Mitochondrial Protein in Cardiac Muscle Cells Linked to Heart Failure, Study Finds

Reducing a protein found in the mitochondria of cardiac muscle cells initiates cardiac dysfunction and heart failure, a finding that could provide insight for new treatments for cardiovascular diseases, a study led by Georgia State University has shown.

The researchers discovered that reducing an outer mitochondrial membrane protein, FUN14 domain containing 1 (FUNDC1), in cardiac muscle cells, also known as cardiomyocytes, activates and worsens cardiac dysfunction. Also, disrupting how FUNDC1 binds to a particular receptor inhibited the release of calcium from another cell structure, the endoplasmic reticulum (ER), into the mitochondria of these cells and resulted in mitochondrial dysfunction, cardiac dysfunction and heart failure. The findings are published in the journal Circulation.

Mitochondria play numerous roles in the body, including energy production, reactive oxygen species generation and signal transduction. Because the myocardium, the muscular wall of the heart, is a high-energy-demand tissue, mitochondria play a central role in maintaining optimal cardiac performance. Growing evidence suggests deregulated mitochondrial activity plays a causative role in cardiovascular diseases.

In the body, mitochondria and ER are interconnected and form their own endomembrane networks. The points where mitochondria and ER make physical contact and communicate are known as mitochondria-associated ER membranes (MAMs). MAMs play a major role in regulating the transfer of calcium between ER and mitochondria. Dysfunctional MAMs are involved in several neuronal disorders, including Alzheimer’s disease and Parkinson’s disease. Until now, the role of MAMs in cardiac pathologies has not been well understood.

“Our study found the formation of MAMs mediated by the mitochondrial membrane protein FUNDC1 was significantly suppressed in patients with heart failure, which provides evidence that FUNDC1 and MAMs actively participate in the development of heart failure,” said Dr. Ming-Hui Zou, director of the Center for Molecular and Translational Medicine at Georgia State and a Georgia Research Alliance Eminent Scholar in Molecular Medicine. “This work has important clinical implications and provides support that restoring proper function of MAMs may be a novel target for treating heart failure.”

The researchers used mouse neonatal cardiomyocytes, mice with a genetic deletion of the FUNDC1 gene, control mice with no genetic deficiencies and the cardiac tissues of patients with heart failure.

The cardiac functions of the mice were monitored using echocardiography at 10 weeks of age. Mice with the genetic deletion of FUNDC1 had markedly reduced ventricular filling velocities, prolonged left ventricular isovolumic relaxation time, diastolic dysfunction, decreased cardiac output (which indicates impaired systolic functions) and interstitial fibrosis of the myocardium, among other issues. The mitochondria in the hearts of mice with FUNDC1 gene deletion were larger and more elongated, a 2.5-fold increase of size compared to mitochondria in the control mice.

To determine if FUNDC1 reduction occurred in human hearts and contributed to heart failure in patients, the researchers examined four heart specimens from heart failure patients and four heart specimens from control donors. They found the levels of FUNDC1 were significantly reduced in patients with heart failure compared to control donors. Also, the contact between ER and mitochondria in failed hearts was significantly reduced. In addition, the mitochondria in heart failure hearts were more elongated compared to those in control donors.

Re-Interventions Are Common in Long-Term Survivors of Childhood Heart Operations

Among patients who undergo childhood heart surgery for the severe birth defect single-ventricle disease, two-thirds of survivors require a surgical or catheter-based procedure within 20 years. Pediatric cardiology researchers note that doctors should counsel families about the likelihood of re-interventions.

“Unfortunately, for many patients, the Fontan is not the final intervention,” said study leader Andrew Glatz, MD MSCE, referring to the Fontan operation, the third in a series of reconstructive operations performed on children with a severely underdeveloped ventricle, one of the heart’s two pumping chambers. Glatz is a pediatric interventional cardiologist in the Cardiac Center at Children’s Hospital of Philadelphia (CHOP).

Glatz and colleagues published their study on September 1, 2017 in Circulation: Cardiovascular Interventions. Other key members of the study team include Tacy Downing, MD and Kiona Allen, MD (both were pediatric cardiology fellows at CHOP during the work); and David Goldberg, MD and William Gaynor, MD (current faculty members in the Cardiac Center at CHOP).

The study team performed a retrospective review of 773 patients who underwent the Fontan operation at CHOP between 1992 and 2009.

Although the Fontan procedure offers high survival rates for a condition that previously was universally fatal during infancy, it cannot provide normal blood circulation, and carries long-term risks of complications that continue to be analyzed. Clinicians and researchers were aware of the need for re-interventions in long-term Fontan survivors, but there was little detailed knowledge of re-intervention rates until now.

In the current study, the researchers found that 65 percent of Fontan survivors underwent a re-intervention by 20 years after their operation, with a median time to first re-intervention slightly less than 10 years. The re-interventions were either operations or catheterizations, with catheterizations being more common—often to close unwanted openings or to widen narrowed blood vessels. Among operations, the most common were to place or revise a pacemaker.

“The important message from this work is that, for many patients, the Fontan operation is not the ‘final’ procedure, as it is sometimes referred to. Instead, many patients require further interventions after the Fontan to continue to try to optimize the circulation as best as possible. It’s important for families and doctors to understand this, so expectations are clear. This also highlights the need for close and careful ongoing follow-up after the Fontan operation by pediatric cardiologists familiar with potential complications that could befall a Fontan patient,” said Glatz.

Stem Cell Breakthrough Unlocks Mysteries Associated With Inherited And Sometimes Lethal Heart Conditions

Using advanced stem cell technology, scientists from the Icahn School of Medicine at Mount Sinai have created a model of a heart condition called hypertrophic cardiomyopathy (HCM) — an excessive thickening of the heart that is associated with a number of rare and common illnesses, some of which have a strong genetic component. The stem cell lines scientists created in the lab, which are believed to closely resemble human heart tissue, have already yielded insights into unexpected disease mechanisms, including the involvement of cells that have never before been linked to pathogenesis in a human stem-cell model of HCM. The research was published in the journal Stem Cell Reports.

The genetic disorder discussed in the new study is called cardiofaciocutaneous syndrome (CFC), which is caused by a mutation in a gene called BRAF. The condition is rare and affects fewer than 300 people worldwide, according to the National Institutes of Health. It causes abnormalities of the head, face, skin, and major muscles, including the heart.

To learn more about HCM associated with various genetic diseases, Mount Sinai scientists took skin cells from three CFC patients and turned them into highly versatile stem cells, which were then converted into cells responsible for the beating of the heart. This model has relevance for research on several related and more common genetic disorders, including Noonan syndrome, which is characterized by unusual facial features, short stature, heart defects, and skeletal malformations.

“At present, there is no curative option for HCM in patients with these related genetic conditions,” said Bruce D. Gelb, MD, Director of The Mindich Child Health and Development Institute and Professor in the Departments of Pediatrics, Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. “If our findings are correct, they suggest we might be able to treat HCM by blocking specific cell signals—which is something we know how to do.”

Dr. Gelb says that about 40 percent of patients with CFC suffer from HCM (two of the three study participants had HCM). This suggests a pathogenic connection, though the link has never been fully explored or explained. The primary goal of the current research was to understand the role of a cell-signaling pathway called RAS/MAPK in the cascade of events leading to HCM in patients with CFCs — and by association, with Noonan syndrome, Costello syndrome, and other similar illnesses.

Observing the disease progression in these heart cells, called cardiomyocytes, Dr. Gelb and his team found that some of the changes were caused by interactions with cells that resemble fibroblasts — the same kinds of cells that produce collagen and other proteins. Fibroblasts make up a significant portion of total heart tissue, although it is the cardiomyocytes that are primarily responsible for pumping blood. “These fibroblast-like cells seem to be producing an excess of a protein growth factor called TGF-beta, which, in turn, caused the cardiomyocytes to hypertrophy, or grow larger,” Dr. Gelb said. “We believe this is the first time the phenomenon has been observed using a human induced pluripotent stem cell model of the disease.”

Prior to this observation, Dr. Gelb and his team assumed hypertrophy was “cell autonomous,” meaning intrinsic to the cardiomyocytes themselves. “Based on our cell culture model, we saw that fibroblasts are playing a key role in giving the heart cells the signal that causes them to get big,” Dr. Gelb said. “That was quite unexpected.”

The therapeutic implications may also be profound. “We were able to block TGF-beta in vitro using antibodies that bind to the protein. When we did that, the cardiomyocytes no longer hypertrophy,” Dr. Gelb said. It’s not certain the same effect would be seen in the many clinical cases of HCM that are not influenced by BRAF or the RAS pathway—essentially a chain of cellular proteins that help transmit signals from surface receptors on the cell to DNA in the nucleus –but researchers believe this could be the case.

The bigger surprise, said Dr. Gelb, “is that we may be talking about a signaling circle” in which fibroblasts trigger the release of a growth factor, which causes cardiomyocytes to hypertrophy, which in turn, prompts fibroblasts to release more of the growth factor.” Dr. Gelb didn’t witness this last part of the circle in his stem cell culture, but evidence of fibroblast stimulation has been reported in mouse models that don’t express the RAS mutation. If the circle theory is validated, Dr. Gelb said, there could be new and broad therapeutic interventions for HCM in both RAS and non-RAS contexts. “In theory, at least, a therapy could be useful for both,” 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.

A Personalized Virtual Heart Predicts the Risk of Sudden Cardiac Death

When electrical waves in the heart run amok in a condition called arrhythmia, sudden death can occur. To save the life of a patient at risk, doctors currently implant a small defibrillator to sense the onset of arrhythmia and jolt the heart back to a normal rhythm. But a thorny question remains: How should doctors decide which patients truly need an invasive, costly electrical implant that is not without health risks of its own?

To address this, an interdisciplinary Johns Hopkins University team has developed a non-invasive 3-D virtual heart assessment tool to help doctors determine whether a particular patient faces the highest risk of a life-threatening arrhythmia and would benefit most from a defibrillator implant. In a proof-of-concept study published May 10 in the online journal Nature Communications, the team reported that its new digital approach yielded more accurate predictions than the imprecise blood pumping measurement now used by most physicians.

“Our virtual heart test significantly outperformed several existing clinical metrics in predicting future arrhythmic events,” said Natalia Trayanova, the university’s inaugural Murray B. Sachs Professor of Biomedical Engineering. “This non-invasive and personalized virtual heart-risk assessment could help prevent sudden cardiac deaths and allow patients who are not at risk to avoid unnecessary defibrillator implantations.”

Trayanova, a pioneer in developing personalized imaging-based computer models of the heart, supervised the research and was senior author of the journal article. She holds faculty appointments within Johns Hopkins’ Whiting School of Engineering and its School of Medicine, and she is a core faculty member of the university’s Institute for Computational Medicine. For this study, she joined forces with cardiologist and co-author Katherine C. Wu, associate professor in the Johns Hopkins School of Medicine, whose research has focused on magnetic resonance imaging approaches to improving cardiovascular risk prediction.

For this landmark study, Trayanova’s team formed its predictions by using the distinctive magnetic resonance imaging (MRI) records of patients who had survived a heart attack but were left with damaged cardiac tissue that predisposes the heart to deadly arrhythmias. The research was a blinded study, meaning that the team members did not know until afterward how closely their forecasts matched what happened to the patients in real life. This study involved data from 41 patients who had survived a heart attack and had an ejection fraction—a measure of how much blood is being pumped out of the heart—of less than 35 percent.

To protect against future arrhythmias, physicians typically recommend implantable defibrillators for all patients in this range, and all 41 patients in the study received the implants because of their ejection fraction scores. But research has concluded that this score is a flawed measure for predicting which patients face a high risk of sudden cardiac death.

The Johns Hopkins team invented an alternative to these scores by using pre-implant MRI scans of the recipients’ hearts to build patient-specific digital replicas of the organs. Using computer-modeling techniques developed in Trayanova’s lab, the geometrical replica of each patient’s heart was brought to life by incorporating representations of the electrical processes in the cardiac cells and the communication among cells. In some cases, the virtual heart developed an arrhythmia, and in others it did not. The result, a non-invasive way to gauge the risk of sudden cardiac death due to arrhythmia, was dubbed VARP, short for virtual-heart arrhythmia risk predictor. The method allowed the researchers to factor in the geometry of the patient’s heart, the way electrical waves move through it and the impact of scar tissue left by the earlier heart attack.

Eventually, the VARP results were compared to the defibrillator recipients’ post-implantation records to determine how well the technology predicted which patients would experience the life-threatening arrhythmias that were detected and halted by their implanted devices. Patients who tested positive for arrhythmia risk by VARP were four times more likely to develop arrhythmia than those who tested negative. Furthermore, VARP predicted arrhythmia occurrence in patients four-to-five times better than the ejection fraction and other existing clinical risk predictors, both non-invasive and invasive.

“We demonstrated that VARP is better than any other arrhythmia prediction method that is out there,” Trayanova said. “By accurately predicting which patients are at risk of sudden cardiac death, the VARP approach will provide the doctors with a tool to identify those patients who truly need the costly implantable device, and those for whom the device would not provide any life-saving benefits.”

Wu agreed that these encouraging early results indicate that the more nuanced VARP technique could be a useful alternative to the one-size-fits-all ejection fraction score.

“This is a ground-breaking proof-of-concept study for several reasons,” Wu said, “As cardiologists, we obtain copious amounts of data about patients, particularly high-tech imaging data, but ultimately we use little of that information for individualized care. With the technique used in this study, we were able to create a personalized, highly detailed virtual 3-D heart, based on the patient’s specific anatomy. Then, we were able to test the heart virtually to see how irritable it is under certain situations. We could do all this without requiring the patient to undergo an invasive procedure. This represents a safer, more comprehensive and individualized approach to sudden cardiac death risk assessment.”

Wu pointed out that an implantable defibrillator also has a few risks of its own and that avoiding implantation of this device when it is not truly needed eliminates these risks. Implantable defibrillators, she said, require invasive access to the heart, frequent device checks and intermittent battery changes. Complications, she added, can include infection, device malfunction and, in rare instances, heart or blood vessel damage.

In addition to eliminating unnecessary device implantations, Trayanova noted that this new risk prediction methodology could also be applied to patients who had prior heart damage, but whose ejection fraction score did not target them for therapy under current clinical recommendations. Thus, Trayanova said, VARP has the potential to save the lives of a much larger number of at-risk patients.

Study Shows How Different People Respond to Aspirin — an Important Cardioprotective Drug

Researchers have learned new information about how different people respond to aspirin, a globally prescribed drug in cardioprotection. The research team, led by scientists at Cardiff University in the United Kingdom and including representatives from the University of Alabama at Birmingham and the University of Colorado, identified more than 5,600 lipids — or fats — in blood platelets and gained new insights into how these cells respond to aspirin.

“Aspirin is a widely used cardiovascular preventive drug and also has an emerging role in cancer treatment and prevention,” said Valerie O’Donnell, Ph.D., Division of Infection and Immunity, Cardiff University, and the study’s lead author. “Understanding how people respond to aspirin is key in terms of knowing who will benefit from it.”

The findings, published April 28 in Cell Metabolism, are the first comprehensive lipidomic profile of human platelets in response to stimulation and aspirin treatment.

“Our research shows a new link between energy metabolism and inflammation, as well as giving early insights into the fundamentals of precision medicine regarding the variation of the lipidome among individuals,” said Victor Darley-Usmar, Ph.D., Endowed Professor of Mitochondrial Medicine and Pathology at UAB and a co-investigator on the study.

Lipids play essential structural roles, act as nutrients, and control a broad range of physiological and pathophysiological events in cells, according to the researchers.

“While several lipid families are well-characterized at the molecular level, the total diversity and number of unique lipids in cells, how they change during cellular activation, and how they differ in individuals is unknown,” said Darley-Usmar. “This hampers integration of lipidomics into systems biology, and addressing it will improve our fundamental understanding of lipid biology, help identify new drug targets for therapy and discover lipid biomarkers from disease cohorts.”

“This work led by Professor O’Donnell is a technical tour de force, providing a wonderful resource for other biomedical researchers,” said Mike Murphy, Ph.D., programme leader, Mitochondrial Biology Unit at Cambridge University, U.K. “A particularly important aspect is the focus on platelets, which are readily available from patients’ blood in diagnosis, prognosis or as a biomarker in assessing therapies. In addition to its future use, this work also demonstrated an unexpected link between mitochondrial fat metabolism and platelet activation during inflammation.”

“Given the importance of aspirin as both a cardioprotective and possible cancer therapeutic, a full understanding of how it regulates platelet lipids will be the focus of a follow-on study with a larger number of volunteers,” said Robert Murphy, Ph.D., professor in the Department of Pharmacology, University of Colorado, and a study co-investigator. “The stability of the global lipidome with age, diet and over time is unknown, and the influence of external factors such as epigenetic control of lipid metabolizing enzymes could be considerable.”

In Child Heart Patients, a Novel Approach Improves Symptoms of Hazardous Lymph Blockage

Pediatric researchers have devised an innovative, safe and minimally invasive procedure that helps relieve rare but potentially life-threatening airway blockages occurring in children who had surgery for congenital heart defects.

The physician-researchers developed new imaging tools and used minimally invasive catheterization techniques to treat plastic bronchitis, a condition in which abnormal circulation causes lymphatic fluid to dry into solid casts that clog a child’s airways.

The authors reported their retrospective study of 18 children with plastic bronchitis at The Children’s Hospital of Philadelphia (CHOP), online ahead of print on Feb. 10, 2016 in Circulation, the journal of the American Heart Association.

The study, which describes the pathophysiological mechanism of plastic bronchitis and a treatment approach, arose from collaboration between Maxim Itkin, M.D., an associate professor of Radiology in the Perelman School of Medicine at the University of Pennsylvania, and Yoav Dori, M.D., a pediatric cardiologist in the Cardiac Center at The Children’s Hospital of Philadelphia. They co-lead a specialized team dedicated to the care of lymphatic disorders as part of the Center for Lymphatic Imaging and Interventions at The Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania.

“This is a new treatment option for children with plastic bronchitis, and has the potential to offer long-term improvement of this condition,” said Dori. “This procedure may even provide cure and avoid the need for a heart transplant.”

The current study builds on the team’s 2014 article in Pediatrics, the first case report of the successful use of their technique in a patient with plastic bronchitis. “We have expanded on that study to report short-term outcomes in a larger group, and to share insights into the development of plastic bronchitis, which has been poorly understood,” said Itkin. In addition to heart patients, children and adults with idiopathic plastic bronchitis, in which the cause is unknown, have also been treated successfully using these techniques.

Itkin and Dori discovered that the primary cause of plastic bronchitis is a lymphatic flow disorder, due to abnormal lymphatic flow into lung tissue. Because physical examinations and conventional imaging may not provide specific findings, lymphatic flow disorders often go undiagnosed.

Over the past several years, Itkin and Dori developed a customized form of magnetic resonance imaging (MRI), called dynamic contrast enhanced MR lymphangiogram, to visualize the anatomy and flow pattern of a patient’s lymphatic system. This technique allows clinicians to locate the site at which lymph leaks into the airways.

Plastic bronchitis may occur in children as a rare complication of early-childhood heart surgeries used for single-ventricle disease, in which one of the heart’s pumping chambers is severely underdeveloped. Approximately 5 percent of children surviving this surgery experience plastic bronchitis because the surgery alters venous and lymphatic pressure. The authors argue that this altered pressure may interact with pre-existing anatomical differences in the patients’ lymphatic vessels.

The abnormal circulation causes lymph to ooze backward into a child’s airways, drying into a caulk-like cast formation that takes the shape of the airways. The first sign of plastic bronchitis may be when a child coughs out the cast. However, if unable to cough it up, a child may suffer fatal asphyxiation.

After identifying the leakage site in a lymphatic vessel, the lymphatic team intervenes, using a technique called lymphatic embolization. Through small catheters, the team blocks the abnormal flow with a variety of tools: coils, iodized oil, and covered stents, based on an individual patient’s needs.

In the current report, the team was able to perform lymphatic embolization in 17 of their 18 patients, ranging from age two to age 15 (median age 8.6 years). Fifteen of those 17 patients had significantly improvements in cast formation, in some cases being cast-free longer than two years. Patients had transient side effects of abdominal pain and hypotension (low blood pressure), but the authors reported the procedure appeared safe in their patient group.