Literature and Commentary

Discrepant Observations in the Field of Atherosclerosis

By Gregory Sloop
The scientific method dictates that a single discrepant observation falsifies a hypothesis. Fatty streaks are found in the children of all populations, regardless of the prevalence of atherosclerosis. This observation falsifies the hypothesis that accumulation of cholesterol, apoB, or oxidized LDL in the arterial intima causes atherosclerosis. However, the notion that accumulation of one of these, or perhaps another elusive factor, is still widely held to cause atherosclerosis, as incorporated in the mainstream "Response to injury" hypothesis.
There are several possible reasons why discrepant observations have not caused a paradigm shift in the field of atherosclerosis research. In this age of quantum uncertainty, can one reject a theory because of a few discrepant observations? Isn't the majority opinion almost always right, especially in science? It certainly is much easier to get published when one hews to the mainstream. Funding for contrarian views is almost impossible to obtain. Cholesterol-lowering therapy definitely saves lives. Finally, there is the view that discrepant observations merely reflect our imperfect knowledge of an exceedingly complex disease.

Alternatively, atherosclerosis may be a straightforward process, and the seeming complexity is due to the imperfect fit of facts with mainstream theory. Atherosclerotic plaques develop from organization of mural thrombi, as originally postulated by Rokitansky and later strongly supported by Duguid in the 20th century. This theory makes several testable predictions. First, patients on long-term antiplatelet therapy should have a decreased prevalence of symptomatic atherosclerosis. A review of autopsies of arthritis patients on aspirin has shown that the prevalence of symptomatic atherosclerosis decreased after eight years on aspirin, at which time the prevalence became inversely proportional to the duration of arthritis and aspirin use.1

Virchow identified that stasis of blood is a risk factor for thrombosis. One reason for this is that endothelial production of molecules with anti-thrombotic activity, such as nitric oxide and prostacyclin, is modulated by shear. Because flow is inversely proportional to viscosity, risk factors for atherosclerosis should increase blood viscosity, and protective factors should be associated with decreased blood viscosity. Low-density lipoprotein cholesterol is directly associated and high-density lipoprotein inversely associated with blood viscosity.2

If oxidative stress causes atherosclerosis, areas of oxidative stress should be limited to lesions and vessels at risk for atherosclerosis. This is not the case. Oxidized low-density lipoprotein is widely distributed, being present in non-atherosclerotic arterial intima with diffuse intimal thickening, and coronary veins, which will not develop atherosclerosis.3

In "Atherosclerotic plaque-like lesions in synthetic arteriovenous grafts: implications for atherogenesis,"4 I present data which test the response to injury hypothesis. Synthetic arteriovenous grafts should have a very limited ability to respond to injury. Certainly, host cells migrate through the interstices of these grafts, which could impart a limited ability to respond to a stimulus. However, a graft with no living cells in the graft wall should have no ability to respond to injury. On the other hand, if atherosclerotic plaques develop from the organization of mural thrombi, then they should be prevalent in these grafts, which are prone to thrombosis because of the very high velocity blood flowing through them. Flow of sufficient velocity will be non-laminar, resulting in the uneven distribution of shear in the vessel, so that areas of very high shear will exist in proximity to areas of low shear. Platelets activated by high shear will form thrombi in areas of low shear. If these do not occlude the graft, their organization will result in development of atherosclerotic plaques.

In the study, 69% of grafts (54 of 78) contained eccentric, fibrous lesions morphologically similar to atherosclerotic plaques. Similarities to atherosclerotic plaques in native arteries included the presence of dystrophic calcifications, superimposed thrombi, foam cells, and immunoreactivity for smooth-muscle actin. One eccentric fibrous lesion developed in a graft which had no living cells in the interstices, and should not have been able to respond in any way to an injury. Atherosclerotic-plaque like lesions developed as early as 16 months following graft placement. Although the origin of the cells composing these plaques was not addressed in the study, previous work has shown that circulating stem cells can differentiate into all the cellular components of atherosclerotic plaques: smooth muscle cells capable of synthesizing matrix, macrophages, and endothelial cells, within 55 days. Fatty streaks were not identified on Sudan IV staining of two grafts, one of which contained an atherosclerotic-plaque like lesion.

I have proposed the hemorheologic-hemodynamic theory of atherogenesis,5 which states that all risk factors accelerate atherosclerosis by creating larger areas of lower shear in arteries by increasing blood viscosity, peak blood velocity, or both. Besides the novel observations discussed previously, this theory predicted that hypertension should be associated with increased peak blood velocity, which has been confirmed.6 The most important test of this theory will be if measurement of blood viscosity and peak blood velocity will predict an individual's risk of symptomatic atherosclerosis better than is currently possible. Traditional risk factors such as blood pressure, smoking status, and cholesterol account for only 28% of variation in risk of cardiovascular disease in men in the Framingham study.7 The hemorheologic-hemodynamic theory also suggests other potential variables which are yet to be studied. Is there inter-individual variation in shear-mediated platelet activation and shear-modulated endothelial synthesis? Finally, what are the other variables besides blood pressure which determine peak blood velocity and propensity for development of areas low shear in the arterial tree? Possibilities include arterial geometry and determinants of vascular compliance such as arterial elastin and collagen content. It is likely that in the future, the angle of arterial branches and other geometric variables will have defined risks for developing atherosclerosis.

References
1. Sloop GD. Decreased prevalence of symptomatic atherosclerosis in arthritis patients on long term aspirin therapy. Angiology 1998; 49: 827-832.
2. Sloop GD, Garber DW. The effects of low-density lipoprotein and high-density lipoprotein correlate with their association with risk of atherosclerosis in humans. Clinical Science 1997;92: 473-479
3. Sloop GD, Fallon KB, Lipscomb G, Takei H, Zieske AW. The distribution of oxidatively-modified lysine in the human vasculature. Atherosclerosis 2000;148: 255-263
4. Sloop GD, Fallon KB, Zieske AW. Atherosclerotic plaque-like lesions in synthetic arteriovenous grafts: implications for atherogenesis. Atherosclerosis 2002;160/161: 133-139
5. Sloop GD. A unifying theory of atherogenesis. Medical Hypotheses 1996;47: 321-325
6. Perret RS, Sloop GD. Increased peak blood velocity in association with elevated blood pressure. Ultrasound in Medicine & Biology 2000;26: 1387-1391
7. Stokes III J, Kannmell WB, Wolf PA, Cupples LA, D'Agostino RB. The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study. Circulation 1987;75 (suppl V): v65-v73

My comments in 2011: I found this editorial searching for myself on Google Scholar. I don’t know where it is from, and I don’t think it was ever published. At least, I couldn’t find it anywhere on the International Atherosclerosis Society’s website. I completely understand why it was never published, and am very glad I wrote it anyways.
I like the phrase “quantum uncertainty.” I feel that there is a belief in science that we are now studying such difficult questions, paradoxes are acceptable. For example, students of science for many years accepted that Schrodinger’s cat was neither dead or alive until it was observed in person to be one or the other. For this, I blame my nominee for worst scientist of the 20th Century, Neils Bohr. My understanding is that thoughtful physicists struggled with interpreting the implications of the Schrodinger equation in the 1950’s. Bohr was not up to the task, evidently, and protected by mystique and a personality cult, foisted the “Copenhagen Interpretation” on quantum physicists. He made uncritical, fuzzy thinking acceptable in science. He also managed to stifle Hugh Everett’s “Many Worlds Interpretation” of the Schrodinger Equation, which took the implications of the equation at face value. Fortunately, Everett’s work is being taken seriously now that the influence of Bohr and his followers has waned. But we still have too much uncritical, fuzzy thinking in science. I am not the first to feel this way regarding atherosclerosis research:

Those who may seek now, or in the future, to denigrate the achievements of medical science in the 20th century will find numerous examples within the general field of atherosclerosis research of oversimplification, extrapolation, and near-total abandonment of the principles of the scientific method.

Scott, P.J. Clinically integrated studies in Pathology: their contribution to atherosclerosis research. Pediatric Pathology and Molecular Medicine 21: 239-257, 2002.

I suspect there is also a feeling that atherogenesis is such a subtle process, uncertainty is acceptable. Certainly, biologic variability exists, but it is no excuse for loose thinking. If physicists, generally regarded as practitioners of the hardest science (as opposed to softer sciences such as sociology) accept uncertainty, shouldn’t uncertainty be acceptable in biomedicine? I say not if a phenomenon is understood.

I have read nonsense that if serum LDL levels can be lowered enough, coronary artery disease can be completely eliminated. I believe recommendations for optimal serum LDL levels will continue to be lowered until there is no more benefit. Unfortunately, coronary artery disease will still exist. I’m afraid that only then will mainstream thinking be questioned and the hemorheologic-hemodynamic theory of atherosclerosis is taken seriously.


Atherosclerotic plaque-like lesions in synthetic arteriovenous grafts: implications for atherogenesis

Atherosclerosis Volume 160, Issue 1, January 2002, Pages 133-139
Gregory D. Sloop, Kenneth B. Fallon, and Arthur W. Zieske

Abstract
Atherosclerotic plaque-like lesions are prevalent in synthetic arteriovenous shunts
created to provide vascular access for hemodialysis. Similarities to atherosclerotic
plaques in native arteries include eccentric location, immunoreactivity for smooth
muscle actin, dystrophic calcifications, superimposed thrombi, and foam cells. Fatty
streaks were not grossly identified on Sudan IV staining. Because of the similarities
to atherosclerosis in native vessels, these findings may have several implications for
atherogenesis. The development of raised, fibrous lesions does not require decades.
The presence of smooth muscle in atherosclerotic plaque-like lesions does not
require a source from tunica media. A precursor fatty streak may not be required for
the development of raised, fibrous lesions. Finally, development of atherosclerotic
plaque-like lesions does not require putative inflammatory effects from cholesterol
or LDL accumulation, or even a native vessel that can respond to injury. The
atherosclerotic plaque-like lesions in this study probably developed from
organization of mural thrombi.

Comments in 2011: I presented this work for the first time to my department. It was at that occasion, I believe, that my boss, the very-well know atherosclerosis researcher, Jack Strong, M.D., said something like, “I’m just an old anatomic Pathologist, but one day, maybe some young guy like Gregory will win a Nobel Prize.” He said that he didn’t believe the lesions in the dacron grafts were atherosclerotic plaques, but merely organized thrombi. The only difference between these plaques and plaques in native arteries is that the latter contain lipid cores. These are inconstant but distinctive finding in atherosclerosis in native arteries. I now believe that lipid cores are derived from degeneration of intraplaque hemorrhage. They are not found in plaques which develop in synthetic grafts because these grafts do not contain a layer of smooth muscle and do not contract.


Disturbed flow in radial-cephalic arteriovenous fistulae for haemodialysis: low and oscillating shear stress locates the sites of stenosis

Nephrology Dialysis Transplantation (2012) 27(1): 358-368
Bogdan Ene-Iordache and Andrea Remuzzi

Abstract
Background.
Despite recent clinical and technological advancements, the vascular access (VA) for haemodialysis still has significant early failure rates after arteriovenous fistula (AVF) creation. VA failure is mainly related to the haemodynamic conditions that trigger the phenomena of vascular wall disease such as intimal hyperplasia (IH) or atherosclerosis.

Methods. We performed transient computational fluid dynamics simulations within idealized three-dimensional models of ‘end-to-side’ and ‘end-to-end’ radio-cephalic anastomosis, using non-Newtonian blood and previously measured flows and division ratio in subjects requiring primary access procedure as boundary conditions.

Results. The numerical simulations allowed full characterization of blood flow inside the AVF and of patterns of haemodynamic shear stress, known to be the major determinant of vascular remodeling and disease. Wall shear stress was low and oscillating in zones where flow stagnation occurs on the artery floor and on the inner wall of the juxta-anastomotic vein.

Conclusions. Zones of low and oscillatory shear stress were located in the same sites where luminal reduction was documented in previous experimental studies on sites stenosis distribution in AVF. We conclude that even when exposed to high flow rates, there are spot regions along the AVF exposed to athero-prone shear stress that favour vessel stenosis by triggering IH.

My comments in 2011: This paper cited “Atherosclerotic Plaque-like lesions…” in 2011. Maybe there is hope. It is the force of contraction which causes plaque fracture and intraplaque hemorrhage.  The decreased shear which led to the formation of the plaque would also predispose the affected stretch of artery to contraction or vasospasm due to decreased local production of nitric oxide and prostacyclin.  Besides having antiplatet activity, these molecules also have vasodilatory activity.


A critical analysis of the role of cholesterol in atherogenesis

Gregory D. Sloop
Atherosclerosis Volume 142, Issue 2, February 1999, Pages 265-268

Abstract
Serum hypercholesterolemia is theorized to accelerate atherogenesis by
augmenting cholesterol accumulation (insudation) in the arterial intima.
The author views this theory as an example of what the noted philosopher
of science Imre Lakatos called ‘degenerative science’, because data have
forced several modifications of the theory. Although the theory that some
fraction of intimal cholesterol causes atherosclerosis is not yet disproved,
the author favors the hypothesis that serum hypercholesterolemia accelerates
atherogenesis and contributes to symptomatic atherosclerosis by increasing
blood viscosity and the mechanical fragility of atherosclerotic plaques, making
them vulnerable to rupture and thrombosis.

My comments in 2011: Degenerative science should have more stink associated
with it. See below.


The distribution of oxidatively-modified lysine in the human vasculature

Gregory D Sloop, Kenneth B Fallon, Gary Lipscomb, Hidehiro Takei and Art Zieske
Atherosclerosis Volume 148, Issue 2, 1 February 2000, Pages 255-263

Abstract
Fifty-seven sections of human vessels, collected in the Pathobiological Determinants of Atherosclerosis in Youth study from individuals aged 25–34, were stained with two monoclonal antibodies to oxidatively-modified lysine. Intensity and extent of immunoreactivity were graded by three pathologists. Aorta from a Watanabe heritable hyperlipidemic (WHHL) rabbit was stained as a positive control. Intimal immunoreactivity in the rabbit was predominantly localized to lesions. Although immunoreactivity in humans was somewhat more intense in atherosclerotic plaques, substantial staining was present in intima with diffuse intimal thickening and coronary veins. Localization of oxidatively-modified lysine in humans did not correlate with localization or severity of atherosclerosis. Localization of immunoreactivity for oxidatively-modified lysine to intimal lesions in the WHHL rabbit may be due to absence of diffuse intimal thickening, which prevents retention of epitopes throughout the intima.

My comments in 2011: One of the basic rules of biomedical science is, or at least should be, that laboratory observations must be confirmed in vivo. It is shocking to me the extent to which this has not happened in the field of atherosclerosis. The whole mainstream paradigm, from oxidative modification to the response to injury hypothesis to reverse transport of cholesterol, is based on test tube data.

If oxidation plays a role in the development of atherosclerosis, via mechanisms demonstrated in the test tube, the location of oxidative change should correlate with the presence of lesions. A very simple prediction, which this paper unequivocally refutes. To my knowledge, only one other photograph of human vasculature stained for oxidative epitopes was ever published. This showed staining in an atherosclerotic plaque, but was cropped so you could barely see the staining in the diffuse intimal thickening next to it.

Oxidative change is widespread and not associated with pathology detected by the light microscope. No wonder clinical trials of vitamin E and beta-carotene have shown no benefit at all in prevention of atherosclerosis! However, the true believer never says die. In a textbook example of degenerative science, Daniel Steinberg writes: “Do these disappointingly negative results mean that the oxidative modification hypothesis is irrelevant in the human disease? Not necessarily.” (Journal of Lipid Research, April Supplement, pp S376-381, 2009. For a fine example of desperate wriggling to avoid the death grip of refutation, read what follows in his paper (free full text is available on the internet). I might be tempted to sit in my comfortable rut of wrongness, too, if I couldn’t come up with a better theory. I am reminded of the playwright in the original movie of “The Producers,” who made fun of the producers for being miserable cowards, clinging to life, rather than accepting an honorable death. Now that you know what really causes atherosclerosis, gentle reader, you may engage in schadenfreude and enjoy the image of arrogant, well-funded true believers desperately clinging to their wrong hypothesis!

Thomas Kuhn recognized that discrepant observations could be swept under the rug by the mainstream in order to preserve the mainstream paradigm. My paper has been cited only three times, all by me.

Like most of my data, this work was presented initially to a Department of Pathology Conference at LSU. After I presented this work, I remember one of the Pathology residents, Vince, cupping his hands wide and deep below his nutsack to show how big my balls were. Thanks, Vincent R.


Increased peak blood velocity in association with elevated blood pressure

Ultrasound in Medicine & Biology Volume 26, Issue 9, November 2000, Pages 1387-1391 Robert S. Perret and Gregory D. Sloop

Abstract
To test the hypothesis that peak blood velocity in the common carotid artery is
increased in association with elevated blood pressure, the authors measured peak
common carotid blood velocity in 458 subjects by color Doppler ultrasonography.
Blood pressure was measured at the time of ultrasound examination by automated
sphygmomanometer. Peak blood velocity was increased in subjects with elevated
blood pressure (right common carotid: 72.5 ± 2.0 cm/s vs. 62.7 ± 2.5 cm/s, left
common carotid: 72.0 ± 1.8 cm/s vs. 63.9 ± 2.0 cm/s, p < 0.001). Peak blood
velocity was significantly correlated with systolic blood pressures between 135 and
160 mmHg (r = 0.47 in right common carotid, 0.45 in left common carotid, n = 123,
p < 0.001). No correlation was found between peak blood velocity and blood
pressures less than 135 mmHg or greater than 160 mmHg. By increasing
erythrocyte momentum, increased peak blood velocity may play a role in the
pathogenesis of arterial diseases associated with hypertension.

My comments in 2011: I can sorta understand how the mainstream paradigm claims to explain how cholesterol causes atherosclerosis, but not how hypertension causes the disease, except in the most wishful thinking way. One day, Dr. Strong, my boss, challenged our atherosclerosis working group at our weekly meeting to figure out how hypertension accelerated atherosclerosis. At the next meeting, I proposed that hypertension increased peak arterial velocity. I collaborated with Dr. Bob Perret, to demonstrate this. I couldn’t believe it, but Bob had already collected all the data we needed! This was the only time in my career when my results were ever confirmed, if that’s what you call it when the “confirmatory” data comes out when your data are still in press. Interestingly, a reviewer of our paper recommended its rejection because everyone already knew hypertension increased peak arterial velocity.

I presented my theory once to the Department of Physiology at LSU School of Medicine in New Orleans. I got a question which I couldn’t answer at the time. One of the professors asked me if increased arterial blood velocity was bad, then why was exercise good? Thinking about it, there are times when exercise isn’t beneficial. Anyone who works in an emergency department has seen heart attacks in out of shape people shoveling snow. Also, the cyclists who doped with erythropoietin were obviously in fabulous cardiovascular shape and yet died in competition (see below). The benefit of exercise is to decrease your resting heart rate which decreases fatigue on elastin molecules in the aorta, preserving compliance for as long as possible.

In the same way that degenerative science should have more stink associated with it, bold, new predictions like hypertension is associated with increased peak arterial blood velocity should be given great credit. See below.


The effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis in humans

Clinical Science 1997; 92;5: 473-479
Sloop, GD, and Garber, DW

Abstract
Increased blood or plasma viscosity has been observed in almost all
conditions associated with accelerated atherosclerosis. Cognizant of the
enlarging body of evidence implicating increased viscosity in atherogenesis,
we hypothesize that the effects of low-density lipoprotein and high-density
lipoprotein on blood viscosity correlate with their association with risk of
atherosclerosis. 2. Blood viscometry was performed on samples from 28
healthy, non-fasting adult volunteers using a capillary viscometer. Data were
correlated with haematocrit, fibrinogen, serum viscosity, total cholesterol,
high-density lipoprotein-cholesterol, triglycerides and calculated low-density
lipoprotein-cholesterol
. 3. Low-density lipoprotein-cholesterol was more
strongly correlated with blood viscosity than was total cholesterol (r = 0.4149,
P = 0.0281, compared with r = 0.2790, P = 0.1505). High-density
lipoprotein-cholesterol levels were inversely associated with blood viscosity
(r = -0.4018, P = 0.0341). 4. To confirm these effects, viscometry was
performed on erythrocytes, suspended in saline, which had been incubated in
plasma of various low-density lipoprotein/high-density lipoprotein ratios.
Viscosity correlated directly with low-density lipoprotein/high-density
lipoprotein ratio (n = 23, r = 0.8561, P<0.01). 5. Low-density lipoprotein
receptor occupancy data suggests that these effects on viscosity are mediated
by erythrocyte aggregation. 6. These results demonstrate that the effects of
low-density lipoprotein and high-density lipoprotein on blood viscosity in
healthy subjects correlate with their association with risk of atherosclerosis.
These effects on viscosity may play a role in atherogenesis by modulating the
dwell or residence time of atherogenic particles in the vicinity of the
endothelium.

My comments in 2011: Who’da thunk that HDL would decrease blood viscosity?
I did these experiments knowing I would have to go back to the drawing board if
the prediction was wrong. In that case, I would have gone gently into that
good night, instead of miserably clinging to life like a degenerative scientist.


A description of two morphologic patterns of aortic fatty streaks, and a hypothesis of their pathogenesis

Gregory D Sloop, Robert S Perret, Jody S Brahney and Margaret Oalmann
Atherosclerosis Volume 141, Issue 1, 5 October 1998, Pages 153-160

Abstract
Two morphologic patterns of fatty streak were identified on examination of 74
aortas from the Pathobiological Determinants of Atherosclerosis in Youth study.
Pattern 1, which predominated in 78% of aortas, is characterized by broad bands
of intense stain which extend to the proximal edge of ostia. Pattern 2, which
predominated in 11%, is characterized by less intense staining which is concave
to the associated ostium. Pattern 1 predominated in older subjects and smokers.
Aging and smoking decrease arterial elasticity, thereby decreasing the volume
and duration of retrograde blood flow in diastole. Doppler ultrasonography of
the posterior intercostal arteries and aorta in 42 healthy subjects revealed that
retrograde blood flow in late systole/early diastole is normal in subjects in the
15–34 age group. Transition from retrograde to antegrade flow was associated
with transient blood stasis. This stasis should prolong the residence time of
lipid-rich particles, enhancing diffusion into the vessel wall. A region of lower
flow velocity was noted in the periostial region in all patients during diastole.
The anatomic, hemodynamic, and risk factor data suggest that the morphology of
fatty streaks is determined by interaction of retrograde with antegrade blood flow as
modulated by arterial elasticity.


Insights into the relationship of fatty streaks to raised atherosclerotic lesions provided by the hemorheologic-hemodynamic theory of atherogenesis

Medical Hypotheses Volume 51, Issue 5, November 1998, Pages 385-388
G. D. Sloop

Abstract
The hemorheologic-hemodynamic theory of atherogenesis suggests that
atherosclerosis is a disease of low shear, which prolongs the residence time of
atherogenic particles on the endothelium. Prolonged residence of lipid-rich
particles results in a fatty streak. Prolonged residence of platelet microthrombi
results in a raised lesion (atherosclerotic plaque). Thus, fatty streak and raised
lesion development are independent processes. In contrast, received wisdom
holds that fatty streaks are the precursors to raised lesions. The author examines
anatomic and risk factor data for fatty streaks and raised lesions, including the
results of the recent multicenter Pathobiological Determinants of Atherosclerosis
in Youth study, in light of these two theories.

My comments in 2011: The work in these two papers convinced me that fatty
streaks are not the precursor lesion to atherosclerotic plaques. Then, it was
easy to conclude that it is not the accumulation of cholesterol, LDL, or any
fraction thereof in the arterial wall which leads to atherosclerotic plaques. One
need not invoke oxidation, inflammation, or any other fairytale to explain
atherosclerosis. By eliminating the problematic progression of fatty streaks to
atherosclerotic plaques, the disease is no longer mysterious. In a twist of fate,
I was involved in the description of a lesion supposedly transitional between them.
I had misgivings about taken a co-author credit on the paper describing
that work, but talked with my boss and decided to add my name. As I recall, I
added one sentence raising an alternative interpretation in the discussion. It
has been cited more than any of my other atherosclerosis work, not surprisingly,
because it buttressed the mainstream. But having participated in the work, I
don’t believe the lesion we described was a transitional form.


Water, other fluids, and fatal coronary heart disease: the Adventist Health Study.

Am J Epidemiol. 2002 May 1;155(9):827-33.
Chan J, Knutsen SF, Blix GG, Lee JW, Fraser GE.

Abstract
Whole blood viscosity, plasma viscosity, hematocrit, and fibrinogen are considered independent risk factors for coronary heart disease and can be elevated by dehydration. The associations between fatal coronary heart disease and intake of water and fluids other than water were examined among the 8,280 male and 12,017 female participants aged 38-100 years who were without heart disease, stroke, or diabetes at baseline in 1976 in the Adventist Health Study, a prospective cohort study. A total of 246 fatal coronary heart disease events occurred during the 6-year follow-up. High daily intakes of water (five or more glasses) compared with low (two or fewer glasses) were associated with a relative risk in men of 0.46 (95% confidence interval (CI): 0.28, 0.75; p trend = 0.001) and, in women, of 0.59 (95% CI: 0.36, 0.97). A high versus low intake of fluids other than water was associated with a relative risk of 2.47 (95% CI: 1.04, 5.88) in women and of 1.46 (95% CI: 0.7, 3.03) in men. All associations remained virtually unchanged in multivariate analysis adjusting for age, smoking, hypertension, body mass index, education, and (in women only) hormone replacement therapy. Fluid intake as a putative coronary heart disease risk factor may deserve further consideration in other populations or using other study designs.

My comments in 2011: I found out about this study reading about urban legends. The benefit of drinking a lot of water was listed among the urban legends, but the authors did say there might be some truth to the legend, and cited this study. Now that you know what causes atherosclerosis, gentle reader, this observation makes sense.


The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.

New Engl J Med. 1998 Aug 27;339(9):584-90.
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA.

BACKGROUND:
In patients with end-stage renal disease, anemia develops as a result of erythropoietin deficiency, and recombinant human erythropoietin (epoetin) is prescribed to correct the anemia partially. We examined the risks and benefits of normalizing the hematocrit in patients with cardiac disease who were undergoing hemodialysis.

METHODS:
We studied 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis: 618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42 percent, and 615 were assigned to receive doses of epoetin sufficient to maintain a hematocrit of 30 percent throughout the study. The median duration of treatment was 14 months. The primary end point was the length of time to death or a first nonfatal myocardial infarction.

RESULTS:
After 29 months, there were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infarctions among those in the low-hematocrit group (risk ratio for the normal-hematocrit group as compared with the low-hematocrit group, 1.3; 95 percent confidence interval, 0.9 to 1.9). Although the difference in event-free survival between the two groups did not reach the prespecified statistical stopping boundary, the study was halted. The causes of death in the two groups were similar. The mortality rates decreased with increasing hematocrit values in both groups. The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group.

CONCLUSIONS:
In patients with clinically evident congestive heart failure or ischemic heart disease who are receiving hemodialysis, administration of epoetin to raise their hematocrit to 42 percent is not recommended.

My comments in 2011: The authors of this study could not explain their results. I think changes in blood viscosity explain their findings. Interestingly, the word “viscosity” is not used once in their paper. I also believe increased viscosity explains the death of several world class cyclists who died in competition after doping with erythropoietin. During competition, they no doubt got a little dehydrated, their viscosity increased, causing decreased flow in areas of changing vascular geometry, further increasing viscosity, etc. This is an example of unremitting positive feedback. One of my professors at the University of New Orleans taught us that unremitting positive feedback is incompatible with life.


Possible association of a reduction in cardiovascular events with blood donation.

Heart. 1997 Aug;78(2):188-93.
Meyers DG, Strickland D, Maloley PA, Seburg JK, Wilson JE, McManus BF.

BACKGROUND: The iron hypothesis suggests that females are protected from atherosclerosis by having lower iron stores than men, thus limiting oxidation of lipids.

OBJECTIVE: To test the iron hypothesis by comparing cardiovascular event rates in whole blood donors compared with nondonors.

DESIGN: Prospective cohort with telephone survey follow up.

SETTING: The State of Nebraska, USA.

PARTICIPANTS: A sample was selected from the Nebraska Diet Heart Survey (NDHS) restricting for age > or = 40 years and absence of clinically apparent vascular diseases at time of enrollment in to NDHS (1985-87).

MAIN OUTCOME MEASURES: The occurrence of cardiovascular events (myocardial infarction, angina, stroke), procedures (angioplasty, bypass surgery, claudication, endarterectomy), nitroglycerin use, or death (all cause mortality), and level of blood donation.

RESULTS: Participants were 655 blood donors and 3200 non-donors who differed in education, physical activity, diabetes, and frequency of antihypertensive treatment; 889 were lost to follow up. Sixty four donors and 567 non-donors reported cardiovascular events (crude odds ratio = 0.50, 95% confidence interval (CI) 0.38-0.66). The benefit of donation was confined to non-smoking males (adjusted odds ratio 0.67, 95% CI 0.45-0.99). Benefit was limited to current donors (the most recent three years). No additional benefit resulted from donating more than once or twice over three years.

CONCLUSION: In support of the iron hypothesis, blood donation in non-smoking men in this cohort was associated with reduced risk of cardiovascular events. A randomized clinical trial is warranted to confirm these findings as the observed personal health benefit of donation has public policy ramifications.

My Comments in 1998:


Possible association of a reduction in cardiovascular events with blood donation

SIR,—As Meyers et al note, data regarding the iron hypothesis of atherogenesis are inconsistent,1 and data regarding the closely allied oxidation hypothesis are also conflicting.2 Thus, I suggest that the beneficial effect of blood donation on cardiovascular disease is caused by a reduction in haematocrit and blood viscosity. Haematocrit
was shown to be a risk factor for atherosclerosis in the Framingham study.3 Haematocrit is also a very powerful determinant of blood viscosity.4 Increased blood viscosity is thought to accelerate atherogenesis by perpetuating areas of low shear in the vascular
tree, prolonging the residence time of atherogenic particles, such as platelets and lipoproteins, on the endothelium.5 This prolonged residence time would facilitate microthrombus formation and lipoprotein diffusion. A decrease in blood viscosity, as well as reducing residence time, would increase the shear dependent expression of atheroprotective molecules such as nitric oxide and prostacyclin.6 The decreased expression of these molecules in atherosclerosis is usually ascribed to a putative endothelial dysfunction caused by the cytotoxic effects of oxidized low density lipoprotein (LDL). LDL increases blood viscosity, presumably by fostering erythrocyte aggregation.4 Thus, the decrease in blood viscosity associated with blood donation might be most pronounced in individuals with the highest serum LDL. This is consistent with the observation of Meyers et al, who noted that the benefit of blood donation was greatest in males with the highest serum LDL.1 Atherosclerosis is a non-specific condition affecting nearly everyone in industrialized societies, not simply those with hypercholesterolaemia. In my view, theories of atherogenesis that focus on lipids and do not adequately explain the accelerated atherogenesis associated with other risk factors, such as increased haematocrit, hypertension, hyperfibrinogenaemia, and raised plasma viscosity, are unlikely to be correct. Increased blood viscosity is found in association with each of these risk factors.5 The Principle of Simplicity (Ockham’s Razor), which holds that the simplest theory that explains all possible cases is most likely to be correct, suggests to me that a non-specific effector such as blood viscosity must play a more central role in atherogenesis than accumulation of cholesterol in the vessel wall.

1 Meyers DG, Strickland D, Maloley PA, et al. Possible association of a reduction in cardiovascular events with blood donation. Heart 1997;78:188–93.

2 Stehbens WE. Atherosclerosis and degenerative diseases of the heart. In: Stehbens WE, Lie JT, eds. Vascular pathology. London: Chapman and Hall Medical, 1995:240–1.

3 Gagnon DR, Zhang T-J, Brand FN, et al. Hematocrit and the risk of cardiovascular
disease—the Framingham study: a 34-year follow-up. Am Heart J 1994;127:674–82.

4 Sloop GD, Garber DW. The effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis in humans. Clin Sci 1997;92:473–9.

5 Sloop GD. A unifying theory of atherogenesis. Med Hypotheses 1996;47:321–5.

6 Reinhart WH. Shear-dependence of endothelial functions. Experientia 1994;50:87–93.

My comments in 2011: I’ve been told that whatever agency it is that makes blood bank policy made a decision to not publicize the benefit of blood donation because it would lower the safety of the donor pool, although I don’t know this for a fact. One of the guiding principles of blood banking is that the safest donor is purely altruistic, not donating for any personal gain. However, I say if you can donate with a clear conscience, just do it.


Atherosclerosis in ancient Egyptian mummies: the Horus study.

JACC Cardiovasc Imaging. 2011 Apr;4(4):315-27.
Allam AH, Thompson RC, Wann LS, Miyamoto MI, Nur El-Din Ael-H, El-Maksoud GA, Al-Tohamy Soliman M, Badr I, El-Rahman Amer HA, Sutherland ML, Sutherland JD, Thomas GS.

Abstract
OBJECTIVES:

The purpose of this study was to determine whether ancient Egyptians had atherosclerosis.

BACKGROUND:
The worldwide burden of atherosclerotic disease continues to rise and parallels the spread of diet, lifestyles, and environmental risk factors associated with the developed world. It is tempting to conclude that atherosclerotic cardiovascular disease is exclusively a disease of modern society and did not affect our ancient ancestors.

METHODS:
We performed whole body, multislice computed tomography scanning on 52 ancient Egyptian mummies from the Middle Kingdom to the Greco-Roman period to identify cardiovascular structures and arterial calcifications. We interpreted images by consensus reading of 7 imaging physicians, and collected demographic data from historical and museum records. We estimated age at the time of death from the computed tomography skeletal evaluation.

RESULTS:
Forty-four of 52 mummies had identifiable cardiovascular (CV) structures, and 20 of these had either definite atherosclerosis (defined as calcification within the wall of an identifiable artery, n = 12) or probable atherosclerosis (defined as calcifications along the expected course of an artery, n = 8). Calcifications were found in the aorta as well as the coronary, carotid, iliac, femoral, and peripheral leg arteries. The 20 mummies with definite or probable atherosclerosis were older at time of death (mean age 45.1 ± 9.2 years) than the mummies with CV tissue but no atherosclerosis (mean age 34.5 ± 11.8 years, p < 0.002). Two mummies had evidence of severe arterial atherosclerosis with calcifications in virtually every arterial bed. Definite coronary atherosclerosis was present in 2 mummies, including a princess who lived between 1550 and 1580 BCE. This finding represents the earliest documentation of coronary atherosclerosis in a human. Definite or probable atherosclerosis was present in mummies who lived during virtually every era of ancient Egypt represented in this study, a time span of >2,000 years.

CONCLUSIONS:
Atherosclerosis is commonplace in mummified ancient Egyptians.

Comments from National Public Radio:
Heart disease is supposedly a modern affliction, the result of a diet rich in animal fat and too many hours spent on the sofa. But recent discoveries suggest that strokes and heart attacks may have been bedeviling humans for millennia.

Greg Thomas is part of a team of scientists that recently discovered the earliest known case of atherosclerosis — clogged arteries — in ancient Egyptian mummies. The startling findings mean scientists may not understand heart disease as well as they think they do…..

"Our hypothesis was that they wouldn't have [heart disease], because they were active, their diet was much different, they didn't have tobacco," he says.

But they were wrong.

One of the mummies the team scanned was a princess in her 40s, who presumably ate fresh food and wasn't sedentary. "That she would have atherosclerosis," Thomas says, "I think we're missing a risk factor. Right now we know that high blood pressure, smoking, cholesterol, inactivity and other things cause atherosclerosis, but I think that we're less complete than we think."

Ancient Egyptians did have access to meat, though Thomas says their diet consisted mostly of grains, fruits and vegetables….

My comments in 2011: Of course I liked this paper and the commentary by NPR because it raises questions about the mainstream paradigm. But the major reason I included it on this website is because it highlights the fear of food in our culture. This fear exists only because mainstream science doesn’t understand atherosclerosis. Until the effect of dietary elements on viscosity is known, the fact is that we don’t know what are best for us.


Whole-blood viscosity and the insulin-resistance syndrome

Høieggen A, Fossum E, Moan A, Enger E, and Kjeldsen SE.
Journal of Hypertension 1998; 16:  203-210.

Background: In a previous study we found that elevated blood viscosity was linked to the insulin resistance syndrome, and we proposed that high blood viscosity may increase insulin resistance.   That study was based on calculated viscosity.

Objective: To determine whether directly measured whole-blood viscosity was related to the insulin-resistance syndrome in the same way as calculated viscosity had been found to be. 

Methods:  Healthy young men were examined with the hyperinsulinemic isoglycemic glucose clamp technique, and we related insulin sensitivity (glucose disposal rate) to other metabolic parameters and to blood viscosity.  We established a technique for direct measurement of whole-blood viscosity.

Results: There were statistically significant negative correlations between glucose disposal rate and whole-blood viscosity at low and high shear rates (r=-0.41, P=0.0007 for both, n=42).  Whole-blood viscosity was correlated positively (n=15) to serum triglyceride (r=0.54, P=0.04) and total cholesterol (r=0.52, P=0.06), and negatively with high-density lipoprotein cholesterol (r= -0.53, P=0.04) concentrations.  Insulin sensitivity index was correlated positively to high density lipoprotein cholesterol (r=0.54, P=0.04) and negatively to serum triglyceride (r= -0.69, P=0.005) and to total cholesterol (r= -0.81, P=0.0003) concentrations.

Conclusions: The present results demonstrate for the first time that there is a negative relationship between directly measured whole-blood viscosity and insulin sensitivity as part of the insulin-resistance syndrome.  Whole-blood viscosity contributes to the total peripheral resistance, and these results support the hypothesis that insulin resistance has a hemodynamic basis. 

Comments in 2012:  I wish I had written this paper.  The good folks who wrote the next paper probably didn’t read it. 


Effects of phlebotomy-induced reduction of body iron stores on metabolic syndrome:  results from a randomized clinical trial.

Houschyar KS, Ludtke TR, Dobos GJ, Kalus U, Brocker-Preuss M, Rampp T, Brinkhaus B, Michalsen A.  BMC Medicine 2012;10:54   
http://www.biomedcentral.com/1741-7015/10/54

Background: Metabolic syndrome (METS) is an increasingly prevalent but poorly understood clinical condition characterized by insulin resistance, glucose intolerance, dyslipidemia, hypertension, and obesity.  Increased oxidative stress catalyzed by accumulation of iron in excess of physiologic requirements has been implicated in the pathogenesis of METS, but the relationships between cause and effect remain uncertain.  We tested the hypothesis that phlebotomy-induced reduction of body iron stores would alter the clinical presentation of METS, using a randomized trial.

Methods:  In a randomized, controlled, single-blind clinical trial, 64 patients with METS were randomly assigned to iron reduction by phlebotomy (n=33) or to a control group (n=31), which was offered phlebotomy at the end of the study (waiting-list design).  The iron-reduction patients had 300 ml of blood removed at entry and between 250 and 500 ml removed after 4 weeks, depending on ferritin levels at study entry.  Primary outcomes were change in systolic blood pressure (SBP) and insulin sensitivity as measured by Homeostatic Model Assessment (HOMS) index after 6 weeks.  Secondary outcomes included HbA1c, plasma glucose, blood lipids and heart rate (HR).

Results:  SBP decreased from 148.5 ± 12.3 mm Hg to 130.5 ± 11.8 mmHg in the phlebotomy group, and from 144.7 ± 14.4 mmHg to 143.8 ± 11.8 mmHg in the control group (difference -16.6 mmHg; 95%CI -20.7 to -12.5; p<0.001).  No significant effect on HOMA index was seen.  With regard to secondary outcomes, blood glucose, HbA1c, low-density lipoprotein/high-density lipoprotein ratio, and HR were significantly decreased by phlebotomy.  Changes in BP and HOMA index correlated with ferritin reduction.

Conclusions:  In patients with METS, phlebotomy, with consecutive reduction of body iron stores, lowered BP and resulted in improvements in markers of cardiovascular risk and glycemic control.  Blood donation may have beneficial effects for blood donors with METS.

My comments in 2012:  Unlike the authors of “Possible association of a reduction in cardiovascular events with blood donation” (see above), at least the authors of this paper recognized that phlebotomy would affect blood viscosity.  Nevertheless, the authors still attributed the beneficial effect of phlebotomy to a reduction of iron stores and decreased oxidative stress.  Whole body oxidative stress is fiction as I discuss below.

No one should be surprised that the metabolic syndrome is associated with pathologically increased blood viscosity.  After all, diabetes hypertension, hypercholesterolemia, and obesity are all associated with increased blood viscosity.  Thus, in patients with metabolic syndrome, phlebotomy will improve blood viscosity.  Because viscosity is inversely proportional to flow, decreased viscosity will increase tissue perfusion, tissue glucose uptake, and decrease serum glucose.  Simple.  Like the authors of “Whole-blood viscosity and the insulin-resistance syndrome” before me, I believe that insulin resistance is simply a consequence of pathologically increased blood viscosity and decreased tissue perfusion.  You’ll have to measure the redox potential of blood before and after the experiment for me to believe that “oxidative stress” had anything to do with observed changes in blood glucose.

In their abstract, the authors call the metabolic syndrome “poorly understood.”  This is another example of how mysterious a disease can be if one ignores viscosity and blood flow. 


The role of oxidative stress in the metabolic syndrome

Whaley-Connell A, McCullough PA, Sower JR. 
Reviews in Cardiovascular Medicine 2011;12(1):21-29.

Loss of reduction-oxidation (redox) homeostasis and generation of excess fee oxygen radicals play an important role in the pathogenesis of diabetes, hypertension, and consequent cardiovascular disease.  Reactive oxygen species are integral in routine physiologic mechanisms.  However, loss of redox homeostasis contributes to proinflammatory and profibrotic pathways that promote impairments in insulin metabolic signaling, reduced endothelial-mediated vasorelaxation and associated cardiovascular and renal structural and functional abnormalities.  Redox control of metabolic function is a dynamic process with reversible pro- and anti-free radical processes.  Labile iron is necessary for the catalysis of superoxide anion, hydrogen peroxide, and the generation of the damaging hydroxyl radical.  Acute hypoxia and cellular damage in cardiovascular tissue liberate larger amounts of cytosolic and extracellular iron that is poorly liganded; thus, large increases in the generation of oxygen free radials are possible, causing tissue damage.  The understanding of iron and the imbalance of redox homeostasis within the vasculature is integral in hypertension and progression of metabolic dysregulation that contributes to insulin resistance, endothelial dysfunction, and cardiovascular and kidney disease.

My comments in 2012:  Would you believe that not a single value of redox potential is reported in this review of oxidative stress?  From my brief review of measurement of redox potential on Wikipedia, I understand that measuring  redox potential is difficult, but still, it should not be okay to skip the measurement and just write the paper.  Thus, we have another shining example of near-total abandonment of the scientific principle in atherosclerosis research.  I’ve heard that libraries devoted to alchemy once existed.  I always wondered how that could be, with no positive findings to write about.  Now I know.  Oxidative stress is the alchemy of the 21st century.  Absolutely pitiful.  Whole issues of Arteriosclerosis, Thrombosis, and Vascular Biology, the #3 ranked journal in peripheral vascular disease, will be useful only as kindling once oxidative stress is debunked.

Today, there is a tendency to impart toxicity to physiological levels of normal molecules such as ferritin and angiotensin.  Give Mother Nature credit for doing a better job than that.  Iron is stored in ferritin as the nearly insoluble, fully oxidized, non-toxic ferric ion.  I really doubt whether physiologic levels of ferritin have any impact at all on the systemic redox state.   


Have we reached the point of diminishing returns from lipid-based theories of atherogenesis, and has the time come for a paradigm shift?  The failure of a large study of sophisticated lipid markers to significantly improve prediction of cardiovascular risk reported in 2012 1, failures of HDL-raising therapy to decrease mortality, most recently reported with dalcetrapib in May, 2012 2, and the consistent failure of anti-oxidant therapy to reduce cardiovascular mortality 3 all suggest that a new paradigm is needed to improve therapy and risk prediction.  This commentary will briefly recount these results, analyze how they have been rationalized, and suggest a new paradigm-recalling the words of historian of science Mara Beller: “One cannot overestimate the impact of the authority figure in the evaluation and acceptance of ideas 4.”

Improved prediction of cardiovascular risk is necessary because 50% of myocardial infarctions occur in individuals without overt hyperlipidemia 5.  In 2012, the Emerging Risk Factors Collaborators reported the results of a study analyzing several novel lipid-associated markers, chosen in the belief that they better reflected the underlying atherosclerotic process, to determine if their utilization could improve prediction of cardiovascular risk over total cholesterol and HDL-C 1.  The failure to meaningfully improve risk prediction in a large study of 165, 544 subjects cautions that we are at a point of diminishing returns from lipid-based testing and theories.  In the accompanying editorial, University of Texas Southwestern internist and lipidologist Scott Grundy rationalized and upheld the lipid-centric view rather than accept the clear limitations of lipidology in atherosclerosis: “The results of epidemiological studies cannot be taken as the final word on the risk factor 6.”

Inhibition of cholesterol-ester transfer protein (CETP), as by dalcetrapib and torcetrapib, increases the size of HDL particles.  However, normal HDL particle size may be crucial for its atheroprotective effect.  Normal HDL particles are too small to simultaneously bind two erythrocytes, and thus antagonize LDL-mediated erythrocyte aggregation, preventing the resultant increase in blood viscosity 7.  Indeed, prospective studies have shown that very large HDL particles are associated with increased cardiovascular risk 8.  Assessing the failure in clinical trials of the two CETP antagonists, University of Michigan Ross School of Business professor Erik Gordon, an academician who specializes in the biomedical industry, said, “all the possible drugs in development that are based on the mechanism will similarly fail” which was in stark contrast with the stubborn impartiality of world-leading cardiologists like Steven Nissen, who said, “People are starting to say HDL isn’t going to work.  We don’t know that yet.  It’s too early to bury the HDL hypothesis 2.”

In another blow to the mainstream lipid theory, antioxidant therapy has been convincingly shown to have little or no impact on cardiovascular disease.  A meta-analysis reported in Lancet in 2003 spanning 81,788 patients on vitamin E and 138,113 on beta carotene showed no beneficial effect on cardiovascular mortality 3. Why is there persistent belief in a pathogenic role for oxidation in the etiology of atherosclerosis?  An answer can be found by consulting the historians of science.  Thomas Kuhn recognized that conflicting data could be ignored in order to preserve the mainstream paradigm 9.  Imre Lakatos, a leading contemporary of Thomas Kuhn, described the dilemma of the degenerative research programme, that is, a theory which cannot be abandoned and is forced to undergo modification after experimental refutation, so that it is no longer able to make useful, groundbreaking predictions while at the same time becoming even harder to refute.  In a spectacular example of such intellectual sclerosis, the pathogenic role for oxidative modification of lipoproteins has been persistently defended as late as 2009 by University of California at San Diego internist and lipidologist Daniel Steinberg:  “Vitamin E may be the wrong antioxidant in humans, the dosage may have been too low, treatment may have been started too late in life, or antioxidant treatment may be beneficial only in some subset of patients subject to unusual oxidative stress….  After all, the hypothesis is not that any antioxidant, at any dosage, in any individual will necessarily be effective 10.”  Stated thus, refuting a role for oxidation in atherogenesis would involve studying all antioxidants at all dosages as early in life as possible, clearly an impossibility.  At the same time, Steinberg’s argument is enough for the casual reader, as well as the true believer, to maintain belief in entrenched theory.  

If we hope to prospectively identify the 20% of myocardial infarctions which occur in the absence of any classic risk factor 5, perhaps it is time to consider candidate theories for a paradigm shift.   There are still relatively overlooked aspects of atherogenesis with the potential to generate more accurate predictions of cardiovascular risk and more effective therapy 11.   To give just one example, blood viscosity is directly associated with all classic risk factors for atherosclerosis including LDL-C 9, and significantly, inversely associated with HDL-C 7.   Evidence for the link between blood viscosity and cardiovascular events was reported by the Edinburgh Artery Study in a random population of 1,592 adult men and women.  After adjustment for age and gender, blood viscosity was shown to be significantly higher in patients who had ischemic heart attacks and strokes relative to those who did not (p= 0.0003 ) 12.  The association with cardiovascular events was as strong as that of LDL-C.  Low-shear viscosity was measured in a separate prospective study of 331 hypertensive men, who were divided into tertiles by blood viscosity:  those in the highest viscosity tertile had greater than threefold cardiovascular events than the lowest viscosity tertile (p=0.006) 13.

1. The Emerging Risk Factors Collaboration (2012)  Lipid-related markers and cardiovascular disease prediction.    JAMA  307(23):2499-2506

2. Roche drops after halting cholesterol drug development.  May 7, 2012.  www.bloomberg.com/news/2012-05-07/roche-halts-testing-on-dalcetrapib-cholesterol-treatment-1-html.  Accessed 10/12/12.

3. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ (2003)  Use of Antioxidant vitamins for the prevention of cardiovascular disease:  meta-analysis of randomized trials.  Lancet   361(9374):2017-23.

4. Beller M.  Quantum Dialogue (1999)  Chicago, The University of Chicago Press p 270.

5. Ridker PM, Libby P (2011)  Risk Markers for Atherothromobtic Diseases.  In: Bonow., RO, Mann DL, Zipes DP, Libby P, eds.  Braunwald’s Heart Disease-A Textbook of Cardiovascular Medicine, 9th ed.    Elsevier Saunders, Philadelphia p 922.

6. Grundy SM (2012)  Use of emerging lipoprotein risk factors in assessment of cardiovascular risk.  JAMA  367(23):2540-2.

7. Sloop GD, Garber DW (1997)  The effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis in humans.  Clinical Science 92:473-9.

8. Van der Steeg WA, Holme I, Boekholdt SM, et al (2008)  High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-1:  Significance for cardiovascular risk.  J Am Coll Cardiol 51(6):634-642.

9. Sloop GD (1998)  A critical analysis of the role of cholesterol in atherogenesis  Atherosclerosis  142:265-268.

10. Steinberg, D (2009)  The LDL modification hypothesis of atherogenesis: an update.  Journal of Lipid Research 50:S376-381. 

11. Cowan AQ, Cho DJ, Rosenson RS (2012)  Importance of blood rheology in the pathophysiology of atherothrombosis.  Cardiovasc Drugs Ther 26:339-348.

12. Lowe GD, Lee AJ, Rumley A, et al.  (1997) Blood viscosity and risk of cardiovascular events:  the Edinburgh Artery Study.  Br J Haematol 96:168-173. 

13. Ciuffetti G, Schillaci G, Lombardini R, Pirro M, Vaudo G, Mannarino E (2005)  Prognostic impact of low-shear whole blood viscosity in hypertensive men.  Eur J Clin Invest 35:93-8. 

Comments in 2013:  This is an unpublished manuscript which I submitted unsuccessfully to more than a half dozen journals.  I wanted to make two points:  why torcetrapib and dalcetrapib therapy didn’t work, and how unscientific opinion leaders can sound when trying to rationalize results which are contrary to the mainstream.   The former point needs to be made, and is important.  I’ll sneak this point into another manuscript someday.  The latter point may be uncharitable, but it needs to be made anyways.   I decided that my own website is really the best place to express it.   

When I started out in medicine, I remember immediately turning to the editorial accompanying results that might conflict with the mainstream and skimming until I was satisfied that the opinion leader was unswayed, and I wouldn’t have to strain my brain learning something new.  There was also something comforting about knowing that the mainstream was correct.  Now, I see myself as a gadfly like Socrates.  If I’m not going to question the mainstream, who will? 

I was surprised, gratified, and saddened all at the same time by how easy it was to find examples of scientific opinion leaders sounding ridiculous defending the mainstream.  I suppose it’s hard to sound intelligent when you’re in that position.   Daniel Steinberg sounds like the poster child for degenerative science.  Steve Nissen is the king of wishful thinking.    One more pearl from Scott Grundy:  “Even if individual studies are entirely consistent, this does not ensure reproducibility across studies.”   WTF?  Someone has to say the emperor is wearing no clothes.  Compounding the problem of unscientific thinking by experts is that physicians are not taught the scientific method.  I didn’t really learn it until I was junior faculty.  How many clinicians who read JAMA are going to critically read Grundy’s editorial?    My guess is that most clinicians are like I used to be, content to know that the experts were holding the line and that what I was taught still held true.  Unfortunately, I now think Thomas Kuhn was more right than wrong, at least in the short run.   According to Publishers Weekly, in a review of John Horgan’s book The End of Science, Kuhn felt that science is an “irrational process that does not converge with the truth.”   I found this quote on the Amazon website offering The End of Science for sale.

I still have faith in Science over the long haul, though.  Serious doubt is being raised about the “reverse transport of cholesterol hypothesis” thanks to torcetrapib and dalcetrapib.  The notion of “oxidative stress” is taking on water, too.  In the February 2013 issue of Scientific American there is an article entitled “The Myth about Antioxidants.”  My comment that oxidative stress is the Alchemy of the 21st Century is looking prescient (see above).   


Congratulations, you have made it to the end.

Author’s note: Please do not misinterpret this website as anti-science. Sure, I wish those engaged in atherosclerosis research followed the scientific method more, made sure their in vitro observations were relevant in vivo, and thought more critically, but what I wish doesn’t matter one bit. I know many, many smarter people than myself, but I was the one who was able to wade through the mainstream hs and find the truth, simply because I followed the scientific method. So, the scientific method is very, very powerful. I look at science like I look at Christianity. I still love Christianity even though not enough people act like Jesus. Peace.


Further Reading:
The Blood Thinner Cure. Kensey, KR, and Turkington, CA. Contemporary Books, Chicago, 2001.

The Pathogenesis of Coronary Occlusion. Morgan, A.D. Blackwell Scientific Publications, Oxford, 1956.

McDonald’s Blood Flow in Arteries. Nichols, WW, and O’Rourke, MF. Arnold, London, 1998.