Local delivery of a synthetic antithrombin with a hydrogel-coated angioplasty balloon catheter inhibits platelet-dependent thrombosis.

OBJECTIVES: This study evaluated the efficacy of local administration of an antithrombin agent with a hydrogel-coated percutaneous transluminal coronary angioplasty balloon catheter. BACKGROUND: Intravenous infusion of antithrombin compounds has been shown to inhibit platelet-dependent thrombosis. However, hemorrhage is a common side effect associated with the systemic administration of antithrombin compounds. METHODS: The potent, irreversible thrombin inhibitor D-Phe-L-Pro-L-Arginyl chloromethyl ketone (PPACK) was used to inhibit thrombus formation in chronic porcine arteriovenous shunts. Platelet deposition was quantitated with gamma camera imaging of 111In-labeled platelets. RESULTS: Intravenous administration of PPACK in swine, in doses sufficient to maximally inhibit thrombus formation, was associated with prolongation of bleeding parameters. The inhibition of thrombosis associated with intravenous PPACK was dose related. The amount of intravenous PPACK necessary for maximal inhibition of thrombus formation for a period of 45 min was 16.9 mg. In contrast, local delivery of PPACK with a hydrogel-coated angioplasty balloon deployed at the site of the thrombus inhibited platelet deposition for at least 45 min after the balloon was removed. Using 3H-labeled PPACK, the calculated amount of PPACK delivered was 33.5 micrograms. There was no change in bleeding time or activated partial thromboplastin time when swine received an intravenous bolus greater than the total amount of PPACK adsorbed onto the balloon (70 micrograms). CONCLUSIONS: These results suggest that in this model, a hydrogel-coated coronary angioplasty balloon catheter can be used to deliver enough antithrombin agent to inhibit platelet-dependent thrombosis for at least 45 min at doses that are several orders of magnitude less than those required for systemic administration. In addition, local delivery can provide effective inhibition of thrombus formation without alteration of bleeding parameters.

[Acute occlusion after coronary angioplasty. Early management and late course]. / Oclusão aguda pós-angioplastia coronária. Manuseio precoce e evolução tardia.

PURPOSE: Assess the efficacy of the different strategies employed in the management of acute closure and verify the late prognosis of patients who develop this complication. METHODS: From january 1987, through December 1990, 2315 consecutive patients underwent percutaneous transluminal coronary angioplasty (PTCA) in our Institution. We analyzed 100 patients who had had acute closure of the dilated vessel determining the total incidence of myocardial infarction and death, the effectiveness of the different treatment strategies and clinical and angiographic predictors of poor in-hospital outcome. Late follow-up was obtained in the hospital survivors. RESULTS: The incidence of acute myocardial infarction in the group of 100 patients was 57%; death occurred in 12% of the patients. Forty-one individuals were referred to emergency bypass surgery, 35 received clinical treatment and 24 underwent redilatation of the vessel. Those managed clinically had a higher incidence of myocardial infarction compared to the ones who underwent either redilatation or surgery (74.3% versus 50% and 48.8%). The in-hospital mortality rate was significantly higher in patients with left ventricular ejection fraction < 45% (44.4%, p < 0.001) and in procedures involving the left anterior descending artery (20%, p < 0.05); patients undergoing repeat dilatation had the lower death rate (4.2% versus 8.6% in the clinical group and 17.1% in the surgical group). Late follow-up was obtained in 65 of 88 hospital survivors (mean follow-up = 17 months). Patients who underwent repeat dilatation were significantly less symptomatic in the follow-up than those who received medical therapy during the acute phase (89% versus 60.9% of patients without symptoms respectively, p < 0.05). Patients who were referred to surgery had also a tendency towards having less symptoms (87.5% of asymptomatic patients in the late follow-up) although the difference was not statistically significant (0.01 > p > 0.05). CONCLUSION: Acute coronary occlusion is a serious complication of angioplasty and is associated with high rates of major complications (myocardial infarction, death). Low left ventricular ejection fraction and PTCA involving the left anterior descending are predictors of higher in-hospital mortality in patients with acute closure. Late outcome is less favourable in patients submitted to clinical treatment in the acute phase.

[Current complications of heart catheterization. Analysis of 100 cases]. / Complicações atuais do cateterismo cardíaco. Análise de 1000 pacientes.

PURPOSE: To analyse the impact of the new cardiac catheterization techniques on the complication profile of these procedures. PATIENTS AND METHODS: One thousand consecutive patients who underwent cardiac catheterization from August through December, 1989 (739 diagnostic and 201 therapeutic procedures), who were followed up until hospital discharge. Complications were classified accordingly to their type and severity, and were related to the procedure employed and to the left ventricular ejection fraction. RESULTS: There were no complications in 77.7% of the population studied. In the remaining 236 patients the incidence of mild, moderate and severe complications were, respectively: 11.2%, 7.3% and 3.8%. Severe vascular complications occurred in 0.5%, cardiac perforation requiring emergency surgical repair in 0.1%, severe arrhythmias in 1.4%, acute myocardial infarction in 0.4%, acute pulmonary edema in 0.3% and fatal events in 0.5% patients. CONCLUSION: Despite the increasing application of interventional techniques and the greater number of acutely ill patients referred to cardiac catheterization, these procedures have proved to be safe with a low complication rate.

[Coronary angioplasty in patients with restenosis. Characterization of clinical and angiographic profiles, hospital clinical course, and implications for the selection of patients]. / Angioplastia coronária em pacientes com lesões reestenóticas. Caracterização do perfil clínico e angiográfico, evolução hospitalar e implicações para seleção de pacientes.

PURPOSE: To define the clinical and angiographic profile of patients undergoing to a 2nd or a 3rd coronary angioplaty (PTCA) for the treatment of restenosis, and assess the safety and efficacy of redilatation. METHODS: Patients submitted to PTCA for a 1st (1stRE) or a 2nd (2ndRE) restenosis, from Jan/1980 through Dec/1993, were retrospectively identified, and compared to those undergoing to PTCA for de novo lesions (DN). RESULTS: A total of 5,736 underwent to dilatation of primary lesions, 610 of a 1stRE, and 64 of a 2ndRE. Patients with restenotic lesions had a higher prevalence of diabetes, smoking, history of prior infarction (1stRE e 2ndRE) and hyperlipidemia (2ndRE) as compared with primary lesions (p < 0.05). Besides patients with a 2ndRE had a higher incidence of left ventricular dysfunction, as compared to those with DN or a 1stRE (31.3% with EF < 45% in group 2ndRE, vs 19.8% and 23.1% in groups 1stRE and DN, respectively, p < 0.05). Primary success, infarct rate and mortality were similar in all groups, but emergency bypass surgery was significantly higher in the DN (2.1% vs 0.8% in 1stRE and 0% in 2ndRE, p < 0.05). CONCLUSION: Restenosis can be effectively treated by redilatation. Patients with clinical and angiographic features predisposing to further recurrence can be better treated with other interventions (i.e., coronary stents, bypass surgery).

[Influence of the clinical presentation on immediate and long-term results after rotational atherectomy]. / Influência do quadro clínico nos resultados imediatos e tardios após aterectomia rotacional.

PURPOSE: To analyse the influence of unstable coronary syndromes (UCS) in the early and late prognosis after rotational atherectomy (RA). METHODS: We treated 236 patients with RA between Aug/1992 and May/1996. Patients were divided into two groups: A) stable coronary syndromes 120 (51%) patients; B) UCS: 116 (49%) patients. DEFINITIONS: 1) procedure success (PS)--lesion success in all locations were RA use was attempted, without a major complication; 2) late coronary events (LCE)--angina, MI, additional revascularization or death. RESULTS: There was a significant predominance of age > 70 (A = 14% x B = 24%, p = 0.03) in B and previous MI (A = 32% x B = 11%, p = 0.0001) in A. Other characteristics were similar in both groups, including complex lesions (type B2/C), which were observed in 77% A stenosis and 80% B lesions. PS was 95% in A and 92% in B (p = NS). In-hospital major complications were observed in 2.5% A and 4.3% B patients, (p = NS). One patient died in each group. A and B patients had similar time of follow-up. LCE occurred in 25% A and 39% B patients (p = 0.002). Recurrence of angina (36% x 23%; p = 0.01) and target lesion revascularization (29% x 18%; p = 0.03) were also more frequently required in B cases. CONCLUSION: This study suggests that UCS (group A) does not implicate in worse acute results after RA. However, UCS patients present greater incidence of late coronary events, particularly recurrence of angina and target-lesion revascularization.

Inhibition of platelet-dependent thrombosis by local delivery of heparin with a hydrogel-coated balloon.

BACKGROUND: Systemic administration of heparin can decrease mortality and morbidity of acute ischemic coronary syndromes such as unstable angina and myocardial infarction. Hemorrhage is the major limiting factor in the clinical use of systemic heparin. The objective of the present study was to determine whether local delivery of heparin could inhibit platelet-dependent thrombosis without altering systemic bleeding parameters. METHODS AND RESULTS: Hydrogel-coated angioplasty balloon catheters were dipped in a heparin solution, dried, and applied to a platelet-rich mural thrombus in a chronic ex vivo porcine arteriovenous shunt. 111In-labeled platelet deposition was quantified by gamma camera imaging. In a separate series of experiments, 3H-heparin was used to estimate the amount of heparin delivered to the thrombus with the coated balloon. Systemic heparin administration produced a dose-dependent decrease in platelet-dependent thrombus formation that was maximal at 200 units/kg. Bleeding times and activated partial thromboplastin times were prolonged at this dose. An equal inhibition of thrombus formation was achieved after the coated balloon was dipped in a heparin solution (10,000 units/mL) and deployed at the mural thrombus. In contrast to systemic heparin administration, there was no alteration in bleeding parameters associated with local heparin delivery. The estimated amount of heparin delivered with the coated balloon was 40 units. CONCLUSIONS: Local delivery of heparin in amounts sufficient to inhibit platelet-dependent thrombosis can be accomplished with a hydrogel-coated coronary angioplasty balloon catheter. Local heparin delivery can inhibit thrombus formation in amounts that are several orders of magnitude lower than the required systemic dose. Local delivery of heparin was not associated with prolongation of bleeding parameters.

Vitamins C and E inhibit O2- production in the pig coronary artery.

BACKGROUND: We previously found in a pig coronary balloon injury model that vitamins C and E as well as probucol had beneficial effects on the vessel response to injury measured by morphometry These effects correlated with an inhibition in the ability to oxidize LDLs ex vivo, suggesting that the morphological response was due to the antioxidant effect of the treatments. METHODS AND RESULTS: In the present study, the production of O2- by vessels 14 days after balloon injury was determined and correlated with circulating and tissue levels of vitamins C and E. Twenty-five domestic pigs were divided into four groups: control (n=7), vitamin C (500 mg/d, group C, n=6), vitamin E (1000 IU/d, group E, n=6), and vitamins C and E (500 mg/d and 1000 IU/d, group C+E, n=6). Vitamins were administered 7 days before oversized balloon injury of the left anterior descending coronary artery (LAD) and continued for 14 days after injury. Vitamin C and E concentrations were determined in plasma and lymphocytes as an index for tissue levels. Vessels were harvested after animals were killed, and O2- production was measured by lucigenin chemiluminescence. O2- production by the injured LAD was 2.5-fold greater than O2- production by the uninjured LAD or right coronary artery (RCA). The increase in O2- was caused primarily by cells present in the media and neointima. All vitamin-treated groups showed significantly decreased O2- production in both the RCA and LAD (approximately 45% inhibition) relative to vessels in the control, untreated group. There was a significant correlation between LAD O2- production and lymphocyte vitamin E levels. CONCLUSIONS: The present study is the first to show increased O2- production in injured vessels and to demonstrate that antioxidant vitamins reduce O2- production. These results suggest that beneficial effects of antioxidant vitamins in coronary artery disease are related, in part, to alterations in vessel redox state.

Local delivery of an antithrombin inhibits platelet-dependent thrombosis.

BACKGROUND: Platelet-dependent thrombosis can be effectively inhibited by intravenous administration of direct thrombin antagonists. However, an increased propensity for abnormal bleeding has been associated with systemic administration of these agents. The goal of this study was to determine whether local delivery of a potent thrombin inhibitor, D-Phe-L-Pro-L-Arg chloromethyl ketone (PPACK), could inhibit platelet-dependent thrombosis without altering systemic hemostatic function. METHODS AND RESULTS: Thrombus formation was measured by quantitative imaging of 111In-labeled platelet deposition on segments of thrombogenic vascular graft interposed in arteriovenous shunts in a porcine model. Intravenous administration of PPACK inhibited platelet deposition at a dose of 12.5 micrograms/kg per minute, which was associated with significant prolongations of both template bleeding times and activated partial thromboplastin times. By contrast, local infusion of PPACK at a dose of 0.02 micrograms/kg per minute (ie, a 600-fold smaller dose) into the fluid boundary layer at the interface between flowing blood and the thrombogenic segment produced equivalent inhibition of platelet deposition without prolonging either the bleeding time or the activated partial thromboplastin time. In addition, static exposure of a mural thrombus to solutions of PPACK at concentrations > or = 2.5 mg/mL for 15 minutes produced sustained inhibition of platelet-dependent thrombosis with no change in hemostatic measurements. CONCLUSIONS: These results indicate that local delivery of the direct antithrombin PPACK, by either boundary layer infusion or static application techniques, effectively inhibits platelet-dependent thrombosis at doses that are several orders of magnitude less than the systemic dose required for an equivalent antithrombotic effect. In contrast to the systemic administration of PPACK, local delivery produced maximal inhibition of thrombosis without alterations in hemostasis.

Combination of vitamins C and E alters the response to coronary balloon injury in the pig.

Restenosis is the major limitation of the long-term success of percutaneous transluminal coronary angioplasty. The process of restenosis involves repair of vascular injury and remodeling of vessel architecture. Therapeutic interventions that improve vascular function may therefore be beneficial in the treatment of restenosis. Antioxidants such as probucol and vitamins C and E have proved effective in improving endothelial function in hypercholesterolemia, inhibiting lipid accumulation in animal models of atherosclerosis, and decreasing cardiovascular mortality in humans. Forty-two female domestic swine were divided into four study groups: control (n = 12); vitamin C (500 mg/d, group C, n = 9); vitamin E (1000 U/d, group E, n = 10); and vitamins C and E (500 mg/d + 1000 U/d, group C+E, n = 11) before oversized balloon injury of the left anterior descending and circumflex coronary arteries. Vitamins were administered 7 days before balloon injury and continued until the swine were killed 14 days after injury. Significant differences in morphometric parameters were present only in group C+E, with increases in vessel and lumen area in the segment with maximal injury. Although there was no decrease in intima area or in maximal intima thickness, the ratio of intima area to vessel area was significantly reduced, consistent with a positive effect in group C+E. Graphic analysis of the relationship between initial vessel injury (using internal elastic lamina fracture length/lumen perimeter) and vessel response to injury (using intima area/vessel area) for all segments showed improved indices for group C+E (P < .005). The beneficial effect of vitamins correlated with changes in lipid redox state. Low-density lipoprotein (LDL) thiobarbituric acid-reactive substances showed an approximately 70% decrease in all treatment groups, and the lag phase for LDL-conjugated diene formation was significantly increased, with group C+E > group E > group C. The combination of vitamins C and E improved vascular response to injury because of an apparent beneficial effect on vascular remodeling. The fact that the combination of vitamins C+E was better than vitamin E or vitamin C alone is consistent with the ability of vitamin C to improve the antioxidant effect of vitamin E, suggesting that the improved vessel response was due to a change in redox state. This study suggests an important role for oxygen radicals in the vascular response to injury and suggests that vascular remodeling and intimal proliferation are important to the restenotic process.

Comparison of the thrombogenicity of stainless steel and tantalum coronary stents.

This study was designed to compare the thrombogenicity of stainless steel and tantalum coronary stents of the same design. Stainless steel and tantalum coronary stents are being evaluated for their utility in treating acute closure and restenosis. A major disadvantage of stainless steel stents is radiolucency. To determine whether radioopaque tantalum stents may be safely substituted for stainless steel stents, we compared the relative thrombogenicity of these materials in stents of identical design. Total platelet and fibrin deposition on the stents were determined from measurements of indium 111-labeled platelet and iodine 125-labeled fibrinogen accumulation after deployment into exteriorized chronic arteriovenous shunts in seven untreated baboons. In another series of experiments, 111In-platelet deposition was compared 2 hours after stent implantation in coronary arteries of pigs. In baboons, platelet thrombus formation on stainless steel and tantalum stents was equivalent and plateaued at approximately 2.5 x 10(9) platelets after 1 hour (p > 0.05). Fibrin deposition averaged approximately 1 mg/stent and did not differ between the stainless steel and tantalum stents (p > 0.05). In the porcine coronary model there was no significant difference in 111In-labeled platelet deposition between the stainless steel and tantalum stents (p > 0.05). This result was confirmed by scanning electron microscopic analysis of the coronary stents. Based on these two models, we conclude that there is no significant difference in the thrombogenicity of stainless steel and tantalum wire coil stents.