Uncovering the Dark Side of Good Cholesterol

Daniel Miranda Prieto, University of Oviedo and Javier Rodriguez-Carrio, University of Oviedo

It is very common to associate rheumatoid arthritis with an illness that affects older people, joint deformity and pain. It is a consequence of aging. It is rare. It cannot be cured. However, its autoimmune and inflammatory nature is often ignored, as well as its effects on the body, which include a high cardiovascular risk.

Behind this increased risk lies inflammation and an unexpected protagonist: HDL, also known as “good cholesterol.”

Neither exclusive to aging nor a minority

Rheumatoid arthritis is a chronic inflammatory disease that primarily affects the joints, but also has other complications. Although it is more common in women and usually begins between the ages of 40 and 60, it affects both sexes and can appear at any age.

In Spain, for example, it affects 1 in 200 adults, making it the most common rheumatic disease. It is neither exclusive to aging nor a minority.

Its causes are not clear, but it is known that there is an interaction between genetics, the environment and our defenses.

In normal situations, the immune system is responsible for defending us from microorganisms, identifying them as intruders and destroying them. This is what we know as immunity. However, some factors, such as smoking or obesity, can produce changes in our joints that make these defenses identify them as foreign entities and initiate an attack. We are then talking about autoimmunity.

This attack begins with a type of cell (lymphocytes) that, through a sort of cell phone (cytokines), call and activate other components of the immune system to attack cartilage and bone, producing arthritis lesions.

Not just joints: arthritis and cholesterol plaques

Although joint injuries are the most visible symptom, cardiovascular diseases are the leading cause of death in these patients. In fact, suffering from arthritis doubles the cardiovascular risk. That is, the same as diabetes!

However, studies tell us that people with arthritis do not have substantially more risk factors for developing cardiovascular diseases such as hypertension, smoking, obesity or high cholesterol, when compared to the rest of the population. So, what is the reason for this striking propensity?

Joints and arteries are closer than they seem, and arthritis injuries can contribute to the formation of cholesterol plaques. This is because inflammation and cytokines also affect cholesterol levels.

The lipid paradox: is LDL really the bad guy?

A couple of decades ago, studies of cholesterol in arthritis provided some striking results. It is common for these people to have lower levels than the rest of the population. Lower cholesterol levels but more cardiovascular disease? Yes, you read that right. This situation – called the “lipid paradox” – is explained, once again, by inflammation.

Under normal conditions, LDL (known as “bad cholesterol”) provides cholesterol to the tissues, while HDL (the “good cholesterol”) is responsible for transporting it to the liver to eliminate it, in addition to preventing it from oxidizing and controlling its dialogue with our defenses. It seems that inflammation is capable of molding this natural fat, removing and adding components at will, so that its behavior is also altered.

In patients with arthritis, the call of lymphocytes causes LDL to become stickier. This makes this type of cholesterol adhere more easily to our arteries and form plaques, which are also more unstable due to the action of the lymphocytes themselves. To top it off, the inflamed LDL is able to call and activate even more lymphocytes. And it doesn’t end there.

HDL is also influenced by inflammation and removes less cholesterol, losing its protective function. In other words, inflammation does this lazier.

In addition, it loses the ability to prevent oxidation and becomes an inflammatory molecule in itself. Therefore, high levels of this cholesterol not so good anymore may pose a greater risk and normal amounts are no guarantee of protection.

Maybe the bad guys aren’t so bad and the good guys aren’t so good, but bad company leads them to the dark side.

The effect of inflammation on HDL and its passage to the dark side. Modified from Ansell et al., 2005

What has arthritis taught us?

These observations could be a simple curiosity, a specific mechanism of a specific disease. Nothing could be further from the truth: in recent years, interest in cardiology in the role of inflammation has been increasing.

Understanding that simply tracking cholesterol levels may not be enough was a big step. We need to understand how it works, how it calls and how it responds to calls. Understanding the role of inflammation in plaque formation is a hot topic.

Can you guess how this phenomenon can be studied? For a long time, researchers tried to reproduce this interaction in the laboratory. But arthritis had already shown us its own “experiments.” And, most importantly, by replacing the laboratory with humans.

There have been many recent advances in how to block inflammation to reduce cardiovascular disease. Acronyms such as LoDoCo, CIRT, LoDoCo2 or CANTOS sum up huge clinical trials that have studied various drugs to curb these diseases. You can probably guess where these drugs were used in the past.

In short, arthritis is a much more complex disease than it seems. Despite everything, the key to combating joint and cardiovascular problems is to start treatment as soon as possible.

New research has opened up new possibilities for reducing mortality from cardiovascular causes and helps us better understand the role of cholesterol and its relationship with inflammation. These advances are useful for many patients: let us remember that the leading cause of death globally is cardiovascular disease.

This is a great example of how continuing to research in certain traditionally neglected areas can provide answers to global health problems. Let us always look beyond. The answers are often on the dark side.

Daniel Miranda Prieto, Predoctoral Researcher in Immunology, University of Oviedo and Javier Rodríguez-Carrio, Professor at the University, University of Oviedo

This article was originally published on The Conversation. Read the original.