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Disease of Blood Vessels

Congenital

- berry aneurysm in cerebral vessels


- AV fistula after trauma, surgery, etc
- Fibromuscular dysplasia of intima and media

Endothelial dysfunction is defined as an altered phenotype that affects vasoreactivity, induces a


thrombogenic surface, or is abnormally adhesive for inflamatory cells.

Vascular Smooth Muscle Cells


- Migrate and proliferate in response to. platelet-derived growth factor, endothelin, thrombin, and
fibroblast growth factor
- Elaborate cytokines and growth factors
- Synthesize and remodel extracellular matrix (ECM)

Intimal ThickeningA Stereotypical Response to Vascular Injury


- SMC ingrowth
- ECM production
- The neointimal cells derive from vessel wall or circulating precursors.
- Luminal stenosis in small-medium sized arteries

Hypertensive Vascular Disease (p. 492)


Hypotension

- inadequate organ perfusion

Hypertension
- vessel and end-organ damage major risk factor for coronary
heart disease, cerebrovascular accidents, heart failure, renal failure, and aortic
dissection
- Diabetes can lower the threshold for what is deleterious.
Malignant hypertension - 200/120 mm Hg
- renal failure
- retinal hemorrhages.
Vascular resistance is determined primarily at the level of the arterioles

Vasoconstrictors angiotensin II, catecholamines, thromboxane, leukotrienes, and


endothelin

Vasodilators kinins, prostaglandins, nitric oxide, and adenosine


Hypotension:
Renin converts angiotensinogen angiotensin I angiotensin II
vasoconstriction
aldosterone Na
reabsorption

Mechanisms of Essential Hypertension


- idiopathic cumulative effects of non-genetic environmental factors (e.g., stress,
salt intake) and multiple (individually minor) genetic polymorphisms in vasomotor
tone or blood volume regulation c
Sodium homeostasis in the distal tubule is a key element of blood volume control and is influenced by
angiotensin system
Single gene defects

- Mutations in 11bhydroxylase, 17a-hydroxylase lead to increased aldosterone


production
- Liddle syndrome mutations in the renal epithelial Na channel
protein lead to increased sodium resorption

Secondary hypertension
Causes - intrinsic renal disease
- renal artery stenosis (renovascular hypertension)
- endocrine abnormalities
- vascular malformations
- neurologic disorders

Vascular Pathology in Hypertension


Hypertension causes

- atherosclerosis
- aortic dissection
- cerebrovascular hemorrhage.

Hypertension is also associated with two forms of small arteriolar disease:


- Hyaline arteriolosclerosis
- EC injury plasma leakage into arteriolar walls
increased SMC
matrix synthesis stenosis
- occurs in diabetes (hyperglycemic injury)

- Hyperplastic arteriolosclerosis - malignant hypertension


- onion-skin arteriolar thickening with reduplicated basement membrane
- SMC proliferation
- necrotizing arteriolitis.

Arteriosclerosis
Arteriosclerosis is a term denoting arterial wall thickening and loss of elasticity
1. Arteriolosclerosis primarily affects small and medium-sized arteries and arterioles, and associated with
downstream ischemia (see preceding discussion).
2. Monckeberg medial sclerosis is characterized by medial calcification in muscular arteries typically
occurring after age 50 years. The calcific deposits are non-obstructive and not usually clinically
significant.
3. Atherosclerosis is the most frequent and clinically important (see later discussion).

Atherosclerosis
Atherosclerosis is a slowly progressive disease of large- to mediumsized muscular and elastic arteries.
The lesions are characterized by elevated intimal-based plaques composed of lipids, proliferating SMC,
inflammatory cells, and increased ECM. They cause pathology by:
Mechanically obstructing flow, especially in smaller-bore vessels Plaque rupture leading to vessel
thrombosis Weakening the underlying vessel wall and leading to aneurysm formation
Epidemiology (p. 496)
The prevalence and severity of atherosclerosis and its complications are related to a number of risk
factors, some constitutional and some modifiable. The major classic risk factors emerging from the
Framingham Heart Study are family history, hypercholesterolemia, hypertension, smoking, and
diabetes.264
Systemic Pathology
Constitutional Risk Factors in Ischemic Heart
Disease (p. 496)
Age: Atherosclerotic burden progressively increases with age,
typically reaching a critical mass with clinical manifestations
beginning between ages 40 and 60 years.
Gender: Relative to age-matched men, premenopausal women are
relatively protected against atherosclerosis and its complications.
In postmenopausal women, the risk rapidly increases and can
exceed that for men. Besides affecting the progression to atherosclerosis, female gender also influences hemostasis, infarct healing, and
myocardial remodeling.
Genetics: Family history is the most significant independent risk

factor for atherosclerosis. Monogenic disorders such as familial


hyperchosterolemia account for only a minor percentage, and
numerous genetic polymorphisms (including predilection for
hypertension and diabetes) are contributory.
Modifiable Risk Factors in Ischemic Heart
Disease (p. 497)
Hypercholesterolemia: Increased risk is associated with increased
low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL; clears cholesterol from vessel wall lesions). Levels
can be favorably modified by diet, exercise, moderate alcohol
intake, and statins (inhibitors of hydroxymethylglutaryl-coA
reductase, the rate-limiting enzyme in cholesterol biosynthesis).
Hypertension: Both diastolic and systolic hypertension are important and independent of other risk factors; high blood pressure
increases the risk ofatherosclerotic ischemic heart disease by 60%.
Smoking: Smoking of one pack of cigarettes daily over many
years doubles the death rate from ischemic heart disease.
Diabetes mellitus: Directly and indirectly (by inducing hypercholesterolemia), diabetes accelerates atherosclerosis and doubles
the risk of myocardial infarction and markedly increases the risk
of stroke or extremity gangrene.
Additional Risk Factors (p. 498)
Up to 20% of all cardiovascular events occur in the absence of the
major identified risk factors, suggesting other contributions:
Inflammation: Present at all stages of atherosclerosis, inflammation plays a significant causal role. A number of circulating
markers ofinflammation correlate with risk ofischemic heart disease; C-reactive protein (CRP; a liver-synthesized acute phase
reactant involved in bacterial recognition and complement activation) has emerged as one of the simplest and most sensitive to
measure. It strongly and independently predicts risk ofcardiovascular events, even in healthy individuals.
Hyperhomocystinemia: Elevated levels of homocysteine are
associated with increased atherosclerotic vascular disease. Levels
can be increased in the setting of low folate or vitamin B12 or
with hereditary homocystinuria.
Metabolic syndrome: A constellation of findings including central
obesity, hypertension, glucose intolerance, dyslipidemia, and a
systemic pro-inflammatory state. Adipose tissue cytokines have
been implicated.
Lipoprotein(a): This is an altered form of the lipoprotein
constituent in LDL; elevated levels confer increased risk
independent ofLDL or total cholesterol levels.
Hemostatic factors: Systemic markers of hemostasis or fibrinoly-

sis are predictors of risk for atherosclerotic events.Blood Vessels Pathogenesis of Atherosclerosis (p. 498)
Atherosclerosis is a chronic inflammatory and healing response ofthe arterial wall to EC injury. In turn,
EC injury causes increased endothelial permeability, white blood cell (WBC) and platelet adhesion, and
coagulation activation. These events induce chemical mediator (e.g., growth factors and inflammatory
mediators) release and activation, followed by recruitment and subsequent proliferation of SMC in the
intima to produce the characteristic intimal lesion (Fig. 11-2).
Endothelial Injury (p. 499)
Even without causing EC loss, endothelial injury leads to endothelial cell dysfunction with increased
adhesivity and procoagulant activity; injury mechanisms include hypercholesteromia, hemodynamic
disturbances (e.g., disturbed flow), smoking, hypertension, toxins, and infectious agents. Regardless of
the inciting stimulus, the vessel responds with a fairly stereotyped intimal thickening; in the presence of
circulating lipids, typical atheromas ensue.