“Doctor, you had put me on high dose statins since my CAC score was high. Now, my CAC is increased further. What is this ? should I not get anxious ?”
“No.Not at all . It is a good sign and it indicates your plaques are getting stabilised”
How is that possible ?
It is a therapeutic paradox. We start statins based on a CAC score in a low-risk population only to find the CAC score increase further in many people. In multiple analyses, we have seen the CAC score even increase up to 30 % . Feel happy about it, as we presume it is a sign of plaque stabilization.
That’s interesting Doctor. Now,.. Doctor, my dad already has a good CAC score of 300 , without statins he should be lucky , is it not ?
No you are wrong. “Natural CAC score is a marker of plaque burden, and we can never consider it as an index of stability, while the statin-induced high CAC score is absolute bliss & index of pure stability“
Patient no 2 : My CAC is not increasing with statins , what to do ? Is it sign of statin failure ?
May be yes. I am not sure . It may indicate a poor response to statin and inability to convert the plaques to its logical destination ie hardening and micro calcification.
Final message
Most coronary calcification whether God or statin made , imply that plaques are stable biologically. (Except the nodular /eruptive ones or those in the shoulder region of the plaque, which can make a plaque physically stressed . Cardiologists hate calcium essentially because, it is a hinderance to deploy a stent)
We rarely realise , how often we formulate important concepts in cardiology based on very superficial or incomplete knowledge
We know south Asians (who constitute about 2 billion people) consistently develop premature and severe atherosclerosis despite largely normal or only mildly elevated LDL-C levels. This “Lipid Paradox” is driven by small dense LDL particles, elevated ApoB, high triglycerides, low HDL, and insulin resistance not classical high LDL cholesterol.
This reveals a fundamental flaw in the current LDL-centric model of atherosclerosis genesis. When one-quarter of humanity develops CAD without high LDL, we must question whether LDL reduction is the primary target or merely a convenient proxy. A broader focus on ApoB, metabolic health, and visceral fat may be more scientifically honest and cost-effective.
Further, HDL molecule has its own problems in being a savior. At a level more than 60 mg/dl, it loses its protective value; rather, excess dysfunctional HDL is harmful as well. Since we have failed to increase HDL by pharmacological means, LDL reduction has gained more attention.(Franczyk B Et all , 2021)
Forget the patient .. target the LDL
Yet, aggressive marketing promotes expensive drugs like, PCSK antagonists, SiRNAs like Inclisiran and ATP citrate blocker Bempedoic acid to target ultra-low LDL levels (<55 or <50 mg/dL) in a population where LDL-C is often a weak tentative target. The latest to join the LDL rat race is the VERVE* 102 yearly Injection , a dramatic temporary RNA editing drug by the pharma giant Eli lilly.
*VERVE-102 consists of a messenger RNA encoding an adenine base-editor protein and a guide RNA targeting PCSK9, which are encapsulated in a lipid nanoparticle incorporating N-acetylgalactosamine(NEJM 2026)
Final message
LDL is definitely one of the culprit in human Atherosclerosis , but it is very difficult to prove , it is a major, universal, risk factor in isolation.This is not mocking the science. This is true at least in our part of the world. To treat a South Asian patient exclusively on standard LDL lowering protocols and projecting it as villain de chief, is not a scientically sound cardiology practice.
Reference
Volgman AS, Palaniappan LS, Aggarwal NT, et al. Atherosclerotic Cardiovascular Disease in South Asians in the United States: Epidemiology, Risk Factors, and Treatments: A Scientific Statement From the American Heart Association. Circulation. 2018;138(1):e1-e34.
Agarwala A, Satish P, Al Rifai M, et al. Identification and Management of Atherosclerotic Cardiovascular Disease Risk in South Asian Populations in the U.S. JACC Adv. 2023;2(2):100258.
Bilen O, Kamal A, Virani SS. Lipoprotein abnormalities in South Asians and its association with cardiovascular disease: Current and future perspectives. J Clin Lipidol. 2016;10(3):543-552.
Postamble
The word “wrong culprit” in the title is intentional. It actually means “not a primary culprit”
15 % of body weight is fat. (10kg) Out of which just 250 mg of cholesterol is streaming in blood. We must understand fat, lipid and cholesterol are different entities. LDL is obviously a target against atherosclerosis. While the total body fat seems to do little in determining blood cholesterol levels, what is more scientifically shocking is the slope of curve between blood LDL levels and plaque burden is rarely linear. Mind you, LDL constitutes .000025% of total fat. We have many other targets in dyslipidemia like free cholesterol, harmful fatty acids, remnant cholesterol, TGLs, dysfunctional HDLs
LDL is not innocent
Cone electron microscopic Image : A macrophage after a diet full of LDL molecules
There are innumerable evidence for LDL, being the enemy number one in human atherosclerosis .It don’t know but, it fully deserve the name bad cholesterol.It looks like it may be counting its last few decades, as the whole pharma industry is activated to destroy this physiological molecule that carries some critical functions in our body. In one of the hyper-educated debate, I asked how low we can bring LDL down ? One leading professor of lipidology with a H index possibly crossing his LDL levels, said, we can go as low as possible , even to zero. He argued for possible eradication of this heinous molecule. No surprise, there was a thunderous applause from the industry benches.
How to go about lowering the LDL ?
Statins are the first line drugs. We have found it is not enough, it doesn’t bring down LDL below 70 in many , enhancing the residual risk .Now, we have found a God sent weapon. PCSK has got into our hands after some stunning collaborative research between geneticists, biochemist and pharma guys. Let us use it judiciously . This LDL receptor regulatory chaperone , prevents its recycling so blocking or reducing its function
This cartoon from the Dr. Libby’s article (Ref. 1) image depicts the potential pathways beyond Evolocumab (Repatha) and Alirocumab (Praluent). PCSK can either be blocked after its synthesis or paralyzed before it is synthesized (RNA manipulation therapy SiRNA). There is one hidden face for PCSK trials as exposed by BMJ report of FOURIER methodology that will argue some caution with this new target.
Bembidoic acid is a also can also join the death game of LDL .It just acts two step above the HMG-CoA axis blocking ATP citrate lyase, . BM-Acid is approved by FDA well before the CLEAR trial by Steven E. Nissen et al NEJM 2023Leqvio ® (Inclisiran) is also approved in 2023. Soon, we will get vaccines that will promote lipid catabolism.
Ok let us be practical : What does the current guidelines say about LDL target?
It depends upon the risk profile and the guidelines you follow. Numbers to remember are 70, 55, 40 mg
One of my suggestion is to try keep both LDL and HDL as narrow as possible. This would mean both LDL &HDL should hover around 55-60mg in high risk category
Can we allow the proposed free fall of LDL ? (Ref 2)
If we apply the 50% reduction from baseline criteria, if someone develops CAD at 50 mg, it would mean to reduce LDL to 25 mg, right? This is where the problem starts. LDL, apart from being a carrier of hormones, may have a role in the structural stability of every cell membrane. While, the relationship between LDL and atherosclerosis is so intimate, funnily we have heaps of data that show South Asian population with tons & tons of plaque with normal LDL. The lesson we haven’t learned from the Indian paradox is that there are more unknown and invisible culprits in promoting atherosclerosis and CAD.
*In fact, for the future generations, there is more exciting ignorance waiting to be decoded. CAD without standard modifiable risk factor SMURF is the new agenda (nearly 25% of CAD occurs in the absence of SMURF – Ref -3). In this scenario, whipping a single known culprit and playing the LDL number game among the public mind is not welcome.
Final message
The tendency to portray a physiological molecule LDL , as a sole villain for CAD is not correct. Further ,trying to eradicate it, Implies, inadequate understanding of human lipidology.
I’m trying to get a right answer for this question for quiet some time. The literature on lipids is so vast , one can never finish reviewing it.There are nearly two dozen journals that deal with lipids ,Atherosclerosis, obesity ,and vascular biology .
Yet , the answer to this simple question is elusive to us.The Irony is complete when we have evidence for two diagonally opposite responses 4 and 5 .
My interpretation of the issue
Any lipid molecule if exceeds a critical level ( Only if . . . associated with hypertension, or diabetes or smoking ) can penetrate the vascular endothelium. ( HT-pressure injury , Smoke- Endothelial dysfunction due to Nitric oxide depletion) DM -Glycation of cell membrane , finally some unknown inflammatory component )
Though evidence for direct endothelial injury is more for LDL , less for TGL (Almost nil for VLDL , but TGL has more VLDL in it !)
Strangely ,these molecules , express a mob psychological behavior .In isolation they appear innocuous. But ,in an unfavorable setting it shows signs of revolt. If a group of LDL molecule start attacking a dysfunctional segment of endothelium , the other molecules like TGL and VLDL fractions would love to join the crowd and inflict further damage . (Of course ,the lonely HDL may watch the chaos silently !)
Questions to ponder
If LDL is a sharp knife like molecule trying to injure the blood vessel , every normal human being is potentially threatened by this lipid fraction . Mind you, this is a physiological molecule traversing the human vascular system at concentration of 130mg/dl at the velocity of blood .
So it is foolish to blame this physiological molecule for all our ignorance.
I recall one recent definition for hyperlipidemia
The lipid levels at which a patient develops vascular injury is considered high for him !
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 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 .
Atherosclerosis remains the number one cause for all vascular disease of human beings. It probably kills more patients than all other causes put together .
Modern medicine has never conquered the disease. How the vascular system ages and why some develop premature atherosclerosis remains largely speculative. While it is true , we have identified some major risk factor for development and progression of the atherosclerosis , patients with out any of those risk factors do develop severe atherosclerosis !So researchers sought to look for some other risk factors . There lies the difficulty and irony .
We always tend to the research with the affected population .When we know millions of people with the so called risk factors live comfortably , there lies an opportunity to analyse why they are protected against the onslaught of atherosclerosis .It is always convenient to blame it or bless it on the genetic predisposition .But we need to look beyond that .Of course . every genetic expression has to manifest phenotypically .
While the search for all those hidden secrets has to continue , we should also realize in pursuit of breakthrough we some times waste our energy in false targets for too many decades !
The reality as on today is , there is no reliable & undisputed drug available to arrest atherosclerosis (Some would love to call statin so . . . )
While our basic science colleagues struggle in molecular factories and biological models in pursuit of answer against atherosclerosis , our elite cardiac physicians carry on with the cosmetic touches over this progressive disease in sophisticated cath labs.
This was written originally in 2009 early days of this blog. Now, re-posting it in 2021 , wonder any one has new data on this!
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 .
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.
Statins are projected to be the saviours of human race against the killer atherosclerosis .Now we have reached a stage soon , where every healthy individual may be administered this drug. There are consistent evidence for statins to reduce , retard , prevent progression of existing atheroscelorosis and possibly prevent future atherosclerosis.
This wonder drug acts by blocking the HMG COA enzyme a vital enzyme that regulates the lipid metabolism within the cells. It is made to appear as if , the God has created this enzyme with the only purpose for human suffering , by blocking this we expect all errors in lipid metabolism is corrected.
This enzyme is part of the house keeping system that is meant to service the human cellular lipid layers 24hrs a day. If it is impaired intentionally one can imagine the consequences. That’s what modern science is all about. Luckily God is kind enough the side effects of blocking this enzyme is seen only in minority. The myopathies that are classically described with statins are due to possible mitochondrial dysfunction .
As the debate still continues to find the optimal bottom levels of LDL , we have more worries , real world experiences have brought us a new issue namely the reduction of HDL with statins. While literature search on statins and HDL tell us there is marginal increase in HDL up to 10% the fact is there is marginal fall or significant fall in many of the patients .
How can this happen ? A huge difference between real world and trial world ?
* Brands shown not intentional
Readers are welcome to add their input on this question .
HT management has been made easier with the availability of many good drugs , at the same time it has become a complex issue with as many classification and guidelines.
The management of HT has evolved over the decades. Now we have realised HT is not a simple number game. Reducing the blood pressure to target levels is not sufficient and is not the primary aim !.
In fact we now know controlling the numbers alone is never going to work , combined risk factor reduction is of paramount importance.
HT per se is less lethal but when it combines with hyperlipidemia and diabetes or smoking it becomes aggressive.The blood lipids especially the LDL molecule enjoy the high pressure environment , penetrate and invade the vascular endothelium.
ASCOT LLA study has taught us, for blood pressure reduction to be effective and reduce CAD events one has to reduce thier lipid levels also.So , for every patient with HT there is not only a target BP but also a target LDL level .
Final message
The tip for better vascular health is, all hypertensive patients should keep their lipids to optimal levels and all hyperlipidemia patients should keep their BP as low as possible .
“Keep your LDL as low as your diastolic blood pressure and let us keep it around 70 -80
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Please Note
The author acknowledges all the queries posted by the readers and wishes to answer them .Due to logistic reasons only few could be responded. Inconvenience caused is regretted.
Dr.S.Venkatesan MD 