Radio-frequency ablation as primary management of well-tolerated sustained monomorphic ventricular tachycardia in patients with structural heart disease and left ventricular ejection fraction over 30%.

AIMS: Patients with well-tolerated sustained monomorphic ventricular tachycardia (SMVT) and left ventricular ejection fraction (LVEF) over 30% may benefit from a primary strategy of VT ablation without immediate need for a 'back-up' implantable cardioverter-defibrillator (ICD). METHODS AND RESULTS: One hundred and sixty-six patients with structural heart disease (SHD), LVEF over 30%, and well-tolerated SMVT (no syncope) underwent primary radiofrequency ablation without ICD implantation at eight European centres. There were 139 men (84%) with mean age 62 ± 15 years and mean LVEF of 50 ± 10%. Fifty-five percent had ischaemic heart disease, 19% non-ischaemic cardiomyopathy, and 12% arrhythmogenic right ventricular cardiomyopathy. Three hundred seventy-eight similar patients were implanted with an ICD during the same period and serve as a control group. All-cause mortality was 12% (20 patients) over a mean follow-up of 32 ± 27 months. Eight patients (40%) died from non-cardiovascular causes, 8 (40%) died from non-arrhythmic cardiovascular causes, and 4 (20%) died suddenly (SD) (2.4% of the population). All-cause mortality in the control group was 12%. Twenty-seven patients (16%) had a non-fatal recurrence at a median time of 5 months, while 20 patients (12%) required an ICD, of whom 4 died (20%). CONCLUSION: Patients with well-tolerated SMVT, SHD, and LVEF > 30% undergoing primary VT ablation without a back-up ICD had a very low rate of arrhythmic death and recurrences were generally non-fatal. These data would support a randomized clinical trial comparing this approach with others incorporating implantation of an ICD as a primary strategy.

High bi-atrial organization in patients with long-standing persistent atrial fibrillation terminated within the left atrium

Sustained atrial fibrillation (AF) is maintained by sites displaying high dominant frequency (DF). In patients (pts) with long-standing persistent AF (LS-pAF), their spatial distribution and the presence of a left-to-right atrial DF gradient remain poorly known. We hypothesized that the pre-ablation bi-atrial frequency characteristics of LS-pAF pts terminated within the left atrium (LT) are different from that of non terminated (NT) ones. Methods: 23 consecutive pts (59±7y, LS-pAF duration 19±12m) underwent stepwise catheter ablation (step-CA) consisting in pulmonary veins isolation, left atrial (LA) defragmentation, and right atrial (RA) ablations for non terminated AF. A quadripolar catheter (CAT) was placed into the RA appendage (RAA), a decapolar CAT into the coronary sinus (CS) and a duodecapolar CAT into the LA divided into 8 segments. For each segment, 20-sec of bipolar recording was acquired. The DF was defined as the largest peak in the power spectrum (3-15 Hz). The inter-atrial DF gradient was defined as the DF difference between LA and RA appendages. Results: LS-pAF was terminated in 83% (19/23) of the pts: 17 LT, 2 during RA ablation and 4 NT. The figure shows that before ablation bi-atrial DF values of LT pts are significantly lower than that of NT pts for each LA segment as well as for the RAA (p < 0.05). No significant LA-to-RA DF gradient was observed both for LT (0.3±0.5 Hz, p=ns) and NT (0.5±0.03 Hz, p=ns) pts. No significant difference in DF values was observed between LA segments. Conclusions: The lower DF of LT pts is suggestive of a higher organization within both atria compared to NT pts. Our findings suggest that low bi-atrial DF values, but not inter-atrial DF gradient, might be of interest for selecting LS-pAF candidates for sinus rhythm restoration by step-CA.

Late Jurassic oceanic crust and Upper Cretaceous Caribbean plateau picritic basalts exposed in the Duarte igneous complex, Hispaniola

Four distinct rock units have been recognized near El Aguacate, in the Janico-Juncalito-La Vega area of the Duarte complex (Dominican Republic): (1) serpentinites crosscut by numerous diabasic dikes, (2) basalts interbedded with Late Jurassic ribbon cherts, (3) picrites and ankaramites relatively enriched in incompatible trace elements, and (4) amphibolites and gneissic amphibolites chemically similar to Oceanic Plateau Basalts. Similar Ar-Ar ages of late magmatic amphibole from a picrite, and hornblende from an amphibolite (86.1 +/- 1.3 Ma and 86.7 +/- 1.6 Ma, respectively), suggest that the Duarte picrites are contemporaneous with the Deep Sea Drilling Program Leg 15 and Ocean Drilling Program Leg 126 basalts drilled from the Caribbean oceanic plateau. These basalts are associated with sediments containing Late Cretaceous faunas. Sr, Nd, and Pb data show that enriched picrites and amphibolites are isotopically similar to mafic lavas from previously described Caribbean plateau and Galapagos hotspot basalts. Major element, trace element, and lead isotopic features of Late Jurassic basalts and diabases are consistent with those of normal oceanic crust basalt. However, these basalts differ from typical N-MORB because they have lower epsilon Nd ratios that plot within the range of Ocean Island Basalts. These rocks appear to represent remnants of the Caribbean Jurassic oceanic crust formed from an oceanic ridge possibly close to a hotspot. Later, they were tectonically juxtaposed with Late Cretaceous slices of the Caribbean-Colombian plateau.

Arrhythmogenesis in the developing heart during anoxia-reoxygenation and hypothermia-rewarming: an in vitro model.

INTRODUCTION: The spatio-temporal pattern of arrhythmias in the embryonic/fetal heart subjected to a transient hypoxic or hypothermic stress remains to be established. METHODS AND RESULTS: Spontaneously beating hearts or isolated atria, ventricles, and conotruncus from 4-day-old chick embryos were subjected in vitro to 30-minute anoxia and 60-minute reoxygenation. Hearts were also submitted to 30-minute hypothermia (0-4 degrees C) and 60-minute rewarming. ECG disturbances and alterations of atrial and ventricular electromechanical delay (EMD) were systematically investigated. Baseline functional parameters were stable during at least 2 hours. Anoxia induced tachycardia, followed by bradycardia, atrial ectopy, first-, second-, and third-degree atrio-ventricular blocks and, finally, transient electromechanical arrest after 6.8 minutes, interquartile ranges (IQR) 3.1-16.2 (n = 8). Reoxygenation triggered also Wenckebach phenomenon and ventricular escape beats. At the onset of reoxygenation QT, PR, and ventricular EMD increased by 68%, 70%, and 250%, respectively, whereas atrial EMD was not altered. No fibrillations, no ventricular ectopic beats, and no electromechanical dissociation were observed. Arrhythmic activity of the isolated atria persisted throughout anoxia and upon reoxygenation, whereas activity of the isolated ventricles abruptly ceased after 5 minutes of anoxia and resumed after 5 minutes of reoxygenation. During hypothermia-rewarming, cardiac activity stopped at 17.9 degrees C, IQR 16.2-20.6 (n = 4) and resumed at the same temperature with no arrhythmias. All preparations fully recovered after 40 minutes of reoxygenation or rewarming. CONCLUSION: In the embryonic heart, arrhythmias mainly originated in the sinoatrial tissue and resembled those observed in the adult heart. Furthermore, oxygen readmission was by far more arrhythmogenic than rewarming and the chronotropic, dromotropic, and inotropic effects were fully reversible.

Evolution of the sources of Moroccan volcanism during the Neogene

New major and trace element analyses, Sr-Nd isotopic data and K-40-Ar-40 ages on Neogene and Quaternary lavas from Morocco lead to the conclusion that the observed temporal changes from calc-alkaline to transitional and finally alkaline magmatic activity reflect the contributions of distinct sources. According to our model, magmas originally derived from the melting of an European/Western Mediterranean-type asthenospheric mantle source interact during their ascent with either a subcontinental Ronda - Beni Bousera-/type lithospheric mantle (alkaline magmas) or a lithospheric mantle containing a crustal component, and the overlying continental crust (calc-alkaline and, to a lesser extent, transitional magmas). ( (C) Academie des sciences/Elsevier, Paris.).

The chemokine CCL2 protects against methylmercury neurotoxicity.

Industrial pollution due to heavy metals such as mercury is a major concern for the environment and public health. Mercury, in particular methylmercury (MeHg), primarily affects brain development and neuronal activity, resulting in neurotoxic effects. Because chemokines can modulate brain functions and are involved in neuroinflammatory and neurodegenerative diseases, we tested the possibility that the neurotoxic effect of MeHg may interfere with the chemokine CCL2. We have used an original protocol in young mice using a MeHg-contaminated fish-based diet for 3 months relevant to human MeHg contamination. We observed that MeHg induced in the mice cortex a decrease in CCL2 concentrations, neuronal cell death, and microglial activation. Knock-out (KO) CCL2 mice fed with a vegetal control food already presented a decrease in cortical neuronal cell density in comparison with wild-type animals under similar diet conditions, suggesting that the presence of CCL2 is required for normal neuronal survival. Moreover, KO CCL2 mice showed a pronounced neuronal cell death in response to MeHg. Using in vitro experiments on pure rat cortical neurons in culture, we observed by blockade of the CCL2/CCR2 neurotransmission an increased neuronal cell death in response to MeHg neurotoxicity. Furthermore, we showed that sod genes are upregulated in brain of wild-type mice fed with MeHg in contrast to KO CCL2 mice and that CCL2 can blunt in vitro the decrease in glutathione levels induced by MeHg. These original findings demonstrate that CCL2 may act as a neuroprotective alarm system in brain deficits due to MeHg intoxication.

Post-collisional Neogene magmatism of the Mediterranean Maghreb margin: a consequence of slab breakoff

A 1 200 km-long linear magmatic belt extends along the Mediterranean coast the Maghreb from Eastern Tunisia to Morocco. This belt is mainly composed of Langan calc-alkaline metaluminous to peraluminous granitoids and associated andesites/cites Central and Eastern Algeria. In Tunisia and Oranie/Western Morocco, calc alkaline activity started later (during the Serravallian) and was followed by the placement of alkali basalts and basanites since the Tortonian to the Pliocene and, in me places, the Pleistocene. Available data on the tectonic setting, petrology, age and biochemistry of this belt show that most of its striking features, e.g. (1) very low magma production rate, subduction-related geochemical imprint, extensive crustal contamination the calc-alkaline magmatism and (2) progressive magmatic change from calc-alkaline alkaline, are consistent with magma generation during a slab breakoff process as proposed Carminati et al, in 1998. The magmatism associated with this breakoff started in Central Eastern Algeria at 16 Ma, then propagated eastwards and westwards, The upward of asthenospheric enriched plume-type mantle through the tear in the downgoing first triggered melting of the overlying lithospheric mantle which had been metasomatised during a previous subduction period. Heat supply from this uprising asthenosphere may have warmed up the continental crust and made its involvement in assimilation processes easier. As the asthenosphere ascended through the `window' in the slab, partial melting occurred at the uprising boundary between asthenosphere and lithosphere, generating basalts with transitional characteristics between those of calc-alkaline and alkaline basalts. As the asthhenospheric upwelling proceeded partial:melting then occurred in the sole asthenospheric mantle, producing alkali basalts. (C) 2000 Academie des sciences Editions scientifiques et medicales Elsevier SAS.

Multiple plume events in the genesis of the peri-Caribbean Cretaceous oceanic plateau province

The oceanic crust fragments exposed in central America, in north-western South America, and in the Caribbean islands have been considered to represent accreted remnants of the Caribbean-Colombian Oceanic Plateau (CCOP). On the basis of trace element and Nd, Sr, and Pb isotopic compositions we infer that cumulate rocks, basalts, and diabases from coastal Ecuador have a different source than the basalts from the Dominican Republic. The latter suite includes the 86 Ma basalts of the Duarte Complex which are light rare earth element (REE) -enriched and display (relative to normal mid-ocean ridge basalts, NMORB) moderate enrichments in large ion lithophile elements, together with high Nb, Ta, Pb, and low Th contents. Moreover, they exhibit a rather restricted range of Nd and Pb isotopic ratios consistent with their derivation from an ocean island-type mantle source, the composition of which includes the HIMU (high U-238/Pb-204) component characteristic of the Galapagos hotspot. In contrast, the 123 Ma Ecuadorian oceanic rocks have flat REE patterns and (relative to NMORB) are depleted in Zr, Hf, Th, and U. Moreover, they show a wide range of Nd and Pb isotopic ratios intermediate between those of ocean island basalts and NMORB. It is unlikely, on geochemical grounds, that the plume source of the Ecuadorian fragments was similar to that of the Galapagos. In addition, because of the NNE motion of the Farallon plate during the Early Cretaceous, the Ecuadorian oceanic plateau fragments could not have been derived from the Galapagos hotspot but were likely formed at a ridge-centered or near-ridge hotspot somewhere in the SE Pacific.

The alkaline intraplate volcanism of the Antalya nappes (Turkey): a Late Triassic remnant of the Neotethys

Late Triassic submarine alkali basalts and hawaiites were collected from two superimposed tectonic slices belonging to the Kara Dere - Sayrun unit of the Middle Antalya nappes, southwestern Turkey. New determinations on conodont faunas allow to date this sequence to the Lower Carnian (Julian). The volcanic rocks show rather homogeneous compositions, with high TiO2 and relatively low MgO and Ni contents which suggest olivine fractionation. Their primitive mantle-normalised multi-elements plots show Nb and Ta enrichments relative to La, Pb negative anomalies and heavy rare earth element and Y depletions typical of intraplate ocean island basalts. These characteristics are consistent with the major and trace element compositions of their primary clinopyroxene phenocrysts, which do not show any feature ascribable to crustal contamination. The studied lavas display a restricted range of epsilon Nd (+4.6 to +5.2) which falls within the range of ocean island basalts. Their initial (Nd-143/Nd-144)i ratios are too low to be explained by a simple mixing line between depleted MORB mantle (DMM) and HIMU components. Their Pb and Nd isotopic compositions plot along a mixing line between HIMU component and an enriched mantle, the composition of which could be the result of the addition of about 5 to 8% of an EM2 component (recycled marine sediments) to DMM. The lack of evidence for any continental crustal component. in their genesis could be consistent with their emplacement in an intra-oceanic setting.

Ventricular but not atrial electro-mechanical delay of the embryonic heart is altered by anoxia-reoxygenation and improved by nitric oxide.

BACKGROUND/AIM: Excitation-contraction coupling is modulated by nitric oxide (NO) which otherwise has either beneficial or detrimental effects on myocardial function during hypoxia-reoxygenation. This work aimed at characterizing the variations of electromechanical delay (EMD) induced by anoxia-reoxygenation within the developing heart and determining whether atrial and ventricular EMD are modulated by NO to the same extent. METHODS: Hearts of 4 or 4.5-day-old chick embryos were excised and submitted in vitro to normoxia (45 min), anoxia (30 min) and reoxygenation (60 min). Electrocardiogram and atrial and ventricular contractions were simultaneously recorded throughout experiment. Anoxia-reoxygenation-induced chrono-, dromo-and inotropic disturbances and changes in EMD in atrium (EMDa) and ventricle (EMDv) were investigated in control hearts and in hearts exposed to 0.1, 1, 10, 50 and 100 microM of DETA-NONOate (a NO donating agent) or to 50 microM of L-NAME (a NOS inhibitor). RESULTS: Under normoxia, heart rate, PR interval, ventricular shortening velocity, EMDa and EMDv were similar in control, L-NAME-treated and DETA-NONOate-treated hearts. Under anoxia, cardiac activity became markedly erratic within less than 10 min in all groups. At the onset of reoxygenation, EMDv was increased by about 300% with respect to the preanoxic value while EMDa did not vary significatively. Compared to control conditions, L-NAME or DETA-NONOate had no influence on the negative chrono-, dromo- and inotropic effects induced by anoxia-reoxygenation. However, L-NAME prolonged EMDv during anoxia and delayed EMDv recovery during reoxygenation while 100 microM DETA-NONOate had the opposite effects. EMDa was neither affected by NOS inhibitor nor NO donor. At the end of reoxygenation, all the investigated parameters returned to their basal values. CONCLUSION: This work provides evidence that a NO-dependent pathway is involved in regulation of the ventricular excitation-contraction coupling in the anoxic-reoxygenated developing heart.

Is Less Chemotherapy Detrimental in Adults with Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) Treated with High-Dose Imatinib? Results of the Prospective Randomized Graaph-2005 Study

Aim: To compare a less intensive regimen based on high-dose imatinib (IM) to an intensive IM/HyperCVAD regimen in adults with Ph+ ALL, in terms of early response and outcome after stem cell transplantation (SCT). Methods: Patients aged 18-60 years with previously untreated Ph+ ALL not evolving from chronic myeloid leukemia were eligible if no contra-indication to chemotherapy and SCT (ClinicalTrials.gov ID, NCT00327678). After a steroid prephase allowing Ph and/or BCR-ABL diagnosis, cycle 1 differed between randomization arms. In arm A (IM-based), IM was given at 800 mg on day 1-28, combined with vincristine (2 mg, day 1, 8, 15, 22) and dexamethasone (40 mg, day 1-2, 8-9, 15-16, and 22-23) only. In arm B (IM/HyperCVAD), IM was given at 800 mg on day 1-14, combined with adriamycin (50 mg/m2, day 4), cyclophosphamide (300 mg/m2/12h, day 1, 2, 3), vincristine (2 mg, day 4 and 11), and dexamethasone (40 mg, day 1-4 and 11-14). All patients received a cycle 2 combining high-dose methotrexate (1 g/m2, day 1) and AraC (3 g/m2/12h, day 2 and 3) with IM at 800 mg on day 1-14, whatever their response. Four intrathecal infusions were given during this induction/consolidation period. Minimal residual disease (MRD) was centrally evaluated by quantitative RQ-PCR after cycle 1 (MRD1) and cycle 2 (MRD2). Major MRD response was defined as BCR-ABL/ABL ratio <0.1%. Then, all patients were to receive allogeneic SCT using related or unrelated matched donor stem cells or autologous SCT if no donor and a major MRD2 response. IM/chemotherapy maintenance was planned after autologous SCT. In the absence of SCT, patients received alternating cycles 1 (as in arm B) and cycles 2 followed by maintenance, like in the published IM/HyperCVAD regimen. The primary objective was non-inferiority of arm A in term of major MRD2 response. Secondary objectives were CR rate, SCT rate, treatment- and transplant-related mortality, relapse-free (RFS), event-free (EFS) and overall (OS) survival. Results: Among the 270 patients randomized between May 2006 and August 2011, 265 patients were evaluable for this analysis (133 arm A, 132 arm B; median age, 47 years; median follow-up, 40 months). Main patient characteristics were well-balanced between both arms. Due to higher induction mortality in arm B (9 versus 1 deaths; P=0.01), CR rate was higher in the less intensive arm A (98% versus 89% after cycle 1 and 98% versus 91% after cycle 2; P= 0.003 and 0.006, respectively). A total of 213 and 205 patients were evaluated for bone marrow MRD1 and MRD2. The rates of patients reaching major MRD response and undetectable MRD were 45% (44% arm A, 46% arm B; P=0.79) and 10% (in both arms) at MRD1 and 66% (68% arm A, 63.5% arm B; P=0.56) and 25% (28% arm A, 22% arm B; P=0.33) at MRD2, respectively. The non-inferiority primary endpoint was thus demonstrated (P= 0.002). Overall, EFS was estimated at 42% (95% CI, 35-49) and OS at 51% (95% CI, 44-57) at 3 years, with no difference between arm A and B (46% versus 38% and 53% versus 49%; P=0.25 and 0.61, respectively). Of the 251 CR patients, 157 (80 arm A, 77 arm B) and 34 (17 in both arms) received allogeneic and autologous SCT in first CR, respectively. Allogeneic transplant-related mortality was similar in both arms (31.5% versus 22% at 3 years; P=0.51). Of the 157 allografted patients, 133 had MRD2 evaluation and 89 had MRD2 <0.1%. In these patients, MRD2 did not significantly influence post-transplant RFS and OS, either when tested with the 0.1% cutoff or as a continuous log covariate. Of the 34 autografted patients, 31 had MRD2 evaluation and, according to the protocol, 28 had MRD2 <0.1%. When restricting the comparison to patients achieving major MRD2 response and with the current follow-up, a trend for better results was observed after autologous as compared to allogeneic SCT (RFS, 63% versus 49.5% and OS, 69% versus 58% at 3 years; P=0.35 and P=0.08, respectively). Conclusions: In adults, the use of TK inhibitors (TKI) has markedly improved the results of Ph+ ALL therapy, now close to those observed in Ph-negative ALL. We demonstrated here that chemotherapy intensity may be safely reduced when associated with high-dose IM. We will further explore this TKI-based strategy using nilotinib prior to SCT in our next GRAAPH-2013 trial. The trend towards a better outcome after autologous compared to allogeneic SCT observed in MRD responders validates MRD as an important early surrogate endpoint for treatment stratification and new drug investigation in this disease.

Ectopic pacing at physiological rate improves postanoxic recovery of the developing heart.

Recently, rapid and transient cardiac pacing was shown to induce preconditioning in animal models. Whether the electrical stimulation per se or the concomitant myocardial ischemia affords such a protection remains unknown. We tested the hypothesis that chronic pacing of a cardiac preparation maintained in a normoxic condition can induce protection. Hearts of 4-day-old chick embryos were electrically paced in ovo over a 12-h period using asynchronous and intermittent ventricular stimulation (5 min on-10 min off) at 110% of the intrinsic rate. Sham (n = 6) and paced hearts (n = 6) were then excised, mounted in vitro, and subjected successively to 30 min of normoxia (20% O(2)), 30 min of anoxia (0% O(2)), and 60 min of reoxygenation (20% O(2)). Electrocardiogram and atrial and ventricular contractions were simultaneously recorded throughout the experiment. Reoxygenation-induced chrono-, dromo-, and inotropic disturbances, incidence of arrhythmias, and changes in electromechanical delay (EMD) in atria and ventricle were systematically investigated in sham and paced hearts. Under normoxia, the isolated heart beat spontaneously and regularly, and all baseline functional parameters were similar in sham and paced groups (means +/- SD): heart rate (190 +/- 36 beats/min), P-R interval (104 +/- 25 ms), mechanical atrioventricular propagation (20 +/- 4 mm/s), ventricular shortening velocity (1.7 +/- 1 mm/s), atrial EMD (17 +/- 4 ms), and ventricular EMD (16 +/- 2 ms). Under anoxia, cardiac function progressively collapsed, and sinoatrial activity finally stopped after approximately 9 min in both groups. During reoxygenation, paced hearts showed 1) a lower incidence of arrhythmias than sham hearts, 2) an increased rate of recovery of ventricular contractility compared with sham hearts, and 3) a faster return of ventricular EMD to basal value than sham hearts. However, recovery of heart rate, atrioventricular conduction, and atrial EMD was not improved by pacing. Activity of all hearts was fully restored at the end of reoxygenation. These findings suggest that chronic electrical stimulation of the ventricle at a near-physiological rate selectively alters some cellular functions within the heart and constitutes a nonischemic means to increase myocardial tolerance to a subsequent hypoxia-reoxygenation.

Short-Term Heparin Kinetics during Catheter Ablation of Atrial Fibrillation.

BACKGROUND: Percutaneous catheter ablation of atrial fibrillation (CA-AF) is a treatment option for symptomatic drug-refractory atrial fibrillation (AF). CA-AF carries a risk for thromboembolic complications that has been minimized by the use of intraprocedural intravenous unfractionated heparin (UFH). The optimal administration of UFH as well as its kinetics are not well established and need to be precisely determined. METHODS AND RESULTS: A total 102 of consecutive patients suffering from symptomatic drug-refractory AF underwent CA-AF. The mean age was 61 ± 10 years old. After transseptal puncture of the fossa ovalis, weight-adjusted UFH bolus (100 U/kg) was infused. A significant increase in activated clotting time (ACT) was observed from an average value of 100 ± 27 seconds at baseline, to 355 ± 94 seconds at 10 min (T10), to 375 ± 90 seconds at 20 min (T20). Twenty-four patients failed to reach the targeted ACT value of ≥300 seconds at T10 and more than half of these remained with subtherapeutic ACT values at T20. This subset of patients showed similar clinical characteristics and amount of UFH but were more frequently prescribed preprocedural vitamin K1 than the rest of the study population. CONCLUSIONS: In a typical intervention setting, UFH displays unexpected slow anticoagulation kinetics in a significant proportion of procedures up to 20 minutes after infusion. These findings support the infusion of UFH before transseptal puncture or any left-sided catheterization with early ACT measurements to identify patients with delayed kinetics. They are in line with recent guidelines to perform CA-AF under therapeutic anticoagulation.