Abstract:
Methods and systems for treating patients suffering from or at risk of cardiac arrhythmias rely on the injection of amiodarone and other class III anti-arrhythmic drugs into the perivascular space surrounding a cardiac blood vessel. Injection may be achieved using intravascular catheters which advance needles radially outward from a blood vessel lumen or by transmyocardial injection from an epicardial surface of the heart.

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS  
       [0001]     This is an application claiming the benefit under 35 USC 119(e) of U.S. Provisional Patent Application Ser. No. 60/503,560 (Attorney Docket No. 021621-001900), filed Sep. 16, 2003, the full disclosure of which is incorporated herein by reference. 
     
    
     BACKGROUND OF THE INVENTION  
       [0002]     1. Filed of the Invention  
         [0003]     The present invention relates generally to medical methods and devices. More particularly, the present invention relates to methods and systems for treating and inhibiting cardiac arrhythmias by the direct injection of a class III anti-arrhythmic drug into cardiac tissue.  
         [0004]     Abnormal heart rhythms are referred to generally as arrhythmias. Arrhythmias may be characterized by increased heart rates, referred to as tachycardias, or by slower heart rates, referred to as bradycardias. Arrhythmias may occur in the atria, ventricles, or both. Generally, ventricular tachycardias are the most dangerous to the patient, although atrial arrhythmias are also problematic.  
         [0005]     A variety of intravascular and pharmaceutical therapies have been developed for treating cardiac arrhythmias. For example, cardiac ablation catheters have been developed for altering the conductive pathways on the endocardial surfaces within the heart chambers. Alternatively, a variety of sodium channel blockers, calcium channel blockers, and beta blockers are now available for drug-based inhibition of cardiac arrhythmias and related conditions. Although both the catheter-based and pharmaceutical approaches have been effective, each suffer form shortcomings, and alternative and improved treatment modalities remain desirable.  
         [0006]     Of particular interest to the present invention, amiodarone has been an anti-arrhythmic drug in wide spread use since the 1970s. It is a class III anti-arrhythmic drug, and is widely used in the treatment of ventricular tachycardias. It also possesses class I, class II, and class IV actions which affords a unique pharmacological and anti-arrhythmic profile. While amiodarone has been found particularly suitable for treating patients after acute myocardial infarction and/or after cardiac surgery during the period where patients are at increased risk of having fatal arrhythmias, the drug has significant side effects that make systemic treatment difficult. Moreover, as the onset of effectiveness of the drug is generally slow, it can be difficult to achieve the desired pharmakinetic profiles.  
         [0007]     For these reasons, it would be desirable to provide improved methods and systems for delivering amiodarone and other class III anti-arrhythmic agents to patients, particularly to patients who have recently suffered an acute myocardial infarction or have recently undergone cardiac surgery. It would be particularly desirable if such methods and systems delivered the amiodarone and/or other agents directly to cardiac tissue, preferably to most or all tissues which can benefit from such drug treatment. Such methods and systems will preferably be catheter-based and permit introduction of the amiodarone and other agents into cardiac and other tissue near the coronary and peripheral vasculature, including both arteries and veins, should further provide delivery of such agents to precisely controlled locations within or adjacent to the target tissues, and should still further provide for the direct delivery of such agents into tissue without dilution in the systemic circulation. Further preferably, the methods and system should allow for the injection of the amiodarone and other agents in the tissue surrounding the coronary and peripheral vasculature in regions which permit the rapid and wide spread migration and distribution of the agents to remote regions of cardiac tissue in amounts and at levels sufficient to provide the desired therapeutic benefits. At least some of these objectives will be met by the inventions described hereinafter.  
       BRIEF SUMMARY OF THE INVENTION  
       [0008]     The present invention provides improved methods and systems for treating patients at risk of or suffering from cardiac arrhythmias, including tachycardias, bradycardias, and other arrhythmias which occur in either or both of the ventricles and/or atria. Methods and systems will be particularly suitable for treating patients who have recently suffered from an acute myocardial infarction (AMI), who have undergone cardiac surgery, including open chest surgery, closed chest surgery, stopped heart surgery, beating heart surgery, and variations thereof. Methods and systems of the present invention rely on the direct delivery of anti-arrhythmic drugs and biological agents, including cells, usually class III anti-arrhythmic drugs, particularly amiodarone, to cardiac tissue, usually employing a catheter for injection of the drugs through the endothelium of a cardiac artery or vein into the perivascular space beyond the outside of the external elastic lamina so that the drug is able to permeate through the vessel wall and into the adventitia.  
         [0009]     The preferred amiodarone drugs utilized in the methods of the present invention are described in detail in Sloskey (1883) Clin. Pharm. 2:330-40 and Doggrell (2001) Expert Opin Pharmacother. 2:1877-90. Other class III anti-arrhythmic drugs and still other anti-arrhythmics useful in the present invention are well described in the medical literature, e.g., in Nacarelli et al. (2003) Am. J. Cardiol. 91:150-260.  
         [0010]     A particular advantage of the present invention is the ability to deliver the class III anti-arrhythmic drug widely throughout the cardiac tissue with only one or a limited number of injections. It is presently believed that such wide distribution of the drug is best achieved when the drug is delivered into the perivascular space at a depth (measured from the interior of the associated blood vessel) which is within an annular space or envelope having a width from 10% to 50% of the vessel diameter measured from the exterior of the vessel. Typically, the annular envelope around the blood vessel into which the drug is to be injected will have a width in the range from 0.1 mm to 5 mm, preferably from 0.2 mm to 3 mm, with the greater widths corresponding to larger vessel diameters.  
         [0011]     It is further believed that the wide distribution of the drug throughout the cardiac tissue may result from entry of the drug into the lymphatic system which surrounds the individual blood vessels. While this understanding of the potential mechanism of action may help understand and define the present invention, the present invention in no way depends on the accuracy of understanding this mechanism of distribution.  
         [0012]     The methods and systems of the present invention preferably utilize injection from an intravascular device in order to deliver the class III anti-arrhythmic drugs to the perivascular space as defined above. Use of intravascular delivery is particularly preferred with those patients who are not undergoing procedures which would result in either open chest, intercostal, thoracoscopic or other direct access to the epicardial surface. One such direct access is provided, however, the methods of the present invention may be performed by injection transmyocardially from an epicardial surface to the target perivascular space surrounding the blood vessel. Accurate positioning of the needle may be achieved using, for example, transesophogeal imaging, flouroscopic imaging, or the like.  
         [0013]     In particular, the preferred intravascular injection methods of the present invention comprise injecting a class III anti-arrhythmic drug into the adventitial and perivascular tissues by advancing a needle from a lumen of a cardiac blood vessel to the target location beyond the endothelium. The class III anti-arrhythmic drug is then delivered through the needle to the target tissues. The needle is at least into the perivascular space beyond the outside of the endothelium of the blood vessel, and usually is advanced into the adventitia surrounding the blood vessel.  
         [0014]     The class III anti-arrhythmic drugs will be injected under conditions and in an amount sufficient to permeate circumferentially around the perivascular space of the blood vessel and into the adventitia over an axial length of the blood vessel of at least about 1 cm, usually at least about 2 cm, and more usually at least 3 cm, 5 cm, 10 cm, or greater. Thus, the needle may be advanced in a radial direction to a depth in the tissue surrounding the blood vessel equal to at least 10% of the mean luminal diameter of the blood vessel at the site of direct injection, more typically being in the range from 10% to 150%, usually from 10% to 50% of the mean luminal diameter.  
         [0015]     Systems according to the present invention for treating a patient suffering from a cardiac arrhythmia comprise an amount of a class III anti-arrhythmic drug, particularly an amiodarone, sufficient to treat the heart and an intravascular catheter having a needle for injecting the drug into a location beyond the endothelium of the blood vessel as described above. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0016]      FIG. 1A  is a schematic, perspective view of an intravascular injection catheter suitable for use in the methods and systems of the present invention.  
         [0017]      FIG. 1B  is a cross-sectional view along line  1 B- 1 B of  FIG. 1A .  
         [0018]      FIG. 1C  is a cross-sectional view along line  1 C- 1 C of  FIG. 1A .  
         [0019]      FIG. 2A  is a schematic, perspective view of the catheter of  FIGS. 1A-1C  shown with the injection needle deployed.  
         [0020]      FIG. 2B  is a cross-sectional view along line  2 B- 2 B of  FIG. 2A .  
         [0021]      FIG. 3  is a schematic, perspective view of the intravascular catheter of  Figs. 1A-1C  injecting drug into an adventitial space surrounding a coronary blood vessel in accordance with the methods of the present invention.  
         [0022]      FIG. 4  is a schematic, perspective view of another embodiment of an intravascular injection catheter useful in the methods of the present invention.  
         [0023]      FIG. 5  is a schematic, perspective view of still another embodiment of an intravascular injection catheter useful in the methods of the present invention, as inserted into a patient&#39;s vasculature.  
         [0024]      FIGS. 6A and 6B  are schematic views of other embodiments of an intravascular injection catheter useful in the methods of the present invention (in an unactuated condition) including multiple needles.  
         [0025]      FIG. 7  is a schematic view of yet another embodiment of an intravascular injection catheter useful in the methods of the present invention (in an unactuated condition).  
         [0026]      FIG. 8  is a perspective view of a needle injection catheter useful in the methods and systems of the present invention.  
         [0027]      FIG. 9  is a cross-sectional view of the catheter  FIG. 8  shown with the injection needle in a retracted configuration.  
         [0028]      FIG. 10  is a cross-sectional view similar to  FIG. 9 , shown with the injection needle laterally advanced into luminal tissue for the delivery of drug according to the present invention. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0029]     The present invention provides methods and systems for treating patients at risk of or suffering from cardiac arrhythmias. In particular, these patients will have been diagnosed or otherwise determined to be suffering from a tachycardia, bradycardia, or other cardiac arrhythmia relating to aberrant electrical conduction within the heart. In other cases, however, patients who have recently suffered from an acute myocardial infarction (AMI) or who have or will be undergoing cardiac surgery may also be candidates for receiving treatment according to the present invention in order to reduce the risk associated with future cardiac arrhythmias.  
         [0030]     The present invention will preferably utilize microfabricated devices and methods for intravascular injection of the drug. The following description provides several representative embodiments of microfabricated needles (microneedles) and macroneedles suitable for the delivery of the drug into a perivascular space or adventitial tissue. The perivascular space is the potential space between the outer surface and the endothelium or “vascular wall” of either an artery or vein. The microneedle is usually inserted substantially normal to the wall of a vessel (artery or vein) to eliminate as much trauma to the patient as possible. Until the microneedle is at the site of an injection, it is positioned out of the way so that it does not scrape against arterial or venous walls with its tip. Specifically, the microneedle remains enclosed in the walls of an actuator or sheath attached to a catheter so that it will not injure the patient during intervention or the physician during handling. When the injection site is reached, movement of the actuator along the vessel terminated, and the actuator is operated to cause the microneedle to be thrust outwardly, substantially perpendicular to the central axis of a vessel, for instance, in which the catheter has been inserted.  
         [0031]     As shown in  FIGS. 1A-2B , a microfabricated intravascular catheter  10  includes an actuator  12  having an actuator body  12   a  and central longitudinal axis  12   b . The actuator body more or less forms a C-shaped outline having an opening or slit  12   d  extending substantially along its length. A microneedle  14  is located within the actuator body, as discussed in more detail below, when the actuator is in its unactuated condition (furled state) ( FIG. 1B ). The microneedle is moved outside the actuator body when the actuator is operated to be in its actuated condition (unfurled state) ( FIG. 2B ).  
         [0032]     The actuator may be capped at its proximal end  12   e  and distal end  12   f  by a lead end  16  and a tip end  18 , respectively, of a therapeutic catheter  20 . The catheter tip end serves as a means of locating the actuator inside a blood vessel by use of a radio opaque coatings or markers. The catheter tip also forms a seal at the distal end  12   f  of the actuator. The lead end of the catheter provides the necessary interconnects (fluidic, mechanical, electrical or optical) at the proximal end  12   e  of the actuator.  
         [0033]     Retaining rings  22   a  and  22   b  are located at the distal and proximal ends, respectively, of the actuator. The catheter tip is joined to the retaining ring  22   a , while the catheter lead is joined to retaining ring  22   b . The retaining rings are made of a thin, on the order of 10 to 100 microns (μm), substantially rigid material, such as Parylene (types C, D or N), or a metal, for example, aluminum, stainless steel, gold, titanium or tungsten. The retaining rings form a rigid substantially “C”- shaped structure at each end of the actuator. The catheter may be joined to the retaining rings by, for example, a butt-weld, an ultra sonic weld, integral polymer encapsulation or an adhesive such as an epoxy.  
         [0034]     The actuator body further comprises a central, expandable section  24  located between retaining rings  22   a  and  22   b . The expandable section  24  includes an interior open area  26  for rapid expansion when an activating fluid is supplied to that area. The central section  24  is made of a thin, semi-rigid or rigid, expandable material, such as a polymer, for instance, Parylene (types C, D or N), silicone, polyurethane or polyimide. The central section  24 , upon actuation, is expandable somewhat like a balloon-device.  
         [0035]     The central section is capable of withstanding pressures of up to about 100 psi upon application of the activating fluid to the open area  26 . The material from which the central section is made of is rigid or semi-rigid in that the central section returns substantially to its original configuration and orientation (the unactuated condition) when the activating fluid is removed from the open area  26 . Thus, in this sense, the central section is very much unlike a balloon which has no inherently stable structure.  
         [0036]     The open area  26  of the actuator is connected to a delivery conduit, tube or fluid pathway  28  that extends from the catheter&#39;s lead end to the actuator&#39;s proximal end. The activating fluid is supplied to the open area via the delivery tube. The delivery tube may be constructed of Teflon© or other inert plastics. The activating fluid may be a saline solution or a radio-opaque dye.  
         [0037]     The microneedle  14  may be located approximately in the middle of the central section  24 . However, as discussed below, this is not necessary, especially when multiple microneedles are used. The microneedle is affixed to an exterior surface  24   a  of the central section. The microneedle is affixed to the surface  24   a  by an adhesive, such as cyanoacrylate. Alternatively, the microneedle maybe joined to the surface  24   a  by a metallic or polymer mesh-like structure  30  (See  FIG. 4F ), which is itself affixed to the surface  24   a  by an adhesive. The mesh-like structure may be-made of, for instance, steel or nylon.  
         [0038]     The microneedle includes a sharp tip  14   a  and a shaft  14   b . The microneedle tip can provide an insertion edge or point. The shaft  14   b  can be hollow and the tip can have an outlet port  14   c , permitting the injection of a pharmaceutical or drug into a patient. The microneedle, however, does not need to be hollow, as it may be configured like a neural probe to accomplish other tasks.  
         [0039]     As shown, the microneedle extends approximately perpendicularly from surface  24   a . Thus, as described, the microneedle will move substantially perpendicularly to an axis of a vessel or artery into which has been inserted, to allow direct puncture or breach of vascular walls.  
         [0040]     The microneedle further includes a pharmaceutical or drug supply conduit, tube or fluid pathway  14   d  which places the microneedle in fluid communication with the appropriate fluid interconnect at the catheter lead end. This supply tube may be formed integrally with the shaft  14   b , or it may be formed as a separate piece that is later joined to the shaft by, for example, an adhesive such as an epoxy.  
         [0041]     The needle  14  may be a 30-gauge, or smaller, steel needle. Alternatively, the microneedle may be microfabricated from polymers, other metals, metal alloys or semiconductor materials. The needle, for example, may be made of Parylene, silicon or glass. Microneedles and methods of fabrication are described in U.S. application Ser. No. 09/877,653, filed Jun. 8, 2001, entitled “Microfabricated Surgical Device”, assigned to the assignee of the subject application, the entire disclosure of which is incorporated herein by reference.  
         [0042]     The catheter  20 , in use, is inserted through an artery or vein and moved within a patient&#39;s vasculature, for instance, a vein  32 , until a specific, targeted region  34  is reaches (see  FIG. 3 ). The targeted region  34  may be the site of tissue damage or more usually will be adjacent the sites typically being within 100 mm or less to allow migration of the therapeutic agents. As is well known in catheter-based interventional procedures, the catheter  20  may follow a guide wire  36  that has previously been inserted into the patient. Optionally, the catheter  20  may also follow the path of a previously-inserted guide catheter (not shown) that encompasses the guide wire.  
         [0043]     During maneuvering of the catheter  20 , well-known methods of fluoroscopy or magnetic resonance imaging (MRI) can be used to image the catheter and assist in positioning the actuator  12  and the microneedle  14  at the target region. As the catheter is guided inside the patient&#39;s body, the microneedle remains unfurled or held inside the actuator body so that no trauma is caused to the vascular walls.  
         [0044]     After being positioned at the target region  34 , movement of the catheter is terminated and the activating fluid is supplied to the open area  26  of the actuator, causing the expandable section  24  to rapidly unfurl, moving the microneedle  14  in a substantially perpendicular direction, relative to the longitudinal central axis  12   b  of the actuator body  12   a , to puncture a vascular wall  32   a . It may take only between approximately 100 milliseconds and two seconds for the microneedle to move from its furled state to its unfurled state.  
         [0045]     The ends of the actuator at the retaining rings  22   a  and  22   b  remain rigidly fixed to the catheter  20 . Thus, they do not deform during actuation. Since the actuator begins as a furled structure, its so-called pregnant shape exists as an unstable buckling mode. This instability, upon actuation, produces a large-scale motion of the microneedle approximately perpendicular to the central axis of the actuator body, causing a rapid puncture of the vascular wall without a large momentum transfer. As a result, a microscale opening is produced with very minimal damage to the surrounding tissue. Also, since the momentum transfer is relatively small, only a negligible bias force is required to hold the catheter and actuator in place during actuation and puncture.  
         [0046]     The microneedle, in fact, travels so quickly and with such force that it can enter perivascular tissue  32   b  as well as vascular tissue. Additionally, since the actuator is “parked” or stopped prior to actuation, more precise placement and control over penetration of the vascular wall are obtained.  
         [0047]     After actuation of the microneedle and delivery of the cells to the target region via the microneedle, the activating fluid is exhausted from the open area  26  of the actuator, causing the expandable section  24  to return to its original, furled state. This also causes the microneedle to be withdrawn from the vascular wall. The microneedle, being withdrawn, is once again sheathed by the actuator.  
         [0048]     Various microfabricated devices can be integrated into the needle, actuator and catheter for metering flows, capturing samples of biological tissue, and measuring pH. The device  10 , for instance, could include electrical sensors for measuring the flow through the microneedle as well as the pH of the pharmaceutical being deployed. The device  10  could also include an intravascular ultrasonic sensor (IVUS) for locating vessel walls, and fiber optics, as is well known in the art, for viewing the target region. For such complete systems, high integrity electrical, mechanical and fluid connections are provided to transfer power, energy, and pharmaceuticals or biological agents with reliability.  
         [0049]     By way of example, the microneedle may have an overall length of between about 200 and 3,000 microns (μm). The interior cross-sectional dimension of the shaft  14   b  and supply tube  14   d  may be on the order of 20 to 250 um, while the tube&#39;s and shaft&#39;s exterior cross-sectional dimension may be between about 100 and 500 μm. The overall length of the actuator body may be between about 5 and 50 millimeters (mm), while the exterior and interior cross-sectional dimensions of the actuator body can be between about 0.4 and 4 mm, and 0.5 and 5 mm, respectively. The gap or slit through which the central section of the actuator unfurls may have a length of about 4-40 mm, and a cross-sectional dimension of about 100-500 μm. The diameter of the delivery tube for the activating fluid may be about 100 μm. The catheter size may be between 1.5 and 15 French (Fr).  
         [0050]     Variations of the invention include a multiple-buckling actuator with a single supply tube for the activating fluid. The multiple-buckling actuator includes multiple needles that can be inserted into or through a vessel wall for providing injection at different locations or times.  
         [0051]     For instance, as shown in  FIG. 4 , the actuator  120  includes microneedles  140  and  142  located at different points along a length or longitudinal dimension of the central, expandable section  240 . The operating pressure of the activating fluid is selected so that the microneedles move at the same time. Alternatively, the pressure of the activating fluid may be selected so that the microneedle  140  moves before the microneedle  142 .  
         [0052]     Specifically, the microneedle  140  is located at a portion of the expandable section  240  (lower activation pressure) that, for the same activating fluid pressure, will buckle outwardly before that portion of the expandable section (higher activation pressure) where the microneedle  142  is located. Thus, for example, if the operating pressure of the activating fluid within the open area of the expandable section  240  is two pounds per square inch (psi), the microneedle  140  will move before the microneedle  142 . It is only when the operating pressure is increased to four psi, for instance, that the microneedle  142  will move. Thus, this mode of operation provides staged buckling with the microneedle  140  moving at time t 1 , and pressure p 1 , and the microneedle  142  moving at time t 2  and P 2 , with t 1 , and p 1 , being less than t 2  and P 2 , respectively.  
         [0053]     This sort of staged buckling can also be provided with different pneumatic or hydraulic connections at different parts of the central section  240  in which each part includes an individual microneedle.  
         [0054]     Also, as shown in  FIG. 5 , an actuator  220  could be constructed such that its needles  222  and  224 A move in different directions. As shown, upon actuation, the needles move at angle of approximately 90° to each other to puncture different parts of a vessel wall. A needle  224 B (as shown in phantom) could alternatively be arranged to move at angle of about 180° to the needle  224 A.  
         [0055]     Moreover, as shown in  FIG. 6A , in another embodiment, an actuator  230  comprises actuator bodies  232  and  234  including needles  236  and  238 , respectively, that move approximately horizontally at angle of about 180° to each other. Also, as shown in  FIG. 7B , an actuator  240  comprises actuator bodies  242  and  244  including needles  242  and  244 , respectively, that are configured to move at some angle relative to each other than 90° or 180°. The central expandable section of the actuator  230  is provided by central expandable sections  237  and  239  of the actuator bodies  232  and  234 , respectively. Similarly, the central expandable section of the actuator  240  is provided by central expandable sections  247  and  249  of the actuator bodies  242  and  244 , respectively.  
         [0056]     Additionally, as shown in  FIG. 7 , an actuator  250  may be constructed that includes multiple needles  252  and  254  that move in different directions when the actuator is caused to change from the unactuated to the actuated condition. The needles  252  and  254 , upon activation, do not move in a substantially perpendicular direction relative to the longitudinal axis of the actuator body  256 .  
         [0057]     The above catheter designs and variations thereon, are described in published U.S. Patent Application Nos. 2003/005546 and 2003/0055400, the full disclosures of which are incorporated herein by reference. Co-pending application Ser. No. 10/350,314, assigned to the assignee of the present application, describes the ability of substances delivered by direct injection into the adventitial and pericardial tissues of the heart to rapidly and evenly distribute within the heart tissues, even to locations remote from the site of injection. The full disclosure of that co-pending application is also incorporated herein by reference. An alternative needle catheter design suitable for delivering the drug of the present invention will be described below. That particular catheter design is described and claimed in co-pending application Ser. No. 10/393,700 (Attorney Docket No. 021621-001500 U.S.), filed on Mar. 19, 2003, the full disclosure of which is incorporated herein by reference.  
         [0058]     Referring now to  FIG. 8 , a needle injection catheter  310  constructed in accordance with the principles of the present invention comprises a catheter body  312  having a distal end  314  and a proximal  316 . Usually, a guide wire lumen  313  will be provided in a distal nose  352  of the catheter, although over-the-wire and embodiments which do not require guide wire placement will also be within the scope of the present invention. A two-port hub  320  is attached to the proximal end  316  of the catheter body  312  and includes a first port  322  for delivery of a hydraulic fluid, e.g., using a syringe  324 , and a second port  326  for delivering the pharmaceutical agent, e.g., using a syringe  328 . A reciprocatable, deflectable needle  330  is mounted near the distal end of the catheter body  312  and is shown in its laterally advanced configuration in  FIG. 8 .  
         [0059]     Referring now to  FIG. 9 , the proximal end  314  of the catheter body  312  has a main lumen  336  which holds the needle  330 , a reciprocatable piston  338 , and a hydraulic fluid delivery tube  340 . The piston  338  is mounted to slide over a rail  342  and is fixedly attached to the needle  330 . Thus, by delivering a pressurized hydraulic fluid through a lumen  341  tube  340  into a bellows structure  344 , the piston  338  may be advanced axially toward the distal tip in order to cause the needle to pass through a deflection path  350  formed in a catheter nose  352 .  
         [0060]     As can be seen in  FIG. 10 , the catheter  310  may be positioned in a coronary blood vessel BV, over a guide wire GW in a conventional manner. Distal advancement of the piston  338  causes the needle  330  to advance into luminal tissue T adjacent to the catheter when it is present in the blood vessel. The drug may then be introduced through the port  326  using syringe  328  in order to introduce a plume P of drug in the cardiac tissue, as illustrated in  FIG. 10 . The plume P will be within or adjacent to the region of tissue damage as described above.  
         [0061]     The needle  330  may extend the entire length of the catheter body  312  or, more usually, will extend only partially in drug delivery lumen  337  in the tube  340 . A proximal end of the needle can form a sliding seal with the lumen  337  to permit pressurized delivery of the drug through the needle.  
         [0062]     The needle  330  will be composed of an elastic material, typically an elastic or super elastic metal, typically being nitinol or other super elastic metal. Alternatively, the needle  330  could be formed from a non-elastically deformable or malleable metal which is shaped as it passes through a deflection path. The use of non-elastically deformable metals, however, is less preferred since such metals will generally not retain their straightened configuration after they pass through the deflection path.  
         [0063]     The bellows structure  344  may be made by depositing by parylene or another conformal polymer layer onto a mandrel and then dissolving the mandrel from within the polymer shell structure. Alternatively, the bellows  344  could be made from an elastomeric material to form a balloon structure. In a still further alternative, a spring structure can be utilized in, on, or over the bellows in order to drive the bellows to a closed position in the absence of pressurized hydraulic fluid therein.  
         [0064]     After the drug is delivered through the needle  330 , as shown in  FIG. 10 , the needle is retracted and the catheter either repositioned for further agent delivery or withdrawn. In some embodiments, the needle will be retracted simply by aspirating the hydraulic fluid from the bellows  344 . In other embodiments, needle retraction may be assisted by a return spring, e.g., locked between a distal face of the piston  338  and a proximal wall of the distal tip  352  (not shown) and/or by a pull wire attached to the piston and running through lumen  341 .  
         [0065]     While the above is a complete description of the preferred embodiments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.