Some people’s hearts just can’t catch a break — literally.

For patients with a prevalent subtype of heart failure, their hearts contract properly but never fully relax. This constant tension impairs the heart’s ability to fill up and replenish blood flow.

The Fralin Biomedical Research Institute at VTC recently recruited molecular biologist Sumita Mishra to investigate new treatments for this increasingly common cardiometabolic disease: heart failure with preserved ejection fraction, or HFpEF. She started in October.

“Our lab will help define the precise mechanisms underlying HFpEF, so we can develop more effective, targeted treatments and help millions of people living with this condition,” Mishra said. She joins the institute’s Center for Exercise Medicine Research, which opened last year, as an assistant professor.

Mishra’s laboratory studies the molecular pathways that go awry in heart failure. In particular, the lab examines biological differences underlying cardiometabolic processes in men and women with heart failure.

“We know that postmenopausal, obese women have the highest risk of developing this form of heart failure, yet the molecular differences between men and women are still largely a mystery,” said Mishra, who also holds an appointment in Virginia Tech’s Department of Human Nutrition, Foods, and Exercise.

A first line of defense for postmenopausal obese women with HFpEF, among lifestyle interventions, is usually estrogen hormone replacement therapy — but it’s largely ineffective.

“I kept wondering, why isn’t estrogen therapy helping these patients? This question kept me up at night — then, I found a clue,” Mishra said.

In 2021, Mishra authored a study in the Journal of Clinical Investigation describing a promising treatment for obesity and cardiometabolic syndrome — both precursors to HFpEF. The study’s drug, now in phase II clinical trials at Johns Hopkins, works by inhibiting phosphodiesterase 9A (PDE9) protein, leading obese mice to shed body fat and improve cardiac health — all without altering diet, appetite, or exercise levels.

It has all the makings of a weight loss miracle drug, but there’s a catch.

While the drug yielded dramatic benefits for obese male mice and obese female mice without ovaries, it did not affect fertile, obese female mice. This finding puzzled Mishra, leading her to discover that under specific conditions, estrogen signaling interacts with other pathways, effecting changes at the DNA level that reduce suppression of genes involved in metabolizing lipids.

“There is a broader mechanism at play that needs to be manipulated. Heart failure is still largely misunderstood because multiple variables and organs are implicated,” Mishra said. “We’re finding this intricate crosstalk between the cardiovascular, endocrine, and digestive systems that needs further investigation.”

Zhen Yan, professor and director of the Center for Exercise Medicine Research, feels fortunate to have recruited Mishra to the institute.

“Dr. Mishra came with such a strong track record of research in cardiovascular biology for more than a decade. Her seminal findings that activation of protein kinase G effectively mitigates obesity and a common type of heart failure are groundbreaking,” Yan said. “Her joining has significantly contributed to the significant momentum we have here. I am confident that with the excellent support at the research institute, she will soon make highly impactful new discoveries about the mechanisms underlying the health benefits of regular exercise.”

Mishra’s laboratory also studies why prescribed lifestyle modifications, such as exercise, improve symptoms in heart failure patients. Her research team will explore how aerobic exercise adapts cardiometabolic signaling at the molecular level, hoping to discover more therapeutic targets for future medications.

Her research is funded by a three-year American Heart Association award for her project studying PDE9’s control of cardiometabolic disease. She has also received pre- and postdoctoral grants from the American Heart Association, the National Institutes of Health, and the Government of India.

Previously a postdoctoral fellow and then a research associate at Johns Hopkins University School of Medicine, Mishra completed her undergraduate and master’s degrees at Calcutta University and her doctoral degree in chemical biology at the Indian Institute of Chemical Biology. She has completed competitive research fellowships at the Indian Institutes of Science and Chemical Biology and the Gwangju Institute of Science and Technology in South Korea.

Mishra has received numerous awards, including the 2020 W. Leigh Thompson Excellence in Research Award for Basic Science, the 2019 American Heart Association Basic Cardiovascular Science Scientific Sessions Honorable Mention Award, and the 2018 Johns Hopkins School of Medicine Division of Cardiology Stanley Blumenthal Award for Best Research in Basic Science. She has authored 24 peer-reviewed articles, including a 2021 review of heart failure pathobiology in Nature Reviews Cardiology and a 2020 review of cardiac protein quality control mechanisms in Frontiers in Physiology.

Raised in India, Mishra comes from a long line of theoretical physicists who helped stoke her love for science. “We were always encouraged to explore the unknown,” Mishra said.

Starting an independent research program has been her dream, and she has high praise for Michael Friedlander, Virginia Tech’s vice president for health sciences and technology and executive director of the Fralin Biomedical Research Institute. “Dr. Friedlander was incredible from day one. I felt supported and saw that the institute would help me achieve my goals,” Mishra said. “As a child, I lived in the Himalayan mountains, and Roanoke reminds me of that time. Compared to a large city, this mountain town gives you peace of mind and calmness, so you can focus on what you want to achieve.”

Mishra has begun recruiting to fill postdoctoral associate, research assistant, graduate, and undergraduate positions.

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