Historical perspective.

Development of the first percutaneous catheters for local delivery is described. Understanding of the mechanisms by which circulating materials gain entrance to the artery wall, and the importance of hypertension in accelerating that process were crucial to the conceptual basis of these devices. The double balloon catheter and the porous balloon catheter were systematically studied to quantify the local pressure-wall penetration relationship. Designs for many new catheters that claim advantage over early models require similar systematic demonstration of their performance with normal and diseased arteries. Only in this way can this promising new technique become a clinical advance against human vascular disease.

Use of the perforated balloon catheter to infuse marker substances into diseased coronary artery walls after experimental postmortem angioplasty.

A perforated balloon catheter was used in human coronary arteries after postmortem angioplasty had been performed. The catheter used has a standard angioplasty balloon with a pattern of laser-produced holes, 25 microns in size, which generate streams of fluid under pressure. Studies of the routes by which marker substances enter diseased arterial tissue when infused by the perforated balloon after experimental angioplasty are described. A colored marker dye entered the new crevices and dissection planes created by the angioplasty, but did not extend greater than 2 cm either proximal or distal to the perfused segment. Horseradish peroxidase entered tissue not only from the lumen and adventitia as occurs with its infusion into normal tissue with the perforated balloon, but also extended from new crevices and dissection planes created by the angioplasty. Platelet aggregation, coagulation and cell proliferation, the likely causes of restenosis after angioplasty, originate in the sites of greatest tissue disruption and blood stasis. These postmortem studies suggest that active drugs are delivered to the arterial wall in a manner likely to be effective in preventing these events.

Use of a perforated balloon catheter to deliver concentrated heparin into the wall of the normal canine artery.

A perforated catheter was used to deliver either horseradish peroxidase or fluoresceinated heparin under pressure to the canine arterial wall. Depth of penetration of the media by horseradish peroxidase was dependent on perfusion pressure. At 5 bar pressure for 1 min, the entire media showed a reaction product for horseradish peroxidase. Fluoresceinated heparin delivered under the same conditions could be demonstrated to traverse the entire media as well. A pressure of 5 bars caused medial necrosis at 48 h after perfusion, even when the perfusing solution was saline. (This did not differ from the effect of standard angioplasty at the same pressure.) However, heparin at 5,000 U/ml did not cause medial alteration at 48 h when delivered at the lower pressure of 500 mm Hg. It is feasible to deliver heparin over 1 min in high concentration to the arterial wall by means of this balloon catheter. This method may permit the use of commercially prepared heparin in high concentration as an antiproliferative agent to control the problem of restenosis after angioplasty.

The effects of beta-adrenergic blocking agents on blood lipid levels.

This review examines the effects of beta-adrenergic blocking agents on blood lipids. These agents have been effective in the treatment of angina and hypertension and in the reduction of recurrence of ischemic cardiac disease, such as myocardial infarction. Many beta blockers, however, have an adverse effect on blood lipids, especially by reducing high-density lipoprotein (HDL) cholesterol and increasing triglycerides. One result is an unfavorable influence on the cholesterol ratio (expressed either as low-density lipoprotein [LDL]/HDL or total cholesterol/HDL). These cholesterol parameters have been shown to have a strong influence on coronary heart disease (CHD) risk. Studies have shown that antihypertensive therapy has reduced the incidence of cerebrovascular disease but, in many instances, has not reduced the incidence of CHD. A hypothesis for this lesser effect on coronary disease is that antihypertensive agents may be adversely affecting blood lipids. Thus, while one major risk factor for CHD is reduced, another may be somewhat enhanced. Pharmacologic properties of some beta blockers such as peripheral alpha blockade (e.g., with labetalol) or intrinsic sympathomimetic activity (ISA) (e.g., with pindolol) may counteract some of these negative lipid effects. An investigational beta blocker, bevantolol, which will be marketed shortly in the United States, has been effective in antihypertensive therapy. Bevantolol has been shown to lower LDL cholesterol and not adversely affect HDL cholesterol; in this way, bevantolol favorably influences the serum lipoprotein profile. Whether this effect will have clinical significance remains to be seen.

Insights into coronary angioplasty-induced restenosis from examination of atherogenesis.

Atherogenesis is a complex tissue reaction involving both vascular and circulating cells and components. The former include endothelial and smooth muscle cells, the latter circulating monocytes, platelets and lipoproteins. The role of growth factors secreted by platelets and all the cells involved in setting into motion a fibrocellular vascular reaction has been recently elucidated. Repeated injury or the presence of hyperlipidemia leads to occlusive disease. Many of these cellular events are also likely to be stimulated by the vascular injury that occurs as part of the angioplasty procedure. Restenosis, a major complication of the latter, may reflect the vascular response to iatrogenic injury. Progress in understanding the mechanisms involved in restenosis should also clarify important aspects of atherogenesis.

Influence of pressure on permeability of normal and diseased muscular arteries to horseradish peroxidase. A new catheter approach.

The effects of different distending pressures on permeability of dog and human arteries to horseradish peroxidase (HRP) were studied. A new catheter was employed to achieve the distention of defined vessel segments to the desired pressure. Normal dog brachial arteries were studied both post mortem and in vivo. Mildly to moderately diseased human coronary arteries were studied post mortem. A predictable linear relationship between pressure and penetration of HRP into the dog arterial media was found, using pressures of 0, 150, 300 and 500 mm Hg. Postmortem vessels were consistently less permeable than those studied in vivo. Full penetration of the media by HRP was achieved by application of 300 mm Hg pressure for 45 sec with the new catheter. When human coronary lesions were examined under these same conditions, plaques were readily demonstrated to be permeable to HRP, even to a depth of many hundreds of micrometer. Thus, penetration of arterial wall thickness by HRP (Mr 40,000 dalton) is related to the distending pressure applied. Human coronary plaques also show ready penetrance by HRP. The new catheter described allows the application of these pressures to defined segments of the arterial tree.