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Posts Tagged ‘dyslipidemia’

Hyperlipidimia is one of the well-known coronary  risk factor.Serum cholesterol ( Various fractions ) levels are measured to represent that risk. Epidemiologically ,it does a perfect job , however , the fact is , circulating lipids has little correlation with the lipids that’s deposited in the vessel wall.

Time and again , we have proven this as severity of CAD has little  to do with the absolute levels of lipid levels.The number  volume of plaques , the thickness of lipid core, and degree of vulnerability  show  poor correlation with circulating lipid levels than  what we would expect.It tempts us to make a statement , that serum lipid is a poor surrogate marker for CAD. (Still, it may predict the risk of developing it !)

Why this paradox ? What are the  missing links and hidden secrets ?

If you plot a simple graph with serum lipids with  plaque mass, volume and content in CAD population , we might get an  answer .I don’t know whether such a study exist. (Those who find one , please share)

A new concept called cholesterol crystalisation 

It’s not the lipids alone that are responsible for CAD . There is a whole lot of factors , circulating  pro inflammatory  mediators, altered blood coagulation system  , various  inflammatory molecules, , heightened  intra-coronary pressures, genetic vulnerabilities .

Most importantly ,the format  of lipid molecule in side  the plaque seems to matter more  rather the  absolute content.(Small dense LDL, oxidised lipids,Lipid fed macrophages etc )

There is lesser reported phenomenon  called cholesterol crystalisation , with sharp edges (Lipid knife ?) that are responsible random episodes  plaque fissure and rupture.

It was reported in  one of the  rare research paper that came from  (Abela Am J Cardiol.2009)  Factors that crysalise cholesterol include local saturation,  PH, temperature , hydration and plaque RBC contact.

If you argue lipid levels are not  correlating with CAD , how is that reducing it with statins dramatically reduce  CAD and the events ?

Like blood pressure the normality of serum lipids itself is not defined.One insightful definition was proposed , that the level at which a person develops CAD is high for that patient however low it may be..A person who develops extensive CAD  say at a level of  90mgLDL what to infer ? We do not know exact  answer.

That’s why the  concept of satin for all with clinical CAD looked attractive. Still , statin’s action doesn’t help  answer the original query about the relationship between blood lipids and plaque lipids.

Statins beneficial effect is not by reduction of serum cholesterol.It primary acts by  regressing intra-plaque lipids by blocking synthesis of lipids in every cell.The anti inflammatory,plaque stabilisation action of  statin may be  independent of lipid reduction.How much it contributes to overall benefits is not known.

The mystery will deepen

Not every LDL is bad.(I will be slapped if I call them Good LDL !) Small dense LDL , LDL P (Particle) ApoB (The real culprit on which LDL piggybacks ) lipoprotein little a and so many other lipid sub particles are being studied.

Final message

The purpose of this post is not to confuse our understanding about coronary  lipidology but to widen our vision . Serum lipids remain a poor surrogate marker for plaque lipids. This is because , It’s rather a small fraction of sample volume we catch in the  circulating blood , while loads of lipids gets deposited elsewhere in the body ! This also make it clear,no single risk factor in isolation is really CAD risky.It is the combination of risks , genetic susceptibility , LDL subfractions, few unknown risk/protective factors and finally a mandatory trigger(Hemodynamic, Emotional ?) that determine the outcome of  CAD.

So ladies and gentle men , just don’t over react to mildly abnormal lipid levels you often find in  master health checks .There is much more untold stories behind the true CAD risk than the glossy lab printouts would suggest !

Reference

2.

3.The Role of Lipids and Lipoproteins in Atherosclerosis MacRae F Linton, MD, Patricia G Yancey, 

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I share my thoughts after going through this  85 page  land mark document !

acc aha 2013 guidelines cholesterol ncep

In whatever way I look at it  ,It  keeps  both physicians and their patient population guessing  in a  confused sate regarding their cholesterol levels  the treatment modalities !

It seems to revolve around a single point agenda,  how to fit a single drug called statin in the scheme of things !

What  if  ,  a new  drug comes and statin is  proved  not an angel  in our fight against the evil  of  atheroscerosis !

 

acc aha lipid guidelines atp 3 ncep  nhlbi dyslipidemia

Summary as  I interpreted

“All healthy and unhealthy human beings should ask only one  question

whether they can some how  benefit from taking statins  ? “

If your answer is yes ,  administer the statin  not in  low dose but in moderately high dose ! (It  appears  there is little role for low intensity statins )

There  is generally no  need to to monitor the lipid levels as long as patient is comfortable.

Disclaimer :  *Sorry , the Intention is not to  hurt the hard work of a elite panel who toiled for years to bring this much awaited guidelines on lipids and atherosclerosis! but to express my view , biased though !)

A mini research

To confirm my assumption I did a curious word search in this 85  page document .

For words statin , diet and exercise

  1. Statin appeared  814 times
  2. Diet appeared 8 times
  3. and exercise just once in the entire document !

statin search acc document statin acc aha 2013 guidelines statin acc aha 2013 guidelines 2

The importance of  diet and  body activity  which  are  the  primary   determinant of serum lipid levels is mentioned  in a cursory fashion in this  global guideline meant to control the total  cholesterol load  and atherosclerosis of our population .

Meanwhile . a drug which  acts in a  physiological  cell servicing  metabolic path way in a complex fashion  is glorified 814  times !Do  you still  think this post is is biased ?

 

 

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Whatever  is your answer .   It will be   far off from the truth .

What causes  Atheroscerosis ?

The perception  that , circulating lipids directly damage  the coronary endothelium is an  ill proven concept.  Isolated hyperlipidemia  rarely leads to full blown Atherosclerois .

If  LDL moelcules  can penetrate the endothelium  , why the circulating LDL  at a normal concentration of 130mg/dl  fail to do so in vast number of humans   as they criss cross the human circulatory system  at-least a  trillion times  every year ?  So , there  must be something else  operating *It requires a high blood pressure, diabetes , smoking or some form of endothelial injury  (That includes chronic Inflammation )  for the  lipids to  enter the sub endothelial planes and start depositing.

The relationship between serum lipids and plaque burden lacks clarity.

* The argument that 130mg LDL is injurious to endothelium  while  100mg  is not  ,  can  easily be disputed !

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Statins have revolutionised the treatment of coronary artery disease .Intensive lipid lowering is the fundamental prerequisite in the management of both acute and chronic coronary syndromes. One question  is  always difficult to answer , ( rather reluctant to find the answer )   “The effect of statins on the HDL cholesterol”. Logic and the mechanisms of action would suggest HDL is not much affected , but in reality  I believe , in a given patient statins  do  reduce the HDL by at-least 10-20 % .This might have some significance. However ,  the marked  reduction in LDL  may nullify the adverse effects of lowering HDL.   Does this happen in all

What does the scientific evidence say ?

It says the opposite .  It seems  HDL is raised by statins that too significantly . The following paper also  suggests mechanism of  HDL  elevation by statins .It is Independent  to that of LDL reduction , I believe .

This JAMA article  adds more evidence

http://jama.jamanetwork.com/data/Journals/JAMA/5100/jpc70001_499_508.pdf

This paper  from  the  premier  Journal  of   Lipid research  agrees  to the   mechanism of  HDL reduction by statin  is a complex process  but still  it vouches for it .

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035518/?report=printable

In spite of  all these  evidence . . .   it  remains a  huge suspect . . . from my personal point of  view ( My patients are  my evidence !  )

Coming soon

The above articles also raise an important  concept of dysfunctional HDL.  Simple raise  in HDL is not suffice . . .it should be functional as well !

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We know diabetes, smoking, hyperlidemia, hypertension are major risk factors for progressive vascular disease. They damage the vascular endothelium either directly or indirectly ,   by aggravating the atheroscelortic process .  Diabetes apart from affecting the medium sized arteries , also affect the microvasculature.  Smoking  has a direct effect on endothelial function .It depletes vascular nitric oxide. High levels of circulating lipids injures the sub endothelial structures and invades the media by entering macrophages .So , all these 4 risk factors either operate independently or interact with each other and result in progressive vascular    disease.

While we  believe  , these risk factors do not have any bias in attacking the human vascular  tree, in the real world it is observed they have their own  behavior pattern and  have unique predilection and a deadly alliance .

For example , in  chronic smokers TAO is the commonest manifestation , thrombo angitis is far too less common to occur in the coronary arteries.

Similarly  hypertension  per se  rarely results in an acute coronary syndrome while it is  the  single  important  cause for cerebro vascular  disease. Diabetes especially in women has very strong predilection for CAD , while diabetic per se is a lesser risk for stroke. Hyperlipedimia may be the one which has fairly even risk throughout the vasculature. Similarly there is  a difference in renal and   carotid arterial involvement with reference to  the conventional  risk factors .

SHT diabetes dyslipidemia coroanry risk factor

Why this apparent difference ?

We are unlikely  to get an answer to this question in the near future .  Left to the youngsters  . . . of tomorrow !

* Note of  clarification

The source for the above chart is collected from various studies and also a huge observational data from our hospital. There could be some geographical variation , a given individual may respond differently to these risk factor depending upon his genetic predisposition and susceptibility . So the above data can be applied to general population and not to a individual.

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