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The Cardiovascular Research Center (CVRC) at the Cardiovascular Institute and the Warren Alpert Medical School at Brown University was founded in 2005 and is home to scientists, physician-scientists, and graduate and undergraduate students dedicated to basic cardiovascular research.
Our mission is to unravel fundamental mechanisms of heart disease and to discover novel cardiac therapies. The research focus of CVRC investigators is on the molecular mechanisms of rhythm disorders of the heart (cardiac arrhythmias), sudden cardiac arrest, heart enlargement (hypertrophy) and heart failure.
The CVRC is located in 8,000 sq ft of newly renovated, state-of-the-art laboratory space in the “Jewelry District” of Providence, RI, a rapidly growing center for biomedical research. CVRC facilities include a sophisticated invasive animal catheterization and electrophysiology laboratory, and a brand new state-of-the-art research facility that is used for the studying of genetically modified mouse and rabbit models of cardiac diseases. These studies include cellular electrophysiology, optical mapping, single cell analyses of calcium transients and contractility, sophisticated imaging tools, as well as biochemical, molecular and cell biological experimental approaches. An important goal of the CVRC is to enhance and promote education and training in molecular cardiology and life sciences. Research is supported through grants to affiliated faculty from the NIH and AHA.
Rhode Island Hospital’s Cardiovascular Research Center (CVRC) has been awarded a $7.36 million research project grant (R01) from the National Heart, Lung and Blood Institute of the National Institutes of Health to study sudden cardiac arrest. The research will be focused on mechanisms to develop new therapies and strategies to prevent sudden cardiac arrest and to measure the impact of genetic and environmental factors on risk for sudden cardiac death. The grant will be paid out over five years and is the largest grant of its kind to be paid to a Lifespan partner hospital.
The grant is an R01 grant, the original and oldest grant mechanism used by the National Institutes of Health. Typically, R01 grants are for less than $250,000, and any organization requesting more than $500,000 per year must secure prior approval from the NIH to apply for the specialized grant. The grant issued to the CVRC at Rhode Island Hospital will be approximately $1.5 million per year, and is specific to the research project A Multi-Scale Approach to Cardiac Arrhythmia: from the Molecule to the Organ.
“R01 grants from the National Institutes of Health are incredibly difficult to come by and are highly competitive,” said Gideon Koren, M.D., director of the Cardiovascular Research Center at Rhode Island Hospital. “Major academic medical centers around the country bid for these grants each year in an effort to further their research to find cures, diagnostic tools and new therapies for the most pervasive and life-threatening diseases.”
Koren continued, “Receiving this award demonstrates that the NIH recognizes the quality and importance of the research being conducted at Rhode Island Hospital and specifically in the Cardiovascular Research Center. It also demonstrates the commitment of its researchers to discover new ways to prevent sudden cardiac arrest.” In sudden cardiac arrest, which affects more than 300,000 people in the U.S. each year, the heart stops beating suddenly and unexpectedly, preventing blood from flowing to the brain and organs. The majority of those who suffer from sudden cardiac arrest die within minutes. According to the NIH, the risk of sudden cardiac arrest increases with age and men are two to three times more likely than women to suffer such an arrest.
“This award from the NIH is a remarkable achievement,” said Peter Snyder, Ph.D, senior vice president and chief research officer for Lifespan. “It underscores the quality of the research at Rhode Island Hospital and provides our researchers with the means to continue to explore new treatments and preventative measures of an illness that takes thousands of lives each year in the U.S.”
Koren was recruited to Rhode Island Hospital in 2005 to launch the Cardiovascular Research Center. Among the largest cardiovascular research programs in the country, the CVRC now is home for 43 investigators including undergraduate students, graduate students, postdoctoral fellows, research associates and faculty, and receives over $3.8 million in direct costs from the federal government.
The CVRC will work in collaboration with researchers at Brown University; Northeastern University; Pennsylvania State University; and the University of California, Los Angeles. The grant was funded by the NIH funding agency the National Heart, Lung and Blood Institute, (NHLBI), grant number HL110791.
Researchers in Rhode Island Hospital's Cardiovascular Research Center have published two new studies focusing on the causes of arrhythmia and sudden cardiac death (SCD) when a genetic disorder is present. The studies use a first-ever genetic animal model the researchers developed in 2008 to further their understanding of a genetic disorder known as Long QT Syndrome (LQTS).
The first study identified differential conditions and cellular mechanisms that can trigger SCD when LQTS is a factor, and the second study, for the first time, directly links sex hormones to the incidence of arrhythmia and SCD. Their findings are published in the Journal of Physiology and the HeartRhythm Journal.
It is known that genetic mutations can predispose individuals to arrhythmia and/or SCD, a leading cause of death in the United States. Between one in 2,500 and one in 5,000 individuals are born with mutations that cause LQTS, a disorder of the heart's electric system, and a determining factor in the development of arrhythmia and/or SCD. Ninety percent of the known mutations cause loss of function of ion channels responsible for LQTS types 1 and 2 (LQT1 and LQT2).
LQTS leads to a prolonged "QT interval" on electrocardiograms. The QT interval refers to the time it takes the chambers of the heart to "repolarize" themselves so that the heart is ready for another contraction cycle. When this timeframe is lengthened, it is associated with triggering irregular arrhythmia that can cause sudden cardiac arrest.
In 2008, Gideon Koren, M.D., a physician researcher and director of the Cardiovascular Research Center at Rhode Island Hospital, and his colleagues developed a first-of-its-kind genetic rabbit model to study arrhythmia and SCD that mirrors what happens in individuals who have mutations of the LQT1 or LQT2 genes.
In a new study published in the Journal of Physiology, the researchers used this animal model to identify differential conditions and cellular mechanisms that trigger arrhythmia in LQT1 or in LQT2 syndrome. In this study, Koren and the researchers studied early afterdepolarizations (EADs), an abnormal depolarization during the plateau phase of the heart electrical activity (action potential) that can initiate arrhythmia, and is a hallmark of LQTS. The focus was on mechanisms underlying different high-risk conditions that trigger EADs.
Their findings indicate that the conditions required for EAD to occur in the animal models are genotype specific. For LQT2, the researchers found that conditions such as a slow heart rate or a slightly lower potassium ion concentration outside the heart cells (as seen in hypokalemia) can cause a dramatic prolongation of action potential and produce EADs. In LQT1, however, these conditions result in relatively limited prolongation and no EADs. In contrast, isoproterenol that mimics cardiac stimulation by the sympathetic nervous system causes arrhythmias in single cells only in LQT1 heart cells.
Koren summarizes, "This study takes single cells out of the heart and reveals how arrhythmias are being initiated. What we are showing in this study is that single cells are responsible for generating an arrhythmia. Further, we found that different types of increased autonomic nervous system activity play a critical role in the cause of arrhythmias and sudden cardiac death, but it differs based on genotype."
The autonomic nervous system is what controls "fight or flight" response. In their research, Koren and his colleagues found that sympathetic "surge" activity was responsible for triggering arrhythmia in LQT2. In LQT1, however, an increased steady sympathetic tone was associated with arrhythmias.
Surge is a sudden rise of the sympathetic tone. That surge is very important in triggering arrhythmia in LQT2. As Koren explains, "In LQT2, you need the startle response - like an alarm clock. However, in LQT1, we found the increased steady sympathetic tone is very important in inducing arrhythmia, like in patients swimming for an extended period of time. So there are different ways that arrhythmia will be induced depending on the genotype."
In a second study, published in the HeartRhythm Journal, Koren and his colleagues furthered their understanding of arrhythmias by studying the impact of sex hormones, and confirming for the first time a direct link between the hormones and SCD.
Koren explains, "Quite simply, we demonstrate that estrogen promotes major cardiac events - such as polymorphic ventricular tachycardia (pVT) and SCD - while progesterone prevents them when LQT2 is a factor. Estrogen has a pro-arrhythmic effect."
Sex differences in long-QT-related arrhythmias with a higher risk of pVT and SCD have been well-documented in the clinical setting, and the risk is higher in women than in men, particularly during the postpartum period. In this study, Koren says, "We show for the first time a direct link between sex hormones and the incidence of arrhythmias and sudden cardiac death. Through our research in our animal models, we have demonstrated that progesterone significantly reduces triggers for polymorphic ventricular tachycardia. At the same time, we were able to show that progesterone is protective and prevents SCD when LQT2 is present."
Koren explains that this finding suggests that high progesterone levels during pregnancy likely account for the reduced risk of SCD in LQT2 patients during pregnancy. The marked reduction in progesterone during the postpartum period, however, likely promotes arrhythmias and SCD in these patients. Their findings also indicate that estrogen increases both trigger and sustainability of pVT, and thereby promotes major cardiac events.
He concludes that while further studies are needed in clinical trials, the clinical implications of this study will impact on the standard treatment of patients who are diagnosed with LQT2. Specific hormone-based therapies may be prescribed to protect them from arrhythmia and potentially avoid sudden cardiac death.
The National Institutes of Health provided funding for these studies. Koren's principal affiliation is Rhode Island Hospital, a member hospital of the Lifespan health system in Rhode Island. He is also a professor of medicine at The Warren Alpert Medical School of Brown University.
Other researchers with Koren involved in the study published in the Journal of Physiology include Gong-Xin Liu, Bum-Rak Choi, Ohad Ziv, Weiyan Li also of Rhode Island Hospital and Alpert Medical School as well as Enno de Lange and Zhilin Qu of the David Geffen School of Medicine at the University of California. Other researchers involved in the study in HeartRhythm Journal include Katja Odening, Bum-Rak Choi, Gong-Xin Liu, Kathryn Hartmann, Ohad Ziv, Leonard Chaves, Lorraine Schofield and Jason Centracchio, all of Rhode Island Hospital and Alpert Medical School, Manfred Zehender and Michael Brunner of the University Medical Center Freiburg, in Germany, and Xuwen Peng of the Pennsylvania State University College of Medicine.
When NBC news journalist Tim Russert died suddenly at age 58 of heart failure in 2008, public reaction ranged from shock to sorrow to fear. The premature death of this respected, seemingly healthy man also focused a spotlight on sudden cardiac death, intensifying public awareness of this issue.
Since its founding in 2005, the Cardiovascular Research Center (CVRC) at Rhode Island Hospital, in affiliation with The Warren Alpert Medical School of Brown University, has been engaged in research that seeks to unlock the mysteries of sudden cardiac death. The CVRC focuses its research on the molecular mechanisms of cardiac arrhythmias, sudden cardiac arrest, hypertrophy (heart enlargement) and heart failure.
Gideon Koren, MD, CVRC director and professor of medicine at Alpert Medical School, has another way to describe the center's focus: "The specific question that we are interested in is, 'why do we die Wednesday and not Tuesday?' What is exactly the trigger that causes someone to die suddenly?"
In its first five years, the CVRC successfully developed a genetically modified animal model that allows researchers to study various mechanisms that can trigger arrhythmia, a rhythm disorder associated with sudden cardiac arrest. The model is the first of its kind that can mimic what happens during arrhythmia in humans. While that accomplishment is impressive, the 30-member CVRC team has its sights fixed on a far loftier achievement: a therapy that can largely eradicate sudden cardiac death, especially in women, who are more at risk for the disease than men.
From a broad perspective, Koren says, the research focus at the CVRC has always been studying myocyte biology and abnormalities related to the cardiac muscle. There are three branches of the research that, auspiciously, are coming together. The research of Koren's CVRC colleague, Ulrike Mende, PhD, associate professor of medicine at Alpert Medical School, is more related to signal transduction and cardiac hypertrophy in heart failure, and the research of CVRC colleague Bum-Rak Choi, PhD, assistant professor of medicine at Alpert Medical School, is specifically related to abnormal heart rhythm formation and its relationship with the autonomic nervous system, explains Koren. "My research centers on the consequences of abnormal electrical functioning in the heart, and sudden cardiac death, a disease that claims 350,000 lives in the United States each year. There is no other disease that kills more people than sudden cardiac death."
This ongoing research is beginning to produce some diverse connections. "The first connection is related to hormones and how they affect sudden cardiac death," Koren says. He adds that data suggesting a strong link between sex hormones and sudden cardiac death have provided corroborative support for the animal models developed by the CVRC and, even as the CVRC animal model helps researchers to understand sudden cardiac death, this approach may have broader commercial applications. Koren says, "From a pharmaceutical industry perspective, it seems to me that the animal models we've developed could help to screen drugs-not for safety, because the industry has screens for that-but to differentiate drugs that prolong the QT interval, and thereby distinguish between drugs that may cause arrhythmia and those that will not cause arrhythmia."
While Koren's lab is focused on the changes and irregularities in heart rhythm, Mende says her lab more interested in the pumping function of the heart. "For example, adrenalin reaches the cellular membrane of a heart cell, but then how does that signal get transmitted inside the cell, and how do intracellular mechanisms get started that change the phenotype of the cell-change its size, change its protein expression, change its ability to contract and therefore pump?"
For some time, Mende's lab has focused on cardiac myocytes, the muscle cells that form the heart. She notes that heart muscle cells are primarily unable to divide and replicate. "There might be some cells that have the ability to regenerate, but the majority can't," she says. "Typically, when an organ is exposed to stress, one response is that the cell numbers increase. But heart muscle cells don't have that option, so they increase in size." Initially, this can be a good thing, she says. But over time it leads to decompensation and failure, meaning the inability to contract properly. "We have discovered a model that we can use to study ways to delay the development of hypertrophy enlargement before the transition into heart failure, or even reverse the effect." Another focus of Mende's lab is how myocytes cross-talk and interact with other cell types. "When people think about the heart they immediately think about the heart muscle cells, and they do make up the majority of the heart. But there are several other cell types in the heart,"she says, including fibroblasts. "These surround the heart muscle cells and basically provide some structural support. And if the heart is stressed-if one has an infarct, for example-these cell types are activated and a scar forms."
Mende says that the entire CVRC has become interested in the potential role of fibroblasts. "My lab is particularly interested in finding out how signaling is received and basically converted inside the cell into a cellular response-how these two cells cross-talk to each other. So this is a new project in which we've done a lot of work over the last two years, and for which we are now in the process of applying for federal funding."
Choi's lab has been tracking electrical signals in the heart to understand how irregular heart rhythm can be formed under pathological conditions. The answer to the question why do we die Wednesday and not Tuesday, Choi says, may be related to autonomic imbalance such as sympathetic surge during emotional events, and adds, "My lab is interested in the mode of sympathetic nerve activity that initiates arrhythmias."
CVRC researchers are also studying the aging heart and connecting blood vessels as a possible factor in sudden cardiac death. Noting that the incidence and prevalence of sudden cardiac death increases exponentially-as much as eightfold- as we grow older, Koren says, "As we age, our arteries become stiffer. That's not atherosclerosis, that's just characteristic of the blood vessels, primarily the large blood vessels. It's the main cause of systemic hypertension, which affects more than half of the population."
Koren's lab is looking at a genetic link to arterial stiffness. "Somehow the abnormal mechanics of the aorta as we age could be related to sudden cardiac death, because there is cross-talk between the heart and the aorta, and the aging of the large vessels in the heart may have some common processes."
The CVRC is pursuing myriad research models-from hormone therapy to the role of fibroblasts and the effects of aging-all in the hope of being able to answer that question of why a person dies on Wednesday and not Tuesday. The ultimate goal is that the person will not die on Wednesday but instead live a long life.