Michael E. Staab

Porcine model of stent thrombosis: Platelets are the primary component of acute stent closure

Acute stent thrombosis remains a major concern of coronary stent implantation. Animal studies using stents do not adequately mimic this clinical problem, since stent placement is rarely associated with acute closure. The purpose of this study was to develop and characterize a porcine model of stent thrombosis. Improved understanding through such a model may be useful toward preventing and treating acute stent closure. Whole blood was drawn from domestic crossbred swine one day before study. Platelets were isolated, labeled with 111-In tropolone, and reinjected within 18 hr of the study. Bilateral carotid arteries were exposed, and severe injury induced by a series of mechanical crushes. This method produced histologic injury similar to human coronary angioplasty, with medial disruption and large dissections protruding into the lumen. Stenting was performed in standard fashion with 3.5-mm JJIS stents. Local platelet deposition was measured and recorded as 111-In radioactivity using a miniaturized scintillation detector (Dosimeter Corp.) mounted directly at the artery injury site. This measurement was made in real time at 1-min intervals. Similarly, volumetric blood flow was measured in real time by Doppler flowmeter. Eighteen arteries of nine pigs were studied. In nine arteries from nine pigs, crush injury only was performed and monitored. In the contralateral artery, crush injury was followed immediately by placement of a 3.5-mm Palmaz-Schatz (coronary) stent. Blood flow decreased rapidly following injury in both groups and followed a cyclic pattern. Eight arteries of the crush alone and two arteries of the crush plus stent groups were totally occluded 1 hr after crush. 111-In counts normalized to baseline were significantly higher at 1 hr in both groups compared to baseline; in the stented group, counts were higher than in the unstented group. Blood flow was higher in the stented group than in unstented group for 1 hr. Histopathologic observation of the thrombi forming in both crush-only and crush-stent injuries showed severe medial dissections with obstructing medial flap formation. The thrombi forming in both groups were highly platelet rich. This model of stent and arterial thrombosis showed rapid formation of platelet-rich thrombus, cyclic blood flow variations, and acute occlusion in 20% of cases. Stent placement at arterial injury sites is associated with thrombus that is predominantly platelet rich. Stent placement at injury sites enhances platelet deposition over crush injury alone. Despite greater numbers of platelets, as shown by increased 111-In counts, stenting improved vessel patency. These were likely due to higher volumetric blood flow, continuous deposition, and embolization of labeled platelets.

Arterial remodeling after experimental percutaneous injury is highly dependent on adventitial injury and histopathology

BACKGROUND The extent and nature of unfavorable geometric remodeling, especially related to the adventitia, has not been studied previously. The purpose of this study was to examine two methods of experimental arterial injury, characterize the extent of remodeling, and determine if remodeling is injury-specific. METHODS Two methods for producing coronary stenoses in pigs were used: heat injury using thermal balloon angioplasty (resulting in adventitial fibrosis), and copper stent implantation (resulting in intense inflammation). Histomorphometric parameters included changes in neointimal thickness (delta neointima) from uninjured to injured sections, and differences in area circumscribed by the internal and external elastic laminas (delta internal elastic lamina area and delta external elastic lamina area, respectively). Remodeling was calculated for each lesion as the enlargement of the external elastic lamina area or internal elastic lamina area for incremental neointimal thickening, expressed as the slopes delta external elastic area/delta neointima and delta internal elastic lamina area/delta neointima. RESULTS Remodeling indices for the heat lesions for the heat lesions were negative (delta internal elastic lamina area/delta neointima = 0.15, delta external elastic lamina area/delta neointima = 0.64) and indicated little remodeling in contrast to copper stent injury (delta internal elastic lamina area/delta neointima = 0.95, delta external elastic lamina area/delta neointima = 1.20). CONCLUSIONS Remodeling in fibrotic compared to inflammatory lesions differs markedly, and may explain increased restenosis rates observed in thermal balloon angioplasty in patients. This formulation may be useful to study remodeling and restenosis following interventional technologies.

Aortic Valve Homografts in Adults: A Clinical Perspective

Aortic valve replacement is a lifesaving measure in patients with severe aortic valve disease. In the United States, the most commonly used prostheses are the mechanical and bioprosthetic valves. With mechanical valves, long-term anticoagulation is necessary because of high thrombogenic potential. Bioprosthetic valves have a relatively high incidence of structural failure, especially in younger patients. Aortic valve homografts, derived from human heart donors or autopsy material, provide an alternative to mechanical or animal valves. The advantages of the homograft in comparison with the mechanical prostheses are the low incidence of thromboembolism without anticoagulation and lower valvular gradients in smaller sizes. Homografts are relatively resistant to endocarditis and are the valve of choice during active endocarditis. Their major mode of failure has been aortic regurgitation; however, recent advances in preservation and operative techniques have decreased this problem. Whether implantation of an aortic valve homograft should be the procedure of choice in subsets of patients remains controversial. Herein we review the history, techniques, results, complications, and current indications for aortic valve homografts.

Enhanced angiogenesis and unfavorable remodeling in injured porcine coronary artery lesions: Effects of local basic fibroblast growth factor delivery

There is interest in the role of growth factors in the genesis of arterial remodeling. We studied local administration of basic fibroblast growth factor (bFGF) to coronary lesions to determine whether there is a difference in remodeling and whether neovascularization could be induced in such stenoses and distal myocardium. Pigs were randomized to balloon infusion of either saline or bFGF at each thermally injured arterial site. After the animals were killed, their internal elastic lamina, neointima, and lumen areas were measured. Capillaries were counted in the arteries and myocardium. There was a greater loss of lumen and internal elastic lamina in the bFGF group. The neointima, media, and myocardium in the bFGF treated arteries had statistically more capillaries. This study showed that local intracoronary bFGF, at a dose that results in arterial luminal revascu larization in injured segments, adversely affects arterial remodeling. Thus, the angio genic response to exogenous bFGF may be offset by concomitant shrinkage of injured arterial segments.

Restenosis and Remodeling: Is the Adventitia Involved?

Vascular remodeling has assumed great importance as a cause of coronary restenosis. Yet understanding of this complex phenomenon is only recently beginning to grow as more data has emerged. In its most fundamental form, remodeling may be defined as any change in vessel diameter (enlargement or constriction) in response to chronic changes in hemodynamic conditions or humoral factors [1]. With atherosclerosis or after vascular intervention, the coronary artery may exhibit three separate remodeling responses 1) compensatory enlargement, 2) absence of compensation or 3) vascular constriction/shrinkage [2]. Each has substantial implications for the artery lumen.

Vascular Cell Proliferation Dynamics: Implications for Gene Transfer and Restenosis

Pharmacologic treatment of restenosis following coronary angioplasty has completely failed. The most widely accepted cause is formation of neointimal hyperplasia, considered a result of uncontrolled medial smooth muscle cell proliferation [1–5]. Studies in the rat carotid artery injury model has been the basis of this paradigm, having been documented in many studies [6, 7]. Therapies aimed at inhibiting proliferation have been quite successful in rat arterial injury [8, 9]. Yet when applied to large scale patient trials, these therapies have failed to exhibit any effect whatsoever on the loss of minimal lumen diameter (MLD) [10]. Reasons for these failures are unclear, but may relate in part to an incomplete understanding of cell kinetics in the growth of human neointimal hyperplasia. The literature is conflicting regarding the role of proliferation in human restenosis. Two studies of human restenotic lesions obtained using directional atherectomy demonstrated opposite conclusions. Pickering and colleagues [11] found peak cellular proliferation rates of about 20%, while in a similar study, O’Brien [12] reported a proliferation rate of less than 1%. Much debate has surfaced about the reasons for these divergent results, but centers on questions of technical factors such as tissue fixation methods and visual interpretation of positive cells by proliferating cell nuclear antigen (PCNA) staining.

Systolic aortic valve compression from partial dehiscence of an aortic valve homograft

Implantation of valve prostheses provide improvement of symptoms and prolongation of life in selected patients with valvular heart disease. Meticulous follow-up of patients after valve surgery is essential as complications of valve failure, valve dehiscence, valve thrombosis, and infection may occur. The major mode of failure of aortic valve homografts is valve regurgitation, which is readily detected by physical examination. We report a case of left ventricular outflow obstruction after implantation of an aortic valve homograft.