Has decades of research into the role of arterial plaques in cardiovascular disease been a wild goose chase?
Has decades of research into the role of arterial plaques in cardiovascular disease been a wild goose chase?
For more than two decades, the vulnerable plaque has been the holy grail of the cardiovascular community, so why are people now lining up for its funeral?
The appeal of the vulnerable plaque theory rests on the premise that clinicians can identify a plaque at high risk of rupture, and then intervene to prevent an infarct.
“It’s been known for many years that people without symptoms develop heart attacks, and unfortunately possibly one third of them die when they have a major heart attack,” said Associate Professor Andrew MacIsaac, past president of the Cardiac Society of Australia and New Zealand.
“So the thought has been to find a spot in the artery that is likely to cause a problem in the future, and fix it to prevent that from happening,” he said.
But despite thousands of trials, and the development of numerous diagnostic and treatment techniques, this approach to plaques in the coronary arteries has failed to deliver on its promise.
The plaque rupture theory first took off in the 1980s. Previously, it had been believed that atherosclerotic plaques had done their damage by progressive stenosis to a chronically flow-limiting lesion, rather than physical disruption of the plaque.
However, autopsy findings showed the final cause of death in most people who suffered a fatal acute myocardial infarction was the rupture of a plaque’s fibrous cap and subsequent thrombosis.
Other research found one half to three quarters of cases of thrombosis-related acute coronary syndrome were caused by plaque rupture.
And seminal studies identified three major imaging predictors of a cardiovascular event within the following three years – the amount of plaque in the coronary arteries, the size of the lumen, and the presence of a thin-cap fibroatheroma.
Since then, a great deal of energy has gone into developing and improving imaging and treatment techniques, in the hope it would help identify coronary artery lesions modifiable by percutaneous techniques.
The discovery of lesions with a lipid-rich necrotic core and a cap heavily infiltrated with inflammatory cells appeared to be the fruit of this effort.
Critics
Peter Libby, professor of medicine at Harvard Medical School, has been a vocal critic of the ongoing usefulness of the vulnerable plaque concept.
In a 2015 journal article, Requiem For The Vulnerable Plaque, Professor Libby said that expending further effort into identifying a single “vulnerable’ lesion” would be a fool’s errand in light of current knowledge.
Professor Libby claims that plaque rupture is much less common than previously thought.
“Thin-capped plaques do not inevitably rupture and cause thrombotic events. Contemporary data do not support the ‘vulnerability’ of [thin-cap fibroatheroma], and indeed plaques of other morphologies may also
give rise to thrombotic events,” he wrote.
In fact, one study found only around 5% of thin-capped plaques caused a coronary event over a 3.4 year follow up, he said.
Professor Stephen Nicholls, deputy director of the South Australian Health and Medical Research Institute, said the focus was shifting from the vulnerable plaque to the vulnerable patient.
Speaking at the recent Cardiac Society of Australia and New Zealand conference, Professor Nicholls said that when you look at the so-called culprit lesions in patients with an acute coronary syndrome, you’re lucky if half of them actually showed evidence of plaque rupture.
“Even when the thin-cap fibroatheroma might indicate that you were at a high risk of having the event, the event was just as likely to occur in another artery. This illustrates that the vulnerable lesion doesn’t necessarily have to be where all the action is,” he told The Medical Republic.
“Instead, it reflects the patient who ultimately is more vulnerable and will be more likely to benefit from more aggressive intervention,” he said.
In an article called The Vulnerable Plaque “Hypothesis”: Promise, But Little Progress, renowned cardiologist Dr Steven Nissen criticised the underlying assumptions of the hypothesis.
There is no evidence that any specific plaque characteristic is associated with a poorer prognosis, and even if we assumed that a specific thin-cap fibroatheroma was the vulnerable lesion, it has limited clinical use, he argues.
A 2007 study found PCI didn’t provide any benefit in terms of risk of death, myocardial infarction or other major cardiovascular events when compared to medical therapy in patients with stable coronary artery disease.
Patients are not likely to have just one plaque either. Research suggests that, when they are present, these lesions are present throughout the coronary arteries.
Not only did most of these plaques never rupture, but clinicians might be surprised to find they also often disappeared, Professor Nicholls said.
“A report done from virtual histology in Japan found that for every 25 so-called thin-cap fibroatheromas, when you come back and look at the same artery in the next 12 months, most of them have disappeared. In fact, the overwhelming majority of them have disappeared – if you’re lucky, 20% are still there.”
Professor MacIsaac added that, in any case, just looking at coronary artery lesions in asymptomatic patients was not very predictive of who was going to have a heart attack and when.
“We have the problem that we know what groups of people are vulnerable, but when it comes to specific patients, we don’t know what’s going to happen tomorrow or the next day. We could see someone at high risk or low risk but we don’t have a way of saying ‘you’re going to have a heart attack next week and we’ve got to do something to prevent it’,” he said.
“It is clear that putting a stent in one part of one coronary artery doesn’t prevent someone necessarily from having a future heart attack,” he said.
Risky patients
What we now know is that looking at baseline plaque burden is a strong predictor of disease progression, according to Professor Nicholls.
And it looks like more systemic treatments are the way forward.
Using intravascular ultrasound, researchers have looked at the impact of statins on patients with spotty calcification – a feature considered to be characteristic of vulnerable plaque – and positive remodelling.
Those with a high-risk plaque experienced much more benefit in terms of atheroma regression from statins than those without.
This confirmed the expectation that high-risk plaques had the machinery to progress the disease, but also that the biology could be modified by interventions, Professor Nicholls said.
“If you’re treated with a statin you had more bang for your buck,” he said. “So a vulnerable lesion really reflects a patient who is at much higher risk, but they have potentially much more to gain.
“It really goes hand in hand with observations from clinical trials that therapies such as statins have a much greater impact in the setting of patients who have had acute, as opposed to stable, ischaemic syndromes.”
A key point is that the plaque is only the first part of the problem.
“Ultimately you have to form a blood clot,” Professor Nicholls said. “So people may vary in their potential to develop a blood clot, and somebody who may clot with much greater ease may be much more likely to have an event in relation to a plaque than someone who is much less likely to clot.
“And then finally you have to think about the organ that’s going to undergo the insult
– so your heart muscle might tolerate relative deprivation of oxygen and glucose and nutrients for a longer period of time than mine might.”
These fundamental differences support the shift towards the concept of the vulnerable patient, he says.
The spanner in the works
“If you ask a pathologist to cut up a bunch of coronary arteries from people who have had heart attacks, it turns out that they can only find ‘rupture’ in about half of them, which is really interesting, because that’s been the notion for the last 20 years is that plaques rupture and cause heart attacks,” said Professor Nicholls.
And the discovery that plaques can not only rupture, but also erode, threw a spanner in the works.
“It turns out that probably about a third of patients have this ‘erosion’, and we’re learning more about that,” he said. “We’re learning that perhaps the biology of the plaque that erodes is different from the biology of the plaque that ruptures.”
Professor Nicholls says the types of plaque with a tendency to erode are different to those that rupture, with the former having thicker fibrous caps, fewer inflammatory cells and a smaller or non-existent lipid pool. But eroding plaques will still cause clotting, and eventually block arteries.
So the big challenge is to identify a plaque before it erodes.
Professor Nicholls and colleagues are excited about a paper to be published later this year, which found major differences in plaque erosion between the sexes, with the process being much more prevalent in women.
They hope that understanding the mechanisms behind erosion may provide some clarity around the sex differences in heart attacks, and better treatments for a disease that kills three times as many women than breast cancer.
Plaque rupture is more strongly associated with STEMIs than non-STEMIs and autopsies have found rupture is responsible for around three quarters of cases.
But the face of ACS is changing across the world, with rates of STEMI decreasing and non-STEMI increasing.
“In fact, the non-STEMI situation is probably potentially the much more predominant form of pathology driving the disease now – and that has certain implications because those lesions look different,” said Professor Nicholls.
Superficial erosion is more common among women, those with diabetes and the elderly, says Professor Libby.
“This clinical profile reflects in many ways the changing demographics of individuals who present with ACS today,” he writes.
One interesting explanation of the changing picture of cardiovascular disease is that therapies such as lipid lowering, blood pressure lowering, reductions in smoking, and statin therapy may have been responsible for stabilising plaques.
Such interventions may reduce the risk of rupture by thickening the fibrous cap, reducing lipid accumulation, dispelling inflammation and shrinking the volume of the lipid core, he says.
Quite possibly, the shift towards superficial erosion from rupture as a mechanism of thrombosis may have led to the rise in non-STEMI and the decline in STEMI.
But more research is needed.
While there was currently no evidence that directly treating a vulnerable plaque would be of benefit, Professor Nicholls said he did not think the two decades on the vulnerable plaque story had been a waste or distraction.
“It has stimulated immense efforts to develop better diagnostic and therapeutic approaches, and has evolved the story.”
Thanks to the pursuit of the vulnerable plaque, the medical community understands more about the role of inflammation, lipids and cholesterol in heart attack, and the mechanisms involved in plaque rupture and erosion.
But research has overturned any assumption that stenting stable patients would prevent future heart attack and now the shift is towards more simple, systemic interventions which have been proven to have a major impact.
So critics of the vulnerable plaque theory say the next battlefront should focus resources and efforts on effective preventative treatments such as treating lipid levels, lowering blood pressure, stopping smoking and increasing exercise.
Systemic approach
We know the more plaque a patient has, the more likely they are to have an event, and calcium scoring is an analogy for the systemic nature of the disease, Professor Nicholls says.
“The calcium score tells us the more calcium you have, the more likely you are to have an event. And we know the more calcium you have, the more plaque you have,” he said.
“Now where the calcium is, isn’t going to cause an event. Those plaques never do anything. They’re dead. So the calcium score is a great analogy of reflecting a vulnerable patient and not identifying the plaque itself.”
In terms of treating the event and preventing the event, the approaches that had been successful and continued to be successful were the ones that were systemic, he said.
“As opposed to this fanciful notion that we’re going to identify a plaque that looks like it might rupture, and do something specifically about it,” he said. “That’s wishful thinking, it’s not going to pan out, it’s not panned out.”
So is the vulnerable plaque dead?
“No, the vulnerable plaque is not dead per se, in that we clearly know that most of the plaques that have caused those events follow that paradigm,” said Professor Nicholls.
“But in terms of using the vulnerable plaque as the entry point for how we should approach the management of our patients, then I absolutely think it’s dead.”
References:
1 Heart. 1999;82(3):269
2 Eur Heart J 2015;36(43):2984-7
3 JACC Cardiovasc Imaging 2009;2(4):483-5
4 NEJM 2007;356(15):1503-16
