Irregular heartbeat linked to higher thyroid hormone levels

 Individuals with higher levels of thyroid hormone (free thyroxine, FT4) circulating in the blood were more likely than individuals with lower levels to develop irregular heartbeat, or atrial fibrillation, even when the levels were within normal range, according to new research in the American Heart Association’s journal Circulation.

“Our findings suggest that levels of the thyroid hormone, free thyroxine, circulating in the blood might be an additional risk factor for atrial fibrillation,” said study lead author Christine Baumgartner, M.D., specialist in General Internal Medicine from the University Hospital of Bern, Switzerland, and currently a postdoctoral scholar at University of California San Francisco. “Free thyroxine hormone levels might help to identify individuals at higher risk.”

In the United States, irregular heartbeat (atrial fibrillation) affects between 2.7 to 6.1 million people and is estimated to affect up to 12.1 million people by 2030. It occurs when the two upper chambers of the heart, called the atria, beat irregularly and faster than normal. Symptoms may include heart palpitations, dizziness, sweating, chest pain, anxiety, fatigue during exertion and fainting, but sometimes patients with atrial fibrillation have no symptoms at all. Although people can live with irregular heartbeat, it can cause chronic fatigue and increase the risk of serious illnesses, such as stroke and heart failure, potentially associated with lifelong disability and even death. Fortunately, medication and other therapies are available to treat irregular heartbeat and reduce the risk of the associated symptoms and complications.

The thyroid gland is a small gland in the neck. In response to thyroid-stimulating hormone released by the pituitary gland, the thyroid gland secretes thyroid hormones required to regulate energy metabolism. Patients with low levels of thyroid hormone, or hypothyroidism, may require medications containing thyroid hormone (thyroxine) to increase their hormonal levels. Sometimes intake of thyroxine sometimes can increase these levels too much.

Previous studies showed that the risk of irregular heartbeat is greater among individuals who produce too much thyroid hormone than among those with normal hormonal levels. What was unclear, however, was whether levels that were high but still within the normal range could also increase the risk of irregular heartbeat.

To understand this relationship, investigators looked at the occurrence of irregular heartbeat among individuals with thyroid hormone levels that were still within normal range. They found that individuals with higher blood levels of FT4 within the normal range at the beginning of the study were significantly more likely than those with lower levels to subsequently develop irregular heartbeat.

When separated into four equal-sized groups, the group with the highest FT4 levels had a 45 percent increased risk of irregular heartbeat, compared to the group with the lowest levels. Even more modest increases in thyroid hormone were associated with an increased risk. Among individuals with the second highest levels, the risk was 17 percent greater, and among those with the third highest levels the risk was 25 percent greater, compared to those with the lowest levels. High levels of thyroid-stimulating hormone (TSH) within the normal range, however, were not associated with an increased risk of atrial fibrillation.

“Patients who are treated with thyroxine, one of the most frequently prescribed drugs in the United States, generally have higher circulating free thyroxine levels compared to untreated individuals,” Baumgartner said. “So, an important next step is to see whether our results also apply to these patients, in order to assess whether target free thyroxine thyroid hormone concentrations for thyroid-replacement therapy need to be modified.”

The investigators analyzed data from 11 studies from Europe, Australia, and the United States that measured thyroid function and the occurrence of irregular heartbeat. Overall, the studies included 30,085 individuals. Their average age was 69 years, and slightly more than half were women. On average, follow-up ranged from 1.3 to 17 years. The investigators obtained the studies by searching the MEDLINE and EMBASE medical databases through July 2016.

Newly Published Data Highlights the Potential of Placenta-based Cell Therapy in Protecting the Heart Affected by Diabetes

Results from a peer-reviewed study in the peer-reviewed journal STEM CELLS Translational Medicine. showed that treating the heart with placenta-based cell therapy called PLX cells, led to improved diastolic function by significantly decreasing cardiomyocyte stiffness, endothelial inflammation, and improving vascularization in preclinical studies. The study’s authors believe the study holds the promise that PLX cells could potentially treat cardiac damage in diabetic patients, particularly in early-stage diabetic cardiomyopathy.

The article, titled “Placenta-derived adherent stromal cells improve diabetes mellitus-associated left ventricular diastolic performance”, highlights the ability of PLX cells, created by Haifa-based Pluristem Therapeutics, to significantly improve cardiac function and describes the underlying mechanism of action. Investigators from the Berlin-Brandenburg Center for Regenerative Therapies, (BCRT) and the Charité-Universitätsmedizin Berlin, Germany, led by Professor Carsten Tschöpe led the study.  Dr. Tschöpe is also a member of the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology.

Diastolic heart failure or diastolic dysfunction refers to a decline in performance of one or both ventricles of the heart during diastole, when the heart is filling with blood. The National Heart, Lung, and Blood Institute reports that approximately 4.8 million Americans suffer from heart failure, with approximately 400,000 new cases appearing annually. Additionally, it has been reported that 50% of these heart failure patients are afflicted with diastolic heart failure (Curr Cardiol Rep, 2017). Heart Failure with Preserved Ejection Fraction and Future Pharmacological Strategies: a Glance in the Crystal Ball. Tschöpe C, Van Linthout S, Kherad B. Curr Cardiol Rep. 2017 Aug;19(8):70

In the study, diabetes mellitus was induced in immune competent mice by streptozotocin application during 5 subsequent days. Seven days after the first streptozotocin injection, animals were intravenously (IV) treated with either PLX cells or saline (placebo). Cardiac parameters were assessed two weeks later. The treatment using PLX cells led to improved diastolic function as indicated by the heart-rate independent 1.2-fold (p<0.005) lower time constant of LV relaxation parameter Tau and the 1.2-fold (p<0.05) increase of the relaxation parameter dP/dtmin.

“Currently, there are limited treatment options for diastolic dysfunction and even fewer for diabetes-induced diastolic dysfunction,” said Dr. Tschöpe. “This study holds promise that PLX cells could potentially treat cardiac damage in diabetic patients, particularly in early-stage diabetic cardiomyopathy. PLX cells are particularly well suited for this indication because they can be used without the need for tissue matching or immunosuppression.”

“Diabetes-induced diastolic dysfunction is a chronic disease that represents a large unmet need. In this study, PLX cells were able to improve cardiac function when administered by simple IV injection. This opens a potentially new method for an effective, low risk treatment for diastolic dysfunction,” said Zami Aberman, Chairman and Co-CEO of Pluristem. “These new data, combined with findings published in the Journal of Surgical Research, which showed that PLX cells were effective in treating cardiac ischemia, suggest that PLX cells have the potential to address a wide range of cardiac disorders.”

Blood pressure medication does not completely restore vascular function

Treatments for high blood pressure do not totally reverse its damaging effects on the vascular rhythms that help circulation of the blood say researchers.

The World Health Organisation says hypertension affects about 40% of those aged over 25 and is a major risk factor for heart disease, stroke and kidney failure.

An interdisciplinary group of scientists from Lancaster University found that conventional medication aimed at reducing high blood pressure restored normal vascular rhythms only in the largest blood vessels but not the smallest ones.

Professor Aneta Stefanovska said: “It is clear that current anti-hypertensive treatments, while successfully controlling blood pressure, do not restore microvascular function.”

Based on a networks physiology approach, the researchers compared a group aged in their twenties and two older groups aged around 70 – one with no history of hypertension and the other taking medications for high blood pressure.

In the older group being treated for high blood pressure the drug treatment restored normal function at the level of arterioles and larger vessels.

But when the researchers studied the nonlinear dynamical properties of the smallest blood vessels in the body, they found differences between the two older groups.

“Specifically, current hypertensive treatment did not fully restore the coherence or the strength of coupling between oscillations in the heart rate, respiration, and vascular rhythms (vasomotion).

“These are thought to be important in the efficient and adaptive behaviour of the cardiovascular system. Indeed, one aspect of ageing is the progressive physiological weakening of these links that keep the cardiovascular system reactive and functional.

“The results have not only confirmed previous observations of progressive impairment with age of the underlying mechanisms of coordination between cardiac and microvascular activity, but for the first time have revealed that these effects are exacerbated in hypertension.

“Current antihypertensive treatment is evidently unable to correct this dysfunction. Our novel multiscale analysis methods could help in optimising future drug developments that would benefit from taking microvascular function into account.”

Breakthrough discovery presents hope for treating fibrotic diseases which cause organ impairment

 A breakthrough discovery in the field of cardiovascular fibrosis research made at Duke-NUS Medical School (Duke-NUS) and National Heart Centre Singapore (NHCS) has been licensed to a newly launched company Enleofen Bio Pte Ltd, a Singapore-funded biotechnology start-up.

Enleofen Bio plans to use the intellectual property (IP) derived from the Duke-NUS and NHCS research to develop first-in-class therapeutics for the treatment of multiple fibrotic human diseases including cardiac and pulmonary fibrosis. Fibrosis is the formation of excessive connective tissue, similar to the formation of scar tissue during the healing process; however, the excessive connective tissue in fibrotic disease does not heal but rather disrupts the structure and function of the organ and tissue where it forms, rendering it diseased. This process may affect many tissues within the body and is the main pathology behind heart and renal failure.

Professor Stuart Cook along with Assistant Professor Sebastian Schafer, who are both from NHCS and Duke-NUS’ Programme in Cardiovascular & Metabolic Disorders, carried out the translational research to identify the key drivers of chronic fibrotic disease in heart, kidney and other tissues.

The team’s findings will be presented at the Annual Congress of the European Society of Cardiology in Barcelona, on 28 August 2017, 8:30hrs CET.

“We discovered that a specific cytokine1 is a key driver and potentiator of TGF-beta2 in cardiac fibrosis. Ironically, it has been in plain sight for many years, but unfortunately for patients, this target was completely mischaracterised and hence overlooked,” explained Professor Cook, who is Director of the Programme in Cardiovascular & Metabolic Disorders at Duke-NUS Medical School, Director of the National Heart Research Institute Singapore, as well as a scientific founder of Enleofen Bio.

The development of the IP was facilitated by a unique collaborative model between Duke-NUS, NHCS and the National Health Innovation Centre of Singapore. All three organisations partnered with Professor Cook to de-risk the discovery and prepare therapeutic technologies for commercial readiness as part of an ‘Active Translation Model’. The Enleofen Bio agreement represents a significant milestone in the development and commercialisation of fundamental biomedical research conducted at Duke-NUS and SingHealth, which promises to lead to improved healthcare outcomes.

“We are very excited to see this great Singapore-derived therapeutics platform now under development at Enleofen Bio,” said Centre for Technology and Development’s (CTeD) Director and Duke-NUS Vice Dean for Innovation and Entrepreneurship, Professor David Epstein. “We have found the right partners to take Professor Cook’s work to the next level of clinical application to improve peoples’ health and lives.”

“The licensing of this IP demonstrates Duke-NUS and SingHealth’s dedication to doing impactful research and translating that science to medical solutions,” said Senior Vice Dean of Research at Duke-NUS, Professor Patrick Casey.

Professor Terrance Chua, Medical Director of NHCS, who is also Group Chairman Medical Board, SingHealth, and Academic Chair of the SingHealth Duke-NUS Cardiovascular Academic Clinical Programme added: “Professor Cook led a group of dedicated clinicians and scientists within SingHealth and Duke-NUS to do ground-breaking research on fibrosis, and SingHealth and CTeD accelerated that progress to commercialisation. We are confident that such innovative research, which plays a significant role in setting new healthcare standards and transforming models of care, will continue to aid healthcare professionals to apply the science into practical and clinical solutions to improve patient care and treatment.”

Repairing damaged hearts with self-healing heart cells

New research has discovered a potential means to trigger damaged heart cells to self-heal. The discovery could lead to groundbreaking forms of treatment for heart diseases. For the first time, researchers have identified a long non-coding ribonucleic acid (ncRNA) that regulates genes controlling the ability of heart cells to undergo repair or regeneration. This novel RNA, which researchers have named “Singheart”, may be targeted for treating heart failure in the future. The discovery was made jointly by A*STAR’s Genome Institute of Singapore (GIS) and the National University Health System (NUHS), and is now published in Nature Communications.

Unlike most other cells in the human body, heart cells do not have the ability to self-repair or regenerate effectively, making heart attack and heart failure severe and debilitating. Cardiovascular disease (CVD) is the leading cause of death worldwide, with an estimated 17.7 million people dying from CVD in 2015 (1). CVD also accounted for close to 30% of all deaths in Singapore in 2015 (2).

In this project, the researchers used single cell technology to explore gene expression patterns in healthy and diseased hearts. The team discovered that a unique subpopulation of heart cells in diseased hearts activate gene programmes related to heart cell division, uncovering the gene expression heterogeneity of diseased heart cells for the first time. In addition, they also found the “brakes” that prevent heart cells from dividing and thus self-healing. Targeting these “brakes” could help trigger the repair and regeneration of heart cells.

“There has always been a suspicion that the heart holds the key to its own healing, regenerative and repair capability. But that ability seems to become blocked as soon as the heart is past its developmental stage. Our findings point to this potential block that when lifted, may allow the heart to heal itself,” explained A/Prof Roger Foo, the study’s lead author, who is Principal Investigator at both GIS and NUHS’ Cardiovascular Research Institute (CVRI) and Senior Consultant at the National University Heart Centre, Singapore (NUHCS).

“In contrast to a skin wound where the scab falls off and new skin grows over, the heart lacks such a capability to self-heal, and suffers a permanent scar instead. If the heart can be motivated to heal like the skin, consequences of a heart attack would be banished forever,” added A/Prof Foo.

The study was driven by first author and former Senior Research Fellow at the GIS, Dr Kelvin See, who is currently a Postdoctoral Researcher and Mack Technology Fellow at University of Pennsylvania.

“This new research is a significant step towards unlocking the heart’s full regenerative potential, and may eventually translate to more effective treatment for heart diseases. Heart disease is the top disease burden in Singapore and strong funding remains urgently needed to enable similar groundbreaking discoveries,” said Prof Mark Richards, Director of CVRI.

Executive Director of GIS, Prof Ng Huck Hui added, “This cross-institutional research effort serves as a strong foundation for future heart studies. More importantly, uncovering barriers that stand in the way of heart cells’ self-healing process brings us another step closer to finding a cure for one of the world’s biggest killers.”

Risk of infection higher for patients with obesity after bypass surgery: University of Alberta research

Patients with obesity have a higher risk of infection within 30 days after receiving heart bypass surgery, according to a series of studies conducted by University of Alberta researchers at the Faculty of Rehabilitation Medicine.

The team analyzed data from 56,722 patients in the provincial registry to examine associations between body mass index (BMI) and various outcomes following coronary artery bypass grafting (CABG) surgery and percutaneous coronary intervention (PCI), also known as coronary angioplasty.

“Compared to patients with normal BMI, we found that patients with BMI greater than 30 were 1.9 times more likely to report infections after bypass surgery,” said Tasuku Terada, a rehabilitation science postdoctoral research fellow who recently presented the series of studies at the Canadian Obesity Summit. “A better understanding is needed in order to improve clinical outcomes for patients with obesity and heart disease.”

In addition, another study in the series published in the Canadian Journal of Cardiology found that 88 per cent of patients who received PCI were classified as obese, compared to 55 per cent of the patients who received CABG. PCI is a non-surgical procedure that opens up narrowed arteries in the heart due to plaque buildup. The physician places a small stent to keep the artery open and help to prevent re-narrowing.

Terada says the risk of infection following CABG may explain why patients with obesity are more likely to receive PCI.

“We need to look at why there is more infection following CABG and whether more patients with obesity are receiving PCI because they should be, or because the risk is a factor in the decision made by health-care professionals,” he says.

Postsurgical infection means an increase in the length of stay at the hospital for patients, resulting in increased medical costs and use of resources. Knowing the risks and potential outcomes can help health-care providers and patients make more informed choices on treatment and better use of resources.

Mary Forhan, obesity expert and assistant professor in occupational therapy at the Faculty of Rehabilitation Medicine, believes that further investigation will help researchers develop tools to help decrease the risk of infection, and to ensure that patients are receiving proper care.

“For example, are the chest binders that are used after surgery the right size and are they working the right way?” she says. “Our team is currently looking at the re-design of postsurgical chest binders so that patients have better outcomes following bypass surgery.”

Cancer-cardiac connection illuminates promising new drug for heart failure

A team of researchers at the Gladstone Institutes uncovered a new strategy to treat heart failure, a leading contributor to mortality and healthcare costs in the United States. Despite widespread use of currently-approved drugs, approximately 40% of patients with heart failure die within 5 years of their initial diagnosis.

“The current standard of care is clearly not sufficient, which highlights the urgent need for new therapeutic approaches,” said Saptarsi Haldar, MD, an associate investigator at Gladstone and senior author of a new study featured on the cover of the scientific journal Science Translational Medicine. “In our previous work, we found that a drug-like small molecule called JQ1 can prevent the development of heart failure in mouse models when administered at the very onset of the disease. However, as the majority of patients requiring treatment already have longstanding cardiac dysfunction, we needed to determine if our strategy could also treat established heart failure.”

As part of an emerging treatment strategy, drugs derived from JQ1 are currently under study in early-phase human cancer trials. These drugs act by inhibiting a protein called BRD4, a member of a family of proteins called BET bromodomains, which directly influences heart failure. With this study, the scientists found that JQ1 can effectively treat severe, pre-established heart failure in both small animal and human cell models by blocking inflammation and fibrosis (scarring of the heart tissue).

“It has long been known that inflammation and fibrosis are key conspirators in the development of heart failure, but targeting these processes with drugs has remained a significant challenge,” added Haldar, who is also a practicing cardiologist and an associate professor in the Department of Medicine at the University of California, San Francisco. “By inhibiting the function of the protein BRD4, an approach that simultaneously blocks both of these processes, we are using a new and different strategy altogether to tackle the problem.”

Currently available drugs used for heart failure work at the surface of heart cells. In contrast, Haldar’s approach goes to the root of the problem and blocks destructive processes in the cell’s command center, or nucleus.

“We treated mouse models of heart failure with JQ1, similarly to how patients would be treated in a clinic,” said Qiming Duan, MD, PhD, postdoctoral scholar in Haldar’s lab and co-first author of the study. “We showed that this approach effectively treats pre-established heart failure that occurs both after a massive heart attack or in response to persistent high blood pressure (mechanical overload), suggesting it could be used to treat a wide array of patients.”

Using Gladstone’s unique expertise, the scientists then used induced pluripotent stem cells (iPSCs), generated from adult human skin cells, to create a type of beating heart cell known as cardiomyocytes.

“After testing the drug in mice, we wanted to check whether JQ1 would have the same effect in humans,” explained co-first author Sarah McMahon, a UCSF graduate student in Haldar’s lab. “We tested the drug on human cardiomyocytes, as they are cells that not only beat, but can also trigger the processes of inflammation and fibrosis, which in turn make heart failure progressively worse. Similar to our animal studies, we found that JQ1 was also effective in human heart cells, reaffirming the clinical relevance of our results.”

The study also showed that, in contrast to several cancer drugs that have been documented to cause cardiac toxicity, BRD4 inhibitors may be a class of anti-cancer therapeutics that has protective effects in the human heart.

“Our study demonstrates a new therapeutic approach to successfully target inflammation and fibrosis, representing a major advance in the field,” concluded Haldar. “We also believe our current work has important near-term translational impact in human heart failure. Given that drugs derived from JQ1 are already being tested in cancer clinical trials, their safety and efficacy in humans are already being defined. This key information could accelerate the development of a new heart failure drug and make it available to patients more quickly.”

Photo caption: Saptarsi Haldar (right), Qiming Duan (left) and Sarah McMahon (center) find a new strategy to treat heart failure. [Photo: Chris Goodfellow, Gladstone Institutes]

Scientists confirm correlation between malignant hyperthermia and exertional heat stroke

New research published online in The FASEB Journal may ultimately help athletes and trainers better understand who may be more at risk for heat stroke. In the report, scientists use animals to show that there is a link between the susceptibility to malignant hyperthermia (MH) and exertional heat stroke.

“Global warming and increasing frequency of heat waves, which are particularly dangerous in large urban areas, in future years will represent a reason of concern for human health,” said Feliciano Protasi, Ph.D., a researcher involved in the work at the Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio, Chieti, Italy. “However, in spite of the increased incidence, severity and life-threatening nature of heat stroke, there are currently no safe and effective drug interventions to protect or reverse this deadly syndrome. We hope that our study will contribute to develop preventive measures and/or acute treatments for heat stroke caused by environmental heat and physical exertion.”

Scientists used three groups of mice to reach their conclusion. The first two groups (RYR1Y522S/WT and CASQ1-null mice) had altered genes that made them susceptible to lethal hyperthermic crises when exposed to anesthetics, while the third group was normal (wild-type mice). When the three sets of mice were exposed to a protocol of exertional stress (incremental running at 34 degrees Celsius and 40 percent humidity) the MH-susceptible mice (but not the normal mice) suffered lethal overheating episodes.

“This work addresses a dangerous, often lethal, physiological maladjustment that animals and humans can undergo,” said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal. “The door now stands open to finding effective preventative drugs.”

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.

With $8.6 Million Grant From Nih, UCLA-Led Consortium Will Map the Heart’s Nervous System

A consortium directed by UCLA’s Dr. Kalyanam Shivkumar has received a three-year, $8.6 million grant from the National Institutes of Health to map the heart’s nervous system. The group’s goal: To conduct research that leads to new ways to treat cardiovascular disease by targeting nerves in the heart’s nervous system.

More than 800,000 people in the U.S. die each year from cardiovascular diseases such as heart failure, arrhythmia and hypertension. These problems often are linked to the autonomic nervous system, the part of the nervous system that signals the heart to beat and controls breathing, digestion and other body processes that typically happen without conscious effort.

Researchers believe that modulating those electrical signals holds promise as a way to treat heart failure and other common cardiovascular problems.

“Understanding the nervous system’s control of the heart is such a complex problem that it requires a collaborative approach, and we’re pleased that so many experts are coming together for this initiative,” said Shivkumar, the study’s lead investigator and director of the UCLA Cardiac Arrhythmia Center and Electrophysiology Programs.

“Our goal is to precisely map the heart’s anatomy and code the function of the nerves that control the heart from a very basic level all the way to clinical studies in humans.”

UCLA is one of seven institutions participating in the project. Principal investigators at the other universities are Dr. Viviana Gradinaru of Caltech, Dr. Stephen Liberles of Harvard University, Dr. Charless Fowlkes of UC Irvine, Dr. Irving Zucker of the University of Nebraska Medical Center, Dr. Beth Habecker of Oregon Health and Science University and Dr. David Paterson of Oxford University.

The information the consortium produces could point the way to new therapies that target neural structures, and it could suggest ways for scientists to create more effective electrical stimulation therapies based on the methods being used today, said Shivkumar, who is also chief of the UCLA Cardiovascular Interventional programs and a professor of medicine, radiology and bioengineering at the David Geffen School of Medicine at UCLA.

“Understanding how the nervous system controls the heart offers researchers a tremendous opportunity to open up new paths to treat cardiac disease,” said Dr. Kelsey Martin, dean of the David Geffen School of Medicine. “We are thrilled that our UCLA team is leading the charge on this exciting new research.”

The award is from an NIH program called Stimulating Peripheral Activity to Relieve Conditions, or SPARC, which supports research on how the electrical signals of the peripheral nerves that connect the brain and spinal cord to the rest of the body control internal organ function. The UCLA-led consortium is one of 27 multidisciplinary research teams that received SPARC awards in 2016; the grants totaled more than $20 million.

Synthetic Stem Cells Could Offer Therapeutic Benefits, Reduced Risks

Researchers from North Carolina State University, the University of North Carolina at Chapel Hill and First Affiliated Hospital of Zhengzhou University have developed a synthetic version of a cardiac stem cell. These synthetic stem cells offer therapeutic benefits comparable to those from natural stem cells and could reduce some of the risks associated with stem cell therapies. Additionally, these cells have better preservation stability and the technology is generalizable to other types of stem cells.

Stem cell therapies work by promoting endogenous repair; that is, they aid damaged tissue in repairing itself by secreting “paracrine factors,” including proteins and genetic materials. While stem cell therapies can be effective, they are also associated with some risks of both tumor growth and immune rejection. Also, the cells themselves are very fragile, requiring careful storage and a multi-step process of typing and characterization before they can be used.

Ke Cheng, associate professor of molecular biomedical sciences at NC State University, associate professor in the joint biomedical engineering program at NC State and UNC and adjunct associate professor at the UNC Eshelman School of Pharmacy, led a team in developing the synthetic version of a cardiac stem cell that could be used in off-the-shelf applications.

Cheng and his colleagues fabricated a cell-mimicking microparticle (CMMP) from poly (lactic-co-glycolic acid) or PLGA, a biodegradable and biocompatible polymer. The researchers then harvested growth factor proteins from cultured human cardiac stem cells and added them to the PLGA. Finally, they coated the particle with cardiac stem cell membrane.

“We took the cargo and the shell of the stem cell and packaged it into a biodegradable particle,” Cheng says.

When tested in vitro, both the CMMP and cardiac stem cell promoted the growth of cardiac muscle cells. They also tested the CMMP in a mouse model with myocardial infarction, and found that its ability to bind to cardiac tissue and promote growth after a heart attack was comparable to that of cardiac stem cells. Due to its structure, CMMP cannot replicate – reducing the risk of tumor formation.

“The synthetic cells operate much the same way a deactivated vaccine works,” Cheng says. “Their membranes allow them to bypass the immune response, bind to cardiac tissue, release the growth factors and generate repair, but they cannot amplify by themselves. So you get the benefits of stem cell therapy without risks.”

The synthetic stem cells are much more durable than human stem cells, and can tolerate harsh freezing and thawing. They also don’t have to be derived from the patient’s own cells. And the manufacturing process can be used with any type of stem cell.

“We are hoping that this may be a first step toward a truly off-the-shelf stem cell product that would enable people to receive beneficial stem cell therapies when they’re needed, without costly delays,” Cheng says.

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.

Heart disease, leukemia linked to dysfunction in nucleus

We put things into a container to keep them organized and safe. In cells, the nucleus has a similar role: keeping DNA protected and intact within an enveloping membrane. But a new study by Salk Institute scientists, detailed in the November 2 issue of Genes & Development, reveals that this cellular container acts on its contents to influence gene expression.

“Our research shows that, far from being a passive enclosure as many biologists have thought, the nuclear membrane is an active regulatory structure,” says Salk Professor Martin Hetzer, who is also holder of the Jesse and Caryl Philips Foundation chair. “Not only does it interact with portions of the genome to drive gene expression, but it can also contribute to disease processes when components are faulty.”

Using a suite of molecular biology technologies, the Salk team discovered that two proteins, which sit in the nuclear envelope, together with the membrane-spanning complexes they form, actively associate with stretches of DNA to trigger expression of key genes. Better understanding these higher-level functions could provide insight into diseases that appear to be related to dysfunctional nuclear membrane components, such as leukemia, heart disease and aging disorders.

Historically, the nuclear membrane’s main purpose was thought to be keeping the contents of the nucleus physically separated from the rest of the cell. Complexes of at least thirty different proteins, called nucleoporins, form gateways (pores) in the membrane, controlling what goes in or out. But as the Hetzer lab’s work on nucleoporins shows, these nuclear pore complexes (NPCs), beyond being mere gateways into the nucleus, have surprising regulatory effects on the DNA inside.

“Discovering that key regulatory regions of the genome are actually positioned at nuclear pores was very unexpected,” says Arkaitz Ibarra, a Salk staff scientist and first author of the paper. “And even more importantly, nuclear pore proteins are critical for the function of those genomic sites.”

Curious about all the regions of DNA with which nucleoporins potentially interact, the team turned to a human bone cancer cell line. The scientists used a molecular biology technique called DamID to pinpoint where two nucleoporins, Nup153 and Nup93, came into contact with the genome. Then they used several other sequencing techniques to understand which genes were being affected in those regions, and how.

The Salk team discovered that Nup153 and Nup93 interacted with stretches of the genome called super-enhancers, which are known to help determine cell identity. Since every cell in our body has the same DNA, what makes a muscle cell different from a liver cell or a nerve cell is which particular genes are turned on, or expressed, within that cell. In the Salk study, the presence of Nup153 and Nup93 was found to regulate expression of super-enhancer driven genes and experiments that silenced either protein resulted in abnormal gene expression from these regions. Further experiments in a lung cancer cell line validated the bone cancer line results: Nucleoporins in the NPC were found to interact with multiple super-enhancer regions to drive gene expression, while experiments that altered the NPC proteins made related gene expression faulty, even though the proteins still performed their primary role as gatekeepers in the cell membrane.

“It was incredible to find that we could perturb the proteins without affecting their gateway role, but still have nearby gene expression go awry,” says Ibarra.

The results bolster other work indicating that problems with the nuclear membrane play a role in heart disease, leukemia and progeria, a rare premature aging syndrome.

“People have thought the nuclear membrane is just a protective barrier, which is maybe the reason why it evolved in the first place. But there are many more regulatory levels that we don’t understand. And it’s such an important area because so far, every membrane protein that has been studied and found to be mutated or mis-localized, seems to cause a human disease,” says Hetzer.

Calcium Supplements May Damage The Heart

After analyzing 10 years of medical tests on more than 2,700 people in a federally funded heart disease study, researchers at Johns Hopkins Medicine and elsewhere conclude that taking calcium in the form of supplements may raise the risk of plaque buildup in arteries and heart damage, although a diet high in calcium-rich foods appears be protective.

In a report on the research, published Oct. 10 in the Journal of the American Heart Association, the researchers caution that their work only documents an association between calcium supplements and atherosclerosis, and does not prove cause and effect.

But they say the results add to growing scientific concerns about the potential harms of supplements, and they urge a consultation with a knowledgeable physician before using calcium supplements. An estimated 43 percent of American adult men and women take a supplement that includes calcium, according the National Institutes of Health.

“When it comes to using vitamin and mineral supplements, particularly calcium supplements being taken for bone health, many Americans think that more is always better,” says Erin Michos, M.D., M.H.S., associate director of preventive cardiology and associate professor of medicine at the Ciccarone Center for the Prevention of Heart Disease at the Johns Hopkins University School of Medicine. “But our study adds to the body of evidence that excess calcium in the form of supplements may harm the heart and vascular system.”

The researchers were motivated to look at the effects of calcium on the heart and vascular system because studies already showed that “ingested calcium supplements — particularly in older people — don’t make it to the skeleton or get completely excreted in the urine, so they must be accumulating in the body’s soft tissues,” says nutritionist John Anderson, Ph.D., professor emeritus of nutrition at the University of North Carolina at Chapel Hill’s Gillings School of Global Public Health and a co-author of the report. Scientists also knew that as a person ages, calcium-based plaque builds up in the body’s main blood vessel, the aorta and other arteries, impeding blood flow and increasing the risk of heart attack.

The investigators looked at detailed information from the Multi-Ethnic Study of Atherosclerosis, a long-running research project funded by the National Heart, Lung, and Blood Institute, which included more than 6,000 people seen at six research universities, including Johns Hopkins. Their study focused on 2,742 of these participants who completed dietary questionnaires and two CT scans spanning 10 years apart.

The participants chosen for this study ranged in age from 45 to 84, and 51 percent were female. Forty-one percent were white, 26 percent were African-American, 22 percent were Hispanic and 12 percent were Chinese. At the study’s onset in 2000, all participants answered a 120-part questionnaire about their dietary habits to determine how much calcium they took in by eating dairy products; leafy greens; calcium-enriched foods, like cereals; and other calcium-rich foods. Separately, the researchers inventoried what drugs and supplements each participant took on a daily basis. The investigators used cardiac CT scans to measure participants’ coronary artery calcium scores, a measure of calcification in the heart’s arteries and a marker of heart disease risk when the score is above zero. Initially, 1,175 participants showed plaque in their heart arteries. The coronary artery calcium tests were repeated 10 years later to assess newly developing or worsening coronary heart disease.

For the analysis, the researchers first split the participants into five groups based on their total calcium intake, including both calcium supplements and dietary calcium. After adjusting the data for age, sex, race, exercise, smoking, income, education, weight, smoking, drinking, blood pressure, blood sugar and family medical history, the researchers separated out 20 percent of participants with the highest total calcium intake, which was greater than 1,400 milligrams of calcium a day. That group was found to be on average 27 percent less likely than the 20 percent of participants with the lowest calcium intake — less than 400 milligrams of daily calcium — to develop heart disease, as indicated by their coronary artery calcium test.

Next, the investigators focused on the differences among those taking in only dietary calcium and those using calcium supplements. Forty-six percent of their study population used calcium supplements.

The researchers again accounted for the same demographic and lifestyle factors that could influence heart disease risk, as in the previous analysis, and found that supplement users showed a 22 percent increased likelihood of having their coronary artery calcium scores rise higher than zero over the decade, indicating development of heart disease.

“There is clearly something different in how the body uses and responds to supplements versus intake through diet that makes it riskier,” says Anderson. “It could be that supplements contain calcium salts, or it could be from taking a large dose all at once that the body is unable to process.”

Among participants with highest dietary intake of calcium — over 1,022 milligrams per day — there was no increase in relative risk of developing heart disease over the 10-year study period.

“Based on this evidence, we can tell our patients that there doesn’t seem to be any harm in eating a heart-healthy diet that includes calcium-rich foods, and it may even be beneficial for the heart,” says Michos. “But patients should really discuss any plan to take calcium supplements with their doctor to sort out a proper dosage or whether they even need them.”

According to the U.S. Centers for Disease Control and Prevention, coronary heart disease kills over 370,000 people each year in the U.S. More than half of women over 60 take calcium supplements — many without the oversight of a physician — because they believe it will reduce their risk of osteoporosis.

Northwestern Medicine First In Illinois To Implant New FDA-Approved Aortic Valve

A Northwestern Medicine cardiac surgeon was the first in Illinois and second in the United States to implant a sutureless aortic valve in a patient with coronary artery disease through a newly U.S. Food and Drug Administration-approved, minimally invasive delivery system.

Patrick McCarthy, MD, executive director of Northwestern Medicine Bluhm Cardiovascular Institute and chief of cardiac surgery at Northwestern Memorial Hospital, led the team that implanted the aortic valve in Robert Kurinsky, a 74-year-old retiree from Oak Brook, Ill. who had been treating his slowly deteriorating heart valve since 2012 primarily through medication.

“Using this newly approved valve system helped replace Mr. Kurinsky’s valve in only 12 minutes, which means less trauma to the body and a quicker recovery time,” said Dr. McCarthy, who is also the Heller-Sacks Professor of Medicine at Northwestern University Feinberg School of Medicine. “The valve opening is slightly larger than a standard valve, a positive feature for heart function in the coming years. We are always looking to find the safest and most effective means of treating our patients, and I was pleased we could offer this option to Mr. Kurinsky days after the FDA approved it.”

Traditionally, open heart surgery is the preferred method for valve replacement but increasingly cardiologists and cardiac surgeons are turning to minimally invasive approaches, a critical sea change in the field of cardiac care. Dr. McCarthy led the clinical trial at Northwestern Medicine Feinberg School of Medicine for the new valve prior to its approval by the FDA.

The FDA approved, in August 2016, the advanced EDWARDS INTUITY Elite valve system, a deployment device that incorporates some elements of transcatheter aortic valve replacement (TAVR), a minimally invasive valve replacement system.

Kurinsky said he was thrilled to learn of a less invasive option to replace his aortic valve just days before his scheduled surgery. His wife Carol Kurinsky said she could not believe when he picked up the phone in the intensive care unit and said hello the morning after the surgery. She had left him late the night before and he was on a breathing tube.

“I was told my aortic valve was closing, and we came to Northwestern for a second opinion,” said Kurinsky, who works part-time as a golf starter and is an avid international traveler, two avocations he plans to return to soon. “Coming to Northwestern and Dr. McCarthy was the best decision we made.”

Lights, Camera, Action: New Catheter Lets Doctors See Inside Arteries For First Time

Removing plaque from clogged arteries is a common procedure that can save and improve lives. This treatment approach was recently made even safer and more effective with a new, high-tech catheter that allows cardiologists to see inside the arteries for the first time, cutting out only the diseased tissue. Interventional cardiologists at Sulpizio Cardiovascular Center at UC San Diego Health are the first in the region to use this technology.

The new image-guided device, Avinger’s Pantheris™ Lumivascular atherectomy system, allows doctors to see and remove plaque simultaneously during an atherectomy – a minimally invasive procedure that involves cutting plaque away from the artery and clearing it out to restore blood flow.

The new technology treats patients suffering from the painful symptoms of peripheral artery disease (PAD), a condition caused by a build-up of plaque that blocks blood flow in the arteries of the legs and feet, preventing oxygen-rich blood from reaching the extremities. Patients with PAD frequently develop life threatening complications, including heart attack, stroke, and in some severe cases, patients may even face amputation.

“Peripheral artery disease greatly impacts quality of life, with patients experiencing cramping, numbness and discoloration of their extremities,” said Mitul Patel, MD, cardiologist at UC San Diego Health. “This new device is a significant step forward for the treatment of PAD with a more efficient approach for plaque removal and less radiation exposure to the doctor and patient.”

X-ray technology was previously used during similar procedures, but those images are not nearly as clear and do not allow visualization inside the blood vessel. The new catheter, with a fiber optic camera the size of a grain of salt on the tip, is fed through a small incision in the groin that does not require full anesthesia. Once inside, the interventional cardiologist is able to see exactly what needs to be removed without damaging the artery wall, which can cause further narrowing.

PAD affects nearly 20 million adults in the United States and more than 200 million globally. September is PAD Awareness Month, which has a personal meaning to one of Patel’s patients, who recently underwent an atherectomy at UC San Diego Health with the new catheter.

Patel said the patient had severe scar tissue and plaque build-up at a previously treated site in his right leg, limiting blood flow to his calf muscle and his ability to exercise or even walk a short distance.

“He was a good candidate for the new image-guided catheter approach. The device allowed for excellent visualization inside his leg artery as we removed only the diseased tissue,” said Patel.

Now able to walk several miles with this wife without any limitations, the patient’s quality of life has improved, and with some lifestyle changes, he hopes to manage his PAD and prevent another blockage.

Scientists Find Culprit Responsible For Calcified Blood Vessels In Kidney Disease

Scientists have implicated a type of stem cell in the calcification of blood vessels that is common in patients with chronic kidney disease. The research will guide future studies into ways to block minerals from building up inside blood vessels and exacerbating atherosclerosis, the hardening of the arteries.

The study, led by researchers at Washington University School of Medicine in St. Louis, appears Sept. 8 in the journal Cell Stem Cell.

“In the past, this calcification process was viewed as passive — just mineral deposits that stick to the walls of vessels, like minerals sticking to the walls of water pipes,” said senior author Benjamin D. Humphreys, MD, PhD, director of the Division of Nephrology and an associate professor of medicine. “More recently, we’ve learned that calcification is an active process directed by cells. But there has been a lot of controversy over which cells are responsible and where they come from.”

The cells implicated in clogging up blood vessels with mineral deposits live in the outer layer of arteries and are called Gli1 positive stem cells, according to the study. Because they are adult stem cells, Gli1 cells have the potential to become different types of connective tissues, including smooth muscle, fat and bone.

Humphreys and his colleagues showed that in healthy conditions, Gli1 cells play an important role in healing damaged blood vessels by becoming new smooth muscle cells, which give arteries their ability to contract. But with chronic kidney disease, these cells likely receive confusing signals and instead become a type of bone-building cell called an osteoblast, which is responsible for depositing calcium.

“We expect to find osteoblasts in bone, not blood vessels,” Humphreys said. “In the mice with chronic kidney disease, Gli1 cells end up resembling osteoblasts, secreting bone in the vessel wall. During kidney failure, blood pressure is high and toxins build up in the blood, promoting inflammation. These cells may be trying to perform their healing role in responding to injury signals, but the toxic, inflammatory environment somehow misguides them into the wrong cell type.”

The researchers also studied donated tissue from patients who died of kidney failure and who showed calcification in the aorta, the body’s largest artery.

“We found Gli1 cells in the the calcified aortas of patients in exactly the same place we see these cells in the mice,” Humphreys said. “This is evidence that the mice are an accurate model of the disease in people.”

About 20 million adults in the U.S. have some degree of chronic kidney disease, according to the Centers for Disease Control and Prevention. But most of these patients never develop late-stage kidney failure that requires dialysis or kidney transplantation because they succumb to cardiovascular disease first, Humphreys said. The buildup of plaque in the arteries that is characteristic of cardiovascular disease is worsened in patients with diseased kidneys because of the additional mineral deposits.

Further supporting the argument that Gli1 cells are driving the calcification process, Humphreys and his colleagues showed that removing these cells from adult mice prevented the formation of calcium in their blood vessels.

“Now that we have identified Gli1 cells as responsible for depositing calcium in the arteries, we can begin testing ways to block this process,” Humphreys said. “A drug that works against these cells could be a new therapeutic way to treat vascular calcification, a major killer of patients with kidney disease. But we have to be careful because we believe these cells also play a role in healing injured smooth muscle in blood vessels, which we don’t want to interfere with.”

Humphreys is continuing to focus on the kidney in studying ways to guide Gli1 cells away from bone-building osteoblasts and toward vessel-healing smooth muscle cells. The study’s first author, Rafael Kramann, MD, a former postdoctoral researcher in Humphreys’ lab and who is now at Aachen University in Germany, is studying the same process with a focus on the heart.

Out Of Sync How Genetic Variation Can Disrupt The Heart’S Rhythm

new research from the University of Chicago shows how deficits in a specific pathway of genes can lead to the development of atrial fibrillation, a common irregular heartbeat, which poses a significant health risk.

Researchers describe a complex system of checks and balances, including the intersection of two opposing regulatory methods that work to maintain normal cardiac rhythm, and offer insights that could lead to individualized treatment in humans.

“We hope that this and similar studies contribute to a mechanistic understanding underlying the genetic basis of heart arrhythmias” said study author Ivan Moskowitz, MD, PhD, associate professor in the Department of Pediatrics, Pathology, and Human Genetics at the University of Chicago. “Such studies will allow clinicians to stratify patients based on their likely natural history of disease and potentially their response to specific therapeutics.”

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world. It affects more than 2.7 million Americans, according to the American Heart Association. AF occurs when the normal rhythm of the heart goes awry, causing a rapid, irregular heartbeat. When blood is not properly ejected from the heart, blood clots can form, leading to high risk of stroke.

Patients with other forms of heart disease, such as congestive heart failure or hypertension, have an increased risk of AF. For decades this observation caused doctors to believe that AF was just a side effect of other heart-related issues. However, some patients with AF have no other cardiac issues and not all patients with congestive heart failure have AF. Having a family member with AF is associated with a greatly increased risk for the arrhythmia, suggesting a genetic component.

One of the regions in the genome implicated in AF is near a gene named Tbx5. Although its role in AF was not understood, Tbx5 is known to control other genes and to be important in both the structure and the rhythm of the heart.

It was long thought that a mouse heart could not develop primary AF, but when first author Rangarajan Nadadur and others in Moskowitz’s team knocked out the Tbx5 gene from adult mice, they found that the mice developed spontaneous AF. Using this model system the researchers investigated what role Tbx5 played by looking for the genes it controlled. About 30 genes have been linked to AF in humans. The researchers found that half of those genes were decreased in the absence of Tbx5 and that Tbx5 directly targeted some of those genes.

Pitx2, a gene controlled by Tbx5, is the most commonly identified gene in genome wide association studies for AF. This finding prompted the researchers to reach out to James Martin’s research group at Baylor College of Medicine, collaborators on a Leducq Foundation grant to study AF, who were studying Pitx2.

“Both Tbx5 or Pitx2 directly control important rhythm genes in the heart, but in opposite directions” said Moskowitz. “Removing either causes a susceptibility to AF.”

“The clinical application of this model is that we may be able to provide more precisely targeted treatments to AF patients depending on whether their cardiac rhythm network is up- or down-regulated,” said Moskowitz. For example, if an important calcium channel is too active and causing AF, blocking it with medication would be helpful. However, if that calcium channel is not active enough and contributing to AF, prescribing a calcium channel blocker may be ineffective or even harmful. “We believe that a better understanding of the mechanisms underlying the genetic risk of the disease will ultimately have a significant impact on treatment.”

Uthealth Researchers Identify Genetic Marker For Heart Failure

A team of scientists at The University of Texas Health Science Center at Houston (UTHealth) and Baylor College of Medicine, led by Eric Boerwinkle, Ph.D., Richard Gibbs, Ph.D., and Bing Yu, Ph.D., have identified powerful predictors of congestive heart failure, a major cause of hospitalization and death in the United States. The discovery, published today in Science Advances, was made through an analysis of how gene mutations affect circulating metabolites in the human body.

The human metabolome is a collection of small molecules called metabolites that result from cellular and biological processes in the body and can act as predictors of future disease. Researchers studied how naturally occurring gene mutations can affect metabolites in the genomes of 1,361 African-American participants in the Atherosclerosis Risk in Communities (ARIC) study. ARIC is a longitudinal, population study designed to investigate the origins and predictors of heart disease, stroke and other chronic diseases.

A mutated gene, SLCO1B1, was found to be associated with high levels of blood fatty acid, which is a strong predictor for the development of future heart failure and the mutation itself has a direct effect on heart failure risk.

Because of the aging population, the estimated prevalence and cost of care for heart failure is expected to increase dramatically. By 2030, it’s estimated that more than 8 million people in the United States will have heart failure with $70 billion total costs, according to the American Heart Association. A major risk factor of heart failure is high blood pressure, or hypertension, which is more common among African-Americans.

“The key to heart failure is to identify those at increased risk early. Our hope with this discovery is that we can be more aggressive in treating hypertension if we know someone is genetically predisposed to heart failure,” said Boerwinkle, Kozmetsky Family Chair in Human Genetics and dean of UTHealth School of Public Health.

While the finding was made in a population of African-American participants, the researchers were able to confirm the relationship among European Americans as well.

“African-Americans have higher rates of hypertension, heart failure and mortality. We would expect our findings can help in the prediction and prevention of heart failure among African Americans,” said Yu, assistant professor in the Department of Epidemiology, Human Genetics and Environmental Sciences at UTHealth School of Public Health.

The research builds upon the group’s work on “knockout humans,” which are naturally occurring mutations that inactivate a certain gene. A typical human exome has dozens of these loss-of-function gene variants. Last year, using this technique, the team identified eight new relationships between genes and diseases.

This paper is the first to examine how mutated genes directly affect the metabolome on a genome-wide scale and then go on to influence disease risk. By studying these relationships, the researchers have discovered a new pathway to identify how genes influence disease, according to Boerwinkle.

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.