USF Health Heart Institute Archives - USF Health News /blog/tag/usf-health-heart-institute/ USF Health News Tue, 22 Aug 2023 14:32:35 +0000 en-US hourly 1 https://wordpress.org/?v=6.5.5 USF Health $5.6 million study to define link between genetics and heart disease in many Friedreich’s ataxia patients /blog/2023/08/22/usf-health-5-6-million-study-to-define-link-between-genetics-and-heart-disease-in-many-friedreichs-ataxia-patients/ Tue, 22 Aug 2023 14:32:35 +0000 /?p=38339 Researchers at the USF Health Morsani College of Medicine were awarded $5.6 million of expected funds for a 4-year study from the U.S. Department of Defense to examine […]

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Researchers at the USF Health Morsani College of Medicine were awarded $5.6 million of expected funds for a 4-year study from the U.S. Department of Defense to examine why many people with Friedreich’s Ataxia (FA) go on to also develop heart disease, a major cause of death for those with FA.

Principal investigator for the USF study is Thomas McDonald, MD, professor in the Department of Internal Medicine (Division of Cardiology) and the Department of Molecular Pharmacology and Physiology in the USF Health Morsani College of Medicine. Dr. McDonald is also a researcher in the USF Health Heart Institute and director of the USF Health Cardiogenetics Clinic.

“We still don’t have a full understanding of the genetic mutation for Friedrich’s ataxia to determine why so many patients go on to get heart disease – we need to know,” Dr. McDonald said. “The physiology is not well characterized. This study will help us gain a better understanding of the basic mechanisms of the gene that carries FA, and help identify clinical predictors of the FA-associated heart disease.”

The new study dovetails with current work taking place in Dr. McDonald’s lab, including an R56 grant from the National Institutes of Health, which focuses on the fundamental mechanisms of LMNA-associated heart disease passed from one generation to the next — and what can be done to help prevent disease and its consequences.

This FA-heart disease study will follow FA patients and their parents over four years, and will involve careful clinical monitoring of heart health, examination of biomarkers, whole genome sequencing, stem cell modeling of heart tissue, and mitochondrial function studies.

From left, Dr. Kami Kim, Dr. Aarti Patel, Dr. Thomas McDonald, and Dr. Theresa Zesiewicz. Not pictured is Sami Noujaim, PhD.

Spearheading the work in the DoD study is a multidisciplinary team of USF Health experts representing cardiology, genetics, neurology, molecular pharmacology, cardiac electrophysiology and predictive modeling. The diverse expertise will help distinguish the clinical, genetic, and biological factors that contribute to cardiac disease in FA patients. Data from FA families and basic science models will be integrated with clinical data to identify unique factors in the heart that influence the cardiac phenotype and separate cardiac-specific traits from those influencing the neurological phenotype.

“Study results could lead to tools used in patient care settings to identify those FA families most at risk for cardiomyopathy and allow for potential intervention and treatment that could help delay onset of the heart disease,” Dr. McDonald said.

The USF Health interdisciplinary team for the study includes:

  • Thomas McDonald, MD: clinical cardiology, molecular pharmacology and cardiogenetics (Division of Cardiology, Department of Internal Medicine, MCOM)
  • Aarti Patel, MD: neurocardiogenetics and cardiac imaging (Division of Cardiology, Department of Internal Medicine, MCOM)
  • Sami Noujaim, PhD: molecular pharmacology and cardiac electrophysiology (Department of Molecular Pharmacology and Physiology, MCOM)
  • Kami Kim, MD: machine learning and clinical predictive modeling (Division of Infectious Diseases, Department of Internal Medicine, MCOM; Center for Global Health Infectious Diseases Research, COPH)
  • Theresa Zesiewicz, MD, clinical neurology (Department of Neurology, MCOM)

Dr. Zesiewicz, professor in MCOM and director of the USF Health Ataxia Research Center, has specialized in clinical research and patient care for ataxias and other movement disorders’ for more than 20 years and is recognized as an international expert and leader in the field of hereditary ataxias. Her movement disorders clinic supports the evaluation of over 3,000 patients per year, likely the busiest in the world.

“Dr. Zesiewicz will play a vital role in recruiting research participant and in overseeing neurological assessments of patients as they are longitudinally followed in this study,” Dr. McDonald said.

The funding for the study came from the DoD through its Congressional Directed Medical Research Programs (CDMRP), a section of DoD that funds novel approaches to biomedical research. Link: https://cdmrp.health.mil/

The team will begin recruiting study participants next month.

Photo by Ryan Rossy, USF Health Communications



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Cardiology specialist first to earn PhD from USF Health Heart Institute program /blog/2022/05/24/cardiology-specialist-first-to-earn-phd-from-usf-health-heart-institute-program/ Tue, 24 May 2022 15:24:01 +0000 /?p=36533 Scientific research is often a low-key exercise, with fastidious people peering into microscopes and working under the radar. Seldom are they described as rising stars, but Jiajia Yang […]

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Scientific research is often a low-key exercise, with fastidious people peering into microscopes and working under the radar. Seldom are they described as rising stars, but Jiajia Yang may have broken the mold.

This month, Dr. Yang became the first person to earn a PhD from USF through a new degree program within the newly opened USF Health Heart Institute.

The 30-year-old earned her degree in medical sciences from the USF Health Morsani College of Medicine, with a focus on heart disease, specifically genetic arrhythmia and cardiomyopathy gene mutations within a family.

The Heart Institute is housed within the new Morsani College of Medicine + Heart Institute building in the Water Street Tampa district of downtown Tampa. The facility, which also includes the MD degree program, opened in January 2020.

“You can’t imagine how excited I am,’’ Dr. Yang said of her degree and new career. “The most exciting part for me is that our research is really translational for patients. This isn’t just bedside to bench, but bench to bedside.’’

Originally from a small village in rural China, Dr. Yang attended medical school in Shanghai, then won a scholarship in 2015 at Descartes University in Paris. While there, she earned her Masters and learned to speak French ─ adding to her verbal portfolio of Chinese and English.

Dr. Thomas McDonald with Dr. Jiajia Yang.

After a year, she accepted a position as a research assistant at the USF Health Morsani College of Medicine and quickly showed promise as a fast and inquisitive learner, said Thomas McDonald, MD, professor in the Department of Molecular Pharmacology & Physiology. He would later work with Dr. Yang on a variety of heart-related research projects, including the role of patient-specific induced pluripotent stem cells.

“This is all technically difficult and she overcame so many obstacles,’’ Dr. McDonald said. “She really laid the ground work to help this take off.’’

During her time at USF, Dr. Yang published five research papers in peer-reviewed journals, including new findings on using patient-specific stem cells to study disease in human tissue.

“That had not been on the map at USF until now,’’ Dr. McDonald said. “Jiajia’s papers were the first.’’

Dr. Yang wasn’t shy about sharing her love for discovery.

“I don’t think I’ve ever run across anyone as enthusiastic about her work,’’ Dr. McDonald added. “She was literally jumping up and down in the hallways screaming (about the stem cells) ‘They’re beating! They’re beating!’ Her enthusiasm was contagious.’’

Armed with her degree, Dr. Yang accepted a job as resident physician in internal medicine at the University of New Mexico School of Medicine in Albuquerque. She expects to be there at least three years, but could stay longer if needed: Heart disease is the leading cause of death in New Mexico, according to the state’s Department of Health. When not working, Dr. Yang will devote time to her other passions: cooking, hiking and biking, tennis, and working out at the gym.

Dr. McDonald expects big things from his former colleague, and has no reservations about asking her to return to Tampa: “I’d like to see her career blossom and recruit her to come back to USF.’’

For more on the USF Heart Institute, visit: https://health.usf.edu/medicine/heart-institute

Written by Kurt Loft



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Quality of fat input determines output of kidney and cardiac health and repair, says USF Health study /blog/2022/04/11/quality-of-fat-input-determines-output-of-kidney-and-cardiac-health-and-repair-says-usf-health-study/ Mon, 11 Apr 2022 15:19:17 +0000 /?p=36352 Dr. Ganesh Halade’s investigation in how “good’’ fats repair the heart could enhance treatment of cardiovascular disease. TAMPA, FL (April 11, 2022) – New breakthrough research by a […]

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Dr. Ganesh Halade’s investigation in how “good’’ fats repair the heart could enhance treatment of cardiovascular disease.

TAMPA, FL (April 11, 2022) – New breakthrough research by a University of South Florida lab team describing how certain fats can harm or repair the heart after injury has been accepted by a journal of the American Physiological Society.

A manuscript by Ganesh Halade, PhD, an associate professor of cardiovascular sciences at the USF Health Morsani College of Medicine and a researcher in the USF Health Heart Institute, appears  in the American Journal of Physiology-Heart and Circulatory Physiology, published March 25.

Dr. Ganesh Halade.

Dr. Halade’s research article is titled “Metabolic Transformation of Fat in Obesity Determines the Inflammation Resolving Capacity of Splenocardiac and Cardiorenal Networks in Heart Failure.’’

A key message of the manuscript is how a certain type of healthy fat known as docosahexaenoic acid (DHA) – which is present in Omega-3 fish oil, as found in salmon and tuna – works in tandem with enzymes from the spleen to clear the inflammation in a damaged heart. The spleen plays an important role because it sends immune cells with bags of healthy fat that operates cardiac repair after major injury such as a heart attack.

“So the fat intake needs to be of optimal quality and used by the right enzyme of immune cells,’’ Dr. Halade said. “This is all about cardiac repair and the inflammation clearing molecules (resolution mediators) involved in that repair. It’s essential to the resolution process.’’

Another key message is more about prevention and the genesis of cardiovascular disease: How a chronic and surplus dietary intake of safflower oil (SO, omega-6) can lead to residual inflammation of spleen, kidney, heart, and biosynthesis of pro-inflammatory mediators after an ischemic event. SO is a type of fat commonly used in processed and fast foods that drives chronic inflammation.

“The big question for most people is whether a fat is good or bad, or is omega-3 helpful for heart health?’’ Dr. Halade said. “Everyone is dealing with this question. We’re thinking beyond that by looking at how fat is used in the body after a heart attack and in what forms.’’

“All fats are not created equal,’’ he added, “and despite the extensive literature, the effect of fat intake is the most debated question in obesity, cardiovascular, and cardiorenal research.’’

In his research, Dr. Halade and his team put 100 mice on a 12-week diet of processed (SO) foods to develop residual inflammation and then 50 mice randomized on a primarily DHA-enriched diet for next eight weeks before subjecting to ischemic surgery in mice.

The team made sure both diets had same quantity of calorie per gram of diet. The surplus and chronic intake of SO increased inflammation along with a dysfunctional cardiorenal network. In contrast, DHA increased survival following such heart damage (heart attack).

A result of the study was that the alignment of immune cell enzymes from the spleen and DHA fats are essential to cardiac repair. These so-called “resolution mediators (a family of specialized pro-resolving mediators) is the body’s natural defense process without a negative impact on the body’s physiological response,’’ Dr. Halade said.

Among the key findings in the study:

  • DHA supplement improved survival after experimental heart attack to mice
  • DHA boost safe clearance of inflammation (resolution) from an injured heart without change in the acute phase of the inflammatory response (day 1), with increased expression of Arg-1, MRC-1, and YM-1 in spleen and infarcted area. These agents are resolution and reparative markers of immune response.
  • DHA, along with the body’s natural enzymes, enhanced the ability for the spleen and heart to work together in repairing damage.
  • SO primed the spleen and kidney to induce pro-inflammatory pathways and renal inflammation.

“Our next step is to determine the enzymatic machinery or immune responsive enzymes that biosynthesize resolution mediators after ischemic (decreased blood flow commonly called a heart attack) event,’’ Dr. Halade said.

Part of Dr. Halade’s research focuses on how unresolved chronic inflammation and immune responsive metabolic dysregulation contributes to ischemic and non-ischemic heart failure. He is involved in studies of heart failure etiology with an integrative approach focusing on splenic leukocytes and heart, as well as the measurement of inflammatory mediators that impair cardiac repair and resolving lipid mediators that facilitate cardiac repair after a heart attack.

Related story on Dr. Halade’s heart research at USF: /blog/2021/05/10/blocking-lipoxygenase-leads-to-impaired-cardiac-repair-in-acute-heart-failure/

Dr. Halade hopes his latest work can shed new light on controlling chronic inflammation and treating heart failure — a progressively debilitating condition in which weakened or stiff heart muscle cannot pump enough blood to meet the body’s demand for nutrients and oxygen.

It has become a growing public health problem, fueled in part by an aging population, poor diet and obesity epidemic. About 6.2 million adults in the U.S. suffer heart failure, and nearly have died within five years of diagnosis, according to the Federal Centers for Disease Control and Prevention.

The American Physiological Society (APS), which publishes the journal, is a nonprofit devoted to fostering education, scientific research, and dissemination of information in the physiological sciences.

“The editors commend you on your outstanding contribution to the journal,’’ the accepting team wrote to Dr. Halade. “We would like to thank you for contributing this novel and important article.’’

The USF Health study was supported by grants from the National Center for Complementary and Integrative Health (NCCIH, formerly known as National Center for Complementary and Alternative Medicine; (NCCAM), and the National Heart, Lung and Blood Institute.

Written by Kurt Loft



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MCOM researchers win state grants to combat Alzheimer’s, heart disease /blog/2022/02/16/mcom-researchers-win-state-grants-to-combat-dementia-heart-disease/ Wed, 16 Feb 2022 23:44:21 +0000 /?p=35984 Two researchers from the USF Health Morsani College of Medicine have received Florida Department of Health (FDOH) grants to help advance discoveries in Alzheimer’s disease and in tobacco-related […]

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Hariom Yadav, PhD, of the USF Center for Microbiome Research, and Ji Li, PhD, of the USF Health Heart Institute  — Photos by Allison Long, USF Health Communications

Two researchers from the USF Health Morsani College of Medicine have received Florida Department of Health (FDOH) grants to help advance discoveries in Alzheimer’s disease and in tobacco-related heart disease.

Hariom Yadav, PhD, an associate professor of neurosurgery and brain repair and director of the USF Center for Microbiome Research, was awarded total expected funds of $743,661 over four years from the FDOH Ed and Ethel Moore Alzheimer’s Disease Research Program. The multidisciplinary consortium project is titled “Role of Microbiome in the Aging of Gut and Brain in Floridian Older Adults.”

Researchers at USF and several other sites across Florida will study how diet affects the gut and oral microbiomes linked to brain health in adults ages 60 and older. Age is a key risk factor for Alzheimer’s disease and related dementias (ADRD); no effective treatment exists, and early risk detection remains a challenge. The FDOH-supported research seeks to determine whether unique microbiome signatures can differentiate older adults suffering cognitive decline and ADRD from their healthy counterparts and predict disease progression. The study will also examine whether abnormalities in microbe-derived metabolites, excessive gut “leakiness” and inflammation definitively contribute to cognitive impairment and ADRD—with the ultimate aim of identifying measures to prevent or delay these devastating conditions.

Ji Li, PhD, professor of surgery and a member of the USF Health Heart Institute, was awarded total expected funds of $583,200 over three years from the FDOH James and Esther King Biomedical Research Program. The grant is titled “Sirtuin 1 and Cardiovascular Impairment by Cigarette Smoking.”

Dr. Li’s laboratory has shown that the anti-aging protein sirtuin 1 (SIRT1) plays a role in cardiovascular disease development, and emerging evidence suggests that SIRT1 is a component of signaling pathways that allow cells to sense and react to cigarette smoking. The FDOH-supported preclinical project will test whether and how SIRT1 signaling helps control the harmful effects of cigarette smoking on the heart’s pumping function in hypertension (abnormally high blood pressure). The study’s outcome could lead to the discovery of SIRT1 agonists or other drugs that may reduce damage and death from hypertensive heart disease associated with chronic smoking.



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Researchers identify protein complex critical in helping control cell death /blog/2022/02/16/researchers-identify-protein-complex-critical-in-helping-control-cell-death/ Wed, 16 Feb 2022 20:03:48 +0000 /?p=35938 USF Health-UT Southwestern Medical Center preclinical study suggests inhibiting PPP1R3G/PP1γ may protect against tissue damage from heart attacks, other diseases linked to inflammation TAMPA, Fla. (Feb. 16, 2022) […]

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USF Health-UT Southwestern Medical Center preclinical study suggests inhibiting PPP1R3G/PP1γ may protect against tissue damage from heart attacks, other diseases linked to inflammation

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TAMPA, Fla. (Feb. 16, 2022) – Cell death plays an important role in normal human development and health but requires tightly orchestrated balance to avert disease. Too much can trigger a massive inflammatory immune response that damages tissues and organs. Not enough can interfere with the body’s ability to fight infection or lead to cancer.

Zhigao Wang, PhD, associate professor of cardiovascular sciences at the University of South Florida Health (USF Health) Morsani College of Medicine, studies the complex molecular processes underlying necroptosis, which combines characteristics of apoptosis (regulated or programmed cell death) and necrosis (unregulated cell death).

During necroptosis dying cells rupture and release their contents. This sends out alarm signals to the immune system, triggering immune cells to fight infection or limit injury. Excessive necroptosis can be a problem in some diseases like stroke or heart attack, when cells die from inadequate blood supply, or in severe COVID-19, when an extreme response to infection causes organ damage or even death.

A new preclinical study by Dr. Wang and colleagues at the University of Texas Southwestern Medical Center identifies a protein complex critical for regulating apoptosis and necroptosis — known as protein phosphatase 1 regulatory subunit 3G/protein phosphatase 1 gamma (PPP1R3G/PP1γ, or PPP1R3G complex). The researchers’ findings suggest that an inhibitor targeting this protein complex may help reduce or prevent excessive necroptosis.

The study was reported Dec. 3, 2021, in Nature Communications.

Zhigao Wang, PhD, associate professor of cardiovascular sciences, in his laboratory at the USF Health Heart Institute. Images on the monitor depict two types of cell death: apoptosis (left) and necroptosis. — Photo by Allison Long, USF Health Communications

“Cell death is very complicated process, which requires layers upon layers of brakes to prevent too many cells from dying,” said study principal investigator Dr. Wang, a member of the USF Health Heart Institute. “If you want to protect cells from excessive death, then the protein complex we identified in this study is one of many steps you must control.”

Dr. Wang and colleagues conducted experiments using human cells and a mouse model mimicking the cytokine storm seen in some patients with severe COVID-19 infection. They applied CRISPR genome-wide screening to analyze how cell function, in particular cell death, changes when one gene is knocked out (inactivated).

Receptor-interacting protein kinase (RIPK1) plays a critical role in regulating inflammation and cell death. Many sites on this protein are modified when a phosphate is added (a process known as phosphorylation) to suppress RIPK1’s cell death-promoting enzyme activity. How the phosphate is removed from RIPK1 sites (dephosphorylation) to restore cell death is poorly understood. Dr. Wang and colleagues discovered that PPP1R3G recruits phosphatase 1 gamma (PP1γ) to directly remove the inhibitory RIPK1 phosphorylations blocking RIPK1’s enzyme activity and cell death, thereby promoting apoptosis and necroptosis.

Dr. Wang (back) and laboratory associate Ken Chen. — Photo by Allison Long, USF Health Communications

Dr. Wang uses the analogy of a car brake help explain what’s happening with the balance of cell survival and death in this study:  RIPK1 is the engine that drives the cell death machine (the car). Phosphorylation applies the brake (stops the car) to prevent cells from dying. The car (cell death machinery) can only move forward if RIPK1 dephosphorylation is turned on by the PPP1R3G protein complex, which releases the brake.

“In this case, phosphorylation inhibits the cell death function of protein RIPK1, so more cells survive,” he said. “Dephosphorylation takes away the inhibition, allowing RIPK1 to activate its cell death function.”

The researchers showed that a specific protein-protein interaction – that is, PPP1R3G binding to PP1γ — activates RIPK1 and cell death. Furthermore, using a mouse model for “cytokine storm” in humans, they discovered knockout mice deficient in Ppp1r3g were protected against tumor necrosis factor-induced systemic inflammatory response syndrome. These knockout mice had significantly less tissue damage and a much better survival rate than wildtype mice with the same TNF-induced inflammatory syndrome and all their genes intact.

Overall, the study suggests that inhibitors blocking the PPP1R3G/PP1γ pathway can help prevent or reduce deaths and severe damage from inflammation-associated diseases, including heart disease, autoimmune disorders and COVID-19, Dr. Wang said. His laboratory is working with Jianfeng Cai, PhD, a professor in the USF Department of Chemistry, to screen and identify peptide compounds that most efficiently inhibit the PPP1R3G protein complex. They hope to pinpoint promising drug candidates that may stop the massive destruction of cardiac muscle cells caused by heart attacks.

The research was supported by grants from the Welch Foundation and the National Institute of General Medical Sciences, a part of the National Institutes of Health.

Cell death graphic

Graphic created with Biorender app by Zhigao Wang, USF Health Heart Institute.



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USF Health physician-scientist pinpoints genes to predict lung fibrosis outcomes /blog/2021/12/06/usf-health-physician-scientist-pinpoints-genes-to-predict-lung-fibrosis-outcomes/ Mon, 06 Dec 2021 22:23:28 +0000 /?p=35581 Dr. Jose Herazo-Maya’s research may help identify new treatments to improve survival in patients with idiopathic pulmonary fibrosis and severe COVID-19   Caring for patients struggling to breathe […]

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Dr. Jose Herazo-Maya’s research may help identify new treatments to improve survival in patients with idiopathic pulmonary fibrosis and severe COVID-19

 

Caring for patients struggling to breathe drives Dr. Jose Herazo-Maya’s research to find effective treatments for pulmonary fibrosis — an incurable, debilitating and often fatal disease that causes progressive lung scarring.

“The primary goal of our research team is to identify genes that predict survival (a low vs. high risk of dying) in patients with lung fibrosis,” said Herazo-Maya, MD, an associate professor and associate chief of pulmonary, critical care and sleep medicine at the USF Health Morsani College of Medicine. “We believe that if you target these genes, you can develop new treatments to help improve survival in these patients.”

The only two drugs currently approved to treat patients with idiopathic pulmonary fibrosis (pirfenidone and nintedanib) may help slow disease progression, but they do not stop lung scarring or prolong survival, and adverse effects can occur in up to half of people with IPF. Lung transplantation can improve survival, but organs are limited and not every patient with pulmonary disease is eligible for the complex surgery.

CT scans of (Above) normal lungs and (Below) lungs with  idiopathotic pulmonary fibrosis, characterized by scars and cysts. Images courtesy of Dr. Jose Herazo-Maya, USF Health

Pulmonary fibrosis is a disease in which the tissue in and between the air sacs of the lungs (alveoli) becomes damaged and scarred. As the tissue (interstitium) thickens and stiffens, it affects the ability to breathe and get enough oxygen into the bloodstream. While toxic environmental exposures, smoking and certain other diseases have been associated with pulmonary fibrosis, in most cases the cause is unknown (idiopathic). Median survival for patients diagnosed with idiopathic pulmonary fibrosis (IPF) is three to five years.

“IPF is a devasting disease that needs better therapeutic options to improve quality of life and save lives,” Dr. Herazo-Maya said. “For me, taking care of these patients is a constant reminder that we need to do better.”

A return to academic medicine

Dr. Herazo-Maya joined USF Health in January 2021 from NCH Healthcare System in Naples, Fla., where he spent nearly four years directing a growing Interstitial Lung Disease Program. Before that, the physician-scientist was an assistant professor at Yale University School of Medicine. He is an expert in genomics, with a focus on studying how gene expression influences immunity and its association with disease progression and outcomes.

USF Health physician scientist Jose Herazo-Maya, MD, (far right) in his USF Health Heart Institute laboratory with his research team. Photographed (l to r) are Carole Perrot, PhD; Bochra Tourki, PhD; Alyssa Arsenault, LPN; and Brenda Juan-Guardela, MD. — Photo by Allison Long, USF Health Communications and Marketing

At Yale Dr. Herazo-Maya was part of team that discovered a gene expression signature in blood that reliably forecasts the likelihood of mortality and poor outcomes from IPF. The team subsequently led an international study that validated this risk profile based on 52 genes. He was among the inventors on the patent for the IPF gene risk profile, since acquired by a global company seeking to develop the scientific breakthrough into a simple blood test to be used for patient care.

Dr. Herazo-Maya returned to academic medicine after several years of private practice in Naples, in part he says because he was frustrated by the lack of research progress to identify pulmonary fibrosis treatment options. A surge in patients battling severe lung scarring from COVID-19 complications also prompted his decision to recommit to translating discoveries from the laboratory back to the patient bedside.

Soon after arriving at the USF Health Heart Institute last year, Dr. Herazo-Maya quickly began building a pulmonary fibrosis research program with the generous support of a $1 million gift made by philanthropist Timothy Ubben to the USF Foundation. (In December 2021, Mr. Ubben gave an additional $5 million to create the Ubben Family Center for Pulmonary Fibrosis that will accelerate research leading to new tests and treatments for patients.)

Dr. Herazo-Maya, a member of the pulmonary and critical care team at Tampa General Hospital, also treats patients at the TGH Center for Advanced Lung Disease — including those being evaluated for lung transplant. Along with fellow USF Health pulmonologists Dr. Kapilkumar Patel and Dr. Debabrata Bandyopadhyay at this leading TGH Center, Dr. Herazo-Maya is an investigator for clinical trials testing potential new drugs to treat lung fibrosis.

Bochra Tourki, PhD, looks at a computer slide of immune cells from the lung tissue of a COVID-19 patient with pulmonary fibrosis. – Photo by Allison Long

The impact of witnessing “air hunger”

From the start of his medical career, Dr. Herazo-Maya was interested in both critical care and science. While conducting a postdoctoral fellowship at the University of Pittsburgh School of Medicine’s Simmons Center for Interstitial Lung Disease, he was invited by his faculty mentor and center director Nafali Kaminski, MD, to accompany a group of the center’s patients, physicians, and scientists on a boat trip along the city’s rivers.

“I remember the patients using oxygen had a very hard time getting into the boat. They could not even take a few steps without becoming short of breath,” Dr. Herazo-Maya said. “Seeing how those patients struggled to breathe – their feeling of air hunger – had a big impact on me wanting to take care of them.”

While certain patients with IPF can live well for years, others develop worsening disease and die quickly. No prognostic tool yet exists to tell doctors which patients will experience rapid progression of pulmonary fibrosis, and which will progress slowly. But Dr. Herazo-Maya and colleagues are working on a molecular-level test to do just that.

A tool to predict the clinical course of IPF or any other type of lung fibrosis could help patients and clinicians make better informed decisions about care, Dr. Herazo-Maya said. “For instance, if a rapid test indicated that a patient’s genetic predisposition to mortality was high, they might need to get to the hospital to receive more aggressive medical care, and possibly be evaluated for lung transplant while they are still relatively healthy enough to withstand transplant surgery.”

Dr. Herazo-Maya (far left) consults with (l to r) staff scientist Carole Perot, PhD; postdoctoral scholar Bochra Tourki, PhD; and clinical research coordinator Alyssa Arsenault, LPN. – Photo by Allison Long

Genomic risk prediction can also increase opportunities for drug discovery, he said. “Each one of the genes we analyze is a potential drug target. We can study them in the lab to understand how they work and possibly come up with novel therapies.”

Pivoting genomic research to COVID-19

As the COVID-19 pandemic unfolded in 2020, pulmonologists and other critical care clinicians were inundated by patients in respiratory distress.

As he helped treat the influx of hospitalized patients, Dr. Herazo-Maya noticed that, like IPF, severe COVID-19 could also damage the lung interstitium leading to severe scarring. He thought about finding more precise ways to distinguish between symptomatic individuals likely to recover at home with appropriate monitoring and those likely to end up in the intensive care unit (ICU) and die. A prognostic tool capable of detecting which patients were apt to do worse before they became seriously ill could help health care providers better allocate limited resources like ICU beds and ventilators, tailor interventions, and potentially save lives.

“At the time investigators were scrambling to identify gene profiles predictive of COVID-19 outcomes,” Dr. Herazo-Maya said. “So, our basic question was ‘Can we repurpose a gene risk profile known to predict mortality in IPF to predict mortality in those infected with a new coronavirus that can cause lung fibrosis as well?’”

The preliminary answer appears to be yes.

Dr. Herazo-Maya’s computer monitor displays heat maps depicting clusters of COVID-19 subjects identified as having a low vs. high risk of mortality (Below), based on a gene expression signature in blood. The recent research showed that a previously validated technique for predicting idiopathic lung fibrosis outcomes could be repurposed for COVID-19. – Photo by Allison Long | Heat map image courtesy of Dr. Herazo-Maya, USF Health

Earlier this year, a multicenter retrospective study led by USF Health’s Dr. Herazo-Maya demonstrated that a 50-gene signature associated with a high risk of dying from IPF can also predict poor outcomes (ICU admissions, mechanical ventilation, and death) in patients with COVID-19. The findings were reported in EBioMedicine, a publication of THE LANCET.

More studies are needed, but researchers and clinicians may soon be able to apply the gene risk profile to help advance the care of both COVID-19 and IPF patients, Dr. Herazo-Maya said. His laboratory is currently developing a blood test, based on a more selective group of the 50 genes, that can be easily applied in clinical practice.

Two distinct diseases, same gene risk profile

The overlapping gene expression profiles for COVID-19 and IPF look remarkably similar, Dr. Herazo-Maya said. “That suggests there are immune pathways shared between these two diseases.”

Using single-cell gene analyses, Dr. Herazo-Maya has identified specific immune cells – monocytes, neutrophils, and dendritic cells — as the primary source of gene expression changes in the high-risk COVID-19 gene profile. Interestingly, he said, monocytes can give rise to macrophages involved in triggering scar formation.

Brenda Perrot, PhD, works on an experiment.

Dr. Herazo-Maya received his MD degree from the University of Cartagena School of Medicine in Colombia. He completed a research fellowship in interstitial lung disease and residency training in internal medicine at the University of Pittsburgh School of Medicine. Specializing in pulmonary and critical care, he conducted postdoctoral training in genomics, computational biology, bioinformatics and molecular biology at Yale and Pittsburgh universities.

The Robert Wood Johnson Foundation and the Pulmonary Fibrosis Foundation funded his research in the past, and his current work is supported by the USF Foundation-Ubben Family Fund.

Dr. Herazo-Maya has published numerous peer-reviewed papers, including in such high-impact journals as the Nature Medicine, the Journal of Clinical Investigation, Lancet Respiratory Medicine, Science Translational Medicine and the American Journal of Respiratory and Critical Care Medicine. He is the coauthor of several book chapters on topics ranging from biomarkers in assessing and managing IPF to applying personalized medicine (‘omics) to lung fibrosis.

Dr. Herazo-Maya and his wife Dr. Brenda Juan-Guardela (right), assistant professor of medicine at USF Health and medical director of Respiratory Care Services at TGH, have collaborated on pulmonary fibrosis research throughout their medical careers. – Photo by Allison Long

Some things you may not know about Dr. Herazo-Maya

If he did not become a physician and researcher, Dr. Herazo-Maya says he would have been a marine biologist. Growing up near the beach in Cartagena, he snorkeled and was “fascinated by all the sea creatures.”

Dr. Herazo-Maya is married to pulmonologist Brenda Juan-Guardela, MD, an assistant professor of medicine at USF Health Morsani College of Medicine and medical director of Respiratory Care Services at TGH. They met in medical school, trained in the same laboratory as postdoctoral scholars, and continue to collaborate on pulmonary fibrosis research. They live in Tampa with their two sons Christian, 6, and Lucas, 4.

In his spare time, Dr. Herazo-Maya enjoys playing soccer and baseball with his sons in their yard and watching their youth soccer league games.

 



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Blocking lipoxygenase leads to impaired cardiac repair in acute heart failure /blog/2021/05/10/blocking-lipoxygenase-leads-to-impaired-cardiac-repair-in-acute-heart-failure/ Mon, 10 May 2021 13:27:59 +0000 /?p=34085 USF Health preclinical study finds that inhibiting lipoxygenase with a drug alters innate inflammatory response, delaying heart tissue repair after cardiac injury TAMPA, Fla. (May 10, 2021) — […]

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USF Health preclinical study finds that inhibiting lipoxygenase with a drug alters
innate inflammatory response, delaying heart tissue repair after cardiac injury

TAMPA, Fla. (May 10, 2021) — Blocking the fat-busting enzyme lipoxygenase with a synthetic inhibitor throws the immune system’s innate inflammatory response out of whack, compromising cardiac repair during acute heart failure, USF Health researchers found.

Their new preclinical study was published April 13 in Biomedicine & Pharmacotherapy.

In search of individualized heart failure therapies, Ganesh Halade, PhD, leads a USF Health Heart Institute team studying unresolved inflammation after heart attack. | Photo by Allison Long, USF Health Communications

Acute heart failure – triggered by a heart attack, severely irregular heartbeats, or other causes — occurs suddenly when the heart cannot pump enough blood to meet the body’s demands.

Following a heart attack or any cardiac injury, signals to immune cells called leukocytes carefully control physiological inflammation. Normally, there are two distinct but overlapping processes: an acute inflammatory response (“get in” signal), where leukocytes travel from the spleen to the injured heart to start removing dead or diseased cardiac tissue, and a resolving phase (“get out” signal), where inflammation is cleared with the help of macrophages that arrive to further repair the damage and form a stable scar.

A delay in either the initiation of inflammation or its timely clearance (resolution) can lead to impaired cardiac healing and progression to heart failure, said study principal investigator Ganesh Halade, PhD, an associate professor of cardiovascular sciences at the USF Health Morsani College of Medicine and a member of the USF Health Heart Institute.

The USF Health researchers applied three investigational approaches (in vitro, ex vivo, and in vivo) to assess whether a potent lipoxygenase (12/15 LOX) inhibitor ML351 could selectively alter inflammatory responses in adult mice following cardiac injury similar to a heart attack. Previous studies by Dr. Halade’s laboratory reported that lipoxygenase-deficient mice showed improved cardiac repair and heart failure survival after cardiac injury.

“We wondered if blocking a lipoxygenase with an external pharmacological compound (drug) would have the same beneficial effect — but the answer was no,” Dr. Halade said. “Instead, the collective results of our study indicate that ML351 dysregulated control of the normal physiological pathway of inflammation in cardiac repair, causing collateral damage.”

In the mice treated mice with ML351, leukocyte recruitment to the site of cardiac injury was delayed, which subsequently amplified inflammation at the site. At the same time, instead of leaving once the repair job was done, the immune cells remained at the site beyond the typical acute (and beneficial) inflammatory response phase. Basically, the late arrival (get-in signal) and delayed clearance (get-out signal) of immune cells impaired cardiac repair, Dr. Halade said.

A delay in either the initiation of inflammation or its timely clearance (resolution) can lead to impaired cardiac healing and progression to heart failure.

The latest study helps explain one more piece of the puzzle about the important role of immune-mediated acute inflammation and its clearance – both in promoting cardiac health and stopping the progression of heart failure, Dr. Halade said. Lipoxygenases, fatty-acid modifying enzymes that control metabolic and immune signaling, can promote either resolving (beneficial) or nonresolving (harmful) inflammation, he added.

“The take-home message is do not mess with (block) the lipoxygenase. Preserve it, because it’s a key enzyme for our defensive, innate immune response,” he said. “Knowing how drugs interact with the body’s precisely-balanced immune responses will be critical for understanding mechanisms to prevent, delay or treat the unresolved inflammation influencing heart failure.”

The USF Health study was supported by grants from the NIH’s National Heart, Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases.



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Saulius Sumanas uses versatile fish model system to study how regulation of gene activity affects blood vessel growth /blog/2021/03/10/saulius-sumanas-uses-versatile-fish-model-system-to-study-how-regulation-of-gene-activity-affects-blood-vessel-growth/ Wed, 10 Mar 2021 22:26:29 +0000 /?p=33615 The research could help identify new drugs or advance tissue regeneration for vascular diseases, including brain aneurysms USF Health’s Saulius Sumanas, PhD, focuses on understanding both normal blood […]

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The research could help identify new drugs or advance tissue regeneration for vascular diseases, including brain aneurysms

Saulius Sumanas, PhD, associate professor of pathology and cell biology, studies the critical regulation of blood vessel formation in health and disease. He joined the USF Health Heart Institute in August 2020. | Photo by Allison Long, USF Health Communications

USF Health’s Saulius Sumanas, PhD, focuses on understanding both normal blood vessel formation and what goes wrong with the critical regulation of these vessels when disease develops.

Arteries and veins and the tiny capillaries connecting them are responsible for transporting blood to organs and tissues throughout the body, among other functions. The molecular factors responsible the growth and health of these blood vessels are important in nearly all diseases.

Dr. Sumanas joined USF Health in August 2020 as an associate professor of pathology and cell biology at the USF Health Heart Institute. He moved his laboratory to Tampa from Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine. He says he was attracted by the Heart Institute’s strong cardiovascular research group, with its emphasis on bridging basic science and clinical translational research to create new therapies.

To help define molecular and cellular abnormalities that occur when blood vessels networks do not work as they should, the Sumanas laboratory uses zebrafish to model human diseases, including intracranial (brain) aneurysms associated with cardiovascular risk factors.

“Too little vascular supply can promote some diseases like chronic heart and kidney failure, whereas uncontrolled vascular growth can incite diseases like cancer. For regenerative medicine, the intention is to grow new heart tissue, but there is a simultaneous need to grow new blood vessels to supply nutrients to stem cells that are creating the new heart muscle,” said Samuel Wickline, MD, professor of cardiovascular sciences and director of the USF Health Heart Institute.

“The zebrafish model established by Dr. Sumanas will be a powerful resource to tease out the molecular signals that either need to be enhanced or suppressed to combat these diseases, or to regenerate new functional heart tissue.”

At least 70% of the genes in humans are like those in zebrafish. Zebrafish models, such as the one established by the Sumanas laboratory, can be used to identify molecular signals that need to be enhanced or inhibited to combat diseases, or to regenerate functional heart tissue. | Photo by Allison Long, USF Health Communications

An efficient system for modeling human disease

At least 70% of the genes in humans are like those in zebrafish, and 84% of genes associated with human disease have a zebrafish counterpart.

“The mechanisms regulating vertebrate blood vessel growth are remarkably conserved (across species) from zebrafish to humans,” Dr. Sumanas said. “Even drugs that suppress new blood vessel formation, like the vascular endothelial growth factor (VEGF) inhibitors used to treat tumors in patients, work the same way in zebrafish as they do in humans.”

Other attributes make zebrafish, a member of the minnow family, an efficient model system well suited for scientists searching for genetic clues to disease, including during early blood vessel formation. The fish reproduce and mature rapidly, they are easy to maintain in large numbers for accelerated gene function studies and drug screening, and their eggs are fertilized outside the body. Since zebrafish embryos are virtually transparent, researchers can watch their development in real time. They observe with light and fluorescent microscopy how blood vessels grow from progenitor cells and how the organism’s anatomy and physiology changes when DNA with human genetic mutations is introduced and expressed in the zebrafish.

Ultimately, the Sumanas team hopes to apply what they learn about vascular genetics and developmental biology from this versatile model system to discover new, more targeted treatments for several cardiovascular diseases.

“For example,” Dr. Sumanas said, “now that we have a fish model that shows an increased incidence of hemorrhages (brain bleeds) and defects similar to those of humans with intracranial aneurysms, we can use this model to quickly screen various chemical compounds.” That will help researchers identify if any of the most promising compounds can prevent or reduce the incidence of hemorrhages caused by some intracranial aneurysms. The lead compounds can then be further tested and refined as potential drug candidates for patients.

USF Health’s Saulius Sumanas, PhD, with some of the team members In his laboratory: (L to R) Sanjeeva Metikala, PhD, research associate; Shane Alexander, undergraduate researcher; and Diandra Rufin, biological scientist | Photo by Allison Long, USF Health Communications

Searching for genetic causes of brain aneurysms

While he was a faculty member at Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Dr. Sumanas collaborated with a group of clinicians looking for genetic variants (mutations) that predispose several members of the same families to intracranial aneurysm, a bulge that forms in a weak area of a blood vessel in the brain. If the aneurysm leaks blood or ruptures, it can cause brain damage and be fatal. (President Joe Biden underwent surgery at age 45, while he was a Delaware senator, to correct a life-threatening brain aneurysm at the base of his brain.)

The Cincinnati group performed functional genomic sequencing of individuals from several families affected by intracranial aneurysms, and subsequently Dr. Sumanas used a zebrafish model to study the functional role of the gene collagen XXII (COL22A1). The researchers demonstrated that COL22A1 plays a role in maintaining blood vessel stability, and their work suggests that mutations in COL22A1 may be a cause of intracranial aneurysms in humans.

Another study led by Dr. Sumanas, reported last year in Nature Communications, discovered that a deficiency of one gene, Etv2, in zebrafish embryos can convert vascular endothelial progenitor cells into skeletal muscle. (Progenitor cells are stem cell descendants that can further differentiate into specialized cell types belonging to the same tissue or organ.) The study concluded that functioning Etv2 actively suppresses these progenitors from differentiating into muscle cells, thereby keeping the cells committed to their vascular destiny: developing into the endothelial cells that are critical building blocks of all blood vessels.

Besides deepening the understanding of complex processes required to differentiate stem cells and grow healthy blood vessels, the work has potential for regenerative therapies, Dr. Sumanas said.

 

Discovering a gene critical to vascular regulation

Zebrafish embryos are virtually transparent, so researchers can observe blood vessel development in real time. | Image courtesy of Saulius Sumanas, PhD

As a postdoctoral fellow at UCLA in 2006, Dr. Sumanas was the first to identify Etv2 function in forming blood vessels in any organism – and has since studied this gene extensively. “There is a lot of interest in Etv2, because it functions as a master regulator of vascular development and allows you to create vascular endothelial cells in a (petri) dish,” he said. “Eventually, we may be able to grow healthy endothelial cells that could be used to repair damaged blood vessels or contribute to tissue or organ regeneration.”

More research is needed to determine precisely how Etv2-regulated vascular “cell fate” is modified to form skeletal muscle cells, but that too could be clinically useful, Dr. Sumanas said. “It may allow a way to make extra muscle, which could be important for treating different types of muscular dystrophies.”

Dr. Sumanas received his PhD degree in biochemistry, molecular biology, and biophysics from the University of Minnesota. He subsequently completed a postdoctoral fellowship in cell and developmental biology at UCLA. He was a faculty member for 13 years in the Division of Developmental Biology at Cincinnati Children’s Hospital Medical Center/University of Cincinnati before joining USF Health. His awards include a 2004 Vascular Biology Training Grant and a Scholars in Oncologic Molecular Imaging Training Award, both from UCLA; a March of Dimes Basil O’Connor Starter Scholar Research Award; and a Perinatal Institute Pilot Research Award, to name a few.

Dr. Sumanas’ research on the role of collagen COL22A1 in intracranial aneurysms and vascular stability is funded by a four-year $1.8 million grant from the National Institutes of Health’s National Heart, Lung, and Blood Institute. He has published more than 40 peer-reviewed papers in the journals such as Nature Communications, Developmental Cell, Development, Arteriosclerosis, Thrombosis, and Vascular Biology and others. He has served on the NIH Cardiovascular Disease and Differentiation review panel (2021), and as an American Heart Association study section member (2014-2020).

An 11-year-old Saulius Sumanas (left), as he appears in a scene from a 1986 TV miniseries titled “Sesiolikmeciai,” which translates to “Sixteen Year Olds” in Lithuanian. He played a younger version of a teenager appearing in later episodes of the World War II drama.

Something you may not know about Dr. Sumanas

Dr. Sumanas was born in Kaunas, Lithuania. At age 11, he was cast as an actor in the first episode of a dramatic TV mini-series titled “Sesiolikmeciai,” which translates to “Sixteen Year Olds” in Lithuanian. He played the similar-looking, younger boy version of a teenage character who lives through Nazi Germany’s occupation of Lithuania (then the Soviet Union) during World War II.

Dr. Sumanas performed other roles in some amateur theater groups as an undergraduate and postdoctoral student, but his pursuit of a biomedical research career did not waver. “Acting was a lot of fun, but my passion for science was stronger,” he said.

Photo by Allison Long | USF Health Communications

 



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Cell-selective nanotherapy prevents vessel renarrowing and promotes healing of arteries opened by angioplasty /blog/2021/02/09/cell-selective-nanotherapy-prevents-vessel-renarrowing-promotes-healing-of-arteries-opened-by-angioplasty/ Tue, 09 Feb 2021 17:54:29 +0000 /?p=33425 A USF Health preclinical study indicates nanoparticles containing a micro-RNA switch offers promising biotechnology to advance the fight against atherosclerotic cardiovascular disease Tampa, FL (Feb. 9, 2021) – […]

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A USF Health preclinical study indicates nanoparticles containing a micro-RNA switch offers promising biotechnology to advance the fight against atherosclerotic cardiovascular disease

Angioplasty with stent illustration

Illustration of angioplasty with a stent

Tampa, FL (Feb. 9, 2021) – Percutaneous coronary intervention (PCI), commonly known as angioplasty with a stent, opens clogged arteries and saves lives. Despite its benefit in treating atherosclerosis that causes coronary artery disease, this common minimally invasive procedure still poses severe complications for some patients.

Angioplasty involves inflating a balloon at the tip of a catheter to compress fatty deposits (plaques) against the artery wall, thereby restoring blood flow to the narrowed or blocked vessels. The image-guided procedure is often combined with the placement of either uncoated stents — tiny expandable mesh devices– or stents coated with slowly-released antiproliferative drugs. The drug-eluting stents help avert the growth of scar tissue (smooth muscle cell proliferation) in the artery so that the vessel does not eventually close again, known as restenosis.

However, current antiproliferative drugs indiscriminately inhibit the growth of all nearby cells, including the layer of endothelial cells lining the blood vessels. These endothelial cells prevent blood clots (thrombosis) within the stent and the formation of more plaques (neoatherosclerosis), which can trigger a heart attack or sudden cardiac death.

Focused on tackling this treatment complication, University of South Florida Health (USF Health) Morsani College of Medicine researchers recently developed a next-generation nanotherapy. Their preclinical findings are detailed in a study published Feb. 2 in Molecular Therapy.

Hana Totary-Jain, PhD, of USF Health

Hana Totary-Jain, PhD, USF Health associate professor of molecular pharmacology and physiology, was principal investigator for the nanotherapy study.

The nanotherapy comprised of a nontoxic peptide known as p5RHH and a synthetic messenger RNA (mRNA) that carries the genetic instructions, or code, needed by cells to make proteins. By simply mixing up the p5RHH with the mRNA, they spontaneously self assemble into compacted nanoparticles that specifically target the injured regions of the arteries in mouse models mimicking angioplasty. The nanoparticles contain an microRNA switch added to the mRNA.

“One of the main challenges of cardiovascular disease remains the delivery of targeted therapies specifically to the plaque regions and the cells that form plaques, including the smooth muscle cells and inflammatory cells — without affecting the endothelial cells or the healthy regions,” said the study’s principal investigator Hana Totary-Jain, PhD, an associate professor of molecular pharmacology physiology at USF Health Morsani College of Medicine.

To do this, the researchers used mRNA that encodes for p27 protein, which blocks cell growth, and added to the mRNA an endothelial cell-specific microRNA to generate a microRNA switch. The design of this microRNA switch allowed the researchers to turn on the mRNA in smooth muscle cells to inhibit their growth and the formation of restenosis. It also enabled them to turn off the mRNA in endothelial cells so these cells could grow uninhibited and quickly heal the damaged blood vessel.

John Lockhart, PhD

John Lockhart, PhD, was the paper’s lead author.

“If we can come up with an antiproliferative therapy that specifically targets the cardiovascular smooth muscles cells and the infiltrating inflammatory cells but spares the endothelial cells – which we’ve done with the design of our microRNA switches – then we should be able to achieve the therapeutic effects of drug-eluting stents without the downside of thrombosis and neoatherosclerosis,” said the paper’s lead author John Lockhart, PhD, who worked on the study as a doctoral student at USF Health Molecular Pharmacology and Physiology. Dr. Lockhart is continuing his postdoctoral training at Moffitt Cancer Center.

The latest study builds upon previous research by Dr. Totary-Jain, indicating that a microRNA-based therapy worked better than drug-eluting stents in a rat model of angioplasty. That work used an adenovirus vector to carry the cell-selective therapy to injured arteries. In this study the viral vector was replaced with a nanoparticle alternative – a change needed to avoid safety concerns and advance the therapy toward use in patients.

The investigational nanoparticles were injected into mice with arteries mimicking post-angioplasty vessel injury every three days for two weeks (5 doses total). Mice treated with the nanoparticles containing the miRNA switch had significantly reduced restenosis and completely restored endothelial cell growth in the injured artery, compared to animals treated with nanoparticles containing mRNA without the miRNA switch, the researchers report.

Above: Injured control artery treated with near infrared florescent protein, depicts restenosis in center. Below: Injured artery treated with the microRNA switch nanotherapy shows open artery (no restenosis) and clear endothelial cell layer marked in green. | Images courtesy of Hana Totary-Jain, USF Health

In addition, the nanoparticles efficiently delivered its mRNA cargo, without degradation, solely to regions of the artery where endothelial cells were damaged. The particles did not toxically accumulate either in the cells of healthy organs (the liver, spleen. lungs or kidneys), or in uninjured arteries adjacent to those requiring treatment. The researchers observed no adverse reactions or outcomes in mice treated with the nanoparticles.

Overall, the findings suggest that the miRNA-switch nanoparticles could be applied clinically to selectively prevent restenosis after PCI by specifically targeting areas of endothelial cell damage to allow quicker cell regrowth and repair of injured arteries.

The USF Health researchers next plan to investigate the potential of the microRNA-switch nanoparticles to directly treat atherosclerotic plaques, thereby eliminating the need for PCI.

“Cardiovascular disease is still the number one cause of death,” said Dr. Totary-Jain, a member of the USF Health Heart Institute. “This research offers promise for the development of novel biomolecular therapies to advance the fight against coronary artery disease and peripheral artery disease,”

One person dies of cardiovascular disease every 36 seconds in the U.S., according to the Centers for Disease Control and Prevention.

The USF Health research was supported by grants from the National Institutes of Health. Samuel Wickline, MD, director of the USF Health Heart Institute, and Hua Pan, PhD, assistant professor at the Heart Institute, collaborated on the study.



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Focused on the root causes of cardiac inflammation /blog/2020/09/30/focused-on-the-root-causes-of-cardiac-inflammation/ Wed, 30 Sep 2020 13:47:45 +0000 /?p=32394 In search of individualized heart failure therapies, Ganesh Halade leads a USF Health Heart Institute team studying unresolved inflammation after heart attack //www.youtube.com/watch?v=KarBPXZs1rs Short-term inflammation is one of […]

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In search of individualized heart failure therapies, Ganesh Halade leads a USF Health Heart Institute team studying unresolved inflammation after heart attack

//www.youtube.com/watch?v=KarBPXZs1rs

Short-term inflammation is one of the body’s key defense mechanisms to help repair injury and fight infection. But low-level inflammation that does not subside has been linked to many common chronic conditions, including cardiovascular diseases such as atherosclerosis, atrial fibrillation and heart failure.

Ganesh Halade, PhD, an associate professor of cardiovascular sciences at the USF Health Morsani College of Medicine, investigates the safe clearance of acute inflammation – and what happens at the molecular and cellular levels when initially beneficial inflammation becomes harmful to the heart.  His team at the USF Health Heart Institute works on bridging the gap between the immune-responsive metabolism of fat and cardiac health by more clearly defining two distinct but simultaneous processes: the inflammatory response and how inflammation is safely cleared, or resolved.

In particular, Dr. Halade’s laboratory focuses on discovering ways to prevent, delay or treat the unresolved inflammation after a heart attack, which plays a key role in the pathology leading to heart failure. Their goal is to contribute to individualized therapies that may account for possible sex, racial/ethnic or age-related physiological differences in heart failure, a leading cause of hospitalizations and deaths worldwide.

Ganesh Halade, PhD, associate professor of cardiovascular sciences, joined the USF Health Heart Institute in February 2020. [Photo by Allison Long, USF Health Communications]

Heart failure — a progressively debilitating condition in which weakened or stiff heart muscle cannot pump enough blood to meet the body’s demand for nutrients and oxygen — has become a growing public health problem, fueled in part by an aging population and obesity epidemic. About 6.2 million adults in the U.S. suffer heart failure, according to the Centers for Disease Control and Prevention. Nearly half will die within five years of diagnosis, and the annual cost for health care, medications and missed work is estimated at more than $30 million.

“Although several treatments and devices exist to help manage heart failure, the challenge remains the growth of metabolic risk factors like obesity, diabetes, hypertension and aging that amplify heart failure – and inflammation underlies all these conditions,” Dr. Halade said. “We’re in the early stages of understanding how the inflammatory response becomes chronic, or unresolved” after heart attack-induced injury.

Honing in on “the roots

Dr. Halade’s late father, a farmer in Nashik close to Mumbai, India, emphasized to his young son that if he wanted to make a difference in life to “look to the roots, rather than the fruits.”

That philosophy drives Dr. Halade’s research endeavors. “We focus on the root causes of inflammation so that we can successfully treat the chronic inflammation that leads to heart failure,” he said.

Dr. Halade (center) with his research team, postdoctoral fellow Bochra Tourki, PhD, (left) and research associate Vasundhara Kain, PhD, (right). [Allison Long, USF Health Communications]

When a blocked coronary artery triggers a heart attack, inflammation caused by the tissue injury has two overlapping phases, Dr. Halade explains. During the inflammatory response, over-activated leukocytes (white blood cells of the immune system) rush from the spleen to the heart to remove dead cardiac tissue and start repairs. In the resolving phase, acute inflammation is cleared with the help of macrophages (another type of immune cell) that arrive to further repair the damage, and form a stable scar. Both timely responses are governed by coordinated ‘get in’ and ‘get out’ signals to leukocytes infiltrating the site of heart muscle injured by the heart attack. If the leukocytes do not receive a ‘get out’ signal, the sustained presence of inflammation impairs cardiac repair and eventually leads to heart failure.

Clinical trials of several anti-inflammatory therapies so far have failed to show benefit in heart failure patients. Dr. Halade suggests that the investigational compounds intended to suppress inflammation very early in the cardiovascular disease process likely disrupt the tight control of immune-responsive signaling needed for timely resolution of inflammation.

“The inflammatory response and its resolution are two sides of the same coin – and they roll together. Blocking one side will affect the other,” he explained. “So, we don’t want to block the ‘get in signal’ needed to promote the early, ‘good’ inflammation. We want to accelerate the ‘get out’ signal to immune cells, so that as soon as repair of cardiac injury is done the acute inflammation leaves without becoming chronic.”

Dr. Halade views a high-resolution image (below) of a normally beating heart. [Photos by Anne DeLotto Baier, USFH Research Communications]

Connecting dysfunctional inflammation control and heart failure

A class of immune-system molecules orchestrates the resolution of tissue inflammation, an active process essential for advancing cardiac healing after a heart attack. These specialized proresolving mediators, or SPMs, are signaling molecules that form when fatty acids metabolize in response to immune activation of leukocytes.

Dr. Halade’s work is helping uncover new details on how heart failure-inducing inflammation may be limited (without promoting immunosuppression) – either by administering pharmacological SPMs, or activating enzymes that help stimulate the body’s own SPMs.

Over the last two years, he has published significant findings in several leading journals (papers summarized below) making the connections between fatty acids, inflammation control, and heart failure. Among Dr. Halade’s study collaborators is Charles Serhan, PhD, of Harvard Medical School, a pioneer in the emerging field of inflammation resolution.

  • Science Signaling: This study followed the time course of inflammation and its resolution in a mouse heart attack model. The research showed for the first time that the active inflammation-resolving phase coincided with the acute inflammatory response facilitating cardiac repair after a heart attack. Among other factors, the researchers looked at types and amounts of SPMs, and the expression of enzymes that synthesize SPMs, both in the spleen and at the injured site of the heart. Macrophages, a type of white blood cell, are needed to generate SPMs as opposed to other immune cells, they reported.

Dr. Halade’s laboratory focuses on discovering ways to prevent, delay or treat the unresolved inflammation after a heart attack, which plays a key role in the pathology leading to heart failure. [Anne DeLotto Baier]

  • Journal of the American Heart Association: The preclinical study discovered male-female cardiac repair differences in heart failure survival after heart attack, including improved recovery of cardiac function and greater survival of acute and chronic heart failure in female mice. Females generated higher levels of a particular fatty acid-derived signaling molecule (EET; epoxyeicosatrienoic acids) known to facilitate healing after a heart attack.

 

  • ESC Heart Failure: The researchers profiled bioactive lipids (inflammatory biomarkers) in blood samples from hospitalized Black and White patients soon after a severe heart attack. They found a potent SPM signature (resolvin E1) was significantly lower in Black men and women than in Whites. The study concluded bioactive lipids are key for the diagnosis and treatment of cardiac repair after heart attack to delay heart failure.

 

  • The FASEB Journal: Halade and colleagues identified a mouse model to study heart failure with preserved ejection fraction (HFpeF), a common form of heart failure linked to age-related obesity. Using this unique model of obese aging, they defined how the deficiency of a single resolution receptor triggers obesity in mice at an early age, which can give rise to many of the molecular and cellular processes ultimately leading to HFpEF.

Vasundhara Kain (seated) and Bochra Tourki, look at slides for a paper on age-related obesity and heart failure. [Allison Long, USF Health Communications]

Insight into potential inflammation-resolving therapies

As they learn more about the metabolic and immune-responsive signals that control acute cardiac inflammation, researchers hope to harness the capacity of fatty acid-derived bioactive molecules to prevent, diagnose and treat heart failure, Dr. Halade said. SPMs are derived primarily from omega-3 fats in our diet – the polyunsaturated “good” fats in foods like salmon, avocados, almonds, and walnuts.

Some evidence indicates that omega 3-rich diets and/or SPM supplements, as well as getting enough exercise and quality sleep may help prevent the unresolved inflammation leading to heart failure, Dr. Halade said. If SPMs are not produced due to risk factors like obesity or aging, or because enzymes required to metabolize fatty acids are deficient, then drugs specifically designed to facilitate cardiac repair and calm inflammation might delay or treat heart failure, he added. Distinctive biochemical signatures acquired by analyzing SPMs or other metabolites might even be used to help diagnose heart failure or predict which treatments will work best for certain patients.

Dr. Halade joined USF Health this February from the University of Alabama at Birmingham, where he was a faculty member since 2013. He received his PhD in pharmacology from the University of Mumbai Institute of Chemical Technology in 2007. He completed two postdoctoral fellowships at the University of Texas Health Science Center in San Antonio. The first fellowship focused on nutritional immunology. The second was conducted with mentor Merry Lindsey, PhD, to examine the effects of obesity on post-heart attack cardiac structure and function.

Foods rich in omega-3 fatty acids (including salmon, walnuts and avocados), as well as enough exercise and quality sleep, may help prevent unresolved inflammation contributing to cardiovascular disease.

Dr. Halade’s research is supported by funding from the NIH’s National Heart, Lung and Blood Institute. In 2018, he received American Physiological Society Research Career Enhancement Award to train in lipidomics at the RIKEN Center for Integrative Medical Sciences in Japan.

His inflammation resolution research has been recognized with two awards for studies published in the American Journal of Physiology-Heart and Circulatory. An Article Impact Award 2020 was conferred this March by the American Physiological Society for Dr. Halade’s work defining the impact of the cancer drug doxorubicin on the heart and spleen. He also received a 2017 Best Paper Award from the Unbound Science Foundation. Dr. Halade is associate editor for the American Journal of Physiology-Heart and Circulatory and for Scientific Reports, and serves on the editorial boards of several other high-impact journals in cardiovascular sciences.

At left: Beneficial resolution of inflammation following cardiac repair. At right: Risk factors like aging, obesity and some medications can contribute to unresolved (chronic) inflammation, which impairs cardiac repair and can lead to heart failure. [Graphic courtesy of Ganesh Halade]

Some things you may not know about Dr. Halade

  • As an undergraduate student in India, Dr. Halade won the gold medal in fencing at a statewide collegiate competition.
  • To help promote a heart healthy lifestyle, he enjoys recreational bicycling and gardening in his backyard, where he grows vegetables and chiles.
  • Halade lives in Tampa with his wife Dipti, an information technology engineer, and their son Arav, 13.

Top:  Sources of inflammation include injury (like damage from a heart attack), infection (viruses, bacteria or other pathogens), and factors associated with lifestyle (such as poor diet and lack of exercise). Below: Ways to help prevent unresolved cardiac inflammation associated with lifestyle. [Graphics courtesy of Ganesh Halade]

-Video by Allison Long, USF Health Communications and Marketing



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