Ranolazina en cardiopatía isquémica crónica: un factor protector frente a la fibrilación auricular de novo / Ranolazine in chronic ischaemic heart disease: a protective factor against de novo atrial fibrillation

Resumen Introducción: en pacientes con cardiopatía isquémica crónica, ranolazina se ha mostrado eficaz ante casos de angina. Estudios recientes la valoran como fármaco para prevenir la fibrilación auricular poscardioversión eléctrica, posquirúrgica o posinfarto. Objetivos: valorar la presencia a largo plazo de episodios de fibrilación auricular de novo en pacientes con cardiopatía isquémica crónica y nuevo episodio de angina inestable que inician ranolazina 350 o 500 mg/12 h, en comparación con el tratamiento habitual. Métodos: estudio observacional retrospectivo que compara la incidencia de fibrilación auricular de novo en 77 pacientes consecutivos, con diagnóstico de cardiopatía isquémica no revascularizable y nuevo ingreso por síndrome coronario agudo durante el año 2013, en comparación con los que iniciaron ranolazina frente a tratamiento convencional, en los 12 meses siguientes al evento. La detección de fibrilación auricular se basó en su presencia en un primer registro electrocardiográfico. Resultados: de 77 pacientes, 38 iniciaron ranolazina, sin diferencias en cuanto a las características basales de las dos poblaciones, con similares tasas de factores de riesgo cardiovascular clásicos, datos ecocardiográficos como tamaño auricular, o tratamiento previo empleado. Se observó una tasa de fibrilación auricular de novo del 5,3% en los pacientes tratados con ranolazina, frente al 23,1% en el grupo sin ranolazina (p<0,001). Al analizar el subgrupo de pacientes que presentó fibrilación auricular en su seguimiento, únicamente es significativa la no toma de ranolazina (p<0,001). Conclusión: el uso de ranolazina en pacientes con cardiopatía isquémica crónica no revascularizable podría suponer un efecto protector para el desarrollo de fibrilación auricular durante un seguimiento de al menos doce meses.

Abstract Introduction: Ranolazine has shown to be effective in cases of angina in patients with chronic ischaemic heart disease. Recent studies have evaluated it as a drug to prevent electrical post-cardioversion, post-surgical or post-infarction atrial fibrillation. Objectives: To perform a long-term evaluation of de novo atrial fibrillation episodes in patients with chronic ischaemic heart disease and a new episode of unstable angina that are taking 350 or 500 mg/12 h of ranolazine, in comparison with usual treatment. Methods: An observational, retrospective study was performed to compare the incidence of de novo atrial fibrillation in 77 consecutive patients with a diagnosis of non-revascularisable ischaemic heart disease and a new hospital admission due to acute coronary syndrome during the year 2013. These were compared with those that started with ranolazine and those on conventional treatment in the 12 months following the event. The detection of atrial fibrillation was based on its presence in a first electrocardiographic register. Results: Of the 77 patients, 38 were started on ranolazine, with no differences as regards the baseline characteristics of the two populations. They had similar rates of classic cardiovascular risk factors, echocardiographic data, such as atrial size, or previous treatment employed. A de novo atrial fibrillation rate of 5.3% was observed in the patients treated with ranolazine, compared to 23.1% in the non-ranolazine group (P<.001). On analysing the sub-group of patients that had an atrial fibrillation in their follow-up, only not taking of ranolazine was significant (P<.001). Conclusion: The use of ranolazine in patients with non-revascularisable ischaemic heart disease could have a protective effect against the development of atrial fibrillation during a 12 months follow-up.

Ações Transmurais Inotrópicas e Antiarrítmicas da Ranolazina em um Modelo Celular da Síndrome do QT Longo Tipo 3 / Inotropic and Antiarrhythmic Transmural Actions of Ranolazine in a Cellular Model of Type 3 Long QT Syndrome

Resumo A Ranolazina (RANO), conhecida na clínica como Ranexa, é um fármaco que previne a arritmia cardíaca através da inibição da corrente de sódio tardia (INaT). Um gradiente de voltagem transmural do canal Nav1.5 encontra-se na parede ventricular esquerda do coração. Assim, investigamos os efeitos da RANO em cardiomiócitos saudáveis e em modelo celular da Síndrome do QT longo tipo 3 (SQTL tipo 3). Usamos células isoladas do endocárdio (ENDO) e do epicárdio (EPI) e um software de medição com detecção de bordas por vídeo e microscopia de fluorescência para monitorar os transientes de cálcio. A RANO (0,1, 1, 10 e 30 uM, a 25OC) em uma série de frequências de estimulação teve impacto pouco significativo sobre ambos os tipos de células, mas a RANO (30uM) a 35OC minimizou o encurtamento dos sarcômeros em ~21% para células do endocárdio. Em seguida, para simular a SQTL tipo 3, as células do ENDO e EPI foram expostas à toxina ATX-II da anêmona do mar, que aumenta a INaT. As arritmias celulares induzidas por ATX-II foram suprimidas com o uso da RANO (30 µM) a 35OC. Com base nesses resultados, podemos concluir que a RANO tem um impacto pouco significativo sobre o encurtamento dos sarcômeros de células saudáveis do ENDO e EPI. Além disso, ela suprime as arritmias induzidas por INaT para níveis semelhantes nas células do ENDO e EPI.

Abstract Ranolazine (RANO) prevents cardiac arrhythmia by blocking the late sodium current (INaL). A transmural gradient of Nav1.5 is found in the left ventricular wall of the heart. Thus, we investigated the effects of RANO in healthy cardiomyocytes and in a cellular model of type 3 long QT syndrome (LQT3). We used isolated endocardium (ENDO) and epicardium (EPI) cells and a video edge detection system and fluorescence microscopy to monitor calcium transients. RANO (0.1, 1, 10 and 30 uM, at 25oC) at a range of pacing frequencies showed a minor impact on both cell types, but RANO at 30uM and 35oC for ENDO cells attenuated sarcomere shortening by~21%. Next, to mimic LQT3, we exposed ENDO and EPI cells to anemone toxin II (ATX-II), which augments INaL. Cellular arrhythmias induced by ATX-II were abrogated by RANO (30 µM) at 35oC. Based on our results we can conclude that RANO has a minor impact on sarcomere shortening of healthy ENDO and EPI cells and it abrogates arrhythmias induced by INaLto a similar level in ENDO and EPI cells.

Nuevos enfoques farmacológicos en el manejo de la angina de pecho estable / New pharmacological approaches in the management of stable angina

RESUMEN En años recientes han sido introducidos nuevos antianginosos al mercado con mecanismos de acción novedosos, complementarios a los del arsenal farmacoterapéutico existente. Aunque el tratamiento de primera línea continúan siendo los betabloqueadores, antagonistas de canales de calcio y nitratos, el descubrimientos de nuevos aspectos fisiopatológicos de la enfermedad permitieron el desarrollo de blancos terapéuticos innovadores a nivel celular y molecular. El nicorandil, la trimetazidina, la ivabradina y la ranolazina se consideran nuevos fármacos antianginosos y constituyen la segunda línea de tratamiento de la angina de pecho estable; están indicados en pacientes que persisten sintomáticos a pesar del manejo de primera línea o en aquellos que presentan intolerancia o contraindicación a los betabloqueadores o antagonistas de canales de calcio. La trimetazidina, a través de su mecanismo de acción metabólico, mejora la tolerancia al ejercicio y puede ser útil en pacientes con falla cardíaca y contraindicación al uso de digitales; la ivabradina tiene un efecto cronotrópico negativo sin afectar el inotropismo ni la tensión arterial por lo que se puede usar en pacientes con taquiarritmias o falla cardíaca concomitante; en contraste, la ranolazina no afecta el cronotropismo por lo que se usa en pacientes con bradiarritmias aunque puede generar prolongación del intervalo QTc. La elección de alguno de estos medicamentos antianginosos de primera o segunda línea debe ser individualizado para cada paciente y se basa en las comorbilidades, contraindicaciones y preferencias del paciente. MÉD.UIS. 2016;29(3):79-93.

ABSTRACT In recent years, new antianginal agents with novel mechanisms of action have been launched to the market, as a complement to the existing therapeutic arsenal. Even though the beta-blockers, calcium channel blockers and nitrates continue to be the first line of treatment, recent discoveries of pathophysiological aspects of the disease led to the development of innovative therapeutic targets on both cellular and molecular level. Nicorandil, trimetazidine, ivabradine and ranolazine are novel antianginal drugs and constitute the second line of treatment of stable angina; these drugs are indicated for those patients who persist symptomatic despite treatment with first line agents or in those with contraindication or intolerance to beta-blockers o calcium channel blockers. Trimetazidine, through its metabolic mechanism of action, improves exercise tolerance and might be useful in patients with concomitant heart failure and contraindication to digitalis; ivabradine can be used in patients with concomitant tachyarrhythmias due to its negative chronotropic effect without affecting inotropism or blood pressure; in contrast, ranolazine doesn't affect chronotropism and can be used in patients with bradyarrhythmias, however, it might cause prolongation of the QTc interval. The choice of treatment with either of the first line or second line antianginal agents must be individualized for each patient and based on comorbidities, contraindications and patient's preference. MÉD.UIS. 2016;29(3):79-93.