~2× total plaque volume, 5 yrs | 112 mean baseline LDL (mg/dL) | 54% had a calcium score of zero |
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| Clinical Takeaway | | Domain | Key Finding | Evidence Level | | Cohort & design | 205 adults; mean age ~55; mean baseline LDL ~112 mg/dL; 54% with CAC = 0. Two serial CCTAs (median ~5 yr apart), AI-QCT quantified, with no lipid-lowering therapy between scans and no diabetes, FH, or CKD — an untreated natural-history cohort. | Context | | Progression | Total plaque volume roughly doubled (median ~30 → ~59 mm³; +6.7 mm³/yr). Percent atheroma volume rose ~0.17%/yr. | Observational | | Composition | Growth was overwhelmingly non-calcified (+4.9 mm³/yr) vs. calcified (+0.4 mm³/yr); low-attenuation (lipid-rich) plaque prevalence rose from 9% to 23%. | Observational | | Risk distribution | Most progressed gradually rather than explosively: ~11% met an intermediate-progression threshold (PAV ≥0.59%/yr) and ~3% qualified as rapid progressors (PAV ≥1%/yr). | Observational | | CAC = 0 | A zero score is reassuring for short-term risk but does not signal absence of plaque or of progression; among the rescanned subset, the share with a zero fell from 41% to 31%. | Observational | | Limitations | Retrospective, single-region, two-center; small and homogeneous (72% White men); no randomized treatment arm and no adjudicated clinical outcomes. Describes natural history, not the effect of an intervention. | Caveat | | My take | Consistent with the causal, cumulative-exposure model of LDL — supports starting LDL-lowering earlier and aiming lower, not waiting for calcium, symptoms, or events. | Opinion |
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Most patients ask me for a coronary calcium score because they want a number that gives them permission to do nothing. A zero feels like a clean bill of health — proof the arteries are quiet, the future is far away, and the statin conversation can wait. |
I understand the appeal. I also think it is one of the most consequential misreadings in preventive cardiology. A study published this month gave me the cleanest illustration of why I have seen in years. |
A study built around an absence |
NATURE-CT, in the Journal of Cardiovascular Computed Tomography, is unusual because of what it deliberately left out. The investigators identified 205 adults from two Los Angeles imaging centers who each had two clinically indicated coronary CT angiograms at least two years apart, a baseline calcium score of 100 or less, and no heart attack or revascularization in between. The defining feature: no lipid-lowering therapy of any kind between scans — no statin, no ezetimibe, no PCSK9 inhibitor, nothing. They excluded diabetes, familial hypercholesterolemia, and chronic kidney disease. |
What that design produces is something we almost never get to see ethically: untreated atherosclerosis, measured serially, in people who look low-risk on paper. A natural-history cohort. The closest thing to the control arm we are not allowed to randomize. |
And the population was reassuring by every conventional metric. Mean age 55. Mean baseline LDL of 112 mg/dL — a number most clinicians would not blink at. Over half had a calcium score of zero. These are exactly the patients who walk out of the office relieved. |
What five years of doing nothing looked like |
Over a median of roughly five years, total plaque volume essentially doubled — from a median of about 30 mm³ to 59 mm³, an annualized increase near 6.7 mm³ per year. The growth was overwhelmingly non-calcified: soft plaque climbed about 4.9 mm³ per year while calcified plaque crept up just 0.4. And low-attenuation plaque — the lipid-rich, inflamed tissue most tightly linked to events — was present in 9% at baseline and 23% at follow-up. |
To put that rate in context: in statin-treated cohorts imaged the same way, total plaque tends to climb far more slowly, and the dangerous non-calcified fraction often stalls or shrinks even as calcium rises. Here, untreated, both kept climbing. That is the comparison worth holding in mind — not whether 59 mm³ is a frightening number in isolation, but the direction and pace of travel when nothing is done. |
This was not a story of a few outliers dragging the average. Most of the cohort progressed gradually rather than explosively — only about 3% qualified as rapid progressors by the usual percent-atheroma-volume threshold, and roughly 11% crossed an intermediate one. The point is the baseline: in an untreated, low-risk group, the default direction of travel was forward, not flat. |
By the Numbers | Median annualized change — mm³/yr | +6.7 Total plaque
volume | +4.9 Non-calcified
plaque | +0.4 Calcified
plaque | +0.17% Percent atheroma
volume |
| | Prevalence — baseline → follow-up | 9% → 23% Low-attenuation plaque present | 41% → 31% CAC = 0 (rescanned subset) |
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Read that last line again. Among the subjects who were rescanned with a calcium image, the share with a score of zero fell from 41% to 31%. The zeros were converting. The reassurance had an expiration date. |
Why a zero isn’t a clean bill of health |
This is the part I want every patient who has ever clutched a zero to understand. A calcium score of zero is a genuinely good prognostic sign for your short-term risk. It is not a statement that your arteries are clean, and it is emphatically not a promise that nothing is happening. |
Calcium is the scar tissue of atherosclerosis — the healed, stabilized end-stage of a process that begins as soft, non-calcified plaque years or even decades earlier. A calcium scan measures the smoke after part of the fire has already burned out. It is structurally blind to the very thing growing fastest in this cohort. NATURE-CT makes the invisible visible: the plaque these people were accumulating was precisely the kind a calcium score cannot see. |
Why I treat LDL early — and low |
Here is where I will be direct about my own practice, because the whole point of this newsletter is signal over hedging. I treat LDL early, and I treat it aggressively — earlier and lower than a literal reading of any single risk calculator would demand. NATURE-CT is a clean illustration of the logic behind that bias. |
The causal LDL hypothesis is not a hypothesis anymore — the link is one of the most thoroughly established causal chains in all of medicine, consistent across Mendelian randomization, the full arc of statin and non-statin outcome trials, and the dose-response biology. The operative variable is not your LDL on a single morning. It is cumulative LDL exposure: the area under the curve of every mg/dL-yr your arteries have absorbed since birth. |
An LDL of 112 is not a number that does nothing. It is a number that does a little damage, quietly, every day, for decades. NATURE-CT is what that arithmetic looks like rendered in plaque: 205 untreated people with an “acceptable” LDL and a disease that marched forward anyway. |
Lowering LDL does not stop time. It changes the slope. Every year spent at 70 instead of 112 is a year of slower accumulation — and because exposure is cumulative, the years you buy early are worth more than the years you buy after the first event. That is why I do not wait for a calcium score to climb, for symptoms to appear, or for a patient to cross a threshold before I start the conversation. By the time the calcium shows up, the soft plaque that drives events has already been building — exactly as this study documents. |
What the study can’t tell us |
I want to be careful not to let NATURE-CT carry more than it weighs. This is a retrospective, observational study. There was no treatment arm — nobody was randomized to a statin — so it cannot tell us that lowering LDL in these specific patients would have flattened their curves. The cohort was small and strikingly homogeneous (72% White men), drawn from two centers in one city, with no adjudicated clinical outcomes. Undocumented therapy cannot be fully excluded. These are real constraints, and they make this a description of natural history, not a trial of intervention. |
But that is also what makes it useful. We already have an enormous body of interventional evidence that lowering LDL slows, halts, or reverses plaque and reduces events. What we rarely get is a clean look at the untreated counterfactual. NATURE-CT supplies that side of the equation: this is the trajectory therapy is working against. |
There is one statistic I think about constantly. In a large registry of first ST-elevation heart attacks, roughly 15% of patients had no standard modifiable risk factors at all, and nearly half had only one. The plaque did not care that they looked clean. It had been building silently — the way it built silently in NATURE-CT. |
Speculation · Extrapolation beyond the data A treated counterfactual NATURE-CT has no treated arm, so the honest way to read it is against what treatment does to the very same measurements. In statin-treated serial-CCTA cohorts, total plaque climbs more slowly than it did here; the non-calcified and high-risk components — exactly the substrate that drove this cohort’s growth — tend to stall or regress; and the calcium that remains shifts toward a denser, more stable form. That is the trajectory these untreated curves were running against. I’ll keep the claim modest, because the comparison isn’t randomized and the populations differ. NATURE-CT cannot tell us that treating these particular patients would have flattened their curves. But the direction isn’t much in doubt: every treated cohort bends the opposite way from the five untreated years documented here — and the same way the outcome trials already established. That convergence, natural history pushing one way and therapy pushing the other, is the whole argument. |
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The bottom line |
The clean takeaway, for me, is small and stubborn: “low-risk” is a statement about probability, not about biology. The biology, as NATURE-CT shows, keeps moving regardless. A zero calcium score and a middling LDL bought these patients nothing but the illusion of time. |
I would rather treat the slope than admire the snapshot. |
| The author is Chief Medical Officer of Vineyard, a telehealth obesity medicine practice. If early, evidence-based metabolic and cardiovascular prevention is the kind of care you want to be part of, you can learn more about Vineyard here. |
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REFERENCES |
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