Beta-blocker treatment of patients with atrial fibrillation attenuates spontaneous calcium release-induced electrical activity.

AIMS: Atrial fibrillation (AF) has been associated with excessive spontaneous calcium release, linked to cyclic AMP (cAMP)-dependent phosphorylation of calcium regulatory proteins. Because ß-blockers are expected to attenuate cAMP-dependent signaling, we aimed to examine whether the treatment of patients with ß-blockers affected the incidence of spontaneous calcium release events or transient inward currents (ITI). METHODS: The impact of treatment with commonly used ß-blockers was analyzed in human atrial myocytes from 371 patients using patch-clamp technique, confocal calcium imaging or immunofluorescent labeling. Data were analyzed using multivariate regression analysis taking into account potentially confounding effects of relevant clinical factors RESULTS: The L-type calcium current (ICa) density was diminished significantly in patients with chronic but not paroxysmal AF and the treatment of patients with ß-blockers did not affect ICa density in any group. By contrast, the ITI frequency was elevated in patients with either paroxysmal or chronic AF that did not receive treatment, and ß-blocker treatment reduced the frequency to levels observed in patients without AF. Confocal calcium imaging showed that ß-blocker treatment also reduced the calcium spark frequency in patients with AF to levels observed in those without AF. Furthermore, phosphorylation of the ryanodine receptor (RyR2) at Ser-2808 and phospholamban at Ser-16 was significantly lower in patients with AF that received ß-blockers. CONCLUSION: Together, our findings demonstrate that ß-blocker treatment may be of therapeutic utility to prevent spontaneous calcium release-induced atrial electrical activity; especially in patients with a history of paroxysmal AF displaying preserved ICa density.

Impact of R-Carvedilol on ß2-Adrenergic Receptor-Mediated Spontaneous Calcium Release in Human Atrial Myocytes.

A hallmark of atrial fibrillation is an excess of spontaneous calcium release events, which can be mimicked by ß1- or ß2-adrenergic stimulation. Because ß1-adrenergic receptor blockers (ß1-blockers) are primarily used in clinical practice, we here examined the impact of ß2-adrenergic stimulation on spontaneous calcium release and assessed whether the R- and S-enantiomers of the non-selective ß- blocker carvedilol could reverse these effects. For this purpose, human atrial myocytes were isolated from patients undergoing cardiovascular surgery and subjected to confocal calcium imaging or immunofluorescent labeling of the ryanodine receptor (RyR2). Interestingly, the ß2-adrenergic agonist fenoterol increased the incidence of calcium sparks and waves to levels observed with the non-specific ß-adrenergic agonist isoproterenol. Moreover, fenoterol increased both the amplitude and duration of the sparks, facilitating their fusion into calcium waves. Subsequent application of the non ß-blocking R-Carvedilol enantiomer reversed these effects of fenoterol in a dose-dependent manner. R-Carvedilol also reversed the fenoterol-induced phosphorylation of the RyR2 at Ser-2808 dose-dependently, and 1 µM of either R- or S-Carvedilol fully reversed the effect of fenoterol. Together, these findings demonstrate that ß2-adrenergic stimulation alone stimulates RyR2 phosphorylation at Ser-2808 and spontaneous calcium release maximally, and points to carvedilol as a tool to attenuate the pathological activation of ß2-receptors.

Early clinical outcomes after transaxillary versus transfemoral TAVI. Data from the Spanish TAVI registry.

INTRODUCTION AND OBJECTIVES: Transaxillary access (TXA) has become the most widely used alternative to transfemoral access (TFA) in patients undergoing transcatheter aortic valve implantation (TAVI). The aim of this study was to compare total in-hospital and 30-day mortality in patients included in the Spanish TAVI registry who were treated by TXA or TFA access. METHODS: We analyzed data from patients treated with TXA or TFA and who were included in the TAVI Spanish registry. In-hospital and 30-day events were defined according to the recommendations of the Valve Academic Research Consortium. The impact of the access route was evaluated by propensity score matching according to clinical and echocardiogram characteristics. RESULTS: A total of 6603 patients were included; 191 (2.9%) were treated via TXA and 6412 via TFA access. After adjustment (n=113 TXA group and n=3035 TFA group) device success was similar between the 2 groups (94%, TXA vs 95%, TFA; P=.95). However, compared with the TFA group, the TXA group showed a higher rate of acute myocardial infarction (OR, 5.3; 95%CI, 2.0-13.8); P=.001), renal complications (OR, 2.3; 95%CI, 1.3-4.1; P=.003), and pacemaker implantation (OR, 1.6; 95%CI, 1.01-2.6; P=.03). The TXA group also had higher in-hospital and 30-day mortality rates (OR, 2.2; 95%CI, 1.04-4.6; P=.039 and OR, 2.3; 95%CI, 1.2-4.5; P=.01, respectively). CONCLUSIONS: Compared with ATF, TXA is associated with higher total mortality, both in-hospital and at 30 days. Given these results, we believe that TXA should be considered only in those patients who are not suitable candidates for TFA.

[The role of chemotherapy in advanced oral cavity cancer]. / El papel de la quimioterapia en el cáncer de la cavidad oral avanzado.

OBJECTIVE: To evaluate the role of chemotherapy in advanced cancer of the oral cavity by assessing its influence on the survival of patients receiving palliative care and its ability to improve the expectations of curative surgery. PATIENTS AND METHOD: Ninety-nine consecutive patients were analyzed to assess their course, the prognostic factors for tumour progression, and overall survival after treatment with two different chemotherapy regimes: cisplatin plus bleomycin (n=45) or cisplatin plus 5-fluorouracil (n=52). For the analysis, patients were split into groups depending on the treatment intention: palliative (n=41) or neo-adjuvant (n=56). RESULTS: The response rate was 56.7%. The response was greater in the neo-adjuvant group (73.2%) than among the palliative patients (36.6%) (P<0.001); greater with the bleomycin regime (73.3%) than with 5-fluorouracil (44.2%) (P=0.003); and greater in patients with stage III (77.8%) than stage IV (50%) (P=0.021). Survival was higher among patients receiving bleomycin than in those on 5-fluorouracil (P=0.019) and among those with stage III than stage IV (P=0.013). In the palliative treatment group, the response was associated with greater survival (P<0.001). In the neo-adjuvant group, 30 patients (53.6%) underwent surgery, with complete resection in 26 of them (86.7%). Sixteen cases (61.5%) presented recurrence. Chemotherapy response was not associated with operability. Survival was higher in the group with complete tumour resection (P<0.041). CONCLUSIONS: The response to chemotherapy in oral cavity tumours was greater in patients with stage III and in those receiving bleomycin. Chemotherapy may improve survival in palliative cases. In neo-adjuvant cases, no great influence was seen in the conversion of doubtful cases into candidates for surgery.

El papel de la quimioterapia en el cáncer de la cavidad oral avanzado / The role of chemotherapy in advanced oral cavity cancer

Objetivo: Valorar el papel de la quimioterapia en el cáncer avanzado de cavidad oral valorando su influencia en la supervivencia de los pacientes considerados como paliativos y su capacidad para mejorar las expectativas de cirugía curativa. Pacientes y método: Noventa y nueve pacientes consecutivos fueron analizados para valorar su evolución, los factores pronósticos de la progresión del tumor y la supervivencia global después del tratamiento con dos regímenes diferentes de quimioterapia: cisplatino más bleomicina (BLM) (n ¼ 45) o más 5-fluorouracilo (5-FU) (n ¼ 52). El análisis se realizó dividiendo los pacientes de acuerdo con la finalidad del tratamiento: paliativo (n ¼ 41) o neoadyuvante (n ¼ 56). Resultados: La tasa de respuesta fue del 56,7%. La respuesta fue mayor en el grupo neoadyuvante (73,2%) que en el grupo paliativo (36,6%) (po 0,001), mayor con el régimen de BLM (73,3%) que con 5-FU (44,2%) (p ¼ 0,003) y mayor en pacientes con estadio III (77,8%) que IV (50%) (p ¼ 0,021). La supervivencia fue mayor en pacientes que recibieron BLM que en los que recibieron 5-FU (p ¼ 0,019) y en el estadio III que en el IV (p ¼ 0,013). En el grupo paliativo, la respuesta se asoció a una mayor supervivencia (po0,001). En el grupo neoadyuvante, 30 pacientes (53,6%) fueron intervenidos y la resección fue completa en 26 de ellos (86,7%). Dieciséis casos (61,5%) presentaron una recidiva. La respuesta a la quimioterapia no se asoció a la operabilidad. La supervivencia fue mayor en el grupo con una resección completa del tumor (p ¼ 0,041). Conclusiones: La respuesta a la quimioterapia en los tumores de cavidad oral fue mayor en los pacientes con estadio III y en los que recibieron BLM. La quimioterapia puede mejorar la supervivencia en casos paliativos. En los casos neoadyuvantes no se demostró una gran influencia para convertir casos dudosos de cirugía en tributarios para cirugía (AU)

Objective. To evaluate the role of chemotherapy in advanced cancer of the oral cavity by assessing its influence on the survival of patients receiving palliative care and its ability to improve the expectations of curative surgery. Patients and method. Ninety-nine consecutive patients were analyzed to assess their course, the prognostic factors for tumour progression, and overall survival after treatment with two different chemotherapy regimes: cisplatin plus bleomycin (n=45) or cisplatin plus 5-fluorouracil (n=52). For the analysis, patients were split into groups depending on the treatment intention: palliative (n=41) or neo-adjuvant (n=56). Results. The response rate was 56.7%. The response was greater in the neo-adjuvant group (73.2%) than among the palliative patients (36.6%) (P <0 001 greater with the bleomycin regime 73 3 than 5-fluorouracil 44 2 P=0.003); and greater in patients with stage III (77.8%) than stage IV (50%) ( P=0.021). Survival was higher among patients receiving bleomycin than in those on 5-fluorouracil (P=0.019) and among those with stage III than stage IV (P=0.013). In the palliative treatment group, the response was associated with greater survival (P <0 001). In the neo-adjuvant group, 30 patients (53.6%) underwent surgery, with complete resection in 26 of them (86.7%). Sixteen cases (61.5%) presented recurrence. Chemotherapy response was not associated with operability. Survival was higher in the group with complete tumour resection (P <0 041). Conclusions. The response to chemotherapy in oral cavity tumours was greater in patients with stage III and in those receiving bleomycin. Chemotherapy may improve survival in palliative cases. In neo-adjuvant cases, no great influence was seen in the conversion of doubtful cases into candidates for surgery (AU)