Antiarrhythmic Effect of Reverse Ventricular Remodeling Induced by Cardiac Resynchronization Therapy The InSync ICD (Implantable Cardioverter-Defibrillator) Italian Registry

Objectives: We investigated whether the reverse remodeling after cardiac resynchronization therapy (CRT) might reduce the occurrence of ventricular arrhythmias (VAs). Background: It is currently debated whether CRT has an effect on the burden of VAs. Methods: The study included 398 patients treated with a CRT defibrillator and with a follow-up of at least 12 months. Spontaneous VAs detected by the device were reviewed and validated. Results: A significant reduction in VA episodes and shock therapies was evident during the follow-up with greater decrease after 1 month. After 6 months of CRT, 227 patients (57%) showed a reduction in end-systolic volume of ≥10% and were defined as "responders." The baseline characteristics were similar between the responders and the nonresponders. Nonetheless, the proportion of patients with recurrence of VA after 1 month of CRT was significantly lower in responders (32% vs. 43%, p = 0.024). Among baseline variables no parameters emerged as predictors of tachyarrhythmia recurrence. However, receiver-operating curve analysis recognized a reduction of left ventricular end-systolic volume at 6 months of 13% as the best cutoff to identify the reduction of VAs (with a sensitivity of 58% and a specificity of 54%). Conclusions: In patients treated with CRT defibrillators, a reduction in ventricular arrhythmic events occurs during the initial 12 months after implant and is correlated with the degree of ventricular remodeling induced by the therapy. Patients demonstrating reverse remodeling at midterm follow-up show a reduction in arrhythmias soon after the implant, pronounced improvements at long-term, and a better survival. © 2008 American College of Cardiology Foundation

Phase Ib study of NGR–hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours

Contains fulltext : 81937timmer-bonte.pdf (publisher's version ) (Closed access)BACKGROUND: Asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF) is a vascular targeting agent exploiting a tumour-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13, overexpressed on tumour blood vessels. Significant preclinical synergy was shown between low doses of NGR-TNF and doxorubicin. METHODS: The primary aim of this phase I trial was to verify the safety of low-dose NGR-hTNF combined with doxorubicin in treating refractory/resistant solid tumours. Secondary objectives included pharmacokinetics (PKs), pharmacodynamics, and clinical activity. In all 15 patients received NGR-hTNF (0.2-0.4-0.8-1.6 microg m(-2)) and doxorubicin (60-75 mg m(-2)), both given intravenously every 3 weeks. RESULTS: No dose-limiting toxicity occurred and the combination was well tolerated. Around two cases of neutropenic fevers, lasting 2 days, and two cases of cardiac ejection-fraction drops, one asymptomatic and the other symptomatic, were registered. Only 11% of the adverse events were related to NGR-hTNF and were short-lasting and mild-to-moderate in severity. There was no apparent PK interaction and the shedding of soluble TNF-receptors did not increase to 0.8 microg m(-2). One partial response (7%), at dose level 0.8 microg m(-2), and 10 stable diseases (66%), lasting for a median duration of 5.6 months, were observed. CONCLUSIONS: NGR-hTNF plus doxorubicin was administered safely and showed promising activity in patients pre-treated with anthracyclines. The dose level of 0.8 microg m(-2) NGR-hTNF plus doxorubicin 75 mg m(-2) was selected for phase II development

Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses fr symptomatic heart failure

AIMS: We performed a randomized, double blind, crossover study of cardiac contractility modulation (CCM) signals in heart failure patients. METHODS AND RESULTS: One hundred and sixty-four subjects with ejection fraction (EF) < 35% and NYHA Class II (24%) or III (76%) symptoms received a CCM pulse generator. Patients were randomly assigned to Group 1 (n = 80, CCM treatment 3 months, sham treatment second 3 months) or Group 2 (n = 84, sham treatment 3 months, CCM treatment second 3 months). The co-primary endpoints were changes in peak oxygen consumption (VO2,peak) and Minnesota Living with Heart Failure Questionnaire (MLWHFQ). Baseline EF (29.3 +/- 6.7% vs. 29.8 +/- 7.8%), VO2,peak (14.1 +/- 3.0 vs. 13.6 +/- 2.7 mL/kg/min), and MLWHFQ (38.9 +/- 27.4 vs. 36.5 +/- 27.1) were similar between the groups. VO2,peak increased similarly in both groups during the first 3 months (0.40 +/- 3.0 vs. 0.37 +/- 3.3 mL/kg/min, placebo effect). During the next 3 months, VO2,peak decreased in the group switched to sham (-0.86 +/- 3.06 mL/kg/min) and increased in patients switched to active treatment (0.16 +/- 2.50 mL/kg/min). MLWHFQ trended better with treatment (-12.06 +/- 15.33 vs. -9.70 +/- 16.71) during the first 3 months, increased during the second 3 months in the group switched to sham (+4.70 +/- 16.57), and decreased further in patients switched to active treatment (-0.70 +/- 15.13). A comparison of values at the end of active treatment periods vs. end of sham treatment periods indicates statistically significantly improved VO2,peak and MLWHFQ (P = 0.03 for each parameter). CONCLUSION: In patients with heart failure and left ventricular dysfunction, CCM signals appear safe; exercise tolerance and quality of life (MLWHFQ) were significantly better while patients were receiving active treatment with CCM for a 3-month period

Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation

AIMS: To investigate the effects of cardiac resynchronization therapy (CRT) on survival in heart failure (HF) patients with permanent atrial fibrillation (AF) and the role of atrio-ventricular junction (AVJ) ablation in these patients. METHODS AND RESULTS: Data from 1285 consecutive patients implanted with CRT devices are presented: 1042 patients were in sinus rhythm (SR) and 243 (19%) in AF. Rate control in AF was achieved by either ablating the AVJ in 118 patients (AVJ-abl) or prescribing negative chronotropic drugs (AF-Drugs). Compared with SR, patients with AF were significantly older, more likely to be non-ischaemic, with higher ejection fraction, shorter QRS duration, and less often received ICD back-up. During a median follow-up of 34 months, 170/1042 patients in SR and 39/243 in AF died (mortality: 8.4 and 8.9 per 100 person-year, respectively). Adjusted hazard ratios were similar for all-cause and cardiac mortality [0.9 (0.57-1.42), P = 0.64 and 1.00 (0.60-1.66) P = 0.99, respectively]. Among AF patients, only 11/118 AVJ-abl patients died vs. 28/125 AF-Drugs patients (mortality: 4.3 and 15.2 per 100 person-year, respectively, P < 0.001). Adjusted hazard ratios of AVJ-abl vs. AF-Drugs was 0.26 [95% confidence interval (CI) 0.09-0.73, P = 0.010] for all-cause mortality, 0.31 (95% CI 0.10-0.99, P = 0.048) for cardiac mortality, and 0.15 (95% CI 0.03-0.70, P = 0.016) for HF mortality. CONCLUSION: Patients with HF and AF treated with CRT have similar mortality compared with patients in SR. In AF, AVJ ablation in addition to CRT significantly improves overall survival compared with CRT alone, primarily by reducing HF death

the world wide randomized antibiotic envelope infection prevention wrap it trial long term follow up

Abstract Background The WRAP-IT trial reported a 40% reduction in major CIED infection within 12 months of the procedure with the antibacterial-eluting envelope (TYRX). Objective This report describes the longer-term (>12 months) envelope effects on infection reduction and complications. Methods All trial patients that underwent CIED replacement, upgrade, revision, or initial CRT-D implant received standard-of-care infection prophylaxis and were randomized 1:1 to receive the envelope or not. CIED infection incidence, and procedure and system-related complications were characterized through all follow-up (36 months) using Cox proportional hazard regression modeling. Results In total, 6800 patients received their intended randomized treatment (3371 envelope; 3429 control; mean follow-up 21.0±8.3 months). Major CIED-related infection occurred in 32 envelope patients and 51 control patients (KM estimate, 1.3% vs. 1.9%; HR: 0.64, 95% CI: 0.41-0.99; P=0.046). Any CIED-related infection occurred in 57 envelope patients and 84 control patients (KM estimate, 2.1% vs. 2.8%; HR: 0.69, 95% CI: 0.49-0.97; P=0.030). System- or procedure-related complications occurred in 235 envelope patients and 252 control patients (KM estimate, 8.0% vs. 8.2%; HR, 0.95, 95% CI: 0.79-1.13; P Conclusions The effects of the TYRX envelope in reducing the risk of CIED infection are sustained beyond the first year post-procedure, without increased risk of complication

Inhibition of APN/CD13 leads to suppressed progressive potential in ovarian carcinoma cells

<p>Abstract</p> <p>Background</p> <p>Aminopeptidase N (APN/CD13), a 150-kDa metalloprotease, is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that APN/CD13 plays an important role in tumor progression of several human malignancies. In the current study, we investigated the role of APN/CD13 in ovarian carcinoma (OVCA) progression.</p> <p>Methods</p> <p>We first examined the expression of APN/CD13 at the protein level in a variety of OVCA cell lines and tissues. We subsequently investigated whether there was a correlation between APN/CD13 expression and invasive potential of various OVCA cell lines. Moreover, we investigated the function of APN/CD13 in OVCA cells using bestatin, an APN/CD13 inhibitor, or transfection of siRNA for APN/CD13.</p> <p>Results</p> <p>We confirmed that APN/CD13 was expressed in OVCA tissues and cell lines to various extents. There was a positive correlation between APN/CD13 expression and migratory potential in various OVCA cell lines with accordingly enhanced secretion of endogenous MMP-2. Subsequently, we found a significant decrease in the proliferative and migratory abilities of OVCA cells after the addition of bestatin or the inhibition of APN/CD13 expression by siRNA. Furthermore, in an animal model, daily intraperitoneal administration of bestatin after inoculation of OVCA cells resulted in a decrease of peritoneal dissemination and in prolonged survival of nude mice.</p> <p>Conclusion</p> <p>The current data indicate the possible involvement of APN/CD13 in the development of OVCA, and suggest that clinical use of bestatin may contribute to better prognosis for ovarian carcinoma patients.</p