Cardiovascular DiseasesPathology

Medicine & Surgery

Bologna-University Medical School

Prof. Pier Paolo PiccalugaDepartment of Experimental, Diagnostic and Specialty Medicine

Institute of Hematology and Medical Oncology “L. and A. Seràgnoli”

Bologna University Medical School

Cardiovascular Diseases• Congenital heart diseases: principal alterations.

• Ischemic heart disease: anatomic alterations and histopathology of chronic ischemic heart disease and myocardial infarction (timing and evolution of morphologic changes, complications of myocardial infarction).

• Valvular heart disease: anatomic alterations and histopathology of rheumatic heart disease, aortic stenosis, mitral valve prolapse, infective endocarditis, non-bacterial thrombotic endocarditis.

• Myocardial diseases: anatomic alterations and histopathology of myocarditis and cardiomyopathies.

• Pericardial diseases: anatomic alterations and histopathology of pericarditis.

• Blood vessel diseases: anatomic alterations and histopathology of arteriosclerosis, atherosclerosis, aneurysms and vasculitis.

• Vascular tumors: classification and histopathological diagnosis.

Arteriosclerosis

Arteriosclerosis

• Arteriolosclerosis affects small arteries and arterioles. The two anatomic variants, hyaline and hyperplastic, are both associated with vessel wall thickening and luminal narrowing that may cause downstream ischemic injury. Arteriolosclerosis is most often associated with hypertension and/or diabetes mellitus

Arteriosclerosis

• Mönckeberg medial calcific sclerosis is characterized by calcific deposits in muscular arteries, typically in persons older than age 50.

• The radiographically visible, often palpable calcifications, do not encroach on the vessel lumen and are usually not clinically significant.

Atherosclerosis

• From Greek root words for "gruel" and "hardening," is the most frequent and clinically important pattern of arteriosclerosis

• Atherosclerosis is characterized by intimal lesions called atheromas (also called atheromatous or atherosclerotic plaques), that protrude into vascular lumina.

Risk factors

• Multiple risk factors have a multiplicative effect; two risk factors increase the risk approximately fourfold. When three risk factors are present (e.g., hyperlipidemia, hypertension, and smoking), the rate of myocardial infarction is increased seven times

Risk factors

Major Risks Lesser, Uncertain, or Nonquantitated Risks

Nonmodifiable Obsesity

Increasing age Physical inactivity

Male gender Stress ("type A personality)

Family history Postmenopausal estrogen deficiency

Genetic abnormalities High carbohydrate intake

Lipoprotein(a)

Potentially Controllable Hardened (trans)unsaturated fat intake

Hyperlipidemia

Hypertension Chlamydia pneumoniae infection

Cigarette smoking

Diabetes

C-reactive protein

Pathogenesis

• The contemporary view of atherogenesis is expressed by the response-to-injury hypothesis.

• This model views atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury.

• Lesion progression occurs through interactions of modified lipoproteins, monocyte-derived macrophages, T lymphocytes, and the normal cellular constituents of the arterial wall

Pathogenesis

• Chronic endothelial injury,with resultant endothelialdysfunction, causing(among other things) increased permeability, leukocyte adhesion, and thrombosis

• Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall

Pathogenesis

• Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophagesand foam cells

• Platelet adhesion factor releasefrom activated platelets, macrophages, and vascular wall cells, inducing SMC recruitment,either from the media or from circulating precursors

Pathogenesis

• SMC proliferation and ECM production

• Lipid accumulation both extracellularlyand within cells (macrophages and SMCs)

• The accumulation of lipid-containing macrophages in the initima gives rise to "fatty streaks"

• With further evolution, a fibrofatty atheroma consisting of proliferated SMC, foam cells, extracellular lipid, and ECM is formed

Pathogenesis

Morphology - Fatty Streaks

• Fatty streaks are composed of lipid-filled foam cells but are not significantly raised and thus do not cause any disturbance in blood flow.

• They begin as multiple minute yellow, flat spots that can coalesce into elongated streaks, 1 cm long or longer.

• Fatty streaks can appear in the aortas of infants younger than 1 year and are present in virtually all children older than 10 years, regardless of geography, race, sex, or environment.

Morphology - Fatty Streaks

• Coronary fatty streaks begin to form in adolescence, at the same anatomic sites that later tend to develop plaques. The relationship of fatty streaks to atherosclerotic plaques is uncertain; although they may evolve into precursors of plaques, not all fatty streaks are destined to become advanced atherosclerotic lesions.

Morphology - Atherosclerotic Plaque

• The key processes in atherosclerosis are intimal thickening and lipid accumulation.

• Atheromatous plaques (also called fibrous or fibrofatty plaques) impinge on the lumen of the artery and grossly appear white to yellow;

• thrombosis superimposed over the surface of ulcerated plaques is red-brown in color.

• Plaques vary from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses

Morphology - Atherosclerotic Plaque

• Atherosclerotic lesions are patchy, usually involving only a portion of any given arterial wall.

• On cross-section, the lesions therefore appear "eccentric"

• The focality of atherosclerotic lesions-despite the uniform exposure of vessel walls to insults is due to the vagaries of vascular hemodynamics.

Lesions distribution

The most extensively involved vessels are

• lower abdominal aorta,

• the coronary arteries,

• the popliteal arteries,

• the internal carotid arteries,

• Vessels of the circle of Willis.

• Vessels of the upper extremities are usually spared, as are the mesenteric and renal arteries, except at their ostia.

• The severity of atherosclerosis in one artery does not predict its severity in another. Moreover, in any given vessel, lesions at various stages often coexist.

Morphology

Atherosclerotic plaques have three principal components:

(1) cells, including SMCs, macrophages, and T cells;

(2) ECM, including collagen, elastic fibers, and proteoglycans; and

(3) intracellular and extracellular lipid

• These components occur in varying proportions and configurations in different lesions.

Morphology

• Typically, the superficial fibrous cap is composed of SMCs and relatively dense collagen.

• Beneath and to the side of the cap (the "shoulder") is a more cellular area containing macrophages, T cells, and SMCs.

• Deep to the fibrous cap is a necrotic core, containing lipid (primarily cholesterol and cholesterol esters), debris from dead cells, foam cells (lipid-laden macrophages and SMCs), fibrin, variably organized thrombus, and other plasma proteins;

Morphology

• The cholesterol content is frequently present as crystalline aggregates that are washed out during routine tissue processing and leave behind only empty "clefts."

• At the periphery of the lesions, there is usually neovascularization (proliferating small blood vessels).

• Typical atheromas contain relatively abundant lipid, but some plaques ("fibrous plaques") are composed almost exclusively of SMCs and fibrous tissue.

Pathologic changes of atheromas

• Rupture, ulceration, or erosion of the luminal surface of atheromatous plaques exposes the bloodstream to highly thrombogenic substances and induces thrombus formation.

• If the patient survives the initial vascular occlusion, thrombi may become organized and incorporated into the growing plaque.

• Hemorrhage into a plaque. Rupture of the overlying fibrous cap or of the thin-walled vessels in the areas of neovascularization can cause intra-plaque hemorrhage; a contained hematoma may expand the plaque or induce plaque rupture.

Rupture and thrombosis

Pathologic changes of atheromas

• Atheroembolism. Plaque rupture can discharge debris into the bloodstream, producing microemboli composed of plaque contents.

• Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes weakness of the vessel wall and development of aneurysms that may rupture.

Natural history

Vascular Pathology in Hypertension

Vascular Pathology in Hypertension

1. Accelerating atherogenesis,

2. Hypertension-associated degenerative changes in the walls of large and medium arteries can potentiate both aorticdissection and cerebrovascularhemorrhage.

3. Hypertension is also associated with twoforms of small blood vessel disease: hyalinearteriolosclerosis and hyperplasticarteriolosclerosis

Hyaline Arteriolosclerosis

• This vascular lesion consists of a homogeneous pink hyaline thickening of the walls of arterioles with loss of underlying structural detail and with narrowing of the lumen

• Frequent in elderly patients, whether normotensive or hypertensive,

• More generalized and more severe in patients with hypertension.

• Common as part of the characteristic microangiography in diabetes

Hyaline Arteriolosclerosis

• Hyaline arteriolosclerosis is a major morphologic characteristic of benign nephrosclerosis, in which the arteriolar narrowing causes diffuse impairment of renal blood supply, with loss of nephrons

• The lesions reflect leakage of plasma components across vascular endothelium and excessive ECM production by SMCs secondary to the chronic hemodynamic stress of hypertension.

Hyperplastic Arteriolosclerosis

• Related to more acute or severe elevations of blood pressure, hyperplastic arteriolosclerosis is characteristic of (but not limited to) malignant hypertension

Diastolic pressures over 120 mm Hg

associated with acute cerebral

and/or renal injury

• Hyperplastic arteriolosclerosis is associated with "onion-skin," concentric, laminated thickening of the walls of arterioles with luminal narrowing

Hyperplastic Arteriolosclerosis

• The laminations consist of SMCs and thickened, duplicated basement membrane.

• In malignant hypertension, these hyperplastic changes are accompanied by

fibrinoid deposits and vessel wall necrosis (necrotizing arteriolitis), particularly prominent in the kidney

ANEURYSMS AND DISSECTIONS

Aneurysms

• An aneurysm is a localized abnormal dilation of a blood vessel or the heart.

• When an aneurysm involves all three layers of the arterial wall (intima, media, and adventitia) or the attenuated wall of the heart, it is called a "true" aneurysm

Aneurysms

• False aneurysm (pseudoaneurysm) is a breach in the vascular wall leading to an extravascular hematoma that freely communicates with the intravascular space ("pulsating hematoma").

Aneurysms

• Examples include ventricular ruptures after myocardial infarctions that are contained by a pericardial adhesion, or a leak at the junction of a vascular graft with a natural artery.

Arterial Dissection• Arises when blood enters the wall of the artery,

as a hematoma dissecting between its layers. Dissections are often but not always aneurysmal.

• Both true and false aneurysms as well as dissections can rupture, often with catastrophic consequences

Aneurysms Classification

• Based on macroscopic shape and size

• Saccular aneurysms are essentially spherical outpouchings

– involve only a portion of the vessel wall

– they vary from 5 to 20 cm in diameter

– often contain thrombi.

• Fusiform aneurysms involve diffuse, circumferential dilation of a long vascular segment;

– they vary in diameter (≤20 cm) and in length

– can involve extensive portions of the aortic arch, abdominal aorta, or even the iliacs.

Ethiology

• The two most important causes of aortic aneurysms are atherosclerosis and cystic medial degeneration of the arterial media.

• Other causes that weaken vessel walls and lead to aneurysms include

– trauma,

– congenital defects (e.g., berry aneurysms),

– infections (mycotic aneurysms) → syphilis.

– Arterial aneurysms can also be caused by systemic diseases, such as vasculitis

Infectious Aneurysms

• Infection of a major artery that weakens its wall is called a mycotic aneurysm;

• Mycotic aneurysms can originate:

(1) from embolization of a septic thrombus, usually as a complication of infective endocarditis;

(2) as an extension of an adjacent suppurative process;

(3) by circulating organisms directly infecting the arterial wall

• Thrombosis and rupture are possible complications

Abdominal Aortic Aneurysm

• Atherosclerosis causes thinning and weakening of the media secondary to intimal plaques.

• Such plaques compress the underlying media and also compromise nutrient and waste diffusion from the vascular lumen into the arterial wall.

• The media consequently undergoes degeneration and necrosis, thus allowing the dilation of the vessel.

Abdominal Aortic Aneurysm

• Atherosclerotic aneurysms occur most frequently in the abdominal aorta (AAA)

• Common iliac arteries,

• Aortic arch,

• Descending parts of the thoracic aorta

AAA Pathogenesis

• More frequent in men

• Rarely develops before age 50.

• Atherosclerosis is a major cause of AAA,

– clearly other contributors, since the incidence is less than 5% in men older than 60 years, despite almost universal abdominal aortic atherosclerosis in that population.

• There can be a familial predisposition independent of atherosclerosis or hypertension.

• Hereditary defects in structural components of the aorta can produce aneurysms (e.g., defective fibrillin production in Marfan disease affects elastic tissue synthesis)

AAA Pathogenesis

Local inflammatory infiltrates:

• Altered balance of collagen degradation and synthesis

• Production of destructive proteolytic enzymes

• Thus, abnormal collagen or elastic tissue-or inadequate remodeling of these ECM components-provide a background on which atherosclerosis or hypertension weaken the aortic wall.

AAA Pathogenesis

• Matrix metalloproteinases (MMPs) have been increasingly implicated in AAA development (>> macrophage production).

• Expressed in AAA at elevated levels compared with the normal vessel wall;

• Capacity to degrade virtually all components of the ECM in the arterial wall (collagens, elastin, proteoglycans, laminin, fibronectin).

• Concurrently, decreased level of tissue inhibitor of metalloproteinases (TIMP) can also contribute to overall ECM degradation

AAA Pathogenesis - Summary

Genetic contribution:

Quality of connective tissue

MMP and TIMP SNPs

Skewing to Th2

Morphology

• Usually positioned below the renal arteries and above the bifurcation of the aorta,

• AAA can be saccular or fusiform,

• As large as 15 cm in diameter, and as long as 25 cm.

• There is severe complicated atherosclerosis with destruction and thinning of the underlying aortic media;

• Frequently contains a bland, laminated, poorly organized mural thrombus

Morphology

Morphology

• Occasionally, the aneurysm can affect the renal and superior or inferior mesenteric arteries,

– direct pressure

– mural thrombi.

• Not infrequently, AAA is accompanied by smaller aneurysms of the iliac arteries

Morphology

• Inflammatory AAAs are characterized by dense periaortic fibrosis containing abundant lymphoplasmacytic infiltrate with many macrophages and often giant cells

• Cause??

Morphology

• Mycotic AAAs are atherosclerotic lesions infected by lodging of circulating microorganisms in the wall, particularly in the setting of bacteremia from a primary Salmonella gastroenteritis.

• In such cases, suppuration further destroys the media

– rapid dilation and rupture.

Aspergillus mycotic aneurism

Syphilitic Aneurysm

• The obliterative endarteritis(tertiary stage) can involve small vessels in any part of the body.

• Involvement of the vasa vasorum of the aorta is particularly devastating;

– ischemic medial injury,

– aneurysmal dilation of the aorta and aortic and aortic annulus,

– eventually valvular insufficiency.

– Currently rare complication in the U.S. and Western Europe

Syphilitic Aneurysm

• Obliterative endarteritis

– vasa vasorum, in the aortic adventitia.

– luminal narrowing and obliteration,

– scarring of the vessel wall,

– a dense surrounding rim of lymphocytes and plasma cells that may extend into the media (syphilitic aortitis).

– The spirochetes are difficult to demonstrate in tissues

Syphilitic Aneurysm

• Ischemic injury of the aortic media,

• Patchy loss of the medial elastic fibers and muscle cells,

• Inflammation and scarring.

• Favor superimposed atherosclerosis of the aortic root,

• With weakening of the aortic root, the valvular annulus becomes dilated, resulting in valvular insufficiency and massive volume overload hypertrophy of the left ventricle. "cor bovinum"

Aortic Dissection

• Aortic dissection is a catastrophic event whereby blood splays apart the laminar planes of the media to form a blood-filled channel within the aortic wall

• This channel often ruptures through the adventitia and into various spaces, where it causes either massive hemorrhage or cardiac tamponade (hemorrhage into the pericardial sac).

• Aortic dissection may or may not be associated with aortic dilation.

• Principally in two epidemiologic groups:

(1) men aged 40 to 60 years, with antecedent hypertension (more than 90% of cases of dissection),

(2) younger patients with systemic or localized abnormalities of connective tissue affecting the aorta (e.g., Marfan syndrome)

• Dissections can also be iatrogenic (e.g., complicating arterial cannulations during diagnostic catheterization or cardiopulmonary bypass).

Clinical classification

• The most serious complications occur with dissections that involve the aorta from the aortic valve to the arch.

• Proximal lesions (type A dissections), involving either the ascending aorta only or both the ascending and descending aorta (more common and dangerous)

• Distal lesions not involving the ascending part and usually beginning distal to the subclavian artery (Type B)

Pathogenesis

Hypertension

• Aortas show medial hypertrophy of the vasa vasorum

• ECM degenerative changes

• Variable loss of medial SMCs,

→ pressure-related mechanical injury and/or ischemic injury (due to diminished flow through the vasa vasorum) is somehow contributory.

Morphology

• Intimal tear marking the point of origin of the dissection is found in the ascending aorta, usually within 10 cm of the aortic valve (A)

• Such tears are usually transverse or oblique and 1 to 5 cm in length, with sharp, jagged edges.

Morphology

• The dissection can extend along the aorta

• The dissecting hematoma spreads characteristically along the laminar planes of the aorta, usually approximately between the middle and outer thirds (B).

• If ruptures out through the adventitia: hemorrhage

Morphology

• Variable nonspecific changes in aortic wall histology ranging from mild fragmentation of elastic tissue (most commonly) to overt CMD (>> Marphan).

• CMD is characterized by elastic tissue fragmentation and separation of the elastic and SMC elements of the media by cystic spaces filled with the amorphous proteoglycan-rich ECM.

• Inflammation is characteristically absent.

NormalFragmented

Vasculitis

• Vessels of any type in virtually any organ can be affected;

• Most forms can affect all small vessels from arterioles to

capillary to venules;

• Several of them tend to affect only vessels of particular

caliber or tissue beds.

Vasculitis

• Many forms of vasculitis are recognized and grouped by:

– vessel size,

– role of immune complexes,

– presence of specific autoantibodies,

– granuloma formation,

– organ tropism,

– population demographics.

• There is considerable clinical and pathologic overlap among many of these disorders.

Vasculitis

Pathogenesis

• Two most common pathogenic mechanisms

1. immune-mediated inflammation

2. direct invasion of vascular walls by infectious pathogens.

– infections can also indirectly induce a noninfectious vasculitis (eg generating immune complexes or triggering cross-reactivity).

• Physical and chemical injury, such as from irradiation, mechanical trauma, and toxins, can also cause vasculitis

Non-infectious Vasculitis

• The main immunologic mechanisms thatinitiate noninfectious vasculitis are

(1) immune complex deposition,

(2) antineutrophil cytoplasmic antibodies(ANCAs),

(3) anti-endothelial cell antibodies

Giant-Cell (Temporal) Arteritis

• Most common

• Chronic, typically granulomatous inflammation of large to small-sized arteries;

• Principally affects the arteries in the head-especially the temporal arteries-but also the vertebral and ophthalmic arteries, as well as the aorta (giant-cell aortitis).

– Ophthalmic artery involvement can lead to sudden and permanent blindness.

Pathogenesis

• The cause remains elusive;

• Most evidences supports a T cell-mediated immune response to an unknown, possibly vessel wall, antigen.

– Granulomatous response with associated helper T cells,

– Correlation with certain major histocompatibility complex (MHC) class II haplotypes,

– Therapeutic response to steroids.

Morphology

• Nodular intimal thickening

– reduction of the lumen

– occasional thrombosis.

• Granulomatous inflammation within the inner media centered on the internal elastic membrane;

• CD4+ / macrophage infiltrate, with multinucleated giant cells, and fragmentation of the internal elastic lamina

• Inflammatory lesions are not continuous along the vessel

• The healed stage is marked by collagenous thickening of the vessel wall

Takayasu Arteritis

• Granulomatous vasculitis of medium and larger arteries

• Ocular disturbances and marked weakening of the pulses in the upper extremities (pulseless disease).

• Transmural fibrous thickening of the aorta and great vessels-with severe luminal narrowing of the major branch vessels

• Most frequently in women younger than 40 years of age

Morphology (Gross)

• Aortic arch

• 30% of cases also other aorta and its branches; – pulmonary arteries are involved in 50% of

patients.

• Gross changes include intimal hyperplasia and irregular thickening of the vessel wall; when the aortic arch is involved, the origin for the great vessels can be markedly narrowed or even obliterated – Such narrowing explains the weakness of the

peripheral pulses;

• Coronary and renal arteries may be similarly affected.

Morphology (Micro)

• Adventitial mononuclear infiltrates with perivascular cuffing of the vasa vasorum,

• Intense mononuclear inflammation in the media,

• Granulomatous inflammation, replete with giant cells and patchy medial necrosis. – The histology may be indistinguishable from

temporal arteritis → age and clinics

• Advanced stages: Collagenous scarring, with admixed chronic inflammatory infiltrates, occurs in all three layers of the vessel wall.

Polyarteritis Nodosa

• Polyarteritis nodosa (PAN) is a systemic vasculitis of small or medium-sized muscular arteries (but not arterioles, capillaries, or venules), typically involving renal and visceral vessels but sparing the pulmonary circulation

Morphology

• Segmental transmural necrotizing inflammation of small to medium-sized arteries.

• Lesions usually involve only part of the vessel circumference, (>> branch points).

• Aneurysms or even rupture. Impaired perfusion with ulcerations, infarcts, ischemic atrophy, or hemorrhages in the distribution of affected vessels may be the first sign of disease.

Morphology

• Acute phase: transmural inflammation of the arterial wall with a mixed infiltrate of neutrophils, eosinophils, and mononuclear cells, frequently accompanied by fibrinoid necrosis

• Luminal thrombosis can occur.

• Late: Fibrous thickening of the vessel wall that can extend into the adventitia.

• All stages of activity (from early to late) may coexist

Wegener Granulomatosis

• WG is a necrotizing vasculitis characterized by

1. Acute necrotizing granulomas of the upperrespiratory tract (ear, nose, sinuses, throat) or the lower respiratory tract (lung) or both

2. Necrosis

3. Vasculitis affecting small to medium-sized vessels(e.g., capillaries, venules, arterioles, and arteries), most prominent in the lungs and upper airwaysbut affecting other sites as well

– Renal disease in the form of focal necrotizing, oftencrescentic, glomerulonephritis

• cANCA 95% of cases

Morphology

• From inflammatory sinusitis with mucosal granulomas

• To ulcerative lesions of the nose, palate, or pharynx, rimmed by granulomas with geographic patternsof central necrosis and accompanyingvasculitis

geographic

patterns of

necrosis

Morphology

• The necrotizing granulomas are surrounded by a zone of fibroblasticproliferation with giant cells and leukocyte infiltrate,

• Multiple granulomata can coalesce to produce radiographically visiblenodules that can also cavitate;

• Late-stage disease may be marked by extensive necrotizing granulomatousinvolvement of the parenchyma and alveolar hemorrhage.

• Lesions may ultimately undergoprogressive fibrosis and organization

Prof. Pier Paolo Piccaluga

Department of Experimental, Diagnostic and Specialty Medicine

Institute of Hematology and Medical Oncology “L. and A. Seràgnoli”Bologna University Medical School

Pierpaolo.Piccaluga@unibo.it

051-2144043

www.unibo.it