J o u r n a l o f P h o t o c h e m i s t r y a n d Photobiology, B: Biology, 6 (1990) 249-257

249

XeC1 E X C I M E R L A S E R C O R O N A R Y A N G I O P L A S T Y : A CONVERGENCE OF FAVOURABLE FACTORS* S. AVRILLIER L a b o r a t o i r e de P h y s i q u e des Lasers, Universitd P a r i s XIII, 93430 V i l l e t a n e u s e (France)

J. P. OLLMER and I. GANDJBAKHCH H.LA. d u Val d e Grace - 74, Bd. d e Port Royal, 75005 P a r i s (France)

E. DELETTRE L a b o r a t o i r e de P h y s i q u e des Lasers, Universitd P a r i s XIII, 93430 V i l l e t a n e u s e (France)

J. L. BUSSIERE H.I.A. d u Val d e GrSce - 74, Bd. d e Port Royal, 75005 P a r i s (France)

(Received November 24, 1989; accepted December 14, 1989)

L a s e r a n g i o p l a s t y , c o r o n a r y a n g i o p l a s t y , e x c i m e r laser, p h o t o a blation, c a t h e t e r i z a t i o n .

Keywords.

Summary T h e r e s u l t s o f r e c e n t s t u d i e s o n t h e a p p l i c a t i o n o f an XeC1 l a s e r to c o r o n a r y a n g i o p l a s t y a r e p r e s e n t e d . S e v e r a l p o i n t s are e x a m i n e d : t h e quality o f the cut in h u m a n p o s t - m o r t e m artery, t h e cutting r a t e s a n d t h r e s h o l d fluences in different m e d i a , t h e risks o f c a r c i n o g e n e s i s a n d t h r o m b o s i s , a n d t h e t r a n s m i s s i o n o f suitable f l u e n c e s in o p t i c a l fibres. R e c e n t h u m a n i n v i v o p r o c e d u r e s are r e p o r t e d .

1. Introduction The l o n g - t e r m a n d m i d - t e r m r e s u l t s o f m y o c a r d i a l r e v a s c u l a r i z a t i o n b y direct s u r g i c a l c o r o n a r y b y p a s s or p e r c u t a n e o u s b a l l o o n a n g i o p l a s t y are o f t e n c o m p r o m i s e d b y p r o g r e s s i v e distal a t h e r o s c l e r o s i s . M o r e o v e r , as m a n y as 2 0 % of c o r o n a r y a r t e r i e s a r e i n o p e r a b l e b e c a u s e o f diffuse a n d / o r calcified disease. This p r o b l e m calls f o r the d e v e l o p m e n t o f o t h e r t e c h n i q u e s . It s e e m s m o r e logical to t r y to r e m o v e t h e a t h e r o s c l e r o t i c m a t e r i a l t h a t fills the v a s c u l a r l u m e n r a t h e r t h a n to b y p a s s or flatten it. This i d e a h a s led to the d i s c o v e r y o f v a r i o u s ablative m e t h o d s u s i n g m e c h a n i c a l e n e r g y ( r o t a t i o n a l a t h e r e c t o m y *Paper presented at the Photomedicine Meeting organized by the French Society of

Photobiology, Paris, November, 1989. 1011-1344/90/$ 3.50

© Elsevier Sequoia/Printed in The Netherlands

250 device) [1, 2], ultrasonic energy [3] or photonic energy with lasers coupled to optical fibres [4]. Several types of laser have been applied in i n vi t ro and i n vivo studies of atheromatous plaque photoablation, and laser angioplasty has b ee n used experimentally as a balloon angioplasty complement or as a self-governing m e t h o d for the recanalization of peripheral and coronary arteries [4, 5]. The selection of the appropriate laser for coronary angioplasty is based on the following criteria: the quality of the cuts which is related to the structural integrity of the adjacent tissues and their short-term or long-term response, the ability to control the ablation process precisely to avoid perforation or dissection, the suitability of the fibre optic delivery system with r es p ect to the fluences required for the arterial plaque ablation and the laser size, reliability and serviceability for current use in hospitals. In this paper, we examine these criteria for the XeC1 excimer laser (308 nm) and show that it offers many advantages for use in coronary laser angioplasty.

2. T i s s u e a b l a t i o n 2.1. Q u a l i t y a n d control o f the cuts The quality of the cuts and the extent of injury to the surrounding tissue mainly depend on two characteristics of the laser. The first is the delivery mode and the second is the wavelength. Preliminary studies have be e n per f or med with continuous wave (CW) lasers such as argon, Nd-YAG and CO2 [6, 7]. Typically thermal diffusion during the CW ablation process leads to necrosis, coagulations and gross charring of the surrounding tissues. The use of a pulsed m ode at low repetition rates and high intensity significantly r e duc e s these drawbacks [8]. The extent of the irradiated region depends on the absorption and scattering coefficients of the tissue for the laser wavelength: a strong absorption reduces the penetration depth of the radiation which results in better control of the ablation and a narrower area of tissue exposed to damaging intensities. As a consequence, excimer lasers, which deliver short pulses (few tens of nanoseconds) of UV light that is strongly absorbed by biological materials, can a p r i o r i give better results than lasers which operate in the more weakly absorbed visible and near-IR regions. Moreover, many experimental studies have shown that, above a threshold fluence, UV lasers can etch clean, precise and almost cylindrical patterns in arterial walls [9]. The boundaries of the cuts are microscopically very sharply defined, with minimal and often negligible charring or damage to the environment. The width of the incision can be precisely controlled by selection of the laser spot size and its depth is determined by the n u m b e r of pulses and the energy density per pulse (Fig. 1). This typical and very accurate process is named "UV photoablation" and its mechanism is far from completely understood [ 10]. UV photoablation obviously cannot be com pared with pure

251

Fig. 1. Microphotograph of post-mortem human atherosclerotlc aorta: effect of 20 XeC1 laser pulses of 12 mJ and 20 ns duration delivered through a 600 ~m core fibre in contact with the arterial wall. The fibre was directed perpendicular to the internal surface of the artery. The medium was fresh heparinized human blood. The incision depth is about 700 /~m and the width about 550 pxa. There is no thermal injury on the incision margins (note the small disruptions of the intimal layer probably due to a shock wave induced in the blood by the laser pulse).

t h e r m a l vaporization; for example, with a 20 ns pulse of 12 m J at 3 0 8 n m in air, the ablated v o l u m e in the arterial wall is usually of the o r d e r of 1.5 × 10 -2 m m 8 [11 ], w h i c h c o r r e s p o n d s to a specific ablation e n e r g y o f 0.8 J m m -3. It is interesting to n o t e that the specific e n e r g y for h e a t i n g the tissue f r o m r o o m t e m p e r a t u r e to 100 °C plus its v a p o r i z a t i o n ( a s s u m i n g that the t i s s u e ' s t h e r m a l p r o p e r t i e s are the s a m e as t h o s e of water) is 2.8 J m m -3, i.e. a b o u t 3.5 times the e n e r g y r e q u i r e d for 3 0 8 n m p h o t o a b l a t i o n . After the a b s o r p t i o n o f a UV p h o t o n , w h i c h g e n e r a t e s electronic excitation, m a n y r e l a x a t i o n c h a n n e l s are possible, e.g. direct d e c o m p o s i t i o n into p r i m a r y p r o d u c t s or internal r e l a x a t i o n leading to heat dissipation or b o n d breaking. The kinetics of t h e s e p h e n o m e n a are v e r y c o m p l i c a t e d ; the p r e s e n c e of water, w h i c h d o e s n o t a b s o r b in the UV region, d o e s n o t significantly affect the c o u r s e of the p h o t o a b l a t i v e p r o c e s s [10]. As a g e n e r a l trend, t h e r m a l r e l a x a t i o n prevails at low irradiation intensity, w h e r e a s efficient d e g r a d a t i o n with a small b u t p r o p o r t i o n a l p r o d u c t i o n of heat o c c u r s at high irradiation intensity. The quality o f the incisions p r o b a b l y arises f r o m the fact that the radiation is a b s o r b e d in a s h o r t d e p t h a n d a n y e x c e s s e n e r g y over that w h i c h is r e q u i r e d to b r e a k the b o n d s r e m a i n s in the ejected p r o d u c t s . In an extensive i n v i t r o quantitative s t u d y o f 3 0 8 n m p h o t o a b l a t i o n 0 f p o s t - m o r t e m h u m a n aortic walls [ 11, 12 ], the cutting rates in different m e d i a (air, saline a n d b l o o d ) h a v e b e e n m e a s u r e d as a f u n c t i o n o f the incident e n e r g y density a n d the t h r e s h o l d fluences have b e e n e s t i m a t e d (Fig. 2). In spite of the fact that the differences b e t w e e n the s a m p l e s a n d the diversity o f p a t h o l o g i c a l states m a y lead to a large variability in the m e a s u r e d properties, several i m p o r t a n t points c a n be e m p h a s i z e d .

252

Fiber

Holder

t Focuaing

Lena

Silica

Fiber

-~

".m°. Fig. 2. Internal surface of fresh p o s t - m o r t e m h u m a n atherosclerotic aortic f r a g m e n t s i m m e r s e d in different m e d i a (air, saline, blood) a n d irradiated by an XeC1 laser coupled to a 600 ~ m core diameter fibre. The energy density p e r pulse at the exit of the fibre was varied in the range 1 . 4 - 7 J c m -z. The s e g m e n t s irradiated by a series of 5--100 p u l s e s were s u b m i t t e d to histologic examination.

(i) P h o t o a b l a t i o n ( 3 0 8 n m ) o f the plaque, e v e n w h e n calcified, c a n b e a c h i e v e d efficiently in air, saline a n d blood. F o r e x a m p l e , w i t h 20 p u l s e s o f 12 m J delivered b y a fibre ( 6 0 0 /zm c o r e d i a m e t e r ) in c o n t a c t with the s a m p l e , the cut d e p t h s in the fibrous intimal a n d m e d i a l layers o f a n aortic h u m a n a r t e r y are 9 9 0 ~ m , 8 5 0 ~tm a n d 8 1 0 ~ m in air, saline a n d b l o o d respectively. (ii) The a b l a t i o n t h r e s h o l d fluence f o r 20 n s p u l s e s is 1.4 J c m -2 in air a n d blood, w h i c h is in g o o d a g r e e m e n t with p r e v i o u s r e s u l t s [ 13]. H o w e v e r , in saline the t h r e s h o l d s e e m s to b e slightly h i g h e r a n d c l o s e to 1.7 J c m -2. (iii) The a b l a t i o n efficiency i n c r e a s e s w i t h the e n e r g y density, a n d the t h e r m a l l y d a m a g e d l a y e r o n the e d g e s o f the cut n e v e r e x c e e d s 50 /zm. H o w e v e r , in liquid m e d i a , s u c h as saline or blood, small d i s r u p t i o n s of the intimal layer m a y a p p e a r a n d are p r o b a b l y due to a s h o c k w a v e i n d u c e d in the m e d i u m b y the l a s e r pulse. (iv) In all m e d i a t h e r e is a definite r e s i s t a n c e o f the a d v e n t i t i o u s a r t e r y wall ( e x t e r n a l ) l a y e r to 3 0 8 n m p h o t o a b l a t i o n (Fig. 3). This p h e n o m e n o n , p r o b a b l y due to a m u c h h i g h e r t h r e s h o l d fluence for this tissue, is a v e r y i m p o r t a n t s a f e t y f a c t o r for t h e u s e o f the XeCI l a s e r in h u m a n c o r o n a r y angioplasty.

2.2. E x a m i n a t i o n o f the risks Let us n o w e x a m i n e t h e p o t e n t i a l risks r e l a t e d to UV p h o t o a b l a t i o n . F o r E. coli t r p i r r a d i a t e d at 3 0 8 n m w i t h a d o s e o f 10 J c m -2, T i p h l o v a et al. [14] h a v e f o u n d t h a t the p r o p o r t i o n o f s u r v i v o r s is 1% a n d the n u m b e r o f m u t a n t s is 100 p e r 108 survivors, i.e. a b o u t 1 p e r 106 initial b a c t e r i a . T h e n u m b e r o f s p o n t a n e o u s m u t a n t s ( n o n - i r r a d i a t e d ) is 0.1 p e r 108 cells. In a p r e l i m i n a r y u n p u b l i s h e d study, w e i r r a d i a t e d a s o l u t i o n o f native p l a s m i d DNA a n d c o u l d n o t d e m o n s t r a t e a n y significant effect o f 3 0 8 n m r a d i a t i o n

253

1000-

~ i

E=L

o E----4.23.J/CM

2

Adv

r n. 0

n

500-

f

Meal

/

J. Int I

5

t

2'0

100

5'0 Number

of

ehote

Fig. 3. XeC1 laser ablation depth as a function of the number of shots for a constant energy density of 4.23 J cm -2. The sample is a highly fibrous human aortic fragment. The thickness of each arterial layer is indicated (intima, media, adventitia). The cutting rate is much smaller in the adventitia than in the intima or media: the adventitial tissue is reached after only 5 pulses and a perforation is obtained after over 100 pulses. This type of curve is also observed for all arteries in saline and blood. at a dose o f 10 J c m - 2 ; n o additional nucleic chain b r e a k s w e r e o b s e r v e d . It s e e m s that in c o n t r a s t with 2 4 9 n m irradiation [ 15 ], the risk o f c a r c i n o g e n e s i s i n d u c e d by 3 0 8 n m irradiation is v e r y low. This is even m o r e true for UV p h o t o a b l a t i o n b e c a u s e only a small n u m b e r o f ceils in the first 10 ~ m o f the s u b j a c e n t tissue are affected. A n o t h e r risk m a y arise f r o m the b y p r o d u c t s expelled during laser ablation of the plaque; however, it has b e e n d e m o n s t r a t e d [16] that w a t e r is the m a i n g a s - p h a s e p r o d u c t o f 3 0 8 n m p l a q u e d e s t r u c t i o n a n d that the tissue f r a g m e n t s are t o o small to c a u s e m i c r o v a s c u l a r o b s t r u c t i o n [ 17]: the f r a g m e n t s ejected in the gas p h a s e axe in the laser b e a m a n d r e a b s o r b m a n y p h o t o n s b e f o r e the e n d o f the laser pulse; c o n s e q u e n t l y , t h e y are t r a n s f o r m e d into smaller f r a g m e n t s (80% are smaller t h a n 3 ]zm). Finally, to evaluate the risk o f t h r o m b o g e n e s i s during i n vivo 3 0 8 n m angioplasty, we irradiated freshly c o l l e c t e d h u m a n b l o o d (less t h a n 1 min after collection) with n o r m a l p l a q u e p h o t o a b l a t i o n e n e r g y densities ( 1 . 4 - 1 0 J c m - 2): the risk s e e m s to be negligible since we did n o t obtain a n y coagulation. Moreover, small f r e s h b l o o d clots irradiated with pulses of 3 J c m -2 at 3 0 8 n m were c o m p l e t e l y liquefied b y a few pulses.

3. XeC1 laser and fibre optic delivery system 3.1. L a s e r p a r a m e t e r s Many XeC1 lasers are c o m m e r c i a l l y available. T h e y are e a s y to o p e r a t e a n d reliable, and in c o n t r a s t with o t h e r e x c i m e r lasers (KrF, 249 nm; ArF,

254

193 nm; XeF, 351 nm) no gas filtration is needed. However, their size and running cost may still cause problems for clinical use. For our in vitro and in vivo experiments we employed a new generation of excimer lasers (SOPRA) which use a phot on switching technique. The laser head is very com pa c t (994 c m x 3 4 c m x 2 5 cm) and delivers, in its original design, 300 mJ pulses of 40 ns duration at 308 nm. By modifying the discharge impedance, we increased the pulse duration to 100 ns full width at half-maximum (FWHM) with an output pulse energy of 120 mJ at a repetition rate of 3 Hz. For clinical applications we integrated the laser head, power supply, vacuum pump, gas mixture bottles and fibre optical coupling device in a movable self-contained medical apparatus (120 c m × 6 0 c m × 100 cm).

3.2. Coupling of 308 n m laser to optical fibres A very important point in the choice of a laser for angioplasty is the availability of flexible, non-toxic fibres with sufficiently high transmission and damage threshold at the laser wavelength. For example, up to the present time the absence of commercially available fibres which transmit 10 ~m light has b een a serious drawback for CO2 laser angioplasty. In the UV region, commercially available step index fused silica fibres can be efficiently coupled to XeC1 and XeF (351 nm) lasers [13], but at 249 nm (KrF) their attenuation seems to be too high [18]. At 308 nm, it has already been demonstrated [11, 12, 19] that it is possible to obtain a sufficient fluence for plaque ablation at the exit of a fibre a few metres in length. For example, Table 1 summarizes the values of the m a x i m um energy per pulse that can be reliably obtained using some commercial fibres (HCN, Ensign Bickford) and our apparatus: the laser b e a m (cross-section, 20 m m x 20 mm) is simply focused by a 100 mm lens on the cleaved and striped tip of a carefully aligned fibre of 1 m in length. For angioplasty, the optimum operating fluence is of the order of 6 - 7 J cm -2 to prevent damage to the distal end of the fibre and to minimize thermal and acoustic damage to the arterial wall.

TABLE 1 Experimental values of energy and fluence of XeC1 laser coupled to HCN fibres of various core diameters (duration of laser pulses, 100 ns; length of fibres, 1 m)

Core diameter

Output energy per pulse

Energy density p er pulse

0zm)

(mJ)

(J cm -2)

1000 600 400 200

90 48 19 4

11.5 17 15.1 12.7

255

4. I n v i v o

preliminary experiments

4.1. I n t r a - o p e r a t i v e X e C l l a s e r c o r o n a r y a r t e r y e n d a r t e r e c t o m y

A number of angioplasties were performed during coronary artery bypass surgery [20, 21]. Prior to bypass grafting, a specifically tipped fibre (1 mm core diameter) was introduced via the coronary arteriotomy and was positioned in contact with the atheromatous lesion upstream or downstream from the bypass graft implantation site. A successful endarterectomy ( 1 - 2 0 mm in length) was achieved in 11 out of 12 segments using 100-3200 pulses of 16-28 mJ (Table 2). In both 8 day and 6 month angiocoronarographic controls, all laser treated segments, except one, were unobstructed. No immediate complications were observed, except a small intimal haemorrhage in patient 2, that could have been secondary to the fracture of the plaque remaining at the periphery of the vessel lumen. 4.2. P e r c u t a n e o u s XeC1 l a s e r c o r o n a r y a n g i o p l a s t y

Although XeC1 coronary endarterectomy performed during bypass procedures can now be considered as a useful therapeutic method, percutaneous XeC1 laser coronary angioplasty is the main challenge of this technique. In order to follow a percutaneous route, a family of multifibre flexible catheters has been developed [21]. The small diameter fibres (100-300 /~m) are concentrically arranged around a lumen as a guide wire: by advancing the TABLE 2 XeC1 l a s e r a n g i o p l a s t i e s d u r i n g b y p a s s s u r g e r y . In t h r e e 1 w e e k a n d t h r e e 6 m o n t h a n g i o g r a p h i c a l l y controlled patients and two anatomically controlled patients , only one angioplasty was not p a t e n t (8). All o t h e r u p s t r e a m l a s e d s e g m e n t s w e r e p a t e n t d e s p i t e t h e g r a f t c o m p e t i t i v e flow

Angioplasty

Length of angioplasty

Degree of calco2cation I

(mm)

Number of

Energy density

pulses

per pulse

Intra-operative control

Angioplastic coronarography

Unobstructed Unobstructed (post-mortem) Unobstructed Unobstructed Unobstructed Planned Planned Occluded Unobstructed N o change Unobstructed Unobstructed (post-mortem)

1 2

15 20

+ + + + + + +

220 1831

3.18 3.18

Unobstructed Unobstructed

3 4 5 6 7 8

18 4 3 10 10 10 20 1 5 10

+ + + + + + + + + +

+ + + + + + +

1110 100 165 207 3172 233

+ + +

859

2.92 3.18 3.56 2.03 3.18 4.20 4.20 2.92 2.92 3.56

Unobstructed Unobstructed Unobstructed Unobstructed Unobstructed LAD: unobstructed MAR: unobstructed LAD: o c c l u d e d MAR: unobstructed Unobstructed

9 i0

+ +

645

" D e g r e e o f c a l c i f i c a t i o n : + , w e a k l y calcified; + + + + , v e r y c a l c i fi e d. ( I n t r a o p e r a t i v e q u a l i t a t i v e e s t i m a t i o n b y m a n u a l p a l p a t i o n . ) LAD, left a n t o r i o r d e s c e n d i n g a r t e r y ; MAR, m a r g i n a l c o r o n a r y ar tery.

256 guide t h r o u g h t o r t u o u s v a s c u l a r s e g m e n t s , it is possible to p o s i t i o n the c a t h e t e r tip in c o n t a c t with the lesion. F o r example, one o f the c a t h e t e r s d e v e l o p e d in o u r l a b o r a t o r y uses 16 individual 2 0 0 t~m fibres a n d has an external d i a m e t e r o f 2 mm. In J u n e 1989 Litvack et al. [22] t r e a t e d 63 patients with 76% p r i m a r y s u c c e s s . Most o f the i m m e d i a t e failures s e e m to be due to a lack o f flexibility o f the c a t h e t e r s a n d the c o m p l i c a t i o n s are mainly v a s c u l a r dissection ( m e c h a n i c a l o r p h o t o a b l a t i v e ) a n d v a s c u l a r s p a s m s . The mid- a n d l o n g - t e r m healing p r d c e s s e s are u n k n o w n .

5. C o n c l u s i o n s Since the first r e p o r t s o n the i n v i t r o effects o f XeC1 e x c i m e r laser e n e r g y o n h u m a n v a s c u l a r tissue in 1985 [19, 23], the d e v e l o p m e n t o f h u m a n c o r o n a r y 308 n m a n g i o p l a s t y has b e e n v e r y fast. There are a n u m b e r of f a v o u r a b l e factors. (i) XeC1 e x c i m e r laser p h o t o a b l a t i o n p r o d u c e s c o n t r o l l e d submillimetre r e m o v a l o f a t h e r o s c l e r o s i s plaques, even w h e n calcified, with n o (or minimal) d a m a g e to n e i g h b o u r i n g tissues. (ii) The risk o f p e r f o r a t i o n is r e d u c e d b y a clear r e s i s t a n c e o f the adventitial layer. (iii) T h e r e is n o evidence for c a r c i n o g e n e s i s i n d u c e d b y 3 0 8 n m radiation. (iv) Radiation at 308 n m does n o t i n d u c e b l o o d c o a g u l a t i o n a n d c a n liquefy clots. (v) XeC1 lasers o f r e a s o n a b l e size, c o s t a n d serviceability c a n be c o u p l e d to flexible multifibre c a t h e t e r s to deliver the r e q u i r e d fluences safely. (vi) The first i n v i v o h u m a n investigations are v e r y promising. However, a lot o f w o r k r e m a i n s to be done. The multifibre c a t h e t e r s m u s t be modified to i m p r o v e their flexibility a n d to allow the p h y s i c i a n to c h o o s e a c a t h e t e r a p p r o p r i a t e for the a r t e r y b e i n g treated. The m i d - t e r m a n d l o n g - t e r m healing p r o c e s s e s n e e d to be carefully studied. A m o r e a c c u r a t e c o n t r o l o v e r the i n s i t u ablation p r o c e s s w o u l d also i n c r e a s e the safety o f this technique. This c o u l d be a c h i e v e d b y s p e c t r a l identification o f the a t h e r o s c l e r o t i c tissue [24] o r b y direct a n g i o s c o p i c visualization u s i n g one c h a n n e l of the a n g i o p l a s t y catheter.

References 1 K. Kensey, J. Nash, C. Abrahams, K. Lake and C. K. Zarins, Recanalisation of obstructed arteries using a flexible rotating tip catheter (abstract), Circulation, Suppl., 74 (II) (1986) 457. 2 N. Zacca, A Raizner, D. Short, G. Noon, C. D. Weflbaecherd, J. Roehm, A. Gotto and R. Roberts, First in vivo human experience with a recently developed rotational atherectomy device (abstract), Circulation, Suppl., 76 (IV) (1987) 46. 3 R. J. Siegel, M. C. Fishbein, J. Forrester, K. Moore, E. De Castro, L. Daykhovsky and T. A. Don Michael, Ultrasonic plaque ablation, a new method for recanalisation of partially or totally occluded arteries, Circulation, 78 (1988) 1448-1451. 4 J. S. Forrester, Laser angioplasty: now and the future, Circulation, 78 (1988) 777-779. 5 T. A. Sanborn, Laser angioplasty: what has been learned from experimental studies and clinical trials, Circulation~ 78 (1988) 769-776.

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