Heart cells cozy up to prevent deadly arrhythmias

arrhythmia

Blood may seem like a simple fluid, but its chemistry is complex. When too much potassium, for instance, accumulates in the bloodstream, patients may experience deadly irregular heart rhythms.

Cardiovascular scientists at Virginia Tech’s Fralin Biomedical Research Institute at VTC are studying why.

In a new study, published in Pflügers Archiv European Journal of Physiology, the research team led by Steven Poelzing, associate professor at the institute, describes how subtle changes in potassium, calcium, and sodium levels regulate heartbeats.

Poelzing says that the results could help researchers and physicians understand the nuances of cardiac arrythmias, as well as a group of genetic disorders that impact sodium channel function, such as Brugada syndrome.

The scientists elevated blood potassium in guinea pigs, creating a condition called hyperkalemia, which causes some of the heart’s key electrical conduits, sodium channels, to shut down. Next, they increased calcium levels and observed the heart muscle cells pressing closer together. This miniscule motion—spanning mere nanometers—helps preserve electrical conduction in the heart.

“We know the heart is extremely sensitive to changes in blood electrolyte levels, but until recently we didn’t have a great picture of how the heart’s molecular landscape is remodeled, and how these muscle cells adapt,” said Poelzing, who is also an associate professor in the Virginia Tech College of Engineering’s department of biomedical engineering and mechanics.

Heart muscle cells primarily pass electrical signals via a network of protein bridges called gap junctions and sodium channels. These pathways let nutrients and positively charged minerals flow between cells. When there are too many positively charged potassium ions in the blood, however, the cells get overstimulated and temporarily block signaling channels.

“This can be dangerous when sodium channels get stuck in a half-closed state. The cell isn’t dying, but it’s not as electrically active as it once was. This can cause dangerous heart arrythmias and sudden cardiac death,” Poelzing said.

When the heart’s core electrical pathways falter, heart muscle cells press closer together, allowing them to sense subtle electric fields generated by neighboring cells. This secondary form of cell-to-cell signaling is known as ephaptic coupling.

“Ephaptic coupling appears to address the effects of a functional loss of sodium channels, in this case caused by high potassium, and helps keep the current flowing properly across the heart muscle,” Poelzing said.

Over the course of the eight-year study, Poelzing’s team tested different concentrations of sodium and calcium to treat the electrical defects associated with high potassium to see how the heart would respond. They discovered that increasing sodium and calcium levels together greatly reduced the distances between cells, providing a substantial improvement in cardiac conduction.

In the clinic, human patients with hyperkalemia who develop abnormal heart rhythms are administered intravenous calcium gluconate. Poelzing’s findings help explain why elevating calcium levels under these certain clinical conditions is beneficial.

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Study suggests drug intervention may prevent doxorubicin-induced cardiac injury

chemotherapy

There could be an intervention on the horizon to help prevent heart damage caused by the common chemotherapy drug doxorubicin, new research suggests.

Scientists found that this chemo drug, used to treat many types of solid tumors and blood cancers, is able to enter heart cells by hitchhiking on a specific type of protein that functions as a transporter to move a drug from the blood into heart cells.

By introducing another anti-cancer drug in advance of the chemo, the researchers were able to block the transporter protein, effectively stopping the delivery of doxorubicin to those cardiac cells. This added drug, nilotinib, has been previously found to inhibit activation of other, related transport proteins.

The current findings are based on lab experiments in cell cultures and mice. The researchers are continuing studies with hopes to start designing human trials of the drug intervention later in 2021.

“The proposed intervention strategy that we’d like to use in the clinic would be giving nilotinib before a chemotherapy treatment to restrict doxorubicin from accessing the heart,” said first author Kevin Huang, who graduated in December from The Ohio State University with a Ph.D. in pharmaceutical sciences. “We have pretty solid preclinical evidence that this intervention strategy might work.”

The study is published today in Proceedings of the National Academy of Sciences.

Doxorubicin has long been known for its potential to increase patients’ risk for serious heart problems, with symptoms sometimes surfacing decades after chemo, but the mechanisms have been a mystery. The risk is dose-dependent—the more doses a patient receives, the higher the risk for cardiac dysfunction later in life that includes arrhythmia and a reduction in blood pumped with each contraction, a hallmark symptom of congestive heart failure.

Huang worked in the lab of senior study authors Shuiying Hu and Alex Sparreboom, faculty members in pharmaceutics and pharmacology and members of the Ohio State Comprehensive Cancer Center’s Translational Therapeutics program. This research and other studies targeting different transport proteins to prevent chemo-related nerve pain were also part of Huang’s dissertation.

“Our lab works on the belief that drugs don’t naturally or spontaneously diffuse into any cell they would like to. We hypothesize that there are specialized protein channels found on specific cells that will facilitate movement of internal or external compounds into the cell,” Huang said.

For this work, the team focused on cardiomyocytes, cells composing the muscle behind the heart contractions that pump blood to the rest of the body. The researchers examined cardiomyocytes that were reprogrammed from skin cells donated by two groups of cancer patients who had been treated with doxorubicin—some who suffered cardiac dysfunction after chemo, and others who did not.

The scientists found that the gene responsible for production of the transport protein in question, called OCT3, was highly expressed in the cells derived from cancer patients who had experienced heart problems after treatment with doxorubicin.

“We used mouse models and engineered cell models to demonstrate doxorubicin does transport through this protein channel, OCT3,” Huang said. “We then looked prospectively into what this means from a therapy perspective.”

Blocking OCT3 became the goal once researchers found that genetically modified mice lacking the OCT3 gene were protected from heart damage after receiving doxorubicin. Further studies showed that inhibiting OCT3 did not interfere with doxorubicin’s effectiveness against cancer.

Hu and Sparreboom have specialized in a class of drugs called tyrosine kinase inhibitors, which block specific enzymes related to many cell functions. Nilotinib, a chronic myeloid leukemia drug, is a tyrosine kinase inhibitor that is also known to act on OCT3.

Additional experiments showed that cardiac function was preserved in mice that were pretreated with nilotinib before receiving doxorubicin—and the pretreatment did not interfere with doxorubicin’s ability to kill cancer cells.

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Transcranial stimulation to prevent fear memories from returning

A research group from the University of Bologna has succeeded in modifying the negative effect of a returning memory that triggers fear, and developed a new non-invasive experimental protocol. The result of this study, published in the journal Current Biology, is an innovative protocol that combines fear conditioning—a stimulus associated with something unpleasant that induces a negative memory—and the neurostimulation of a specific site of the prefrontal cortex.

This process alters the perception of an unpleasant (aversive) event so that it will no longer induce fear. “This experimental protocol combining transcranial stimulation and memory reconsolidation allowed us to modify an aversive memory that the participants had learned the day before,” explains Sara Borgomaneri, a researcher at the University of Bologna and first author of the study. “This result has relevant repercussions for understanding how memory works. It might even lead to the development of new therapies to deal with traumatic memories.”

Can memories be altered?

The primary focus of the research group is the process of reconsolidation. This process maintains, strengthens and alters those events that are already stored in long-term memory. “Every time an event is recalled in our memory, there is a limited period of time in which it can be altered,” explains Simone Battaglia, researcher and co-author of this study. “The protocol we developed exploits this short time window and can, therefore, interfere with the reconsolidation process of learned aversive memories.”

Researchers used TMS (Transcranial Magnetic Stimulation) to “erase” the fear induced by a negative memory. With an electromagnetic coil placed on the head of the participant, TMS creates magnetic fields that can alter the neural activity of specific brain areas. TMS is a non-invasive procedure that does not require surgery or any action on the participant and for this reason, is widespread in research as well as in clinic and rehabilitation programs.

“With TMS, we could alter the functioning of the prefrontal cortex, which proved to be fundamental in the reconsolidation process of aversive memories,” says Sara Borgomaneri. “Thanks to this procedure, we obtained results that, until now, were only possible by delivering drugs to patients.”

The trial

The research group developed this protocol through a trial involving 98 healthy people. Every participant had learned an aversive memory and the next day underwent a TMS session over the prefrontal cortex.

“First, we created the aversive memory by combining an unpleasant stimulation with some images,” explains Borgomaneri. “The day after, we presented a group of participants with the same stimulus, which, in their memory, was recorded as aversive. Using TMS immediately afterwards, we interfered with their prefrontal cortex activity.”

To test the effectiveness of the protocol, other groups of participants underwent TMS without their aversive memory to be recalled (no reconsolidation was triggered), and some other groups were stimulated with TMS in control brain areas, not involved in memory reconsolidation.

At that point, the only thing left to do for researchers was to evaluate the effectiveness of TMS. They waited for another day and once again tested how the participants reacted when the aversive memory was recalled. And they obtained encouraging results. Participants who had their prefrontal cortex activity inhibited by TMS showed a reduced psychophysiological response to the unpleasant stimulus. They remembered the event (explicit memory) but its negative effect was substantially reduced.

“This trial showed that it is feasible to alter the persistence of potentially traumatic memories. This may have crucial repercussions in the fields of rehabilitation and clinical medicine,” says Professor Giuseppe di Pellegrino, who coordinated the study. “We’re dealing with a new technique that can be employed in different contexts and can assume a variety of functions, starting from treating PTSD, which will be the focus of our next study.”

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Scientists ‘re-train’ immune system to prevent attack of healthy cells

The body’s immune system can be re-wired to prevent it from recognizing its own proteins which, when attacked by the body, can cause autoimmune diseases like multiple sclerosis, a significant new study by UK scientists has found.

Autoimmune diseases are caused when the immune system loses its normal focus on fighting infections or disease within and instead begins to attack otherwise healthy cells within the body. In the case of multiple sclerosis (MS), the body attacks proteins in myelin—the fatty insulation-like tissue wrapped around nerves—which causes the nerves to lose control over muscles.

Led by a multi-disciplinary team from the University of Birmingham, scientists examined the intricate mechanisms of the T-cells (or white blood cells) that control the body’s immune system and found that the cells could be ‘re-trained’ to stop them attacking the body’s own cells. In the case of multiple sclerosis, this would prevent the body from attacking the Myelin Basic Protein (MBP) by reprogramming the immune system to recognize the protein as part of itself.

Supported by the Medical Research Council, the two-part study, published today in Cell Reports, was a collaboration between two research groups led by Professor David Wraith from the Institute of Immunology and Immunotherapy and Professor Peter Cockerill from the Institute of Cancer and Genomic Sciences.

The first stage, led by Professor Wraith showed that the immune system can be tricked into recognizing MBP by presenting it with repeated doses of a highly soluble fragment of the protein that the white blood cells respond to. By repeatedly injecting the same fragment of MBP, the process whereby the immune system learns to distinguish between the body’s own proteins and those that are foreign can be mimicked. The process, which is a similar type of immunotherapy to that previously used to desensitize people against allergies, showed that the white blood cells that recognize MBP switched from attacking the proteins to actually protecting the body.

The second stage, saw gene regulation specialists led by Professor Peter Cockerill probe deep within the white blood cells that react to MBP to show how genes are rewired in response to this form of immunotherapy to fundamentally re-program the immune system. The repeated exposure to the same protein fragment triggered a response that turns on genes that silence the immune system instead of activating it. These cells then had a memory of this exposure to MBP embedded in the genes to stop them setting off an immune response. When T cells are made tolerant, other genes which function to activate the immune system remain silent.

Professor David Wraith said: “These findings have important implications for the many patients suffering from autoimmune conditions that are currently difficult to treat.”

Professor Peter Cockerill, said: “This study has led us to finally understand the underlying basis of immunotherapies which desensitize the immune system”

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There’s no evidence chloroquine helps treat or prevent COVID-19

In new Practice Points, the American College of Physicians (ACP) says that evidence does not support the use of chloroquine or hydroxychloroquine alone or in combination with azithromycin to prevent COVID-19 after infection with novel coronavirus (SARS-CoV-2), or for treatment of patients with COVID-19. The ACP Practice Points also state that physicians, in light of known harms and very uncertain evidence of benefit, may choose to treat the hospitalized COVID-19 positive patients with chloroquine or hydroxychloroquine alone or in combination with azithromycin in the context of a clinical trial using shared and informed decision-making with patients and their families. “Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or In Combination with Azithromycin for the Prophylaxis or Treatment of COVID-19? Living Practice Points from the American College of Physicians (Version 1)” was published today in Annals of Internal Medicine.

The ACP Practice Points provide rapid clinical advice based on a concise summary of the best available evidence on the benefits and harms of the use of chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19. The Practice Points are based on a rapid systematic review conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group.

ACP Practice Points are developed by ACP’s Scientific Medical Policy Committee and provide advice to improve the health of individuals and populations and promote high value care based on the best available evidence derived from assessment of scientific work (e.g. clinical guidelines, systematic reviews, individual studies). ACP Practice Points aim to address the value of screening and diagnostic tests and therapeutic interventions for various diseases, and consider known determinants of health, including but not limited to genetic variability, environment, and lifestyle.

“With the rapid emergence of COVID-19, physicians and clinicians have found themselves managing the frontlines of the pandemic with a paucity of evidence available to inform treatment decisions,” said Jacqueline W. Fincher, MD, MACP, president, ACP. “ACP rapidly developed its Practice Points as concise, synthesized summaries of the current state of evidence in order to address urgent questions related to the transmission, diagnosis, and treatment of COVID-19. As such, these Practice Points give frontline physicians guidance to provide patients with the care based on the best available evidence.”

Chloroquine and hydroxychloroquine are used to manage other major ailments with a known benefit and are in short supply in the United States. These medications also have known harms in non-COVID patients such as cardiovascular effects; diarrhea; abnormal liver function; rash; headache; ocular issues; and anemia.

Using chloroquine or hydroxychloroquine, with or without azithromycin, to prevent or treat COVID-19 infection began to receive attention following preliminary reports from in vitro and human studies. While several studies are planned or underway, the Practice Points provide details about the lack of and/or insufficient current research about the benefits and harms for prevention and treatment of COVID-19.

At this time, the authors of the Practice Points have identified that chloroquine or hydroxychloroquine alone or in combination with azithromycin to prevent COVID-19 after infection with novel coronavirus (SARS-CoV-2), or for treatment of patients with COVID-19 should not be used. The Practice Points also state that the drugs may only be used to treat hospitalized COVID-19 positive patients in the context of a clinical trial following shared and informed decision-making between clinicians and patients (and their families) that includes a discussion of known harms of chloroquine and hydroxychloroquine and very uncertain evidence of benefit for COVID-19 patients.

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