By Ariaratnam Gobikrishna –

Ariaratnam Gobikrishna MD

I remember back in the ’70s, my high school teacher was a chain smoker, yet he lived well into old age without any apparent harm. Fast forward to today, and smoking is banned in public indoor spaces, especially in schools, due to the well-documented dangers of secondhand smoke. These stories seem contradictory, but they don’t shake our understanding because we know that not everyone who smokes will develop cancer. Yet, despite knowing someone like my teacher, we wouldn’t dare proclaim from the rooftops that smoking is safe.

When it comes to cholesterol and heart disease, however, that line of reasoning falls apart for many vocal critics of cholesterol lowering. Despite clear evidence supporting the benefits of lowering cholesterol, conspiracy theories about big Pharma often overshadow the facts. These theories are often fueled by anecdotes of people with high cholesterol who never experienced a heart attack or stroke, or by instances where low cholesterol levels are observed during life-threatening heart conditions or terminal illnesses, leading some to mistakenly believe that low cholesterol is the cause rather than a consequence.

We don’t have many clues as to why some smokers escape cancer, but we have a clearer understanding of why some people with high cholesterol suffer severe consequences. In other words, we have some insights into why cholesterol gets trapped in the arteries in some more than others. To grasp this, we need to consider the complex interplay of several factors: the total amount of cholesterol, the balance of its different types, the body’s defenses against cholesterol penetration into artery walls, and the mechanisms that clear these deposits.

Before delving deeper, it’s essential to establish that cholesterol trapping in the arteries is indeed harmful. Over time, cholesterol that gets trapped becomes calcified and can be detected by a CAT scan, and higher levels of calcification indirectly denotes presence of higher levels of non-calcified plaques and that is strongly correlated with an increased risk of heart disease, while its absence correlates with a very low risk. This is the rationale behind measuring coronary calcium scores.

Cholesterol buildup in the walls of arteries isn’t as simple as it might seem. It’s a complex process influenced by many factors. Some people are lucky to have strong blood vessel walls due to their genetics, which helps keep cholesterol from accumulating. However, others are at a higher risk for heart disease because of certain genetic factors. For example, mutations in blood cells linked to a condition called clonal hematopoiesis of indeterminate potential (CHIP) can cause white blood cells to behave abnormally, leading to more inflammation and cholesterol buildup in the arteries. Other conditions like high blood pressure, diabetes, smoking, and chronic inflammation can also weaken blood vessel walls, making them more prone to cholesterol buildup. Lowering cholesterol levels is particularly beneficial for those with these weakened walls, as it can significantly reduce their risk of heart disease. Meanwhile, people with stronger vessel walls or better natural mechanisms for clearing cholesterol might not experience as dramatic a benefit from lowering their cholesterol levels.

Identifying people with resilient artery walls and robust cholesterol clearance mechanisms early in life has proven to be a fool’s errand. However, those who naturally maintain low blood cholesterol levels, whether due to genetic factors or a healthy lifestyle, tend to have a very low incidence of heart attacks and strokes. This is why advocating for low cholesterol levels, through lifestyle changes or medications, is so important.

Cholesterol and triglycerides are transported in the blood in various forms, including HDL, LDL, IDL, chylomicrons, and VLDL. While chylomicrons and VLDL are too large to penetrate vessel walls, the other forms can do so more easily. Over the past few decades, numerous clinical trials have consistently shown the benefits of lowering LDL cholesterol. However, efforts to reduce VLDL and IDL (remnant cholesterol) have largely fallen short, with many trials failing to demonstrate significant reductions in heart attacks and strokes.

However, these remnant particles are linked to the residual risk of heart attacks and strokes in people who have achieved low LDL levels. This is because, unlike LDL, which must be oxidized to become trapped in artery walls, remnant cholesterol can become trapped without this process, making it potentially more dangerous.

Despite many setbacks in targeting remnant cholesterol, one notable success came from a trial using a specialized form of fish oil, purified eicosapentaenoic acid ethyl (an omega-3 fatty acid), administered in high doses. This treatment has been shown to reduce the incidence of heart attacks and strokes.

People with insulin resistance or dietary indiscretions with processed carbohydrates face a particularly challenging situation. They tend to have higher levels of remnant cholesterol, more small, dense LDL particles, and poorly functioning HDL. Coupled with significantly elevated inflammation, these factors make their arterial walls more vulnerable to cholesterol penetration, creating the worst possible scenario for heart disease risk.

Efforts to improve cholesterol clearance from artery walls, specifically by raising HDL levels, have largely failed. The relationship between HDL levels and cardiovascular protection is complex and not fully understood. High HDL levels are not always protective, and in some cases, they can even be detrimental. This suggests that the functionality of HDL in removing cholesterol is more important than its levels, but identifying whose HDL is most effective in this role has, so far, proven to be another elusive goal.

While several medications are available for lowering LDL and remnant cholesterol, their high cost limits access to only a small fraction of the population. Treatments such as PCSK9 inhibitors, Bempedoic acid for statin intolerance, Vascepa for remnant cholesterol, siRNA technology for biannual injections for LDL reduction, and various inhibitors targeting ApoC3 and ANGPTL3 for remnant cholesterol reduction remain largely theoretical or aspirational for many, even in the USA.

Just as PCSK9 inhibitors were discovered serendipitously during the Dallas Heart Study, when certain African American families were found to naturally have low levels of PCSK9 and a corresponding low incidence of heart attacks and strokes, a similarly intriguing case study has emerged around remnant cholesterol targets, focusing on the Amish population in Pennsylvania. Living in pre-industrial conditions, some Amish families display remarkably low levels of triglycerides and remnant cholesterol, coupled with a significantly reduced incidence of heart disease. This advantage is linked to a genetic mutation—a loss-of-function mutation in the ApoC3 gene—that results in naturally low ApoC3 levels and, consequently, very low triglycerides.

Amidst the challenges of accessing costly cholesterol-lowering medications, there’s a silver lining that hasn’t received much attention—likely because it isn’t backed by big Pharma, speaking of conspiracy theories. This often-overlooked treatment is colchicine, an ancient medication originally used for gout. Its use dates back to ancient times, with significant contributions from Persian physician Avicenna in the 10th century, who advocated its use for joint pain.

Inflammation has long been recognized as a trigger for plaque rupture, which causes heart attacks and strokes, and it was hypothesized that inflammation could also exacerbate cholesterol penetration and trapping in the arteries. This hypothesis was put to the test in the Jupiter trial, which examined inflammation in people with reasonably low LDL levels. Using a blood test known as high-sensitivity C-reactive protein to detect inflammation, researchers administered Rosuvastatin and found that, at equal LDL levels, it was the reduction of inflammation that led to a significant decrease in heart attacks, strokes, and all-cause mortality.

This discovery spurred the development of many expensive medications targeting inflammation, but one of the most effective turned out to be the inexpensive, age-old gout medication, colchicine. Trial after trial has shown that colchicine reduces the risk of recurrent heart attacks and strokes in people who already have cholesterol deposits. This success has led the FDA to approve colchicine for people who have had heart attacks and strokes, as well as those at high risk for these events. This is a groundbreaking development that could make a significant impact on global public health, yet it has occurred with little fanfare, remaining under the radar while pharmaceutical companies continue to pursue costly alternatives—although these may be necessary for those who cannot take colchicine due to liver or kidney issues.

The long-term safety of colchicine has been indirectly supported by its use in treating a relatively obscure condition known as Familial Mediterranean Fever (FMF). This genetic disorder, primarily affecting families in Turkey and Israel, causes widespread inflammation, affecting joints and various organs, accompanied by intermittent fever. Patients with FMF require lifelong colchicine treatment, and studies have shown that, among these long-term colchicine users, the incidence of heart attacks and strokes is lower. This not only highlights colchicine’s potential cardiovascular benefits but also provides reassurance regarding its safety over extended use.

Can we toss out the cholesterol theory in favor of focusing solely on inflammation? Not so fast. While it’s true that inflammation is a critical factor in heart disease, all the successful trials targeting inflammation have been conducted on top of statin therapy. Hence, statins remain the cornerstone of treatment. Moreover, thankfully, it’s an affordable treatment worldwide. There may come a day when we can prevent heart attacks and strokes without worrying about blood cholesterol levels, but we’re not there yet. So, it’s important to remain grounded in evidence-based medicine rather than getting swept up in speculation or conspiracy theories.