With Sudden Death, Don't Automatically Blame the Heart

Gayatri Acharya, MD; Michael Ackerman, MD, PhD; Peter Noseworthy, MD


October 09, 2017

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Gayatri Acharya, MD: Greetings, I'm Dr Gayatri Acharya, cardiology fellow at Mayo Clinic. Today we will be discussing the evaluation of patients with sudden death. I am joined by my colleagues, Dr Michael Ackerman and Dr Peter Noseworthy, who both specialize in this area. Welcome.

There have been some recent studies evaluating sudden death.[1,2] Can you summarize those studies for us?

Peter Noseworthy, MD: We would like to talk about a series of studies that examined the causes of sudden cardiac death. [An estimated] 300,000 people die per year in the United States of sudden cardiac death.

But what exactly is sudden cardiac death? Researchers in San Francisco performed systematic evaluation of every out-of-hospital sudden death over approximately 18 months. That included autopsies in over 80% of cases and a review of the medical records in adjudication with a multidisciplinary panel—[comprising] neurologists, cardiologists, electrophysiologists, and pathologists—to try to [determine the cause of death].[1,2] Although we consider sudden cardiac death as death within 24 hours of last being seen healthy or within an hour of symptom onset and assume that these are cardiac, what the researchers found was that about 40% of the deaths were actually noncardiac; about 5%were neurologic. It allows us to challenge the idea that all of these sudden deaths are of cardiac origin.

Dr Acharya: Dr Ackerman, does that surprise you at all, those results?

Michael Ackerman, MD: Yes and no. The real challenge with this is the rigor to which we are doing the detective work after somebody dies suddenly and the false notion, like Dr Noseworthy said, that when you do meet that definition—1 hour or 24 hours—it must be the heart. We get tunnel vision and we prematurely and erroneously conclude that it must be the heart at fault, or it must be the heart because of coronary artery disease. We continue to invoke these reflexive reactions rather than asking, "Do we really understand what is killing people, whether they are 65 or 15?"

I am not surprised that there are a significant number of noncardiac organs involved in the death of a person, whether we are talking about sudden unexplained death in epilepsy (SUDEP) that has gone underappreciated. Many deaths are due to drug use (eg, the opioid epidemic). Just because you die within 24 hours from being previously presumed healthy does not mean it is the heart.

What is surprising to me is the researchers did that many autopsies. That is one of the highest number of systematic autopsies performed. When we have made conclusions in the past based upon an autopsy rate of 10% to 20%, it is not surprising that we have not understood the situation fully. That was quite impressive that these investigators were able to systematically get almost every out-of-hospital arrest individual autopsied.

Preventing Sudden Death

Dr Acharya: How much of sudden death is preventable?

Dr Noseworthy: We tend to think of sudden death as a disease of the defibrillator, for instance; and in every paper you read about implantable cardioverter defibrillators (ICDs), the first line is there are 300,000, 350,000 deaths per year—the idea being that if we could only implant devices in the right people and address their coronary disease.

But this research underscores that there are many ways to die suddenly, and we have to reevaluate that periodically. Some of our old estimates are probably out of date with changing epidemiologic patterns in the country. For example, the opioid epidemic, increasing use of anticoagulants and antiplatelets (often in combination), which probably predisposed intracranial bleeds, and some of the other previously relatively underreported or underdetected causes. Not all of those are preventable, but that is our public-health goal. Until we understand the problem, we will not know how to address it.

Dr Ackerman: You also have [to consider the] phenotype of a sudden death victim: some phenotypes are clearly preventable, others are not. If you think of sudden death in the young, we and others have shown that potentially half of those cases are preventable. That is, half of them are due to either legitimate pre–sudden death warning signs that went unrecognized or were not reacted to (eg, exertional faint happened during the 100-m track event, the unexplained car accident with possibility of a genetic heart disease as a cause). We think that legitimately half of sudden deaths in young people are preventable if we recognize warning signs, react to them, and evaluate them carefully.

The only chance to prevent the other half of youthful sudden deaths is a screening program to identify those with sudden death–predisposing heart disease. But now, when we see a study like this, [heart disease] may not be the only reason.[1,2] So [it is important to consider] other organs besides the heart that can kill [individuals] suddenly.

Implications of Noncardiac Causes

Dr Acharya: What are the implications with that in mind for going forward in our clinical practice, or how this will drive further research?

Dr Ackerman: We need to be better detectives. With sudden death of a person, we ask, "Young or not young?" in our questions about the circumstances of the death. We move too quickly past that as opposed to trying to [ascertain whether the] death signals a genetic condition lurking in the family or a nongenetic condition that is potentially modifiable/addressable. We have to be better.

In our sudden-death clinic here at Mayo, we think of ourselves as detectives. When you put on a detective mind-set, it is a very different assessment of the evidence from what you sometimes do in ordinary clinical practice.

Dr Noseworthy: It's equally important to understand that some of these deaths are not due to heritable causes. We essentially stigmatize a family or give them a sense of unease if they think that there is something in their family that poses an ongoing threat. A rigorous evaluation at the time of an unexpected death is valuable regardless of the outcome of the evaluation.

Dr Ackerman: It is powerful for these families to give them closure as to the cause and to provide clarity as to whether it has any relevance to the surviving family members. When we prematurely or erroneously declare that it was due to a genetic heart disease X, Y, or Z, they immediately think, "Who is next in line to be knocked off?" when, in fact, it had nothing to do with genetics. It is really important that we get it right, and there has been a tremendous amount of sloppiness in the literature and in the field.

The way we evaluate sudden death, the decedent, and the surviving first-degree relatives is all over the map. It ranges from condolences only to performing every possible cardiac test on every living family member—and doing it yearly because, after all, these things evolve. There is a tremendous amount of heterogeneity that goes into the postmortem evaluation of the decedent as well as the postmortem evaluation of the living family members left behind and a tremendous gap in gradient in how it is done from the conventional autopsy, which is hardly ever done—95% in this study was incredibly impressive—to some places now conducting whole-exome molecular autopsy.

Molecular Autopsy in Suspicious Death

In whole-exome autopsy, if the death is unexplained after a conventional autopsy, we go on and do postmortem genetic testing, which raises additional questions about vetting genetic test results to avoid ascribing that death to mutation X when that mutation had nothing to do with that death. That can have disastrous consequences for the family, like you said, when you make an erroneous presumption and conclusion that it is due to the genes. We need to do a better job getting it right.

Dr Acharya: Does that further testing gear primarily toward cardiovascular molecular issues, or is it broader in the context of this article?[1,2]

Dr Noseworthy: This article did not address molecular autopsy specifically. That is an evolving practice, and how to deploy that most effectively is yet to be determined. We are furthest along in identifying potentially heritable cardiac causes of sudden death, but it is still early days for the molecular autopsy.

Dr Ackerman: I think molecular autopsy is going to have the highest yield in phenotypically suspicious death where the initial reaction is, "That just feels like a heritable channelopathy, or maybe we should have the medical examiner take a second look at the heart muscle because this feels like it certainly could be a cardiomyopathy."

The younger you are when you die suddenly and unexpectedly, the higher the likelihood of a genetic culprit. To suggest doing postmortem genetic testing in the 70-year-old who dies suddenly would be a tremendous waste of resources. Concluding that it is the heart just because he or she was 70 and died within 24 hours of seemingly being healthy is also narrow-minded, and that is what this article draws attention to.

Dr Acharya: Thank you to Dr Ackerman and Dr Noseworthy for these very important insights today, and thank you for joining us on on Medscape Cardiology.


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