Steven T. Minor

Assessment of myocardial perfusion in humans by contrast echocardiography. I: Evaluation of regional coronary reserve by peak contrast intensity

Myocardial contrast echocardiography was performed during coronary angiography with 2 ml of sonicated meglumine diatrizoate sodium 76% (meglumine) in 40 patients (ranging in age from 25 to 79 years) before and 10 to 15 s after intracoronary injection of papaverine, 8 mg into the right coronary artery (n = 43) and 10 mg into the left (n = 46). The same protocol was repeated in 17 patients 5 to 10 min after completion of coronary angioplasty. In 13 patients with normal coronary angiograms, peak contrast intensity corrected for background myocardial intensity was measured in 36 regions and was found to increase after papaverine from 36 +/- 16 to 55 +/- 22 U (p less than 0.001). In contrast, in the 27 patients with angiographic evidence of coronary artery disease, peak intensity in 64 regions remained unchanged after papaverine (35 +/- 22 versus 36 +/- 23 U). An increase in peak intensity greater than or equal to 10 U was 80% sensitive and 92% specific for coronary artery disease. After successful coronary angioplasty, peak intensity in the involved regions improved significantly (p less than 0.001) during baseline contrast injections (from 32 +/- 16 to 50 +/- 25 U) as well as in the postpapaverine contrast injections (from 30 +/- 12 to 60 +/- 26 U). In conclusion, measurement of peak contrast intensity after intracoronary injections of sonicated meglumine provides a relative index of myocardial perfusion that allows assessment of regional coronary reserve in patients with coronary artery disease. This may be of particular value in evaluating the immediate effects of coronary angioplasty on myocardial perfusion.

Comparison of quantitative coronary angiography to visual estimates of lesion severity pre and post PTCA

Quantitative coronary angiographic measurements and visual estimates of coronary lesion severity were compared prospectively before, immediately following, and 6 months following percutaneous transluminal coronary angioplasty. Mean percent diameter stenosis before angioplasty was 87.9 +/- 9.9% by visual analysis and 64.6 +/- 9.2% by quantitative coronary angiography (p = 0.0001). Differences between these two techniques were also found immediately post-angioplasty (visual analysis 29.5 +/- 11.8%, quantitative coronary angiography 22.8 +/- 11.8%, p = 0.0002) and at 6 months (visual analysis 46.5 +/- 27.4%, quantitative coronary angiography 30.2 +/- 20.4%, p = 0.0001). These differences significantly affected the determination of restenosis by three definitions. (1) Lesion recurrence with greater than or equal to 50% stenosis at follow-up: 38 of 92 (41%) by visual analysis versus 20 of 92 (22%) by quantitative coronary angiography (p less than 0.01). (2) Increase of greater than or equal to 30% stenosis: 34 of 92 (37%) by visual analysis versus 20 of 92 (22%) by quantitative coronary angiography (p less than 0.01). (3) Loss of 50% of previous improvement: 31 of 92 (34%) by visual analysis versus 24 of 92 (26%) by quantitative coronary angiography (p = 0.08). In addition, determination of success or failure of percutaneous transluminal coronary angioplasty was affected by the interpretative technique, but these differences were not statistically significant. We conclude that visual estimates of lesion severity are consistently and significantly higher than quantitative measurements. Consequently, restenosis rates, using currently applied definitions, differ considerably depending on the method of analyzing lesion severity.

Adjuvant therapy for intracoronary stents. Investigations in atherosclerotic swine.

Early thrombosis has complicated human stent implantation in several trials. To determine the best anticoagulation/antiplatelet therapy to maintain stent patency after percutaneous transluminal coronary angioplasty, we implanted the flexible balloon-expandable coil stent into the left anterior descending coronary artery of 28 atherosclerotic 8-month-old Hanford miniature swine. Animals were randomly assigned to one of three treatment groups: group A, aspirin (1 mg/kg/day) and dipyridamole (1 mg/kg three times a day); group B, aspirin and dipyridamole (same doses) plus Coumadin (dose required to prolong prothrombin time 1.3-1.5-fold that of normal); and group C, control. Adjuvant therapy was begun 3 days before stenting. Two pigs (one from group A and one from group B) died during implantation, both without thrombosis. Twenty-six animals survived until follow-up angiography and sacrifice at 1 month. No occlusive thrombosis of the stent occurred in survivors. Reduction of the stent lumen diameter was observed in every case at follow-up. Percent lumen reduction was 19% in group A, 26% in group B, and 24% in group C. Marked smooth muscle cell hyperplasia was seen by light and transmission electron microscopy at stent struts. Scanning electron microscopy of the luminal surface showed a variable morphology consisting of normal endothelium, adherent leukocytes, stellate periluminal cells, and occasional fibrin strands and red blood cells. Luminal narrowing was not affected by anticoagulation therapy, antiplatelet drugs, cholesterol level, or stent sizing. We conclude that occlusive thrombosis does not complicate stent implantation in this model but that substantial luminal narrowing due in part to smooth muscle hyperplasia does occur. The significance of luminal narrowing at the stent site requires further study.

Factors determining improvement in left ventricular function after reperfusion therapy for acute myocardial infarction: Primacy of baseline ejection fraction

Improvement in left ventricular ejection fraction is a measure of salvage of ischemic myocardium after reperfusion therapy for acute myocardial infarction. The degree of improvement in left ventricular ejection fraction may be influenced by many factors. Therefore, 137 patients in whom paired radionuclide angiograms were obtained within 24 h of acute infarction and before hospital discharge were retrospectively evaluated to determine which factors most affect improvement in ejection fraction. Only baseline ejection fraction correlated significantly with improvement in ejection fraction by both univariate analysis (ejection fraction as a continuous variable; p less than 0.001; ejection fraction as a categorical variable, less than or equal to 45% versus greater than 45%, p less than 0.0001) and multivariate analysis (p less than 0.0001). Reperfusion status (patent versus occluded infarct artery) and extent of coronary artery disease (one, two or three vessel) were significant factors by multivariate but not by univariate analysis. Location of infarction, treatment modality and time to treatment did not correlate with change in ejection fraction by either statistical technique. Thus, of those factors tested, baseline left ventricular ejection fraction is the most potent predictor of improvement in ventricular function after acute infarction. Knowledge of baseline ejection fraction may be helpful in deciding whether to treat some patients with equivocal indications or contraindications for reperfusion therapy. Clinical trials of reperfusion strategies should stratify patients on the basis of baseline ejection fraction if ejection fraction is to be used as an end point for myocardial salvage.

The coronary artery response to implantation of a balloon-expandable flexible stent in the aspirin- and non-aspirin-treated swine model

Intracoronary stents may potentially alleviate some of the problems associated with coronary angioplasty. Since the anatomy and physiology of swine coronary arteries closely resemble those of humans, the response to implantation of the Glanturco-Roubin, balloon-expandable, flexible stent was studied in this model. Additionally, the effect of aspirin, 1 mg/kg/day orally, on this response was evaluated. Eighteen Hanford minature swine underwent stenting of the left anterior descending coronary artery. Two died within 24 hours of stent implantation. The 16 survivors were put to death at 4 (n = 4), 11 (n = 4), 28 (n = 4), 56 (n = 3), and 180 (n = 1) days. Angiographically, reduction of stent lumen diameter of 0.1 to 1.3 mm was observed and was maximum at 11 days, with gradual improvement at subsequent time periods. Scanning electron microscopy, transmission electron microscopy, and light microscopy showed early disruption of subjacent endothelium, and adherence of platelets to exposed subendothelium and stent wires. Microthrombi were readily apparent. At 11 days, intimal thickening, made up predominantly of smooth muscle cells with abundant extracellular matrix, was observed and covered the stent wires. At 28 days, regression of intimal thickening was apparent and a confluent endothelium with flow-directed orientation was seen. At 56 and 180 days, the luminal surface was smooth; intimal thickening averaged 525 microns over the stent wires and 55 microns away from the wires. Findings in aspirin-treated animals were similar to results in those that did not receive aspirin. Thus in this swine model, stent implantation results in a time-dependent and self-limited vascular response.

Bretylium and Diltiazem in Porcine Cardiac Procedures

The use of miniature swine as a model for cardiovascular diseases of humans is becoming more popular for many reasons. One of the problems involved in using swine is their propensity for fatal cardiac arrhythmias during surgical procedures requiring general anesthetics, especially cardiac procedures. In preparation for use as a model of human atherosclerotic coronary artery disease, 30 three-month-old (15 kg) Hanford miniature swine underwent left heart catheterization, coronary angiography, and abrasion of the left anterior descending coronary artery. All pigs were treated with diltiazem HCl 30-60 mg (2-4 mg/kg) three times daily and aspirin 25 mg once daily, both given orally for three days before surgery. General anesthesia was induced with a combination of ketamine HCl 25 mg/kg, atropine sulfate 0.1 mg/kg, and acepromazine 0.22 mg/kg, all given intramuscularly. Halothane 1-2% and nitrous oxide 30% were used to maintain general anesthesia after endotracheal intubation. After successful cannulation of the femoral artery, all animals were given 200 units/kg heparin and 5 mg/kg bretylium tosylate intravenously. The electrocardiogram and mean blood pressure were monitored throughout the procedure. No significant change in blood pressure was noted during the procedure. Intracoronary nitroglycerin 200 micrograms was administered prior to abrasion of the left anterior descending with a 2.0-mm angioplasty balloon. The pigs were allowed to recover after routine closure of the incision. One pig (1/30) died during the abrasion procedure as a result of ventricular fibrillation. This represents a low, acceptable mortality using the present regimen compared with other regimens.

Factors influencing the outcome of balloon aortic valvuloplasty in the elderly

This study describes the short- and long-term outcome of 44 consecutive percutaneous balloon aortic valvuloplasty procedures performed in 42 elderly patients (age 77.8 +/- 7 years) with calcific aortic stenosis. The initial success rate was 95%, with the peak aortic valve pressure gradient declining from a mean of 82 +/- 32 mm Hg to 44 +/- 23 mm Hg and aortic valve area increasing from a mean of 0.59 +/- 0.15 cm2 to 0.83 +/- 0.40 cm2. One procedure-related death occurred and an additional three patients died less than or equal to 30 days after balloon aortic valvuloplasty. These patients all had New York Heart Association (NYHA) class IV heart failure symptoms prior to the procedure and their mean left ventricular ejection fraction (LVEF) (28 +/- 7%) was lower than that of hospital survivors (52 +/- 13%) (as was their ratio of left ventricular [LV] wall thickness-to-cavity ratio [0.50 +/- 0.10 versus 0.70 +/- 0.15]). At the time of hospital discharge after valvuloplasty, 76% of patients were asymptomatic or markedly improved (NYHA class I or II). After a mean follow-up of 15.5 months (range 2 to 26 months), however, 10 patients had died and 15 had undergone aortic valve replacement for recurrence of NYHA class III or IV symptoms. The adjusted 1- and 2-year survivals were 0.68 and 0.62, respectively, and adjusted 2-year event-free survival was 0.25. Proportional hazard regression analysis indicated that LVEF less than 40% was the only variable affecting survival (p less than 0.01) and was a possible indicator of event-free survival (p = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of bradycardia on dispersion of ventricular refractoriness

The effect of bradycardia on dispersion of ventricular refractoriness was evaluated. Refractory periods were measured at 3 right ventricular sites in 16 patients with severe bradycardia (average heart rate 39 +/- 5 beats/min) and were compared with those measured in 11 control subjects, (average heart rate 72 +/- 12 beats/min). Patients with bradycardia had significantly longer effective (377 +/- 36 ms) and functional (421 +/- 39 ms) refractory periods (ERP and FRP) than control subjects (ERP 296 +/- 25 ms, FRP 346 +/- 18 ms) (p less than 0.001). However, dispersion of refractoriness was similar in the 2 groups. Dispersion of ERP was 43 +/- 38 ms and FRP was 48 +/- 35 ms in patients with bradycardia. In control subjects dispersion of ERP was 37 +/- 12 ms, and FRP was 36 +/- 20 ms. Pacing of 120 beats/min significantly decreased ERP and FRP in both groups. Pacing shortened dispersion significantly in control subjects. In patients with bradycardia, pacing failed to significantly decrease dispersion. Compared with control subjects with normal heart rates, patients with bradycardia have longer absolute refractory periods but do not have significantly increased dispersion of refractoriness. Single and double, twice threshold ventricular extrastimuli (S2 and S3) failed to induce ventricular tachycardia in any patient during bradycardia. Bradycardia alone does not appear to be a factor in the induction of ventricular tachyarrhythmias.

Warfarin sodium for anticoagulation of atherosclerotic miniature swine.

Warfarin sodium (Coumadin) has been used as an effective anticoagulating agent in human medicine for many years, although careful monitoring of its effects are necessary to avoid excessive anticoagulation. Previous experience with this drug for chronic anticoagulation therapy in miniature swine has been limited. The effect of warfarin sodium was studied by measuring prothrombin time in twelve 8-month-old Hanford miniature swine. The pigs had been fed a high-cholesterol diet and had undergone a prior coronary artery abrasion procedure for development of an atherosclerotic coronary disease model. Atherosclerosis was induced by feeding a high-cholesterol diet. Baseline prothrombin time ranged from 12.8 to 15.0 s (13.7 s mean). Prothrombin time was determined daily for the first 5 days of treatment and at least twice weekly thereafter until the animals were sacrificed. Animals received warfarin for 37-41 days. Prothrombin time could be increased 33-50% by once daily oral administration of warfarin 0.04-0.08 mg/kg. Oral administration of more than 0.08 mg/kg as a maintenance dose resulted in the death of two pigs. Most animals responded well to 0.08 mg/kg for the first 3 days of treatment followed by a maintenance dose of 0.06 mg/kg. Dosage was adjusted periodically when prothrombin times exceeded 50% above baseline. It is our experience that monitoring prothrombin time at least twice weekly and adjusting the maintenance dose can eliminate death losses due to warfarin intoxication.