Doctors are in the middle of a major rethink about the causes of heart attacks and strokes – among the commonest 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 for preventing cardiovascular disease in the UK. But a growing number of researchers say that overlooks another key contributor: inflammation, or the background activity of the immune system.
This week, research showed that in people taking statins to lower their cholesterol, inflammation is a bigger risk factor for heart attacks or strokes than whether they still have high cholesterol levels. “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 was involved in the research. “It’s no longer a hypothesis; it’s proven fact.”
The cholesterol theory is mainly based on large studies that found higher levels of “bad cholesterol” correlate with higher rates of heart attacks.
The other clue was that cholesterol is one of the main components of fatty plaques in artery walls that can restrict blood flow to major organs. Heart attacks and strokes usually happen because such a plaque ruptures, with bits breaking off and blocking smaller blood vessels downstream.
Once this was understood, cholestrol-lowering statins became one of the commonest medicines in use. More than 200 million people worldwide are taking a statin – either because they have survived a heart attack or stroke or they are thought to be at risk of having one. Many large trials have found that statins are very effective at reducing heart attacks, reinforcing the cholesterol theory of heart disease.
So where does inflammation come in? The revised idea is that those plaques are not just inert blockages but are alive with immune cell activity. Studies in animals have shown that plaques that are more inflamed are more likely to burst and shed the deadly fragments into the bloodstream. And recent evidence suggests statins may work by dampening inflammation as well as lowering cholesterol.
Despite mounting evidence of the importance of inflammation, it has not so far translated into new ways to prevent or treat cardiovascular disease. But that may be about to change.
Ridker’s team have analysed figures from three large trials that each tested a different therapy aimed at reducing heart attacks and strokes in people who were taking statins.
The results for those therapies are not what’s relevant here. At the start of the trials, participants’ blood was put through a battery of tests, including for cholesterol and a compound that is a hallmark of inflammation, called C-reactive protein (CRP).
All three trials found that high CRP was linked with more deaths from cardiovascular disease than high cholesterol. People in the quarter of participants with the highest CRP had a 268 per cent higher risk than the quarter with the lowest. In comparison, having high cholesterol only raised risk by 27 per cent.
Knowing that inflammation is part of the disease process is little use unless we can do something about it. But in the past few years, several drugs designed to do just that have been tested.
One of the most promising is a plant-derived compound called colchicine, which is already used for dampening inflammation in people with gout. Two recent randomised trials have shown that colchicine also cuts strokes and heart attacks by about 30 per cent, a similar amount as statins.
Colchicine is not licensed for preventing cardiovascular disease outside of Canada, although in 2021 it was considered an option in guidelines from the European Society for Cardiology. If it were to be recommended by a similar body in the UK, doctors could prescribe it “off-label”, says Nilesh Samani at 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 many tablets, and the more drugs someone takes, the more likely they will interact with each other and cause unwanted effects – not to mention the inconvenience for patients.
Nevertheless, the evidence is growing that to prevent heart disease and strokes, doctors need to place the same importance on tackling inflammation as on cholesterol. “It’s not either-or – it’s both,”, says Jean-Claude Tardif at the Montreal Heart Institute in Canada, who was involved in one of the colchicine trials.
“Often in science, it’s a series of incremental steps that eventually lead to a sea change. This paper has brought this to the fore.”