Cardiology
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December 12, 2024

Redefining Cardiovascular Disease: Integrating Immunity, Genetics, and Lipidology

Medically Reviewed by
Updated On
December 12, 2024

Understanding cardiovascular disease is a complex and evolving process.Β 

Is cholesterol itself the primary issue in coronary artery disease, or is it merely responding to underlying inflammation, autoimmunity, dysbiosis, or infection? Why do we need cholesterol in the first place? Is dietary cholesterol the main concern, or is it the type produced endogenously by the body? Could genetic mutations affect lipoprotein receptorsβ€”which help clear cholesterol from the bloodstreamβ€”play a crucial role? Or is it a combination of many different factors?Β 

These questions will be explored in more depth throughout this article.

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What is Coronary Artery Disease?

Coronary artery disease, also known as atherosclerosis, is the condition that ultimately leads to heart attacks. But what exactly is atherosclerosis? At its core, it’s an inflammatory process that starts in the arterial wall of the heart’s blood vessels, often at a very early age. Over many years, this process gradually narrows the coronary arteries, eventually culminating in what we recognize as a heart attack.Β 

The term β€œatherosclerosis” comes from two parts: β€œathero,” referring to a gruel-like or fatty substance, and β€œsclerosis,” indicating hardening. The resulting plaque is composed of cholesterol, lipids, immune cells (macrophages), fibrin, and calcium. This multifactorial etiology underscores the complexity of the disease.

Reevaluating Cholesterol’s Role in Heart Disease

Medical education in the 1990s taught that cholesterol was the root cause of heart disease and that lowering it would solve the problem. The reality is far more complex. Lipidologyβ€”the study of lipids and, therefore, atherosclerosisβ€”is among the most intricate areas of cardiovascular science. Simply putting an adult on a cholesterol-lowering medication for primary prevention of a cardiovascular event is often insufficient. There must be more to the storyβ€”and there is.

Seeking the true root causes of heart disease is especially important, as this condition is interwoven into the family histories of countless Americans. Early prevention is crucial, considering that atherosclerotic processes begin in infancy and continue throughout life. Before we dive deeper, it’s helpful to understand what cholesterol is and review studies detailing its functions and the roles of lipids in the human body.

Cholesterol: Essential Building Block and More

Cholesterol is a molecule critical for making steroid hormones, maintaining cell membranes, and producing bile acids and vitamin D. It’s essential for human survival. While dietary sources from animal products add some cholesterol, most cholesterol is produced internallyβ€”mainly in the liverβ€”in response to low blood levels.Β 

Plant foods contain phytosterols rather than cholesterol, and these plant sterols are not utilized by humans. Because cholesterol can’t move freely through the bloodstream, it’s transported by lipoproteins such as low-density lipoprotein (LDL). We can think of these lipoproteins as β€œcars” that carry cholesterol along our body’s β€œhighways” to deliver this vital substance where it’s needed.

Lipoproteins: Transporters of Energy and Cholesterol

Lipoproteins, composed of fat and protein, carry both triglycerides (energy) and cholesterol. They transport triglycerides to various tissues, with cholesterol delivery often viewed as a secondary task. These carriers vary in size and composition.Β 

The largest, known as chylomicrons (like β€œbuses”), lose triglycerides and become smaller, denser LDL particles (like β€œcars”) as they deliver energy. LDL is often referred to as β€œbad” cholesterol, but nothing in the human body is inherently β€œbad” or β€œgood.” Rather, imbalances can turn something normally beneficial into a problem.

The Importance of Lipoprotein Particle Number

Recent research suggests that the number of LDL particles (LDL-P), as well as the level of apolipoprotein B (apo B) attached to these particles, is crucial in assessing heart disease risk.Β 

When LDL particles are elevated, they create a concentration gradient that encourages cholesterol infiltration into the arterial wall, sparking plaque formation. Higher apo B and LDL-P values correlate with greater atherosclerotic risk. This understanding has refined our approach to cholesterol assessment.

Reframing the β€œGood or Bad” Lipid Debate

The prevailing hypothesis: Cholesterol and lipoproteins like LDL are inherently good and necessary unless genetic factors and/or lifestyle choices cause them to become unbalanced. Before we condemn LDL as purely harmful, it’s worth exploring why these lipoprotein β€œcars” evolved and how they serve protective roles in the body.

Lipoproteins and the Innate Immune System

Emerging evidence suggests that LDL and HDL particles are integral components of our innate immune system. For example, HDL particles have antimicrobial properties, helping protect against parasites and bacteria.Β 

An inverse correlation exists between HDL levels and infection risk. Similarly, LDL appears to play a role in pathogen clearance.Β 

Infection, Cholesterol, and Clinical Observations

Research supports the idea that lower cholesterol levels can sometimes predispose individuals to higher infection rates. For instance, one study associated LDL levels under 70 mg/dL with increased risks of hematological cancers, fever, and sepsis.Β 

A 2019 study also noted that lower LDL levels were tied to a higher risk of sepsis and ICU admission among infected patients. While some attribute this to other illnesses, other models disagree.

Balancing Lipid Levels and Infection Risk

These findings raise the possibility that driving lipid levels too low might increase susceptibility to infections in certain patients. On the other hand, not all high cholesterol is harmful. Various populations and conditions don’t follow the simple β€œhigh cholesterol equals high risk” rule.Β 

About half of all heart attacks occur in people with β€œnormal” cholesterol levels, highlighting that many other factorsβ€”like smoking, diabetes, hypertension, obesity, and air pollutionβ€”are at play.

Inflammation at the Core

The common denominator in these risk factors is inflammation. While lowering LDL can be part of a strategy to reduce cardiovascular events, it’s not the entire solution. High-risk patients, especially those with previous heart attacks or strong family histories of early heart disease, may benefit from lowering apo B particle volumes. Yet, for many people, the underlying inflammatory processes and lifestyle factors are as critical as the lipid numbers themselves.

Genetics, Evolution, and the Infectious Environment

Genetic mutations like APOE4 or PCSK9 variants increase circulating lipoproteins. Historically, when infection posed a greater threat to survival than heart disease, these genetic traits might have been advantageous, allowing more effective clearance of pathogens.Β 

Today, in a world of antibiotics and better sanitation, these once-beneficial adaptations may predispose us to heart disease if our lifestyle choices create chronic inflammation.

Gut Dysbiosis: The Hidden Trigger

Research into the human microbiome suggests that gut dysbiosisβ€”an unhealthy gut bacterial environmentβ€”could be a significant driver of inflammation and lipid changes. Bacterial endotoxins like lipopolysaccharides (LPS) can enter the bloodstream, prompting the body to produce more lipoproteins to trap and remove these harmful molecules.Β 

This response could explain why some individuals have elevated cholesterol: their bodies are responding to chronic, low-level infections or dysbiosis rather than just accumulating plaque β€œout of nowhere.”

Studies suggest in severe human infections, higher lipid levels correlate with better outcomes, indicating that lipoproteins serve as immediate responders in the immune system’s fight against pathogens.Β 

Chronic dysbiosis and dietary patterns that encourage low-grade infections can potentially lead to persistently elevated cholesterol as the body tries to manage ongoing threats. This can ultimately contribute to cardiovascular disease risk if left unchecked.Β 

However, elevated cholesterol is often a sign of underlying issues like inflammation, gut imbalance, and lifestyle factorsβ€”rather than an isolated cause of heart disease.

A More Nuanced Understanding of Cardiovascular Risk

This does not mean that elevated cholesterol levels are irrelevant; they still correlate with unfavorable cardiovascular outcomes. However, evidence suggests that high cholesterol is not necessarily the most significant upstream issue in coronary artery disease. Instead, it may serve as a marker of underlying imbalancesβ€”such as gut dysbiosis, chronic infections, inflammation, and certain genetic predispositionsβ€”that drive the disease process over time.

In other words, inflammation, microbiome health, and long-term dietary habits often play larger roles than previously recognized. For example, individuals with autoimmune conditions face twice the risk of cardiovascular disease compared to those without such conditions.Β 

These insights emphasize that while addressing lipoprotein levels is important, achieving truly effective prevention and management requires a more holistic approach. By focusing on reducing chronic inflammation, improving gut health, and considering genetic and lifestyle factors, we may move closer to genuine disease prevention and lasting heart health.

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Integrating Cholesterol’s Immune Role into the Bigger Picture

Now that we have a basic understanding of cholesterol’s potential immune functions, we can consider it as a marker of underlying chronic infectionβ€”particularly in the gut and oral cavityβ€”as well as systemic inflammation and an enhanced cholesterol synthesis response in genetically susceptible individuals.Β 

In those with certain single nucleotide polymorphisms (SNPs) affecting lipoprotein receptors or intestinal reabsorption, elevated cholesterol may not be effectively cleared by the liver or intestines once it’s upregulated. As a result, the persistently high levels of circulating cholesterol can create a concentration gradient that encourages lipoprotein infiltration into the arterial wall. Over time, through immune sensing, engulfment, and deposition, this process sets the stage for atherosclerotic events.

At this point, the conventional cardiovascular modelβ€”which places elevated lipoproteins at the center of plaque formationβ€”comes into sharper focus. With a more complete understanding of cholesterol’s multifaceted role and the underlying triggers that lead to its abnormal accumulation, we are better equipped to interpret lab findings and appreciate their implications in a broader, more holistic clinical context.

The information in this article is designed for educational purposes only and is not intended to be a substitute for informed medical advice or care. This information should not be used to diagnose or treat any health problems or illnesses without consulting a doctor. Consult with a health care practitioner before relying on any information in this article or on this website.

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