The Power of CAC = 0. When Does LDL Cholesterol Matter?

Management of heart disease is changing. With technological advancements, we can collect more information – better information – to help risk stratify individual care.

Medical management of heart disease is changing. With technological advancements, particularly in cardiac imaging, we can collect more information – better information – to help risk stratify individuals and direct individual care. If you’re watching this video, you probably know that LDL cholesterol (LDL-C) has historically been the focus of the heart disease world.

The algorithm couldn’t get simpler: Have high “bad” cholesterol, lower it. But that simple idea is fading.

Now, to present the caveat up front, I am not saying LDL particles containing cholesterol and ApoB aren’t part of the pathway of cardiovascular disease. What I am saying, however, is “high cholesterol” ≠ “bad, and needs to be lowered.”

When CAC = 0, LDL Doesn’t Predict Atherosclerotic Cardiovascular Disease

But don’t take me on faith. Let’s discuss data. One landmark study published in the journal Circulation in 2023 followed 23,132 middle-aged people (median age 57) from the Western Denmark Heart Registry for a median follow-up of 4.3 years. Over this time, 552 had cardiovascular events. And the researchers sought to answer the question, “What predicted who would have a cardiovascular event, like a heart attack?”

But there’s more…

They broke those 23,132 participants into those who had a positive coronary artery calcium (CAC) scan and those who had a CAC = 0. A CAC scan is an imaging technique that measures calcified plaque in the arteries of your heart. In this population, about half had CAC = 0, and half had CAC > 0.

They found that, among those with CAC > 0, LDL-C did predict who would have a cardiovascular event. However, among those with CAC = 0, there was no association between LDL-C and cardiovascular disease events.

You can see that in Figure 1, below.

Starting with those with CAC > 0: Below, you see the association between LDL-C and heart attacks (left) and atherosclerotic cardiovascular disease (right) for CAC > 0. As LDL-C rises, the “adjusted Hazard Ratio” (aHR) increases. aHR is a ratio of how likely an event is to occur in one group compared to another over time. Here, we are comparing people across LDL-C cholesterol levels. Among those with CAC > 0, higher LDL-C has an aHR > 1, meaning higher risk of heart events and cardiovascular disease in those with higher versus those with lower LDL-C.

And if you’re wondering about the “adjusted” in “adjusted Hazard Ratio,” they adjusted for age, sex, smoking status and diabetes.

Now, look here. This is the aHR for those with CAC = 0. What you can clearly see is a flat red line at 1. This suggests higher LDL-C does not associate with higher risk of heart events and cardiovascular disease in those with CAC = 0.

What’s more, even when they took those with very high LDL cholesterol >193 mg/dl and compared them with those with LDL cholesterol <116 mg/dl, when CAC = 0 there was no observed benefit of having lower cholesterol (aHR = 0.95).

They Reproduced their Findings in a Second Cohort, with Longer Follow-up

The researchers also replicated these findings in an entirely separate cohort, the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Notably, in this study, the median age was 62 and median follow-up was 16.6 years.

Despite the older age and longer timeframe, the results remained the same: higher LDL-C was not associated with heart attacks or cardiovascular disease when CAC = 0.

Brief Summary

Among those with CAC = 0 in the initial population of >23,000 middle-aged adults, there was no significant association between LDL-C and heart attacks or atherosclerotic cardiovascular disease. These results were replicated in another cohort with 16 years of follow-up.

**In the rest of the letter, we discuss other risk factors, when CAC = 0 may fail, my personal case, and what’s on the horizon…

Diabetes, Smoking, and HDL Cholesterol