Mikrobit sydäntautien taustalla?

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Liittynyt3.9.2015

Keskitytään tässä säikeessä ainoastaan otsikon mukaiseen aiheeseen.

Hypoteesi (Annals of Clinical & Laboratory Science, vol. 39, no. 1, 2009),
Uffe Ravnskov and Kilmer S. McCully:
http://mercola.fileburst.com/PDF/Ravnsk ... mation.pdf

Kritiikkiä DrOiVo:

post1492579.html#p1492579

Vastine Ravnskov:

post1493615.html#p1493615

Kritiikkiä Paletaani:

post1493853.html#p1493853

Vastine Maria de Lourdes Higuchi:

post1494174.html#p1494174

Kritiikkiä Paletaani:

post1494324.html#p1494324

Kritiikkiä DrOiVo:

post1494383.html#p1494383

Sivut

Kommentit (18)

Vierailija

^Ja edellisiin lisäyksenä Ravnskovin vastine:

There are obviously many ways to interprete the microscopic findings. What we have done is to suggest a mechanism that hasn't been considered before. The problem with the current interpretation is that there are a host of clinical observations that simply do not fit, where our does. But first a few words about the microscopic findings.

DrOiVo claims that there are only neutrophils present around broken plaques. This is not true. According to Naruko et al (Circulation 2002;106:2894-2900) there are just as many neutrophils in the intact as in the ruptured plaques.

DrOiVo also declares that "ateroskleroosin kehittyminen rasvajuosteesta pikkuhiljaa kypsäksi plakiksi on kuvattu aikas moneen otteeseen ja keskeistä on että muutokset syntyvät ensin intimaan (lipoproteiiniretention myötä)".

There is no proof that mature fibrous plaques starts as fatty streaks. Fibrous plaques are according to our hypothesis scars created when the vulnerable plaque heals.

Paletaani thinks that 2/3 of patients with acute infarction haven't had an infection. What he/she forgets is that we are talking about acute clinical infections. The studies we referred to did not include chronic infections such as periodontal disease. The latter is a strong risk factor for CVD, and other chronic infections may participate as well. But we do not exclude that vasa vasorum may be blocked by other things than microbial complexes.

DrOiVo argues that Japanese people with low cholesterol do not get heart disease although they are exposed to the same pathogens. What we say, however, is that it is not the microorganisms themselves, that cause atherosclerosis, but the conditions that allow them to invade us and here we have presented many factors: smoking, diabetes, stress, lack of vitamin C and D, lack of iron etc etc. It is not the water, that causes the boat to go down; it is the iceberg that has stoved in the keel!

[Huomio: pitäisikö tuossa olla "excess of iron" eikä "lack of iron"?]

DrOiVo also mention FH as a counterargument. Let me remind him/her about the fact that even among homozygous FH people, the cerebral arteries are not more atherosclerotic than in healthy people (Postiglione et al. Atherosclerosis 1991;90:23-30; Rodriguez et al. Stroke 1994;25:831-6). Atherosclerosis in FH is only seen in arteries that are exposed to physical stress such as the coronary and the leg arteries.

Now let me mention some of the observations that contradict the current hypothesis.

According to that LDL particles invade the artery wall through the endothelium. How come then that high LDL is not a risk factor for women, not for diabetics, not for Russians, not for Maori people, not for people with kidney diseae and not for old people? And how come that no one has ever found an association between blood cholesterol and a degree of atherosclerosis in unselected individuals? And how come that old people with high cholesterol live the longest? (References are available in my books).

High LDL cholesterol is said to cause endothelial dysfunction, the prerequisite for LDL invasion. How come then that there is no association between the concentration of LDL cholesterol in the blood and the degree of endothelial dysfunction? (Reis et al.Am Heart J 2001;141:735-741).

Any hypothesis must be able to explain all observations. The current one doesn't and should therefore have been discarde long ago.

Vierailija
kujala
DrOiVo claims that there are only neutrophils present around broken plaques. This is not true. According to Naruko et al (Circulation 2002;106:2894-2900) there are just as many neutrophils in the intact as in the ruptured plaques.



Either your knowledge or your quotation concerning the subject is not accurate.

Quote from "Naruko et al (Circulation 2002;106:2894-2900)":

All culprit lesions of patients who had died of AMI had neutrophils within the plaques, although the number varied widely. In contrast, neutrophils were extremely rare in coronary lesions obtained from patients who had died ) of noncardiovascular diseases; in only 2 of the 87 atherosclerotic lesions neutrophils were identified. Similar observations were made in patients in whom atherectomy material was studied. In patients with UAP, neutrophils within the culprit lesion were detected in 14 of 32 (44%), whereas this was the case in only 2 of 35 (6%) patients with SAP. These observations suggest that neutrophils are actively associated with acute coronary events.



And even in the abstract it says that neutrophils are abundantly present in eroded and ruptured plaques. Plaque erosion is a similar, yet not as acute event as plaque rupture: there's slight rupturation and hemorrage, but not a full rupture.

Nevertheless, it seems that neutrophil infiltration is associated with end-stage atherosclerosis (UAP/infarctation). Stable plaques (which might become unstable later) are free from neutrophils. It is likely that the neutrophil infiltration is secondary to plaque destabilization.

kujala
There is no proof that mature fibrous plaques starts as fatty streaks. Fibrous plaques are according to our hypothesis scars created when the vulnerable plaque heals.



No proof?

Original Contribution
JAMA. 1999;281(8):727-735. doi: 10.1001/jama.281.8.727
Prevalence and Extent of Atherosclerosis in Adolescents and Young Adults
Implications for Prevention From the Pathobiological Determinants of Atherosclerosis in Youth Study

1. Jack P. Strong, MD;
2. Gray T. Malcom, PhD;
3. C. Alex McMahan, PhD;
4. Richard E. Tracy, MD, PhD;
5. William P. Newman III, MD;
6. Edward E. Herderick;
7. J. Fredrick Cornhill, DPhil;
8. for the Pathobiological Determinants of Atherosclerosis in Youth Research Group

from discussion..

The PDAY results presented herein show that fatty streaks in some locations—the thoracic aorta and portions of the ventrolateral intimal surface of the abdominal aorta—are not likely to be replaced by raised lesions during the 15- to 34-year age period (Figure 2). On the other hand, the distribution pattern of raised lesions in the dorsolateral portion of the abdominal aorta (Figure 2) and the distribution pattern of raised lesions in the right coronary artery of older persons ( Figure 3) follow those of the distribution of fatty streaks in younger persons.

Among the most persuasive evidence for the fatty streak being the precursor of the raised lesions is that derived from the microscopic examination of lesions of the coronary arteries. Stary,34​-35 using light and electron microscopy of the unopened pressure perfusion-fixed left coronary arteries, studied 691 men and women who died between full-term birth and age 39 years to assess the earliest microscopic changes of atherosclerosis. More than 50% of children aged 10 to 14 years had lesions characterized by accumulations of macrophage foam cells, lipid-containing smooth muscle cells, and thinly scattered extracellular lipid. These changes represent the microscopic counterpart of gross fatty streaks. Approximately 8% of the subjects, aged 10 to 14 years, had lesions with larger accumulations of extracellular lipid that were thought to be in transition to fibrous plaques (ie, the lesions that are known to be associated with clinical disease in adults). These results indicate a progression from fatty streaks through intermediate or transitional lesions to atheromatous lesions (comparable with fibrous plaques by gross classification) in a defined segment of the left anterior descending coronary artery that is predisposed to clinically significant lesions.

Other evidence linking the fatty streak to the raised lesions includes topographic, chemical, physical chemical, and other histologic studies.36​-44 These studies are consistent with Stary's34​-35 demonstration of a continuous spectrum of lesions that begin with a collection of lipid-filled macrophages and progress to a lesion with a core of necrotic debris, extracellular lipid, and a fibromuscular cap, which is the typical raised lesion that directly leads to thrombotic occlusion and CHD. These results suggest that, although fatty streaks may be innocuous if they remain as such, under certain conditions and at certain anatomic sites, they represent the first stage of a process leading to clinical disease.




This is a nice review concerning the subject
The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. [Review] [48 refs]
Insull W Jr.
American Journal of Medicine. 122(1 Suppl):S3-S14, 2009 Jan.
[Journal Article. Research Support, Non-U.S. Gov't. Review]
UI: 19110086
Authors Full Name
Insull, William Jr.

AB Atherosclerosis develops over the course of 50 years, beginning in the early teenage years. The causes of this process appear to be lipid retention, oxidation, and modification, which provoke chronic inflammation at susceptible sites in the walls of all major conduit arteries. Initial fatty streaks evolve into fibrous plaques, some of which develop into forms that are vulnerable to rupture, causing thrombosis or stenosis. Erosion of the surfaces of some plaques and rupture of a plaque's calcific nodule into the artery lumen also may trigger thrombosis. The process of plaque development is the same regardless of race/ethnicity, sex, or geographic location, apparently worldwide. However, the rate of development is faster in patients with risk factors such as hypertension, tobacco smoking, diabetes mellitus, obesity, and genetic predisposition. Clinical trial data demonstrate that treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) favorably alters plaque size, cellular composition, chemical composition, and biological activities centered on inflammation and cholesterol metabolism, as well as the risk of clinical events due to atherosclerosis. Even with advanced atherosclerosis, statins begin to improve clinical risk within 4 months. During long-term follow-up in clinical trials for up to 11 years with or without further treatment, clinical benefit remains significant, indicating the durability of treatment-induced changes in the development of plaque. Thus, atherosclerosis, a disease heretofore viewed as inevitably progressive, can be treated to significantly alter arterial lesions and reduce their clinical consequences. [References: 48]




kujala
DrOiVo argues that Japanese people with low cholesterol do not get heart disease although they are exposed to the same pathogens. What we say, however, is that it is not the microorganisms themselves, that cause atherosclerosis, but the conditions that allow them to invade us and here we have presented many factors: smoking, diabetes, stress, lack of vitamin C and D, lack of iron etc etc. It is not the water, that causes the boat to go down; it is the iceberg that has stoved in the keel!



People have atherosclerosis even in the absence of smoking, diabetes, lack of micronutrients etc...

And it should be noted that many of these notorious Japanese fishermen did smoke and their diet included lots of sodium (at least according my Cardiology book..). So the argument that the absence of atherosclerosis in these guys was simply because they were "protected from infection" in not a plausible argument.

kujala
DrOiVo also mention FH as a counterargument. Let me remind him/her about the fact that even among homozygous FH people, the cerebral arteries are not more atherosclerotic than in healthy people (Postiglione et al. Atherosclerosis 1991;90:23-30; Rodriguez et al. Stroke 1994;25:831-6). Atherosclerosis in FH is only seen in arteries that are exposed to physical stress such as the coronary and the leg arteries.



Yeah, maybe not their cerebral arteries (which aren't even near as prone to develop atherosclerosis than coronary arteries, probably because much thinner intima), but their coronary arteries gets stiff occluded in early adulthood without treatment. Occluded by what? Atherosclerotic mass filled with LDL!

For example...

Familial hypercholesterolemia: a challenge of diagnosis and therapy. [Review] [40 refs]
Sibley C. Stone NJ.
Cleveland Clinic Journal of Medicine. 73(1):57-64, 2006 Jan.

CORONARY DISEASE BEGINS EARLY
People with FH begin to develop obstructive
and progressive atherosclerotic disease and
impaired endothelial function at a young
age.12 Homozygous FH can result in symptomatic
angina in childhood and adolescence.13
Patients with heterozygous FH can develop
clinically evident coronary heart disease in
their 30s or 40s, especially if they have other
risk factors such as cigarette smoking and a
strong family history of premature coronary
heart disease.6,9,14
In one large case series,9 higher LDL-C
values, low HDL-C levels, and elevated
lipoprotein(a) levels in the offspring predicted
coronary heart disease in the parents. Indeed,
elevated levels of lipoprotein(a) and homocysteine
have been thought to be markers of an
adverse prognosis in some15,16 but not all
analyses.17
On coronary angiography, two striking
features of heterozygous FH are that obstructive
lesions tend to be proximal rather than
distal18 and that, in those with low HDL-C,
coronary ectasia is common.19 The aortic
valve may be thickened, and in homozygous
cases a characteristic form of supravalvular
aortic stenosis is present.13

[Journal Article. Review]
UI: 16444917




kujala
According to that LDL particles invade the artery wall through the endothelium. How come then that high LDL is not a risk factor for women, not for diabetics, not for Russians, not for Maori people, not for people with kidney diseae and not for old people? And how come that no one has ever found an association between blood cholesterol and a degree of atherosclerosis in unselected individuals? And how come that old people with high cholesterol live the longest? (References are available in my books).



As noted before, atherosclerosis is a multifactorial disease, e.g. lots of things can compensate the deletrous effects of hyperlipidemia, and vice versa, lots of risk factors can aggravate the disease even in the absence of distinct hyperlipidemia.

But still, I feel that the evidence that points to the central role of dyslipidemia in the development of atherosclerosis is quite convincing.

Of course there's still lots of unknowns, but this infection-theory alone is far from sufficient to explain the issue and it has its definite downfalls..

Vierailija

Miksi arterioskleroosi on liki tuntematon tauti luonnonkansojen ml. perinteisesti syövät eskimot keskuudessa?

Tuskin asia ihan basilleista johtuu?

Vierailija

Siis taas kirjoittajat vouhkaa...ja vieläpä vääristä asioista.

Vesikkelit ne sydäntautien takana ovat, ei mikrobit.

Vierailija

Uffelle kyllä pointsit siitä, että viitsii nähdä vaivaa näinkin tyhjänpäiväiseen asiaan kuin toisen maan keskusteluforumilla esitetyn kritiikin käsittelyyn Taisi kiireessä unohtua ainakin se huikaisevan vakuuttava plakin lämpötila-argumentti...

Uffe

There is no proof that mature fibrous plaques starts as fatty streaks. Fibrous plaques are according to our hypothesis scars created when the vulnerable plaque heals.

Fibrosis is indeed part of the normal healing response. However, it can also be problematic. Too much fibrosis can obstruct the flow of blood in the arteries and too little can lead to plaque rupture. Fibrosis is also linked to restenosis in angioplasties. The origins of fibrosis are most likely related to prolonged inflammation and frankly I don't see how your interpretation challenges the mainstream view.

Uffe
Paletaani thinks that 2/3 of patients with acute infarction haven't had an infection. What he/she forgets is that we are talking about acute clinical infections. The studies we referred to did not include chronic infections such as periodontal disease. The latter is a strong risk factor for CVD, and other chronic infections may participate as well.

Actually I don't think that. I was merely pointing out a different interpretation of the data you were referring to. In my opinion those studies don't give convincing evidence to question the current theory. At best, they may give knowledge about further risk factors.

Oh, and Paletaani is a 'he'

Uffe
But we do not exclude that vasa vasorum may be blocked by other things than microbial complexes.

Here's a related question that's bugging me about this whole vasa vasorum-hypothesis: have you completely excluded the possibility that lipid accumulation could be the cause of vasa vasorum blockade? Because even if some of the plaques were originating from the vasa vasorum, that still wouldn't discard dyslipidemia as a risk factor.

A clarification to this matter would be much appreciated.

Uffe
DrOiVo argues that Japanese people with low cholesterol do not get heart disease although they are exposed to the same pathogens. What we say, however, is that it is not the microorganisms themselves, that cause atherosclerosis, but the conditions that allow them to invade us and here we have presented many factors: smoking, diabetes, stress, lack of vitamin C and D, lack of iron etc etc. It is not the water, that causes the boat to go down; it is the iceberg that has stoved in the keel!

I doubt that any qualified researcher of atherosclerosis would claim that it's caused solely by slightly elevated LDL. It is a widely recognized fact that atherosclerosis is a multifactorial disease involving several risk factors. Even in terms of dyslipidemia, we can also identify both low HDL and high triglycerides as independent risk factors of atherosclerosis. In that vein, I find your criticism of the current theory as being somewhat mistargeted.

Uffe
...Atherosclerosis in FH is only seen in arteries that are exposed to physical stress such as the coronary and the leg arteries.

To the best of my knowledge, this is not accurate since there is also systemic sclerosis in other arteries too. And even if this was completely true, how is this a problem to the current theory?

Uffe
High LDL cholesterol is said to cause endothelial dysfunction, the prerequisite for LDL invasion. How come then that there is no association between the concentration of LDL cholesterol in the blood and the degree of endothelial dysfunction? (Reis et al.Am Heart J 2001;141:735-741).

Because high LDL is not the sole contributor to endothelial dysfunction. Other factors include smoking, hypertension and obesity. We know that both visceral and subcutaneous adipose tissue is also an endocrine organ which has a role in endothelial dysfunction as well.

Uffe
Any hypothesis must be able to explain all observations. The current one doesn't and should therefore have been discarde long ago.

This is a classic example of the Nirvana-fallacy; "the theory is not absolutely perfect, therefore it should be discarded". Why so? Why not struggle to improve the theory by learning from its flaws?

My view is that the many contributing factors of atherosclerosis are widely accepted and not very many people blame LDL as the single culprit. Besides, the current view on the role of lipoproteins is based on the ratio of LDL and HDL within the tissue rather than the absolute amount of LDL. There is very good data ranging from basic molecular mechanisms to large clinical trials suggesting that this balance has an important role. I'm not saying that microbes couldn't play a part in atherosclerosis - maybe they do. But I don't think that we can reject the role of lipoproteins and replace it with micro organisms.

And for the record, I greatly appreciate you taking the time to respond to our criticism. I'm sure you're a very busy man and have lots of better things to do

Vierailija

Ravnskovin vastaus DrOiVon viimeisimpään...

DrOlVo, please read Naruko once again (p2895): ”In eroded plaques, a trans-cap rupture was not found despite serial sectioning.” The neutrophils had obviously arrived before the rupture, and in addition, it was a different kind of neutrophils than those present at the ruptured plaques.

That neutrophils were extremely rare in coronary lesions obtained from patients who had died of noncardiovascular diseases is precisely what we mean. Coronary lesions in such patients are not vulnerable plaques, but healed atherosclerotic lesions, and there is no evidence that stable plaques are transformed to vulnerabe plaques. The latter have even been identified in otherwise normal arteries.

Now to the fatty streaks. That raised lesions appear at the same places (most often, but not always) does not mean that they develop into atherosclerotic plaques. Fatty streaks are present in the fetus and are more frequent in early than late childhood (ref 98 and 99 in our paper). Do you mean that atherosclerosis starts in fetal life? We think that the foam cells in the fatty streaks are macrophages on their way back to the circulation. We also think that macrophages do not fagocytose oxidized cholesterol; most likely cholesterol is oxidized during the macrophages´ oxidative destruction of the microorganisms and may afterwards be converted back to normal by HDL).

Please note that the conclusions in Strong´s paper are built on speculation. According to Strong et al´s ”strongest proof” the children had ”lesions with larger accumulations of extracellular lipid that were thought to be (my italics) in transition to fibrous plaques (ie, the lesions that are known to be associated with clinical disease in adults).”

Not only is it speculation, fibrous plaques are not associated with clinical disease, it is the vulnerable plaque, and there is no evidence either that they may develop into vulnerable plaques.

About the Japanese Fishermen. I did not say that they were protected from infection. What I said was that it is not the infection itself that causes atherosclerosis. Nobody knows why the Japanese Fishermen were protected; you cannot use epidemiologic observations to prove anything. (But they are excellent for disproving!)

I do not deny that FH people become atherosclerotic. What I mean is that it is not caused by hypercholesterolemia, or else the cerebral vessels in homozygous FH would be more atherosclerotic than in normal people.Please recall that cholesterol may be 3-4 times higher in these people than normally

Atherosclerosis is a multifactorial disease, true, but high cholesterol is evidently not among the factors, or else it should be a risk factor for all people, both sexes and all ages, in particular for old people, because more than 90% of all cardovascular deaths occur in people after age 65.

Finally, please note that we have presented a new hypothesis. We have speculated, just as have the proponents of the cholesterol hypothesis. We do not claim that our idea is the final truth. But the current idea should have been abandoned decades ago because of the many contradictory observations.

Vierailija
kujala
DrOlVo, please read Naruko once again (p2895): ”In eroded plaques, a trans-cap rupture was not found despite serial sectioning.” The neutrophils had obviously arrived before the rupture, and in addition, it was a different kind of neutrophils than those present at the ruptured plaques.



But plaque erosion had still taken place already. Meaning the endothelium had already been damaged, along with formation of microtrombus etc.

Why wouldn't the neutrophils be present in eroded/ruptured plaques simply because the damaged endothelium and activated platelets secrete IL-8 and other neutrophil attractants?

kujala
That neutrophils were extremely rare in coronary lesions obtained from patients who had died of noncardiovascular diseases is precisely what we mean. Coronary lesions in such patients are not vulnerable plaques, but healed atherosclerotic lesions, and there is no evidence that stable plaques are transformed to vulnerabe plaques. The latter have even been identified in otherwise normal arteries



Yes, but it points to the fact that local infection isn't the main etiological factor behind atherosclerosis. Something (else than microbes) causes excess lipids to accumulate in the vessel wall. And, as pointed out by Paletaani, stable plaques are definitely pathological as well (causing clinical disease as well, not as dramatic though as vulnerable plaques).'

kujala
Fatty streaks are present in the fetus and are more frequent in early than late childhood (ref 98 and 99 in our paper). Do you mean that atherosclerosis starts in fetal life?



No, fatty streaks in themselves are normal phenomenon, no doubt about it. But when they start to form actual atheromas (usually in early adulthood) things get pathological).

kujala
We think that the foam cells in the fatty streaks are macrophages on their way back to the circulation. We also think that macrophages do not fagocytose oxidized cholesterol; most likely cholesterol is oxidized during the macrophages´ oxidative destruction of the microorganisms and may afterwards be converted back to normal by HDL).



Macrophages don't express the LDL-receptor, LDL has to be modified in some way for the scavenger receptors do recognize it. Apparently macrophages can recognize and phagocytose VLDL and chylomicron remnants, which might be the reason for the non-pathological foam cells in fatty streaks.

And it has been proven that macrophages indeed do phagocytose ox-LDL ( for example: Cellular and Molecular Life Sciences Volume 54, Number 7, 628-640, DOI: 10.1007/s000180050191
Y. Yamada, T. Doi, T. Hamakubo and T. Kodama: Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system)

There's also evidence that LDL oxidation doesn't require the presence of inflammatory cells:
Napoli, C., D'Armiento, F.P., Mancini, F.P., Postiglione, A., Witztum, J.L., Palumbo, G. and Palinski, W., 1997. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J. Clin. Invest. 100, pp. 2680–2690.

kujala
Not only is it speculation, fibrous plaques are not associated with clinical disease



They are the main cause for SAP, a clinical disease I presume.

kujala
I did not say that they were protected from infection. What I said was that it is not the infection itself that causes atherosclerosis.



...But their lipoprotein profile was excellent and for some reason they didn't develop clinical atherosclerosis. Why's that?

You're saying that these two things together are purely coincidental?

kujala
I do not deny that FH people become atherosclerotic. What I mean is that it is not caused by hypercholesterolemia, or else the cerebral vessels in homozygous FH would be more atherosclerotic than in normal people.Please recall that cholesterol may be 3-4 times higher in these people than normally



As mentioned before, cerebral arteries don't develop atherosclerosis easily compared to extracranial sites:
Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis.
D'Armiento FP. Bianchi A. de Nigris F. Capuzzi DM. D'Armiento MR. Crimi G. Abete P. Palinski W. Condorelli M. Napoli C.
Stroke. 32(11):2472-9, 2001 Nov.
[Comparative Study. Journal Article. Research Support, Non-U.S. Gov't. Research Support, U.S. Gov't, P.H.S.]
UI: 11692003
Authors Full Name
D'Armiento, F P. Bianchi, A. de Nigris, F. Capuzzi, D M. D'Armiento, M R. Crimi, G. Abete, P. Palinski, W. Condorelli, M. Napoli, C.

AB BACKGROUND AND PURPOSE: Atherosclerosis occurs later and is less extensive in intracranial arteries than in extracranial arteries. However, the mechanisms responsible are poorly understood. A previous study has suggested a better antioxidant protection of intracranial arteries. METHODS: To assess the influence of age on arterial activity of antioxidant enzymes and atherogenesis, we compared intracranial and extracranial arteries of humans of different ages who retrospectively lacked confounding classic risk factors (48 premature fetuses aged 6.4+/-0.8 months [mean+/-SD], 58 children aged 7.9+/-3.8 years, 42 adults aged 42.5+/-5.1 years, and 40 elderly subjects aged 71.8+/-3.4 years; all males). Lesions were quantified by computer-assisted imaging analysis of sections of the middle cerebral and basilar arteries, the left anterior descending coronary artery, the common carotid artery, and the abdominal aorta. Macrophages, apolipoprotein B, oxidized LDL, and matrix metalloproteinase-9 in lesions were determined by immunocytochemistry. The effect of aging on atherogenesis was then compared with that on the activity of 4 antioxidant enzymes in the arterial wall. RESULTS: Atherosclerosis was 6- to 19-fold greater (P<0.01) in extracranial arteries than in intracranial arteries, and it increased linearly with age. Intracranial arteries showed significantly greater antioxidant enzyme activities than did extracranial arteries. However, the antioxidant protection of intracranial arteries decreased significantly in older age, coinciding with a marked acceleration of atherogenesis. An increase in matrix metalloproteinase-9 protein expression and in gelatinolytic activity consistent with the degree of intracranial atherosclerosis was also observed. CONCLUSIONS: These results suggest that a greater activity of antioxidant enzymes in intracranial arteries may contribute to their greater resistance to atherogenesis and that with increasing age intracranial arteries respond with accelerated atherogenesis when their antioxidant protection decreases relatively more than that of extracranial arteries.




So youre saying that the fact that FH patients have huge loads of LDL circulating in their veins (and arteries ) and the rapid development of coronary artery disease are two separate things? How's that? How does the infection-theory explain the clinical course of FH better?

And why is lipid lowering therapy effective treatment for FH if lipids aren't the problem?

kujala
Atherosclerosis is a multifactorial disease, true, but high cholesterol is evidently not among the factors, or else it should be a risk factor for all people, both sexes and all ages, in particular for old people, because more than 90% of all cardovascular deaths occur in people after age 65.



But things just aren't that simple. And there's billions of confounders that have to be adressed, starting from lipid measurements: a single measurement doesn't tell you much about the life-long mean lipid levels. And for older people, it is widely known that lots of chronic diseases and malignancies lower LDL, thus biasing the benefits of lower lipids in epidemiological studies. Also different LDL subfractions (especially sdLDL) should be taken to account; patient might have elevated LDL-levels but low sdLDL, thus having much smaller risk. And vice versa....

And it also has to be remembered that cardiovascular death is the end-point of a pathological process started decades ago. It is easy to see that at that point (for the elderly) when the damage is already largely done (fully developed atherosclerosis) correlation of lipids at that point to the clinical disease can be anything from significant to utterly non-significant. It's what has taken place in the past decades that counts.

New theories and speculations are of course always needed.
I think that it's fairly logical to think that infections can aggravate atherosclerosis, just as any other clinical entity that causes systemic inflammation (just like rheumtoid arthitis, for example..). But that microbes would be the main etiological factor behind atherosclerosis or even just vulnerable plaques... Well, the evidence doesn't support that, at least not yet.

Vierailija

Ei ole tarkoitus hyppiä DrOiVon varpaille mutta tähän yhteen kohtaan on pakko itsekin tarttua...

Uffe

We also think that macrophages do not fagocytose oxidized cholesterol; most likely cholesterol is oxidized during the macrophages´ oxidative destruction of the microorganisms and may afterwards be converted back to normal by HDL).

This is what I would call an 'extraordinary claim'. I would be most interested to see the 'extraordinary evidence' backing it up.

As DrOiVo pointed out, not only does this assumption disregard a wide array of studies concerning scavenger receptor function, it is also confronted by evidence regarding the histological distribution of ox-LDL. For example, in a study by Mehrabi et al. (Cardiovasc Res 2000 45 (4): 874-882. ) we can see that once the ox-LDL is stained by a specific antibody, it is spread throughout the intima. We can also see that some of the ox-LDL is co-localized with the macrophages indicating that they are indeed being phagocytosed.

Vierailija

Ravnskovin viimeisin vastaus:

I consider this discussion meaningless as our opponents obviously have read the abstract of our paper only. Almost all of their objections are explained in detail in our paper. I shall give you a few examples.

You claim that local infections cant participate because there are no neutrophils around stable plaques. Of course stable plaques may obstruct the lumen, but thrombs causing infarction are always located to vulnerable plaques. This is accepted by most researchers today. Stable plaques are, as we see it, scars after healed vulnerable plaques and there are no neutrophils around scars, whether they are situated in the skin or in the arterial wall.

Macrophages take up LDL and other lipoproteins by phagocytosis when they have bound microorganisms and their toxins and form circulating aggregates. Read our paper! It is these aggregates that we think are obstructing vasa vasorum.

Intracranial arteries are less atherosclerotic than extracranial, true, but acording to conventional wisdom it is caused by hypercholesterolemia. Accordingly, intracranial atherosclerosis should be more pronounced in FH than normally, in particular in homozygous FH. As it isnt, the cholesterol hypothesis falls apart.

Lipid lowering therapy is not effective for FH. In the ENHANCE trial, that included FH people only, the worst outcome was seen in the group where cholessterol was lowered the most

You still come back to the many confounders explaining why high cholesterol is not a risk factor for most people. Obviously you have forgotten, or you dont know that the whole cholesterol hypothesis is built on the idea that high cholesterol is a risk factor for myocardial infarction. There arent other arguments! The reason why cholesterol lowering with statins is able to lower the risk is because the statins have many other effects that are more beneficial than cholesterol lowering. Cholesterol lowering with other drugs have never been able to lower heart mortality, read my BMJ paper:
http://www.ncbi.nlm.nih.gov/pmc/article ... 1-0019.pdf

If you are not impressed by the fact that old people with high cholesterol live the longest I dont know what to say. Why then lower it? Why should we lower cholesterol when we become old if high cholesterol is a sign of good health? And please note that the large majority of people on statin treatment have passed the age of 60.

This is my last comment. I have obviously been unable to convince my opponents about the many fallacies of the cholesterol hypothesis. Hopefully other readers have realized that we have been conned for many years. More information is available on the website of our organization THINCS, The International Netework of Cholesterol Skeptics http://www.thincs.org On my own homepage http://www.ravnskov.nu/uffe you will find a list of my publications. In case you havent read our hypothesis paper it is freely available here: http://tinyurl.com/yf6hq3v

Vierailija

Noniin, nyt kun hra Ravnskov heitti yllättäen lusikan nurkkaan voimme jatkaa omalla kielellämme.

kujala
I consider this discussion meaningless as our opponents obviously have read the abstract of our paper only.



Luin koko tekstin.

kujala
Stable plaques are, as we see it, scars after healed vulnerable plaques and there are no neutrophils around scars, whether they are situated in the skin or in the arterial wall.



Tästä ei ole näyttöä. Ja toisaalta hieman epälooginen selitys kun ajattelee että fibroottiset plakit voivat alkaa kehittymään jo melko varhaisella iällä, jolloin taas infarktit ovat harvinaisia.

kujala
Macrophages take up LDL and other lipoproteins by phagocytosis when they have bound microorganisms and their toxins and form circulating aggregates.



Onko in-vivo näyttöä näistä toksiini-LDL-aggregaateista? Tai siitä että ne tukkivat päätevaltimoita? Miksi vain vasa vasorumissa? Miksei esim aivoissa?

kujala
Intracranial arteries are less atherosclerotic than extracranial, true, but acording to conventional wisdom it is caused by hypercholesterolemia. Accordingly, intracranial atherosclerosis should be more pronounced in FH than normally, in particular in homozygous FH. As it isnt, the cholesterol hypothesis falls apart.



Miksi teoria tuon vuoksi kaatuisi? Miksei ole mahdollista että FH:ssa ateroskleroosi etenee hieman eri tavalla, esim niin että suurimmat muutokset syntyvät ensin herkimpiin paikkoihin, ja vasta myöhemmin (esim ikääntymisen myötä kompensaatiomekanismien heiketessä) intra-kraniaalisesti?

kujala
I have obviously been unable to convince my opponents about the many fallacies of the cholesterol hypothesis.



You got that right

kujala
... that we have been conned for many years.



Kenties, kukapa tietää... Mutta hiukka eksaktimpaa argumentaatiota kaivataan että nykyisiä valtahypoteeseja lähdetään muuttamaan.

Vierailija

Vähän ajattelinkin, ettei Uffe enää kauaa viitsi vääntää anonyymien amatöörien kanssa Hän vaikuttaa melko vilpittömältä kaverilta ja kyllä tuota julkaisuluetteloa kelpaa esitellä.

Minua jäi vielä askarruttamaan ainakin:
- Mikä sen plakin lämpötila-argumentin lopullinen merkitys olikaan. Uffe oli melko selkeästi lukenut kyseisestä tutkimuksesta pelkän abstraktin ja silti syytti meitä samasta asiasta.
- Millä perusteella voidaan sivuuttaa iso kasa scavenger-reseptoreita ja ox-LDL:n lokalisoitumista koskevaa tutkimusaineistoa ja todeta, etteivät makrofagit todella syö hapettunutta LDL:ää. Tähän ei kyllä löydy selvennystä Uffen paperista vaikka kuinka tavailee. Siellä kyllä yritetään sanoa, että makrofagit syövät muullakin tavoin modifioitua LDL:ää sekä muita lipoproteiineja mutta sehän ei ole mikään ihme. Minun käsitykseni mukaan scavenger-reseptoreilla on jonkin verran affiniteettia normaaleja LDL-partikkeleita kohtaan mutta ox-LDL:ää kohtaan se on moninkertainen.
- OK, lipoproteiinit voivat muodostaa aggregaatteja mikrobijämien kanssa. Samalla perusteella voitaisiin sanoa, että ylimäärä lipoproteiineja altistaa myös liialliselle aggregaattien muodostukselle. Ylimääräinen riskitekijä/mekanismi? Ehkäpä. Ongelma vallitsevalle käsitykselle? Ei niinkään.
- Uffen mielestä intrakraniaalisen skleroosin puuttuminen FH-potilailla murtaa koko teorian, vaikka sille on paljon muitakin selityksiä (DrOiVon manitsema intiman paksuus, hemodynaamiset tekijät yms)
- Pahamaineiset japanilaiset sivuutetaan melko huolettomasti
..jne

Ehkäpä näihin löytyisi jotain kannanottoja kun lukisi enemmän Uffen juttuja mutta päällisin puolin nämä argumentit eivät herätä riittävää mielenkiintoa. Ateroskleroosia on tutkittu niin monella eri tavalla ja monesta eri näkökulmasta, että kirjallisuudesta löytyy väkisinkin aineistoa vaikka minkälaisiin hypoteeseihin. Omaan sähköpostiini tipahtelee säännöllisesti esim. Circulationin, Circ Resin, Hypertensionin, ATVB:n ja Atherosclerosiksen sisällysluettelot ja kun noita seuraa niin Uffen argumentointi näyttää väkisinkin kirsikanpoiminnalta.

Tällä hetkellä voin melkoisella varmuudella todeta, ettei tästä bakteeriteoriasta ole nykyisen haastajaksi. Kyseenalaistaminen ja uusien teorioiden muotoilu kuuluu tieteeseen mutta kyllä sen pitäisi perustua paljon kovempaan dataan kuin tämä.

Niin joo, ja laitetaan vielä pari THINCS-aiheista linkkiä vastapainoksi:
http://www.sciencebasedmedicine.org/?p=22
http://www.sciencebasedmedicine.org/?p=219#more-219
http://skepdic.com/refuge/bunk28.html

Vierailija
Paletaani
- Mikä sen plakin lämpötila-argumentin lopullinen merkitys olikaan. Uffe oli melko selkeästi lukenut kyseisestä tutkimuksesta pelkän abstraktin ja silti syytti meitä samasta asiasta.



Niin, Ravnskov sanoi mulle tuossa kohtaa henk.koh. mailissa, että "meillä ei ole vielä kaikki yksityiskohdat kohdillaan", joten kaiketi hän vain oli alkanut huomaamattaan käyttää argumenttia, jolle ei löytynyt perustetta. Aika isoa huolimattomuutta, kun kyse on kuitenkin keskeisestä vasta-argumentista.

Toinen argumentointi, jota Ravnskov on viime aikoina kaiketi käyttänyt, liittyy sairaalaan joutuneiden LDL-tasoihin:

Recently Sachdeva et al. reported that the mean LDL cholesterol in 136,905 patients admitted because of an acute myocardial infarction was lower than normally.3 These authors also concluded that cholesterol lowering should be intensified, as did Al-Mallah et al. who came up with similar results.4 However, at a three-year follow-up, all cause mortality for those whose LDL cholesterol was below 105 mg/dl at admission was almost twice as high as those whose LDL cholesterol was higher.4

#3
Sachdeva A, Cannon CP, Deedwania PC, Labresh KA, Smith SC Jr, Dai D, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J 2009;157:111-7
#4
Al-Mallah MH, Hatahet H, Cavalcante JL, Khanal S. Low admission LDL-cholesterol is associated with increased 3-year all-cause mortality in patients with non ST segment elevation myocardial infarction. Cardiol J 2009;16:227-33.

Onko tuossa kohtaa mielestänne argumentointi kohdillaan vai löytyisikö siitäkin jotain viilattavaa?

Muuten omaksi kuvaksi edelleen jäi, ettei Ravnskovin huolellisuus ja tarkkuus oikein ole sillä tasolla, millä sen voisi olettaa olevan, ja lisäksi kanta on ikään kuin liian fiksattu, mikä estää aidon vuorovaikutuksen synnyn.

Vierailija
kujala
Onko tuossa kohtaa mielestänne argumentointi kohdillaan vai löytyisikö siitäkin jotain viilattavaa?



No tuo että nimenomaan all-cause kuolleisuus on korkeampi (ei kardiovaskulaari yksittäisenä) viittaa enemmän siihen että matalien LDL-tasojen takana on kroonisia sairauksia / (piileviä) maligniteetteja mitkä sitten kuolleisuutta lisäävät.

Paletaani
Circulationin, Circ Resin, Hypertensionin, ATVB:n ja Atherosclerosiksen sisällysluettelot ja kun noita seuraa niin Uffen argumentointi näyttää väkisinkin kirsikanpoiminnalta.



Tismalleen sama vaikutelma tuli itsellenikin.

Paletaani
Tällä hetkellä voin melkoisella varmuudella todeta, ettei tästä bakteeriteoriasta ole nykyisen haastajaksi. Kyseenalaistaminen ja uusien teorioiden muotoilu kuuluu tieteeseen mutta kyllä sen pitäisi perustua paljon kovempaan dataan kuin tämä.



Siinäpä se.

Neonomide
Seuraa 
Viestejä14020
Liittynyt23.6.2005
DrOiVo
kujala
Onko tuossa kohtaa mielestänne argumentointi kohdillaan vai löytyisikö siitäkin jotain viilattavaa?

No tuo että nimenomaan all-cause kuolleisuus on korkeampi (ei kardiovaskulaari yksittäisenä) viittaa enemmän siihen että matalien LDL-tasojen takana on kroonisia sairauksia / (piileviä) maligniteetteja mitkä sitten kuolleisuutta lisäävät.

Voidaanko tuosta siis päätellä, että matalat LDL-tasot voivat olla seuraus kuolleisuuden lisäntymiselle, eivätkä syy?

Entäpä statiinien vähän puutteellinen kyky vähentää kokonaiskuolleisuutta, eikös se pelaa siihen pussiin että kolesterolia itsessään tarvitaan johonkin?

Pretending to be certain about propositions for which no evidence is even conceivable—is both an intellectual and a moral failing. —Sam Harris

Vierailija
Neonomide
Voidaanko tuosta siis päätellä, että matalat LDL-tasot voivat olla seuraus kuolleisuuden lisäntymiselle, eivätkä syy?



Näinhän se on yleensä tulkittu, eli sairaudet jotka tuon kuolleisuuden lisääntymisen taustalla ovat laskevat myös LDL-tasoa.

Neonomide
Entäpä statiinien vähän puutteellinen kyky vähentää kokonaiskuolleisuutta, eikös se pelaa siihen pussiin että kolesterolia itsessään tarvitaan johonkin?



Eipä se statiini esim. sitä mahdollisesti taustalla olevaa syöpää paranna... Eli siinä mielessä statiinin vaikutus kokonaiskuolleisuuteen on väkisinkin hiukka puutteellinen.

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