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Local intracoronary heparin delivery with a microporous balloon catheter
Local intracoronary heparin delivery with a microporous balloon catheter Clifford N. Thomas, MD, Keith A. Robinson, PhD, Gus D. Cipolla, DVM, Spencer B. King III, MD, and Neal A. Scott, MD, PhD Atlanta, Ga. Arterial thrombosis plays a major role in the pathogenesis of acute coronary syndromes such as unstable angina and acute myocardial infarction. Heparin is efficacious in treating both disorders; however, systemically administered heparin is associated with bleeding complications. Local intracoronary delivery of heparin may be a safer, more effective method of administration. This study was performed to determine the fate of heparin infused with a specially designed catheter for local intracoronary delivery. To quantitate hepadn delivery, tritiated-labeled heparin was dissolved in a solution of unlabeled heparin (1,000 U/ml). A microporous balloon catheter was placed in the left anterior descending (LAD) and left circumflex arteries of anesthetized pigs (n = 15), and 1 ml of the heparin solution was infused. The animals were euthanized within 1 hour, and the treated arteries and controls were harvested, processed, and the tritiated activity was measured. To assess the distribution of the heparin in the arterial wall, 1 ml of fluorescein-isothiocyanate (FITC)-Iabeled heparin was locally delivered into the walls of the LAD and left circumflex arteries with the microporous balloon catheter. To visualize the dynamic fluid transfer of the device, a microporous balloon catheter was inflated in the LAD, and I ml of diluted contrast medium was infused under cinefluoroscopy. The arteries treated with tritiated-labeled heparin contained 0.6% ± 0.2% of the infused heparin dose. Control arteries contained 0.01% of the administered heparin. Animals that were infused with FiTC-labeled heparin displayed fluorescence throughout all layers of the artery, especially in the adventitia, in animals that were injected with 1 ml of diluted contrast medium through the microporous balloon, a relatively large amount of the infusate appeared in the arterial lumen proximal to the balloon, in conclusion, these results suggest that heparin can be delivered to coronary arteries with a microporous balloon catheter. However, <1% of the infused dose can be found in the artery I hour after delivery. Infused heparin is distributed throughout the arterial wall, but most o f the infused solution appears in the arterial lumen proximal to the inflated balloon and is probably washed downstream after balloon deflation. (Am Heart J 1996; 132:969-72,)
Systemic heparin administration, when used in treating unstable angina, causes a reduction in the frequency and duration of anginal episodes and in the incidence of subsequent myocardial infarction. 1, 2 However, bleeding complications are associated with systemic heparin administration and commonly limit its use. 3, 4 Local delivery of heparin has been shown to inhibit thrombus formation in a microvascular model of thrombosis without prolonging bleeding parameters.5, 6 Local delivery of drugs to the coronary arteries is a novel method that has the potential to decrease the complications associated with coronary angioplasty. 7, s One prototype catheter designed for local drug delivery, the double balloon, is limited by a relatively large catheter size and drug loss down side branches. Another device, the perforated or porous balloon catheter, is a balloon catheter with holes in the central portion of the balloon. Tissue damage in the form of dissections caused by high-velocity jets of fluid exiting the holes has been described with this device. The microporous infusion catheter was developed to obviate these problems. The catheter consists of a percutaneous transluminal coronary angioplasty (PTCA) balloon with laserdrilled holes (30 pm) in its central portion. This perforated balloon has an outer polyester membrane with pores that are 0.8 ~m in diameter (Fig. 1). The major advantage of this balloon is the ability to infuse into the arterial wall at relatively high pressures with minimal arterial injury. 9 This study was performed to determine the fate ofheparin delivered to an injured coronary artery with the microporous balloon catheter. METHODS
From the Andreas R. Gruentzig Cardiovascular Center, Emory University Hospital. Received for publication Jan. 17, 1996; accepted Feb. 22~ 1996. Reprint requests: Neal A. Scott, MD, PhD, Andreas R. Gruentzig Cardiovascular Center, Emory University Hospital, F-606, 1364 Clifton Rd., Atlanta, GA 30322. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/1/74431
Normal female domestic swine (n = 15) were used in these studies. The animals weighed 28 to 35 kg and were observed to be disease free for at least 1 week before use. All procedures were approved by the Emory University Institutional Animal Care and Use Committee in accordance with federal guidelines. 1° Animals were sedated with an intramuscular injection of ketamine (20 mg/kg), acepromazine maleate (1 mg/kg), and atropine (0.04 rag/ 969
November 1996
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Thomas et al.
Fig. 1. Top, Schematic representation of microporous balloon. Catheter consists of perforated angioplasty balloon with outer microporous (polyester) covering. Bottom, Photo of microporous balloon infusing Evan's blue dye at pressure of 5 atm in water.
kg). Intravenous access was established in an ear vein with an 18-gauge angiocatheter. Endotracheal intubation was performed with a 7F endotracheal tube. General anesthesia was established and maintained with 1% to 2% isofluorane in 30% nitrous oxide/70% oxygen. A cut down on the right femoral artery was performed, and an 8F sheath (USCI, Billerica, Mass.) was inserted in the artery under direct vision. An 8F guide catheter (SciMed, Minneapolis, Minn.) with a hockey stick curve was advanced to the ostium of the left coronary artery under fluoroscopic guidance. After administration of intracoronary nitroglycerin (0.66 ~g/kg), coronary angiography was performed in orthogonal views. The microporous balloon (Cordis Corp., Miami Lakes, Fla.) was then loaded and introduced into the guide catheter. The microporous balloon was positioned in the left anterior descending and circumflex coronary arteries of anesthetized pigs where the nominal balloon size: artery ratio approximated 1:1.3 on the fluoroscopic images. One mi of either tritiated-labeled heparin, fluorescein isothiocyanate (FITC)-labeled heparin, or diluted iodinated ionic contrast medium was infused at a hub pressure of 5 atm. To ensure that the infusion pressure re-
AmericanHeartJournal
mained constant, a carbon dioxide-powered infusion device (Hercules Syringe, Cordis Corp.) was used to deliver the solutions with a square-wave pressure pattern. Previous studies with this device have shown that an infusion of i ml at 5 arm pressure is accomplished in approximately I minute. In the pigs treated with tritiated heparin (n = 10), the tritiated heparin was dissolved in a cold hepann solution (1000 U/m]) to yield a solution with a specific activity of 770,000 cpm/ml. The microporous balloon was placed in either the left anterior descending or circumflex coronary artery. The animal was euthanized within 60 minutes with an overdose of barbiturate, the heart was rapidly removed, and the left coronary was perfused with heparinized lactated Ringer's solution at a pressure of 110 mm Hg to clear the artery of blood. The right coronary artery was also perfused and was used as a control. To ensure that the infused segment was included in the sample, a 40 mm segment containing the 15 mm infused segment was carefully removed, weighed, minced, and dissolved in 1 ml of Solvable (DuPont-New England Nuclear, Boston, Mass.) at 50 ° C for at least 4 hours. After cooling, 0.1 ml of 30% hydrogen peroxide was added, and the mixture was allowed to settle. Scintillation fluid (10 ml) was then added. ~-emission (total counts per minute in the 40 mm segment) was then assessed. Counting was performed 48 hours after processing the sample to minimize turbidity and chemiluminescence. For the FITC-labeled heparin experiments (n = 4), the microporous balloon was deployed in the same manner as previously described. One hour after FITC-labeled heparin infusion, the heart was rapidly removed and the left coronary artery was cannulated. After a brief injection of saline to clear the blood, the infused coronary segment was removed in block fashion and cut into 6 to 8 segments approximately 3 mm in length and placed in molds containing optimal cutting temperature compound (O.C.T., Miles Laboratories, Elkhart, Ind.). The molds were then snapfrozen in liquid nitrogen and stored at -70 ° C. Cryosections (7 to 10 pm) were thaw-mounted on Vectabond-coated (Vector Laboratories, Burlingame, Calif.) slides and examined and photographed on a Nikon fluorescent microscope equipped with a 100 watt mercury lamp with a 470 to 490 nm excitation filter and a 520 nm barrier filter. In the experiments with diluted contrast, a 1:1 dilution of ionic contrast (Hypaque 76, Sanofi-Winthrop, New York, N. Y.) and 0.9% sodium chloride was used as the infusate. One ml of this solution was infused in the same manner as previously described. Statistics. All data are displayed as mean +- SEM. All statistical analyses were done by statistical analysis software available for an IBM 486 personal computer (SigmaStat, San Rafael, Calif.). Statistical comparisons were made with the student's t test (two-tailed) for unpaired sample groups. RESULTS Tritiated heparin delivery. By u s i n g q u a n t i t a t i v e ang i o g r a p h y on the a n g i o g r a p h y films, the ratio of the n o m i n a l balloon size to the t a r g e t a r t e r y s e g m e n t
Volume 132, Number5 American Heart Journal
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971
Fig. 2. Photo of coronary artery with FITC-labeled heparin. Animal received I ml offluoresceinated heparin in LAD with microporous balloon catheter. Note fluorescence throughout arterial wall with intense fluorescence of adventitia.
was 1.37:1.0. The arteries treated with the microporous balloon had an average of 0.6% --_ 0.2% (4620 _+ 1540 cpm) of the infused heparin dose. The right coronary arteries, which were uninjured, untreated controls, had 0.01% (640 _+ 80 cpm) of the infused tritiated heparin. The background scintillation value from vessels harvested in animals who were not treated with tritiated heparin had an average of 46 _+ 15 cpm. FITC-labeled heparin delivery. Local infusion of FITC-labeled heparin documented t h a t heparin was present in the media and adventitia of the injured vessel, with the most intense fluorescence in the adventitia (Fig. 2). Minimal fluorescence was evident in the right coronary arteries, which were exposed to only the recirculating FITC heparin. Control vessels from untreated pigs displayed background fluorescence throughout the vessel wall. I n f u s i o n o f c o n t r a s t . In a coronary artery infused with 1 ml of a 1:1 mixture of radiographic contrast and 0.9% sodium chloride, the majority of the infusate was observed by cinefluoroscopy to propagate retrograde within the arterial lumen immediately proximal to the inflated balloon (Fig. 3).
Arlery
/
Inllated microporous inlusion balloon
/
Inlused con~rasl
Fig. 3. Drawing of coronary artery with inflated microporous balloon immediately after infusion of 1 ml of diluted contrast. Relatively large amount of infusate was seen in artery lumen proximal to inflated balloon. DISCUSSION
This study was performed to determine the fate of heparin that was locally delivered with a microporous infusion catheter. These results demonstrate that a microporous balloon catheter can effectively deliver heparin to a coronary artery. Heparin delivery appears to be distributed throughout the arterial wall and is especially prominent in the adventitia. However, the efficiency of delivery to the artery appears to be <1% of the administered dose. The finding t h a t approximately 1% of the infused dose was found
972
November 1996 American Heart Journal
Thomas et al.
within the treated segment of coronary artery approximates values obtained with other local delivery devices.11 Other factors that may influence the efficiency of delivery, such as the presence ofintraluminal disease, stenosis geometry, and the presence of calcification, were not addressed in this study because pigs with normal coronary arteries were used. In a separate experiment to determine the fate of the infused heparin solution, a significant amount of the infusate appeared to accumulate in the arterial lumen proximal to the inflated balloon. Because coronary arteries taper along their length, 12 the infusate is probably forced into a space created between the balloon and the vessel wall and follows a path of least resistance, that is, proximally--where the arterial diameter is larger. These studies cannot exclude the possibility that some of the infusate may also have traveled distal to the balloon. The heparin in the lumen probably distributed throughout the blood stream after balloon deflation and could be responsible for the radioactivity found in the uninjured, untreated right coronary arteries. This finding suggests that deposition of the infusate in the arterial lumen proximal to the inflated balloon may contribute significantly to the low efficiency of delivery. Methods that alter catheter design to minimize this problem may improve transport into the vessel wall. Nevertheless, an effective inhibition of thrombosis should be obtainable because extremely high local levels of heparin are obtained even with low delivery efficiency. For example, if 1 ml of heparin solution (10,000 U/ml) is delivered, then approximately 100 units would be deposited in the vessel wall. Prior studies with another local delivery catheter device, a hydrogel-coated angioplasty balloon, have shown that local delivery of approximately 50 units of heparin produces an inhibition of plateletdependent thrombosis that lasts for at least 90 minutes. 13 The documentation of adventitial delivery with this catheter is encouraging because recent d a t a have shown that most of the proliferation after coronary overstretch injury may occur in the adventitia.14 Additionally, the adventitia could potentially serve as a depot for infused drugs. The short retention time for heparin has been observed -with other methods of drug delivery andis most likely related to its high solubility in aqueous solutions. Lipophilic agents have been demonstrated to have long retention times when locally delivered to arteries in vivo 15 and may be more efficacious than hydrophilic agents in the local treatment of thrombotic and proliferative processes in blood vessels. These results, although promising, highlight the
pitfalls of local delivery. The retention time of infused substances such as heparin and hirudin 16 is relatively short and can be measured in terms of hours. Although it is unclear at this time whether a significant clinical benefit will be obtained with treatments that persist for short periods, data suggest that intracoronary thrombosis can be effectively treated with local delivery of urokinase. 17 The data from this study suggest that heparin, when locally delivered, may potentially benefit the treatment of intracoronary thrombus. REFERENCES
1. Serueri GGN, Gensiui GF,.Poggesi L, Trotta F, Modesti PA, Boddi M, et al. Effect ofheparin, aspirin, or alteplase in reduction of myocardial ischemia in refractory unstable angina. Lancet 1990;335:615-8. 2. Theroux P, Ouimet H, McCans J, Latour JC, Joly P, Levy G, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988;319:1105-10. 3. Landefeld CS, Beyth RJ. Anticoagulant*related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993;95:315-28. 4. Antman EM. Hirudin in acute myocardial infarction. Safety report from the thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9A trial. Circulation 1994;90:1624-30. 5. Jones NS, Glenn MG, OrloffLA, Mayberg MR. Prevention ofmicrovascular thrombosis with controlled-release transmural heparin. Arch Otolaryagol Head Neck Surg 1990;116:779-85. 6. Okada T, Bark DH, Mayberg MR. Local anticoagulation without systemic effect using a polymer heparin delivery system. Stroke 1988; 19:1470-6. 7. Riessen R, Isner JM. Prospects for site-specific delivery of pharmacologic and molecular therapies. J Am Coll Cardiol 1994;23:1234-44. 8. Scott NA. Current status and potential applications of drug delivery balloon catheters. J Intervent Cardiol 1995;8:406-19. 9. Lambert CR, Leone JE, Rowland SM. Local drug delivery catheters: functional comparison of porous and microporous designs, Coronary Artery Dis 1993;4:469-75. 10. Committee on the Care and Use of Laboratory Animals. Guide for the care and use of laboratory animals. Bethesda, MD: National Institutes of Health publication #86-23, 1985. 11. Hong MK, Wong SC, Farb A, Mehlman MD, Virmani R, Barry JJ, et al. Feasibility and drug delivery efficiency of a new balloon angioplasty catheter capable of performing simultaneous local drug delivery. Coronary Artery Dis 1995. 12. Javier SP, Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, et al. Intravascular ultrasound assessment of the magnitude and mechauism ofcoronary artery and lumen tapering. Am J C ardiol 1995 ;75:177 80. 13. Nunes GL, Thomas CN, Hanson SR, Barry JJ, King SB III, Scott NA. Local heparin delivery with a hydrogel-coated PTCA balloon catheter inhibits platelet dependent thrombosis. Circulation 1995;92:1697700. 14. Scott NA, Cipolla GD, Ross CE, Dunn B, Martin F, Simonet L, et al. Potential role of the adventitia in vascular lesion formation after balloon overstreteh injury of porcine arteries. Circulation 1996;93:217887. 15. Lambert TL, Dev V, Rechavia E, Forrester JS, Litvack F, Eigler NL. Localized arterial wall drug delivery from a polymer-coated removable metallic stent. Kinetics, distribution, and bioactivity of forskolin. Circulation 1994;90:1003-11. 16. Fernandez-Ortiz A, Meyer BJ, Mailhac A, Falk E, Badimon L, Fallon JT, et al. A new approach for local intravascular drug delivery. Iontophoretic balloon. Circulation 1994;89:1518-22. 17. Mitchel JF, Fram DB, Palme DF, Foster R, Hirst JA, Azrin MA, et al. Enhanced intracoronary thrombolysis with urokinase using a novel, local drug delivery system: in vitro, in vivo and clinical studies. Circulation 1995;91:785-93.
Systemic heparin administration, when used in treating unstable angina, causes a reduction in the frequency and duration of anginal episodes and in the incidence of subsequent myocardial infarction. 1, 2 However, bleeding complications are associated with systemic heparin administration and commonly limit its use. 3, 4 Local delivery of heparin has been shown to inhibit thrombus formation in a microvascular model of thrombosis without prolonging bleeding parameters.5, 6 Local delivery of drugs to the coronary arteries is a novel method that has the potential to decrease the complications associated with coronary angioplasty. 7, s One prototype catheter designed for local drug delivery, the double balloon, is limited by a relatively large catheter size and drug loss down side branches. Another device, the perforated or porous balloon catheter, is a balloon catheter with holes in the central portion of the balloon. Tissue damage in the form of dissections caused by high-velocity jets of fluid exiting the holes has been described with this device. The microporous infusion catheter was developed to obviate these problems. The catheter consists of a percutaneous transluminal coronary angioplasty (PTCA) balloon with laserdrilled holes (30 pm) in its central portion. This perforated balloon has an outer polyester membrane with pores that are 0.8 ~m in diameter (Fig. 1). The major advantage of this balloon is the ability to infuse into the arterial wall at relatively high pressures with minimal arterial injury. 9 This study was performed to determine the fate ofheparin delivered to an injured coronary artery with the microporous balloon catheter. METHODS
From the Andreas R. Gruentzig Cardiovascular Center, Emory University Hospital. Received for publication Jan. 17, 1996; accepted Feb. 22~ 1996. Reprint requests: Neal A. Scott, MD, PhD, Andreas R. Gruentzig Cardiovascular Center, Emory University Hospital, F-606, 1364 Clifton Rd., Atlanta, GA 30322. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/1/74431
Normal female domestic swine (n = 15) were used in these studies. The animals weighed 28 to 35 kg and were observed to be disease free for at least 1 week before use. All procedures were approved by the Emory University Institutional Animal Care and Use Committee in accordance with federal guidelines. 1° Animals were sedated with an intramuscular injection of ketamine (20 mg/kg), acepromazine maleate (1 mg/kg), and atropine (0.04 rag/ 969
November 1996
970
Thomas et al.
Fig. 1. Top, Schematic representation of microporous balloon. Catheter consists of perforated angioplasty balloon with outer microporous (polyester) covering. Bottom, Photo of microporous balloon infusing Evan's blue dye at pressure of 5 atm in water.
kg). Intravenous access was established in an ear vein with an 18-gauge angiocatheter. Endotracheal intubation was performed with a 7F endotracheal tube. General anesthesia was established and maintained with 1% to 2% isofluorane in 30% nitrous oxide/70% oxygen. A cut down on the right femoral artery was performed, and an 8F sheath (USCI, Billerica, Mass.) was inserted in the artery under direct vision. An 8F guide catheter (SciMed, Minneapolis, Minn.) with a hockey stick curve was advanced to the ostium of the left coronary artery under fluoroscopic guidance. After administration of intracoronary nitroglycerin (0.66 ~g/kg), coronary angiography was performed in orthogonal views. The microporous balloon (Cordis Corp., Miami Lakes, Fla.) was then loaded and introduced into the guide catheter. The microporous balloon was positioned in the left anterior descending and circumflex coronary arteries of anesthetized pigs where the nominal balloon size: artery ratio approximated 1:1.3 on the fluoroscopic images. One mi of either tritiated-labeled heparin, fluorescein isothiocyanate (FITC)-labeled heparin, or diluted iodinated ionic contrast medium was infused at a hub pressure of 5 atm. To ensure that the infusion pressure re-
AmericanHeartJournal
mained constant, a carbon dioxide-powered infusion device (Hercules Syringe, Cordis Corp.) was used to deliver the solutions with a square-wave pressure pattern. Previous studies with this device have shown that an infusion of i ml at 5 arm pressure is accomplished in approximately I minute. In the pigs treated with tritiated heparin (n = 10), the tritiated heparin was dissolved in a cold hepann solution (1000 U/m]) to yield a solution with a specific activity of 770,000 cpm/ml. The microporous balloon was placed in either the left anterior descending or circumflex coronary artery. The animal was euthanized within 60 minutes with an overdose of barbiturate, the heart was rapidly removed, and the left coronary was perfused with heparinized lactated Ringer's solution at a pressure of 110 mm Hg to clear the artery of blood. The right coronary artery was also perfused and was used as a control. To ensure that the infused segment was included in the sample, a 40 mm segment containing the 15 mm infused segment was carefully removed, weighed, minced, and dissolved in 1 ml of Solvable (DuPont-New England Nuclear, Boston, Mass.) at 50 ° C for at least 4 hours. After cooling, 0.1 ml of 30% hydrogen peroxide was added, and the mixture was allowed to settle. Scintillation fluid (10 ml) was then added. ~-emission (total counts per minute in the 40 mm segment) was then assessed. Counting was performed 48 hours after processing the sample to minimize turbidity and chemiluminescence. For the FITC-labeled heparin experiments (n = 4), the microporous balloon was deployed in the same manner as previously described. One hour after FITC-labeled heparin infusion, the heart was rapidly removed and the left coronary artery was cannulated. After a brief injection of saline to clear the blood, the infused coronary segment was removed in block fashion and cut into 6 to 8 segments approximately 3 mm in length and placed in molds containing optimal cutting temperature compound (O.C.T., Miles Laboratories, Elkhart, Ind.). The molds were then snapfrozen in liquid nitrogen and stored at -70 ° C. Cryosections (7 to 10 pm) were thaw-mounted on Vectabond-coated (Vector Laboratories, Burlingame, Calif.) slides and examined and photographed on a Nikon fluorescent microscope equipped with a 100 watt mercury lamp with a 470 to 490 nm excitation filter and a 520 nm barrier filter. In the experiments with diluted contrast, a 1:1 dilution of ionic contrast (Hypaque 76, Sanofi-Winthrop, New York, N. Y.) and 0.9% sodium chloride was used as the infusate. One ml of this solution was infused in the same manner as previously described. Statistics. All data are displayed as mean +- SEM. All statistical analyses were done by statistical analysis software available for an IBM 486 personal computer (SigmaStat, San Rafael, Calif.). Statistical comparisons were made with the student's t test (two-tailed) for unpaired sample groups. RESULTS Tritiated heparin delivery. By u s i n g q u a n t i t a t i v e ang i o g r a p h y on the a n g i o g r a p h y films, the ratio of the n o m i n a l balloon size to the t a r g e t a r t e r y s e g m e n t
Volume 132, Number5 American Heart Journal
Thomas et al.
971
Fig. 2. Photo of coronary artery with FITC-labeled heparin. Animal received I ml offluoresceinated heparin in LAD with microporous balloon catheter. Note fluorescence throughout arterial wall with intense fluorescence of adventitia.
was 1.37:1.0. The arteries treated with the microporous balloon had an average of 0.6% --_ 0.2% (4620 _+ 1540 cpm) of the infused heparin dose. The right coronary arteries, which were uninjured, untreated controls, had 0.01% (640 _+ 80 cpm) of the infused tritiated heparin. The background scintillation value from vessels harvested in animals who were not treated with tritiated heparin had an average of 46 _+ 15 cpm. FITC-labeled heparin delivery. Local infusion of FITC-labeled heparin documented t h a t heparin was present in the media and adventitia of the injured vessel, with the most intense fluorescence in the adventitia (Fig. 2). Minimal fluorescence was evident in the right coronary arteries, which were exposed to only the recirculating FITC heparin. Control vessels from untreated pigs displayed background fluorescence throughout the vessel wall. I n f u s i o n o f c o n t r a s t . In a coronary artery infused with 1 ml of a 1:1 mixture of radiographic contrast and 0.9% sodium chloride, the majority of the infusate was observed by cinefluoroscopy to propagate retrograde within the arterial lumen immediately proximal to the inflated balloon (Fig. 3).
Arlery
/
Inllated microporous inlusion balloon
/
Inlused con~rasl
Fig. 3. Drawing of coronary artery with inflated microporous balloon immediately after infusion of 1 ml of diluted contrast. Relatively large amount of infusate was seen in artery lumen proximal to inflated balloon. DISCUSSION
This study was performed to determine the fate of heparin that was locally delivered with a microporous infusion catheter. These results demonstrate that a microporous balloon catheter can effectively deliver heparin to a coronary artery. Heparin delivery appears to be distributed throughout the arterial wall and is especially prominent in the adventitia. However, the efficiency of delivery to the artery appears to be <1% of the administered dose. The finding t h a t approximately 1% of the infused dose was found
972
November 1996 American Heart Journal
Thomas et al.
within the treated segment of coronary artery approximates values obtained with other local delivery devices.11 Other factors that may influence the efficiency of delivery, such as the presence ofintraluminal disease, stenosis geometry, and the presence of calcification, were not addressed in this study because pigs with normal coronary arteries were used. In a separate experiment to determine the fate of the infused heparin solution, a significant amount of the infusate appeared to accumulate in the arterial lumen proximal to the inflated balloon. Because coronary arteries taper along their length, 12 the infusate is probably forced into a space created between the balloon and the vessel wall and follows a path of least resistance, that is, proximally--where the arterial diameter is larger. These studies cannot exclude the possibility that some of the infusate may also have traveled distal to the balloon. The heparin in the lumen probably distributed throughout the blood stream after balloon deflation and could be responsible for the radioactivity found in the uninjured, untreated right coronary arteries. This finding suggests that deposition of the infusate in the arterial lumen proximal to the inflated balloon may contribute significantly to the low efficiency of delivery. Methods that alter catheter design to minimize this problem may improve transport into the vessel wall. Nevertheless, an effective inhibition of thrombosis should be obtainable because extremely high local levels of heparin are obtained even with low delivery efficiency. For example, if 1 ml of heparin solution (10,000 U/ml) is delivered, then approximately 100 units would be deposited in the vessel wall. Prior studies with another local delivery catheter device, a hydrogel-coated angioplasty balloon, have shown that local delivery of approximately 50 units of heparin produces an inhibition of plateletdependent thrombosis that lasts for at least 90 minutes. 13 The documentation of adventitial delivery with this catheter is encouraging because recent d a t a have shown that most of the proliferation after coronary overstretch injury may occur in the adventitia.14 Additionally, the adventitia could potentially serve as a depot for infused drugs. The short retention time for heparin has been observed -with other methods of drug delivery andis most likely related to its high solubility in aqueous solutions. Lipophilic agents have been demonstrated to have long retention times when locally delivered to arteries in vivo 15 and may be more efficacious than hydrophilic agents in the local treatment of thrombotic and proliferative processes in blood vessels. These results, although promising, highlight the
pitfalls of local delivery. The retention time of infused substances such as heparin and hirudin 16 is relatively short and can be measured in terms of hours. Although it is unclear at this time whether a significant clinical benefit will be obtained with treatments that persist for short periods, data suggest that intracoronary thrombosis can be effectively treated with local delivery of urokinase. 17 The data from this study suggest that heparin, when locally delivered, may potentially benefit the treatment of intracoronary thrombus. REFERENCES
1. Serueri GGN, Gensiui GF,.Poggesi L, Trotta F, Modesti PA, Boddi M, et al. Effect ofheparin, aspirin, or alteplase in reduction of myocardial ischemia in refractory unstable angina. Lancet 1990;335:615-8. 2. Theroux P, Ouimet H, McCans J, Latour JC, Joly P, Levy G, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988;319:1105-10. 3. Landefeld CS, Beyth RJ. Anticoagulant*related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993;95:315-28. 4. Antman EM. Hirudin in acute myocardial infarction. Safety report from the thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9A trial. Circulation 1994;90:1624-30. 5. Jones NS, Glenn MG, OrloffLA, Mayberg MR. Prevention ofmicrovascular thrombosis with controlled-release transmural heparin. Arch Otolaryagol Head Neck Surg 1990;116:779-85. 6. Okada T, Bark DH, Mayberg MR. Local anticoagulation without systemic effect using a polymer heparin delivery system. Stroke 1988; 19:1470-6. 7. Riessen R, Isner JM. Prospects for site-specific delivery of pharmacologic and molecular therapies. J Am Coll Cardiol 1994;23:1234-44. 8. Scott NA. Current status and potential applications of drug delivery balloon catheters. J Intervent Cardiol 1995;8:406-19. 9. Lambert CR, Leone JE, Rowland SM. Local drug delivery catheters: functional comparison of porous and microporous designs, Coronary Artery Dis 1993;4:469-75. 10. Committee on the Care and Use of Laboratory Animals. Guide for the care and use of laboratory animals. Bethesda, MD: National Institutes of Health publication #86-23, 1985. 11. Hong MK, Wong SC, Farb A, Mehlman MD, Virmani R, Barry JJ, et al. Feasibility and drug delivery efficiency of a new balloon angioplasty catheter capable of performing simultaneous local drug delivery. Coronary Artery Dis 1995. 12. Javier SP, Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, et al. Intravascular ultrasound assessment of the magnitude and mechauism ofcoronary artery and lumen tapering. Am J C ardiol 1995 ;75:177 80. 13. Nunes GL, Thomas CN, Hanson SR, Barry JJ, King SB III, Scott NA. Local heparin delivery with a hydrogel-coated PTCA balloon catheter inhibits platelet dependent thrombosis. Circulation 1995;92:1697700. 14. Scott NA, Cipolla GD, Ross CE, Dunn B, Martin F, Simonet L, et al. Potential role of the adventitia in vascular lesion formation after balloon overstreteh injury of porcine arteries. Circulation 1996;93:217887. 15. Lambert TL, Dev V, Rechavia E, Forrester JS, Litvack F, Eigler NL. Localized arterial wall drug delivery from a polymer-coated removable metallic stent. Kinetics, distribution, and bioactivity of forskolin. Circulation 1994;90:1003-11. 16. Fernandez-Ortiz A, Meyer BJ, Mailhac A, Falk E, Badimon L, Fallon JT, et al. A new approach for local intravascular drug delivery. Iontophoretic balloon. Circulation 1994;89:1518-22. 17. Mitchel JF, Fram DB, Palme DF, Foster R, Hirst JA, Azrin MA, et al. Enhanced intracoronary thrombolysis with urokinase using a novel, local drug delivery system: in vitro, in vivo and clinical studies. Circulation 1995;91:785-93.