Taking the Lead in Cardiovascular Disease Research

by BRIDGET M KUEHN

Northwestern Medicine investigators are developing better treatments and care
for patients with the most prevalent of diseases.

 

 

 

 

 

 

Above: Cardiac muscle cells (cardiomyocytes) with their nuclei stained blue, from the lab of Hossein Ardehali, MD, PhD. Below left: 4-D flow MRI from Michael Markl, PhD, the Lester B. and Frances T. Knight Professor of Cardiac Imaging in Radiology, visualizes complex 3-D blood flow in a patient with bicuspid aortic valve. With Cynthia Rigsby, MD, professor of Radiology and Pediatrics, Markl’s research group has developed this kind of imaging test to identify hemodynamic biomarkers that better characterize congenital heart disease. The ongoing work has already been translated to clinics.

This January, the American Heart Association (AHA) released updated heart disease statistics. The report contained many all-too-familiar facts and figures: Cardiovascular diseases remain the No. 1 cause of death in the world and in the United States. But it also shared new findings: An estimated 103 million people — nearly half of all U.S. adults — have high blood pressure and are at risk for heart attacks and strokes, following AHA guidelines published last fall that redefine the metric.

The numbers highlight the critical importance of cardiovascular disease (CVD) research: basic science studies to understand its underpinnings; translational work to turn findings in the lab into viable treatments for patients; clinical trials to test new behavioral interventions, medications and care models; and population studies to understand how we can minimize risk factors so the disease doesn’t manifest in the first place.

Across Northwestern departments and within the Feinberg Cardiovascular and Renal Research Institute, an illustrious cohort of investigators is doing just that.

 

 

The fruit of the school’s growing cardiovascular research portfolio is evident in high-impact scientific publications, 50-plus ongoing clinical trials and patient care at Northwestern Memorial Hospital’s Bluhm Cardiovascular Institute ranked No. 7 for cardiology and heart surgery in the nation by U.S. News & World Report.

Northwestern’s leadership in this domain is apparent: The medical school is part of four AHA-funded research networks — more than any other institution in the country — one concentrating on vascular disease, a second on preventing risk factors for CVD, a third on disparities in CVD rates and a fourth on cardiovascular health in children.

“With our depth of research expertise in clinical, translational, basic and outcomes sciences, there is no area of contemporary cardiovascular medicine that we can’t explore,” says Clyde Yancy, MD, Msc, chief of Cardiology in the Department of Medicine, Magerstadt Professor and vice dean for Diversity and Inclusion. “A wealth of talent, determined vision and array of resources allow us to build unparalleled research networks and proceed with pivotal research capable of changing life and living for those with known, or for those at risk for, cardiovascular disease.”

The medical school’s faculty are many of the leaders behind the clinical practice guidelines and performance measures that inform clinicians nationwide. Yancy, for example, chairs the AHA’s Get With The Guidelines heart failure registry, a quality improvement initiative that holds more than 1 million patient records and captures data from over 35 percent of all U.S. hospitals.

“Part of our growth and success reflects the momentum generated by recruitment of world-class senior faculty in an environment that already housed world-class population scientists and stellar clinical investigators,” says Douglas Vaughan, MD, chair and the Irving S. Cutter Professor of Medicine. In his own research, Vaughan studies a protein overexpressed in CVD called plasminogen activator inhibitor-1 and has developed a new drug to inhibit its action.

Discover more of the wide-reaching CVD research led by Northwestern faculty, including studies exploring home-based interventions for a common form atherosclerosis, the molecular roots of heart failure and improvements for cardiovascular care in low- and middle-income settings around the world.

Recent CVD News at Northwestern

  • Obese people live shorter lives and have a greater proportion of life with cardiovascular disease, a finding that debunks the “obesity paradox” previously suggesting that people diagnosed with cardiovascular disease live longer if they are overweight or obese compared with people who are normal weight at the time of diagnosis. (Khan/Llyod-Jones: JAMA Cardiology)
  • Among patients with HIV, higher levels of HIV-related immunosuppression are associated with substantially higher odds of atrial arrhythmias. (Sanders/Feinstein: PLOS One)
  • After performing whole genome sequencing on a family with a strong preponderance of genetic heart disease, scientists discovered that a mutation in a newly discovered gene, MYBPHL, increases the risk of arrhythmia and cardiomyopathy. The gene could eventually be included on gene panels, while better understanding its function could lead to new targets for therapy. (Barefield/McNally: Circulation)
  • Reprogrammed stem cells can be used to identify patients with cancer who are likely to experience cardiotoxicity — heart muscle damage so severe that it can lead to heart failure — after taking a common chemotherapy drug. (Burridge/Wu: Nature Medicine)
  • Heart muscle cells called cardiomyocytes are a principal source of the molecular signals that drive scarring in the heart, a common manifestation of aging and nearly every form of heart disease. (Flevaris/Vaughan: Circulation)
  • Northwestern is leading one of the first international randomized trials designed to treat heart failure with preserved ejection fraction using a dime-sized shunt device to lower pressure in the left upper heart chamber. (Shah/Ricciardi: ongoing clinical trial)
  • Northwestern investigators are validating the accuracy of wearable devices that record heart rhythm over time for patients with arrhythmias. (Passman: ongoing clinical trial)

Mobilizing Patients

Peripheral Artery Disease

Many patients with peripheral artery disease (PAD) are sidelined from activities they love because of difficulty walking. They can’t travel, go out with friends, keep up with grandkids or walk to the store, explains Mary McDermott, MD, ’92 GME, the Jeremiah Stamler Professor of Medicine in the Division of General Internal Medicine and Geriatrics.

One in five people age 75 and older develop PAD, which occurs when the arteries that supply the legs narrow or are blocked by a buildup of cholesterol and other substances. Despite how life-altering and common PAD is, many physicians incorrectly attribute their patients’ mobility problems to old age or arthritis, and miss opportunities to minimize patients’ risk of heart attack or stroke and to improve their mobility, McDermott says.

While tried-and-true medications like statins and antiplatelet therapies can help reduce cardiovascular events in patients with PAD, options to improve mobility are limited. Physicians may use a stent to improve blood flow, but the benefit typically only lasts a few years and not all patients with PAD are good candidates for these procedures. Supervised exercise three times a week at a medical center can help, but that intervention is not always feasible.

McDermott’s team has been testing home-based exercise strategies. In one trial, published in JAMA, patients who came in to a medical center just once per week and completed the rest of their exercise at home improved their six-minute walk by more than 50 meters, compared to a 30-meter improvement for patients doing supervised exercise. During their weekly visits, they met with other patients and a coach who helped them set walking exercise goals and monitor progress.

“Based on what we know in 2018, patients need to come in to the medical center occasionally and meet with a coach and really feel accountable to that coach,” says McDermott, also a professor of Preventive Medicine and director of Northwestern’s AHA center focused on calf muscle pathology and disability in PAD.

McDermott’s group is also testing experimental medications. Currently, there are only two drugs for PAD approved by the Food and Drug Administration. One offers only a modest benefit and recent trials suggest the other doesn’t work at all, she says.

“We need new drugs that can be combined with exercise or help get patients to the point where they’re able to exercise,” McDermott says. She has a clinical trial underway testing whether the diabetes drug metformin may benefit patients with PAD who don’t have diabetes.

“Scientists have successfully reduced rates of heart attack in older people, so people are living longer,” McDermott explains. “Now we’re really trying to focus on the ability of patients with PAD to engage in life fully and have a better quality of life.”

Scientists have successfully reduced rates of heart attack in older people, so people are living longer. Now we’re really trying to focus on the ability of patients with PAD to engage in life fully and have a better quality of life.

Molecular Metabolism

Mitochondria and Cardiac Metabolism

Scientists in the Feinberg Cardiovascular and Renal Research Institute (FCVRI), are also opening up new avenues for treating CVD, but they’re taking a different approach, looking at what goes wrong in the heart from a basic science perspective.

Hossein Ardehali, MD, PhD, director of the FCVRI’s Center for Molecular Cardiology, focuses on understanding the role of mitochondria in heart failure. These cellular powerhouses produce energy in the form of a chemical called adenosine triphosphate (ATP). The heart is a huge consumer of this energy, using more than six kilograms of ATP a day as it pushes blood throughout the body.

“Understanding cardiac metabolism is really important,” says Ardehali, also a professor of Medicine in the Division of Cardiology and of Pharmacology. “We think that if we target metabolism, we can reverse some CVD processes.”

Historically, studying cellular metabolic processes has been the focus of endocrinologists studying diseases like diabetes; Ardehali applies methods he learned training with an endocrinologist to CVD.

“We are going into an area that has not been studied in the past to understand the pathways involved in energy production,” he says. For example, his lab published a paper in Nature Communications showing that a novel protein that regulates both sugar and fat metabolism is critical for normal heart function, and that its deletion leads to heart failure in mice. Now, the group is turning its focus to how changes in cardiac metabolic processes regulate epigenetics in the heart.

“There is crosstalk between all of these pathways,” Ardehali says. “It makes perfect sense because there are no isolated systems in our bodies.”

His lab has also shown that elevated levels of iron in the mitochondria contribute to heart muscle weakening caused by inadequate blood flow or the cancer drug doxorubicin, findings published in the Journal of the American Heart Assocation and the Journal of Clinical Investigation. The team is now working with Northwestern’s Department of Chemistry to develop iron-chelators, drugs that help strip excess iron from the body.

“We are trying to target mitochondrial iron in the heart as a way of protecting the heart from getting damaged,” Ardehali says. The research is very timely because some patients with heart failure who are iron deficient are currently given infusions of iron, which he worries could be harmful.

As a physician-scientist, Ardehali is also collaborating with colleagues in the clinic to apply his findings to patients. “We are at the stage where we can translate our findings to clinical practice,” he says.

Worldwide Quality Improvement

CVD Care in India

We think that if we target metabolism, we can reverse some CVD processes.

Above: Adam De Jesus, a fifth-year MD-PhD student in the Medical Scientist Training Program, Hossein Ardehali, PhD, and postdoctoral fellow Paulina Stanczyk, PhD, working in Ardehali’s lab. Photography by Bruce Powell

Mark Huffman, MD, MPH, ’11 GME, joined Northwestern to pursue his interest in cardiovascular research with an international impact. His work has focused on the south Indian state of Kerala.

Asian Indians bear a disproportionate burden of CVD without a clear cause to their underlying predilection for vascular disease, Huffman says. Plus, India is a middle-income country that’s seen rapid economic and technological growth in the past 25 years, so there are many opportunities for improvement.

“Places like India seem poised for innovation and new ideas that can help all of us,” says Huffman, an associate professor of Preventive Medicine and of Medicine in the Division of Cardiology.

Managers in Indian hospitals often lack the training they need to be effective, according to research by Northwestern medical student Kyle Yoo. There is also a shortage of clinicians, so physicians may see more than 100 patients in an afternoon, Huffman says. In addition, electronic medical systems are just now becoming available in Kerala. Huffman and his colleagues in India have worked hard over the past decade to provide safe and effective cardiovascular care despite these hurdles.

Earlier this year, the team published in JAMA the results of a randomized trial testing a quality improvement toolkit in 63 Indian hospitals. More than 21,000 patients with acute myocardial infarction participated. The investigators demonstrated improvements in the quality and safety of care delivered, but not in the rate of major cardiovascular events over 30 days, despite similar programs being used in the United States.

“We think it’s useful to identify not only what works, but also what doesn’t, and why not,” Huffman says. One of the reasons for the neutral trial results might be major improvements in cardiovascular care in Kerala over the past decade. Survival rates after heart attacks in Kerala now mirror rates in the U.S., but other states have much lower survival rates after heart attacks.

“It’s exciting to think about what Kerala is doing that can serve as a model for other states in India,” Huffman says. “It also demonstrates how high-quality, safe care is possible in a low- or middle-income country setting.”

In fact, Huffman says there is much the U.S. healthcare system, which faces ballooning costs, can learn from these countries about delivering effective care inexpensively. For example, he noted the success of using community health workers in sub-Saharan Africa to deliver pre-exposure prophylaxis and antiretroviral therapy, a strategy that can serve as a model for longitudinal, chronic disease care in the United States.

“If we’re going to solve big problems, we need to be working with a diverse and inclusive set of partners,” Huffman says.

“Places like India seem poised for innovation and new ideas that can help all of us.