Citations

Abstract Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632–45. ©2016 AACR.

Heart failure (HF) is associated with changes in cardiac substrate utilization and energy metabolism, including a decline in high‐energy phosphate content, mitochondrial dysfunction, and phosphotransfer enzyme deficiency. A shift toward glucose metabolism was noted in the end stage of HF in animals, although HF in humans may not be associated with a shift toward predominant glucose utilization. Deficiencies of micronutrients are well‐established causes of cardiomyopathy. Correction of these deficits can improve heart function. The genes governing the energy metabolism were predominantly underexpressed in nonischemic cardiomyopathy and hypertrophic cardiomyopathy but were overexpressed in ischemic cardiomyopathy. Cardiac resynchronization therapy (CRT) has been proven to increase cardiac efficiency without increasing myocardial oxygen consumption. Altered myocardial metabolism is normalized by CRT to improve ventricular function.

VT Ablation in LVAD RecipientsBackgroundPatients with advanced heart failure (HF) are predisposed to ventricular arrhythmias (VAs), particularly following implantation of a left ventricular assist device (LVAD). There is minimal evidence for appropriate management strategies.ObjectivesThis study aimed to compare the burden of VA and response to ablation performed either before or following LVAD implantation.MethodsWe created a retrospective cohort of patients who underwent both VA ablation and Heart Mate II (Thoratec, Pleasanton, CA, USA) LVAD implantation at Mayo Clinic (Rochester, MN, USA). Patients were stratified based on whether they underwent VA ablation before (pre‐LVAD) or after LVAD (post‐LVAD) implantation. Descriptive analyses assessed 6‐month arrhythmia burden in relation to LVAD implantation and VA ablation.ResultsA total of 9 patients underwent both LVAD implantation and VA ablation. There were 3 and 6 patients, respectively, in the pre‐LVAD and post‐LVAD cohorts. Among patients in the pre‐LVAD cohort, the median number of VAs tended to increase after ablation (9 vs. 72) and decreased after LVAD implantation (72 vs. 63). Similarly among patients in the post‐LVAD cohort, the median burden of VAs increased after LVAD implantation (1 vs. 22) and the median burden decreased after ablation (22 vs. 13). Two of 6 patients had substrate related to the LVAD inflow cannula site, while other substrate was not related directly to the cannula.ConclusionsIn patients with progressive HF and LVAD implantation, ablation is associated with reduced VA rates. In LVAD patients, most VAs arise from substrate unrelated to the inflow cannula site.

Background: The spectrum of central nervous system–idiopathic inflammatory demyelinating disease (CNS-IIDD) in the elderly is uncertain. Objective: To describe the clinical, radiological, and pathological features of a cohort of 30 pathologically proven CNS-IIDD patients ⩾65 years. Methods: Elderly multiple sclerosis (MS)/clinically isolated syndrome (CIS) patients were compared to a cohort of 125 patients with pathologically proven MS/CIS and symptom onset <65 years. Results: Median age at symptom onset was 69 years (interquartile range (IQR) = 68–75). Median follow-up was 1.9 years (IQR = 1.0–5.6). Diagnoses were MS (14/30), CIS (11/30), neuromyelitis optica (NMO; 4/30), and acute disseminated encephalomyelitis (ADEM; 1/30). Disability was higher in patients with MS/CIS ⩾65 compared to patients <65 (median Expanded Disability Status Scale (EDSS) 4 (IQR = 2.5–7) vs 2.5 (IQR = 1.5–4); p = 0.002). When compared to patients <65 years, there was no difference in the lesion size, number of patients fulfilling Barkhof’s criteria, edema, or mass effect. Confluent demyelination was observed in 27 patients (MS/CIS (23/25), NMO (4)), 2 had a mixed perivenular/confluent pattern (MS (1), ADEM (1)), and 1 patient with MS had a mixed confluent/perivenular/coalescent pattern. Early active lesions were found in 19/30 patients ((MS (4), CIS (13), NMO (2); 53%). Cortical demyelination was present in 7/12 (58%) patients (MS (3), CIS(3), ADEM (1)). Conclusion: A spectrum of CNS-IIDD can develop in the elderly, with presenting symptoms similar to younger patients. Early diagnosis of CNS demyelinating disease is essential to avoid invasive and disabling procedures.

BackgroundAlthough sudden death (SD) is a rare complication after atrioventricular junction (AVJ) ablation and permanent pacemaker implantation, the risk factors leading to this SD remain unknown. The purpose of this study was to investigate SD and its risk factors after ablate‐and‐pace strategy for rate control in atrial fibrillation (AF) patients during long‐term follow‐up.HypothesisMethodsFrom January 2005 to December 2009, we enrolled into this study 517 AF patients with AVJ ablation and right ventricular pacemaker implantation. Patients were divided into 2 groups, SD and non‐SD. Cox proportional hazards models were used to assess potential risk factors for overall mortality and SD.ResultsDuring a mean follow‐up of 25.8 ± 18.6 months (range, 3 days to 63.8 months), 53 patients died (15 with SD). Cox proportional hazards models showed that the presence of congestive heart failure, New York Heart Association functional class, chronic renal failure, and nonsustained ventricular tachycardia were risk factors that predicted overall mortality. For SD, the presence of dilated cardiomyopathy and mitral stenosis were associated risk factors. SD was exclusively seen in patients who had narrow QRS complex or right bundle branch block prior to AVJ ablation and pacemaker implantation; SD was not seen in any patient with preexisting complete left bundle branch block.ConclusionsDilated cardiomyopathy, mitral stenosis, and baseline QRS morphology should be examined as potential risk factors for SD after AVJ ablation and pacemaker implantation.

Background— Lead-related or valve-related endocarditis can complicate cardiovascular implantable electronic device (CIED) infection in patients with both CIED and prosthetic valves. The objective of this study was to determine the outcomes of transvenous lead extraction for CIED infection in patients with prosthetic valves. Methods and Results— We retrospectively screened 794 transvenous lead extraction procedures, between September 1, 2001 and August 31, 2012, at Mayo Clinic to identify patients with prosthetic valves who underwent lead extraction for infection. Demographic, clinical, and follow-up characteristics were analyzed. In total, 51 patients (6%) met the study inclusion criteria, of whom 20 had pocket infection and 31 had lead-related or valve-related, or both, endocarditis or bloodstream infection (mean age, 67 [18] years). Staphylococcal species were the most common pathogens, including Staphylococcus aureus in 20 cases (39%) and coagulase-negative staphylococci in 19 cases (37%). Overall, 127 transvenous leads (median lead age, 52 months) were extracted. Of these leads, 123 (97%) were removed completely. The in-hospital mortality rate was 9.8%; no deaths were attributable to the extraction procedure. Ninety-five percent of patients who survived had no evidence of recurrent device-related or valve-related infection. Conclusions— Transvenous lead extraction seems safe and curative in patients with CIED infection and prosthetic valves. Cure of infection can be achieved in the majority of patients with complete CIED removal and antimicrobial therapy and without valve surgery.

ABSTRACT Inflammatory response of blood–brain barrier (BBB) endothelial cells plays an important role in pathogenesis of many central nervous system inflammatory diseases, including multiple sclerosis; however, the molecular mechanism mediating BBB endothelial cell inflammatory response remains unclear. In this study, we first observed that knockdown of neuropilin-1 (NRP1), a co-receptor of several structurally diverse ligands, suppressed interferon-γ (IFNγ)-induced C-X-C motif chemokine 10 expression and activation of STAT1 in brain microvascular endothelial cells in a Rac1-dependent manner. Moreover, endothelial-specific NRP1-knockout mice, VECadherin-Cre-ERT2/NRP1flox/flox mice, showed attenuated disease progression during experimental autoimmune encephalomyelitis, a mouse neuroinflammatory disease model. Detailed analysis utilizing histological staining, quantitative PCR, flow cytometry and magnetic resonance imaging demonstrated that deletion of endothelial NRP1 suppressed neuron demyelination, altered lymphocyte infiltration, preserved BBB function and decreased activation of the STAT1–CXCL10 pathway. Furthermore, increased expression of NRP1 was observed in endothelial cells of acute multiple sclerosis lesions. Our data identify a new molecular mechanism of brain microvascular endothelial inflammatory response through NRP1–IFNγ crosstalk that could be a potential target for intervention of endothelial cell dysfunction in neuroinflammatory diseases.

BackgroundMany patients with atrial fibrillation (AF) or atrial flutter (Aflutter) have concomitant sinus node dysfunction (SND). Ablation may result in injury to the sinus node complex or its blood supply resulting in sinus arrest and need for temporary pacing. We sought to characterize patients who develop acute SND (ASND) during/immediately after AF/Aflutter ablation.MethodsWe performed a retrospective analysis of AF/Aflutter ablation patients between January 1, 2010 and February 28, 2015 to characterize those who required temporary pacemaker (TPM) implantation due to ASND (sinus arrest, sinus bradycardia <40 beats/min, or junctional rhythm with hemodynamic compromise) following atrial ablation.ResultsOf 2,151 patients, eight patients (<0.5%) with ASND manifesting as sinus arrest (n = 2), severe sinus bradycardia (n = 2), and junctional rhythm with hemodynamic compromise (n = 4) were identified (all male, age 66 ± 9.9 years, 4/8 [50%] persistent AF). AF ablation was performed in four, atypical Aflutter in one, and AF/Aflutter in three patients. The ablation set consisted of: pulmonary vein (PV) isolation (n = 6), roof line ablation (n = 6), mitral annulus‐left inferior PV line ablation (n = 5), left atrial appendage‐mitral annulus ablation (n = 1), cavotricuspid isthmus ablation (n = 5), and isolation or ablation near the superior vena cava (SVC, n = 4). Patients with peri‐SVC ablation were more likely to develop ASND (P = 0.03). All patients received TPM; six received permanent pacemaker before discharge, performed 3.5 days postablation (range 2–6 days). At 3‐month device interrogation, all patients were atrially paced >50%.ConclusionASND is a rare complication of atrial ablation. It may be more common when peri‐SVC ablation is performed and may necessitate permanent pacemaker implantation.