The role of inflammation in heart disease is overlooked

Doctors are in the midst of a major review of the causes of heart attacks and strokes – among the most common causes of death worldwide.

For decades, much of the focus has been on cholesterol: statin drugs, prescribed to lower cholesterol, are the most commonly prescribed drugs to prevent heart disease in the UK. But a growing number of researchers say this overlooks another key factor: inflammation, or immune system activity.

This week, research showed that in people taking statins to lower their cholesterol, inflammation is a greater risk factor for heart attacks or strokes than if they still have high cholesterol. “It’s clear that if you don’t start addressing the inflammatory response, you’re never going to beat this disease,” says Paul Ridker at Brigham and Women’s Hospital in Boston, who participated in the research. “It’s no longer a case. it is a proven fact.”

The cholesterol theory is based primarily on large studies that found higher levels of “bad cholesterol” correlated with higher rates of heart attacks.

The other clue was that cholesterol is one of the main components of fatty plaques on artery walls that can restrict blood flow to major organs. Heart attacks and strokes usually occur because such a plaque ruptures, with pieces breaking off and blocking smaller blood vessels downstream.

Once this was understood, cholesterol-lowering statins became one of the most common drugs used. More than 200 million people worldwide take a statin – either because they have survived a heart attack or stroke or because they are thought to be at risk of one. Several large trials have found statins to be very effective in reducing heart attacks, bolstering the cholesterol theory of heart disease.

So where does the inflammation come in? The revised idea is that these plaques are not just inert blockages, but are alive with the activity of immune cells. Animal studies have shown that plaques that are more inflamed are more likely to burst and release deadly fragments into the bloodstream. And recent evidence suggests that statins may work by reducing inflammation as well as lowering cholesterol.

Despite growing evidence of the importance of inflammation, it has so far not translated into new ways to prevent or treat cardiovascular disease. But that may be about to change.

Ridker’s team analyzed data from three large trials that each looked at a different treatment aimed at reducing heart attacks and strokes in people taking statins.

The results for these treatments are not relevant here. At the start of the trials, the participants’ blood was subjected to a series of tests, including cholesterol and a compound characteristic of inflammation, called C-reactive protein (CRP).

All three trials found that high CRP was associated with more deaths from cardiovascular disease than high cholesterol. People in the quarter of participants with the highest CRP had a 268 percent higher risk than the quarter with the lowest. By comparison, high cholesterol increased the risk by only 27%.

Knowing that inflammation is part of the disease process is of little use unless we can do something about it. But in recent years, several drugs designed to do just that have been tested.

One of the most promising is a plant compound called colchicine, which is already used to reduce inflammation in people with gout. Two recent randomized trials showed that colchicine also reduced strokes and heart attacks by about 30 percent, a similar amount to statins.

Colchicine is not licensed for the prevention of cardiovascular disease outside of Canada, although it was considered an option in the European Society of Cardiology guidelines in 2021. If a similar body were to recommend it in the UK, doctors could prescribe it “off-label”, says Nilesh Samani from the University of Leicester, who was not involved in the latest study.

One caveat is that people who have had a heart attack or stroke may already be taking multiple pills, and the more drugs someone takes, the more likely they are to interact with each other and cause side effects – not to mention the inconvenience for patients.

However, there is growing evidence that to prevent heart disease and stroke, doctors need to give the same importance to treating inflammation as they do cholesterol. “It’s not one-or–it’s both,” says Jean-Claude Tardif at the Montreal Heart Institute in Canada, who participated in one of the colchicine trials.

“Often in science, it’s a series of incremental steps that eventually lead to a sea change. This document brought it to the fore.”