In the first stage of the atherosclerotic disease, an abnormal constellation of plasma lipoproteins, carrying an excess of cholesterol, penetrate sites with minute endothelial damages due to high shear stress in the arterial tree. The lipid deposits in the intima (fatty streaks) then start a plethora of reactions aimed at modifying (by oxidation), retaining or removing the lipids. Now the inflammatory orchestra enters the stage with all its members such as monocytes, macrophages,¹ T-helper cells, cytotoxic T cells, regulatory T cells, natural killer T cells,² dendritic cells,³ cytokines, and differentiation factors. Even B-cells have been implicated, although more at a distance than in the plaques. The studies on the roles of these inflammatory components have been marred by the variability between species and also by the changing phenotypes of certain cells with different cytokine environments.¹ Platelets are also involved relatively early and become activated, release platelet-derived growth factor and transforming growth factor β, resulting in proliferation of smooth muscle cells, and they interact with the inflammatory process. The coagulation cascade is participating with thrombin generation that can be beneficial for tissue repair but also stimulate more inflammation. Early thrombin formation occurs at the site of small endothelial denudations that uncover lipid laden foam cells.

A protective fibrous cap over the plaque is generated via several mechanisms, including platelet-induced collagen synthesis, smooth muscle cell migration, and inhibited fibrinolysis by locally deposited plasminogen activator inhibitor type 1.

When the overloaded atherosclerotic plaque has reached a certain size, large endothelial denudations, perhaps due to apoptosis, or fractures of the fibrous cap can occur; thrombi form and may then occlude the artery resulting in infarction. A detailed description of the pathophysiologic process rather than this simplified summary will meet the reader in Chapter 89. It is interesting to note that the large number of participants in this disease process challenges us to find new and very different therapeutic options to complement the antithrombotic agents.

Atherosclerosis in large vessels is the etiology for only 20% of ischemic stroke in the Western world⁴ and more commonly in Southeast Asia. Cardioembolism accounts for about 30% of the ischemic strokes,⁴ and of those, only a small and rather questionable percentage of events are due to paradoxical embolism from true venous vessels. It has been difficult to establish the causal relationship between an often small patent foramen ovale and ischemic stroke.⁵

The focus has instead been on the intracardiac clot formation, most commonly in the left atrial appendix, sometimes in the left ventricle and rarely on the mitral valve or from an atrial myxoma. Atrial fibrillation has been strongly associated with the generation of left atrial clots, typically ascribed to stasis and accounting for 25% of ischemic strokes in the Western world.⁶ In addition to stasis as the etiologic factor, there have been many speculations that other mechanisms are involved in the atrial clot formation. Thrombophilic abnormalities have usually demonstrated an association with stroke in small studies, but whenever large studies or meta-analyses were performed, the results became negative or contradictory. The role of an inflammatory component or the lack of atrial boost with resulting cerebral hypoperfusion is even more speculative.⁶ More details on the etiology and risk factors for stroke are provided in Chapter 91.

After excluding atherosclerotic or cardioembolic origin for ischemic stroke, we remain with the lacunar infarcts due to cerebral microangiopathic disease and a number of rare conditions as well as a proportion of cases with unexplained origin. The size of this residual proportion depends on how well the patient has been investigated.

The pathogenesis of fibromuscular degeneration is still an enigma, but there is no atherosclerosis or inflammation in the lesions. The most common form is medial fibroplasia, which has predominance in women of 20 to 60 years of age.⁷ Hence, female hormones might play a pathogenetic role. Fibromuscular degeneration is responsible for 5% to 10% of cases with renal artery stenosis, as described in Chapter 95, and it appears to have an asymptomatic prevalence of 2% in the general Western population.⁸ The second most common location is the coronary artery, but the pathology has been reported in almost every artery in
the body. The clinical picture corresponds to the affected site: renal artery—hypertension; coronary artery—angina; carotid or vertebral artery—transient ischemic attacks (TIAs), stroke, or dissection.

The heterogeneous groups of vasculitides reflect the diversity of the immune system with a large variety of clinicopathologic pictures. The diseases can be classified as large, medium-sized, or small-vessel vasculitis, and important members are giant cell arteritis, Takayasu arteritis, rheumatoid vasculitis, IgG4-related aortitis, polyarteritis nodosa, Kawasaki disease, Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, Henoch-Schönlein purpura, cryoglobulinemic vasculitis, druginduced vasculitis, infection-related vasculitis, systemic lupus erythematosus-related vasculitis, Behçet disease, and Cogan syndrome. The pathology includes granulomatous—sometimes caseating, giant cell, necrotizing, lymphoplasmacytic, leukocytoclastic, neutrophilic (with microabscesses), eosinophilic, aneurysmatic, and/or arteriovenous shunting components. The vasculitides are described outside of this section in Chapter 100.