Neuromodulation of peripheral nerves with bioelectronic devices is a promising approach for treating a wide range of disorders. Wireless powering could enable long-term operation of these devices, but achieving high performance for miniaturized and deeply placed devices remains a technological challenge. We report the miniaturized integration of a wireless powering system in soft neuromodulation device (15 mm length, 2.7 mm diameter) and demonstrate high performance (about 10%) during in vivo wireless stimulation of the vagus nerve in a porcine animal model. The increased performance is enabled by the generation of a focused and circularly polarized field that enhances efficiency and provides immunity to polarization misalignment. These performance characteristics establish the clinical potential of wireless powering for emerging therapies based on neuromodulation.

AIMSThoracic spinal cord stimulation (SCS) has been shown to improve left ventricular ejection fraction (LVEF) in heart failure (HF). Nevertheless, the optimal duration (intermittent vs. continuous) of stimulation and the mechanisms of action remain unclear.METHODS AND RESULTSWe performed chronic thoracic SCS at the level of T1-T3 (50 Hz, pulse width 0.2 ms) in 30 adult pigs with HF induced by myocardial infarction and rapid ventricular pacing for 4 weeks. All the animals were treated with daily oral metoprolol succinate (25 mg) plus ramipril (2.5 mg), and randomized to a control group (n = 10), intermittent SCS (4 h ×3, n = 10) or continuous SCS (24 h, n = 10) for 10 weeks. Serial measurements of LVEF and +dP/dt and serum levels of norepinephrine and B-type natriuretic peptide (BNP) were measured. After sacrifice, immunohistological studies of myocardial sympathetic and parasympathetic nerve sprouting and innervation were performed. Echocardiogram revealed a significant increase in LVEF and +dP/dt at 10 weeks in both the intermittent and continuous SCS group compared with controls (P < 0.05). In both SCS groups, there was diffuse sympathetic nerve sprouting over the infarct, peri-infarct, and normal regions compared with only the peri-infarct and infarct regions in the control group. In addition, sympathetic innervation at the peri-infarct and infarct regions was increased following SCS, but decreased in the control group. Myocardium norepinephrine spillover and serum BNP at 10 weeks was significantly decreased only in the continuous SCS group (P < 0.05).CONCLUSIONSIn a porcine model of HF, SCS induces significant remodelling of cardiac sympathetic innervation over the peri-infarct and infarct regions and is associated with improved LV function and reduced myocardial norepinephrine spillover.

Background: Currently, the lack of well-established large animal models of heart failure with preserved ejection fraction (HFpEF) is one of the major hurdles for developing effective therapies for HFpEF. Here, we describe a large animal model of HFpEF induced by sustained hypertension (HT) that mimics human diseases. Methods: We induced sustained severe hypertension in 9 adult pigs using a combination of intravenous Angiotensin-II (Ang-II, 0.015mg/hr) delivery with an osmotic infusion pump and subcutaneous implantation of deoxycorticosterone acetate (DOCA) pellets (100mg/kg) for 10 weeks. All animals underwent invasive blood pressure (BP) telemetry monitoring and serial invasive pressure-volume (PV) loop assessment as well as echocardiographic examination at baseline, 10 weeks and 18 weeks. Results: Mean systolic and diastolic BP at baseline was 88/61 mmHg which increased immediately after Ang-II infusion plus DOCA (Week 0,158/105 mmHg) and progressively elevated up to Week 10 (171/126mmHg) that persisted out to Week 18 (183/137mmHg) despite termination of Ang-II infusion. Serial echocardiograms showed the development of left ventricular hypertrophy with significant increase in left ventricular mass with preserved left ventricular ejection fraction (Figure, upper panel). PV loop showed progressive elevation of pulmonary artery capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP) and end-diastolic pressure volume relationship (EDPVR) without change in end-systolic pressure volume relationship, suggestive of left ventricular diastolic dysfunction (Figure, lower panel). Conclusions: We successfully established a clinically relevant large animal model of HFpEF induced by sustained HT, which can be used for future investigation of new treatments for HFpEF.

Background: Catheter-based radiofrequency (RF) renal denervation (RD) has been shown to decrease renal norepinephrine (NE) spillover in animal models and humans with hypertension. Nevertheless, the effect of RD on renal NE spillover in systolic heart failure (HF) is unknown. Methods: Ischemic HF model was created in 16 porcine by inducing myocardial infarction (MI) via coronary embolization of the left circumflex artery followed by rapid ventricular pacing for 4 weeks (MI+HF). Of these, 8 porcine underwent bilateral RD using the EnligHTN System (St. Jude Medical) and the remaining 8 served as control. All animals were given daily oral metoprolol ZOK (50 mg) plus ramipril (2.5 mg). Serum NE levels at different sites and index of cardiac contractility (dP/dt max /IP) were measured at baseline, immediately after MI (post-MI), at MI+HF and at 10 weeks follow-up. Renal arteries were then prepared for histological analysis. Results: RD significantly increased the dP/dt max /IP as compared with the control group (P<0.05, Figure 1a). RD also decreased the arterial and coronary sinus NE (P<0.05), and renal NE spillover (-54%, P=0.06) at 10 weeks as compared with MI+HF (Figures 1b & 1c). Histological examination showed significant reduction of renal sympathetic efferent nerves (tyrosine hydroxylase+) at proximal, middle and distal portions of the renal artery after RD as compared with the control group (-65%, P<0.05, Figure 1d). Conclusions: In a porcine model of ischemic HF, bilateral RD using catheter-based RF effectively destroys renal nerves to decrease renal NE spillover, and improves LV contractile function compared with medical therapy alone.

BACKGROUND:Preclinical studies suggest that neuromodulation with thoracic spinal cord stimulation (SCS) improves left ventricular (LV) function and remodeling in systolic heart failure (HF). OBJECTIVE:The purpose of this study was to evaluate the safety and efficacy of a SCS system for the treatment of systolic HF. METHODS:We performed a prospective, multicenter pilot trial in patients with New York Heart Association (NYHA) class III HF, left ventricular ejection fraction (LVEF) 20%-35%, and implanted defibrillator device who were prescribed stable optimal medical therapy. Dual thoracic SCS leads were used at the T1-T3 level. The device was programmed to provide SCS for 24 hours per day (50 Hz at pulse width 200 μs). RESULTS:We enrolled 22 patients from 5 centers:17 patients underwent implantation of a SCS device and 4 patients who did not fulfill the study criteria served as nontreated controls. No deaths or device-device interactions were noted during the 6-month period in the 17 SCS-treated patients. Fifteen of 17 completed the efficacy endpoint assessments: composite score improved by 4.2 ± 1.3, and 11 patients (73%) showed improvement in ≥4 of 6 efficacy parameters. There was significant improvement in NYHA class (3.0 vs 2.1, P = .002; 13/17 improved); Minnesota Living with Heart Failure Questionnaire (42 ± 26 vs 27 ± 22, P = .026; 12/17 improved); peak maximum oxygen consumption (14.6 ± 3.3 vs 16.5 ± 3.9 mL/kg/min, P = .013; 10/15 improved); LVEF (25% ± 6% vs 37% ± 8%, P<.001; 14/16 improved); and LV end-systolic volume (174 ± 57 vs 137 ± 37 mL, P = .002; 11/16 improved) but not in N-terminal prohormone brain natriuretic peptide. No such improvements were observed in the 4 nontreated patients. CONCLUSION:The results of this first-in-human trial suggest that high thoracic SCS is safe and feasible and potentially can improve symptoms, functional status, and LV function and remodeling in patients with severe, symptomatic systolic HF.

Background: Pre-clinical studies to date have demonstrated potential improvements in renal blood flow after renal sympathetic denervation, however such effects are yet to be confirmed in patients with resistant hypertension. We assessed the effects of renal sympathetic denervation in these patients on renal artery blood flow and diameter at multiple time points. Methods and results: Patients (n = 15) with systolic blood pressures ≤ 160mmHg despite taking ≥ 3 antihypertensive medications concurrently at maximum tolerated dose were recruited into this single centre, prospective, non-blinded study. MRI indices included renal blood flow and renal artery diameters at baseline, 1 month and 6 months. In addition to significant decreases in blood pressures (p < 0.05) renal blood flow (total volume per cardiac cycle) increased 20% from (6.9 ± 2 mls) at baseline to (8.7 ± 2 mls; p=0.001) at one month and (8.0 ± 2mls; p=0.01) six months post procedure. There was a significant decrease in renal artery diameters from (6.8 ± 2 mm) at baseline to (6.2 ± 1 mm; p<0.03) at 1 month post procedure and this decrease was associated with increases of maximum velocity of blood flow from (73 ± 19 cm/sec) at baseline to (78 ± 19 cm/sec) at one month post procedure and notably, both parameters revert to 6.9 ± 2 mm and 72 ± 18 cm/sec respectively. Thus, this study is the first to provide evidence of an early reduction in renal artery diameters (potentially due to oedema and inflammation) post intervention that has resolved by 6 months. Conclusion: Renal sympathetic denervation improves renal physiology as evidenced by significant improvements in renal blood flow. Additionally, this study for the first time identifies a transient decrease in renal artery diameters immediately after procedure and further demonstrates that these changes revert to baseline values six months post procedure.

Background and aims: Echocardiographic studies have shown improvements in cardiac indices associated with renal sympathetic denervation (RDN), however, the benefits on myocardial perfusion have never been assessed. This trial was designed to study the effects of RDN on myocardial perfusion using cardiac magnetic resonance (CMR) imaging.& para;& para;Methods: A total of 14 patients with resistant hypertension were recruited for RDN and myocardial perfusion, alongside other CMR indices, was assessed at baseline and at 6 months.& para;& para;Results: RDN showed significant reduction of mean office blood pressures from 181/100 +/- 19/16 mmHg to 147/85 +/- 19/17 mmHg, 6 months after the procedure (p < 0.0001). This was combined with significant improvement in regional aortic distensibility (p < 0.02) and associated with trends of improved myocardial perfusion reserve index (baseline = 2.2 +/- 1; 6 months = 2.9 +/- 1 units) (p = 0.08). Left ventricular end systolic volume index decreased from baseline to 6 months post procedure, 27 +/- 13 ml/m(2) vs. 22 +/- 10 ml/m(2) (p = 0.03), but there was no significant change in left ventricular end diastolic volume index (p = 0.09). There was significant improvement in mean left ventricular ejection fraction from 68 +/- 10% to 72 + 9%, 6 months post procedure (p = 0.04). T1 mapping failed to detect fibrosis in these patients at baseline and therefore no change was noted, however, extracellular volume percent improved from 46 +/- 4% at baseline to 41 +/- 8% at 6 months (p = 0.002).& para;& para;Conclusions: This study demonstrates that renal sympathetic denervation increased myocardial perfusion by 32% as assessed by CMR, and, this was associated with improvements in cardiac volumes and function. Larger well controlled and randomized studies are required to assess the clinical significance of these findings. Crown Copyright (C) 2018 Published by Elsevier B.V. All rights reserved.

Thoracic Spinal Cord Stimulation . Background: Prior experimental studies show that thoracic spinal cord stimulation (SCS) improves left ventricular (LV) ejection fraction (LVEF). The mechanism of this improvement in the LV contractile function after SCS and its effects on the myocardial oxygen consumption remains unknown. Methods and Results: We performed thoracic SCS (T1‐T2 level) followed by 4 weeks of rapid ventricular pacing in 9 adult pigs with ischemic heart failure (HF) induced by myocardial infarction (MI). At 24 hours off‐pacing, detailed echocardiogram and invasive hemodynamic assessment were performed to determine LV contractile function and myocardial oxygen consumption. Serum norepinephrine level was measured before and after SCS. SCS was performed on 2 occasions for 15 minutes, 30 minutes apart (recovery) with 50 Hz frequency (pulse width 0.2 millisecond, 90% of motor threshold at 2 Hz output). Echocardiogram revealed significant decrease in LVEF (33.8 ± 1.8% vs 66.5 ± 1.7%, P < 0.01) after induction of MI and HF. Compared with MI and HF, acute SCS significantly increased LVEF and +dP/dt (all P < 0.05). Withdrawal of SCS during recovery decreased +dP/dt, but not LVEF that increased again with repeated SCS. Myocardial oxygen consumption also significantly decreased during SCS compared with MI and HF (P = 0.006) without any change in serum norepinephrine level (P = 0.9). Speckle tracking imaging showed significant improvement in global and regional circumferential strains over the infarcted mid and apical regions, decreased in time to peak circumferential strain over the lateral and posterior wall after SCS, and the degree of intraventricular dyssynchrony during SCS compared with MI and HF (P < 0.05). Conclusions: In a porcine model of ischemic HF, acute SCS improved global and regional LV contractile function and intraventricular dyssynchrony, and decreased myocardial oxygen consumption without elevation of norepinephrine level. (J Cardiovasc Electrophysiol, Vol. 23, pp. 534‐540, May 2012)

Background Prior experimental studies showed that thoracic spinal cord stimulation (SCS) improved left ventricular (LV) ejection fraction (LVEF) in animal model of ischemic cardiomyopathy. While, it is unclear whether increased LV contractile function with thoracic SCS is associated with increased myocardial oxygen consumption that may subsequently lead to further worsening of LV function and heart failure (HF) progression. Methods We performed acute thoracic SCS in 11 adult pigs with ischemic HF induced by coronary embolization of left circumflex artery followed by rapid ventricular pacing for 4 wks. At 24 hours off -pacing, all animals underwent invasive hemodynamic assessment to determine LV contractile function, myocardial oxygen consumption and blood sampling to measure serum norepinephrine levels before (baseline) and after short-term SCS. SCS was performed twice for 15 minutes with 30 minutes apart (recovery) at T1-T2 level with 50Hz frequency, pulse width 0.2ms, and the same 90% of motor threshold as determined by 2Hz output. Results Echocardiogram showed significant decreased in LVEF (34.1±1.9% vs. 66.5±1.7%, P Conclusions In porcine model of ischemic HF, acute SCS Improves LV contractile function and decreases myocardial oxygen consumption without evidence of excessive sympathetic activation as measured serum norepinephrine levels. These findings have important implication on the long-term application of SCS for treatment of ischemic HF.

Atrial fibrillation, the most common type of cardiac arrhythmia, now affects more than 2.2 million adults in the US alone. Currently, electrophysiological interventions are performed under fluoroscopy guidance, a procedure that introduces harmful ionizing radiation without providing adequate soft-tissue resolution. Intracardiac echocardiography (ICE) provides real-time, high-resolution anatomical information, reduces fluoroscopy time, and enhances procedural success. We have previously developed a forward-looking, volumetric ICE catheter using a ring-shaped, 64-element capacitive micromachined ultrasonic transducer (CMUT) array with a 10MHz center frequency. The Ring array was flip-chip bonded to a flexible PCB along with 8 identical custom ASICs providing a total of 64 dedicated preamplifiers. The flex was then reshaped for integration with the catheter shaft. In the second-generation catheter, 72 micro-coaxial cables (reduced from 100) are terminated on a newly designed flex to provide the connection between the array electronics and the imaging system. The reduced number of cables enhances the catheter's steerability. Furthermore, the new flex allows grounding of the top CMUT electrode through proper level-shifting of the ASIC supplies without additional circuitry. This feature enables complete ground shielding of the catheter, which improves its noise susceptibility and is an important safety measure for its clinical use. Beyond real-time, forward-looking imaging capability, the Ring catheter provides a continuous central lumen, enabling convenient delivery of other devices such as HIFU transducers, RF ablation catheters, etc. Using a PC-based imaging platform from Verasonics and a commercial Vivid7 imaging system from GE, we have demonstrated the in vivo, volumetric, real-time imaging capability of the finalized Ring catheter in a pig heart.

A method is introduced to monitor cardiac ablative therapy by examining slope changes in the thermal strain curve caused by speed of sound variations with temperature. The sound speed of water-bearing tissue such as cardiac muscle increases with temperature. However, at temperatures above about 50°C, there is no further increase in the sound speed and the temperature coefficient may become slightly negative. For ablation therapy, an irreversible injury to tissue and a complete heart block occurs in the range of 48 to 50°C for a short period in accordance with the well-known Arrhenius equation. Using these two properties, we propose a potential tool to detect the moment when tissue damage occurs by using the reduced slope in the thermal strain curve as a function of heating time. We have illustrated the feasibility of this method initially using porcine myocardium in vitro. The method was further demonstrated in vivo, using a specially equipped ablation tip and an 11-MHz microlinear intracardiac echocardiography (ICE) array mounted on the tip of a catheter. The thermal strain curves showed a plateau, strongly suggesting that the temperature reached at least 50°C.

Tissue temperature is critically related to the success or failure of catheter ablation procedures. Temperature imaging using ultrasound techniques is attractive because of the potential to provide real-time information at low cost. The signal-processing methods used here were developed to investigate the feasibility of monitoring ablative therapy by identifying the point at which the slope of the thermal strain curve changes sign caused primarily by speed of sound variations with temperature. Previously, we have demonstrated the feasibility of this method in-vivo using porcine models. In this paper, we present recent results with temperature validation for this method in-vivo using an integrated intracardiac echocardiography (ICE) probe. Also preliminary results on thermal strain imaging using a cMUT array integrated into the ICE probe are presented.

Capacitive micromachined ultrasonic transducer (CMUT) arrays are conveniently integrated with frontend integrated circuits either monolithically or in a hybrid multichip form. This integration helps with reducing the number of active data processing channels for 2D arrays. This approach also preserves the signal integrity for arrays with small elements. Therefore CMUT arrays integrated with electronic circuits are most suitable to implement miniaturized probes required for many intravascular, intracardiac, and endoscopic applications. This paper presents examples of miniaturized CMUT probes utilizing 1D, 2D, and ring arrays with integrated electronics.