Cryotherapy methods for treating vessel dissections and side branch occlusion

[0002] This application is a continuation-in-part of and claims priority from U.S. Provisional Patent Application No. 60/312,295, filed on Aug. 13, 2001, the full disclosure of which is incorporated herein by reference.

[0003] 1. Field of the Invention

[0004] The present invention relates generally to medical methods and kits. More particularly, the present invention provides methods and kits for cryogenically cooling a blood vessel within a patient's vasculature to treat potential or existing dissections in the blood vessel. The present invention further provides methods and kits for cryogenically cooling a bifurcated blood vessel to treat side branch occlusion. Vessel dissections and side branch occlusion often result from angioplasty or other intravascular procedures for treating atherosclerosis and other diseases of the vasculature.

[0005] Atherosclerotic plaque is present to some degree in most adults. Plaques can severely limit the blood flow through a blood vessel by narrowing the open vessel lumen. This narrowing effect or stenosis is often responsible for ischemic heart disease. Fortunately, a number of percutaneous intravascular procedures have been developed for treating atherosclerotic disease in a patient's vasculature. The most successful of these treatments is percutaneous transluminal angioplasty (PTA). PTA employs a catheter having an expansible distal end, usually in the form of an inflatable balloon, to dilate a stenotic region in the vasculature to restore adequate blood flow beyond the stenosis. Other procedures for opening stenotic regions include directional arthrectomy, rotational arthrectomy, laser angioplasty, stents and the like. While these percutaneous intravascular procedures, particularly PTA, have provided significant benefits for treatment of stenosis caused by plaque, they continue to suffer from significant disadvantages. Particularly common disadvantages are the subsequent occurrence of vessel dissection, vessel recoil (acute and delayed), side branch occlusion, restenosis, and other procedure related trauma. Such disadvantages may affect up to 80% of all angioplasty patients to some extent.

[0006] During conventional PTA, the inflated balloon tends to create large fissures or tears in the intima of the blood vessel wall, particularly at a junction between the plaque and the vessel wall. Such tears or fissures are referred to as dissections. Vessel dissections compromise the dilated vessel, often constricting or blocking blood flow within the vessel. A number of strategies have been proposed to treat vessel dissections. Previously proposed strategies include prolonged balloon inflation, treatment of the blood vessel with a heated balloon, stenting of the region following balloon angioplasty, and the like. While these proposal have enjoyed varying levels of success, no one of these procedures is proven to be entirely successful. In particular, stenting of the dilated region may address acute problems of intimal dissection and vessel recoil, however stents are believed to actually cause a marked increase in the degree of intimal restenosis or hyperplasia (re-narrowing of the an artery following an initially successful angioplasty). This in turn leads to greater late luminal loss, especially in smaller vessels which are more susceptible to re-closure due to restenosis. Moreover, stents may prove to be an impractical solution when dilating long periphery arteries that may require multiple stent placements. Stents may additionally not always be easily maneuvered to and positioned in dilated regions, especially in the coronary arteries.

[0007] Another limitation associated with angioplasty is side branch occlusion in a bifurcated blood vessel during dilatation of a primary vessel lesion. Side branch occlusion can occur by several mechanisms. The “snow plow” effect may be the most common mode of side branch occlusion, in which plaque from a primary vessel is literally “plowed” or “shifted” into the adjacent side vessel during dilatation, narrowing or occluding the side vessel lumen. Known procedures for treating side branch occlusion include the “kissing balloon technique” where two guiding catheters are positioned in the bifurcated vessel, one in the primary vessel and the other in the side branch, and the balloons are inflated simultaneously or sequentially so that they potentially touch or “kiss.” However, such angioplasty techniques alone or in combination with stents, has not been entirely successful in preventing side branch occlusion.

[0008] For these reasons, it would be desirable to provide methods and kits for the treatment of dissections in a blood vessel. It would be further desirable to provide methods and kits for the treatment of side branch occlusion in a bifurcated blood vessel. The methods should be suitable for intravascular and intraluminal introduction, preferably via a percutaneous approach. It would be particularly desirable if the new methods were able to deliver the treatment in a very controlled and safe manner with minimum side effects. At least some of these objectives will be met by the invention described herein.

[0009] 2. Description of the Background Art

[0010] Cryoplasty methods and devices are described in U.S. patent application Ser. No. 08/982,824, now U.S. Pat. No. 5,971,979; U.S. patent application Ser. No. 09/203,011 (Attorney Docket No. 018468-000110US) ; U.S. patent application Ser. No. 09/510,903 (Attorney Docket No. 018468-000410US), U.S. patent application Ser. No. 09/619,583 (Attorney Docket No. 018468-000610US), assigned to the assignee of the present application. A cryoplasty device and method are also described in WO 98/38934. Balloon catheters for intravascular cooling or heating a patient are described in U.S. Pat. No. 5,486,208 and WO 91/05528. A cryosurgical probe with an inflatable bladder for performing intrauterine ablation is described in U.S. Pat. No. 5,501,681. Cryosurgical probes relying on Joule-Thomson cooling are described in U.S. Pat. Nos. 5,275,595; 5,190,539; 5,147,355; 5,078,713; and 3,901,241. Catheters with heated balloons for post-angioplasty and other treatments are described in U.S. Pat. Nos. 5,196,024; 5,191,883; 5,151,100; 5,106,360; 5,092,841; 5,041,089; 5,019,075; and 4,754,752. Cryogenic fluid sources are described in U.S. Pat. Nos. 5,644,502; 5,617,739; and 4,336,691. The following U.S. patents may also be relevant to the present invention: 5,458,612; 5,545,195; and 5,733,280.

[0011] Side branch occlusion is described by Stephen N. Oesterle in Angioplasty Techniques for Stenoses Involving Coronary Artery Bifurcations,Am J Cardiol, vol. 61, pp. 29G-32G (1988); Lefevre et al. in Stenting of Bifurcation Lesions: Classification. Treaments, and Results,Catheterization and Cardiovascular Interventions, vol. 49, pp. 274-283 (2000); Chevalier et al. in Placement of Coronary Stent in Bifurcation Lesions by the “Culotte” Technique,Am J Cardiol, vol. 82, pp. 943G-949G (1998). Cutting balloons are described at http://www.interventionaltech.com/Products/CuttingBallon.html.

[0012] The full disclosures of each of the above references are incorporated herein by reference.

[0013] The present invention provides cryotherapy treatment of dissections in a blood vessel of a patient. The present invention further provides cryotherapy treatment of side branch occlusion in a bifurcated blood vessel. The blood vessel may be any blood vessel in the patient's vasculature, including veins, arteries, and particularly coronary arteries. The blood vessel will be at least partially stenosed, typically by eccentric calcified plaque (i.e. the plaque compromises a vessel lumen predominantly from one side) in the coronary and peripheral arteries. In particular, the present invention may limit, reduce, minimize, prevent, mitigate, and/or inhibit potential or existing dissections of a vessel and/or plaque shift from a main branch into a side branch of a bifurcated blood vessel so as to inhibit acute coronary syndrome.

[0014] In a first aspect, the present invention provides a method for treating potential or existing dissections in a blood vessel. The method comprises cooling the blood vessel to a temperature and for a time sufficient to remodel the blood vessel such that dissections of the blood vessel are reduced. The cooling treatment will often be directed against all or a portion of a circumferential surface of a lumen of the blood vessel.

[0015] Cooling of a vessel may be effected by introducing a catheter into a lumen of a blood vessel. A balloon is positioned within the vessel lumen adjacent the potential or existing dissection. Cryogenic cooling fluid is introduced into the balloon and exhausted. The balloon expands to radially engage the vessel lumen. Generally, the cooling temperature at the cell surface of the blood vessel lumen is in a range from about −3° C. to about −15° C. The tissue is typically maintained at the desired temperature for a time period in the range from about 10 seconds to about 60 seconds, more preferably from about 20 seconds to 40 seconds. Vessel dissection treatment may be enhanced by repeating cooling in cycles, typically with from about 1 cycle to 3 cycles, with the cycles being repeated at a rate of about one cycle every 60 seconds.

[0016] The dissections may comprise flaps, residual plaque, and/or pieces of tissue resulting from fissuring or tearing of the intima of the blood vessel wall or plaque thereon. Typically, such dissections occur at a junction between the plaque and the vessel wall, wherein the plaque tears at its margins and sends a plane of dissection deep into the media of the vessel wall. Dissections are undesirable as they often compromise the integrity of the blood vessel by at least partially blocking the blood vessel. Such blockage can limit blood flow and potentially create a threat to acute vessel closure. The dissections may further create flow in an abnormal pattern (i.e. flow in planes other than the true vessel lumen or non laminar flow.)

[0017] The blood vessel is subject to dissections resulting from treatment of a stenosis, wherein the treatment of the stenosis typically comprises percutaneous transluminal angioplasty. The cooling step may be performed before or after balloon angioplasty, and will preferably be performed during balloon angioplasty. Surprisingly, work in connection with the present invention has shown that cooling of the blood vessel reduces and/or inhibits potential or existing dissections so as to produce a “stent-like” angiographic result (i.e. dissection free lumen without the use of a stent). Moreover, cooling may further minimize or inhibit restenosis or hyperplasia (re-narrowing of the an artery following an initially successful angioplasty) and help maintain the patency of a body lumen. Cooling may also be efficiently effected in long periphery arteries and the cooling apparatus easily maneuvered to and positioned in the treatment vessel, especially in the coronary arteries, so that cooling may be effected in difficult to access areas.

[0018] The cooling step may alter mechanical properties of the blood vessel wall or plaque thereon so the that fissuring or tearing of the blood vessel wall or plaque thereon is reduced. Particularly, the blood vessel wall and/or plaque is solidified so that there is not such a great disparity in compliance between the two. As such, the dilatation force applied by the angioplasty cooling balloon is more evenly distributed around a circumference of the vessel wall so that tearing of the vessel at the junction between the vessel wall and plaque is minimized (i.e. any resulting fissures in the vessel wall and plaque are small or micro cracks that do not compromise flow in the vessel). Cooling may also alter a fail mode of the vessel resulting from the modified mechanical properties. Cooling may alternatively or additionally enhance bonding between layers of the blood vessel wall so that fissuring or tearing of the blood vessel wall is reduced. In other applications, the cooling step may tack or re-attach existing vessel dissections, resulting from a prior angioplasty procedure, into the blood vessel wall.

[0019] In some instances, cooling may soften or weaken the vessel wall or plaque thereon, particularly eccentric calcified plaque, so that the vessel can be dilated or expanded at much lower pressures than is used with conventional angioplasty. Specifically, cooling temperatures of about −10° C. may freeze fluid between spaces in the calcium which in turn breaks up the calcified plaque, softening the vessel so that it can dilated at a lower pressure. In addition to the softening or weakening of the vessel wall or plaque thereon, cooling at low temperatures may also freeze and harden non-treatment tissue adjacent to the calcified plaque so that the vessel wall may exhibit more uniform properties against the dilation force applied by the angioplasty cooling balloon.

[0020] In another aspect, the present invention provides a method for treating potential or existing dissections in a blood vessel, said method comprising introducing a catheter into a lumen of the blood vessel and positioning a balloon within the vessel lumen adjacent the potential or existing dissection. Cryogenic cooling fluid is introduced into the balloon and exhausted. The balloon is expanded to radially engage the vessel lumen and cool the vessel lumen to a temperature and for a time sufficient to remodel the blood vessel such that dissections of the blood vessel are reduced and/or inhibited. Cooling may comprise adhering the cooling balloon to the blood vessel or plaque thereon so as to minimize any slippage of the cooling balloon. This is particularly advantageous in the treatment of a stenosis as plaque is often amorphous and slippery and as such conventional uncooled angioplasty balloons often slip and cause additional dissections or tears proximal and distal of the stenosis. Hence, cooling prevents the creation of any additional dissections by minimizing such slippage of the cooling balloon and in so doing further allows for controlled dilatation at the stenosis.

[0021] In another aspect, the present invention provides a method for treating side branch occlusion in a bifurcated blood vessel, the bifurcated blood vessel having a side branch and a main branch, the main branch having plaque disposed thereon. In some instances, the side branch may also be at least partially stenosed. The method comprises introducing a catheter into a lumen of the main branch and positioning a balloon within the main branch adjacent the plaque. Cryogenic cooling fluid is introduced into the balloon and exhausted. The balloon is expanded to radially engage the main branch lumen and an inner surface of the main branch is cooled to a temperature and for a time sufficient to inhibit plaque shift from the main or primary branch into the adjacent or side branch.

[0022] The plaque comprises a combination of calcified, fatty, and fibrous tissues and is fairly amorphous and slippery so that it easily shifts by its structural nature. As such, the side branch is often subject to occlusion by plaque shift from the main branch into the side branch as a result of treatment of plaque in the main branch. Treatment of the plaque typically comprises balloon angioplasty, wherein the cooling step may be performed before, after, or preferably during balloon angioplasty. In some instances, the treatment of plaque in the main branch may be accompanied by simultaneous or sequential treatment of stenosis in the side branch. It is believed that the cooling step alters mechanical properties of the plaque (i.e. plaque compliance) so that plaque shift from the main branch to the side branch is inhibited. In particular, cooling may solidify the plaque so that it less amorphous and thus less susceptible to shifting. Plaque solidification may further be enhanced by the formation of a temporary ice cap on an orifice of the side branch due to a small portion of the cryoplasty balloon coming into contact with blood cells.

[0023] In yet another aspect, the present invention provides a kit for treating potential or existing dissections in a blood vessel. The kit comprises a catheter having a proximal end, a distal end, and a cooling member. Instructions are included in the kit for use of the catheter. These instructions may comprise the step of cooling the blood vessel adjacent the potential or existing dissection to remodel the blood vessel such that dissections of the blood vessel are reduced. The kit may additionally or alternatively provide for the treatment of side branch occlusion in a bifurcate vessel, wherein the instructions recite the step of cooling a main branch lumen adjacent the plaque to inhibit plaque shift from the main branch into the side branch. Such kits may include instructions for performing one or more of the above described methods. The instructions will often be printed, optionally being at least in-part disposed on packaging. The instructions may alternatively comprise a videotape, a CD-ROM or other machine readable code, a graphical representation, or the like showing any of the above described methods.

[0024] In another aspect, the present invention provides a method for treating potential elastic recoil in a blood vessel, the method comprising introducing a catheter into a lumen of the blood vessel and positioning a balloon within the vessel lumen adjacent tissue that may potentially recoil. The balloon is expanded to radially engage the vessel lumen and cool the vessel lumen to a temperature and for a time sufficient to remodel the blood vessel such that actual elastic recoil is inhibited.

[0025] The cooling step may alter structural properties of collagen fibers of the vessel wall such that elastic recoil of the vessel is reduced. In particular, induction of a phase change in an aqueous component of the adjacent tissue during cooling may cause acute structural changes to the tissue matrix. Dilatation of the vessel by the cooling balloon may be accompanied by a drop in a balloon surface temperature below a phase transition threshold of physiologic saline. Thus, as the balloon expands and experiences a temperature drop, the aqueous saline in interstitial spaces (i.e. spaces between cells and fibers that constitute the vessel wall) in the adjacent tissue begin to freeze. As such, ice may be nucleated in the interstitial spaces and propagate radially outward through the tissue. The expanding ice may in turn impose mechanical compressive forces on collagen fibers and vessel cells. Correspondingly, the collagen fibers and cells may undergo morphological deformation in response to the mechanical forces. Any plastic deformation of the collagen fibers may produce permanent or semi-permanent alteration of the vessel tissue, and consequently may yield an alternation in the structural properties of the tissue. Specifically, possible compacting or compression of collagen fibers by cooling may substantially alter structural properties, such as elasticity, of the collagen fibers so that elastic recoil of the vessel is reduced.

[0026] The blood vessel is typically subject to elastic recoil resulting from treatment of a stenosis. The treatment of stenosis typically comprises balloon angioplasty, wherein the cooling step may be performed before, after, or preferably during balloon angioplasty. Moreover, during balloon angioplasty the vessel is being expanded by balloon expansion which may exert radially directed mechanical forces on the vessel tissue. Hence, the dual action of mechanical compressive forces generated by concurrent dilation and cooling may produce a more beneficial effect than can be achieved by conventional angioplasty.

[0027] In a still further aspect, the present invention provides a method for producing a smooth luminal surface in a blood vessel that is at least partially stenosed by fatty plaque, said method comprising introducing a catheter in a lumen of the blood vessel and positioning a balloon within the vessel lumen adjacent the fatty plaque. The balloon is expanded to radially engage the vessel lumen and cool the vessel lumen to a temperature and for a time sufficient to remodel the blood vessel so as to produce a smooth luminal surface. In particular, fatty lipid based plaque may undergo chemical or physical alterations in response to cooling of the plaque below a lipid phase change temperature (typically being in a range from about +15° C. to about 0° C.). This remodeling of the vessel and plaque thereon may in turn produce a smoother luminal surface than can be achieved with conventional angioplasty. A smoother luminal surface advantageously provides more laminar flow through the vessel wall, and further reduces any shear stresses on the vessel wall.

[0028] FIGS. 1A-1C are cross-sectional views of blood vessels having dissections.

[0029] FIG. 2A is a cross-sectional view of a stenosed bifurcated blood vessel.

[0030] FIG. 2B is a cross-sectional view illustrating plaque shift in the bifurcated blood vessel.

[0031] FIG. 3 illustrates an exemplary cryotherapy catheter for treating vessel dissections and side branch occlusion constructed in accordance with the principles of the present invention.

[0032] FIG. 4 is a cross-sectional view of the catheter taken along line 4—4 in FIG. 3.

[0033] FIG. 5 is a functional flow diagram illustrating the operation of automatic fluid shutoff mechanism of the catheter of FIG. 3.

[0034] FIG. 6 illustrates a cross-sectional view of a cryotherapy catheter with multiple vacuum lumens.

[0035] FIG. 7 illustrates an inflation unit for use with the cryotherapy catheter of FIG. 3.

[0036] FIGS. 8A-8D illustrate use of the catheter of FIG. 3 for treatment of potential vessel dissections.

[0037] FIGS. 9A-9C illustrate use of the catheter of FIG. 3 for treatment of existing vessel dissections.

[0038] FIGS. 10-10C illustrate use of the catheter of FIG. 3 for treatment of side branch occlusion.

[0039] FIG. 11 illustrates a vessel dissection or side branch occlusion treatment kit including the apparatus of FIG. 3 and instructions for use.

[0040] FIGS. 12A through 13E are angiographic results of experiments showing an actual and observed reduction in stenosis with a minimum amount of vessel dissection and side branch occlusion as described in the two Experimental sections provided hereinbelow.

[0041] The present invention provides cryotherapy treatment of dissections in a blood vessel of a patient. FIGS. 1A-1C illustrate cross-sectional views of a blood vessel 100 having dissections 102 within a lumen 104 of the vessel. The dissections 102 generally comprise flaps, residual plaque, and/or pieces of tissue resulting from fissuring or tearing of the intima of the blood vessel wall or plaque thereon from primary treatments like balloon angioplasty. Typically, such dissections 102 occur at a junction between the plaque and the vessel wall, wherein the plaque tears at its margins and sends a plane of dissection deep into the media of the vessel wall. As shown in FIG. 1B, dissections 102 are undesirable as they often compromise the integrity of the blood vessel by at least partially blocking the blood vessel 100. For example, the dissection 102 may shift in direction 106 to limit blood flow and potentially create a threat to acute vessel closure (FIG. 1B). Dissections 102 may further create flow in planes other than the true vessel lumen as depicted by arrow 108.

[0042] The present invention further provides cryotherapy treatment of side branch occlusion in a bifurcated vessel. FIG. 2A illustrates a bifurcated blood vessel having a main or primary branch 112 and an adjacent or side branch 114. The main branch 112 is at least partially stenosed 116. The plaque 116 generally comprises a combination of calcium, fat, and lipids and is fairly amorphous and slippery so that it easily shifts by its structural nature. As such, the side branch 114 is often subject to occlusion by plaque shift from the main branch 112 into the side branch 114, as depicted by arrows 118, as a result of treatment of plaque in the main branch. Treatment of plaque typically comprises balloon angioplasty, wherein balloon dilatation shifts the plaque 116 into the side branch 114 as shown in FIG. 2B, narrowing or occluding the side branch lumen and potentially creating a threat to acute vessel closure.

[0043] Referring now to FIGS. 3 and 4, an exemplary cryotherapy catheter 10 (which is more fully described in co-pending application Ser. No. 09/619,583 filed Jul. 19, 2000 (Attorney Docket No. 018468-000610US) and in application Ser. No. 09/953,464 being filed herewith (Attorney Docket No. 081468-000620US), the full disclosure of which is incorporated herein by reference) for treating dissections 102 in a blood vessel 100 (see FIG. 1A) and/or side branch occlusion (see FIG. 2B) will be described. The catheter 10 comprises a catheter body 12 having a proximal end 14 and a distal end 16 with a cooling fluid supply lumen 18 and an exhaust lumen 20 extending therebetween. A first balloon 22 is disposed near the distal end 16 of the catheter body 12 in fluid communication with the supply and exhaust lumens. A second balloon is disposed 24 over the first balloon 22 with a barrier 26, typically a thermal barrier, therebetween. It will be appreciated that the following depictions are for illustration purposes only and does not necessarily reflect the actual shape, size, or dimensions of the cryotherapy catheter 10. This applies to all depictions hereinafter.

[0044] The balloons 22, 24 may be an integral extension of the catheter body 12, but such a structure is not required by the present invention. The balloons 22, 24 could be formed from the same or a different material as the catheter body 12 and, in the latter case, attached to the distal end 16 of the catheter body 12 by suitable adhesives, heat welding, or the like. The catheter body 12 may be formed from conventional materials, such as polyethylenes, polyimides, nylons, polyesters, and copolymers and derivatives thereof. The balloons 22, 24 may also be formed from conventional materials used for angioplasty, preferably being inelastic, such as nylon, polyethylene terephthalate (PET), or polyethylene, elastic, such as urethane, latex, or silicone, or other medical grade material suitable for constructing a strong non-distensible balloon. Additionally, balloons 22 and 24 could be formed from different material to provide improved protection. For example, the first balloon 22 could be formed from PET to provide strength while the second balloon 24 could be formed from polyethylene to provide durability. The balloons 22, 24 have a length of at least 1 cm each, more preferably in the range from 2 cm to 5 cm each in a coronary artery and 2 cm to 10 cm each in a periphery artery. The balloons 22, 24 will have diameters in the range from 2 mm to 5 mm each in a coronary artery and 2 mm to 10 mm each in a periphery artery.

[0045] The thermal barrier 26 may comprise a separation or gap maintained between the balloons 22, 24 by a polyester layer. The polyester layer typically comprises a woven, braided, helically wound, or knotted polyester material (e.g., Saatifil Polyester PES 38/31 M sold commercially by SaatiTech located in Somers, N.Y.) which may be affixed to the first balloon 22 by adhesion bonding, heat welding, fasteners, or the like. The polyester layer may be puncture resistant so as to provide further protection against any leakage of fluid from the first balloon 22. The polyester material may additionally help retain balloon folds of the first and/or second balloons 22, 24 after they are expanded so that the balloons may be more easily drawn back after a treatment procedure.

[0046] A radiopaque marker 30 may be disposed on the polyester layer 26 for proper positioning of the cryotherapy balloons 22, 24 within the target portion of the blood vessel under fluoroscopy. For example, the radiopaque marker 30 may be disposed on the polyester layer 26 in a stent-like pattern as depicted in FIG. 3. The radiopaque marker 30 is preferably a non-toxic contrast medium, such as, gold, and preferably tungsten and does not significantly alter the thermal insulation properties of the barrier. The marker 30 may be incorporated into an ink and printed onto the polyester layer itself. Areas of the polyester layer adjacent the balloon folds 32 may be free of any radiopaque marking so as to further minimize the balloon profile. The radiopaque marker 30 may also be electrically conductive so as to monitor any leaks in the separation between the balloons 22, 24.

[0047] The thermal barrier 26 may alternatively comprise a separation maintained between the balloons by a fluid layer. The fluid will be chosen dependent on its specific thermal properties (e.g., predetermined phase change temperature), viscosity effects, miscibility with a radiopaque contrast agent, and like characteristics. The fluid layer will generally comprise at least one liquid selected from the group consisting of propylene glycol, propylene glycol 200, propylene glycol 300, propylene glycol 400, propylene glycol 600, glycerin, ethyl alcohol 75%, ethyl alcohol 95%, dimethyl sulfoxide, glyceryl formal, N-methyl-2-pyrrolidose, tetrahydrofurfuryl, dimethyl acetamide, and monthiol glycerol. The liquid will generally be diluted with an aqueous solution, such as saline, dextrose 5%, or lactated Ringer's® solution. The gap thickness maintained by the fluid layer depends on several criteria, such as, the pressure or temperature within the first balloon, the desired surface temperature of the second balloon, and the thermal transport properties of the fluid within the gap. Typically, the gap thickness maintained between the balloons 22, 24 by the fluid layer will be in a range from about 0.1 mm to about 0.4 mm, preferably from about 0.25 mm to about 0.3 mm.

[0048] Hubs 38 and 40 are secured to the proximal end 14 of the catheter body 12. Hub 38 provides a port 42 for a guidewire which extends through a guidewire lumen 44 in the catheter body 12. Typically, the guidewire lumen 44 will extend through the exhaust lumen 20, as shown in FIG. 4. The guidewire lumen 44 may also extend axially outside the exhaust lumen 20 to minimize the occurrence of cryogenic fluid entering the blood stream via the guidewire lumen 44. Optionally, the guidewire lumen 44 may extend outside the inner surface of the first balloon 22 or the guidewire lumen 44 may allow for a guidewire to extend outside both balloons 22, 24. Hub 38 further provides a balloon deflation port 43 which allows final deflation of the balloon after a treatment procedure. Hub 40 provides a port 46 for connecting a cryogenic fluid source to the fluid supply lumen 18 which in turn is in fluid communication with the inner surface of the first balloon 22. Hub 40 further provides a port 48 for exhausting the cryogenic fluid which travels from balloon 22 in a proximal direction through the exhaust lumen 20.

[0049] In some instances, the proximal and distal balloon stems of the first 22 and second 24 balloon may be staggered along the distal end 16 of the catheter body 10. The balloons stems or bond joints are staggered to provide a lower balloon folding profile and to allow positioning of a vacuum port 54, which will be discussed in more detail below, between the proximal balloon stems of the first and second balloons 22, 24. The balloon stems of the first and second balloons will be staggered from each other by a distance of 5 mm or less, preferably from about 2 mm to about 3 mm. The cryotherapy catheter may further comprise at least one rupture disk molded into a proximal or distal balloon stem of the first balloon. In some instances, the cryotherapy balloons may fail or burst on inner bond joints in a peel mode or the inner balloon may simply burst. As such, it is desirable to mold rupture discs or thin spots into the balloons stems so that in the event of a failure, the rupture disc will allow a small amount of fluid leakage at a slow rate into a vacuum space (which is described in more detail below), allowing the cryotherapy system to shut down before the balloon bursts. Such discs will reduce a stem thickness to about 0.0005 inches or less.

[0050] The cryotherapy catheter 10 in FIG. 3 additionally illustrates several safety mechanisms that monitor the containment of the cryotherapy system. The first balloon 22 defines a volume in fluid communication with the supply 18 and exhaust 20 lumens. A fluid shutoff couples a cryogenic fluid supply with the supply lumen 18. The second balloon 24 is disposed over the first balloon 22 with a vacuum space 60 therebetween. The vacuum space 60 is coupled to the fluid shutoff by a plurality of vacuum lumens 62, as shown in FIG. 6, or optionally by a single vacuum lumen 62, as shown in FIG. 4. The fluid shutoff inhibits flow of cryogenic fluid into the first balloon 22 in response to a change in at least one of the vacuum lumens 62 and/or in response to a change in the vacuum space 60.

[0051] FIG. 5 illustrates a functional flow diagram of the automatic fluid shutoff mechanism 64. The fluid shutoff 64 typically comprises a vacuum switch 66 connected to a shutoff valve 68 by a circuit, the circuit being powered by a battery 70. The switch 66 may remain closed only when a predetermined level of vacuum is detected. The closed switch 66 allows the shutoff valve 68, in fluid communication with the cryogenic fluid supply 72, to be open. Alternatively, the circuit may be arranged so that the switch 66 is open only when the predetermined vacuum is present, with the shutoff valve 68 being open when the switch is open. The vacuum is reduced when there is a breach in the catheter body 12, allowing cryogenic fluid or blood to enter at least one vacuum lumen 62, the first balloon 22 is punctured, allowing cryogenic fluid to enter the vacuum space 52, or the second balloon 24 is punctured, allowing blood to enter the vacuum space 52. In addition to monitoring the containment of both the catheter body 12 and the balloons 22, 24 during cooling, in the event of a failure, the vacuum switch 66 will be triggered to prevent the delivery of additional cryogenic fluid from the fluid supply 72 into the supply lumen 18. The second balloon 24 also acts to contain any cryogenic fluid that may have escaped the first balloon 22. The exhaust lumen 20 is fluidly connected to a pressure relief valve 21 which in turn will typically vent to atmosphere.

[0052] Referring now to FIG. 7, the vacuum may be provided by a positive displacement pump, such as a syringe 74, coupled to the vacuum space 60 by a plurality of vacuum lumens 62 of the body 12 via vacuum ports 76, 54. The syringe 74 is disposed within an inflation unit handle 78. A valve, such as a simple stopcock 80, may be disposed between the syringe 74 and the vacuum lumens 62 so as to isolate a relatively large syringe volume from a relatively small vacuum volume. This in turn facilitates detection of small fluid leaks, as a change in the vacuum as small as 0.2 mL may be monitored. The vacuum space 60 comprises a small volume of vacuum in the range from 1 mL to 100 mL, preferably 10 mL or less. The battery 70 may be electrically coupled to a heater 61 for heating the fluid supply 72 and cryogenic fluid therein to room temperature or warmer so as to enhance the fluid pressure and cooling system performance, as is more fully described in co-pending application Ser. No. 09/268,205. The cryogenic fluid supply 72, battery 70 for powering the circuit, and heater 61 may be packaged together in an energy pack 82 that is detachable from the inflation unit 78 via a latch 84 and disposable. An overlay 86 of the cryo-inflation unit handle 78 is also illustrated in FIG. 7.

[0053] The fluid supply 72 will typically comprise a metallic canister or cartridge that may be transported, stored, and optionally, used at room temperature or warmer. Suitable canisters will hold quantities of cryogenic cooling fluid that are sufficient to cool the target tissue to the treatment temperature range for a time in the predetermined time range. Canisters might have volumes between 10 cc and 20 cc (depending in part on flash expansion temperatures of the cryogenic fluid), and may contain between about 8 g to about 25 g of cooling fluid. Conveniently, such canisters are commercially available for use in whipped cream dispensers. As explained above, the canister 72 may be at room temperature or even chilled, but will preferably be warmed by heater 61 prior to use. Suitable cryogenic fluids will preferably be non-toxic and may include liquid nitrous oxide, liquid carbon dioxide, cooled saline and the like. The cryogenic fluid will flow through the supply lumen 18 as a liquid at an elevated pressure and will vaporize at a lower pressure within the first balloon 22. For nitrous oxide, a delivery pressure within the supply lumen 18 will typically be in the range from 600 psi to 1000 psi at a temperature below the associated boiling point. After vaporization, the nitrous oxide gas within the first balloon 22 near its center will have a pressure typically in the range from 50 psi to 150 psi. Preferably, the nitrous oxide gas will have a pressure in the range from 75 psi to 125 psi in a peripheral artery and a range from about 75 psi to 125 psi in a coronary artery.

[0054] The cryotherapy catheter may additionally comprise a thermocouple 90, pressure transducer, capillary tube, thermistor, or the like coupled to the first balloon 22 to determine the pressure and/or temperature of fluid in the first balloon 22. This allows for accurate real time measurements of variables (pressure, temperature) that effect the efficacy and safety of cryotherapy treatments. Moreover, an indicator, such as a warning light or audio signal on the handle overlay 86, may additionally be coupled to the thermocouple 90 to provide a signal to an operator of the system when the first balloon temperature is above 0° C. As cryoplasty often results in adhesion of the cooling balloon to the vessel wall during treatment, an indicator lets an operator of the system know when to safely remove the cooling balloon following treatment so that any potential tearing of the vessel resulting from a frozen cooling balloon is minimized.

[0055] The cryotherapy catheter 10 in FIG. 3 may also monitor the containment of the system (i.e. catheter body 12, supply lumen 18, guidewire lumen 44, balloons 22, 24) prior to any treatment procedures. A pressure transducer 23 is coupled to the exhaust lumen 20 so as to measure a gas pulse pressure therein. The pressure transducer 23 is also coupled to the fluid shutoff valve 68 so as to inhibit flow of cryogenic fluid into the first balloon 22 if the pressure measured by the pressure transducer 23 is below 60 psi or above 80 psi. Alternatively, the fluid shutoff valve 68 may inhibit flow of cryogenic fluid into the first balloon 22 if a pressure decay measured by the pressure transducer 23 is greater than 5 psi. The pretreatment test may be effected by introducing a short pulse of gas, typically nitrous oxide, for a fraction of a second into the first balloon 22 with the supply lumen and exhausting the gas. Containment of the supply lumen 18, balloon 22, guidewire lumen 44, and catheter body 12 are monitored by measuring a gas pulse pressure therein. In the case of a breach in the system, the system will not enter the treatment mode.

[0056] Referring now to FIGS. 8A through 8D, use of the cryotherapy catheter 10 of FIG. 3 for treatment of potential vessel dissections 102 will be described. As illustrated in FIGS. 8A and 8B, catheter 10 will be introduced into a lumen 104 of the blood vessel 100 over a guidewire GW. The blood vessel 100 may be any blood vessel in the patient's vasculature, including veins, arteries, and particularly coronary arteries. The blood vessel 100 will typically be at least partially stenosed 116. The first balloon 22 is positioned within the blood vessel lumen 104 adjacent the potential dissection 102. Cryogenic cooling fluid is introduced into the first balloon 22 (in which it often vaporizes) and exhausted. The second balloon 24 expands to radially engage the vessel wall, as illustrated by FIG. 8C. The vaporized fluid serves to inflate balloon 22 (and expand balloon 24) so as to simultaneously dilate and cool the stenosed blood vessel 100. The blood vessel 100 is cooled to a temperature and for a time sufficient to remodel the blood vessel such that dissections 102 of the blood vessel wall 100 are reduced. The cooling treatment will be directed at all or a portion of a circumferential surface the vessel lumen 104.

[0057] Preferably cooling will reduce and/or inhibit potential dissections so as to produce a “stent-like” angiographic result (i.e. dissection free lumen without the use of a stent), as shown in FIG. 8D. Cooling may alter mechanical properties of the blood vessel 100′ or plaque 116′ thereon so the that fissuring or tearing of the blood vessel wall or plaque thereon is reduced. Particularly, the blood vessel wall 100′ and/or plaque 116′ is solidified so that there is not such a great disparity in compliance between the two. As such, the dilatation force applied by the angioplasty cooling balloon is more evenly distributed so that tearing of the vessel at the junction between the vessel wall and plaque is minimized. Cooling may further enhance bonding between layer of the blood vessel wall 100′ (i.e., intimal layer, medial layer, adventitial layer) so that fissuring or tearing of the blood vessel wall is reduced. Heat transfer will also be inhibited between the first and second balloons 22, 24 by the thermal barrier 26 so as to limit cooling to a desired temperature profile. Additionally, containment of the first and second balloons 22, 24 will be monitored during cooling by the fluid shutoff mechanism (see FIG. 5).

[0058] Suitable cryogenic fluids will preferably be non-toxic and may include liquid nitrous oxide, liquid carbon dioxide, cooled saline and the like. The cryogenic fluid will flow through the supply lumen 18 as a liquid at an elevated pressure and will vaporize at a lower pressure within the first balloon 22. For nitrous oxide, a delivery pressure within the supply lumen 18 will typically be in the range from 600 psi to 1000 psi at a temperature below the associated boiling point. After vaporization, the nitrous oxide gas within the first balloon 22 near its center will have a pressure typically in the range from 50 psi to 150 psi. Preferably, the nitrous oxide gas will have a pressure in the range from 75 psi to 125 psi in a peripheral artery and a range from about 75 psi to 125 psi in a coronary artery.

[0059] Generally, the temperature of the outer surface of the first balloon 22 will be in a range from about 0° C. to about −50° C. Preferably, the temperature of the outer surface of the first balloon 22 in a peripheral artery will be in a range from about 0° C. to about −40° C. The temperature of the outer surface of the second balloon 24 will be in a range from about −3° C. to about −15° C. This will provide a desired treatment temperature in a range from about −3° C. to about −15° C. The tissue is typically maintained at the desired temperature for a time period in the range from about 1 to 60 seconds, preferably being from 20 to 40 seconds. Vessel dissection minimization may be further enhanced by repeating cooling in cycles, typically with from about 1 to 3 cycles, with the cycles being repeated at a rate of about one cycle every 60 seconds.

[0060] Referring now to FIGS. 9A through 9C, the cooling step may also tack or re-attach existing vessel dissections 102 resulting from a prior angioplasty procedure into the blood vessel wall 100 to produce a “stent-like” angiographic result, as shown in FIG. 9C. Cooling may additionally comprise adhering the cooling balloon 24 to the blood vessel or plaque thereon so as to minimize any slippage of the cooling balloon and in so doing further allow for controlled dilatation of the vessel.

[0061] Referring now to FIGS. 10A through 10C, use of the cryotherapy catheter 10 of FIG. 3 for treatment of side branch occlusion in a bifurcated blood vessel 110 will be described. As illustrated in FIG. 10A, the bifurcated blood vessel 110 has a side branch 114 and a main branch 112, the main branch 112 having plaque 116 disposed thereon. In some instances, the side branch 114 may also be at least partially stenosed 116. A catheter 10 is introduced into a lumen of the main branch 112 and a first balloon 22 positioned within the main branch 112 adjacent the plaque 116. Cryogenic cooling fluid is introduced into the balloon 22 and exhausted. A second balloon 24 is expanded to radially engage the main branch lumen, as seen in FIG. 10B, and an inner surface of the main branch 112 is dilated and cooled to a temperature and for a time sufficient to inhibit plaque shift from the main or primary branch 112 into the adjacent or side branch 114. Cooling may alter mechanical properties of the plaque 116′ (i.e. plaque compliance) so that plaque shift from the main branch 112 to the side branch 114 is inhibited, as seen in FIG. 10C. In particular, cooling may solidify the plaque 116′ so that it is less amorphous and thus less susceptible to shifting. Plaque solidification 116′ may further be enhanced by the formation of a temporary ice cap on an orifice of the side branch 114 due to a small portion of the cryoplasty balloon 24 coming into contact with blood cells (not shown).

[0062] A kit 126 including a catheter 10 and instructions for use 128 is illustrated in FIG. 11. Catheter 10 may comprise the dual balloon catheter of FIG. 3 or a catheter having a proximal end, a distal end, and a cooling member near its distal end. Instructions for use 128 may describe any of the associated method steps set forth above for treatment of vessel dissections and/or side branch occlusion. Instructions for use 128 will often be printed, optionally appearing at least in part on a sterile package 130 for balloon catheter 10. In alternative embodiments, instructions for use 128 may comprise a machine readable code, digital or analog data graphically illustrating or demonstrating the use of balloon catheter 10 to treat vessel dissections and/or side branch occlusion. Still further alternatives are possible, including printing of the instructions for use on packaging 132 of kit 126, and the like.

[0063] In the following Experimental sections, protocol and results of human clinical studies are given. In particular, angiographic images show a baseline where a significant amount of plaque is present within a lumen of a vessel wall, particularly the superficial femoral artery or popliteal artery. The effects of cryoplasty dilatation are captured by another set of angiographic images which generally show alleviation of the stenotic condition with a minimum amount of vessel dissection and side branch occlusion.

[0064] Purpose

[0065] Human clinical cases were conducted to evaluate the safety and effectiveness of the CVSi CryoPlasty Catheter and CryoInflation Unit in the dilation of stenotic lesions in diseased superficial femoral and popliteal arteries. Patients with peripheral vascular disease were treated with the CVSi CryoPasty System. This was a non-randomized registry of fourteen (14) patients.

[0066] Patient Selection

[0067] The interventionalists for these cases identified patients with stenotic lesions in the superficial femoral artery (SFA) and popliteal arteries, which were amenable to percutaneous treatment. Eligibility requirements included the following: the patient was at least 18 years of age; the patient had stenotic lesions within the SFA or popliteal artery which required treatment; the target lesion contained a stenosis between 50% and 100%; the patient had a clinical examination within one month prior to treatment including ABI measurement. Patients were excluded if any of the following applied: the patient had an evolving myocardial infarction, or suffered a myocardial infarction within the past 48 hours; the patient was participating currently in another investigational drug or device trial; or the patient suffered a stroke or transient ischemic neurological attack (TIA) within the past two months.

[0068] Equipment

[0069] Equipment used for these cases may be found in any interventional catheterization laboratory (including but not limited to fluoroscopy unit with cine film acquisition; sterile accessories such as sheaths and guidewires). The test equipment was the CVSi CryoPlasty System, which is composed of the CryoPlasty Catheter, CryoInflation Unit and accessories (battery, battery receptacle, nitrous oxide cylinder). The operating parameters of the current cases are treatment time of 50 seconds and surface temperature of −10±5° C.

[0070] Methods

[0071] Procedures used were no different than typical interventional percutaneous transluminal angioplasty (PTA) procedures. The investigators had a thorough understanding of the technical principals, clinical applications, and risks associated with PTA. In addition, training on the CVSi CryoPlasty System and its Instructions For Use were given prior to clinical use of the device. After diagnostic angiography of the target vessel confirmed the presence of a lesion suitable for endovascular therapy, the patients received the following treatment. The patient was pre-treated with conventional doses of heparin and aspirin. Baseline angiographic images were recorded as illustrated in FIGS. 12A through 12L. The operators chose whether or not to predilate the lesion with other percutaneous transluminal devices. If they did predilate, an angiographic image of the interim outcome was recorded. Next, the CVSi CryoPlasty Catheter was advanced across the lesion, and inflated with the CryoInflation Unit. After deflation, the catheter was either repositioned for additional cryoinflations, or removed. At the conclusion of the procedure, final cryoplasty angiograms were recorded as illustrated in FIGS. 12A through 12L.

[0072] Data Collection

[0073] Results of the percutaneous interventions were assessed for acute outcomes and in-hospital adverse events. Baseline and post-cryoplasty dilation angiography were compared in each treated section. In addition, ankle-brachial indexes (ABI) were measured and recorded prior to intervention, 24 hours post-intervention, and at one-month (see Results Table I). ABI is an assessment of flow distal to the treated sections. Technical success was based primarily on the acute angiographic appearance and flow characteristics (24-hour ABI) immediately post-cryoplasty dilation compared to the baseline image and the pre-procedural ABI, respectively.

[0074] Conclusions and Discussion

[0075] Procedural safety was demonstrated by the absence of any incidence of acute serious adverse events or acute percutaneous access site and hemorrhagic adverse events. Investigators were able to use the CryoPlasty device for primary treatment (i.e. were able to cross severe stenosis and dilate the lesion with the CVSi device without predilation) in ten of the fourteen cases (71%). Twelve of the fourteen cases (86%) were technical successes based on acute angiographic appearance and flow characteristics, with <30% residual stenosis by visual assessment of the final angiographic results in the treated segments. Within that 12 patient subset of technical success, the 24-hour post-procedural ABI showed improved blood flow to the lower extremity compared to the pre-procedural measurement. Bail-out stenting was not required in any of the cryotreated segments. Some observations that were noted that contributed to the high technical success rate were: minimum amount of vessel dissection post-CryoPlasty dilation (also known as “vessel annealing”) and maintained patency of the side branch and collateral vessels at the treated segments (no/minimal plaque shift), as illustrated in FIGS. 12A through 12L and the ABI data in Results Table I.

[0076] The registry demonstrated the safety and effectiveness of the CVSi CryoPlasty System in the dilation of stenotic lesions in diseased vessels, and brought to light some distinct advantages of CryoPlasty over conventional PTA dilation that often requires bail-out stenting due to dissection or poor flow characteristics.

[0077] Purpose

[0078] Five patients with coronary artery disease were treated with the CVSi CryoPlasty System to evaluate the safety and effectiveness of the CVSi System in the treatment of de novo and in-stent restenotic lesions. Patients were assessed for acute outcomes and in-hospital adverse events.

[0079] Patient Selection

[0080] Patients with either a de novo or in-stent restenosis lesion in a coronary artery that was amenable to percutaneous treatment were identified by experienced intervention-alists. Lesion inclusion criteria was very broad and included very complex lesions, such as, lesion lengths ranging from 10 mm to 25 mm, stenoses from 90% to total occlusions, and calcified, fibrotic, and soft plaque. Other contributing factors were severe access angulations, high cholesterol, diabetes, and smoking.

[0081] Methods

[0082] After diagnostic angiography of the target vessel confirmed the presence of a lesion suitable for endovascular therapy, each patient received the following treatment. The patient was pretreated with conventional doses of heparin and aspirin. Baseline angiographic images were recorded as illustrated in FIGS. 13A through 13E. The operator could choose whether or not to predilate the lesion with conventional transluminal percutaneous procedures. Next, the CVSi CryoPlasty Catheter was advanced across the lesion, and the balloon inflated one or more times with the CVSi CryoInflation Unit. After the final cryotreatment, the balloon was deflated and the CVSi Catheter was removed. At the conclusion of the procedure, a final angiography was recorded as illustrated in FIGS. 13A through 13E.

[0083] Results

[0084] The operators were able to use the CryoPlasty device for primary therapy (i.e. were able to cross severe stenosis and dilate the lesion with the CVSi device without predilation) in all the lesions (100%). Additionally, the CryoPlasty device provided good tracking in vessels with >90° turns. A total of six lesions were treated (including one patient who had two lesions in one vessel). All of the lesions treated had <30% residual angiographic stenosis in the dilated artery, as illustrated in FIGS. 13A through 13E and the Results Table II. Patients tolerated the procedure well (i.e. no patient sensation of treatment) and four to six week clinical follow-up reports 0% major adverse cardiac events (MACE).

[0085] Conclusion

[0086] Cryogenic treatment of atherosclerotic stenoses may effectively limit restenosis in both coronary and peripheral arteries, as well as minimize the amount of vessel dissections and plaque shift post-CryoPlasty dilation. Clinical trial data illustrates that CryoPlasty may represent a simple solution to one of the most vexing problems experienced to date in interventional therapy.

[0087] Although certain preferred embodiments and methods have been disclosed herein, it will be apparent from the foregoing disclosure to those skilled in the art that variations and modifications of such embodiments and methods may be made without departing from the true spirit and scope of the invention. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.