Soon We'll Forget What Heart Attacks Are

Table of Contents

• What a heart attack was
• Cigarettes
• The pressure
• Diet
• The driver that grew
• Cholesterol, and how far down this can go
• Why heart attacks might become a distant memory
• References

What a heart attack was

The public's understanding of this disease changed on September 23rd, 1955. The President of the United States is playing golf in Denver when his stomach starts to hurt. He blames the hamburger he had for lunch.

Shortly after midnight the pain is unmistakable, and it isn't his stomach. Dwight Eisenhower is having a heart attack.

Here is what the best medical care on Earth could offer the most powerful man alive at the time. An oxygen tent. Morphine. Four other drugs: papaverine, atropine, heparin, warfarin. Then bed, from September 24th until November 11th. Nearly seven weeks [2].

That was all the medical community could offer for heart attack treatment. Let alone how to prevent one.

The cardiologist they flew in from Boston was Dr Paul Dudley White. The next day he put out a bulletin: "The president yesterday had a moderate attack of coronary thrombosis without complications. His present condition is satisfactory" [4].

Then he did something almost no doctor did in 1955. He stood in front of a hundred and fifty reporters and taught. What a coronary thrombosis was: a clot, starving the heart muscle. Then the things that might be behind it. Diet. Alcohol. Tobacco. Exercise. Family history. A radical idea then: that the thing had causes, and you could do something about them [3].

It didn't turn the line around straight away. Heart disease overall was already drifting down. But the coronary kind, the blocked artery that causes a heart attack, was still climbing. It rose right through the 1950s, flattened out in the 1960s, and only turned into a real fall at the end of that decade [5].

Figuring out which risk factors mattered for heart disease took the rest of the century, and it was answered one item at a time, starting in 1963, when American cigarette consumption peaked.

Cigarettes

In January 1964 the US Surgeon General's report tied smoking to disease, and consumption fell that year and never came back. By 2011 the average American adult was smoking 72 percent fewer cigarettes than in 1963, down from 4,345 cigarettes a year to 1,236 [6].

As smoking rates dropped, so too did heart attacks. Compared with people who kept smoking, those who quit within five years had far fewer cardiovascular events: 6.94 per 1,000 person-years against 11.56, a hazard ratio of 0.61. And compared with people who had never smoked, the extra risk stopped being statistically detectable somewhere between 10 and 15 years after quitting [7].

But many people who'd never smoked still had heart attacks. Stopping smoking clearly isn't the reason heart attacks may soon become a distant memory. So what else was going on?

The pressure

The next lever wasn't on Dr Paul Dudley White's list at all, and the case for even looking at it had been made ten years before Eisenhower's heart attack, by a death nobody could ignore.

On April 12th, 1945, Franklin Roosevelt died of a brain haemorrhage. His blood pressure was 300 over 190, and for years his doctors had written that down as roughly what you'd expect at his age. Three years later Congress funded a study of one ordinary town, and on October 11th, 1948, the Framingham Heart Study began collecting health data on 5,209 residents [8].

In the years that followed, it was found that high blood pressure carried 2.6 times the coronary heart disease risk in men aged 40 to 59. That 1961 paper is also widely credited with coining the term "risk factor" [9].

But Framingham only watched. It could show that pressure travelled with risk. It couldn't show that lowering it lowered the risk.

That took a trial, and the trial came out of the Veterans Administration. 1967: 143 men, every one with a diastolic pressure, the bottom number, between 115 and 129, when normal by today's standards is under 80. They were randomly assigned to blood pressure lowering drugs or dummy pills. They stopped it after about eighteen months, because they had to [10], [11].

Twenty-seven severe complicating events in the placebo group, compared with two in the treated group. Four deaths on placebo. But none on treatment [10].

Over the years, as more blood pressure trials came out, the target blood pressure steadily dropped. No, it's not a conspiracy to sell more blood pressure drugs. The lower targets have come from trials like SPRINT.

That trial involved 9,361 people, split into two groups: to a systolic under 120 instead of under 140. Cardiovascular events fell by a quarter, deaths by 27 percent [12]. The same benefit held in adults aged 75 and over, including frail participants [13].

Two caveats on that target:

• Measure properly, ideally at home, seated and rested
• Very frail patients, or anyone who gets dizzy, may need a higher target

And reaching it does not necessarily have to mean reaching for medications.

In 1997 a trial called DASH fed 459 people for eight weeks. It's a diet rich in fruit, vegetables, fibre, potassium and low-fat dairy. Systolic pressure fell 5.5 points further than the control diet, and 11.4 points in the 133 who actually had hypertension [14]. A second trial then put low salt on top, and that combination beat a typical American diet by 8.9 points [15].

Diet

Speaking of diet and heart disease, where do dietary fats come in?

The CORDIOPREV study involved 1,002 people who already had coronary heart disease, randomised to a Mediterranean diet rich in unsaturated fats, or a low-fat diet, and followed for seven years.

Heart disease events were about 25 percent lower on the Mediterranean diet than on the low-fat diet. The primary endpoint occurred in 198 participants: 87 in the Mediterranean diet group and 111 in the low-fat group [16].

So unsaturated fats from extra-virgin olive oil, avocado, fish, nuts and seeds are definitely on the menu.

Saturated fats, not so much. Across 12 long-term trials and 53,758 participants, reducing dietary saturated fat cut combined cardiovascular events by 17 percent [17].

But this can't be the reason heart attacks might soon become a distant memory.

Many people still have heart attacks who don't smoke, have a systolic blood pressure below 120, or a bit higher if they're frail, and eat a good diet rich in potassium, fibre, unsaturated fats, and proteins such as chickpeas, lentils, beans and fish. And exercise, of course.

Fibre needs some nuance if you have irritable bowel syndrome or inflammatory bowel disease.

So what's missing? Well, despite all of this progress,

The driver that grew

adult obesity went from 23 percent in the early nineties to four in ten today, and diagnosed diabetes nearly tripled [18], [19].

When researchers worked out what drove the fall in US coronary deaths between 1980 and 2000, rising body-mass index and rising diabetes were the two factors pushing the other way, costing roughly 25,905 and 33,465 deaths prevented or postponed [20].

An abundance of food, particularly highly processed foods that people reliably eat more of, along with sedentary work, are significant contributors [21].

And for fifty years we had nothing that worked. Then the answer arrived from the strangest possible direction.

In 1980, a gastroenterologist named Jean-Pierre Raufman started at the National Institutes of Health, working on a question about venom and the pancreas. He later called it the kind of "fishing expedition" a grant committee today would throw out, and said he "would never have conceived that there was any potential therapeutic benefit" [22].

Of all the venoms his team tested, the one that provoked the biggest reaction came from a Gila monster.

The Gila monster is one of the few lizards on Earth with a venomous bite. It lives underground in the deserts of the American Southwest, and it eats about four or five times a year, taking as much as a third of its own body weight in a single meal. Researchers have long noted that its blood sugar stays remarkably steady between those meals [23].

At the VA hospital in the Bronx, an endocrinologist named John Eng saw something in that work nobody else did. He'd trained under Rosalyn Yalow, the Nobel laureate who invented a way to detect vanishingly small amounts of hormone in blood, and he turned her technique on the lizard venom [25].

In 1992 he isolated a compound nobody had described before. He called it exendin-4. It was about 53 percent identical to a human hormone called GLP-1, the signal that tells the pancreas to release insulin when blood sugar rises [24].

And here was the thing that mattered. Human GLP-1 is destroyed within a couple of minutes of appearing. The lizard version lasted for hours.

Then nothing happened. The VA declined to patent the discovery. Eng spent years trying to interest drug companies in a peptide from lizard venom, and got nowhere. One of the field's leading researchers later described it to Science magazine like this: "He was extremely frustrated. Nobody was interested in his work. None of the important people. It was too strange for people to accept."

So in the mid-1990s, Eng did the least glamorous thing in science. He put up a poster at a diabetes conference [25]. A researcher called Andrew Young, from a small company named Amylin, stopped to read it. "It was the most effective antidiabetic agent anyone had ever seen," Young later said [26].

The FDA approved the first GLP-1 drug in late April 2005. Byetta. Derived from Gila monster venom, off a poster almost nobody stopped to look at.

It was a modest drug. Twice-daily injections, decent blood-sugar control, and a few kilograms of weight loss over several months. Useful. Unremarkable. But it proved the target worked, and that opened the door.

Liraglutide followed in January 2010, once daily instead of twice. Semaglutide in December 2017, once weekly. Each generation more potent and longer-lasting than the last.

And then the surprise. At the higher dose tested for obesity rather than diabetes, 2.4 milligrams weekly, sold as Wegovy, people lost about 15 percent of their body weight. A level no drug had reached before. The FDA approved it for obesity in June 2021 [27].

But losing weight is not the same as living longer, and for a long time no drug given for weight loss had ever been shown to prevent a heart attack. That changed in 2023.

SELECT: 17,604 people with heart disease and a BMI over 27, no diabetes, weekly semaglutide or placebo for about three years. Major cardiac events: 6.5 percent on the drug, 8 percent on placebo. A fifth fewer, relatively. One and a half in a hundred, absolutely [28].

Tirzepatide then appeared. It combines GLP-1 with a second gut hormone, GIP, and in its big trial the top dose took off 21 percent of body weight [29].

Next in line is retatrutide, which adds a third hormone, glucagon. It's still in trials, but in the first phase 3 result this year, 2,339 people over 80 weeks, the top dose took off 28 percent, against 2 on placebo [30].

We are witnessing obesity's downfall.

And blood pressure comes down with the weight. As a rule of thumb, for every kilogram lost, systolic pressure drops by about one point [31].

So now the question from the start. If we'd found the causes, why did deaths go back up after 2019?

That's when the pandemic hit, and risk factor control for heart disease got worse during the lockdowns. The national cardiovascular death rate had fallen 8.9 percent from 2010 to 2019, then rose 9.3 percent from 2019 to 2022, which works out at 228,524 excess cardiovascular deaths and almost a decade of lost progress [32]. Statin prescriptions dipped in the spring of 2020 before climbing again [33].

But that still doesn't explain why we'll soon forget what heart attacks are, because after all, plenty of lean, non-diabetic people with great blood pressure, good diet, regular exercise, and no smoking still have heart attacks.

Cholesterol, and how far down this can go

Here's where we need to address cholesterol.

Does high cholesterol in the blood cause heart attacks? Does lowering blood cholesterol wreck memory and increase dementia rates?

Answers start in the 1990s, where a team in Paris led by the geneticist Catherine Boileau was studying French families with the hallmarks of familial hypercholesterolaemia.

That's the inherited condition that sends cholesterol sky-high and causes heart attacks before fifty. Except the genes that cause it were normal in these families.

Together with other labs, they found a gene called PCSK9 that, when overactive, causes cholesterol in the blood to skyrocket [34].

But that was only half the picture. What happens when the PCSK9 gene is broken?

Those broken copies turned out to be common. About one in fifty African Americans carried one. And the people who had them ran their LDL cholesterol about 40 percent lower than everyone else [35].

Then the scientists asked the question that mattered. Did those people get fewer heart attacks?

They took a long-running study of nearly 13,000 Americans, followed for fifteen years, and sorted them by whether they carried a broken copy. Among the black participants, 2.6 percent carried one: their LDL ran 28 percent lower, and their risk of coronary heart disease was 88 percent lower. Among the white participants, a milder variant meant 15 percent lower LDL and 47 percent less coronary disease [36].

Nothing else about these people was different. They hadn't taken a drug. They hadn't changed their diet. They were born with a broken gene that resulted in less cholesterol in their blood, and they got radically less heart disease.

Nature ran the experiment, for a lifetime, in thousands of people.

And then they found someone with no working copy at all. Two broken versions, no PCSK9 in her blood whatsoever, an LDL of 14. The paper describes her as a healthy, fertile college graduate [37].

And across more than 200 studies and two million people, every way of lowering LDL cholesterol, whether statin, ezetimibe, antibody therapy or lucky gene, lowers heart attacks in proportion to how far LDL cholesterol falls. The authors' conclusion is that the evidence "unequivocally establishes that LDL causes ASCVD" [38].

But why then do people with normal cholesterol still have heart attacks?

In 2009 researchers took 136,000 Americans admitted to hospital with heart disease and measured their cholesterol on the way in. Half had an LDL under 100. Three quarters were under 130. All of those read as normal on a lab report [39].

Even though an LDL of 100 is in the "normal range", plaque still develops in the blood vessel walls.

A Spanish study called PESA shows this. They took 1,779 middle-aged adults, 40 to 54, with none of the conventional risk factors, and scanned their arteries. Half already had plaque. And the higher the LDL, the more plaque, even among the 740 whose blood pressure, blood sugar and total cholesterol were all in the optimal range. The authors' reading is that plaque starts forming above an LDL of roughly 50 to 60 [40].

So guidelines started suggesting that, to prevent a second heart attack, we should aim for an LDL of less than 70. But from the PESA study, we see that plaque can still develop at that level.

So in March this year a trial called Ez-PAVE tested even lower. 3,048 people randomised to a target under 55 or under 70, and the way they got there was by adding ezetimibe, a cheap, old, non-statin tablet, on top of a statin.

Over three years, 6.6 percent of the lower-target group had an event against 9.7 percent of the higher. A third fewer relatively, three in a hundred absolutely. It tested a target rather than a drug, everyone knew which target they were aiming for, and most of the margin was fewer stents rather than fewer deaths [41].

But what about dementia rates? The brain needs cholesterol, doesn't it?

It does, and it makes its own. Almost all the cholesterol in your brain is made there, behind a barrier that keeps the cholesterol in your blood out [42]. Lowering the blood number doesn't starve the brain.

And it's been tested directly: 1,200 people on a PCSK9-blocking antibody or placebo, a formal battery of memory tests for a year and a half, LDL down around 30, and no difference [43].

The big observational study this year points the same way: in 132,585 Danes with new diabetes, of whom 2.7 percent developed dementia, the ones who started a statin within a year had about 15 percent less dementia, not more. That's a small absolute difference on a base rate under 3 percent, and it can't prove cause. But it's the opposite of the fear [44].

One more number, and it's the one I'd rather you knew than LDL. ApoB. Every particle that can get into an artery wall carries exactly one ApoB protein, so ApoB is a particle count, and the count does the damage. Across 430,000 people, put ApoB, LDL and triglycerides in one model and ApoB is the only one still predicting heart attacks [45].

When we're born, our ApoB is around 20 to 40. That's a physiological, normal level [46]. Above that, ApoB particles can start depositing cholesterol into our blood vessel walls and contribute to heart attacks.

During the 2010s a loud backlash against lowering cholesterol spread online, and we can measure what that does to people. In Denmark, after negative news stories about statins, more people stopped taking theirs. And the ones who stopped early had more heart attacks than the ones who kept going [47]. Thankfully the tide has turned, because doctors are communicating the overwhelming data that lowering ApoB lowers heart attack rates [48].

So how do we get to these low levels, and why might heart attacks become a distant memory?

We have very cheap medications such as rosuvastatin that are particularly effective when paired with ezetimibe, as Ez-PAVE showed us. But about one to two people in a hundred develop muscle aches from the statin itself and feel generally unwell [49], and many more blame the statin for aches that turn up just as often on a placebo. In the SAMSON trial, mean symptom intensity was 8.0 in months with no tablet, 15.4 in placebo months, and 16.3 in statin months [50].

But now, with PCSK9 inhibitors, no one gets left behind.

Drug companies built an antibody that does what the broken gene does, and the FDA approved two of them in 2015 [51].

The VESALIUS-CV study, presented last November, demonstrated that a PCSK9 inhibitor reduced heart attacks, strokes and coronary deaths by about a quarter, compared to a placebo, in 12,257 people who had never had a heart attack or stroke: 8 percent on placebo, 6.2 on the drug over five years [52].

And the earlier you start, the more you get. In genetic studies of 312,000 people, a lifetime of lower LDL cut coronary disease about three times as much, per unit of LDL, as a statin started in mid-life [53].

But there's a problem. PCSK9 inhibitors had to be injected, and they're expensive.

Part of that changed on July the 16th this year. The FDA approved enlicitide. A PCSK9 inhibitor you swallow [54]. One tablet a day on an empty stomach, and it lowers LDL by 56 to 59 percent, the same range as the injections [55], [56]. In the trials, side effects looked like placebo. It isn't cheap yet, a few hundred dollars a month at US list price [57], but the needle is gone.

And there's a gene therapy in the works that permanently switches off PCSK9 with one treatment. It's early, a phase 1 study of 35 people, but a single infusion cut LDL by up to 62 percent and held it there for a year and a half [58].

And the line from the start? In 2023 the heart disease death rate turned back down, from 167.2 to 162.1 per 100,000 [59]. What's left is mostly tools sitting on a shelf. Among 600,000 Americans who already had heart disease, only about half were on any statin, and only one in five on a high-intensity one [60].

Why heart attacks might become a distant memory

So here's why heart attacks might soon become a distant memory. We have identified, and largely solved, the risk factors that cause heart disease:

• Smoking
• Blood pressure
• Diet
• Exercise
• Obesity, with GLP-1 therapies
• ApoB above the level we were born with

And if those risk factors are controlled, I see no reason to get a coronary artery calcium score, because it wouldn't change anything: you're already maximally controlling your risk factors. The scan's job is to settle whether to treat when that's uncertain. Once you're treating, the guidelines say don't rescan [61], [62].

References

1. https://www.cdc.gov/nchs/data/hus/2020-2021/SlctMort.pdf

2. https://doi.org/10.1056/NEJMp2031046

3. https://www.heart.org/en/news/2024/02/15/the-presidential-heart-attack-that-changed-america

4. https://protomag.com/cardiology/the-heart-of-a-president/

5. https://www.cdc.gov/nchs/nvss/mortality/hist293.htm

6. https://pmc.ncbi.nlm.nih.gov/articles/PMC3910051/

7. https://pubmed.ncbi.nlm.nih.gov/31429895/

8. https://pmc.ncbi.nlm.nih.gov/articles/PMC4159698/

9. https://pmc.ncbi.nlm.nih.gov/articles/PMC9316391/

10. https://jamanetwork.com/journals/jama/fullarticle/336799

11. https://profiles.nlm.nih.gov/spotlight/xf/feature/study

12. https://www.nejm.org/doi/full/10.1056/NEJMoa1511939

13. https://jamanetwork.com/journals/jama/fullarticle/2524266

14. https://pubmed.ncbi.nlm.nih.gov/9099655/

15. https://pubmed.ncbi.nlm.nih.gov/11136953/

16. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00122-2/abstract

17. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011737.pub3/full

18. https://jamanetwork.com/journals/jamacardiology/fullarticle/2530594

19. https://www.cdc.gov/nchs/products/databriefs/db508.htm

20. https://doi.org/10.1056/NEJMsa053935

21. https://doi.org/10.1016/j.cmet.2019.05.008

22. https://whyy.org/segments/ozempic-how-gila-monster-venom-led-to-weight-loss-drugs/

23. https://askabiologist.asu.edu/gila-monster-food

24. https://www.research.va.gov/research_in_action/Diabetes-drug-from-Gila-monster-venom.cfm

25. https://www.goldengooseaward.org/01awardees/diabetes-medication

26. https://www.discovermagazine.com/planet-earth/the-venomous-gila-monster-helped-spark-the-discovery-of-ozempic

27. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

28. https://www.nejm.org/doi/full/10.1056/NEJMoa2307563

29. https://doi.org/10.1056/NEJMoa2206038

30. https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-delivered-powerful-weight-loss-in-pivotal-phase-3-obesity-trial-302778859.html

31. https://doi.org/10.1161/01.HYP.0000094221.86888.AE

32. https://pubmed.ncbi.nlm.nih.gov/37972797/

33. https://pmc.ncbi.nlm.nih.gov/articles/PMC10033441/

34. https://pubmed.ncbi.nlm.nih.gov/12730697/

35. https://pubmed.ncbi.nlm.nih.gov/15654334/

36. https://www.nejm.org/doi/full/10.1056/NEJMoa054013

37. https://pubmed.ncbi.nlm.nih.gov/16909389/

38. https://academic.oup.com/eurheartj/article/38/32/2459/3745109

39. https://pubmed.ncbi.nlm.nih.gov/19081406/

40. https://www.jacc.org/doi/10.1016/j.jacc.2017.10.024

41. https://www.nejm.org/doi/full/10.1056/NEJMoa2600283

42. https://doi.org/10.1161/01.ATV.0000120374.59826.1b

43. https://doi.org/10.1056/NEJMoa1701131

44. https://www.escardio.org/news/press/press-releases/statins-are-associated-with-a-lower-risk-of-dementia-in-patients-with-type-2-diabetes/

45. https://doi.org/10.1001/jamacardio.2021.5083

46. https://pubmed.ncbi.nlm.nih.gov/16810415/

47. https://doi.org/10.1093/eurheartj/ehv641

48. https://doi.org/10.1001/jamacardio.2016.4700

49. https://doi.org/10.1016/j.jacl.2022.09.001

50. https://www.nejm.org/doi/full/10.1056/NEJMc2031173

51. https://www.accessdata.fda.gov/scripts/cder/daf/

52. https://www.nejm.org/doi/full/10.1056/NEJMoa2514428

53. https://www.jacc.org/doi/10.1016/j.jacc.2012.09.017

54. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2026/220848Orig1s000ltr.pdf

55. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=100ec543-fbd0-44fc-b740-db9cdff39145

56. https://jamanetwork.com/journals/jama/article-abstract/2841258

57. https://www.healthline.com/health-news/fda-approves-new-cholesterol-pill-lipfendra

58. https://lilly.mediaroom.com/2026-05-25-A-single-dose-of-Lillys-PCSK9-base-editor,-VERVE-102,-reduced-PCSK9-by-up-to-88-and-LDL-C-by-up-to-62-,-with-durable-effects-supporting-its-potential-as-a-one-time-treatment-for-hypercholesterolemia

59. https://www.ncbi.nlm.nih.gov/books/NBK611296/

60. https://www.jacc.org/doi/10.1016/j.jacc.2022.02.048

61. https://www.uptodate.com/contents/coronary-artery-calcium-cac-scoring-overview-and-clinical-utilization

62. https://www.jacc.org/doi/10.1016/j.jacc.2026.04.005