Pre-existing Atherosclerotic Plaque Research Articles

Abstract 133: Trem2 Agonist Promotes Atherosclerotic Plaque Stability

Atherosclerosis is an inflammatory disease of the arteries that is a major cause of cardiovascular disease (CVD). Atherosclerotic plaque progression is driven by the deposition of low-density lipoprotein (LDL) within the intima, which is internalized by macrophages, forming lipid-engorged foamy cells. Importantly, the accumulation of excess LDL within foamy macrophages is cytotoxic, driving apoptosis, which ultimately promotes necrotic core formation and increased potential for plaque rupture. Recently, our lab identified the lipid receptor Trem2 to be highly expressed by foamy macrophages and regulate cell survival, proliferation, and cholesterol efflux. Thus, we tested whether agonizing Trem2 could drive macrophage survival to promote plaque stability. Using a Trem2 agonist antibody (AL002a, Alector Inc.), we treated Ldlr -/- mice that had preexisting atherosclerotic plaque with either isotype control or AL002a antibody for 8 weeks. AL002a treated mice showed an increase in plaque size in the aortic arch and aortic sinus. Plaque analysis determined that this was primarily due to an expansion of macrophage cellularity, through promotion of cell survival and proliferation. Furthermore, we found that plaques from AL002a treated mice had decreased necrotic core formation, increased fibrous cap size, and increased collagen deposition, consistent with improved stability. Single cell RNA-sequencing of atherosclerotic aortae from isotype and AL002a treated mice found that Trem2-agonism dramatically reshaped transcriptomes of both foamy macrophages and smooth muscle cells, including upregulation of oxidative phosphorylation (OXPHOS), cholesterol efflux, collagen, and pro-survival genes while downregulating inflammatory pathways. In vitro studies using bone marrow derived macrophages confirmed AL002a’s ability to drive cell survival, proliferation, OXPHOS, and cholesterol efflux in culture. Finally, we determined that AL002a’s ability to reshape aspects of foamy macrophage function was dependent on its ability to activate the kinase SYK downstream of Trem2. Overall, this data identifies Trem2 as a viable therapeutic target for promoting atherosclerotic plaque stability and improving outcomes in CVD.

Retrograde thrombectomy of acute common carotid artery occlusion with mobile thrombus: illustrative cases.

Acute embolic occlusion of the common carotid artery (CCA) alone is rare. However, once it occurs, recanalization is challenging due to the large volume of the clot, larger diameter of the CCA, and risk of procedure-related distal embolism into the intracranial arteries. The authors report two cases of acute embolic occlusion of CCA alone, caused by a cardiac embolus trapped at the proximal end of a preexisting atherosclerotic plaque at the cervical carotid bifurcation. In both cases, the CCA was successfully recanalized using retrograde thrombectomy in a hybrid operating room. In case 1, a 78-year-old male with acute right CCA occlusion underwent retrograde thrombectomy, where the cervical carotid bifurcation was exposed and incised, and the entire embolus was retrieved with forceps. Despite successful revascularization, massive bleeding from the CCA just after the retrieval remained a concern. In case 2, a 79-year-old female with acute right CCA occlusion underwent retrograde thrombectomy in the same manner. Because manual retrieval failed, a Fogarty balloon catheter inserted from the arteriotomy successfully retrieved the entire thrombus with minimal blood loss. Retrograde thrombectomy through the arteriotomy of the cervical carotid bifurcation safely and effectively recanalizes acute embolic occlusion of the CCA alone.

Abstract 704: Autophagy Activation Promotes Atherosclerosis Regression

Atherosclerosis is characterized by the deposition of cholesterol-rich plaques within the artery wall that are primarily comprised of macrophage and vascular smooth muscle cell (VSMC) foam cells. Atherogenesis is associated with a progressive defect in autophagy, a cell process that promotes cellular cholesterol homeostasis by degrading excess lipids and promoting cholesterol efflux. We recently showed that during atherosclerosis progression, autophagy and cholesterol efflux to HDL was particularly defective in VSMC foam cells as compared to macrophage foam cells. While previous studies have shown that autophagy activation of transcription factor EB by trehalose protects against atherosclerosis, the ability of this therapeutic compound to shrink pre-existing atherosclerotic plaque (atherosclerosis regression ) is unknown. We hypothesized that activating autophagy with trehalose would promote atherosclerosis regression in mice by enhancing macrophage and VSMC reverse cholesterol transport. Mice were injected with a gain of function PCSK9 adeno-associated virus and fed a Western Diet for 16 weeks to promote atherosclerotic plaque progression, followed by a switch to chow diet for 6 weeks to induce plaque regression. During the regression phase, mice received sub-cutaneous injections of saline or trehalose biweekly. Aortic sinuses were evaluated for changes in plaque size and lipid content. Circulating immune cells were quantified by flow cytometry. A switch to chow diet decreased circulating inflammatory and patrolling monocytes as compared to baseline, although no changes between the trehalose and saline treatment groups were observed. Oil Red O staining revealed a decrease in plaque lipid content in trehalose-treated mice as compared to the saline group, suggesting that autophagy activation in mice during atherosclerosis regression promotes favorable plaque remodeling. Our data demonstrates the therapeutic potential of autophagy activation in reducing atherosclerotic plaque burden. Further analysis of autophagy and inflammatory markers to characterize the mechanisms by which trehalose improves atherosclerosis regression is ongoing.

Vascular "Long COVID": A New Vessel Disease?

Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as "Long Covid (LC)" disease, when occurring 12weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from the original Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection (In a microcirculatory system, a first "endotheliitis," is often followed by production of "Neutrophil Extracellular Trap," and can evolve into a more complex leukocytoklastic-like and hyperimmune vasculitis. In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading to an accelerated progression of pre-existing atherosclerotic plaques through an increased deposition of platelets, circulating inflammatory cells and proteins. Associated dysregulated immune and pro-coagulant conditions can directly cause thrombo-embolic arterial or venous complications. In order to implement appropriate treatment, physicians need to consider vascular pathologies observed after SARS-Cov-2 infections as possible "LC" disease.

286 A CASE REPORT OF TYPE II KOUNIS SYNDROME

Abstract Case presentation and management A 81-years old female presented to the emergency department of our hospital with dyspnea and chest pain. She had a history of chronic kidney disease and left bundle brunch block (LBBB) never further investigated. Non diagnostic ECG was performed in the setting of pre-existing LBBB. HS-T-Troponin level was significantly elevated (986 ng/L). A transthoracic echocardiogram (TTE) revealed inferior and posterior wall hypokinesis. NSTEMI was diagnosed and coronary angiography via the femoral artery revealed subocclusive stenosis of the right coronary artery (RCA) and 80% stenosis of left anterior descending artery (LAD). Coronary stent positioning was performed for the RCA culprit lesion and staged complete revascularization was planned. Complications After two days, the patient experienced sharp pain in the right groin and a femoral pseudoaneurysm was diagnosed by Ultrasound Color Doppler. Subsequently anemia suggested the development of retroperitoneal hematoma but it was excluded by contrast CT. Unfortunately, the patient developed acute chest pain, wheezing and erythematous pruritic rash 10 minutes after injection of contrast medium agent. The ECG didn't show any new ischemic abnormalities in the setting of pre-existing LBBB. The peak CK- MB level was significantly elevated (87 ng/mL). New onset apical region akinesia and anterior wall hypokinesia were detected on TTE. Acute coronary syndrome (ACS) was suspected consistent with symptoms, new onset wall motion abnormalities and CK-MB elevations. The patient was diagnosed with allergic reaction and coronary vessel spasm secondary to contrast agent injection in pre-existing atherosclerotic plaque. Due to the high probability of an hypersensitivity reaction to the contrast medium agent we did not perform a new coronary angiography to confirm the diagnosis. Promethazine, Urbason and Nitroglicerin were administered with clinical improvement. The next day we observed recovery of the anterior and apex wall motion abnormalities consistent with coronary vessel spasm. Echocardiographic wall motion abnormalities before and after coronary spasm: Take home message We presented the case of an allergic reaction leading to the release of inflammatory mediators responsible of coronary vessel spasm causing acute myocardial infarction. It can also be induced by injection of contrast medium like in the presented case. Therefore, clinicians and radiologist should recognize this rare but critical disease to ensure prevention and appropriate management.

MI-derived alarmins activate B cells to accelerate atherosclerosis.

Alarmins released by infarcted myocardium stimulate B cells to differentiate into antibody-producing plasma cells, which then remotely drive the progression of atherosclerosis by producing autoantibodies that accumulate in pre-existing atherosclerotic plaques, increasing local inflammation and accelerating the progression towards a vulnerable plaque phenotype.

Relation between pre-existing plaque size and neointimal healing in an adult porcine model of familial hypercholesterolemia

Abstract Background Despite the efficacy of novel drug eluting stents (DES) in preventing restenosis, this complication still occurs, as do neo-atherosclerosis development and poor stent strut coverage that are associated with stent thrombosis. Safety and efficacy of novel coronary stents are preclinically being tested using an established porcine coronary model. However, the use of young healthy animal only allow limited conclusions to be drawn on the long-term effects, as the artieries do not reflect human pathology of advanced atherosclerosis. A key unresolved question is whether and how the presence, size and composition of pre-existing atherosclerotic plaque affect neointimal healing. Purpose The objective of this study is to understand the role of atherosclerotic plaque in neointimal response following DES placement in a large animal model of coronary artery disease by using optical coherence tomography (OCT) analysis. Methods The study was approved by the animal ethics committee. Familial hypercholesterolemia (FH) swine (n=6 Bretoncelles-Meishan) were given a high fat diet for 12 months to develop atherosclerosis. Stents (n=14) were implanted in n=14 coronary arteries under guidance of OCT with a stent-artery ratio of 1.1:1 at sites of atherosclerotic plaque, and animals were sacrificed after 28 days. Two types of Sirolimus eluting stents with different release profiles were implanted. Serial OCT pullbacks were taken before and after stent placement and after 28 days (follow-up), quantitatively analyzed and compared using dedicated software. The lumen area, stent area, plaque size (calculated as external elastic lamina (EEL) area - lumen area) and neointima (calculated as stent area – lumen area) were evaluated for each frame and averaged per stent. The plaque burden before stent implantation was evaluated at the same site of stent placement using coronary side branches as reference. Results The graph shows the association between the pre-existing plaque size before stenting and neointima formation after 28 days. Surprisingly, more pre-existing plaque size resulted in less neointima (P<0.01). There was one outlier, a stent with long dissection and extensive malapposition at baseline which showed an excessive tissue response at follow-up. The response in this animal model shows similarity to human vessel response as both regions with thin neointima formation as well as poor strut coverage were observed for both stent types. Conclusion The novel model of adult FH swine shows long-term vessel response to DES, that is similar to human response. This work shows that pre-existing atherosclerotic plaque affects the neointima after DES implantation. This insight highlights the necessity to use relevant disease models for safety and efficacy testing. Plaque size and neointima relation Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Netherlands Organisation for Health Research and Development (ZonMw)

Targeting Coagulation Factor Xa Promotes Regression of Advanced Atherosclerosis in Apolipoprotein-E Deficient Mice

Atherosclerosis is a progressive inflammatory vascular disorder, complicated by plaque rupture and subsequently atherothrombosis. In vitro studies indicate that key clotting proteases, such as factor Xa (FXa), can promote atherosclerosis, presumably mediated through protease activated receptors (PARs). Although experimental studies showed reduced onset of atherosclerosis upon FXa inhibition, the effect on pre-existing plaques has never been studied. Therefore, we investigated effects of FXa inhibition by rivaroxaban on both newly-formed and pre-existing atherosclerotic plaques in apolipoprotein-e deficient (ApoE−/−) mice. Female ApoE−/− mice (age: 8–9 weeks, n = 10/group) received western type diet (WTD) or WTD supplemented with rivaroxaban (1.2 mg/g) for 14 weeks. In a second arm, mice received a WTD for 14 weeks, followed by continuation with either WTD or WTD supplemented with rivaroxaban (1.2 mg/g) for 6 weeks (total 20 weeks). Atherosclerotic burden in aortic arch was assessed by haematoxilin & eosin immunohistochemistry (IHC); plaque vulnerability was examined by IHC against macrophages, collagen, vascular smooth muscle cells (VSMC) and matrix metalloproteinases (MMPs). In addition, PAR1 and -2 expressions and their main activators thrombin and FXa in the plaque were determined in the plaque. Administration of rivaroxaban at human therapeutic concentrations reduced the onset of atherosclerosis (−46%, p < 0.05), and promoted a regression of pre-existing plaques in the carotids (−24%, p < 0.001). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (−39.03%, p < 0.05), enhanced collagen deposition (+38.47%, p < 0.05) and diminished necrotic core (−31.39%, p < 0.05). These findings were accompanied with elevated vascular smooth muscle cells and reduced MMPs. Furthermore, expression of PARs and their activators, thrombin and FXa was diminished after rivaroxaban treatment. Pharmacological inhibition of FXa promotes regression of advanced atherosclerotic plaques and enhances plaque stability. These data suggest that inhibition of FXa may be beneficial in prevention and regression of atherosclerosis, possibly mediated through reduced activation of PARs.

Silencing of Anticoagulant Protein C Evokes Low-Incident but Spontaneous Atherothrombosis in Apolipoprotein E-Deficient Mice-Brief Report.

Murine atherosclerosis models do not spontaneously develop atherothrombotic complications. We investigated whether disruption of natural anticoagulation allows preexisting atherosclerotic plaques to progress toward an atherothrombotic phenotype. On lowering of plasma protein C levels with small interfering RNA (siProc) in 8-week Western-type diet-fed atherosclerotic apolipoprotein E-deficient mice, 1 out of 4 mice displayed a large, organized, and fibrin- and leukocyte-rich thrombus on top of an advanced atherosclerotic plaque located in the aortic root. Although again at low incidence (3 in 25), comparable thrombi at the same location were observed during a second independent experiment in 9-week Western-type diet-fed apolipoprotein E-deficient mice. Mice with thrombi on their atherosclerotic plaques did not show other abnormalities and had equally lowered plasma protein C levels as siProc-treated apolipoprotein E-deficient mice without thrombi. Fibrinogen and thrombin-antithrombin concentrations and blood platelet numbers were also comparable, and plaques in siProc mice with thrombi had a similar composition and size as plaques in siProc mice without thrombi. Seven out of 25 siProc mice featured clots in the left atrium of the heart. Our findings indicate that small interfering RNA-mediated silencing of protein C in apolipoprotein E-deficient mice creates a condition that allows the occurrence of spontaneous atherothrombosis, albeit at a low incidence. Lowering natural anticoagulation in atherosclerosis models may help to discover factors that increase atherothrombotic complications.

Treatment with a GnRH receptor agonist, but not the GnRH receptor antagonist degarelix, induces atherosclerotic plaque instability in ApoE(-/-) mice.

Androgen-deprivation therapy (ADT) for prostate cancer has been associated with increased risk for development of cardiovascular events and recent pooled analyses of randomized intervention trials suggest that this primarily is the case for patients with pre-existing cardiovascular disease treated with gonadotropin-releasing hormone receptor (GnRH-R) agonists. In the present study we investigated the effects of the GnRH-R agonist leuprolide and the GnRH-R antagonist degarelix on established atherosclerotic plaques in ApoE−/− mice. A shear stress modifier was used to produce both advanced and more stable plaques in the carotid artery. After 4 weeks of ADT, increased areas of necrosis was observed in stable plaques from leuprolide-treated mice (median and IQR plaque necrotic area in control, degarelix and leuprolide-treated mice were 0.6% (IQR 0–3.1), 0.2% (IQR 0–4.4) and 11.0% (IQR 1.0-19.8), respectively). There was also evidence of increased inflammation as assessed by macrophage immunohistochemistry in the plaques from leuprolide-treated mice, but we found no evidence of such changes in plaques from control mice or mice treated with degarelix. Necrosis destabilizes plaques and increases the risk for rupture and development of acute cardiovascular events. Destabilization of pre-existing atherosclerotic plaques could explain the increased cardiovascular risk in prostate cancer patients treated with GnRH-R agonists.

Elimination of macrophages drives LXR-induced regression both in initial and advanced stages of atherosclerotic lesion development

While numerous studies have aimed to develop strategies to inhibit the development and progression of atherosclerosis, recent attention has focussed on the regression of pre-existing atherosclerotic plaques. As important regulator of total body cholesterol homeostasis, the liver X receptor (LXR) could possibly be an important target to induce regression.Here, we describe the effect of LXR activation by the synthetic agonist T0901317 on lesion regression in different mouse models with early fatty streak lesions or advanced collagen-rich lesions. Although T0901317 caused a dramatic increase in plasma (V)LDL levels in low-density lipoprotein (LDL) receptor knockout mice, no further increase in lesion size was observed, which points to beneficial LXR activity in the vascular wall. In normolipidemic C57BL/6 mice with cholate diet-induced atherosclerotic lesions, T0901317 treatment improved plasma lipoprotein levels and induced lesion regression (−43%, p<0.05). Apolipoprotein E (APOE) reconstitution in APOE knockout mice by means of bone marrow transplantation dramatically improved plasma lipoprotein profiles and resulted in a marked regression of initial (−45%, p<0.001) and advanced lesions (−23%, p<0.01). Atherosclerosis regression was associated with a decrease in the absolute macrophage content (−84%, p<0.001). T0901317 supplementation further decreased the size of early (−71%, p<0.001 vs baseline; −48%, p<0.01 vs chow diet alone) and more advanced atherosclerotic lesions (−36%, p<0.001 and −17%, p=0.06 respectively).In conclusion, our study highlights the potential of LXR agonist T0901317 to stimulate removal of macrophages from atherosclerotic lesions ultimately leading to a highly significant plaque regression of both early and advanced atherosclerotic lesions.

Small Carotid Thrombus and Minimal Stenosis Causing Repeated Embolic Strokes

Despite current developments in neuroradiology, the sources of infarctions go undiagnosed in 28% of cases. An embolic source in the setting of minimal stenosis at the carotid bifurcation has rarely been reported. The authors report a previously healthy 48-year-old woman, without any risk factors for cerebrovascular events, sustained multiple cerebral infarctions in the right anterior and middle cerebral artery territory. Repeated imaging of the heart and cerebral vessels missed a very small abnormality arising from the posterior wall of the internal carotid artery, until it was diagnosed by computed tomographic angiography. This is problematic because by North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria, minimal stenosis essentially excludes the carotid artery as an embolic source. Despite maximum antiplatelet and anticoagulation therapy, she continued to have neurological deteriortation by progression of her strokes. She underwent standard carotid endarterectomy and sustained no new embolic phenomena. Histopathological examination showed an endothelial hyperplasia with organizing thrombus, which on the posterior wall of the internal carotid artery, is likely a hemodynamically induced on top of preexisting atherosclerotic plaque.

Exercise attenuates matrix metalloproteinase activity in preexisting atherosclerotic plaque

ObjectiveFew studies have investigated if exercise by itself has anti-atherosclerotic effects, without combining interventions with a low-fat diet. We studied the effects of exercise as a stand-alone intervention on preexisting atheromata by measuring not only plaque size but also the levels of plaque-destabilizing matrix-metalloproteinase (MMP) activity in vivo. Methods and resultsWe used near-infrared fluorescent (NIRF) molecular imaging with an MMP-2/9 activatable NIRF probe to visualize the inflammatory protease activity within preexisting atheromata of 17-week-old ApoE−/− mice on: (a) normal chow diet (NCD), (b) Western diet (WD), and (c) WD with treadmill exercise for 10 weeks. We also measured tissue levels of aortic lipid peroxidation (LPO) and plasma levels of glucose/lipid/cytokine profiles. Exercise did not attenuate growth of preexisting atheromatous plaques. However, exercise strongly decreased proteolytic activity in plaques for animals on WD, with levels decreasing almost to NCD levels. Exercise was associated with decreased aortic LPO levels and increased blood adiponectin/leptin levels; however, exercise did not affect WD-consumption/weight-gain or improve blood glucose/lipid profiles. ConclusionsExercise training reduced aortic MMP activity in mice with preexisting atheromata, even though they remained on a high fat diet and plaque-growth was not attenuated.

Occlusive Thrombosis With Neovascularization of the Internal Carotid Artery -Two Case Reports-

Two patients presented with sudden onset of occlusive thrombosis of the atherosclerotic carotid artery. The patients underwent carotid endarterectomy. Histological examination of the specimens clearly showed the presence of pre-existing atherosclerotic plaque with moderate stenosis and occlusive organized thrombus. Blood flow was maintained through a honeycomb pattern of multiple neovascularization within the organized thrombus. These cases suggest that both the degree of stenosis and the plaque characteristics should be considered when evaluating the risk of stroke in patients with carotid artery stenosis.

INSULIN-LIKE GROWTH FACTOR 1 PREVENTS ATHEROSCLEROSIS PROGRESSION IN AGED APOLIPOPROTEIN E-DEFICIENT MICE.

Insulin-like growth factor 1 (IGF-1) is an important endocrine and autocrine/paracrine factor that produces a wide range of biologic effects via activation of IGF-1 receptor (IGF-1R). Recently, we reported that continuous IGF-1 infusion suppresses development of atherosclerotic plaques in relatively young (3 months old) apolipoprotein E-deficient mice (apoe null mice) fed a cholesterol-rich diet, presumably by decreasing inflammatory responses. To examine whether IGF-1 administration prevents preexisting atherosclerotic plaque progression, we infused 7-month-old apoe null mice with 1.5 mg/kg/d IGF-1 or saline for 8 weeks using osmotic minipumps and evaluated changes in atherosclerotic burden. In saline-infused control animals, atherosclerotic lesion size in the aortic sinus root was increased by 30% (baseline; 439 ± 59 × 1,000 μm2 vs saline infusion; 573 ± 41 × 1,000 μm2, n = 6, p

Low-Dose FK506 Blocks Collar-Induced Atherosclerotic Plaque Development and Stabilizes Plaques in ApoE-/- Mice

Since atherosclerosis is a chronic inflammatory disease, we tested the hypothesis that the immunosuppressive drug FK506 would attenuate the development of atherosclerosis using a mouse model of collar-induced atherosclerosis. ApoE-/- mice were treated for 4 weeks with the immunosuppressive drug FK506 (0.05 mg/kg/day), yielding sustained blood levels (approximately 0.2 ng/mL) without systemic side effects. Atherosclerotic plaque development of FK506-treated mice was significantly reduced (63%) while plaque cell density was increased (52%) compared to controls. Importantly, FK506 also blocked progression of pre-existing atherosclerotic plaques. Plaque area of pre-existing plaques was 35% reduced by FK506. Cell density (35%) and collagen content (51%) were significantly increased, whereas necrotic core content was decreased (42%), indicating a more stable plaque morphology. Similar results were found during spontaneous atherosclerotic plaque development in ApoE-/- mice (treatment 17-25 weeks of age). Flow-cytometric analysis showed no peripheral effects on blood cell count or T-cell activation after FK506-treatment. In vitro, FK506 decreased vascular smooth muscle cell (VSMC) apoptosis and inhibited nuclear factor of activated T cells (NFAT)-luciferase reporter activity at concentrations in the range of the in vivo concentration. Low-dose FK506 inhibits collar-induced atherosclerotic plaque development and progression and induces more stable plaque phenotypes in ApoE-/- mice without any peripheral side effects.

Prevention of restenosis after percutaneous transluminal coronary angioplasty: The search for a “magic bullet”

Percutaneous transluminal coronary angioplasty (PTCA) is an accepted treatment for providing relief of angina pectoris in patients with single-and multivessel disease. Increased experience and advances in technology have resulted in a high primary success rate (90 % to 95 % ) and a lower complication rate (4 % to 5 % ). Despite the therapeutic success of coronary angioplasty, the exact mechanisms of dilatation remain speculative and involve multiple processes including stretching of the vessel at the site of the dilatation and disruption and fissuring of the plaque.’ Angiographic renarrowing at the site of PTCA, frequently accompanied by recurrence of symptoms of angina, is a common phenomenon (30 % ) and has a negative bearing on the long-term results of PTCA. This usually occurs within the first 6 months after PTCA.“, ” Although many of the risk factors for restenosis have been identified (Table 1),4-25 most of these are difficult to influence. Until now we have not found a technical or pharmacologic cure, and we are unable to predict which patients or vessel segments will have restenosis. The reason why a clinically significant restenosis occurs in only a minority of the dilated vessels (30%) remains an enigma. Although the typical restenotic lesion differs from the usual atherosclerotic plaque in architecture and lipid content, both contain smooth muscle cells and fibrous tissue,P6. 27 and it is even likely that the factors responsible for restenosis are similar to those that effect de novo atherosclerosis. In some cases of “restenosis” it is conceivable that it is caused by progression of the preexisting atherosclerotic plaque. An important step in the restenosis process is activation of the hemostatic system with platelet adhesion, platelet aggregation, and fibrin formation. This is followed by smooth muscle cell proliferation, which is mediated by growth factors produced by cellular constituents in the blood and damaged vessel wa11.2”~2g Each of these steps could be sites of intervention that might halt the restenosis process. The drugs that could reduce or prevent restenosis in the animal model are listed in Table II. Some of these have been investigated in prospective randomized angioplasty trials and although efficacy has not been demonstrated, they continue to be used and prescribed in daily routine. In this review we will concentrate on the drugs (Fig. 1) that have been tested to prevent restenosis in the animal model (Table III) and in postangioplasty patients (Table IV). Animal models are of limited value in restenosis research because it is impossible to create arterial stenoses in animals (e.g., pigs, rabbits, or dogs) that resemble human coronary artery disease (Table V). Most models use an inflated balloon to “injure” the intimal and medial layers of the vessel wall, although infused air has also been used. Some investigators have performed experiments in iliac or carotid arteries rather than in coronary arteries; others have fed the animals an atherogenic diet for brief periods of time to induce an “atherosclerotic lesion.” Several studies in animals have examined the degree of platelet deposition after arterial injury to test the hypothesis that platelet aggregation and platelet-derived substances are responsible for the restenosis process.2g-“’ Other studies use angiographic or histologic findings in damaged arteries to assess restenosis (Table IV). Recently a model of human restenosis

The pathophysiology of acute myocardial infarction.

Recent work has now clearly established that coronary arterial thrombosis is the direct cause of acute myocardial infarction. This thrombotic event occurs when a pre-existing atherosclerotic plaque ruptures or fissures, thereby exposing underlying thrombogenic material to the circulation. Platelets are thus activated and the clotting cascade is initiated. It is as yet unclear why a previously stable atherosclerotic plaque should fissure or rupture. However, suggested mechanisms include release of vasoactive substances from activated platelets, coronary arterial vasomotion, mechanical stress fatigue of the atherosclerotic plaque, and rupture of vasa vasorum within the atherosclerotic plaque. The resultant cessation of myocardial blood flow produces specific biochemical and physiological alterations secondary to myocardial ischemia. Intracellular acidosis, loss of high-energy phosphates, reduced sensitivity of contractile proteins to calcium, and accumulation of inorganic phosphate and lipid, all occur within the ischemic myocyte. Diastolic compliance is markedly reduced by ischemia followed by cessation of systolic contractile activity. Most of these alterations are reversible if ischemia is relieved promptly. Prolonged ischemia leads to delayed biochemical and physiological recovery and/or cell necrosis.

Pathological changes induced by repeated percutaneous transluminal coronary angioplasty.

The histopathological appearances of seven coronary arteries obtained from four patients after repeated percutaneous transluminal coronary angioplasty were analysed. A complex picture was found; typically there were ruptured atherosclerotic plaques, plaque dissection, and a fibrous tissue response. The histopathological appearance of older and more recent fibrous lesions was different. Older lesions contained more collagen and elastin fibres, whereas recent ones had more loosely arranged connective tissue containing abundant glycosaminoglycan and readily identifiable cells. The fibrous tissues tended to be damaged at the sites of previous injury and where the vessel wall was thinnest. In five of the seven arteries there was evidence of a repeated fibrous response to injury with partial or total rupture of the original media. In one instance a repair response within a pre-existing atherosclerotic plaque had caused restenosis. The results indicate that restenosis after repeated percutaneous transluminal coronary angioplasty, like restenosis after a first procedure, is mainly the result of fibrocellular tissue response to injury of the wall tissues. Because older (that is more mature) repair tissue contains fewer cells and more connective elements than younger repair tissue (that is the loosely arranged connective tissue found soon after angioplasty), when it is disrupted by a further angioplasty procedure it is less capable of producing tissue that will obstruct the lumen. This may explain why in the majority of patients with restenosis repeated percutaneous transluminal coronary angioplasty is successful. The present study also showed that occasionally plaque haemorrhages may become organised and incorporated into the pre-existing atherosclerotic lesion.

A study of atherosclerosis regression in Macaca mulatta: II. Chemical changes in arteries from animals with atherosclerosis induced for 19 months then regressed for 24 months at plasma cholesterol concentrations of 300 or 200 mg/dl

A clinically important question in people with existing atherosclerosis is whether a low concentration of plasma cholesterol attainable with diet or drug therapy influences preexisting atherosclerotic plaques and at what level of plasma cholesterol do these changes occur. Groups of young adult male rhesus monkeys were fed atherogenic diets for 19 months, then regression diets for 24 months. Regression diets contained sufficient cholesterol to maintain plasma cholesterol concentrations either at 302 ± 8 mg/dl, mean ± SEM (a concentration associated with a high risk for continued progression of atherosclerosis in man) or 194 ± 4 mg/dl (low risk for continued atherosclerosis development). A significantly greater amount of the accumulated arterial cholesterol, esterified cholesterol and phospholipid was removed in monkeys that underwent regression at 200 in comparison to 300 mg/dl. Decreases in arterial cholesterol in animals after 24 months at 200 mg/dl amounted to 100, 100, 93, and 96%, respectively, for carotid artery, thoracic aorta, abdominal aorta and iliaco-femoral artery in sharp contrast to decreases of only 80, 25, 56, and 72% in similar vessels of monkeys at the higher plasma cholesterol concentration. No major difference in arterial collagen or elastin was seen between the two regression groups. The frequency of mineralized plaques as assessed by aortic calcium accumulation was greater in the rhesus monkeys at the higher plasma cholesterol concentration during regression. Translated to human beings, these results suggest that for relatively uncomplicated fatty atherosclerotic lesions the plasma cholesterol concentration influences the degree of plaque regession and that significantly greater regression (as measured by a reduction in arterial lipid content) may be expected to occur at plasma cholesterol concentrations of 200 mg/dl as opposed to 300 mg/dl.