Role of Mutagenicity in Asbestos Fiber-Induced Carcinogenicity and Other Diseases

The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases. This article summarizes the findings from existing literature with a focus on genetic changes, specifically, mutagenicity of asbestos fibers. Thus far, experimental evidence suggesting the involvement of mutagenesis in asbestos carcinogenicity is more convincing than asbestos-induced fibrotic diseases. The potential contributions of mutagenicity to asbestos-induced diseases, with an emphasis on carcinogenicity, are reviewed from five aspects: (1) whether there is a mutagenic mode of action (MOA) in fiber-induced carcinogenesis; (2) mutagenicity/carcinogenicity at low dose; (3) biological activities that contribute to mutagenicity and impact of target tissue/cell type; (4) health endpoints with or without mutagenicity as a key event; and finally, (5) determinant factors of toxicity in mutagenicity. At the end of this review, a consensus statement of what is known, what is believed to be factual but requires confirmation, and existing data gaps, as well as future research needs and directions, is provided

P5422Long-term performance of vagus nerve stimulation lead: low rate of complications and failures

Abstract Background Autonomic Regulation Therapy (ART) is a novel therapy for heart failure (HF) that has been shown in a pilot study to be associated with improvement in left ventricular function, 6-minute walk distance, NYHA class, and quality of life. ART is provided using chronic stimulation through a self-sizing lead that is placed on the cervical vagus nerve without any need for response-mapping. The lead is functionally identical in its design and manufacture to a commercially available lead that has been implanted since February 2009 for the treatment of refractory epilepsy and treatment-resistant depression. Purpose A survival analysis was performed to evaluate long-term lead performance. Methods Lead survival was calculated for those patients whose survival status was obtainable from public records. All devices registered as implanted in the United States for any indication were included for the analysis. All available data on device explants, device replacements, returned product analyses, and customer complaints were collected and used to identify failures and out-of-specification conditions. Device survival probability was defined as the likelihood of the implanted device remaining implanted and performing as intended. Results As of the time of this analysis, there have been 26467 registered system implantations and a total of 53200 device-years of lead use. Survival status was obtainable for 9700 patients from public records. After 1 year, 99.5% of implanted leads have remained implanted and performing as intended. At 7 years, 95.8% of leads have remained implanted and performing as intended. The most common causes of lead failure have been infection (0.87%), vocal cord dysfunction (0.68%), lead protrusion (0.36%), and lead extrusion (0.27%). At implant 1 year 2 year 3 year 5 year 7 year Cumulative Survival Probability (%) 100 99.5 (99.4–99.6) 99.1 (98.8–99.2) 98.6 (98.4–98.9) 97.4 (96.9–97.7) 95.8 (94.9–96.5) Number of Patients 9700 8500 7200 6000 3300 700 Conclusions Lead performance during chronic vagus nerve stimulation has included over 5ehz746.0379 device-years of use in over 25000 patients. A low rate of long term complications and failures have been reported, and the cumulative survival probability of the lead appears to be high. Acknowledgement/Funding LivaNova PLC </jats:sec

Circadian rhythms govern cardiac repolarization and arrhythmogenesis

Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada’s syndrome)6 of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel- interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis

Multi-year improvement in autonomic tone, baroreceptor sensitivity, and cardiac electrical stability using vagus nerve stimulation in patients with HFrEF in the ANTHEM-HF study

Abstract Background HFrEF patients experience long-term deterioration of autonomic function and cardiac electrical stability linked to increased sudden cardiac death risk. ANTHEM-HF (NCT01823887) reported improved baroreceptor sensitivity (heart rate turbulence, HRT), heart rate variability (rMSSD), and reduced cardiac electrical instability (T-wave alternans, TWA) after 12 months of chronic vagus nerve stimulation (VNS). It is unknown whether these benefits persist long-term. Methods HRT, rMSSD, TWA, and VT occurrence were evaluated during chronic VNS in all patients with symptomatic HFrEF with available 36-month follow-up data (n=25). ECGs were analyzed before Autonomic Regulation Therapy system implantation (LivaNova USA) and after chronic cervical VNS. Results Improvement in HRT slope persisted at 24 months (8.1±1.2 ms/RR interval, p=0.02) and 36 months (7.9±0.9 ms/RR interval, p=0.03) of VNS compared to baseline. RMSSD increase continued at 24 months (34.6±2.7 ms2, p&amp;lt;0.02) and 36 months (36.4±2.0 ms2, p=0.002). Peak TWA levels remained reduced at 24 months (47.8±1.3 μV, p&amp;lt;0.0001) and 36 months (46.1±1.6 μV, p&amp;lt;0.0001). No sudden death, VF, or sustained VT occurred, and patients with nonsustained VT decreased from 11 (44%) at baseline to 1 (5%) at 24 months (p&amp;lt;0.003) and 2 (11%) at 36 months (p&amp;lt;0.02). Conclusion In patients with HFrEF, chronic VNS appears to confer persistent 3-year improvements in autonomic tone, baroreceptor sensitivity, and cardiac electrical stability. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): LivaNova PLC </jats:sec

P3522Vagus nerve stimulation for chronic heart failure: differences in therapy delivery and clinical efficacy in ANTHEM-HF, INOVATE-HF, and NECTAR-HF

Abstract Background Vagus Nerve Stimulation (VNS) is meant to deliver Autonomic Regulation Therapy (ART) to neurological targets with sufficient neuromodulation (NM) to ameliorate chronic heart failure (CHF). VNS delivery consists of its intensity (a combination of pulse amplitude, pulse frequency, and pulse duration), polarity, duty cycle (DC; stimulation “on” time and “off” time), and mode (continuous, or intermittent and periodic). In the ANTHEM-HF Pilot Study patients with CHF and reduced ejection fraction (HFrEF), VNS intensity was up-titrated until a change in heart rate (HR) dynamics was objectively confirmed. This did not require any change in GDMT and was associated with significant improvements in LVEF, 6-minute walk distance (6MWD), Minnesota Living with HF (MLWHF) score, and HR variability. Methods Qualitative and quantitative analyses used data from peer-reviewed publications and other sources in the public domain to compare VNS delivery in ANTHEM-HF, INOVATE-HF, and NECTAR-HF. Results (Table): Up-titration of VNS intensity was attempted in all 3 studies. In contrast to ANTHEM-HF, INOVATE-HF aimed only at peripheral neural targets. VNS intensity was delivered at a lower pulse frequency, and had a variable DC as a consequence of R-wave synchronization and only intermittent, periodic stimulation. In NECTAR-HF VNS intensity was delivered at a higher pulse frequency, and this was associated with intolerable adverse off-target effects which restricted VNS up-titration. Significant improvements in EF, 6MWD, MLWHF, and SDNN occurred in ANTHEM-HF relative to the other studies. ANTHEM-HF (n=60) INOVATE-HF (n=436) NECTAR-HF (n=63) Neural Target Central/Peripheral Peripheral Central/Peripheral Delivery Site Left or right CVN Right CVN Right CVN Delivery Intensity:   Amplitude (milliamperes) 2.0±0.6 3.9±1.0 1.4±0.8   Frequency (Hertz) 10 1–2 20   Duration (microseconds) 250 500 300 Electrode Polarity (Cathode) Caudal Cephalad Caudal Duty Cycle 23% 25% 17% On Time/Off Time (seconds) 18/62 Variable 10/50 Mode of Delivery Cyclic/Continuous Intermittent/Periodic Cyclic/Continuous Clinical Efficacy at 6 Months:   EF 32.4±7.2 to 37.2±10.4 Not available 30.5±6.0 to 32.7±6.4   6MWD 287±66 to 346±78 317±109 to 347±123 Not available   MLWHFS 40±14 to 21±10 Not available 44.2±22.2 to 35.8±20.8   SDNN 94±26 to 111±50 Not available 146±48 to 130±52 Values reported as mean ± standard deviation; CVN = Cervical vagus nerve. *p&lt;0.05 versus NECTAR-HF; **p&lt;0.05 versus INOVATE-HF; ***p&lt;0.025 versus NECTAR-HF; ****p&lt;0.001 versus NECTAR-HF (Analysis using two-sample t-test of the means). Conclusion VNS differed in ANTHEM-HF when compared to INOVATE-HF and NECTAR-HF. The neural targets, pulse frequencies for titration, and the DC for NM were different. VNS in ANTHEM-HF was clinically efficacious. The ongoing ANTHEM-HFrEF Pivotal Study uses a similar paradigm. Acknowledgement/Funding LivaNova PLC </jats:sec