High cholesterol level not sole cause of heart attacks, strokes

High cholesterol level not sole cause of heart attacks, strokes
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Have you ever wondered why in some patients, despite good control of cholesterol and other risk factors, the arteries continue to progressively narrow?

In recent years, researchers have begun to understand the presence of other mechanisms beyond the conventional risk factors for heart attacks and strokes.

Even as we age, our body is constantly attempting to renew itself.

You may be surprised that in every passing second, our body renews more than one million cells.

This process ensures that ageing cells in the body are removed and newer cells replace it.

To remove these ageing cells, the human body has in place a mechanism called programmed cell removal or efferocytosis.

In efferocytosis, the dying cell is engulfed by cells called phagocytes.

"Eat me" and "Don't eat me"

To ensure that the body removes only dead cells and does not attempt to engulf healthy cells, there is in place a highly regulated protocol in the process of efferocytosis.

This communication between a dying cell and a phagocyte involves dozens of "signalling" molecules.

These molecules include:

- "find me" molecules that attract the phagocytes to the site of cell death,

- bridging molecules (such as MFGE8, also known as lactadherin) that have dual roles of making the dying cell more "appetising" to the phagocyte and physically linking the phagocyte to the dying cell, and

- "eat me" molecules on the surface of the dying cell which upon physical contact with the phagocyte will activate sensors (such as Mer receptor tyrosine kinase or mertk) on the cell surface of the phagocyte to initiate efferocytosis.

To avoid removal of healthy cells, there are also the "don't eat me" molecules present on the surface of all healthy cells.

Ultimately, the balance between "eat me" and "don't eat me" molecules will determine whether a cell is viewed as "appetising" or "inedible" to a phagocyte.

In almost all organs and tissues, this removal process is very efficient and cells that have been identified for programmed death are targeted for removal within minutes.

So it is extremely difficult for physicians to see "dead cell debris" in active organs from tissue samples.

An exception is seen in degeneration of arteries (also called atherosclerosis), especially heart arteries where an accumulation of cell material and cholesterol in the heart artery wall (atherosclerotic plaque) narrows the arterial lumen.

Unlike other tissues where "dead cell debris" are rarely seen because of the efficient efferocytosis, studies have estimated that there is about a 20-fold reduction in efferocytosis capacity in the plaque.

This impaired clearance of cell debris increases plaque accumulation and instability.

Plaque formation

When a phagocyte ingests a dying cell, the cholesterol contents of the dying cell cannot be easily assimilated and are therefore expelled through the wall of the phagocyte to other cholesterol carriers in the blood stream.

If this expulsion of cholesterol is defective, the accumulated cholesterol in the phagocyte transforms the cell into a "foam cell".

This high cholesterol content "foam cell" is an important cause of atherosclerosis and plaque formation.

When a dying cell is removed successfully by a phagocyte, beneficial molecules are released to the surroundings to inform other cells that all is well and there is no need to attract other inflammatory cells to the site.

If, however, the phagocyte fails to remove the dying cell, the cell breaks up before it is ingested, releasing cell contents that will include chemicals that attract other inflammatory cells and weaken the wall of the plaque, thereby promoting instability of the plaque.

Current investigations suggest that the accumulation of cell debris within the plaque is not due to excessive cell death but due to reduced capacity for clearance of cell debris by the phagocytes and the dying cell becoming inedible due to inflammation-induced modification of the signalling molecules and accumulation of oxidised or "toxic" low density lipoprotein (LDL) cholesterol.

Inherited risk for heart artery disease

Those who inherit the highest risk genes for heart artery disease have been found to have reduced production of an important "eat me" molecule known as calreticulin (Calr).

Hence, carriers of this commonest high risk gene for atherosclerosis, at chromosome site 9p21, develop significantly larger plaques in the heart arteries due to dying cells being rendered inedible by phagocytes.

These gene carriers are at risk of heart artery disease independent of all conventional risk factors (such as high blood pressure, high cholesterol, diabetes mellitus and smoking).

The most important cell programmed death pathway linked to atherosclerosis is the one that involves the balance between the "eat me" molecule Calr and the "don't eat me molecule" CD47.

Calr molecules increases in number in dying cells, comes into contact with another "eat me" molecule (phosphatidylserine), and then activates a sensor (LRP1) on the surface of a phagocyte inducing it to engulf the dying cell.

Studies have shown that the loss of this sensor (LRP1) on phagocytes will increase cell debris in the plaque highlighting the importance of this mechanism in plaque formation.

The "don't eat me" molecule CD47 has a counterbalancing role to Calr.

In plaque formation, production of CD47 is increased, rendering the dying cells "inedible" and thereby increasing the heap of dead cell debris in the plaque culminating in the development of a soft necrotic core of broken down cell material.

This weakens the overlying arterial wall and increases the likelihood or rupture of the lining.

Rupture of the lining, in turn, triggers a cascade of biological reactions which results in blood clot formation which then occludes the narrowed arterial lumen and triggers a heart attack.

New therapies

The significant improvements in the treatment of heart disease seen in the last few decades have gradually petered out.

The latest understanding of the role of impaired efferocytosis in the development of atherosclerosis and an unstable plaque have opened up new avenues to treat heart disease.

Therapies that can reduce inflammation and improve efferocytosis, making the removal of dying cells efficient and preventing the accumulation of cell debris in arterial wall plaques present new avenues in therapy.

Studies in mouse models have demonstrated that injection of antibodies that can block CD47 function have significant anti-atherosclerotic effects, including preventing plaque progression, preventing plaque rupture, and reducing the necrotic core.

Therapies that reduce inflammation also appear to improve efferocytosis.

The use of the anti-inflammatory agent, anti-TNF (Infliximab or Etanercept) has been shown to reduce plaque formation and protect heart attacks.

This balance between "eat me" and "don't eat me" molecules extends beyond heart arterial plaques to plaques in the neck that predispose to stroke and also to the realm of cancer.

In cancer therapy, reduction of "don't eat me" molecules on cancer cells can increase their removal.

For example, anti-tumour antibodies (such as rituximab) synergise with therapies that promote efferocytosis to significantly increase the clearance of cancer cells.

The advent of therapies promoting efficient efferocytosis to enhance clearance of diseased and dying cells opens up an entirely new realm of treatment that can potentially provide better and safer solutions for heart disease, stroke prevention and cancers.


This article was first published on February 6, 2017.
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