The idea of preventing disease by managing measurable risks like cholesterol was a paradigm shift in medicine, born from observing 5,000 residents of Framingham, MA over decades, an unprecedented study that began in 1948.
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The 1945 death of President Roosevelt from a stroke highlighted medicine's profound ignorance about cardiovascular disease. This high-profile event spurred the government to create the National Heart Institute and fund the groundbreaking Framingham Heart Study.
The number of Americans recommended for statins ballooned from 13 million to 56 million due to progressively lowered cholesterol thresholds. The expert committees setting these guidelines often had members with financial ties to drug makers, creating a conflict of interest.
Inspired by penicillin's origin story, chemist Akiro Endo methodically screened molds, believing one could inhibit cholesterol production. He found the first statin, mevastatin, in a blue-green mold from a Kyoto grain shop, laying the foundation for all subsequent statin drugs.
HDL cholesterol, typically seen as protective, can become dysfunctional in the presence of risk factors like smoking or obesity. This dysfunctional HDL then contributes to atherosclerosis instead of preventing it, challenging the simplistic 'good vs. bad' cholesterol narrative.
Focusing solely on LDL is a mistake. Even individuals with a genetic mutation leading to lifelong low LDL levels can still have cardiovascular events if they have other unmanaged risk factors like metabolic syndrome, obesity, or diabetes, highlighting the need for a comprehensive approach.
Chronic illnesses like cancer, heart disease, and Alzheimer's typically develop over two decades before symptoms appear. This long "runway" is a massive, underutilized opportunity to identify high-risk individuals and intervene, yet medicine typically focuses on treatment only after a disease is established.
The economic boom after WWII led to widespread adoption of unhealthy habits: sedentary suburban lives, car dependency, and diets high in processed foods. This prosperity paradoxically created the perfect conditions for the rise of heart disease.
The silent nature of high cholesterol creates a psychological barrier. Patients who feel perfectly healthy are often unwilling to commit to lifelong treatment, even when their risk is high, leading to preventable cardiovascular events.
Universal cholesterol screening in young children acts as a trigger for cascade screening, where parents (often in their 30s) and grandparents (50s) are also tested. This uncovers and allows for treatment of familial hypercholesterolemia across three generations from a single pediatric test.
The development of PCSK9 inhibitors, a powerful class of cholesterol-lowering drugs, originated not from studying disease but from studying healthy people with a genetic mutation causing exceptionally low LDL. This highlights the value of investigating positive outliers in human biology.