Frank D. Kolodgie

Effect of perfluorochemical (Fluosol-DA) on infarct morphology in dogs.

SummaryTo assess the effect of Fluosol-DA treatment on infarct morphology, detailed histologic examination was performed in 17 dogs with permanent proximal left anterior descending coronary artery occlusion. Two of the three groups of dogs received an equal blood volume exchange (40 ml/kg i.v.) with either Fluosol-DA (F) or heparinized autologous blood (H) 30 min post occlusion while being ventilated with 100% oxygen. A third group received no therapy (C). Animals were sacrificed 3 days post occlusion and sections were obtained for light and electron microscopy. Histologic studies showed that infarct size was statistically smaller in dogs treated with F 54 ± 7% versus heparin 64 ± 10% treatment or no therapy 79 ± 6%. Fluosol-DA animals demonstrated decreased inflammatory infiltrate, larger viable subepicardial zones and greater endocardial sparing in the area surrounding the central zone of necrosis. By electron microscopy, perfluorochemical particles were found within endothelial and inflammatory cells in subepicardial zones of infarction. In midmyocardial zones, Fluosol-DA particles were present in capillaries, extracellular spaces and necrotic myocytes. In the normal myocardium Fluosol-DA particles were rarely seen within endothelial cells and never within the interstitium or myocytes. Thus, Fluosol-DA reduces infarct size and alters infarct morphology in the 3 day post permanent coronary occlusion model.

Carotid Disease: Pathology of carotid artery atherosclerotic disease

Stroke is the third leading cause of death in the United States, accounting for 600 000 cases each year, of which about 500 000 are first attacks (American Heart Association, 2001; Heart and Stroke Statistical Update. Dallas, TX, 2001). The pathologic events leading to stroke are complex, and involve atherosclerosis of the aorta and its branches, especially the carotid artery, obstruction of blood flow by increasing plaque burden, embolization of plaque components, especially of thrombotic material, and cerebrovascular factors. The importance of plaque components that predispose to plaque disruption, in addition to the degree of stenosis, has relatively recently been appreciated in relation to cerebral ischemic events. The purpose of this chapter is to characterize atherosclerotic carotid disease in light of our knowledge of coronary atherosclerosis and relate carotid plaque morphology to cerebral ischemic syndromes with special focus on features of plaque instability. A precise understanding of the histologic features of carotid atherosclerosis should help target specific treatments that are likely to be beneficial in the prevention of a subsequent event.

Atherosclerotic Plaque Angiogenesis as a Mechanism of Intraplaque Hemorrhage and Acute Coronary Rupture

From a clinical perspective, the contribution of pathologic angiogenesis to the development of high-risk plaques is substantial, since the immature ‘leaky’ vasa vasorum (Vv) are considered a primary source of intraplaque hemorrhage. The occurrence of hemorrhagic events is beginning to emerge as a leading factor contributing to necrotic core expansion in late plaques based on accumulated erythrocyte-derived cholesterol and complications of secondary inflammation. Therefore, a further understanding of neovascularization of coronary atheroma may impact new treatment strategies targeted at plaque stabilization. While the Vv of normal arteries represents a quiescent, but functional microvascular network localized to the adventitia, atherosclerotic plaques express a latent proangiogenic phenotype represented by invading adventitial vasa vasorum (Vv). The development of intraplaque Vv represents a complex process supported by a multitude of factors involving endothelial proliferation and migration and a microenvironment enriched in growth factors, inflammatory cells, and extracellular matrix proteases. Initiating factors of angiogenesis constitute a physiologic response strongly driven by molecular signals triggered by hypoxia along with a positive association with hypercholesterolemia. The development of necrosis however, in complicated plaques, further provides a chronic inflammatory milieu consisting of a wide array of infiltrating immune cells and their secretory cytokines, chemokines, and growth factors in addition to bioactive lipid oxidation products. Moreover, immune activators also produce many proteases, ranging from urokinase Plasminogen Activator (uPA) to a variety of matrix metalloproteinases, to help degrade the basement membrane thereby facilitating the directional invasion of microvessels from the adventitia. Finally, restoring the balance of pro- and anti-angiogenic factors in plaques to that of a ‘normalized’ physiologic setting may provide a therapeutic strategy thereby reducing or eliminating intraplaque hemorrhage. The mechanisms of how a lipid rich inflammatory microenvironment contributes to the development of plaque angiogenesis will be a crucial step for furthering an understanding of plaque biology as well as for developing innovative approaches for treating atherosclerosis ahead of current lipid lowering therapies and stents.

Evaluation of Vulnerable Atherosclerotic Plaques

Acute coronary syndromes represent a clinical spectrum that includes unstable angina, acute myocardial infarction, and sudden coronary death. The most common cause of coronary thrombosis is plaque rupture followed by plaque erosion, and least frequently calcified nodule. The lesion that mostly resembles acute rupture is the thin-cap fibroatheroma (TCFA), which is characterized by a necrotic core with an overlying fibrous cap measuring <65 μm, containing rare smooth muscle cells but numerous macrophages. TCFAs are most frequently observed in patients dying with acute myocardial infarction from plaque rupture and least common in plaque erosion. They are most frequently observed in proximal and mid coronary arteries, least frequent in the distal arteries. Vessels demonstrating TCFA have a significant plaque area occupied by a necrotic core, and the vessel shows positive remodeling. Intraplaque hemorrhage contributes to the expansion of necrotic core by accumulation of excess red cell membrane free cholesterol. An increase of hemoglobin by extravasated erythrocytes induces oxidative stress and subsequent vulnerability of the plaque. It is likely that plaques progress through repeated thrombosis which usually occurs in the absence of symptoms, and increasing luminal stenosis is associated with presence of greater healed plaque ruptures. Currently no distinct morphological features of erosion-prone plaques have been identified and therefore it is not possible to predict which plaques are likely to induce thrombosis. In addition, prognostic significance of presence of calcified nodules remains to be elucidated, especially since they occur in highly calcified arteries. Identification of precursor lesion of acute thrombosis is a pivotal step towards reducing the morbidity and mortality of coronary artery disease, where newer imaging modalities should play a significant role.

Insights into the Natural History of Atherosclerosis Progression

Pathology of high risk atherosclerotic plaque provides the basis for understanding the imaging and treatment of atherosclerosis. The earliest vascular change described microscopically are adaptive intimal thickening and fatty streaks, whereas pathologic intimal thickening are the first of the progressive plaques subtypes. Fibroatheromas are characterized by an acellular necrotic core, accumulated cellular debris and cholesterol monohydrate, and a lack of extracellular matrix. The development of the necrotic core is believed to originate from apoptotic macrophages. Thinning of the fibrous cap leads to plaques vulnerable to rupture, or thin-cap fibroatheromas. Overlying thrombosis can arise from one of several mechanisms including ruptures, erosion, or calcified nodules. Calcium within atherosclerosis is a common imaging target which increases with lesion progression and is present in greatest frequent in healed plaque ruptures and fibrous plaques. Thin cap fibroatheromas most frequently contain speckled calcification but may show heavily calcified areas or an absence of calcification. which is not very useful in diagnosing these lesions by calcium-based imaging. Coronary lesions with thrombi in the absence of rupture (erosions) exclusively show stippled or no calcification. Rupture in the absence of calcification is rare. In contrast, diffuse calcification is almost always associated with healed ruptures.

Atherogenesis: The Development of Stable and Unstable Plaques

Cardiovascular diseases (CVDs) as reported by the World Health Organization (WHO) represent the foremost cause of death worldwide [1]. Recent estimates in 2012 indicate 17.5 million deaths from CVDs, corresponding to 31 % deaths worldwide. Of these, an estimated 7.4 million were attributed to coronary artery disease (CAD) and 6.7 million strokes, while assessments in 2000 were lower at 6 million for CAD and 5.7 million for stroke, thus indicating a substantial rise over the past decade. As society is aging, the number of CVD-related deaths is expected to increase further to 23.6 million by 2030 [2].

Preclinical Model and Histopathology Translational Medicine and Renal Denervation

The prevalence of resistant hypertension, which is defined as failure to achieve control of blood pressure (BP) (<140/90) despite treatment with optimal doses of three or more antihypertensive medications (including diuretics), is as high as 12–15 % of all hypertensive patients. Renal sympathetic denervation is a new treatment option for resistant hypertension. Catheter-radiofrequency renal denervation has demonstrated its efficacy and safety in the SYMPLICITY I, SYMPLICITY II and EnligHTN trials. However, there are still many unanswered questions in this field, and preclinical studies using animal models may help researchers and clinicians to find answers to those questions. Generally, larger animals such as pig, dog, or sheep are needed for the preclinical study. The swine model is frequently used for the preclinical study, since the anatomy of renovascular system is similar to that of humans. A semi-quantitative ordinal grading system is useful, when the changes of nerves, renal artery, and peri-arterial soft tissue induced by renal denervation are evaluated.

A Polymer-Free Drug-Eluting Stent: In Vitro and In Vivo Analysis

Drug-eluting stents (DES) have significantly improved restenosis rates as compared to bare metal stents (BMS), however, an increased risk in late stent thrombosis (LST) has been observed due to delayed healing and incomplete endothelialization. These adverse events have been associated to the high level of anti-proliferative drugs eluted from 1st generation DES, as well as non-erodible polymers that remain intact. The purpose of this study was to fist determine optimal surface modification in vitro and to then assess trends in endothelial coverage and recovery of the modified non-polymeric DES in a rabbit iliac stent model.Copyright

Coronary Disease in Women

There are pathologic and physiologic differences in coronary artery disease in women as compared to men. Hormone replacement therapy: failure of a promise? Risk factors: do they have the same impact in women as in men with coronary disease? Small vessel coronary disease plays a role in women. Plaque erosion is important in premenopausal women.