Pharmacological investigation in a swine model of chronic left ventricular dysfunction

In this thesis we first investigated the cardiovascular actions of several classes of drugs in conscious pigs in which heart failure was induced by occluding a coronary artery 3-4 weeks before the studies were performed and compared the results to those observed in normal conscious animals. Positive inotropic agents and vasodilators are frequently used to treat heart failure as they may improve the depressed myocardial contractility and lower the elevated systemic vascular resistance. In chapter 2 and 3 the effects of the 1.4- dihydropyridine derivative calcium antagonists nisoldipine and elgodipine are studied because of their capability to unload the heart by reducing systemic vascular resistance in normal anesthetized pigs (Duncker et al., 1986 and Sassen et al.. 1990) and by increasing cardiac output in normal conscious pigs (Duncker et aL, 1987). To study the potential advantage of vasodilators with positive inotropic properties to vasodilators alone we also investigated the actions of the phosphodiesterase inhibitor pimobendan with nisoldipine in the porcine model for heart failure (Chapter 4 ). In chapter 5 we describe the effects of a novel class of drugs which causes systemic vasodilation by potassium channel activation. The results of bimakalim are compared to the nicotinamide derivative nicorandil, which in addition to their nitrate-like properties, also possess potassium channel activator properties (Taira, 1989). One of the most prominent drugs in the treatment of ischaemic heart disease is nitroglycerin, despite the frequent occurrence of tolerance. In chapter 6 we first evaluated 5 novel nitrate-esters in normal conscious pigs. In the second part nitroglycerin and one of the novel compounds, CEDO 8956, were selected for further study of distribution of cardiac output in conscious pigs with chronic coronary artery occlusion. Tachycardia is an unwanted situation, especially in patients with coronary artery disease. Selective bradycardic agents, which exert an anti-ischemic effect because of their ability to reduce oxygen demand and improve oxygen supply of the myocardium and especially of the subendocardial layers (Schamhardt et aL, 1981, Krumpl eta!., 1988 and lndolfi et a!., 1989), may thus have some benefit in patients with left ventricular dysfunction, provided that the negative chronotropic properties are not accompanied by negative inotropic properties. We therefore studied the effects of UL-FS 49, a specific bradycardic agent and compared the results to those of the non-selective beta-adrenoceptor antagonist propranolo

The selective bradycardic effects of zatebradine (UL-FS 49) do not adversely affect left ventricular function in conscious pigs with chronic coronary artery occlusion

Summary 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 μg/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<0.05) and a decrease in LVdP/dtmax (3020±210 mmHg vs. 3720±210 mmHg, respectively; p<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<0.05). Up to 100 μg/kg UL-FS 49 did not affect arterial blood pressure, whereas LVdP/dtmax and cardiac output decreased by less than 10% in either group. With the highest dose there were decreases in cardiac output (20%) and LVdP/dtmax (15%) and a 5–6 mmHg increase in left ventricular end-diastolic pressure in both groups. The data suggest that UL-FS 49 in doses up to 100 μg/kg may also, in the setting of chronic mild left ventricular dysfunction, be an attractive agent when heart rate has to be reduced selectively

Arterial stenting with self-expandable and balloon-expandable endoprostheses

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 μm 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

Coronary stenting with a new, radiopaque, balloon-expandable endoprosthesis in pigs

BACKGROUND. Intracoronary stents may be effective when used as "bail-out" devices for acute complications after percutaneous transluminal coronary angioplasty. Furthermore, preliminary reports have demonstrated some promising results with stents with regard to the reduction of restenosis. Several stent devices are available for preclinical and clinical evaluation. The use of these stainless-steel stents has been limited by poor visibility during fluoroscopy and thrombogenicity during the first days to weeks after implantation. We therefore investigated the immediate and short-term effects on arterial patency of a new, radiopaque, balloon-expandable coil stent in normal coronary arteries of pigs. METHODS AND RESULTS. In 10 animals, a stent was placed in two of the three epicardial coronary arteries. During the implantation procedure, the animals received heparin; after the procedure, no antithrombotic drugs were administered. After 1 week (five animals and 10 stents) or 4 weeks (five animals and 10 stents), repeat angiography was performed, followed by pressure-fixation of the coronary arteries for light and electron microscopic examination. Angiographic analysis revealed that all stented coronary segments were patent and without signs of intraluminal defects. Scanning electron microscopy showed complete endothelial covering of all stents within 7 days. Light microscopy showed a reduced tunica media locally under the stent wires, which resulted from exerted pressure. The neointima on top of the stent wires measured 56 microns (range, 42-88 microns) after 1 week and 139 microns (range, 84-250 microns) after 4 weeks. CONCLUSIONS. Results from this study show that this radiopaque endoprosthesis can be safely placed in normal coronary arteries of pigs. After 4 weeks, all stents were patent and there was no need for additional antithrombotic treatment, whereas neointimal proliferation was limited