Connective Tissue Growth Factor Modulates Adult β-Cell Maturity and Proliferation to Promote β-Cell Regeneration in Mice

Stimulation of endogenous β-cell expansion could facilitate regeneration in patients with diabetes. In mice, connective tissue growth factor (CTGF) is expressed in embryonic β-cells and in adult β-cells during periods of expansion. We discovered that in embryos CTGF is necessary for β-cell proliferation, and increased CTGF in β-cells promotes proliferation of immature (MafA⁻) insulin-positive cells. CTGF overexpression, under nonstimulatory conditions, does not increase adult β-cell proliferation. In this study, we tested the ability of CTGF to promote β-cell proliferation and regeneration after partial β-cell destruction. β-Cell mass reaches 50% recovery after 4 weeks of CTGF treatment, primarily via increased β-cell proliferation, which is enhanced as early as 2 days of treatment. CTGF treatment increases the number of immature β-cells but promotes proliferation of both mature and immature β-cells. A shortened β-cell replication refractory period is also observed. CTGF treatment upregulates positive cell-cycle regulators and factors involved in β-cell proliferation, including hepatocyte growth factor, serotonin synthesis, and integrin β1. Ex vivo treatment of whole islets with recombinant human CTGF induces β-cell replication and gene expression changes consistent with those observed in vivo, demonstrating that CTGF acts directly on islets to promote β-cell replication. Thus, CTGF can induce replication of adult mouse β-cells given a permissive microenvironment.     

Lengthier cryoablation and a bonus cryoapplication is associated with improved efficacy for cryothermal catheter ablation of supraventricular tachycardias in children

Introduction Cryoablation is an effective treatment for children with supraventricular tachycardias (SVT). The present study documents the effect of two different cryoablation protocols on acute and chronic success rates. Methods and results Fifty-three consecutive patients (age range, 5–20 years) were treated; patients 1 to 17 were treated by a standard ablation protocol and patients 18 to 53 were treated by a modified ablation protocol that required lengthier cryoablations plus delivery of a bonus cryoapplication to consolidate the acutely successful irreversible lesion created at intervention. Electrophysiological study (EPS) was performed with diagnostic catheters and cryoablations were performed with a 7FR 4 mm tip catheter (CryoCath Technologies). Acute endpoints for non-inducibility of atrioventricular nodal re-entrant tachycardia (AVNRT) by programmed atrial stimulation at baseline or during isoproterenol performed 30 min post procedure, as well as non-inducibility and conduction block over the accessory pathway (AP). The chronic endpoint was arrhythmia recurrence post intervention. No permanent cryo-related complications or adverse outcomes were reported. Acute success rates for patients 1 to 17 and 18 to 53 were 88 and 100%, respectively. The cumulative percentage of patients without arrhythmia recurrence at 12 month follow-up was significantly different at 73 and 90%, respectively. Conclusions Lengthier cryoablation delivery, approximating 7 min per cryoablation, increases the acute success rate at intervention. Moreover, these lengthier cryoablation deliveries plus a bonus cryoapplication to consolidate the acutely successful irreversible lesion created at intervention may also significantly improve the chronic success rate, while also maintaining an excellent safety profile for cryoablation treatment of children with SVT such as AVNRT and AP located near the AV junction.     

Patients with a history of stable or unstable coronary heart disease have different acute phase responses to an inflammatory stimulus

Increased levels of acute phase proteins (APP) in serum are associated with vulnerability of atherosclerotic plaques and acute manifestations of coronary heart disease (CHD). APP have been viewed as indexes of active vascular inflammation or as mediators of atherothrombosis. In the present study we tested the hypothesis that individuals who develop stable or unstable forms of CHD might have different innate responses to an inflammatory stimulus. We compared changes in plasma C-reactive protein (CRP) and serum amyloid A (SAA) concentrations 48 h after a standardized inflammatory stimulus (adjuvanted influenza vaccination) in patients with quiescent CHD that had been manifested at onset as inducible myocardial ischemia (Group 1, n=26) or as acute coronary syndromes (ACS) (Group 2, n=34). Selected patients were free from inflammatory or other conditions that might affect the immune response. CRP concentration increased significantly after vaccination in both groups (Group 1: 0.47 [0.21-0.86] to 0.56 [0.32-1.17]mg/L, p=0.005; Group 2: 0.64 [0.21-1.09] to 0.75 [0.33-1.48]mg/L, p=0.003), without significant differences between groups in absolute or percentage changes. By contrast, SAA did not change after vaccination in Group 1 (14.4 [8.9-19.5] to 14.8 [10.3-18.8]mg/L, p=0.88) but increased significantly in Group 2 (16.9 [10.0-21.5] to 19.2 [11.3-29.1]mg/L, p=0.002), with significant differences between the groups in absolute and percentage terms (p=0.015 and 0.019, respectively). Changes in CRP and SAA, both absolute and percentage, were significantly correlated in Group 2 (r=0.60 and 0.66, both p<0.001). The responsiveness of plasma SAA to an inflammatory stimulus in Group 2 alone suggests a pro-inflammatory status in patients prone to acute coronary syndrome but not in those with inducible myocardial ischemia.     

ESC position paper on cardiovascular toxicity of cancer treatments: challenges and expectations

The recent position paper of the European Society of Cardiology (ESC) on cardiovascular toxicity of cancer treatments has attracted considerable interest by healthcare professionals, since it is the first concrete help in the difficult task of monitoring and approaching cardiovascular side effects of anticancer treatments. The ESC expert opinion was not intended as a clinical practice guideline; however, it reports major cardiovascular complications grouped into nine categories, addressing current clinical strategies for prevention and mitigation. In this point of view, we discuss key challenges emerging from critical appraisal of the ESC position paper: (1) the wide spectrum of cardiovascular toxicities associated with oncological drugs, focusing on targeted agents, (2) managing strategies in patients with cardiac implantable devices, (3) the underappreciated (but emerging) immune-related cardiovascular toxicities of checkpoint inhibitors, which may also result in severe heart failure and fulminant myocarditis, (4) the evolving role of anticoagulation in oncology, and the evidence supporting (or not) the use of direct-acting oral anticoagulants in cancer-associated thrombosis.