Data drives decisions.
When it comes to protocols and guidelines, they aren't based on emotions, random assumptions, or opinions but on data.
Heart disease is the #1 killer worldwide. I believe it is essential for you to be aware of 4 landmark studies that provide findings proven to reduce the risk of heart disease.
In today's newsletter article, we will look at studies that build the backbone of our suggestions, guidelines, and protocols.
Let's jump into it.
The Framingham Heart Study
Started in 1948 in a small Massachusetts town with 5,209 ordinary men and women.
At the time, heart disease was treated as a tragedy that happened to you, not as something we could prevent.
Cardiovascular disease had already become the number one cause of mortality among Americans, accounting for one in every two deaths, and most people simply accepted early death from heart disease as unavoidable.
Framingham changed that by doing something almost nobody had done before: following the same people, generation after generation, and simply observing what happened to them.
The investigators popularized the term “cardiovascular risk factor” in the medical lexicon and proposed a prediction algorithm — the Framingham Risk Score — built around age, sex, cholesterol, HDL, diabetes, smoking, and systolic blood pressure, which is still in clinical use today.
That 1961 work identifying high blood pressure, high cholesterol, and ECG evidence of an enlarged heart muscle as major risk factors later formed the basis of the 10-year and 30-year risk calculators cardiologists still use at the bedside.
Before Framingham, a heart attack was bad luck. After Framingham, it was a tangible equation that you could change.
INTERHEART
This study set out to answer the question: which risk factors for heart attack prevention are within my control?
Published in 2004, INTERHEART enrolled more than 29,000 people across 52 countries, comparing patients who had just experienced a first heart attack with matched controls who hadn’t.
The finding reshaped how we think about prevention globally.
Nine modifiable risk factors:
- Abnormal ApoB
- Smoking
- Hypertension
- Diabetes
- Abdominal obesity
- Psychosocial stress
- Poor diet
- Low alcohol intake
- Physical inactivity
Together, these variables explained more than 90% of the risk of a first heart attack across all regions and ethnic groups studied.
Smoking and an abnormal ratio of blood lipids were the two heaviest hitters, together predicting two-thirds of global heart attack risk.
Ninety percent is a massive number, and subsequent studies do push back on this statistic, but the general consensus is roughly around 70% of heart attacks are preventable.
You have more control than you think.
ApoB is Causal for Heart Disease
For many years, LDL cholesterol was regarded as a “risk marker"—indicating a possible association with heart disease, though its exact relationship remained uncertain.
Could high LDL just be a bystander?
Mendelian randomization is how we finally answered that question properly.
The idea works like this: certain people are born, purely by the luck of their genetics, with lifelong lower LDL-C/ApoB—the way people are randomly born tall or short. Because that genetic difference is determined at conception, before any lifestyle choices are made, it eliminates the confounding that plagues typical observational studies.
If people born with genetically lower LDL-C/ApoB have dramatically less heart disease over a lifetime, that isn’t a coincidence you can explain away with diet or exercise. That’s causation.
In 2017, the European Atherosclerosis Society Consensus Panel, led by Dr. Brian Ference, addressed this question. The panel reviewed more than 200 prospective cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies, spanning more than 2,000,000 participants and over 150,000 cardiovascular events.
The conclusion was clear: LDL-C’s link to atherosclerotic cardiovascular disease meets the criteria for causality, showing a consistent, dose-dependent relationship—indicating that your risk is influenced by both LDL-C levels and the duration of exposure.
This is also why I talk about ApoB as much as I do.
Now, we also know LDL-C and ApoB are not the only villains in the room, but their roles should not be taken lightly.
This matters clinically: lowering your LDL-C and ApoB isn’t just an assumption. It is one of the few interventions in medicine we can say actually removes the fuel from the fire, with genetic-level certainty.
SPRINT Trial
For decades, “under 140” was the finish line for systolic blood pressure. SPRINT asked a simple question: is 140 the magic number for blood pressure?
Researchers randomized over 9,300 adults at elevated cardiovascular risk to systolic blood pressure targets of either under 140 or under 120 and followed them for years.
Intensively managing systolic blood pressure to 120 or lower reduced the risk of major cardiovascular events by 27% and the risk of death by 25%, compared to the previous standard target of under 140.
The benefit persisted both during the active treatment period and after the trial ended.
SPRINT significantly influenced why the goalposts shifted, making a blood pressure nearing 120 more desirable.
What All Four Studies Have in Common
Notice the trend here.
Framingham told us risk factors exist.
INTERHEART told us how much they matter, worldwide, in real numbers.
The Mendelian randomization evidence told us that at least one of the biggest risk factors — LDL-C and ApoB — isn’t just correlated with heart disease; it’s a genuine cause of it.
SPRINT told us exactly how aggressively to treat blood pressure.
Four different research designs. Four different decades. Four different populations.
All converging on the same practical message: know your numbers and treat the causal ones, not just the convenient ones.
That’s it. That’s the whole game.
Manage what you measure to stack the deck in your favor.
Knowing Your ApoB Levels
Apolipoprotein B (ApoB) is not included in a standard lipid panel and is rarely included on routine annual labs.
That's starting to change. The new 2026 ACC/AHA cholesterol guidelines now recommend ApoB testing to sharpen cardiovascular risk assessment — because ApoB directly quantifies the number of atherogenic lipoproteins, providing a more accurate measure of atherogenic particle burden than LDL-C.
Essentially, ApoB counts the actual number of artery-clogging particles in your blood, which can be a more accurate measure of risk than LDL-C alone.
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If you are interested in knowing your ApoB level, see if Function is a good fit for you.
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Only the best,
Jeremy London, MD
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