier la fibrose myocardique interstitielle diffuse dans un modèle de souris diabétiques. La fibrose a été significativement corrélée à une survenue plus importante des arythmies ventriculaires en comparaison avec un groupe de souris contrôles. L’étape suivante a été de transposer cette technique de mesure de T2 en IRM clinique chez des patients devant bénéficier d’une procédure d’ablation de FA. La deuxième technique, cette fois-ci invasive pour évaluer la fibrose (notamment atriale) pour les patients atteints de FA est la cartographie de voltage au niveau de l’oreillette gauche. Nous avons utilisé un nouveau système de cartographie à ultra-haute définition afin de quantifier la fibrose (zones cicatricielles denses) correspondant aux régions dont les signaux enregistrés avaient une amplitude bipolaire inférieure à 0,015 mV, soit très en deçà des seuils précédemment rapportés concernant la fibrose. / Fibrosis represents the main substrate for cardiac arrhythmias, either atrial or ventricular. MRI has become a critical tool to not only diagnose the presence of cardiac fibrosis, but also provides important informations on the prognosis and the follow-up of patients with atrial fibrillation (AF), especially in its persistent type. The gold standard is the Late Gadolinium Enhancement, allowing to reveal localized regions of fibrosis. Our study reported a technique for non invasive quantification of interstitial diffuse ventricular fibrosis in diabetic mice (T2 measurement high field MRI at 11,75 T). This fibrosis was significantly correlated to the occurrence of ventricular arrhythmias in comparison with the control group. The next step was the transposition of this T2 measurement with MRI in the clinical setup of patients who undergo an AF ablation procedure. The second technique for atrial fibrosis assessment for patients suffering from AF is the invasive realization of left atrial voltage mapping. A new ultra-high definition system was used to quantify the fibrosis (dense scar) in regions with bipolar amplitude electrograms of less than 0,015 mV. This cutoff was far lower than the previously published definition of the dense scar in the literature (< 0,1 mV).