HDL Function & Atherosclerosis Study, Daniel J. Rader, MD, University of Pennsylvania School of Medicine
"Recent scientific findings have directed increasing interest toward the concept that measures of the function of HDL, rather than simply its level in the blood, might be more important to assessing cardiovascular risk and evaluating new HDL-targeting therapies.
Our study is the first to relate a measure of HDL function--its ability to remove cholesterol from macrophages--to measures of cardiovascular disease in a large number of people."
Dr. Daniel J. Rader, Director of Preventive Cardiology at the University of Pennsylvania, lead author of "Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis," New England Journal of Medicine, January 13, 2011.
If you received this post via email click here to get to the web version with links & comments.
OK, fair warning. Some of you are going to seriously zone out with this post. Perhaps be bored to tears. Drs. A & E, I'd love to hear your professional feedback on this one! Some posts are fun to write. Some are just a lot of work. This one fell into the work category--but I did learn something.
Think you're protected from atherosclerosis just because you have high HDL levels? Think again.
Concerned about your low HDLs levels in spite of having very low LDL levels? You might not need to be.
We've been told for years that high HDLs are enviable. And low HDLs are bad news. For years I thought I was in good shape having super-high HDLs, even though my LDLs were also way-too-high. But a recent study out of the University of Pennsylvania's Preventive Cardiology Department has put a new spin on that old-school thinking.
Turns out, when Penn researchers examined both the HDL blood levels & the functionability of HDLs in 3 different groups of people--the only measure that was related to the prevention of atherosclerosis was the HDL Efflux Capacity--the ability of HDL to do its job & remove bad cholesterol (LDL) from macrophages.
This study begins to explain why some people with high HDLs still get heart disease--while others with low HDLs are protected from heart disease. It's all about how well your HDLs' Efflux Capacity is functioning--and that's not necessarily related to how high or how low your HDL blood levels are. After looking into this whole area, puzzle pieces are coming together & I better underderstand the importance of lowering my LDLs, as well as lowering any inflammation. More about the study specifics, below.
When High HDL Increases Atherosclerosis and Heart Disease
A case of high HDLs gone bad. Back in 2005-6 a cholesterol drug called Torcetrapib looked like it was going to be a miracle drug. It increased HDLs by 60-100%. It decreased LDLs by 25%. Too bad it also increased the rate of major cardiovascular events by 25%--and death from cardiovascular causes by 40%. Because of these high increases in mortality & adverse events, the large Phase 3 trial of Torcetrapib (that included more than 15,000 patients) was abruptly ended in December 2006. And the kicker: Based on follow-up imaging trials, Torcetrapib had no effect on the progression of atherosclerosis!
Bottom Line: Not all high HDLs are created equal or function the same way.
And then there's Lawrence Rudel's Green African Monkey & olive oil study. The olive oil raised the monkeys HDLs--too bad it also increased their atherosclerosis.
I've covered this at length in I'm Going to Miss My Olive Oil - Who Knew It Wasn't So Healthy After All? Drs. Esselstyn, Ornish, Vogel & Rudel Did but here's the short story: Dr. Lawrence Rudel fed African Green monkeys (who are close substitutes to humans for study purposes) olive oil for 5 years, and then compared their arteries to those of Green monkeys who were given saturated fat to eat. Rudel was shocked by the results--he expected the olive oil monkeys would be disease-free. Turns out even though the olive oil monkeys had high HDLs, they also had just as much coronary heart disease as the monkeys who ate saturated fat.
Bottom Line: Not all high HDLs are created equal or function the same way.
Maybe It's time to Rethink HDL Cholesterol Levels. Looks Like There's a Lot More to the HDL Story than Just Blood Level Numbers.
When It Comes to HDLs - Think Efflux Capacity - Not Blood Levels
Thanks to researchers at the University of Pennsylvania's Preventive Cardiology program we can better understand the relationship between HDLs & atherosclerosis. Sometimes high HDLs are helpful. But sometimes they're not. And sometimes low HDLs do a better job than expected.
The one thing the University of Pennsylvania researchers do know--your HDL blood level doesn't reliably tell you how good a job your HDL is doing in protecting you from cardiovascular disease. If you want to know that, you'll need to know the "Efflux Capacity of Your HDL" - how well it's able to remove the bad cholesterol (LDLs) from the blood vessels--or specifically, from the macrophages.
In the "more information than you want to know department": "Macrophages in our blood vessels become inflammatory foam cells when they accept lipids from cholesterol-rich low-density lipoproteins (LDLs). Foam cells play critical roles in atherosclerosis by promoting inflammation." N Engl J Med 364(2):171, Jan. 13, 2011. When HDLs are working right--they can prevent this process through "reverse cholesterol transport".
Big Finding: We can't depend upon our blood level of HDL to predict how well it's removing inflammatory LDLs from our blood vessels. Low HDLs can have a workhorse ability to do the job--excellent efflux capacities. High HDLs can sometimes have poor efflux capacities.
How Do You Know How Well Your HDLs are Functioning?
Unfortunately, this is an expensive, time-consuming process, limited to the research lab. Rader's lab used a special incubator to measure the efflux capacity of HDL in almost 1000 volunteers--442 with confirmed coronary artery disease, 351 without confirmed atherosclerosis, and 203 healthy volunteers.
What Did the Study Find?
- High HDL efflux capacity meant lower levels of atherosclerosis and obstructive coronary artery disease. In contrast, the low HDL efflux capacity meant higher levels of atherosclerois and obstructive coronary artery disease.
- Statins did not increase the HDL efflux capacity--in a 4 month trial.
- High HDL efflux capacity protects against atherosclerosis.
- HDL blood levels are not indicative of HDLs "efflux capacity"
- HDL levels--whether high or low--don't predict the quality of HDL efflux capacity.
- Smokers had low HDL efflux capacity in spite of their HDL levels.
- In the healthy volunteers, the researchers found a significant relationship between carotid artery thickening--a marker for atherosclerosis--in volunteers who had lower levels of HDL efflux capacity--and this was independent of their HDL blood cholesterol levels. It also turned out that higher HDL efflux capacity was protective. " [However], no significant relationship between HDL cholesterol levels and carotid artery thickening was found."
- The proportion of patients with coronary artery disease decreased consistently with increases in HDL efflux capacity.
A Hot-Off-the-Press UCLA Article Sheds More Light on HDLs
Just last week Mohamad Navab & Srinivasa T. Reddy, of the David Geffen School of Medicine at UCLA, published an "ahead of print" article that better explains the "good guy--bad guy" properties of HDLs. Turns out, a component of HDL called Apolipoprotein A-1 (apo A-1) is responsible for removing the bad LDLs from the blood--that all important "reverse cholesterol transport".
But guess what? The apo A-1 can be damaged by oxidative mechanisms that make it useless at doing the job it's supposed to do. When the apo A-1 protein is damaged by oxidative or inflammatory processes in the body or blood vessels it can change the HDL from anti-inflammatory & protective to pro-inflammatory and atherogenic. Other proteins in the HDL can also be damaged in an inflammatory/oxidative environment. Navab & Reddy, "HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms," Nat Rev Cardiol. 2011 Feb 8. [Epub ahead of print]
Looks like a Catch-22 to me. HDL seems to work best when you're also taking care of yourself--and it's not overwhelmed by constant systemic inflammation! When there is an inflammatory state going on in the blood vessels--the HDL is modified. It's efflux capacity is reduced. The HDL changes from an anti-inflammatory particle to a pro-inflammatory particle. Which is why in spite of how high one's HDLs are--it looks to me like it's a wise move to lower the LDLs & reduce inflammation by not smoking, eating a high-nutrient plant-based diet, reducing inflammatory belly fat and exercising! But we already knew that, didn't we?
Consider this: If you're not eating anything that's going to inflame or damage the endothelial linings of your blood vessels, you're eating high-antioxidant greens, fruits, vegetables, whole grains, beans--and not a bit of oil or animal products--then your LDLs are the light fluffy kind and they aren't causing a bit of damage to your blood vessels. (paraphrase from Dr. Caldwell Esselstyn) Neither is there any inflammation to disable or harm your HDLs! So, they're able to do their job, whether your HDL numbers are high or low.
After all, according to Navab & Reddy, HDL-cholesterol levels only tell us about the size of the HDL pool--they don't predict how it will function if it's threatened with a highly inflammatory environment.
What's Going on When HDL Stops Being "the Good Cholesterol" and is No Longer Cardioprotective?
HDL has also been described as a "chameleon-like" lipoprotein. It prevents inflammation in the absence of systemic inflammation. However, with the onset of systemic inflammation, HDL becomes pro-inflammatory and enhances the inflammatory response. Navab, M. Circulation 104:2386, 2001.
- HDL can become pro-inflammatory, actually enhancing the inflammatory response, in the presence of chronic systemic inflammation--like smoking, chronic dental infections, and rheumatoid arthritis. Wouldn't obesity and a typical Western inflammatory diet fit right into this group? H.L.'s comment.
- HDL is altered in the presence of systemic inflammation and its ability to inhibit inflammation & transport LDL becomes compromised.
- Perhaps there's a tipping point when HDL becomes impotent & then destructive? HDL works just fine protecting us from atherosclerosis, until the system is overwhelmed with just too much inflammation--like the chronic everyday assaults from a poor diet, low intake of antioxidants, low intake of omega-3s, high intake of omega-6s, high intake of animal protein, and high intake of fats. And maybe those high HDL levels we seem to get from nuts & oils aren't going to be as protective as we think they'll be. To read more about omega-6s, oils & inflammation click here. And think about those Green African monkeys on olive oil. H.L.'s comment.
Consider the effect of obesity & excess belly fat on the body & perhaps on HDLs:
"Belly fat is completely different from the subcutaneous fat that surrounds our bodies. It's called omentum, and it acts just like an organ, secreting its own chemicals and hormones like adipokines that produce angiotensin II, that raises blood pressure. It also secretes tumor necrosis factor, interleukin 6, and C-reactive protein which lead to high blood pressure, insulin resistance, high cholesterol and inflammation that damages our brains & blood vessels." Read more about the damaging effects of belly fat here.
- A 2007 Beijing study looked at 500 patients & found that HDL played a protective role in coronary stenosis in patients under age 55. But after age 55, high HDL's were not significantly protective, and they were an independent risk factor for unstable resting angina. The authors concluded that high HDL is not always good for coronary artery disease. Click here for the article, "Is elevated high-density lipoprotein cholesterol always good for coronary heart disease? Clin Cardiol 30:576-80, 2007
- A recent study published in Menopause that looked at 316 premenopausal women and 224 post-menopausal women also suggests that the protective effects of HDLs may diminish once women hit menopause--and the effects of damaging LDLs may strengthen. Click here for the study. Woodard, GA "Lipids, menopause, and early atherosclerosis in Study of Women's Health Across the Nation Heart women " Menopause 2010 Nov 19. [Epub ahead of print] Is it more of that "tipping point" of accumulated age & inflammation turning HDL pro-inflammatory in post-menopausal women? H.L.'s comment.
Good News for Those with Low HDLs and Very Low LDLs
If you are concerned about low levels of HDLs, according to a new study published in Lancet, as long as your LDL levels are very low--around 55 mg/dL--you're at a low risk of a future cardiac event. The study was based on an a post-analysis of data from the JUPITER study.
The article was published by Paul Ridker and colleagues in the Lancet in July 2010. The patients in the JUPITER Study had lowered their LDL with statins--but I'm (perhaps naively) extrapolating the Jupiter results to be relevant to those who have lowered their LDLs with a plant-based diet or in combination with a statin. To read more about the study, click here.
"Does HDL remain an important predictor of risk when we drop the LDL to low ranges? Based on this new analysis, the answer looks to be no."
-Dr. Paul RIdker, Brigham & Women's Hospital, Boston, MA-
What Does Dr. Esselstyn Have to Say About Low HDLs When You're on a No-Oil Plant-Based Diet?
Dr. Esselstyn stresses that the health of our blood vessels is dependent upon what we are eating--in spite of low HDL levels. If one is really eating 100% plant-based, no-oil, all whole grain, very heavy on the greens, beans, fruits, & legumes--no problem! Your blood vessels will be thanking you! In light of what I just learned about HDL Efflux Capacity and how HDL can become pro-inflammatory & pro-atherogenic in the presence of an oxidative/inflammatory state--this makes perfect sense.
Turns out, even the Tarahumara Indians, who had no heart disease to speak of--had LDL levels from 80-115--and some had HDLs as low as 26--the kind of numbers that might make a cardiologist pull out a prescription pad. They were eating only beans, squash, & sweet potatoes--not a bit of oil. Their LDLs were the light fluffy kind and they weren't causing a bit of damage. And their lower HDLs weren't a problem either, because the Tarahumara's weren't eating anything that was going to turn their LDLs into the small dense dangerous bad guys. If you aren't eating any inflammatory endothelial-damaging foods like fats, oils, and animal products---and you're loading up on high anti-oxidant greens you've reached the most important goal of all! Your numbers will probably reflect this--but don't worry if they don't.
Side Note on the follow-up HDL levels of Dr. Esselstyn's original study patients: the mean HDL was 38 (with a range of 27-68) after 12 years on a plant-based diet, with no new cardiac events. Am J Cardiol. 1999 Aug 1;84(3):339-41, A8.
More Studies Needed: As always, Dr. Daniel Rader's HDL Efflux Capacity article, and every other article I looked at said the usual, "We'll need more studies to confirm these findings." So stay tuned.
As for me, I'm going to continue to eat in a way that protects my blood vessels from inflammation--and not depend on just my HDLs to protect me.
At the end of Heartwire's story about Rader's HDL Efflux Capacity, a physician wrote the following "interesting-to-me" comment:
"Great stuff. But not unexpected. The ability of HDL to efflux cholesterol from macrophage (reverse macrophage cholesterol transport), its anti-inflammatory, antioxidative properties and its ability to upregulate NO (nitric oxide) are just a few of the abilities that make HDL functional.
These properties have nothing to do with its cholesterol content. The only problem is we have none of these assays available clinically to sort out who has functional HDL and who doesn't. Even more troubling, how do we deterimine whether our interventions truly improve HDL functionality? There is an urgent need to get HDL functionality assays available in clinical practice."