Cardiovascular disease: inflammation, not just cholesterol

Cardiovascular disease remains the leading cause of death worldwide. Yet the way it is detected, treated, and prevented in most medical offices does not reflect what science has learned over the past 20 years. This compilation of conversations with Drs. Cindy Guyire, Eric Topol, and Aseem Malhotra summarizes where we are and where cardiology is heading.

The incomplete story we have been told

For decades, LDL cholesterol has been the protagonist of the heart disease narrative. If LDL was high, the solution was a statin. If the statin failed, the solution was a more potent statin. Everything else, diet, stress, sleep, glucose, weight, took a back seat.

The problem is that fewer than 3% of the US population meets the four basic criteria for low cardiovascular risk: not smoking, performing at least 150 minutes of moderate exercise per week, eating primarily whole foods, and maintaining a healthy body fat percentage. Only 12.2% of Americans are metabolically healthy by standard criteria.

Inflammation as the root cause

A paper published in the New England Journal of Medicine over 20 years ago by cardiologists Peter Libby and Paul Ridker established that cardiovascular disease is primarily an inflammatory process. Cholesterol does not act alone: without an inflammatory environment, LDL particles are far less capable of oxidizing and penetrating the arterial wall.

The causes of that low-grade chronic inflammation are largely preventable:

• Insulin resistance and elevated blood glucose (even within what is considered the normal range)
• Chronic stress and excess cortisol
• Loneliness and social isolation
• Insufficient or poor-quality sleep
• Sedentary behavior
• Trans fats and refined oils

What is not the primary cause: saturated fat alone. Cardiologist Aseem Malhotra published in the BMJ in 2013 that there is no clear association between saturated fat consumption and heart disease when triglycerides and HDL are controlled.

The role of insulin and metabolic health

Two out of three people with normal weight are metabolically unhealthy. This means that even without visible obesity there can be hyperinsulinemia, elevated fasting glucose, and peripheral insulin resistance that fuel arterial inflammation.

The problem is that most physicians measure fasting glucose and HbA1c, but not fasting insulin or the insulin response to a glucose load. A patient can have perfect blood glucose while producing five times the normal insulin to maintain it, signaling that the pancreas is compensating for advanced resistance.

Fasting insulin should be below 5 mIU/L. Postprandial insulin (after an oral glucose load) should remain below 25-30 mIU/L. When those values rise well before blood glucose changes, there is already significant metabolic and cardiovascular risk.

Diagnostic tests that change the picture

The standard cholesterol panel calculates LDL using a formula that does not measure particles directly and does not distinguish between LDL pattern A (large, buoyant particles, less atherogenic) and LDL pattern B (small, dense particles, highly atherogenic).

Tests that provide more information:

• NMR lipoprotein profile (LDL and HDL particle number and size)
• Fasting insulin and insulin response to an oral glucose load
• Apolipoprotein B (ApoB) and lipoprotein(a) or Lp(a)
• High-sensitivity C-reactive protein (hs-CRP)
• Polygenic cardiovascular risk score
• AI retinal scan (predicts cardiac risk years in advance)
• CT angiography with AI-based pericoronary inflammation analysis (in development)

Statins: what they do and what they don't do

Statins work partly through anti-inflammatory and antithrombotic effects, not just by reducing LDL. Paul Ridker's JUPITER trial showed that patients with high LDL but no inflammation (low CRP) had far lower risk than those who combined high LDL with elevated inflammation.

Side effects include an increased risk of type 2 diabetes (1-2% per year, more pronounced with potent statins) and possible mitochondrial damage in muscle biopsies. Alternative options include PCSK9 inhibitors (injectable, without the diabetes risk) and emerging drugs targeting Lp(a), which will arrive in the coming years.

Prevention: the weight of lifestyle

80% of cases of heart disease and type 2 diabetes could be prevented with proper diet and lifestyle. Practicing the basic habits (regular exercise, a whole-foods-based diet, stress management, and adequate sleep) can add 7 to 10 years of active cardiovascular health.

Conclusion

Cardiovascular disease is not primarily a plumbing problem with too much cholesterol in the pipes. It is a chronic inflammatory process rooted in insulin resistance, stress, sleep, and diet. Detecting it earlier requires tests that most physicians do not routinely order. And preventing it remains within reach of lifestyle habits, not pills.