God’s World gives us some really good examples of “non-atherosclerotic” animal models. Many wild mammalian species exist with natural total cholesterol level of 2.0-2.5 mmol/l (LDL-C levels around 0.8 to 1.8 mmol/l). To convert mg/dL to mmol/l divide by 40.
Humans are born with LDL-C levels in this range, but the level gradually increases with age. At least 2 adult human populations, however, do not exhibit this progressive increase in LDL-C with age. One population consists of hunter-gatherer societies, diverse in geographic location and ethnic origin but arguably living the way humans did 40,000 years ago. LDL-C levels remain in the 1.0-1.8 mmol/l range. In modern societies, rural Chinese blood levels often fall within this range. In neonates and these 2 adult groups, atherosclerotic coronary disease is rare. The consistency of these diverse human data sources, taken together with the mammalian species data, supports the speculation that the putative NORMAL range of LDL-C in adult humans may be approximately 1.0-1.8 mmol/l and NOT ~ 3.0 as currently quoted. The speculation being; that modern Man and Woman have corrupted this process (as seen in the graphic) with total cholesterol > 5.0 and LDL-C > 3.0.
Intravascular ultrasound (IVUS) imaging has demonstrated the extent of atherosclerosis in American youngsters.
An incredible study was performed on 262 young people who died prematurely and whose hearts were being transplanted. Just prior to the transplantation the coronaries of these “hearts” underwent IVUS and images reviewed at 2,014 sites within 1,477 segments in 574 coronary arteries. Lesions with an intima thickness >0.5 mm were defined as atherosclerotic.
In this population, 52% had lesions, ranging from 17% in individuals younger than 20 years to 85% in those older than 50 years of age. In those with lesions, intima thickness averaged 1.1 mm and area stenosis was 33%. Data taken from a large number of age-stratified autopsy studies establish the fact that coronary atherosclerosis begins in youth. If many of these individuals are those destined to become those who compose the >50% mortality statistic, therapeutic lowering of the LDC-C to the putative normal range might LOGICALLY begin during this point in pathogenesis, provided that they can be accurately identified.
Two recent randomized clinical trials allow the next logical step: examining the effect of therapeutic LDL-C lowering into this putative normal range. In ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound), reduction of LDL-C from 3.2 mmol/l to 1.5 mmol/l (12% < 1.0 mmol/l LDL-C and 41% between 1.0 and 1.5 mmol/l) resulted in regression of carotid atherosclerosis using transvascular ultrasound. In JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin), reduction of LDL-C from 2.7 mmol/l to 1.4 mmol/l in an asymptomatic intermediate-risk population resulted in a 44% reduction in adverse cardiac events to 1.4% in those with on-treatment LDL-C < 1.8 mmol/l. Neither trial identified increased statin-induced toxicity with CRESTOR 20 mg/d at lower on-treatment LDL-C levels.
These new data are supported by linear extrapolation of on-treatment LDL-C levels in both secondary angiographic and primary prevention trials. In the former, lesion progression reaches zero at an LDL-C of 1.7 mmol/l and coronary events reach zero at approximately 0.8 mmol/l. In primary prevention trials, major adverse cardiac events reach zero at an on-treatment LDL-C level of 1.4 mmol/l. Thus, to the lipid profiles in mammals, neonatal humans, and isolated human societies, we may add clinical trials that suggest the putative normal LDL-C level may be approximately 0.8 to 1.8 mmol/l.
If this is still not enough have a look at the “talk of the town this week”, as a paper has just been published in the New England Journal of Medicine describing a new gene importantly involved in regulation of the LDL receptor. This gene, PCSK9, codes for a secreted protease that acts to decrease the number of LDL receptors expressed in the liver cells.
Plasma LDL is governed entirely by the number or LDL receptors; the rate at which the receptor binds apo-B100 in the LDL particle in the plasma (to clear the blood of LDL) and the recycling of the receptor back onto the cell membrane for re-use.
When PCSK9 binds the LDL receptor, it causes them to degrade. Individuals have been found with naturally occurring “loss-of-function mutations” in this PCSK9 gene causing increased expression of LDL receptors due to loss of function of PCSK9 and protection from heart disease due to very low LDL-C levels. This loss-of-function mutation occurs in 2% of African-Americans, with LDL-C levels naturally reduced by about 80%. This gets to the concept of another approach that could result in lifelong low LDL. Rather than hitting people late in life with intensive therapies (Statins), perhaps you could start earlier with more moderate reductions.
Over expression of the gene (or gain-of-function mutations) lowers LDL receptor number and thus raises plasma LDL levels; knocking out the gene (or a loss-of-function mutation) increases LDL receptor number and thus lowers LDL levels.
The key point here is that the vascular disease in subjects with nonsense mutations in PCSK9 that cause low plasma LDL levels, presumably from birth resulted in an 88% reduced risk for vascular disease. Having a low LDL from birth almost triples the magnitude of the effect on risk compared with the risk reduction found in a 5-year trial of middle-aged people. Drugs that regulate the expression and function of PSCK9 have already been tested in early trials with staggering LDL-C reduction to the levels described above where atherosclerosis is reduced to ZERO (LDL 1.0 to 1.8 mmol/L) and may fairly soon join the ranks of cholesterol-lowering agents. Working by a different mechanism, PCSK9 inhibitors would probably have effects additive to those of other drugs like Statins.
So what am I saying?
Based on the information gathered over 3 decades of research it seems we need to keep our LDL around 1.0-1.8 mmol/l lifelong. The longer and earlier we keep LDL-C at these putative NORMAL levels we will NEVER get vascular disease. If you can’t do this with good lifestyle (exercise and diet) you need modern pharmacology to help you.
Presently we only have Statins but with the potent, effective and safe Statins like Crestor, we are blessed we can influence LDL levels.
To help you make an informed decision you can be guided by transvascular ultrasound of your Carotid arteries.
This technology can define the state of your arteries and is extremely accurate in diagnosing “sub clinical” atherosclerosis. If your arteries are entirely normal (smooth thin initima-media with no plaque)you can manage your cholesterol (LDL) profile more conservatively.
If you have any subclinical atherosclerosis then you are advised to lower LDL to the optimal level ~ 1.8 mmol/l to prevent progression to clinical disease and clinical cardiovascular events.
Please DON’T be complacent about your LDL-C level even if your HDL-C (good) cholesterol is preserved as I see many (Women) with great HDL levels but with LDL level above the putative optimal with Carotid arteries like the image above packed with atherosclerotic plaque, feeling well, asymptomatic and “healthy” and in some cases quite beautiful on the outside?