Field of Science

Sudden death: cardiac arrest, heart attack, and what you should do

Two weeks ago, a man who had come to our house to deliver a box for storage/moving died of a either a heart attack or sudden cardiac arrest in front of our house. I've already blogged the personal aspects of this episode over at my personal blog. What I'd like to blog here is simply a health warning of sorts, an alert for anyone who reads this in the hope that maybe that one person can avoid an early, sudden death like this one.

The man who died was only 56. But from what we experienced, he had at least three of the risk factors for having heart disease:
  • he was male
  • he was over age 45
  • he had central obesity
I'd infer from his physical condition that he likely also had another risk factor, a sedentary lifestyle. Even though his work had been for many years delivering these boxes--with a smile and a lovely friendliness, I add--it was not necessarily physically demanding work, as it primarily involved using a forklift to load and unload the crates.

The thing is, I learned from one of his co-workers that he had come in the previous day complaining about feeling unwell in an odd, indescribable way and of unusual fatigue. I wish--I'm sure everyone who knew him wishes--that he'd taken that as a sign to get checked out. With his risk factors, it would have been a reasonable thing to have done.

Complicating his situation was the fact that he had asthma. The symptoms of an asthma attack and of a heart attack can seem very similar and difficult to tease apart. The key distinction seems to be that asthma doesn't involve a feeling of chest pressure, and a heart attack does not respond to the use of inhaled asthma medication.

Add to that that his asthma may also have been a risk factor for heart disease, and you've got someone who had four or five risk factors for a heart attack. He was certainly a good candidate for a full health workup had he presented the previous day with his symptoms of "not feeling quite right" and "fatigue" and his risk factors.

His death was a terrible loss for his family. It's also terrible to think that recognition of some of the risk factors compounded by what may have been some warning signs went unheeded and ended in this loss. These issues aren't close to my heart only because this man died at our home. My grandfather also died at a relatively young age and without warning, lying in bed, reading a news magazine. He also had a number of risk factors for heart disease, including a family history, smoking, and other lifestyle factors. His visits to the doctor were few and far between, and he likely had never had a workup for heart disease. The night before he died in his bed, he'd complained about not feeling quite right, an upset feeling in his stomach. And then he...just died.

Everyone is going to die. Obviously, we can't get away from that. But an awareness of risk factors and of lifestyle factors you can modify can mean the difference between dying suddenly and all too young or dying in your sleep at a grand old age with your life in order and some expectation that Death is on its way.

Here is a list of risk factors for heart attack:
  • Age: Men over 45, women over 55
  • Family history
  • Smoking
  • Diabetes
  • High blood pressure
  • Poor lipid profile (high cholesterol, triglycerides)
  • Obesity, especially accumulated around the waist
  • Lack of physical activity/sedentary lifestyle
  • Stress

And here is a list of some of the warning signs of a heart attack
  • Chest discomfort
  • Discomfort in the torso/upper body (this is what my grandfather had)
  • Shortness of breath
  • Sweating, nausea

Another form of sudden death related to heart problems can be sudden cardiac arrest. We were told that the man who died did so of a heart attack, but I'm not sure if that was a term arising from a layperson's understanding or because that was the final medical determination. A sudden cardiac arrest results from electrical misfiring in the heart muscle. It differs from a heart attack, which results from blockage of blood flow to the heart so that the heart tissue dies. Either can cause sudden death. The fact that he may have been having some sort of prodrome the previous day could have indicated either. If he was fibrillating, he also would have felt "odd" and "fatigued."

Some things about what happened make me think that the man who died may have experienced sudden cardiac arrest. He was unresponsive and not breathing when we found him, and after the EMTs arrived, they continued the CPR we'd begun and tried de-fib on him three times. Given these factors, it sounds to me as though he'd had sudden cardiac arrest, rather than a heart attack. The risk factors for the two are similar. And the outcome in this case, regardless, was death.

Finally, there is the matter of what a bystander who finds themselves in our position can do. We immediately began chest compressions. Thanks to my work as a scientific editor, I've just recently edited several papers in emergency medicine and had learned that chest compressions are the thing to do--no mouth-to-mouth is necessary. Further, the compressions really need to be deep enough. In essence, you are trying to be the heart for the victim, to imitate what the heart would be doing.

So, the current response to a sudden cardiac death is pretty simple: Chest compressions only, 100 times a minute. Count them out loud as you go. It's a fast clip. For more information on what you can do in an emergency situation like this one, see the Red Cross guidelines (pdf). Learning these may someday help you save a life, although in our case, that was not the outcome.

Endocrine disrupting compounds: study one million permutations, or just get rid of the damned things?

Do these cans provide a route for an endocrine disruptor invasion of you?

Bisphenol A, also known as BPA, has become the bugbear endocrine disruptor du jour. It recently hit the headlines for occurring at higher levels in the U.S. population than in Canadians and for threatening you via everything from consuming canned foods to touching ATM receipts. But BPA is not alone in accessing your body by way of packaged foods. Phthalates, organotins, and benzophenone, a carcinogen, also can move from your food packaging to you. According to Jane Muncke, author of a recent review in the Journal of Steroid Biochemistry and Molecular Biology, these additional endocrine-disrupting compounds, or EDCs, in our “food contact materials” may pose a threat to us, and she calls for testing of complex mixtures of these chemicals in specific populations.

The mystery here is that her words echo almost precisely what EDC researchers have been saying for more than a decade: We need more tests using mixtures to reflect real life. Why are such studies still lacking?

The study of endocrine disruption once was my field. As far back as the 1990s, researchers focused on endocrine disruption, including Yours Truly (PDF), were calling for studies of mixtures of these chemicals. Standard toxicology testing tended to home in on a single compound at a time, assessing its effects at lower and lower exposures until no more effects could be detected, indicating a safe exposure. But what this approach ignores is real life: We are all exposed to multiple compounds, and how they interact with each other in affecting us can be a real puzzle.

What’s not puzzling is their presence in our food packaging and food and in our bodies. Studies of everything from blood to breast milk have revealed unsettling amounts of these compounds, which often, like a steroid hormone, have a love for fat. Once in you, an endocrine disruptor can do exactly what the term implies: disrupt hormone signaling. Given that everything we do involves an interaction of hormones with our nervous system and other body systems, these disruptions can range from the paltry to the profound.

One of the key features of hormones is that they operate in subtle, exquisitely refined pathways of feedback and interaction at very low concentrations. The introduction into that system of a foreign compound that acts like a hormone can bollix up the works and derail the signaling. What sounds like negligible amounts—like one part per billion or trillion, a drop in a billion or trillion drops—can send hormone signaling astray and disrupt an entire system.

If you’re grown, the results of that disruption may not be so noticeable. But for a developing fetus or a pubescent teen, these derailments of the endocrine system can derail development, too. It’s analogous to the influence of alcohol exposure. An acute high exposure for a fetus can have a disruptive and permanent effect, while an acute high exposure in an adult may cause no more trouble than some unpleasant toilet hugging and a bad headache.

One of the biggest problems with testing mixtures of these compounds is the immensity of the undertaking. The different structures of polychlorinated biphenyls (PCBs) alone number in the hundreds. Add to that a few developmental periods—embryonic, fetal, puberty—and a few specific populations (e.g., male, female, obese)—and the experimental design matrix for the PCBs alone (without including mixtures), each in only a single dose, would require 1,881 groups, not including controls. Double that to test pairs of PCBs. To add in everything we face on a daily basis? Overwhelming.

Tack onto this unwieldy complexity the confusing behavior of the endocrine disruptors themselves. Some of these compounds act like an estrogen in some contexts, an anti-estrogen in others, or an anti-androgen in still others. The differences in their effects can rely on the smallest molecular rearrangements between compounds or even reverse at different doses. Predicting how they will behave has proved to be an intractable problem. And then there's the hormesis factor--these compounds often don't have a linear dose-response effect. Instead, low doses or high doses might cause exactly the same outcome, while middlin' doses might not do much at all.

The key word that EDC researchers and the EPA were throwing around at the dawn of the aughties was “high-throughput.” That jargony term means “doing thousands of tests at once using a fast, preferably cheap system.” Unfortunately, a feasible quick, accurate system of this kind has yet to be established for regulatory use, although many groups are focused on developing such a system.

In her review paper of endocrine-disrupting compounds in food contact materials, Jane Muncke calls for more studies focused on testing multiple EDCs at once. She also points out that studies should target different populations to tease out how these mixtures might affect, say, an obese person or a child entering adolescence. It’s an important call to action, but unfortunately, it’s a call to action that has entered its own adolescence, now aged about 15 years. A better approach may be from each end of the equation: food packagers identifying packaging that carries less of an endocrine-disruption threat, and food consumers investing more in less-processed food. Muncke asks for more testing, but as Japan demonstrated more than ten years ago, elimination from food packaging is another way to say bye-bye to EDC bugbears like BPA. Edited to add: And only today, I see that China's planning to eliminate BPA from baby products. CHINA, people.

Sussing out the spit: on genetic analysis, Y chromosomes, and Vikings

(As Field of Science seems to be having an impromptu 23andMe festival, I thought I'd resurrect this post from October): A few months ago, it was National DNA Day or something like that, and one of the genetics analysis companies had a sale on their analysis kits, offering a full panel of testing for only $100. Giddy with the excitement of saving almost $1000 on something I'd long been interested in doing, I signed on, ordering one kit each for my husband (a.k.a. "The Viking") and me. Soon, we found ourselves spending a romantic evening spitting into vials and arguing about whether or not we'd shaken them long enough before packaging them.
The company promised results in six weeks, but they came much faster than that, in about three weeks. Much to my relief, I learned that neither of us carries markers for cystic fibrosis and that I lack either of the two main mutations related to breast cancer. Those basic findings out of the way, things then got more complex and more interesting.
How it works
First, a bit of background. These tests involve sequencing of specific regions to look for very small changes, a single nucleotide, in the DNA. If there is a study that has linked a specific mutation to a change in the average risk for a specific disorder or trait, then the company notes that. The more data there are supporting that link, the stronger the company indicates the finding is. Thus, four gold stars in their nomenclature means, "This is pretty well supported," while three or fewer slate stars means, "There are some data for this but not a lot," or "The findings so far are inconsistent."
Vikings and Ireland
The Viking is a private person, so I can't elaborate on his findings here except to say that (a) he is extraordinarily healthy in general and (b) what we thought was a German Y chromosome seems instead to be strictly Irish and associated with some Irish king known as Niall of the Nine Hostages. Why hostages and why nine, I do not know. But it did sort of rearrange our entire perception of his Y chromosome and those of our three sons to find this out. For the record, it matches exactly what we learned from participating in the National Geographic Genographic project, so we've even managed a replication. I'd ask the Viking if he were feeling a wee bit o' the leprachaun, but given his somewhat daunting height and still Viking-ish overall demeanor (that would be thanks to his Scandinavian mother), I'm thinking he doesn't. Lord of the Dance, he is not.

Markers that indicate an increased risk for me
I have an increased risk of...duh
Looking at the chart to the left (it's clickable), you can see where I earned myself quite a few four gold stars, but the ones that seem most relevant are those with a 2x or greater increased risk: lupus, celiac disease, and glaucoma. The first two do not surprise me, given my family's history of autoimmune disorders.
If you focus on a list like this too long, you can start to get a serious case of hypochondria, worrying that you're gonna get all of these things thanks to those glaring golden stars. But to put it into context, for the lupus--for which my risk is 2.68 times higher than a regular gal's--that still leaves me in the population in which 0.66 persons out of every 100 will develop this disorder. Compare that to the 0.25 out of every 100 in the regular-gal population, and it doesn't strike me as that daunting.
Some of those other things on there? Well, let's just say they're close. My risk of thyroid cancer might be raised...but I no longer have a thyroid. Hypertension risk is increased--and I have stage 2 hypertension. Gallstones, gout, alcholism, asthma...based on family history, it's no surprise to me to see some mixed or clear risk involved with these, although I have none of them. Does that mean that someone else with these increased risks will have related real-life findings? No. It only means that you're at a bit more risk. It's like riding a motorcycle vs. driving a car. The former carries more risk of a fatal wreck, but that doesn't mean you're absolutely gonna die on it if you ride it.

Disorders for which my risk is allegedly decreased
I have a decreased risk of...
None of my decreased risk findings are very eye catching in terms of actual drop in risk except for Type II diabetes (now where is my bag of sugar?). As I have been under evaluation for multiple sclerosis and have a family member with it, it's interesting to see that my risk for it, based on existing studies and known polymorphisms, is decreased. And even though I know that much of this is largely speculative and based on little firm data, it's still sort of comforting to see "decreased risk" and things like "melanoma" in the same group.
Don't make my brown eyes blue!
And they didn't. They nailed the eye color and other trait-related analysis, such as level of curl to the hair, earwax type, alcohol flush reaction, lactose intolerance (unlikely), and muscle performance (I am not nor have I ever been a sprinter). And even though I do not have red hair, they reported that I had a good chance of it, also true given family history. I am not resistant to malaria but allegedly resistant to norovirus. I wish someone had informed my genes of that in 2003 when I was stricken with a horrible case of it.
Ancestral homeland
Yep. They nailed this one. One hundred percent European mutt. Mitochondria similar to...Jesse James...part of a haplogroup that originated in the Near East about 45,000 years ago then traveled to Ethiopia and Egypt and from there, presumably, into Europe. It's a pretty well traveled haplotype and happens to match exactly with the one identified by the National Geographic Genographic project. When it comes to haplotypes, we're batting 1000.
In summary
Some of these findings are reliable, such as the absence of the standard breast cancer mutations or the presence of certain mutations related to autoimmune disorders, while other findings are iffy. The company duly notes their iffiness in the reports, along with the associated citations, polymorphisms, and level of risk identified in each study. They don't promise to tell you that your ancestors lived in a castle 400 years ago or hailed from Ghana. From this company, at any rate, the results are precise and precisely documented, and as I noted, pretty damned accurate. And they're careful to be a clear as possible about what "increased risk" or "decreased risk" really means.
It's fascinating to me that a little bit of my spit can be so informative, even down to my eye color, hair curl, and tendency to hypertension, and I've noted that just in the days since we received our results, they've continually updated as new data have come in. Would I be so excited had I paid $1100 for this instead of $200? As with any consideration of the changes in risk these analyses identified, that answer would require context. Am I a millionaire? Or just a poor science writer? Perhaps my genes will tell.

A play date with snakes

Three boys, ages 7, 7, and 6, had a play date and discovered a pair of garter snakes "wrestling." The commentary is priceless.

Autism, RORA, and testosterone

Autism, RORA, and testosterone

Autism and high testosterone (or androgen) levels have been linked for a long time in part because autism appears to be so much more prevalent among boys compared to girls (more on that later). Thanks to this apparent male bias, the connection between androgens and autism, the “extreme male brain hypothesis” of autism, gets a lot of attention. Adding to this attention is recent intriguing work from Valerie Hu and colleagues, published in PLoSOne, connecting an androgen to the regulation of a specific gene, called RORA, that may be associated with autism.

The RORA finding has the news media, well, ROR-ing about it with headlines promising that “Testosterone may bump autism rates in males” and “Faulty testosterone cycle may explain male autism bias.” This latter story even concludes in the lede that the association demonstrates that it is more likely that “males will accumulate testosterone in the dangerous amounts that are thought to lead to autism.” A bit of a leap, that, especially as the researchers did not strictly use testosterone in this work and did not show a male bias in RORA levels.

A pause for a few observations before we move on

1. This study was an in vitro study in which a nerve cell line participated through direct exposure to hormones in a culture dish and a protein from the brain tissues from autistic and non-autistic people was measured.

2. None of the work was done in a living organism. That’s not an indictment of the work, just a caution against leaping to conclusions. That’d be you, news media.

3. The male brain in mammals forms as male and males act like males in part thanks to estradiol, a kind of estrogen that an enzyme called aromatase makes from testosterone. Aromatase also converts androstenedione into another estrogen, estrone (see figure).

4. Another enzyme, 5-alpha-reductase, also can act on testosterone to turn it into dihydrotestosterone (DHT), a powerful androgen that binds the androgen receptor about three times more tightly than testosterone itself.

5. Hormone pathways are usually tightly regulated, engaged in a number of feedback loops to maintain the hormone levels within a very narrow concentration range. Many proteins are involved in this maintenance, some grabbing hormones and making them unavailable and others converting excess hormone into another form until levels return to a balance.

RORA and autism

In previous work, Hu and her group assessed the gene expression patterns between sets of identical twins, one of whom had autism. They found that RORA (retinoic acid-related orphan receptor alpha) stood out as a gene tagged more often for shutdown in the autistic twins, so it wasn’t used as much. They looked at brain slices from autistic people and compared RORA expression levels in these slices to those from non-autistic people and found that RORA expression was lower in the autistic brains. Not all autistic brains, but most. RORA was officially identified as a “candidate gene” in autism.

RORA and aromatase

Their current work involved both a nerve cell line (a neuroblastoma cell line) growing in a dish and brain tissue samples from autistic people and sex- and age-matched controls. To evaluate how hormones affect RORA expression, Hu’s team exposed the nerve cells either to dihydrotestosterone (DHT) or estradiol. A hormone called 5-alpha-reductase is required to make DHT, which is a more powerful androgen than testosterone, and a hormone called aromatase is required to make estradiol. The DHT and estradiol receptors, the proteins that receive the hormone messages, both have the job of turning genes off or on. In this study, DHT caused its receptor to inhibit the RORA gene, while estradiol caused its receptor to activate RORA. Finally, RORA itself also turns genes on or off. Hu’s team showed that one of RORA’s targets is the aromatase gene.

Low RORA because of too much androgen, or too much androgen because of low RORA?

Quote from the Discussion:

On the other hand, we observed reductions in RORA in brain tissues from both male and female subjects with ASD, suggesting that RORA deficiency is not gender-specific. Interestingly, RORA and ER share a consensus binding site on DNA (AGGTCA) and consequently common target genes. The existence of shared gene targets may explain why females, with higher levels of estrogens, are less susceptible to autism. That is, estrogens may not only protect females against autism by increasing the level of RORA expression, but also by inducing shared target genes of RORA through ER, thus compensating in part for RORA deficiency.

Hu’s previous work identified differences in RORA chemical tagging between identical twins with and without autism. Their current work looks at levels of RORA expression. A chicken–egg question arises for anyone focused on an androgen framework: Do people with autism appear to have low RORA because of too much androgen, or do they have too much androgen because of low RORA? Their statement above seems to allow for both scenarios. Yet RORA levels didn’t differ between autistic males and females, and without a sex bias in RORA and aromatase levels, these findings aren’t easily used to explain the presumed sex bias in autism. Unless you change the question.

Do people with autism have too much brain androgen…or too little brain estrogen?

When Hu’s team looked at the brains of people with autism, the RORA decrease didn’t differ between males and females, and we can only assume that both also shared low aromatase levels (the authors do not specify). The authors note findings suggesting that a female’s more abundant estrogens could engage in crosstalk with a RORA pathway to make up for any deficiency.

Their cell culture outcomes indicate that an estrogen deficiency would lead to less RORA activation, further reduced aromatase, and worsened estrogen deficiency. Even normal androgen levels could exacerbate this decrease if aromatase isn’t making enough estrogen to balance androgen action. Hu’s group doesn’t seem to have tested both hormones at once. The brain tissue findings suggest that both males and females have low RORA and aromatase, which points to an autism association based on estrogen deficiency with no confirmation of excess androgen.

An estrogen deficiency in the presence of normal androgen levels, which studies indicate is a reasonable scenario, would result in the overall systemic normalcy of autistic children (e.g., no hyperandrogenized sex characteristics). Yet it would leave the potential for more prominent androgen-based outcomes in the sex that already has less estrogen: the males. If females do have a compensatory mechanism because of overall higher estrogen levels in the first place (thanks to ovaries), then the “cross-talk” the authors suggest would likely result in a lesser severity of autism symptoms in many girls.

Brains are funny things

The features of a brain-related disorder or difference in a male can vary considerably from the features of the same disorder in a female, which takes me to another observation: It is possible that one reason for this male bias is underdiagnosis among girls? Females often manifest autism in more subtle ways and are more likely to be misdiagnosed with depression or personality disorder, are less likely to be referred for help at an early age, and show less aggression that might lead to a referral or diagnosis. Again, this scenario falls right into the framework of an estrogen deficiency hypothesis in which girls compensate to some extent with their naturally higher starting levels of estrogen.

I’m not suggesting that retinoic acid-related orphan receptor alpha isn’t a candidate gene to pursue further as part of one of the many potential paths that lead to autism; in fact, I just spent about 1300 words focusing on how it might work along with aromatase to reduce estrogen levels. In the PLoSOne paper and in interviews, Valerie Hu and her team also made sure to note that RORA was just one among many possibilities. That didn’t stop the dramatized headlines, though. As always with any results having to do with a candidate autism gene, if it turns out to be involved in autism, it’s likely a part of only one of several pathways that are.