QUIZBANK: Hemodynamic #'s 1-30, Vessels (all)

Atherosclerosis: Hemodynamic 1-30
Tumors / Aneurysms / Vasculitis: Vessels (all)

The term "arteriosclerosis" (literally, "hardening of the arteries") should be avoided by physicians. It includes (1) atherosclerosis; (2) Monckeberg's medial calcific sclerosis; and (3) arteriolar sclerosis (hyaline, hyperplastic, intimal fibrosis). Unqualified, the term usually means "atherosclerosis".

The vascular intima looks simple but isn't. Endothelial cells must maintain their no-stick inner surfaces, help constrict and dilate vessels, and heal damaged vessels. Myointimal cells and macrophages, located between the endothelium and the internal elastic membrane, are the principal actors in atherosclerosis.

Atherosclerosis is a stereotyped response of the inner surfaces of large arteries to a variety of insults. In this disease, the cells between the endothelium and the internal elastic membrane take up cholesterol-rich lipid, which then causes harm. Lesions progress from fatty steaks to fibrous plaques to complicated fibrous plaques; they can also regress.

Atherosclerosis may calcify, but the problem in atherosclerosis is not the dystrophic calcification. Monckeberg's medial calcific sclerosis just means dystrophic calcification of the media of an artery, but it is almost never a real problem.

Atherosclerosis was the great killer of 20th century North Americans. The epidemic peaked in 1968, and since then the decline has been spectacular, due more than anything else to healthier lifestyles (JAMA 277: 535, 1997; it's been steady since the mid-1980's: NEJM 339: 861, 1998). We are beginning to understand how the common risk factors relate to its pathogenesis. Americans are taking steps to protect themselves, and lifestyle changes can almost certainly reverse much of the damage in all but the most advanced lesions.

Hyaline arteriolar sclerosis results from damage to arterioles usually from increased pressure or increased blood glucose. Hyperplastic arteriolar sclerosis involves hyperplasia of the intimal cells; it results from processes that do severe, acute damage to the endothelium. Fibrosis of the intima results from high blood pressure or "just getting older."

Cardiovascular Diseases First Section Chaing Mi, Thailand

Cardiovascular Diseases Second Section Chaing Mi, Thailand

Cardiovascular Diseases Third Section Chaing Mi, Thailand

Cardiovascular Diseases Mark W. Braun, M.D. Photomicrographs

Georgetown Med School Cardiovascular Pathology

Cardiovascular System I Great pathology images Indiana Med School

Cardiovascular System II Great pathology images Indiana Med School

Tulane Pathology Course Great for this unit Exact links are always changing

Aorta Exhibit Virtual Pathology Museum University of Connecticut

Cardiovascular Pathology Virginia Commonwealth U. Great pictures

OBJECTIVES: This is mastery material.

Give a full account of atherosclerosis, its causes and effects, its full range of anatomic pathology, and its complications. Make sense of its risk factors in terms of what we know about its chemistry and pathophysiology.

Recognize each of these anatomic lesions, grossly and/or microscopically as applicable:

atheroembolization
atherosclerotic aneurysm
fatty streak
fibrous plaque
hemorrhage into an atherosclerotic plaque
ulcerated atherosclerotic plaque


Give a full account of the vascular changes contributing to, and resulting from, high blood pressure.

Give a full account of each of these clinical syndromes, with anatomic and clinical pathology as applicable:

arteriovenous malformation
Buerger's thromboangiitis obliterans
Churg-Strauss disease
Kawasaki mucocutaneous lymph node syndrome
leukocytoclastic vasculitis
Takayasu's pulseless disease
temporal arteritis
varicose veins
Wegener's granulomatosis


Describe the range of infections that can affect the blood vessels.

Review the causes of deep vein thrombosis ("thrombophlebitis"), and describe its symptoms, signs, and principal complication.

Give accounts of each of the following, and be able to recognize them clinically:

inferior vena cava syndrome
lymphangitis
lymphedema
superior vena cava syndrome


Recognize each of these anatomic lesions, grossly and/or microscopically as applicable:

aortic dissection
berry aneurysm
cystic medial necrosis
hyaline arteriolar sclerosis
intimal fibrosis
medial calcific sclerosis
syphilitic aneurysm
Weibel-Palade body


Describe the important tumors, hamartomas, and proliferations of blood and lymph vessels, how they behave clinically, and the pitfalls in making the diagnosis.

NORMAL ANATOMY

Arteries carry blood from the heart.

Elastic arteries ("large arteries") include the aorta and at least the beginnings of its largest branches. These arteries both propel and dampen the pulse wave. These are distinguished by a preponderance of elastic fibers in their media. The subendothelium of their intimal layers thickens over the course of life through the accumulation of collagen fibers and myointimal cell. The elastic tissue proliferates here. You already know that all elastic tissue slowly breaks down as we age. In older adults, the elastic is largely replaced by collagen. This also results in lengthening and thus tortuosity seen in older people. The adventitia and outer media is nourished by vasa vasora. All arteries depend on the blood within their lumens to nourish their intima and inner media.

Muscular arteries ("medium-sized arteries", "distributing arteries") exhibit smooth muscle in their walls, and may expand and contract to regulate the caliber of the lumen and thus the flow of blood. The intima is similar to that of the elastic arteries, and it thickens similarly. Smooth muscle may pass into the intima through fenestrae in the internal elastic membrane. These fenestrae may become wide in old age and be mistaken for damage from previous vasculitis. The media is bounded on either side by an inner and outer elastic membrane.

Small arteries are the major site of autonomic regulation of blood flow, and take the worst beating in hypertension. A rule of thumb is that the wall and lumen should have the same thickness. Thickening of the intima occurs here as well. In sites of inflammation or tumor, it may be quite impressive (* "Friedlander's endarteritis obliterans", discovered by the real Dr. Friedlander, 19th century pathologist Carl, 1847-1887). Hyaline arteriolar sclerosis becomes a problem as we age, especially if we get diabetes or hypertension. There's no outer elastic membrane, and the layers become progressively less distinct as the arteries get smaller.

Arterioles continue the anatomy of the small arteries. Two definitions that have been offered: (1) Arterioles have five or fewer layers of smooth muscle; (2) Arterioles have total diameter 100 microns or less.

Veins and lymphatics have histologic features that you know. In disease, veins do not usually show so much intimal proliferation and fibrosis as do arteries. The muscle in the wall of a vein is thinner, and in the larger veins tends to be less organized. Very large veins have some layers of elastic outside their muscular layer. Lymphatics run very close to arteries (even closer than the veins), and tend to be small and to have thinner walls than the vein that runs with that artery. It's not always possible to tell lymphatics from veins; if the vessel contains red cells, it's most likely a vein.

Endothelium is special stuff. It is permeable to water and the small inorganic ions. It transports a little bit of blood protein by pinocytosis. Electron microscopists recognize it by the Weibel-Palade bodies (puh-LAH-dee, made of von Willebrand's factor). It can contract, to regulate capillary flow. It produces some of the subendothelial connective tissue. It also makes substances: (1) Prostacyclin (to keep its surface slippery); (2) Von Willebrand's factor; (3) Endothelin (a vasoconstrictor peptide); (4) Endothelial-derived relaxation factor (nitric oxide, EDRF; see Nature 368: 62, 1994).

Vascular smooth muscle is also special. It has LDL receptors. It can get into the intima through holes in the internal elastic membrane. Both facts will become important when we study atherogenesis.

BIRTH DEFECTS INVOLVING VESSELS

There are many variations on the normal anatomy of arteries.

Malformations of the coronary arteries may first announce themselves by causing sudden death. More about this soon.

The familiar red "birthmarks" are hemangiomas, and will be covered with "tumors".

The only other birth defects worth mentioning are berry aneurysms and arteriovenous malformations ("AV malformations", "AV fistulas", "AV aneurysms", etc.)

AV malformations involve a tangle of abnormal medium-sized vessels connecting a large artery and a large vein. The problem is shunting of the blood away from the territory that should be supplied by the artery. The vein will tend to expand ("aneurysm").

Sometimes the AV malformation is a mass of wormy vessels ("cirsoid aneurysm", "racemose aneurysm"; apparently endemic among Klingons). This is most common in the brain, where subarachnoid hemorrhage is the dread complication.

Future pathologists: It's good to be able to distinguish an baby's AV malformation (which won't go away) from a baby's hemangioma (which probably will go away), An AV malformation does not stain for WT1; a hemangioma that will involute does stain for WT1 (Arch. Derm. 141: 1297, 2005).

ATHEROSCLEROSIS (review still good Am. J. Card. 70: 3, 1992; DeBakey tries to sort out what puts you at risk for what Am. J. Card. 85: 1045, 2000)

{03476} coronary artery atherosclerosis
{06485} coronary artery atherosclerosis, mild
{06491} coronary artery atherosclerosis, severe
{06497} coronary artery atherosclerosis, total
{09440} atherosclerosis of vertebral and basilar arteries
{09446} êtat cribilé from multiple atheroemboli

Mild, moderate & severe atherosclerosis WebPath Photo

Cholesterol emboli KU Collection

Atherosclerosis Photo and mini-review Brown U.

Occluded common iliac Spectacular x-ray Brazilian Medical Students

Probably still the #1 killer of Americans.

Atherosclerosis causes harm by (1) occluding arteries slowly over time (angina, ischemic scarring of the myocardium, atherosclerotic dementia, leg claudication, intestinal angina); (2) occluding arteries suddenly by rupture of plaques (thrombosis, atheroembolization) or hemorrhages into plaques (myocardial infarct, atherosclerotic stroke, gangrene of the bowel); (3) weakening the walls of arteries (atherosclerotic aneurysms, penetrating atherosclerotic ulcers of the aorta).

Claudication is the least subtle of these. Patients will have calf pain after walking a certain distance (usually about the same each time); the stenosis will of course be way proximal from the pain. Review Lancet 358: 1257, 2001.

* The radiologists are now able to see a fresh rupture of a fibrous cap, and correlating it with clinical findings: Circulation 105: 181, 2002; ultrasonography shows that, not surprisingly, the most common site is at the origin of the LAD (J. Am. Coll. Card. 46: 261, 2005).

{06737} atherosclerosis has caused ischemic fibrosis of the heart
{09443} atherosclerosis of middle cerebral artery
{10889} atheroembolus

Kidney
ERF/KCUMB

Severe atherosclerosis of a coronary artery WebPath Photo

Atheroembolus WebPath Photo

You're already familiar with atheroembolization, which is a major cause both of stroke and of lower-extremity ischemia ("blue toes disease").

Atherosclerosis is a stereotyped response to injury featuring the accumulation of cholesterol-rich fat in the intima of the large and medium-sized arteries of the body. Typically these are phagocytes ("myointimal cells", visiting macrophages). These masses form plaques, or atheromas.

* Philologists: "Atheros" means "gruel", "porridge", or "grits"; you ate that stuff as Malt-o-Meal. Think about blobs of 7-day-old dried buttery Malt-o-Meal lining a dirty sink, and you have a pretty good idea about atherosclerosis.

For whatever reason, these cells have a great appetite for LDL cholesterol. When the LDL is abnormal (Ox-LDL, lipoprotein A; see below), or the LDL is processed down the "bad" (non-apoprotein B receptor-mediated) breakdown pathway, these cells accumulate lipid that damages them and their neighbors. The two pathways: Proc. Nat. Acad. Sci. 91: 4431, 1994.

A good working rule: The pulmonary arteries do not get serious atherosclerosis. Otherwise, if an artery has its own name, it can be significantly affected by atherosclerosis. The aortic surfaces of the aortic valve cusps are also prone to the disease at all stages (Heart 91: 576, 2005 documents what all pathologists already knew).

Atherosclerosis seems to be the stereotyped way in which most of the large named arteries respond to a variety of injuries. Don't expect a unified theory of atherogenesis yet. However, the manageable risk factors are, in descending order (1-5 at least) of importance:

1. High levels of LDL cholesterol. This is the over-riding risk factor. Review Lancet 345: 362, 1995.

Your LDL level is a reflection of your heredity, your diet (cholesterol-rich diets raise LDL), and your exercise habits.

Also remember cholestatic jaundice, nephrotic syndrome, hypothyroidism (* you need T₃ to express LDL receptors on liver cells), amiodarone (* keeps T₃ from letting you make LDL receptors) and (less striking) Cushingism.

As total cholesterol rises above 160 mg/dL, coronary risk rises roughly linearly.

* The Swedish simvastatin study, which laid to rest concerns about excess mortality from lowering LDL's: 345: 1274, 1995.

2. Cigaret smoking, "which damages the intima".

* "Cigaret" is the preferred spelling. The suffix "-ette" makes the practice sound cute and harmless.

The old story about tobacco "damaging the intima" is giving way to the better-evidenced fact that tobacco smoke oxidizes LDL, making them into the poorly-digested form that accumulates in the intima.

This is for me still the most interesting work in atherosclerosis. Oxidized LDL is chemotactic for macrophages, makes them proliferate, and is cytotoxic once they ingest it, it can make cells produce cytokines like α-TNF that may be fibrogenic, and it there can even be autoantibodies.

Smoking oxidizes LDL, HDL protects it from oxidation, vitamin E prevents LDL oxidation (kind of, antioxidants seem to slow atherosclerosis JAMA 273: 1899, 1995), and so forth and so forth.

* Update on Ox-LDL in atherogenesis: J. Am. Coll. Card. 43: 1731, 2004. Pathologists: J. Clin. Inv. 92: 471, 1993. Superoxide plus NO^. generates the noxious ONOO^- peroxynitrite radical that oxidizes LDL (Proc. Nat. Acad. Sci. 91: 1044, 1994).

* A variety of other modifications of LDL also result in increased phagocytosis by macrophages, render it toxic to endothelium, smooth muscle, and macrophages, etc., etc.

3. High blood pressure "which damages the intima". Review Lancet 345: 362, 1995.

Angiotensin II itself is now one of the "usual suspects" in discussions of molecules that mediate atherogenesis: Am. J. Med. Sci. 323: 17, 2002.

4. Diabetes from any cause.

You'll read a tremendous amount about different effects of hyperglycemia, insulin, and so forth on lipoproteins (Diabetes 41 S 2: 102, 1992), protein chemistry, and so forth. The most interesting work right now (Science 258: 651, 1992) focuses on advanced glycosylation end-products ("glycation products"), proteins that have been non-enzymatically glycosylated (* Schiff-base --> Amadori product --> durable fluorescent product). Binding of these to endothelium makes it permeable, they inactivate nitric oxide, there are receptors for these substances which, when they bind, cause cells to produce fibrous tissue, glycosylated LDL probably can't be processed normally, etc., etc.

Once advanced glycation products have accumulated on board, runaway atherosclerosis affects even diabetics who have been restored to euglycemia.

Exciting news: Giving the soluble form of the glycation product receptor removes the products and suppresses accelerated atherosclerosis. See Nat. Med. 4: 1025, 1998.

* Another idea: High blood glucose levels cause overexpression of CD36, the LDL scavenger pathway receptor: Nat. Med. 7: 840, 2001.

5. Lack of exercise (made "official" in 1992), independent of the above (NEJM 330: 1565, 1992).

The effects of physical exercise are numerous. Possibly "getting in shape" changes lipoprotein receptor counts, etc., etc. However, contrary to popular mythology, people who are very physically fit can and do still get serious atherosclerosis.

* Couch potatoes wishing to increase the numbers of LDL-receptors without exercising may benefit from a new class of drugs that bind to the sterol regulatory element-binding protein cleavage-activating protein (Nature Med. 7: 1332, 2001).

In the meantime, exercise capacity actually seems to be the best predictor of not dying of cardiovascular disease: NEJM 346: 793, 2002.

And the famous step-two diet for improving LDL and HDL status actually fails in men and post-menopausal women if they refuse also to exercise: NEJM 339: 12, 1998.

Despite some pop claims, the "big four" (cholesterol, smoking, hypertension, diabetes) still account for the vast majority of heart attacks: JAMA 290: 898, 2003.

6. A variety of biochemical lesions (hereditary, acquired) that promote thrombosis NEJM 338: 79, 1998, Circulation 86(S III): III-95, 1992, lots more). Not yet "official", it is probably at least as important a risk factor as diabetes.

7. Other heredity: Important. Currently being sorted out as a risk factor.

You already are familiar with familial hypercholesterolemia, in which there is a defective apoprotein B-100 receptor (there are many different molecular variants), IDL's are not properly cleared by the liver and become excess LDL instead, and the "good" receptor-mediated pathway of LDL uptake by other cells is unavailable.

There are also birth defects involving other apolipoproteins, and those in which there is excess Lipoprotein A (see below).

Polymorphisms involving apolipoprotein B itself are clearly important in determining coronary risk. Outstanding as a cause of high LDL is "familial defective apo-B-100", an autosomal dominant (NEJM 338: 1577, 1998; this alone may kill around 1 person in 1000).

* Some folks, however, have trouble making apo-B at all, which is good if you want to eat lots of greaseburgers and never raise your LDL: Proc. Nat. Acad. Sci. 92: 1772, 1995.

* Protease inhibitors for HIV infection cause hyperlipidemia and lipodystrophy by interfering with the breakdown of apolipoprotein B: Nat. Med. 7: 1327, 2001.

* The lipoprotein A allele Lp^S2 was once reported to be a potent risk factor for coronary artery atherosclerosis (Lancet 343: 1194, 1994); this evidently was never confirmed.

HDL is composed of A1 and A2 apolipoproteins.

Apo-A1 seems to have the most to do with removal of cholesterol from membranes. This is by now quite well-established (Am. J. Card. 91 12E, 2003. There's even been talk of using A1 instead of HDL as your measure of "good" cholesterol (Arch. Path. Lab. Med. 121: 678, 1997), but so far it remains a research topic (Circulation 97: 1784, 1998) Thie may change.

It's been known for over a decade that transgenic mice with lots of A1 get much less atherosclerosis; those with lots of A2 paradoxically get more. Science 261: 469, 1993. A mutated apoA-1 that causes severe atherosclerosis in humans: J. Am. College Card. 44: 1429 2004.

Familial combined hyperlipidemia, i.e., high VLDL's, high LDL's, low HDL's ("my triglycerides and LDL both run high"), affects about 1% of folks and is a major coronary risk (3-10x increase over baseline). Patients are now considered a subgroup of the "syndrome X" family since most show central adiposity.

The biochemical lesion is overproduction of apo B in the lipoproteins (review J. Clin. Endo. Metab. 89: 2601, 2004).

The illness is obviously polygenic. It is expressed only in adults. A mouse model has mutations at both apoprotein C-III and the LDL receptor (Science 275: 391, 1997). One human gene is apolipoprotein A-II (Nat. Gen. 18: 369, 1998.

Tangier disease is an autosomal recessive disease in which patients have near-zero HDL levels, low LDL levels, and extensive deposition of cholesterol esters in the tissues. Patients have orange tonsils, a neuropathy, and precocious atherosclerosis. Even heterozygotes have many foam cells, low HDL's, and increased coronary risk. Gene (ABCA1) and syndrome: Nat. Genet. 22: 352, 1999; the missing protein is responsible for taking cholesterol to the surface of cells to be carried off by apo-A-I. There is also a dominant low-LDL syndrome at this locus ("familial hypoalphalipoproteinemia, also an atherosclerosis risk: Lancet 354 134, 1999).

Despite older ideas, people with hereditary lipoprotein lipase deficiency ("type I hyperlipidemia") are indeed prone to accelerated atherosclerosis (NEJM: 335 848, 1996).

* TLR4 is a newly-discovered molecule that has to do with how brisk one's inflammatory responses are. People with alleles that produce a subdued response to bacterial invasion are more susceptible to serious infection, but protected from atherosclerosis (NEJM 347: 185, 2002).

And yet other folks run high Lp(a) ("lipoprotein Lp(a)", LDL with an apoprotein A attached), which puts them at risk.

Excess Lp(a) runs in families and is constant through life. It can and often does kill somebody with no other coronary risk factors (Arch. Int. Med. 157: 1170, 1997). Known mechanisms include:

• LDL oxidizes too easily;


• extra cholesterol gets deposited


• impaired fibrinolysis (it probably blocks plasmin binding sites)



* Lp(a) is lowered by niacin, male and female hormones, and alcohol drinking, but not by other means (Am. J. Med. 110: 22, 2001). Lp(a) review NEJM 349: 2108, 2003.

* Polymorphisms for Apolipoprotein E received considerable attention during the 1990's, but there were apparently no reproducable findings.

* Platelet glycoprotein IIIa variant, rendering platelets stickier and therefore placing a person at risk for coronary disease??? Yes: NEJM 334: 1090, 1996; Blood 94: 46, 1999; Circulation 104: 140, 2001. No: Lancet 349: 385, 1997' Lancet 353: 708, 1999; Circulation 102: 1901, 2000. Also watch the "human platelet antigens".

The good news is that these genetic factors (as well as the havoc of hypertension) can be more or less neutralized by lowering LDL levels, by whatever means (Science 272: 629, 1996; Br. Med. J. 313: 1273, 1996).

* Common longevity mutation in cholesterol-ester transfer protein, which produces abnormally large LDL's and HDL's: JAMA 290: 2030, 2003.

8. Low HDL & elevated fasting triglycerides.

Perhaps the HDL assay is most useful as a marker for the as-yet-poorly-understood metabolic syndrome X or insulin resistance syndrome, with hypertension, insulin resistance, low HDL, high fasting triglycerides, truncal and a serious coronary risk even with normal LDL / total cholesterol.

This is a hot topic right now. Of course, the mainstay of therapy is diet and exercise (weight loss is key: Am. J. Card. 87: 827, 2001). Reviews Am. J. Epidem. 152: 897, 2000, Am. J. Card. 84(1A): 11J, 1999; Circulation 100: 123, 1999.

* Some fat in the liver, and elevated liver enzymes, is also typical: QJM 92: 73, 1999.

* Watch for

• resistin, produced by the adipocytes, as etiologic
• inclusion of Stein-Leventhal, hirsutism-obesity in older women, non-alcoholic steatohepatitis, and endometrial cancer in the constellation
• more on the rat model, induced by feeding a greasy American-type diet (Hypertension 37: 1323, 2001)
• treating it with diet and exercise
• new categories of medications to treat the defect at the cellular level (* including the altered nuclear membrane receptors: NEJM 353: 604, 2005)

9. Elevated levels of homocysteine.

Homocysteine can be elevated because of (1) an inborn error of metabolism, or (2) low intake of folic acid, or (3) low intake of vitamin B₁₂. People with the inborn errors get horrendous atherosclerosis early in life.

* Even a common, mild mutation in methylenetetrahydrofolate reductase is a serious risk factor for atherosclerosis: Circulation 99: 2361, 1999.

Most vegetarians have mildly elevated serum homocysteine levels because of a relative B₁₂ deficiency (Clin. Chim. Acta 326: 47, 2002; Am. J. Clin. Nutr. 78: 131, 2003; Ann. Nutr. Metab. 46: 73, 2002). Of course vegetarians overall have less, rather than more, atherosclerotic morbidity and mortality, though this is not under intensive study recently; pure vegetarians with good genes usually have total cholesterol less than 150 unless they eat a lot of saturated vegetable oil (Am. J. Card. 83: 816, 1999). Stay tuned.

Homocysteine, in turn...

• is a mitogen for vascular smooth muscle;
• damages endothelium (possible mechanism Circulation 105: 1037, 2002);
• makes blood hypercoagulable.

There's now pretty good evidence that elevated blood homocysteine (as in folks who are deficient in folic acid, which is still probably true for many Americans) is a major independent risk factor for atherosclerosis (NEJM 332: 234, 1995; JAMA 281: 1817, 1999; lancet 355: 523, 2000;). and a prospective series (JAMA 275: 1929, 1996). Review for everybody: Am. Fam. Phys. 56: 1607, 1997.

Among the homocysteine-challenged.... Making early atherosclerosis shrivel with B₆ and folic acid works: Lancet 355: 511, 2000. Soon everybody may be taking betaine supplements.

NOTE: Despite all of the above, women are relatively protected from atherosclerosis until menopause. Afterwards, their risk increases rapidly to equal men's. Post-menopausal estrogen is protective (other bad press notwithstanding: Ann. Int. Med. 135: 939, 2001), and the addition of progesterone does not remove this protection: NEJM 335: 453, 1996.

* The mechanism by which estrogens protect remains obscure. One idea is that estradiol greatly up-regulates FasL expression on endothelium, which keeps out the inflammatory cells: Circulation 104: 2576, 2001.

NOTE: People of Japanese ancestry, living in Japan, have traditionally relatively low risk for atherosclerosis. This has changed dramatically over the past two decades (Arch. Int. Med. 160: 2297, 2000). When they move to America and become Americanized, their risk approaches that of the rest of us.

NOTE: Finland and Scotland have slightly higher rates of atherosclerosis (reflected in rates of death from ischemic heart disease). The United States probably ranks next, followed by the rest of the "Western World", and far more than Japan or the poor nations. When a third-world country develops rapidly, so does atherosclerosis (Atherosclerosis 153: 9, 2000).

NOTE: The French, with a very high-saturated-fat diet (that's part of why French cooking is so good), have a relatively low rate of atherosclerosis. This is probably due to their tremendous alcohol consumption; there was talk in the 1990's about tannins in red wine inhibiting oxidation of LDL's in the French, but nothing much lately.

NOTE: * Watch the impact of carotenoids and their close kin in preventing atherosclerosis. Works for mice.... Circulation 103: 2922, 2001.

NOTE: The Inuit ("Eskimos"), who eat a lot of fat, are supposedly protected by omega-three fatty acids.

You already know that a diet high in saturated fat (mostly of animal origin) or trans-unsaturated fat ("hardened" fat, think of margarine) raises LDL cholesterol.

NOTE: "No-cholesterol" dietary items are still LDL-raisers and supposedly atherogenic if rich in saturated fat.

NOTE: After 1991, the coronary artery mortality in Poland plummeted. Probably it's from a better diet, with more fresh fruits and vegetables and vegetable fats and less lard (BMJ 316: 1047, 1998).

NOTE: You can go nuts trying to keep track of which factors and their remediation affect, correlate with, and "are associated with" which other factors, listed or rumored to be important in atherogenesis. I seriously doubt that "stress", independent of these other variables, is a significant risk factor for atherosclerosis. However, higher serum epinephrine levels probably would increase a person's risk of sudden cardiac death in a potentially rhythm-disturbing situation, all other things being equal.

NOTE: I am still not aware of any reason to believe that obesity is a risk factor for atherosclerosis except insofar as it is related to the above (i.e., high cholesterol from bad diet, smoking, hypertension, diabetes, lack of exercise, metabolic syndrome X). Obesity (especially "central obesity", i.e., the dude's butt-crack shows over his beltline when he squats) produces the hormone resistin, which renders muscle and liver resistant to the effects of insulin and maybe does other things.

I am also not impressed with isolated fasting triglyceride levels as an independent risk factor (neither is the NIH consensus panel JAMA 269: 505, 1993). Iron overload may also be a risk factor maybe by oxidizing LDL (yes! Circulation 96: 3300, 1997; no! NEJM 330: 1119, 1994), right now the no's seem to have won. Claims about coffee has repeatedly flopped. The "baldness is an independent risk factor" article (JAMA 269: 998, 1993; even a bright kid could point out methodologic howlers) was sponsored by the hair-restorer folks anticipating some lawyer finding "a higher rate of MI's in people using hair-restorer".

NOTE: Consensus panel on lipid profiling (JAMA 269: 505, 1993) recommends screening HDL-C along with routine cholesterol screens, but can't find much reason to check triglycerides or consider them an independent risk factor.

"Atherosclerosis as an infectious disease."

You will be told that that micro-organisms cause atherosclerosis, both by acting at the sites of the lesion or and by "increasing the total body burden of inflammation." Your lecturer does not believe this is true. You can decide for yourself, of course, but here are the facts.

From time to time, people find what seem to be bits of microbes in atherosclerotic plaques and suggest the bugs are etiologic. DNA sequences from various bugs get reported fairly often in plaque debris. Immunofluorescence identifies antigens from these bugs in the debris as well. Since many different "microbes" have been identified in this way (including the very unlikely Helicobacter pylori), and since the bacteria themselves are never convincingly visualized, the obvious explanation is that the plaque grunge itself soaks up whatever microbial debris may be in the bloodstream.

The CMV-causes-atherosclerosis flap of the 1980's came to nothing. Now it's chlamydia-in-your-plaques (J. Inf. Dis. 175: 883, 1997; negative study Br. Med. J. 318: 1035, 1999, J. Am. Coll. Card. 41: 1482, 2003; two more Br. Med. J. 321: 204 & 208, 2000). Even the proponents admit the case is hardly made: JAMA 288: 2724, 2002. The inflammation in plaques hardly resembles what you see in trachoma, psittacosis, lymphogranuloma venereum or other known chlamydial illnesses -- these display spectacular proliferation of lymphoid germinal centers and abundant plasma cells, and/or suppurating granulomas. Chlamydia are easy to see in the illnesses they obviously cause, but in atherosclerosis the actual organisms (rather than just their DNA or antigens) remain incredibly elusive. The most recent sighting is Acta. Biol. Hung. 86: 233, 2005 and the "chlamydia" were calcified... Draw your own conclusions.

Correlating the presence of a microbe and severity of atherosclerosis makes for an extremely easy "scientific study." And these studies are driven by the hope that atherosclerosis might respond to an antibiotic-based regimen as has worked so well for stomach ulcers. A key difference is that anybody can see the bacteria in stomach ulcers, and nobody can actually see them in athersclerosis. And a conspicuous lack of controls distinguishes most of the "positive" studies I've seen. For example, a handful of studies finding that people with helicobacter in their stomachs get worse cornary atherosclerosis fail to control for tobacco smoking and dietary habits. (We'll let you find this stuff on your own.)

Most recently the talk is about "infectious burden", i.e., the more different usual suspects that you're making antibodies against, the greater your risk of dying of a heart attack (Circulation 105: 15, 2002). The fact that the "usual suspects" now include genital herpes and stomach helicobacter invites the idea that old folks who are sicker are more likely to have polyclonal B-cell activation, which is simply common sense.

C-reactive protein is presently the subject of much excitement, since serum levels in the absence of the acute phase reaction seem to correlate with the extent of atherosclerosis in both humans and animal models of atherosclerosis.

In animals, C-reactive protein is found in the plaques between the cells in all stages of their development (co-localizing with apolipoprotein B), and seems to be soaked up from the plasma (Am. J. Path. 167: 923, 2005).

There's much talk about the "proinflammatory phenotype" (J. Clin. Endo. Metab. 90: 4549, 2005), i.e., the person who's likely to have high C-reactive protein levels in the absence of obvious inflammation. Surprise! These people are older and have much fatter, have higher triglyceride levels, higher insulin levels (i.e., insulin resistance), and higher leptin levels -- all obviously involved with atherosclerosis. For some reason, other acute-phase-reaction markers (fibrinogen, stimulated interleukin beta, some more obscure proteins) also average higher. All this says to me is that there is some link between the C-reactive protein system and lipid metabolism. The conclusion that people with atherosclerosis harbor more smoldering infections hardly seems warranted.

Supporting your lecturer's skepticism is a single study that addressed the obvious question. Mice with a genetic predisposition to atherosclerosis get exactly the same lesions whether they are germ-and-virus free or have the usual microflora (J. Exp. Med. 191: 1437, 2000.) No one has repeated this work, and this fact alone tells me something about the whole field.

NOTE: There are several situations in which development of atherosclerosis is accelerated. These include

• previous radiation to an artery;
• arteries in transplanted hearts (inflammation, of course: Circulation 106: 1536, 2002)
• vein grafts in coronary bypass surgery
• coronary arteries after angioplasty
• situations in which the walls of arteries are burdened with immune complexes.

In these situations, "endothelial damage" and "thrombosis" appear to be critical. Read all about it: Mayo Clin. Proc. 66: 818, 1991. Okay, atherosclerosis is actually a pattern of injury.