1 See “Race for the $1000 Genome Is On” in www.newscientist.com/news/news.jsp?id5ns99992900.
3 J. Cohen. “Big-picture biotech.” MIT Technology Review
V, December 2003–January 2004.
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/
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.
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):
13 J. Rosamond and A. Allsop. 2000. “Harnessing the power of the
genome in the search for new antibiotics.” Science. Mar 17;287(5460):
14 A. Dove. 2002. “Antisense and sensibility.” Nature Biotechnology.
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.
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/
19 Emory Health Sciences news release. March 27, 2003. www.emory.edu/WHSC/HSNEWS/
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,
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
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.
1 P. M. Ridker et al. 1998. “Prospective study of C-reactive protein
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2 R. N. Kalaria. 2002. “Small vessel disease and Alzheimer’s
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3 E. M. Castano et al. 1995. “Fibrillogenesis in Alzheimer’s
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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.
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
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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
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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
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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
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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
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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.
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):
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.
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):
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.
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
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):
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.
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):
14 J. M. Ellis and K. S. McCully. 1995. “Prevention of myocardial
infarction by vitamin B6.” Res Commun Mol Pathol Pharmacol. Aug;89(2):
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,
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):
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):
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:
23 E. Arnesen et al. 1995. “Serum total homocysteine and coronary
heart disease.” Int J Epidemiol. Aug;24(4): 704–709.
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.
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
04a.html) and Environmental Defense (www.environmentaldefense.org/system/templates/page/focus.cfm?
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.
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):
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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):
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):
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.
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
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.
24 S. Duke. 2003. “Weeding with transgenes.” Trends in Biotechnology.
25 E. Baard. “Plants have a way with metals.” Wired News,
September 5, 2003; www.wired.com/
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/
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
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,
39 A. Szutowicz. 2001. “Aluminum, NO, and nerve growth factor
neurotoxicity in cholinergic neurons.” J Neurosci Res. Dec 1;66(5):
40 P. Fairley. “Saving Lives with Living Machines.” Technology
Review. July/August 2003. www.
42 R. Zacks. “The Liver Chip.” Technology Review. March
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.
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
50 P. Hammarstrom, F. Schneider, and J. W. Kelly. 2001. “Trans-suppression
of misfolding in an amyloid disease.” Science Sep 28;293(5539):
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.
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
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.
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.
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
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/
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
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):
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
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/
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
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.
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/
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):
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/
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
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):
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):
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_
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
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):
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,
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.
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,”
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):
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):
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
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:
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.
Voyage: Live Long Enough to Live Forever by Ray Kurzweil and Terry
Grossman M.D. Rodale: 11/2004 ISBN#1-57954-954-3