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In a model of early and aggressive vein graft stenosis in pigs, an intervention was performed with a single stent (n = 12 grafts), multiple stents (n = 6), or balloon angioplasty (n = 6), while grafts with mild stenoses were left untreated (n = 8). Four weeks after intervention, angiography showed that grafts with single stents, balloon angioplasty, or untreated grafts had patency rates of 92%, 83%, and 83%, respectively. Grafts receiving multiple stents, however, showed only a 17% patency rate (p < 0.05). Balloon dilatation or placement of a single stent improved the angiographic minimal diameter by 0.6 +/- 0.2 and 0.8 +/- 0.3 mm, respectively, over the short term, but this gain was lost during the follow-up period. Multiple stents showed a similar gain (0.5 +/- 0.2 mm) but more loss occurred during the follow-up period (2.4 +/- 0.2 mm). Histology revealed no significant differences between the treatment groups except for the prolonged presence of thrombus remnants in association with the stent wires. In conclusion, single stents and balloon angioplasty show good patency in early saphenous vein graft narrowing but multiple stents show a high occlusion rate.

A polyethylene-terephthalate (PETP, polyester), self-expanding, braided mesh stent has been developed for percutaneous (coronary) arterial implantation. In vitro measurements showed that the radial pressure delivered by this device was similar to a self-expanding, stainless steel stent. Due to hysteresis-like behaviour, it proved necessary to mount the polymer stent on the delivery system immediately before the placement procedure, and to select a diameter in the unconstrained condition, which was 60% larger than the diameter of the target vessel. Eight polyester stents were implanted in peripheral arteries of four pigs. Except for heparin during the implantation procedure, antithrombotic or antiplatelet drugs were not administered. After four weeks repeat angiography revealed that one of the stents was subtotally occluded. At autopsy, two other stents proved to be located in the aortic bifurcation, probably due to failure of the delivery system. Quantitative angiographic assessment showed that the mean luminal diameters at the site of stent placement were 3.3 +/- 0.2 mm before, 3.2 +/- 0.2 mm immediately after, and 2.7 +/- 0.5 mm at four weeks after implantation. Intravascular ultrasound (IVUS) examination after 4 weeks could identify the individual struts of the stents, as well as their length. In addition, a description of the extent of neointimal hyperplasia was feasible. The IVUS assessment was validated by histological examination. In conclusion, polyester stents can be constructed with mechanical properties similar to stainless steel stents. After implantation in porcine peripheral arteries, five of six correctly placed stents were patent at four weeks. Imaging of stents by angiography and IVUS provided complementary information.

In the Cardiovascular Measurement System (CMS) the edge-detection algorithm, which was primarily designed for the Philips digital cardiac imaging system (DCI), is applied to cinefilms. Comparative validation of CMS and DCI was performed in vitro and in vivo with intracoronary insertion of stenosis phantoms in anesthetized pigs. The "obstruction diameter" (OD) was measured at the artificial stenoses visualized by angiography with calibration at the isocenter (ISO) and catheter calibration (CATH) and compared with the true phantom diameters. A clinical comparison of OD, reference diameter (RD), and percentage diameter stenosis (DS) was performed on 70 corresponding images from post-PTCA angiograms. In vitro, OD (CMS) yielded an accuracy of 0.18 +/- 0.14 mm with 100% (correlation coefficient: r = 0.97, y = 0.06 + 0.75x, standard error of estimate [SEE] = 0.09) and 0.19 +/- 0.15 mm with 50% contrast (r = 0.94, y = 0.02 + 0.81 x). OD (DCI) yielded an accuracy of 0.11 +/- 0.06 mm with 100% (r = 0.99, y = -0.03 + 0.91 x, SEE = 0.05) and 0.24 +/- 0.13 mm with 50% contrast (r = 0.94, y = 0.29 + 6.69 x, SEE = 0.12). In vivo, OD (CMS) yielded an accuracy of 0.18 +/- 0.23 mm with ISO (r = 0.89, y = 0.02 + 0.83 x, SEE = 0.22) and 0.26 +/- 0.24 mm with CATH (r = 0.89, y = 0.06 + 0.72 x, SEE = 0.19). OD (DCI) yielded an accuracy of 0.08 +/- 0.15 mm with ISO (r = 0.96, y = 0.08 + 0.86 x, SEE = 0.14) and 0.18 +/- 0.21 mm with CATH (r = 0.92, y = 0.09 + 0.76 x, SEE = 0.17). The clinical comparison showed reasonable agreement for OD only (r = 0.81, y = 0.26 + 0.81 x, SEE = 0.29). Transformation of an edge-detection algorithm from a digital to a cinefilm-based system can lead to impairment of measurement reliability.

At present, there is an exponential use of new interventional techniques whose proper role and value have not yet been defined. The intracoronary stent is just one example. There is no doubt that stents can be implanted with a high technical success rate associated with highly predictable immediate angiographic results and that they appear to be superior to all other interventional techniques. However, the intrinsic thrombogenicity of all devices currently available for clinical use warrants a vigorous anticoagulation, exposing the patient either to the risk of (sub)acute stent thrombosis or to the risk of hemorrhage and vascular complications. It remains to be determined whether stent implantation will reduce the incidence of restenosis and whether this results in an improved long-term event and symptom-free survival. Experimental studies indicate that the thrombogenic nature of stents may be controlled by coating the struts with endothelial cells or polymers. With respect to restenosis, it is evident that as long as mechanical injury is applied to the vessel wall, the vessel wall will respond with neointimal thickening. The intracoronary stent has the potential to control this tissue response by serving as a carrier for local antiproliferative drug delivery or eventually for genetic manipulation. The intensive research which is now going on in combination with experimental animal data, human postmortem pathologic observations, and angiographic studies is yielding clear insights and future directions to address these issues.

Objective: To test the hypothesis that the cardiovascular responses of dopamine and dobutamine might be affected by the cardiovascular conditions., Design: Prospective, controlled dose-response comparison of dopamine and dobutamine., Setting: Laboratory for Experimental Cardiology at a university., Subjects: Normal conscious pigs and conscious pigs with chronic left ventricular dysfunction induced by occlusion of a coronary artery 3 to 4 wks before measurements were obtained., Interventions: Intravenous infusions of dopamine and dobutamine at rates of 1 to 25 micrograms/kg/min., Measurements and Main Results: Left ventricular function was characterized by a lower cardiac output in the pigs with left ventricular dysfunction (23%), stroke volume (34%), and left ventricular pressure (15%), and a higher heart rate (16%), peripheral resistance (41%), and left ventricular end-diastolic pressure (96%) than the normal pigs. Dopamine increased cardiac output to the same extent in the animals with failure as in the normal animals; stroke volume increased only in the animals that had left ventricular dysfunction. The vasodilatory response to dopamine was also similar, but the increase in left ventricular pressure was attenuated similar, in the animals with left ventricular dysfunction, compared with normal animals. Dobutamine showed cardiovascular effects equivalent to dopamine. Left ventricular work, depressed at baseline, increased more rapidly during infusion of dopamine (or dobutamine) in the animals with heart failure than in normal animals., Conclusions: Both dopamine and dobutamine increased cardiac output in conscious pigs with chronic heart failure. Unlike the response in normal conscious pigs, in which only heart rate increased, in animals with heart failure, these agents enhanced both stroke volume and heart rate.

Objectives: To gain insight into the mechanism of stenting in humans and its short- and long-term implications, we studied the vascular wall of saphenous vein aortocoronary bypass grafts after implantation of the Wallstent., Background: The implantation of a stent in aortocoronary bypass grafts may provide an alternative solution for revascularization in patients who are poor candidates for reoperation. Because human histopathologic findings after stenting with the Wallstent have not previously been described in detail, we examined graft segments that were surgically retrieved from 10 patients (21 stents) at 3 days to 10 months after implantation of the stent., Methods: The grafts were examined by a combination of the following techniques: light microscopy, immunocytochemistry and both scanning and transmission electron microscopy., Results: Early observations revealed that large amounts of platelets and leukocytes adhered to the stent wires during the first few days. At 3 months, the wires were embedded in a layered new intimal thickening, consisting of smooth muscle cells in a collagenous matrix. In addition, foam cells were abundant near the wires. Extracellular lipids and cholesterol crystals were found after 6 months. Smooth muscle cells and extracellular matrix formed the predominant component of restenosis. This new intimal thickening was lined with endothelium, in some cases showing defect intercellular junctions and abnormal adherence of leukocytes and platelets as late as 10 months after implantation., Conclusions: This type of stent is potentially thrombogenic and seems to be associated with extracellular lipid accumulation in venous aortocoronary bypass grafts.

A novel approach for the treatment of acute complications and the prevention of restenosis after percutaneous transluminal angioplasty may be the placement of endovascular prostheses (stents). Stents constructed of metal have proven to be thrombogenic, and although they show a tendency to reduce restenosis, they do not prevent it. Pursuant to the search for stents with improved material and surface characteristics, we report in this paper the histological results obtained with a synthetic polymer (polyethylene terephthalate) stent after placement in porcine peripheral arteries. Eight stents were placed at a preselected site and resulted in a 87.5% angiographic patency rate at four weeks' follow-up examination. The neointima measured 114 ± 38 μm (mean ± SEM) on top of the fibers and 246 ± 44 μm between the fibers. Medial impression by the stent measured 27% ± 5%. The neointima consisted mainly of smooth muscle cells. A variable inflammatory reaction and foreign body response to the polymer was observed in all vessels. The present study shows the feasibility of the arterial implantation of polymer stents, in that they result in good intermediate-term arterial patency and limited neointimal hyperplasia. The observed inflammatory reaction, if prolonged, may limit the use of this polymer stent., (Copyright © 1993. Published by Elsevier Inc.)

A polyethylene-terephthalate braided mesh stent has been developed for application in the (coronary) arterial tree. In vitro measurements showed that the radial pressure delivered by this device was in the same range as that of a stainless steel stent. Hysteresis-like behavior, however, occurred after constraining the polyester stent for a period of only 15 minutes on a delivery system for percutaneous implantation. This implies that the polymer stent must be mounted on this delivery system immediately before the placement procedure, and that either a diameter in the unconstrained condition must be selected, which is considerably larger than the diameter of the target vessel, or stent expansion has to be enhanced by balloon expansion. Taking into account the results obtained during the in vitro studies, we investigated the angiographic patency and histologic features after implantation of this polyester stent in peripheral arteries of pigs. In four animals eight stents were placed. Except for heparin during the implantation procedure only, antithrombotic or antiplatelet drugs were not administered. After 4 weeks repeat angiography was performed. Angiography revealed that five of the six correctly placed stents were patent. At autopsy, two additional patent stents proved to be located in the aortic bifurcation, probably due to failure of the delivery system. Quantitative assessment showed that the mean luminal diameters of the site of stent placement were 3.3 +/- 0.2 mm before, 3.2 +/- 0.2 mm immediately after, and 3.1 +/- 0.3 mm at 4 weeks after implantation. Histology demonstrated an inflammatory reaction of variable severity around the stent fibers. Quantitative histologic measurements showed that the thickness of the neointima was 114 +/- 38 mum after 4 weeks. In conclusion, polyester stents can be constructed with mechanical properties similar to stainless steel stents. Hysteresis-like behavior of polyester stents, however, influences the selection of the nominal stent diameter as well as the forces exerted to the vessel wall. After implantation in porcine peripheral arteries, five of six correctly placed stents were patent at 4 weeks. The extent of neointimal proliferation was similar to that observed after placement of metal stents in swine, despite the presence of a more pronounced inflammatory reaction.

Geometric coronary artery measurements with the Phillips Digital Cardiac Imaging System (DCI) and the Cardiovascular Angiography Analysis System (CAAS) were validated using percutaneous insertion of radiolucent stenosis phantoms in swine coronary arteries. Angiographic visualization of the stenosis lumens (phi 0.5, 0.7, 1.0, 1.4, 1.9 mm) was simultaneously recorded on DCI and cinefilm. The acquisition systems were calibrated by either the diameter of the guiding catheter (catheter CAL) or the isocenter method (isocenter CAL). Minimal luminal diameters (MLD) obtained with CAAS and DCI on 20 corresponding cineframes were compared with the true phantom diameters (PD). The accuracy of MLD measurements with the CAAS using isocenter CAL was -0.07mm, the precision 0.21 mm (r = 0.91; y = 0.30 + 0.79x; SEE = 0.19), with catheter CAL the accuracy was 0.09 mm, the precision 0.23 mm (r = 0.89; y = 0.19 + 0.74x; SEE = 0.19). The accuracy of MLD measurements using the DCI with isocenter CAL was 0.08 mm, the precision 0.15 min (r = 0.96; y = 0.08 + 0.86x; SEE = 0.14), with catheter CAL the accuracy was 0.18 mm, the precision 0.21 mm (r = 0.92; y = 0.09 + 0.76x; SEE = 0.17). DCI underestimated PD with isocenter CAL (p less than 0.05) and with catheter CAL (p less than 0.001). MLD can be measured with high accuracy, both applying on-line digital as well as off-line cineangiographic analysis. The results of digital measurements demonstrate high reliability of the new digital software package.

The benzopyran-derivative bimakalim is an ATP-dependent potassium channel activator that has been shown to be a potent arterial vasodilator in anesthetized pigs. In the present study we evaluated the cardiovascular profile of bimakalim in normal conscious animals and conscious animals with chronic left ventricular dysfunction and compared the results to those obtained with nicorandil. In normal conscious pigs, bimakalim (37.5-300 ng/kg/min, n = 6) and nicorandil (10-80 micrograms/kg/min, n = 8) increased cardiac output from 2.7 +/- 0.1 l/min to 3.8 +/- 0.2 l/min and from 2.7 +/- 0.1 l/min to 3.9 +/- 0.3 l/min (both p less than .05) due to increases in heart rate (up to 62 +/- 14% and 74 +/- 9%, respectively, both p less than .05). The mean arterial blood pressure decreased gradually from 104 +/- 4 mmHg to 91 +/- 5 mmHg with bimakalim and from 98 +/- 3 mmHg to 84 +/- 5 mmHg with nicorandil (both p less than .05), due to similar decreases in systemic vascular resistance. LVdP/dtmax also increased with both drugs (up to 48 +/- 11% and 69 +/- 7%, respectively, p less than .05), but left ventricular end-diastolic pressure remained unchanged with bimakalim, while it gradually decreased from 9 +/- 1 mmHg to 5 +/- 1 mmHg (p less than .05) with nicorandil. In pigs with a 3- to 4-week-old myocardial infarction, the vasodilator responses to bimakalim (n = 8) and nicorandil (n = 9) were not affected, but the increases in heart rate and LVdP/dtmax were attenuated compared to the effects in the normal animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous (i.v.) infusions (1, 2.5, 5, and 10 micrograms/kg/min for 10 min) were used to evaluate the cardiovascular effects of epinine (N-methyl-dopamine) in 8 conscious pigs. Epinine is a nonselective and nonspecific dopamine (DA) agonist, that also stimulates alpha- and beta-adrenoceptors. Epinine (1-5 microgram/kg/min) increased cardiac output (CO) by up to 15 +/- 5% (p less than 0.05), owing to an increase in heart rate (HR, 24 +/- 6%), but an increase in stroke volume (SV, 16 +/- 4%) caused the further increase in CO at 10 micrograms/kg/min. Mean arterial blood pressure decreased gradually from 100 +/- 5 mm Hg to 84 +/- 4 mm Hg during infusions up to 5 microgram/kg/min, but increased to 89 +/- 4 mm Hg during infusion of 10 micrograms/kg/min (p less than 0.05). Systemic vascular resistance had decreased from 36.5 +/- 2.8 to 27.5 +/- 3.0 mm Hg/L/min after infusion of 5 micrograms/kg/min but did not change further during infusion of 10 micrograms/kg/min. LV dP/dtmax increased only at 10 micrograms/kg/min. Myocardial blood flow did not change at any dose, owing to metabolically regulated coronary vasodilatation (myocardial work did not change). Flow to the adrenals (up to 110 +/- 37%) and the spleen (up to 95 +/- 13%) increased dose dependently. Cerebral blood flow increased only at the highest dose (15 +/- 5%, p less than 0.05); flow to the kidneys, liver, small intestine, and skeletal muscle did not change. Flow decreased to the stomach (21 +/- 5%) and skin (for doses less than 2.5 micrograms/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to test whether the selective bradycardic effects of zatebradine (UL-FS 49) were altered in the setting of chronic mild left ventricular dysfunction secondary to a myocardial infarction. We therefore administered four doses of UL-FS 49 at 15-min intervals (cumulative doses of 10, 30, 100, and 300 micrograms/kg) to eight normal conscious pigs and to seven pigs in which the left circumflex coronary artery was occluded 3 weeks previously. Left ventricular dysfunction in this second group of animals was manifested by an increase in left ventricular end-diastolic pressure (LVEDP, 11 +/- 2 mmHg vs. 7 +/- 1 mmHg, respectively; p less than 0.05) and a decrease in LVdP/dtmax (3020 +/- 210 mmHg vs. 3720 +/- 210 mmHg, respectively; p less than 0.05). The results showed that UL-FS 49 was equally effective in reducing heart rate in both groups of animals [from 126 +/- 4 to 95 +/- 2 beats/min and from 140 +/- 5 to 98 +/- 6 beats/min for the normal animals and for the animals with a chronic myocardial infarction (MI), respectively]. The duration of left ventricular systole was not affected, but the duration of diastole was prolonged from 290 +/- 10 msec to 420 +/- 20 msec in the normal animals and from 250 +/- 10 msec to 430 +/- 30 msec in the animals with MI (both p less than 0.05). Up to 100 micrograms/kg UL-FS 49 did not affect arterial blood pressure, whereas LVdP/dtmax and cardiac output decreased by less than 10% in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Four cumulative 10 min intravenous infusions of 0.05, 0.2, 0.5 and 2.0 mg min-1 were used to compare the cardiovascular profile of 5 novel nitrate-esters dissolved in Intralipid 10% to that of nitroglycerin (GTN) in conscious pigs. 2. Infusion of Intralipid 10% alone had no effect on any of the systemic haemodynamic parameters. GTN infusions decreased mean arterial blood pressure dose-dependently from 94 +/- 2 mmHg to 79 +/- 3 mmHg (P less than 0.05) and raised cardiac output from 2.74 +/- 0.09 l min-1 to 3.40 +/- 0.18 l min-1 (P less than 0.05) due to an increase in heart rate (by up to 43 +/- 3%), as stroke volume decreased slightly. Systemic vascular resistance decreased (by 32 +/- 3%) and left ventricular end-diastolic pressure fell from 5.2 +/- 0.4 mmHg to 2.2 +/- 0.5 mmHg (both P less than 0.05). 3. The novel compounds CEDO 8811, CEDO 8834 and CEDO 8901 increased cardiac output only at the highest dose (7%, 8% and 9%, respectively). There was no change in mean arterial blood pressure as the increase in cardiac output was counterbalanced by arterial vasodilatation. All three compounds reduced left ventricular end-diastolic pressure slightly. 4. CEDO 8816 was a more potent arterial and venodilator than the aforementioned CEDO compounds, as the decreases in systemic vascular resistance and left ventricular end-diastolic pressure were already significant at lower doses. The fall in stroke volume was fully compensated by the increase in heart rate and as a result cardiac output increased by 11 +/- 3% (P less than 0.05) at the highest dose. 5. CEDO 8956 was the most potent vasodilator of the novel compounds and exhibited a cardiovascular profile similar to that of GTN. Left ventricular end-diastolic pressure decreased significantly during infusion of 0.2mgmin-'. Mean arterial blood pressure decreased by 11 +/- 2% (P < 0.05) in spite of an increase in cardiac output by up to 20 +/- 2% (P < 0.05), due to a decrease (by 27 +/- 1%, P <0.05) in systemic vascular resistance. The increases in heart rate (20 +/- 5%, P < 0.05) and LVdP/dtmax (38 +/- 4%, P < 0.05) were, however, considerably less after CEDO 8956 than after GTN. 6. The potential of CEDO 8956 in the treatment of chronic left ventricular dysfunction was evaluated during administration to conscious pigs (21-23 kg), in which the left circumflex coronary artery was ligated 4 weeks earlier. In these animals, baseline values for cardiac output and LVdP/dtx were lower and those of systemic vascular resistance and left ventricular end-diastolic pressure were higher than in the first group of experiments. 7. Both GTN and CEDO 8956 in doses of 0.05 to 2.0 mg inm increased cardiac output dosedependently (by up to 34% and 19%, respectively). The decrease in systemic vascular resistance was larger with GTN (35%) than with CEDO 8956 (17%), which resulted in a 13% decrease in mean arterial pressure during infusion of GTN, whereas there was no change in mean arterial pressure during infusion of CEDO 8956. Both compounds increased LVdP/dt,,,,X (by 48% and 30%, respectively) and lowered left ventricular end-diastolic pressure to normal levels. 8. At a dose of 1.0Omg min- 1, both GTN and CEDO 8956 increased left ventricular blood flow parallel to the increase in myocardial oxygen demand. At this dose, GTN also caused vasodilatation in the vascular beds of the brain, kidneys and adrenals. With CEDO 8956 no significant changes were achieved. 9. We conclude that the cardiovascular profile of CEDO 8956 in both normal animals and in animals with chronic left ventricular dysfunction warrants further study on its usefulness in the treatment of a number of cardiovascular disorders.

Bipyridine derivatives have recently been introduced as a new class of inodilator drugs in the intravenous therapy of heart failure. A member of this class is milrinone, which improves the inotropic state and reduces ventricular afterload, leading to improved hemodynamics. Because systolic and diastolic function are intimately related, it can be expected that the diastolic muscle properties are influenced by changes in systolic function and therefore by milrinone therapy. Since end-diastolic pressure may shift as a result of a change in ventricular volume alone, a complete left ventricular diastolic pressure volume (LVDPV) relationship must always be measured before one can make firm conclusions regarding changes in diastolic function. After a LVDPV relationship is obtained, one should identify the variables that can modify this relationship without directly affecting the intrinsic diastolic muscle properties. These variables can be divided into static effects (coronary vascular bed volume, right ventricular pressure, and pericardial pressure) and dynamic effects (viscoelasticity and myocardial active relaxation). Increments in coronary perfusion pressure of perfusion flow (vascular bed volume) are known to stiffen the cardiac wall (turgor effect). Changes in right ventricular pressure or pericardial pressure are other factors affecting the LVDPV relationship by changing transmural pressure. This effect is more pronounced when the ventricle is already stiff, such as in patients with myocardial hypertrophy. Dynamic effects become important when a LVDPV relationship is measured during isolated cardiac cycles; they include viscoelasticity and abnormal myocardial relaxation. Clinical assessment of diastolic cardiac performance assumes a model in which the heart is considered an elastic body (while in fact it is viscoelastic).(ABSTRACT TRUNCATED AT 250 WORDS)

The cardiovascular effects of the phenyldihydropyridine derivative elgodipine (0.3, 1, 3, 10, and 30 microgram/kg/min) were studied in normal conscious pigs and in pigs with chronic left ventricular dysfunction (LVD, caused by coronary artery occlusion) without and after beta-adrenoceptor blockade with propranolol (0.5 mg/kg + 0.5 mg/kg/h). In normal pigs, elgodipine increased cardiac output from 2.57 +/- 0.09 to 5.21 +/- 0.24 L/min (p less than 0.05) as a result of a doubling of the heart rate. Mean arterial blood pressure decreased from 94 +/- 2 to 76 +/- 3 mm Hg (p less than 0.05) as a result of a decrease in systemic vascular resistance. Left ventricular (LV) dP/dtmax increased (by up to 78 +/- 9%), but left ventricular end-diastolic pressure (LVEDP) remained unchanged. After propranolol administration elgodipine did not increase LV dP/dtmax, and the increase in heart rate was attenuated, resulting in a smaller increase in cardiac output (from 2.11 +/- 0.13 to 3.09 +/- 0.23 L/min, p less than 0.05), but an unchanged vasodilator response. In pigs with LVD, elgodipine increased cardiac output and LV dP/dtmax less than in normal animals, but the vasodilator response was not affected. LVEDP decreased from 14.6 +/- 1.6 to 11.7 +/- 2.5 mm Hg (p less than 0.05). In animals with LVD, propranolol caused a more severe depression of systemic hemodynamics, but did not modify the cardiovascular responses to elgodipine. Its cardiovascular profile suggests that elgodipine may not only be useful in the treatment of cardiovascular disorders for which other dihydropyridines are already in use, but also in mild chronic heart failure.

Interventional cardiology has recently witnessed the growth of several alternatives to percutaneous transluminal angioplasty, including coronary stenting. Although stenting appears to be useful in treating abrupt closure after coronary angioplasty, its effectiveness in limiting the complex processes responsible for late restenosis is much less certain. Pathologic examination of stented human saphenous bypass grafts shows extensive deposits of platelets, fibrin and leukocytes along the stent wires within the 1st week and formation of a neointima of variable thickness after 3 months without evidence of foreign body reaction. The long-term effects of continuous barotrauma induced by the expanded stent remain unknown. It is difficult to assess the relative merits of the new devices, but stenting has several theoretic advantages. It seems less disruptive to the underlying architecture of the vessel wall and enjoys favorable theoretic and effective expansion ratios. Wide-spread clinical acceptance for stenting will depend on demonstrating that its safety, efficacy and cost efficiency are superior to those of balloon angioplasty.

The beta-adrenoceptor antagonist dilevalol in a total dose of 430 micrograms/kg i.v., potently suppressed isoprenaline-induced increases in heart rate and max LVdP/dt (dose ratios of 42 +/- 6 and 38 +/- 5, respectively, in anesthetized pigs), but a dose of 1430 micrograms/kg did not appreciably modify phenylephrine-induced increases in arterial blood pressure (dose ratio less than 4) in both anesthetized and conscious pigs. The actions of dilevalol on ischemic myocardium of anesthetized pigs were investigated following a reduction of left anterior descending artery flow by 85-90%. Dilevalol (300 micrograms/kg), administered after 15 minutes of ischemia, did not affect the ischemia-induced changes in systemic hemodynamics (such as heart rate, max LVdP/dt and cardiac output), myocardial perfusion, and wall-thickening of the ischemic segment during the following 15 minutes of ischemia and 2 hours of reperfusion. The reasons for the lack of antiischemic actions are most likely the absence of negative chronotropy and an absence of afterload reduction by dilevalol.

The effects of the butyrophenone, azaperone 5 mg kg-1 i.m. alone and after addition of the imidazole derivative metomidate 6 mg kg-1 i.v. were studied in eight conscious pigs. Fifteen minutes after administration of azaperone, systemic arterial pressure was reduced by 35% as a result of a 45% increase in systemic vascular conductance and 10% decrease in cardiac output (Q). After azaperone, 23% of the radioactive labelled microspheres (15 (SD 1) microns) injected into the left atrium were detected in the lungs as a result of opening of arteriovenous anastomoses (baseline 3%). The increase in arteriovenous anastomotic blood flow was at the expense of the nutritional (= capillary) channels. Flow to the brain was maintained, but that to the left ventricle decreased in parallel with the reduction in arterial pressure. Vascular conductance of most other organs, except the skin, increased or was maintained. The addition of metomidate had no effect on Q because an increase in stroke volume (by 30%) compensated for the decrease in heart rate. Systemic vascular conductance decreased, most noticeably in the brain, left ventricle and skeletal muscle. We conclude that azaperone alone and in combination with metomidate had only a moderate effect on Q, but caused a redistribution in favour of arteriovenous anastomoses.

1. We studied the effects of four doses of nimodipine (0.5, 1, 2 and 4 micrograms kg-1 min-1) on systemic haemodynamics and on regional vascular beds, in particular the cerebral circulation, in conscious pigs. 2. Nimodipine caused dose-dependent, probably reflex-mediated, increases in heart rate (42% with the highest dose) and cardiac output (54%), while arterial blood pressure was only minimally affected. Left ventricular end-diastolic pressure and systemic vascular resistance decreased dose-dependently (35-40% at the highest dose) while stroke volume remained unchanged. 3. Total brain blood flow was not affected by the drug. Furthermore, we could not demonstrate any regional cerebral differences, as blood flows to both cerebral hemispheres as well as the diencephalon, cerebellum and brain stem remained unchanged. 4. Blood flow to the kidneys, liver, small intestine and skin also did not change. Nimodipine caused dose-dependent increases in blood flow to the stomach (95%), myocardium (97%) and adrenal glands (102%), while blood flow to skeletal muscles (267%) increased most. 5. It is concluded that in the conscious pig, nimodipine is an arterial vasodilator which shows some selectivity for the skeletal muscle vasculature but does not increase total or regional cerebral blood flow.

We studied the acute effects of the calcium antagonist nisoldipine in 10 conscious pigs with chronic heart failure. Left ventricular dysfunction was induced by permanent ligation of the left circumflex coronary artery. Two to three weeks after myocardial infarction the effects of four consecutive 10 min intravenous infusions of nisoldipine (0.05; 0.1; 0.25 and 0.5 micrograms kg-1 min-1) or its solvent on systemic haemodynamics were evaluated. In addition, we used the radioactive microsphere technique to study the distribution of cardiac output after each dose of nisoldipine. Nisoldipine significantly (P less than 0.05) increased heart rate (from 144 +/- 9 to 161 +/- 8 beats min-1), cardiac output (from 2.1 +/- 0.1 to 2.9 +/- 0.2 l min-1), stroke volume (from 14 +/- 1 to 18 +/- 1 ml) and left ventricular dP/dtmax (from 2600 +/- 100 to 3500 +/- 250 mmHg s-1), but had no effect on arterial blood pressure. Left ventricular end-diastolic pressure (from 19 +/- 2 to 16 +/- 1 mmHg) and systemic vascular resistance (from 52 +/- 3 to 37 +/- 3 mmHg min l-1) decreased after nisoldipine. The nisoldipine-induced increase in cardiac output did not affect blood flow to the kidneys, brain, liver or skin, but perfusion of the stomach (84%), adrenals (84%) and normal myocardium (from 200 +/- 25 to 321 +/- 38 ml min-1 100 g-1) as well as infarcted myocardium (from 41 +/- 8 to 61 +/- 19 ml min-1 100 g-1) increased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of L-propionylcarnitine (50 mg/kg) were studied in open-chest anesthetized pigs in which the blood flow in the left anterior descending coronary artery was reduced to 20% of baseline. A group of 7 animals given L-propionylcarnitine after 30 minutes of ischemia was compared with a group of 8 animals treated only with saline. After 60 minutes of ischemia the myocardium was reperfused for 2 hours. In both groups, the reduction of coronary artery blood flow abolished contraction of the affected myocardium and caused similar decreases in mean arterial blood pressure, the maximal rate of rise in left ventricular pressure, cardiac output, and ATP level and energy charge of the affected zone. L-propionylcarnitine did not affect any of these changes. Two hours of reperfusion caused further deterioration of systemic hemodynamics in both groups, although the decreases in cardiac output (P greater than 0.05) and mean arterial blood pressure (P less than 0.05) were smaller in the animals treated with L-propionylcarnitine. Left ventricular work, which decreased similarly in both groups during ischemia, deteriorated further in the saline treated group during reperfusion. This decrease was significantly attenuated by L-propionylcarnitine. Two hours of reperfusion resulted in only a partial return of blood flow to the reperfused ischemic myocardium, amounting to 53% of baseline in the saline-treated and to 72% of baseline in the L-propionylcarnitine-treated animals. The energy charge increased in both groups, but the increment tended to be less (P greater than 0.05) in the animals which had received L-propionylcarnitine.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary angioplasty is complicated by acute occlusion (within 24 hours) and late restenosis (within 6 months) in 2-5% and 20-40% of the cases, respectively. Vascular endoprostheses (stents) may provide the cardiologist with a solution to some of these complications. Several stent-devices are now available for experimental and clinical evaluation. In this study we describe our experience with two metallic stents in normal arteries of swine. Self-expandable, stainless steel stents (3.5 mm diameter) were implanted in 17 peripheral arteries, eight of which were deendothelialized by prior balloon angioplasty. Following implantation, the animals received antithrombotic therapy with acenocoumarol and aspirin (8 stents), or aspirin alone (9 stents). After 1 week repeat angiography was performed, which showed patency of all stented arteries. Microscopy showed complete covering by neointima, 80 microns in thickness. This self-expandable stent (SES) and a balloon-expandable stent (BES), constructed of tantalum, were implanted in normal coronary arteries. SES (3.0 and 3.5 mm) receiving animals were treated with coumadines (10 stents) or received no antithrombotic treatment (16 stents) after implantation. BES receiving animals were also not treated (10 stents). Three untreated animals with SES died suddenly within 48 hours. Postmortem examination showed partial or complete thrombosis of all six stents in these animals, resulting in a patency rate of 62% after 1 week. All animals with SES, which were treated with coumadines, and all animals with BES (untreated) had patent stents after one week. It is concluded that SES implanted in normal coronary arteries of pigs, which do not receive additional antithrombotic treatment, show a 38% occlusion rate within 48 hours, but show 100% patency after 1 week, when the animals are treated with coumadines. BES implanted in normal coronary arteries of pigs, which do not receive antithrombotic drugs, are 100% patent after 1 week.

In the present study 12 of 13 untreated pigs died of ventricular fibrillation during three 10 min episodes of left anterior descending coronary artery occlusion interrupted by 20 min of reperfusion. The selective beta-adrenoceptor antagonist bevantolol in a dose of 1.5 mg X kg-1, but not 0.5 mg X kg-1, offered nearly complete protection against this fatal arrhythmia. Evidence is also presented that bevantolol enhanced the recovery of regional myocardial function after these ischaemic events.

An overview is provided of current thinking regarding the origin(s) of atherosclerosis on the basis of clinical evidence, experimental models and pharmacological investigations with calcium antagonists. Because this group of drugs inhibits the influx of Ca2+ into the smooth muscle cell of the cardiovascular wall, it has been argued that when endothelial damage is anticipated or has occurred, the 'protective' action of calcium antagonists might avoid, delay or even help to repair the calcium overload seen with cell membrane damage. In the real world the situation must be far more complex as will become evident but as a concept the avoidance of Ca2+ overloading is enticing. In fact, based on circumstantial evidence, a major clinical trial is currently in progress in which the long term effect of nifedipine on coronary atherosclerosis is being evaluated in a double blind randomized fashion. The end-point of this study lies in the reduction of the severity and number of coronary artery lesions. Although not yet completed, the design and goals of that study are provided.

Changes in myocardial membrane biochemistry and ultrastructure, determined shortly (2 h) after reperfusion of ischaemic myocardium, were compared with the long term (4 wk) recovery of regional myocardial function. Anaesthetised pigs were subjected to 30 min (n = 14, group I) or 60 min (n = 14, group II) of left circumflex coronary artery occlusion. Seven animals of each group were studied 2 h and the others 4 weeks after flow was reinstated. After 2 h of reperfusion, regional myocardial function was absent in both groups. At 4 weeks regional function had returned to normal in group I, but was still significantly depressed in group II. Biochemical studies after 2 h of reperfusion showed that a functional index of the cardiac membrane, the in vitro cyclic AMP dependent 32P incorporation into phospholamban, was 71 (SEM 9)% compared to non-ischaemic myocardium in group I and 31 (6)% in group II (p less than 0.05). After 4 weeks this index had completely recovered in group I, 114 (13)%, but a significant decrease to 79 (2)% could still be observed in group II (p less than 0.05). After 2 h of reperfusion as well as after 4 weeks of recovery the myocytes in group II were more severely damaged than in group I. This study suggests that determination of in vitro phosphorylation of phospholamban shortly after reperfusion of ischaemic myocardium may be of value in the prediction of long term recovery of regional myocardial function.

Ligation of the left anterior descending coronary artery in open-chest pigs for 20 min caused a complete loss of regional myocardial function, which did not recover during the first two hours of reperfusion. Infusion of the stable prostacyclin analogue Iloprost (100 ng kg-1 min-1) did not prevent the loss of systolic wall function during ischaemia. Recovery of regional myocardial function during the first two hours of reperfusion was enhanced to 40% of baseline by Iloprost. This effect of Iloprost cannot be explained by a decreased O2-demand during ischaemia or an enhanced recovery of myocardial ATP content.

The purpose of this study was to explore the relationship between the extent of sarcolemmal damage observed 2 h after reperfusion of myocardium which had been ischemic for either 0.5 or 1 h and the long-term recovery of function of that same myocardium. For this purpose we studied the Ca2+ pumping ATPase activity and protein phosphorylation of sarcolemmal vesicles isolated after 2 h reperfusion. Both activities declined depending on the duration of ischemia, which suggests the development of sarcolemmal Ca2+ pump failure. Morphological examination of the sarcolemma by thin-section and freeze-fracture electronmicroscopy, in biopsies obtained after 2 h of reperfusion, showed severe clustering of intramembranous particles and formation and extrusion of lipidic liposomal structures which also depended on the duration of ischemia. Except for the occurrence of minor particle aggregation in the samples which had been ischemic for 0.5 h, sarcolemmal disruption was only seen in those myocardial segments which had been subjected to 1 h of coronary artery ligation. Recovery of regional myocardial function, assessed by 2-D-echocardiography after 2 weeks of reperfusion, was closely related to the degree to which sarcolemmal integrity was maintained after 2 h reperfusion.

The acute systemic hemodynamic effects of the calcium antagonist nisoldipine and the pyridazinone-derivative pimobendan, a phosphodiesterase inhibitor with vasodilating as well as positive inotropic properties, were studied in conscious pigs with chronic heart failure. Left ventricular (LV) dysfunction, manifested by a 25% decrease in cardiac output (CO), a 35% increase in systemic vascular resistance (SVR), and a doubling of the left ventricular filling pressure, was induced by a proximal ligation of the left circumflex coronary artery. Two to three weeks after myocardial infarction, cumulative 10-min infusions of either nisoldipine (0.05, 0.1, 0.25, and 0.5 micrograms/kg/min), pimobendan (2.5, 5, 12.5, and 25 micrograms/kg/min) or the solvents were administered. Infusion of the solvents did not affect any of the hemodynamic variables. Both nisoldipine and pimobendan normalized CO and exhibited a similar cardiac profile [systemic vasodilatation, reduction in left ventricular filling pressure, and an increase in heart rate (HR)] except for the significantly (p less than 0.05) larger increase in LVdP/dtmax with pimobendan (85%) than with nisoldipine (45%). In animals with heart failure, lower doses of both nisoldipine (twice) and pimobendan (four times) were needed to elicit a 30% reduction in SVR than in animals with normal pump function. For both drugs, the slope of the line describing the vasodilatory and positive inotropic properties shifted more in favor of the vasodilatory actions during heart failure (p less than 0.05). We conclude that in swine with chronic LV dysfunction nisoldipine, despite its lack of inotropic properties, appeared to improve ventricular function to the same extent as the primary positive inotropic agent pimobendan.

We studied the effect of pretreatment with two doses of the thromboxane antagonist BM 13.177 and its solvent on the development of electrically induced coronary artery thrombosis in pigs. Results were compared with those obtained in animals pretreated with intravenously administered acetylsalicylate and its solvent. The effects of both compounds on the overall cardiovascular performance (heart rate, mean arterial blood pressure, cardiac output, systemic vascular resistance) were minimal. In the animals receiving solvent or acetylsalicylate the time to occlusive coronary thrombosis was 33 +/- 4 and 32 +/- 6 min, respectively. BM 13.177, in a dose of 5 mg.kg-1, did not modify the time to thrombotic occlusion (35 +/- 7 min), but in six of the eight animals that had received 10 mg.kg-1 BM 13.177, there was no occlusion within 120 min. In the acetylsalicylate-treated animals, collagen-induced platelet aggregation and plasma thromboxane B2 declined by 72 and 82%, respectively. The decreases were 46 and 20%, respectively, with the higher dose of BM 13.177. It is concluded that, in this porcine model of coronary artery thrombosis, the thromboxane antagonist BM 13.177 effectively suppressed formation of occlusive thrombi whereas acetylsalicylate was ineffective at a dose that lowered arterial thromboxane levels.

The hemodynamic and antithrombotic action of ZK 36374, a stable carbacyclin derivative of prostacyclin, was studied during electrically-induced coronary artery thrombosis in the open chest anesthetized pig. Infusion of ZK 36374 (100 ng/kg/min, n = 6) had no effect on heart rate and cardiac output, but caused a 20% reduction in mean arterial blood pressure by peripheral vasodilation. In animals receiving solvent or no drug prior to thrombosis induction, the time to occlusive coronary artery thrombosis (TOT) was 30 +/- 2 minutes (mean +/- SEM, n = 17). Pretreatment with an i.v. infusion of ZK 36374 (100 ng/kg/min) prolonged TOT by 50% to 47 +/- 7 minutes (p less than 0.005, n = 6). This prolongation of TOT was not due to the lower blood pressure in the ZK 36374 group, as dihydralazine in a dose that lowered arterial blood pressure to the same extent had no effect on TOT (32 +/- 4 minutes, n = 4). The results indicate that ZK 36374 may be useful in delaying (or preventing) occlusive coronary artery thrombi.