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Posted on Saturday September 28, 2024 in Naked Heart
An article written by Dr Edward Leatham, Consultant Cardiologist
Tags: Cholesterol, Coronary heart disease, LDL, NH1 search website using Tags to find related stories.
When people think of cholesterol, most immediately associate it with something bad. However, cholesterol is an essential molecule required by every cell in our body. It plays a key role in the production of hormones, the structure of cell membranes, and other vital functions. But like many things in the body, it’s all about balance. And when it comes to cholesterol, the balance between “good” and “bad” cholesterol, particularly low-density lipoprotein (LDL) cholesterol, is critical for our health.
LDL cholesterol, often referred to as “bad cholesterol,” is the principle cause of the buildup of plaque in the coronary arteries, which leads to coronary heart disease (CHD). This type of heart disease can result in heart attacks, strokes, and other cardiovascular events. By the age of 50 near half of westernised populations have coronary plaque detectable by contrast CT.
In this article, we will explore what determines your LDL cholesterol levels, the role of the liver in cholesterol production, and how genetic and lifestyle factors influence cholesterol levels and heart disease risk.
LDL (low-density lipoprotein) is the primary vehicle that transports cholesterol through the bloodstream. While our cells need some cholesterol to function properly, too much LDL in our blood leads to an accumulation of LDL-rich plaque in the walls of arteries. Over time, this buildup, known as atherosclerosis, can restrict blood flow and increase the risk of heart attacks and strokes.
For years, the focus on reducing LDL levels to prevent heart disease was centered on dietary changes. It was believed that lowering the intake of saturated fats and cholesterol in food would reduce blood cholesterol levels and, in turn, lower the risk of heart disease. However, modern research has revealed that while diet may be important in some people, the liver’s role in producing cholesterol is even more significant in most. This explains the saying ‘90% of your cholesterol is made by the liver and only 10% is from what you eat’.
Cholesterol is such a vital molecule that our bodies have a sophisticated system to ensure its continuous supply. There are two main sources of cholesterol in the body:
The liver is the central hub for cholesterol production, responsible for synthesizing about 90% of the cholesterol in the blood. The enzyme HMG-CoA reductase plays a key role in this process, and this is the target for cholesterol-lowering medications like statins.
In addition to producing cholesterol, the liver removes LDL particles from the blood through LDL receptors (LDLRs). These receptors are located on the surface of liver cells and act as a clearing mechanism for LDL cholesterol. When LDL receptors are numerous and active, more LDL cholesterol is removed from the blood, leading to lower blood cholesterol levels.
LDL receptors play a crucial role in supplying cells with the cholesterol needed for various cellular functions and in maintaining low levels of LDL cholesterol (often called “bad cholesterol”) in the blood. These receptors attach to LDL particles in the bloodstream and transport them into liver cells, where the cholesterol can be used or stored. The more active LDL receptors a person has, the more efficiently their body can remove LDL cholesterol from the blood.
In people with highly active LDL receptors, blood levels of LDL cholesterol tend to stay low, regardless of dietary fat intake. On the other hand, individuals with fewer or less efficient LDL receptors will have higher LDL cholesterol levels, which increases plaque buildup in the arteries over many years and leads to coronary heart disease.
PCSK9 is a protein that plays a key role in cholesterol regulation. It influences how many LDL receptors are available to remove LDL cholesterol from the bloodstream. PCSK9 binds to LDL receptors and marks them for destruction, reducing the number of receptors available to clear LDL particles.
When PCSK9 activity is high, fewer LDL receptors are available, and LDL cholesterol levels rise. This process explains why many people have high cholesterol levels even with a healthy diet. In recent years, PCSK9 inhibitors have emerged as a new class of cholesterol-lowering medications. These drugs prevent PCSK9 from inactivating LDL receptors, allowing more LDL to be cleared from the blood, thus significantly lowering cholesterol levels.
While diet and lifestyle are important for overall health, genetic factors play the most significant role in determining LDL cholesterol levels. One well-known genetic condition affecting cholesterol regulation is familial hypercholesterolemia (FH). In the UK, it is estimated that about 1 in 250 people have FH, totaling approximately 220,000 individuals, though fewer than 8% are diagnosed. People with FH are at a significantly higher risk of developing heart disease and experiencing premature death. Heart attacks can occur before the age of 50 in men and before age 60 in women. The rarer and more severe form of the condition, homozygous FH (HoFH), can cause heart attacks as early as two or three years old, and without treatment, death may occur before the age of 20.
FH is caused by defective or absent LDL receptors, leading to extremely high LDL cholesterol levels from birth. If untreated, FH can result in early coronary heart disease, with symptoms potentially appearing in individuals as young as 20. Mutations in the low-density lipoprotein receptor gene (LDLR), apolipoprotein B-100 gene (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, and one particular mutation in the APOE gene are the most common genetic causes of FH.
The diagnosis of possible FH is based on the UK Simon Broome FH Register criteria, which include elevated LDL cholesterol levels (>4.9mmol/l) and a family history of early coronary heart disease or elevated cholesterol, or clinical features such as tendon xanthomas. A DNA test can confirm the diagnosis of FH with certainty. In cases where no mutation is found, studies have shown that the cause of hypercholesterolemia is often polygenic, meaning it results from the combined effects of many genes, rather than a single gene mutation. Beyond FH, other genetic mutations, particularly those involving the PCSK9 pathway, can also influence cholesterol levels. Many individuals inherit mutations that cause overactive PCSK9, which reduces the number of LDL receptors and leads to higher cholesterol levels. These mutations are relatively common and contribute to the variation in cholesterol levels seen across the general population.
It’s interesting to consider the evolutionary roots of high LDL cholesterol. Some theories suggest that low LDL receptor levels (causing high serum LDL), may have provided an advantage in early human history. LDL receptors are used by certain bacteria to gain entry to cells, thus genetic mutations that lowered LDL R density might have helped our ancestors survive infections. Before the 1800s, when infections were a leading cause of death and most people didn’t live past the age of 30, low LDL R activity, associated with high LDL levels, may therefore have been protective.
However, in modern times, where people are living longer, these same genetic traits that once conferred survival advantages are now contributing to higher rates of coronary heart disease in later life.
As we age, cholesterol regulation becomes less efficient. LDL receptor activity tends to decline, and cholesterol levels naturally rise. This increase in LDL cholesterol with age is one reason why heart disease becomes more prevalent in older adults. Even individuals who had normal cholesterol levels in their youth may see a rise in cholesterol as they reach middle age and beyond.
This age-related rise in LDL cholesterol underscores the importance of regular cholesterol screenings, especially for those with additional risk factors like a family history of heart disease.
For many people, their genetic makeup means that cholesterol-lowering diets make only a small difference to LDL concentration, if any at all. This reduction is seldom sufficient to counteract the development of atherosclerosis. In patients at risk with elevated LDL levels, adopting a strict vegetarian and/or dairy-free diet, devoid of saturated fats, typically does not lower LDL enough to slow the progression of plaque buildup in the arteries. It is estimated that only about 10% of individuals can achieve LDL reduction through dietary changes alone, and even in those cases, the reduction is generally no more than 4%. Unfortunately, this minimal reduction is insufficient to prevent the progression of coronary plaque, making medication necessary for most patients.
Fortunately, modern medicine offers several effective strategies for managing high cholesterol levels in individuals who cannot achieve sufficient LDL reduction through diet alone. Statins, the most commonly prescribed class of cholesterol-lowering drugs, work by inhibiting the HMG-CoA reductase enzyme in the liver, which reduces cholesterol synthesis. This triggers the liver to produce more LDL receptors, effectively lowering LDL cholesterol levels in the bloodstream.
For individuals who cannot tolerate statins or have genetic mutations affecting PCSK9, other treatment options are available. These include oral bile acid sequestrants, ATP citrate lyase inhibitors, and injectable PCSK9 inhibitors. In the UK, injectable treatments, including PCSK9 inhibitors and omega-3 fish oils (such as icosapent ethyl), are typically reserved for patients in secondary prevention cohorts. These injectable therapies can lower LDL cholesterol by 50-60%, providing a highly effective option for individuals at high risk of coronary heart disease.
The latest evidence is that your intake of saturated fat isn’t the main determinant of your blood LDL and thus risk of developing the ubiquitous ‘coronary plaque’. However the number of times your coronary plaque ruptures over your lifetime and how your body deals with each rupture IS all about what you eat, but the evidence points to it being your intake of carbohydrates and lifestyle, not intake of fat, that ultimately determine your fate. This theme will be explored over the coming months and is touched on in the Swiss cheese model of heart attacks. Swiss cheese model of heart attacks.
In summary, while diet does play a role in cholesterol levels, the liver’s production and regulation of cholesterol are the primary determinants of LDL cholesterol levels in most individuals. The body’s intricate system of cholesterol synthesis, LDL receptor activity, and PCSK9 regulation works together to maintain cholesterol balance.
For other stories related to cholesterol, coronary heart disease, and LDL, explore the archives by entering a tag under the search function above.
Next up: ‘let’s talk about salt’ . Due for release 8/10/24.
The Naked Heart is an educational project owned and operated by Dr Edward Leatham. It comprises a series of blog articles, videos and reels distributed on Tiktok, Youtube and Instagram aimed to help educate both patients and healthcare professionals about cardiology related issues.
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