Modificaciones farmacológicas de las propiedades electrofisiológicas cardíacas. Estudio experimental y simulación con modelos matemáticos.

RESUMEN INTRODUCCIÓN: Se ha estudiado en un modelo experimental y mediante simulación con modelos matemáticos, el efecto de tres fármacos (flecainida, dofetilide y pinacidil) sobre las propiedades electrofisiológicas ventriculares en condiciones basales y en circunstancias tales como la fibrilación ventricular (FV) y la isquemia aguda regional (IAR). MATERIAL Y MÉTODOS: se han utilizado 56 preparaciones de corazón aislado y perfundido de conejo según la técnica de Langendorff. El sistema de registro ha sido mediante placas electrodo situadas en la superficie epicárdica, compuestas bien por 121, 114 o 235 electrodos unipolares según el protocolo experimental. La estimulación se ha realizado mediante un electrodo bipolar de acero inoxidable. Se han realizado tres grupos experimentales para el estudio de cada fármaco. En 11 experimentos se ha estudiado el efecto de 1 μmolar de flecainida sobre las velocidades de conducción ventricular longitudinal (VL) y transversal (VT) con tres intervalos de acoplamiento decrecientes, así como la influencia del intervalo de acoplamiento (IA) en el mismo y el predominio de los efectos del fármaco sobre la VL versus VT. En 17 experimentos se ha estudiado el efecto de 0.5 μmolar de dofetilide sobre los periodos refractarios ventriculares (PR) y sobre la velocidad de conducción ventricular (VC) con cuatro ciclos base diferentes, así como el efecto de concentraciones crecientes de fármaco (1-5-10 μmolar) sobre el patrón fibrilatorio. El patrón fibrilatorio se ha estudiado mediante análisis espectral según la técnica de Welch, mediante análisis en el dominio del tiempo y mediante el estudio de los mapas de activación epicárdicos. En 28 preparaciones se ha estudiado el efecto de 10 μmolar de pinacidil sobre los PR y la inducibilidad de FV en condiciones basales y de isquemia aguda, así como los patrones de activación ventricular de la arritmia en su inicio. El estudio del pinacidil se ha completado con simulación de tejidos unidimensionales y bidimensionales mediante modelos matemáticos modernos basados en las características del potencial de acción y de las corrientes iónicas transmembrana. RESULTADOS Y CONCLUSIONES: la flecainida acortó significativamente la VL y VT para cada intervalo de acoplamiento estudiado, mostrando mayor efecto conforme se acortó el IA sólo en el caso de la VL. Para IA largos la flecainida afectó más a la VT, efecto que se igualó entre ambas VC para IA cortos. El dofetilide alargó los PR de forma significativa con un efecto inverso dependiente de la frecuencia, sin afectar a la VC. Este efecto se tradujo en una reducción en la complejidad del patrón fibrilatorio en ambos ventrículos, pero de forma mas acusada en el ventrículo derecho. Se produjo el cese de la arritmia únicamente en tres casos. El pinacidil acortó los PR, efecto que quedó encubierto, según los resultados con modelos matemáticos, por un aumento de la refractariedad postrepolarización en condiciones de IAR. El fármaco mostró un efecto protector contra la FV en el minuto 5 de isquemia, efecto que se perdió al analizar el fenómeno globalmente a los 30 minutos de isquemia, donde el pinacidil no mostró efecto protector aunque tampoco aumentó la incidencia de FV con respecto al grupo control. El efecto protector del pinacidil en el minuto 5 de isquemia se relacionó, según los resultados con modelos matemáticos, con la concentración del fármaco utilizada. Los resultados con modelos sugirieron como mecanismo protector del pinacidil, la tendencia del fármaco a producir bloqueos bidireccionales y no unidireccionales, como consecuencia de la reducción de la excitabilidad celular derivada de la fuerte activación de la corriente IKATP en presencia de corrientes de sodio deprimidas por la isquemia. __________________________________________________________________________________________________INTRODUCTION: The effects of three drugs (flecainide, dofetilide and pinacidil) on ventricular electrophysiological properties were studied in both an experimental model of rabbit heart (perfused Langendorff preparation) and with mathematical simulation models (only for pinacidil). METHODS: in 11 experimental preparations, the effect of flecainide 1 μmol/L on longitudinal and transversal conduction velocity was tested using three different coupling intervals. In 17 preparations, the effect of 0.5 μmol/L dofetilide on conduction velocity and refractoriness was studied using four different cycle lengths, as well as the effects of dofetilide (1, 5 and 10 µmol/L) on ventricular fibrillatory patterns. The effects of 10 µmol/L pinacidil on ventricular refractoriness and on ventricular fibrillation induction in basal conditions and in acute myocardial ischemia were studied using 28 experimental preparations and mathematical models. RESULTS: flecainida decreased both longitudinal and transversal conduction velocity, showing a use-dependent effect only in the case of longitudinal conduction velocity. With short coupling intervals, the effect of flecainida was greater for transversal than for longitudinal conduction velocity. Dofetilide (0.5 µmol/L) caused an increase in ventricular refractoriness in a reverse-use-dependent manner, without affecting ventricular conduction times. Increasing drug concentration from 1 to 10 µmol/L caused a reduction on the complexity of ventricular fibrillation patterns specially on the right ventricle, suppressing the arrhythmia only in three cases. Pinacidil (10 μmol/L) caused a decrease in ventricular refractoriness in basal conditions but not in ischemic conditions, due to an increase of post-repolarization refractoriness in the latter, as suggested by simulation results. Pinacidil showed protection action against ventricular fibrillation in the fifth minute of acute regional ischemia in a concentration dependent manner, due (as suggested by simulation results) to the induction of bidirectional (and not unidirectional) conduction block as a consequence of a reduction in cellular excitability caused by the strong activation of the IK(ATP) current in the presence of an ischemic-depressed sodium current

Primary results of the Spanish Cryoballoon Ablation Registry: acute and long-term outcomes of the RECABA study

Cryoablation is safe and effective for the treatment of atrial fibrillation (AF) in controlled clinical trials, but contemporary real-world usage and outcomes are limited. The Report of the Spanish Cryoballoon Ablation Registry (RECABA) was designed to evaluate acute and 12-month outcomes of cryoballoon ablation for the treatment of AF in Spain. Patients from 27 Spanish centers were prospectively enrolled. Patients were treated with cryoballoon ablation and managed according to standard of care protocols at each center. The primary endpoint was ≥ 30 s freedom from AF at 12-month after a 3-month blanking period. Secondary endpoints included a description of patient characteristics, cryoablation procedural strategy and safety, and predictors of efficacy. In total, 1742 patients (71.4% PAF, 68.8% male, mean age 58.02 ± 10.40 years, 76.1% overweight or obese, CHA2DS2-VASc index 1.40 ± 1.28) were enrolled. Patients received 7.2 ± 2.67 cryo-applications. PV potentials could be detected in 61% of the PVs during ablation, with a mean time to block of 52.9 ± 37.02 s. Acute PVI was observed in 97% of PVs with 75.8% isolated with the first cryo-application. Mean procedural time was 113 ± 41 min. Acute complications occurred in 4.4% of the cases. With follow-up in 1628 patients, AF-free survival was 78.5% (PAF: 80.6% vs PersAF 73.3%; p < 0.001). Left atrium enlargement, female sex, non-PAF, and early recurrence were independent predictors of AF recurrence (p < 0.05). RECABA provides detailed insight into current dosing practices and demonstrates cryoablation is safe and effective in real-world use

Cardiac magnetic resonance outperforms echocardiography to predict subsequent implantable cardioverter defibrillator therapies in ST-segment elevation myocardial infarction patients

Altres ajuts: Conselleria de Educación-Generalitat Valenciana (PROMETEO/2021/008); Sociedad Española de Cardiología (Grant SEC/FEC-INVCLI 21/024)Implantable cardioverter defibrillators (ICD) are effective as a primary prevention measure of ventricular tachyarrhythmias in patients with ST-segment elevation myocardial infarction (STEMI) and depressed left ventricular ejection fraction (LVEF). The implications of using cardiac magnetic resonance (CMR) instead of echocardiography (Echo) to assess LVEF prior to the indication of ICD in this setting are unknown. We evaluated 52 STEMI patients (56.6 ± 11 years, 88.5% male) treated with ICD in primary prevention who underwent echocardiography and CMR prior to ICD implantation. ICD implantation was indicated based on the presence of heart failure and depressed LVEF (≤ 35%) by echocardiography, CMR, or both. Prediction of ICD therapies (ICD-T) during follow-up by echocardiography and CMR before ICD implantation was assessed. Compared to echocardiography, LVEF was lower by cardiac CMR (30.2 ± 9% vs. 37.4 ± 7.6%, p < 0.001). LVEF ≤ 35% was detected in 24 patients (46.2%) by Echo and in 42 (80.7%) by CMR. During a mean follow-up of 6.1 ± 4.2 years, 10 patients received appropriate ICD-T (3.16 ICD-T per 100 person-years): 5 direct shocks to treat very fast ventricular tachycardia or ventricular fibrillation, 3 effective antitachycardia pacing (ATP) for treatment of ventricular tachycardia, and 2 ineffective ATP followed by shock to treat ventricular tachycardia. Echo-LVEF ≤ 35% correctly predicted ICD-T in 4/10 (40%) patients and CMR-LVEF ≤ 35% in 10/10 (100%) patients. CMR-LVEF improved on Echo-LVEF for predicting ICD-T (area under the curve: 0.76 vs. 0.48, p = 0.04). In STEMI patients treated with ICD, assessment of LVEF by CMR outperforms Echo-LVEF to predict the subsequent use of appropriate ICD therapies

Time to –30°C as a predictor of acute success during cryoablation in patients with atrial fibrillation

Background: Freezing rate of second-generation cryoballoon (CB) is a biophysical parameter that could assist pulmonary vein isolation. The aim of this study is to assess freezing rate (time to reach –30°C ([TT-30C]) as an early predictor of acute pulmonary vein isolation using the CB. Methods: Biophysical data from CB freeze applications within a multicenter, nation-wide CB ablation registry were gathered. Successful application (SA), was defined as achieving durable intraprocedural vein isolation with time to isolation in under 60 s (SA-TTI&lt;60) as achieving durable vein isolation in under 60 s. Logistic regressions were performed and predictive models were built for the data set. Results: 12,488 CB applications from 1,733 atrial fibrillation (AF) ablation procedures were included within 27 centers from a Spanish CB AF ablation registry. SA was achieved in 6,349 of 9,178 (69.2%) total freeze applications, and SA-TTI&lt;60 was obtained in 2,673 of 4,784 (55.9%) freezes and electrogram monitoring was present. TT-30C was shorter in the SA group (33.4 ± 9.2 vs 39.3 ± 12.1 s; p &lt; 0.001) and SA-TTI&lt;60 group (31.8 ± 7.6 vs. 38.5 ± 11.5 s; p &lt; 0.001). Also, a 10 s increase in TT-30C was associated with a 41% reduction in the odds for an SA (odds ratio [OR] 0.59; 95% confidence interval [CI] 0.56–0.63) and a 57% reduction in the odds for achieving SA-TTI&lt;60 (OR 0.43; 95% CI 0.39–0.49), when corrected for electrogram visualization, vein position, and application order. Conclusions: Time to reach –30°C is an early predictor of the quality of a CB application and can be used to guide the ablation procedure even in the absence of electrogram monitoring.

Repeat cryoablation as a redo procedure for atrial fibrillation ablation: Is it a good choice?

Background: Ablation of atrial fibrillation (AF), both cryoablation ablation (CBA) and radiofrequency catheter ablation (RFCA), have demonstrated to be safe and effective. About 1 in 3 patients may face a redo due to recurrence and the best technique is unknown. The aim of this study is to assess the efficacy of CBA as a repeat procedure in patients with prior CBA or RFCA. Methods: A nation-wide CBA registry (RECABA) was analyzed and patients were compared who had previously undergone CBA (Prior-CB) or RFCA (Prior-RF). The primary endpoint was AF recurrence at 12 months after a 3-month blanking period. A survival analysis was performed, univariate and multivariate Cox models were also built. Results: Seventy-four patients were included. Thirty-three (44.6%) were in the Prior-CB group and 41 (55.4%) in the Prior-RF. There were more reconnected pulmonary veins in the Prior-RF than in Prior-CB group (40.4% vs.16.5%, p = 0.0001). The 12-month Kaplan–Meier estimate of freedom from AF recurrence after the blanking period was 61.0% (95% confidence interval [CI] 41.4–75.8%) in the Prior-CB, and 89.2% (95% CI 73.6–95.9%) in the Prior-RF group (p = 0.002).  Multivariate Cox regression pointed Prior-CB as the sole independent predictor of AF recurrence, with an adjusted HR of 2.67 (95% CI 1.05–6.79). Conclusions: Repeat CBA shows higher rates of AF recurrences compared to CBA after a previous RFCA despite presenting less reconnected veins at the procedure. These data suggest that patients with AF recurrence after CBA may benefit from other ablation techniques after a recurrence. RECABA is registered at clinicaltrials.gov with the Unique Identifier NCT02785991

Primary results of the Spanish Cryoballoon Ablation Registry: acute and long-term outcomes of the RECABA study

Cryoablation is safe and effective for the treatment of atrial fibrillation (AF) in controlled clinical trials, but contemporary real-world usage and outcomes are limited. The Report of the Spanish Cryoballoon Ablation Registry (RECABA) was designed to evaluate acute and 12-month outcomes of cryoballoon ablation for the treatment of AF in Spain. Patients from 27 Spanish centers were prospectively enrolled. Patients were treated with cryoballoon ablation and managed according to standard of care protocols at each center. The primary endpoint was ≥ 30 s freedom from AF at 12-month after a 3-month blanking period. Secondary endpoints included a description of patient characteristics, cryoablation procedural strategy and safety, and predictors of efficacy. In total, 1742 patients (71.4% PAF, 68.8% male, mean age 58.02 ± 10.40 years, 76.1% overweight or obese, CHA2DS2-VASc index 1.40 ± 1.28) were enrolled. Patients received 7.2 ± 2.67 cryo-applications. PV potentials could be detected in 61% of the PVs during ablation, with a mean time to block of 52.9 ± 37.02 s. Acute PVI was observed in 97% of PVs with 75.8% isolated with the first cryo-application. Mean procedural time was 113 ± 41 min. Acute complications occurred in 4.4% of the cases. With follow-up in 1628 patients, AF-free survival was 78.5% (PAF: 80.6% vs PersAF 73.3%; p < 0.001). Left atrium enlargement, female sex, non-PAF, and early recurrence were independent predictors of AF recurrence (p < 0.05). RECABA provides detailed insight into current dosing practices and demonstrates cryoablation is safe and effective in real-world use.ClinicalTrials.gov number: NCT02785991