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For the 4 decades that I’ve been a cardiologist, we’ve been obsessed with obstructive, blood flow-limiting narrowings and blockages in the coronary arteries, and using procedures like stenting and bypass surgery to fix them. This year we’ve gotten signals that a major shift is ongoing, from fixation on obstructive coronary artery disease (simply put “blockages”) to the focus on non-obstructive arterial disease (simply put “atheroma”), as visualized non-invasively to be high-risk, so-called vulnerable atherosclerotic plaque, and/or exhibiting inflammation (Figure below). This Ground Truths edition will take you through the evolution of the thinking and capabilities, with new non-invasive A.I. imaging, and new drugs, that may ultimately lead to a major reduction in heart attacks.
The dream of eradicating heart attacks was articulated in 1996 in a Science editorial entitled: ”Heart Attacks: Gone with the Century?” It was written by Michael Brown and Joseph Goldstein, awarded the Nobel Prize in 1985 for their groundbreaking cholesterol metabolism work that led to statins. Although statins have helped reduce the risk of heart attack, we still have over 800,000 each year in the United States, which is similar to the data spanning 2012 to 2022, and heart disease remains the number 1 killer despite a marked reduction in death rates over the past 2 decades. Even with 1 in 4 Americans taking statins now, it’s clear we’re far away from their disappearance. One prescient note in the Science editorial was “The challenge is to develop noninvasive screening methods to detect coronary atherosclerosis in its earliest stages.”
We’ve long known that it takes decades for atherosclerotic plaque to develop, as visualized to be prevalent (albeit not obstructive, i.e severe narrowing, blood flow-liming) at significant frequency in teenagers and young adults (Figure). Yes, it’s an age-related disease, but it typically starts very young.
The pathology studies from post-mortem studies have provided clearcut features of arteries in heart attack victims. Chief among them is the thin fibrous cap of the atheroma (TCFA) plaque (Figure) which leaves it prone to erosion, cracking or rupture, the immediate event (usually accompanied by a blood clot) that precedes a heart attack. A lipid-rich necrotic plaque (dead cells, cellular debris, cholesterol and other lipids) is typically underneath the thin cap, and inside the plaque there is inflammation with accumulation of macrophages and T cells. Unlike stable plaque, the vulnerable plaque does not contain dense calcification. (This one of the reasons I have never ordered a CT calcium score for any patient since they are often highly misleading). The minimal lumen area (MLA, channel for blood) is reduced. The artery can enlarge outwardly, known as positive remodeling, to compensate for accumulation of plaque.
But until there were ways to image inside the coronary artery, we relied on angiograms, a 2-dimensional silhouette of the lumen—the channel through which the blood flows. The 1995 paper I co-authored entitled “Our Preoccupation With Coronary Luminology” reviewed the serious problems and limitations of relying on angiograms. That was near the time when intracoronary imaging was receiving increasing attention for illuminating what was going on inside the artery wall, not just in the lumen. Both intravascular ultrasound (IVUS, middle images below) and optical coherence tomography (OCT) (left images below) provide exquisite images from within the artery, that is they require a catheter to be inserted into the artery being assessed, thus considered a form of invasive imaging.
From intracoronary imaging we learned the natural history of atheroma progression. As seen below from a prospective study of nearly 700 patients, subsequent major cardiovascular events during 3.4 years of follow-up were mostly in atheroma that were mild by angiogram (non-obstructive) but by IVUS had thin-cap fibroatheroma (TCFA), high plaque burden (PB) or small luminal area (MLA). Features that would not be picked up by an angiogram.
So now that we could identify these high-risk atheroma—vulnerable plaques—there was thought they might be stabilized or “sealed” with ballon angioplasty. Bernhard Meier advanced this idea, as did an insightful perspective by Kern and Meier.
That concept hung is suspension, unproven, for a number of years until a recent randomized trial was conducted in South Korea, Japan, Taiwan and New Zealand of plaque sealing known as PREVENT, demonstrating for the first time that intervention of vulnerable plaque (determined by IVUS) with optimal medical therapy led to reduced major events compared with optimal medical therapy alone (Figure). The study concluded “These findings support an expansion of the indications for percutaneous coronary intervention to include non-flow-limiting, high-risk, vulnerable plaques.”
In June 2024, here at Ground Truths, I wrote about the Big Miss: Inflammation and Cardiovascular Disease emphasizing the need to detect arterial inflammation and acknowledge the importance, redirecting our attention to non-obstructive coronary disease. In April 2025, The Lancet Commission, Rethinking Coronary Artery Disease: moving from ischemia to atheroma” highlighted the opportunity to save 8.7 million lives per year globally by focusing on early detection of atheroma (Cover of that issue below).
More recently, in September 2025, the American College of Cardiology published a scientific statement on inflammation and cardiovascular disease. A key conclusion:
“The time is also ripe for the development of strategies to promote increased physician awareness of the crucial role of inflammation in CVD and accelerate the adoption of evidence-based, guideline-directed anti-inflammatory therapy through dissemination and implementation research.”
Taken together, these recent papers are indicative of the shift of thinking and embracement of the need to detect vulnerable, inflamed, high-risk plaque if we are going to make further progress for avoiding heart attacks and cardiovascular deaths.
Detection of the high-risk atheroma has been made possible without a catheter placed into the artery using CT imaging with an injection of contrast dye (angiography), known as CCTA (for coronary computed tomography angiography) There are 4 companies that have used A.I. of the images obtained to identify high-risk, non-obstructive plaque. I’ve made this Table below to summarize what each company does, since they are quite different. CLEERLY, which as a tag line on its website “Creating A World Without Heart Attacks,” detects plaque features with the ground truths (reference markers) shown below, and has a clinical validation study to link their detection to events. ELUCID focuses on plaque composition, using histology as the reference marker, but has no clinical event validation. HEARTFLOW uses fluid dynamics and 3D plaque reconstruction and has published a paper for clinical event validation. CARISTO, which is pending but not yet FDA-cleared (the other 3 are), uses the fat attenuation index (FAI), the peri-vascular fat tissue when by histologic study to be rich indicative of inflammation and rich in T cells (see also Top Figure of this post). This is the only technology that has thus far been linked to cardiac mortality.
Below are data from 40,000 consecutive patients with CCTA in 8 centers in the UK with up to 10 year follow-up using the CARISTO FAI. Even 1 inflamed artery raised the risk of death 13-fold compared with no inflamed arteries! Take a look a the paper for data partitioning obstructive and non-obstructive lesions, inflamed or non-inflamed.
Last week it was announced that Medicare will reimburse for the FDA-cleared non-invasive coronary imaging A.I. companies more than $1,000 per scan. Another sign of a big shift.
Besides the new non-invasive image algorithms, last week’s American Heart Association presentations were noteworthy for many new drugs emerging for treating abnormal lipids and preventing progression of atherosclerosis. This Wall Street Journal article below provided a useful summary. The toolkit is rapidly expanding with the anticipated introduction of potent oral PCSK9 blockers, Lp(a) inhibitors, more ANGPTL3 blockers, along with anti-inflammatory drugs such as different interleukin blockers and the possibility of using GLP-1 drugs for this purpose. GLP-1 drugs have already been shown to reduce heart attacks in people with obesity and we recently learned that only about a third of the benefit was weight-loss dependent.
We’ve gone from the miscue of statins ending heart attacks to now A.I. purportedly “creating a world without heart attacks.” The problem, once again (besides exuberance), is that there is far too much fixation on just the atheroma, the vulnerable plaque, instead of on the high-risk patient. We have far better ways to identify vulnerable patients and we’re not doing it. I wrote extensively in SUPER AGERS about the many missed opportunities to do this, such as polygenic risk scores (PRS) for coronary artery disease. They are the most extensively validated of all PRS common diseases, available from more than 10 companies, getting initial uptake in some health systems, but have not reached general use. The value of PRS for assessing risk is independent of family history or risk factors of diabetes, smoking, hypertension, high cholesterol, sedentary behavior, or obesity. We don’t generally measure blood inflammation markers such as high-sensitivity C-reactive protein, and have no assay for clonal hematopoiesis of indeterminate potential (CHIP) even though they CHIP is clearly linked with risk of cardiovascular disease. The protein organ clocks that quantify the pace of aging a person’s arteries and heart are prime candidates to add to the way of finding high-risk individuals. A retina photo or OCT, easy and inexpensive to obtain during an eye exam, can be used with A.I. interpretation to detect subclinical coronary artery atherosclerosis (figure below), or predict heart attacks. The latter report concluded: “Our results indicate that one could identify patients at high risk of future myocardial infarction from retinal imaging available in every optician and eye clinic.” Importantly, each layer of data about heart risk can be corroborated and integrated with the other layers.
In a recent Ground Truths I reviewed the Delphi2m large health model which predicted over 1,200 diseases and health events at the individual level for the next 20 years, not just what events but when. That was just from the electronic health record without the other layers of data I allude to here, and with a GPT-2 model with very low parameters compared to current models.
The accurate and comprehensive identification of high-risk individuals needs to be inexpensive, so it can be applied globally. The cost of obtaining and interpreting a person’s data for their genomics, proteins, biomarkers and eye grounds could be extremely low.
I do think there is a highly promising way forward to markedly reduce heart attacks. Even with new reimbursement, we cannot do CCTA and A.I. in most people, no less on a serial basis. But by accurately determining who are the individuals at high-risk—with multiple layers of data— genes, proteins, inflammation markers, imaging—the way to get ahead of their progression of atherosclerotic disease has never been more impressive. And an expansive array of drugs adds to the mix. Medications not just to address high LDL cholesterol but also Lp(a), for which we’ve never had a drug, and ways to suppress arterial inflammation that is not just mediated by abnormal lipids. While we’ve recently seen a big shift in thinking, we have no indication of any shift in action. That’s highly warranted. That’s what we need.
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Engineering Cairn, UBC (December 3, 2025)
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