The TIMP protein family: diverse roles in pathophysiology.

The tissue inhibitors of matrix metalloproteinases (TIMPs) are a family of four matrisome proteins classically defined by their roles as the primary endogenous inhibitors of metalloproteinases (MPs). Their functions however are not limited to MP inhibition, with each family member harboring numerous MP-independent biological functions that play key roles in processes such as inflammation and apoptosis. Because of these multifaceted functions, TIMPs have been cited in diverse pathophysiological contexts. Herein, we provide a comprehensive overview of the MP-dependent and -independent roles of TIMPs across a range of pathological conditions. The potential therapeutic and biomarker applications of TIMPs in these disease contexts are also considered, highlighting the biomedical promise of this complex and often misunderstood protein family.

A randomized clinical trial of catheter ablation and antiarrhythmic drug therapy for suppression of ventricular tachycardia in ischemic cardiomyopathy: The VANISH2 trial.

BACKGROUND: Recurrent ventricular tachycardia (VT) in patients with prior myocardial infarction is associated with adverse quality of life and clinical outcomes, despite the presence of implanted defibrillators (ICDs). Suppression of recurrent VT can be accomplished with antiarrhythmic drug therapy or catheter ablation. The Ventricular Tachycardia Antiarrhythmics or Ablation In Structural Heart Disease 2 (VANISH2) trial is designed to determine whether ablation is superior to antiarrhythmic drug therapy as first line therapy for patients with ischemic cardiomyopathy and VT. METHODS: The VANISH2 trial enrolls patients with prior myocardial infarction and VT (with one of: ≥1 ICD shock; ≥3 episodes treated with antitachycardia pacing (ATP) and symptoms; ≥5 episodes treated with ATP regardless of symptoms; ≥3 episodes within 24 hours; or sustained VT treated with electrical cardioversion or pharmacologic conversion). Enrolled patients are classified as either sotalol-eligible, or amiodarone-eligible, and then are randomized to either catheter ablation or to that antiarrhythmic drug therapy, with randomization stratified by drug-eligibility group. Drug therapy, catheter ablation procedures and ICD programming are standardized. All patients will be followed until two years after randomization. The primary endpoint is a composite of mortality at any time, appropriate ICD shock after 14 days, VT storm after 14 days, and treated sustained VT below detection of the ICD after 14 days. The outcomes will be analyzed according to the intention-to-treat principle using survival analysis techniques RESULTS: The results of the VANISH2 trial are intended to provide data to support clinical decisions on how to suppress VT for patients with prior myocardial infarction. CLINICALTRIALS: gov registration NCT02830360.

The Continuing Saga of Tissue Inhibitor of Metalloproteinase 2: Emerging Roles in Tissue Homeostasis and Cancer Progression.

Tissue inhibitors of metalloproteinases (TIMPs) are a conserved family of proteins that were originally identified as cytokine-like erythroid growth factors. Subsequently, TIMPs were characterized as endogenous inhibitors of matrixin proteinases. These proteinases are the primary mediators of extracellular matrix turnover in pathologic conditions, such as cancer invasion and metastasis. Thus, TIMPs were immediately recognized as important regulators of tissue homeostasis. However, TIMPs also demonstrate unique biological activities that are independent of metalloproteinase regulation. Although often overlooked, these non-protease-mediated TIMP functions demonstrate a variety of direct cellular effects of potential therapeutic value. TIMP2 is the most abundantly expressed TIMP family member, and ongoing studies show that its tumor suppressor activity extends beyond protease inhibition to include direct modulation of tumor, endothelial, and fibroblast cellular responses in the tumor microenvironment. Recent data suggest that TIMP2 can suppress both primary tumor growth and metastatic niche formation. TIMP2 directly interacts with cellular receptors and matrisome elements to modulate cell signaling pathways that result in reduced proliferation and migration of neoplastic, endothelial, and fibroblast cell populations. These effects result in enhanced cell adhesion and focal contact formation while reducing tumor and endothelial proliferation, migration, and epithelial-to-mesenchymal transitions. These findings are consistent with TIMP2 homeostatic functions beyond simple inhibition of metalloprotease activity. This review examines the ongoing evolution of TIMP2 function, future perspectives in TIMP research, and the therapeutic potential of TIMP2.

Retrograde coronary venous ethanol ablation for ventricular tachycardia in a patient with inaccessible substrate due to previous surgery.

INTRODUCTION: Catheter-based radiofrequency (RF) ablation is generally regarded as the standard approach for patients with ventricular tachycardia (VT) refractory to antiarrhythmic drug therapy and may be considered as a first-line approach when there is a preference to avoid these agents. Patients with a history of cardiac surgery may have VT substrate inaccessible to catheter ablation due to intervening prosthetic materials or scar. METHODS AND RESULTS: This article describes a 55-year-old patient with a history of surgically repaired subvalvular aortic stenosis and subsequent valve-sparing root replacement who presented with sustained VT. After RF ablation failed due to VT substrate "guarded" by graft material, retrograde coronary venous ethanol ablation (RCVEA) was employed to successfully treat the clinical VT. CONCLUSION: RCVEA ablation can be useful for treating VT when conventional ablation is limited by inaccessible substrate due to prior cardiac surgery.

Intramural needle ablation or repeated standard ablation in patients referred for repeat ablation of scar-related ventricular tachycardia.

INTRODUCTION: When ventricular tachycardia (VT) recurs after standard RF ablation (sRFA) some patients benefit from repeat sRFA, whereas others warrant advanced methods such as intramural needle ablation (INA). Our objectives are to assess the utility of repeat sRFA and to clarify the benefit of INA when repeat sRFA fails in patients with VT due to structural heart disease. METHODS: In consecutive patients who were prospectively enrolled in a study for INA for recurrent sustained monomorphic VT despite sRFA, repeat sRFA was considered first. INA was performed during the same procedure if repeat sRFA failed or no targets for sRFA were identified. RESULTS: Of 85 patients enrolled, acute success with repeat sRFA was achieved in 30 patients (35%), and during the 6-month follow-up, 87% (20/23) were free of VT hospitalization, 78% were free of any VT, and 7 were lost to follow-up. INA was performed in 55 patients (65%) after sRFA failed, or no endocardial targets were found abolished or modified inducible VT in 35/55 patients (64%). During follow-up, 72% (39/54) were free of VT hospitalization, 41% were free of any VT, and 1 was lost to follow-up. Overall, 59 out of 77 (77%) patients were free of hospitalization and 52% were free of any VT. Septal-origin VTs were more likely to need INA, whereas RV and papillary muscle VTs were less likely to require INA. CONCLUSIONS: Repeat sRFA was beneficial in 23% (18/77) of patients with recurrent sustained VT who were referred for INA. The availability of INA increased favorable outcomes to 52%.

Arrhythmias as Presentation of Genetic Cardiomyopathy.

There is increasing evidence regarding the prevalence of genetic cardiomyopathies, for which arrhythmias may be the first presentation. Ventricular and atrial arrhythmias presenting in the absence of known myocardial disease are often labelled as idiopathic, or lone. While ventricular arrhythmias are well-recognized as presentation for arrhythmogenic cardiomyopathy in the right ventricle, the scope of arrhythmogenic cardiomyopathy has broadened to include those with dominant left ventricular involvement, usually with a phenotype of dilated cardiomyopathy. In addition, careful evaluation for genetic cardiomyopathy is also warranted for patients presenting with frequent premature ventricular contractions, conduction system disease, and early onset atrial fibrillation, in which most detected genes are in the cardiomyopathy panels. Sudden death can occur early in the course of these genetic cardiomyopathies, for which risk is not adequately tracked by left ventricular ejection fraction. Only a few of the cardiomyopathy genotypes implicated in early sudden death are recognized in current indications for implantable cardioverter defibrillators which otherwise rely upon a left ventricular ejection fraction ≤0.35 in dilated cardiomyopathy. The genetic diagnoses impact other aspects of clinical management such as exercise prescription and pharmacological therapy of arrhythmias, and new therapies are coming into clinical investigation for specific genetic cardiomyopathies. The expansion of available genetic information and implications raises new challenges for genetic counseling, particularly with the family member who has no evidence of a cardiomyopathy phenotype and may face a potentially negative impact of a genetic diagnosis. Discussions of risk for both probands and relatives need to be tailored to their numeric literacy during shared decision-making. For patients presenting with arrhythmias or cardiomyopathy, extension of genetic testing and its implications will enable cascade screening, intervention to change the trajectory for specific genotype-phenotype profiles, and enable further development and evaluation of emerging targeted therapies.

Patient selection, ventricular tachycardia substrate delineation and data transfer for stereotactic arrhythmia radioablation. A Clinical Consensus Statement of the European Heart Rhythm Association (EHRA) of the ESC and the Heart Rhythm Society (HRS).

Stereotactic arrythmia radioablation (STAR) is a novel, non-invasive and promising treatment option for ventricular arrythmias (VA). It has been applied in highly selected patients mainly as bail-out procedure, when (multiple) catheter-ablations, together with anti-arrhythmic drugs, were unable to control the VAs. Despite the increasing clinical use there is still limited knowledge of the acute and long-term response of normal and diseased myocardium to STAR. Acute toxicity appeared to be reasonably low but potential late adverse effects may be underreported. Among published studies, the provided methodological information is often limited, and patient selection, target volume definition, methods for determination and transfer of target volume, and techniques for treatment planning and execution differ across studies, hampering pooling of data and comparison across studies. In addition, STAR requires close and new collaboration between clinical electrophysiologists and radiation oncologists, which is facilitated by shared knowledge in each collaborator's area of expertise and a common language. This clinical consensus statement provides uniform definition of cardiac target volumes. It aims to provide advice in patient selection for STAR including etiology specific aspects, and advice in optimal cardiac target volume identification based on available evidence. Safety concerns and the advice for acute and long-term monitoring including the importance of standardized reporting and follow-up are covered by this document. Areas of uncertainty are listed, which require high-quality, reliable pre-clinical and clinical evidence before expansion of STAR beyond clinical scenarios in which proven therapies are ineffective or unavailable.

Safety of ventricular arrhythmia radiofrequency ablation with half-normal saline irrigation.

AIMS: Failure of radiofrequency (RF) ablation of ventricular arrhythmias is often due to inadequate lesion size. Irrigated RF ablation with half-normal saline (HNS) has the potential to increase lesion size and reduce sodium delivery to the patient if the same volume of RF irrigant were used for normal saline (NS) and HNS but could increase risks related to steam pops and lesion size. This study aims to assess periprocedural complications and acute ablation outcome of ventricular arrhythmias ablation with HNS. METHODS AND RESULTS: Prospective assessment of outcomes was performed in 1024 endocardial and/or epicardial RF ablation procedures in 935 consecutive patients (median age 64 years, 71.2% men, 73.4% cardiomyopathy, 47.2% sustained ventricular tachycardia). Half-normal saline was selected at the discretion of the treating physician. Radiofrequency ablation power was generally titrated to a ≤15â€…Ω impedance fall with intracardiac echocardiography monitoring. Half-normal saline was used in 900 (87.9%) and NS in 124 (12.1%) procedures. Any adverse event within 30 days occurred in 13.0% of patients treated with HNS RF ablation including 4 (0.4%) strokes/transient ischaemic attacks and 34 (3.8%) pericardial effusions requiring treatment (mostly related to epicardial access). Two steam pops with perforation required surgical repair (0.2%). Patients who received NS irrigation had less severe disease and arrhythmias. In multivariable models, adverse events and acute success of the procedure were not related to the type of irrigation. CONCLUSION: Half-normal saline irrigation RF ablation with power guided by impedance fall and intracardiac echocardiography has an acceptable rate of complications and acute ablation success while administering half of the saline load expected for NS irrigation.

Intracardiac thrombi fluttering like hair in the wind at VT ablation.

INTRODUCTION: Intracardiac echocardiography (ICE) reveals mobile thrombus on implantable electronic device leads in some patients undergoing electrophysiologic procedures. METHODS: ICE was performed in a patient undergoing ventricular tachycardia (VT) ablation. RESULTS: ICE showed extensive mobile thrombi on the implantable cardioverter defibrillator lead. Radiofrequency catheter ablation of VT from perimitral scar was safely performed via a retrograde aortic approach. After the procedure, chronic anticoagulation was initiated. CT-angiography of the chest 2 months later showed no pulmonary emboli. CONCLUSIONS: The significance of these thrombi, as related to chronic pulmonary embolization, warrants further study.

Design and characteristics of the prophylactic intra-operative ventricular arrhythmia ablation in high-risk LVAD candidates (PIVATAL) trial.

BACKGROUND: The use of a Left Ventricular Assist Device (LVAD) in patients with advanced heart failure refractory to optimal medical management has progressed steadily over the past two decades. Data have demonstrated reduced LVAD efficacy, worse clinical outcome, and higher mortality for patients who experience significant ventricular tachyarrhythmia (VTA). We hypothesize that a novel prophylactic intra-operative VTA ablation protocol at the time of LVAD implantation may reduce the recurrent VTA and adverse events postimplant. METHODS: We designed a prospective, multicenter, open-label, randomized-controlled clinical trial enrolling 100 patients who are LVAD candidates with a history of VTA in the previous 5 years. Enrolled patients will be randomized in a 1:1 fashion to intra-operative VTA ablation (n = 50) versus conventional medical management (n = 50) with LVAD implant. Arrhythmia outcomes data will be captured by an implantable cardioverter defibrillator (ICD) to monitor VTA events, with a uniform ICD programming protocol. Patients will be followed prospectively over a mean of 18 months (with a minimum of 9 months) after LVAD implantation to evaluate recurrent VTA, adverse events, and procedural outcomes. Secondary endpoints include right heart function/hemodynamics, healthcare utilization, and quality of life. CONCLUSION: The primary aim of this first-ever randomized trial is to assess the efficacy of intra-operative ablation during LVAD surgery in reducing VTA recurrence and improving clinical outcomes for patients with a history of VTA.

Long-term outcomes of corticosteroid graft versus host disease prophylaxis in peripheral blood allogeneic haemopoietic stem cell transplant: a comparative cohort analysis.

BACKGROUND: Corticosteroids (CSs) have previously been incorporated into graft versus host disease (GVHD) prophylaxis regimens for bone marrow (BM) and haemopoietic stem cell transplant (HSCT). AIMS: To assess the impact of prophylactic CS in HSCT using peripheral blood (PB) stem cells. METHODS: Patients were identified from three HSCT centres receiving a first PB-HSCT between January 2011 and December 2015 from a fully human leukocyte antigen (HLA)-matched sibling or unrelated donor for acute myeloid leukaemia or acute lymphoblastic leukaemia. To enable meaningful comparison, patients were divided into two cohorts. RESULTS: Cohort 1 included only myeloablative-matched sibling HSCT, where the only variation in GVHD prophylaxis was the addition of CS. In these 48 patients, there were no differences in GVHD, relapse, non-relapse mortality, overall survival or GVHD-relapse-free-survival (GRFS) at 4 years after transplant. Cohort 2 included the remaining HSCT recipients, where one group received CS-prophylaxis and the non-CS group received an antimetabolite, ciclosporin and anti-T-lymphocyte globulin. In these 147 patients, those receiving CS-prophylaxis experienced higher rates of chronic GVHD (71% vs 18.1%, P < 0.001) and lower rates of relapse (14.9% vs 33.9%, P = 0.02). Those receiving CS-prophylaxis had a lower 4-year GRFS (15.7% vs 40.3%, P = 0.002). CONCLUSIONS: There does not appear to be a role for adding CS to standard GVHD prophylaxis regimens in PB-HSCT.

Unravelling the distinct biological functions and potential therapeutic applications of TIMP2 in cancer.

Tissue inhibitors of metalloproteinases (TIMPs) are a conserved family of proteins that were originally identified as endogenous inhibitors of matrixin and adamalysin endopeptidase activity. The matrixins and adamalysins are the major mediators of extracellular matrix (ECM) turnover, thus making TIMPs important regulators of ECM structure and composition. Despite their high sequence identity and relative redundancy in inhibitory profiles, each TIMP possesses unique biological characteristics that are independent of their regulation of metalloproteinase activity. As our understanding of TIMP biology has evolved, distinct roles have been assigned to individual TIMPs in cancer progression. In this respect, data regarding TIMP2's role in cancer have borne conflicting reports of both tumor suppressor and, to a lesser extent, tumor promoter functions. TIMP2 is the most abundant TIMP family member, prevalent in normal and diseased mammalian tissues as a constitutively expressed protein. Despite its apparent stable expression, recent work highlights how TIMP2 is a cell stress-induced gene product and that its biological activity can be dictated by extracellular posttranslational modifications. Hence an understanding of TIMP2 molecular targets, and how its biological functions evolve in the progressing tumor microenvironment may reveal new therapeutic opportunities. In this review, we discuss the continually evolving functions of TIMP proteins, future perspectives in TIMP research, and the therapeutic utility of this family, with a particular focus on TIMP2.

Intracardiac MR imaging (ICMRI) guiding-sheath with amplified expandable-tip imaging and MR-tracking for navigation and arrythmia ablation monitoring: Swine testing at 1.5 and 3T.

PURPOSE: Develop a deflectable intracardiac MR imaging (ICMRI) guiding-sheath to accelerate imaging during MR-guided electrophysiological (EP) interventions for radiofrequency (500 kHz) ablation (RFA) of arrythmia. Requirements include imaging at three to five times surface-coil SNR in cardiac chambers, vascular insertion, steerable-active-navigation into cardiac chambers, operation with ablation catheters, and safe levels of MR-induced heating. METHODS: ICMRI's 6 mm outer-diameter (OD) metallic-braided shaft had a 2.6 mm OD internal lumen for ablation-catheter insertion. Miniature-Baluns (MBaluns) on ICMRI's 1 m shaft reduced body-coil-induced heating. Distal section was a folded "star"-shaped imaging-coil mounted on an expandable frame, with an integrated miniature low-noise-amplifier overcoming cable losses. A handle-activated movable-shaft expanded imaging-coil to 35 mm OD for imaging within cardiac-chambers. Four MR-tracking micro-coils enabled navigation and motion-compensation, assuming a tetrahedron-shape when expanded. A second handle-lever enabled distal-tip deflection. ICMRI with a protruding deflectable EP catheter were used for MR-tracked navigation and RFA using a dedicated 3D-slicer user-interface. ICMRI was tested at 3T and 1.5T in swine to evaluate (a) heating, (b) cardiac-chamber access, (c) imaging field-of-view and SNR, and (d) intraprocedural RFA lesion monitoring. RESULTS: The 3T and 1.5T imaging SNR demonstrated >400% SNR boost over a 4 × 4 × 4 cm3 FOV in the heart, relative to body and spine arrays. ICMRI with MBaluns met ASTM/IEC heating limits during navigation. Tip-deflection allowed navigating ICMRI and EP catheter into atria and ventricles. Acute-lesion long-inversion-time-T1-weighted 3D-imaging (TWILITE) ablation-monitoring using ICMRI required 5:30 min, half the time needed with surface arrays alone. CONCLUSION: ICMRI assisted EP-catheter navigation to difficult targets and accelerated RFA monitoring.

Inhibition of Hepatic Stellate Cell Activation Suppresses Tumorigenicity of Hepatocellular Carcinoma in Mice.

Transdifferentiation (or activation) of hepatic stellate cells (HSCs) to myofibroblasts is a key event in liver fibrosis. Activated HSCs in the tumor microenvironment reportedly promote tumor progression. This study analyzed the effect of an inhibitor of HSC activation, retinol-binding protein-albumin domain III fusion protein (R-III), on protumorigenic functions of HSCs. Although conditioned medium collected from activated HSCs enhanced the migration, invasion, and proliferation of the hepatocellular carcinoma cell line Hepa-1c1c7, this effect was not observed in Hepa-1c1c7 cells treated with conditioned medium from R-III-exposed HSCs. In a subcutaneous tumor model, larger tumors with increased vascular density were formed in mice transplanted with Hepa-1c1c7+HSC than in mice transplanted with Hepa-1c1c7 cells alone. Intriguingly, when Hepa-1c1c7+HSC-transplanted mice were injected intravenously with R-III, a reduction in vascular density and extended tumor necrosis were observed. In an orthotopic tumor model, co-transplantation of HSCs enhanced tumor growth, angiogenesis, and regional metastasis accompanied by increased peritumoral lymphatic vessel density, which was abolished by R-III. In vitro study showed that R-III treatment affected the synthesis of pro-angiogenic and anti-angiogenic factors in activated HSCs, which might be the potential mechanism underlying the R-III effect. These findings suggest that the inhibition of HSC activation abrogates HSC-induced tumor angiogenesis and growth, which represents an attractive therapeutic strategy.

HeartMate 3: new challenges in ventricular tachycardia ablation.

AIM: To describe clinical characteristics, procedural details, specific challenges, and outcomes in patients with HeartMate3™ (HM3), a left ventricular assist device system with a magnetically levitated pump, undergoing ventricular tachycardia ablation (VTA). METHODS AND RESULTS: Data were collected from patients with an HM3 system who underwent VTA in seven tertiary centres. Data included baseline patient characteristics, procedural data, mortality, and arrhythmia-free survival. The study cohort included 19 patients with cardiomyopathy presenting with ventricular tachycardia (VT) (53% with VT storm). Ventricular tachycardias were induced in 89% of patients and a total of 41 VTs were observed. Severe electromagnetic interference was present on the surface electrocardiogram. Hence, VT localization required analysis of intra-cardiac signals or the use of filter in the 40-20 Hz range. The large house pump HM3 design obscured the cannula inflow and therefore multi imaging modalities were necessary to avoid catheter entrapment in the cannula. A total of 32 VTs were mapped and were successfully ablated (31% to the anterior wall, 38% to the septum and only 9% to the inflow cannula region). Non-inducibility of any VT was reached in 11 patients (58%). Over a follow-up of 429 (interquartile range 101-692) days, 5 (26%) patients underwent a redo VT ablation due to recurrent VTA and 2 (11%) patients died. CONCLUSIONS: Ventricular tachycardia ablation in patients with HM3 is feasible and safe when done in the appropriate setup. Long-term arrhythmia-free survival is acceptable but not well predicted by non-inducibility at the end of the procedure.

Asymmetric Hsp90 N domain SUMOylation recruits Aha1 and ATP-competitive inhibitors.

The stability and activity of numerous signaling proteins in both normal and cancer cells depends on the dimeric molecular chaperone heat shock protein 90 (Hsp90). Hsp90's function is coupled to ATP binding and hydrolysis and requires a series of conformational changes that are regulated by cochaperones and numerous posttranslational modifications (PTMs). SUMOylation is one of the least-understood Hsp90 PTMs. Here, we show that asymmetric SUMOylation of a conserved lysine residue in the N domain of both yeast (K178) and human (K191) Hsp90 facilitates both recruitment of the adenosine triphosphatase (ATPase)-activating cochaperone Aha1 and, unexpectedly, the binding of Hsp90 inhibitors, suggesting that these drugs associate preferentially with Hsp90 proteins that are actively engaged in the chaperone cycle. Importantly, cellular transformation is accompanied by elevated steady-state N domain SUMOylation, and increased Hsp90 SUMOylation sensitizes yeast and mammalian cells to Hsp90 inhibitors, providing a mechanism to explain the sensitivity of cancer cells to these drugs.

Prevalence and natural history of variants in the ANKRD26 gene: a short review and update of reported cases.

ANKRD26 is a highly conserved gene located on chromosome 10p12.1 which has shown to play a role in normal megakaryocyte differentiation. ANKRD26-related thrombocytopenia, or thrombocytopenia 2, is an inherited thrombocytopenia with mild bleeding diathesis resulting from point mutations the 5'UTR of the ANKRD26 gene. Point mutations in the 5'UTR region have been shown to prevent transcription factor-mediated downregulation of ANKRD26 in normal megakaryocyte differentiation. Patients with ANKRD26-related thrombocytopenia have a predisposition to developing hematological malignancies, with acute myeloid leukemia and myelodysplastic syndrome most commonly described in the literature. We review the clinical features and biological mechanisms of ANKRD26-related thrombocytopenia and summarize known cases in the literature.

Building platelet phenotypes: Diaphanous-related formin 1 (DIAPH1)-related disorder.

Variants of the Diaphanous-Related Formin 1 (DIAPH-1) gene have recently been reported causing inherited macrothrombocytopenia. The essential/"diagnostic" characteristics associated with the disorder are emerging; however, robust and complete criteria are not established. Here, we report the first cases of DIAPH1-related disorder in Australia caused by the autosomal dominant gain-of-function DIAPH1 R1213X variant formed by truncation of the protein within the diaphanous auto-regulatory domain (DAD) with loss of regulatory motifs responsible for autoinhibitory interactions within the DIAPH1 protein. We affirm phenotypic changes induced by the DIAPH1 R1213X variant to include macrothrombocytopenia, early-onset progressive sensorineural hearing loss, and mild asymptomatic neutropenia. High-resolution microscopy confirms perturbations of cytoskeletal dynamics caused by the DIAPH1 variant and we extend the repertoire of changes generated by this variant to include alteration of procoagulant platelet formation and possible dental anomalies.

Poor mobilization of autologous CD34+ peripheral blood stem cells in haematology patients undergoing autologous stem cell transplantation is associated with the presence of variants in genes implicated in clonal haematopoiesis of indeterminant potential.

Clonal haematopoiesis of indeterminant potential (CHIP) increases in frequency with age. The effect of CHIP on the mobilization of autologous CD34+ peripheral blood stem cells (PBSC) has not been reported. This study uses a DNA-based targeted candidate gene approach to identify the presence of somatic mutations in ASXL1, DNMT3A, JAK2, SF3B1, TET2 and TP53 in CD34+ haematopoietic progenitor cell-apheresis products of 96 patients who undergo PBSC mobilization for autologous stem cell transplantation (ASCT). Variants were identified in a significantly greater proportion of patients who experience poor CD34+ PBSC mobilization. A DNA-based targeted candidate gene array is able to predict poor CD34+ PBSC mobilization and may be deployed pre-emptively to minimize mobilization and graft failures.

A challenging VT ablation with a large cardiac tumor.

INTRODUCTION: Ventricular tachycardia (VT) normally occurs from an abnormal structural substrate. CASE: We report a case in which VT was caused by a large tumor in the interventricular septum. Surgical intervention was not an option due to the location of the tumor and its proximity to the coronary arteries. CONCLUSION: The patient underwent ablation and upgrade to CRT before ultimately receiving a heart transplant.