Inflammation may be just as important as cholesterol in causing heart attacks, and is frequently overlooked, say researchers, suggesting different treatments should be considered for prevention.
Heart attacks and strokes are among the commonest causes of death worldwide, and for years, much of the focus has been on cholesterol: statin drugs, used to lower cholesterol, are generally the most commonly prescribed medication for preventing cardiovascular disease.
But now researchers say inflammation, which is linked to the background activity of the immune system, is another key contributor.
A recent study 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,” said 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.”
Targeting cholesterol to treat cardiovascular disease is mainly the result of large studies that found higher levels of “bad cholesterol” correlate with higher rates of heart attacks, reports New Scientist.
Additionally, cholesterol is one of the main components of fatty plaques that can form in artery walls and restrict blood flow to major organs. Heart attacks and strokes usually happen because such a plaque ruptures, which can result in the blockage of smaller blood vessels downstream.
Once this was understood, cholesterol-lowering statins became one of the commonest medicines in use. More than 200m 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 aren’t 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 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, thus far it hasn’t translated into new ways to prevent or treat cardiovascular disease. But that may be about to change.
In the new research, Ridker’s team analysed figures from three large trials that each tested a different therapy aimed at reducing heart attacks and strokes in people taking statins.
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% greater risk than the quarter with the lowest. In comparison, having high cholesterol only raised risk by 27%.
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, 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%, a similar amount as statins.
Colchicine isn’t licensed for preventing cardiovascular disease other than in Canada, although in 2021 it was considered an option in guidelines from the European Society of Cardiology.
One caveat is that people who have had a heart attack or stroke may already be taking many tablets, and the more drugs being swallowed, the more likely they will interact with each other and cause unwanted effects – not to mention the inconvenience of multiple medications.
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.”
Study details
Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials
Paul Ridker, Deepak Bhatt, Aruna Pradhan, Robert Glynn, Jean MacFadyen, Steven Nissen,
et al
Published in The Lancet on 6 March 2023
Summary
Background
Inflammation and hyperlipidaemia jointly contribute to atherothrombotic disease. However, when people are treated with intensive statin therapy, the relative contributions of inflammation and hyperlipidaemia to the risk of future cardiovascular events might change, which has implications for the choice of adjunctive cardiovascular therapeutics. We aimed to evaluate the relative importance of high-sensitivity C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDLC) as determinants of risk for major adverse cardiovascular events, cardiovascular death, and all-cause-death among patients receiving statins.
Methods
We did a collaborative analysis of patients with—or at high risk of—atherosclerotic disease, who were receiving contemporary statins and were participants in the multinational PROMINENT (NCT03071692), REDUCE-IT (NCT01492361), or STRENGTH (NCT02104817) trials. Quartiles of increasing baseline high-sensitivity CRP (a biomarker of residual inflammatory risk) and of increasing baseline LDLC (a biomarker of residual cholesterol risk) were assessed as predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death. Hazard ratios (HRs) for cardiovascular events and deaths were calculated across quartiles of high-sensitivity CRP and LDLC in analyses adjusted for age, gender, BMI, smoking status, blood pressure, previous history of cardiovascular disease, and randomised treatment group assignment.
Findings
A total of 31 245 patients were included in the analysis from the PROMINENT (n=9988), REDUCE-IT (n=8179), and STRENGTH (n=13 078) trials. The observed ranges for baseline high-sensitivity CRP and LDLC, and the relationships of each biomarker to subsequent cardiovascular event rates, were almost identical in the three trials. Residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (highest high-sensitivity CRP quartile vs lowest high-sensitivity CRP quartile, adjusted HR 1·31, 95% CI 1·20–1·43; p<0·0001), cardiovascular mortality (2·68, 2·22–3·23; p<0·0001), and all-cause mortality (2·42, 2·12–2·77; p<0·0001). By contrast, the relationship of residual cholesterol risk was neutral for major adverse cardiovascular events (highest LDLC quartile vs lowest LDLC quartile, adjusted HR 1·07, 95% CI 0·98–1·17; p=0·11), and of low magnitude for cardiovascular death (1·27, 1·07–1·50; p=0·0086) and all-cause death (1·16, 1·03–1·32; p=0·025).
Interpretation
Among patients receiving contemporary statins, inflammation assessed by high-sensitivity CRP was a stronger predictor for risk of future cardiovascular events and death than cholesterol assessed by LDLC. These data have implications for the selection of adjunctive treatments beyond statin therapy and suggest that combined use of aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk.
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