Abstract:
A method is disclosed for revascularizing ischemic tissue by creating a continuous channel from a non-ischemic to an ischemic area of the myocardium. A penetrating tip at the distal end of a catheter is advanced through specific areas of the myocardium. Healing of the channel results in angiogenesis of new blood vessels along its path, thus establishing a continuous vascular connection between the vascular beds in the non-ischemic myocardium and in the ischemic myocardium. The channel may originate from a blood vessel on the heart or from the inner or outer surface thereof. Preferably, the channel comprises a split path, formed by separating a thin layer of myocardium rather than creating a hole therethrough. Growth of the new blood vessels is further enhanced by placing an angiogenic growth factor in at least a portion of the channel.

Description:
RELATED APPLICATION DATA  
       [0001]    This application claims priority on U.S. Provisional Patent Application S/N [not-yet-assigned; Lyon &amp; Lyon attorney docket 259/237], filed Dec. 12, 2000, the disclosure of which is fully incorporated herein by reference. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    The invention relates to methods and medical apparati used to revascularize ischemic tissue. In particular, the invention relates to the revascularization of ischemic myocardial tissue.  
         BACKGROUND  
         [0003]    A number of different diseases can affect the human heart. Coronary artery disease, for example, is caused by a buildup of plaque in coronary arteries. This can result in the blockage of blood flow within one or more arteries of the heart, which may lead to ischemia (i.e., lack of oxygen) in tissues normally supplied with blood through the blocked arteries. Ischemic tissue is tissue at a low oxygen state, usually due to an obstruction of the arterial blood supply or inadequate blood flow that leads to hypoxia in the tissue; non-ischemic tissue is tissue at a normal oxygen state. Coronary arteries seem to be particularly vulnerable both to gradual plaque buildup and to a catastrophic heart attack when a plaque ruptures and triggers a total thrombotic occlusion of the artery. If the occlusion remains for a period of more than about six hours, myocardium (heart muscle) that is devoid of oxygenated blood flow will die.  
           [0004]    Discrete plaque formations may be effectively treated by percutaneous transluminal coronary angioplasty (PTCA). In PTCA, a catheter incorporating an inflatable balloon at the distal end is inserted into the patient&#39;s femoral artery and advanced up the aorta and into the diseased coronary artery. After positioning the balloon within the obstruction, the balloon is inflated, compressing the plaque and stretching the artery wall. The action of the balloon results in an enlargement in the restricted area, or stenosis, providing increased blood flow to the area of myocardium fed by that artery. Plaque may also form in a diffuse manner within a vessel and is much more difficult to treat with PTCA. A gradual build up of plaque in an artery, whether diffuse or discrete, reduces the flow of blood and prevents the myocardium in the affected area from contracting. Often the muscle tissue is still alive if a minimal quantity of blood flow is maintained. This type of ischemic myocardial tissue is characterized as dormant, wherein, if blood flow to the tissue is re-established, a portion or all of its contractile function may be restored.  
           [0005]    One treatment that has been attempted to restore blood flow to dormant myocardial tissue is percutaneous myocardial revascularization (PMR). In one version of PMR, a catheter incorporating an optical fiber is threaded from the femoral artery of the patient into a chamber of the heart, such as the left ventricle. The tip of the fiber is placed against the inner surface of the ventricle in a location of the affected myocardium. A high power laser is pulsed through the fiber, ablating a portion of myocardial tissue and forming a discrete channel approximately one millimeter in diameter and several millimeters deep in the myocardium. Generally, channels formed by this process run perpendicular to the inner surface of the ventricle. The process is repeated in a square grid pattern of about one centimeter in the area of targeted ischemic tissue. An example of the resulting channel formation is illustrated in FIG. 1.  
           [0006]    Originally, PMR was thought to perfusion direct perfusion of the myocardial tissue with oxygenated blood from a chamber of the heart. Many patients treated in this manner reported a decrease in pain upon exertion. Further investigation, however, has shown that the channels actually clot off and heal with formation of scar tissue, resulting in no direct blood flow through the channels. Interestingly, localized new arteries and arterioles were seen in close proximity encircling each channel. From these observations it was then theorized that these new blood vessels, formed by a process during wound healing called angiogenesis, were the actual source of patient improvement. In angiogenesis, tissue revascularizes by developing new blood vessels near the site of an injury. Tissue injury that stimulates angiogenesis can be caused by any type of damage to the tissue in which energy is applied to it by means including mechanical, electromagnetic, thermal (hot or cold), chemical, nuclear radiation, and biological. It is now believed that macrophages at the surface of a wound express angiogenic growth factors that promote revascularization in wound healing. An angiogenic growth factor is a substance that causes proliferation of new blood vessels by angiogenesis.  
           [0007]    A promising new genre of therapeutic agents are termed “gene therapy” agents. The therapeutic agents supplement the normal angiogenic growth factors that are present during normal wound healing. Gene therapy is a technique where DNA is inserted directly into cells to replace, alter, or supplement a gene within the cell. One such gene therapy promotes angiogenesis in an affected heart muscle. The therapy may simply comprise delivering the angiogenic protein, such as vascular endothelial growth factor (VEGF). Alternately, placement of genetic material that manufactures the protein in-situ may be used—for example, the use of viral vectors to transfer genetic material to target cells. This method involves the use of incorporating heterologous DNA sequences into the genome of the virus. Additionally, both RNA and DNA recombinant viruses have been employed.  
           [0008]    Recently, a placebo-controlled clinical study of PMR showed equal or superior results in patients who were treated with the sham procedure compared with patients who actually received PMR. This indicates that even though new blood vessels were formed, they were ineffective in improving perfusion to the ischemic tissue; thus, the placebo effect was the primary factor for the apparent improvement. It is theorized that the failure of PMR to produce results better than the sham procedure is because the new vessels that are formed within the ischemic tissue are not supplied with oxygenated blood from outside the ischemic tissue. Many variations of laser PMR have been proposed, however, all rely on the placement of channels in grid patterns within the ischemic area. For example, U.S. Pat. No. 6,053,911 to Ryan et al., the contents of which are fully incorporated herein by reference, teaches a method of transvascular transmyocardial revascularization (TMR). In this method, a channel originates from a coronary blood vessel and enters the myocardium, traversing it in a direction substantially parallel to the walls of the heart. Because these channels must originate from coronary blood vessels, they are limited as to their positioning and orientation.  
           [0009]    Despite the existing techniques for myocardial revascularization, there remains a need for an effective method and apparatus that will take advantage of the phenomenon of angiogenesis to provide actual and useful revascularization of ischemic myocardial tissue.  
         SUMMARY OF THE INVENTION  
         [0010]    Methods and apparatus are disclosed for revascularizing ischemic tissue by creating a continuous channel from an area of the myocardium having an adequate arterial blood supply (non-ischemic) to an area that has inadequate blood supply (ischemic). A resulting network of new blood vessels are formed within the affected myocardium that are adequately supplied with blood from healthy myocardial tissue. In this manner, stimulating angiogenesis is provided in the needed locations, while minimizing or eliminating the distribution of angiogenic growth factors to undesirable areas of the body.  
           [0011]    One method for delivery of angiogenic growth factors according to one aspect of the invention includes advancing a catheter through a patient&#39;s vasculature to a coronary artery or coronary vein. A penetrating tip at the distal end of the catheter is pushed through the vessel wall and then advanced into specific areas of the myocardium. In particular, the tip is advanced through both normal myocardial tissue and adjacent ischemic myocardial tissue, creating a continuous channel between the two. The order of passing through normal and ischemic myocardium is not significant, but the path must cross both types of tissue to establish a continuous path of new vascular vessels between the vascular beds in the non-ischemic and ischemic myocardial tissue, thereby supplying the non-ischemic tissue with blood. The catheter path preferably runs parallel to the inner and outer surfaces of the heart chamber, or at a very shallow angle relative to the chamber wall. In the latter case, the catheter path may continue for a substantial distance without encountering either the inner or outer surface of the heart chamber. Healing of the channel results in angiogenesis of new blood vessels along the entire path, thus establishing a continuous vascular connection between the vascular beds in the non-ischemic myocardium and in the ischemic myocardium.  
           [0012]    In another embodiment, a channel is formed from the inner surface of the heart chamber and penetrating into the myocardium, passing continuously through both ischemic and non-ischemic tissue in the myocardium. Alternatively, a similar channel may be formed from the outer surface of the heart, although that approach requires surgical access through the pericardium and may be less desirable.  
           [0013]    In accordance with another aspect of the invention, the path created by the advancing catheter is a hole formed by removing or ablating tissue with a channeling catheter. If a discrete hole is desired, a number of energy sources, such as laser, radio frequency, or mechanical ablation techniques, e.g., ultrasonic or lower frequency vibrations or rotations, are suitable for removing tissue. Preferably, the channel comprises a split path formed by a catheter tip that merely separates or dissects the myocardial tissue substantially in a plane as the tip is advanced, removing little or no tissue. A split path, as compared with a hole, results in less undesirable scar tissue and may have a greater cross sectional surface area, which results in more revascularization.  
           [0014]    In accordance with another aspect of the invention, the growth of the new blood vessels may be further enhanced by placing an angiogenic growth factor in at least a portion of the channel. A channel may be formed long, narrow, and blind, i.e., without an outlet. Angiogenic growth factors deposited such a channel are unlikely to be expressed or washed out, even with the compressing action of the beating heart. Accordingly, growth factors are prevented from reaching other parts of the patient.  
           [0015]    In accordance with yet another aspect of the invention, diagnostic agents may be deposited in the channel for verifying the correct location of the path. Suitable diagnostic agents include ionic and non-ionic fluoroscopic contrast agents in conjunction with x-ray equipment.  
           [0016]    Other aspects and features of the present invention will become apparent from consideration of the following description taken in conjunction with the accompanying drawings.  
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0017]    Preferred embodiments are illustrated by way of example, and not by way of limitation, in the figures of the accompanying drawings, in which like reference numerals refer to like components, and in which:  
         [0018]    [0018]FIG. 1 is an anterior view of the heart in partial cross section, showing prior art PMR channels within the wall of the heart;  
         [0019]    [0019]FIG. 2 is an anterior view of the heart, showing a myocardial revascularizing catheter in a coronary artery;  
         [0020]    [0020]FIG. 3 is a cross section of the wall of the heart, showing the distal end of a myocardial revascularization catheter in an artery and a continuous path of angiogenesis;  
         [0021]    [0021]FIG. 4 is an anterior view of the heart in partial cross section, showing a continuous path of angiogenesis within the left ventricle;  
         [0022]    [0022]FIG. 5 is a cross section of the wall of the heart, showing a continuous path of angiogenesis starting at a location within the left ventricle;  
         [0023]    [0023]FIG. 6 is a side view of the distal end of the myocardial revascularizing catheter;  
         [0024]    [0024]FIG. 7 is a cross section of the distal end of the myocardial revascularizing catheter;  
         [0025]    [0025]FIG. 8 is a cross section side view of the distal end of the myocardial revascularizing catheter;  
         [0026]    [0026]FIG. 9 is an anterior view of the heart in partial cross section, showing the distal end of a myocardial revascularization catheter in the left ventricle; and  
         [0027]    [0027]FIG. 10 is a view of the wall of the heart, showing the distal end of the myocardial revascularizing catheter creating a path within the left ventricle.  
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0028]    An anterior view of the human heart  20  is shown in FIG. 2. It includes the right atrium  22 , the right ventricle  24 , the left ventricle  26 , the pulmonary artery  28 , and the aortic arch  30 . A coronary artery is a blood vessel that supplies the heart tissues with oxygenated blood, and a coronary vein is a blood vessel that removes deoxygenated blood from the heart tissues. Originating at the base of the aorta is the right coronary artery (RCA)  32  and the left coronary artery (LCA)  34 . The LCA  34  divides into the left anterior descending artery (LAD)  36  and the circumflex  38  artery. A stenosis  40  is shown in the LAD  36 , resulting in the shaded ischemic area  42  in the lower portion of the left ventricle  26 .  
         [0029]    The distal portion of a myocardial revascularization catheter  44  is shown extending over the aortic arch  30 , into the RCA  32 , and down the first diagonal artery branch  46 . The catheter  44  forms a continuous path (or channel)  52  from a point  54  located in non-ischemic myocardial tissue  48  to a point  56  located in ischemic myocardial tissue (shaded)  42 . The healing of tissue along the path  52  produces a corresponding continuous revascularization path  50  by angiogenesis.  
         [0030]    Additional revascularization paths may be generated from the same diagonal artery branch  46  or from another artery  58  that lies within the non-ischemic area. Similarly, the coronary veins generally lie next to the arteries, and similar revascularization paths may be generated from any of the veins that lie within the non-ischemic area. Alternatively, paths may be formed by advancing the catheter down an artery or vein to a point within an ischemic area and directed to a non-ischemic area. Whether the path begins or ends in an ischemic area is not material, as long as there results in a continuous path from ischemic to non-ischemic myocardial tissue.  
         [0031]    In one embodiment, a diagnostic agent is injected into the channel  52  to verify the location of the path within the myocardium. A diagnostic agent is any chemical or other material that is used to determine the cause of illness or to provide any visual display of structural or functional patterns of organs, tissues or of a given therapy. It also includes physiologic and metabolic responses to physical or chemical stimuli or to a given therapy. Examples of suitable diagnostic agents include radiographic, ultrasonic, or magnetic resonance visualizing agents; fluorescing dyes responsive to temperature, pH, oxygen, CO 2 , sodium, potassium, or calcium levels; and the like. A preferred diagnostic agent is a radiopaque contrast imaging solution, which is capable of being visualized with a fluoroscope.  
         [0032]    With regard to the catheter  44 , radiopacity may be created by, e.g., impregnating the catheter with a radiopaque substance, impregnating the outer surface of the catheter with a radiopaque substance, coating the carrier with a radiopaque substance, or attaching a radiopaque component to the catheter. A carrier is any fluid or solid vehicle material used to transport an agent, and suitable carrier materials include aqueous fluids, solvents, detergents, lipids, biological cells, electrolytes, nutrients, oncotic agents, buffers, alcohols, thixotropics, stimuli-sensitive polymers (liquid to gel), phase changeable solid polymers (liquid to solid), hydrogels, and the like.  
         [0033]    In another embodiment, an angiogenic growth factor is deposited within the channel  52  to stimulate additional angiogenesis and increase the rate of growth. Many angiogenic growth factors occur naturally within the body, for example, fibroblast growth factors (FGF) and vascular endothelial growth factors (VEGF). Synthetic forms or equivalents are also suitable, as are various organisms that express such factors such as viral vectors. Autologous endothelial cells are also thought to be helpful in promoting angiogenesis and may be added to the channel  52  in combination with other angiogenic growth factors. Other angiogenic growth factors that generate sub lethal tissue damage may also stimulate angiogenesis without creating scar tissue. Typical substances suitable for this purpose include acids or bases that cause chemical injury and substances that cause a thermal injury, thus stimulating increased angiogenesis.  
         [0034]    [0034]FIG. 3 shows a cross section of the wall of the heart in FIG. 2 showing the continuous path  52  extending from the wall of artery  46  through non-ischemic myocardial tissue  48  to ischemic tissue  42 . Alternatively, the path  52  could be made to extend continuously from the artery  46  through ischemic myocardial tissue  42  to non-ischemic tissue  48 .  
         [0035]    [0035]FIG. 4 depicts another anterior view of a human heart  20 , showing a revascularization path  62  from within the wall of the left ventricle. FIG. 5 is a cross section of the wall of the left ventricle of the heart showing the continuous revascularization path  62  between non-ischemic myocardial tissue  48  and ischemic tissue (shaded)  42 . In this illustration, the continuous revascularization path  62  has been formed starting from the inside surface (endocardium)  64  of the left ventricle by a catheter percutaneously placed within the left ventricle.  
         [0036]    [0036]FIGS. 6, 7, and  8  show the distal portion  68  of a catheter for creating a continuous path in myocardial tissue as illustrated in the previous figures. The catheter includes a shaft  70  located within which are two lumens  78 , 88 . A radiopaque band  72  is attached to the shaft  70 . The catheter shaft  70  may be constructed of a flexible polymer, such as polyamide, polyethylene, polypropylene, polyurethane, poly vinyl chloride, or polyether block amides. The radiopaque band  72  is preferably made of a suitably high density material so that it can be readily detected, such as tungsten, platinum or gold. Radiopacity of lower density materials may be increased by coating them with high density materials, such as platinum or gold, by processes known in the art like plating or ion implantation. Radiopaque band  72  has a distal face  74  formed at an oblique angle to the axis of the catheter shaft  70 , which creates a point  76  that rotationally aligns with oval lumen  78  on the cross section of the catheter shaft  70 .  
         [0037]    Within oval lumen  78  is an oval wire  80  slidably disposed in the lumen  78 . Wire  80  may be made of a variety of suitable materials, including metals such as tungsten, stainless steel, or nickel-titanium alloys, or polymers such as polyamide, polyimide, or polycarbonate. Wire  80  extends from the distal end of the catheter through the entire catheter and out of the proximal end (not shown). Wire  80  is formed with a curve bias at its distal end  82 , wherein the curvature of the wire  80  approximately matches the curvature of the wall of a typical human heart. The oval shape of catheter lumen  78  and slidable wire  80  insures that wire curve  82  aligns properly with radiopaque marker point  76 , thereby allowing a user of the catheter to properly align it. Wire  80  has a point  84  formed at the distal end to easily penetrate the myocardial tissue, and wire  80  also contains therewithin a lumen  86 , which extends the full length of the wire.  
         [0038]    The point  84  is preferably of a standard non-coring design, such as those found on standard hypodermic needles, to prevent tissue from entering and thus occluding the lumen  86 . Lumen  86  is further adapted for depositing a therapeutic agent within the path formed through myocardial tissue by the slidable wire  80 .  
         [0039]    The myocardial tissue that is removed is replaced by non-functional scar tissue in the voids where the tissue was removed. It is thus desirable to minimize the replacement of functional myocardial tissue with scar tissue, whether in ischemic or non-ischemic areas of the myocardium. Accordingly, in another aspect of a preferred embodiment, wire  80  is adapted to cut a split path through the myocardial tissue when advanced therethrough. The wire  80  adapted to cut a split path is one that merely separates or dissects the myocardial tissue substantially in a plane, removing little or no tissue. Typically, the split path collapses after the catheter is removed. A split path, as compared with a hole, more closely resembles a blade&#39;s cut than a bored hole. Accordingly, a split path channel generally results in less undesirable scar tissue and greater cross sectional surface area, which results in more revascularization.  
         [0040]    Generally, a therapeutic agent is any chemical or other material that is used in the treatment of a disease or disorder. Examples of therapeutic agents are gene therapy agents, biological cells, tissues or precursors, antibiotics, antineoplastics, enzymes, vitamins, hormones, antivirals, radiation (via radiation sources such as cobalt, radium, and radioactive sodium iodide), anticoagulants, hemostatic agents, hepatoprotectants, vasodilators, acids, bases, inflammatory agents, and the like. Further, any therapeutic agent that can be adhered to the surface of a carrier material or impregnated into the carrier material may be administered using the devices and methods disclosed herein by administering the carrier material.  
         [0041]    A method for myocardial revascularization according to one embodiment of the invention comprises first creating an access site in the femoral artery. Such a technique is standard in the arts of, e.g., performing angioplasties and other similar procedures. Using standard techniques, the catheter shaft  70  is advanced through the arterial system until radiopaque marker  70  is located within an artery overlying an ischemic  42  or non-ischemic  48  area of the myocardium. If placement of the catheter tip is to be made in a coronary vein, the access site would be the femoral vein, the jugular vein, or another easily accessible vein large enough to accommodate the catheter.  
         [0042]    The catheter  68  is then rotated until the radiopaque marker point  76  is aligned so that the point  76  lies toward the myocardium. The proximal end of slidable wire  80  is then advanced to extend from the proximal end of the catheter, thereby puncturing the wall of the coronary vessel and extending into the myocardium. This action creates a continuous channel  52  that passes through ischemic  42  and non-ischemic  48  areas of the myocardium.  
         [0043]    Also formed within catheter shaft  70  is a lumen  88 , with guide wire  86  slidably inserted therein. Guide wire  86  may be of any standard type known in the art. Lumen  88  may extend through the entire length of shaft  70  to the proximal end in a standard “over the wire” style of catheter. In an alternate preferred embodiment, lumen  88  may extend about 25 centimeters proximally, before breaking out through the outer surface of catheter shaft  70  in a standard “rapid exchange” style of catheter, also well known in the art.  
         [0044]    Referring to FIGS. 9 and 10, an anterior view of the human heart  20  is shown. A section of the heart has been cut away to show the left atrium chamber  92  and the left ventricle chamber  94 . The heart comprises an area of ischemic myocardial tissue (shaded)  42  in the apex  90  of the left ventricle chamber  94 . The ischemic tissue could have been caused by, e.g., a blockage in an artery that deprived the tissue of oxygenated blood flow. A guide catheter  96  and guide wire  98  have been advanced over the aortic arch  30  and into the left ventricle chamber  94 . Guide wire  98  preferably has a pre-curved end  104  to match the shape of the inner surface of the left ventricle chamber. Catheter  100  is advanced over guide wire  98  and within guide catheter  96  until its distal end  102  is at a desired location on the ventricle wall next to a non-ischemic portion  48  of the myocardium. The catheter  100  is rotated until the radiopaque marker point  76  is aligned with the heart so that the point  76  lies toward the myocardium  48 . Advancing slidable wire  80  distally punctures the wall of the left ventricle  94  and creates a continuous path  104  through non-ischemic myocardial tissue  48  and into ischemic myocardial tissue  42 . Slidable wire  80  may also contain a lumen  88  and a non-coring point  84  adapted to administer a therapeutic or diagnostic agent into the continuous path  104 .  
         [0045]    While preferred embodiments and applications have been shown and described, as can be appreciated by those of ordinary skill in the art, the invention can be embodied in other specific forms without departing from the inventive concepts contained herein. The presently disclosed embodiments, therefore, should be considered as illustrative, not restrictive. Accordingly, the invention should not be limited except by the scope of the appended claims and their equivalents.