In this educational monologue, the speaker examines how coronary artery calcium (CAC) scoring reshapes cardiovascular risk assessment, especially regarding LDL cholesterol. He reviews a 2023 Circulation study of 23,132 Danish adults (median age 57, 4.3‑year follow‑up) and its replication in the Multi‑Ethnic Study of Atherosclerosis (MESA), showing that LDL predicts events only when CAC > 0; when CAC = 0, LDL has no association with heart attacks or atherosclerotic cardiovascular disease, even at very high levels. The speaker highlights that other factors—diabetes, smoking, low HDL—remain predictive in CAC‑zero individuals, underscoring metabolic health. He cautions that CAC’s “warranty” weakens in people under 40, where non‑calcified plaque can cause severe disease despite a zero score, illustrated by a 31‑year‑old patient with obstructive lesions on coronary CT angiography. The presenter shares his own lipid panel (LDL 573 mg/dL, favorable HDL/triglycerides, low inflammatory markers) and notes a plaque‑free CT, using it to discuss emerging AI‑driven imaging. He argues for nuanced, patient‑centered decision‑making: CAC can guide statin initiation or deferral, balancing statin benefits against risks (mitochondrial harm, diabetes). The talk concludes with open questions about plaque progression, dangerous plaque types, and future therapeutic targets, urging clinicians and patients to move beyond a simplistic “lower‑LDL‑is‑always‑better” mindset.
Chapters
The medical management of heart disease is changing radically. With technological advancements, particularly in cardiac imaging, we can collect more information, better information, to help risk stratify individuals and direct individual-level care. That's personalized medicine. Now, if you're watching this video, you probably know that LDL cholesterol has historically been the focus of the heart disease world. The algorithm, the past algorithm, it couldn't get simpler. Have high LDL, bad cholesterol? Lower it. Here's a medication. But that simple idea is fading. Now, to present the caveat up front, I'm not saying LDL particles containing cholesterol and ApoB aren't part of the pathway of cardiovascular disease. They are. What I'm saying, however, is high doesn't simply equal bad and needs to be lowered. But don't take me on faith. Let's discuss data. One landmark study published in the cardiovascular journal Circulation in 2023 followed 23,132 middle-aged people—the median age was 57—from the Western Denmark Heart Registry for a median follow-up period of 4.3 years. And over this time, 552 of these people had cardiovascular events. And the researchers sought to answer the important question: What predicted who would have a cardiovascular event, like a heart attack? But there's more. The researchers broke those 23,132 participants into those who had a positive coronary artery calcium scan in those who had a CAC score of 0. A CAC scan is an imaging technique that measures calcified plaques in the arteries of your heart. And in this population, about half had a CAC of 0, and about half had a CAC that wasn't 0, that was greater than 0. And what they found was amazing. Among those with CACs greater than 0, LDL did predict who would have a cardiovascular event. However, among those with a CAC of 0, there was no association between LDL cholesterol and cardiovascular disease events. You can see that here. I'm showing parts of Figure 1. You can see the association between LDL cholesterol and heart attacks on the left and atherosclerotic cardiovascular disease on the right for those who had a CAC greater 0. And you can see as LDL cholesterol rises, the adjusted hazards ratio increases. The adjusted hazards ratio is a ratio of how likely an event is to occur in a group compared to another group over time. Here we are comparing people across the LDL cholesterol spectrum. And among those with a CEC 0, higher LDL has a hazards ratio above 1, meaning higher risk of heart events and cardiovascular disease. As compared to those with lower cholesterol. And if you're wondering about the "adjusted" in the adjusted hazards ratio, they adjusted for age, sex, smoking status, and diabetes. But now, here's what I find interesting. Look here. This is the adjusted hazards ratio for those with the CAC of 0. And what you can clearly see is a flat red line at 1. This suggests higher LDL cholesterol does not associate with higher risk of heart events and cardiovascular disease in those with a CAC of 0. It provides a sort of warranty, if you will. What's more, when the researchers took those with very, very high LDL above 193 mg/dL and compared them to those with lower LDL under 116 mg/dL, When CAC was zero, there was no observed benefit of having lower cholesterol. The hazards ratio was actually slightly under 1 at 0.95. The researchers also replicated these findings. Importantly, they replicated them in an entirely separate cohort, the Multi-Ethnic Study of Atherosclerosis cohort. And notably, in this replication cohort, the median age was 62, slightly older, and the median follow-up time period was 16.6 years. And despite the older age and longer time frame, the results remained the same. Higher LDL cholesterol was not associated with heart attacks or atherosclerotic cardiovascular disease when CAC was zero. So, zooming out and summarizing, among those with a CAC of zero, in the initial population of greater than 23,000 middle-aged adults, there was no significant association between LDL cholesterol and heart attacks or between LDL cholesterol and atherosclerotic cardiovascular disease. These results were then replicated in another cohort of slightly older patients with a 16.6-year follow-up period. Pretty striking, right? And I'll also add that even among those with a CAC of 0, there were other variables that did associate with heart attacks and cardiovascular disease, including diabetes, smoking, and low HDL cholesterol, a marker of metabolic syndrome. I think this reinforces the importance of metabolic health in predicting your cardiovascular health. I'm not saying that low cholesterol and metabolic health are a binary choice, and I caution against people presenting this false dichotomy. But I do think it's important emphasizing that metabolic health is the foundation of cardiovascular health and overall health. Now I want to get on to another nuance, an interpretive caution. About CACs. Age matters. Most plaque in the coronary arteries of young people is non-calcified. Therefore, for those under 40 years old, CAC of 0 may not provide the same warranty as it does for those who are slightly older. Here's a real cautionary tale to hammer home the point. A 31-year-old man presents to his doctor with chest pain radiating to his left arm. He has obesity, high blood pressure, and diabetes. However, his CAC is zero. But then, on coronary CT angiography scanning, which can see soft plaque as well as calcified plaque, it revealed complete blockage of his left anterior descending artery, his LAD, and his proximal first obtuse marginal artery, OM1 on this image. This man with a CAC of 0 had severe 2-vessel disease despite his CAC of 0. Admittedly, this was an extreme case. His HbA1c was 14.1%, which basically means his blood was a Skittle short of flowing soda, and his triglycerides were 1,146 with an HDL of only 24 mg/dL. Basically, if metabolic syndrome were a primate, this was a King Kong case. So yes, this was an extreme case, but I use it to illustrate a point on which we do have some more useful and generalizable statistics. In another study published on the same Western Denmark Heart Registry population, while only 3% of people under 40 who had symptoms suggestive of coronary artery disease actually had obstructive coronary artery disease, which means at least 50% blockage of an artery in their heart, 58% of those 3% with symptoms who were under 40 who had obstructive disease also had a CAC of zero. I know that's a lot of numbers. So, to be clear about what I'm saying, if a young person, say under 40, has symptoms suggestive of heart disease and other risk factors, presumably, a CAC of zero doesn't provide the same warranty, the same reassurance as it would in an older person. So, for these younger patients with symptoms or other significant risk factors, coronary CT angiography, CCTA, which can detect non-calcified plaque, may provide more useful information. Now, to call out the coronary elephant in the room, I'm in that group. The under 40 group. And in terms of my risk factors, well, my LDL cholesterol on last check was 573. My Lp runs between 120 and 160 from my father's side. That was a Nick note. Come on, man. Come on, Dad. You left Mom to donate all the mitochondria and then you dump me with this crappy Lp? Not cool. Alright, vent over. My HDL cholesterol and triglycerides on last check were 125 and 39 respectively, And for those who want even more statistics, I'm happy to be transparent. My HbA1c is 5%, my fasting insulin is less than 3 μU/mL, my hs-CRP is less than 1, my omega-6 to omega-3 ratio is a perfect 1:1, and my TMAO is 3.2. I don't know how this is the case given all the fish and eggs I eat. I really don't know. But anyway, on last check, getting to the point, via coronary CT angiography, I had no visible plaque. However, like any smart patient, my personal choices are subject to change with the evolution of technology and data collection. We are now in an evolving era of AI-guided scans that can detect plaque in almost everyone. Now, with great tools comes great questions, and I'm looking forward to them. What predicts plaque progression and in whom? What types of plaque are most dangerous and under what circumstances? What are the different thresholds at which different types of plaque become problematic? And how can we use our evolving understanding of metabolism and the heart to get innovative new treatments, target new pathways in ways that are smarter, safer, and effective? These are all great questions, non-dogmatic questions, questions that should be stimuli for open discussion. But zooming out and summarizing, I think it's both fair and important to highlight data supporting the key point that while LDL cholesterol might associate with heart disease in the overall population, this deserves far more nuance and refinement. Not everyone with high LDL cholesterol is at high risk for heart disease or heart attacks. CAC scores can help differentiate and determine who may be more likely to benefit from treatment and who may not. Please keep in mind, pharmacotherapy, modern pharmacotherapy, at least first-line pharmacotherapy, comes with risks. Statins, for example, the frontline therapy for cholesterol lowering, can harm mitochondria and increase diabetes risk. These are accepted risks, and I'm not even saying it makes statins a bad tool per se. You'd use a chainsaw to fell a tree, but would you use it to open a bag of nuts? Probably not. So the question is, is your medical case a tree or a bag of nuts? That's a question for you to answer. Clearly, I'm a nutbag, but that's another matter. In fact, in the original paper we were discussing itself, it quotes from the American College of Cardiology American Heart Association cholesterol guidelines, a statement that says, "It is reasonable to use CAC score in the decision to withhold postpone, or initiate statin therapy. And it also reads, the decision to initiate or withhold statin therapy should also be guided by shared decision-making. That means patient-centered care—you, in a collaboration with your healthcare team, deciding on what's best for you. So should everyone with high LDL change their lifestyle or take a medication to lower it? These data show us that context matters. Medicine isn't one-size-fits-all, and we shouldn't treat lab numbers like they are the disease. The goal isn't just low cholesterol, nor is it cholesterol denialism. It's about context and making the point that the path to living a long, vibrant, heart-healthy life requires a better map than just LDL cholesterol, lower is better, and ApoB alone. I hope that was of value. I hope you thought this was nuanced and responsible. Stay curious, stay safe, stay thoughtful, and I hope you have a heart-healthy day.
