Can Atherosclerosis be Prevented via Early, Large Reductions in LDL Cholesterol?

Atherosclerosis is a universally suffered condition of aging in which oxidized lipids are the seeds for ever-expanding fatty deposits in blood vessel walls. Blood vessels are progressively weakened and narrowed, and this ultimately leads to the catastrophic structural failure of a stroke or heart attack. Atherosclerosis is one of the largest single causes of death in our species.

Cholesterol is carried in the bloodstream, attached to low density lipoprotein (LDL) particles. Lacking any other viable approach to the condition, methods of reducing LDL cholesterol such as statin drugs are widely use to slow atherosclerosis. They reduce one of the inputs to the progression of the condition, the supply of cholesterol, but haven't been shown to produce any sizable reversal of established atherosclerotic lesions in humans. The animal evidence suggests that greater benefit may occur in the earlier stages of the disease, when it might be possible for lowered LDL cholesterol to allow repair mechanisms to catch up sufficiently to remove smaller, more recent lesions. In general, intervening early is a good idea: fixing smaller problems is easier than fixing larger ones. Researchers are now seeking to trial this concept in humans.

I think it remains the case, however, that any meaningful therapy for atherosclerosis must remove or at least significantly diminish the larger and more widespread lesions present in later stages of the condition. This sort of therapy will likely involve mechanisms capable of enhancing reverse cholesterol transport. This describes the way in which macrophages mine cholesterol from lesions and then hand it off to high density lipoprotein (HDL) particles that carry the cholesterol back to the liver. There are many places in which this process might be made more efficient: increased HDL particle count; improved cholesterol export in macrophages; greater macrophage resilience to cholesterol overload; and so forth.

Variants on most of these approaches have been shown to produce some degree of reversal of atherosclerosis in mice, as much as 50% reversal in some cases. Unfortunately, of these potential therapies, only increases in HDL particle numbers have been tried in humans. Those efforts didn't work well at all, which raises a number of interesting questions. There is some uncertainty as whether any of the other approaches presently in the pipeline will do any better in humans, as clearly the dynamics of the process must be substantially different between humans and animal models to produce such different results for the HDL particle trials.

Researchers suggest way to possibly eliminate artery-clogging condition

Researchers have proposed a unique study in humans to reduce the early onset of atherosclerosis, the buildup of the artery-clogging plaque that can lead to heart attacks and strokes. The proposed trial, CURing Early ATHEROsclerosis, or CURE ATHERO, would set out to determine if atherosclerosis in high-risk adults ages 25 to 55 might be reversed by using medicines called statins and PCSK9 inhibitors over the course of three years. "The idea is to get the cholesterol very low for a short period of time, let all the early cholesterol buildup dissolve, and let the arteries heal. Then patients might need to be retreated every decade or two if the atherosclerosis begins to develop again."

The proposal is a "very compelling idea" that might show whether older adults can avoid heart attacks and strokes by making sure they have low LDL and apo B levels earlier in their lives. "It's a very important question that we really need to answer, because we have therapies now to lower apo B lipoproteins and LDL cholesterol. We know that people who have low LDL cholesterol for genetic reasons have a very low risk of having cardiovascular events, so if we can replicate one of these genetic states and get people's LDL cholesterol really low in early adulthood, perhaps these people won't have downstream complications like heart attack and stroke."

Eradicating the Burden of Atherosclerotic Cardiovascular Disease by Lowering Apolipoprotein B Lipoproteins Earlier in Life

A new paradigm for preventing atherosclerotic cardiovascular disease (ASCVD) is needed. The most recent US data show the long-term decline in cardiovascular deaths has stopped, and has started to increase in the most at-risk populations.

Systemic approaches to improving lifestyle habits and better risk factor control are clearly needed. Given the difficulty of these endeavors to date, and the persistently high burden of ASCVD when risk factor modification is started later in adulthood, we propose a new paradigm for ASCVD prevention. We consider that it is now time to investigate whether intensively lowering plasma apolipoprotein (apo) B lipoprotein levels in younger and early midlife adults will regress earlier stages of atherosclerosis, thereby eliminating the risk of developing clinical ASCVD events later in life.

As a next step, we describe a proposed clinical trial to test early intervention to profoundly lower the concentration of low-density lipoprotein (assessed by its cholesterol component, LDL-C) and other apo B-containing lipoprotein in individuals aged 25 to 55 years who have image-documented preclinical atherosclerosis. Such a trial may provide the first direct evidence to support marked or even complete regression of early atherosclerosis in humans, and lay the ground work for definitive trials to support a new prevention paradigm of intensive regression therapy followed by intermittent retreatment for eradication of the clinical burden of ASCVD.

Comments

Probably it could delay the onset of the atherosclerosis symptoms by a few years, which alone could increase the life expectancy by a couple of years, if not more. Eradicating it would be a completely different story, where SENS like approaches have promising, yet quite remote results...

Posted by: Cuberat at October 27th, 2018 6:53 AM

I'm male 54yo. I probably have a genetic variation that lowers my triglycerides (30mg/dl). It also lower a bit my LDL (60mg/dl) and rises my HDL (85mg/dl). The same happens for my mother and my sister.
But my work and my life is sedentary. I hate gyms. I love to think (math). I'm also a high sugar consumer.
My bad lifestyle likely affected my veins more then my gene protection because I have plaques in carotids (1.1 mm) and sclerosis in aorta (visible by X-Ray examination)

Posted by: Marco at October 27th, 2018 7:28 AM

@Marco
If the plaque is visible on x Ray it means you have an easy test to verify whether the first wave of senolitics can reduce them.

Posted by: Cuberat at October 27th, 2018 2:51 PM

@cuberat
Wrong.

In my practice, a combinations of arb, statins, evolocumab snd victoza reversed plaque in humans already on statins

Posted by: D.V. at October 27th, 2018 11:38 PM

@D.V.
How was the plaque reduction measured? What was the rate of reduction? Do you think a periodic treatments, say annually, would be enough or the protocol had to be administered on a regular basis?

Posted by: Cuberat at October 28th, 2018 2:18 AM

@DV
Am I right that arb`s are needed only for hypertensive, and victoza only T2D patients?
BTW victoza seems scary to me - increasing insulin production works for mitigating hyperglycemia but will drain out B cells quicker, forcing quicker disease progression to an injectable insulin.

Posted by: Andey at October 28th, 2018 3:08 AM

@Andre
I did some reading on victoza and it seems quite and interesting medication. It might be replaced by between generations using the same target, which can be administered once a week and have proven reduction in cardiovascular disease.

It seems that victoza actually protects the B cells. However, the studies in rodents show that it significantly increased the risk of thyroid cancer.

Posted by: Cuberat at October 28th, 2018 8:14 AM

Expert Rev Clin Pharmacol. 2018 Oct;11(10):959-970.
doi: 10.1080/17512433.2018.1519391. Epub 2018 Oct 11.

LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature.

Abstract
For half a century, a high level of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) has been considered to be the major cause of atherosclerosis and cardiovascular disease (CVD), and statin treatment has been widely promoted for cardiovascular prevention. However, there is an increasing understanding that the mechanisms are more complicated and that statin treatment, in particular when used as primary prevention, is of doubtful benefit. Areas covered: The authors of three large reviews recently published by statin advocates have attempted to validate the current dogma. This article delineates the serious errors in these three reviews as well as other obvious falsifications of the cholesterol hypothesis. Expert commentary: Our search for falsifications of the cholesterol hypothesis confirms that it is unable to satisfy any of the Bradford Hill criteria for causality and that the conclusions of the authors of the three reviews are based on misleading statistics, exclusion of unsuccessful trials and by ignoring numerous contradictory observations.

Posted by: Bill Sardi at October 28th, 2018 8:57 AM

I always pay attention to the VLDL levels on my annual blood tests, as some research seems to support the idea that it is the very small LDL particles that play an important part in the development of atherosclerosis and heart attack and stroke increases in later life. I have a VLDL level someone less than 20 on VLDL blood tests.

Posted by: Biotechy Marcks at October 29th, 2018 7:57 AM

@biotechy, unless you are paying $100+ more for direct measurement of LDL and VLDL both LDLand VLDL are estimated based upon a forumla, so you are not learning anything by looking at VLDL. I always use the cheap test, my LDL is always high but my VLDL is very low, which makes no sense since it is the same forumla. The formula is also known to over estimate LDL if have low Triglicerides from a low carb diet such as I eat. I frankly do not care about moderatelly increased LDL, I get frequent blood tests for other reasons.

Bill thanks for the reference

Posted by: JohnD at October 29th, 2018 8:48 PM

@JohnD: Thanks for the info on VLDL. On my last blood test LDL was 105.2 and VLDL was 16.8. Like you I don't think a slightly high LDL level is much of a concern.

Posted by: Biotechy Marcks at October 30th, 2018 12:22 PM

@Biotechy
Last time a did detailed blood test, I had high cholesterol level. As the doctor said, you should try to lower it but nothing birthing and the sky is not falling. However, it is a long term risk factor....

Posted by: Cuberat at October 30th, 2018 1:35 PM

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