Published papers

This study constructed a new non-linear model of myocardial electrical conduction block during photosensitization reaction to identify the vulnerable cell population and generate an index for recurrent risk following catheter ablation for tachyarrhythmia. A three-compartment model of conductive, vulnerable, and blocked cells was proposed. To determine the non-linearity of the rate parameter for the change from vulnerable cells to conductive cells, we compared a previously reported non-linear model and our newly proposed model with non-linear rate parameters in the modeling of myocardial cell electrical conduction block during photosensitization reaction. The rate parameters were optimized via a bi-nested structure using measured synchronicity data during the photosensitization reaction of myocardial cell wires. The newly proposed model had a better fit to the measured data than the conventional model. The sum of the error until the time where the measured value was higher than 0.6, was 0.22 in the conventional model and 0.07 in our new model. The non-linear rate parameter from the vulnerable cell to the conductive cell compartment may be the preferred structure of the electrical conduction block model induced by photosensitization reaction. This simulation model provides an index to evaluate recurrent risk after tachyarrhythmia catheter ablation by photosensitization reaction. Graphical abstract: [Figure not available: see fulltext.].

Background: Local impedance (LI) can indirectly measure catheter contact and tissue temperature during radiofrequency catheter ablation (RFCA). However, data on the effects of catheter contact angle on LI parameters are scarce. This study aimed to evaluate the influence of catheter contact angle on LI changes and lesion size with two different LI-sensing catheters in a porcine experimental study. Methods: Lesions were created by the INTELLANAV MiFi™ OI (MiFi) and the INTELLANAV STABLEPOINT™ (STABLEPOINT). RFCA was performed with 30 W and a duration of 30 s. The contact force (CF) (0, 5, 10, 20, and 30 g) and catheter contact angle (30°, 45°, and 90°) were changed in each set (n = 8 each). The LI rise, LI drop, and lesion size were evaluated. Results: The LI rise increased as CF increased. There was no angular dependence with the LI rise under all CFs in the MiFi. On the other hand, the LI rise at 90° was lower than at 30° under 5 and 10 g of CF in STABLEPOINT. The LI drop increased as CF increased. Regarding the difference in catheter contact angles, the LI drop at 90° was lower than that at 30° for both catheters. The maximum lesion widths and surface widths were smaller at 90° than at 30°, whereas there were no differences in lesion depths. Conclusion: The LI drop and lesion widths at 90° were significantly smaller than those at 30°, although the lesion depths were not different among the 3 angles for the MiFi and STABLEPOINT.

In hemodialysis, normal venipuncture cannot deliver large amounts of blood, so about 90% of patients make an arteriovenous anastomosis called an internal shunt. In addition, since dialysis is performed multiple times a week, frequent puncture and pressure hemostasis are required. As a result, blood vessels are stressed, resulting in stenosis and occlusion. In order to detect and treat such shunt troubles at an early stage, daily shunt management is important. Laser speckle contrast analysis is of interest in the field of visualization of the hemodynamics of living tissues. In this study, the relationship between the flow rate and the contrast value was investigated by a technique for quantifying the amount of change in the dynamic speckle pattern.

Immunotherapy, including immune checkpoint inhibitors, has revolutionized cancer treatment, but only a minor fraction of patients shows durable responses. A new approach to overcome this limitation is yet to be identified. Recently, we have shown that photobiomodulation (PBM) with near-infrared (NIR) light in the NIR-II window reduces oxidative stress and supports the proliferation of CD8+ T cells, suggesting that PBM with NIR-II light could augment anti-cancer immunity. Here, we report a novel approach to support tumor-infiltrating CD8+ T cells upon PBM with NIR-II laser with high tissue penetration depth. Brief treatments of a murine model of breast cancer with dual 1064 and 1270 nm lasers reduced the expression of the programmed cell death protein 1 (PD-1) in CD8+ T cells in a syngeneic mouse model of breast cancer. The direct effect of the NIR-II laser treatment on T cells was confirmed by the enhanced tumor growth delay by the adoptive transfer of laser-treated CD8+ T cells ex vivo against a model tumor antigen. We further demonstrated that specific NIR-II laser parameters augmented the effect of the immune checkpoint inhibitor on tumor growth. PBM with NIR-II light augments the efficacy of cancer immunotherapy by supporting CD8+ T cells. Unlike the current immunotherapy with risks of undesirable drug–drug interactions and severe adverse events, the laser is safe and low-cost. It can be broadly combined with other therapy without modification to achieve clinical significance. In addition, our study established a path to develop a novel laser-based therapy to treat cancer effectively.

The mechanical properties of the myocardium in the left ventricle and right atrium were estimated by simultaneously measuring the local impedance (LI) and contact force (CF) using an ablation catheter. Radiofrequency catheter ablation (RFCA) is a well-established arrhythmia treatment. Monitoring the RF power, CF and properties of myocardium during RFCA are necessary to estimate the effect of ablation. Indices, such as CF, lesion size index and ablation index, do not include the myocardium mechanical properties. Therefore, there is the risk of side effects, such as cardiac tamponade, by excessive catheter indentation into vulnerable areas. We propose the simultaneous measurement of LI and CF for estimating the myocardial mechanical properties to reduce the side effects. In this study, an in vitro experimental system was constructed to measure LI and CF via the catheter. The relationship between the porcine myocardial tissue thickness and CF–LI curve was investigated using the left ventricle and right atrium. Power function coefficients approximating the CF–LI curve increased with thicker left ventricle. The thickness of the myocardium can be estimated by simultaneously measuring LI and CF. Intraoperative measurement of the myocardial mechanical properties can be used to determine the ablation conditions at each site.

There is solid evidence of the beneficial effect of photobiomodulation (PBM) with low-power near-infrared (NIR) light in the NIR-I window in increasing bioavailable nitric oxide (NO). However, it is not established whether this effect can be extended to NIR-II light, limiting broader applications of this therapeutic modality. Since we have demonstrated PBM with NIR laser in the NIR-II window, we determined the causal relationship between NIR-II irradiation and its specific biological effects on NO bioavailability. We analyzed the impact of NIR-II irradiation on NO release in cultured human endothelial cells using a NO-sensitive fluorescence probe and single-cell live imaging. Two distinct wavelengths of NIR-II laser (1064 and 1270 nm) and NIR-I (808 nm) at an irradiance of 10 mW/cm2 induced NO release from endothelial cells. These lasers also enhanced Akt phosphorylation at Ser 473, endothelial nitric oxide synthase (eNOS) phosphorylation at Ser 1177, and endothelial cell migration. Moreover, the NO release and phosphorylation of eNOS were abolished by inhibiting mitochondrial respiration, suggesting that Akt activation caused by NIR-II laser exposure involves mitochondrial retrograde signaling. Other inhibitors that inhibit known Akt activation pathways, including a specific inhibitor of PI3K, Src family PKC, did not affect this response. These two wavelengths of NIR-II laser induced no appreciable NO generation in cultured neuronal cells expressing neuronal NOS (nNOS). In short, NIR-II laser enhances bioavailable NO in endothelial cells. Since a hallmark of endothelial dysfunction is suppressed eNOS with concomitant NO deficiency, NIR-II laser technology could be broadly used to restore endothelial NO and treat or prevent cardiovascular diseases.

BACKGROUND: The current management of patients with stroke with intravenous thrombolysis and endovascular thrombectomy is effective only when it is timely performed on an appropriately selected but minor fraction of patients. The development of novel adjunctive therapy is highly desired to reduce morbidity and mortality with stroke. Since endothelial dysfunction is implicated in the pathogenesis of stroke and is featured with suppressed endothelial nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency, restoring endothelial nitric oxide represents a promising approach to treating stroke injury. METHODS: This is a preclinical proof-of-concept study to determine the therapeutic effect of transcranial treatment with a low-power near-infrared laser in a mouse model of ischemic stroke. The laser treatment was performed before the middle cerebral artery occlusion with a filament. To determine the involvement of eNOS phosphorylation, unphosphorylatable eNOS S1176A knock-in mice were used. Each measurement was analyzed by a 2-way ANOVA to assess the effect of the treatment on cerebral blood flow with laser Doppler flowmetry, eNOS phosphorylation by immunoblot analysis, and stroke outcomes by infarct volumes and neurological deficits. RESULTS: Pretreatment with a 1064-nm laser at an irradiance of 50 mW/cm2improved cerebral blood flow, eNOS phosphorylation, and stroke outcomes. CONCLUSIONS: Near-infrared II photobiomodulation could offer a noninvasive and low-risk adjunctive therapy for stroke injury. This new modality using a physical parameter merits further consideration to develop innovative therapies to prevent and treat a wide array of cardiovascular diseases.

Nitric oxide (NO) is a well-known gaseous mediator that maintains vascular homeostasis. Extensive evidence supports that a hallmark of endothelial dysfunction, which leads to cardiovascular diseases, is endothelial NO deficiency. Thus, restoring endothelial NO represents a promising approach to treating cardiovascular complications. Despite many therapeutic agents having been shown to augment NO bioavailability under various pathological conditions, success in resulting clinical trials has remained elusive. There is solid evidence of diverse beneficial effects of the treatment with low-power near-infrared (NIR) light, defined as photobiomodulation (PBM). Although the precise mechanisms of action of PBM are still elusive, recent studies consistently report that PBM improves endothelial dysfunction via increasing bioavailable NO in a dose-dependent manner and open a feasible path to the use of PBM for treating cardiovascular diseases via augmenting NO bioavailability. In particular, the use of NIR light in the NIR-II window (1000–1700 nm) for PBM, which has reduced scattering and minimal tissue absorption with the largest penetration depth, is emerging as a promising therapy. In this review, we update recent findings on PBM and NO.

Herein, we propose an impedance spectroscopy method using a mode-switching nonsinusoidal oscillator and apply this method for measuring the impedance of biological tissues and continuous impedance measurement. To obtain impedance spectra over a wide frequency range, we fabricated a novel nonsinusoidal oscillator incorporating binary counters and analog switches. This oscillator could periodically switch oscillation frequency through the mode switching of the feedback resistor. From the oscillation waveform at each oscillation frequency of this circuit (oscillator), we determined the impedance spectrum of a measured object using the discrete-time Fourier transform. Subsequently, we obtained the broad impedance spectrum of the measured object by merging odd-order harmonic spectral components up to the 19th order for each oscillation frequency. From the measured spectrum, the resistive and capacitive components of the circuit simulating bioimpedance were estimated with high accuracy. Moreover, the proposed method was used to measure the impedance of porcine myocardium; changes in the impedance spectrum of the myocardial tissue due to coagulation could be measured. Furthermore, rapid variations in the resistance value of a CdS photocell could be continuously measured using the proposed method.

Background: Novel diamond-embedded catheter enables precise temperature-controlled ablation. However, the effects of contact angle on lesion formation of this catheter are poorly understood. Objective: The purpose of this study was to evaluate lesion formation using the temperature-controlled ablation catheter embedded with diamond at different angles in a porcine experimental model. Methods: Freshly sacrificed porcine hearts were used. Radiofrequency catheter ablation was performed at 50 W for 15 seconds at an upper temperature setting of 60°C. The contact force (5g, 10g, 30g) and catheter contact angles (30°, 45°, 90°) were changed in each set (n = 13 each). Surface width, maximum lesion width, lesion depth, surface area, distance from the distal edge to the widest area, and impedance drop were evaluated. Results: Surface width and maximum lesion width were longer at 30° than at 90° (P <.05). There were no significant differences in the lesion depth by catheter angle except at 30g. Surface area was larger at 30° than at 90° (P <.05). Distance from the distal edge to the widest area was longer at 30° than at 90° (P <.05). There were no significant differences in impedance drop according to catheter angle. Conclusion: With diamond-embedded temperature-controlled ablation catheters, lesion width increased at a shallower contact angle, whereas lesion depth did not. Surface area also increased at a shallower contact angle. This catheter created a large ablation lesion on the proximal side of the catheter, which looked like a “honey pot.”