Revolutionary research on the ever-changing risk of a heart attack

by Donna Chisholm / 05 October, 2016
RelatedArticlesModule - Rod Jackson research

Till you drop: we know more than ever about what contributes to heart attacks and strokes, but population-based risk and personal risk are two quite different things. Photo/Getty Images

Half the people admitted to hospital after a heart attack have no prior warning. Donna Chisholm investigates new research helping doctors understand your ever-changing risk of a heart attack or stroke.

If you’ve ever thought we’re pretty clued up by now about what causes heart attacks, consider Auckland cardiologist and professor of heart health Rob Doughty. At 51, his estimated risk was as low as possible for a man of his age – about 1% over five years. He was a healthy weight, he didn’t smoke or have diabetes, his blood pressure and cholesterol were within the normal range, he biked and ran regularly and he had no family history of the disease. And then in April 2015, as he emerged from the underground carpark at Auckland School of Medicine, he defied the odds stacked in his favour and had a heart attack.

The chest pains, he rationalised, might be linked to the flu he was recovering from. But as the pain radiated down his left arm and into his throat and he began to feel sick and faint, he knew he was in trouble.

Doughty admits it’s taken some time to “adjust his head” to the knowledge he’s had a heart attack. “You struggle with every­thing, including the fact that you realise you could have died.

Cardiologist, professor of heart health and heart-attack survivor Rob Doughty. Photo/Victor Carter

Risky business

We know more than ever about how the multiple factors that combine to cause heart attacks and strokes affect population-based estimates of risk, thanks to Auckland professor of epidemiology Rod Jackson’s pioneering work over 30 years that’s produced the Predict algorithm for New Zealand patients. It’s about to be incorporated into new Ministry of Health treatment guidelines, replacing those that are based on American patients – largely of white European descent – in the long-running Framingham Heart Study. The new guidelines, which advise doctors about when to start treating patients and with what, are expected to be finalised by the end of February.

Doctors calculate the risk of heart attack or stroke based on a combination of factors including age, blood pressure, cholesterol level, smoking and diabetes. But as Doughty has shown, population-based risk can be one thing and personal risk quite another. Given his risk was low by every conventional and easily measurable score, genetics probably played a part.

Already, 50 genetic variations known as SNPs have been associated with an increased risk of cardiovascular disease, and research is gathering momentum here and overseas to work out their precise role – and more importantly, what can be done about it.

Photo/Getty Images

Doughty, the New Zealand Heart Foundation professor of heart health since 2011, hasn’t had a gene test. “The fundamental question is: how does it change what we do? At the moment I don’t believe we understand that properly, so it’s not the right time. We’re a long way away from saying a genetic test should be done for everyone at the time they have their cholesterol taken. Cost in the end won’t be a problem, but it’s how do we use that information meaningfully to do something different?”

In New Zealand, researchers in two large studies are genetically testing blood samples from heart attack patients in the hope of answering these questions. Since 2012, the Wellington Cardiovascular Research Group has gathered genetic data from 1500 patients who’ve had angiography after a heart attack, to better understand how it might be able to inform treatment. Co-director Peter Larsen, an associate professor at the University of Otago, Wellington, believes it may be only three to five years before genetic testing could routinely be incorporated into the assessment tests GPs use on middle-aged patients.

“What we have to find are genetic markers of risk that add to the information we can easily measure clinically. If I measure your blood pressure and it’s high, and then I measure genetic markers that tell me it’s likely to be high, the genetics haven’t really helped me. We’re not advocating genetics replacing things we can easily measure, interpret and treat with existing technologies.”

After the tests of 27 SNPs, about 20% of the patients have been identified as being at high risk and the majority as at intermediate risk. Only 4-5% were genetically at low risk.

“Professor Predict” Rod Jackson. Photo/Justin Lambert

A powerful combo

The researchers are particularly interested in why some patients have heart attacks much younger than others – about 13% of New Zealanders have their first event before they reach 50. “A sub-group of those patients, about a third, don’t have what we’d call a traditional risk marker for coronary disease. Another two-thirds are having heart attacks young because they smoke, have high blood pressure or are diabetic. That’s not a mystery to us. But in that third, when we look at them clinically, it doesn’t make sense to us that they’re having a heart attack.”

They’re more likely to have a family history, says Larsen, but not all of them do. “Nothing is simple.”

The genetic risk scores appear to help doctors predict which people are going to have bad outcomes. “The idea we’re exploring is that there are a number of SNPs that have a modest ability to predict risk. Individually, they’re not really worth it, but by the time you combine a whole lot of those, it becomes quite a powerful tool. We could be more aggressive in how we manage [those] people after a heart attack.”

It’s too simplistic to say people in the high-risk group are heart attacks waiting to happen, says Larsen. “We wouldn’t propose you ever use a genetic risk score in isolation.”

Auckland cardiologist Patrick Gladding, founder of Theranostics Lab, which offers DNA testing for coronary artery and atrial fibrillation risk, says although the algorithms produced by Jackson’s work won’t be overtaken by personalised medicine, genomic medicine is “moving exponentially. Costs are decreasing exponentially and knowledge is increasing exponentially.”

Photo/Getty Images

Only about one or two patients a week have the test privately, but Gladding says the main reason for developing it was as a tool for researchers to validate.

Testing also has ramifications for health insurance and employment, and the privacy issues need to be addressed, he says. “Insurers and employers shouldn’t be able to discriminate based on a person’s genetics.”

When taking out life insurance, he was asked if he’d had a genetic test. He answered yes, and the company asked for the results. “I said no and they were happy with that, and I still got the policy.”

Gene tests are also part of the information being gathered for MENZACS (Multi-Ethnic NZ Study of Acute Coronary Syndromes), led by one of Doughty’s cardiologist colleagues, University of Auckland associate professor Malcolm Legget. “The question is: why do people have heart attacks? We see people who come into coronary care in their forties, sometimes in their thirties, who have never smoked, don’t have high cholesterol, etc, and bang, heart attack. So what’s driving that?”

Launched a year ago, MENZACS aims to recruit 3000 patients admitted to hospital with a heart attack or unstable angina in Auckland, Waikato and Christchurch and compare their lifestyle and genetic information with a control group with no coronary history. More than 330 have been enrolled so far.

“It’s going to be the biggest study ever in New Zealand of first-time heart attacks, looking at the whole landscape of why people have [them]. We know about 50% of the factors are environmental and 50% are genetic, but we understand only about 10% of the genetic influence.”

Molecular biologist Anna Pilbrow.

Biomarker potential

At the University of Otago’s Christchurch Heart Institute, molecular biologist Anna Pilbrow, who has a PhD in cardiovascular genetics, is working to increase that know­ledge. She’s looking for genetic biomarkers in the blood rather than genetic variations themselves, which may be able to be predict heart attack risk, testing the blood from a group of 3500 healthy Canterbury volunteers, of whom 15% have gone on to have heart attacks.

In a pilot study, the blood of 35 of the volunteers who had attacks within a year of their blood being taken was compared with those who’d stayed event-free for five years. Pilbrow found some small pieces of genetic material, known as microRNAs, that appeared to increase in the group who had the attacks.

MicroRNAs are produced from the non-coding regions of DNA – so-called “junk” DNA – and act in cells to turn genes off. The material can be detected in various body fluids such as blood, urine and saliva. “They’re very stable, and it’s this that makes them such good potential biomarkers.”

Pilbrow is one year into a three-year Heart Foundation project, at the end of which she hopes to know if the biomarker has potential for use as a test in primary care.

Wellington Cardiovascular Research Group co-director Peter Larsen.

A disease of deprivation

Jackson’s work and another University of Auckland study, ANZACS QI (All New Zealand Acute Coronary Syndrome Quality Improvement), mean New Zealand is “well poised” to make significant advances in cardiovascular risk prediction in primary and secondary care, says Legget.

“More events are occurring in people who are at low to intermediate risk than at high risk, because there are many more people in those [first two] groups. So in the middle-aged baby-boomer group, we have this massive bulge of people who have intermediate risk just by nature of their age, gender and one risk factor.”

The ANZACS-QI project has collected clinical data on more than 25,000 patients hospitalised with heart attacks and more than 50,000 referred for angiography, and Jackson has data on 500,000 patients who’ve had coronary-risk assessments with GPs since 2002.

Cardiologist Andrew Kerr, who works with Jackson on Predict and is principal investigator on the ANZACS QI work, says for half the patients admitted to hospital, their heart attack was the first symptom of their disease. For those who’d had a previous heart attack or stroke, about 50-60% were on a combination of medicines – statins, blood-pressure-lowering drugs and anti-platelet therapy, usually aspirin. But 20% of patients who’d had a prior event weren’t taking the drugs consistently, “so that’s a group where there could be an opportunity to improve things”.

Anecdotal evidence suggests patients admitted to hospital now compared with decades ago tend to be older people with more complicated disease.

“The other thing we’re seeing is a very big difference in the sort of people coming in young. It used to be that cardiovascular disease was a disease of affluence.” Now in the young, it’s a disease more often associated with deprivation, with risk factors such as obesity, diabetes and smoking clustered in the lower socio-economic groups, particularly Maori and Pasifika and some South Asian people. “The [older] survivors really are the people from more well-off areas. On a population level, the biggest gains we can still make are in dealing with known modifiable risk.”

False reassurance

Another prediction technique gaining traction clinically is calcium scoring, which measures levels of calcium in the coronary arteries with a CT scanner. American research has found a calcium score of more than 300 is more accurate than the Framingham-based algorithm alone, and is particularly useful for people at intermediate risk – those with a 10-19% chance of a coronary event within 10 years.

This is “the category for whom decision-­making is most uncertain”, the Chicago-based researchers wrote in JAMA, the journal of the American Medical Association. Calcium scores don’t change the predicted risk for people with a 10-year risk of less than 10% or more than 20%.

In a New Zealand study of 1000 patients that Legget co-authored, published in the New Zealand Medical Journal in 2011, 10% of women and nearly 9% of men had very high predicted risk of heart disease based on their calcium scores (above 400), but were regarded as low risk by the Framingham-based guidelines. “Currently promoted methods of risk assessment may be inadvertently falsely reassuring these patients,” the paper concluded.

Statin therapy, which stabilises the arterial plaques that rupture in heart attacks, could be used in people with high calcium scores. Paradoxically, research published last year suggests high-intensity statin therapy makes plaques smaller, but more calcified.

Legget says a calcium score of anything greater than 100 is not good, and “greater than 400 is very bad. Zero is fantastic. We have lots of zeros.”

But knowing you have a zero score for calcium can be a double-edged sword for patients, he adds. “They might say, ‘I’ll go and do whatever I like, even though my cholesterol is 7’, but we really try to caution against that and say, ‘Don’t be complacent. If you have a family history, or high cholesterol or blood pressure, etc, you still really need to be concerned about your risk factors.’”

Associate professor of radiology Nigel Anderson.

That said, the 10-year risk for someone with a calcium score of zero is 1% or less. The same as Rob Doughty’s.

Researchers know that not all plaque is created equal. As the statin work shows, more-calcified plaques are less likely to rupture and cause artery-blocking blood clots than those that are softer and feature more lipids – the fatty component – and inflammation. But detecting those dangerous plaques and predicting how they’re likely to behave are more difficult.

At the universities of Canterbury and Otago in Christchurch, a group of scientists are using revolutionary technology – the same as that which detected the Higgs boson, the so-called “God particle” – to find out whether it can also be used to identify the potential killer plaques. They’ve developed the MARS scanner, the world’s first human colour X-ray scanner, which detects the different energies of the plaque’s components. “We’re measuring the wavelength of the X-rays that have come from every single part,” says the project’s principal investigator, Nigel Anderson, an associate professor of radiology at the University of Otago.

The machine is being used to image specimens of the plaque removed from the carotid arteries of patients at risk of stroke.

“The current treatment is to assume [the artery] is a pipe that’s narrowed, but the majority of strokes and heart attacks aren’t coming from pipes that are too narrow, but ones that have these nasty bits of friable material on them that break off. What we need to do is treat the plaque that’s going to break off and harden it up so it doesn’t. We want a method for identifying this vulnerable plaque in people before they’re symptomatic, and for that method to be used to develop better treatments.”

The technology can also be used in orthopaedic and cancer research, and the first volunteers to have human scans – probably of the knee, because the machine is not yet able to image in a beating heart – will be imaged later this year. Anderson hopes clinical trials using the machine in atherosclerosis and joint disease will start in 2020.

No get-out-of-jail-free

Eighteen months after his heart attack, Doughty is none the wiser about the cause of his coronary artery disease, but his experience emphasises what cardiologists like him already know – that a low-risk score isn’t a get out-of-jail-free card.

“I’d encourage people to have a risk assessment done – and understand it. And secondly, to do something about it if they’re not right; if they develop pains in the chest or other symptoms, don’t think it isn’t an attack because the risk is low.”

He was doing the right things before his coronary – in 2010, he even cycled the length of the country to raise money for the Heart Foundation – and what he does now is “fine-tuning”. The medicines he’s on have reduced his blood pressure about 10 points and his LDL cholesterol to 1.4 from “the 2s”.

The experience has changed his approach to his job – and his life. “I’m more aware of issues and discussions that previously I wouldn’t have spent so much time on. It’s about coping strategies and readjustments in your life.

“These sorts of events do make you stop and think. Having a heart attack fundamentally changes your life. I didn’t think I was going to have a heart attack at that point in my life. So as a medical person, however much you think you understand something, if you go through it, you really do understand it.”

This article was first published in the September 17, 2016 issue of the New Zealand Listener.

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