Endnotes Chapters 11,12,13,14,15

Chapter 11
1 See “Race for the $1000 Genome Is On” in www.newscientist.com/news/news.jsp?id5ns99992900.
2 www.research.ibm.com/resources/news/20031114_bluegene.shtml.
3 J. Cohen. “Big-picture biotech.” MIT Technology Review V, December 2003–January 2004.
4 Ibid.
5 R. J. Williams. 1998. Biochemical Individuality: The Basis for the Genetotrophic Concept. New York: Keats.
6 Interestingly, over the past dozen years or so since the Human Genome Project began, about $3 billion has been spent to complete the sequencing or about $1 per base pair.
7 The completion of the Human Genome Project occurred in the “fiftieth anniversary year of the discovery of the double-helical structure of DNA. . . . The genomic era is now a reality.” F. S. Collins et al. 2003. “A vision for the future of genomics research.” Nature. Apr 24;422: 835–847. To celebrate, entire issues of the major scientific journals Nature and Science were dedicated to discussions of the implications. For more information, see the Human Genome Project Information site (www.ornl.gov/TechResources/
Human_Genome/project/50yr.html).
Among the challenges is applying the lessons learned from the Human Genome Project to understanding thousands of other organisms. See, for example, M. E. Frazier et al. 2003. “Realizing the potential of the genome revolution: the Genomes to Life Program.” Science. 300: 290; F. S. Collins, M. Morgan, and A. Patrinos. “The Human Genome Project: lessons from large-scale biology.” Science. 300: 286. See also M. Ridley. 1999. Genome: The Autobiography of a Species in 23 Chapters. New York: Perennial.
8 Andi Braun, chief medical officer of Sequenon, as quoted in Wired, November 2002, p.183.
9 R. Carlson. 2003. “The pace and proliferation of biological technologies.” Biosecurity and Bioterrorism. 1(3); published online August 20, 2003, at www.molsci.org/~rcarlson/Carlson_Pace_and_Prolif.pdf.
10 D. Weatherall. 2003. “Evolving with the enemy.” NewScientist. 802(2422): 44.
11 Each chip contains synthetic oligonucleotides that replicate sequences that identify specific genes. “To determine which genes have been expressed in a sample, researchers isolate messenger RNA from test samples, convert it to complementary DNA (cDNA), tag it with fluorescent dye, and run the sample over the wafer. Each tagged cDNA will stick to an oligo with a matching sequence, lighting up a spot on the wafer where the sequence is known. An automated scanner then determines which oligos have bound, and hence which genes were expressed.” E. Marshall. 1999. “Do-it-yourself gene watching.” Science. Oct 15;286(5439): 444–447.
12 Ibid.
13 J. Rosamond and A. Allsop. 2000. “Harnessing the power of the genome in the search for new antibiotics.” Science. Mar 17;287(5460): 1973–1976.
14 A. Dove. 2002. “Antisense and sensibility.” Nature Biotechnology. Feb;20: 121–124.
15 K. Philipkoski. “Next big thing in biotech: RNAi.” Wired News. November 20, 2003; www.wired.com/news/medtech/0,1286,61305,00.html.
16 A. Goho. “Life made to order.” MIT Technology Review, April 2003; www.technologyreview.
com/articles/print_version/goho20403.asp.
17 Pima Indians in Arizona maintained their traditional way of life until the late 19th century. Then farmers diverted their water supply, resulting in many relying on the lard, sugar, and white flour provided by the government. During World War II, many Pimas entered military service or migrated to cities
to work in factories. Though many Pimas returned to the reservations in the 1950s, their way of life
was “profoundly affected.” See “Obesity associated with high rates of diabetes in the Pima Indians,” http://diabetes.niddk.nih.gov/dm/pubs/pima/obesity/obesity.htm.
According to a recently published theory, the reason only 2 percent of Europeans suffer from diabetes is that a diabetes epidemic centuries ago killed many people and prevented them from passing on the gene. Other populations, particularly indigenous peoples, carry the genes that make them highly prone to the risk factors found in urbanized settings. This is one reason 50 percent of Native Americans have diabetes. J. Diamond. 2003. “The double puzzle of diabetes.” Nature. Jun 05;423: 599–602. See also D. L. Coleman. 1978. “Diabetes and obesity: thrifty mutants?” Nutr Rev. May;36(5): 129–132.
18 J. Hahm and C. M. Lieber. 2004. “Direct Ultrasensitive Electrical Detection of DNA and DNA Sequence Variations Using Nanowire Nanosensors.” Nano Letters. 4(1): 51–54. See also http://pubs.acs.org/
cgi-bin/sample.cgi/nalefd/2004/4/i01/html/nl034853b.html.
19 Emory Health Sciences news release. March 27, 2003. www.emory.edu/WHSC/HSNEWS/
releases/mar03/nanotech.html.
20 R. A. Freitas Jr. 1999. Nanomedicine, Volume I: Basic Capabilities. Austin, Texas: Landes Bioscience. Or see www.nanomedicine.com.
21 Currently available risk panels include those for cardiac risk, high blood pressure, osteoporosis, immune function, detoxification capability, alcoholism, obesity, and more. For additional information, see Fantastic-Voyage.net.
22 R. Kurzweil. 1999. The Age of Spiritual Machines. New York: Viking, p. 30.
23 See the NIH National Human Genome Institute Web site: www.genome.gov/11511175.
24 Lifetime risk of developing breast cancer in women who test positive for the BRCA 1 mutation has been estimated at 80 percent, while lifetime risk for noncarriers is about 10 percent. See J. M. Lancaster. 1997. “BRCA 1 and 2—A Genetic Link to Familial Breast and Ovarian Cancer.” Medscape Women’s Health. Feb;2(2): 7. Other studies cite a 92 percent total lifetime risk.
In one Dutch study, 50 percent of healthy women whose mothers had breast cancer refused testing for BRCA1, preferring not to know whether they harbored such a potent cancer risk. The National Center for Technology Information (www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id5113705), with Johns Hopkins University, has summarized studies conducted on the BRCA gene.
25 Using genomics information to adversely prejudice against an individual is now called “genism.”
26 J. Zhang et al. 2003. “Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes.” Proc Natl Acad Sci USA. Feb 4;100(3): 1116–1121.
27 Some studies are focusing on the patterns of variations in apolipoproteins across populations. Their focus is to determine “the usefulness of apolipoproteins as genetic markers for clinical, population, and anthropological studies.” P. P. Singh, M. Singh, and S. S. Mastana. 2002. “Genetic variation of apolipoproteins in North Indians.” Hum Biol. Oct;74(5): 673–682.
Other studies are exploring the significance of a particular genetic pattern for a specific disease. X. Li, Y. Du, and X. Huang. 2003. “Association of apoliproprotein E gene polymorphism with essential hypertension and its complications.” Clin Exp Med. Feb;2(4): 175–179. See also M. Eto et al. 1988. “Familial hypercholesterolemia and apolipoprotein E4.” Atherosclerosis. Aug;72(2-3): 123–128.
28 R. H. Myers et al. 1996. “Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study.” Neurology. Mar;46(3): 673–677.
29 M. I. Kamboh. 1995. “Apolipoprotein E polymorphism and susceptibility to Alzheimer’s disease.” Hum Biol. Apr;67(2): 195–215.
30 L. A. Farrer et al. 1997. “Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer’s disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium.” JAMA. Oct 22–29;278(16): 1349–1356.
31 R. H. Myers et al. 1996. “Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study.” Neurology. Mar;46(3): 673–677.
32 See, for example, A. J. Slooter et al. 1998. “Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study.” Arch Neurol. Jul;55(7): 964–968.
33 H. K. Hamdi and C. Keney. 2003. “Age-Related Macular Degeneration: A New Viewpoint.” Frontiers in Bioscience. May1;8: e305–314.
34 W. Retz et al. 1998. “Free radicals in Alzheimer’s disease.” J Neural Transm Suppl. 54: 221–36.

Chapter 12
1 P. M. Ridker et al. 1998. “Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women.” Circulation. 98: 731–733.
2 R. N. Kalaria. 2002. “Small vessel disease and Alzheimer’s dementia: pathological considerations.” Cerebrovasc Dis. 13(Suppl 2): 48–52.
3 E. M. Castano et al. 1995. “Fibrillogenesis in Alzheimer’s disease of amyloid beta peptides and apolipoprotein E.” Biochem J. Mar 1;306( Pt 2): 599–604.
4 R. A. Floyd. 1999. “Neuroinflammatory processes are important in neurodegenerative diseases: an hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development.” Free Radic Biol Med. May;26(9–10): 1346–1355.
5 In fact, the Apo E4 polymorphism is often called the Alzheimer’s gene. The connection between the gene and Alzheimer’s was discovered in 1993 at Duke University. The risks of harboring the Apo E4 genotype are discussed more fully in chapter 11, “The Promise of Genomics.”
6 W. Marz et al. 1996. “Apolipoprotein E polymorphism is associated with both senile plaque load and Alzheimer-type neurofibrillary tangle formation.” Ann NY Acad Sci. Jan 17;777: 276–280.
7 T. G. Ohm et al. 1999. “Apolipoprotein E isoforms and the development of low and high Braak stages of Alzheimer’s disease-related lesions.” Acta Neuropathol (Berl). Sep;98(3): 273–280. D. S. Yang et al. 1997. “Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma.” J Neurochem. Feb;68(2): 721–725.
8 R. B. Pyles. 2001. “The association of herpes simplex virus and Alzheimer’s disease: a potential synthesis of genetic and environmental factors.” Herpes. Nov;8(3): 64–68. R. F. Itzhaki et al. 1997. “Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease.” Lancet. Jan 25;349(9047): 241–244.
9 M. R. Hayden. 2002. “Islet amyloid, metabolic syndrome, and the natural progressive history of type 2 diabetes mellitus.” JOP. J Pancreas (Online). 3(5): 126–138. See www.joplink.net/prev/200209/02.html.
10 C. Gorman and A. Park. 2004. “The fires within.” Time. Feb 23; 163(8): 41.
11 B. S. Reddy et al. 1992. “Inhibition of colon carcinogenesis by prostaglandin synthesis inhibitors and related compounds.” Carcinogenesis. Jun;13(6): 1019–1023.
12 A. Akhmedkhanov et al. 2002. “Aspirin and lung cancer in women.” Br J Cancer. Jul 1;87(1): 49–53.
13 Y. Y. Fan, K. S. Ramos, and R. S. Chapkin. 1997. “Dietary gamma-linolenic acid enhances mouse macrophage-derived prostaglandin E1 which inhibits vascular smooth muscle cell proliferation.” 1997. J Nutr. Sep;127(9): 1765–1771. U. N. Das et al. 1989. “Prostaglandins can modify gamma-radiation and chemical induced cytotoxicity and genetic damage in vitro and in vivo.” Prostaglandins. Dec;38(6): 689–716.
14 J. I. Kreisberg and P. Y. Patel. 1983. “The effects of insulin, glucose and diabetes on prostaglandin production by rat kidney glomeruli and cultured glomerular mesangial cells.” Prostaglandins Leukot Med. Aug;11(4): 431–442.
15 T. Hishinuma, T. Yamasaki, and M. Mizugaki. 1999. “Effects of long-term supplementation of eicosapentaneoic and docosahexaneoic acid on the 2-, 3-series of prostacyclin production by endothelial cells.” Prostaglandins Other Lipid Mediat. Jul;57: 333–340; V. E. Kelley et al. 1985. “A fish oil diet rich in eicosapentaneoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice.” J Immunol. Mar;134(3): 1914–1919.
16 The best vegetarian source of preformed EPA is wakame, a type of seaweed that contains 186 mg of EPA per 100 grams of seaweed. Yet vegans and vegetarians are still advised to supplement with flaxseed oil, because to obtain 650 mg of EPA, the minimum daily requirement, over 12 ounces of wakame a day would be needed.
17 M. Laimer et al. 2002. “Markers of chronic inflammation and obesity: a prospective study on the reversibility of this association in middle-aged women undergoing weight loss by surgical intervention.” Int J Obes Relat Metab Disord. May;26: 659–662; M. Visser. 2001. “Higher levels of inflammation in obese children.” Nutrition. Jun;17: 480–481.
18 J. K. Kiecolt-Glaser et al. 2003. “Chronic stress and age-related increases in the proinflammatory cytokine IL-6.” Proc Natl Acad Sci USA. Jul 22;100(15): 9090–9095.
19 H. Bucher et al. 2002. “n-3 Polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials.” Am J Med. 112: 298–304.
20 A multicenter double-blind study of 500 patients is an example of the ongoing work to further investigate this link. I. A. Brouwer et al. 2003. “Rationale and design of a randomised controlled clinical trial on supplemental intake of n-3 fatty acids and incidence of cardiac arrhythmia: SOFA.” Eur J Clin Nutr. Oct;57(10): 1323–1330. See also I. Rosenberg. 2002. “Fish-food to calm the heart.” New Engl J Med. 346(15): 1102–1103.
21 For more information on gum disease and health, see the American Academy of Periodontology site (www.perio.org/consumer/2a.html). The link between heart disease and gum disease has still not been conclusively established. See S. Abou-Raya, A. Naeem, and K. H. Abou-El. 2002. “Coronary artery disease and periodontal disease: is there a link?” Angiology. Mar–Apr;53(2): 141–148; P. Hujoel et al. 2000. “Periodontal disease and coronary heart disease risk.” JAMA. Sept 20;284(11): 1406–1410.
22 P. P. Zandi, J. C. Breitner, and J. C. Anthony. 2002. “Is pharmacological prevention of Alzheimer’s a realistic goal?” Expert Opin Pharmacother. Apr;3(4): 365–380; B. M. McLendon, G. G. Chen, and P. M. Doraiswamy. 2000. “Current and future treatments for cognitive deficits in dementia.” Curr Psychiatry Rep. Feb;2(1): 20–23.
23 W. F. Stewart et al. 1997. “Risk of Alzheimer’s disease and duration of NSAID use.” Neurology. Mar;48(3): 626–632.
24 P. S. Sanmuganathan et al. 2001. “Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials.” Heart. Mar;85(3): 265–271.
25 Chronic NSAID use is associated with a very high incidence of adverse drug reactions, such as gastrointestinal hemorrhage. Over 16,500 deaths and 100,000 hospitalizations annually have been associated with prescription NSAID usage (and the number would be even higher if over-the-counter usage were included). See M. Wolfe, D. Lichtenstein, and S. Gurkirpal. 1999. “Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs.” N Engl J Med. Jun 17;340(24): 1888–1899.
26 F. E. Silverstein et al. 2000. “Gastrointestinal toxicity with celecoxib versus nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial.” JAMA. 284: 1247–1255; C. Bombardier et al. for the VIGOR Study Group. 2000. “Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.” N Engl J Med. 343: 1520–1528.
27 P. Libby, op cit, p.55.
28 B. Lindahl et al. 2000. “Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during instability in coronary artery disease.” N Engl J Med. Oct 19;343(16): 1139–1147; D. J. Rader. 2000. “Inflammatory markers of coronary risk.” N Engl J Med. Oct 19;343(16): 1179–1182; C. J. Packard et al. 2000. “Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group.” N Engl J Med. Oct 19;343(16): 1148–1155.
29 J. Danesh et al. 2000. “Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses.” BMJ. Jul 22;321(7255): 199–204.
30 P. M. Ridker et al. 1998. “C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction.” Circulation. May 26;97(20): 2007–2011.
31 I. Kushner. 2001. “C-reactive protein elevation can be caused by conditions other than inflammation and may reflect biologic aging.” Cleve Clin J Med. Jun;68(6): 535–537.
32 N. Rifai and P. M. Ridker. 2001. “High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease.” Clin Chem. Mar; 47(3): 403–411; P. M. Ridker et al. 2000. “C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.” N Engl J Med. Mar 23;342(12): 836–843.
33 In this slight variation from normal, the 31st nucleotide in the DNA chain that codes for IL-1b, one nucleotide, cytosine, is replaced by thymidine (31CÆT polymorphism).
34 N. Sueoka et al. 2001. “A new function of green tea: prevention of lifestyle-related diseases.” Ann NY Acad Sci. Apr; 928: 274–280.

Chapter 13
1 The risk of defective homocysteine metabolism rises with age and varies with ethnicity; hence the wide spread between 10 and 44 percent. See G. L. Booth and E. E. Wang. 2000. “Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care.” CMAJ. Jul 11;163(1): 21–29.
2 Medicare does not pay for homocysteine testing, regarding it as neither medically reasonable nor necessary. Although controversial, we feel that by paying a few tens of dollars for routine homocysteine screening, it would help identify many individuals at significant risk of heart attack, stroke, and Alzheimer’s diseases that Medicare then pays tens of thousands of dollars to treat.
3 In the same paragraph on their Web site that the American Heart Association doesn’t acknowledge homocysteine as a “major risk factor for cardiovascular disease,” they also “don’t recommend widespread use of folic acid and B vitamin supplements to reduce the risk of heart disease and stroke.” See www.
americanheart.org/presenter.jhtml?identifier54677. See also, M. R. Malinow et al. 1999. “Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association.” Circulation. 99: 178–182.
4 Any product containing more than 800 mcg of folic acid requires a prescription.
5 More precisely, cytosine first undergoes another chemical reaction known as “deamination” to form uracil, which is then methylated to form thymine.
6 J. Yokota et al. 2003. “Genetic alterations responsible for metastatic phenotypes of lung cancer cells.” Clin Exp Metastasis. 20(3): 189–193. According to this study, one gene associated with lung cancer is “inactivated in 50% of lung cancers by deletions, mutations, and methylation.” See also K. S. McCully. 1994. “Chemical pathology of homocysteine. II. Carcinogenesis and homocysteine thiolactone metabolism.” Ann Clin Lab Sci. Jan–Feb;24(1): 27–59.
7 See M. Iscan et al. 2002. “The organochlorine pesticide residues and antioxidant enzyme activities in human breast tumors: is there any association?” Breast Cancer Res Treat. Mar;72(2): 173–182; C. Charlier and G. Plomteux. 2002. “Environmental chemical pollution and risk of human exposure: the role of organochlorine pesticides.” Ann Biol Clin (Paris). Jan–Feb;60(1): 37–46; M. S. Wolff and P. G. Toniolo. 1995. “Environmental organochlorine exposure as a potential etiologic factor in breast cancer.” Environ Health Perspect. Oct;103(Suppl 7): 141–145.
8 K. Nilsson et al. 1996. “Hyperhomocysteinaemia—a common finding in a psychogeriatric population.” Eur J Clin Invest. Oct;26(10): 853–859.
9 S. R. Maxwell. 2000. “Coronary artery disease—free radical damage, antioxidant protection and the role of homocysteine.” Basic Res Cardiol. 95(Suppl 1): 165–171.
10 W. P. Castelli. 1996. “Lipids, risk factors and ischaemic heart disease.” Atherosclerosis. Jul;124(Suppl): S1–9.
Many other studies have also shown such a connection. For example, an Irish study showed a fivefold increase in the risk of stroke with elevated homocysteine levels. The lead author suggested that the unavailability of fortified foods, particularly cereals, in the United Kingdom made supplementation even more important. S. P. McIlroy et al. 2002. “Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase geneotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland.” Stroke. Oct;33(10): 2351–2356.
11 M. J. Stampfer et al. 1992. “A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in U.S. physicians.” JAMA. Aug 19;268(7): 877–881.
12 R. Clarke et al. 1998. “Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.” Arch Neurol. Nov;55(11): 1449–1455.
13 While elevated homocysteine confers a cardiovascular risk equal to smoking, the combination is even worse. One study “suggests that smokers with high plasma homocysteine are at greatly increased risk of cardiovascular disease and should therefore be offered intensive advice to help them cease smoking.” P. O’Callaghan et al. 2002. “Smoking and plasma homocysteine.” Eur Heart J. Oct;23(20): 1580–1586; S. Tonstad and P. Urdal. 2002. “Does short-term smoking cessation reduce plasma total homocysteine concentrations?” Scand J Clin Lab Invest. 62(4): 279–284. See also I. M. Graham et al. 1997. “Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project.” JAMA. Jun 11;277(22): 1775–1781.
14 J. M. Ellis and K. S. McCully. 1995. “Prevention of myocardial infarction by vitamin B6.” Res Commun Mol Pathol Pharmacol. Aug;89(2): 208–220.
15 Functional levels refer to amounts in the blood that prevent biochemical abnormality and are distinct from the absolute bloodstream level. D. G. Savage et al. 1994. “Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies.” Am J Med. Mar;96(3): 239–246.
16 D. J. DeRose et al. 2000. “Vegan diet-based lifestyle program rapidly lowers homocysteine levels.” Prev Med. Mar 30: 225–33.
17 L. L. Husemoen et al. 2004. “Effect of lifestyle factors on plasma total homocysteine concentrations in relation to MTHFR(C677T) genotype.” Eur J Clin Nutr. Advance online publication March 31, 2004.
18 M. S. van der Gaag et al. 2000. “Effect of consumption of red wine, spirits, and beer on serum homocysteine.” Lancet. Apr 29;355(9214): 1522.
19 J. F. Toole et al. 2004. “Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.” JAMA. Feb 4;291(5): 565–575.
20 Homocysteine Lowering Trialists’ Collaboration. 2000. “Lowering blood homocysteine with folic acid-based supplements: meta-analysis of randomised trials.” Indian Heart J. Nov–Dec;52(7 Suppl): S59–64.
21 I. M. Graham et al. 1997. “Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project.” JAMA. Jun 11;277(22): 1775–1781.
22 See, for example, M. R. Malinow et al. 1998. “Reduction of Plasma Homocyst(e)ine Levels by Breakfast Cereal Fortified with Folic Acid in Patients with Coronary Heart Disease.” N Engl J Med. 338: 1009–1015.
23 E. Arnesen et al. 1995. “Serum total homocysteine and coronary heart disease.” Int J Epidemiol. Aug;24(4): 704–709.
24 www.labcorp.com/datasets/labcorp/html/chapter/mono/sr021700.htm.
25 I. M. Graham et al. 1997, op cit.
26 E. K. Amouzou et al. 2004. “High prevalence of hyperhomocysteinemia related to folate deficiency and the 677C—>T mutation of the gene encoding methylenetetrahydrofolate reductase in coastal West Africa.” Am J Clin Nutr. Apr;79(4): 619–624.
27 L. D. Botto and Q. Yang. 2000. “5,10-Methylenetetrahydrofolate reductase (MTHFR) Gene Variants and Congenital Anomalies.” Am J Epidemiol. 151(9): 862–877. W. Herrman et al. “Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and the B-vitamins: a facet of nature-nurture interplay.” Clin Chem Lab Med. Apr;41(4): 547–553; S. S. Kang et al. 1991. “Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations.” Am J Hum Genet. Mar;48(3): 546–551.
28 L. A. Kluijtmans et al. 1996. “Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.” Am J Hum Genet. Jan;58(1): 35–41.
29 M. Goodman et al. 2001. “Association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate with the risk of cervical dysplasia.” Cancer Epidemiol Biomarkers Prev. Dec;10(12): 1275–1280.
30 S. Matsushita et al. 1997. “The frequency of the methylenetetrahydrofolate reductase-gene mutation varies with age in the normal population [letter].” Am J Hum Genet. 61: 1459–1460.

Chapter 14
1 “Louisiana led the nation in toxic waste generated, with more than nine billion pounds generated, or approximately one quarter of the nation’s toxic waste. Nevada led the nation in direct releases, with 14 percent of the nation’s pollution, mostly from the mining industry.” U.S. PIRG news release, “Toxic waste production increased by eight billion pounds in 2000: New dioxin data show high amounts of hazardous pollution,” May 23, 2002, www.uspirg.org/uspirgnewsroom.asp?id257030&id35USPIRGnewsroom&.
2 B. C. Wolverton et al. “Interior Landscape Plants for Indoor Air Pollution Abatement,” NASA/ALCA Final Report, Plants for Clean Air Council, Davidsonville, Maryland, 1989.
3 The U.S. EPA maintains information on air and radiation at www.epa.gov/air/concerns. See information on environmental sites such as the Rainforest Action Network (www.ran.org/info_center/factsheets/
04a.html) and Environmental Defense (www.environmentaldefense.org/system/templates/page/focus.cfm?
focus53).
NOVA Online (www.pbs.org/wgbh/nova/ice/greenhouse.html) provides useful background: “Greenhouse gas concentrations in the atmosphere have been naturally rising and falling for billions of years, creating cold and warm periods in the Earth’s history. For example, as the Ice Age progressed, scientists believe the amount of natural carbon dioxide in the atmosphere dropped over thousands of years, reducing the greenhouse effect, and making the Earth cooler. But many disagree on how that change in carbon dioxide occurred. Today, scientists are looking at effects of global warming as they debate the long-term impact of man-made carbon dioxide and CFCs entering the atmosphere. Many climatologists argue that we are artificially increasing the greenhouse effect, warming the Earth faster than would occur naturally, which could cause problems for the Earth in the future.”
4 T. J. Woodruff et al. 1998. “Public health implications of 1990 air toxics concentrations across the United States.” Environ Health Perspect. May;106(5): 245–251.
5 EPA Office of Air and Radiation. 1993. “Targeting Indoor Air Pollution: EPA’s Approach and Progress.” EPA 400R 92012; EPA Office of Air and Radiation. 2001. “Healthy Buildings, Healthy People: A Vision for the 21st Century.” EPA 402K01003, p. 8.
6 B. O. Brooks et al. 1991. “Indoor air pollution: an edifice complex.” J Toxicol Clin Toxicol. 29(3): 315–374. Both the EPA (www.epa.gov/iaq/pubs/sbs.html) and the National Safety Council (www.nsc.org/ehc/indoor/sbs.htm) maintain information about sick buildings.
7 www.epa.gov/ogwdw/dwh/health.html.
8 J. A. Varner et al. 1998. “Chronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water: alterations in neuronal and cerebrovascular integrity.” Brain Res. Feb 16; 784(1–2): 284–298.
9 A. Hoshi et al. 2001. “Concentrations of trace elements in sweat during sauna bathing.” Tohoku J Exp Med. Nov;195(3): 163–169.
10 B. C. Kross et al. 1996. “Proportionate mortality study of golf course superintendents.” Am J Ind Med. May;29(5): 501–506.
11 Interestingly, this same group of refinery workers was noted to have significantly decreased mortality from respiratory tuberculosis (29 percent), esophageal cancer (45 percent), rectal cancer (49 percent), and cancers of the bladder and other urinary organs (40 percent), suggesting a multifactorial cause for the expression of exposure to petrochemicals at refineries and genetic expression of cancer-causing potential. J. M. Dement et al. 1998. “Proportionate mortality among union members employed at three Texas refineries.” Am J Ind Med. Apr;33(4): 327–340.
12 B. A. Evanoff, P. Gustavsson, and C. Hogstedt. 1993. “Mortality and incidence of cancer in a cohort of Swedish chimney sweeps: an extended follow up study.” Br J Ind Med. May;50(5): 450–459.
13 “Estimated daily doses of dieldrin alone exceed US Environmental Protection Agency and US Agency for Toxic Substances Disease Control reference dose for children. Given the widespread occurrence of POPs in the food supply and the serious health risks associated with even extremely small levels of exposure, prevention of further food contamination must be a national health policy priority in every country.” K. S. Schafer and S. E. Kegley. 2002. “Persistent toxic chemicals in the U.S. food supply.” J Epidemiol Community Health. Nov;56(11): 813–817.
14 See www.foodnews.org/reportcard.php.
15 G. Hyland. 2001. “The Physiological and Environmental Effects of Non-Ionising Electromagnetic Radiation.” European Parliament Directorate General for Research.
16 H. Lai and N. P. Singh. 1996. “Single- and double-strand DNA breaks in rat brain cells after acute exposure to radiofrequency electromagnetic radiation.” Int J Radiat Biol. Apr;69(4): 513–521.
17 D. Leszczynski et al. 2002. “Non-thermal activation of the hsp27/p38MAPK stress pathway by mobile phone radiation in human endothelial cells: Molecular mechanism for cancer- and blood-brain barrier-related effects.” Differentiation. May;70(2–3): 120–129.
18 R. O. Becker. 1990. Cross Currents: The Promise of Electromedicine, the Perils of Electropollution. New York: J. P. Tarcher.
19 Ibid.
20 S. Boseley. “Hands-Free Mobiles Increase Radiation Risk.” The Guardian. April 4, 2000.
21 S. Overell. “Scientists Believe a Ferrite Choke Clipped to the Wire of a Hands-Free Set Could Dramatically Lower Radiation.” Financial Times, February 12, 2001.
22 The Institute for Genomic Research (TIGR) deciphered the genome. The “extraordinary” capabilities of Geobacter come from over 100 genes that code c-type cytochromes, which are proteins involved in electron transfer and metal reduction. This is the largest number of this type of gene yet found in a bacterial species. “Scientists decipher genome of bacterium that remediates uranium contamination
and generates electricity through its metabolism.” TIGR news release at www.tigr.org/new/
press_release_12-11-03.shtml, referring to B. A. Methe et al. 2003. “Genome of Geobacter sulfurreducens: metal reduction in subsurface environments.” Science. Dec 12(302): 1967–1969.
23 A. Goho. “Life made to order.” MIT Technology Review, April 2003; www.technologyreview.
com/articles/print_version/goho20403.asp.
24 S. Duke. 2003. “Weeding with transgenes.” Trends in Biotechnology. 21(5): 192–195.
25 E. Baard. “Plants have a way with metals.” Wired News, September 5, 2003; www.wired.com/
news/print/0,1294,60302,00.html.
26 S. Duke, op cit.
27 H. Y. Ha et al. 2003. “Chronic restraint stress massively alters the expression of genes important for lipid metabolism and detoxification in liver.” Toxicol Lett. Dec(146): 49–63.
28 L. Carroll. 2004. “Genes, toxins, and Parkinson’s.” International Herald Tribune, February 12, at www.iht.com/articles/129155.html.
29 A. D. de Grey. 2003. “An Engineer’s Approach to the Development of Real Anti-Aging Medicine.” Sci SAGE KE. Jan 8: VP1. See http://sageke.sciencemag.org/cgi/content/full/2003/1/vp1 and also A. D. de Grey. 2002. “Bioremediation meets biomedicine: therapeutic translation of microbial catabolism to the lysosome.” Trends Bioltechnol. 20(11): 452–455.
30 “The notion of ‘vaccinating’ individuals against a neurodegenerative disorder such as Alzheimer’s disease is a marked departure from classical thinking about mechanism and treatment, and yet therapeutic vaccines for both Alzheimer’s disease and multiple sclerosis have been validated in animal models and are in the clinic. Such approaches, however, have the potential to induce unwanted inflammatory responses as well as to provide benefit.” H. L. Weiner and D. J. Selkoe. 2002. “Inflammation and therapeutic vaccination in CNS diseases.” Nature. Dec 19–26;420(6917): 879–884. These researchers showed that a vaccine in the form of nose drops could slow the brain deterioration of Alzheimer’s. H. L. Weiner et al. 2000. “Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease.” Ann Neurol. Oct;48(4): 567–579.
31 D. Beyersmann. 2002. “Effects of carcinogenic metals on gene expression.” Toxicol Lett. Feb 28;127(1–3): 63–68.
32 P. Weihe et al. 2002. “Neurobehavioral performance of Inuit children with increased prenatal exposure to methylmercury.” Int J Circumpolar Health. Feb;61(1): 41–49.
33 S. A. Thompson et al. 1998. “Alterations in immune parameters associated with low level methylmercury exposure in mice.” Immunopharmacol Immunotoxicol. May;20(2): 299–314.
34 “Coal-fired power plants are the largest industrial emitters of mercury, producing over one
third of all mercury pollution in the U.S.,” per the Clear the Air public education campaign (http://cta.policy.net/mercury/).
“In very small quantities, [mercury] conducts electricity, measures temperature and pressure, and forms alloys with almost all other metals. With these and other unique properties, mercury plays an important role as a process or product ingredient in several industrial sectors.” Background Information on Mercury Sources and Regulations, available along with other mercury information at www.epa.gov/mercury/
information.htm#fact_sheets.
35 A 2001 report by U.S. PIRG (the national lobbying office for the state Public Interest Research Groups, which are nonprofit, nonpartisan public interest advocacy groups) and the Environmental Working Group found that mercury contamination of fish is so great that 25 percent of pregnant women who eat fish regularly expose their unborn babies to levels of mercury that could threaten a developing fetus. The situation will only get worse with full enactment of the Bush administration’s “Clear Skies Initiative,” which would allow three times more mercury pollution than full enforcement of the current Clean Air Act.
36 Farm-raised salmon are fed fish food containing high levels of pollutants. Unlike wild ocean salmon that consume phytoplankton, which they then turn into EPA, farm-raised salmon have little EPA. A recent report by the Environmental Working Group suggests farmed salmon may also be high in PCBs due to contamination of their food (www.ewg.org/news/story.php?id51871).
37 The Environmental Working Group’s fish list is at www.ewg.org/reports/BrainFood/sidebar.html.
38 The health benefits of amalgam removal are more theoretical than proven, although it would seem that having mercury inside one’s mouth is less than ideal. To learn more about mercury toxicity, read It’s All in Your Head, Hal Huggins (New York: Avery Penguin Putnam, 1993).
39 A. Szutowicz. 2001. “Aluminum, NO, and nerve growth factor neurotoxicity in cholinergic neurons.” J Neurosci Res. Dec 1;66(5): 1009–1018.
40 P. Fairley. “Saving Lives with Living Machines.” Technology Review. July/August 2003. www.
technologyreview.com/articles/print_version/fairley0703.asp.
41 Ibid.
42 R. Zacks. “The Liver Chip.” Technology Review. March 2003. www.technologyreview.com/
articles/demo0303.asp?x538&y511.
43 R. A. Freitas Jr. “Death is an Outrage.” KurzweilAI.net Jan. 9, 2003. www.kurzweilai.net/
articles/art0536.html. (Based on a lecture by the author at the Fifth Alcor Conference on Extreme Life Extension.)
44 This test is called the Comprehensive Detoxification Profile and is available through your health care practitioner from Great Smokies Diagnostic Laboratory (www.gsdl.com).
45 N. Song et al. 2001. “CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: a case-control study in China.” Carcinogenesis. Jan;22(1): 11–16.
46 H. Payami et al. 2001. “Parkinson’s disease, CYP2D6 polymorphism, and age.” Neurology 2001; May 22;56(10): 1363–1370.
47 T. Konishi et al. 2003. “The ADH3*2 and CYP2E1 c2 alleles increase the risk of alcoholism in Mexican American men.” Exp Mol Pathol. Apr;74(2): 183–189.
48 H. Zheng et al. 2004. “Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism.” J Clin Pharmacol. Feb;44(2): 135–140.
49 V. Fonte et al. 2002. “Interaction of intracellular beta amyloid peptide with chaperone proteins.” Proc Natl Acad Sci USA. Jul 9;99(14): 9439–9444.
50 P. Hammarstrom, F. Schneider, and J. W. Kelly. 2001. “Trans-suppression of misfolding in an amyloid disease.” Science Sep 28;293(5539): 2459–2462.
51 P. M. Harrison et al. 1999. “Thermodynamics of model prions and its implications for the problem of prion protein folding.” J Mol Biol. Feb 19;286(2): 593–606.

Chapter 15
1 “Chronic Disease Overview,” National Center for Chronic Disease Prevention and Health Promotion (www.cdc.gov/nccdphp/overview.htm). See also the 2003 Heart Disease and Stroke Statistical Update, American Heart Association (www.americanheart.org/presenter.jhtml?identifier53000090).
2 Even though women’s comparable risk trails that of men by 10 years, “more than half of persons who die each year of heart disease are women.” “Chronic Disease Overview,” op. cit. Also, “38 percent of women compared to 25 percent of men will die within one year after a heart attack.” “Statistics You Need to Know,” American Heart Association (www.americanheart.org/presenter.jhtml?identifier5107).
3 In the United States, for example, approximately 75,000 bypass surgeries were performed in
1979 and over 520,000 in 2000. Angioplasties were first tracked by the AHA in 1986; by 2002, close to 570,000 were performed per year in the United States. “Trends in Cardiovascular Operations and Procedures,” in “2003 Heart Disease and Stroke Statistical Update,” American Heart Association (www.americanheart.org/presenter.jhtml?identifier53009972). See also A. Michaels and K. Chatterjee. 2002. “Angioplasty versus bypass surgery for coronary artery disease.” Circulation. Dec 3;106(23):187–190.
4 Recent data suggest that the volume of cases handled by the hospital and the surgeon in particular has an impact on the mortality rate from bypass surgery. See E. L. Hannan et al. 2003. “Do hospitals and surgeons with higher coronary artery bypass graft surgery volumes still have lower risk-adjusted mortality rates?” Circulation. Aug 19;108(7):795–801.
5 Public information materials often claim that the mental decline is temporary; see, for example, “Coronary bypass surgery,” MayoClinic.com (www.mayoclinic.com/invoke.cfm?id5HB00022). However, recent research has found “early improvement followed by later decline”; see, for example, M. F. Newman et al. 2001. “Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery.” N Engl J Med. Feb 8;344(6):395–402.
6 Bypass surgery and angioplasty cannot fix the injured heart tissue or the microvessel obstructions that are most likely to cause post-heart-attack complications. Johns Hopkins Magazine, April 1998, “Treating heart attacks through MRI,” www.jhu.edu/~jhumag/0698web/health.html. This study showed a higher risk of death for patients with invasive treatment: L. F. Wexler et al. 2001. “Non-Q-wave myocardial infarction following thrombolytic therapy: a comparison of outcomes in patients randomized to invasive or conservative post-infarct assessment strategies in the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) Trial.” J Am Coll Cardiol. Jan;37(1):19–25.
In this study, patients treated invasively experienced less angina but significantly more critical events, including death. H. C. Bucher et al. 2000. “Percutaneous transluminal angioplasty versus medical treatment for non-acute coronary heart disease: meta-analysis of randomized controlled trials.” BMJ. Jul 8;321(7253): 73–77. Another study showed many repeat operations in patients treated invasively and a 22-year cumulative survival rate of 20 percent in the surgically treated group compared with 25 percent in the medically treated group. “This trial provides strong evidence that initial bypass surgery did not improve survival for low-risk patients and that it did not reduce the overall risk of myocardial infarction.” P. Peduzzi, A. Kamina, and K. Detrie. 1999. “Twenty-two-year follow-up in the VA Cooperative Study of coronary artery bypass surgery for stable angina.” Am J Cardiol. Jan 15;83(2): 301–304.
In yet another study, “patients undergoing coronary angioplasty had twice the rate of adverse outcomes as normal subjects, seven times the rate of angina, almost four times the number of heart attacks and twice the rate of congestive heart failure.” G. A. Van Norman and K. Posner. 2000. “Coronary stenting or percutaneous transluminal coronary angioplasty before noncardiac surgery increases adverse events: the evidence is mounting.” J Am Coll Cardiol. Dec;36(7): 2351–2352 (as described on the Noninvasive Heart Center site, www.heartprotect.com/comparison-studies.shtml). See also note 7 below and note 82 on page 418.
7 Note 6 above cites several studies that show improved outcomes for treatment with medication as compared to treatment with surgery. Two studies that show a slightly better outcome with surgery are: C. Espinoza-Klein et al. 2000. “Ten-year outcome after coronary angioplasty in patients with single-vessel coronary artery disease and comparison with the results of the Coronary Artery Surgery Study (CASS).” Am J Cardiol. Feb 1;85(3): 321–326. This study showed relative rates of survival after 10 years was 86 percent after balloon angioplasty, 85 percent after bypass surgery, and 82 percent with medical treatment alone.
M. M. Graham et al. 2002. “Survival after coronary revascularization in the elderly.” Circulation. May 21: 105(20): 2378–2384. This study showed 17 percent better survival in older patients (greater than 80 years old) who had surgery versus those who did not. This study also showed a small survival increase in patients under 70 years old who had surgery versus those who did not (95 percent versus 91 percent).
Studies have shown that angioplasty improves survival when applied during a heart attack to clear away the thrombus (blood clot).
Additional studies on treatment with medication include the following:
R. Conti. 1999. “Single-Vessel Disease: What is the Evidence Favoring Medical Versus Interventional Therapy?” Clin. Cardiol. 22, 3–5 (1999) at www.clinicalcardiology.org/briefs/9901briefs/22-003.html; “Treatment with a combination of statin and niacin can slash the risk of a fatal or non-fatal heart attack or hospitalization for chest pain by 70 percent among patients who are likely to suffer heart attacks and/or death from coronary heart disease, according to a study by University of Washington researchers in the Nov. 29 New England Journal of Medicine.”; B. G. Brown et al. 2001. “Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.” N Engl J Med. Nov 29;345(22): 1583–92. Summary for patients in: Curr Cardiol Rep. Nov 2002;4(6): 486. See also notes 6 and 82 on pages 411 and 418.
8 L. L. Demer et al. 1994. “Mechanism of calcification in atherosclerosis.” Trends Cardiovasc Med. 4: 45–49; L. L. Demer. “Effect of calcification on in vivo mechanical response of rabbit arteries to balloon dilation.” Circulation. June 1;83(6): 2083–2093.
9 In addition to the new model of heart disease presented in the next section, another primary reason for the failure of invasive procedures is that these procedures address symptoms of the problem, not the problem itself. “There is a common misconception that most of the excess risk accumulated over many years can be erased by aggressive short-term prevention introduced later in life.” S. Grundy et al. 1999. “Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations.” Circulation. 100: 1481–1492. The importance of behavioral changes in preventing future cardiovascular events and mortality has been shown by many studies, including N. C. Campbell et al. 1998. “Secondary prevention in coronary heart disease: a randomized trial of nurse-led clinics in primary care.” Heart. Nov;80(5): 447–452. With regard to the elderly, see last reference in note 7 above.
“Insulin resistance with or without frank type 2 diabetes has emerged as a major determinant of accelerated coronary artery disease and its sequelae.” Thus, a number of randomized clinical trials have been performed to compare the efficacy of these procedures for diabetic patients who fall into the subset of patients with severe multivessel disease who benefit from surgery. B. E. Sobel et al. 2003. “Burgeoning dilemmas in the management of diabetes and cardiovascular disease: rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial.” Circulation. Feb 4;107(4): 636–642.
10 K. S. Prediman. 2003. “Mechanisms of plaque vulnerability and rupture.” J Am Coll Cardiol. Feb 19;41(4 Suppl 1): S15–S22; M. Takano et al. 2001. “Mechanical and structural characteristics of vulnerable plaques analysis by coronary angioscopy and intravascular ultrasound.” J Am Coll Cardiol. Jul;38(1): 99–104.
11 New Studies Question Value of Opening Arteries, www.cse.buffalo.edu/~rapaport/510/
nyt-heart-printerfriendly.htm; B. G. Brown et al. 1986. “Incomplete Lysis of Thrombus in the Moderate Underlying Atherosclerotic Lesion during Intracoronary Infusion of Streptokinase for Acute Myocardial Infarction: Quantitative Angiographic Observations,” Circulation. 73: 653–661.
12 S. E. Nissen and J. C. Curley. 1991. “Application of intravascular ultrasound for detection and quantitation of coronary atherosclerosis.” Int J Card Imaging. Jan; 6(3–4): 165–177; P. Schoenhagen,
E. S. McErlean, and S. E. Nissen. 2000. “The vulnerable coronary plaque.” J Cardiovasc Nurs. Oct;15(1): 1–12.
13 D. D. Waters. 2000. “Medical therapy versus revascularization: the atorvastatin versus revascularization treatment AVERT trial.” Can J Cardiol. Jan;16(Suppl A): 11A–3A.
14 G. Kolata. “New Heart Studies Question the Value of Opening Arteries,” New York Times, March 21, 2004.
15 Ibid.
16 R. J. Aiello et al. 2002. “Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice,” Arteriosclerosis Thromb Vasc Biology. Mar;22(3): 361–363. The study states, “Compared with
age-matched controls, lipid accumulation and monocyte infiltration were significantly reduced in treated apoE(-/-) mice at all time points tested. Lesion area reduction was also demonstrated in LDLr(-/-) mice maintained on a high-fat diet.”
17 “Accumulating evidence indicates that the arteries of a cardiac patient become inflamed with white blood cells and other immune system agents in much the same way as arthritic joints and asthmatic airways.” R. Langreth. 2004. “Prevention Puzzle.” Forbes.com, Feb. 9, at www.forbes.com/global/
2004/0209/060_print.html; J. H. Dwyer et al. 2004. “Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis.” N Engl J Med. Jan 1;350(1): 29–37; I. Wickelgren. 2004. “Heart disease. Gene suggests asthma drugs may ease cardiovascular inflammation.” Science. Feb 13;303(5660): 941.
18 J-C Tardif et al. 2003. “Effects of AGI-1067 and probucol after percutaneous coronary interventions.” Circulation. 107: 552.
For more information on how AGI-1067 was developed, see M. Herper. 2003. “Inflamed Hearts.” Forbes.com, July 23, www.forbes.com/forbes/2003/0623/168_print.html; G. Coté et al. 1999. “Effects of probucol on vascular remodeling after coronary angioplasty.” Circulation. 99: 30–35.
19 M. Herper and R. Langreth. 2004. “Cardiovascular drugs to watch.” Forbes.com, April 27, www.forbes.com/2004/01/22/cx_mh_rl_cardiotear_9.html; Y. Hirakawa and H. Shimokawa. 2001. “Lipid-lowering drugs.” Nippon Yakurigaku Zasshi. Dec 1;118(6): 389–395.
20 J. A. Blackie et al. 2003. “The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.” Bioorg Med Chem Lett. 13(6) (Mar 24): 1067–1070; D. P. Rotella. 2004. “SB-480848. GlaxoSmithKline.” Curr Opin Invest Drugs. Mar;5(3): 348–351; M. Herper and R. Langreth. 2004. “Cardiovascular drugs to watch.” Forbes.com, April 27, www.forbes.com/2004/
01/22/cx_mh_rl_cardiotear_2.html.
21 G. Kolata, ibid.
22 G. Kolata, ibid.
23 National Cholesterol Education Program, Adult Treatment Panel III Report, 2001 (www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.pdf); J. Berliner et al. 1995. “Atherosclerosis: basic mechanisms.” Circulation. May 1;91(9): 2488–2496.
24 M. R. Naghavi et al. 2001. “New developments in the detection of vulnerable plaque.” Curr Ather Rep. 3(2): 125–135; M. R. Naghavi et al. 2001. “MRI detection of atherosclerotic vulnerable plaque using superparamagnetic iron oxide contrast media.” Am J Cardiol. July 19;88(2 Suppl 1): 82.
25 “. . . [T]he conditions provided by a chronic inflammatory environment are so essential for the progression of the neoplastic process that therapeutic intervention aimed at inhibiting inflammation . . . and stimulating cell-mediated immune responses may have a major role in reducing the incidence of common cancers.” K. J. O’Byrne and A. G. Dalgleish. 2001. Br J Cancer. Aug;85(4): 473–483.
Another of the many possible examples: “Mild chronic inflammation may play a significant role in the incidence of HBP [high blood pressure].” L. E. Bautista. 2003. “Inflammation, endothelial dysfunction and the risk of high blood pressure: epidemiologic and biological evidence.” J Hum Hypertens. April;17(4): 223–230.
26 “Heart and Stroke Facts.” American Heart Association (www.americanheart.org/
presenter.jhtml?identifier53000333); National Cholesterol Education Program, Adult Treatment Panel III Report, 2001 (www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.pdf).
27 The role of iron in atherosclerosis is still controversial. Some studies support such a role: “These results provide direct evidence for a key role of iron in initiating atherogenesis” (D. Ponraj et al. 1999. “The onset of atherosclerotic lesion formation in hypercholesterolemic rabbits is delayed by iron depletion.” FEBS Lett. Oct 8;459(2): 218: 222). Others do not: “Overall the results do not support the hypothesis that positive body iron stores, as measured by serum ferritin, are associated with an increased risk of cardiovascular diseases (CVD), coronary heart disease (CHD), or myocardial infarction (MI) . . . ” (C. T. Sempos et al. 2000. “Serum ferritin and death from all causes and cardiovascular disease: The NHANES II mortality study.” Ann Epidemiol. Oct 1;10(7): 441–448).
28 E. Falk et al. 1995. “Coronary plaque disruption.” Circulation. Aug 1;92(3): 657–671; A. P. Schroeder and E. Falk. 1995. “Vulnerable and dangerous coronary plaques.” Atherosclerosis. Dec;118 (Suppl): S141–149.
29 A. C. van der Wal and A. E. Becker. 1999. “Atherosclerotic plaque rupture: pathologic basis of plaque stability and instability.” Cardiovasc Res. 41: 334–344; E. Falk et al. 1995. “Coronary plaque disruption.” Circulation. Aug 1;92(3): 657–671; E. Falk. 1992; “Why do plaques rupture?” Circulation. 86(Suppl III): III-30-III-42.
30 G. Chiesa. 2002. “Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks.” Circ Res. May 17;90(9): 974–980; P. K. Shah et al. 2001. “High-dose recombinant apolipoprotein A-I milano mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice.” Circulation. Jun 26;103(25): 3047–3050.
31 S. E. Nissen et al. 2003. “Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.” JAMA. Nov 5;290(17): 2292–2300.
32 A recent Phase 2 study reported in the New England Journal of Medicine “markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels . . . ” M. E. Brousseau et al. 2004. “Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.” N Engl J Med. Apr 8; 350(15): 1505–1515. Global Phase 3 trials began in late 2003.
Information on Torcetrapib is available on the Pfizer site: www.pfizer.com/are/investors_reports/
annual_2003/review/p2003ar14_15.htm.
33 G. Etgen et al. 2002. “A tailored therapy for the metabolic syndrome.” Diabetes. 51: 1083–1087.
Information on the PPAR alpha agonist is available in the 2003 Eli Lilly annual report: www.lilly.com/
investor/annual_report/lillyar2003complete.pdf; M. Herper and R. Langreth. 2004. “Cardiovascular drugs to watch.” Forbes.com, April 27, www.forbes.com/2004/01/22/cx_mh_rl_cardiotear_10.html.
34 Coronary calcium scores courtesy of Dr. Melvin E. Clouse of Boston’s Beth Israel Deaconess Medical Center and Imatron. Data based on 13,073 asymptomatic men and 5,227 asymptomatic women.
35 B. G. Brown. 2002. “Measurement of coronary calcification: a new clinical tool.” University of Washington Regional Heart Center Consult. Issue #3, Winter; W. Stanford. “Coronary artery calcification: significance and methods of detection.” Society of Thoracic Radiology (www.thoracicrad.org/
STR_Archive/PostGraduatePapers/StandfordW.html), based on W. Stanford et al. 1993. “Coronary artery calcification.” AJR Am J Roentgenol. Dec;161(6): 1139–1146.
Dropping calcium from the diet will not reduce your calcium score. “It’s not the milk you’re drinking that’s causing the problem,” says Dr. Larry Dean, professor of medicine at the University of Washington Medical Center. “It’s the butterfat in the milk that’s causing the cholesterol problem, which is then causing the inflammatory process in the blood vessels. The calcium is a marker of the underlying disease process” (quoted in “Calcium scoring: A new technique useful for some with heart risk factors,” University Week, University of Washington. Vol. 19(25), May 2, 2002; (www.depts.washington.edu/uweek/archives/
2002.05.MAY_02/hs_e.html).
36 Calcium scoring is a new technique used to help identify patients at risk of heart disease. A series of quick images of the heart taken by a computed tomography (CT) scanner allows doctors to “score” the level of calcium deposits in the coronary arteries. Numerous studies are now examining the relationship between high calcium scores and other risk factors in predicting illness. N. D. Wong et al. 1994. “Coronary calcium and atherosclerosis by ultrafast computed tomography in asymptomatic men and women.” Am Heart J. Feb;127(2): 422–430; A. S. Agatston et al. 1990. “Quantification of coronary artery calcium using ultrafast computed tomography.” J Am Coll Cardiol. Mar 15;15(4): 827–832; A. S. Fiorino. 1998. “Electron-beam computed tomography, coronary artery calcium and evaluation of patients with coronary heart disease.” Ann Int Med. May 15;128: 839–847.
37 C. Francis et al. 2003. “Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement.” N Engl J Med. Oct 30;349: 1703–1712; S. B. Olsson et al. 2003. “Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial.” Lancet. Nov 22;362(9397): 1691–1698.
38 A. Eisenberg. “An Ultrasound that Navigates Every Nook and Cranny.” New York Times, January 15, 2004.
39 D. Ornish. 1996. Dr. Dean Ornish’s Program for Reversing Heart Disease: The Only System Scientifically Proven to Reverse Heart Disease Without Drugs or Surgery. New York: Ballantine Books.
40 “The study provides further evidence that genes play a large role in early-onset coronary heart disease (CHD) and that it clusters in families, regardless of environmental factors,” according to M. Laakso, senior author of A. Kareinen et al. 2001. “Cardiovascular risk factors associated with insulin resistance cluster in families with early-onset coronary heart disease.” Arterioscler Thromb Vasc Biol. Aug;21(8): 1346–1352. Quotation from AMA August 9, 2001, news release (www.americanheart.org/
presenter.jhtml?identifier510964).
41 G. H. Gibbons and V. J. Dzau. 1994. “The emerging concept of vascular remodeling.” N Engl J Med. May 19;330(20): 1431–8.
42 See discussion in the text of this chapter “Elevated Cholesterol, LDL, and Triglyceride Levels and Diminished HDL Levels.” See also C. P. Cannon et al. 2004. “Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes.” N. Engl. J. Med. 350(15): 1495–1504. The research compared the experimental group, which took 80 mg per day of Lipitor, to the control group, which took 40 mg a day of Pravachol. The LDL-C comparison was 62 for the experimental group versus 95 for the control group. The experimental group had substantially fewer heart attacks and recommendations for surgery.
43 See www.womens-health.org/press/Releases/prheartstudy.htm. The survey, conducted by International Communications Research, included 1,019 women. Studies such as this have served as catalysts for the Heart Truth campaign sponsored by the National Heart, Lung and Blood Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services.
44 “Chronic Disease Overview,” National Center for Chronic Disease Prevention and Health Promotion (www.cdc.gov/nccdphp/overview.htm). See also the 2003 Heart Disease and Stroke Statistical Update, American Heart Association (www.americanheart.org/presenter.jhtml?identifier53000090).
45 “Smoking costs Americans over $157 billion annually in medical care.” 2003 Heart Disease and Stroke Statistical Update, American Heart Association, op cit. Stroke is as much a concern as heart attacks; see, for example, G. A. Colditz et al. 1988. “Cigarette smoking and risk of stroke in middle-aged women.” N Engl J Med. Apr 14;318(15): 937–941. Even regular exposure to secondhand smoke has been shown to nearly double a woman’s risk of a heart attack (I. Kawachi et al. 1997. “A prospective study of passive smoking and coronary heart disease.” Circulation. 95: 2374–2379).
46 S. Kenchaiah et al. 2002. “Obesity and the risk of heart failure.” N Engl J Med. Aug 1;347(5): 305–313; P. W. Wilson et al. 2002. “Overweight and obesity as determinants of cardiovascular risk: the Framingham experience.” Arch Intern Med. Sep 9;162(16): 1867–1872.
W. B. Kannel et al. 1988. “Cardiac failure and sudden death in the Framingham Study.” Am Heart J. Apr;115(4): 869–875.
47 A number of studies citing low cholesterol as a factor in hemorrhagic stroke have been reported widely (see, for example, www.cnn.com/HEALTH/9902/06/strokes/). According to the American Heart Association, these results should be considered cautiously: study sizes have often been small and no cause-and-effect mechanism has been identified. Furthermore, “there is no trend for an increase in total mortality unless the total cholesterol level is less than 160 mg/dL. It is estimated that in the United States less than 10% of middle-aged men and women have serum cholesterol levels below this range.” M. Criqui. 1994. “A statement for healthcare professionals from the American Heart Association Task Force on Cholesterol Issues” (www.americanheart.org/presenter.jhtml?identifier51208).
48 T. Partonen et al. 1999. “Association of low serum total cholesterol with major depression and suicide.” Br J Psych. 175: 259–262.
As with the link to stroke, however, some researchers are cautious about results that might deter clinicians from “prescribing cholesterol-lowering drugs, to reduce the risk of death from coronary heart disease.” “Many confounding factors, e.g., poor health, depression and loss of appetite may play a role in the apparent relationship between serum cholesterol levels and suicide.” R. Manfredini et al. 2000. “The association of low serum cholesterol with depression and suicidal behaviors: new hypotheses for the missing link.” J Int Med Res. Nov 1;28(6): 247–257.
49 C. P. Cannon et al. “Comparison of Intensive and Moderate Lipid Lowering with Statins after Acute Coronary Syndromes.” New England Journal of Medicine, March 8, 2004 (http://content.nejm.org/cgi/
content/abstract/NEJMoa040583). The research compared the experimental group, which took 80 mg per day of Lipitor, to the control group, which took 40 mg a day of Pravachol. The LDL-C comparison was 62 for the experimental group versus 95 for the control group. The experimental group had substantially fewer heart attacks and recommendations for surgery.
50 HDL2 and HDL3 are the two major HDL subclasses. See, for example, M. C. Bakogianni et al. 2001. “Clinical evaluation of plasma high-density lipoprotein subfractions (HDL2, HDL3) in insulin-dependent diabetics with coronary artery disease.” J Diabetes Complications. Sep–Oct;15(5): 265–269.
Regarding the debate over the more protective subfraction, see, for example, “Antioxidative activity of HDL subfractions increased with increment in density, as follows: HDL2b <HDL2a <HDL3a <HDL3b <HDL3c . . . ” A. Kontush et al. 2003. “Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress.” Arterioscler Thromb Vasc Biol, published online before print, August 14, 2003.
In addition, “from a statistical standpoint, the present data suggest that the HDL2 subfraction may be more closely related to the development of IHD than the HDL3 subfraction. However, the qualitative difference in the relative predictive value of each subfraction was trivial, since it only corresponded to a modest quantitative difference. Thus, the possibility that a significant proportion of the cardioprotective effect of elevated HDL cholesterol levels may be mediated by the HDL3 subfraction still cannot be excluded.” B. Lamarche et al. 1997. “Associations of HDL2 and HDL3 subfractions with ischemic heart disease in men: Prospective results from the Quebec Cardiovascular Study.” Arterioscler Thromb Vasc Biol. Jun 1;17(6): 1098–1105.
51 A number of recent news stories have highlighted the importance of cholesterol tests “that look
beyond the usual definitions of good and bad cholesterol, that separate the bad from the really bad and
the mildly good from the angelic.” D. Franklin. 2001. “What this CEO didn’t know about his cholesterol almost killed him.” Fortune, March 19 (and reported on www.berkeleyheartlab.com/GENERAL/news_
fortune.html).
52 LDL particle size and density gained attention in the early 1990s, when their role in heart disease was uncovered (see R. M. Krauss et al. 1994. “A prospective study of LDL particle diameter and risk of myocardial infarction.” Circulation. 90:I–460; described in D. Gilbert. 1994. “Small dense cholesterol particles worse for your heart.” November 29, www.lbl.gov/Science-Articles/Archive/cholesterol-pArticles.phpl). See also P. T. Williams et al. 2003. “Smallest LDL particles are most strongly related to coronary disease progression in men.” Arterioscler Thromb Vasc Biol. Feb 1:23(2): 314–321; and note 39 on page 415.
53 At a 1999 colloquium, R. M. Krauss, a researcher at the E. O. Lawrence Berkeley National Laboratory, explained: “Small LDL bind more tightly to the artery wall, they are oxidized more rapidly and they may cause greater endothelial dysfunction. There is an increasing body of evidence that suggest that some of the damage caused by higher levels of triglyceride is mediated by this effect on LDL, as well as some of the other metabolic conditions that are associated with high triglyceride, including low HDL and insulin resistance. We call this an atherogenic phenotype. It is a collection of abnormalities that together comprise a real significant coronary disease risk profile that is above and beyond what we can detect just by measuring the levels of LDL.” Sante Fe Colloquium on Preventive Cardiovascular Therapy, October 7–9, 1999; Sante Fe, New Mexico (www.acc.org/education/online/sante_fe/krauss.htm).
R. Krauss is also an author on a study that supports triglycerides as an independent risk factor for myocardial infarction. See M. J. Stampfer et al. 1996. “A prospective study of triglyceride level, low-density lipoprotein particle diameter and risk of myocardial infarction.” JAMA. Sep 18;276(11): 882–888.
54 “Policosanol is a mixture of higher primary aliphatic alcohols isolated from sugar cane wax, whose main component is octasanol. This mixture has been shown to lower cholesterol in animal models, healthy volunteers and patients with type II hypercholesterolemia.” I. Gouni-Berthold and H. K. Berthold. 2002. “Policosanol: clinical pharmacology and therapeutic significance of a new lipid-lowering agent.” Am Heart J. Feb;143(2): 356–365.
55 Ibid. “Because higher doses have not been tested up to now, it cannot be excluded that effectiveness may be even greater. Daily doses of 10 mg of policosanol have been shown to be equally effective in lowering total or LDL cholesterol as the same dose of simvastatin or pravastatin. Triglyceride levels are not influenced by policosanol.”
56 S. Nityanand et al. 1989. “Clinical trials with gugulipid: a new hypolipidaemic agent.” J Assoc Physicians India. 37: 323–328.
57 N. G. Stephens et al. 1996. “Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS).” Lancet. Mar 23;347(9004): 781–786.
58 M. N. Nanjee et al. 2001. “Intravenous apo A-I/lecithin discs increase pre-Beta-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans,” Journal of Lipid Research. Oct(42): 1586–1593. The study examined “intravenous infusion of apolipoprotein A-I/phosphatidylcholine discs in humans” and concluded “Intravenous apoA-I/lecithin discs increase pre-Beta-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans.”
59 A. Gotto Jr. 2003. “Safety and statin therapy: reconsidering the risks and benefits.” Arch Intern Med. 163: 657–659; J. Tobert. 2003. “Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors.” Nature Rev Drug Discov. 2: 517–526.
60 Lipitor is produced by Pfizer, Inc. (www.lipitor.com). See also, for example, B. R. Krause and R. S. Newton. 1995. “Lipid-lowering activity of atorvastatin and lovastatin in rodent species: triglyceride-
lowering in rats correlates with efficacy in LDL animal models.” Atherosclerosis. Oct 1;117(2): 237–244.
61 P. M. Ridker et al. 1998. “Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women.” Circulation. 98: 731–733; P. M. Ridker et al. 1997. “Inflammation, aspirin and the risk of cardiovascular disease in apparently healthy men.” N Engl J Med. Apr 3;336(14): 973–979. For a later report, see P. M. Ridker. 2001. “High-sensitivity C-reactive protein.” Circulation. 103: 1813–1818.
62 K. Miura et al. 2001. “Relationship of blood pressure to 25-year mortality due to coronary heart disease, cardiovascular diseases and all causes in young adult men: The Chicago Heart Association Detection Project in Industry.” Arch Int Med. Jun 25;161(12): 1501–1508.
63 For the different types of drugs for hypertension and how they work, see the list on the American Heart Association site: “Blood pressure-lowering drugs” (www.americanheart.org/presenter.jhtml?
identifier5159). One study observed that losartan (Cozaar) had fewer side effects than calcium channel blockers in a community-based setting, which meant that patients would be more likely to adhere to their treatment regimens (J. P. Grégoire et al. 2001. “Tolerability of antihypertensive drugs in a community-based setting.” Clin Ther. May;23(5): 715–726). Another research compared angiotensin II antagonists and calcium channel blockers and suggested a role for each. (M. Weir. 2001. “Appropriate use of calcium antagonists in hypertension.” Hosp Pract (Off Ed). Sep 15;36(9): 47–48, 53–55.)
64 S. Jacob et al. 1998. “Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents?” Am J Hypertens. Oct;11(10): 1258–1265. Impotence may also be a problem with beta-blockers: R. Fogari. 1998. “Sexual function in hypertensive males treated with lisinopril or atenolol: a cross-over study.” Am J Hypertens. Oct;11(10): 1244–1247.
65 “Hostility is an independent risk factor for coronary heart disease (CHD).” T. Q. Miller et al. “A meta-analytic review of research on hostility and physical health.” Psychol Bull. Mar;119(2): 322–348. For the link between adrenaline and inflammation, see, for example, P. H. Black. 2002. “Stress and the inflammatory response: a review of neurogenic inflammation.” Brain Behav Immun. Dec;16(6): 622–653.
66 J. Denollet and D. Brutsaert. 1998. “Personality, disease severity and the risk of long-term cardiac events in patients with a decreased ejection fraction after myocardial infarction.” Circulation. Jan;97: 167–173; J. Denollet. 2000. “Type D personality. A potential risk factor defined.” J Psychosom Res. Oct;49(4): 255–266.
67 I. Wilcox et al. 1998. “‘Syndrome Z’: The interaction of sleep apnoea, vascular risk factors and heart disease.” Thorax. Oct;53(Suppl 3): S5–S28; J. E. Muller et al. 1997. “Mechanisms precipitating acute cardiac events.” Circulation. 96: 3233–3239.
68 Companies developing heart simulations include Artesian Therapeutics and Immersion Medical, both in Gaithersburg, Maryland; Insillicomed in La Jolla, California; and Predix Pharmaceuticals in Woburn, Massachusetts.
69 D. H. Freedman. “The Virtual Heart.” Technology Review, March 2004.
70 “Plaque rupture was significantly associated with high fibrinogen levels.” A. Mauriello et al. 2000. “Hyperfibrinogenemia is associated with specific histocytological composition and complications of atherosclerotic carotid plaques in patients affected by transient ischemic attacks.” Circulation. 101: 744. See also A. Maseri and V. Fuster. 2003. “Is there a vulnerable plaque?” Circulation. Apr;107: 2068–2071.
71 P. Lotufo et al. 2000. “Male pattern baldness and coronary heart disease.” Arch Int Med. Jan 24;160(2): 165–71.
72 For general information about hemochromatosis, see “Hemochromatosis,” National Digestive Diseases Information Clearinghouse (http://digestive.niddk.nih.gov/ddiseases/pubs/hemochromatosis/index.htm). For recent research, see, for example, M. Rasmussen et al. 2001. “A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) study.” Atherosclerosis. Feb 15;154(3): 739–746.
73 Contradictory results have been reported on the link between periodontal disease and coronary heart disease. P. P. Pussinen et al. (2003) reported that “men with antibodies to the dental bacteria were 50 percent more likely to have heart disease than men without these antibodies,” per a Reuters Health news report (“Bugs in mouth bad for heart,” http://12.31.13.29/HealthNews/Reuters/NewsStory0717200318.htm). “Antibodies to periodontal pathogens are associated with coronary heart disease.” Arterioscler Thromb Vasc Biol. Apr 24;23: 1250. However, P. P. Hujoel et al. (2000) had different results: “This study did not find convincing evidence of a causal association between periodontal disease and CHD risk.” “Periodontal disease and coronary heart disease risk.” JAMA. 284(11): 1406–1410.
74 M. Christ-Crain et al. 2003. “Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind placebo-controlled trial.” Atherosclerosis. Feb;166(2):379–386; I. Klein. 2003. “Thyroid hormone and cardiac contractility.” Am J Cardiol. Jun;91(11): 1331–1332.
75 See his book Nanomedicine (vol. 1, 1999, and vol. 2, 2003; Georgetown, Texas: Landes Bioscience). Also see the Foresight Institute’s “Nanomedicine” page by Robert Freitas Jr., which lists his current technical works (www.foresight.org/Nanomedicine/index.html#MedNanoBots).
76 One of the authors of this book, Ray Kurzweil, and his company, Kurzweil Technologies, Inc., is working with Medicomp (a subsidiary of United Therapeutics, Inc.), a leader in Holter and event monitoring, to create a new generation of computer-based pattern recognition to automatically evaluate ECG recordings from holster and event monitors.
77 For general information about external counterpulsation, see “Enhanced external counterpulsation (EECP)” (www.americanheart.org/presenter.jhtml?identifier54577). Clinic sites also have descriptions; see, for example, http://cardiology/ucsf.edu/clinical/eecp/. For studies supporting the technique’s efficacy, see, for example, A. D. Michaels et al. 2002. “Left ventricular systolic unloading and augmentation of intracoronary pressure and Doppler flow during enhanced external counterpulsation.” Circulation. Aug 19;106: 1237.
78 Many labs and universities have received funding to research tiny fuel cells. See the University of Notre Dame news release, “Team receives $1.6 million grant for fuel cell research,” http://newsinfo.nd.edu/content.cfm?topicId53311. To follow government support for fuel cells, see the U.S. Department of Energy Hydrogen, Fuel Cells & Infrastructure Technologies Program Web page, www.eere.energy.gov/hydrogenandfuelcells/). Also see A. V. Chadwick. 2000. “Nanotechnology: solid progress in ion conduction.” Nature. Dec 21;408: 925–926.
79 “Angiogram: what risks are there from the test?” Harvard Medical School Family Health Guide (www.health.harvard.edu/fhg/diagnostics/angiogram/angiogramRisks.shtml).
80 No significant differences in outcome were noted between:
Veterans treated medically and surgically (R. J. Scott et al. 1987. “Comparison of medical and surgical treatment for unstable angina pectoris.” N Engl J Med. Apr 16;316(16): 977–984).
Hospitalized patients in Sweden receiving dramatically less surgical intervention than in the U.S. (P. G. McGovern et al. 1997. “Comparison of medical care and one and 12-month mortality of hospitalized patients with acute myocardial infarction.” Am J Cardiol. Sept 1;80(5): 557–562).
Patients in different parts of the U.S. receiving radically different types of care (L. Pilote et al. 1995. “Regional variation across the United States in the management of acute myocardial infarction.” N Engl J Med. Aug 31;333(9): 589–590).
At the same time, significant differences in outcome have been associated with better oversight of patients and lifestyle changes. Note, however, that the selection of patients can influence the results from comparative studies. Studies that screen out sicker patients will inevitably show fewer differences between surgical and medical treatment.
81 C. M. Winslow et al. 1988. “The appropriateness of performing coronary artery bypass surgery.” JAMA. Jul 22–29;260(4): 505–509; R. Lange and D. L. Hillis. “Use and overuse of angiography and revascularization for acute coronary syndromes.” N Engl J Med. 338(25): 1838–1839.
While the health care system in the United States is set up to encourage the overuse of expensive treatments, patients and patients’ families play their part as well by assuming that more expensive options are necessarily better.
82 S. G. Ellis et al. 1992. “Randomized trial of late angioplasty versus conservative management for patients with residual stenosis after thrombolytic treatment of myocardial infarction.” Circulation. Nov;86(5): 1400–1406. This study “strongly suggests” patients who had an “uncomplicated myocardial infarction” should be treated medically (with drugs) rather than with surgery.
Another study concluded, “because conservative strategy achieves equally good short and long term outcomes with less morbidity and a lower use of [angioplasty], it seems to be the preferred initial management strategy.” W. J. Rogers et al. “Comparison of immediate invasive, delayed invasive and conservative strategies after tissue-type plasminogen activator.” Circulation. May;81(5): 1457–1476. For the guidelines the medical profession uses to grade the seriousness of occluded arteries, see the report from the American College of Cardiology Foundation and American Heart Association, “ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina.”
E. Schneider et al. 2001. “Overuse of coronary artery bypass graft surgery and percutaneous transluminal coronary arngioplasty.” Annals of Internal Medicine. Sept 4;135(5): S35; E. Schneider et al. 2001. “Racial differences in cardiac revascularization rates: does ‘overuse’ explain higher rates among white patients?” Annals of Internal Medicine. Sept 4;135(5): 328–337; W. E. Boden et al. 1998. “Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy.” N Engl J Med. 338: 1785; E. Braunwald. 1988. “Evolution of the management of acute myocardial infarction: a 20th-century saga.” Lancet. 352: 1771–1774.
The following articles speak to the “sickest subset” issue:
www.clevelandclinic.org/heartcenter/pub/news/archive/2004/survival4_29.asp and
www.dukemednews.org/news/article.php?id56479.
See also notes 6 and 7 on page 412.
83 M. F. Newman et al. 2001. “Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery.” N Engl J Med. Feb 8;344(6): 395–402.
84 “No development in interventional cardiology has created a stir like the drug-eluting stent for preventing restenosis. . . . Finally, in our excitement about the potential for interventional cardiology, we must remember that atherosclerosis will not be cured by drug-eluting stents. Prevention of progression of this disease requires changing the metabolic milieu of the patient who has it. Interventional procedures are superb for alleviating the current ischemia and related symptoms, but a concerted effort by the healthcare team and the patient are necessary to change the ultimate outcome. Although the restenosis mouse ‘has roared,’ it may not be necessary in all cases to use an elephant gun to eliminate him.” S. King. “Restenosis: the mouse that roared.” Circulation. 108: 248.
In addition, “sirolimus-eluting stent edge restenosis is frequently associated with local trauma outside the stent.” P. A. Lemos et al. “Coronary restenosis after sirolimus-eluting stent implantation: morphological description and mechanistic analysis from a consecutive series of cases.” Circulation. Jul 22;108(3): 256–260.

Chapters: 1-5, 6-10, 16-20, 21-23