Preventing heart attacks – a peek into the future
Scientists are targeting various steps in the process of a heart attack in their attempts to reduce or eliminate risks
DESPITE lifestyle changes and the consumption of cholesterol-lowering tablets, why is the risk of a heart attack not completely eliminated?
In this article, we explain the predominant mechanism of heart attacks and look at how scientists are finding ways to virtually eliminate them.
Mechanism of a heart attack
Understanding the mechanism of a heart attack will help you comprehend how scientists are targeting various steps of the process to prevent one from occurring. When the levels of “bad” cholesterol (also called low-density lipoprotein cholesterol or LDL-C) are higher than normal, the LDL-C will begin to passively pass through gaps between the cells lining the inner wall of the artery (endothelium cells) and accumulate in the arterial wall.
This LDL-C accumulation will trigger the lining endothelium cells to release chemicals that attract certain types of white blood cells – called monocytes – to migrate to the plaque to remove the LDL-C. Upon arrival, the monocytes will transform into “fat-eating” cells called macrophages which become fat-laden macrophages or “foam” cells after “eating” up the fat in the plaque. The foam cells eventually break down and leave a core of fat-laden debris in the plaque.
The entire process involves the release of messenger chemicals called cytokines – a term for proteins that are released by one cell to regulate the function of another cell. These cytokines produced by white blood cells cause inflammation and are also termed interleukins (ILs).
This chronic inflammation in the plaque over time results in an increase in size of the atherosclerotic plaque and narrowing of the lumen (the hollow passageway through which blood flows) in the artery, thereby reducing blood flow to the heart muscle.
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If the inflammation worsens and the fat-laden debris increases, the thinned-out plaque lining may eventually rupture. This will expose the plaque content to the blood, triggering a biological cascade which results in the formation of a blood clot over the site of the ruptured plaque. This can significantly obstruct flow or block the artery completely, resulting in a heart attack.
Increasing the removal of cholesterol from the blood
When blood flows through the liver, there are binding sites, also known as LDL receptors, on the surface of liver cells which specifically “capture” excess LDL-C to remove it from the blood circulation. During this process, the LDL-C particle, together with the LDL receptor, are removed from the surface of the cell into the cell to be broken down. The liver has abundant LDL receptors and hence has an important role in removing most of the excess cholesterol from the blood.
Getting in the way of this is the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, which is produced in multiple tissues, with the liver, small intestine and kidney being major contributors.
The PCSK9 protein binds to the LDL receptor and prevents it from being recycled. It thus controls the number of LDL receptors available on the surface of cells and directly impacts the effectiveness of cholesterol removal from the blood circulation.
Both the PCSK9 protein and gene are now the targets of many drug developments. In recent years, there have been two FDA-approved medications which are fortnightly or monthly antibody injections which block the action of the PCSK9 protein – namely alirocumab (Praluent) and evolocumab (Repatha).
By blocking the action of the PCSK9 protein and thereby increasing the number of LDL receptors available on the surface of liver cells, these medications can potentially reduce LDL cholesterol by up to 70 per cent and cut the chance of heart attacks by one-third.
More recently, a six-monthly injectable drug, inclisiran, became available. It works by binding to the messenger Ribo Nucleic Acid (mRNA) precursor of PCSK9 – the mRNA being the molecule containing instructions that direct the cells to make a protein. By doing so, inclisiran prevents the PCSK9 gene from functioning, resulting in increased LDL receptor availability and a 40 to 50 per cent decrease in LDL cholesterol level.
For high-risk individuals with stubbornly high LDL-C despite lifestyle changes and oral cholesterol-lowering medications, these anti-PCSK9 drugs provide a complementary option. More importantly, not only are these drugs very effective, they are safe and well tolerated by a large majority of patients as well.
Editing the gene
What if the PCSK9 gene were switched off permanently? We can then have a very efficient system of removing excess cholesterol from our blood without the need for subsequent medication. The good news is that this is no longer a dream, and such drugs are already undergoing trials.
VERVE-101 and VERVE-102 are single-course liver gene-editing medications designed to permanently inactivate the PCSK9 gene in the liver, resulting in permanently low LDL-C levels. It is likely that within the coming decade, this class of drugs will be available clinically and provide a solution to those born with genetically high LDL-C levels requiring lifelong medication.
Inflammation and heart attacks
While advances in cholesterol-lowering therapy have resulted in a decrease in heart attacks, this trend appears to be plateauing. Despite the significant reduction in LDL-C, there remains a large residual risk of atherosclerotic cardiovascular disease. Recent clinical trials suggest that inflammation contributes to this risk.
Inflammation is a normal part of the body’s response to injury or infection. However, inflammation is harmful when it lasts too long, persisting for months or years. Risk factors such as smoking, high LDL-C, diabetes and high blood pressure can cause a damaging buildup of fatty deposits in the wall of the heart arteries. This eventually leads to an inflammatory response with the release of ILs.
In particular, the IL-1 family of cytokines has been shown to increase the size of the atherosclerotic plaque in the heart artery and thin the lining of the plaque, resulting in plaque instability and an increased risk of a heart attack.
Anti-inflammatory medications such as canakinumab and colchicine have been shown in trials to decrease the risk of a heart attack. Further advances in this area of anti-inflammatory therapy may help to reduce or eliminate residual heart attack risk.
RNA therapeutics
The use of RNA to influence the expression of various genes in cardiovascular disease is an important area of development in cardiovascular medicine. Besides inclisiran which is clinically available, other recent examples are drugs that target lipoprotein a, also called Lp(a).
High Lp(a) is associated with increased cardiovascular disease and is not significantly lowered by taking oral statins. Two investigational RNA-based drugs – ISIS-APO(a)Rx and Olpasiran – have been shown to lower Lp(a) by demonstrating a decrease of Lp(a) by more than 90 per cent in early-phase trials. Currently, there is also research into the use of RNA therapy for hypertension and other forms of heart diseases.
As we gaze into the crystal ball, we take solace that in the next 10 to 20 years, medical therapeutics will be able to prevent the onset of heart attacks in a majority of people, and stenting and open heart bypass surgery will increasingly become less common options.
This article is part of a monthly series on health and well-being, produced in collaboration with Royal Healthcare
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