6 research outputs found
Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy: A multicenter north american registry
Objectives: The purpose of the study is to identify the predictors of clinical outcome (mortality and survival without repeat septal reduction procedures) of alcohol septal ablation for the treatment of patients with hypertrophic obstructive cardiomyopathy. Background: Alcohol septal ablation is used for treatment of medically refractory hypertrophic obstructive cardiomyopathy patients with severe outflow tract obstruction. The existing literature is limited to single-center results, and predictors of clinical outcome after ablation have not been determined. Registry results can add important data. Methods: Hypertrophic obstructive cardiomyopathy patients (N = 874) who underwent alcohol septal ablation were enrolled. The majority (64%) had severe obstruction at rest, and the remaining had provocable obstruction. Before ablation, patients had severe dyspnea (New York Heart Association [NYHA] functional class III or IV: 78%) and/or severe angina (Canadian Cardiovascular Society angina class III or IV: 43%). Results: Significant improvement (p \u3c 0.01) occurred after ablation (∼5% in NYHA functional classes III and IV, and 8 patients in Canadian Cardiovascular Society angina class III). There were 81 deaths, and survival estimates at 1, 5, and 9 years were 97%, 86%, and 74%, respectively. Left anterior descending artery dissections occurred in 8 patients and arrhythmias in 133 patients. A lower ejection fraction at baseline, a smaller number of septal arteries injected with ethanol, a larger number of ablation procedures per patient, a higher septal thickness post-ablation, and the use beta-blockers post-ablation predicted mortality. Conclusions: Variables that predict mortality after ablation, include baseline ejection fraction and NYHA functional class, the number of septal arteries injected with ethanol, post-ablation septal thickness, beta-blocker use, and the number of ablation procedures. © 2011 American College of Cardiology Foundation
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Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
Background: Mutations in the SF3B1 splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood. Methods: RNA-seq data from SF3B1 mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 (IRAK4) isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in preclinical models of MDS/AML. Results: RNA-seq splicing analysis of SF3B1 mutant MDS samples revealed retention of full-length exon 6 of IRAK4, a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteasomal degradation. Expression of IRAK4-long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models. Conclusions: SF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models.</p