- Email: [email protected]
Usefulness of hyperbaric oxygen therapy to inhibit restenosis after percutaneous coronary intervention for acute myocardial infarction or unstable angina pectoris
The limitations of our study are the retrospective character of our analysis and the relatively small number of patients in this single-center experience. Furthermore, about 1/4 of the successfully treated patients did not undergo repeat angiography. In addition, the necessity of stent implantation may indicate complex index lesions. 1. Loop FD, Lytle BW, Cosgrove DM, Stewart RW, Goormastic M, Williams
GW, Golding LAR, Gill CC, Taylor PC, Sheldon WC, et al. Influence of the internal-mammary-artery graft on 10-year survival and other cardiac events. N Engl J Med 1986;314:1–6. 2. Zeff RH, Kongtahworn C, Iannone LA, Gordon DF, Brown TM, Phillips SJ, Skinner JR, Spector M. Internal mammary artery versus saphenous vein graft to the left anterior descending coronary artery: prospective randomized study with 10-year follow-up. Ann Thorac Surg 1988;45:533–536. 3. Acinapura AJ, Rose DM, Jacobowitz IJ, Kramer MD, Robertazzi RR, Feldman J, Zisbrod Z, Cunningham JN. Internal mammary artery bypass grafting: influence on recurrent angina and survival in 2,100 patients. Ann Thorac Surg 1989;48:186 –191. 4. Cameron A, Davis KB, Green G, Schaff HV. Coronary bypass surgery with internal-thoracic-artery grafts— effects on survival over a 15-year period. N Engl J Med 1996;334:216 –219. 5. Shimshak TM, Giorgi LV, Johnson WL, McConahay DR, Rutherford BD, Ligon R, Hartzler GO. Application of percutaneous transluminal coronary angioplasty to the internal mammary artery graft. J Am Coll Cardiol 1988;12:1205– 1214.
6. Dimas AP, Arora RR, Whitlow PL, Hollman JL, Franco I, Raymond RE,
Dorosti K, Simpfendorfer CC. Percutaneous transluminal angioplasty involving internal mammary artery grafts. Am Heart J 1991;122:423–429. 7. Popma JJ, Cooke RH, Leon MB, Stark K, Satler LF, Kent KM, Hunn D, Pichard AD. Immediate procedural and long-term clinical results of internal mammary artery angioplasty. Am J Cardiol 1992;69:1237–1239. 8. Najm HK, Leddy D, Hendry PJ, Marquis J-F, Richardson D, Keon WJ. Postoperative symptomatic internal thoracic artery stenosis and successful treatment with PTCA. Ann Thorac Surg 1995;59:323–327. 9. Ishizaka N, Ishizaka Y, Ikari Y, Isshiki T, Tamura T, Suma H, Yamagucchi T. Initial and subsequent angiographic outcome of percutaneous transluminal angioplasty performed on internal mammary artery grafts. Br Heart J 1995;74:615– 619. 10. Hearne SE, Davidson CJ, Zidar JP, Philips HR, Stack RS, Sketch MH Jr. Internal mammary artery graft angioplasty: acute and long-term outcome. Cathet Cardiovasc Diagn 1998;44:153–156. 11. Gruberg L, Dangas G, Mehran R, Hong MK, Waksman R, Mintz GS, Kent KM, Pichard AD, Satler LF, Lansky AJ, et al. Percutaneous revascularization of the internal mammary artery graft: short- and long-term outcomes. J Am Coll Cardiol 2000;35:944 –948. 12. Kaul TK, Fields BL, Wyatt DA, Jones CR, Kahn DR. Reoperative coronary artery bypass surgery: early and late results and management in 1300 patients. J Cardiovasc Surg 1995;36:303–312. 13. Kastrati A, Scho¨ mig A, Elezi S, Schu¨ hlen H, Dirschinger J, Hadamitzky M, Wehinger A, Hausleiter J, Walter H, Neumann F-J. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol 1997;30:1428 –1436. 14. Akiyama T, Moussa I, Reimers B, Ferraro M, Kobayashi Y, Blengino S, Di Francesco L, Finci L, Di Mario C, Colombo A. Angiographic and clinical outcome following coronary stenting of small vessels: a comparison with coronary stenting of large vessels. J Am Coll Cardiol 1998;32:1610 –1618.
Usefulness of Hyperbaric Oxygen Therapy to Inhibit Restenosis After Percutaneous Coronary Intervention for Acute Myocardial Infarction or Unstable Angina Pectoris Mohsen Sharifi, MD, Wassim Fares, MD, Isam Abdel-Karim, MD, J. Michael Koch, MD, Joseph Sopko, MD, and Dale Adler, MD, for the Hyperbaric Oxygen Therapy in Percutaneous Coronary Interventions (HOT-PI) Investigators The purpose of this trial was to assess whether the addition of hyperbaric oxygen to percutaneous coronary intervention can reduce clinical restenosis. Major adverse cardiac events at 8 months were found in only 1 of 24 patients (4%) who received hyperbaric oxygen compared with 13 of 37 patients (35%) who did not. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1533–1535)
yperbaric oxygen therapy (HOT) is a safe and very effective modality in the management of H slow or poorly healing wounds. It has successfully been employed in a variety of clinical conditions, including chronic osteomyelitis, diabetic and pressure ulcers, necrotizing fascitis, crush injuries, compartFrom the Department of Cardiology, St. Vincent Charity Hospital, Case Western Reserve University and the University Hospitals of Cleveland, Cleveland, Ohio; and Texas Tech University Health Sciences Center, Odessa, Texas. Dr. Sharifi’s address is: Texas Tech University Health Sciences Center, 701 W. 5th Street, Suite 3106, Odessa, Texas 79763. E-mail: [email protected]. Manuscript received December 22, 2003; revised manuscript received and accepted March 1, 2004. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 June 15, 2004
ment syndromes, and acute traumatic peripheral ischemia.1,2 Other uses include radiation-induced hemorrhagic cystitis, optic neuritis, air embolism, carbon monoxide intoxication, and air embolism.1,2 Percutaneous coronary interventions (PCIs) invariably create miniature wounds by the disruptive effects of the interventional hardware on the vessel wall, thereby triggering the wound-healing process and leading to restenosis. It is intriguing to hypothesize that the early healing of these miniature wounds by HOT may decrease restenosis.3 We therefore embarked to evaluate the safety and efficacy of HOT in PCI. •••
The trial was approved by St. Vincent Charity Hospital’s institutional review board. Informed consent was obtained from each patient before enrollment in the study. Of the initial 69 patients who were enrolled in the study, 33 were randomized to the HOT arm and 36 to the control group. All patients had presented with unstable angina or acute myocardial infarction. They had stabilized on medical therapy, with the resolution of chest pain and normalization of ST-segment changes. According to protocol, patients who had evidence of ongoing ischemia after the first 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.03.009
1533
TABLE 1 Clinical and Angiographic Characteristics of Study Patients Characteristic Age (yrs) Men Hypertension Hypercholesterolemia (total cholesterol ⬎200 mg/dl) Current smoking Diabetes mellitus Unstable angina Myocardial infarction Left ventricular ejection fraction (%) Saphenous vein graft intervention (patients) Stent length (mm) Stent diameter (mm) Use of glycoprotein IIb/IIIa inhibitors Type C lesion
HOT Group (n ⫽ 24)
Control Group (n ⫽ 37)
63 14 20 8
⫾ 12 (58%) (83%) (33%)
65 21 23 21
⫾ 13 (57%) (62%) (57%)
14 8 15 9 50
(58%) (33%) (63%) (38%) ⫾ 15
21 10 26 11 52
(57%) (27%) (70%) (30%) ⫾ 12
2
3
14 ⫾ 5 3.1 ⫾ 0.4 22 (92%)
15 ⫾ 4 3.0 ⫾ 0.4 37 (100%)
14 (58%)
23 (62%)
1/2 hour of medical therapy were excluded from enrollment. Patients were also excluded if they had any acute or chronic ear disease, histories of spontaneous pneumothorax, or current therapy with doxorubicin or cisplatinum. Of the 33 patients randomized to the HOT group, 4 declined to receive HOT, and 1 did not complete the hyperbaric protocol because of claustrophobia. These 5 patients crossed over to the control group. Three other patients of the HOT group required coronary artery bypass surgery, and 1 was found to have no significant lesion to warrant PCI. Consequently, there remained 24 patients in the HOT group who completed the hyperbaric protocol. Of the initial 36 patients in the control group, 4 were excluded because they required coronary artery bypass surgery or did not have significant disease to require PCI. With the 5 patients who crossed over from the HOT group, the remaining control group consisted of 37 patients. Patients in the HOT group underwent 2 hyperbaric dives using the Sechrist 2500 B Monoplace Hyperbaric System (Sechrist Industries, Anaheim, California): a dive 2 hours before (for the first 8 patients) or immediately after PCI (for all subsequent patients) and another ⱕ18 hours after the first dive. The HOT protocol was modified from a dive before PCI to a dive immediately after PCI because the former protocol would have exposed some patients who did not require PCI to unnecessary HOT. Each dive consisted of 100% oxygen at 2 bars for 90 minutes, with a total chamber dwell time of 120 minutes. Fifteen minutes were required to increase the hyperbaric chamber pressure to 2 bars and another 15 minutes for the decompression phase. The control group received standard PCI without HOT. All patients underwent PCI in de novo native or saphenous vein grafts and received ⱖ1 stent. All patients received aspirin 325 mg/day and heparin during PCI and 1 month of therapy with clopidogrel 75 mg/day. Throughout HOT, patients were continuously 1534 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 93
TABLE 2 Adverse Cardiac Events at Eight Months Variable Composite: death, myocardial infarction, coronary artery bypass, or revascularization of target lesion Death Myocardial infarction Coronary artery bypass Revascularization of target lesion Late angina (after 8 mo)
HOT (n ⫽ 24)
Control (n ⫽ 37)
1
13
0.001
0 1 0 0 1
3 7 0 8 9
NS 0.06 — ⬍0.003 ⬍0.05
p value
monitored visually and hemodynamically. The special ports located on the hatch of the hyperbaric chamber allowed arterial and venous line connections. The intercom system of the chamber provided communication with the patient, and the transparent chamber walls ensured visual monitoring. A successful procedure was defined as that resulting in ⬍20% stenosis in the luminal diameter immediately after intervention without death, myocardial infarction, coronary artery bypass surgery, or stent thrombosis. Myocardial infarction was defined as an elevation of troponin I or creatinine kinase-MB fraction to a value 2 times the upper limit of the normal range. Clinical follow-up was performed at 1, 8, and 18 months after discharge. The predetermined end points were the composite of death, myocardial infarction, and the need for target lesion revascularization at 8 months. The secondary end point was the late recurrence or worsening of anginal symptoms (after 8 months). For the analysis of continuous data, 2-tailed t tests were used to assess the difference between the 2 treatment groups. The results are expressed as means ⫾ SDs. Categorical data were compared with the use of the chi-square test or Fisher’s exact test. The patients’ clinical and angiographic characteristics were similar between the 2 groups (Table 1). Procedural success was obtained in all patients. In general, except for 1 patient, all patients who were placed in the hyperbaric chamber tolerated the procedure well. One elderly patient developed tympanic membrane rupture 3 days after treatment. She had a history of chronic otitis, which was not diagnosed at enrollment. Oxygen toxicity, with its potential manifestations of seizures, disorientation, tremors, and visual disturbances, did not develop in any patient. With the administration of HOT, appreciable changes were noted in the heart rate and blood pressure. The mean blood pressure increased by 20 ⫾ 6 mm Hg, and the mean heart rate decreased by 10 ⫾ 4 beats/min. The increase in blood pressure responded to the intravenous administration of nitroglycerin and enalaprilat. The 8-month adverse cardiac events are listed in Table 2. Although this study did not have a prespecified angiographic follow-up, repeat coronary angiography was performed for chest pain or myocardial infarction at the discretion of the attending cardioloJUNE 15, 2004
gist. Within the first 8 months after the index operation, 3 patients in the HOT arm and 8 in the control group had repeat coronary angiography. Angiographic restenosis (stenosis of ⱖ50% of the luminal diameter) was found in 0 patients of the HOT group and 7 of the control group (p ⬍0.05). •••
The results indicate that patients who received adjunctive HOT in the early peri-PCI period had a lower clinical restenosis rate. Additionally, the recurrence of late anginal symptoms was less frequent in these patients. Several reasons may account for these results. It is well established that the healing of wounds is accelerated with HOT. It is also known that restenosis is triggered by the wound-healing process. It is therefore plausible to postulate that the early closure of these miniature wounds by HOT may attenuate the restenotic process. HOT exerts several beneficial effects at the cellular and molecular level. In a rabbit model of aortic atherosclerosis, not only was progression of disease halted by HOT, but the regression process was markedly accelerated.4 HOT has been shown to induce the expression of a number of antioxidant enzymes in tissues, including hemeoxygenase, by increasing glutathione levels.5,6 These enzymes offer protection against atherosclerosis and reduce oxidation products in high-density lipoprotein.7 Similarly, the activity of serum antioxidant enzymes, such as paraoxonase, is enhanced, leading to a reduction in the oxidation of tissue and plasma lipids.8 This “detoxification” of lipid peroxides has been shown to suppress the recruitment and proliferation of macrophages and the formation of foam cells.4 In tissue cultures of bovine aortic endothelial cells, the expression of intracellular adhesion molecule-1 was downregulated by HOT through the induction of endothelial nitric oxide synthase.9 Furthermore, a sustained increase in nitric oxide production was observed.10 Nitric oxide combines with reactive oxygen species, thereby preventing them from initiating stress responses.9 HOT may reduce the transcription factors involved in intracellular adhesion molecule-1 expression, such as NF-B.11 In addition, synthesis of the heat shock protein HSP70, which has a protective role against oxidative stress, was significantly increased with HOT.12Another potential mechanism for HOT in reducing restenosis is its role as an “antibiotic.” Although a causal relation has not been established,
microorganisms such as Chlamydia and Helicobacter have been associated with the development of coronary artery disease and there have been suggestions of a beneficial role of antibiotics in unstable coronary syndromes.13 HOT has been shown to have potent inhibitory effects on the growth of various microorganisms.14 Furthermore, endothelial cell-derived fibrinolysis and blood flow are enhanced by HOT, which may result in a reduction in recurrent thrombosis.15 In conclusion, HOT is safe and feasible in PCI and may be associated with a reduction in clinical and angiographic restenosis and the development of late anginal symptoms. 1. Tibbles PM, Edelsberg JS. Hyperbaric-oxygen therapy. N Engl J Med 1996; 334:1642–1648. 2. Grim PS, Gottlieb LJ, Boddie A, Batson E. Hyperbaric oxygen therapy. JAMA 1990;263:2216 –2220. 3. Sharifi M, Koch JM, Petrea D, Abdel-Karim I, Steele R, Adler D, Pompili VJ, Sopko J. Hyperbaric oxygen therapy to inhibit restenosis in percutaneous coronary interventions: a preliminary report. Catheter Cardiovasc Intervent 2002;56: 136. 4. Kudchodkar BJ, Wilson J, Lacko A, Dory L. Hyperbaric oxygen reduces the progression and accelerates the regression of atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 2000;20:1637–1643. 5. Harabin AL, Braisted JC, Flynn ET. Response of antioxidant enzymes to intermittent and continuous hyperbaric oxygen. J Appl Physiol 1990;69:328 –335. 6. Padgaonkar VA, Giblin FJ, Fowler K, Leverenz VR, Reddan JR, Dziedzic DC. Heme oxygenase synthesis is induced in cultured lens epithelium by hyperbaric oxygen or puromycin. Exp Eye Res 1997;65:435–443. 7. Ishikawa K, Navab M, Leitinger N, Fogelman AM, Lusis AJ. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. J Clin Invest 1997;100:1209 –1216. 8. Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parma SL, LaDu B. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its function: a possible peroxidative role for paraoxonase. J Clin Invest 1998;101:1581– 1590. 9. Buras JA, Stahl GL, Svoboda KK, Reenstra WR. Hyperbaric oxygen downregulates ICAM-1 expression induced by hypoxia and hypoglycemia: the role of NOS. Am J Physiol 2000;278:C292–C302. 10. Rengasamy A, Johns RA. Characterization of endothelium-derived relaxing factor/nitric oxide synthase from bovine cerebellum and mechanism of modulation by high and low oxygen tensions. J Pharmacol Exp Ther 1991;259:310 –316. 11. Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redoxsensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci USA 1996;93:9114 –9119. 12. Dennog C, Radermacher P, Barnett YA, Speit G. Antioxidant status in humans after exposure to hyperbaric oxygen. Mutat Res 1999;16:83–89. 13. Higgins JP. Chlamydia pneumoniae and coronary artery disease: the antibiotic trials. Mayo Clin Proc 2003;78:321–332. 14. Bornside GH, Pakman LM, Ordonez AA. Inhibition of pathogenic enteric bacteria by hyperbaric oxygen: enhanced antibacterial activity in the absence of carbon dioxide. Antimicrob Agents Chemother 1975;7:682–687. 15. Tjarnstrom J, Holmdahl L, Falk P, Falkenberg M, Arnell P, Risberg B. Effects of hyperbaric oxygen on expression of fibrinolytic factors of human endothelium in a simulated ischaemia/reperfusion situation. Scand J Clin Lab Invest 2001;61: 539 –545.
BRIEF REPORTS
1535
GW, Golding LAR, Gill CC, Taylor PC, Sheldon WC, et al. Influence of the internal-mammary-artery graft on 10-year survival and other cardiac events. N Engl J Med 1986;314:1–6. 2. Zeff RH, Kongtahworn C, Iannone LA, Gordon DF, Brown TM, Phillips SJ, Skinner JR, Spector M. Internal mammary artery versus saphenous vein graft to the left anterior descending coronary artery: prospective randomized study with 10-year follow-up. Ann Thorac Surg 1988;45:533–536. 3. Acinapura AJ, Rose DM, Jacobowitz IJ, Kramer MD, Robertazzi RR, Feldman J, Zisbrod Z, Cunningham JN. Internal mammary artery bypass grafting: influence on recurrent angina and survival in 2,100 patients. Ann Thorac Surg 1989;48:186 –191. 4. Cameron A, Davis KB, Green G, Schaff HV. Coronary bypass surgery with internal-thoracic-artery grafts— effects on survival over a 15-year period. N Engl J Med 1996;334:216 –219. 5. Shimshak TM, Giorgi LV, Johnson WL, McConahay DR, Rutherford BD, Ligon R, Hartzler GO. Application of percutaneous transluminal coronary angioplasty to the internal mammary artery graft. J Am Coll Cardiol 1988;12:1205– 1214.
6. Dimas AP, Arora RR, Whitlow PL, Hollman JL, Franco I, Raymond RE,
Dorosti K, Simpfendorfer CC. Percutaneous transluminal angioplasty involving internal mammary artery grafts. Am Heart J 1991;122:423–429. 7. Popma JJ, Cooke RH, Leon MB, Stark K, Satler LF, Kent KM, Hunn D, Pichard AD. Immediate procedural and long-term clinical results of internal mammary artery angioplasty. Am J Cardiol 1992;69:1237–1239. 8. Najm HK, Leddy D, Hendry PJ, Marquis J-F, Richardson D, Keon WJ. Postoperative symptomatic internal thoracic artery stenosis and successful treatment with PTCA. Ann Thorac Surg 1995;59:323–327. 9. Ishizaka N, Ishizaka Y, Ikari Y, Isshiki T, Tamura T, Suma H, Yamagucchi T. Initial and subsequent angiographic outcome of percutaneous transluminal angioplasty performed on internal mammary artery grafts. Br Heart J 1995;74:615– 619. 10. Hearne SE, Davidson CJ, Zidar JP, Philips HR, Stack RS, Sketch MH Jr. Internal mammary artery graft angioplasty: acute and long-term outcome. Cathet Cardiovasc Diagn 1998;44:153–156. 11. Gruberg L, Dangas G, Mehran R, Hong MK, Waksman R, Mintz GS, Kent KM, Pichard AD, Satler LF, Lansky AJ, et al. Percutaneous revascularization of the internal mammary artery graft: short- and long-term outcomes. J Am Coll Cardiol 2000;35:944 –948. 12. Kaul TK, Fields BL, Wyatt DA, Jones CR, Kahn DR. Reoperative coronary artery bypass surgery: early and late results and management in 1300 patients. J Cardiovasc Surg 1995;36:303–312. 13. Kastrati A, Scho¨ mig A, Elezi S, Schu¨ hlen H, Dirschinger J, Hadamitzky M, Wehinger A, Hausleiter J, Walter H, Neumann F-J. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol 1997;30:1428 –1436. 14. Akiyama T, Moussa I, Reimers B, Ferraro M, Kobayashi Y, Blengino S, Di Francesco L, Finci L, Di Mario C, Colombo A. Angiographic and clinical outcome following coronary stenting of small vessels: a comparison with coronary stenting of large vessels. J Am Coll Cardiol 1998;32:1610 –1618.
Usefulness of Hyperbaric Oxygen Therapy to Inhibit Restenosis After Percutaneous Coronary Intervention for Acute Myocardial Infarction or Unstable Angina Pectoris Mohsen Sharifi, MD, Wassim Fares, MD, Isam Abdel-Karim, MD, J. Michael Koch, MD, Joseph Sopko, MD, and Dale Adler, MD, for the Hyperbaric Oxygen Therapy in Percutaneous Coronary Interventions (HOT-PI) Investigators The purpose of this trial was to assess whether the addition of hyperbaric oxygen to percutaneous coronary intervention can reduce clinical restenosis. Major adverse cardiac events at 8 months were found in only 1 of 24 patients (4%) who received hyperbaric oxygen compared with 13 of 37 patients (35%) who did not. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1533–1535)
yperbaric oxygen therapy (HOT) is a safe and very effective modality in the management of H slow or poorly healing wounds. It has successfully been employed in a variety of clinical conditions, including chronic osteomyelitis, diabetic and pressure ulcers, necrotizing fascitis, crush injuries, compartFrom the Department of Cardiology, St. Vincent Charity Hospital, Case Western Reserve University and the University Hospitals of Cleveland, Cleveland, Ohio; and Texas Tech University Health Sciences Center, Odessa, Texas. Dr. Sharifi’s address is: Texas Tech University Health Sciences Center, 701 W. 5th Street, Suite 3106, Odessa, Texas 79763. E-mail: [email protected]. Manuscript received December 22, 2003; revised manuscript received and accepted March 1, 2004. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 June 15, 2004
ment syndromes, and acute traumatic peripheral ischemia.1,2 Other uses include radiation-induced hemorrhagic cystitis, optic neuritis, air embolism, carbon monoxide intoxication, and air embolism.1,2 Percutaneous coronary interventions (PCIs) invariably create miniature wounds by the disruptive effects of the interventional hardware on the vessel wall, thereby triggering the wound-healing process and leading to restenosis. It is intriguing to hypothesize that the early healing of these miniature wounds by HOT may decrease restenosis.3 We therefore embarked to evaluate the safety and efficacy of HOT in PCI. •••
The trial was approved by St. Vincent Charity Hospital’s institutional review board. Informed consent was obtained from each patient before enrollment in the study. Of the initial 69 patients who were enrolled in the study, 33 were randomized to the HOT arm and 36 to the control group. All patients had presented with unstable angina or acute myocardial infarction. They had stabilized on medical therapy, with the resolution of chest pain and normalization of ST-segment changes. According to protocol, patients who had evidence of ongoing ischemia after the first 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.03.009
1533
TABLE 1 Clinical and Angiographic Characteristics of Study Patients Characteristic Age (yrs) Men Hypertension Hypercholesterolemia (total cholesterol ⬎200 mg/dl) Current smoking Diabetes mellitus Unstable angina Myocardial infarction Left ventricular ejection fraction (%) Saphenous vein graft intervention (patients) Stent length (mm) Stent diameter (mm) Use of glycoprotein IIb/IIIa inhibitors Type C lesion
HOT Group (n ⫽ 24)
Control Group (n ⫽ 37)
63 14 20 8
⫾ 12 (58%) (83%) (33%)
65 21 23 21
⫾ 13 (57%) (62%) (57%)
14 8 15 9 50
(58%) (33%) (63%) (38%) ⫾ 15
21 10 26 11 52
(57%) (27%) (70%) (30%) ⫾ 12
2
3
14 ⫾ 5 3.1 ⫾ 0.4 22 (92%)
15 ⫾ 4 3.0 ⫾ 0.4 37 (100%)
14 (58%)
23 (62%)
1/2 hour of medical therapy were excluded from enrollment. Patients were also excluded if they had any acute or chronic ear disease, histories of spontaneous pneumothorax, or current therapy with doxorubicin or cisplatinum. Of the 33 patients randomized to the HOT group, 4 declined to receive HOT, and 1 did not complete the hyperbaric protocol because of claustrophobia. These 5 patients crossed over to the control group. Three other patients of the HOT group required coronary artery bypass surgery, and 1 was found to have no significant lesion to warrant PCI. Consequently, there remained 24 patients in the HOT group who completed the hyperbaric protocol. Of the initial 36 patients in the control group, 4 were excluded because they required coronary artery bypass surgery or did not have significant disease to require PCI. With the 5 patients who crossed over from the HOT group, the remaining control group consisted of 37 patients. Patients in the HOT group underwent 2 hyperbaric dives using the Sechrist 2500 B Monoplace Hyperbaric System (Sechrist Industries, Anaheim, California): a dive 2 hours before (for the first 8 patients) or immediately after PCI (for all subsequent patients) and another ⱕ18 hours after the first dive. The HOT protocol was modified from a dive before PCI to a dive immediately after PCI because the former protocol would have exposed some patients who did not require PCI to unnecessary HOT. Each dive consisted of 100% oxygen at 2 bars for 90 minutes, with a total chamber dwell time of 120 minutes. Fifteen minutes were required to increase the hyperbaric chamber pressure to 2 bars and another 15 minutes for the decompression phase. The control group received standard PCI without HOT. All patients underwent PCI in de novo native or saphenous vein grafts and received ⱖ1 stent. All patients received aspirin 325 mg/day and heparin during PCI and 1 month of therapy with clopidogrel 75 mg/day. Throughout HOT, patients were continuously 1534 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 93
TABLE 2 Adverse Cardiac Events at Eight Months Variable Composite: death, myocardial infarction, coronary artery bypass, or revascularization of target lesion Death Myocardial infarction Coronary artery bypass Revascularization of target lesion Late angina (after 8 mo)
HOT (n ⫽ 24)
Control (n ⫽ 37)
1
13
0.001
0 1 0 0 1
3 7 0 8 9
NS 0.06 — ⬍0.003 ⬍0.05
p value
monitored visually and hemodynamically. The special ports located on the hatch of the hyperbaric chamber allowed arterial and venous line connections. The intercom system of the chamber provided communication with the patient, and the transparent chamber walls ensured visual monitoring. A successful procedure was defined as that resulting in ⬍20% stenosis in the luminal diameter immediately after intervention without death, myocardial infarction, coronary artery bypass surgery, or stent thrombosis. Myocardial infarction was defined as an elevation of troponin I or creatinine kinase-MB fraction to a value 2 times the upper limit of the normal range. Clinical follow-up was performed at 1, 8, and 18 months after discharge. The predetermined end points were the composite of death, myocardial infarction, and the need for target lesion revascularization at 8 months. The secondary end point was the late recurrence or worsening of anginal symptoms (after 8 months). For the analysis of continuous data, 2-tailed t tests were used to assess the difference between the 2 treatment groups. The results are expressed as means ⫾ SDs. Categorical data were compared with the use of the chi-square test or Fisher’s exact test. The patients’ clinical and angiographic characteristics were similar between the 2 groups (Table 1). Procedural success was obtained in all patients. In general, except for 1 patient, all patients who were placed in the hyperbaric chamber tolerated the procedure well. One elderly patient developed tympanic membrane rupture 3 days after treatment. She had a history of chronic otitis, which was not diagnosed at enrollment. Oxygen toxicity, with its potential manifestations of seizures, disorientation, tremors, and visual disturbances, did not develop in any patient. With the administration of HOT, appreciable changes were noted in the heart rate and blood pressure. The mean blood pressure increased by 20 ⫾ 6 mm Hg, and the mean heart rate decreased by 10 ⫾ 4 beats/min. The increase in blood pressure responded to the intravenous administration of nitroglycerin and enalaprilat. The 8-month adverse cardiac events are listed in Table 2. Although this study did not have a prespecified angiographic follow-up, repeat coronary angiography was performed for chest pain or myocardial infarction at the discretion of the attending cardioloJUNE 15, 2004
gist. Within the first 8 months after the index operation, 3 patients in the HOT arm and 8 in the control group had repeat coronary angiography. Angiographic restenosis (stenosis of ⱖ50% of the luminal diameter) was found in 0 patients of the HOT group and 7 of the control group (p ⬍0.05). •••
The results indicate that patients who received adjunctive HOT in the early peri-PCI period had a lower clinical restenosis rate. Additionally, the recurrence of late anginal symptoms was less frequent in these patients. Several reasons may account for these results. It is well established that the healing of wounds is accelerated with HOT. It is also known that restenosis is triggered by the wound-healing process. It is therefore plausible to postulate that the early closure of these miniature wounds by HOT may attenuate the restenotic process. HOT exerts several beneficial effects at the cellular and molecular level. In a rabbit model of aortic atherosclerosis, not only was progression of disease halted by HOT, but the regression process was markedly accelerated.4 HOT has been shown to induce the expression of a number of antioxidant enzymes in tissues, including hemeoxygenase, by increasing glutathione levels.5,6 These enzymes offer protection against atherosclerosis and reduce oxidation products in high-density lipoprotein.7 Similarly, the activity of serum antioxidant enzymes, such as paraoxonase, is enhanced, leading to a reduction in the oxidation of tissue and plasma lipids.8 This “detoxification” of lipid peroxides has been shown to suppress the recruitment and proliferation of macrophages and the formation of foam cells.4 In tissue cultures of bovine aortic endothelial cells, the expression of intracellular adhesion molecule-1 was downregulated by HOT through the induction of endothelial nitric oxide synthase.9 Furthermore, a sustained increase in nitric oxide production was observed.10 Nitric oxide combines with reactive oxygen species, thereby preventing them from initiating stress responses.9 HOT may reduce the transcription factors involved in intracellular adhesion molecule-1 expression, such as NF-B.11 In addition, synthesis of the heat shock protein HSP70, which has a protective role against oxidative stress, was significantly increased with HOT.12Another potential mechanism for HOT in reducing restenosis is its role as an “antibiotic.” Although a causal relation has not been established,
microorganisms such as Chlamydia and Helicobacter have been associated with the development of coronary artery disease and there have been suggestions of a beneficial role of antibiotics in unstable coronary syndromes.13 HOT has been shown to have potent inhibitory effects on the growth of various microorganisms.14 Furthermore, endothelial cell-derived fibrinolysis and blood flow are enhanced by HOT, which may result in a reduction in recurrent thrombosis.15 In conclusion, HOT is safe and feasible in PCI and may be associated with a reduction in clinical and angiographic restenosis and the development of late anginal symptoms. 1. Tibbles PM, Edelsberg JS. Hyperbaric-oxygen therapy. N Engl J Med 1996; 334:1642–1648. 2. Grim PS, Gottlieb LJ, Boddie A, Batson E. Hyperbaric oxygen therapy. JAMA 1990;263:2216 –2220. 3. Sharifi M, Koch JM, Petrea D, Abdel-Karim I, Steele R, Adler D, Pompili VJ, Sopko J. Hyperbaric oxygen therapy to inhibit restenosis in percutaneous coronary interventions: a preliminary report. Catheter Cardiovasc Intervent 2002;56: 136. 4. Kudchodkar BJ, Wilson J, Lacko A, Dory L. Hyperbaric oxygen reduces the progression and accelerates the regression of atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 2000;20:1637–1643. 5. Harabin AL, Braisted JC, Flynn ET. Response of antioxidant enzymes to intermittent and continuous hyperbaric oxygen. J Appl Physiol 1990;69:328 –335. 6. Padgaonkar VA, Giblin FJ, Fowler K, Leverenz VR, Reddan JR, Dziedzic DC. Heme oxygenase synthesis is induced in cultured lens epithelium by hyperbaric oxygen or puromycin. Exp Eye Res 1997;65:435–443. 7. Ishikawa K, Navab M, Leitinger N, Fogelman AM, Lusis AJ. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. J Clin Invest 1997;100:1209 –1216. 8. Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parma SL, LaDu B. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its function: a possible peroxidative role for paraoxonase. J Clin Invest 1998;101:1581– 1590. 9. Buras JA, Stahl GL, Svoboda KK, Reenstra WR. Hyperbaric oxygen downregulates ICAM-1 expression induced by hypoxia and hypoglycemia: the role of NOS. Am J Physiol 2000;278:C292–C302. 10. Rengasamy A, Johns RA. Characterization of endothelium-derived relaxing factor/nitric oxide synthase from bovine cerebellum and mechanism of modulation by high and low oxygen tensions. J Pharmacol Exp Ther 1991;259:310 –316. 11. Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redoxsensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci USA 1996;93:9114 –9119. 12. Dennog C, Radermacher P, Barnett YA, Speit G. Antioxidant status in humans after exposure to hyperbaric oxygen. Mutat Res 1999;16:83–89. 13. Higgins JP. Chlamydia pneumoniae and coronary artery disease: the antibiotic trials. Mayo Clin Proc 2003;78:321–332. 14. Bornside GH, Pakman LM, Ordonez AA. Inhibition of pathogenic enteric bacteria by hyperbaric oxygen: enhanced antibacterial activity in the absence of carbon dioxide. Antimicrob Agents Chemother 1975;7:682–687. 15. Tjarnstrom J, Holmdahl L, Falk P, Falkenberg M, Arnell P, Risberg B. Effects of hyperbaric oxygen on expression of fibrinolytic factors of human endothelium in a simulated ischaemia/reperfusion situation. Scand J Clin Lab Invest 2001;61: 539 –545.
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