UC San Diego researchers have identified a new inflammatory mechanism in the heart’s borderzone after a heart attack, driven by stressed cardiomyocytes. This discovery may lead to novel therapies aimed at preventing heart failure by targeting mechanical stress, DNA sensing, and IFN signaling.
Ischemic heart disease is the leading cause of death globally. It typically starts with a heart attack, or myocardial infarction (MI), during which part of the heart muscle dies because it doesn’t receive enough blood from the coronary arteries. This event triggers intense inflammation, changes to the structure of the heart wall, and eventually can lead to heart failure.
Anti-inflammatory drugs have been surprisingly ineffective at preventing heart failure. As a consequence, they are not a routine part of post-MI care. However, it is possible that the most potent molecular and cellular inflammation targets have yet to be discovered.
Discovery of a New Inflammatory Mechanism
In the August 28, 2024 issue of Nature, researchers from the University of California San Diego in the laboratory of Dr. Kevin King, associate professor of bioengineering and medicine, and a cardiologist at the Sulpizio Cardiovascular Center, report the discovery of a novel mechanism of cardiac inflammation that may expand therapeutic opportunities to prevent heart attacks from becoming heart failure.
Inflammation after MI is classically credited to professional immune cells like neutrophils and macrophages that infiltrate the infarcted heart and respond to molecules in the debris of dying cells. So the team was surprised when they discovered that the proinflammatory “type I interferon (IFN) response” was activated, not in the infarct where immune cells were concentrated, but instead in the borderzone, surrounding the infarct.
The borderzone has been a fascinating yet understudied area of the infarcted heart. It is where surviving heart muscle cells attempt to stabilize and even proliferate after being disconnected from their dying neighbor cells. Unfortunately, the borderzone has proven a challenging region to study because it is not easily isolated from the rest of the heart. Researchers overcame this obstacle using methods they recently reported based on single-cell RNAseq and spatial transcriptomics where cells of the borderzone are recognized based on their patterns of gene expression.
Cardiomyocytes as Key Initiators of Inflammation
To determine which cell type initiates borderzone inflammation, the team created a library of conditional knockout mice, each unable to initiate IFN signaling in a different cell type. To their surprise, heart muscle cells called cardiomyocytes emerged as the dominant initiators of borderzone IFN signaling. They found that mechanically stressed cardiomyocytes in the borderzone frequently suffered nuclear envelope rupture, which allowed the escape of nuclear DNA and sensing by cytosolic DNA sensors, leading to activation of IFN signaling. This in turn caused mechanical weakening of the heart wall and made it vulnerable to dilation, thinning, and rupture, providing a mechanistic explanation for the team’s previously reported observation that mice lacking IFN responses exhibited improved survival after MI.
“In the hospital, we care for patients with heart attacks and heart failure every day. New therapeutic targets for MI with the potential to prevent the development of heart failure are incredibly important, said Dr. King, senior author of the study and on the faculty in the Shu Chien Gene Lay Department of Bioengineering and the Division of Cardiology at UC San Diego.
Many questions remain, however, the newly reported findings suggest that limiting mechanical stress at the borderzone, inhibiting DNA sensing, and preventing type I IFN signaling may represent new opportunities for patients to avoid the development of heart failure after MI.
Reference: “Spatially clustered type I interferon responses at injury borderzones” by V. K. Ninh, D. M. Calcagno, J. D. Yu, B. Zhang, N. Taghdiri, R. Sehgal, J. M. Mesfin, C. J. Chen, K. Kalhor, A. Toomu, J. M. Duran, E. Adler, J. Hu, K. Zhang, K. L. Christman, Z. Fu, B. Bintu and K. R. King, 28 August 2024, Nature.
DOI: 10.1038/s41586-024-07806-1
Funding support for the study came, in part, from the NIH DP2 New Innovator Award.
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20 Comments
This is high tech animal abuse. They genetically engineer mice to not have certain genes, and then give them heart attacks to see what happens. You can’t trust people who do this to animals. This is why I left medicine. It is rife with animal abuse being excused as essential for medical progress. But you can’t trust psychopaths. See my article, Animal Research: The Rot at the Core of Medicine. https://www.academia.edu/123055005/Animal_Research_The_Rot_at_the_Core_of_Medicine
Exactly. Shows a mentality of cruelty.
Suggest a alternative instead of being vituperative
Absolutely! Shall the researchers just choose people at random, knock on their door, and say, “You’re it.” And lead you away to study your heart-for humanity’s sake???
The disease mechanism they were investigating cannot be studied in a petri dish. It involves physiological stress (ischemia) acting on differentiated cardiac tissue, followed by complex mechanical stress in different “zones” on that same tissue. We have therefore just described the minimum requirements of this research: a beating heart, inside of an animal, possessing among other things, blood vessels, and an intact immune system.
I have atherosclerosis and am at high risk for heart attack. Yes I read your “paper”.
“Sydney Ross Singer” –your name
“Medical Anthropologist” –your made up “specialty”(WTF???)
“Director, Institute for the Study of Culturogenic Disease” –exists only in your head, but you’re the Director of it. And you’re NOT a real scientist. One can indeed Google this “Institute”, but that’s also where it becomes clear that it’s nothing but a DBA (Sydney the All Knowing, Doing Business As…)
We’ve all heard of “useful idiot”. I classify you more as a narcissist and a blowhard, but if you’re also an idiot, you’re the absolutely useless kind. Your “paper” is just a screed, a long and error-riddled list of wack doodle. You’ve spread your unresearched ideas far and wide for a long time. You’re the “bras cause breast cancer because I said so” guy.
You seem to “know” everything right off the top of your head with a certainty so vivid, that no research is necessary. And in this fantasy world, the whole world needs to listen to you.
Well, in my own fantasy world, blowhards like you are banished to an alternate universe where the supreme blowhard himself is World Dictator. And in Sydney Ross Singer Universe, there are no real scientists, real scientific research isn’t conducted, and Sydney has heart disease. In fact, when we sent him to his own fantasy universe, we are allowed to give him one gift, and I chose to give him my own heart disease. See ya around, Sydney.
Meanwhile in our universe, I don’t oppose heart disease research even though I no longer have the disease it myself (thanks Sydney). I support that research because other people still have CVD.
Nature is full of pain. My cats kill one or two rodents every night. I eat meat. Lions kill zebras on the Serengeti by crushing their windpipe. Lions eat meat. They KILL. It HURTS. It’s TERRIFYING. Zebras live frightened lives. If Zebras weren’t eating the grass, something else would eat the grass, and be eaten by lions. If lions died out, that’s just more meat for the hyenas. Prey animals die violently in Nature and it has always been so. An ecosystem would collapse without this dynamic, and there would be no evolution.
You are a human with a large brain because your ancestors evolved into predatory apes.
Sydney, you’re invited back to the real world, if you’ll keep your know-nothing trap shut.
Unless you are a doctor and are researching this topic on your own…stop trying to call people out on whatever gets you upset in your fantasy world and stay in your lane Karen.
This is very ethical research, well designed, that produced medically significant and potentially promising results. Sydney is the non-scientist “Karen” who excoriated a team of real scientists doing real research that required in-vivo methods, therefore it is Sydney who needs to stay in his own UNSCIENTIFIC lane.
I called out a self-promoting charlatan, which is quite different from criticism of a scientist, or trashing valid, well designed research by a team of (real) scientists at a respected research institution. And unlike Sydney, a seller of seminars and books, I have nothing to sell… Which ALSO makes it different, doesn’t it?
Was I harsh? Yes. Because he deserved it.
I don’t wish you or Sydney any ill, but if either of you want to be morally consistent with your expressed holier than thou opinions, make a commitment to eschew all medical treatment that was discovered or perfected by “unethical” research. That rules out treatments for stroke, heart disease, cancer, any surgeries and medical interventions that were tried out on animals first or further developed using animals, such as transfusions, pharmaceutical treatments for infections, high blood pressure, diabetes, diseases of various the organs that you need to stay alive and happy (liver, kidney, brain, and almost everything else).
Once you swear off all of that, I sincerely hope that whatever ails you in future isn’t one of those things that needs modern medicine, because you’re down to a very short list of interventions available in the 18th Century. Setting broken bones, amputations, leeches (blood letting), and bed rest.
It’s true that some animal research is completely unnecessary and therefore unethical (such as when new in-vitro methods make older in-vivo methods unnecessary), and I’m strongly against ANY unnecessary use of animals. But I also eat bacon and terminate rat infestations with whatever works, and none of the effective vermin control methods are pleasant for the rats. I’m practical, and make no bones about it.
All of the pets owned and loved by everyone in my family, have been rescues (many of them dogs dropped off in the desert I grew up in by unknown owners who didn’t want them anymore). My Dad and I have adopted a total of 5 pitbulls that were set to be euthanized. I vote for legislation that improves the living conditions of livestock.
I try, with sincere effort but imperfect success, not to be a hypocrite about anything, and that includes not posing as a saint.
And I have heart disease, so I want that research to happen, even over your objections.
Brett, where would you draw the line to cause suffering to others for your own potential benefit? You don’t seem to mind killing innumerable mice and rats. How about dogs and cats, which are also used? How many monkeys would you be willing to see killed in experiments? Do you know that over 100 million animals are killed annually for experiments with promises of a potential benefit to people? Would you be willing to use humans? How about re****** people? Or how about an ethnicity we consider inferior? This has all happened. Doctors participate in this. Nazi doctors experimented on Jews. US doctors experimented on blacks in the south with a syphilis experiment. We were all experimented on with COVID vaccines. This is all being done by people who are willing to torture animals in the name of science, but really in the name of profit.
There is a better way, and it involves looking at yourself and the things you are doing, eating, and thinking that are making you sick. We have more control over our own bodies and health than most people realize. The answer is not in vivisection (animal research). The answer is in yourself and the way you live, and the kind of culture we have. We are causing our own disease. You won’t discover that from torturing rats.
Best of health to you.
Wow, mad much. I think you’re the psycho.
Wow…. Hahaha!!!! How does one come back from this??? I couldn’t help but respond to let you know how loudly I laughed, reading this!!
All the psychopaths seem to be angry at being called out for their cruelty to animals. My background is in medicine, biochemistry, and anthropology. I have 12 years of college and graduate school training, from Duke and UTMB at Galveston. And I know animal cruelty is wrong, ethically and scientifically. For those who make a living at animal research, you clearly have an empathy problem regarding animals. For many people who have empathy, there is no justification for causing suffering to others, period.
Alternatives include moving away from the biochemistry-focused model of modern medicine, which sees no difference between the brains of mice, fruit flies, and humans. If needed, use human volunteers. Lots of people will be willing to participate in trials.
Better yet, let’s look at the cultural causes of disease, which is the leading cause. Our culture is killing us, while scientists study mutated mice in labs to figure out some esoteric biochemical process that may have nothing to do with human health.
I left medicine because of its cruelty to animals. If you can be cruel to helpless, innocent animals, then you can’t be trusted with human healthcare. You can’t trust people with empathy problems who are willing to subject animals to experiments. It’s a slippery slope, and medicine has a history of human abuse, as well.
Lol, please stick to your “morals” and eschew the use of all modern medicine then. They systematically narrowed which cells are causing the inflammation and you think it is “unnecessary”? This discovery will likely savr millions of human lives over the next 2 or 3 decades. How many 10s or 100s of millions (or more?) of rodents die “unnecessarily” each year because people enjoy the companionship of cats and dogs? Same for mouse/rat traps and poison.
Maybe try to have some perspective. There are plenty of other animal cruelty incidences that are actually worth prioritizing.
So basically………save the mice and let the humans suffer. You’re an imbecile. End of story.
I hear these days they are using computer models instead of corpses to teach medical students. Perhaps someday they will use AI models to replicate an area of the body that needs closer study. These mouse studies do not always transfer to the human anatomy. So alot of the time it’s just unnecessary mouse suffering that doesn’t help you at all
Micro organisms are to blame for a lot of medical issues through out the world. One day technology will discover the once thought plant parasites such as Nematoda Meliodgyne Javanica can and does infect human and other mamal host through oral consumption and infect the host with major viral and bacterial infections which are actually responsible for things such as this…..
The massive increase in heart attacks is 100 % due to the bioweapon known as the Covid 19 Vaccine. Covid 19 is fake. Here is the proof. CVHOAX.COM
100% CORRECT !
The Sheeple have been duped
Exactly. Instead of ruthlessly abusing animals to come up with some high sounding worthless theory why don’t they study people and their own habits, the food production shortfalls and even the ingredients fed to us in our everyday diets? Or how about GMA,s? Oh and here is one…how about Pharma and how all of these factors play into human disease and death?
While that is a valid point (stop the diet and behavior that leads to heart attacks), we already know that. Hard to change when the elite want to keep making money off our bad health. This research will help people with all kinds of heart attacks, not just those issues by poor diet. Live long enough due to other advancements in medicine and you may eventually have a heart attack despite a lifetime of good choices.