Predicting the Future – CRP, Inflammation and Heart Attacks

Anil Kumar, PhD
Jun 24 2020 00:00

Background

Just outside Boston, MA, the small town of Framingham resembles any other suburban community. However, it happens to be the town with one of the longest experiment in healthcare.

In 1948, after President Franklin Roosevelt succumbed to his off-the-charts blood pressure, a new National Institute of Heart Health was setup. Cardiologists from Harvard and across US started monitoring a cohort of volunteers in Framingham to unravel the mysteries of heart health.

After 70 years and three generations of volunteers, we now conclusively know that age, smoking, diabetes, blood pressure, total cholesterol, HDL cholesterol, and BMI (weight relative to height) are key contributors to heart disease.

Based on these findings, we can now get a single number—called Framingham Risk Score —to predict the risk of heart disease in next 10-years or even 30-years.

Why do we need to care so much about just one disease? Because heart disease is the number one cause of death today: one in three deaths relates to heart.

Beyond Risk Score of Heart Health

Focus has now moved beyond these factors. One of them is the role of genetics. At the beginning of this millennium, Framingham Heart Study has pushed towards understanding the role of genetic contributions to heart disease.

Around the same time, C-reactive protein has appeared as another important markers for predicting future heart disease. It is especially useful to predict low level of inflammation observed at the early stage of atherosclerosis—the slow built of plaque in arteries—that later results in stroke and heart attacks.

Paul Ridker, of Brigham and Women’s Hospital in Boston, was the first researcher to demonstrate how a simple blood test for CRP can be useful in predicting future heart attacks. He calls it “the thermometer to take the temperature of a patient’s inflammation.”

C-reactive protein (CRP)

CRP is a protein that liver produces as part of our body’s immune response. Almost hundred years ago, it was first observed in people with very high inflammation caused by bacterial infection.

Because it was first noticed as a result of reaction to the antibodies formed against the outer C-polysaccharide wall of bacteria—hence the unique name.

In the most stable form, CRP exists as a characteristic ring of five molecules. Whenever the immune response is called to defend a site of infection, interleukins (IL-1 and IL-6) are produced that subsequently initiate CRP release in the body.

The levels can rise and drop within hours due to infection, inflammation or allergies. This rapid response can double CRP levels within 8 hours. And levels can peak as soon as 48 hours of the trigger event.

Except for inflammation, CRP in relatively unaffected by other events in the body except in the extreme case of liver failure. This unique property—coupled with no seasonal variation—makes it an excellent diagnostic marker.

Factor affecting CRP levels

Based on our understanding so far, here are few factors that modulate CRP levels:

  • Age (levels rise with age)
  • Gender (men tend to have higher levels compared to women for a given age)
  • Late stage of pregnancy
  • Fungal infections, Viral infections (10-40 mg/L) and bacterial infection (40-200 mg/L)
  • Injuries, burns, and other inflammations
  • Chronic conditions, e.g., arthritis, lupus, gout, inflammatory bowel syndrome (IBS), kidney failure
  • Sleep apnea – use of a CPAP machine has shown to lower the levels

Consistently high levels—among those who do not have genetic pre-disposition—can compromise health.

Potential risks associated with high CRP levels include increased risk of diabetes, hypertension and cardiovascular disease.

They may result in stroke, myocardial infarction, atherosclerosis, and kidney failure. Moderate levels of 2-3 mg/L and above signal slow build-up of plaque in arteries.

Prediction of the risk of heart disease

Risk of Cardiovascular disease and heart attack:

  • Below 1 mg/L – Low risk
  • 1 – 3 mg/L – Average risk
  • 3 – 10 mg/L – High risk
  • 10 – 40 mg/L – levels observed during viral infection
  • 40 – 200 mg/L – levels observed during bacterial infection

The American Heart Association believes there is enough evidence to support the usefulness of hs-crp test for a healthy heart.

Their 2013 guideline says “clinicians can employ the recommendations confidently to reduce the risks of atherosclerotic cardiovascular disease (ASCVD) events” by testing for crp in risk groups.

A recent review of 23 different studies found crp as an excellent inflammation marker in blood.

CRP gene

CRP gene is located on chromosome 1. Some people might be genetically susceptible to higher CRP levels. But causal studies show these do not contribute to higher risk of heart disease.

This is different from APOE gene. Certain variants for it can contribute to higher cholesterol and an increase in the risk of heart disease.

Anatomy of metabolic inflammation

Only recently we have started to understand how increased body mass index (BMI) manifests into inflammation.

It turns out that the fat cells—loaded with triglycerides and at constant stress of rupturing—have ability to call the immune system for help.

Therefore, among those with abnormally high BMI, excess fat in the body constantly stresses the immune system. The result is chronic stress and inflammation.

The fat cells in the walls of blood vessels can produce interleukin-1 that summons the immune systems to fight any damage. CRP is produced at these sites during the immune response. Continuation of this process starts to show up at elevated CRP levels which reflects the plaque build up inside the blood vessels.

The same argument explains elevated CRP levels among those with chronic inflammation. For example, in cases of arthritis, lupus and other inflammatory conditions arising from bacterial or viral infections.

That’s why recently, CRP has also been identified as a critical marker in the diagnosis and prediction of severity of COVID-19 coronavirus disease.

In search of clarity

Although elevated levels have high predictability value, an hs-CRP test doesn’t check for heart disease. It’s the underlying inflammation causing higher levels that correlates to the risk of heart disease.

And, many other factors including genetic predisposition, Vitamin D, BMI, and lifestyle can modulate the risk.

Another limitation is that a C-reactive protein test checks for systemic inflammation and can not pinpoint the exact location of inflammation.

Levels often correlate with Vitamin D, and that’s why Inflammation and Vitamin D are often tested together. Because of rapid rise and fall in response to infections and allergies, it’s best to test again within next few days to confirm results that show elevation.

CRP test might be highly valuable to some people as a complementary test to other symptoms. However, they should always be viewed together for a thorough assessment. Standalone measurement might not be as meaningful, but a great tool in understanding the complete picture.

To lower the levels and reduce the risk of heart disease, general guidelines from American Heart Association should be considered.

Eating healthy diets in combination with regular exercise, low stress, optimal weight and drinking alcohol in moderation, are few factors to consider. Smoking is a well-known risk factor of cardiovascular disease. High blood sugar levels (A1c) and blood pressure also increase the risk of heart disease.

A thorough analysis of 52 different studies by University of Cambridge, UK, concluded that measurement of CRP has the predictive ability to avoid one future heart attack in about 440 people without prior known risk.

That may not sound much. But it’s a considerable population of over 3.5 million Americans–out of the 160 million that are over the age of 40 and potentially at risk of a future heat attack.