Cholesterol & Statins (Part I)
by Yusuf M. Saleeby, MD
to be published in American Fitness magazine (Jan/Feb 2013)
Today when one hears the
word “cholesterol” it conjures up thoughts of “something bad”. Whether we hear about a cholesterol level
over 200 from a neighbor, or one of many TV shows preaching the avoidance of
cholesterol rich foods, cholesterol always seems to drum up connotations of
bad, evil or unhealthy. This two part
series will dispel the myths and urban legends about cholesterol and expand the
reader’s knowledge of this rather important steroid compound. Part II of this series will encompass the
atherogenic (plaque forming properties of oxidized native LDL-Cholesterol) and
what measures can be taken to minimize the risk of stroke and heart attack
specifically focusing on a class of medication call statin drugs.
Although Cholesterol as a
solid fatty substance was first isolated a half-century before, recognition was
given to the scientist who named it in the early 1800’s. A French chemist named
Michel Eugène Chevreul,
while studying bile acids and animal fats, christened
this new compound. He derived the name
we use today from two Greek words Chole (of
the bile) and stereos (solid) adding
the –ol usually used to denote an
alcohol component [(3β)-cholest-5-en-3-ol
is the chemist’s nomenclature for cholesterol] (Olson, 1998).
Cholesterol is essential to
mammalian cells as a major component in cell membranes. This steroid molecule allows for membrane
permeability and the flexibility and fluidity integral to our cells. Additionally, cholesterol is the substrate or
building block of other essential biologic end-products, namely the steroid
hormones (testosterone, progesterone, estrogens and DHEA to name a few), the
bile acids that help with digestion, and as a precursor substrate to the
important vitamin/hormone vitamin D (Hanukogul, 1992).
Essential to life and proper
bodily functions as we know it cholesterol is a double edged sword and has in
fact a dark side. Too much either by
dietary intake or endogenous production can cause damage to arteries and lead
to cardiovascular disease.
Cardiovascular events such as acute myocardial infarction (heart attack)
and cerebral vascular accident (stroke) are the consequence in part to the
narrowing of blood carrying vessels to the heart and brain respectively. This narrowing occurs in great part to the
formation of plaques rich in cholesterol that line the lumen of arterial
vessels. After a period of time, growth
and maturation these plaques “clog” those vessels.
Breaking down cholesterol
into further sub-components sometimes adds to the confusion of the part
cholesterol plays in health. For example
there are two major subcomponents of total serum cholesterol called low-density
lipoprotein (LDL-C) and high-density lipoprotein (HDL-C). One is often referred to as the “bad
cholesterol.” Because LDL-C is
responsible for building up on artery walls when there is too much in
circulation it is referred to as bad.
Produced in the liver and transported to cells, LDL is rather harmless
until levels in the serum get too high or the native-LDL is oxidized by
free-radicals and becomes atherosclerogenic (that which forms plaques)
(Rosenson, 2010). On the other hand
HDL-C is called the “good cholesterol” in part because the smaller
subcomponents are themselves protective and also because it’s main function is to
transports cholesterol away from the cells and back to the liver for recycling
or disposal. The higher levels you have
of HDL-C in your serum, the lower your chances for cardiovascular disease and
its sequelae (Brunzell, 2008; Durrington, 2003). A caveat recently realized is that lowering
LDL-C is not the end-all-be-all of lipid management. It turns out there are other players in
plaque forming dyslipidemia such as triglycerides (TG), apolipoprotein B
(apoB), and others that may be as important (or more so) in controlling
cardiovascular disease (Miller, 2009; Sierra-Johnson, 2009; Handrean, 2011). Apolipoproteins are proteins that bind lipids
(including cholesterol) making the non-water-soluble lipids easier for
transport through the water-based blood and lymphatic systems (Saito, 2004).
The Good, Bad and Ugly of cholesterol.
Firstly let us discuss the
body’s requirements and utilization of cholesterol, that we will call the
“good”; then we can discuss how some types of cholesterol can hurt our
cardiovascular system, that discussion we will call the “bad.” And finally, we will reserve the discussion
of controlling elevated levels of cholesterol with statin drugs
(HMG-coA-reductase inhibitors) and by other means as the “ugly” aspect of our
two part series. Ugly you may ask? Well there is much controversy and debate on
how to lower, what to lower and how far or aggressive we need to get in
lowering cholesterol. There are schools
of thought about lowering LDL and others on raising HDL. Then there are the lipoproteins and
triglycerides and their role in this game.
From its formation, cholesterol
is made predominately in the liver. A
complex 37-stage enzymatic process has to occur to derive cholesterol from the
base substrate substances of acetyl coenzyme A.
An important enzyme called 3-hydroxy-3-methylglutaryl CoA reductase (or
HMG-CoA reductase) is critical for the formation of cholesterol in the
liver. This concept is important for our
discussion on statin drug therapy.
Statin drugs are effective at lowering cholesterol as they inhibit this
crucial enzyme.
Production of cholesterol is
in full force at night while we sleep.
Our bodies produce up to 1000 mg of cholesterol per day on average,
while the typical 70 Kg (~150lb) person contains about 35 grams of cholesterol
by weight. Our diet, even the standard
American high-fat diet, provides us with only between 200 and 300 mg of
cholesterol per day. So our bodies make
more cholesterol than what we can possibly take in orally. This becomes an important fact in how we can
effectively treat elevated cholesterol, and in a way reveals the true etiology
of dyslipidemia. It shows the importance
of genetics versus environment. [Hint: Dietary restriction of high cholesterol foods
is a poor way of controlling dyslipidemia.] can be used
in a side bar
Cholesterol is recycled,
first excreted by the liver, making a round trip to our cells and back via
LDL-C and HDL-C, and then reabsorbed back into the liver to be excreted as bile
acid. This bile is stored in the
gallbladder until needed to help digest ingested foods that contain fats and
oils. Approximately 50% of the excreted
bile acids are then reabsorbed in the small intestines and returned into
circulation. These facts are again important
when we consider how to manager elevated LDL-C.
The use of drugs that inhibit bile acid reabsorption can in theory work,
as can phytosteroils from some plants that mimic bile acids. Phytosteroils are preferentially secreted back
into the gut, thus interfering with normal recirculating of bile acids.
Cholesterol is responsible
for the absorption of critically important nutrients via the digestive system as
the component of bile acids in bile. The
body’s requirements for vitamins A, D, E and K (all fat soluble) are linked to
how well they are absorbed in our intestines when solubilized by bile. Additionally, fats necessary for good health
and energy production also require bile for intestinal absorption. Cholesterol as a metabolic building block is
necessary for the synthesis of vitamin D, and our steroid hormones (sex
hormones) as well as those of the adrenal gland such as cortisol and
aldosterone (Hanukogul, 1992).
So why all the fear about high levels of cholesterol?
Well it goes back to
research showing a strong link between elevated total cholesterol and LDL-C
specifically and heart disease. While
not the only major risk factor for coronary artery disease, it remains one of
intense focus and scrutiny. Researchers
and drug companies hustled into the arena of determining how to control LDL and
how best to drive the numbers down in the masses to relieve our industrialized
society of the burden of sudden death by heart attack. Reduce LDL and total cholesterol and the
thinking was increased longevity and a better quality of life.
To put things into
perspective if too much LDL is abound and not being utilized by the cells in a
productive way, they eventually become oxidized as the lazy loiterers they are
and start doing bad things to our artery wall lining. The process is assisted by macrophages (part
of our body’s immune system) which takes up this oxidized-LDL and becomes
engorged forming what we refer to as “foam cells”. These foam cells are trapped in the walls of
blood vessels and when they mature over time, become atherosclerotic plaques (Weingärtner, 2010; Tymoczko, 2002). They form on
arterial walls of our carotid artery, our larger vessels and even the smaller
coronary artery vessels. There may be other factors as to why they develop here
versus there and it has been theorized that micro-trauma, inflammation or even
infectious organisms may play a role.
Non-the-less, as these plaques get larger, they narrow the lumen of the
arteries and thus set up a situation for bottlenecking of blood corpuscles
passing through. Add a few clotted
platelets and presto, you have a recipe for disaster, a clotted artery unable
to provide critical oxygenated blood to distal tissues (myocardium in the case
of a heart attack and brain tissue in the case of a thrombotic stroke). Without the oxygenated blood servicing our
cells there is injury and eventual death of those cells which lead to one
clutching their chest in pain or loosing neurological function.
To the rescue comes HDL-C,
remember this is the good cholesterol.
This high density cholesterol and its lipoproteins are given credit for
removing excess cholesterol from peripheral tissues and transporting them back
to the liver. This process known as reverse cholesterol transport is one of
the chief functions of this beneficial type of cholesterol thus lowering risk
for coronary disease (Gordon, 1989). So
what would do our bodies better, lowering LDL-C or raising HDL-C? That argument continues.
Why
the big focus on total cholesterol and LDL-Cholesterol?
To answer that question one has to consider a few
landmark studies in lipids related to plaques in the aorta. The famous pathologist Dr. Rudolf Virchow
noted back in 1856 lipid like plaques on arteries, this was followed by a celebrated
study by the Russian scientist Dr. Nikolai
Anitschkow in 1913, who fed rabbits high cholesterol diets (Virchow,1856, Steinberg, 2004). Since then these high-lipid diet studies have
been repeated in almost every animal model know. LDL-cholesterol and it’s link to
atherogenesis was what won Drs. Joseph Goldstein and Michael Brown a Nobel
prize in medicine in 1985 for their appreciation of the LCL-C and heart disease
connection (Goldstein,1973).
From that point, there was an explosion of research showing elevated
cholesterol either by overconsumption of bad dietary fats or by poor genes. Either way there was a link to heart disease
(Steinberg, 2004-2006).
In 1984 one of the first
large scale double-blinded interventional trials called the Coronary Primary
Prevention Trial (LRC-CPPT) demonstrated that a decrease in serum cholesterol, by
a sequestrant drug called cholestyramine, significantly reduced heart attacks
(JAMA, 1984). From there pharmaceutical
companies started their marathon race toward producing some of the most
prescribed therapeutics in history that reduces cholesterol. That will
all be discussed in Part II of this series.
Despite the fact that there are other risk factors for heart disease and
heart attack/stroke, the focus currently remains fervently on LDL-C and the
development of statin drugs for lowering cholesterol.
Other risk factors may actually be of
greater importance to the health of the heart and brain, notably among them are
family history/genetics, gender, race, obesity, diabetes, tobacco abuse,
hypertension, hypertriglyceridemia, elevated homocysteine, inflammation,
chronic kidney disease, sedentary lifestyle, Lp(a), fibrinogen, and elevate Lipoprotein B (Watts, 2011). Of these it is currently though that the top
three risk factors for heart disease and stroke are diabetes mellitus (DM),
hypertension (HTN) and tobacco smoking and
not LCL-C elevation. In a 2002
cross-sectional analysis of the Copenhagen City Heart Study lipid disorder as a
cardiac risk factor was ranked fifth and sixth overall in importance given one’s
gender (Schnohr,
2002).
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Yusuf (JP) Saleeby, MD is medical
director of WellnessOne and WellnessFirst which offer extensive and advanced
cardiovascular and stroke biomarker and genetic analysis, including lipid
subtypes, Lp(a), HDL2 and HDL3, LDL1-4, ApoB,
NT-proBNP, and the 4q25, 9p21, ApoE
& KIF6 genotypes, and other evaluations.
He is a regular contributor to American Fitness and is on the medical
advisory board. He can be reached for
comment at ymsaleeby@gmail.com.
