DISEASES OF THE DISEASES OF THE CARDIAC-VASCULAR CARDIAC-VASCULAR

SYSTEMSYSTEMLecture on pathomorphology Lecture on pathomorphology

for the 3-rd year students for the 3-rd year students by V. Vasylykby V. Vasylyk

AtherosclerosisAtherosclerosis Atherosclerosis is a chronic Atherosclerosis is a chronic

disease affecting primarily the disease affecting primarily the intima of large and medium-intima of large and medium-sized muscular arteries and sized muscular arteries and characterized by fibro-fatty characterized by fibro-fatty plaques or atheromasplaques or atheromas

The major background The major background factorsfactors

AgeAge SexSex Genetic factors (familial hypercholesteronemia)Genetic factors (familial hypercholesteronemia) Geographic factorsGeographic factors DietDiet HypertensionHypertension Metabolic diseases: Metabolic diseases: diabetes mellitus,diabetes mellitus, myxedema, myxedema,

nephrosis, xanthomatosisnephrosis, xanthomatosis Cigarette smokingCigarette smoking Lack of physical exercise.Lack of physical exercise. Other risk factors (such asOther risk factors (such as obesity, hyperglycemia, obesity, hyperglycemia,

stress, coffee consumption)stress, coffee consumption)

A. Endothelial injury is accompanied by the attachment of monocytes, platelets, and thrombus formation.

B. Macrophages in the intima phagocytise lipid and transform into foam cells. Macrophages also secrete growth factors that stimulate the proliferation of smooth muscle cells.

C. Ruptured atheromas release thrombogenic material into the circulation, causing thrombus for intimal ulceration.

Pathogenesis of Atherosclerosis

Microscopical stages of Microscopical stages of atherosclerosisatherosclerosis

Pre-lipid stage Pre-lipid stage Stage of fatty stripes Stage of fatty stripes Stage of liposclerosis Stage of liposclerosis Stage of atheromatosis Stage of atheromatosis Stage of ulceration Stage of ulceration Stage of atherocalcinosis Stage of atherocalcinosis

The pale yellow lipid streaks in the aorta are the earliest lesion of atherosclerosis.

Early lesions of atherosclerosis

Accumulations of fat in intima. Intimal plaque composed of foamy cells and proliferated smooth muscle cells

Many foam cells (macrophages and proliferated smooth muscle cells full of lipid material) and a cholesterol cleft are recognized by their typical needle-shaped appearance.

Progressing phase

This is severe atherosclerosis of the aorta in which the atheromatous plaques have undergone ulceration along with formation of overlying mural thrombus.

Late ulcerative stage

There is a severe degree of narrowing in this coronary artery. It is "complex" in that there is a large area of calcification. Complex atheroma have calcification, thrombosis, or hemorrhage. Such calcification would make coronary angioplasty difficult.

Clinical-morphological Clinical-morphological appearencesappearences

Atherosclerosis of aortaAtherosclerosis of aorta Atherosclerosis of coronary arteries Atherosclerosis of coronary arteries

of heartof heart Atherosclerosis of cerebral arteriesAtherosclerosis of cerebral arteries Atherosclerosis of renal arteriesAtherosclerosis of renal arteries Atherosclerosis of mesenteric Atherosclerosis of mesenteric

arteriesarteries Atherosclerosis of femoral arteriesAtherosclerosis of femoral arteries

Atherosclerosis of aortaAtherosclerosis of aorta

Here, the dissection went into the muscular wall.

Atherosclerosis may weaken the wall of the aorta such that it bulges out to form an aneurysm. An atherosclerotic aortic aneurysm typically occurs in the abdominal portion below the renal arteries. Aortic aneurysms that get bigger than 6 or 7 cm are likely to rupture.

This is the gross appearance of severe coronary atherosclerosis, which involves virtually 100% of the surface of the coronary. There is extensive calcification, especially at the right where the lumen is narrowed.

Atherosclerosis of coronary Atherosclerosis of coronary arteriesarteries

Here is a coronary artery with atherosclerotic plaques. There is hemorrhage into the plaque. This is one of the complications of atherosclerosis. Such hemorrhage could acutely narrow the lumen.

An acute cerebral infarct is seen here. Such infarcts are typically the result of arterial thrombosis.

AtherosclerosisAtherosclerosis of cerebral arteriesof cerebral arteries

Atherosclerosis with thrombus of the internal carotid artery is seen here.

Atherosclerosis of renal arteries

Atherosclerosis of renal artery can lead to renal infarction or to development of scars or atrophy of kidney

Atherosclerosis of mesenteric arteriesAtherosclerosis of mesenteric arteries

Hemorrhagic infarct and gangreneof small intestine

This is gangrene of the lower extremity ( "dry" and "wet" gangrene) due to loss of blood supply. Gangrenous necrosis involves the tissues of a body part. Because multiple tissues are non-viable, amputation of such areas is necessary.

Atherosclerosis of femoral arteriesAtherosclerosis of femoral arteries

Clinical effectsClinical effects ( (AtherosclerosisAtherosclerosis)) Slow luminal narrowing causing ischemia Slow luminal narrowing causing ischemia

and atrophyand atrophy Sudden luminal occlusion causing infarction Sudden luminal occlusion causing infarction Propagation of plaque by formation of Propagation of plaque by formation of

thrombi and embolithrombi and emboli Formation of aneurism and eventual ruptureFormation of aneurism and eventual rupture

HypertensionHypertension

Arterial hypertension is Arterial hypertension is defined clinically as defined clinically as borderline when it borderline when it riches 140/90 mm Hg riches 140/90 mm Hg and hypertensive when and hypertensive when 165/95 mm Hg.165/95 mm Hg.

Hypertension is classifiedHypertension is classified into two types into two types

1) Primary or essential hypertension in which the cause of 1) Primary or essential hypertension in which the cause of increase in blood pressure in unknown. This hypertension increase in blood pressure in unknown. This hypertension constitutes about constitutes about 90-95% 90-95% patients of hypertension.patients of hypertension.

2) Secondary hypertension, in which the increase in blood 2) Secondary hypertension, in which the increase in blood pressure is caused by diseases of the, kidneys, endocrine pressure is caused by diseases of the, kidneys, endocrine or some other organs.or some other organs.

According to the clinical course, both typesAccording to the clinical course, both types of hypertension may be benign or malignant. of hypertension may be benign or malignant.

Benign hypertension is moderate elevation of blood Benign hypertension is moderate elevation of blood pressure and the rise is slow as the years pass. About 90% pressure and the rise is slow as the years pass. About 90% patients of hypertension have benign disease.patients of hypertension have benign disease.

Malignant hypertension, is marked and rapid increase of Malignant hypertension, is marked and rapid increase of blood pressure to 200/140 mm Hg or more and the patients blood pressure to 200/140 mm Hg or more and the patients have hemorrhages and hypertensive encephalopathy.have hemorrhages and hypertensive encephalopathy.

Background factors to essential Background factors to essential hypertensionhypertension

genetic factors genetic factors environmental factors including salt intake, obesity, skilled environmental factors including salt intake, obesity, skilled

occupation, higher living standards and patients in high stressoccupation, higher living standards and patients in high stress ageage sex sex atherosclerosis atherosclerosis

The pathogenetic mechanisms are:The pathogenetic mechanisms are: 1) high plasma level of catecholamines;1) high plasma level of catecholamines; 2) increase in blood volume, i.e. arterial overfilling (volume 2) increase in blood volume, i.e. arterial overfilling (volume

hypertension) and arteriolar constriction (vasoconstrictor hypertension) and arteriolar constriction (vasoconstrictor hypertension);hypertension);

3) increased cardiac output;3) increased cardiac output; 4) low-renin essential hypertension found in approximately 20% 4) low-renin essential hypertension found in approximately 20%

patients due to decreased responsiveness to renin release;patients due to decreased responsiveness to renin release; 5) high renin essential hypertension due to decreased adrenal 5) high renin essential hypertension due to decreased adrenal

responsiveness to angiotensin 2responsiveness to angiotensin 2

Classification depending on stage of Classification depending on stage of hypertensive disease.hypertensive disease.

Subclinical stage occurs by hypertrophy of Subclinical stage occurs by hypertrophy of muscular layer and elastic structures of muscular layer and elastic structures of arterioles and small-sized arteries, spasm of arterioles and small-sized arteries, spasm of arterioles.arterioles.

The stage of general changes of arteries The stage of general changes of arteries begins as arterial pressure increases. begins as arterial pressure increases.

The stage of secondary changes of organs.The stage of secondary changes of organs.

Morphological changesMorphological changes– Hypertrophy of muscular layer and elastic Hypertrophy of muscular layer and elastic

structures of arterioles and small-sized arteries, structures of arterioles and small-sized arteries, spasm of arterioles.spasm of arterioles.

– Small muscular arteries show segmental Small muscular arteries show segmental dilatation as a result of necrosis of smooth dilatation as a result of necrosis of smooth muscle cells.muscle cells.

– Fibrinoid necrosis.It is the combination of cell Fibrinoid necrosis.It is the combination of cell necrosis and deposition of plasma proteins in the necrosis and deposition of plasma proteins in the vessel wall.vessel wall.

– Proliferation and a striking increase in the Proliferation and a striking increase in the number of layers of smooth muscle cells, so-number of layers of smooth muscle cells, so-called called onion-skinonion-skin appearance. appearance.

– Arteriosclerosis, elastofibrosis and hylinosis.Arteriosclerosis, elastofibrosis and hylinosis.– Circular atherosclerosis.Circular atherosclerosis.

The main clinical-morphological The main clinical-morphological types of essential hypertensiontypes of essential hypertension

Cardiac typeCardiac type Cerebral typeCerebral type Renal typeRenal type

Hypertrophy of the myocardium occurs. Weight of heart reaches 1 kg, thickness of left ventricle walls is up to 3 cm. Heart is called “cor bovinum”. Ischemic heart disease (IHD).

Cardiac type

In eccentric hypertrophy (hypertrophy and dilation), the heart is decompensated

The large hemorrhage in this adult brain arose in the basal ganglia region of a patient with hypertension. This is one cause for a "stroke".

Cerebral type

In malignant nephrosclerosis, the kidney demonstrates focal small hemorrhages. This is due to an accelerated phase of hypertension in which blood pressures are very high (such as 300/150 mm Hg).

Renal typeRenal type

Sometimes the small arteries and arterioles can be damaged so severely in malignant hypertension that they demonstrate necrosis with a pink fibrin-like quality that gives this process its name--fibrinoid necrosis.

Here is an example of renal vascular disease known as benign nephrosclerosis. The smaller arteries in the kidney have become thickened and narrowed. Hyaline arteriolosclerosis with hypertension is present. It can lead to patchy ischemic atrophy with focal loss of parenchyma that gives the surface of the kidney the characteristic granular appearance as seen here. It is called “primary shrunken kidney”.

Thickening of the arterial wall with malignant hypertension also produces a hyperplastic arteriolitis. The arteriole has an "onion skin" appearance.

The end result of many renal diseases--whether they are renal vascular diseases, glomerulonephritis, or chronic pyelonephritis--is end stage renal disease. In end stage renal disease, the kidneys are small bilaterally, as shown here. This condition is associated with chronic renal failure, and the patient's creatinine are elevated. Chronic renal failure can be treated by dialysis or by transplantation, as shown here.

The microscopic appearance of the "end stage kidney“. The cortex is fibrotic, the glomeruli are sclerotic, there are scattered chronic inflammatory cell infiltrates, and the arteries are thickened.

What is Ischemic Heart Disease?

Ischemic heart disease is caused by an imbalance between the myocardial blood flow and the metabolic demand of the myocardium. Reduction in coronary blood flow is related to progressive atherosclerosis with increasing occlusion of coronary arteries. Blood flow can be further decreased by superimposed events such as vasospasm, thrombosis, or circulatory changes leading to hypoperfusion.

•Decreased aortic diastolic pressure•Increased intraventricular pressure and myocardial contraction•Coronary artery stenosis, which can be further subdivided into the following etiologies:

•Fixed coronary stenosis•Acute plaque change (rupture, hemorrhage)•Coronary artery thrombosis•Vasoconstriction

•Aortic valve stenosis and regurgitation•Increased right atrial pressure

Factors reducing coronary blood flow

1. Angina pectoris - a symptom complex of IHD characterized by paroxysmal attacks of chest pain, usually substernal or precordial, caused by myocardial ischemia that falls short of inducing infarction. There are several patterns:•Stable angina (typical) •Variant or Prinzmetal's angina •Unstable angina•Sudden cardiac death 2. Myocardial Infarction (MI)3. Ischemic Cardiomyopathy

Patterns of Ischemic Heart Disease (IHD)

Sudden cardiac death is defined as death occurring within an hour of onset of symptoms. Such an occurrence often complicates ischemic heart disease. Such patients tend to have severe coronary atherosclerosis (>75% lumenal narrowing). Often, a complication such as coronary thrombosis or plaque hemorrhage or rupture has occurred. The mechanism of death is usually an arrhythmia.

•Occlusive intracoronary thrombus - a thrombus overlying an ulcerated or fissured stenotic plaque causes 90% of transmural acute myocardial infarctions.

•Vasospasm - with or without coronary atherosclerosis and possible association with platelet aggregation.

•Emboli - from left sided mural thrombosis, vegetative endocarditis, or paradoxic emboli from the right side of heart through a patent foramen ovale.

The pathogenesis of Myocardial Infarction (MI)

Patterns include:•Transmural infarct - involving the entire thickness of the left ventricular wall from endocardium to epicardium, usually the anterior free wall and posterior free wall and septum with extension into the RV wall in 15-30%. •Isolated infarcts of RV and right atrium are extremely rare.•Subendocardial infarct - multifocal areas of necrosis confined to the inner 1/3-1/2 of the left ventricular wall. These do not show the same evolution of changes seen in a transmural MI.

The gross appearance of a myocardial infarction can vary.

Gross morphologic changes evolve over time as follows:

Time from Onset Gross Morphologic Finding

18 - 24 Hours Pallor of myocardium

24 - 72 Hours Pallor with some hyperemia

3 - 7 Days Hyperemic border with central yellowing

10 - 21 Days Maximally yellow and soft with vascular margins

7 weeks White fibrosis

Time from

Onset Microscopic Morphologic Finding

1 - 3 Hours Wavy myocardial fibers

2 - 3 Hours Staining defect with tetrazolium or basic fuchsin dye

4 - 12 Hours

Coagulation necrosis with loss of cross striations, contraction bands, edema, hemorrhage, and early neutrophilic infiltrate

18 - 24 Hours

Continuing coagulation necrosis, pyknosis of nuclei, and marginal contraction bands

24 - 72 Hours

Total loss of nuclei and striations along with heavy neutrophilic infiltrate

3 - 7 Days

Macrophage and mononuclear infiltration begin, fibrovascular response begins

10 - 21 Days Fibrovascular response with prominent granulation tissue

7 Weeks Fibrosis

•Arrhythmias and conduction defects, with possible "sudden death"•Extension of infarction, or re-infarction•Congestive heart failure (pulmonary edema)•Cardiogenic shock•Pericarditis•Mural thrombosis, with possible embolization•Myocardial wall rupture, with possible tamponade•Papillary muscle rupture, with possible valvular insufficiency•Ventricular aneurysm formation

Complications of Myocardial Infarction

The interventricular septum of the heart has been sectioned to reveal an extensive acute myocardial infarction. The dead muscle is tan-yellow with a surrounding hyperemic border.

The earliest change histologically seen with acute myocardial infarction in the first day is contraction band necrosis. The myocardial fibers are beginning to lose cross striations and the nuclei are not clearly visible in most of the cells seen here. Note the many irregular darker pink wavy contraction bands extending across the fibers.

This high power microscopic view of the myocardium demonstrates an infarction of about 1 to 2 days in duration. The myocardial fibers have dark red contraction bands extending across them. The myocardial cell nuclei have almost all disappeared. There is beginning acute inflammation.

In this microscopic view of a recent myocardial infarction, there is extensive hemorrhage along with myocardial fiber necrosis with contraction bands and loss of nuclei.

This myocardial infarction is about 3 to 4 days old. There is an extensive acute inflammatory cell infiltrate and the myocardial fibers are so necrotic that the outlines of them are only barely visible.

This is an intermediate myocardial infarction of 1 to 2 weeks in age. Note that there are remaining normal myocardial fibers at the top. Below these fibers are many macrophages along with numerous capillaries and little collagenization.

There is pale white collagen within the interstitium between myocardial fibers. This represents an area of remote infarction.

One complication of a transmural myocardial infarction is rupture of the myocardium. This is most likely to occur in the first week between 3 to 5 days following the initial event, when the myocardium is the softest. The white arrow marks the point of rupture in this anterior-inferior myocardial infarction of the left ventricular free wall and septum. Note the dark red blood clot forming the hemopericardium. The hemopericardium can lead to tamponade.

The infarction was so extensive that, after healing, the ventricular wall was replaced by a thin band of collagen, forming an aneurysm. Such an aneurysm represents non-contractile tissue that reduces stroke volume and strains the remaining myocardium. The stasis of blood in the aneurysm predisposes to mural thrombosis.

A cross section through the heart reveals a ventricular aneurysm with a very thin wall and rupture (arrow). Note how the aneurysm bulges out.

1. There may be previous myocardial infarction (focal cardiosclerosis)

2. Severe coronary atherosclerosis involving all major branches (diffuse cardiosclerosis).

The result is an inadequate vascular supply which leads to myocyte loss, fibrosis, hypertrophy, development of aneurism.

Cardiac dilation results in overload of remaining myocytes. This keeps

the process going, with compensation by continuing myocyte hypertrophy. Eventually, the heart can no longer compensate, and cardiac failure ensues with arrhythmias and/or ischemic events.

Thus, clinically, there is slow, progressive heart failure with or without a history of a previous MI or anginal pain. Ischemic cardiomyopathy is responsible for as much as 40% of the mortality in IHD.

Ischemic Cardiomyopathy

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