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 a 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 (best recent update J. Am. Coll. Card. 46: 937, 2005; 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
{09446} êtat cribilé from multiple atheroemboli

Aortic Atherosclerosis, longstanding Text and photomicrographs. Nice. Human Pathology Digital Image Gallery

Occlusive Atherosclerosis Text and photomicrographs. Nice. Human Pathology Digital Image Gallery

Mild, moderate & severe atherosclerosis WebPath Photo

Cholesterol emboli KU Collection

Occluded common iliac Spectacular x-ray Brazilian Medical Students

Atherosclerosis of the Aorta CDC Wikimedia Commons

Carotid atherosclerosis Severe disease Wikimedia Commons

Probably still the #1 killer of Americans.

Atherosclerosis causes harm by (1) narrowing / occluding arteries slowly over time (angina, sudden cardiac death without coronary occlusion, ischemic scarring of the myocardium, atherosclerotic dementia, leg claudication, intestinal angina, having one kidney waste away to a hypertension-producing nubbin); (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).

* Your lecturer was once taken to task severely by opposing counsel's expert for describing "70% occlusion" of a coronary artery. Of course, it's really "70% narrowing", but as I pointed out, the New England Journal of Medicine has used the same language as your lecturer, and you'll see it often.

{06737} atherosclerosis of coronaries
{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". Think about blobs of 7-day-old dried buttery Malt-o-Meal lining a dirty sink, and you have a pretty good image of 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 anytime soon. 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, saturated fatty acid-rich, trans-unsaturated fatty acid-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.

Now that "atherosclerosis is an inflammatory disease" (ask a clinician), the tendency is to call the cholesterol-laden cells of plaques "macrophages", and assume they have their origin from the blood rather than from the myointimal cells that are normally present.

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).

The claim that oxidized LDL is chemotactic for macrophgaes that become cholesterol-laden, and that it keeps them in the plaque, seems to be robust (J. Clin. Inv. 119: 136, 2009; NEJM 360: 1144, 2009).

You will probably run into the "pop" claim that "oxidized LDL is the cause of atherosclerosis and since there is very little oxygen in veins and in the pulmonary artery, this is why we do not see atherosclerosis here. If this were true, then (1) you'd see atherosclerosis in the smaller arteries, where oxygen tension is just as high; (2) in pulmonary hypertension, where the oxygen tension in the pulmonary artery is even less though the pressure is higher, you'd see less rather than more atherosclerosis; (3) it's not true that there's very little oxygen in venous blood.

* 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. "Advanced lipoprotein testing" goes beyond LDL and HDL, to include non-HDL-cholesterol, apoB, LDL particle size, and other deep stuff. See Endo. Metab. Clin. N.A. 38: 1, 2009. One of many new risk factors is one's lipoprotein-associated phosopholipase A₂, which correlates directly with risk: Lancet 375: 1498, 2010. It's not clear whether any of these will become "routine labs".

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.

As a resident, I observed and was taught that when there is bad atherosclerosis in the smaller arteries (i.e., the ones without names in the anatomy books), there is usually diabetes. This is finally confirmed: Prog. Cardiovasc. Dis. 50: 112, 2007.

You'll read a tremendous amount about different effects of hyperglycemia, insulin, and so forth on lipoproteins, protein chemistry, and so forth. Some classic work (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.

It's been reported that giving the soluble form of the glycation product receptor removes the products and suppresses accelerated atherosclerosis. See Nat. Med. 4: 1025, 1998. Stay tuned.

* 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, 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.

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.

Insurers are now using various "complete" lipid profiles, including a directly-measured LDL plus HDL plus lipoprotein(a), remnant lipids (IDL and small VLDL), apo-B, "small dense LDL" (a marker for the metabolic syndrome), "LDL pattern B". In 2008, the much-promoted screen was "VAP", a marketer's eponym.

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 (more on this below) 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 A2 (Nat. Gen. 18: 369, 1998.) Also watch cholesteryl ester transferring protein.

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 perhaps 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, possibly also an atherosclerosis risk: Lancet 354 134, 1999). Update on the many alleles here that influence health even in heterozygotes: JAMA 299: 2524, 2008.

* LPR6 (LDL receptor protein 6) is definitely worth watching; severe mutants have elevated LDL and BP, diabetes, and coronary artery disease, plus accelerated osteoporosis (Science 315: 1278, 2007).

* "LIPOPROTEIN(A)" (Lp(a)) is LDL with an apoprotein A attached. Levels seem to be mostly genetic. These notes cited it a likely risk factor for atherosclerosis during the 1990's, and seems to have been forgotten for a while. By 2006, the recommendation was against routine measurement (JAMA 296: 1363, 2006); however, since it's now easy to measure, insurers are starting to screen ... and now it does seem to be a real risk factor (JAMA 301: 2331, 2009).

* Common longevity mutation in cholesterol-ester transfer protein, which produces abnormally large LDL's and HDL's: JAMA 290: 2030, 2003; update JAMA 2008: 2777, 2008 (many alleles; correlation with vascular health is real but weak); NEJM 361: 2518, 2009 (two of the alleles are strong risks).

Over the past twenty years, there have been a host of reports of other putative genes placing one at risk for atherosclerosis. In 2007, a huge study (in Kansas City!) examined 86 putative genes at 70 loci and found only one (a fibrinogen variant) that was even nominally statistically significant (JAMA 297: 1511, 2007).

American Heart Association on "genetics and genomics for prevention and treatment of cardiovascular disease": Circulation 115, 2878, 2007.

The GOOD news is that these genetic factors (at least whichever ones are real, 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).

8. LOW HDL AND ELEVATED FASTING TRIGLYCERIDES ("THE METABOLIC SYNDROME X").

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 obesity 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; many have the infamous "non-alcoholic steatohepatitis" that we'll study later.

* No one understands why, but people with the metabolic syndrome also have more oxidized LDL: JAMA 299: 2287, 2008.

* Watch for

• a problem with some hormone (perhaps resistin or adiponectin) as etiologic
* My prediction's coming true... using adiponectin and its oligomers to determine whether metabolic syndrome is present seems to work (Am. J. Clin. Path. 129: 815, 2008; ongoing questions J. Allerg. 121: 326, 2008). This won't replace the physical exam and labs, but supports the idea that this hormone is key.

* There is talk about nicotinic acid being superior to statins for the metabolic syndrome, but this does not seem to be affecting practice.

Remember that some of the antiretroviral therapies cause the metabolic syndrome (especialy, redistribution of fat); we may end up giving these people a growth-hormone releasing factor (NEJM 357: 2359, 2007).

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

* Rimonabant, the diet pill that blocks the cannabinoid type I receptor (the one that gives stoners the munchies) for the metabolic syndrome ("and it raises HDL-C and lowers glycosylated hemoglobin too!"): JAMA 299: 1547, 2008.

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). The traditional wisdom is that vegetarians have less, rather than more, atherosclerotic morbidity and mortality, though this is not under intensive study recently. There hasn't been a real paper in a decade. The most recent review simply points out that people who become vegetarians along "with comprehensive lifestyle changes" can have atherosclerotic angina regress (QJM 92: 531, 1999). 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. Supplementing all post-MI patients with vitamin B₁₂ and folate reduces homocysteine and doesn't seem to hurt, but doesn't improve vascular outcomes (JAMA 303: 2486, 2010 -- darn).

10. Chronic kidney disease. Hard to sort out from the others, but probably real (Am. J. Kid. Dis. 49: 8, 2007.)

11. Being on a protease inhibitor for HIV infection ("dyslipidemia": NEJM 356: 1723, 2007).

* 12. Adult-onset growth-hormone deficiency. Now a robust finding. Still poorly-understood and hard-to-recognize, but supplementing seems to reverse the risk (J. Clin. Endo. Metab. 93: 3416, 2008).

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 historically had 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. There could perhaps be something to this; watch resveratrol (an anti-oxidant from grapes) as an anti-atherosclerosis compond.

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.

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 am unpersuaded that "stress", independent of these other variables, is a significant risk factor for atherosclerosis. (For a review of the claim that the hormones produced by psychological stress slowly promote atherosclerosis, see Lancet 370: 1089, 2007). 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 major 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" / "syndrome X type", 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. Watch this one.

NOTE: Don't ask me to sort out the "trans-fatty acids are evil" prevailing wisdom. The original synthetic trans-fatty acid was Crisco; however, there are a few natural trans-unsaturated fatty acids as well. The huge review in NEJM 354: 1601, 2006 is filled with multivariate stuff on people and effects on molecules, but strangely there is only a single animal experiment, only marginally relevant, cited. And I could not find a single animal study focused on trans-fats in their diet -- ever! The business is political. New York City banned trans-fats from restaurant food (Ann. Int. Med. 151: 129, 2009 -- a diner wouldn't be able to tell any difference.) The authors' claim that trans-fatty acids cause 30,000 premature deaths in the USA each year seems to come from thin air, as it does NOT appear in the NEJM article to which it is referenced but is extrapolated from the assumption that because somebody's group of Crisco-eaters had 30% high C-reactive protein.... well, you can understand how difficult it is to sort everything out. The much-discussed ongoing Nurses' Health Study could find an impressive correlation between red-cell trans-fatty acid concentration and atherosclerosis only in the upper quartile and didn't control for such obvious things as obesity and lack of exercise; to be fair, there was a positive correlation between total LDL cholesterol and trans-fatty acid levels (Circulation 115: 1858, 2007). The recent big French study couldn't find any clear effect of either synthetic or natural trans-fats on lipid profiles or cardiovascular mortality in ordinary, non-hyperlipidemic folks (Am. J. Clin. Nutr. 87: 558, 2008.) Am. J. Clin. Nutr. 90: 88, 2009 refuted the claim that trans-fats impair insulin sensitivity in overweight ladies. Underclass kids have "reduced dietary quality" including eating a lot of trans-unsaturated fats (surprise! J. Am. Diet. Assoc. 109: 1612, 2009) and overall fats as well. Go figure. Given that gorging on Crisco-cooked french-fries may run with other unhealthy habits, sorting everything out is impossibile -- thankfully, nobody will miss trans fats except Crisco stockholders.

NOTE: I have never been impressed with isolated fasting triglyceride levels as an independent risk factor (neither was 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), the no's seem to have won. Claims about coffee has repeatedly flopped; in the most recent study, drinking either the real stuff or decaf actually seems to protect (Am. J. Med. 148: 904, 2008). 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.

CONTROVERSY: "Atherosclerosis as an infectious / inflammatory 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. In the 1990's it was 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 and of varying sizes ... just as in classic dystrophic calcification without any organisms. 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 everybody can see the bacteria in stomach ulcers, and nobody can actually see them in atherosclerosis. 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 coronary 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 still 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). In turn, I wonder whether it's perhaps being produced in the plaques, explaining the elevated levels. Stay tuned.

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 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. People with a mutation that elevates C-reactive protein are not at extra risk for atherosclerosis (told you so.... NEJM 359: 1897, 2008).

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.

Update on the molecules that are supposedly involved in "inflammation as a cause of atherosclerosis": Circulation 109(S2):II-2, 2004. I'm anything but impressed by the "lymphocytic infiltrates" that supposedly abound in plaques, especially as they get worse. Somebody else will tell you that "inflammation is usually what causes the plaques to rupture", which is hard to believe given their strong propensity to rupture at times of hard physical or emotional exertion -- a mechanical explanation would seem easier to believe.

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 (infamous: Cancer 106: 718, 2006);
• 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. Still helpful: Mayo Clin. Proc. 66: 818, 1991. Okay, atherosclerosis is actually a pattern of injury.