Accepted and presented at The Design of Medical Devices Conference (DMD2016)

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a prognostic marker for stroke, heart failure, and even death Successful ablation therapy to terminate AF requires a highly reliable technique to determine ablation sites using raw intra-atrial electrograms of AF patients. Hence, there is a clear need for a robust spatiotemporal mapping technology that can accurately identify the rotor pivot points in a patient-specific manner, which is the motivation for this research. Recently, a novel entropy-based approach was used to identify the rotor pivot point using optical mapping data from rabbit heart [4]. This approach was also used to generate 3D Shannon entropy maps for a persistent AF patient using raw intra-atrial electrograms demonstrating the feasibility to identify rotor pivot points outside the pulmonary vein (PV) region. However, challenges still remain to robustly map and more precisely confirm the exact location of rotor pivot points for AF ablation. It is known that the DF of a rotor is the same throughout the entire spatial area occupied by the rotor and therefore cannot accurately identify the rotor pivot point. This method uses a Fourier transform to calculate the DF and is therefore limited to a single frequency. In contrast, we hypothesize that the chaotic nature of the rotor at the pivot point yields various frequency components. In this work, the authors propose and demonstrate a novel multiscale frequency (MSF) approach that takes into account the contribution from various frequencies to yield valuable information regarding the rotor pivot point, thus allowing for its identification. We validate the feasibility of this technique to identify the pivot point of rotors using optical mapping data from isolated rabbit hearts with induced ventricular tachycardia (VT). Methods Novel MSF Approach. Band-pass quadrature filters are robust for estimating local multiscale information, such as the energy, phase, radial frequency, and orientation/angular frequency. The Hilbert transform operation transforms a real-valued signal to analytic signal with no negative frequencies, and its utility with the quadrature filter can yield MSF information by weighting the various frequency components. In this work, eight log-Gabor/normal filters were designed and used with a relative filter bandwidth B of 2ͱ2, one octave apart as described in Ref. where q i is the output of the ith log-Gabor filter, and q 0 is the center frequency of the first log-Gabor filter Optical Mapping Data From Isolated Rabbit Hearts. Optical Optical mapping experiments were performed with IACUC approval on isolated rabbit hearts which were put in the Langendorffperfusion system, and voltage-sensitive dye di-4-ANEPPS (5 lg/mL) was added to the perfusate. After staining, 532 nm green laser was used to illuminate the epicardial surface of the heart. Fluorescence intensity was captured with two 12-bit CCD cameras, which run at 600 frames per second with 64 Â 64 pixel resolution. VT was induced via burst pacing, and phase movies of the rotors were obtained from optical mapping recordings. The phase movies from one rabbit heart with a known pivot point were used in this work, shown in Result

Chronic Low-Level Vagus Nerve Stimulation Improves Long-Term Survival in Salt-Sensitive Hypertensive Rats

Chronic hypertension (HTN) affects more than 1 billion people worldwide, and is associated with an increased risk of cardiovascular disease. Despite decades of promising research, effective treatment of HTN remains challenging. This work investigates vagus nerve stimulation (VNS) as a novel, device-based therapy for HTN treatment, and specifically evaluates its effects on long-term survival and HTN-associated adverse effects. HTN was induced in Dahl salt-sensitive rats using a high-salt diet, and the rats were randomly divided into two groups: VNS (n = 9) and Sham (n = 8), which were implanted with functional or non-functional VNS stimulators, respectively. Acute and chronic effects of VNS therapy were evaluated through continuous monitoring of blood pressure (BP) and ECG via telemetry devices. Autonomic tone was quantified using heart rate (HR), HR variability (HRV) and baroreflex sensitivity (BRS) analysis. Structural cardiac changes were quantified through gross morphology and histology studies. VNS significantly improved the long-term survival of hypertensive rats, increasing median event-free survival by 78% in comparison to Sham rats. Acutely, VNS improved autonomic balance by significantly increasing HRV during stimulation, which may lead to beneficial chronic effects of VNS therapy. Chronic VNS therapy slowed the progression of HTN through an attenuation of SBP and by preserving HRV. Finally, VNS significantly altered cardiac structure, increasing heart weight, but did not alter the amount of fibrosis in the hypertensive hearts. These results suggest that VNS has the potential to improve outcomes in subjects with severe HTN

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Stochastic vagus nerve stimulation affects acute heart rate dynamics in rats

<div><p>Vagus nerve stimulation (VNS) is an approved therapy for treatment of epilepsy and depression. While also shown to be promising in several preclinical and clinical studies to treat cardiovascular diseases, optimal therapeutic stimulation paradigms are still under investigation. Traditionally, parameters such as frequency, current, and duty cycle are used to adjust the efficacy of VNS therapy. This study explored the effect of novel stochastic VNS (S-VNS) on acute heart rate (HR) dynamics. The effect of S-VNS was evaluated in Sprague Dawley rats by comparing the acute HR and HR variability (HRV) responses to standard, periodic VNS (P-VNS) across different frequencies (FREQs, 10–30 Hz). Our results demonstrate that both S-VNS and P-VNS produced negative chronotropic effects in a FREQ-dependent manner with S-VNS inducing a significantly smaller drop in HR at 10 Hz and 20 Hz compared to P-VNS (p<0.05). S-VNS demonstrated a FREQ-dependent drop in the SD1/SD2 ratio, a measure of HRV, which was absent in P-VNS, suggesting that S-VNS may acutely modulate the nonlinear relationship between short- and long-term HRV. In conclusion, S-VNS is a novel stimulation procedure that may provide different physiological outcomes from standard P-VNS, as indicated by our analysis of HR dynamics. Our study provides a rationale for further detailed investigations into the therapeutic potential of S-VNS as a novel neuromodulation technique.</p></div

Effects of VNS FREQ on HR and heart period.

<p>Mean percent drop in HR for <b>(A)</b> P-VNS, <b>(B)</b> S-VNS (10%), and <b>(C)</b> S-VNS (20%) at different FREQ. Mean percent drop in Heart Period for <b>(D)</b> P-VNS, <b>(E)</b> S-VNS (10%), and <b>(F)</b> S-VNS (20%) at different FREQ. Note data reported here for P-VNS is the mean and SEM of the average of P-VNS #1 and P-VNS #2 protocols (n = 8). (*p < 0.05).</p

Effects of VNS on HRV using Poincaré analysis.

<p>Representative Poincaré plots of <b>(A)</b> P-VNS and <b>(B)</b> S-VNS (10%) during VNS stimulation (<b>ON</b>) at 10 Hz and 30 Hz demonstrating the elliptical fitting of the beat-distribution cloud and the standard deviation of short-term (SD1) and long-term (SD2) variability. <b>(C)</b> Mean SD1/SD2 ratio for <b>PRE</b>, <b>ON</b> and <b>POST</b> across different FREQ. (*p < 0.05).</p

ECG recordings and corresponding HR responses.

<p>Representative segments of ECG recordings and corresponding heart rate (HR) response for an anesthetized rat for <b>PRE</b>, <b>ON</b>, and <b>POST</b> during <b>(A)</b> P-VNS, <b>(B)</b> S-VNS (10%), and <b>(C)</b> S-VNS (20%) of the right cervical vagus nerve. Zoomed-in snapshots of <b>PRE</b> (black), <b>ON</b> (red), and <b>POST</b> (yellow) highlights VNS artifacts during stimulation. Here, VNS was continuously delivered at 20 Hz, 500 µs pulse width, and 1.0 mA for 2 minutes.</p

Effects of VNS FREQ on HR recovery.

<p><b>(A)</b> Schematic representation of different scenarios of HR recovery based on the value of <i>HR</i>_{<i>POST Ratio</i>}. Mean <i>HR</i>_{<i>POST Ratio</i>} values for <b>(B)</b> P-VNS, <b>(C)</b> S-VNS (10%), and <b>(D)</b> S-VNS (20%) at different FREQ. # p<0.05 compared to a mean theoretical value of 1.</p