Photodynamic therapy (PDT) is the result of an interaction between light and a photoactive drug. The interaction produces cytotoxic oxygen radicals and radicals and microvascular collapse, resulting in tissue death. A number of photoactive drugs have been shown to accumulate in greater concentration in atherosclerotic plaque than in normal arterial wall and are potentially useful for PDT. The newer generation agents are safe and have brief skin phototoxicity as the only significant side effect. PDT in several animal models of atherosclerosis has shown plaque removal without damage to the artery wall if appropriate light energy is used, with no perforation, and no distal embolization or obstruction. In one such study we found that PDT using Photofrin and 630 nm laser light reduced the mean percent stenosis of 12 stenoses in 8 pigs from 63% to 40%, and in 7/12 of the segments from 63% to 16%, whereas in 2 untreated control lesions the mean stenosis progressed from 60% to 85%. PDT requires several days for tissue destruction, and immediate luminal enlargement by an adjunct angioplasty intervention may be appropriate. Animal studies suggest that PDT also inhibits the intimal hyperplasia process which follows vascular injury, and PDT may inhibit restenosis following clinical coronary angioplasty. The enthusiasm for PDT of atherosclerosis, therefore, stems from three important potential advantages of the technique: the apparent selectivity and safety of the process, the potential for effective debulking of plaque and the possibility of reduction or inhibition or restenosis.

Smooth muscle cell proliferation plays a major role in restenosis following angioplasty. We have studied the effects of ultraviolet A (UVA) activation of 8-methoxypsoralen (8-MOP) on cultured SMC as well as atherosclerotic rabbit femoral arteries following angioplasty. 8-MOP and UVA display synergistic proliferation inhibition of cultured SMC in a cell-cycle independent manner. At intermediate doses, a cytostatic effect was seen over a 28 day period following a single exposure. In conclusion, a combination of 8-MOP and UVA significantly lowered SMC proliferation and cellularity in cell culture as well as in the neointima and media after balloon-induced vascular injury in the atherosclerotic rabbit model. This approach of systemic administration and local activation is feasible and offers a potential therapy for restenosis.

A study was performed to determine whether intimal hyperplasia can be chronically inhibited and the artery wall integrity maintained after cells are depleted from the artery with photodynamic therapy. Utilizing chloroaluminum sulfonated phthalocyanine or saline for control, limited balloon injury of the common carotid artery was performed before irradiation with 675 mm laser light. Results demonstrated carotid inhibition of intimal hyperplasia in PDT treated arteries without aneurysm formation or artery dilatation. By 4 weeks there was reendothelialization of the intima of the PDT arteries and repopulation of the adventitia with myofibroblasts. This data was encouraging in that PDT can chronically inhibit intimal hyperplasia without precipitating a weakness in the arterial wall.

Restenosis remains the greatest limitation to the success of conventional and newer forms of angioplasty for the treatment of coronary artery disease. Since the armamentarium available to the clinician is presently limited to mechanical forms of intervention, invariably causing an acute response to injury, a pharmacologic alternative is sought. Photodynamic therapy has the potential to provide a combined drug/device therapy to significantly reduce the rate of restenosis through selective cytolysis and cytostasis. In this study Tin Ethyl Etiopurpurin, a second generation photosensitizer, demonstrated selective retention in catheter induced atheromatous plaques in a New Zealand White rabbit model in vitro and in vivo.

Photodynamic therapy (PDT) is a promising treatment for vascular restenosis. Determining the site of the photosensitiser responsible for cytotoxicity during PDT is essential for planning treatment strategies. Vascular smooth muscle cells (VSMCs) were cultured from 6 individuals using substrate attached explant techniques and transferred into microtitire plates at 50,000 cells/well. Cells were arranged in 3 groups; the first group was incubated with 2 (mu) gml^-1 of Photofrin for 48 hours, followed by polychromatic light illumination of 3 Jcm^-2. In the second group the extracellular Photofrin was removed by washing cells just prior to illumination, and in the third group Photofrin was only added immediately prior to illumination. Results are expressed as mean percentage cell survival+/- SEM. Cells were minimally affected by extracellular Photofrin alone (91.9+/- 10.7). Photofrin in the intracellular and (intra+extracellular) compartments reduced VSMCs survival to (7.3+/- 4.9) and (8.8+/- 2.6). The mechanism of ablation appears to be due to activation of the intracellular rather than residual Photofrin in the extracellular medium

Proliferation of vascular smooth muscle cells (VSMCs) is the pathophysiogical basis of the restenoses which occur in 30-55% of patients undergone revascularisation. Prophylactic measures including pharmacotherapy, endovascular stenting and anti-gene therapy have so far failed to contain this problem. Photodynamic therapy (PDT) may selectively suppress VSMCs and decrease restenosis rates. We report 2 studies; the first examines the effect of PDT on an in-vitro model of NIH and the second involves using endoluminal ablation of an in-vivo model of experimental NIH of the rabbit's aorta.

Photodynamic therapy (PDT) represents a novel method of selectively treating atherosclerosis using a combination of photosensitizer drug, low power laser light, and molecular oxygen. In this preliminary study, PDT was used to treat atherosclerotic lesions in a miniswine model. Yucatan miniswine weighing between 20-30 kg, were rendered atherosclerotic by a combination of balloon endothelial injury and dietary supplementation with 2% cholesterol and 15% lard diet for 7 weeks. Following this, miniswine were given a porphyrin-type photosensitizer, Photofrin 2.5 mg/kg IV. Twenty-four hours after receiving Photofrin, swine received a general anesthetic and the infrarenal abdominal aorta was exposed. Through a longitudinal aortotomy, the posterior aortic wall was irradiated with 630 nm laser light at one of the following light doses: 60, 120, and 240 J/cm². Four weeks after PDT, swine were killed and perfusion- fixed with glutaraldehyde. Light microscopy showed a decrease in intimal thickness for all light doses. Decreased cellular elements were seen in the irradiated zones as the laser power was increased. Non-irradiated sites showed typical atherosclerotic lesions with foam cells, fibrosis and calcification. This study demonstrated the feasibility of using PDT for atherosclerotic lesions.

Cardiovascular Photodynamic Therapy requires the uniform application of laser energy over the length of an atherosclerotic lesion, thus ensuring equal treatment to all parts of the lesion. The total amount of laser energy delivered to the lesion also affects the results of the treatment. Uniform light distribution both radially and axially of a cylindrical diffuser during Photodynamic Therapy prevents miscalculated dosimetry and uneven treatment. Maximizing the amount of laser power delivered to the cylindrical diffuser tip (without inducing temperature elevation) minimizes the exposure time thus reducing the overall treatment time. Power output uniformity and power output capabilities are thus crucial factors in the design of a cardiovascular cylindrical diffuser. This paper will discuss the output characteristics and performance of six guidewire compatible cylindrical diffusers. Each diffuser consists of an array of fiber optics surrounding an inner guidewire lumen. This assembly is covered by an outer sheath. The fibers launch into an elastomer which contains a scattering medium. In this way a light diffusing tip is created. The total length of the fiber system is 3.0 meters. The total length of the difffuser tip is 2.0 cm.

Dihydropyridine (DHP) calcium channel blockers have been shown to suppress atherogenesis in various species and controlled angiographic trials suggest that these drugs may retard the progression of occlusive coronary disease in humans. Because mononuclear leukocytes play a key role in the formation of early and advanced atheromatous lesions, we determined effects of DHP calcium channel modulators on calcium uptake by cells of the monocytic lineage. Human peripheral blood monocytes were evaluated before and after undergoing in vitro differentiation induced by two days of culture with fetal calf serum and FMLP. Changes in intracellular calcium activity were estimated with fura-2, a fluorescent calcium indicator. Freshly isolated (unactivated) monocytes were insensitive to DHP drugs both in the presence and absence of high potassium membrane depolarization. In contrast, nisoldipine, a DHP calcium channel blocker, and BAY K 8644, a DHP calcium channel activator, decreased and increased calcium uptake by KC1-depolarized differentiated monocytes. Results suggest that differentiation of monocytes to macrophages may involve a change in the expression and/or regulation of DHP- sensitive calcium channels.

Laser-induced fluorescence (LF) has been developed as a diagnostic tool for the detection of atherosclerosis. We have examined the use of LF for the identification of accelerated atherosclerotic plaque growth induced by Marek's Disease Virus (MDV) infection in White Leghorn rooster chicks (R) as well as plaque regression after treatment. Twenty-eight newborn R were infected with 12,000 cfu of MDV. Twelve parallel control R had saline injection. LF spectra were recorded from the arteries in vitro with a CeramOptec laser angioplasty catheter during 308 nm XeCl excimer laser excitation. Significant differences were detected at 440 to 475, 525, 550, 600, and 650 nm in MDV-R (p<0.05). In a subsequent study, 60 R were infected with 5,000 cfu of MDV, and were then treated with either Pravastatin (PRV) or placebo at 3 months post infection. These PRV-R were followed for 6 months to detect changes in atherosclerotic plaque development. PRV reduced intimal proliferation produced by MDV infection on histological examination (PRV-R 128.0+/- 44.0 micrometers , placebo-R 412.2+/- 91.5 micrometers , pequals0.007). MDV infected, PRV treated R were examined for LF changes that correlated with decreased atherosclerosis. There was an associated significant increase in LF intensity in PRV-R at 405 to 425 nm (p<0.001). In conclusion, LF can detect intimal proliferation in virus- induced atherosclerosis and atherosclerotic plaque regression after PRV therapy.

PUVA therapy may prove effective in preventing restenosis of vessels following balloon angioplasty to open vessels narrowed by atherosclerosis. The technique relies on the ability of PUVA (psoralen administration followed by ultraviolet A irradiation) to cause crosslinks and monoadducts that prevent cellular proliferation without causing cell death. Such PUVA treatment has been successful in controlling cutaneous cell proliferation of psoriasis. The efficacy of PUVA treatment depends on the drug concentration and the light dose. The amount of light delivered is easily modified to adapt to variations in the drug concentration if the drug levels in the vessel wall are known. This paper demonstrates the feasibility of assaying psoralen levels in tissues and in serum samples using psoralen fluorescence as an indictor.

Since the late 1960s atherosclerotic plaque (AP) laser ablation techniques have been developed. Clinical data obtained with CW laser vaporization AP shows significant impairment of tissues close to plaque with following severe complications in postoperation period. The use of excimer pulsed laser decreases the harmful effects of laser radiation. However, data on spectrum of energy absorption by molecular AP structures are required for selective photodynamic action of UV laser emission. The aim of the present study is to estimate IR and UV absorption and fluorescence spectrum of intact and atherosclerosis-induced changes in aorta and brachiocephalic trunk. Autopsied vessel specimens with artery decease were analyzed. Absorption spectrum of frozen vessel slices (15 micrometers ) and oil emulsion was recorded. Characteristic absorption bands in 3000 cm^-1 were noted as for AP as for intact tissue. In 1700 cm^-1 AP IR spectrum has an absorption band which is not seen in normal tissue spectrum. Reflection spectrum of intact vessel wall surface and AP at range 45000 to 11000 cm^-1 was recorded as well. In 32000 cm^-1 reflection was 66% and 43% for AP and intact tissue, respectively. At range 17000 to 13000 cm^MIN1 curve position is changed: reflection for AP-66%, for intact wall-93%. Thus, reflection, absorption and fluorescence spectrum of intact and atherosclerotic vessels vary significantly. It provides us with a basis for intravessel examination and selection of laser parameters for harmless endovascular surgery.

Percutaneous intracoronary angioscopy was used to study the morphological changes occurring in coronary arteries after balloon or laser angioplasty. Angioscopy is thought to provide details on the coronary vessel lumen and the inner wall. Coronary lesion were studied in 44 patients with a 4.5 F Imagecath angioscope before and after each interventional procedure. Balloon and laser angioplasty were performed on 21 (group I) and 23 patients (group II), respectively. There was no difference in age, sex, or angiographic lesion appearance before the procedure between the two groups. Circumferential visualization of the target lesion was successfully completed in 17 group I patients and 19 group II patients. A larger lumen than that observed at control was seen in all 17 dilatation patients and in 13 of the 19 laser patients. Tissue remnants were observed in all balloon and laser patients. Laser irradiation resulted in characteristic sharp edged craters. Dissection was identified in 2 of 19 before versus 9 of 19 patients after balloon angioplasty (p<0.05) and in 0 of 23 before versus 4 of 23 patients after laser angioplasty. Subintimal hemorrhage was observed in 3 of 19 before versus 11 of 19 patients after balloon angioplasty (p<0.05) and in 2 of 23 before versus 4 of 23 patients after laser angioplasty. The frequency of hemorrhage was higher in the post balloon group than in the post laser group (11 of 19 versus 4 of 23, respectively, p<0.02). Angioscopy provides valuable information on lesion morphology after coronary interventions. Balloon dilation results in a high rate of dissection and subintimal hemorrhage. Laser angioplasty is able to ablate obstructing tissue and results in a lower rate of subintimal hemorrhage than balloon dilatation.

A novel approach to imagination of inner surface of arteria during performing laser and balloon angioplasty is suggested. To this end the laser light was transmitted via fiber to the zone of interest and radiation diffused by the walls of the vessel was adopted by receiver. Known technique to determine of contours of an object by measuring the time of the laser pulse propagation is unusable due to the small geometrical scales. Using the CW laser and feeding a portion of the backscattered signal power into the laser cavity (this kind of device was referred to as laser autodyne coherent receiver), the authors have been able to measure the object contour with spatial resolution of up to 2 microns. Such resolution and high sensitivity inherent to this technique should allows one to detect early in the development of the atherosclerosis. To obtain the 3D image of the vessel inside surface we offer two methods. In the first case the vessel side is scanned by moving the end of light quid. In the second one multimode laser is used and the image is drawing by scanning the transverse modes of this laser. The vessel side and atherosclerotic plaques have the different reflectivity spectrum and this fact can be used to increase the image contrast. The correct selection of the laser wavelength makes possible to work into the vessel with circulation of the blood. The calculation of laser autodyne intrascope performance and tentative experimental results are presented in this report. The advantages of this method for the angiography are in speed and adequately of control during performing angioplasty.

During more than five years of investigation with excimer laser angioplasty, several changes have been made in patient selection and laser catheters. It is unclear, however, whether these changes have improved the outcome of excimer laser angioplasty. A total of 2041 patients underwent treatment with excimer laser coronary angioplasty for 2324 lesions with clinical success in 89%, ischemic complications in 7.5%, and vessel perforation in 2.1%. When the entire 5-year period of investigation was divided into four discrete phases, as defined by the successive release of improved laser catheters (prototype, flexible, extremely flexible, and eccentric), clinical success was seen to improve from 86% to 95% (p<0.001) despite the increased incidence of advanced age (pequals0.01) and unstable angina (p<0.001). Multivariable analysis identified improved laser catheters, saphenous vein graft lesions, and unclarified stenoses as predictors of favorable outcome. Operator experience was associated with decreased complications. Reduced catheter size relative to vessel size was associated with decreased risk of vessel perforation. Thus, refinements in patient selection and in laser technique have been associated with enhanced safety and efficacy of excimer laser angioplasty.

Patients who sustain complicated acute myocardial infarction in whom thrombolytic agents either fail or are contraindicated often need mechanical revascularization other than PTCA. In 24 patients with acute infarction complicated by continuous chest pain and ischemia who either received lytics or with contraindication to lytics, a holmium:YAG laser (Eclipse Surgical Technologies, Palo Alto, CA) was utilized for thrombolysis and plaque ablation. Clinical success was achieved in 23/24 patients, with 23 patients (94%) surviving the acute infarction. Holmium:YAG laser is very effective and safe in thrombolysis and revascularization in this complicated clinical setting.

Clinical efficacy of newly developed Holmium YAG laser coronary angioplasty (HLCA) was assessed for 30 patients with angina. There were 12 near left main trunk (LMT) lesions and 4 aorto- ostial lesions. Adjunctive balloon angioplasty was performed for 25 of 30 lesions. Delivered energy ranged from 1.5 to 2.5 watts/pulse and the total exposure time ranged from 6 to 55 seconds. External diameter of laser catheter was 1.5 mm for 13 lesions, 1.4 mm for 17 lesions, and 1.7 mm for 5 lesions. Laser success, defined as 20% reduction of stenotic ratio, was obtained in 21 of 30 (70%) and overall procedural success rate was 93%. There were 3 cases with acute coronary occlusions relieved by adjunctive balloon angioplasty and one coronary perforation without manifestation of cardiac tamponade. There were no large coronary dissection which involved more than 5 mm of the coronary artery. Follow up coronary angiography after 3 months showed restenosis in 14 of 27 patients (52%). Percent stenosis after lasering (56%) was similar to that at 3 months after (62%). HLCA is acutely effective treatment for lesions near LMT, because of low incidence of large coronary dissection. However, angiographical restenosis rate is high at 3 months after HLCA. This may be attributed to the relatively large residual stenosis after the procedure and vessel injury caused by shock wave.

A unique percutaneous transluminal coronary angioplasty system new IR therapy laser with IR glass fiber delivery under novel angioscope guidance was described. Carbon monoxide (CO) laser emission of 5 mm in wavelength was employed as therapy laser to achieve precise ablation of atheromatous plaque with a flexible As-S IR glass fiber for laser delivery. We developed the first medical CO laser as well as As-S IR glass fiber cable. We also developed 5.5 Fr. thin angioscope catheter with complete directional manipulatability at its tip. The system control unit could manage to prevent failure irradiations and fiber damages. This novel angioplasty system was evaluated by a stenosis model of mongrel dogs. We demonstrated the usefulness of our system to overcome current issues on laser angioplasty using multifiber catheter with over-the-guidewire system.

To date, 1201 symptomatic patients with significant coronary artery disease were treated with the mid IR holmium:YAG (2.1 micron) laser in a multicenter study. Updated results of this study, as presented herein, substantiate the important role of this laser in treatment of lesions not ideal for conventional balloon angioplasty. This device is a safe and effective means of coronary revascularization.

Clinical experience with the mid IR holmium:YAG laser in a single medical center (St. Paul Ramsey Medical Center, University of Minnesota Medical School, St. Paul, MN) includes 112 patients who underwent holmium laser coronary angioplasty. Utilizing a unique lasing technique; `pulse and retreat,' we applied this laser to thrombotic and nonthrombotic lesions in patients presenting with unstable angina, stable angina, and acute myocardial infarction. A very high clinical success and very low complication rates were achieved. Holmium:YAG laser is effective and safe therapy for patients with symptomatic coronary artery disease. Unlike excimer lasers, the clinical success, efficacy and safety of holmium laser angioplasty is not compromised when thrombus is present.

Efficient use and specific targeting of laser energy to atherosclerotic lesions necessitate understanding of spectral characteristics of intima and media from normal and diseased segments. We report absorption, transmission, and reflectance spectra from 19 normal and 21 diseased coronary artery segments which were obtained at autopsy within 5 to 10 h post mortem and submerged in oxygenated Ringer's solution. Spectra were obtained from the luminal surface of 1 X 1 cm full thickness arteries or bluntly dissected intima and media segments in the range 250 to 2500 nm. Water peaks were subtracted. Absorption and transmission for full thickness artery, intima, and media from normal and atherosclerotic arteries shared main bands at 1150 and 1700 nm with variation in intensity. Significant differences in reflectance showed bands at 1080, 1340, 1600, 1739 nm in normal intima and media and atherosclerotic intima but absent in media from atherosclerotic arteries. Peaks at 1340, 1600, and 1739 nm in normal intima and media are equalized in atherosclerotic intima and absent in atherosclerotic media. In conclusion, absence of reflectance at 1080, 1340, 1600, and 1739 nm in atherosclerotic media may be selectively utilized to target laser energy and ablation at intimal plaque and spare media of atherosclerotic arteries.

Ventricular tachycardia (VT) is a rapid heart rhythm which is often life threatening. Several surgical and percutaneous ways to destroy the myocardium responsible for VT have been studied. It has been postulated that laser therapy may be ideal for this purpose because it can heat a large volume of tissue. Recent developments in diode lasers have prompted us to evaluate this source (810 nm) for photocoagulation of myocardial tissue. Its size, ease of maintenance, and cost make diode laser suitable for clinical practice in general, and for percutaneous photoablation in particular. Lesions were created in myocardium with contact irradiation using a 600 micron bare tipped optical fiber both in vitro and in vivo. Exposures of 2 to 3 W over 30 to 60 seconds created lesions with no or minimal char formations. In vivo lesions tended to be larger than in vitro, with better defined border zones. Animals tolerated laser irradiation well without significant ventricular ectopy. Diode laser irradiation is a promising means to percutaneously coagulate ventricular myocardium and for cure of VT. Further investigation of the dosimetry and healing response in both healthy and diseased myocardium is warranted.

Photothermal coagulation and ablation lesions were produced in exposed livers of anesthetized rats with a cw Nd:YAG laser ((lambda) equals1064 nm; beam power 3.2 to 10 W; exposure times 3 to 10 s, and spot diameter, 0.7 to 1.9 mm). The surface temperatures produced by the irradiations were derived from IR camera images calibrated with temperature controlled black bodies present in the scene. Targetoid lesions with central white and outer red zones marked areas of surface and deep coagulation grossly. The animals were sacrificed 30 minutes after irradiation. The lesions and surrounding normal liver were collected for light microscopy. Microscopically, characteristic, thermally-induced red blood cell alterations were found in the white and red zones and at the boundaries separating them. The boundaries of the concentric surface zones were measured grossly from the lesion centers and compared to the thermal images to determine the temperatures associated with the red blood cell changes. The temperatures for the surface and deep morphologic isotherms defined by the white/red and red/normal boundaries of rat liver irradiated in vivo are 68+/- 5.0 degree(s)C and 55+/- 2.7 degree(s)C.