The “Forgotten” cholesterol

 

Based on current evidence, there is little  doubt that cholesterol is a major cause of  heart artery disease. For decades, doctors and patients alike have been talking about

“bad cholesterol” ( Low Density Lipoprotein cholesterol or LDL-C ) and “good cholesterol”

(High Density Lipoprotein cholesterol or HDL-C). However, most have forgotten about the remaining cholesterol fractions.  This “forgotten” cholesterol , also termed remnant cholesterol, comprises all the cholesterol in the blood that is not LDL-C or HDL-C.

 

The “Good Cholesterol” myth

Even today, some doctors still tell patients about the need to increase  HDL-C.  However, over the past 15 years, evidence from well designed trials that have failed to show any benefit despite significant HDL-C elevation with medication and evidence from genetic studies have established that a  low HDL-C is not a causal factor for atherosclerotic disease of the heart arteries. Rather, the low HDL-C is just a surrogate indicator of high levels of triglycerides. Triglycerides are a type of non-cholesterol fat (lipid) that is found in your blood. After a meal, the excess unutilized calories in the blood are converted into triglycerides. The relationship between HDL-C and triglycerides is a see-saw relationship, with high triglycerides levels being associated with a low HDL-C and vice versa.

 

With the HDL-C or “good cholesterol” myth busted, researchers are focusing more attention on the role of triglycerides in heart disease as new data emerge from observational studies, genetic studies and bench research. Triglycerides in the blood are not carried independently but as a fat-protein carrier complex called triglyceride-rich lipoproteins (TRL).  TRL does not just contains triglycerides but also cholesterol, phospholipids and proteins. The cholesterol content in TRL makes up  the ”forgotten” cholesterol fraction, also termed remnant cholesterol.

 

High Triglycerides

In the Copenhagen General Population Study, 27% of adults were found to have mild-to-moderately elevated triglycerides of 2 to 10 mmol/L (176–880 mg/dL). Severe elevation of triglycerides  (>10 mmol/L) was rare (0.1% of population).   Obesity and diabetes mellitus are the 2 main causes of triglycerides elevation , though alcohol intake and genetic variations can contribute as well. In addition to the  increase in risk of heart disease, very high levels of triglycerides will also increase the risk of inflammation of the pancreas (acute pancreatitis).

 

Are Triglycerides a cause of heart disease?

Just as low HDL-C is not a cause of heart disease, triglycerides is also not a direct cause of heart disease as most cells in the body can metabolise triglycerides. Hence, it does not accumulate in the wall of the artery and does not form a fatty deposit in the wall unlike cholesterol .  However, its usefulness is that it is a surrogate marker of the quantity of remnant cholesterol present in TRL.

 

As the ratio of triglycerides to cholesterol in TRL varies, a more accurate way to calculate the remnant cholesterol is by taking the total cholesterol minus LDL-C minus HDL-C.  The current evidence shows that the calculated remnant cholesterol is a strong causal risk factor for heart artery disease. In the Copenhagen General Population Study, about 21% of adults have elevated remnant cholesterol >1 mmol/L (39 mg/dL).

 

Remnant cholesterol

Studies have shown that the TRL containing remnant cholesterol  can pass through the inner lining of the arterial wall ,  although at a slightly slower speed than the smaller LDL-C particles. Upon entry into the inner layer of the arterial wall, the larger TRL particles  may get trapped preferentially to the smaller LDL-C—particles.  Accumulation of cholesterol forms a fatty deposit which is called a plaque. The TRL particles , unlike LDL-C particles, can be taken up directly by cells in the arterial wall called macrophages.   These cells become macrophage foam cells rich in indigestible cholesterol droplets; cholesterol rich macrophage foam cells are the typical finding of a plaque.

 

The triglycerides component in TRL is broken down into fatty acids which can potentially damage the inner layer of the arterial wall, thereby facilitating the formation of plaque. In contrast, LDL-C particles have to be modified, by processes such as oxidation, before being  taken up by macrophages.

 

Combined data from more than  82,000 participants from the Copenhagen City Heart Study and Copenhagen General Population Study showed that the risk of heart attack increased continuously with increasing remnant cholesterol similar to that seen for LDL-C. While the risk of death increased continuously with increasing remnant cholesterol concentrations, it did not increase with increasing LDL cholesterol .  Taking clinical, biological and genetic evidence into consideration, the current data show that  TRL have a causative association with heart artery disease whereas low HDL-C levels have no causative association.

 

The Triglyceride Paradox

While the higher the LDL-C , the higher the risk of developing narrowing of heart arteries, the same cannot be said of triglycerides.  The paradox is that for those with extremely high triglycerides, they are protected against the risk of developing blocked heart arteries.

 

For those who are born with the condition called chylomicronemia where there is deficiency of an enzyme that is responsible for breaking down triglycerides, the triglycerides that is absorbed into the blood  following a meal cannot be broken down in the blood stream and the triglycerides levels can even exceed 100 mmol/l (88 000 mg/dl).

 

The irony is that these patients are largely protected from heart artery disease and plaque formation does not develop. The reason for this is that the triglycerides which are absorbed into the blood through the intestine, are carried as a fat-protein complex called chylomicron which is too large to be able to pass through the inner lining of the arterial wall.

 

As a result, it cannot enter into the inner layer of the heart artery wall and cannot cause cholesterol deposits.

 

This is unlike  the smaller LDL-C particles and the TRL particles  which can pass through the inner lining and enter into inner layer of the arterial wall.  However, LDL-C particles and remnant cholesterol are too large to penetrate the elastic lining of the middle layer of the arterial wall , and hence, they accumulate and form a cholesterol deposit between the elastic lining of the middle layer and the inner lining of the inner layer.

 

Clinical Evidence

Although there is substantial evidence to show that remnant cholesterol has a causative role in arterial plaque formation , there is currently no large randomised trial which can provide the answer to the question as to whether reduction of triglycerides and remnant cholesterol can reduce the risk of heart artery disease and death. Unfortunately , most trials have excluded participants with triglycerides more than 4.5 mmol/L (396 mg/dL).

 

The only controlled trial which selected patients with high triglycerides was a Swedish trial involving 555 consecutive post-heart attack patient who were given either medication or no treatment published in Acta Medical Scandinavia in 1988. In this trial, triglycerides reduction was  associated with 26% reduction in total death and 36% reduction in death due to heart artery disease.

 

Although, this effect is larger than the 10% reduction in total death and 22% reduction in death due to heart artery disease per 1-mmol/L (39 mg/dL) reduction in LDL-C in statin trials, the death of large randomised trials on triglycerides reduction may make it difficult to convince many physicians that lowering triglycerides can reduce heart artery disease.

 

More placebo controlled randomised data is on the way with 2 ongoing triglycerides reduction studies using omega-3 fatty acids  (Reduction of Cardiovascular Events Outcomes trial or REDUCE-IT study and  Outcomes Study to Assess Statin Residual Risk Reduction With Epanova in High CV Risk Patients With Hypertriglyceridemia or STRENGTH study ).

 

In addition, another triglycerides reduction study using drugs in high-risk diabetic patients with high triglycerides has also been announced. The results from these studies will help strengthen the current evidence which supports the treatment of patients with high triglycerides.

 

Practical points

The next time you check your blood cholesterol level, pay heed to the LDL-C and triglycerides levels.  Instead of trying to increase your HDL-C , you should focus on getting your triglycerides down.

 

Clinical studies and genetic data have shown that increasing HDL-C did not decrease heart artery disease. Do remember that high triglycerides is a surrogate of a fraction of cholesterol that has been largely neglected and forgotten.  This remnant cholesterol fraction has been shown in clinical, biological and genetic studies to have a causative role in cholesterol plaque formation in heart arteries.

 

The Copenhagan study  showed  that elevated remnant cholesterol and TRL are causally associated with generalised low-grade inflammation, whereas elevated LDL cholesterol is not.

As degeneration of the heart arteries and the onset of an acute heart attack are related to inflammatory processes, reduction of triglycerides and remnant cholesterol can potentially be helpful in preventing inflammation in the arterial wall.  A combination of dietary restriction and treatment with omega-3 fatty acids or fibrate drugs will reduce triglycerides levels to normal in most patients.

 

 

 

 

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