Faculty Spotlight: Dr. Marc Simon - Improving the Flow

Dr Marc Simon
Dr. Marc Simon
Photo credit: Marco Sanchez, UCSF

A healthy cardiovascular system is like a smoothly flowing highway: the right side of the heart pumps blood to the lungs, then the left side of the heart pumps oxygen-rich blood to the body.

But just like freeway accidents cause traffic jams, problems in the heart or lungs can cause difficulties with blood flow. These include heart failure – when the heart is unable to pump enough blood to the body – and pulmonary hypertension (PH), defined by high blood pressure in the lungs.

Marc Simon, MD, MS, applies his expertise in bioengineering, advanced heart failure and research to help pinpoint where these problems originate, what causes them, and how to better treat the resulting conditions. He was recently recruited to UCSF, and serves as director of the  Pulmonary Hypertension Comprehensive Care Center, director of Pulmonary Vascular Disease and Advanced Heart Failure Research, and program director of the Advanced Heart Failure and Transplant Cardiology Fellowship. In addition to caring for patients with PH, heart failure and heart transplant, he spends about half of his time on research to develop better treatments.

“I enjoy matching each patient to the right therapy and having a positive impact,” said Dr. Simon. “I let patients know that we have a lot of ways to treat them. I appreciate the privilege of accompanying them on this journey.”

Heart Failure and Pulmonary Hypertension

Dr. Simon was recruited from the University of Pittsburgh, where he took care of heart failure and PH patients as well as directing the heart failure and translational PH research programs and the clinical hemodynamics core facility.

With his engineering background, Dr. Simon is adept at analyzing entire systems, seeing how heart failure and PH sometimes overlap, and focusing on unsolved problems. For example, there are a number of approved treatments for heart failure with reduced ejection fraction (HFrEF), a type of heart failure in which the heart has difficulty squeezing. Dr. Simon is particularly interested in heart failure with preserved ejection fraction (HFpEF), a different type of heart failure in which the heart retains its ability to squeeze but has difficulty relaxing and filling with blood for the next contraction. There are few effective therapies for HFpEF, even though it causes at least half of all cases of heart failure.

Because HFpEF may only become evident during exercise, Dr. Simon and his colleagues often conduct diagnostic catheterizations – inserting a catheter into a patient’s heart to measure blood pressure and flow – while having patients pedal a semi-recumbent bicycle. “We get a lot more information this way, compared with just having them lie still on a table,” he said. “Most people are symptomatic while they are moving, not lying still. This way, we get to observe dynamic change, which can really redirect therapy tremendously.”

Dr. Simon is also helping to shed light on what causes PH, and what avenues might lead to better therapies. The World Health Organization has defined five distinct groups of PH, each with its own underlying causes and location of where the problem originates. Accurately identifying which PH subtype a patient has is critical to choosing the right treatment – otherwise, back to the traffic jam analogy, it’s like sending a tow truck to the wrong part of the freeway to clear an accident. For example, one type of PH is characterized by high pressure in the pulmonary arteries, which carry blood from the right ventricle to the lungs, and has many approved therapies. Another type is caused by clots in the blood vessels of the lungs, which can be treated with surgery or balloon angioplasty.

The most common form of PH is actually caused by left heart failure – problems with how the left side of the heart squeezes or relaxes, or with valves on that side of the heart. By analyzing a database of more than 10,000 patients who underwent right heart catheterizations, Dr. Simon and his team recently discovered that 46 percent had PH due to left heart disease. Coming full circle, they also found that the most common cause of PH was HFpEF. “Surprisingly, we found that pulmonary hypertension due to HFpEF was more common than pulmonary hypertension due to HFrEF,” said Dr. Simon. “For patients with HFpEF, the outcomes were quite poor in terms of survival and hospitalizations, probably because we just don’t have good treatments for HFpEF.”

Translating Discoveries

This urgent need fuels his wide-ranging collaborations with bioengineers, pulmonologists, ultrasound physicists, and other specialists in a quest to develop better therapies. “I’ve always really enjoyed that sort of multidisciplinary research,” said Dr. Simon.

For example, he has partnered with bioengineers to develop animal models of how hearts remodel, or change, in response to problems with blood flow. They found that while normal hearts have sheets of muscle fibers wrapped in a spiral – a bit like a fanned-out hand of cards in poker – animal hearts with PH had muscle fibers sheets that line up like a stack of cards, and were consequently much stiffer. “This model could give us insight into the underlying physiology, which could serve as a platform for looking at drugs targeting the right ventricle in PH,” said Dr. Simon.

“The mechanics can help provide insight into the underlying physiology of the tissue, but we also wonder, how can we translate this to patients?” he said. To help answer that question, Dr. Simon is also collaborating with an ultrasound physicist. They use three-dimensional echocardiography to noninvasively visualize deformation in the right ventricle of patients. They are currently trying to develop a novel ultrasound algorithm to measure deformation not just on the surface, but throughout the full thickness of the right ventricle.

His passion for translating discoveries into better treatments motivated him to develop a biobank for PH patient samples, and to lead early-phase clinical trials of potential therapies. For example, Dr. Simon and his collaborators are testing whether metformin, a common anti-diabetes drug, could help patients with PH. In animal models of PH due to HFpEF, his collaborators found that an enzyme called AMPK was downregulated in the muscle lining of pulmonary vessels, which was associated with those vessels becoming thicker and stiffer. Metformin appeared to restore AMPK to normal levels and also reduced adverse physiological changes in the pulmonary vessels, improving PH in the animals.

Dr. Simon now leads a clinical trial funded by the National Institute on Aging (NIA) to see whether metformin has a similar beneficial effect in patients with HFpEF-related PH. “Older age, atrial fibrillation, obesity and systemic hypertension are all associated with HFpEF, and the NIA has a lot of interest in HFpEF as a disease of aging,” he said. “Metformin is a medical therapy that is very safe, has been approved for a long time for diabetes, and has the potential to serve as a treatment for a condition that needs new therapies. We are doing a lot of study of enrolled patients, looking at blood samples and conducting exercise testing in the cath lab, to understand whether we’re truly having the physiological impact that we think we’re having. It could be an interesting way to directly target pulmonary hypertension related to HFpEF, which is quite severe and much more prevalent than people think.”

Yet another research question that intrigues Dr. Simon is developing a better way to predict which heart failure patients are most likely to benefit from receiving a left ventricular assist device (LVAD), a miniaturized implanted pump which supports the heart in pumping blood to the rest of the body in patients with advanced heart failure. While LVADs can temporarily keep patients alive who are waiting for a heart transplant, as well as improve quality of life long-term for others who are not transplant candidates, up to 40 percent of patients develop right ventricular failure after receiving an LVAD. Dr. Simon and his collaborators identified a group of inflammatory signaling molecules that were highly associated with poor outcomes and mortality after LVAD implantation. These biomarkers could help cardiologists more precisely identify which patients are best suited to receive an LVAD, and those who are most likely to develop problems.

 “Dr. Simon brings with him a wealth of translational research experience to the Pulmonary Hypertension Comprehensive Care Center,” said Teresa De Marco, MD, the center’s founding director, medical director of Heart Transplantation, and R.H. and Jane G. Logan Endowed Chair in Cardiology. “With his arrival, I am confident we can take the pulmonary hypertension research program to the next level.”

From Engineering to Cardiology

Born and raised in Baltimore, Dr. Simon was initially interested in engineering, and earned his bachelor’s degree in bioengineering from the University of Pennsylvania. During college, he did oncology research and had the opportunity to join some physicians on rounds. “I realized I wanted to more directly help people,” he said.

As a medical student at the University of Maryland School of Medicine, he took care of heart patients at Baltimore VA Medical Center during the early days of beta blocker research. “I knew right then that I was going to do cardiology and heart failure,” said Dr. Simon. “The way that science was translating quickly to patient care was really exciting. Also, cardiovascular physiology was a really good fit with my engineering background.”

Dr. Simon completed his internal medicine residency at the University of Colorado, where he grew to appreciate the complexity behind managing patients with advanced heart failure and PH. “It was eye-opening to see how severe pulmonary hypertension was, and how closely linked it is to advanced heart failure in many ways,” he said.

He then completed fellowships in cardiology and advanced heart failure and cardiac transplantation at the University of Pittsburgh, where he also earned his master’s degree in bioengineering. “I went there because there was a lot happening with ventricular assist device design and development, which really piqued my interest from an engineering perspective,” said Dr. Simon.

Focusing on the Big Picture

After serving on the faculty at the University of Pittsburgh for 14 years, he was drawn to UCSF for the opportunity to work with its outstanding heart failure cardiologists, and particularly the chance to direct the Pulmonary Hypertension Center. “It’s a huge opportunity to build on the amazing work of Dr. De Marco,” said Dr. Simon. “I’m able to do what I love, which is to focus on translational investigations at the cusp of preclinical-to-clinical research. UCSF is such an exciting institution with incredible depth and breadth of knowledge, and everyone is so collaborative. I’m like a kid in a candy shop.”

At UCSF, he hopes to advance his research on tissue biomechanics to better treat right ventricular failure. Dr. Simon also hopes to delve deeper into his biomarker investigations, and to substantially grow UCSF’s biobank of samples from patients with PH and HFpEF, which he hopes can contribute to drug discovery efforts. He also wants to build a robust pipeline of clinical trials, particularly for HFpEF and subtypes of PH for which there are currently few treatments.

He enjoys teaching, and has mentored dozens of engineering and medical trainees, from undergraduates through postdoctoral scholars. He advises them to keep the big picture in mind. “We have this tendency to put on blinders and focus in on the one disease that we specialize in, but a lot of what we do in advanced heart failure and pulmonary hypertension is to look at the patient overall,” said Dr. Simon. “It’s really important to match up the patient with the right therapy. These days, we have a lot of different options, ranging from pills and inhalers to continuous IV pumps, mechanical circulatory support, and ultimately transplant.”

One of the most rewarding parts of his work is getting to care for complex patients over many years, becoming an integral part of their lives. “At Pittsburgh, I developed lifelong relationships with my patients,” said Dr. Simon. “When I left, there were a lot of tears shed. The ability to understand where they’re coming from and make a positive impact in their lives is a passion of mine.”

In addition to medicine, Dr. Simon enjoys sailing, hiking, savoring San Francisco’s restaurant scene, and listening to jazz.

- Elizabeth Chur