List the major constitutional & modifiable risk factors for development of atherosclerosis

Constitutional

Increased age (increased risk with age beginning >40)

Male gender (and postmenopausal women)

            Family history/genetics – single gene and multifactorial

Modifiable

Hyperlipidemia/hypercholesterolemia (elevated LDL/decreased HDL)

Hypertension

Cigarette smoking

Diabetes mellitus

 Explain the pathogenesis of atherosclerosis, &the steps in the development of an atheromatous plaque

Response-to-injury hypothesis

Atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury

Steps in development of atheroma

1. Endothelial dysfunction or injury

2. Accumulation of lipoproteins (LDL and oxidized LDL) in vessel wall

3. Monocyte adhesion and migration into intima

Transformation into macrophages and foam cells

4. Platelet adhesion

5. Factor release by platelets, macrophages, vascular wall

Recruits smooth muscle cells from media and circulating precursors

6. Smooth muscle cell proliferation and ECM production

                                7. Continued lipid accumulation

   Describe the morphology of the typical atheromatous plaque

a.    Atheromatous (atherosclerotic) plaque

                                          i.    White-yellow raised eccentric lesion, may be red-brown in areas of superimposed thrombosis

                                        ii.    Patchy involvement – not circumferential

1.    Location related to local hemodynamic factors and flow disturbances

                                       iii.    Distribution

1.    Large elastic and medium muscular arteries most affected

2.    Abdominal aorta >>> thoracic aorta

3.    Coronary > popliteal > internal carotid > circle of Willis

                                       iv.    Microscopic:

1.    Varying proportions of cellular component, ECM, and lipid

2.    Superficial fibrous cap

a.    Smooth muscle cells and dense collagen

3.    Cellular area under and to side of cap

a.    Macrophages, T cells, smooth muscle cells

b.    Periphery of cap – neovascularization

4.    Necrotic core

a.    Lipid (cholesterol/cholesterol esters)

b.    Debris from dead cells

c.    Foam cells (macrophages and phenotypically altered smooth muscle cells filled with lipid)

d.    Fibrin, other plasma proteins, organized thrombus

5.    Plaques change/evolve/enlarge over time

a.    Cell death, ECM remodeling, organized thrombus

                                          6.  May undergo calcification

List and describe the types of changes that may develop in plaques

a.    Rupture, ulceration, or erosion

                                          i.    Exposes thrombogenic substances to circulating blood, leading to thrombosis

                                        ii.    May later organize and become incorporated into the evolving plaque

b.    Hemorrhage into the plaque from neovascular areas

                                          i.    Rapid expansion of plaque à occusion, or rupture of plaque

                                        ii.    Atheroembolism

                                       iii.    Aneurysm formation

1.    Pressure and ischemic atrophy weakens the underlying media with loss of elastic tissue

    Describe the pathophysiologic and clinical consequences of atherosclerosis

a.    Occlusion

                                          i.    Stenosis (slow)

1.    Initially, outward remodeling may compensate

2.    Eventually impinges

3.    Critical stenosis (usually 70%) – point where demand exceeds supply in distribution of affected vessel

a.    Angina

b.    Chronic diminished perfusion

4.    Collateral circulation may develop over time in some

                                        ii.    Acute plaque change

1.    Thrombosis, hemorrhage into plaque (more rapid)

2.    Acute tissue infarction

3.    Risk: Stability and vulnerability of the plaque is more important than % occlusion

a.    Vulnerable plaques have large areas of foam cells and extracellular lipid and thin or weak fibrous caps

b.    Embolism: distal ischemia

     Describe characteristic changes in endothelial dysfunction

a.    Endothelial dysfunction – Altered phenotype in response to injury

                                        i.    Impaired vasoreactivity

                                        ii.    Increased vascular permeability

                                       iii.    Increased leukocyte adhesion

                                       iv.    Thrombogenic surface

                                        v.    Leads to vascular pathology

      Describe the steps leading to intimal thickening

1. Endothelial dysfunction or injury (any type) stimulates smooth muscle and ECM synthesis, leading to intimal thickening

2. Healing process leads to formation of neointima

Endothelial cells migrate to the injured area

3. Smooth muscle cells and precursors migrate into intima, proliferate, and produce ECM

4. Cell proliferation ultimately ceases, but intimal thickening remains permanently

 List the three types of arteriosclerosis

a.    Arteriolosclerosis

                                          i.    Endothelial injury/dysfunction and chronic hemodynamic stress

                                        ii.    Small muscular arteries and arterioles

                                       iii.    Occurs in hypertension, also diabetes mellitus

b.    Atherosclerosis

                                          i.    Endothelial dysfunction due to risk factors and high lipid diet

                                        ii.    Development of eccentric intimal lesions

                                       iii.    Obstruction, site for thrombus formation

                                       iv.    Weakening of underlying media, predisposing to aneurysm formation

c.    Monckeberg medial sclerosis

                                          i.    Calcified medial deposits in individuals over 50

    Describe the pathogenesis and predisposing factors for aneurysms

1. Intrinsic quality of vascular wall CT is poor

     a. Marfan Syndrome: defective syn of fibrillin

     b. Ehlers Danlos syndrome

     c. Vit C def

2. Balance of collagen degradation and syn is altered by inflammation

     a. atheroslcerosis

     b. vasculitis

3. Loss of smooth muscle cells or dec syn of ECM in vessel wall

    Describe the epidemiology, pathogenesis, distribution, morphology and clinical features of abdominal aortic aneurysms

1. Associated with ATHEROSCLEROSIS

2. Distribution

      a. Below renal a. and above bifurcation

3. Clinical complications

      a. Rupture: can lead to fatal hemorrhage

      b. Obstruction: lead to ischemic injury

      c. Embolism

      d. Impingement: ie of ureter

Epidemiology

Systemic Hypertension: men >40 yo

CT Abnormalities: younger males

Pathogenesis & Morphology

Hypertension major risk factor

Narrowing of vasa vasorum: leads to cystic medial degeneration

Intimal Tear

Clinical Features:

Excruciating pain: from anterior chest radiating to Back

Rupture outwards: most common cause of death

Proximal (Type A): Ascending +/- Descending (dangerous)

Distal (Type B): Distal to subclavian artery

Older men (>50)

Granulomatous disease of medium & large arteries

Temporal a., Ophthalmic a. & Vertebral a.

Granulomatous inflammation in media w/ giant cells

Clinical Presentation

Headache or facial pain

Ocular symptoms: may lead to permanent blindness

Dx: temporal a. biopsy

Young women (<50 y; Asian)

Granulomatous disease of large arteries: involves Aortic Arch

Clinical Presentation

Fatigue, weight loss, fever

Absent or weak pulses esp. in upper extremities

Ocular disturbances

Systemic Hypertensioin

Neurologic defects, MI, Pulm HTN

Thromboangitis Obliterans

"Buerger's Disease"

Immune response to components of Tobacco

Young Smokers (35-45 yo)

Segmental vasculitis & thrombosis of small/medium sized arteries

Esp. tibial & radial arteries

Can afftect: Vein, Artery & Nerve

Thrombus contains microabscesses

Clinical Presentation

Caudication of feet, legs, hands or arms

Pain may be severe, even at rest

Ulcerations of toes, fet or fingers

Tmt: QUIT Smoking

>90% due to obstruction of coronary arteries by Atherosclerosis

The dominant cause of the IHD syndromes is insufficient coronary perfusion relative to myocardial demand, due to chronic, progressive atherosclerotic narrowing of the epicardial coronary arteries, and variable degrees of superimposed acute plaque change, thrombosis, and vasospasm

1.    Obstruction > ischemia in distribution of obstructed vessel à myocardial dysfunction > potential for myocyte death (necrosis)

2.    Outcome depends on severity and duration of flow disruption, along with presence of collateral circulation

3.    Changes in myocardium over time

a.    Seconds (reversible): Inadequate production of ATP, accumulation of lactic acid

1.    Loss of contractility within 60 seconds

2.    May lead to heart failure before actual myocyte death

b.    Minutes (still reversible): Glycogen depletion, cell swelling, other changes consistent with reversible cell injury

c.    ~20-30 minutes (irreversible): Disruption of sarcolemmal membrane integrity

1.    Intracellular macromolecules leak into circulation

2.    Measured to detect myocyte injury (see laboratory evaluation of MI below)

d.    > 1 hour: Microvascular injury

Describe the typical distribution of myocardial infarction resulting from occlusion of the LAD, LCX and RCA

a.    LAD (40-50%) – left anterior descending branch of left coronary artery

1.    Anterior LV wall near apex

2.    Anterior interventricular septum

3.    Circumferential apex

b.    RCA (30-40%) – right coronary artery

1.    Inferior/posterior LV wall

2.    Posterior interventricular septum

3.    Inferior/posterior RV free wall (some patients)

c.    LCX (15-20%) – left circumflex branch of left coronary artery

                         LV lateral wall except apex

   Describe the major gross and microscopic features of myocardial infarction over time, and modification of these features by reperfusion.

Post Infarct             Gross Findings                Microscopic Findings

0-30min                     none                                none

1-2 hr                       none                        few wavy fibers

4-12hr           occassional mottling         early coag., necrosis,

                                                        Contraction Bands

18-24hr         mottling, pale                 Coag. necrosis, early

                                                       neutrophil infiltrate

24-72 hr            pallor                     complete coag., heavy

                                                     neutrophilic inflitrate

4-7 days       hyperemc border         disintegration of myocytes,

                  yellow soft center          early phagocytosis

10days      yellow-tan, depressed      phagocytosis, early granulation

                  margin

7-8 weeks        gray-white scar            collagen deposition, fibrosis

            Explain rationale behind laboratory testing for myocardial infarction, including the most useful markers.

Elevation                          Peak                                Return to

Marker                        Detected Elevation                   Normal

Myoglobin                 2 – 3 hrs.           6 – 8 hrs.                 18 – 24 hrs.

CK-MB                       3 – 4 hrs.           24 hrs.                       72 hrs.

Troponin, TnI            4 – 8 hrs.           48 hrs.                     7 – 10 days

Troponin, TnT           3 – 4  hrs.          48 hrs.                     > 10 days

1.    The most sensitive and specific biomarkers of myocardial damage are the troponins (troponin I and T)

2.    CK-MB is less specific (may be elevated in skeletal muscle injury), but may also be useful

   Consequences and complications of myocardial infarction

1.    Depend on infarct size, location and thickness

2.    Contractile dysfunction (may progress to LV failure)

3.    Arrhythmia (myocardial irritability)

4.    Myocardial rupture

a.    Within 21 days, most frequent 3-7 days after MI (damaged myocardium at its weakest, structurally)

1.    Pre-existing hypertension increases risk

b.    Free wall of LV is most common

1.    Death from cardiac tamponade due to hemopericardium

5.    Ventricular aneurysm formation

6.    Mural thrombus formation à may embolize

7.    Pericarditis overlying infarct

8.    Infarct extension/expansion

9.    Papillary muscle dysfunction or rupture

10.Progressive chronic ischemic heart disease

A.   Forms

1.    Subacute endocarditis

a.    Affects abnormal/diseased valves

b.    Low virulence organisms, e.g., viridians-group streptococci

c.    Host reaction is present on valve

2.    Acute endocarditis

a.    Affects normal valves as well as abnormal or diseased valves

b.    High virulence organisms, such as Staphylococcus aureus

c.    Host reaction generally not present on valve

B.   Predisposing factors

1.    Structural cardiac abnormalities

a.    Valvular disease, congenital valve abnormality (e.g., bicuspid)

b.    Congenital heart disease (ASD, VSD, PDA)

c.    Prosthetic valve

1.    Mechanical – along suture lines and adjacent tissue

2.    Bioprosthetic – valve leaflets and perivalvular tissue

d.    Indwelling catheters

2.    Bacteremia

a.    IV drug use

b.    Dental sepsis (e.g., gingivitis) or dental surgery

c.    Focus of infection elsewhere in the body

3.    Immunosuppression/immune system dysfunction

C.   Complications of endocarditis

1.    Cardiac

a.    Valve perforation or ring abscess

b.    Valve failure leading to rapid overload and heart failure  

c.    Myocardial injury due to …

2.    Septic emboli: Cerebral abscesses

3.    Immune complex-related

                                  a. Renal: Glomerulonephritis, immune complex deposition

NBTE (Marantic endocarditis)

1.    Etiology

a.    Hypercoaguable states

1.    Mucinous adenocarcinomas

2.    Some non-mucinous malignancies (promyelocytic leukemia)

3.    Hyperestrogenic states

b.    Endocardial trauma (e.g., indwelling catheters)

2.    Vegetations

a.    Occur on normal valves

b.    Single or multiple small (1-5mm) sterile vegetations distributed along the line of closure of the leaflets/cusps

c.    Microscopic: Bland thrombus without inflammatory infiltrate or underlying valve damage. Sterile (no organisms present)

Libman-Sacks endocarditis

1.    Associated with systemic lupus erythematosis (SLE)

2.    Single or multiple small sterile vegetations

a.    Undersurface of mitral and  tricuspid valve leaflets

b.    Chordae tendinae

c.    Mural endocardium

3.    Microscopic: Vegetations consist of finely granular material and hematoxylin bodies. Underlying valve shows intense valvulitis with fibronoid necrosis. Mild to dever deformity may be present in late stages.

Chronic rheumatic heart disease – deforming fibrotic valvular abnormalities

1.    Mitral stenosis +/- aortic stenosis

a.    Thickened valve leaflets with commissural fusion and calcification (“fish mouth” or button hole stenosis)

2.    Chordae tendinae thickened, shortened, and may be fused

3.    Microscopic:

a.    Organization of the acute inflammation

b.    Diffuse fibrosis and neovacularization, obliterating the normal layered, avascular leaflet

c.    Aschoff bodies are rarely seen

Describe the etiology, morphology, predisposing factors, and complications of rheumatic fever

A.   Occurs several weeks after group A streptococcal (GAS) phyaryngitis

1.    Anti-streptolysin O (ASO) antibody, DNase B antibody

2.    Culture negative by the time RF manifests clinically

B.   Pathogenesis

1.    Immune response to M protein of GAS cross reacts to self antigens in the heart

2.    Damage caused by both humoral and cell-mediated responses

C.   Clinical features

1.    Major manifestations

a.    Pancarditis

b.    Migratory arthritis of large joints

c.    Subcutaneous nodules

d.    Erythema marginatum of skin

e.    Sydenham chorea (neurologic disorder)

2.    Jones criteria: Evidence of antecedent GAS infection with either two major manifestations OR one major and two minor manifestations

D.   Morphology – focal inflammatory lesions in tissues

1.    Diffuse inflammation in any of three layers

a.    Pancarditis (endocardium, myocardium, pericardium)

2.    Aschoff bodies: foci of lymphocytes, plasma cells and Anitschkow cells (activated macrophages;“caterpillar cells”)

a.    Abundant cytoplasm, central round to ovoid nuclei with chromatin arranged in a central “ribbon”

3.    Affected valves show fibrinoid necrosis in cusps/leaflets or chordate tendinae

4.    Overlying small vegetations along lines of closure