Scientists make a major breakthrough to treat fibrotic diseases that cause organ failure

Researchers from Duke-NUS Medical School (Duke-NUS) and the National Heart Centre Singapore (NHCS) have discovered that a critical protein, known as interleukin 11 (IL11) is responsible for fibrosis and causes organ damage. While it is surprising that the importance of IL11 has been overlooked and misunderstood for so long, it has now been very clearly demonstrated by this work.

A protein known as transforming growth factor beta 12 (“TGFB1”) has long been known as the major cause of fibrosis and scarring of body organs, but treatments based on switching off the protein have severe side effects. The scientists discovered that IL11, is even more important than TGFB1 for fibrosis and that IL11 is a much better drug target than TGFB1.

Fibrosis is the formation of excessive connective tissue, causing scarring and failure of bodily organs and the skin. It is a very common cause of cardiovascular and renal disease, where excessive connective tissue destroys the structure and function of the organ with scar tissue. Compared to other Asians, American, and Europeans, Singaporeans have a higher prevalence of coronary artery disease, hypertension, and diabetes, the three most common diseases that lead to heart failure. In addition, kidney failure is an epidemic in Singapore and around the world. Fibrosis of the heart and kidney eventually leads to heart and kidney failure, thus this breakthrough discovery — that inhibiting IL11 can prevent heart and kidney fibrosis — has the potential to transform the treatment of millions of people around the world.

The international team, led by Professor Stuart Cook, Tanoto Foundation Professor of Cardiovascular Medicine, along with Assistant Professor Sebastian Schäfer, both from NHCS and Duke-NUS’ Programme in Cardiovascular and Metabolic Disorders, carried out the translational research to identify the key drivers of chronic fibrotic disease in heart, kidney, and other tissues. The team also includes researchers from Harvard University and University of California, San Diego/UCSD (USA), Max Delbrück Center for Molecular Medicine/MDC-Berlin (Germany), London Institute of Medical Sciences/MRC-LMS and Imperial College London (the UK), and the University of Melbourne (Australia).

“Fibrotic diseases represent a major cause of illness and death around the world. The discovery that IL11 is a critical fibrotic factor represents a breakthrough for the field and for drug development. It is an incredibly exciting discovery,” explained the study’s senior author, Professor Cook, who is also Director, National Heart Research Institute Singapore.

“Currently, more than 225 million people worldwide suffer from heart and kidney failure and there is no treatment to prevent fibrosis. The team is at the stage of developing first-in-class therapies to inhibit IL11 and this offers hope to patients with heart and kidney disease,” shared Professor Terrance Chua, Medical Director, National Heart Centre Singapore.

“This therapeutic target for fibrotic diseases of the heart, kidney and other organs may be exactly what we need to fill the unmet pressing clinical gap for preventing fibrosis in patients. We are proud to announce that the suite of intellectual property arising from this research has been licensed to a newly launched Singapore-funded biotechnology start-up Enleofen Bio Pte Ltd, which is co-founded by Professor Cook and Assistant Professor Schäfer,” said Professor Thomas Coffman, Dean of Duke-NUS Medical School.

No cardiovascular disease reduction with intensive blood pressure lowering treatment

Blood pressure lowering treatment does not reduce death or cardiovascular disease in healthy individuals with a systolic blood pressure below 140. This is shown in a systematic review and meta-analysis from Umeå University. The results, published in JAMA Internal Medicine, support current guidelines and contradict the findings from the Systolic Blood Pressure Intervention Trial (SPRINT).

Blood pressure treatment goals have been intensively debated since the publication of the SPRINT study in 2015. While current guidelines recommend a systolic blood pressure goal < 140 mm Hg, SPRINT found additional mortality and cardiovascular disease reduction with a goal < 120 mm Hg.

A systematic review and meta-analysis from Umeå University, published today in JAMA Internal Medicine, contradicts these findings. The Umeå study shows that treatment does not affect mortality or cardiovascular events if systolic blood pressure is < 140 mm Hg. The beneficial effect of treatment at low blood pressure levels is limited to trials in people with coronary heart disease.

“Our findings are of great importance to the debate concerning blood pressure treatment goals,” says Dr Mattias Brunström, researcher at the Department of Public Health and Clinical Medicine, Umeå University and lead author.

The study is a meta-analysis, combining data from 74 randomized clinical trials, including more than 300 000 patients. The researchers separated primary preventive studies from studies in people with coronary heart disease or previous stroke. The analysis found that the treatment effect was dependent on how high blood pressure was in previously healthy individuals. If systolic blood pressure was above 140 mm Hg, treatment reduced the risk of death and cardiovascular disease. Below 140 mm Hg, treatment did not affect mortality or the risk of first-ever cardiovascular events.

“Several previous meta-analyses have found that blood pressure lowering treatment is beneficial down to levels below 130 mm Hg. We show that the beneficial effect of treatment at low blood pressure levels is limited to trials in people with coronary heart disease. In primary preventive trials, treatment effect was neutral,” says Mattias Brunström.

Immune Cells Mistake Heart Attacks for Viral Infections

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

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

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

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

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

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

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

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

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

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.

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.”

MDI Biological Laboratory study finds immune system is critical to regeneration

The answer to regenerative medicine’s most compelling question — why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot — may lie with the body’s innate immune system, according to a new study of heart regeneration in the axolotl, or Mexican salamander, an organism that takes the prize as nature’s champion of regeneration.

The study, which was conducted by James Godwin, Ph.D., of the MDI Biological Laboratory in Bar Harbor, Maine, found that the formation of new heart muscle tissue in the adult axolotl after an artificially induced heart attack is dependent on the presence of macrophages, a type of white blood cell. When macrophages were depleted, the salamanders formed permanent scar tissue that blocked regeneration.

The study has significant implications for human health. Since salamanders and humans have evolved from a common ancestor, it’s possible that the ability to regenerate is also built into our genetic code.

Godwin’s research demonstrates that scar formation plays a critical role in blocking the program for regeneration. “The scar shoots down the program for regeneration,” he said. “No macrophages means no cardiac regeneration.”

Godwin’s goal is to activate regeneration in humans through the use of drug therapies derived from macrophages that would promote scar-free healing directly, or those that would trigger the genetic programs controlling the formation of macrophages, which in turn could promote scar-free healing. His team is already looking at molecular targets for drug therapies to influence these genetic programs.

“If humans could get over the fibrosis hurdle in the same way that salamanders do, the system that blocks regeneration in humans could potentially be broken,” Godwin explained. “We don’t know yet if it’s only scarring that prevents regeneration or if other factors are involved. But if we’re really lucky, we might find that the suppression of scarring is sufficient in and of itself to unlock our endogenous ability to regenerate.”

The prevailing view in regenerative biology has been that the major obstacle to heart regeneration in mammals is insufficient proliferation of cardiomyocytes, or heart muscle cells. But Godwin found that cardiomyocyte proliferation is not the only driver of effective heart regeneration. His findings suggest that research efforts should pay more attention to the genetic signals controlling scarring.

The extraordinary incidence of disability and death from heart disease, which is the world’s biggest killer, is directly attributable to scarring. When a human experiences a heart attack, scar tissue forms at the site of the injury. While the scar limits further tissue damage in the short term, over time its stiffness interferes with the heart’s ability to pump, leading to disability and ultimately to terminal heart failure.

In addition to regenerating heart tissue following a heart attack, the ability to unlock dormant capabilities for regeneration through the suppression of scarring also has potential applications for the regeneration of tissues and organs lost to traumatic injury, surgery and other diseases, Godwin said.

Godwin’s findings are a validation of the MDI Biological Laboratory’s unique research approach, which is focused on studying regeneration in a diverse range of animal models with the goal of gaining insight into how to trigger dormant genetic pathways for regeneration in humans. In the past year and a half, laboratory scientists have discovered three drug candidates with the potential to activate regeneration in humans.

“Our focus on the study of animals with amazing capabilities for regenerating lost and damaged body parts has made us a global leader in the field of regenerative medicine,” said Kevin Strange, Ph.D., MDI Biological Laboratory president. “James Godwin’s discovery of the role of macrophages in heart regeneration demonstrates the value of this approach: we won’t be able to develop rational and effective therapies to enhance regeneration in humans until we first understand regeneration works in animals like salamanders.”

Godwin, who is an immunologist, originally chose to look at the function of the immune system in regeneration because its role as the equivalent of a first responder at the site of an injury means that it is responsible for preparing the ground for tissue repairs. The recent study was a follow-up to an earlier study which found that macrophages also play a critical role in limb regeneration.

The next step is to study the function of macrophages in salamanders and compare them with their human and mouse counterparts. Ultimately, Godwin would like to understand why macrophages produced by adult mice and humans don’t suppress scarring in the same way as in axolotls and then identify molecules and pathways that could be exploited for human therapies.

Godwin holds a dual appointment with The Jackson Laboratory, also located in Bar Harbor, which is focused on the mouse as a model animal. The dual appointment allows him to conduct experiments that compare genetic programming in the highly regenerative animals used as models at the MDI Biological Laboratory with genetic programming in neonatal and adult mice.

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.

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.”

Higher BMI linked with increased risk of high blood pressure, heart disease, type 2 diabetes

Results of a new study add to the evidence of an association between higher body mass index (BMI) and increased risk of cardiometabolic diseases such as hypertension, coronary heart disease, type 2 diabetes, according to a study published by JAMA Cardiology.

A connection between higher BMI and cardiometabolic disease risk usually arise from observational studies that are unable to fully account for confounding by shared risk factors. Mendelian randomization (a method of analysis using genetic information) is an approach that partially overcomes these limitations. Using mendelian randomization, Donald M. Lyall, Ph.D., of the University of Glasgow, Scotland, and colleagues conducted a study that included 119,859 participants in the UK Biobank (with medical, sociodemographic and genetic data) to examine the association between BMI and cardiometabolic diseases and traits.

Of the individuals in the study, 47 percent were men; average age was 57 years. The researchers found that higher BMI was associated with an increased risk of coronary heart disease, hypertension, and type 2 diabetes, as well as increased systolic and diastolic blood pressure.

These associations were independent of age, sex, alcohol intake, and smoking history.

The authors write that the results of this study has relevance for public health policies in many countries with increasing obesity levels. “Body mass index represents an important modifiable risk factor for ameliorating the risk of cardiometabolic disease in the general population.”

A limitation of the study was that the sample lacked data on a complete range of potential mediators, such as lipid traits and glucose levels.

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.”

Cardiac stem cells from heart disease patients may be harmful

Patients with severe and end-stage heart failure have few treatment options available to them apart from transplants and “miraculous” stem cell therapy. But a new Tel Aviv University study finds that stem cell therapy may, in fact, harm heart disease patients.

The research, led by Prof. Jonathan Leor of TAU’s Sackler Faculty of Medicine and Sheba Medical Center and conducted by TAU’s Dr. Nili Naftali-Shani, explores the current practice of using cells from the host patient to repair tissue — and contends that this can prove deleterious or toxic for patients. The study was recently published in the journal Circulation.

“We found that, contrary to popular belief, tissue stem cells derived from sick hearts do not contribute to heart healing after injury,” said Prof. Leor. “Furthermore, we found that these cells are affected by the inflammatory environment and develop inflammatory properties. The affected stem cells may even exacerbate damage to the already diseased heart muscle.”

Tissue or adult stem cells — “blank” cells that can act as a repair kit for the body by replacing damaged tissue — encourage the regeneration of blood vessel cells and new heart muscle tissue. Faced with a worse survival rate than many cancers, many heart failure patients have turned to stem cell therapy as a last resort.

“But our findings suggest that stem cells, like any drug, can have adverse effects,” said Prof. Leor. “We concluded that stem cells used in cardiac therapy should be drawn from healthy donors or be better genetically engineered for the patient.”

Hope for improved cardiac stem cell therapy

In addition, the researchers also discovered the molecular pathway involved in the negative interaction between stem cells and the immune system as they isolated stem cells in mouse models of heart disease. After exploring the molecular pathway in mice, the researchers focused on cardiac stem cells in patients with heart disease.

The results could help improve the use of autologous stem cells — those drawn from the patients themselves — in cardiac therapy, Prof. Leor said.

“We showed that the deletion of the gene responsible for this pathway can restore the original therapeutic function of the cells,” said Prof. Leor. “Our findings determine the potential negative effects of inflammation on stem cell function as they’re currently used. The use of autologous stem cells from patients with heart disease should be modified. Only stem cells from healthy donors or genetically engineered cells should be used in treating cardiac conditions.”

The researchers are currently testing a gene editing technique (CRISPER) to inhibit the gene responsible for the negative inflammatory properties of the cardiac stem cells of heart disease patients. “We hope our engineered stem cells will be resistant to the negative effects of the immune system,” said Prof. Leor.

Diabetes drug prevents stiffening of heart muscle in obese mouse model

Overconsumption of a Western diet high in fats and refined sugars has contributed to a global increase in obesity and Type 2 diabetes. Obese and diabetic premenopausal women are more at risk of developing heart disease — even more than men of similar age and with similar health issues. A study by researchers at the University of Missouri School of Medicine found that the diabetes medication linagliptin can protect against stiffening of the left ventricle of the heart in overweight female mice. The finding may have implications for management of cardiovascular diseases in humans.

“In previous studies, we showed that young, female mice consuming a Western diet, high in fat, sucrose and high fructose corn syrup, not only gained weight, but also exhibited vascular stiffening consistent with obese premenopausal women,” said Vincent DeMarco, Ph.D., a research associate professor of endocrinology at the MU School of Medicine and the lead author of the study. “Our current study sought to understand if linagliptin prevents cardiac stiffening caused by eating a Western-style diet.”

Linagliptin is a medication prescribed to lower blood glucose in patients with Type 2 diabetes. The medication works by blocking the enzyme dipeptidyl peptidase-4, or DPP-4. Previous studies have shown that DPP-4 inhibitors offer protection against vascular inflammation and oxidative stress — conditions associated with cardiovascular stiffening.

DeMarco’s team studied 34 female mice that were fed either a normal diet or a simulated Western diet for four months. Another group of mice were fed a Western diet containing a low dose of linagliptin. The team used an ultrasound system, similar to that used in humans, to evaluate the function of the left ventricle of the heart.

“A heartbeat actually is a two-part pumping action that takes less than a second in healthy humans,” DeMarco said. “The first part, known as diastole, involves relaxation of the left ventricle while it fills with oxygenated blood from the lungs. After the left ventricle fills with blood, it then contracts and pushes blood into the aorta. This part of the cardiac cycle is referred to as systole. If the left ventricle becomes stiffer it will not be able to relax normally, and diastole will be impaired. This form of heart disease is known as diastolic dysfunction, which is a risk factor for a more serious heart condition known as diastolic heart failure.”

The mice fed the Western diet alone gained weight, exhibited increased heart weight and developed diastolic dysfunction. However, the mice fed the Western diet along with linagliptin did not develop diastolic dysfunction. They also exhibited less oxidative stress and inflammation in their hearts compared to the mice fed the Western diet alone.

“Oxidative stress and inflammation are two factors that can promote excess accumulation of collagen, also known as fibrosis, in the walls of the left ventricle,” DeMarco said. “In our study, we found that Western diet-fed mice had increased fibrosis in the left ventricle that was prevented by linagliptin.”

The team also found that linagliptin suppressed not only DPP-4 activity, but also TRAF3IP2 production. TRAF3IP2 is a protein responsible for initiating tissue oxidative stress, inflammation and fibrosis in the heart.

“This was a major novel finding of our study,” DeMarco said. “However, further research is required to determine exactly how linagliptin affects the function of this important protein.”

DeMarco also cautioned that linagliptin, like other DPP-4 inhibitors, can be expensive without insurance coverage.

“Based on the results of this research and our previous studies, it is tempting to speculate that linagliptin could reduce the risk of cardiovascular complications associated with obesity and Type 2 diabetes,” DeMarco said. “However, ongoing clinical trials will help determine what, if any, cardio-protective role linagliptin could play in the management of obesity-related heart disease.”

One gene closer to regenerative therapy for muscular disorders

A detour on the road to regenerative medicine for people with muscular disorders is figuring out how to coax muscle stem cells to fuse together and form functioning skeletal muscle tissues. A study published June 1 by Nature Communications reports scientists identify a new gene essential to this process, shedding new light on possible new therapeutic strategies.

Led by researchers at the Cincinnati Children’s Hospital Medical Center Heart Institute, the study demonstrates the gene Gm7325 and its protein – which the scientists named “myomerger” – prompt muscle stem cells to fuse and develop skeletal muscles the body needs to move and survive. They also show that myomerger works with another gene, Tmem8c, and its associated protein “myomaker” to fuse cells that normally would not.

In laboratory tests on embryonic mice engineered to not express myomerger in skeletal muscle, the animals did not develop enough muscle fiber to live.

“These findings stimulate new avenues for cell therapy approaches for regenerative medicine,” said Douglas Millay, PhD, study senior investigator and a scientist in the Division of Molecular Cardiovascular Biology at Cincinnati Children’s. “This includes the potential for cells expressing myomaker and myomerger to be loaded with therapeutic material and then fused to diseased tissue. An example would be muscular dystrophy, which is a devastating genetic muscle disease. The fusion technology possibly could be harnessed to provide muscle cells with a normal copy of the missing gene.”

Bio-Pioneering in Reverse

One of the molecular mysteries hindering development of regenerative therapy for muscles is uncovering the precise genetic and molecular processes that cause skeletal muscle stem cells (called myoblasts) to fuse and form the striated muscle fibers that allow movement. Millay and his colleagues are identifying, deconstructing and analyzing these processes to search for new therapeutic clues.

Genetic degenerative disorders of the muscle number in the dozens, but are rare in the overall population, according to the National Institutes of Health. The major categories of these devastating wasting diseases include: muscular dystrophy, congenital myopathy and metabolic myopathy. Muscular dystrophies are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. The most common form is Duchenne MD.

Molecular Sleuthing

A previous study authored by Millay in 2014 identified myomaker and its gene through bioinformatic analysis. Myomaker is also required for myoblast stem cells to fuse. However, it was clear from that work that myomaker did not work alone and needed a partner to drive the fusion process. The current study indicates that myomerger is the missing link for fusion, and that both genes are absolutely required for fusion to occur, according to the researchers.

To find additional genes that regulate fusion, Millay’s team screened for those activated by expression of a protein called MyoD, which is the primary initiator of the all the genes that make muscle. The team focused on the top 100 genes induced by MyoD (including GM7325/myomerger) and designed a screen to test the factors that could function within and across cell membranes. They also looked for genes not previously studied for having a role in fusing muscle stem cells. These analyses eventually pointed to a previously uncharacterized gene listed in the database – Gm7325.

Researchers then tested cell cultures and mouse models by using a gene editing process called CRISPR-Cas9 to demonstrate how the presence or absence of myomaker and myomerger – both individually and in unison – affect cell fusion and muscle formation. These tests indicate that myomerger-deficient muscle cells called myocytes differentiate and form the contractile unit of muscle (sarcomeres), but they do not join together to form fully functioning muscle tissue.

Looking Ahead

The researchers are building on their current findings, which they say establishes a system for reconstituting cell fusion in mammalian cells, a feat not yet achieved by biomedical science.

For example, beyond the cell fusion effects of myomaker and myomerger, it isn’t known how myomaker or myomerger induce cell membrane fusion. Knowing these details would be crucial to developing potential therapeutic strategies in the future, according to Millay. This study identifies myomerger as a fundmentally required protein for muscle development using cell culture and laboratory mouse models.

The authors emphasize that extensive additional research will be required to determine if these results can be translated to a clinical setting.

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.”

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.

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.

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.

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.”

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.