"There are likely numerous genes that work in concert to predestine some people to heart failure. What we learn from the gracious cooperation of our patients and their families will likely shed light not only on inherited conditions, but on the heart failure that affects many other people.”
Treatment approaches for the individual
Cardiovascular disease does not affect everyone in the same way. One’s susceptibility to disease and response to treatment are a complex interplay of genetics and environmental factors such as diet, exercise and smoking history. Until recently, cardiologists could not integrate all of these factors when making a diagnosis or a treatment regimen, in part because the necessary technology was not available. Therefore, treatment often took a one-size-fits-all approach. UCLA is now taking a different approach by viewing a patient’s cardiovascular health holistically, tailoring care to match both lifestyle and genetics.
The first step in implementing more individualized treatment approaches is to make sure patients receive tried and true treatments that are already available, should they need them. In this effort, UCLA has long been a leader in the area of evidence-based medicine for cardiovascular care. Led by Dr. Gregg C. Fonarow, UCLA launched one of the first hospital-based systems to improve cardiovascular care quality and outcomes.
“This program demonstrated that we improved care quality, improved medication adherence, and achieved a reduction in health care disparities and a 57 percent reduction in mortality — providing the first scientific evidence demonstrating that successfully implementing a hospital-based cardiovascular treatment system reduces fatal and non-fatal cardiovascular events,” said Fonarow, director of the UCLA Cardiovascular Hospitalization Atherosclerosis Management Program, or CHAMP.
Evidence provided by CHAMP resulted in changes in treatment guidelines recommended by the National Heart, Lung and Blood Institute, American Heart Association and American College of Cardiology. The AHA even launched a nationwide program modeled after CHAMP, called Get With the Guidelines, to apply this model of care to hospitals across the country. Now, more than 2,500 U.S. hospitals have implemented it, and more than 7,000,000 patients with coronary artery disease, heart failure, atrial fibrillation or stroke have benefited from the program’s innovations. In short, hospitals participating in the guidelines have demonstrated substantially improved quality of care and clinical outcomes.
The key to success “is to make sure patients are receiving the benefits of prior discoveries,” Fonarow said. “Without a system in place to make sure that happens, it often can take 10 to 15 years from the time a discovery is made for that therapy to be applied clinically. That is a shockingly slow translation of evidence to practice.”
Creating a “molecular EKG”
To better understand cardiovascular disease risk factors and develop therapies targeting those factors, UCLA aims to develop one of the nation’s biggest data troves linking the specific activity of molecules (such as genes, proteins and other factors) with physiological measurement of how well (or poorly) a patient’s heart and blood vessels function.
Soon, patients who visit a UCLA clinic or hospital will, if they provide consent after speaking with a genetic counselor, have their genomes scanned for disease markers. The availability of that information could fundamentally change the way researchers study the cardiovascular system and the way their physicians manage their health to prevent and treat disease. When implemented, genetic screening could become a routine part of medical diagnosis and clinical decision-making, said Dr. Yibin Wang, director of the Cardiovascular Theme at the Geffen School.
“Our goal is to understand, characterize, diagnose and treat cardiovascular disease much more powerfully and accurately than is possible now,” Wang said. “That is the spirit of precision medicine: It is not just genetics. It is consideration of the whole health of each person.”
UCLA plans to collect 500,000 such records in the first several years of the program, which is slated to start in 2017.
“We are trying to develop a molecular EKG,” said Thomas Vondriska, professor of anesthesiology, medicine, and physiology at UCLA. “Analogous to how the electrical activity of the heart informs the doctor about problems with its function, so will evaluation of genes, proteins and other factors provide a doctor with an objective measurement of cardiovascular risk. Combined with the doctor’s clinical decision-making skill and innovative big data tools, these molecular features will revolutionize cardiovascular care.”
Vondriska emphasized that the goal of what some call personalized medicine is not to implement a unique treatment regimen for each patient. Rather, the aim is to define tractable subgroups of patients likely to respond to targeted treatments, an approach that has been successful in oncology and other fields. Borrowing an analogy from his colleague Dr. James Weiss, chief of the Division of Cardiology, Vondriska said that it would be impossible to come up with more than 300 million pairs of shoes to fit everyone in the U.S. but that offering only small, medium and large sizes wouldn’t work either.
“But if you had 10 sizes, you could make shoes that would be comfortable for probably about 99 percent of the population,” Vondriska said. “That is what we are trying to do with our approach to cardiovascular disease at UCLA: assign patients to the right group so that we can accurately diagnose and treat their conditions [and] thereby dramatically improve quality of life and survival.”
Getting to the heart of big data
The search for molecules that affect heart health is underway. As leaders in that effort, UCLA investigators were recently awarded $11 million to lead a National Institutes of Health Center of Excellence for Big Data Computing. The center focuses on cardiovascular disease, said its principal investigator, Peipei Ping, professor of physiology, medicine, and bioinformatics in the Geffen School. It will work with five other institutes worldwide to create and test cloud-based tools for integrating and analyzing data about protein markers linked to heart and blood vessel disorders, she said.
The long-term goal is to integrate existing and to-be-acquired data into a single computer program, enabling a user, most often a physician, to simply push a button to get all of the desired information. “A patient with a chronic disease may have 150 pages of medical records,” Ping said. “Our center will develop computational tools to extract keywords and summarize medical information most critical for physicians to know.”
The big data approach will be a boon to cardiovascular treatment, said Dr. Karol Watson, professor of medicine in the Division of Cardiology. “It is going to show us what patient characteristics correspond to outcomes. For example, it could finally tell us who is going to benefit from statins versus who is likely to be affected by crippling muscle pain sometimes caused by these drugs.”
Research in cardiovascular disease will also flourish, said Watson, who trains cardiology fellows and physicians in how to use and manipulate big data. “All of this information will significantly advance efficient and effective treatment of heart and blood vessel disorders,” she said.
Finding genes involved in heart failure
UCLA hosts one of the world’s longest-running congenital heart disease programs, with physicians and researchers who have treated more than 1,000 patients with inherited heart defects. Dr. Jessica Wang, assistant professor of medicine in the Division of Cardiology, leads an effort to understand how variations in the sequence of some genes, called mutations, cause disease. She is building the Inherited Cardiovascular Disease Registry, an effort to investigate devastating cardiovascular diseases that often strike early in life and run in families.
She and her team, which includes her mentor, Jake Lusis, vice chair of Human Genetics at UCLA, are compiling all patients’ exome sequences, that is the sequences of all 25,000 or so functional human genes, and comparing them to digitized records of patient care at UCLA’s Cardiovascular Genetics Clinic, which Wang also leads.
Wang will use these data to investigate how disruption of gene pathways or networks may cause heart failure. One example is an inherited condition caused by mutations called hypertrophic cardiomyopathy, a disorder often associated with sudden death in young athletes. Between 30 and 70 genes are implicated in the disorder, which affects up to 500,000 people in the United States. If one's parent is a carrier of a mutation associated with the disease, the chance of inheriting the mutation is 50-50. And, as an illustration of how critical it is to consider how environment interacts with genetics, some individuals who inherit the mutation exhibit a mild form of the disorder, while in others outcomes are much more severe.
The ultimate goal is to find effective targeted therapies for patients affected by the disease and for those who carry the mutation. “The best therapy we have now allows us to prevent or slow down heart failure in 11 to14 percent of patients. That modest success is a significant improvement from what we could do 20 years ago,” said Yibin Wang, leader of the Cardiovascular Theme, who also participated in these genetic studies. “We have a long way to go.”
As a researcher, Jessica Wang (no relation to Yibin) also studies mouse models of human heart failure. She and her team have identified 35 genes in mice associated with susceptibility to fibrosis, the stiffening of heart muscle that leads to heart failure as well as other cardiac features associated with disease. Of note: As with human populations, these animal studies reveal strong heritable susceptibility to disease onset and progression.
“We have been able to make mice that are genetically predisposed to develop heart failure become more resilient,” she said, suggesting that similar approaches may mitigate inherited components of cardiovascular disease in humans. Wang is comparing her genetic findings in mice to the human gene information contained in the growing Inherited Cardiovascular Disease Registry, which also contains exome sequencing of patients and their family members.