Abstract:
The present invention relates to providing counter-pulsation heart assist by deforming the aorta. In a preferred embodiment, the deformation pressure is applied by cyclically, preferably in synchrony with the diastolic period of the heart. The deformation pressure may be applied to the outer wall of the aorta or to a patch covering a resected opening in the wall of the aorta.

Description:
RELATED INFORMATION 
   This application claims priority to Australian Provisional Application No. 2002952691 filed on Nov. 15, 2002. The priority of this prior application is expressly claimed, and the disclosure of the provisional application is hereby incorporated by reference in its entirety. 
   FIELD OF THE INVENTION 
   The present invention relates generally to counterpulsation heart assist devices, systems and methods and, more particularly, to heart assist devices utilising aortic deformation and/or aortic resection. 
   BACKGROUND OF THE INVENTION 
   The concept of providing counter-pulsation support for the failing heart has been known since the pioneering work of Kantrowitz. Counter-pulsation causes displacement of a volume of a patient&#39;s blood in the patient&#39;s aorta while the patient&#39;s heart is dilating in diastole and after the aortic valve has closed. This assists to move blood around the patient&#39;s peripheral vasculature as well as into the coronary arteries. The timed volume displacement in the aorta on the blood within the aorta just in advance of systolic ejection of blood from the heart reduces the afterload on the heart, by causing a transient low pressure above the aortic valve. 
   It is known from the use of counter-pulsation in Intra-Aortic Blood Pumps (IABPs) that counter-pulsation can provide short term support for the failing heart. These devices require a balloon to be inserted percutaneously into the descending aorta. The balloon is inflated and deflated in counter-pulsation with the heart by the transmission of a gas, usually helium, between the balloon and a bedside console. These devices suffer from the problem that there is a high risk of thrombo-embolism if the balloon remains in the vasculature for a prolonged period, which can lead to ischemic leg complications. 
   There have been a number of attempts to provide counter-pulsation support for the failing heart by applying counter-pulsation pressure to the outside of the aorta. These proposals are contained in the following patent specifications: 
                                               PCT   99/04833           U.S. Pat. No.   4,014,318           U.S. Pat. No.   4,583,523           U.S. Pat. No.   4,979,936           U.S. Pat. No.   6,030,336           U.S. Pat. No.   6,045,496                        
A similar arrangement is described by Furman, New York Journal of Medicine, Aug. 1, 1970, pp 1964-1969. In all of these arrangements means are provided to surround, or at least substantially surround, the aorta and to apply a squeezing pressure substantially uniformly around the circumference of the aorta. The present inventors have found that there are substantial advantages if the counter-pulsation pressure is applied to only a part of the circumference of the aorta.
 
   It is also known to resect a part of the aorta for the purpose of inserting a patch or other graft into the aorta and to cause such patch or graft to counterpulsate. Such a system is described in the following patent specifications: 
   
     
       
             
             
             
           
         
             
                 
                 
             
           
           
             
                 
               PCT 
               01/13974 
             
             
                 
               U.S. Pat. No. 
               4,630,597 
             
             
                 
                 
             
           
        
       
     
   
   The device described in these specifications is for insertion into the descending aorta which is straight. There is no suggestion of how to deal with the more complex issues that arise in placing the device into the ascending aorta which is curved along its length. 
   OBJECT OF THE INVENTION 
   It would be desirable to have a heart assist device, which may or may not be blood contacting, that could provide assistance to the heart function with reduced risk to the patient and/or of device malfunction than prior art devices. 
   SUMMARY OF THE INVENTION 
   In one aspect, the present invention provides a device for assisting the functioning of the heart of a patient, the device including: 
   an aortic compression means adapted, when actuated, to compress an aorta; and 
   motive means to periodically actuate, and de-actuate, the aortic compression means in counter-pulsation with the patient&#39;s heart rhythm, 
   wherein the aortic compression means is adapted to compress only a portion of the circumference of the aorta. 
   Preferably, the aortic compression means is adapted to compress less than half of the circumference of the aorta. 
   In one form, the aortic compression means is a mechanical device driven, upon actuation, into compressive contact with the exterior of the aorta. In another form, the aortic compression means includes a flexible membrane, which may be elastic or inelastic, driven, upon inflation, into compressive contact with the exterior of the aorta. 
   The aortic compression means is preferably adapted to compress only a portion of the circumference of the ascending aorta, most preferably only the radially outer side of the ascending aorta. 
   In a second aspect, the present invention provides, in a heart assist device of the type which induces counter-pulsation of an artery in the vasculature of a patient, the improvement comprising the application of a counter-pulsation pressure to the exterior of the artery such that the artery is caused to flex along a continuous line which increases in length as the counterpulsation pressure applied to the artery increases. 
   The line preferably has the shape of a conic section. 
   In a third aspect, the present invention provides, in a heart assist device of the type which induces counterpulsation of an artery in the vasculature of a patient, the improvement comprising the application of a counterpulsation pressure to the exterior of the artery such that the artery is caused to compress substantially without stretching or bunching. 
   In a fourth aspect, the present invention provides, in a heart assist device which includes aorta deformation means to apply a counter-pulsation pressure to the ascending aorta of a patient, characterised in that the aorta deformation means applies a deforming force to the outside of the radially outer side of the curvature in the ascending aorta and that the aorta deformation means induces in the aorta a smoothly curved ovate depression as it moves to a position of maximum deformation of the aorta. 
   In a fifth aspect, the present invention provides, in a heart assist device which includes aorta deformation means to apply a counter-pulsation pressure to the descending aorta of a patient, characterised in that the aorta deformation means applies a deforming force to the outside of the descending aorta and that the aorta deformation means induces in the aorta a smoothly curved circular depression as it moves to a position of maximum deformation of the aorta. 
   In a sixth aspect, the present invention provides, in a heart assist device including artery deformation means adapted to periodically apply a deforming force to a curved artery in a direction substantially normal to a tangent to the radially outer surface of the longitudinal curve in the artery, the deforming force being such that the artery is progressively deformed along a line which lies in a plane running through the artery, the plane moving radially inwardly through the artery as the deformation increases. 
   In a seventh aspect, the present invention provides, in a counter-pulsation type heart assist device adapted for insertion into the wall of the ascending aorta of a patient, the device including an inflatable balloon extending around less than one half of the circumference of the aorta and means to inflate the balloon in counter-pulsation with the heart of a patient into which the device has been inserted, the balloon having a substantially inelastic outer layer and an inner layer with a shape which is, when the balloon is deflated, smoothly curved and facing directly inwardly into the lumen of the ascending aorta of the patient into which the device has been inserted. Alternatively the device may be applied to the outside of the wall of the aorta. 
   In an eighth aspect, the present invention provides, in a heart assist device adapted to apply a counter-pulsation force to a patch inserted into at least the radially outer arc of the ascending aorta the force being applied to the radially outer arc of the aorta to cause the wall or the patch to invaginate, the device being characterised in that it includes deformation means for the application of the pressure to the wall or patch which deformation means has, when the wall or patch is fully invaginated, a shape which is substantially a mirror image of the section of the wall or patch which has been invaginated before it was so invaginated. Alternatively the device may be applied to the outside of the wall of the aorta. 
   The above embodiment is designed to apply a compressive force to the artery so as to cause the blood therein to be displaced while causing the minimum trauma to the vessel. In preferred embodiments of the invention the compression of the ascending aorta is induced in a way which reduces the enclosed volume of the aorta while not unduly stretching or bunching the wall of the aorta. 
   The deformation of the artery may be induced by a balloon or by a rigid object. In either case the object inducing the deformation shall be so shaped that the desired form of deformation of the artery is achieved. In the case of a balloon, the balloon should be so shaped that as it is inflated it will take on a shape similar to that which is desired to be achieved in the artery. It must also be so placed on the artery that the desired smoothly flexing and smoothly shaped deformation is achieved. In the case of a rigid object the object should initially be of an appropriate shape to induce the desired deformation of the artery as it is advanced towards the artery either along a linear path or an arcuate one. Preferably, the deforming object will be moved into the artery in a direction which is radial of the artery and either at right angles to its axis, if it is straight, or at right angles to a tangent to the radially outer side of the artery, if it is curved. 
   Preferably, the deformation of the vessel does not extend around more than 180 degrees of the circumference of the vessel, more preferably no more than 160 degrees and even more preferably not more than 140 degrees and most preferably between 100 and 140 degrees. The cuff or balloon may extend further around the aorta than the preferred amount, however, the active deformation of the aorta preferably only extends around an arc of the aorta within the above limits. The desire of this design preference is to avoid the inside surface of the deformed vessel touching the inside surface of the vessel diametrically opposite the deformation. 
   In preferred embodiments the deformational force will be applied directly to the arterial wall. However, if desired a layer of any suitable material may be placed between the deformational member and the wall. In an alternative embodiment of the invention a section of the arterial wall may be resected and a patch applied which substantially replicates the shape of the native artery and the deformational force applied to the outside surface of that patch. In this embodiment of the invention the patch is applied to the radially outer arc of the ascending aorta and preferably has a shape similar to the section of the ascending aorta which has been removed. 
   The heart assist device of the present invention allows, at least in preferred embodiments, partial unloading of the heart and augmenting of the cardiac output of the heart. 
   After use, if the heart has recovered, the device can be left in situ, in an inactive state, until needed again. The device can also be used to administer on-demand, spaced-apart sessions of counterpulsation for treatment or relief from chronic myocardial ischemia and/or heart failure. 
   In a preferred form of the invention, the device is adapted for attachment to the ascending aorta. An upper mid-line sternotomy provides surgical access to the ascending aorta. Alternatively, a thoracotomy may be used to place the device on the descending aorta. 
   The motive means referred to above can be any means that is capable of cyclically introducing fluid, and withdrawing fluid, from an inflatable bladder, balloon or cuff. The motive means can include or be associated with means for detecting speed and completeness of the filling and emptying, and for monitoring the delivered fluid pressure. The motive means can also act to record the ECG, having electrodes positioned on the housing or as separate wires attached to body tissues. 
   In a further aspect, the present invention provides a method for improving cardiac performance in a subject, the method including the steps of: 
   implanting a device in accordance with any one of the preceding aspects of the invention fully within the thoracic cavity of a subject; 
   actuating the motive means to periodically introduce the fluid into the space in synchrony with the diastolic period to reduce the interior volume of the aorta; and 
   alternating the period of actuation with periods of deactivation of the motive means to periodically withdraw the fluid from the space in synchrony with the commencement of the systolic period, thereby allowing the portion of the aorta adjacent the device to return to normal interior volume. 
   The method may include the step of resecting a portion of the ascending aorta in the shape of a toroidal truncate and sealingly attaching the periphery of the device to the periphery of the opening aorta. 
   In another aspect, the present invention provides a device for assisting the functioning of the heart of a patient, the device including: 
   a patch device sealingly attachable to the ascending aorta; 
   a flexible membrane sealingly attached to at least part of the interior of the patch device and defining an inflatable space adjacent the interior of the patch device; and 
   motive means to periodically introduce into, and withdraw from, the space a fluid, in counter-pulsation with the patient&#39;s heart rhythm. 
   The patch device is preferably attachable to the radially outer side of the ascending aorta. In one form, the patch device is attachable to the periphery of an opening in the ascending aorta formed by resecting a portion of the aorta. The membrane has a shape substantially replicating that of the interior surface of the resected portion of the aorta. The flexible membrane preferably also substantially replicates the shape of the interior of the patch device when the fluid is withdrawn from the space. It is believed that this design feature will reduce the incidence of thrombo-embolism by presenting, when deflated, a blood flow path without regions that would cause sluggish blood flow. The patch device is preferably in the shape of a truncated portion of a torus. The aorta is preferably resected along a line on the radially outer side, or passing through, the diameter of the mid point cross section of the aorta. The membrane, when the fluid is introduced into the space, is preferably expanded towards, but not abutting, the adjacent interior wall of the aorta. 
   In another form, the patch device is attachable to the ends of the aorta formed by removing a length of the aorta. The patch device preferably includes a truncated substantially toroidal portion with an externally facing hump that forms the inflatable space. The membrane is preferably attached to the patch device about the periphery of the hump. The surface of the membrane remote the space preferably has a shape, when the fluid is withdrawn from the space, substantially replicating that of the interior surface of the removed portion of the aorta. The flexible membrane preferably also substantially replicates the shape of the interior of the hump when the fluid is withdrawn from the space. The hump is preferably disposed external to a line on the radially outer side, or passing through, the diameter of the mid point cross section of the aorta. The membrane, when the fluid is introduced into the space, is preferably expanded close to, but not abutting, the adjacent interior wall of the aorta. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
     Preferred embodiments of the invention will now be described, by way of examples only, with reference to the accompanying drawings in which: 
       FIG. 1  is a cross sectional ventral view of the aorta of a patient with a first embodiment of a device for assisting the functioning of a heart; 
       FIG. 2  is a schematic lateral view of the device shown in  FIG. 1 ; 
       FIG. 3  is a ventral view of the aorta of a patient showing a series of planes through the aorta in which lines of flexure of the aortic wall will lie during application of a deforming force to the aorta; 
       FIG. 4  is cross sectional view along line  4 - 4  through the aorta of  FIG. 3  showing a sequence of shapes assumed by the aortic wall as it is deformed; 
       FIG. 5  is a part longitudinal cross-sectional view through the aorta of  FIG. 3  along line  5 - 5  of  FIG. 6 , showing a sequence of shapes assumed by the aortic wall as it is deformed; 
       FIG. 6  is a lateral view from the right side of the aorta of  FIG. 3 , showing a sequence of lines of flexure as the aorta is deformed; 
       FIG. 7  is a schematic side view of an ascending aorta showing a resection line; 
       FIG. 8  is a schematic side view of the aorta shown in  FIG. 7  after resection of a portion of the aorta; 
       FIG. 9  is a schematic side view of another embodiment of a device for assisting the functioning of the heart with a withdrawn internal membrane; 
       FIG. 10  is a schematic side view of the device shown in  FIG. 9  with an expanded membrane; 
       FIG. 11  is a schematic side view of the aorta shown in  FIG. 8  after surgical attachment of the device shown in  FIGS. 9 and 10  with the membrane shown in withdrawn and expanded positions; 
       FIG. 12  is a schematic cross sectional end view of the aorta and device shown in  FIG. 11 ; 
       FIG. 13  is a schematic cross sectional view of an aorta of reduced size with a resected portion; 
       FIG. 14  is a cross sectional end view of the aorta of  FIGS. 13 and 15  after surgical attachment of a further embodiment of device for assisting in the functioning of the heart; 
       FIG. 15  is a schematic front view of the resected aorta shown in  FIG. 13 ; 
       FIG. 16  is a schematic front view of the aorta and device shown in  FIG. 15 ; 
       FIG. 17  is a schematic side view of an ascending aorta showing an alternatively positioned resection line; 
       FIG. 18  is a cross sectional ventral view of the aorta of a patient with a further embodiment of a device for assisting the functioning of a heart. 
   

   DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     FIG. 1  is a schematic side view of an ascending aorta  10  and a heart assist device  16  in accordance with an embodiment of the invention. The device  16  has a relatively inelastic, preferably plastic, shell  17  and a flexible membrane  18  sealingly attached to the periphery of the shell  17 . The membrane  18  defines an inflatable space  19  between it and the interior of the shell  17 . The shell  17  also has an inlet/outlet port  20  which is adapted for connection to a motive means that can periodically introduce, and withdraw, a fluid (eg. a gas such as helium or a liquid such as a saline solution or an oil) to and from the space  19  in counter-pulsation with the patient&#39;s heart rhythm. The membrane  18  has a shape which is, when deflated, smoothly curved and facing directly inwardly towards the lumen of the ascending aorta  10 . 
   A relatively inelastic wrap  21  is used to hold the device  16  in the position shown on the radially outer side of the ascending aorta  10 . 
   The solid line  18  illustrates the position of the membrane  18  relative to the shell  17  when fluid has been withdrawn from the space  19  and the membrane  18  has been retracted. In this position the radially outer external side wall  10   e  of the aorta  10  is in its normal or deflated position allowing maximum blood flow there through. 
   The phantom line  18  illustrates the position of the membrane  18  relative to the shell  17  after fluid has been introduced into the space  19  and the membrane  18  has been expanded. When the membrane  18  is expanded in this way, the aorta external wall  10   e  is compressed and inwardly deformed until it is close to, but not abutting, the opposite interior wall of the aorta  10   r.    
   The membrane  18  is sized and positioned to compress only a portion of the circumference of the radially outer side of the ascending aorta  10 . More particularly, the membrane  18  compresses only about 140 degrees of the circumference of the aorta  10 . 
     FIGS. 3 to 6  show, in various orientations and views, the shape the external wall  10   e  of the ascending aorta  10  assumes from initial deformation (line A) through to maximum deformation (line E). The lines A to E show the exterior of the aorta  10  flexing along a continuous line, that preferably has the shape of a conic section, which increases in length as the counter pulsation pressure applied to the artery increases. An advantage of flexing the aorta in this manner is that it is caused to compress substantially without stretching, which reduces the likelihood of damage. Also the line of flexure is constantly moving so that one line of the aorta  10  is not being constantly exposed to flexural movement. Put another way, the exterior of the aorta is deformed to induce a smoothly curved ovate depression as it moves towards a position of maximum deformation (line E) of the aorta  10 . In an alternative embodiment, a smoothly curved circular depression can be formed in the aorta. 
   The lines A to E also show how the artery is progressively deformed along a line which lies in a plane running through the artery  10 , that plane moving radially inwardly through the artery as the deformation increases. 
   The deformation described above can be caused to occur in many other different ways. For example, in another embodiment, deformation can be caused by a patch device inserted into the radially outer arc of the ascending aorta. In such an embodiment, the device includes a means for applying pressure to the wall or patch which, when the wall or patch is fully invaginated, forms a shape which is a mirror image of the section of the wall or patch which as been invaginated before it was so invaginated. 
   Another embodiment of a device for assisting the functioning of a heart according to the present invention will now be described in relation to  FIGS. 7 to 12 . Like reference numerals will be used to indicate like features used in describing to the preceding embodiment. 
     FIG. 7  is a schematic side view of a portion of ascending aorta  10 . Line  12  is a resection line passing through the diameter of the midpoint cross section of the aorta  10  (see also  FIG. 12 ). 
     FIG. 8  is a schematic view of the resected aorta  10   r  after cutting the aorta  10  along the resection line  12  and removal of a resected portion  14 . 
     FIG. 9  is a schematic side view of a heart assist device  16  in accordance with another embodiment of the invention. The device  16  has a relatively inelastic, preferably plastic, shell  17  and a flexible membrane  18  sealingly attached to the periphery of the shell  17 . The membrane  18  defines an inflatable space  19  between it and the interior of the shell  17 . The shell  17  also has an inlet/outlet port  20  which is adapted for connection to a motive means that can periodically introduce, and withdraw, a fluid (eg. a gas such as helium or a liquid such as a saline solution or an oil) to and from the space  19  in counter-pulsation with the patient&#39;s heart rhythm. 
     FIG. 9  illustrates the position of the membrane  18  relative to the shell  17  when fluid has been withdrawn from the space  19  and the membrane  18  has been retracted ( 18   r  in  FIGS. 11 and 12 ).  FIG. 10  illustrates the position of the membrane  18  relative to the shell  17  after fluid has been introduced into the space  19  and the membrane  18  has been expanded ( 18   e  in  FIGS. 11 and 12 ). When the membrane  18  is expanded it is close to, but not abutting, the opposite interior wall of the aorta  10   r.    
   The shell  17  has a peripheral edge of common shape to the opening formed in the aorta  10   r  after removal of the resected portion  14 . This permits the device  16  to be attached to the resected aorta  10   r  by stitching between the periphery of the shell  17  and the periphery of the opening in the resected aorta  10   r , as indicated by stitches  22  in  FIG. 11 . 
   The motive means (not shown) include a fluid reservoir and a pump means adapted to pump the fluid from, the fluid reservoir to the port  20 , and thus the space  19  between the interior of the shell  17  and the flexible membrane  18 , and then withdrawn same, to expand ( 18   e ) and retract ( 18   r ) the membrane  18  as indicated in  FIGS. 5 and 6 . Suitable implantable fluid reservoirs and pump means are disclosed in the applicant&#39;s international PCT patent application Nos. PCT/AUOO/00654 and PCT/AUO2/00974, which are hereby incorporated by cross reference. 
   More particularly, in use, the motive means is periodically actuated to introduce fluid into the space  19  in synchrony with the diastole period to reduce the interior volume of the aorta  10   r  and thereby provide additional pumping of the blood in the aorta  10   r  to assist the functioning of the heart. This introduction of fluid is alternated with periodic withdrawal of the fluid from the space  19  to allow the aorta  10   r  to return to its normal interior volume. As described above, the introduction of fluid expands the membrane  18  to be close to, but not abutting, the opposite interior wall of the aorta  10   r . This maximises pumping volume without risk of the membrane  18  contacting and damaging the aorta  10   r.    
   It will be appreciated that the heart assist device  16  includes a component, namely the membrane  18 , which is blood contacting. However, the previously described disadvantages of blood contacting are minimised by the present invention as when the fluid is withdrawn from the space  19  the membrane  18  is drawn into a shape substantially replicating the original (now resected) aorta wall. As a result, no eddies or pockets are introduced into the blood flow path that may disrupt blood flow when the device  16  is not activated thereby substantially reducing clot risk. 
   Also, if the heart recovers the device  16  can be deactivated with the membrane  18  in the retracted position (see  FIGS. 9 and 18   r  in  FIGS. 11 and 12 ) allowing natural blood flow there through. In this connection, it should also be noted that heart assist devices have been proposed that function in parallel to the aorta and which receive the full diverted flow of blood originally intended for to the aorta. These devices can not be deactivated unlike the device according to the present invention. 
   Further, by installing the device  16  in a position vacated by the resected portion  14  of the aorta  10  it achieves a relatively high pumping volume for a relatively low device volume. 
   The flexible membrane  18  is preferably manufactured from a polyurethane or a polyurethane-polysiloxane block co-polymer material or other similar material, which encourages ingrowth of the passing blood cells and can eventually create a new “natural” cell lining. 
   The device according to the present invention is also particularly advantageous for use in patients whose aortas have become diseased as the device can be implanted in place of the resected damaged section. 
   A further embodiment of the device for assisting the functioning of a heart according to the present invention will now be described in relation to  FIGS. 13 to 16 . Like reference numerals will be used to indicate like features used in describing to the preceding embodiment. This embodiment is particularly suitable for use in patients having a naturally small aorta or an aorta that has shrunk through heart disease or the like. 
     FIG. 13  is a schematic cross sectional end view of a reduced diameter resected aorta  10   r  showing resection line  12  and resected portion  14 . The periphery of the opening formed by removing the resected portion  14  is denoted  24  in  FIG. 15 .  FIG. 14  shows the resected aorta  10   r  after its included angle {acute over (α)} has been increased to {acute over (α)}+ so as to open or stretch out the opening  24  in the aorta  10   r . Such stretching allows the attachment of a heart assist device  16  of a similar size to that used in a healthy aorta. In this way, the effective cross section of the aorta available for pumping by the membrane  18  can be increased. For example, from about 707 mm 2  at an original diameter of 30 mm to about 1257 mm 2  at a stretched diameter of 40 mm. This results in a corresponding increase in the pumping volume of the aorta  10   r.    
     FIG. 17  is a schematic side view of an ascending aorta  10  showing an alternatively positioned resection line  12 . In this form, the resection line  12  is angled towards the top of the aorta  10  to resect the upper, radially outer arc of the aorta  10 . 
   A further embodiment of a device for assisting the functioning of a heart according to the present invention will now be described in relation to  FIG. 18 . Like reference numerals will be used to indicate like features used in describing to the preceding embodiments. 
   In  FIG. 18  the heart assist device is a patch device  16  attachable to the ends of the aorta  10 , at stitches  22 , formed by removing a length of the aorta. The patch device  10  is in the general shape of a truncated toroid with an externally facing hump that forms the inflatable space  19 . The membrane  18  is attached to the patch device  16  about the periphery of the hump. The hump is disposed external to a line on the radially outer side, or passing through, the diameter of the mid point cross section of the aorta  10 . 
   The flexible membrane  18  substantially replicates the shape of the interior of the hump when the fluid is withdrawn from the space  19 . The membrane  18 , when the fluid is introduced into the space  19 , is expanded close to, but not abutting, the adjacent interior wall of the aorta, as is shown in phantom line. 
   Whilst the above embodiments have been described in relation to compressing the radially outer wall of the aorta, it would be appreciated by a person skilled in the art that other portions of the aorta can be deformed or other arteries can be deformed to assist in heart functions. 
   The heart assist devices described above are suitable for short and/or long term treatment for heart failure and/or myocardial ischemia. 
   It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.