Map-guided surgery for atrial fibrillation

BackgroundAlthough current surgical procedures result in a high success rate for atrial fibrillation, they are not guided by electrophysiologic findings in individual patients and thus might include unnecessary incisions in some patients or be inappropriate for other patients. We sought to determine whether intraoperative mapping is beneficial for the surgical treatment of atrial fibrillation.MethodsA 256-channel 3-dimensional dynamic mapping system with custom-made epicardial patch electrodes was used to examine the atrial activation during atrial fibrillation and to determine the optimal procedure in 37 patients with continuous and 9 patients with intermittent atrial fibrillation intraoperatively.ResultsSurgical intervention for atrial fibrillation was not indicated in 3 patients in whom the atrial electrograms had a low voltage over a broad area. Concurrent, multiple, and repetitive activations arising from the pulmonary veins or left atrial appendage were observed in all patients. A simple left atrial procedure consisting of pulmonary vein isolation and left atrial incisions without any right atrial incisions was performed in 8 patients in whom the right atrial activation was passive, and all (100%) were cured of atrial fibrillation. The radial procedure was performed in the remaining 35 patients, and 31 (89%) of the patients were cured of atrial fibrillation. In this subset of patients, 10 exhibited reentrant or focal activation in the posterior left atrium between the right and left pulmonary veins and required an additional linear ablation on the posterior left atrium. The total amount of postoperative bleeding after the simple left atrial procedure was significantly less than after the radial procedure (378 ± 135 vs 711 ± 364 mL, P = .03). The right and left atrial transport functions were well preserved after both the radial and simple left atrial procedures.ConclusionIntraoperative mapping facilitates determining the optimal procedure for atrial fibrillation in each patient

Inappropriate implantable cardioverter defibrillator shocks—incidence, effect, and implications for driver licensing

PurposePatients with implantable cardioverter defibrillators (ICDs) have an ongoing risk of sudden incapacitation that may cause traffic accidents. However, there are limited data on the magnitude of this risk after inappropriate ICD therapies. We studied the rate of syncope associated with inappropriate ICD therapies to provide a scientific basis for formulating driving restrictions.MethodsInappropriate ICD therapy event data between 1997 and 2014 from 50 Japanese institutions were analyzed retrospectively. The annual risk of harm (RH) to others posed by a driver with an ICD was calculated for private driving habits. We used a commonly employed annual RH to others of 5 in 100,000 (0.005%) as an acceptable risk threshold.ResultsOf the 4089 patients, 772 inappropriate ICD therapies occurred in 417 patients (age 61 ± 15 years, 74% male, and 65% secondary prevention). Patients experiencing inappropriate therapies had a mean number of 1.8 ± 1.5 therapy episodes during a median follow-up period of 3.9 years. No significant differences were found in the age, sex, or number of inappropriate therapies between patients receiving ICDs for primary or secondary prevention. Only three patients (0.7%) experienced syncope associated with inappropriate therapies. The maximum annual RH to others after the first therapy in primary and secondary prevention patients was calculated to be 0.11 in 100,000 and 0.12 in 100,000, respectively.ConclusionsWe found that the annual RH from driving was far below the commonly cited acceptable risk threshold. Our data provide useful information to supplement current recommendations on driving restrictions in ICD patients with private driving habits

Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells.

Despite the benefits of imatinib for treating gastrointestinal stromal tumors (GIST), the prognosis for high risk GIST and imatinib-resistant (IR) GIST remains poor. The mechanisms of imatinib resistance have not yet been fully clarified. The aim of the study was to establish imatinib-resistant cell lines and investigate nilotinib, a second generation tyrosine kinase inhibitor (TKI), in preclinical models of GIST and imatinib-resistant GIST. For a model of imatinib-resistant GIST, we generated resistant cells from GK1C and GK3C cell lines by exposing them to imatinib for 6 months. The parent cell lines GK1C and GK3C showed imatinib sensitivity with IC50 of 4.59±0.97 µM and 11.15±1.48 µM, respectively. The imatinib-resistant cell lines GK1C-IR and GK3C-IR showed imatinib resistance with IC50 values of 11.74±0.17 µM (P<0.001) and 41.37±1.07 µM (P<0.001), respectively. The phosphorylation status of key cell signaling pathways, receptor tyrosine kinase KIT (CD117), platelet-derived growth factor receptor alpha (PDGFRA) and downstream signaling kinases: serine-threonine kinase Akt (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) or the non-receptor tyrosine kinase: proto-oncogene tyrosine-protein kinase Src (SRC), was analyzed in established cell lines and ERK1/2 phosphorylation was found to be increased compared to the parental cells. Nilotinib demonstrated significant antitumor efficacy against GIST xenograft lines and imatinib-resistant GIST cell lines. Thus, nilotinib may have clinical potential for patients with GIST or imatinib-resistant GIST

Nilotinib antitumor activity in GIST xenograft models.

<p>(A) Immunohistochemistry staining for KIT in xenograft lines established from human GISTs: GK1X, GK2X and GK3X. (B) Tumor tissue fragments (∼5 mm³) were transplanted s.c. into the backs of BALB/cSlc-<i>nu/nu</i> mice that were randomized into 3 groups (n = 6–8). Doses of 40 mg/kg/day of imatinib, nilotinib or pure water (control) were administered by oral gavage daily for 28 days. Tumor size was measured every two to three days. (C) Tumor growth inhibition (TGI) on the day of evaluation was calculated as the ratio of tumor volume on the evaluation day to that on day 1.</p

Quantitative phosphorylation analysis.

<p>Parental (GK1C and GK3C; red histograms) or imatinib-resistant GIST cell lines (GK1C-IR and GK3C-IR, blue histograms) were fixed and stained with anti phospho-KIT (Tyr719), anti phospho-PDGFRA (Tyr754), anti phospho-SRC (Tyr416), anti phospho-AKT (Ser473) and anti phospho-ERK1/2 (Thr202/Tyr204). Finally, cells were detected with Alexa Fluor 488 donkey anti-rabbit IgG antibody (Isotype control was reacted only with the secondary antibody). The MFI (mean of fluorescence intensity) values were calculated by FlowJo. GK1C: p-KIT = 3.21, p-PDGFRA = 10.3, p-SRC = 7.19, p-AKT = 20.3, p-ERK1/2 = 37.8. GK1C-IR: p-KIT = 3.30, p-PDGFRA = 12.8, p-SRC = 9.35, p-AKT = 20.5, p-ERK1/2 = 94.4. GK3C: p-KIT = 2.65, p-PDGFRA = 7.29, p-SRC = 5.35, p-AKT = 19.5, p-ERK1/2 = 32.2. GK3C-IR: p-KIT = 3.89, p-PDGFRA = 9.82, p-SRC = 8.31, p-AKT = 21.3, p-ERK1/2 = 115.</p

Antitumor activity of nilotinib on GIST and imatinib-resistant GIST cells.

<p>Cells were maintained in supplemented medium for 12 h, and then incubated with nilotinib (0∼100 µM) for 72 h. Cell viability was determined by comparing treated cells with the untreated control. Data are means of triplicates from a representative experiment.</p

Establishment of imatinib-resistant GIST cell lines.

<p>(A, B) Immunohistochemical assay of KIT expression in GK1C-IR and GK3C-IR as determined by staining with DAB (magnification, 400x). (C, D) GK1C and GK1C-IR cells, GK3C and GK3C-IR cells, 2.5×10³ cells (per well) were seeded into 96-well microplates in triplicate 12 h before treatment, and then exposed to different concentrations (0∼100 µM) of imatinib for 72 h. The percentage of cellular proliferation was gauged using the WST-8 method. Imatinib-resistant (IR) cells showed resistance to imatinib with IC₅₀ of 11.74±0.17 µM (<i>p<0.001</i>) or 41.37±1.07 µM (<i>p<0.001</i>). Data are presented as means ± SD and evaluated using Student's <i>t</i> test.</p