James A. Hearn

Trapidil in preventing restenosis after balloon angioplasty in the atherosclerotic rabbit.

Trapidil (triazolopyrimidine) possesses activity against platelet-derived growth factor-induced cellular proliferation in vitro and intimal proliferation in vivo. The objective of this study was to determine if trapidil could prevent restenosis in experimentally induced atherosclerotic rabbits. New Zealand White rabbits with preexisting iliac arterial lesions induced by balloon deendothelialization underwent balloon angioplasty. Arteriography was performed before, immediately after, and 4 weeks after the balloon dilatation. Tissue sections of the dilated arterial segment were also analyzed morphometrically. Seventeen rabbits were randomized to two groups: a control group (n = 8) and a trapidil-treated group (n = 9). The treatment group received 30 mg/kg s.c. trapidil twice daily. The angiographic luminal diameters before and after dilatation were similar. At the 4-week restudy, there was a significant preservation of luminal diameter in the trapidil group compared with the control group (1.27 +/- 0.20 vs. 0.94 +/- 0.48 mm, respectively; p less than 0.005). When luminal diameters immediately after dilatation were compared with diameters at the 4-week restudy (i.e., when the degree of restenosis was assessed), there was a greater luminal diameter reduction in the control group than in the trapidil group (0.70 +/- 0.44 vs. 0.30 +/- 0.25 mm, respectively; p = 0.005). By morphometric analyses, the luminal areas were also greater in the trapidil group than the control group (0.80 +/- 0.25 vs. 0.57 +/- 0.33 mm2, respectively; p = 0.03). Intimal thickness was significantly less for the trapidil group than for the control group (0.33 +/- 0.15 vs. 0.44 +/- 0.15 mm, respectively; p = 0.01), as well as medial thickness (0.09 +/- 0.03 vs. 0.11 +/- 0.03 mm, respectively; p = 0.01). In this study, trapidil significantly increased the luminal area and reduced the intimal thickness in the atherosclerotic rabbit iliac artery after balloon angioplasty.

Usefulness of Serum Lipoprotein (a) as a Predictor of Restenosis After Percutaneous Transluminal Coronary Angioplasty

Serum lipoprotein (a) (Lp[a]) has been associated with coronary artery atherosclerosis. Its association with restenosis after percutaneous transluminal coronary angioplasty (PTCA) has not been previously studied. Serum levels of Lp(a), in addition to other lipoproteins, and their components using standard assays, were determined in subjects undergoing cardiac catheterization within 10 months after PTCA. Clinical (e.g., sex, diabetes, angina class) and angiographic (e.g., PTCA percent diameter reduction) factors were not different between the group without (diameter reduction less than 50%; group A) and the group with (diameter reduction greater than or equal to 50%; Group B) restenosis. Total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein B and Lp(a) were compared. Univariate predictors of restenosis were serum triglycerides (2.50 +/- 1.07 mmol/liter for group A vs 1.72 +/- 0.79 +/- mmol/litre for group B, p = 0.008), and Lp(a) (median: 7.0 mg/dl [range 0 to 44] for group A vs 19 mg/dl [range 1 to 120] for group B; p = 0.006). Stepwise logistic regression revealed the only significant independent predictor of restenosis to be serum Lp(a) (p = 0.018). Each quintile of Lp(a) was associated with a progressively higher risk of restenosis, with the highest quintile (40 to 120 mg/dl) having an odds ratio of 11 (95% confidence interval 9 to 13) compared with the lowest quintile (0 to 3.9 mg/dl) (p = 0.033). A serum Lp(a) of greater than 19 mg/dl was associated with an odds ratio of 5.9 (95% confidence interval 4.6 to 7.2) (restenosis rates of 58% in the group with 0 to 19 mg/dl and 89% in the group with 19 to 120 mg/dl; p = 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

Predictive value of lipoprotein (a) and other serum lipoproteins in the angiographic diagnosis of coronary artery disease

To determine the relation among lipids in predicting coronary artery disease (CAD), 213 patients undergoing diagnostic angiography for suspected CAD were prospectively studied. Twenty-one patients had normal coronary arteries and 192 had CAD in 1 to 3 arteries at arteriography with measurements obtained with digital calipers. Lipoproteins were measured and lipoprotein (a) [Lp(a)] was also assayed in a subset of 98 patients with CAD. Statistical analysis was performed using uni- and multivariate techniques to test the association among age, gender, systemic hypertension, diabetes mellitus, cigarette smoking, family history, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low density lipoprotein cholesterol, apolipoproteins (apo) A-I and apo B, ratio of apo A-I to apo B, and ratio of HDL cholesterol to total cholesterol, to Lp(a) and to CAD. All factors except gender, systemic hypertension, diabetes mellitus and cigarette smoking were univariate predictors of CAD. Multivariate predictors were, in decreasing order of significance, family history, age, HDL/total cholesterol ratio and apo B. When Lp(a) was included, multivariate predictors were age, family history, apo B and Lp(a), in that order. Lipid parameters alone showed that the HDL/total cholesterol ratio and that Lp(a) provide the best predictive tests for the detection of CAD in this referral population and may ultimately become important screening tests for CAD.

Coronary aneurysms after stent placement: a suggestion of altered vessel wall healing in the presence of anti-inflammatory agents.

Coronary aneurysms are rare after conventional angioplasty and have not been reported after coronary stenting. Coronary artery stent sites were examined by follow-up angiography at a median of 4 months in 29 patients who received the Cook stent (Gianturco-Roubin) for acute coronary closure. Nineteen patients were treated with glucocorticoids administered intravenously or orally, or both, with or without colchicine and results were compared with those in 10 patients who were treated with neither agent. Standard therapy for all patients included routine administration of aspirin and heparin before and warfarin sodium (Coumadin) and aspirin after stent placement. Most patients also received dipyridamole and lovastatin during the follow-up period. Compliance with medications was confirmed by telephone conversation with each patient. Six (32%) of the 19 stented arteries showed evidence of coronary artery aneurysm, defined as expansion of the lumen outside the margins of the stent. None of the patients in the control group (who did not receive steroids or colchicine) developed aneurysm. This pattern of altered vascular healing in stented coronary segments appears to be due to the addition of multiple anti-inflammatory drugs rather than to stent presence alone. This observation demonstrates the possibility of medical impairment of normal vascular remodeling after acute injury and stent placement, which may be of benefit in designing future trials on restenosis.

Rate of weight loss during underfeeding: Relation to level of physical activity

The kinetics and bioenergetic-metabolic determinants of weight loss were examined in obese women ingesting 900 kcal/d for 5 weeks. The patients were assigned either to a sedentary group (n = 5) or to an exercise group (n = 6) in which the participants expended an additional (X +/- SD) 346 +/- 61 kcal/d in aerobic physical activity. The percentage weight loss and the fractional rates (K1 = fast component; K2 = slow component) of weight loss were almost identical between the two groups. The failure of added exercise to increase the velocity of weight loss could not be explained by differences between the groups in any of the following: gastrointestinal energy and nitrogen (N) absorption; fractional rates of urinary urea N and total N loss; or the thermic effect of the formula diet. The cumulative and fractional rates of protein (ie N) loss were also similar between the groups. The exercise group lost more fat (5.3 +/- 1.0 kg) than the non-exercise group (4.4 +/- 1.6 kg, P less than .001) as measured by underwater weighing. The maximum between-group difference in the rate of fat loss, as determined by energy-N balance, occurred during early underfeeding. With continuation of the 900 kcal/d diet, the between-group differences in the rate of fat loss diminished. The exercise subjects significantly lowered their resting heat losses relative to the non-exercise subjects (P less than .025). This in turn reduced the degree of negative energy balance in the more energy-deficient exercise group.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphological predictors of acute complications after percutaneous excimer laser coronary angioplasty. Results of a comprehensive angiographic analysis: importance of the eccentricity index.

BackgroundPercutaneous excimer laser coronary angioplasty (ELCA) is a new technique for recanalization of arteries obstructed by coronary atherosclerosis. This study was conducted to assess the complication rate and determine the influence of clinical and angiographic characteristics on complications after ELCA. Methods and ResultsA detailed, quantitative, angiographic core laboratory analysis of patients undergoing ELCA was performed by two experienced angiographers who were not the primary laser angioplasty operators. Two hundred patients underwent 203 separate procedures on 220 lesions at three medical centers. Laser success was achieved in 180 lesions (81.8%) and procedural success in 199 (90.5%). Emergency coronary artery bypass graft (CABG) was required in five patients (2.5%). One patient suffered a Q wave myocardial infarction; there were no deaths. Also, acute closure and perforation occurred in 10 (4.5%) and three (1.4%) vessels, respectively. Coronary dissections after laser treatment were seen in 36 vessels (16.4%). Multivariate analysis found two independent preprocedural factors related to complications: eccentricity index, which is the percent deviation of the lesion lumen from the center of the artery (p=0.0007), and proximal vessel diameter (p =0.033). In addition, an abrupt proximal face of the lesion was associated with angiographic complications by univariate analysis (p=0.051). Multivariate analysis showed the eccentricity index (p=0.032) to be the only independent predictor for the occurrence of any one or more of the important complications (emergency CABG, perforation, acute closure, or Q wave myocardial infarction), whereas lesion angle >45° was a significant univariate predictor (p =0.029). Other predictors of complications with balloon percutaneous transluminal coronary angioplasty, such as increased lesion length, rough edges, calcification, ulceration, and branch point, were not predictive of complications with the excimer laser. ConclusionsThe degree of lesion eccentricity is the most powerful predictor of complications after ELCA. This and other morphological predictors may be of benefit in the selection of patients for ELCA as well as directing future development of this new technology.

Marine lipid concentrate and atherosclerosis in the rabbit model

Twenty-seven New Zealand white rabbits underwent balloon de-endothelialization of the aorta and iliac arteries while consuming a 2% cholesterol, 10% peanut oil rabbit chow. Ten of these rabbits were fed 1 ml of concentrated marine fish lipid (MaxEpaTm) daily. Six weeks after de-endothelialization, angiography of the treated arteries was performed and histologic cross-sections of the terminal aorta were measured with a planimeter. Iliac artery luminal diameters were also measured at consecutive 3-mm divisions from the aortic bifurcation and found to have a mean lumen diameter of 1.60 +/- 0.08 mm in the marine lipid-supplemented group (M) and 1.38 +/- 0.12 mm in the control group (C) (P less than 0.001). Analysis of variance on individual segmental diameters confirmed this difference. However, neither the angiographic diameters nor histologic, cross-sectional, luminal areas of the terminal aorta were different between groups. Instead, the mean cross-sectional area of the terminal aortic wall was significantly greater in the marine lipid-fed group (4.4 +/- 1.2 mm2 in M and 3.1 +/- 0.6 mm2 in C, P less than 0.01). In addition, the vessel wall area showed a positive correlation with red blood cell (RBC) incorporation of docosahexaenoic acid (r = 0.82, P less than 0.005) in both groups. In the M group, RBC eicosapentaenoic acid and docosahexaenoic acids increased 100% and 650%, respectively, over baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of thrombus formation without inhibiting coagulation factors does not inhibit intimal hyperplasia after balloon injury in pig coronary arteries.

BackgroundThe proposed mechanisms of restenosis after coronary angioplasty include neointima formation, vessel wall remodeling and mural thrombus. Poloxamer 188 does not inhibit coagulation factors, but was shown to reduce mural thrombus formation in pig coronary arteries after intracoronary stenting in an acute study. This study was performed to examine whether this agent may reduce neointima formation. MethodsThirty domestic juvenile pigs of weight 20–30 kg were anesthetized. A left angiogram was performed via a femoral artery. Proximal left anterior descending and circumflex arteries were dilated three times with a 20–30% oversized coronary angioplasty balloon catheter. Fifteen animals were allocated randomly to receive intravenous infusions of poloxamer 188. starting 30 min before angioplasty and continuing for 24 h. The remaining 15 received intravenous 0.45% saline and served as controls. The animals were killed 2 weeks after the angioplasty. Histologic studies of the arteries were performed. The severity of the injury and the amount of thrombus material incorporated in the neointima were assessed by semiquantitative methods. ResultsThere was no significant difference between injury scores in the two groups.Thrombus material in the neointima in the treatment group was significantly less than that in those of the control group (thrombus areas 0.013 ± 0.004 compared with 0.029 ± 0.006 mm2, P < 0.02), but there were no significant differences between the neointimal (0.60 < 0.08 and 0.60 <0.13 mm2) and luminal (2.51 < 0.21 and 2.44 < 0.26 mm2) areas in treatment and control groups. ConclusionContinuous 24 h intravenous infusion of poloxamer 188 after balloon injury in pig coronary arteries may reduce mural thrombus formation significantly, but did not reduce neointima formation.

Restenosis after Gianturco-Roubin Stent Placement for Acute Closure

Acute closure of a dilated coronary artery after PTCA results in an increase in morbidity and mortality in patients in whom it occurs [1–5]. Periprocedural occlusions occurred in 6.8% of patients in the 1985–1986 NHLBI Registry and was associated with a five-fold increase in the incidence of death (5% compared to 1%) and an increase in myocardial infarction incidence from a few percent in those without acute closure to 27% in those who closed and were reopened with repeat PTCA alone and to 56% in those requiring emergency coronary artery bypass grafting (CABG) [4]. In addition to suffering an increased early mortality, this acute closure group also tended to have further increases in mortality during the next 18 months of follow-up. It has been shown that one of the most potent predictors of acute closure after PTCA is the occurrence of an intimal tear or coronary artery dissection with an odds ratio of 5.2 [5–7]. Risk factors associated with increased mortality after acute closure include collateral vessels originating from the dilated artery, female gender, and multivessel disease [8]. When multiple repeat inflations, as well as prolonged inflations, fail to resolve an acute closure, patients have traditionally undergone emergency coronary bypass surgery. However, our own experience demonstrates that in-hospital death (1.2%) and new, non-fatal, Q-wave myocardial infarction (21.2%) are not eliminated in the group of patients having emergency CABG after a failed PTCA [9].