Sonodynamic therapy combined with phototherapy: Novel synergistic strategy with superior efficacy for antitumor and antiinfection therapy.

Phototherapy (PT), including photodynamic therapy (PDT) and photothermal therapy (PTT), has recently achieved significant advances in antitumor and antiinfection therapy. Sonodynamic therapy (SDT), as a novel noninvasive therapy with a deeper penetration depth (>8 cm), fewer side effects and non-phototoxicity than PT, has drawn much attention in recent years. However, both PT and SDT have intrinsic limitations. By combining PT with SDT, the dualmodel therapy with advanced sensitizers overcome the intrinsic limitations and show higher efficacy than traditional monotherapy. Moreover, the photo-diagnosis modality could be easily integrated into synergistic therapy so that the sensitizer acts as a tracer for fluorescence/photoacoustic imaging, and the treatment process is visualized in a way that SDT combined with other therapies cannot achieve. This review summarizes the advanced sensitizers and the application of combination therapy, and explores the improvement strategies for promoting clinical transformation.

Light Emitting Diode Therapy Protects against Myocardial Ischemia/Reperfusion Injury through Mitigating Neuroinflammation.

BACKGROUND: Neuroinflammation plays a key role in myocardial ischemia-reperfusion (I/R) injury. Previous studies showed that light-emitting diode (LED) therapy might improve M2 microglia activation and brain-derived neurotrophic factor (BDNF) expression, thereby exerting anti-inflammatory effects. Therefore, we hypothesized that LED therapy might reduce myocardial I/R injury by neuroinflammation modulation. OBJECTIVE: To explore the effect of LED therapy on myocardial I/R-induced injury and seek the underlying mechanism. METHODS: Thirty rats were randomly divided into three groups: Control group (without LED treatment or myocardial I/R, n = 6), I/R group (with myocardial I/R only, n = 12), and LED+I/R group (with myocardial I/R and LED therapy, n = 12). Electrocardiogram was recorded continuously during the procedure. In addition, brain tissue was extracted for BDNF, Iba1, and CD206 analyses, and heart tissue for myocardial injury (ischemic size and infarct size), IL-4 and IL-10 mRNA analysis. RESULTS: In comparison with the I/R group, the ischemia size and the infarct size were significantly attenuated by LED therapy in the LED+I/R group. Meanwhile, the microglia activation induced by I/R injury was prominently attenuated by LED treatment either. And it is apparent that there was also an increase in the beneficial neuroinflammation markers (BDNF and CD206) in the paraventricular nucleus (PVN) in the LED+I/R group. Furthermore, the anti-inflammatory cytokines, IL-4 and IL-10, were greatly decreased by I/R while improved by LED treatment in myocardium. CONCLUSION: LED therapy might reduce neuroinflammation in PVN and decrease myocardium injury by elevating BDNF and M2 microglia.

Light-emitting diode therapy protects against ventricular arrhythmias by neuro-immune modulation in myocardial ischemia and reperfusion rat model.

BACKGROUND: Sympathetic overactivation and inflammation are two major mediators to post-myocardial ischemia-reperfusion (I/R)-induced ventricular arrhythmia (VA). The vicious cycle between microglia and sympathetic activation plays an important role in sympathetic hyperactivity related to cardiovascular diseases. Recently, studies have shown that microglial activation might be attenuated by light-emitting diode (LED) therapy. Therefore, we hypothesized that LED therapy might protect against myocardial I/R-induced VAs by attenuating microglial and sympathetic activation. METHODS: Thirty-six male anesthetized rats were randomized into four groups: control group (n = 6), LED group (n = 6), I/R group (n = 12), and LED+I/R group (n = 12). I/R was generated by left anterior descending artery occlusion for 30 min followed by 3 h reperfusion. ECG and left stellate ganglion (LSG) neural activity were recorded continuously. After 3 h reperfusion, a programmed stimulation protocol was conducted to test the inducibility of VA. Furthermore, we extracted the brain tissue to examine the microglial activation, and the peri-ischemic myocardium to examine the expression of NGF and inflammatory cytokines (IL-1ß, IL-18, IL-6, and TNF-α). RESULTS: As compared to the I/R group, LED illumination significantly inhibited the LSG neural activity (P < 0.01) and reduced the inducibility of VAs (arrhythmia score 4.417 ± 0.358 vs. 3 ± 0.3257, P < 0.01) in the LED+I/R group. Furthermore, LED significantly attenuated microglial activation and downregulated the expression of inflammatory cytokines and NGF in the peri-infarct myocardium. CONCLUSIONS: LED therapy may protect against myocardial I/R-induced VAs by central and peripheral neuro-immune regulation.

Noninvasive light emitting diode therapy: A novel approach for postinfarction ventricular arrhythmias and neuroimmune modulation.

BACKGROUND: Sympathetic neural activation plays a key role in the incidence and maintenance of acute myocardial infarction (AMI) induced ventricular arrhythmia (VA). Furthermore, previous studies showed that AMI might induce microglia and sympathetic activation and that microglial activation might contribute to sympathetic activation. Recently, studies showed that light emitting diode (LED) therapy might attenuate microglial activation. Therefore, we hypothesized that LED therapy might reduce AMI-induced VA by attenuating microglia and sympathetic activation. METHODS: Thirty anesthetized rats were randomly divided into three groups: the Control group (n = 6), AMI group (n = 12), and AMI + LED group (n = 12). Electrocardiogram (ECG) and left stellate ganglion (LSG) neural activity were continuously recorded. The incidence of VAs was recorded during the first hour after AMI. Furthermore, we sampled the brain and myocardium tissue of the different groups to examine the microglial activation and expression of nerve growth factor (NGF), interleukin-18 (IL-18), and IL-1ß, respectively. RESULTS: Compared to the AMI group, LED therapy significantly reduced the incidence of AMI-induced VAs (ventricular premature beats [VPB] number: 85.08 ± 13.91 vs 27.5 ± 9.168, P < .01; nonsustained ventricular tachycardia (nSVT) duration: 34.39 ± 8.562 vs 9.005 ± 3.442, P < .05; nSVT number: 18.92 ± 4.52 vs 7.583 ± 3.019, P < .05; incidence rate of SVT/VF: 58.33% vs. 8.33%, P < .05) and reduced the LSG neural activity (P < .01) in the AMI + LED group. Furthermore, LED significantly attenuated microglial activation and reduced IL-18, IL-1ß, and NGF expression in the peri-infarct myocardium. CONCLUSION: LED therapy may protect against AMI-induced VAs by suppressing sympathetic neural activity and the inflammatory response.

Low-Level Tragus Stimulation for the Treatment of Ischemia and Reperfusion Injury in Patients With ST-Segment Elevation Myocardial Infarction: A Proof-of-Concept Study.

OBJECTIVES: The aim of this study was to investigate whether low-level tragus stimulation (LL-TS) treatment could reduce myocardial ischemia-reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The authors' previous studies suggested that LL-TS could reduce the size of myocardial injury induced by ischemia. METHODS: Patients who presented with STEMI within 12 h of symptom onset, treated with primary percutaneous coronary intervention, were randomized to the LL-TS group (n = 47) or the control group (with sham stimulation [n = 48]). LL-TS, 50% lower than the electric current that slowed the sinus rate, was delivered to the right tragus once the patients arrived in the catheterization room and lasted for 2 h after balloon dilatation (reperfusion). All patients were followed for 7 days. The occurrence of reperfusion-related arrhythmia, blood levels of creatine kinase-MB, myoglobin, N-terminal pro-B-type natriuretic peptide and inflammatory markers, and echocardiographic characteristics were evaluated. RESULTS: The incidence of reperfusion-related ventricular arrhythmia during the first 24 h was significantly attenuated by LL-TS. In addition, the area under the curve for creatine kinase-MB and myoglobin over 72 h was smaller in the LL-TS group than the control group. Furthermore, blood levels of inflammatory markers were decreased by LL-TS. Cardiac function, as demonstrated by the level of N-terminal pro-B-type natriuretic peptide, the left ventricular ejection fraction, and the wall motion index, was markedly improved by LL-TS. CONCLUSIONS: LL-TS reduces myocardial ischemia-reperfusion injury in patients with STEMI. This proof-of-concept study raises the possibility that this noninvasive strategy may be used to treat patients with STEMI undergoing primary percutaneous coronary intervention.

Renal sympathetic stimulation and ablation affect ventricular arrhythmia by modulating autonomic activity in a cesium-induced long QT canine model.

BACKGROUND: Our previous studies showed that renal sympathetic stimulation (RS) may facilitate ischemic ventricular arrhythmia (VA) by increasing left stellate ganglion (LSG) nerve activity, whereas renal sympathetic ablation (RA) may suppress VA. OBJECTIVE: The purpose of this study was to investigate whether renal sympathetic interventions also can affect VA by modulating LSG activity in a cesium-induced long QT canine model. METHODS: Twenty-four dogs were randomly divided into RS group (n = 8), RA group (n = 8), or control group (n = 8). Serum norepinephrine, LSG function, and LSG neural activity were measured before and 3 hours after RS or RA. Increasing doses of cesium chloride then were administered until a "threshold dose" produced sustained ventricular tachycardia or ventricular fibrillation. Early afterdepolarization amplitude, VA prevalence, and tachycardia threshold dose were compared among these groups. Nerve growth factor and c-fos protein expressed in the LSG also were examined. RESULTS: Serum norepinephrine, LSG function, and LSG neural activity were all significantly increased after 3 hours of RS and all were decreased 3 hours after RA. In addition, RS significantly decreased the tachycardia threshold dose, increased the early afterdepolarization amplitude, facilitated the incidence of VAs, and increased the expression of nerve growth factor and c-fos protein. In contrast, RA induced the opposite effects. CONCLUSION: RS promotes, whereas RA suppresses, the incidence of VAs in a canine model of cesium-induced long QT. Modulation of LSG neural activity by RS and RA may be responsible for these different effects.

Noninvasive low-frequency electromagnetic stimulation of the left stellate ganglion reduces myocardial infarction-induced ventricular arrhythmia.

Noninvasive magnetic stimulation has been widely used in autonomic disorders in the past few decades, but few studies has been done in cardiac diseases. Recently, studies showed that low-frequency electromagnetic field (LF-EMF) might suppress atrial fibrillation by mediating the cardiac autonomic nervous system. In the present study, the effect of LF-EMF stimulation of left stellate ganglion (LSG) on LSG neural activity and ventricular arrhythmia has been studied in an acute myocardium infarction canine model. It is shown that LF-EMF stimulation leads to a reduction both in the neural activity of LSG and in the incidence of ventricular arrhythmia. The obtained results suggested that inhibition of the LSG neural activity might be the causal of the reduction of ventricular arrhythmia since previous studies have shown that LSG hyperactivity may facilitate the incidence of ventricular arrhythmia. LF-EMF stimulation might be a novel noninvasive substitute for the existing implant device-based electrical stimulation or sympathectomy in the treatment of cardiac disorders.

Spinal cord stimulation protects against ventricular arrhythmias by suppressing left stellate ganglion neural activity in an acute myocardial infarction canine model.

BACKGROUND: Previous studies have shown that spinal cord stimulation (SCS) may reduce ventricular arrhythmias (VAs) induced by acute myocardial infarction (AMI). Furthermore, activation of left stellate ganglion (LSG) appears to facilitate VAs after AMI. OBJECTIVE: The purpose of this study was to investigate whether pretreatment with SCS could protect against VAs by reducing LSG neural activity in an AMI canine model. METHODS: Thirty dogs were anesthetized and randomly divided into SCS group (with SCS, n = 15) and sham group (sham operation without SCS, n = 15). SCS was performed for 1 hour before AMI. Heart rate variability (HRV), ventricular effective refractory period (ERP), serum norepinephrine level, LSG function measured by blood pressure increases in response to LSG stimulation, and LSG neural activity were measured for 1 minute at baseline and 1 hour after SCS. AMI was induced by left anterior descending coronary artery ligation, and then HRV, LSG neural activity, and VAs were measured. RESULTS: Compared to baseline, SCS for 1 hour significantly prolonged ventricular ERP, increased HRV, and attenuated LSG function and LSG activity in the SCS group, whereas no significant change was shown in the sham group. AMI resulted in a significant decrease in HRV and increase in LSG neural activity in the sham group, which were attenuated in the SCS group (frequency: 99 ± 34 impulses/min vs 62 ± 22 impulses/min; amplitude: 0.41 ± 0.12 mV vs 0.18 ± 0.05 mV; both P <.05). The incidence of VAs was significantly lower in the SCS group than in the sham group. CONCLUSION: SCS may prevent AMI-induced VAs, possibly by suppressing LSG activity.

Low-level transcutaneous electrical stimulation of the auricular branch of vagus nerve ameliorates left ventricular remodeling and dysfunction by downregulation of matrix metalloproteinase 9 and transforming growth factor ß1.

Vagus nerve stimulation improves left ventricular (LV) remodeling by downregulation of matrix metalloproteinase 9 (MMP-9) and transforming growth factor ß1 (TGF-ß1). Our previous study found that low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve (LL-TS) could be substituted for vagus nerve stimulation to reverse cardiac remodeling. So, we hypothesize that LL-TS could ameliorate LV remodeling by regulation of MMP-9 and TGF-ß1 after myocardial infarction (MI). Twenty-two beagle dogs were randomly divided into a control group (MI was induced by permanent ligation of the left coronary artery, n = 8), an LL-TS group (MI with long-term intermittent LL-TS, n = 8), and a normal group (sham ligation without stimulation, n = 6). At the end of 6 weeks follow-up, LL-TS significantly reduced LV end-systolic and end-diastolic dimensions, improved ejection fraction and ratio of early (E) to late (A) peak mitral inflow velocity. LL-TS attenuated interstitial fibrosis and collagen degradation in the noninfarcted myocardium compared with the control group. Elevated level of MMP-9 and TGF-ß1 in LV tissue and peripheral plasma were diminished in the LL-TS treated dogs. LL-TS improves cardiac function and prevents cardiac remodeling in the late stages after MI by downregulation of MMP-9 and TGF-ß1 expression.

Chronic intermittent low-level transcutaneous electrical stimulation of auricular branch of vagus nerve improves left ventricular remodeling in conscious dogs with healed myocardial infarction.

BACKGROUND: Vagus nerve stimulation attenuates left ventricular (LV) remodeling after myocardial infarction (MI). Our previous study found a noninvasive approach to deliver vagus nerve stimulation by transcutaneous electric stimulation of auricular branch of vagus nerve. So we hypothesize that chronic intermittent low-level tragus stimulation (LL-TS) could attenuate LV remodeling in conscious dogs with healed MI. METHODS AND RESULTS: Thirty beagle dogs were randomly divided into 3 groups, MI group (left anterior descending artery and major diagonal branches ligation to introduce MI, n=10), LL-TS group (MI plus chronic intermittent LL-TS, n=10), and control group (sham surgery without stimulation, n=10). Tragus stimulation was delivered to bilateral tragus with ear-clips connected to a custom-made stimulator. The voltage slowing sinus rate was used as the threshold for setting LL-TS at 80% below that. LL-TS group was given 4 hours stimulation at 7-9 am and 4-6 pm on conscious dogs. At the end of 90-day follow-up, LL-TS group significantly reduced LA and LV dilatation, improved LV contractile and diastolic function, reduced infarct size by ≈50% compared with MI group. LL-TS treatment alleviated cardiac fibrosis and significantly decreased protein expression level of collagen I, collagen III, transforming growth factor ß1, and matrix metallopeptidase 9 in LV tissues. The plasma level of high-specific C-reactive protein, norepinephrine, N-terminal pro-B-type-natriuretic peptide in LL-TS group was significantly lower than those in MI group from the 7th day to the end of follow-up. CONCLUSIONS: Chronic intermittent low-level transcutaneous electric stimulation of auricular branch of vagus nerve can attenuate LV remodeling in conscious dogs with healed MI.

Carotid baroreceptor stimulation prevents arrhythmias induced by acute myocardial infarction through autonomic modulation.

: Electrical carotid baroreceptor stimulation (CBS) has shown therapeutic potential for resistant hypertension and heart failure by resetting autonomic nervous system, but the impacts on arrhythmias remains unclear. This study evaluated the effects of CBS on ventricular electrophysiological properties in normal dog heart and arrhythmias after acute myocardial infarction (AMI). In the acute protocol, anesthetized open chest dogs were exposed to 1 hour left anterior descending coronary occlusion as AMI model. Dogs were received either sham treatment (Control group, n = 8) or CBS (CBS group, n = 8), started 1 hour before AMI. CBS resulted in pronounced prolongation of ventricular effective refractory period and reduction of the maximum action potential duration restitution slope (from 0.85 ± 0.15 in the baseline state to 0.67 ± 0.09 at the end of 1 hour, P < 0.05) before AMI. Number of premature ventricular contractions (277 ± 168 in the Control group vs. 103 ± 84 in the CBS group, P < 0.05) and episodes of ventricular tachycardia/ventricular fibrillation (7 ± 3 in the Control group vs. 3 ± 2 in the CBS group, P < 0.05) was decreased compared with the control group during AMI. CBS buffered low-frequency/high-frequency ratio raise during AMI. Ischemic size was not affected by CBS. CBS may have a beneficial impact on ventricular arrhythmias induced by AMI through modulation of autonomic tone.