Asymptomatic Isn't Absent — What the PESA Study Says About the Disease You Already Have

A while back, a patient came to see me. Middle-aged. Trim. Ran a five-K two or three times a week. The kind of person you would look at and assume was doing everything right. His cholesterol was mildly elevated — nothing dramatic. By every visible measure, he was healthy.

I recommended a coronary artery calcium score. Not because anything alarmed me. Because he was middle-aged, and the CAC is one of the best, most underused screening tools we have. He went and got it. The number came back at eight hundred twenty-eight. For some context — a score over four hundred is considered severe coronary calcification, in the highest risk category for cardiac events. He was at eight hundred twenty-eight. He didn't get a phone call asking him to follow up; he got a call telling him to see a cardiologist immediately. The cardiologist did further studies. He was in bypass surgery the following week.

Now, this is a man who, the week before that scan, had no symptoms. He didn't feel sick. His running was fine. His cholesterol was, as I said, mildly elevated. If he had walked into a primary care office and somebody had checked all the standard boxes — blood pressure, weight, basic lipid panel, asked him how he felt — he would have walked out the door labeled low risk. And he would have stayed labeled low risk right up until the day he had a heart attack. In my experience, low risk is rarely that simple.

What was actually happening in his coronaries had been happening for decades. The disease was advanced. It had built itself, plaque by plaque, in complete silence, while he was running five-Ks and feeling great.

That man's experience is not unusual. It's not a fluke. It's the rule. By the time most of the chronic diseases that kill us produce symptoms, those diseases have been present for years — often decades. Our body's ability to alarm us is a late-stage instrument. And if we wait for it, we are choosing to find out about the disease only when it has gotten big enough to do real damage.

What happened in that man's chest is what termites do to a house. They eat through the studs and the joists in complete silence. You don't hear them. You don't see them. The walls don't sag. The floors don't creak. And then one day a load-bearing beam gives way and you realize that the structural integrity of the place you've been living in has been gone for years.

Today we're talking about a study called PESA. The acronym stands for Progression of Early Subclinical Atherosclerosis. It is, in my view, one of the most important cardiovascular studies of the last twenty years, and it has changed the way I think about how we screen the people in front of us for vascular disease.

The reason it matters is this. PESA took more than four thousand asymptomatic middle-aged people who, by every clinical measure, looked fine — and it imaged them. Carotids. Femoral arteries. Aorta. Coronary calcium. And what they found is the kind of finding that ought to change how we practice medicine.

Symptoms are a late-stage instrument

I want to start with a basic observation about how human beings know they're sick. Our intrinsic ability to detect illness — what evolution gave us — is symptom perception. Pain. Fatigue. Shortness of breath. Chest pressure. These are extraordinarily useful for acute injury, for infection, for the kinds of fast-onset problems our ancestors had to survive.

They are useless for the chronic diseases that kill us now.

Look at the CDC's mortality data. The diseases that account for the bulk of American mortality are heart disease, cancer, accidents, chronic lung disease, stroke, Alzheimer's, and diabetes. With the obvious exception of accidents, these are slow diseases. They begin, in most cases, in your twenties or thirties or forties. They progress silently for years or decades. And only at the very end, when they have done enough damage to actually compromise the function of the affected organ, do they cross the threshold of perception.

By that point, the disease isn't starting. It's finishing. The plaque didn't just form — it's been there for thirty years. The cancer didn't just appear — it's been replicating for a long time. The brain wasn't fine yesterday — it just had enough reserve yesterday to compensate.

So our intrinsic detection system is built to catch the late stages, not the early ones. And if we wait for symptoms to tell us something is wrong, we are guaranteeing that the disease we eventually identify is far more advanced than it needed to be when we caught it.

That's the framing I want you to hold onto. The biological systems that drive our perception of being well are late-stage instruments. To catch chronic disease early, we need different instruments. Specifically, we need labs and imaging. This is not a hypothetical claim. It's what PESA demonstrated, in a cohort of more than four thousand people who all thought they were fine.

What PESA is, and what it found

PESA stands for Progression of Early Subclinical Atherosclerosis. The study runs out of the Centro Nacional de Investigaciones Cardiovasculares — the Spanish National Center for Cardiovascular Research, in Madrid — under the leadership of Dr. Valentín Fuster. It's an ongoing prospective cohort study examining the imaging, biological, and behavioral parameters associated with the presence and progression of early subclinical atherosclerosis.

Here's the design in plain English. Between 2010 and 2014, the researchers enrolled four thousand one hundred and eighty-four asymptomatic middle-aged adults — employees of Santander Bank in Madrid — between the ages of forty and fifty-four. Mean age at enrollment, forty-six. Thirty-seven percent women. They were healthy. They had no known cardiovascular disease, no cancer, no chronic kidney disease, no major comorbidity. By every traditional definition of healthy, they were healthy.

Every three years, those participants come back in for a study visit. They get a physical, blood and urine sampling, lifestyle and diet questionnaires, an ECG. And they get imaged. Two-dimensional and three-dimensional vascular ultrasound of the carotids, the femorals, and the aorta. CT for coronary calcium. A subset of about eight hundred gets additional advanced imaging — PET-MR — which lets the researchers see not just the structural presence of plaque, but inflammation in the vessel wall.

I want you to hold one thing in mind as I tell you what they found. These were asymptomatic adults.

At baseline, sixty-three percent of them had subclinical atherosclerosis. Plaque, somewhere, in at least one of the screened vascular territories.

Let me say that again, because it's the most important number here. Sixty-three percent of asymptomatic, middle-aged, working adults — average age forty-six — already had measurable atherosclerotic disease.

In men, that number was seventy-one percent. In women, it was forty-eight percent. The disease was most prevalent in the femoral arteries — forty-four percent of participants had femoral plaque. The carotids were next at thirty-one percent. The aorta at twenty-five percent. Coronary calcium was actually one of the less sensitive markers — only eighteen percent of the cohort had any detectable coronary calcium at all.

And here's the thing about a calcium score of zero. It is not the all-clear it's often treated as. About sixty percent of the PESA participants whose CAC was zero had plaque somewhere else. The coronary tree calcifies relatively late in the disease process. By the time you have CAC, you have advanced disease. The absence of CAC tells you about the coronaries — it does not tell you about the carotids, or the femorals, or the aorta.

So that's the first finding. Sixty-three percent disease prevalence in a population that, by self-report and by clinical exam, would have looked completely healthy. That alone reorients your sense of what middle age actually looks like under the hood.

The risk-factor problem

Now here's the part that I think is the most important conceptual contribution of the entire PESA study. It's the part I want you to take with you into every conversation about cardiovascular risk you ever have, for the rest of your life.

Of the PESA participants who were classified as low risk by traditional risk scores — the kinds of scores your doctor uses, like the Framingham Risk Score — sixty percent of them had subclinical atherosclerosis. And not just a little. More than forty percent of those low-risk individuals had generalized disease — disease in four or more vascular territories.

Sixty percent of the people we would have told to come back in five years had the disease. Forty percent of the people we would have told to come back in five years had it everywhere.

Why does this happen? Because of what traditional risk scores actually are. They are statistical instruments built from large populations, calibrated to estimate, on average, the ten-year risk of an event for a person with a given combination of measurable variables. Age. Sex. Blood pressure. Smoking status. Total cholesterol. HDL. They are useful at the population level. They are notoriously poor at the individual level.

But here's the deeper problem. Even if a risk score perfectly weighted the variables it includes, it can only weight the variables it includes. We measure what we know to measure. There are almost certainly determinants of vascular disease that we have not yet identified — genetic, metabolic, environmental, microbial — and any risk score we have today is, by definition, blind to all of them. So when we tell a patient "you are low risk," what we are actually telling them is "the things we currently know to look for are not present in concerning quantities." That is a profoundly different statement than "you do not have the disease."

There are two things I want you to take from the PESA investigators' own conclusions.

The first is the continuum point. There is no LDL above which atherosclerosis starts and below which it doesn't. There is a dose-response. PESA actually quantified this. Every ten milligram per deciliter increase in LDL cholesterol was associated with about an eighteen percent higher odds of having multi-territorial atherosclerosis. There was no threshold. The relationship was linear. And when they looked at the lowest end of the range to ask how low LDL has to be before atherosclerosis stops developing, the answer was striking. In both men and women, the concentration above which atherosclerosis began to develop was roughly fifty to sixty milligrams per deciliter — dramatically lower than the treatment targets most patients in this country are being held to.

The second is what I'll call the epistemic point. A traditional risk score is a measurement instrument, not a description of reality. It can be a perfectly good instrument and still miss the disease — because the instrument is built from the variables we happened to know about when we built it. The runner from the beginning of this article — the one with the mildly elevated cholesterol and the very high calcium score — would have come out of any standard risk calculation looking fine. The risk calculation was correctly applied. The risk calculation was missing a leg of the table.

Risk factors are useful. The absence of risk factors is not the absence of disease.

What to do about it

So if symptoms are a late-stage instrument, and risk scores are an incomplete instrument, what do we have? We have direct observation. We have labs that go deeper than the panels most people are getting. And we have imaging.

I want to be careful here. I don't want this to slide into "everybody go get every scan." That's not the position. The position is that there are a small number of high-yield, low-risk, increasingly affordable tests that can take you out of the realm of risk estimation and into the realm of direct observation of your own vascular tree. And in the right person — particularly in middle age — those tests are some of the highest-ROI things you can do for your long-term health. I'll mention three.

The coronary artery calcium score (CAC) is the test that found the man in our opening. It is a non-contrast CT scan of the chest. It takes about ten minutes. It involves a small amount of radiation, roughly equivalent to a mammogram. In most parts of the country it costs somewhere between one hundred and a few hundred dollars. And it gives you a number that quantifies the amount of calcified plaque in your coronary arteries. A score of zero is meaningful in your fifties or sixties — it tells you you do not have advanced coronary disease today — but it does not tell you that you don't have plaque elsewhere. A score above zero in your forties is not nothing. It means the disease is already there.

Carotid intima-media thickness (CIMT) and three-D vascular ultrasound of the carotids is even more sensitive at the early end. The carotid is where PESA found thirty-one percent of its participants had plaque. Ultrasound is non-invasive, no radiation, and in experienced hands it picks up the disease earlier than CT does. It is, in my opinion, underused.

And then there are the labs. ApoB. Lipoprotein(a). Fasting insulin and a hemoglobin A1c. A high-sensitivity CRP. The standard lipid panel — total cholesterol, LDL, HDL, triglycerides — is the absolute floor of what we should be looking at, not the ceiling. ApoB in particular gives you a count of the actual atherogenic particles, which is what the disease cares about. The standard lipid panel measures the cholesterol cargo those particles are carrying, which is not the same thing.

The point I want to make is narrow. We have the tools. They are not exotic. They are not expensive, by the standards of how much we spend in this country on healthcare. They are not invasive. And for the population PESA studied — middle-aged adults — they are far more informative than waiting another decade for symptoms to develop.

Key takeaways

• Symptoms are a late-stage instrument. By the time chronic disease produces symptoms, it has been present for years or decades. Do not wait to feel sick — the diseases that will kill you do not announce themselves in time for you to do anything about them.
• The absence of measured risk factors is not the absence of risk. It is the absence of measurement. A traditional risk score can only weight the variables it includes. PESA found advanced disease in sixty percent of its "low-risk" participants.
• Use the tools. A coronary calcium score, a carotid ultrasound, an ApoB level, a fasting insulin — these take you out of the realm of risk estimation and into directly observing your own biology. In middle age, that shift is one of the highest-leverage things you can do for your long-term health.