This summary of the cited genetic studies has important implications for HDL as a biomarker for assessing CVD risk.  While no relation between HDL levels and risk of MI were found, we should all be cautious about allowing findings from the studies to negatively impact on the well established concept that HDL plays important roles in decreasing inflammation and improving vascular health.  Recent reports from several labs clearly demonstrate that assays that measure HDL functionality provide much stronger information about risk than HDL cholesterol.  Recently, the NIH published several RFAs that focused on HDL function and its relationship to CVD with the goal of stimulating new investigations to fill gaps that have hampered progress and understanding.   Traditionally, HDL function is quantified using bioassays.  However, the problem with bioassays is that they are complex, time consuming and difficult to reproduce.  Mary Sorci-Thomas Ph.D. and I recently received funding from the NHLBI to determine whether HDL interactions with native biomolecules can be used as an index of functionality and whether such changes in HDL interactions with the different biomolecules are predictive of CVD.  Where bioassays of HDL function take several days to perform, the automated assay take 3-7 minutes per sample, making it possible for the first time to provide HDL functionality data for large scale clinical studies.  Over the next several years findings from our research as well as from other investigators who were also funded via the RFAs mechanism should provide critical new insight into how HDL works and whether clinical assays of HDL functionality are better biomarkers for assessing risk than HDL cholesterol.  I suspect that the conclusions from the genetic studies were influenced more by the fact HDL functionality was not measured and than by the notion that HDL may not be important. 

How does one reconcile the results of this study with the Framingham data which showed a powerful relationship between low HDL and the development of CAD?

Statistics are like bikinis.  What they reveal is suggestive, but what they conceal is vital. 

Two great comments, by Kirk Prtichard and S. Algeo...thanks!. Yes, the functionality of HDL may be an important issue and is certainly not taken into account by the Mendelian randomization, Lancet study. We already have evidence of individuals who have very low HDL but remarkable scavenging capacity.

And as far as Framingham, the difference between a marker and a driver deserves emphasis. While there has been association of low HDL and CAD in this cohort and many others, that does not establish cause and effect. In the emerging era of "systems medicine" we will increasingly get in touch with what is behind the association.....root cause analysis. 

This study poses interesting questions. Prospective studies have continuously shown that low HDL is a risk factor for CAD. The assesment of risk according to the formula published in the NCEP reports includes HDL. 1. What is the frequency of inherited low HDL's seen in the typical cardiology clinic? 2. If the frequency is very low, then an extensive study should be designed to determine the major reasons why cardiology patients have developed a low HDL. One obvious reason is increased cholesterol ester transfer protein (CETP). What other controllable factors such as obesity increase CETP? A drug that decreases CETP may decrease coronary artery disease.  

As Dr. Topol alluded to in his comment, there are examples of low HDL levels in populations with low prevalence of CVD, notably members of a family with ApoA-1 Milano residing in a village in northern Italy. So the form of ApoA-1/HDL may be critically important. Essentially, if you have a powerful HDL, a little may go a long way. If your HDL is wimpy, large amounts may not help. So sometime in the future the prescription may be for genetic therapy with a vector carrying a gene for a Milano-like ApoA-1. On the other hand, might we all have additional loci coding for ApoA-1's that may be repressed, in which case the question would be how to induce expression?

This new HDL information isn’t profound.  The “genetic” HDL level isn’t the prescription for CVD risk.  The prescription for lowering CVD risk is RAISING HDL, or the delta amount of before/after HDL levels achieved through lifestyle changes, not pharma therapy.  Those of us using rigorous exercise to raise our HDL levels, which is functional HDL, observe and measure the results with a variety of performance and heart measurements.  The medical industry, and primarily doctors, need to put more weight and confidence in patient lifestyle changes that can, will and do deliver the prescription for healthy CV systems.  In layman terms, patients need to produce sweat to produce cardio changes and generate higher HDL levels. It is more difficult than pill popping.  THIS is the holy grail of HDL’s works in providing CVD protection and a decrease in MI.  Sorry, I don’t have the fancy study proof, just my own body.  The medical industry lacks the financial incentive to produce these types of studies that prove that no cost lifestyle changes is the best prescription.  Yes, I sound a little cynical because all doctors prescribe statins FOR LIFE, yet I have individual proof that lifestyle changes raising HDL delivers better results than Pharma, but no one wants to highlight this low cost, effective perscription.

 

CVD Patient,

I agree 100%, you are on target. When I saw that drug companies were developing drugs to raise HDL, I wondered if the HDL/fitness relationship would become visable. The FDA's safety policies concerning short term increases in heart attacks means that medication that stress the heart will never reach the market. Makes one wonder about how cardio level exercise can be viewed as safe.

I think that breakthroughs would occur if data from clinical studies was sorted by HDL, percent body fat, weight, or weight change and then data examined. 

  

Chuck

 Please direct me to links/info about FDA's safety policies RE short term increases in MI.  My source and reliance RE impact of cardio level exercise is Dr.Cooper's many books and his huge accumulation of data.  His work demonstrates the positive impact on cardio health via rigorous cardio exercise and his Running Without Fear book gives the evidence for reducing MI via aerobic exercise.  Yes, I concur that studies sorted with changes in BMI, HDL and weight would be significant in revealing and enlightening on what needs the primary focus for lowering risks.  I continue to be baffled why the insurance companies (who are paying the expenses of poor patient health) don't seem to have a financial incentive to lead the way on using patient centered lifestyle changes as the primary treatment and THE perscription for lowing MIs.  The financial incentive needs to be the foundation for any sustainable change moving from "pills" therapy to a "patient" control for health using lifestyle changes.  It is a hige paradigm shift - both financially and in human actions,  But I remain hopeful that the allure of a higher quality of life, via being healthy, might drive the shift.  But current financial incentives need to challenged too.

I'm a mere patient, not a professional. Tests one day before I was started on amiodatone five years ago showed HDL 53. Now, afrer propafenone, statins, Beta Blackers etc and a serious diet and exercise practice I can't get it above 30. I had an aparently successful stent RCA two years ago.I conttnue to have good days and bad days ad cannot guarantee that I can comply with any social or business appointment. Last lipid test showed HDL 28. Conclusion: utterly indefinable

CVD Patient,

Please check:

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM209087.pdf

for information.

The term short duration clinical studies came from the Avandia FDA hearings where short term studies showed higher heart attack rates and longer studies like VADT and BARI-2D showed large risk lowering, like the BARI-2D showed a 60% reduction in strokes. Although I can't remember the numbers, but the average days were fewer for Actos than Avandia clinical studies. Dosage was not noted in metadata studies, and I believe dosage will affect short term risk of heart attacks. Of course the long term clinical studies to show cardio safety are very expensive and delay the approval of type-2 diabetic drugs.

My diabetic fight is to improve blood flow because that reduces diabetic complications, but blood flow increases, according to an FDA document, can break loose a piece of plaque which will cause a heart attack. Plaque build up is the reason blood flow improvement needs to be done as early in the diabetic process as possible before the build up of plaque that seems so likely in type-2 diabetics. 

 

 

HDL is good cholesterol and LDL is bad cholesterol

--This common concept is prevailing among general population including general practitioners. However,molecular studies have shown that this concept has lot of controversies. Current report in Lancet seems to be a reflection of the same.LDL is carrying cholesterol and cholesterol esters to the peripheral tissues.It is a well established fact that Cholesterol esters are the principal agents which initiates atherosclerotic changes in peripheral arteries. HDL contains LCAT enzyme and converts cholesterol to cholesterol ester. HDL transfers cholesterol esters to LDL. Therefore, LDL takes the blame as bad cholesterol while main initiator molecule HDL remains under cover and is popularly known as good cholesterol.

Current report in Lancent is not a surprise but a confirmation of the above molecular basis of the pathogenesis of atherosclerosis and therefore root cause of myocardial infarction.

It is true that therapeutic agents used for increasing HDL cholesterol may not be necessarily protective one.

Therefore we need to reorganize our background knowledge to correct misconcepts about basic pathogenesis of atherosclerosis and look forward to develop cardioprotective agents in near future.