Wireless Self-Powered Optogenetic System for Long-Term Cardiac Neuromodulation to Improve Post-MI Cardiac Remodeling and Malignant Arrhythmia

Abstract

Autonomic imbalance is an important characteristic of patients after myocardial infarction (MI) and adversely contributes to post-MI cardiac remodeling and ventricular arrhythmias (VAs). A previous study proved that optogenetic modulation could precisely inhibit cardiac sympathetic hyperactivity and prevent acute ischemia-induced VAs. Here, a wireless self-powered optogenetic modulation system is introduced, which achieves long-term precise cardiac neuromodulation in ambulatory canines. The wireless self-powered optical system based on a triboelectric nanogenerator is powered by energy harvested from body motion and realized the effective optical illumination that is required for optogenetic neuromodulation (ON). It is further demonstrated that long-term ON significantly mitigates MI-induced sympathetic remodeling and hyperactivity, and improves a variety of clinically relevant outcomes such as improves ventricular dysfunction, reduces infarct size, increases electrophysiological stability, and reduces susceptibility to VAs. These novel insights suggest that wireless ON holds translational potential for the clinical treatment of arrhythmia and other cardiovascular diseases related to sympathetic hyperactivity. Moreover, this innovative self-powered optical system may provide an opportunity to develop implantable/wearable and self-controllable devices for long-term optogenetic therapy.

Keywords: cardiac remodeling; neuromodulation; triboelectric nanogenerator; ventricular arrhythmia; wireless self-powered optogenetics.

Figure 1

Overview of the self‐powered optical system. The self‐powered optical system consists of a TENG‐based energy harvesting unit, a power manage unit (PMU), and LED opto‐electrode. a) The optogenetic neuromodulation for cardioprotection by the self‐powered optical system is presented. b) Optical image of the TENG. The inset indicates this TENG is flexible and can be bent by a finger. c) SEM image of the Au/PET. d) Resistance of the electrode under different bending angles. e) Schematics diagrams of the working mechanism of TENG. f) FEA simulation results of TENG under pressed and balanced state. g) Corresponding surface charge distribution curves along the surface of the electrode.

Figure 2

Characterization of the TENG and output performance of the PENG‐based optical system. a) V _OC and b) I _SC of the TENG. c) Dependence of the output voltage and instantaneous power density at different external load resistances. d) Output voltage and e) current of PENG fixed at the elbow joint. f) Charging curves of a 2.2 µF capacitor charged by TENG. g) LED lighted by the wearable self‐powered optogenetic modulation system. h) Light intensity of the LED changing with charging time.

Figure 3

Wireless implantable optogenetic system design and implantation diagram, device location examination and heat generation test, and LSG neuronal health. a) Schematic diagram and optical image of the implantable, battery‐free wireless optogenetic system. b) Diagram of the wireless LED device implantation in canines. c) Chest X‐ray examination confirmed that the LED implant was maintained at the corresponding position. d,e) Thermal property measurement on the surface of LED and the surface of the LSG during 1 h illumination. f,g) Representative hematoxylin and eosin images and quantification of infiltrating immune cells from the LSG. The black arrowheads in (f) represent infiltrating immune cells. Scale bar in (f) = 100 µm; Data are mean ± SEM. Statistical analysis was performed using one‐way analysis of variance (ANOVA) (g). Only statistically significant differences are indicated (n = 6 per group).

Figure 4

Long‐term wireless optogenetic modulation inhibited MI‐induced LSG neuronal remodeling. a) Experimental protocol flow. b–d) Immunofluorescent staining and quantification analysis verified that GFP/GFP‐ArchT was successfully and extensively expressed in LSG sympathetic neurons in four groups. Representative images of c‐fos (e, red) and NGF (f, red) expression in LSG TH+ (e,f, pink) sympathetic neurons in four groups. Long‐term wireless optogenetic neuromodulation suppressed MI‐induced LSG neuronal remodeling with reduced c‐fos and NGF expression in TH+ neurons (g,h). NGF, nerve growth factor. Scale bar in (b) = 200 µm; Scale bar in (c,e,f) = 100 µm. Data are mean ± SEM. ^# p < 0.05 versus the control group and *p < 0.05 versus ArchT/LED group by one‐way ANOVA with Tukey's comparisons test (n = 6 per group).

Figure 5

Long‐term wireless optogenetic modulation inhibited MI‐induced LSG hyperactivity and systemic ANS imbalance. a) Representative examples of BP elevation in response to LSG stimulation. b) Long‐term wireless optogenetic modulation significantly inhibited LSG function. The x‐axis numbers 1–5 represent five incremental high‐frequency stimulus voltage levels (level 1 = 1 to 4 V; level 2 = 5 to 7 V; level 3 = 7.5 to 10 V; level 4 = 10 to12.5 V; level 5 = 12.5‐15 V). c) Representative images of LSG neural activity of four groups. Long‐term wireless optogenetic modulation inhibited MI‐induced LSG hyperactivity, with both decreased d) frequency and e) amplitude of LSG neural firing. Long‐term wireless optogenetic inhibition of cardiac sympathetic nerve activity significantly improved HRV, attenuated MI‐induced increase in f) LFnu, h) LF/HF ratio, and g) decrease in HFnu. i,j) Long‐term wireless optogenetic inhibition of cardiac sympathetic nerve activity significantly reduced plasma norepinephrine and neuropeptide Y concentration. HFnu, normalized unit of high frequency; LFnu, normalized unit of low frequency; LF/HF, the ratio between LF and HF; NE, norepinephrine; NPY, neuropeptide Y. Data are mean ± SEM. ^# p < 0.05 versus the control group and *p < 0.05 versus ArchT/LED group by one‐way ANOVA or two‐way repeated‐measures ANOVA with Tukey's multiple comparisons test (n = 6 per group).

Figure 6

Long‐term optogenetic neuromodulation improved MI‐induced LV dysfunction and remodeling. a) Schematic diagram of cardiac four‐chamber and two‐chamber view for volume calculations using biplane Simpson's method. Long‐term wireless optogenetic cardiac sympathetic inhibition improved cardiac function with b) increased LVEF compared with ArchT/LED group and e) increased E/A compared with LED group. There were no significant differences between the optogenetic neuromodulation group and ArchT/LED group in c) LVEDV and d) LVESV. f–h) Long‐term wireless optogenetic cardiac sympathetic inhibition attenuated LV segmental wall thinning with increased % systolic wall thickening at the apex. i) Display of the 17 myocardial segments of the left ventricle. Long‐term wireless optogenetic cardiac sympathetic inhibition increased peak systolic velocity of the LAD‐perfused segments both j,k) at rest and l,m) at dobutamine stress. LVEF, left ventricular ejection fraction; LVEDV, left ventricular end‐diastolic volume; LVESV, left ventricular end‐systolic volume; WTh, wall thickness; LAD, left anterior descending artery; LCX, left circumflex artery; RCA,= right coronary artery. Data are mean ± SEM. ^# p < 0.05 versus the control group and *p < 0.05 versus ArchT/LED group by one‐way ANOVA or two‐way repeated‐measures ANOVA with Tukey's multiple comparisons test (n = 6 per group).

Figure 7

Long‐term optogenetic neuromodulation improved LV structural remodeling. a) Representative images of LV infarct size in the MI group and the optogenetics group. b) Long‐term wireless optogenetic cardiac sympathetic inhibition significantly reduced LV infarct size, c,d) suppressed LV fibrosis, and e,f) fiber innervation. The black arrowheads in (e) represent TH⁺ sympathetic fibers. Data are mean ±SEM. ^# p < 0.05 versus the control group and *p < 0.05 versus ArchT/LED group by one‐way ANOVA with Tukey's multiple comparisons test (n = 6 per group).

Figure 8

Long‐term optogenetic neuromodulation improved ventricular electrophysiological stability and reduced VA susceptibility. Long‐term wireless optogenetic modulation prolonged ventricular a) ERP and b) APD₉₀ with c,d) reduced spatial dispersion. e) Typical images of ECG lead II, ECG lead III, and epicardium ECG (EECG) recorded from RVA when performing programmed electrical stimulation. Long‐term wireless optogenetic modulation significantly f) decreased VA inducibility and g) increased VF threshold. APD90 = 90% repolarization of APD. ERP, effective refractory period; LVA, LV apical peri‐infarct zone; LVM, LV median area; LVB, LV base; RVA, right ventricular apex; RVM, RV median area; RVB, RV base. Data are mean ± SEM. ^# p < 0.05 versus the control group and *p < 0.05 versus ArchT/LED group by one‐way ANOVA or two‐way repeated‐measures ANOVA with Tukey's multiple comparisons test (n = 6 per group).