What Really Predicts Heart Disease?

Insights from the RRS16/RRS24 Models

For decades, we were taught one simple story about heart disease:

“LDL cholesterol is the cause. Lower it and you’re safe.”

But a growing body of research—and many patients’ real experiences—tell a more complex story.

Heart attacks occur in people with “normal” LDL. Others lower their LDL dramatically yet still face cardiovascular events.

A powerful new study published in JACC: Advances (2025) brings this point home with striking clarity. Researchers developed two new 10-year cardiovascular risk models—RRS16 and RRS24—using data from over 80,000 people with established heart disease.

These models were designed to identify who remains at residual risk of heart attack or cardiovascular death despite treatment.

And the results were surprising.

LDL cholesterol—the star of traditional cardiology—was not selected as a predictor in the final models.

Neither was lipoprotein(a).

Instead, the strongest predictors of heart risk were factors that reflect:

• Vitality and perceived health

• Nutritional and physiological reserve

• Chronic inflammation

• Metabolic stress

• Organ function

In short, your body’s resilience matters more than your cholesterol number—especially once heart disease already exists.

The Vitality–Nutrition–Metabolic Axis: A New Way to Understand Heart Risk

This new model aligns closely with the concept of Exposure-Related Malnutrition (ERM)—a framework that explains how chronic stress, inflammation, toxin burden, and metabolic strain drain the body's energetic and nutritional systems long before traditional lab results look “abnormal.”

Let’s explore how this plays out in the new ASCVD models.

1. Self-Rated Vitality: Your body knows before your labs do

One of the strongest predictors in the RRS24 model was a simple question:

“How would you rate your overall health?”

People who rated their health as poor had nearly double the risk of cardiovascular death.

Why?

Because subjective vitality is a real-time signal of:

• Mitochondrial energy production

• Immune system balance

• Recovery capacity

• Hormonal adaptation

• Chronic stress burden

Vitality is not just “how you feel”—it’s a window into your body’s bioenergetic state.

2. Nutritional Status: Beyond vitamins—an index of resilience

Traditional cardiology rarely talks about nutrition markers like:

• Albumin

• Lymphocyte percentage

• Vitamin D

• Total protein

Yet all these were selected by the algorithm as meaningful predictors.

Low albumin? It’s not just a “nutrition number.” It reflects:

• Inflammation

• Protein-energy undernutrition

• Impaired tissue repair

• Weakened antioxidant systems

Low lymphocytes? This suggests immune exhaustion.

Low vitamin D? A sign of chronic inflammation and poor metabolic signaling.

In ERM, these are markers of energy and substrate insufficiency—a weakening of the body’s ability to repair blood vessels, maintain healthy arteries, and resolve inflammation.

3. Metabolic Maladaptation: When energy systems break down

The models also highlighted markers of metabolic stress:

• Elevated glucose

• Elevated HbA1c

• Higher urea

• Chronic kidney strain

These reflect impaired metabolic flexibility—the body’s inability to switch between fuel sources, maintain stable blood sugar, or clear metabolic waste efficiently.

This is not “diabetes risk.” This is metabolic overload, a condition where cells simply cannot keep up with the energetic demands of repair and recovery.

ERM predicts these patterns long before a person develops overt diabetes or organ disease.

Why LDL Cholesterol Faded Out of the Picture

The RRS16 and RRS24 models outperformed traditional risk scores—including those used by the American Heart Association—and yet LDL cholesterol did not improve prediction.

This is not an accident.

Here’s why LDL loses power in modern risk models:

1. LDL is heavily treated in heart-disease patients, shrinking its variability.

2. LDL is not the primary driver of plaque instability—inflammation and metabolic stress are.

3. LDL predicts who gets heart disease, but not who dies from it once disease exists.

4. LDL does not reflect real-time physiology—it is a slow, structural marker, not a dynamic one.

This doesn’t mean LDL is irrelevant.

It means LDL is not the whole story—and never was.

Heart disease is not simply a lipid accumulation disorder. It is an energetic, inflammatory, and metabolic disorder affecting blood vessels, immune cells, and cellular repair systems.

Primary vs. Secondary Prevention: The Story Evolves

Primary Prevention (before heart disease)

LDL and Lp(a) matter more because they contribute to long-term plaque formation.

But even here, vitality, nutrition, and metabolic stability influence whether LDL becomes harmful.

Secondary Prevention (after heart disease develops)

The rules change.

The body’s repair capacity, immune balance, and metabolic health become far more important than LDL levels.

This is where the ERM–vitality–nutrition–metabolic axis outperforms cholesterol-focused thinking.

A More Human, More Accurate Way to Predict Heart Risk

The lesson from this new research is simple:

Heart disease is not just a cholesterol problem.It is a resilience problem.

Poor vitality, low nutritional reserve, chronic inflammation, and metabolic overload create a body that cannot repair vascular injury or resolve inflammation.

Meanwhile, a person with strong vitality, adequate nutrient status, low inflammation, and good metabolic flexibility is far more protected—even if their cholesterol is less than perfect.

This is why empowering lifestyle, restoring metabolic health, improving nutrient status, and reducing chronic stress may lower heart risk more effectively than focusing on LDL alone.

The Takeaway

This groundbreaking study shows us:

• ASCVD risk is multidimensional

• Vitality matters

• Nutritional status matters

• Metabolic resilience matters

• LDL is only one piece of a much bigger picture

And perhaps most importantly:

Your body is not a collection of numbers.It is an adaptive, energetic system trying to stay alive and repair itself.

Supporting that system—through nutrition, stress reduction, toxin avoidance, good sleep, movement, and metabolic balance—is one of the most powerful ways to protect the heart.

And that is exactly what modern research is finally beginning to acknowledge.

Mineeva, O., Li, C., Giulianini, F., Häfliger, S., Bubes, V., Raetsch, G., Mora, S., & Demler, O. V. (2025). Development and validation of novel residual risk scores for patients with ASCVD. JACC: Advances, 4(11), 102162. https://doi.org/10.1016/j.jacadv.2025.102162