Luis Guerrero

Differential Response of Delayed Healing and Persistent Inflammation at Sites of Overlapping Sirolimus- or Paclitaxel-Eluting Stents

Background—Although effective coverage of challenging coronary lesions has warranted the use of overlapping drug-eluting stents, the histopathological response to stent overlap is unknown. Methods and Results—The arterial reaction to overlapping Cypher or Taxus drug-eluting stents was examined in rabbits with bare metal stents, BxVelocity or Express, serving as controls. Single iliac artery balloon injury was followed by placement of 2 overlapping 3.0-mm-diameter drug-eluting stents or bare metal stents in 60 animals (mean length of overlap, 9.8±3.6 mm). Stented arteries were harvested at 28 and 90 days for histology. Overlapped segments exhibited delayed healing compared with proximal and distal nonoverlapping sites at 28 days. Overlapped segments in Taxus stents induced significantly more luminal heterophils/eosinophils and fibrin deposition than Cypher; peristrut giant cell infiltration, however, was more frequent in the latter. Overlapping bare metal stents also showed mild delayed healing compared with nonoverlapped segments, but not to the same extent as drug-eluting stents. Although neointimal thickness within the overlap was similar in 28- and 90-day Cypher stents, there was a significant increase with Taxus (P=0.03). Conclusions—Compared with bare metal stents, drug-eluting stents further delay arterial healing and promote inflammation at sites of overlap. Taxus stents induced greater fibrin deposition, medial cell loss, heterophils/eosinophils, and late neointimal hyperplasia. Patients receiving overlapping drug-eluting stents need more frequent follow-up than patients with nonoverlapping stents.

Restoration of Coronary Flow in Myocardial Infarction by Intravenous Chimeric 7E3 Antibody Without Exogenous Plasminogen Activators Observations in Animals and Humans

BACKGROUND Coronary thrombus is composed of platelets and fibrin, and during thrombolytic treatment, reflow may be slowed by platelet deposition. It may be possible to initiate coronary reflow without exogenous plasminogen activators by blocking platelet aggregation while fibrin generation is impeded with heparin. METHODS AND RESULTS In 14 dogs, left anterior descending coronary artery thrombosis was produced by endothelial trauma and thrombin instillation in the presence of stenosis distally. Reflow was monitored by flow probe during treatment with (1) heparin, (2) heparin and aspirin, and (3) heparin, aspirin, and intravenous 7E3. Eighty percent of dogs treated with the third combination showed stable reflow (> or = 25% of prestenotic flow) in 50 +/- 9 minutes. In addition, 13 patients were studied during intravenous administration of c7E3 10 minutes before primary angioplasty for acute myocardial infarction and Thrombolysis In Myocardial Infarction (TIMI) grade 0 or 1 flow. Pretreatment included heparin and oral aspirin. Flow increased during a 10-minute period by at least one TIMI grade in 11 (85%) of 13 and reached TIMI grade 2 or 3 in 7 (54%) of 13 patients. Average TIMI grade flow increased from 0.31 +/- 0.5 to 1.54 +/- 0.8 (P < .001). Thrombus length 10 minutes after c7E3 was 5.1 +/- 3.5 mm. All but 1 patient then underwent angioplasty. There were no complications. CONCLUSIONS Coronary reflow can be initiated by intravenous 7E3 administration in the presence of heparin and aspirin. In human patients, this flow can be observed in 10 minutes without exogenous thrombolytic agents.

Kistrin, a polypeptide platelet GPIIb/IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activator in a canine preparation.

BackgroundKistrin is a 68-amino acid polypeptide from the venom of the Malayan pit viper Agkistrodon rhodostoma, which inhibits the platelet GPIIb/IIIa receptor. Its effect on thrombolysis, reocclusion, and bleeding associated with administration of recombinant tissue-type plasminogen activator (rt-PA) was studied in a canine model of coronary artery thrombosis. Methods and ResultsCoronary patency was monitored for 2 hours by ulltrasonic flow probe and repeated coronary angiography. The rt-PA was given as 0.45-mg/kg bolus injections at 15-minute intervals until recanalization or to a maximum of four boluses. Four groups of four or five dogs were studied: a control group that received intravenous heparin (4,000-unit bolus and 1,000 units each hour) and three groups that received heparin and 0.48, 0.24, or 0.12 mg/kg kistrin, administered as a 10% bolus injection and an infusion during a 60-minute period. In the control group, reflow occurred in four of five dogs within 37±47 minutes but was followed by cyclic reflow and reocclusion. Kistrin at a dose of 0.48 and 0.24 mg/kg reduced the time to reflow to 6±5 and 10±3 minutes, respectively, and abolished reocclusion. With 0.12 mg/kg kistrin, reflow occurred in all four animals, within 27±23 minutes, and reocclusion occurred in two animals. Kistrin induced a dose-related prolongation of the template bleeding time: with 0.48 mg/kg kistrin, the bleeding time was prolonged from 3.8±1.3 minutes before infusion to 29±2 minutes during infusion, but it was shortened to 8.3 ±2.6 minutes at 90 minutes after the end of infusion. Kistrin also caused a dose-related inhibition of platelet aggregation with ADP and collagen: with 0.48 mg/kg kistrin, platelet aggregation was abolished during the infusion but had partially recovered toward the end of the observation period. Pathological examination of recanalized coronary arterial segments of dogs given 0.48 or 0.24 mg/kg kistrin revealed widely patent arteries with some platelets layered on the damaged intimal surface. ConclusionsKistrin increases the rate and extent of thrombolysis with a reduced dose of rt-PA, and it prevents reocclusion. At an effective dose, it is associated with a transient prolongation of the bleeding time and inhibition of platelet aggregation. Kistrin may offer promise as adjunctive treatment to thrombolytic agents in patients with acute myocardial infarction. (Circulation 1991;83:1038–1047)

Patterns of normal transvalvular regurgitation in mechanical valve prostheses

The magnitude and spatial distribution of normal leakage through mechanical prosthetic valves were studied in an in vitro model of mitral regurgitation. The effective regurgitant orifice was calculated from regurgitant rate at different transvalvular pressure differences and flow velocities. This effective orifice area was 0.6 to 2 mm2 for three tilting disc prostheses (Medtronic-Hall sizes 21, 25 and 29) and 0.2 to 1.1 mm2 for three bileaflet valves (St. Jude Medical sizes 21, 25 and 33). In the single disc valves, Doppler color flow examination disclosed a prominent central regurgitant jet around the central hole for the strut, accompanied by minor leakage along the rim of the disc (central to peripheral jet area ratio 3.3 +/- 1.2). The bileaflet prostheses showed a peculiar complex pattern: in planes parallel to the two disc axes, convergent peripherally arising jets were visualized, whereas in orthogonal planes several diverging jets were seen. Mounting the disc and bileaflet valves on a water-filled tube allowed reproduction and interpretation of this pattern: for the bileaflet valve, the jets originated predominantly from valve ring protrusions that contained the axis hinge points and created a converging V pattern in planes parallel to the leaflets and a diverging V pattern in orthogonal planes. Similar patterns were observed during transesophageal echocardiography in 20 patients with a normally functioning St. Jude prosthesis. In 10 patients with a Medtronic-Hall valve, a dominant central jet was observed with one or more smaller peripheral jets. The median central to peripheral jet area ratio was 5 to 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of changes in ventricular relaxation on early diastolic coronary blood flow in canine hearts.

Since the gradient between aortic pressure and left ventricular diastolic pressure is a major determinant of coronary blood flow, a change in left ventricular relaxation by its effect on early diastole could diminish early diastolic coronary flow. Two interventions that resulted in impaired left ventricular relaxation, hypothermia, and reperfusion following a left anterior descending coronary artery occlusion were studied to evaluate whether there were associated changes in coronary blood flow. With both interventions, there was a significant prolongation of left ventricular relaxation (p<0.01) accompanied by a significant decrease in early diastolic coronary blood flow (p<0.01). Verapamil did not have a significant effect on these hemodynamic changes during hypothermia. However, verapamil significantly blunted the effects of reperfusion following ischemia on ventricular relaxation (p<0.002) and early diastolic coronary blood flow (p<0.01). Thus, impaired left ventricular relaxation has an adverse impact on early diastolic coronary blood flow, which, under the condition of reperfusion following regional myocardial ischemia, can be alleviated with calcium channel blockade. (Circulation Research 1987;61:747-756)

Intravenous and endobronchial administration of G4120, a cyclic Arg-Gly-Asp-containing platelet GPIIb/IIIa receptor-blocking pentapeptide, enhances and sustains coronary arterial thrombolysis with rt-PA in a canine preparation.

G4120, L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-alpha- aspartyl-cyclic(1-->5)-sulfide, 5-oxide, a synthetic cyclic Arg-Gly-Asp-containing pentapeptide, has a high affinity (dissociation constant of 4 nM) for the platelet glycoprotein (GP) IIb/IIIa receptor. The effects of its intravenous or endobronchial administration on thrombolysis, reocclusion, and bleeding time prolongation induced with 0.45 mg/kg bolus injections of recombinant tissue-type plasminogen activator in combination with intravenous heparin (4,000-unit bolus and 1,000 units each hour) were studied in a canine model consisting of an erythrocyte-rich blood clot in the left anterior descending coronary artery. Coronary patency was monitored for 3 hours both by ultrasonic flow probe and by repeat coronary angiography. Four groups of six to 10 dogs were studied with intravenous infusions of 0, 0.1, 0.2, or 0.3 mg/kg G4120 over 60 minutes. G4120 at a dose of 0.3 mg/kg reduced the time to reflow from a mean control value of 45 to 8 minutes (p = 0.036) and delayed reocclusion (p = 0.001). Four groups of five or six dogs were studied with endobronchial instillation of G4120 in a randomized, blinded study design using 0, 0.13, 0.25, or 0.5 mg/kg G4120. Endobronchial G4120 at a dose of 0.5 mg/kg reduced the time to reflow from a mean control value of 52 to 7 minutes (p = 0.039) and abolished cyclic reocclusion and reflow (p = 0.008). G4120 induced a dose-related transient prolongation of the template bleeding time and inhibition of ADP-induced platelet aggregation. G4120, a synthetic low-molecular-weight GPIIb/IIIa inhibitor that may be produced by chemical synthesis, may be of clinical value as a conjunctive agent for thrombolysis in patients with ischemic coronary syndromes.

Simultaneous Thrombolysis and Venous Angioplasty in Acute Ilio-femoral Thrombosis after IVC filter Insertion and Novel Balloon Catheter Models

Four patients with extensive acute iliofemoral and popliteal vein thrombosis and partially extending into the inferior venacava (IVC) with diffuse swelling of lower limb and gluteal region were studied. Initially, Gunther Tulip (Cook) IVC filter was placed in all patients. A 5F multipurpose catheter with side holes was placed in common iliac vein bifurcation and thrombolysis was done for 18 hours with diluted streptokinase infusion at 50,000 U/hr. Thereafter, a 5 mm × 4 cm peripheral balloon was advanced through the clots to mid or lower femoral vein level and thrombolysis was done for 18 hours with streptokinase infusion through the balloon’s 035 wire port. The balloon was pulled back and multiple serial dilatations were done in all four procedures. Post procedure the venous channels were opened and were draining adequately. Limb edema subsided in 4 to 5 days and there were no bleeding or embolic complications in all patients. The first two patients are on follow up for 18 months, the third patient for 5 months, and the fourth patient for 2 weeks. Based on these observations, two novel balloon models for thrombolysis and to perform venous angioplasty simultaneously were developed. The piggyback model has a side lumen catheter with side holes attached to the shaft of the balloon catheter (5 mm width × 4 cm length ). The side lumen terminates before the balloon. The horseshoe models made of polyethylene terephthalate have a 10 cm long and 4 mm wide compliant balloon with a double lumen catheter and multiple side ports till the balloon tip.