Cardiac drug delivery system

A system is disclosed, for administering a therapeutic agent locally and to a depth within cardiac tissue. An elongate, flexible catheter contains a flexible electric conductor and supports at its distal end an implantable electrode incorporating a penetrating element, typically a fixation helix or a linear needle that penetrates cardiac tissue as the electrode is implanted. A therapeutic agent is delivered through the electrode, to the cardiac tissue surrounding the penetrating element. The electrode acts as a sensor, electrically coupled through the flexible conductor, and monitors an electrical condition of the surrounding cardiac tissue. A controller is coupled to the sensor and to a pump or reservoir containing the therapeutic agent, to control delivery of the agent responsive to the sensed electrical condition. The implanted electrode further can be used to deliver RF current to ablate the surrounding tissue. Several embodiments feature a distal reservoir adjacent the electrode, for effecting transient deliveries of the therapeutic agent in minute quantities or chronic delivery of growth factors. Another embodiment incorporates a bilumen catheter and a set of unidirectional valves, to facilitate changing therapeutic agents or purging the catheter of an agent after delivery.

FIELD OF THE INVENTION 
This invention relates to site specific delivery of therapeutic agents, 
structures and catheter systems to achieve site specific delivery of 
therapeutic agents, and means for implanting and using these systems to 
enable delivery of therapeutic agents to the body. More specifically, this 
invention relates to delivery of pharmacological agents to specific 
regions of the heart at a depth within the heart wall. 
BACKGROUND OF THE INVENTION 
It is possible to identify particular sites within the myocardium which may 
benefit from local drug release therapy. Examples of problematic tissue 
which may benefit from local drug release therapy are ischemic sites and 
arrhythmogenic sites. Different means and methods for delivering agents to 
these sites will be disclosed in detail. Ischemic Sites 
Ischemic tissue is characterized by limited metabolic processes which cause 
poor functionality. The tissue lacks oxygen, nutrients, and means for 
disposing of wastes. This hinders the normal functioning of the heart 
cells or myocytes in an ischemic region. If an ischemic, or damaged, 
region of the heart does not receive enough nutrients to sustain the 
myocytes they are said to die, and the tissue is said to become infarcted. 
Ischemia is reversible, such that cells may return to normal function once 
they receive the proper nutrients. Infarction is irreversible. 
Non-invasive systemic delivery of anti-ischemic agents such as nitrates or 
vasodilators allows the heart to work less by reducing vascular 
resistance. Some vascular obstructions are treated by the systemic 
delivery of pharmacological agents such as TPA, urokinase, or 
antithrombolytics which can break up the obstruction. Catheter based 
techniques to remove the vascular obstructions such as percutaneous 
transluminal coronary angioplasty (PTCA), atherectomy devices, and stents 
can increase myocardial perfusion. More drastic, but very reliable 
procedures such as coronary artery bypass surgery can also be performed. 
All of these techniques treat the root cause of poor perfusion. 
It should be noted that these therapies are primarily for the treatment of 
large vessel disease, and that many patients suffer from poor perfusion 
within smaller vessels that cannot be treated with conventional therapies. 
The delivery of angiogenic growth factors to the heart via the coronary 
arteries by catheter techniques, or by implantable controlled release 
matrices, can create new capillary vascular growth within the myocardium. 
Recent work has shown substantial increases in muscular flow in a variety 
of in vivo experimental models with growth factors such as Tumor 
Angiogenic factor (TAF), basic fibroblast growth factor (bFGF), vascular 
endothelial growth factor (VEGF), and acidic fibroblast growth factor 
(aFGF). The methods of delivering these agents to the heart include 
implantable controlled release matrices such as ethylene vinyl acetate 
copolymer (EVAC), and sequential bolus delivery into the coronary 
arteries. Recently similar techniques have been attempted in peripheral 
vessels in human patients with the primary difficulty being systemic 
effects of the agents delivered. 
U.S. Pat. No. 5,244,460 issued to Unger describes a method of introducing 
growth factors over time by delivering them through fluid catheters into 
the coronary arteries, but this does not result in efficient delivery of 
these agents to the ischemic tissue. If these or other agents are 
delivered to the coronary artery, a region of tissue that is equivalent to 
that supplied by the artery will receive the therapeutic agents. This may 
be substantially more tissue than is in need of local drug delivery 
therapy. Further, if a vessel is occluded, the growth factors will act in 
the tissue which the coronary arteries successfully perfuse. As the 
underlying problem of ischemic tissue is poor perfusion, excess growth 
factor must be delivered in order to obtain the desired effects in the 
poorly perfused tissue. Further, growth factors may cause unwanted 
angiogenesis in tissues where inappropriately delivered. The cornea is 
described by Unger as such a location, but perhaps more critical is 
inappropriate delivery of these factors to the brain. Further, placement 
of delivery devices within these coronary arteries as Unger describes 
tends to obstruct these arteries and may augment occlusive thrombosis 
formation. There is a significant need for minimizing the amount of growth 
factors for introducing angiogenesis by delivering these agents only to 
the site where they are most needed. 
There are complications with clinically acceptable procedures where special 
devices for delivering agents to ischemic tissue will be useful. After 
opening vessels using PTCA, the vessels often lose patentcy over time. 
This loss of patentcy due to re-stenosis may be reduced by appropriate 
pharmacological therapy in the region of the artery. There is a need for 
new techniques that will enable pharmacological therapy to reduce the 
incidence of restenosis. Arrhythmogenic sites 
Cardiac arrhythmias are abnormal rhythmic contractions of the myocardial 
muscle, often introduced by electrical abnormalities, or irregularities in 
the heart tissue, and not necessarily from ischemic tissue. In a cardiac 
ablation procedure, the arrhythmogenic region is isolated or the 
inappropriate pathway is disrupted by destroying the cells in the regions 
of interest. Using catheter techniques to gain venous and arterial access 
to the chambers of the heart, and possibly trans septal techniques, 
necrotic regions can be generated by destroying the tissue locally. These 
necrotic regions effectively introduce electrical barriers to problematic 
conduction pathways. 
U.S. Pat. No. 5,385,148 issued to Lesh describes a cardiac imaging and 
ablation catheter in which a helical needle may be used to deliver fluid 
ablative agents, such as ethanol, at a depth within the tissue to achieve 
ablation. Lesh further describes a method of delivering a pharmacological 
agent to the tissue just before performing the chemical ablation procedure 
to temporarily alter the conduction of the tissue prior to performing the 
ablation. Such temporary alteration of tissue has the advantage of 
allowing the physician to evaluate the results of destructive ablation in 
that region prior to actually performing the ablation. This method of 
ablation has the advantage that the ablative fluid agents are delivered to 
essentially the same tissue as the temporary modifying agents. However, 
with ablative fluid agents it is difficult to control the amount of tissue 
which is destroyed--especially in a beating heart, and ablative RF energy 
is in common use because of its reproducible lesions and ease of control. 
There is a need for an ablation catheter that uses a single structure 
within the heart wall for both temporary modification of tissue 
conductivity by delivery of therapeutic agents at a depth within the 
tissue, and delivery of RF energy. 
U.S. Pat. No. 5,527,344 issued to Arzbaecher and incorporated by reference 
herein, describes a pharmacological atrial defibrillator and method for 
automatically delivering a defibrillating drug into the bloodstream of a 
patient upon detection of the onset of atrial arrhythmias in order to 
terminate the atrial arrhythmias. By delivering agents to a blood vessel, 
Arzbaecher requires systemic effects to be achieved in order to terminate 
the atrial arrhythmias. The advantages of local drug delivery are absent 
from the system described. There is a need for a system and method to 
transiently treat atrial arrhythmias by local delivery of pharmacological 
agents which affect the excitation of the cardiac tissue locally. 
Many patents describe systems for delivering anti inflammatory agents to 
the endocardial surface of the heart. Such surface delivery is less viable 
for regions at a depth within the tissue. Further, because of the volume 
of fluid moving by the inner surfaces of the heart, higher concentrations 
may be required at the surface to counteract the effects of dilution. 
These higher doses result in greater likelihood of problematic systemic 
effects from the therapeutic agents. Delivering agents within the tissue 
will minimize the dilution of agents, and decrease the possibility of the 
agents being delivered to inappropriate sites. This is particularly 
important with growth factors whose systemic affects are not well 
documented, just as it is important for antiarrhythmic agents whose 
pro-arrhythmia systemic effects have been recognized. There is a need for 
a means to deliver agents to ischemic and arrhythmogenic sites within the 
myocardium. 
To deliver substances at a depth within the heart, U.S. Pat. Nos. 5,447,533 
and 5,531,780 issued to Vachon describe pacing leads having a stylet 
introduced anti inflammatory drug delivery dart and needle advanceable 
from the distal tip of the electrode. U.S. Pat. No. 5,002,067 issued to 
Berthelson describes a helical fixation device with a groove to provide a 
path to introduce anti-inflammatory drug to a depth within the tissue. 
U.S. Pat. No. 5,324,325 issued to Moaddeb describes a myocardial steroid 
releasing lead whose tip of the rigid helix has an axial bore filled with 
a therapeutic medication such as a steroid or steroid based drug. None of 
these patents provides a means for site specific delivery of agents as all 
applications of the drug delivery systems are at the location selected for 
pacing. None of these provides a means or method for delivering agents to 
ischemic or infarcted tissues. Only Vachon and Moaddeb provide a means for 
effectively delivering the anti-inflammatory agents to a depth within the 
myocardium. U.S. Pat. No. 5,551,427 issued to Altman describes a catheter 
system capable of delivering drugs to the heart at a depth within the 
heart tissue. 
U.S. Pat. No. 5,431,649 issued to Mulier describes a hollow helical 
delivery needle to infuse the heart tissue with a conductive fluid prior 
to ablation to control the lesion size produced. The system does not have 
drug delivery capabilities. 
None of the prior art includes the use of macromolecular controlled release 
matrices such as ethylene vinyl acetate copolymer to deliver agents with 
large molecular weights to a depth within the heart tissue. 
OBJECTS AND ADVANTAGES 
In general it is an object of the present invention to provide a 
biocompatible drug delivery catheter which will improve the ability to 
deliver drugs to a depth within the heart tissue. 
Another object of the invention is the delivery of growth factors to a 
depth within the heart tissue over an extended period of time to increase 
collateral flow in poorly perfused tissue. 
Yet another object of the invention is to provide a permanently implantable 
system that will enable transient delivery of pharmacological agents to a 
depth within the heart tissue such that cardiac arrhythmias may be 
terminated. 
It is also an object of the invention to provide a combination drug 
delivery and ablation catheter that will enable a region of the heart 
tissue to be modified pharmacologically prior to performing RF ablation at 
a depth within the heart tissue. 
It is a further object of the invention to provide catheters with 
implantable osmotic pumps at their distal ends that deliver 
pharmacological agents to a depth within the myocardium. 
Another object of the invention is to provide catheters with controlled 
release matrices at their distal ends that deliver pharmacological agents 
to a depth within the heart tissue. 
A further object of the invention is to provide catheters with fluid 
pathways from proximally located reservoirs which may deliver fluids to a 
depth within the myocardium, with an electrical conductor to sense the 
heart so an external device may determine when to deliver pharmacological 
therapy to a depth within the heart tissue. 
A further object of the invention is to provide catheters with fluid 
pathways from proximally located reservoirs which may deliver fluids to a 
depth within the myocardium, with a high conductivity electrical conductor 
capable of delivering RF therapy to the heart from the metallic structure 
used to deliver drugs to the heart. 
Yet another object of the invention is to provide catheters with a means to 
clear the agents from a catheter and replace them with other agents. 
Further objects and advantages of this invention will become apparent from 
a consideration of the drawings and ensuing description.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
New concepts for delivering agents for the treatment of heart failure, 
ischemia, arrhythmias, and restenosis are disclosed. The main embodiments 
consist of transvenous or transarterial catheter delivery techniques for 
delivering agents directly to a chosen site within the heart at a depth 
within the heart tissue. Hollow helical delivery devices, needle delivery 
devices, and implantable controlled release matrices may be inserted such 
that metabolic agents, anti ischemic agents, growth factors, 
antiarrhythmic agents, anti-inflammatory agents anti-proliferative agents, 
gene therapy preparations, and combinations of these agents may be 
delivered directly to the tissue that can benefit most from these agents. 
These drug delivery structures may be made from different materials 
depending upon whether the device is to be used chronically or acutely. 
For example, metal components in the preferred implantable embodiments, 
formed of a Platinum Iridium alloy consisting of ninety percent Platinum 
and ten percent Iridium, typically are replaced with 316L surgical 
stainless steels in the acute embodiments. Likewise implantable grades of 
silicone and polyurethane are replaced with polyurethanes, polyolefins, 
fluoropolymers, nylon, and the like in the acute uses of the devices. 
Herein the term catheter is used to describe both chronically and acutely 
implantable systems. 
FIG. 1a shows a first cardiac drug delivery catheter with a sectional view 
of the proximal end. A pin 2 is shown mechanically crimped at a crimp 6 to 
an electrically conductive helical coil 8. Crimp 6 is typically covered by 
a compliant polymer molding 4 which may form a seal with a catheter port 
on a drug delivery reservoir or pumping means 16. Such a reservoir, shown 
schematically at 16, may be implanted subcutaneously or located outside 
the patient. A line 18 represents a fluid coupling of reservoir 16 to 
lumen 12, which enables delivery of fluid treatment agents from the 
reservoir to fixation end 24. Further molding 4 and a catheter body or 
sheath 14 may have external sealing rings to provide fluid tight seals 
with such ports. Pin 2 connects to an internal tubing 10 with a lumen 12 
which extends the entire length of the catheter to the distal end 22 and 
allows for fluid agents to be delivered through a fluid pathway in 
fixation end 24. The catheter body or sheath 14, 20, and 22 covers the 
coil 8 along the entire length of the delivery system distal to crimp 4 
such that rotation of pin 2 or crimp 4 relative to proximal catheter body 
14 rotates coil 8 within catheter body 14, 20, and 22 and deploys fixation 
mechanisms at fixation end 24. The central lumen 12 in some embodiments 
may also be used to pass a stylet for use during implantation to 
facilitate the implantation procedure. 
The catheter shown in FIG. 1a is made of permanently implantable materials, 
it has electrical continuity from end to end for sensing cardiac activity, 
it has a lumen for conveying fluidic agents along its length, and a hollow 
fixation means for delivering fluidic agents to a depth within the heart 
tissue. 
Further as to the sensing of cardiac activity, a monitor and control device 
26 is electrically coupled to pin 2 through a line 28, thus to enable a 
sensing of highly localized cardiac electrical activity at device 26. 
Cardiac activity can be recorded at device 26, e.g. stored in a memory 
chip (not shown). Further, sensed cardiac activity may be employed to 
provide controlling signals to reservoir 16 through a line 30, e.g. to 
initiate or terminate the supplying of a fluid agent from the reservoir, 
responsive to sensing a predetermined activity or condition in cardiac 
tissue proximate fixation end 24. The materials selected are suited for 
permanent implantation to provide for transient drug delivery driven by a 
proximal reservoir and energy source. For example, catheter body 14, 20, 
and 22 is an implant grade polyurethane or silicone, and the distal 
fixation mechanism at fixation end 24 is a platinum iridium alloy. The 
catheter has a single electrode to facilitate implantation by sensing the 
electrical potential at the implant site. This combination achieves the 
advantages of ease of implantation, and delivery of fluidic agents to a 
depth within the heart from a proximally located reservoir. 
In another embodiment, the monitor and control device 26 is not required. 
Instead, reservoir 16 pumps at a low, constant rate, supplying infusing 
agents to a depth within the myocardium, thus to locally apply selected 
agents, such as angiogenic growth factors, at a steady rate over an 
extended period, e.g. one week. 
FIG. 1b shows another embodiment of the proximal end of a catheter delivery 
system in which a stylet lumen 66 is provided for insertion of a stylet. 
Such an additional lumen may be useful to prevent contamination of an 
inner drug delivery tubing 62 during implantation. Inner tubing 62 is 
connected to a pin 52 at a connection 56, which may be performed simply by 
pulling tubing 62 over pin 52 at connection 56. An electrically conductive 
coil 60 surrounds tubing 62 and may be rotated relative to outer jacket or 
catheter body 58 of the delivery system. After implantation using a stylet 
in stylet lumen 66, pharmacological agents may be delivered to the heart 
by a fluid pathway defined by a delivery system lumen 64. In this specific 
embodiment, crimp 54 which connects pin 52 and coil 60 is not overmolded, 
and a single set of seals 70 are shown molded over the proximal end of 
catheter body 58. Seals 70 prevent migration of fluids into the catheter 
after connection with a catheter port in a drug delivery reservoir or 
pumping means. In one embodiment, the distal end of the drug delivery 
catheter shown in FIG. 1b would be the distal embodiment shown in FIG. 5b. 
FIG. 1c shows a partial cross sectional view of the distal portion of a 
delivery catheter which is to be implanted endocardially by the 
appropriate venous or arterial access. Here, a simple pathway for fluid to 
pass from a subcutaneous reservoir or delivery pump (not shown) through a 
deployable helical needle is provided. Helical coil 102 is multifilar, but 
could be single filar as well. The number of filars can be varied to 
determine the flexibility of the catheter as well as the coil's ability to 
transmit torque to fixation helix 114. The fixation helix is screwed into 
the heart by turning a coil 102 inside an outer catheter body 106. A fixed 
structure 130, on the inner wall of the catheter body 106, facilitates 
advancement and retraction of the fixation helix 114 by forcing the 
helical fixation structure 114 to advance from the distal end of the 
catheter when the central helical coil 102 and tube for drug delivery 104 
are rotated counterclockwise. Fixed structure 130 is typically formed from 
a radio opaque material to assist the implanting physician in identifying 
when fixation helix 114 has been deployed. Fixed structure 130 also will 
retract the fixation helix 114 from the heart wall when the coil 102 is 
rotated clockwise. These directions could be reversed by varying the 
direction of the winding of the fixation helix 114. The helical coil 102 
which provides torque to implant the fixation helix 114 is welded or 
crimped to a coupling structure or torque delivery structure 110 at a coil 
to torque delivery structure connection 128. Here, the coil is shown 
crimped at connection 128. Proximal stop 124, and distal stop 112 are 
raised portions on the inside of the catheter body 106, and prevent the 
fixation helix 114 from being extended or retracted too far. A fluid path 
is provided from the proximal end of the catheter (not shown) by tube for 
drug delivery 104 which connects to the tube fitting 126 of the hollow 
fixation helix 114. The hollow fixation helix 114 may have a number of 
small holes or helix apertures 116, 118, 120, 122 along its length where 
it is penetrated into the heart tissue. These holes provide a means for 
delivering agents into the heart tissue at a depth within the tissue. 
Helix tip 132 is sharp to facilitate penetration of the heart tissue, and 
acts as a further opening for the agents to migrate from the tissue. In 
some embodiments the helix apertures may be on only the distal portion of 
the helix to minimize the possibility of agents being delivered within the 
heart chambers. In other embodiments, the helix apertures are not present 
to maximize the structural integrity of the fixation helix. Where this is 
the case, agents are delivered to the heart from the aperture at the 
hollow helix tip 132. The fixation helix 114 is rigidly attached to the 
torque delivery structure 110 to provide means for advancement when coil 
102 is rotated. 
FIG. 1c shows a means for delivering agents by a fluid path to a depth 
within the heart tissue, to provide a wide variety of agents by way of a 
fluid pathway to a depth within the tissue from a proximally located 
reservoir. Helix 114 acts as an electrode, with electrical energy being 
transmitted along helical coil 102 to and from fixation helix 114 by way 
of electrically conductive torque delivery structure 110. It can be viewed 
as the distal end of the implantable catheter whose proximal end is shown 
in FIG. 1a or FIG. 1b. In one embodiment, the device of FIG. 1 could be 
used for chronic delivery of antiarrhythmic agents to alter local 
conduction either continuously, or on demand based upon the signals sensed 
through fixation helix 114. Such algorithms have been described for 
pharmacological atrial defibrillation by Arzbaecher in U.S. Pat. No. 
5,527,344. In other embodiments agents for a variety of disease states may 
be continuously infused by the fluid pathway to a specific site within the 
myocardium. The proximal end of the catheter may be connected to a drug 
pumping mechanism or to a proximally located reservoir. Such proximal 
devices may be implanted or located outside the patient. Access to 
implantable proximal devices for refilling agents is achieved with a 
subcutaneous port. 
Transient delivery of pharmacological agents based upon demand requires the 
presence of electrical conductors along the length of the drug delivery 
catheter to monitor the electrical action of the heart, e.g. the heart 
rate as indicated by a time-dependent voltage. Delivering of agents upon 
demand locally alters the conduction or automaticity of the cardiac tissue 
and allows for the arrhythmia to be treated. Only a small amount of drug 
is required to treat a specific location within the tissue, which has 
substantial benefits. Small doses of antiarrhythmic agents minimize the 
need to refill the proximally located reservoir; and reduce the systemic 
effects from large drug doses as well as the effects of the agents on 
normally functioning cardiac tissue. In one application of this 
embodiment, the device is implanted in the right atrium at a location 
determined to be most likely to terminate a patients supraventricular 
arrhythmia. A subcutaneous infusion pump is triggered by the electrical 
activity of the heart, and a very small region of tissue receives local 
drug delivery for a preprogrammed duration. A small region of heart is 
then modified such that cardiac excitation wavefronts are altered by the 
tissue treated. This provides substantial advantages to patients. Typical 
of the drugs delivered are antiarrhythmic agents such as those described 
in U.S. Pat. No. 5,551,427 issued to Altman. 
In another embodiment, the device in FIG. 1c is an acute catheter made of 
nonimplantable materials. Catheter body 106 is formed of polyurethane or a 
fluoropolymer such as ETFE or PTFE; helical fixation structure 114, and 
torque delivery structure 110 are made of Titanium or 316L stainless 
steel. Such a catheter is used for acute ablation procedures in which 
antiarrhythmic agents are delivered to temporarily alter the conduction of 
the heart at the site of the implanted helix. Electrical mapping and 
stimulation measurements are made to determine if the region is 
appropriate to be ablated. If the region is not appropriate the device is 
removed and repositioned. If the region treated by the antiarrhythmic 
agents which affect tissue conduction is desired to be ablated, RF energy 
is delivered from the electrically active helix to a large surface 
electrode, such as that used in electrocautery. Such an electrode is shown 
schematically in FIG. 1a as a patch electrode 32 that can be in contact 
with the patient's skin outside the body. A conductor 34 electrically 
couples electrode 32 with monitor and control device 26, whereby device 26 
is employed in a known manner to utilize a circuit including conductors 28 
and 34, electrode 32, pin 2, crimp 6, coil 8 and a fixation element at the 
distal end of the coil, to generate an RF current through tissue between 
the fixation element and electrode 32. The region ablated is that near the 
surface of the implanted helix. The helical coil 102 is highly conductive 
to enable RF energy to be conducted to the distal fixation structure to 
allow ablation of the region immediately at the fixation structure. Such a 
high conductivity coil can be formed from a number of wires wrapped in 
parallel in which each wire has a high conductivity silver core jacketed 
by an MP35N non corrosive alloy. This catheter provides for both temporary 
modification of tissue conductivity by delivery of therapeutic agents to a 
depth within the tissue, and delivery of RF energy from the same 
structure. 
FIG. 2 shows another distal portion of a delivery catheter for endocardial 
placement. The operation is similar to that just described. However, here 
the fixation structure 202 is solid and does not provide a fluid path for 
delivery of agents. The fluid pathway is instead provided by a centrally 
located hollow needle 204. Apertures could also be made along the needle 
to provide more exposure to the tissue within the heart wall. Fluid agents 
flow through connecting tube 104, inside the hollow needle 204, and out 
through apertures in the surface (not shown) and the needle tip 206. 
Agents are delivered via the needle to a depth within the tissue. Thus, 
needle 204 provides a tissue penetrating element distinct from the 
fixation element, whereas in FIG. 1c the penetrating element and fixation 
element are the same, i.e. helix 114. The solid fixation structure 202 
advances in the same manner as described in FIG. 1, and may be rigidly 
attached to the torque delivery structure 110 by a weld 208. Other methods 
of connection are possible. The primary advantage of this design is that 
the solid helical fixation structure 202 is structurally more robust than 
that of the hollow structure shown in FIG. 1c. This facilitates 
implantation of the structure. 
Other embodiments which incorporate osmotic pumps, controlled release 
matrices, membrane barriers, and catheter based transient delivery means 
increase the ability to control the delivery of agents to a depth within 
the heart tissue. They have substantial advantages in delivering agents 
such as growth factors and gene therapy preparations in that very small 
amounts of the agents are effective, the delivery is controlled over time, 
and the agents are delivered to a depth within the heart. 
FIG. 3a shows an osmotic pump located at distal end of a catheter to drive 
therapeutic agent into heart tissue using a needle 318. Alternatively a 
hollow helix fluid transport system as described can be employed. Agents 
may be delivered via the fluid pathway previously described, through the 
check valve 302, and into the drug volume or drug reservoir 304. After the 
drug reservoir 304 is full, agents migrate out the needle tip 320, and 
apertures 322. Reservoir 304 may be loaded before, during, or after 
implantation from the proximal end of the drug delivery catheter. Once 
advanced into the heart tissue, diffusion of a liquid across the 
semipermeable membrane 312 occurs because of an osmotic salt 310. As this 
salt expands with hydration, pressure is exerted against the flexible 
barrier 306 and the rigid osmotic pump housing 308. The expansion 
constricts the drug volume 304. As check valve 302 is closed to reverse 
flow, the agents are forced through the delivery structure and into the 
heart wall. The pathway to needle tip 320 includes proximal needle 
apertures 316 and proximal needle opening 324 within the reservoir 304. 
The rigid support 314 supports the fixation helix and the needle delivery 
structure. 
Placing an osmotic pump directly at the site where agents are delivered has 
the benefit of limiting the amount of agent in the system. In devices 
where the agent in the filling tube can be removed, the site specific 
osmotic pump does not require a long length of tubing filled with 
pharmacological agent. This may be particularly useful for agents whose 
systemic effects are undesirable or unknown. To deliver agents by a fluid 
pathway along the length of a catheter system requires a length of tubing 
to be filled with the appropriate agent. Although minimizing the cross 
sectional area of such a tube reduces excessive amounts of agents, putting 
the pump at the site for delivery eliminates the problem. Placing the 
osmotic device at the end of the catheter tube provides the advantageous 
means for follow-up delivery after the pump has delivered all of the 
agents in the reservoir 304. Further, only a very small amount of agent is 
required and the osmotic pump is placed on a catheter at the site for 
delivery. A catheter based osmotic pump as in FIG. 3a may be filled 
proximally after implant, and agents may be altered during delivery. Such 
delivery techniques have substantial advantages for macromolecules such as 
growth factors and genetic material. Further, they may allow for very 
controlled delivery of microsphere or micelle encapsulated agents. 
The drug reservoir 304 can contain either a solution or a solid formulation 
in a semipermeable housing with controlled water permeability. The drug is 
activated to release in solution form at a constant rate through a special 
delivery orifice (e.g. either 316 or 322). The release of drug molecules 
or encapsulated drug molecules from this type of controlled release drug 
delivery system is caused by osmotic pressure and controlled at a rate 
determined by the water permeability and the effective surface area of the 
semipermeable housing as well as the osmotic pressure gradient. Devices 
which use hydrodynamic pressure gradients are similar except the 
semipermeable membrane is replaced by an opening, and the osmotic salt is 
replaced by an absorbent and swellable hydrophilic laminate. 
FIG. 3b shows a partially sectional view of another embodiment of the 
distally located osmotic pump. Here a check valve 402 is located at the 
proximal end of a tip 404 which extends through drug volume or reservoir 
304. Needle 404 provides more structural stability to the drug delivery 
device and guarantees a fluid pathway to the delivery needle 320 even 
after the osmotic action has driven all of the agent out of the drug 
volume 304. Further, a section of a seal 406 is shown attached to the 
inside of the catheter body. Osmotic pump housing 308 is moveably 
contained within seal 406, which acts to prevent migration of fluids into 
the catheter body. 
FIG. 4 shows another embodiment of a cardiac drug delivery system. Here the 
fixation mechanism consists of a needle 484 with apertures 486 that 
penetrates the myocardium and is held in place by barbs 466. In a chronic 
implant barb 466 may be composed of either a rigid metallic alloy or a 
biodegradable 5 polymer. If a biodegradable material is used, long term 
tissue attachments will maintain fixation with the heart, and the barb 466 
will not cause undue trauma should the drug delivery system need to be 
explanted. 
In addition, FIG. 4 shows a multilumen catheter and valve system for the 
filling of reservoir 462. Agents are delivered along the fluid path 
defined by a filling lumen 452 in a bilumen tubing 450 such that 
unidirectional check valve 456, shown here as a ball check valve, is 
opened allowing agents to flow through lumen 458 of tube 460 and out the 
distal end of tube 480. The ball check valve has a sphere in a generally 
conical tube which allows unidirectional flow by obstructing the smaller 
diameter fluid pathway to reverse flow and not obstructing the larger 
diameter circular pathway of the open flow direction. In various 
embodiments it could be replaced with a reed check valve, a hinged plate 
check valve, or the equivalent. After the reservoir 462 is filled, the 
fluid will open check valve 472 and flow out clearing lumen 468 in bilumen 
tube 450. This filling action will force ball check valve 470 closed. 
After filling, the remaining agent in the bilumen tube may be cleared by 
delivering sterile distilled water, which may contain anticoagulants such 
as heparin to assure long term patentcy of the catheter lumens, to 
clearing lumen 468. This clearing fluid will force check valve 472 closed, 
and check valve 470 open such that agents may be flushed from the bilumen 
tube and replaced with the distilled water or other flushing agents. If 
the system is chronically implanted, such a bilumen tube and series of 
valves would allow one to fill the reservoir 462 and clear the bilumen 
tube 450 after implant. Further, because the distal end of the tube 480 
allows for filling of the reservoir 462 from the distal end, agents may be 
changed merely by filling via filling lumen 452 which will force the 
existing agents out through proximal reservoir exit 474, through valve 472 
and clearing lumen 468. If the proximal end of such a bilumen delivery 
system were connected to a dual port subcutaneous reservoir (not shown) 
agents would be injected into one port while withdrawn from the second 
port. 
In this delivery catheter, the distal housing also acts as an osmotic 
delivery system with semi permeable membrane 496, hydrophilic salt or 
agent 476, and flexible polymer barrier 464 allowing for controlled 
delivery of agents over a period of time. After the expiration of the 
osmotic energy source, agents may be delivered via the fluid pathway by an 
external pumping means if desired. The valve housing 454 houses the three 
unidirectional valves 456, 470, and 472, and provides tube fittings 488 
and 490 for connection to the bilumen tubing. This valve housing 454 is 
also attached by a crimp 494 to the coil 492. This structure is assembled 
from the separate components and combined. Alternatively, separate valves 
could be fit into openings in a simpler metallic form, and the whole 
mechanically and hermetically attached to the rigid osmotic pump housing 
478. Rigid support 482 is fixed to needle 484, and may also have 
structural elements which enter into the region of the hydrophilic salt, 
and possibly attach to the valve housing 454. 
FIG. 5a shows partially in section an embodiment where a membrane or rate 
controlling barrier 506 stands between the agent reservoir 502 and the 
apertures 518 in the proximal end of the delivery needle 520 which would 
allow the agents to be delivered to the distal end of the delivery needle 
524, and through the apertures 522. The needle could be replaced with a 
hollow helical delivery device as shown in FIG. 1c if desired. An optional 
controlled release structure 508 provides chronic delivery of agents to 
the implant site. As this agent diminishes, new agents can be provided 
through the connecting tube and check valve 402, such that rate of release 
is governed by control barrier 506. Barrier 506 is shown here with 
substantial thickness, but it could be formed of a simple membrane, a 
membrane reinforced with a substantially porous structure, such as a 
laminate of expanded polytetrafluoroethylene (ePTFE), or any other 
structure which could be used to govern the rate of drug delivery to the 
side of the barrier connected by a fluid pathway to the tissue to be 
treated. The design of the control release barrier would be customized for 
the agents to be delivered and may be intentionally designed to specify a 
rate of delivery substantially different from that which the optional 
control release structure 508. Needle plug 516 prevents flow through the 
needle lumen, while maintaining a rigid axial support, and could be formed 
of an inert polymer or metallic material. Rigid support 510 acts to 
support axial location of needle 524 and may be a mechanical base for the 
helical fixation means. Controlled release structure 508 could be composed 
of a macromolecular controlled release matrix such as EVAC housing a 
growth factor such as TAF, bFGF, or aFGF. 
In another preferred embodiment of FIG. 5a, controlled release structure 
508 would be left out and the space would be filled with pharmacological 
agents and act as a reservoir for acute delivery immediately after 
implantation. The fluid path for subsequent agents would then include 
tubing 104, check valve 402, proximal needle 512 and proximal apertures 
514 into agent reservoir 502, contained by drug reservoir housing 504. The 
fluid agent then passes through rate control barrier 506 into the fluid 
reservoir. 
In other embodiments of FIG. 5a, the control barrier 506 could be 
electrically activated to allow rapid delivery of positive pressure and 
agent delivery from one side to the other. In this electrically activated 
embodiment, the optional control release structure or acute reservoir 508 
could merely deliver agents acutely to preserve the viability of the fluid 
pathway for the time when therapy is deemed necessary. Acute delivery of 
antithrombolytics and anti-inflammatory agents would limit blockages and 
tissue inflammation resulting from the implantation of the structure in 
the heart wall and improve the ability of a transient system to deliver 
agents quickly and effectively to the region within the tissue. An 
electrically controlled barrier could be fashioned much like any 
electrically controlled microvalve. 
FIG. 5b is a partially sectional view of the drug delivery system described 
in FIG. 5a which incorporates a separate stylet lumen 552 within the same 
catheter body 550. Such a stylet lumen accommodates a removable wire 
element to allow the implanting physician to control the shape of the 
device to guide it to the appropriate site. This additional lumen 552 
allows the drug delivery tubing to travel the length of the coil in its 
own lumen 554. Although shown here as a continuous part of catheter body 
550, stylet end stop 556 usually is attached as a separate component. FIG. 
5c shows the diameter of stylet lumen 552 to be substantially smaller than 
lumen 554. These lumens may change depending upon the requirements for 
different applications. 
Such an additional lumen for stylet use could easily be combined with any 
of the drug delivery systems presented here. This additional lumen will 
prevent the lumen of the drug delivery tubing 104 from getting obstructed 
with body fluids during stylet use, prevent damage to tubing 104 by the 
stylet, and allow the materials of both stylet and tubing 104 to be chosen 
without regard to the requirements of the other. 
FIG. 6 is a partially sectioned view of one preferred embodiment of a 
subcutaneous reservoir structure 626 and a drug delivery catheter 628. 
Subcutaneous reservoir structure 626 may be connected to the proximal end 
of the delivery catheters shown. Subcutaneous reservoir structure 626 
consists of a housing 602 whose reservoir 606 may be filled with a fluid 
pharmacological agent. The agent is introduced by transcutaneous injection 
into the reservoir 606 through the polymer injection barrier 604. This 
barrier is typically composed of silicone rubber such that it creates a 
seal after removal of the filling needle. In addition, the housing 602 is 
typically constructed of titanium, polyurethane, or other known rigid 
biocompatible and nonreactive materials. 
FIG. 6 shows a means for connecting the drug delivery catheter to the 
subcutaneous reservoir, a constant pressure pumping means, or automatic 
infusion pump. Subcutaneous reservoir structure 626 has a port 610 which 
accepts the proximal end of delivery catheter 628 such that the region of 
separation 622 between the crimp structure 620 and proximal end of the 
jacket body 614 is completely within port 610. This prevents fluids from 
entering the separation 622 which allows the coil and inner tubing 624 to 
rotate relative to the jacket body 614 for advancement of fixation 
structure 616 and needle delivery system 618. After the proximal end is 
inserted into port 610 of subcutaneous reservoir structure 626, a set 
screw may be advanced within threads 608 to secure the catheter in 
position by applying force to pin 612. This set screw connection to the 
pin is common in devices used to deliver electrical therapy to the heart, 
and could be used to perform an electrical connection to the fixation 
means 616 or needle 618 in order to sense the electrical activity of the 
tissue. This electrical signal could be monitored by devices with 
algorithms similar to those designed to deliver electrical therapy to the 
heart, except that instead of electrical therapy they introduce 
pharmacologic therapy. 
FIG. 7 shows another embodiment of an acute drug delivery system. The 
catheter body 702 houses a lumen 704 for fluid transport of therapeutic 
agents and a lumen 706 for stylet use during implantation. Lumen 704 
travels the length of the delivery catheter and connects to needle 
delivery structure 714. During implantation through the vasculature, blood 
soluble coating 710, e.g. as in U.S. Pat. No. 4,827,940 issued to Mayer, 
completely protects the vasculature from the sharp elements of the 
fixation helix 712 and the needle delivery structure 714. Blood soluble 
coatings such as sugars may be used. After the appropriate heart chamber 
is accessed, the physician waits for the coating 710 to dissolve. The 
coating may be combined with a radio opaque material such as barium 
sulfate to identify better when this has been accomplished. After the 
coating 710 has dissolved, the physician implants the fixation helix 712 
by rotating the entire catheter about its own axis. Torque is delivered 
from the catheter body 702 to the fixation helix 712 by the embedded 
portion 708 of the fixation helix. This embedded region can be 
manufactured using molding and bonding technology. The principle advantage 
of this device is the small cost of manufacturing such a simple design 
with no moving parts. 
FIG. 8 shows a hollow fixation helix 802 with apertures 804 along its 
length. FIG. 8a shows the hollow helix to be filled with a second material 
810. Second material 810 in the preferred embodiment is a controlled 
release polymer matrix filled with a therapeutic agent for extended 
delivery of agents through apertures 804 in fixation helix 802. In one 
embodiment the controlled release matrix is comprised of silicone rubber 
and the agent to be delivered is lidocaine. In another embodiment the 
agent may be amiodorone HCL. In another embodiment, the controlled release 
matrix is EVAC and the agent is aFGF. Other variations are also possible. 
After implantation of the structure within the heart wall by penetration 
of helix tip 808, the rest of the helix is rotated such that all apertures 
804 are within the tissue. Agents then migrate from the controlled release 
matrix to the tissue in which it is implanted. Such a controlled release 
matrix filling of the hollow core which penetrates the heart could be 
pursued with other penetrating structures as well. 
FIG. 9 shows a drug delivery system with VEGF in an EVAC matrix 908 housed 
in a reservoir defined by cylinder 906, and ends 904 and 914. In the 
preferred embodiment, these are nonpermeable, although in other 
embodiments permeability may be desirable. End 904 acts both to transmit 
torque to fixation helix 916, but also as a stop for a stylet (not shown) 
which may be used during implantation down the coil lumen 902. After 
implantation of the drug delivery catheter, body fluids migrate through 
apertures in distal needle 920 and into a reservoir through a proximal 
region 912 of the needle and dissolve pharmacological agents in acute 
dosage 910 which may be present to counter inflammation associated with 
implantation. Over time, growth factors are delivered via needle 920 to a 
depth within the heart. Note that the absence of a tube for agent delivery 
enables stylet use during implantation. In variations on this embodiment, 
other controlled release means could be housed within a semi permeable 
structure that would allow increased fluid transport to assist in delivery 
of agents through needle 920 to a depth within the heart wall. 
FIG. 10a shows another drug delivery catheter in which agents may be 
delivered transiently to a depth within the tissue. Here, helical coil 
consists of four coradial wires which are electrically isolated from one 
another by a layer of insulation. The electrical insulation allows a 
current pathway to be defined which allows current to flow through 
electrical connection 1018 from two of the coradial wires and into Nitinol 
thermally activated shape memory ribbon or band 1020, which wraps around 
flexible polymer barrier 1010 as shown in section. Current flowing through 
Nitinol ribbon 1020 completes its circuit to the other two coradial wires 
at electrical connection 1002 to torque delivery structure 1004 via 
conduction through a connection to support structure 1012 which is 
electrically connected to needle 1028. Insulating structure 1032 separates 
the two electrical connection regions on torque delivery structure 1004 
and allows current to pass through ribbon 1020. If the electrical 
resistance of the Nitinol is sufficiently high, ohmic heating causes a 
constricting shape change upon the flexible polymer barrier 1010. 
Contained within flexible polymer barrier 1010 is a partially porous 
polymer controlled release matrix structure 1022 such as silicone rubber 
containing lidocaine, which upon compression by the Nitinol ribbon, forces 
agents out of the controlled release matrix 1022 and into the needle 1028 
within the reservoir 1026, then out the distal region 1016 of the needle 
into the heart. 
FIG. 10b shows another transient drug delivery structure in which a 
reservoir contains a fluid whose vapor pressure provides the energy to 
deliver therapeutic agents. As in FIG. 10a, the different filars in the 
helical coil, such as filar 1068, are electrically insulated from one 
another such that two independent electrical connections may be made at a 
crimp 1050 and a crimp 1072 which are separated from each other by 
electrically insulating barrier 1070. The electrical connections made at 
crimp 1050 and 1072 have an electrical path between them which is defined 
by resistive heating element 1052 which passes through a reservoir 1056. 
Within reservoir 1056 is a fluid gas mixture which provides a constant 
pressure at human body temperature via a plate 1058 to a drug matrix 1060. 
If drug matrix 1060 is a substantially porous controlled release matrix, 
the pores surrounding the matrix will be filled with relatively high 
concentration of agents in fluids. As electrical energy is delivered along 
the two independent electrical conductors to resistive heating element 
1052, the temperature of the fluid within reservoir 1056 increases. As 
reservoir housing 1066 and support structure 1064 are rigid and 
noncompliant, this increases the pressure within reservoir 1056 to cause 
expansion of bellows 1054 and apply pressure to the controlled release 
matrix 1060. This forces the concentrated fluid from within the porous 
controlled release matrix into proximal end of needle delivery system 1074 
and out through the distal end of the needle into the heart wall. Such 
vapor pressure energy sources have been used in infusion pumps such as an 
infusion pump available from Infusaid of Norwood, Mass. However, that 
system has not been implanted on a catheter, nor does that pressure system 
provide a thermal element to increase the temperature within the charging 
fluid and thus deliver the pressure transiently. In addition to the porous 
matrix, there is a soluble anti-thrombogenic and anti inflammatory agent 
for use in acute dosage form 1062 which surrounds proximal length of 
needle 1074, while still leaving the end free for agent administration. 
Such acute dosage forms may be very useful for guaranteeing the long term 
outcome of such controlled delivery systems by minimizing the response of 
the tissue to the trauma of implantation. 
A method for delivering therapy using a combined drug delivery ablation 
catheter proceeds as follows. Initially the arrhythmogenic site is located 
using techniques common to those in the field of cardiac 
electrophysiology. The delivery system is inserted into the appropriate 
site within the heart by the internal or external jugulars, cephalic vein, 
subclavian vein, femoral artery, or the other vascular delivery routes. 
Then, the drug delivery structure is implanted at the arrhythmogenic site 
to supply an appropriate agent for altering the local conduction 
properties. After implantation, agents are delivered and the effect on the 
arrhythmogenic site is evaluated by electrical techniques such as mapping. 
If the location is appropriate, and the agents appear to terminate the 
critical arrhythmia, RF energy is delivered to the tissue by way of the 
same structure used to deliver the agents to the heart. If the position is 
inappropriate and the local pharmacological agents do not correct for the 
arrhythmia, the device is repositioned, and the procedure repeated. 
A method for transient treatment of supraventricular arrhythmias using a 
chronically implantable transient drug delivery catheter proceeds as 
follows. After electrophysiologists have specified the appropriate region 
for implantation based upon the patient's cardiac electrical action, a 
catheter is implanted at this site to deliver antiarrhythmic agents at a 
depth within the heart transiently, as well as to sense the electrical 
activity near the device. The catheter is then connected to an external 
controller and power source, which determines suitability of therapy and 
delivers energy to a device such as those described in FIGS. 10a and 10b 
for transient delivery of pharmacological agents, or to a device such as 
that shown in FIG. 1c coupled to a proximally located pumping means. The 
device then senses cardiac activity through the surface of the drug 
delivery structure. When the heart experiences an arrhythmic event, the 
controller identifies the event and activates the energy source which 
delivers the drug to the heart. This drug modifies the selected area of 
tissue and either terminates the arrhythmia, or substantially reduces the 
magnitude of the required electrical therapy. If the arrhythmia does not 
terminate, the pump may deliver a secondary dosage, or trigger an external 
electrical therapy device. If no arrhythmia is sensed, the device is 
maintained in a monitoring mode. 
Thus the different embodiments of the invention provide a means to 
effectively deliver agents at a depth within the myocardium to provide a 
new means for delivering pharmacological therapy to specific locations 
within the heart. These delivery systems will allow therapies for ischemic 
tissue, arrhythmogenic sites, and other cardiac disease to be delivered 
over an extended period of time through a chronic implant, or rapidly over 
a short period of time during an acute procedure. They enable controlled 
delivery of small amounts of macromolecular agents such as growth factors, 
transient drug delivery to the tissue for treating cardiac arrhythmias, 
and may be used with other cardiac devices. 
Many other variations are possible. For example, the flow of liquid agents 
may be driven by implantable infusion pumps with a variety of energy 
sources, and the device could be made from different biocompatible 
materials. Other examples include distally located electrically activated 
piezoelectric crystals as energy sources for drug delivery, and distally 
located ultrasound transducers for implantation using ultrasound imaging. 
In addition, in the embodiments where unipolar sensing through the drug 
delivery structure is insufficient, it is a simple task to add another 
electrode to enable bipolar sensing. 
Catheters with a straight cylindrical lumen from one end to the other could 
be used with a thin bundle of optical fibers passed through the lumen to 
photoablatively create channels within the heart for improving the flow of 
pharmacological agents within the heart. In other variations, the thin 
optical fiber could be replaced with a thin RF electrode structure which 
could literally burn channels within the tissue. Such procedures could be 
viewed as a combined transmyocardial revascularization (TMR) and drug 
delivery. For example, after a catheter is implanted and agents are 
delivered to minimize reflow damage to the heart, simple TMR could be 
introduced with a centrally placed optical fiber. Subsequent to the TMR, 
angiogenic growth factors could be introduced. 
In other embodiments, the devices described may be used for acute delivery 
of metabolic agents, and anti-ischemic agents to poorly perfused tissue 
just prior to introducing reflow. The agents improve the health of the 
poorly perfused tissue and minimize the amount of reflow injury introduced 
by the white blood cells. In another embodiment the devices described may 
be used to deliver specific antiarrhythmic agents over a time course of 
days to weeks while physicians determine whether an implantable system is 
appropriate. In a another embodiment, the catheters described may be used 
to deliver gene therapy at a depth in the diseased myocardium over a 
period of days to weeks. 
Further, the delivery of the agents could be performed with appropriately 
modified catheter shapes such that curves are located to effect a certain 
position within the heart. Such curves in a catheter could be molded into 
place, or held in place by plastic deformation of the helical coil in the 
region it is desired. Such curved structures may provide improved access 
to certain regions within the right atrium, left atrium, right ventricle 
and left ventricle. 
Further, the implantable versions of the different catheters could have 
their fixation mechanisms coated with radioactive agents such as 
Phosphorous 32 to emit beta radiation for the minimization of tissue 
growth on the fixation structures. This has particular advantages for 
catheters meant to be implanted for durations longer than a few days, to 
be removed after the therapy has been delivered. 
Further, acute embodiments of this device could incorporate standard sensor 
technologies for measuring pH and P 02 within the heart chamber or even 
within the myocardium, and mapping electrodes could be placed along the 
distal portion of the catheter body to facilitate implantation relative to 
measured electrical signals through the myocardium. 
Accordingly, the scope of the invention should be determined not by the 
embodiments illustrated, but by the appended claims and their legal 
equivalents.