Epicardial atrial pacing after the extracardiac Fontan operation: Feasibility of an entirely transvenous approach.

This series describes an innovative technique for pacing in patients with sinus node dysfunction after extracardiac Fontan surgery. This transpulmonary approach to the left atrial epi-myocardium has been successfully applied to three patients at two centers and resulted in excellent acute and midterm pacing characteristics without known complications. The principal advantage of this procedure in comparison to prior iterations is the absence of pacing material within the pulmonary venous atrium, so that future systemic thromboembolism risk is minimized. The transpulmonary approach for permanent atrial pacing offers a novel solution to the unique challenges for patients after extracardiac Fontan operation.

Utilising electroanatomic mapping during ablation in patients with CHD to reduce radiation exposure.

BACKGROUND: Patients with CHD can be exposed to high levels of cumulative ionising radiation. Utilisation of electroanatomic mapping during catheter ablation leads to reduced radiation exposure in the general population but has not been well studied in patients with CHD. This study evaluated the radiation sparing benefit of using three-dimensional mapping in patients with CHD. METHODS: Data were retrospectively collected from the Catheter Ablation with Reduction or Elimination of Fluoroscopy multi-institutional registry. Patients with CHD were selected. Those with previous ablations, concurrent diagnostic or interventional catheterisation and unknown arrhythmogenic foci were excluded. The control cohort was matched for operating physician, arrhythmia mechanism, arrhythmia location, weight and age. The procedure time, rate of fluoroscopy use, fluoroscopy time, procedural success, complications, and distribution of procedures per year were compared between the two groups. RESULTS: Fifty-six patients with congenital heart disease and 56 matched patients without CHD were included. The mean total procedure time was significantly higher in patients with CHD (212.6 versus 169.5 minutes, p = 0.003). Their median total fluoroscopy time was 4.4 minutes (compared to 1.8 minutes), and their rate of fluoroscopy use was 23% (compared to 13%). The acute success and minor complication rates were similar and no major complications occurred. CONCLUSIONS: With the use of electroanatomic mapping during catheter ablation, fluoroscopy use can be reduced in patients with CHD. The majority of patients with CHD received zero fluoroscopy.

Acute outcomes of three-dimensional mapping for fluoroscopy reduction in paediatric catheter ablation for supraventricular tachycardia.

BACKGROUND: Catheter ablation is a safe and effective therapy for the treatment of supraventricular tachycardia in children. Current improvements in technology have allowed progressive reduction in radiation exposure associated with the procedure. To assess the impact of three-dimensional mapping, we compared acute procedural results collected from the Catheter Ablation with Reduction or Elimination of Fluoroscopy registry to published results from the Prospective Assessment after Pediatric Cardiac Ablation study. METHODS: Inclusion and exclusion criteria from the Prospective Assessment after Pediatric Cardiac Ablation study were used as guidelines to select patient data from the Catheter Ablation with Reduction or Elimination of Fluoroscopy registry to compare acute procedural outcomes between cohorts. Outcomes assessed include procedural and fluoroscopy exposure times, success rates of procedure, and complications. RESULTS: In 786 ablation procedures, targeting 498 accessory pathways and 288 atrioventricular nodal reentrant tachycardia substrates, average procedural time (156.5 versus 206.7 minutes, p < 0.01), and fluoroscopy time (1.2 versus 38.3 minutes, p < 0.01) were significantly shorter in the study group. Success rates for the various substrates were similar except for manifest accessory pathways which had a significantly higher success rate in the study group (96.4% versus 93.0%, p < 0.01). Major complication rates were significantly lower in the study group (0.3% versus 1.6%, p < 0.01). CONCLUSIONS: In a large, multicentre study, three-dimensional systems show favourable improvements in clinical outcomes in children undergoing catheter ablation of supraventricular tachycardia compared to the traditional fluoroscopic approach. Further improvements are anticipated as technology advances.

Ultrahigh-density mapping supplemented with global chamber activation identifies noncavotricuspid-dependent intra-atrial re-entry conduction isthmuses in adult congenital heart disease.

OBJECTIVE: To evaluate the role of ultrahigh-density mapping for conduction isthmus (CI) characterization in adult congenital heart disease (ACHD). BACKGROUND: Catheter ablation remains suboptimal for ACHD with atypical intra-atrial reentrant tachycardias (IART) that can be challenging to define using existing mapping technology. METHODS: An ultrahigh-density mapping system was selectively employed over a 1-year period for procedures involving noncavotricuspid isthmus-dependent-IART. A global activation histogram (GAH) was assessed for the ability to predict ablation targets. Procedural characteristics were compared to a group of matched controls. RESULTS: Twenty patients (mean age 43 ± 15, 70% male) underwent 20 procedures targeting 34 tachycardias during the study period. Diagnoses included single ventricle (8), tetralogy of Fallot (2), left heart obstruction (3), Ebstein's anomaly (2) atrial septal defect (2), Mustard operation (2), and Rasteilli operation (1). Prior catheter ablation/Maze operation had been performed in 12 (60%). The median time per map was 21 minutes (interquartile range [IQR], 16-32), representing 14 834 points per map (IQR 9499-43 191; P < .001 vs controls). Review of GAH maps showed lower trough values were associated with more favorable IART CI characteristics (P ≤ =.001 for all). Acute success was achieved in 19/20 (95%) procedures, with tachycardia termination during the first lesion in eight cases (P = .02 vs controls). There was one recurrence during 0.6 years follow-up. CONCLUSIONS: Ultrahigh-density mapping supplemented with the GAH tool was effective for CI identification in a cohort of complex ACHD patients. Catheter ablation was more efficient compared to controls, suggesting precise CI characterization using this technology.

A minimally invasive hybrid approach for cardiac resynchronization of the systemic right ventricle.

BACKGROUND: Patients with systemic right ventricle (RV) often develop progressive heart failure and may benefit from cardiac resynchronization therapy (CRT); however, the optimal strategy for CRT has not been defined. METHODS: A retrospective review of all the patients with systemic RV failure undergoing a hybrid transcatheter-surgical approach was performed. Procedural technique and outcomes are reported. RESULTS: Six patients underwent detailed electroanatomical mapping of the systemic RV followed by a new hybrid approach targeting latest endocardial activation, which was followed by focused epicardial mapping. The exact site of latest endocardial activation was variable but localized to the basolateral RV in all cases. Sites of latest activation tended to be more superior during contralateral ventricular pacing versus intact atrioventricular conduction (P = 0.06). Latest endocardial activation at the targeted site occurred at 157 ms (interquartile range [IQR] = 120-181 ms) and corresponding epicardial activation at 174 ms (IQR = 140-198 ms), after the onset of the QRS complex. Following the hybrid CRT, the QRS duration decreased from a median of 193 to 147 ms and the fractional area of change increased from a median of 15.5% to 30% (P < 0.001). Patients were discharged to home after a median of 4 days. Of the three patients who were initially referred for transplant evaluation, two (66%) of them no longer met the criteria following CRT. CONCLUSIONS: Whereas latest endocardial activation for the systemic RV appears to localize to the basolateral region, the optimal lead position may be variable. An approach utilizing endocardial mapping followed by a limited surgical incision and confirmation of latest activation may result in minimally invasive surgery and a favorable acute CRT response.

Transvenous pacemaker implantation after the bidirectional Glenn operation for patients with complex congenital disease.

INTRODUCTION: The bidirectional Glenn operation for congenital heart disease produces anatomical constraints to conventional transvenous pacemaker implantation. An iliac approach, although not previously described in this population, is potentially a preferable alternative to a thoracotomy for epicardial pacing. METHODS AND RESULTS: A single-center retrospective review was performed for all patients that underwent transvenous pacemaker implantation following the bidirectional Glenn operation with partial biventricular repair. Follow-up data, implant indications, and techniques were recorded. Five patients underwent a transvenous iliac approach (median age 26.9 years, interquartile range [IQR] 25.8-27.6). Pacing indications included AV block in 3 patients (2 requiring cardiac resychronization therapy) and sinus node dysfunction in 2. Implanted leads were atrial in 4 and ventricular in 3 (1 of the latter was placed in the coronary sinus). In two cases, transvenous leads were tunneled to a preexisting epicardial abdominal generator. Median follow-up was 4.1 years (range 1.0-16.7 years). One patient underwent device revision for lead position-related groin discomfort; a second patient developed atrial lead failure following a Maze operation and underwent lead replacement by the iliac approach. Patients were not routinely anticoagulated postprocedure given lead position in the subpulmonary circulation. At last follow-up, all patients were alive. One patient underwent heart transplantation 6 months after implant with only partial resolution of pacing-induced cardiomyopathy. CONCLUSIONS: Trans-iliac pacemaker placement may be an effective alternative to surgery for patients requiring permanent pacing after the Glenn operation.

NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.

Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors Mll-AF9 and a tetracycline-repressible, activated NRAS (NRAS(G12V)). Using computational approaches to explore our gene-expression data sets, we found that NRAS(G12V) enforced the leukemia self-renewal gene-expression signature and was required to maintain an MLL-AF9- and Myb-dependent leukemia self-renewal gene-expression program. NRAS(G12V) was required for leukemia self-renewal independent of its effects on growth and survival. Analysis of the gene-expression patterns of leukemic subpopulations revealed that the NRAS(G12V)-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1(Low) cells, which harbor leukemia stem cells, were preferentially sensitive to NRAS(G12V) withdrawal. NRAS(G12V) maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction.

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency.

Juvenile myelomonocytic leukemia is a rare myeloproliferative neoplasm characterized by hyperactive RAS signaling. Neurofibromin1 (encoded by the NF1 gene) is a negative regulator of RAS activation. Patients with neurofibromatosis type 1 harbor loss-of-function mutations in NF1 and have a 200- to 500-fold increased risk of juvenile myelomonocytic leukemia. Leukemia cells from patients with juvenile myelomonocytic leukemia display hypersensitivity to certain cytokines, such as granulocyte-macrophage colony-stimulating factor. The granulocyte-macrophage colony-stimulating factor receptor utilizes pre-associated JAK2 to initiate signals after ligand binding. JAK2 subsequently activates STAT5, among other downstream effectors. Although STAT5 is gaining recognition as an important mediator of growth factor signaling in myeloid leukemias, the contribution of STAT5 to the development of hyperactive RAS-initiated myeloproliferative disease has not been well described. In this study, we investigated the consequence of STAT5 attenuation via genetic and pharmacological approaches in Nf1-deficient murine models of juvenile myelomonocytic leukemia. We found that homozygous Stat5 deficiency extended the lifespan of Nf1-deficient mice and eliminated the development of myeloproliferative neoplasm associated with Nf1 gene loss. Likewise, we found that JAK inhibition with ruxolitinib attenuated myeloproliferative neoplasm in Nf1-deficient mice. Finally, we found that primary cells from a patient with KRAS-mutant juvenile myelomonocytic leukemia displayed reduced colony formation in response to JAK2 inhibition. Our findings establish a central role for STAT5 activation in the pathogenesis of juvenile myelomonocytic leukemia and suggest that targeting this pathway may be of clinical utility in these patients.

Characterization of Cardiac Troponin Elevation in the Setting of Pediatric Supraventricular Tachycardia.

Cardiac troponin (cTn) is currently considered the gold standard biomarker for detection of myocardial necrosis. Patients with supraventricular tachycardia (SVT) often present with symptoms resulting in cTn assessment; however, there are no data on the results of such testing in childhood. We hypothesized that cTn elevation would be common in the pediatric SVT population and would portend a benign prognosis. A retrospective review of all pediatric patients (≤21 years) presenting with SVT was performed. Clinical and electrocardiographic variables from the emergency department (ED) presentation were reviewed and clinical outcomes during subsequent follow-up assessed. Of 128 patients seen in the ED for SVT, cTn was assessed in 48 (38 %). Of patients with cTn assessment, 14 (29 %) patients demonstrated cTn elevation. Univariate predictors of cTn elevation included presentation with respiratory or gastrointestinal symptoms (50 vs 12 % and 42 vs 9 %; p = 0.008 and p = 0.01, respectively), lower mean arterial blood pressure (73 vs 85 mm Hg, p = 0.009), higher age-adjusted tachycardia rate (z score 9.3 vs 7.2, p < 0.001), and longer tachycardia duration (4.2 vs 1.0 h, p = 0.02). Multivariate logistic regression confirmed the association of age-adjusted tachycardia rate (odds ratio [OR] 3.8 per heart rate z score, confidence interval [CI] 1.9-11.8, p = 0.003) and duration (OR 1.5 per hour, CI 1.1-2.5, p = 0.03). Clinical outcome was excellent with no adverse sequelae during a median of 2.9 years of follow-up. Cardiac Tn elevation is common in the pediatric population presenting with SVT. Episode severity, characterized by respiratory or gastrointestinal symptoms, lower mean blood pressure, and increased tachycardia rate and duration are predictive. Clinical follow-up is favorable.

Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo.

Reversing the aberrant biochemical output of oncogenic Ras proteins is one of the great challenges in cancer therapeutics; however, it is uncertain which Ras effectors are required for tumor initiation and maintenance. To address this question, we expressed oncogenic K-Ras(D12) proteins with "second site" amino acid substitutions that impair PI3 kinase/Akt or Raf/MEK/ERK activation in bone marrow cells and transplanted them into recipient mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins initiated aggressive clonal T-lineage acute lymphoblastic leukemia (T-ALL). Murine T-ALLs expressing second site mutant proteins restored full oncogenic Ras activity through diverse mechanisms, which included acquiring novel somatic third site Kras(D12) mutations and silencing PTEN. T-ALL cell lines lacking PTEN had elevated levels of phosphorylated Akt, a gene expression pattern similar to human early T-cell precursor ALL, and were resistant to the potent and selective MEK inhibitor PD0325901. Our data, which demonstrate strong selective pressure to overcome the defective activation of PI3 kinase/Akt and Raf/MEK/ERK, implicate both Ras effector pathways as drivers of aberrant growth in T-ALL and further suggest that leukemia cells will deploy multiple mechanisms to develop resistance to targeted inhibitors in vivo.

Transpulmonary atrial pacing: an approach to transvenous pacemaker implantation after extracardiac conduit Fontan surgery.

INTRODUCTION: Patients with prior extracardiac (EC) conduit Fontan surgery are considered ineligible for transvenous atrial pacemaker implantation due to lack of venous access to the atrial myocardium. A new technique for atrial lead placement in the setting of this surgical anatomy is proposed. METHODS AND RESULTS: A 30-year-old female with prior EC Fontan surgery, incessant supraventricular tachycardia, sinus node dysfunction, and multi-organ failure was admitted to our hospital. After placement of a transvenous lead in the left pulmonary artery (LPA) for temporary pacing with ensuing clinical improvement, the patient was taken back to the catheterization laboratory for definitive treatment. After ablation of the supraventricular tachycardia and 3D mapping of the common atrium, a puncture through the LPA and into the left-sided atrium was performed. A transvenous lead was then attached to the base of the left-sided appendage where excellent pacing and sensing characteristics were observed. Follow-up transesophageal echocardiography revealed stable lead placement and absence of pericardial effusion. The patient was discharged to home several days later on warfarin therapy. CONCLUSIONS: Transpulmonary access to the left-sided atrium for patients with prior EC Fontan surgery is a feasible strategy for transvenous atrial pacing. Lead placement in this location is associated with excellent pacing characteristics and involves a limited segment of lead within the pulmonary venous atrium. The approach is technically straightforward and avoids the need for surgical pacemaker placement.

Targeting oncogenic Ras signaling in hematologic malignancies.

Ras proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ∼25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanism-based therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer.

Multidetector Computed Tomography Assessment of Anatomical Ventricular Tachycardia Isthmuses in Repaired Tetralogy of Fallot.

BACKGROUND: Tetralogy of Fallot (TOF) is associated with risk for sustained monomorphic ventricular tachycardia (VT). Preemptive electrophysiology study before transcatheter pulmonary valve placement is increasing, but the value of MDCT for anatomical VT isthmus assessment is unknown. OBJECTIVES: The purpose of this study was to determine the impact of multidetector computed tomography (MDCT) in the evaluation of sustained monomorphic VT for repaired TOF. METHODS: Consecutive pre-transcatheter pulmonary valve MDCT studies were identified, and anatomical isthmus dimensions were measured. For a subset of patients with preemptive electrophysiology study, MDCT features were compared with electroanatomical maps. RESULTS: A total of 61 repaired TOFs with MDCT were identified (mean 35 ± 14 years, 58% men) with MDCT electroanatomical map pairs in 35 (57%). Calcification corresponding to patch material was present in 46 (75%) and was used to measure anatomical VT isthmuses. MDCT wall thickness correlated positively with number of ablation lesions and varied with functional isthmus properties (blocked isthmus 2.6 mm [Q1, Q3: 2.1, 4.0 mm], slow conduction 4.8 mm [Q1, Q3: 3.3, 6.0 mm], and normal conduction 5.6 mm [Q1, Q3: 3.9, 8.3 mm]; P < 0.001). A large conal branch was present in 6 (10%) and a major coronary anomaly was discovered in 3 (5%). Median ablation lesion distance was closer to the right vs the left coronary artery (10 mm vs 15 mm; P = 0.01) with lesion-to-coronary distance <5 mm in 3 patients. CONCLUSIONS: MDCT identifies anatomical structures relevant to catheter ablation for repaired TOF. Wall thickness at commonly targeted anatomical VT isthmuses is associated with functional isthmus properties and increased thermal energy delivery.

Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells.

Src homology 2 domain-containing phosphatase 2 (Shp2), encoded by Ptpn11, is a member of the nonreceptor protein-tyrosine phosphatase family, and functions in cell survival, proliferation, migration, and differentiation in many tissues. Here we report that loss of Ptpn11 in murine hematopoietic cells leads to bone marrow aplasia and lethality. Mutant mice show rapid loss of hematopoietic stem cells (HSCs) and immature progenitors of all hematopoietic lineages in a gene dosage-dependent and cell-autonomous manner. Ptpn11-deficient HSCs and progenitors undergo apoptosis concomitant with increased Noxa expression. Mutant HSCs/progenitors also show defective Erk and Akt activation in response to stem cell factor and diminished thrombopoietin-evoked Erk activation. Activated Kras alleviates the Ptpn11 requirement for colony formation by progenitors and cytokine/growth factor responsiveness of HSCs, indicating that Ras is functionally downstream of Shp2 in these cells. Thus, Shp2 plays a critical role in controlling the survival and maintenance of HSCs and immature progenitors in vivo.

Therapy-induced malignant neoplasms in Nf1 mutant mice.

Therapy-induced cancers are a severe complication of genotoxic therapies. We used heterozygous Nf1 mutant mice as a sensitized genetic background to investigate tumor induction by radiation (RAD) and cyclophosphamide (CY). Mutagen-exposed Nf1(+/-) mice developed secondary cancers that are common in humans, including myeloid malignancies, sarcomas, and breast cancers. RAD cooperated strongly with heterozygous Nf1 inactivation in tumorigenesis. Most of the solid tumors showed loss of the wild-type Nf1 allele but retained two Trp53 alleles. Comparative genomic hybridization demonstrated distinct patterns of copy number aberrations in sarcomas and breast cancers from Nf1 mutant mice, and tumor cell lines showed deregulated Ras signaling. Nf1(+/-) mice provide a tractable model for investigating the pathogenesis of common mutagen-induced cancers and for testing preventive strategies.

Sinus rhythm QRS morphology reflects right ventricular activation and anatomical ventricular tachycardia isthmus conduction in repaired tetralogy of Fallot.

BACKGROUND: Patients with repaired tetralogy of Fallot (TOF) are at risk for ventricular tachycardia (VT) related to well-described anatomical isthmuses. OBJECTIVE: The purpose of this study was to explore QRS morphology as an indicator of anatomical isthmus conduction. METHODS: Patients with repaired TOF and complete right bundle branch block referred for transcatheter pulmonary valve replacement (PVR) or presenting with sustained VT underwent comprehensive 3-dimensional mapping in sinus rhythm. Electrocardiographic characteristics were compared to right ventricular (RV) activation and anatomical isthmus conduction properties. RESULTS: Twenty-two patients (19 pre-pulmonary valve replacement and 3 clinical VT) underwent comprehensive 3-dimensional mapping (median 39 years; interquartile range [IQR] 27-48 years; 12 [55%] male). Septal RV activation (median 40 ms; IQR 34-46 ms) corresponded to the nadir in lead V1 and free wall activation (median 71 ms; IQR 64-81 ms) to the transition point in the upstroke of the R' wave. Patients with isthmus block between the pulmonary annulus and the ventricular septal defect patch and between the ventricular septal defect patch and the tricuspid annulus (when present), were more likely to demonstrate lower amplitude R' waves in lead V1 (5.8 mV vs 9.4 mV; P = .005), QRS fragmentation in lead V1 (15 [94%] vs 2 [13%]; P < .001), and terminal S waves in lead aVF (15 [94%] vs 6 [40%]; P < .001) than those with intact conduction. During catheter ablation, these QRS changes developed during isthmus block. CONCLUSION: For patients with repaired TOF, the status of septal isthmus conduction was evident from sinus rhythm QRS morphology. Low-amplitude, fragmented R' waves in lead V1 and terminal S waves in the inferior leads were related to septal isthmus conduction abnormalities, providing a mechanistic link between RV activation and common electrocardiographic findings.

Conduction System Pacing Versus Conventional Cardiac Resynchronization Therapy in Congenital Heart Disease.

BACKGROUND: Dyssynchrony-associated left ventricular systolic dysfunction is a major contributor to heart failure in congenital heart disease (CHD). Although conventional cardiac resynchronization therapy (CRT) has shown benefit, the comparative efficacy of cardiac conduction system pacing (CSP) is unknown. OBJECTIVES: The purpose of this study was compare the clinical outcomes of CSP vs conventional CRT in CHD with biventricular, systemic left ventricular anatomy. METHODS: Retrospective CSP data from 7 centers were compared with propensity score-matched conventional CRT control subjects. Outcomes were lead performance, change in left ventricular ejection fraction (LVEF), and QRS duration at 12 months. RESULTS: A total of 65 CSP cases were identified (mean age 37 ± 21 years, 46% men). The most common CHDs were tetralogy of Fallot (n = 12 [19%]) and ventricular septal defect (n = 12 [19%]). CSP was achieved after a mean of 2.5 ± 1.6 attempts per procedure (38 patients with left bundle branch pacing, 17 with HBP, 10 with left ventricular septal myocardial). Left bundle branch area pacing [LBBAP] vs HBP was associated with a smaller increase in pacing threshold (Δ pacing threshold 0.2 V vs 0.8 V; P = 0.05) and similar sensing parameters at follow-up. For 25 CSP cases and control subjects with baseline left ventricular systolic dysfunction, improvement in LVEF was non-inferior (Δ LVEF 9.0% vs 6.0%; P = 0.30; 95% confidence limits: -2.9% to 10.0%) and narrowing of QRS duration was more pronounced for CSP (Δ QRS duration 35 ms vs 14 ms; P = 0.04). Complications were similar (3 [12%] CSP, 4 [16%] conventional CRT; P = 1.00). CONCLUSIONS: CSP can be reliably achieved in biventricular, systemic left ventricular CHD patients with similar improvement in LVEF and greater QRS narrowing for CSP vs conventional CRT at 1 year. Among CSP patients, pacing electrical parameters were superior for LBBAP vs HBP.

Resistance in the land of molecular cancer therapeutics.

The fusion tyrosine kinase Bcr-Abl plays a fundamental role in the pathogenesis of chronic myeloid leukemia (CML). Imatinib, a potent inhibitor of Bcr-Abl, has shown impressive clinical activity in CML patients. However, primary and acquired resistance occurs in many patients and is associated with reactivation of Bcr-Abl in primary leukemia cells. Studies reported over the past year have begun to elucidate the molecular basis of imatinib resistance, which may involve amplification of BCR-ABL or, more commonly, mutations that introduce amino acid substitutions into the Bcr-Abl kinase. Biochemical analysis and molecular modeling indicate that these mutant proteins retain kinase activity but are less sensitive to inhibition due to structural changes that perturb drug binding. These studies establish a paradigm for elucidating resistance to targeted therapeutics.

Acute leukemia: a pediatric perspective.

The spectrum of hematological malignancies differs markedly between children and adults. Moreover, diseases such as acute lymphoblastic leukemia, acute myeloid leukemia, and myelodysplastic syndrome also demonstrate distinct biologic features and responses to treatment between these populations. In this review, we summarize our current understanding of the molecular pathology of acute leukemia and myelodysplastic syndrome, emphasizing areas in which studies in pediatric patients are providing unique insights into the hematopoietic malignancies of adults.

Hyperactivation of protein kinase B and ERK have discrete effects on survival, proliferation, and cytokine expression in Nf1-deficient myeloid cells.

The Nf1 tumor suppressor encodes a GTPase-activating protein for Ras. Previous work has implicated hyperactive Ras in the aberrant growth of Nf1-deficient cells; however, there are limited data on which effectors modulate specific phenotypes. To address this, we generated myeloid cell lines by infecting fetal liver cells with a retrovirus encoding a truncated allele of c-Myb. Granulocyte-macrophage colony stimulating factor (GM-CSF) promoted the survival of wild-type Myb cells in a dose-dependent manner. By contrast, Nf1-deficient myeloid cells deprived of growth factors, were resistant to apoptosis due to hyperactivation of the phosphoinositide-3-OH kinase/protein kinase B cascade. Nf1(-/-) cells also demonstrated growth factor-independent proliferation and upregulation of GM-CSF mRNA production that were dependent upon Raf/MEK/ERK signaling. These data link specific Ras effectors with discrete cellular phenotypes in Nf1-deficient cells.