Mei Takahashi

Nonthermal Cardiac Catheter Ablation Using Photodynamic Therapy

Background— Radiofrequency ablation has limitations, largely related to creation of lesions by heating. Here, we report the first nonthermal ablation by applying photodynamic therapy (PDT) to cardiac tissues using a custom-made deflectable laser catheter. The present study investigated the feasibility of PDT for cavotricuspid isthmus ablation in a canine model. Methods and Results— We evaluated the pharmacokinetic profiles of 17 canines after administration of a photosensitizer (talaporfin sodium) by various protocols. We succeeded in maintaining the photosensitizer concentration at a level in excess of the clinically effective dose for humans. Using a 4-polar 7-French deflectable laser catheter, we performed PDT-mediated cavotricuspid isthmus ablation in 8 canines. PDT caused oxidative injury only to the irradiated area and successfully produced a persistent electric conduction block. No acute, gross changes such as edematous degeneration, thrombus formation, steam pops, or traumatic injury were observed after irradiation. Hematoxylin and eosin staining of tissues samples also showed well-preserved endothelial layers. Testing of the blood samples taken before and after the procedure revealed no remarkable changes. Lesion size at 2 weeks after the procedure and the temperature data collected during irradiation were compared between the PDT and irrigated radiofrequency ablation procedures. A ventricular cross-section revealed a solid PDT lesion, which was as deep as a radiofrequency lesion. In addition, endocardial, surficial, and intramural temperature monitoring during the PDT irradiation clearly demonstrated the nonthermal nature of the ablation technique. Conclusions— Nonthermal PDT-mediated catheter ablation is a potentially novel treatment for cardiac arrhythmias.

Optimal conditions for cardiac catheter ablation using photodynamic therapy

AIMS Photodynamic therapy (PDT) is based on non-thermal injury mediated by singlet oxygen species and is used clinically in cancer therapy. In our continuing efforts to apply this technology to cardiac catheter ablation, we clarified the optimal condition for creating PDT-mediated lesions using a laser catheter. METHODS AND RESULTS In a total of 35 canines, we applied a laser directly to the epicardium of the beating heart during open-chest surgery at 15 min after administration of a photosensitizer, talaporfin sodium. We evaluated the lesion size (depth and width) using hematoxylin-eosin staining under varying conditions as follows: laser output (5, 10, 20 W/cm(2)), irradiation time (0-60 s), photosensitizer concentration (0, 2.5, 5 mg/kg), blood oxygen concentration (103.5 ± 2.1 vs. 548.0 ± 18.4 torr), and contact force applied during irradiations (low: <20 g, high: >20 g). A laser irradiation at 20 W/cm(2) for 60 s under 5 mg/kg (29 µg/mL) of photosensitizer induced a lesion 8.7 ± 0.8 mm deep and 5.2 ± 0.2 mm wide. The lesion size was thus positively correlated to the laser power, irradiation time, and photosensitizer concentration, and was independent of the applied contact force and oxygen concentration. In addition, the concentration of the photosensitizer strongly correlated with the changes in the pulse oximetry data and fluorescence of the backscattering laser, suggesting that a clinically appropriate condition could be estimated in real time. CONCLUSION Photodynamic therapy-mediated cardiac lesions might be controllable by regulating the photosensitizer concentration, laser output, and irradiation time.

Electrical superior vena cava isolation using photodynamic therapy in a canine model

AIMS With the new era of multi-tip radiofrequency or balloon ablation catheters replacing the point-to-point ablation strategy, we aimed to determine the feasibility of a ring-laser catheter ablation technology to electrically isolate the superior vena cava (SVC) by exploring the advantages of the limitless catheter tip size possibly with the photodynamic therapy (PDT)-mediated ablation. METHODS AND RESULTS We developed a first-generation prototype of a circular-laser-mapping catheter by fitting a 7 cm plastic optical fibre onto a circular variable-loop Lasso™ mapping catheter. Following SVC venography, both the laser catheter and another ring catheter for monitoring the SVC potentials were placed at the SVC. After the systemic infusion of a photosensitizer (talaporfin sodium), we initiated the irradiation with an output of 1 W in three canines and 0.3 W in four. The creation of electrical isolation as well as occurrence of phrenic nerve injury, sinus node injury, and SVC stenosis were evaluated before, immediately after, and 1 month after the procedure. A PDT-mediated SVC isolation was successfully performed in all seven canines. The isolation was completed with a laser irradiation of 70.4 ± 71.4 J/cm under 30.9 ± 5.0 µg/mL of a photosensitizer without any sinus node injury, phrenic nerve palsy, or SVC stenosis in both the acute and chronic evaluations. The minimum isolation time of 270 s was not correlated with the laser input power or the photosensitizer concentration. CONCLUSION The electrical SVC isolation was successfully and instantly achieved using the PDT laser-ring catheter without any complications.

Evaluation of human and bovine serum albumin on oxidation characteristics by a photosensitization reaction under complete binding of talaporfin sodium

BACKGROUND In order to investigate the therapeutic interaction of an extra-cellular photosensitization reaction, we evaluated the oxidation characteristics of human and bovine serum albumin by this reaction with talaporfin sodium under complete binding with albumin by spectroscopic analysis in a cell-free solution. METHODS The solution was composed of 20μg/ml talaporfin sodium and 2.1mg/ml human or bovine serum albumin. A 662nm laser light was used to irradiate the solution. Visible absorbance spectra of solutions were measured to obtain the oxidized and non-oxidized relative densities of albumin and talaporfin sodium before and after the photosensitization reaction. The defined oxidation path ratio of talaporfin sodium to albumin reflected the oxidation of the solution. Absorbance wavelengths at approximately 240 and 660nm were used to calculate normalized molecular densities of oxidized albumin and talaporfin sodium, respectively. RESULTS AND CONCLUSIONS The oxidation path ratio of talaporfin sodium to albumin when binding human serum albumin was approximately 1.8 times larger than that of bovine serum albumin during the photosensitization reaction from 1 to 50J/cm(2). We hypothesized that the oxidation path ratio results might have been caused by talaporfin sodium binding affinity or binding location difference between the two albumins, because the fluorescence lifetimes of talaporfin sodium bound to human and bovine serum albumin were 7.0 and 4.9ns, respectively. Therefore, the photodynamic therapeutic interaction might be stronger with human serum albumin than with bovine serum albumin in the case of extracellular photosensitization reaction.

Basic study of charring detection at the laser catheter-tip using back scattering light measurement during therapeutic laser irradiation in blood

The purpose of this study is to investigate transient process of the charring at the laser catheter-tip in blood during therapeutic laser irradiation by the back scattering light measurement to detect precursor state of the charring. We took account of using photodynamic therapy for arrhythmia in blood through the laser catheter. We observed the influence of the red laser irradiation (λ=663 nm) upon the shape of red blood cells (RBCs). The RBCs aggregation, round formation, and hemolysis were took place sequentially before charring. With a model blood sandwiched between glass plates simulated as a catheter-tip boundary, we measured diffuse-reflected-light power and transmitted-light power simultaneously and continuously by a microscopic optics during the laser irradiation. We found that measured light power changes were originated with RBCs shape change induced by temperature rise due to the laser irradiation. A gentle peak following a slow descending was observed in the diffuse-reflected-light power history. This history might indicate the precursor state of the charring, in which the hemolysis might be considered to advance rapidly. We think that the measurement of diffuse-reflected-light power history might be able to detect precursor state of charring at the catheter-tip in blood.

Fluorescence sensing system by Soret-band LED light excitation for estimating relative talaporfin sodium concentration in skin

The purpose of this study is to establish a sensing system to estimate relative talaporfin sodium concentration in skin to evaluate the risk of skin photosensitivity after photodynamic therapy (PDT) using percutaneous fluorescence spectroscopy. A prototype fluorescence sensing probe was made using a pair of 5-cm-long diffuse tips of plastic optical fibers for excitation light irradiation and fluorescence collection. Talaporfin sodium (2.5mg/kg) was intravenously administrated to three pigs, and the talaporfin sodium concentration in plasma was measured. The fluorescence sensing probe was attached to the skin and excited by a LED light with a peak wavelength of 409 ± 16 nm to obtain the mean area of the talaporfin sodium fluorescence spectral peak (Sfluo). The time history of the talaporfin sodium concentration in tissue was estimated using a two-compartment pharmacokinetic model. The time history of Sfluo was described as a composite function of the time history of the measured talaporfin sodium concentration in plasma and that of the estimated concentration in tissue as a double exponential decay function. The relative talaporfin sodium concentration in tissue and the relative contributions of fluorescence from tissue and plasma to Sfluo were estimated by the fluorescence system with the numerical pharmacokinetic model. Results also show that tissue compression equivalent to venous pressure might be effective to suppress the contribution of talaporfin sodium fluorescence in plasma.

Detection of pre-charring optical behavior at a laser catheter-tip in blood: Ex vivo and in vivo study

We studied a pre-charring optical behavior of blood at a laser catheter-tip during a red laser irradiation (663 nm, CW) with around 50 W/cm2 in blood to prevent charring at the laser catheter-tip. The laser irradiated red-blood-cell shape changes were microscopically observed. A round formation, aggregation, and hemolysis were found until blood charring (ex vivo). A time-history of diffuse-reflected light power and transmitted light power from a thin blood layer which was irradiated by the red laser were measured with microscope optics to investigate the charring process. The diffusereflected light power decreased following a gentle peak before the charring. This decrease indicated the pre-charring behavior which might be induced by scattering and absorption changes due to red-blood-cell degenerations described above. Using the laser catheter located in porcine heart, we successfully detected the pre-charring behavior by a backscattering light power (in vivo). We demonstrated charring prevention availability with the laser power control (ex vivo). We think that the backscattering light power measurement and laser power control via the laser catheter might be useful to detect pre-charring behavior, and to prevent the charring for therapeutic laser irradiation in blood under catheterization such as arrhythmia treatment with photodynamic therapy.

Study of photosensitization reaction progress in a 96 well plate with photosensitizer rich condition using Talaporfin sodium

To quantitatively investigate photosensitization reaction in vitro against myocardial cells with photosensitizer rich condition in solution using Talaporfin sodium in the well of a 96 well plate, we studied photosensitization reaction progress in this well. We have proposed non-thermal conduction block of myocardium tissue using the photosensitization reaction with laser irradiation shortly after Talaporfin sodium injection. In above situation, the photosensitizer is located outside the myocardial cells in high concentration. To understand interaction of the photosensitization reaction in which the photosensitizer distributes outside cells, the photosensitization reaction progress in the well was studied. Talaporfin sodium (799.69 MW) solution and a 663 nm diode laser were used. The photosensitizer solution concentrations of 12.5-37.5 μM were employed. The photosensitizer fluorescence with 0.29 W/cm2 in irradiance, which was optimized in previous cell death study, was measured during the laser irradiation until 40 J/cm2. The photosensitizer solution absorbance and dissolved oxygen pressure after the laser irradiation were also measured. We found that the photosensitization reaction progress had 2 distinctive phases of different reaction rate: rapid photosensitization reaction consuming dissolved oxygen and gentle photosensitization reaction with oxygen diffusion from the solution-air boundary. The dissolved oxygen pressure and photosensitizer solution absorbance were 30% and 80% of the initial values after the laser irradiation, respectively. Therefore, oxygen was rate-controlling factor of the photosensitization reaction in the well with the photosensitizer rich condition. In the oxygen diffusion phase, the oxygen pressure was maintained around 40 mmHg until the laser irradiation of 40 J/cm2 and it is similar to that of myocardium tissue in vivo. We think that our 96 well plate in vitro system may simulate PDT in myocardial tissue with photosensitization reaction parameters mentioned above.

Study of blood charring precursor states using backscattering at 663 nm from blood and optical window boundary

Contact laser irradiation is generally used in therapeutic laser procedures such as plastic surgery and laser catheter lead removal. However, it may induce blood charring on the surface of the optical window in blood circumstance so that the laser beam might be blocked. Various charring detection methods have been proposed, but they detect charring only after charring has occurred. This study investigates the transient behavior of red blood cells (RBCs) prior to the charring on the surface of an optical window during red laser irradiation in blood circumstance.

Study of the Monte-Carlo model based on the measurement of irradiance distribution in myocardium from interventional devices in photodynamic therapy

the measurement of irradiance distribution in myocardium from interventional devices in photodynamic therapy Ryota Matsuzaki, Masahiro Yazima, Emiyu Ogawa, Mei Takahashi, Tsunenori Arai School of Fundamental Science and Technology, Graduated School of Science and Technology, Keio University Abstract: We studied the Monte-Carlo model based on the measurement of the irradiance distribution of 663 nm light in porcine myocardium emitted from interventional devices in photodynamic therapy to investigate the treatment region by a photosensitization reaction. The optical properties of myocardium tissue vary with portion of heart. Since blood content makes mainly this variation, extracted fresh myocardium with blood content was used for the measurement of the irradiance distribution. The irradiance distribution in the porcine left ventricle 3-4 hours passed after the extraction was measured at 1-5 mm in vertical direction, at 0-5 mm in horizontal direction through the thin optical fiber with high NA during the irradiation from the interventional devices in photodynamic therapy. The calculated irradiance distribution in Monte-Carlo model was matched with the measured irradiance distribution by changing the scattering coefficient and the anisotropic parameter under the constant absorption coefficient of the myocardium. The light powers in the measured and the calculated irradiance distribution were approximated with exponential function fitted by least-squares method, and both exponents were compared each other. The treatment region was estimated using the Monte-Carlo model and a published cell lethality measurement data. The estimated treatment region approximately matched to the previous result of a dog experiment.