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 has 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.