At the big-picture level, we understand the risk factors for a heart attack, including high cholesterol, high blood pressure, diabetes, smoking, and genetics. We also know that a heart attack is caused when plaque buildup in the wall of a coronary artery ruptures and blocks the blood vessel. What isn’t clear is the specific mechanism that triggers the rupture in the first place.
Researchers at the University of Ottawa Heart Institute, led by Alexandre Stewart, PhD, have uncovered an intriguing link between heart attack and a protein that is of great interest to drug companies because it’s known to significantly impact cholesterol levels.
The team found that levels of the protein PCSK9 were elevated in the blood of patients having an acute heart attack, but not in those who had never had a heart attack or who had recovered from one previously. The results were replicated in two separate groups of patients, all of whom have coronary artery disease but were not taking a cholesterol-lowering statin drug.
Published on September 2 in the journal PLOS One, the findings point to an important question: “Are PCSK9 levels elevated shortly before you get a heart attack?” asked Dr. Stewart, principal investigator in the Ruddy Canadian Cardiovascular Genetics Centre. “If levels only go up after, that would suggest a side effect of the heart attack. But if they go up before, that suggests it might trigger the event, or make it worse. Right now, the cause or effect question is there and we don’t have the answer.”
The medical community and pharmaceutical companies have already shown considerable interest in PCSK9 for its effects on LDL cholesterol. PCSK9 increases levels of LDL cholesterol in the bloodstream by reducing the ability of liver cells to remove and destroy it.
Several pharmaceutical companies have invested heavily in a new class of drugs to block PCSK9 and thereby lower cholesterol levels. The potential market is estimated to be in the billions of dollars because they lower cholesterol in a manner that is independent of the widely-prescribed statin drugs. In early clinical trials, these new drugs have proved to be effective in reducing LDL cholesterol levels. Various stage 3 trials are planned or underway.
Previous research has shown that people with genetic variations causing lower-than-normal levels of PCSK9 have a substantially reduced risk of heart attack—up to nearly 90 per cent lower than normal. This is significantly more of a reduction than would be expected if the protein only affected LDL cholesterol levels.
“I don’t think this is a one-function protein. It’s probably doing a lot of things in the body,” said Dr. Stewart. Other studies have shown that people with severe gum disease have elevated PCSK9 levels, a relevant fact because gum disease is associated with an increased risk of heart attack. High PCSK9 levels are also associated with infection and with sepsis, the body’s inflammatory over-response to infection. Here again, explained Dr. Stewart, the risk of heart attack is increased in people with an acute infection.
The Ruddy Centre researchers first identified the PCSK9 link to heart attacks using blood samples from patients enrolled in the Ottawa Heart Genomics Study. They then confirmed these results in a group of patients from Emory University in Atlanta, Georgia. Again, they found elevated PCSK9 levels in samples taken from patients at the time of acute heart attack, but not in samples taken from patients with a history of heart attack or from those with coronary artery disease who had never had a heart attack.
“If elevated plasma PCSK9 carries risk beyond its effect on LDL, there may be an additional benefit to lowering plasma PCSK9 in individuals treated with statins,” said the authors in the study. “I think that lowering PCSK9 is probably a good thing,” added Dr. Stewart. “But when you develop drugs, it’s important to know everything they might do.”
“The burning question is: Are PCSK9 levels up shortly before or as a consequence of a heart attack?” he concluded.
The ideal study to answer this question would be to take a first sample from patients immediately after admission to hospital and then again every few hours for days afterwards to see if levels taper off or continue to rise. However, such a study would be difficult to do in Canada, since the standard of care is to start heart attack patients on statins immediately after admission and the statin therapy would interfere with PCSK9 measurements.
Fortunately, a similar clinical trial is underway in Europe, and its results may help clarify the relationship of PCSK9 to heart attack, whether it proves to be a trigger or a result.