I have had a heart attack or a stroke and my cholesterol was normal. How is that possible?

That does not mean cholesterol is innocent.

Current evidence clearly demonstrates that prolonged exposure to ApoB-containing atherogenic particles, especially LDL, plays a causal role in the development of atherosclerosis.

But it also does not mean that every heart attack can be explained by looking at LDL alone.

First we need to review the major risk factors

When a person suffers a heart attack or a stroke, we must reconstruct their complete cardiovascular risk profile.

Do they smoke? Do they have hypertension? Diabetes or insulin resistance? Kidney disease? Abdominal obesity? A family history of premature cardiovascular disease? What are their triglyceride levels? Do they engage in physical activity? Do they use cocaine or other stimulants?

All of these factors can enormously modify risk.

Cocaine use deserves special mention because it can cause coronary vasoconstriction, raise blood pressure and heart rate, and promote thrombotic events, even triggering a heart attack in young people.

What about stress?

Chronic stress is also part of the cardiovascular equation.

It can be associated with poorer sleep, hypertension, metabolic disturbances and less healthy behaviours, in addition to activating various neuroendocrine systems.

But we must avoid reducing everything to 'high cortisol.' Cardiovascular stress is a far more complex phenomenon, and we cannot diagnose hypercoagulability simply because a person leads a stressful life.

1. Lipoprotein(a): one of the first things I want to know

Here we encounter one of the great unknowns in many conventional blood panels.

Lipoprotein(a), or Lp(a), is a particle determined primarily by our genetics and constitutes a causal, independent risk factor for atherosclerotic cardiovascular disease.

You can eat well. You can exercise. You can be slim. You can be a non-smoker. And still have a very high Lp(a).

Current recommendations consider ≥50 mg/dL —approximately ≥125 nmol/L— a level that increases cardiovascular risk. And the higher the concentration, the greater the potential risk.

Furthermore, there is an important peculiarity: lifestyle modifies Lp(a) concentration relatively little.

That does not mean that if you have elevated Lp(a) you are doomed to have a heart attack. It means we must be especially rigorous about controlling all modifiable risk factors and, in particular, reducing the burden of other atherogenic particles.

That is why I currently recommend measuring Lp(a) at least once in adult life.

2. ApoB: perhaps your LDL was not telling the whole story

I find this measurement particularly interesting.

LDL-C tells us approximately how much cholesterol the LDL particles are carrying. ApoB, on the other hand, helps us estimate how many atherogenic particles are circulating.

And the two do not always coincide. You may be carrying a given amount of cholesterol distributed across many relatively small atherogenic particles.

In certain people with diabetes, metabolic syndrome, or elevated triglycerides, this discordance can cause conventional LDL-C to underestimate part of the risk.

That is why, after an apparently inexplicable cardiovascular event, ApoB can provide very valuable additional information.

3. Homocysteine: interesting, but it must be interpreted correctly

Elevated homocysteine may be associated with greater vascular risk, but we must be careful with interpretation.

It can rise for different reasons: folate or vitamin B12 deficiency, kidney disease, certain medications, genetic factors, and other circumstances.

If it is elevated, we must look for the cause. And if a B12 or folate deficiency exists, we naturally need to correct it.

But there is a fundamental difference between lowering a number on a blood test and demonstrating that we are actually preventing heart attacks.

That is why I do not recommend indiscriminately taking large amounts of B vitamins simply because homocysteine is slightly elevated. First we need to understand why it is elevated.

4. Should we study coagulation?

In certain people, yes. But not in everyone.

Hereditary deficiencies of antithrombin, protein C and protein S, as well as factor V Leiden and certain prothrombin variants, are primarily associated with an increased risk of venous thrombosis.

That is why it makes no sense to automatically request the full thrombophilia panel for any person who has suffered an arterial myocardial infarction.

It may be indicated in selected situations: young patients, personal or family history of thrombosis, recurrent episodes, or thrombosis in unusual locations.

It is the clinical history that determines what we should be looking for.

5. Antiphospholipid syndrome

Here we encounter a different situation.

Antiphospholipid syndrome is an autoimmune disease that can cause both venous and arterial thrombosis.

It can present as thrombosis, certain cerebrovascular events, and obstetric complications, among other situations.

For this reason, in the face of an arterial thrombotic event in a young person with no obvious explanation, the physician may consider it appropriate to test for antiphospholipid antibodies.

But this should not become an indiscriminate blood test ordered for the entire population either.

A heart attack does not always mean an artery full of cholesterol

This point is especially important. Not all heart attacks share exactly the same mechanism.

There is the classic atherothrombotic infarction caused by the rupture or erosion of a plaque.

But we can also find: coronary spasm; spontaneous dissection of a coronary artery; coronary embolism; cocaine or other stimulant use; significant coagulation disorders; and situations of extreme imbalance between oxygen demand and oxygen supply to the heart.

There is even the concept of MINOCA — myocardial infarction with non-obstructive coronary arteries — which requires investigating different mechanisms.

That is why a young patient who has suffered a heart attack without the usual risk factors deserves a particularly thorough investigation.

And something similar happens with stroke.

'Stroke' does not describe a single disease either.

Atherosclerosis, atrial fibrillation and cardiac embolism, small vessel disease, arterial dissection, coagulation disorders, and other causes may all be involved.

Therefore, after an unexplained stroke, looking at cholesterol alone is not enough. We must determine which mechanism caused that stroke.

So, what blood tests would you order?

There is no universal panel of 'five hidden tests' that applies to every patient. That would mean oversimplifying medicine all over again.

In a person with premature or apparently unexplained cardiovascular disease, I am particularly interested in reviewing: a full lipid profile, Lp(a), ApoB when indicated, blood glucose and HbA1c, kidney function, blood pressure, family history, and all conventional risk factors.

After that, depending on the clinical history, we can expand the workup to include homocysteine, specific coagulation tests, antiphospholipid antibodies, genetic studies, or targeted cardiovascular investigations.

My final message.

If you have suffered a heart attack or a stroke and someone tells you: 'That's impossible — your cholesterol was normal,' that conclusion is incorrect.

But it would be equally wrong to say: 'Since my cholesterol was normal, LDL doesn't matter at all.' Contemporary cardiovascular medicine sits precisely between those two extremes.

LDL matters. ApoB matters. Lp(a) matters. Blood pressure matters. Smoking matters enormously. Diabetes matters. Genetics matters. Coagulation can matter in certain patients.

And, above all, what matters is discovering which mechanism caused the event in that specific individual.

Because after a heart attack or a stroke, our goal should not be to quickly find someone to blame. Our goal is to understand the mechanism in order to prevent it from happening again. That is personalised medicine.