What becomes of the broken hearted?
Clue by clue, New Zealand researchers are putting together the many pieces of a heart condition that mostly strikes older women. Will Harvie reports.
It turned out that Christchurch was the best place in the world to study the puzzling heart condition called stress cardiomyopathy.
Better known as ‘‘broken heart syndrome’’ and sometimes as ‘‘takotsubo syndrome’’, it almost exclusively strikes postmenopausal women who are otherwise healthy but undergo a hugely stressful event.
Like a Christchurch earthquake. Or the Kaiko¯ ura earthquake. Or more rarely, a relationship break-up. Sometimes major surgery is enough. Something really stressful in any event.
The hearts of these older women stop working properly, usually within 24 hours of the big stressor, and the greatest risk of death is on the third day afterwards.
Their hearts are broken in the sense of not working properly, like a car limping to the mechanic. It’s not a technical heart attack, although it can feel like one, patients say.
Treatment in a hospital cardiology ward is required.
‘‘It’s not rare for this to happen,’’ says Christchurch Hospital cardiologist and researcher Paul Bridgman.
He sees a case about every second week and the rate is increasing, especially in Christchurch.
After the quakes, the city turned out to be the Goldilocks location. About 50 older women presented with the condition after the two big quakes of 2010 and 2011. Lesser numbers took part in aspects of the research.
By comparison, there have been clusters of cases after Australian bushfires but not enough to make much statistical headway.
And there must have been an abundance of cases after Japan’s 2011 earthquake, tsunami and nuclear plant failure.
But those events were so massive that nearby hospitals closed and the population dispersed. Not much data were collected.
‘‘Christchurch Hospital did really well to collect these cases and to be thinking about research while managing such a . . . disaster,’’ says Martin Kennedy, a geneticist at the Christchurch campus of the University of Otago.
In hospital, the patients were first stabilised. Surgery does not help. Drugs returned their hearts to normal functioning and the women are now leading normal lives. None of the cohort died.
The size of the group intrigued the researchers, and a team of psychiatrists, cardiologists and geneticists started a research programme to explore the condition fully.
A review of the scientific literature suggested a link between broken hearts and previous psychiatric conditions such as anxiety, depression and panic disorder.
To test that idea, the researchers compared the psychiatric histories of a group of broken-heart patients with a control group of healthy volunteers, all of whom lived through the Canterbury quakes.
They found ‘‘psychiatric factors do not contribute to the risk’’.
Indeed, in one journal article, members of the team reported that broken-hearted women were the ‘‘most psychologically robust’’ compared with earthquake women with other heart complaints.
Stress isn’t a psychiatric condition. It’s life, says Cameron Lacey, a psychiatrist and OtagoChristchurch researcher.
And sometimes life brings huge stresses. ‘‘These women got through their lives – with kids and families, ups and downs and traumas,’’ says Kennedy. Normal life wasn’t enough to break hearts.
So the stress must be huge. That’s a clue. There are others. Post-menopausal women, mostly.
There are exceptions, including men and premenopausal women. But about 95 per cent are post-menopausal or in the midst of menopause.
One of the biggest changes brought by menopause is decreased oestrogen. That must be a clue, says Kennedy.
Another clue is the flood of adrenalin that a huge stressor brings. Adrenalin spikes immediately as the fight-or-flight response occurs and it is likely to be elevated for several days afterward as aftershocks and other triggers occur, he says.
There must be other biological changes wrought by menopause and huge stress (‘‘a million things’’, exaggerates Kennedy), but oestrogen and adrenalin are the big two for now.
And then we get to genetics. Every human health condition involves something genetic, says Kennedy. As a geneticist, he would say that, but he adds, ‘‘It’s got to be a biological thing.’’
The geneticists first performed exome sequencing, which analyses all of the parts of an individual’s DNA that provide instructions for making proteins.
Most known mutations that cause disease occur in these parts of the DNA, and exome sequencing is a new and useful tool for seeking genetic causes of conditions such as broken heart.
It was a broad look at about 20,000 genes, says Kennedy.
And it was a blind alley. None ‘‘proved to be convincing on closer analysis’’, concludes their scientific paper.
‘‘So then we thought, what about CNVs," he says. CNVs are ‘‘copy number variations’’ and complicated. ‘‘We’ve learned in the last decade . . . that there are a lot of differences in big pieces of DNA.’’
Large rafts of DNA have been randomly deleted or randomly copied twice.
‘‘It means genomes have regions where there is a duplication or complete absence of DNA that you might find in the next person.’’
These differences happened when the genes reproduced themselves, probably in ancient times, although possibly at conception or in utero. Every human probably has CNVs.
Until recently, it was thought they were mostly harmless.
But CNVs are now used to partly understand conditions such as developmental delays and intellectual disabilities. Lots
more research needs to be done in these areas.
When the researchers looked at CNVs in broken heart, they got hits. Frustrating hits, but hits. About 40 per cent of the research subjects had CNVs that have an impact on genes relevant to heart function, Kennedy says.
Forty per cent is a high rate. ‘‘We’re seeing a surprising rate of CNVs with these people.’’
Frustratingly, none of the 40 per cent had the same CNVs. ‘‘We’ve got this smorgasbord of differences.
‘‘It could be these CNVs put you at risk for the disorder and then you have earthquake stress and few other things.’’
‘‘All of these women are older and their biology has changed as well. So it’s not quite an answer but it’s more interesting than previous genetic studies that have been hodge-podge.’’
Moreover, these CNVs are relatively rare and they’re relatively large, says Kennedy.
‘‘Big and rare are interesting. Things that are rare often have a quite big effect on biology. It’s kind of a rule.’’ Big and rare have ‘‘got to be clues’’.
This discovery was enough to get a science article published in the journal Nature, by 15 coauthors, in mid-May.
But it clearly hasn’t solved broken heart. More research is needed and the research team has collected five more cases arising from the 2016 Kaiko¯ ura quake.
They came too late for inclusion in the Nature paper, but the geneticists are exome sequencing as well as looking into the CNVs of those cases. They hope overseas researchers will look further into CNVs.
Waiting for another Goldilocks natural disaster isn’t necessary. There are thousands of one-off cases of broken heart worldwide that could be collated. Researchers need ‘‘consented DNA’’ to carry on the research. ‘‘We need to see if this phenomenon holds up,’’ says Kennedy.
There’s another new approach as well. If broken heart is partly genetic, then it should run in families.
There may be a family situation in New Zealand but privacy prevents further discussion at this point.
Broken-heart syndrome is the ‘‘classic example of where [stress] can kill you very quickly’’, says cardiologist Bridgman.
It’s well known that stress and psychological factors can have an impact on physical illness, he says. This research ‘‘may help us untangle the whole mind-body interaction. It’s real. This is the best example.’’
‘‘Big and rare are interesting. Things that are rare often have a quite big effect on biology. It’s kind of a rule.’’
Dr Martin Kennedy, a geneticist at the Christchurch campus of the University of Otago