Sanjay S. Srivatsa

Histologic Correlates of Angiographic Chronic Total Coronary Artery Occlusions: Influence of Occlusion Duration on Neovascular Channel Patterns and Intimal Plaque Composition

OBJECTIVES Age-related changes in histologic composition and neovascular channel (NC) pattern of angiographic chronic total coronary artery occlusions (CTOs) were studied to define histologic correlates of age-related revascularization profiles and neovascular channel formation. BACKGROUND Revascularization of CTOs is frequently characterized by inability to cross or dilate the lesion and a high incidence of reocclusion or restenosis but low periprocedural ischemic complication rates. Little is known about the histopathologic basis of these observations. METHODS Ninety-six angiographic CTOs from autopsy studies in 61 patients who had undergone coronary angiography within 3 months of death were studied. Abrupt plaque rupture was excluded. Occlusion segments were analyzed for 1) histologic composition as a function of lesion age; and 2) NC pattern as a function of lesion age and intimal plaque (IP) composition. RESULTS Cholesterol and foam cell-laden IP was more frequent in younger lesions (p = 0.0007), whereas fibrocalcific IP increased with CTO age (p = 0.008). IP NCs arose directly from adventitial vasa vasorum and were anatomically and quantitatively related in terms of number and size (p = 0.0001) to the extent of IP cellular inflammation. IP cellular inflammation exceeded that found in the adventitia (p < 0.001) or media (p = 0.0001) across all CTO ages. In CTOs < 1 year old, the adventitia was associated with a larger number and size of NCs relative to the IP (p = 0.0006 and p = 0.009), media (p = 0.0001 and p = 0.002) and recanalized lumen (p = 0.0001 and p = 0.001). In CTOs >1 year old, the adventitia and IP NC numbers were similar and exceeded NC numbers found in the media (p = 0.0001) and recanalized lumen (p = 0.0001 and p = 0.003). CONCLUSIONS Angiographic CTO frequently corresponds to less than complete occlusion by histologic criteria. Age-related changes in IP composition from cholesterol laden to fibrocalcific may explain the adverse revascularization profile of older CTOs. IP NC growth derived from the adventitia increases with age and is strongly associated with IP cellular inflammation. IP NC formation may protect against the flow-limiting effects of IP growth.

Selective αvβ3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury1

Lumen loss from vascular restenosis remains a leading cause of chronic revascularization failure. Objective : We hypothesized that cell-matrix adhesion, migration, and differentiation events that underlie restenosis are mediated by αvβ3 integrin-ligand interactions. Methods : Using immunohistochemistry and in situ hybridization, we examined the spatial and temporal vessel wall expression of αvβ3 and osteopontin following deep coronary arterial injury. Cell migration and adhesion assays were performed to demonstrate the affinity and specificity of XJ735 for various vessel wall integrins. The effects of XJ 735 (a selective cyclic Arg-Gly-Asp (RGD) peptidomimetic αvβ3 antagonist) on neointimal hyperplasia and lumen stenosis were tested in a porcine coronary injury model. Normolipemic swine underwent oversized stent injury followed by XJ 735 administration (9 animals, 28 lesions; 1 mg/kg bolus+7 days 4 mg/kg/d infusion+21 days 2 mg/kg i.v. bolus 12 hourly) or placebo (10 animals, 30 arterial lesions). Results : Maximal αvβ3 immunoreactivity was observed between 7–14 days following injury in the neointima, media, and adventitia. Maximal osteopontin mRNA signal in the neointima, media, and adventitia was observed at 14, 7 and 28 days respectively. IC50 for XJ 735 αvβ3-mediated inhibition of human and porcine endothelial cell adhesion, and vascular smooth muscle cell migration, ranged from 0.6 to 4.4 μM. In contrast, IC50 for porcine or human αIIb/β3, α4β1, αvβ5, and α5β1 inhibition exceeded 100 μM. Steady state XJ 735 plasma levels exceeded 5 μM. Despite slightly higher injury scores in XJ 735 treated animals, significant reductions in mean neointima area (43% reduction; p = 0.0009), and mean percent lumen stenosis (∼2.9 fold reduction; p = 0.04) were observed in XJ 735 treated animals. XJ 735 treatment did not significantly alter the relative size of the arterial injury and reference sites (geometric remodeling). Comparison of neontima area vs. injury score regression lines revealed significant reductions in slope ( p = 0.0001) and intercept ( p = 0.0001) for XJ 735. Conclusions : Selective αvβ3 blockade is an effective anti-restenosis strategy that potently limits neointimal growth and lumen stenosis following deep arterial injury. The co-ordinate spatial and temporal upregulation of αvβ3 expression following vessel wall injury, and the high affinity and specificity of XJ 735 for αvβ3, confirms the importance of this integrin in adhesive and migratory cell-matrix events underlying coronary restenosis.

Diabetes mellitus and outcome after primary coronary angioplasty for acute myocardial infarction: lessons from the GUSTO-IIb angioplasty substudy

OBJECTIVES We sought to compare the efficacy of primary angioplasty in diabetics versus nondiabetics and to evaluate the relative benefits of angioplasty over thrombolytic therapy among diabetics. BACKGROUND Primary angioplasty for myocardial infarction is at least as effective as thrombolytic therapy in the general population. However, the influence of diabetic status on outcome after primary angioplasty versus thrombolysis remains unknown. METHODS Patients in the Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) Angioplasty Substudy were randomized to receive either primary angioplasty or accelerated alteplase. The interaction of diabetic status (diabetics n = 177, nondiabetics n = 961) and treatment strategy with the occurrence of the primary end point (death, nonfatal reinfarction or nonfatal, disabling stroke at 30 days) was analyzed (power to detect a 40% relative reduction in the primary end point with alpha = 0.05 and beta = 0.20). Among patients who were randomized to and underwent primary angioplasty, procedural success (defined as residual stenosis <50% and TIMI grade 3 flow) was assessed based on diabetic status. RESULTS Compared with nondiabetics, diabetics had worse baseline clinical and angiographic profiles. Despite more severe stenosis and poorer flow in the culprit artery, procedural success with angioplasty was similar for diabetics (n = 81; 70.4%) and nondiabetics (n = 391; 72.4%). Outcome at 30 days was better for nondiabetics randomized to angioplasty versus alteplase (adjusted odds ratio, 0.62; 95% confidence interval, 0.41-0.96) with a similar trend for diabetics (0.70, [0.29-1.72]). We noted no interaction between diabetic status and treatment strategy on outcome (p = 0.88). CONCLUSIONS Primary angioplasty was similarly successful in diabetics and nondiabetics and appeared to be more effective than thrombolytic therapy among diabetics with acute infarction.

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.

Rheumatoid vasculitis manifesting as intra-abdominal hemorrhage.

Rheumatoid vasculitis, an extra-articular component of rheumatoid arthritis, causes a wide spectrum of manifestations that range from clinically insignificant to life-threatening disease. As a systemic necrotizing arteritis, rheumatoid vasculitis is usually characterized by end-organ ischemia. Herein we describe a patient with abdominal pain and syncope due to intra-abdominal hemorrhage from a ruptured aneurysm of the inferior pancreaticoduodenal artery in the setting of rheumatoid vasculitis. Although the intra-abdominal hemorrhage was the unusual manifestation of rheumatoid vasculitis in this patient, he had a history of prior extra-articular rheumatoid disease, including pulmonary fibrosis and Sjögrens syndrome with associated parotid lymphoproliferative disease. In patients with rheumatoid arthritis who have abdominal pain and an unexplained rapidly decreasing hemoglobin concentration, the diagnosis of intra-abdominal hemorrhage from a ruptured visceral aneurysm due to rheumatoid vasculitis should be considered, even in the absence of other indications of systemic vasculitis.

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.

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.