Immune Cells Mistake Heart Attacks for Viral Infections

A study led by Kevin King, a bioengineer and physician at the University of California San Diego, has found that the immune system plays a surprising role in the aftermath of heart attacks.  The research could lead to new therapeutic strategies for heart disease.

The team, which also includes researchers from the Center for Systems Biology at Massachusetts General Hospital (MGH), Brigham and Women’s Hospital, Harvard Medical School, and the University of Massachusetts, presents the findings in the Nov. 6 issue of Nature Medicine.

Ischemic heart disease is the most common cause of death in the world and it begins with a heart attack. During this process, heart cells die, prompting immune cells to enter the dead tissue, clear debris and orchestrate stabilization of the heart wall.

But what is it about dying cells in the heart that stimulates the immune system? To answer this, researchers looked deep inside thousands of individual cardiac immune cells and mapped their individual transcriptomes using a method called single cell RNA-Seq. This led to the discovery that after a heart attack, DNA from dying cells masquerades as a virus and activates an ancient antiviral program called the type I interferon response in specialized immune cells. The researchers named these “interferon inducible cells (IFNICs).”

When investigators blocked the interferon response, either genetically or with a neutralizing antibody given after the heart attack, there was less inflammation, less heart dysfunction, and improved survival. Specifically, blocking antiviral responses in mice improved survival from 60 percent to over 95 percent. These findings reveal a new potential therapeutic opportunity to prevent heart attacks from progressing to heart failure in patients.

“We are interested to learn whether interferons contribute to adverse cardiovascular outcomes after heart attacks in humans,” said King, who did most of the work on the study while he was a cardiology fellow at Brigham and Women’s Hospital and at the Center for Systems Biology at MGH in Boston.

The immune system has evolved innate antiviral programs to defend against a diverse range of invading pathogens. Immune cells do this by detecting molecular fingerprints of pathogens, activating a protein called IRF3, and secreting interferons, which orchestrate a defense program mediated by hundreds of interferon-stimulated genes. Investigators found that surprisingly, the antiviral interferon response is also turned on after a heart attack despite the absence of any infection. Their results point to dying cell DNA as the cause of this confusion because the immune system interprets it as the molecular signature of a virus.

Surprisingly, the immune cells participating in the interferon response were a previously unrecognized subset of cardiac macrophages. These cells could not be identified by conventional flow sorting because unique markers on the cell surface were not known. By using single cell RNA Seq, an emerging technique that combines microfluidic nanoliter droplet reactors with single cell barcoding and next generation sequencing, the researchers were able to examine expression of every gene in over 4,000 cardiac immune cells and found the specialized IFNIC population of responsible cells.

Future studies will aim to better understand the interferon response and the IFNIC cell type and explore their roles in the infarcted and remodeling heart. The team is also working to understand the interferon response in other tissues and diseases where cell death occurs.

Study: Breastfeeding Moms May Be at Lower Risk of Heart Attack and Stroke

We have known for a long time that breastfeeding is healthy for babies; however studies have shown that it can provide long term health benefits for the moms too. This new information comes from recent research published in the Journal of the American Heart Association. The comprehensive study followed 300,000 adult women in China.

Previous studies showed different health benefits from breastfeeding were short term including lower cholesterol, blood pressure, glucose levels, and weight loss after pregnancy. However, this study explored long term results for the 300,000 subjects who had breastfed their babies. The research was performed by researchers from the University of Oxford, Peking University, and the Chinese Academy of Medical Sciences. The 300,000 women that took part in the study were between 30 and 79 years old and from 10 urban and rural areas across China, they tracked their health through hospital records and death registries and were part of the prospective China Kadoorie Biobank of half a million adults. The observations were as follows:

  • Nearly all gave birth and 97 percent of the women breastfed each of their babies for an average of 12 months.
  • Compared to women who had never breastfed, mothers who ever breastfed their babies had a 9 percent lower risk of heart disease and an 8 percent lower risk of stroke.
  • Among mothers who breastfed each of their babies for two years or more, heart disease risk was 18 percent lower and stroke risk was 17 percent lower than among mothers who had never breastfed.
  • Each additional 6 months of breastfeeding per baby was associated with a 4 percent lower risk of heart disease and a 3 percent lower risk of stroke.

More research is needed to determine a better correlation between breastfeeding and the health results since it is possible that women who breastfed might also engage in other healthy behaviors that might also lower their risk for cardiovascular diseases. However, the researchers did take into consideration other lifestyle choices and a range of risk factors so the observed benefits from breastfeeding were calculated independently of the other lifestyle factors.

A research fellow from The George Institute for Global Health at the University of Oxford, Dr. Sanne Peters was the study author. He explains, “Although we cannot establish the causal effects, the health benefits to the mother from breastfeeding may be explained by a faster “reset” of the mother’s metabolism after pregnancy.” It is believed that breastfeeding might eliminate the stored fat accrued during pregnancy faster and more completely and that is what leads to reduced risk of cardiovascular diseases later in life. The study co-author is Liming Li from the Peking University explains, “Nearly all women in the study were born before 1970s and the rate of breastfeeding was much higher than that in the Western populations and younger generations in China.”

The American Heart Association suggests trying to maintain breastfeeding for 12 months if possible. According to WHO’s data, about 30 percent of women in the US managed to breastfeed their baby for 12 months in 2016. In China, only 30 percent of rural women and 16 percent of urban women now managed to breastfeed their baby for 6 months or more.

This is just one of many important and informative medical research studies from The George Institute for Global Health, a health and medical research institute. Their mission is to improve the health of millions of people worldwide. One of the ways The George Institute for Global Health achieves their mission is through George Clinical, a leading contract research organization (CRO) headquartered in Sydney, Australia but with operational hubs in ten countries throughout Asia.

New Study Finds Potential Breakthrough in Determining Who’s at Risk for Heart Attacks

Researchers are revisiting their views on the relative dangers soft and hard atherosclerotic plaque deposits pose to heart health. Findings of a new study by researchers at the Intermountain Medical Center Heart Institute may be a “game-changer” for determining who’s at risk of a heart attack, they say.

The notion that soft plaque is more likely to rupture and cause heart attacks than hard calcium deposits in coronary arteries may be wrong, according to the new study that will be presented at the American College of Cardiology Scientific Sessions in Washington, D.C., on March 18.

Atherosclerosis is caused when plaque builds up in the arteries, narrowing and hardening them.

“We previously thought the lipid-laden soft plaque was more likely to rupture and cause heart attacks, but based on our new research, it’s more the calcified plaque that appears to be associated with adverse cardiovascular events” said Brent Muhlestein, MD, one of the study’s authors and co-director of cardiology research at the Intermountain Medical Center Heart Institute in Salt Lake City.

Intermountain Medical Center Heart Institute researchers had earlier teamed with Johns Hopkins School of Medicine and National Institutes of Health scientists to analyze the composition of plaque from 224 patients who had diabetes, but no heart symptoms.

This new research reflects more long-term findings after patients were followed for an average of nearly seven years to see if their plaque composition had predicted whether they’d have a cardiac event.

In this study, through careful quantitative evaluation, the composition of coronary artery plaque identified in the subjects through CT coronary angiography was stratified proportionately into amounts of soft, calcified, and fibrous plaque and compared with future risk of unstable angina, heart attack or death.

Unexpectedly, proportionately higher quantities of calcified plaque best predicted major adverse coronary events, while soft plaque did not, researchers found.

Dr. Muhlestein said further studies are needed to verify the findings, but results from his team’s research may represent a potential paradigm shift. “We need further validation to gauge the importance of why the coronary calcium score is so predictive,” he said.

Although a build-up of coronary calcium doesn’t go away, doctors can successfully treat the patient aggressively with statins. They know no one gets coronary calcium if they don’t have plaque, even if it hasn’t been seen, so anyone with coronary calcium also has atherosclerosis.

“It’s a disease marker, not a risk marker. And we think it’s possibly a very important predictor,” said Dr. Muhlestein, who noted that having a calcium score of zero is like having a five-year warranty against heart attack — even with high levels of low-density lipoprotein, also known as LDL or bad, cholesterol.

“The finding potentially could mean a lot of patients may not require statin therapy, even though they have high cholesterol,” he said. “Maybe we can find and identify them. If there’s no atherosclerosis, you’re not going to have a heart attack. So the coronary calcium score may allow us to much more effectively select who we treat.”

The next step for the researchers is to complete more of the scans to see if the finding holds up, which will make findings more robust.

Tissue Engineering Advance Reduces Heart Failure in Model of Heart Attack

Researchers have grown heart tissue by seeding a mix of human cells onto a 1-micron-resolution scaffold made with a 3-D printer. The cells organized themselves in the scaffold to create engineered heart tissue that beats synchronously in culture. When the human-derived heart muscle patch was surgically placed onto a mouse heart after a heart attack, it significantly improved heart function and decreased the amount of dead heart tissue.

“Our novel technique is the first to achieve resolution of 1 micrometer or less,” the researchers reported in the journal Circulation Research. This tissue engineering advance is an important step toward the goal of preventing heart failure after a heart attack. Such heart failures account for nearly half of the 7.3 million worldwide heart disease-related deaths each year.

The heart cannot regenerate muscle tissue after a heart attack has killed part of the muscle wall. That dead tissue can strain surrounding muscle, leading to a lethal heart enlargement. It has long been the dream of heart experts to create new tissue that could replace damaged muscle and protect the heart from dilatation after a heart attack.

The researchers, led by Jianyi “Jay” Zhang, M.D., Ph.D., the University of Alabama at Birmingham, and Brenda Ogle, Ph.D., the University of Minnesota, modeled the scaffold after a three-dimensional scan of the extracellular matrix of a piece of mouse myocardial tissue. Extracellular matrix is the collection of compounds secreted by cells that gives structural support and cushioning to hold the tissue together.

Using multiphoton three-dimensional printing, the team then created crosslinks among extracellular proteins dissolved in a photoreactive gelatin. When the uncrosslinked gelatin was washed away, the photopolymerized extracellular protein scaffold that remained replicated the shape of the extracellular matrix, with hollows where cells had been.

This native-like scaffold was seeded with a mix of 50,000 cardiomyocytes, smooth muscle cells and endothelial cells derived from human-induced pluripotent stem cells, or hiPSCs. This cardiac muscle patch, about four one-thousandths of an inch thick and eight one-hundredths of an inch square began beating within one day of seeding, and the speed and strength of contractions increased significantly over the next week.

Researchers found that the scaffold had aligned the muscle cells properly, similar to native heart tissue, and the cells showed a smooth wave of electrical signal moving across the patch, a vital part of the electrophysiology that propagates contraction of the heart across the atria or ventricles. It appeared that the native-like structure of the scaffold contributed to the healthy electrical and mechanical function of the cells.

When two of the patches were transplanted onto an infarcted mouse heart, there was significant improvement in measures of cardiac function, blood vessel density and cell proliferation, and reduced infarct size and programmed cell death, or apoptosis.

“Thus, the hiPSC-derived cardiac muscle patches produced for this report may represent an important step toward the clinical use of 3-D-printing technology,” Zhang, Ogle and colleagues wrote. They also said, “To our knowledge, this is the first time modulated raster scanning has ever been successfully used to control the fabrication of a tissue-engineered scaffold, and consequently, our results are particularly relevant for applications that require the fibrillar and mesh-like structures present in cardiac tissue.”

New Study Finds Cardiac PET/CT Imaging Effective In Detecting Calcium Blockages, Assessing Heart Attack Risk

Many people who experience chest pain but don’t have a heart attack breathe a big sigh of relief when a stress test comes back negative for blockages in their blood vessels.

But a new study by cardiac researchers at the Intermountain Medical Center Heart Institute in Salt Lake City found they may not be off the hook after all.

Researchers studied 658 men and women between the ages of 57 and 77 who passed a stress test for blocked arteries and who were later found to have calcium in their arteries after being screened by imaging technology that measured their total coronary artery calcification.

They found that five percent of patients who passed their stress test and later tested high for calcium in their arteries — 31 of 658 patients — went on to have an adverse cardiac event within one year. Such events included death, heart attack and stroke.
Researchers say there is something more doctors can do to assess a patient’s risk of future heart attack: check the calcium — a sign of plaque buildup — in a patient’s arteries.

“We now have the ability to better measure coronary artery calcification,” says Viet Le, MPAS, PA-C, lead author of the Intermountain Medical Center Heart Institute study, who will deliver results at the American Heart Association Scientific Session in New Orleans on Nov 14, at 10:45 am, CST.

“People say, ‘I’m good. They gave me a stress test,’” said Le. “But it doesn’t tell the whole story. The story it tells is that on that day your engine — your heart — passed the test. Some of these people die within a year from a heart attack.”
Cardiac experts have known for years that calcium left by plaque is a good marker of heart disease, but there was not good imaging technology to measure it without exposing the patient to too much radiation, Le said. That changed about five years ago.
PET/CT, an advanced nuclear imaging technology that combines positron emission tomography (PET) and computed tomography (CT) in one machine, allows physicians doing a chemical stress test to also measure coronary artery calcification.

Calcification cannot be reversed, but the plaque that causes it can be reduced or stabilized with proper medication, diet and exercise.

Researchers found that 33 patients in the study, or five percent, had no or mild calcification, and they had no cardiac events. But there was a significant correlation between the amount of calcium and the occurrence of cardiac events in the remainder of the patients.

Twelve of 309 (3.88 percent) patients with moderate calcification had a cardiac event within a year, 10 of 190 (5.26 percent) with severe calcification had a cardiac event within a year, and nine of 126 (7.14 percent) with very severe calcification had a cardiac event within a year. In total, 16.28 percent of calcified patients in the study had a heart event.

The results confirmed for Le the value of assessing calcification in patients suspected of having clogged arteries.

“Right now, it’s a neglected tool that should better be utilized,” he said.

George Washington University Researchers Receive $1.6 Million to Improve Cardiac Function During Heart Failure

Researchers at the George Washington University (GW) received $1.6 million from the National Heart, Lung, and Blood Institute to study a heart-brain connection that could help the nearly 23 million people suffering from heart failure worldwide. The four-year project will study ways to restore parasympathetic activity to the heart through oxytocin neuron activation, which could improve cardiac function during heart failure.

A distinctive hallmark of heart failure is autonomic imbalance, consisting of increased sympathetic activity and decreased parasympathetic activity. Parasympathetic activity is cardiac protective.

“Parasympathetic activity is what you have when you’re reading a book, or relaxing, and counteracts the sympathetic activity you have when you’re stuck on the metro or have an exam tomorrow,” said David Mendelowitz, Ph.D., vice chair and professor in the Department of Pharmacology and Physiology at the GW School of Medicine and Health Sciences. “Heart failure is a disease that effects both neuro and cardiac function.”

Unfortunately, few effective treatments exist to increase parasympathetic activity to the heart. Based upon exciting preliminary results, this study will examine the activation of neurons in the hypothalamus that release oxytocin, which has shown to increase parasympathetic activity in the heart. While oxytocin is often used to start or increase speed of labor, recent research has uncovered its role in feelings of generosity and bonding. It may also have beneficial effects on the heart.

The project is a collaboration between the GW School of Medicine and Health Sciences and the GW School of Engineering and Applied Science.

“While Dr. Mendelowitz’s research is focused on neuroscience and how the brain works, my work is focused on cardiac function. Heart failure is a disease that affects both, which is why it is imperative for Dr. Mendelowitz and I to use our complimentary expertise to solve this problem,” said Matthew Kay, PE, DSc, associate professor in the Department of Biomedical Engineering at the GW School of Engineering and Applied Science.

Kay and his research team will use high-speed optical assessments of heart function to identify heart-specific benefits of oxytocin nerve activation. Working together, Mendelowitz and Kay have the potential to unravel the complex interaction between the brain and the heart during heart failure.

Mouse Study Links Heart Regeneration to Telomere Length

Researchers at the Spanish National Center for Cardiovascular Research have discovered that the ends of heart muscle cell chromosomes rapidly erode after birth, limiting the cells’ ability to proliferate and replace damaged heart tissue. The study, “Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation,” which will be published online May 30 in The Journal of Cell Biology, suggests potential new interventions to boost the heart’s capacity to repair itself after a heart attack.

Newborn babies can repair injured myocardium, but, in adults, heart attacks cause permanent damage, often leading to heart failure and death. Newborn mice can also regenerate damaged heart tissue. Their heart muscle cells, or cardiomyocytes, can proliferate and repair the heart in the first week after birth, but this regenerative capacity is lost as the mice grow older and the majority of their cardiomyocytes withdraw from the cell cycle.

Ignacio Flores and colleagues at the Spanish National Center for Cardiovascular Research (CNIC) in Madrid wondered whether the cause of this cell cycle arrest might involve telomeres, repetitive DNA sequences that protect the ends of chromosomes. If telomeres grow too short—due, for example, to a loss of the telomere-extending telomerase enzyme—cells can mistake chromosome ends for segments of damaged DNA, leading to the activation of a checkpoint that arrests the cell cycle.

Flores and colleagues therefore examined the length of telomeres in newborn mouse cardiomyocytes and found that the telomeres rapidly eroded in the first week after birth. This erosion coincided with a decrease in telomerase expression and was accompanied by the activation of the DNA damage response and a cell cycle inhibitor called p21.

Telomerase-deficient mice have shorter telomeres than wild-type animals, and, the researchers discovered, their cardiomyocytes already begin to stop proliferating one day after birth. When Flores and colleagues injured the hearts of one-day-old mice, telomerase-deficient cardiomyocytes failed to proliferate or regenerate the injured myocardium. In contrast, wild-type cardiomyocytes were able to proliferate and replace the damaged tissue.

They also found that knocking out the cell cycle inhibitor p21 extended the regenerative capacity of cardiomyocytes, allowing one-week-old p21-deficient mice to repair damaged cardiac tissue much more effectively than week-old wild-type animals.

Maintaining the length of cardiomyocyte telomeres might therefore boost the regenerative capacity of adult cells, improving the recovery of cardiac tissue following a heart attack. “We are now developing telomerase overexpression mouse models to see if we can extend the regenerative window,” says Flores.