Method for delivery of therapeutic agents to the heart

A method for delivering a therapeutic agent directly to the heart employing minimally invasive techniques and concepts. In particular, the delivery of vascular endothelial growth factors (VEGF) is performed endovascularly or endoscopically to a region of a patient's heart treated with transmyocardial revascularization (TMR). A system is provided for inducing cardioplegic arrest. An aortic occlusion device has an inflatable balloon which occludes the ascending aorta when inflated. Cardioplegic fluid may be infused through a lumen of the aortic occlusion device to stop the heart while the patient's circulatory system is supported on cardiopulmonary bypass. A side-firing fiberoptic laser is introduced through the aortic occlusion device in the endovascular technique to perform TMR. Subsequently, a therapeutic agent delivery catheter is directed into one of the coronary arteries to deliver and dissipate the VEGF into the surrounding vascular plexus to promote angiogenesis stimulation. Alternatively, a therapeutic agent delivery material saturated or coated with VEGF could be sutured to the epicardial surface of the heart, using thoracoscopic techniques, for timed release delivery of the agent to the TMR treated site.

BACKGROUND OF THE INVENTION 
Recent trends in the advancement of surgical technology have tended toward 
less invasive procedures in order to reduce trauma to the patient. For 
example, an important advancement in the area of cardiac surgery is 
represented by U.S. Pat. No. 5,571,215, and copending patent application 
Ser. No. 08/281,981, which describe systems for arresting the heart, 
maintaining circulation of oxygenated blood in the patient and carrying 
out surgical procedures, such as coronary artery bypass graft (CABG) 
surgery or heart valve replacement surgery, on the heart. 
Another recent therapy is known as Transmyocardial revascularization (TMR) 
which is a treatment for patients suffering from medically refractory 
angina pectoris with coronary artery anatomy unsuitable for treatment with 
more conventional coronary artery bypass grafting or percutaneous 
transluminal coronary angioplasty. Typically, a high-energy laser is 
employed to create 20-30 passageways or channels in an ischemic myocardium 
which penetrate therethrough into the left ventricular chamber. In theory, 
the channels act as conduits to perfuse oxygenated blood from the left 
ventricle into the extensive intramyocardial vascular plexus. In essence, 
at the immediate treated site of the myocardium, the epicardial 
vasculature is bypassed. 
Yet another new technique is molecular enhancement of endothelial cell 
motility and angiogenesis. One such molecular enhancement is the 
application of Vascular Endothelial Growth Factors (VEGF) to further 
stimulate additional angiogenesis. VEGF is a selective mitogen for 
vascular endothelial cells which has been shown to accelerate endothelial 
repaving, and attenuate intimal hyperplasia after in vivo arterial injury. 
D. Weatherford, J. Sackman, T. Reddick, M. Freeman, S. Stevens and M. 
Goldman, Vascular endothelial Growth Factor and Heparin in a Biological 
Glue Promotes Human Aortic Endothelial Cell Proliferation with Aortic 
Smooth Muscle Cell Inhibition, SURGERY, August 1996, 433-439. Vascular 
endothelial growth factor is one of the proangiogenic molecules which 
include members of the fibroblast growth factor family, transforming 
growth factor-.beta., tumor necrosis factor-.alpha., platelet-derived 
growth factors, as well as other factors. These soluble molecules exert 
their angiogenic stimuli by coupling to the cell surface receptor and 
trigger the functions within the endothelial cells through signaling 
cascades. Engler, D., Use of Vascular Endothelial Growth Factor for 
Therapeutic Angiogenesis, CIRCULATION, 1996;94:1496-1498. 
SUMMARY OF THE INVENTION 
The present invention provides a system that includes an aortic occlusion 
device which receives an endovascular device for performing an 
endovascular procedure on the patient's heart or blood vessels. A bypass 
system, such as a femoral-femoral CPB system, may be used in conjunction 
with the aortic occlusion device for maintaining circulation of oxygenated 
blood in the patient while the heart is arrested. The endovascular 
procedure can be the only procedure performed on the patient or the 
procedure can be performed in conjunction with other cardiac surgical 
procedures such as a CABG or valve procedure. 
The aortic occlusion device is preferably introduced percutaneously or by 
direct cut-down through the femoral artery. This catheter has an occluding 
member which is able to completely occlude the ascending aorta. The 
catheter is preferably introduced under fluoroscopic guidance over a 
suitable guidewire. Transesophageal echocardiography can alternatively be 
used for positioning the aortic occlusion device. 
The aortic occlusion device may serve a number of separate functions and 
the number of lumina in the catheter will depend upon how many of those 
functions the aortic occlusion device is to serve. The aortic occlusion 
device can be used to introduce the cardioplegic agent, normally in 
solution, into the aortic root via a perfusion lumen. The luminal diameter 
will preferably be such that a flow of the order of 250-500 ml/min of 
cardioplegic solution can be introduced into the aortic root to perfuse 
the heart by way of the coronary arteries. The same lumen can, by applying 
negative pressure to the lumen from an outside source, effectively vent 
the left heart of blood or other solutions. 
The aortic occlusion device is preferably adapted for introduction of one 
or more endovascular devices through the lumen of the aortic occlusion 
device. It is preferable that the diameter and cross-sectional design of 
the lumens are such that the external diameter of the aortic occlusion 
device in its entirety is small enough to allow its introduction into the 
femoral artery by either percutaneous puncture or direct cut-down. 
The system also preferably includes a device for delivering a therapeutic 
agent to the heart. After the occluding member is properly inflated to 
occlude the ascending aorta, a therapeutic agent delivery device is 
introduced through the aortic occlusion device. The distal end is guided 
into one of the main coronary arteries where a therapeutic agent is 
delivered to the heart through a delivery lumen in the agent delivery 
catheter. The system can be used to deliver any type of drug or agent to 
the heart including, but not limited to, proteins, genes, gene vectors, 
liposome vectors, HJV viral vectors and plasma DNA. 
A stent delivery catheter may also be inserted through the lumen of the 
aortic occlusion device for delivery of a stent. The stent is preferably 
impregnated with a therapeutic agent so that the stent can deliver the 
agent to the coronary vasculature. 
In another embodiment, the agent delivery device is a needle sheath 
catheter configured for sliding receipt in the lumen of the aortic 
occlusion device. An injection catheter is configured for sliding receipt 
in the needle sheath. A needle is resiliently biased outwardly in a 
direction sufficiently skewed from a longitudinal axis of the injection 
catheter to pierce the artery wall upon advancement of the needle. 
Subsequently, the agent may then be injected through the needle and into 
the myocardium. 
In still another embodiment, the agent delivery device is a therapeutic 
agent infusion catheter which is advanced through the aortic occlusion 
device. The infusion catheter includes an expandable infusion array which 
is expanded to contact the coronary artery wall. The infusion array 
includes a plurality of laterally-deflectable delivery conduits in 
communication with a reservoir. The infusion array has a plurality of 
orifices extending into each one of the conduits for jet infusion of the 
agent into the coronary artery wall. 
The present invention is also directed to a method for delivering an agent 
to the patient's coronary arteries. The method includes the steps of: 
placing an aortic occlusion device in a location within a patient's 
ascending aorta, the aortic occlusion device having an occluding member 
and a lumen; expanding the occluding member within the patient's ascending 
aorta to occlude the passageway therethrough; infusing a cardioplegic 
agent into a coronary vasculature of the patient to arrest the patient's 
heart; maintaining circulation of the blood downstream of the occluding 
member; and delivering a therapeutic agent into the coronary vasculature 
through the aortic occlusion device. The delivering step may be carried 
out with the aortic occlusion device or with the agent delivery catheter 
which extends through the aortic occlusion device. 
The procedure may also include the steps of occluding the patient's 
superior and inferior vena cava to isolate the delivery of the therapeutic 
agent and prevent systemic circulation thereof. Another method of 
substantially preventing systemic circulation of the agent is to provide a 
coronary sinus catheter. The coronary sinus catheter is preferably 
advanced through a peripheral vein, such as the internal jugular vein, 
with the distal end extending into the patient's coronary sinus. The 
coronary sinus catheter has an occluding member for occluding the coronary 
sinus. The coronary sinus catheter has a lumen which withdraws the agent 
after the agent has passed through the coronary vasculature. 
In another aspect of the present invention, the agent may be delivered in a 
retrograde direction by infusing the agent through the coronary sinus 
catheter and removing the agent through the lumen in the aortic occlusion 
device. 
In still another aspect of the present invention, the aortic occlusion 
device is adapted to perform other procedures such as a Transmyocardial 
Revascularization (TMR) from within the chambers of the heart. TMR is 
performed by using a side-firing fiberoptic laser catheter introduced 
through the lumen of the aortic occlusion device and advanced through the 
aortic valve and into the left ventricle. The side-firing laser catheter 
is then directed toward the endocardium where a series of channels are cut 
through the myocardium. In this arrangement, the agent delivered directly 
to the coronary arteries is preferably vascular endothelial growth factors 
which stimulate angiogenesis. Although it is preferred to pass the TMR 
laser through the aortic occlusion device, TMR may be accomplished with a 
transseptal approach via the intraatrial septum and into the left 
ventricle. 
A number of important advantages accrue from this combination of the aortic 
occlusion device with these endovascular diagnostic and therapeutic 
devices and agent delivery capabilities. Introducing a side-firing 
fiberoptic laser catheter through the aortic occlusion device and 
subsequent agent delivery allows the patient's heart to be stopped and the 
circulatory system supported on cardiopulmonary bypass while performing 
the endovascular procedure and agent delivery. This may allow the 
application of TMR to patients whose cardiac function is highly 
compromised and therefore might not otherwise be good candidates for the 
procedure. It also allows TMR to be performed as an adjunct to other 
cardiac surgical procedures. With the devices of the prior art, it would 
be difficult to perform TMR and delivery of an agent since standard aortic 
cross-clamps prevent devices from being introduced endovascularly. Both 
TMR and delivery of the agent benefit from performing the procedures while 
the heart is arrested. 
In an alternate mode of operation, the vascular endothelial growth factors 
may be delivered to the patient's heart by introducing a dispensing 
instrument into the patient's thoracic cavity. The vascular endothelial 
growth factors may then be applied to a selected wall of the patient's 
heart through the dispensing instrument. 
To ensure a longer duration of contact between the VEGF and the myocardium 
to further stimulate angiogenesis, the vascular endothelial growth factors 
may be suspended in a viscous liquid, such as a fibrin based glue or a 
bioabsorbable polymer gel. These viscous liquids have a greater likelihood 
of extended exposure to the treated regions where a longer exposure 
duration to VEGF may be advantageous. 
Additionally, timed release delivery of the VEGF to the heart can be 
accomplished with a patch which is placed into direct contact with the 
myocardium. The patch would contain the therapeutic agent which would be 
continuously delivered to the myocardium over an extended period of time. 
The agent delivery material may be provided by various structures 
including a suture composed of an absorbable polymer wherein the growth 
factors are encapsulated therein. In another embodiment, the agent 
delivery material may be provided by a relatively flat absorbent patch 
device sutured to the epicardium of the heart. 
These and other aspects of the present invention will become apparent from 
the following description of the preferred embodiments, drawings and 
claims.

DETAILED DESCRIPTION OF THE INVENTION 
Referring to FIG. 1, a schematic depiction of a system in accordance with 
the present invention is shown. The system includes an aortic occlusion 
device 10 and a coronary sinus catheter 20. The aortic occlusion device 10 
has an occluding member 11 for occluding the ascending aorta 12 and the 
coronary sinus catheter 20 has an occluding member 554 for occluding the 
coronary sinus 21. The aortic occlusion device 10 is advanced through an 
arterial cannula 15 which is positioned in femoral artery 23. A bypass 
system 18 removes blood from the femoral vein 16 through venous cannula 
17, oxygenates the blood, and returns the oxygenated blood to the patient 
through the arterial cannula 15. Cardioplegic fluid is delivered through 
one or both of the aortic occlusion device 10 and the coronary sinus 
catheter 20 to paralyze the myocardium. 
The proximal end 25 of the aortic occlusion device 10 has an adapter 26 
with an inflation lumen 27 coupled to an inflation device 28 for inflating 
the occluding member 11. A main lumen 30 splits into a first arm 30 having 
a hemostasis valve 31 through which an endovascular device may be inserted 
into the main lumen 30. The main lumen 30 is also coupled to a source of 
cardioplegic fluid (not shown) which is delivered through the main lumen 
30 to arrest the patient's heart. A second arm 32, which also leads to the 
main lumen 30, is coupled to a blood filter/recovery unit 37 for venting 
blood from the ascending aorta through the main lumen 30. 
Referring to FIG. 2, a more detailed view of the aortic occlusion device 10 
is provided which shows the main lumen 30, inflation lumen 27 and a 
pressure lumen 318A for measuring pressure in the ascending aorta. Each 
lumen 30, 27, 318A has a connector 319 at a proximal end and the main 
lumen 30 has a bellows 321 connection to increase flexibility and prevent 
kinking. The connector 319 is attached to the hemostasis valve 31 (see 
FIG. 1) and the second arm 32 (see FIG. 1) so that the main lumen 30 can 
be used to deliver cardioplegic fluid, vent the ascending aorta and 
receive an endovascular device. A curved distal portion 317A facilitates 
positioning the occluding member 11 in the ascending aorta. Referring to 
FIG. 3, the curved distal portion 317A is also preferably offset somewhat. 
The resulting curved distal portion 317A generally conforms to the aortic 
arch to facilitate placement of the occluding member 11 in the ascending 
aorta. 
Referring to FIG. 5B, a cross-section of the aortic occlusion device 10 is 
shown. The cross-sectional shape of the aortic occlusion device 10 is 
somewhat egg-shaped but may, of course, also be substantially circular or 
any other suitable shape. An elongate element 310A, which is described 
below, reinforces the aortic occlusion device 10. 
Referring to FIGS. 4A, 4B, and 5A, a preferred method of forming the aortic 
occlusion device 10 is shown. FIG. 4A shows a longitudinal cross-section 
of a tube 331A, preferably a urethane tube, mounted on a mandrel 333A with 
the reinforcing elongate element 310A wound around the tube 331A in a 
helical manner. The elongate element 310A is preferably a wire ribbon 
having a thickness of 0.003 inch and a width of 0.012 inch. The elongate 
element 310A is preferably wrapped around the tube 331A with a spacing of 
0.010 inch. Another tube 335A is positioned over the elongate member 310A 
and a shrink tube (not shown) is positioned over the tube 335A. The entire 
structure is then heated to fuse the tubes together to form a reinforced 
tube 337A which is shown in longitudinal cross-section in FIG. 4B. The 
resulting reinforced tube 337A preferably has an inner diameter of about 
0.100 inch and a wall thickness of about 0.010 inch. 
Referring to FIG. 5A, a two-lumen member 339A is positioned against the 
reinforced tube 337A and a shrink tube 341A is positioned around the 
member 339A and reinforced tube 337A. The two-lumen member 339A has the 
inflation lumen 320A and the pressure lumen. The two-lumen member 339A is 
preferably an extrusion having a D-shaped outer surface in cross-section. 
The member 339A and tube 337A are then heated and the shrink tube 341A is 
removed to obtain the egg-shaped cross-sectional shape shown in FIG. 5B. 
The cross-sectional shape is preferably about 0.145 inch tall and 0.125 
inch wide. The inflation lumen 320A is then pierced to provide an 
inflation path to the occluding member 315 and the occluding member 315 is 
then mounted to the aortic occlusion device 10. 
Although it is preferred to use the aortic occlusion device 10 described 
above, other aortic occlusion devices may be used such as the devices of 
U.S. Pat. No. 5,478,309 to Sweezer, U.S. Pat. No. 5,433,700 to Peters, and 
U.S. Pat. No. 5,556,412 to Hill which are hereby incorporated by 
reference. The arterial cannula may be any conventional arterial cannula 
and is preferably the arterial cannula described in co-pending Ser. No. 
08/749,683, filed Nov. 15, 1996 by David Snow, which is also hereby 
incorporated by reference. Furthermore, the arterial cannula 15 and/or 
aortic occlusion device 10 may be introduced through an artery superior of 
the aortic arch, such as the subclavian artery, as taught by U.S. Pat. No. 
5,584,803 to Stevens or directly into the aortic arch as taught by U.S. 
Pat. No. 5,556,412 to Hill. Although it is preferred to be able to 
separate the aortic occlusion device 10 from the arterial cannula 15, the 
functions of the aortic occlusion device 10 and the arterial cannula 15 
may be combined into a single, multi-channel catheter as shown in U.S. 
Pat. No. 5,433,700 to Peters. 
Referring again to FIGS. 1 and 16, the coronary sinus catheter 20 is 
introduced into the patient's venous system through the right internal 
jugular vein 44 and is advanced through the right atrium 45 and into the 
coronary sinus 21. The coronary sinus catheter 20 is provided with a 
flexible shaft 553 having a occlusion balloon 554 for occluding the 
coronary sinus 21. A vent catheter 54 (FIG. 1) is advanced through the 
internal jugular vein 44 and extends through the right atrium 45 and right 
ventricle 55 into the pulmonary trunk 56. The vent catheter 54 passes 
through tricuspid valve 57 and pulmonary valve 58 for venting blood from 
the pulmonary artery. 
Referring to FIG. 6, a schematic representation of a patient's heart 100 
partly cut-away is shown. The occluding member 11 is inflated to occlude 
the ascending aorta to separate the coronary arteries from the remainder 
of the circulatory system. An endovascular device for performing a 
diagnostic or therapeutic procedure, represented here by a side-firing 
fiberoptic laser catheter 500 coupled to a laser device 531, is introduced 
into the patient through the main lumen 40 of the aortic occlusion device 
10. In this illustrative example, a side-firing fiberoptic laser catheter 
500 has been introduced through the aortic occlusion device 320 for 
performing TMR. The proximal end of laser catheter 500 is coupled to laser 
device 531. The distal tip 501 of the catheter 500 is positioned to direct 
a focused beam of laser energy 502 at the wall 101 of the left ventricle 
13 to open a blood flow passage into the myocardium. In an alternate mode 
of operation, the side-firing fiberoptic laser catheter 500 can be 
introduced into one or more of the patient's coronary arteries and the 
laser beam 502 directed toward the left ventricle 13 to open a blood flow 
passage from the ventricle 13 into the coronary artery. This technique is 
repeated until about twenty to thirty (20-30) one millimeter diameter 
holes 503 are formed in the ventricle as shown in FIGS. 8 and 9. 
Referring to FIG. 7, the side-firing fiberoptic laser catheter 500 has a 
shaft 505 containing an optical fiber 506 surrounded by cladding 507. A 
housing 508, which is preferably made of stainless steel, is attached to 
the shaft 505 with a crimp 510. A reflective insert 511 is positioned 
within the housing 512. The insert 511 has a highly reflective surface 513 
which deflects the laser through an aperture 516 in the side of the 
housing 512. A highly polished gold surface, provided by making the 
reflective insert 511 of gold or by plating a gold coating onto the 
reflective surface 511, can reflect up to 98% of the incident laser 
energy. The reflective surface 511 can be polished in a curve as shown so 
that the laser beam is focused at a selected distance from the catheter 
distal tip 501 to control the depth to which the blood flow passages are 
opened into the myocardium. Specific examples of other suitable laser 
catheters 500 are described in the following patents which are hereby 
incorporated by reference: U.S. Pat. Nos. 5,354,294, 5,366,456, 5,163,935, 
4,740,047, 5,242,438, 5,147,353, 5,242,437, 5,188,634, 5,026,366, and 
4,788,975. 
The combination of the laser catheter 500 with the aortic occlusion device 
10 allows the patient's heart to be stopped and the circulatory system 
supported on cardiopulmonary bypass during the procedure. This allows for 
more precise placement of the myocardial channels. It also allows the 
combination of TMR with other cardiac procedures that may be performed on 
the patient while the heart is stopped. The same holds true if the laser 
catheter 500 is used for ablation of other material within the heart or 
the blood vessels including ablation of an electrophysiological node 
within the heart walls for treatment of atrial or ventricular tachycardia 
or other electrophysiological problems. 
After completion of the first endovascular procedure, another endovascular 
procedure may commence. In particular, once TMR has been performed an 
agent may be delivered to heart. Referring to FIG. 8, a coronary guiding 
catheter 517 is introduced through the lumen 40 of the aortic occlusion 
device 320. After the coronary guiding catheter is properly positioned in 
a coronary ostia, an agent delivery catheter 518 is advanced through lumen 
521 of the coronary guiding catheter 517 and into the coronary artery 51. 
The agent delivery catheter provides a delivery port 520 proximate a 
distal end thereof for delivery of the agent. In most instances, as shown 
in FIGS. 8 and 9, the delivery port 520 of the agent delivery catheter 518 
is to be positioned just upstream from the stenosis 102 for delivery of 
the agent. The agent may be any suitable agent includes vascular 
endothelial growth factor (VEGF). 
Another agent delivery technique is to inject the agent directly into the 
myocardium by piercing the artery wall 103 of the coronary artery. Such 
delivery may be accomplished through either needle injection (FIGS. 9 and 
10B) or jet infusion (FIG. 11A and 11B). For needle injection a needle 
sheath 522 (FIGS. 10A and 10B) is advanced and guided into one of the 
coronary ostia 53 using the guiding catheter 517. The sheath is advanced 
through the coronary artery to a position upstream from the desired region 
of delivery. Once the needle sheath 522 is properly positioned, a needle 
catheter 523 is advanced through the needle sheath 522. A needle 527 
having a delivery tip 528 is configured to pierce the coronary artery wall 
103. As best illustrated in FIG. 10B, the needle 527 is preferably hooked 
or C-shaped and is biased outwardly relative to a longitudinal axis of the 
flexible shaft 526 of the injection catheter 523. It will be understood 
that needle 527 is flexible to enable advancement of the injection 
catheter 523 through the needle sheath 522. Needle 527 is preferably made 
a material sufficiently rigid to enable piercing of the artery wall yet 
sufficiently flexible enough so that the needle 527 can be straightened 
for advancement through the needle sheath 522. Suitable materials for the 
needle 527 include stainless steel and NiTi or other shape memory alloys. 
It will be understood that needle 527 may include two or more tips each 
biased outwardly. Further, the needles can be biased outwardly using 
angled passages extending through the walls of the catheter (not shown). A 
syringe is attached to a fitting 532 (FIG. 1) to supply agent to the 
needle 527. 
An alternative technique for delivery of the agent is jet infusion. 
Referring to FIG. 11A, an infusion catheter 533 has an array 535 formed to 
infuse agent through the coronary artery wall and into the myocardium. The 
catheter 533 has a balloon 536 mounted to a shaft 537 with the array 535 
positioned around the balloon 536. A syringe or other inflation device 
(not shown) is coupled to an inflation lumen 538 for inflating the balloon 
536. 
In a preferred form, the array 535 includes a plurality of spaced-apart 
deflection members 540 extending around the balloon which are formed to 
deflect toward the intimal surface of the coronary artery 51 during 
inflation of the balloon. Each deflection member 540 includes a conduit 
541 which is in fluid communication with an agent lumen 542. In turn, the 
agent lumen 542 is coupled to an injection mechanism (not shown) for 
infusion of the agent. A plurality of orifices 543 (about 10-50 .mu.m) 
extend from the deflection members for jet infusion delivery of the agent. 
After proper positioning of the catheter 533 in the coronary artery, the 
balloon 536 is inflated to expand the infusate array 535 into contact with 
the coronary artery wall. The agent is then delivered through the orifices 
543 so that the agent penetrates the coronary artery wall and is infused 
into the myocardium. After delivery of the agent, which may be VEGF after 
a TMR procedure, the balloon 536 is deflated so that the catheter 518 can 
be withdrawn. Examples of infusion array catheters 533 and other 
intravascular agent delivery catheters are described in the following 
patents which are hereby incorporated by reference: U.S. Pat. Nos.: 
5,419,777; 5,354,279; 5,336,178; and 5,279,565. 
In an alternative embodiment, as shown in FIG. 12, each deflection member 
540 of the infusion array 535 may include a plurality of injection needles 
546 positioned radially outwardly therefrom. Each needle 546 is coupled to 
the corresponding conduit and each is formed to pierce through the 
coronary artery wall when the balloon is inflated to deliver agent into 
the myocardium. 
Turning now to FIGS. 13 and 14A-14C, another agent delivery system is 
illustrated combining a stent delivery catheter 547 with the aortic 
occlusion device 320. In this configuration, a stent 548 is delivered and 
implanted in the coronary artery. The stent is preferably impregnated with 
the desired agent for timed release to the surrounding vascular plexus. 
The stent delivery catheter 547 is advanced through a guiding catheter 517 
which is advanced through the aortic occlusion device 320 in the manner 
described above. 
The stent delivery catheter 547 has a balloon 536 mounted to a shaft 537. 
The stent 548 is mounted, in a compressed state, over the balloon 536. A 
fluid-filled syringe or other inflation device (not shown) is used to 
inflate the balloon 536. A guidewire 560 may be used to advance the stent 
delivery catheter 547 through the coronary artery 51 to the site of a 
coronary stenosis 102. The balloon 536, which is deflated with the stent 
548 mounted thereon, is then advanced across the stenosis 102 as shown in 
FIG. 14A. FIG. 14B illustrates that when the balloon 536 is inflated, the 
stent 548 is expanded to dilate the stenosis 102. The balloon 536 is then 
deflated and the catheter 547 is withdrawn leaving the stent 548 in the 
coronary artery 51 (FIG. 14C). 
The stent 548 is preferably impregnated with a therapeutic agent for 
delivery to the myocardium in a timed release manner. The stent is 
preferably composed of a conventional stent material such as stainless 
steel, NiTi or other shape memory alloys. A bioabsorbable coating 551, 
impregnated with the desired agent, is coated over stent 548 so that the 
agent can be absorbed into the myocardium through the coronary artery 
wall. Accordingly, once the stent 548 is properly positioned and expanded 
in the coronary artery 51 to dilate the stenosis 102 (FIG. 14C), the timed 
release of the agent directly to the vasculature of the myocardium can 
commence. Suitable bioabsorbable coatings may include fibrin based glues, 
absorbable polymers, and ethylene vinyl acetate copolymers, waxes, 
hydrophilic gums, hydrogels, poly(othoesters), poly(orthocarbonates). 
Other bioabsorbable coatings suitable for use with the present invention 
are disclosed in U.S. Pat. No. 5,518,730, hereby incorporated by 
reference. Alternatively, stent 548 itself may be composed of a 
bioabsorbable material which is impregnated with a therapeutic agent. 
Examples of balloons suitable for expanding a coronary artery stent are 
described in U.S. Pat. Nos. 5,055,024 and 4,490,421 which are hereby 
incorporated by reference,. Examples of arterial stents and stent delivery 
catheters are described in U.S. Pat. Nos. 5,041,126, 4,856,516 and 
5,037,392 which are hereby incorporated by reference. 
Referring to FIG. 15, the stent 548 has needles 552 protruding radially 
outward to penetrate the coronary artery wall 103. Upon inflation of the 
balloon 536, the needles 552 are urged through the intimal surface 105 of 
the coronary artery wall. The needles 552 not only provide anchor the 
stent 548 but also provide a conduit for delivery of the agent into the 
surrounding myocardium. 
The agent may also be simply through the main lumen of the aortic occlusion 
device 10 or the coronary sinus catheter 20. Delivery of the agent, such 
as VEGF, may be independent or simultaneous with the delivery of 
cardioplegic fluid. When the agent is VEGF, it is preferable to deliver 
the agent at the end portion of the delivery cycle of the cardioplegic 
agent. Preferably, this delivery occurs during at least about the last 
one-third of the total duration of one full cycle of the infusing step. 
After delivery of the agent, the infusion is stopped for a predetermined 
time to enable absorption of the VEGF or therapeutic agent into the 
vasculature of the heart. 
Since the agent delivered may be potent, such as VEGF, systemic circulation 
may be undesirable. Thus, after delivery of the agent, containment or 
isolation of the therapeutic agent is desirable. One particular advantage 
of the present invention is that the eventual dispersion of the VEGF to 
the systemic circulation can be minimized. The aortic occlusion device 10, 
coronary sinus catheter 20 and vent catheter 54 cooperate to remove the 
agent so that the agent is not released into the systemic circulation. 
When the agent is delivered antegrade through the aortic occlusion device 
10, the coronary sinus catheter 20 withdraws the agent. When the agent is 
delivered retrograde through the coronary sinus catheter 20, the agent is 
withdrawn through the aortic occlusion device 320. The vent catheter 54 
can be used to remove fluids and agents from the pulmonary artery whether 
the fluids or agents are delivered through the aortic occlusion device 10 
or the coronary sinus catheter 20. 
Systemic isolation and withdrawal of the agent may also be performed 
through bi-caval occlusion techniques in combination with the aortic 
occlusion device 320. As best viewed in FIG. 17, a doubled-balloon 
catheter 555 may be employed which is preferably inserted through the 
femoral vein. The double-balloon catheter 555 includes a pair of balloons 
556, 557 each connected to a balloon inflation device (not shown) through 
suitable lumens in the double-balloon catheter 555. The balloon 556 
occludes the superior vena cava 110 and the balloon 557 occludes the 
inferior vena cava 111. A blood withdrawal lumen in the catheter 555 has 
an orifice 558 flush with the upper balloon 556 to avoid venous collapse 
during blood flow into the double-balloon catheter 555. The catheter 555 
also has a series of inlet slots 560 for withdrawing blood from the 
inferior vena cava 111. Blood drawn into the inlet 558 and slots 560 
enters a common lumen and is then directed to the bypass system in the 
manner described above. 
A separate lumen in the double-balloon catheter 555 opens into the right 
atrium 45 through aperture 561 to allow evacuation of the agent from the 
right heart. Bi-caval occlusion is described in commonly owned U.S. Pat. 
Reissue No. 35,352 to Peters and U.S. Pat. No. 5,584,803, which are hereby 
incorporated by reference. Bi-caval occlusion may also be performed using 
two separate balloon catheters. FIG. 18 illustrates occlusion of the 
superior vena cava 110 with a catheter 562 advanced through the jugular 
vein 44 and occlusion of the inferior vena cava with a catheter 566. 
Referring now to FIGS. 19 and 20, an alternative method for delivering a 
therapeutic agent directly to the epicardial surface 104 of the heart 100 
is provided using thoracoscopic techniques. As stated above, timed release 
of VEGF to a TMR treatment site may have more long term success in 
stimulating angiogenesis. In contrast, a one dose regimen of VEGF may be 
absorbed and dissipated too rapidly in the body for effective exposure at 
the treatment site. One technique to increase the duration of VEGF 
stimulation is to suspend the VEGF in a substance capable of timed release 
delivery of the VEGF to the myocardium. Such an extended dosage regimen, 
accordingly, increases the likelihood of a successful exposure between the 
VEGF and the TMR treatment site. A topical solution, for example, may be 
applied directly to the epicardial surface of the heart. This substance 
may include a fibrin based glue or a biocompatible gel which continuously 
delivers the VEGF in a timed release manner up to about 25-30 days after 
the initial application. Alternatively, the VEGF could be encapsulated in 
a bioabsorbable polymer gel, viscous fluid or mixture of a solid and 
viscous fluid (slurry) that could release the VEGF over a longer duration 
of time up to about 2 years. Appropriate polymer gels include absorbable 
polymers based on polyanhydrides, polycaprolactone, lactide, glycolide, 
polydioxanone and blends, and copolymers of the former. Topical 
application of agents, such as VEGF, may also be delivered pericardialy, 
intramyocardialy, or intrapericardialy. 
Initially, TMR could be performed on the heart 100 either endovascularly 
(FIG. 6) from the endocardium out as mentioned above or from the 
epicardium inward using lasers introduced percutaneously through an 
intercostal space 106 (FIGS. 19 and 20). In the latter situation, a small 
incision 2-3 cm in length may be made between the ribs on the left side of 
the patient, usually in the third, fourth, or fifth intercostal spaces. 
When additional maneuvering space is necessary, the intercostal space 
between the ribs may be widened by spreading of the adjacent ribs, or by 
removing portions of the ribs to widen the percutaneous penetration. A 
thoracoscopic access device 107, providing an access port 108, is 
positioned in the incision to retract away adjacent tissue and protect it 
from trauma as instruments are introduced into the chest cavity. In other 
instances, instruments may be introduced directly through small, 
percutaneous intercostal incisions in the chest. 
A laser (not shown) is then introduced to perform TMR on the patient's left 
ventricle. In accordance with the present invention, an agent delivery 
applicator (not shown) may then be introduced through access port 108 of 
access device 107 to apply the suspended VEGF solution directly to the 
epicardial surface 104 of the left ventricle after a TMR channel 503 is 
formed. This applicator may be independent from the endoscopic laser or 
may be integrated or mounted thereto so that the VEGF may be applied 
immediately after the TMR formed channel 503 is created in the epicardial 
surface. For example, the endoscopic laser could include a lumen having a 
delivery port at the distal end of the laser, and a proximal end coupled 
to a syringe applicator. Manual or powered operation of the syringe 
applicator could apply the VEGF bioabsorable polymer gel, or the like, 
directly at or into the TMR created channel. 
Another thoracoscopic technique for delivering VEGF to the TMR treated 
myocardium in a time released delivery manner is through the surgical 
implantation of a VEGF coated or doped agent delivery material directly in 
the myocardium. The medication would then be continuously absorbed into 
the myocardium from the agent delivery material over an extended time. 
Preferably, the present invention of FIG. 19 provides an agent delivery 
material mounted to the epicardial surface of the heart with sutures 
piercing the epicardial surface. These sutures provide a reservoir of 
agent, as well as a capillary means for delivering the agent directly to 
the treatment side. Upon implantation of the sutures in myocardium, the 
agent flows through the suture to be delivered to the myocardium where the 
tissue contacts the suture. Subsequently, the agent is absorbed and 
dissipated into the surrounding vascular plexus. 
Turning to FIG. 19, sutures 572 are applied to the epicardial surface 104 
of heart 100 using thoracoscopic techniques. These suture materials 572 
are introduced through access port 108 using thoracoscopic needle drivers, 
forceps, pliers, or the like, mounted to a curved suture needle (not 
shown). Applying conventional thoracoscopic surgical skills, the needle 
can be negotiated through the epicardial surface 104 preferably piercing 
through the myocardium and tied off on the TMR treated epicardial surface 
104 of the heart 100 to implant the suture therein. These sutures 572 are 
applied either continuously, such as the rows in FIG. 19, or applied in an 
interrupted fashion. In the preferred form, these sutures are 
perioperatively coated or saturated with VEGF or are formulated with the 
VEGF encapsulated in the absorbable polymers composing the suture. 
Absorbable polymers which may be adequately implanted include 
polydioxanone, glycolide, lactide, and polycaprolactones to name a few. 
Alternatively, as viewed in FIG. 20, a patch 573 containing VEGF is 
positioned in contact with the epicardial surface 104 of the heart. The 
patch 573 provides a large reservoir of agent for timed release delivery. 
Similar to the mounting of the sutures, the patch 573 is mounted to the 
epicardial surface 104 of the heart 100 through the same thoracoscopic 
techniques mentioned above. Sutures 572 pierce both the patch 573 and the 
epicardial surface to provide a capillary means for delivering the agent 
to the treated myocardial site from the patch 573. 
The patch 573 may be applied before the TMR procedure so that the TMR 
channels 503 are created through the patch 573. It is understood that both 
the coated or doped sutures or the patch 573 could contain heparin or 
other anti-clotting agents to prevent or moderate the TMR channels from 
closing. Suitable agent delivery materials include any biocompatible 
material capable of absorbing or being doped, loaded, or eluted with a 
therapeutic agent. Other delivery materials include osmotic transmitters 
or those capable of leaching or diffusing. 
In an alternate mode of operation the aortic occlusion device 10 can be 
used as a guiding catheter for introducing an endovascular device and for 
performing an endovascular procedure while the patient is on partial 
cardiopulmonary support without inflating the occlusion balloon or 
inducing cardiac arrest. If and when it is desired, the aortic occlusion 
device 10 can be used to occlude the aorta and arrest the patient's heart 
thereby converting the patient from partial cardiopulmonary support to 
full cardiopulmonary bypass. This mode of operation would be advantageous 
when it is desired to follow the endovascular procedure with another 
procedure on the heart. For example, when performing a high risk 
interventional procedure in which complications arise, the patient can be 
quickly placed on full cardiopulmonary bypass and prepared for surgery 
without delay. 
While the present invention has been described herein in terms of certain 
preferred embodiments, it will be apparent to one of ordinary skill in the 
art that modifications and improvements can be made to the invention 
without departing from the scope thereof.