Synchronous Ventricular Pacing without Crossing the Tricuspid Valve or Entering the Coronary Sinus—Preliminary Results

Background: Right ventricular apical (RVA) pacing promotes tricuspid regurgitation (TR), electromechanical dyssynchrony, and ventricular dysfunction. We tested a novel intramyocardial bipolar lead to assess whether stimulation of the atrioventricular septum (AVS) produces synchronous ventricular activation without crossing the tricuspid valve (TV). Methods: A lead with an active external helix and central pin was placed on the AVS and the RVA in three dogs. High‐density electroanatomic (EA) mapping was performed of both ventricles endocardially and epicardially. Intracardiac echocardiography was used to access ventricular synchrony. Results: The lead was successfully deployed into the AVS in all cases with consistent capture of the ventricular myocardium without atrial capture or sensing. The QRS duration was less with AVS compared with RVA pacing (89 ± 4 ms vs. 100 ± 11 ms [P < 0.0001, GEE P = 0.03]). There was decreased delay between color Doppler M‐mode visualized peak contraction of the septum and the mid left ventricular free wall with AVS compared with RVA pacing (89 ± 91 ms vs. 250 ± 11 ms [P < 0.0001, GEE P = 0.006]). Activation time between the mid septum and mid free wall was shorter with AVS versus RVA pacing (20.4 ± 7.7 vs. 30.8 ± 11.6 [P = 0.01, GEE P = 0.07]). The interval between QRS onset to earliest free wall activation was shorter with AVS vs. RVA pacing (19.2 ± 6.4 ms vs. 31.1 ± 11.7 ms [P = 0.005, GEE P = 0.02]). Conclusion: The AVS was successfully paced in three dogs resulting in synchronous ventricular activation without crossing the TV.     

Short-Long Sequences Prior to Ventricular Tachycardia Onset: Analysis of VAST Trial Electrograms

Background: The recently published Ventricular Arrhythmia Suppression Trial (VAST) found no effect of rate-smoothing (RS) algorithm on frequency of ventricular tachycardia (VT) episodes in patients with implantable defibrillator. A similar recent trial reported an opposite result. In order to determine possible reasons for the discrepancy between the trials and achieve better understanding of events preceding VT onset, we analyzed stored device electrograms preceding 162 VT episodes from 50 VAST trial patients with dual-chamber devices.
Results: In this analysis, short-long sequences were more common prior to polymorphic VTs than before monomorphic VTs. The proportion of VT episodes preceded by short-long sequences was lower during randomization to RS ON (5.3% vs 31.3%, P < 0.001). For patients with multiple episodes of monomorphic VT, there was higher interpatient than intrapatient variability in preceding RR intervals. When adjusting for this similarity of RR interval sequences preceding VT onset in individual patients, the difference in proportion short-long sequences between RS ON and RS OFF programming was no longer significant.
Conclusion: Episodes of VT were preceded by stereotypic, patient-specific sequences of RR intervals in several VAST trial patients. RS reduced the percentage of VTs preceded by short-long sequences, but did not change overall VT incidence.     

Glucocorticoids Increase Repair Potential in a Novel in vitro Human Airway Epithelial Wounding Model

Airway epithelial damage is a cardinal feature of chronic asthma. Agents which enhance epithelial repair without triggering uncontrolled fibrosis of the mesenchyme would be predicted to be useful in the management of asthma. We have developed a repeat wound model using mucociliated human bronchial epithelial cell (HBEC) cultures to define the key pathways involved in airway epithelial repair, and to study the effects of potential therapeutic agents on epithelial repair in a chronic setting. We show that repair occurs primarily by cell migration to close a defect; this process requires activation of the EGF receptor (EGFR) and subsequent tyrosine kinase signalling. Migration is accompanied by up-regulation of CD44 in motile cells at the wound margins with proliferation of non-migrating cells adjacent to the wound area. In long-term studies β2 adrenoceptor agonists and phosphodiesterase (PDE) inhibitors have no effect on repair potential, in contrast chronic treatment with the glucocorticoid dexamethasone extends the lifespan of repeatedly wounded differentiated cultures. We suggest part of the beneficial effects of glucocorticoids in asthma is related to this ability to prolong repair potential following repeated episodes of epithelial injury.     

Granulocyte colony‐stimulating factor (G‐CSF) depresses angiogenesis in vivo and in vitro: implications for sourcing cells for vascular regeneration therapy

Summary. Background: The most common source of hematopoietic progenitor cells (HPCs) for hematopoietic reconstitution comprises granulocyte colony‐stimulating factor (G‐CSF)‐mobilized peripheral blood stem cells (PBSCs). It has been proposed that endothelial progenitor cells (EPCs) share precursors with HPCs, and that EPC release may accompany HPC mobilization to the circulation following G‐CSF administration. Objective: To investigate EPC activity following HPC mobilization, and the direct effects of exogenous G‐CSF administration on human umbilical vein endothelial cells (HUVECs) and endothelial outgrowth cells (EOCs), using in vitro and in vivo correlates of angiogenesis. Patients/Methods: Heparinized venous blood samples were collected from healthy volunteers and from cord blood at parturition. G‐CSF‐mobilized samples were collected before administration, at apheresis harvest, and at follow‐up. PBSCs were phenotyped by flow cytometry, and cultured in standard colony‐forming unit (CFU)‐EPC and EOC assays. The effect of exogenous G‐CSF was investigated by addition of it to HUVECs and EOCs in standard tubule formation and aortic ring assays, and in an in vivo sponge implantation model. Results: Our data show that G‐CSF mobilization of PBSCs produces a profound, reversible depression of circulating CFU‐EPCs. Furthermore, G‐CSF administration did not mobilize CD34+CD133? cells, which include precursors of EOCs. No EOCs were cultured from any mobilized PBSCs studied. Exogenous G‐CSF inhibited CFU‐EPC generation, HUVEC and EOC tubule formation, microvessel outgrowth, and implanted sponge vascularization in mice. Conclusions: G‐CSF administration depresses both endothelial cell angiogenesis and monocyte proangiogenic activity, and we suggest that any angiogenic benefit observed following implantation of cells mobilized by G‐CSF may come only from a paracrine effect from HPCs.     

Apoptosis of Hodgkin–Reed–Sternberg cells in classical Hodgkin lymphoma revisited

Benharroch D, Einav I, Feldman A, Levy A, Ariad S, Gopas J. Apoptosis of Hodgkin–Reed–Sternberg cells in classical Hodgkin lymphoma revisited. APMIS 2010; 118: 339–45. We scrutinized the role of apoptosis of the Hodgkin–Reed–Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) and critically reviewed its features in the light of conflicting evidence. In this study, we found that tumor cells in this neoplasm showed inhibition of apoptosis in 55% of the 217 cHL cases only. It is also suggested that the two factors considered responsible for apoptosis inhibition in HRS cells, nuclear factor‐κB and the latent membrane protein‐1 of the Epstein–Barr virus, do not correlate with apoptosis inhibition, in contrast with the findings in the consensual pathogenetic scheme. The most significant association of HRS cell apoptosis was with p53, the negative expression of which related with a high apoptotic index (p = 0.001). These findings support our contention that the role of apoptosis in the HRS cells of Hodgkin lymphoma has not been completely elucidated and is at variance with that in the consensus.     

Undifferentiated carcinoma of the renal pelvis with osteoclast‐like giant cells: a report of two cases

McCash SI, Unger P, Dillon R, Xiao G‐Q. Undifferentiated carcinoma of the renal pelvis with osteoclast‐like giant cells: a report of two cases. APMIS 2010; 118: 407–12. Undifferentiated carcinoma with osteoclast‐like giant cells arising in the urothelium of the bladder or upper urinary tract is an extremely rare entity. The majority of cases found in the renal pelvis and bladder are associated with either an in situ urothelial malignancy or a conventional high‐grade urothelial carcinoma. These malignancies tend to behave poorly with a grim prognosis and course. We report two additional cases of undifferentiated carcinoma with osteoclast‐like giant cells of the renal pelvis in two patients disease free 42 and 18 months after surgical treatment, respectively.     

Cirrhotic cardiomyopathy: causes and consequences

Abstract   Cirrhotic cardiomyopathy is generally defined as subnormal ventricular response to stress in the face of high resting cardiac output. Although this syndrome was first noticed more than three decades ago in cirrhotic patients, it was originally ascribed to latent alcoholic cardiomyopathy. During the 1980s−1990s, it became clear that blunted ventricular contractility to stress is also present in non-alcoholic patients and animal models of cirrhosis. Mechanistic studies in experimental animal models of cirrhosis indicate that multiple factors are responsible, including abnormal biophysical membrane characteristics, impaired β-adrenergic signal transduction and increased activity of cardiodepressant systems mediated by cGMP. Cirrhotic cardiomyopathy appears to be precipitated or worsened by liver transplantation, insertion of transjugular intrahepatic portosystemic stent-shunts and infections. It may play a role in the pathogenesis of hepatorenal syndrome. Current management recommendations are empiric, non-specific measures; further research in this area is needed.