The discovery of new knowledge to improve patient care and to prevent cardiovascular disease is the motivating force at THI at SLEH. Physicians and scientists work tirelessly to unfold the mysteries of cardiovascular disease, to understand the mechanisms at work, and to envision solutions that will ultimately lead to effective treatments.
Global Leadership in Adult Stem Cell Research
The Stem Cell Center of THI at SLEH was the first such center in the United States to receive US Food and Drug Administration (FDA) approval for a randomized, clinical (human) trial of adult stem cells to treat patients with advanced heart failure. In this trial, stem cells were harvested from the patient's own bone marrow and injected with a special catheter directly into damaged but viable heart muscle. That study recently enrolled its final patient. Results of studies have confirmed that this form of therapy is safe and can improve symptoms, quality of life, and blood flow in some patients who have severe heart failure.
The National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) recently named THI at SLEH and four other centers to be part of a new national consortium called the Cardiovascular Cell Therapy Research Network. The Network is the first ever to receive federal funding for adult stem cell studies, in which patients with cardiovascular disease are treated with stem cells taken from their own bodies. The Network is being supported by a $33.7 million grant.
THI at SLEH also has FDA approval for a study in which bone marrow cells that express the enzyme aldehyde dehydrogenase will be harvested to create a highly purified stem cell population. These stem cells have the potential to build new blood vessels in damaged hearts, thereby ultimately leading to better functional improvement in patients with advanced heart failure.
Of the various types of stem cells, one especially important type is the mesenchymal cell. Physicians and scientists at THI at SLEH have shown that treatment with mesenchymal cells improves recovery from heart attacks in animal models. Earlier this year, physicians began the world's first clinical trial to treat heart attack patients with precursor mesenchymal stem cells taken from young, healthy individuals. This treatment is intended to prevent congestive heart failure, which occurs in many patients after a heart attack. Apparently, mesenchymal stem cells are not rejected and do not cause inflammation when taken from a healthy donor and injected directly into the heart of a patient with heart disease.
The Stem Cell Center is also studying the use of stem cells for the treatment of peripheral vascular disease. The patients in this study have severe blockages in the arteries of their legs, have exhausted all other treatment options, and are at risk for amputation. The stem cells are injected directly into the leg muscle.
The Robert and Janice McNair Foundation established the McNair Scholars Program at THI at SLEH in October 2008. Dr. Edward T.H. Yeh was named the first McNair Scholar. Dr. Yeh is internationally recognized for helping to decipher the role of inflammation in the development of atherosclerosis, for using adult stem cells to repair damaged heart muscle, and for discovering three novel biochemical pathways that revolutionized the understanding of the life cycle of a cell and cell signaling. Dr. Yeh now plans to concentrate on identifying the mechanisms that allow human adult cells to produce new heart muscle tissue. He will also develop methods for reprogramming skin cells to create stem cells for clinical use.
In addition, THI at SLEH has been established as a NOGA Core Lab, the only such laboratory of its kind. The NOGA Cardiac Navigation System is a 3D-imaging method used to identify target sites for delivering stem cells to the heart by measuring cardiac electrical and mechanical function. In addition to serving the needs of THI investigators, the NOGA Core Lab helps researchers from other institutions analyze data and provide feedback about procedures used in stem cell research. The Stem Cell Center is also a Site for Training Excellence in the NOGA procedure. Physicians from around the world travel here for hands-on training in the use of this intricate device.
In summary, research involving adult stem cells is a relatively new discipline, which is rapidly evolving at THI at SLEH as scientists in many different areas of cardiovascular research incorporate adult stem cells into their studies. Support for a portion of the Stem Cell Center's work has come from the Houston Endowment, Inc., The Ewing Halsell Foundation, the Fred and Mabel R. Parks Foundation, and The Hamill Foundation. From their work, researchers have shown stem cell therapy to be a safe, promising treatment for patients with diseases of the heart and blood vessels. Investigators at THI are committed to determining the best approach for using stem cells to repair heart and peripheral tissues. Ideally, stem cell therapy may someday be used not only to treat cardiovascular diseases but also to prevent them.
Unrivaled Experience with Mechanical Assist Devices
For more than 30 years, physician scientists at THI at SLEH have amassed the world’s most extensive experience in the development and use of ventricular (heart) assist devices (VADs) to sustain the failing circulation in patients with severe heart failure. More than 700 patients have received these "blood pumps" since the research program began. More than a dozen different VADs are being studied in clinical trials, and even more are under development in preclinical (experimental) studies.
While some of these devices are for short-term use and are inserted with a catheter through an artery, others are surgically implanted through an incision in the chest. The surgically implanted pumps are used as longer-term "bridges" to heart transplantation. Patients with VADs can be discharged home to await transplantation. While they are waiting, they lead fairly normal lives—an important goal of this research. One VAD, developed and studied at THI at SLEH, has been approved for permanent use (destination therapy) for patients in the United States.
A key area of research at THI at SLEH involves using VADs to allow a patient's heart to rest and recover normal function, after which the VAD can be removed. Investigators are determining what indicators can best show that recovery has occurred, establishing test methods for confirming recovery, and refining surgical methods for removing the VAD in a minimally invasive manner. Over the last three years, nine patients who underwent long-term support with one of the newer VADS called a HeartMate II have recovered, allowing removal of their devices.
Researchers are also working to develop a total artificial heart that will deliver blood by means of continuous flow rather than pulsation and have received a grant from the National Heart, Lung, and Blood Institute to further this research. This new artificial heart has, as its pumping chambers, two continuous-flow VADs and is smaller, less expensive, and more reliable than the previous-generation artificial heart. In addition, this new artificial heart can be implanted in adults of all sizes. Laboratory studies, supported in part by the John S. Dunn Research Foundation, have confirmed the feasibility of this new continuous-flow artificial heart.
Understanding the Biomolecular Mechanisms of Cardiovascular Disease
By identifying genes and proteins that cause cardiovascular diseases, THI scientists are paving the way for a new era in medicine. Identification of genetic risks will allow physician-scientists to find promising treatments, isolate environmental threats, and determine how to improve health by modifying human behavior.
By determining which genes are responsible for heart and vascular diseases, researchers can devise appropriate medical responses. In a study involving 15,000 patients, THI at SLEH scientists have identified four genes associated with heart attacks and are currently evaluating other genes that may be associated with heart failure.
Many medical conditions result from changes, or mutations, in one or more of a person's genes. Mutations can cause the protein encoded by that gene to malfunction. When a protein malfunctions, cells that rely on that protein's function do not behave normally, causing problems for tissues or organs. Over the last decade, more than 100 mutations in a dozen genes have been identified in patients with hypertrophic cardiomyopathy (HCM), a condition in which the heart muscle thickens, thereby blocking or reducing the flow of blood throughout the body. This condition causes several varieties of heart problems―not the least of which is sudden death―and affects an estimated 600,000 to 1.5 million Americans, or one in 500. Genetic information, in combination with clinical data, can be used to personalize disease management and predict the risk of sudden death in HCM patients. The same genetic techniques used in patients with HCM are also being used to identify genes that cause premature heart attacks.
Physician-scientists at THI at SLEH want to be able to reduce a person's likelihood of developing cardiovascular disease by assessing that person's genetic profile, as well as his or her age, gender, and lifestyle habits. Different genes or gene combinations respond differently to changes in diet, exercise, smoking, alcohol consumption, and medications such as cholesterol-lowering drugs. The THI at SLEH physicians have established a preliminary genetic profile that would enable individuals to adopt the habits most likely to reduce risk. As more information comes to light, recommendations for lifestyle changes and new treatments will become available.
Nonsurgical Treatment for Heart Disease
Texas Heart Institute physicians rank as world leaders in devising nonsurgical methods for treating heart disease. For example, by developing specially designed catheters to measure variations of temperatures in atherosclerotic plaques, THI at SLEH physician-scientists in the Advanced Physiologic Monitoring Department, were among the first to identify unstable arterial blockages (atherosclerotic plaques), which are likely to lead to heart attacks and strokes. Their studies showed that the higher the temperature of a plaque, the greater the risk. These studies led to the creation of a successful biotechnology company, Volcano Therapeutics, Inc., which develops catheter-based diagnostic and therapeutic products for detecting and treating unstable plaques. With this technology, patients at risk for heart attacks and strokes may receive appropriate treatment before a life-threatening plaque rupture occurs.
Furthermore, this group of researchers is investigating the core body temperature as a predictor of disease exacerbation or death in patients with decompensated, or suddenly worsening, heart failure. The data show that potentially fatal episodes of cardiac decompensation are preceded by a consistent and significant decline in the core body temperature and, even earlier, by identifiable changes in the circadian rhythm of a patient's temperature variations.
In several studies, THI at SLEH scientists have established that influenza can trigger heart attacks. Patients at risk of heart disease are already encouraged to get a flu vaccine every year. These scientists recently discovered a new generation of anti-influenza agents that work by inhibiting a cellular motor protein that the influenza virus uses to infect healthy cells. Now these scientists are studying the cellular and molecular mechanisms that underlie the inhibitory effect of these agents and are combining the new agents with existing ones to see whether they better protect against the flu. Scientists are also exploring the anti-influenza effects of statin drugs.
Scientists in the Wafic Said Department of Molecular Cardiology Research at THI at SLEH are working on developing a new and unique type of therapy for pulmonary arterial hypertension (PAH), a devastating disease in which the blood vessels in the lungs narrow. Current therapy for PAH often involves the continuous intravenous administration of prostacyclin, a molecule that helps dilate blood vessels and replenishes the reduced levels in PAH patients. However, this intravenous therapy is associated with significant drawbacks and severely reduces a patient's quality of life. The molecular cardiology scientists are seeking to develop a cell-based therapy for PAH by using one or several injections with genetically altered cells that continuously secrete prostacyclin. They plan to study the effects of these cells in animal models of PAH. These studies could lay the groundwork for testing this innovative cell therapy in clinical trials.
In addition to their studies of pulmonary hypertension, molecular cardiology scientists are beginning research to learn how to mobilize from a patient's own bone marrow those subsets of cells best suited to treat heart disease or disease in the peripheral arteries. Once mobilized, the cells would home to the sites where more blood flow is needed and repair damaged tissue, thus avoiding the need for invasive procedures.
Imaging the Heart
Physicians at THI are studying a new ultrasound imaging technique that can detect small differences in the heart's contraction speed that cannot be detected by traditional ultrasound. This technique will allow doctors to identify areas of myocardial dysfunction. A related technology analyzes contractility by detecting the speed at which heart muscle fibers shorten and lengthen. Scientists are also working to improve the diagnostic capabilities of computed tomography for assessing atherosclerotic plaques.
Electrophysiology: The Power Grid of the Heart
Researchers at the Center for Cardiac Arrhythmias and Electrophysiology are conducting a variety of new clinical, translational, and basic research projects involving the prevention, diagnosis, management, and treatment of cardiac arrhythmias (disturbances or irregularities of the heart beat).
In one of their studies, the Center's physician-scientists are exploring the effect of the autonomic nervous system on the development of cardiac arrhythmia and assessing the role of autonomic modulation in the prevention and treatment of different types of arrhythmias. The arrhythmias they are studying include atrial fibrillation, a condition in which the upper chambers of the heart beat irregularly and not in synchrony with the heart's lower chambers (the ventricles), and ventricular tachycardia, a condition in which the heart's lower chambers beat too fast.
In another study, they are learning about the pattern of arrhythmias in patients who have implantable cardiac defibrillators, which are used to prevent sudden cardiac death. Furthermore, they are exploring the use of magnetic resonance imaging to define the anatomic setting that creates ventricular fibrillation, a chaotic quivering of the heart's lower chambers, which can also cause sudden cardiac death.
This group of investigators recently published a report that describes how non-prescription weight-loss products known to cause cardiac arrhythmias are marketed over the Internet, even though they have been banned by the US Food and Drug Administration. They are now conducting a survey to evaluate physicians' awareness of the hidden danger of non-prescription, weight-loss supplements and are also exploring the effects of energy-supplement drinks on the heart.
In another project, the Center's physicians are evaluating the potential effect of new medications intended to prevent pacing-induced cardiomyopathy, a devastating complication that causes the heart muscles to lose their normal function in patients with pacemakers.
The Center's physician-scientists are also developing a device to prevent pneumothorax formation, a potentially life-threatening complication of some cardiac procedures, in which air leaks from the lungs into the chest cavity, potentially causing the lungs to collapse and pressure to be placed on the heart and blood vessels. If the condition goes uncorrected, death can result. The device being developed at THI at SLEH could be used by doctors as a preventive before procedures are undertaken that are known to have pneumothorax as a possible complication.
Working with THI biostatisticians, this group has recently developed a scoring system to predict which patients are likely to develop atrial fibrillation after heart surgery. Using this system, they can devise preventive strategies for use in high-risk patients.
