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: https://hscweb3.hsc.usf.edu/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

USF Health-led research validates crucial role of the spleen in cardiac healing, suggests targeting lipid mediator S1P may offer a promising heart failure treatment

Tampa, FL (Aug. 23, 2021) — Although we can survive without a spleen, evidence continues to mount that this abdominal organ plays a more valuable role in our physiological defenses than previously suspected.

“The spleen holds a whole army of immune cells and signaling molecules that can be rapidly mobilized to respond whenever a major injury like a heart attack or viral invasion occurs,” said Ganesh Halade, PhD, an associate professor of cardiovascular sciences at the University of South Florida Health (USF Health) Morsani College of Medicine.

Principal investigator Ganesh Halade, PhD, is an associate professor of cardiovascular sciences at the USF Health Morsani College of Medicine and a member of the college’s Heart Institute. | Photo by Allison Long, USF Health Communications

Dr. Halade led a new preclinical study that analyzed the interactions of the lipid mediator sphingosine-1-phosphate (S1P) in the spleen and heart during the transition from acute to chronic heart failure. The researchers discovered new cardiac repair mechanisms to help shed light on spleen-heart coordination of physiological inflammation in a mouse model of heart failure.

The study appeared online August 20 in the American Journal of Physiology- Heart and Circulation.

“Simply put, we showed that the spleen and the heart work together through S1P for cardiac repair,” said principal investigator Dr. Halade, a member of the USF Health Heart Institute. “Our study also suggests that early detection of little or no S1P levels after a heart attack and targeted activation of this bioactive lipid mediator may provide a cardioprotective treatment for patients at high risk of heart failure.”

Dr. Halade and colleagues have defined connections between fatty acids, dysfunctional inflammation control, and heart failure. His laboratory focuses on discovering ways to prevent, delay or treat unresolved inflammation after a heart attack. In this latest study, the researchers turned their attention to where S1P is produced and its role in cardiac repair.

S1P is a lipid mediator dysregulated during inflammatory responses, including heart failure. Moreover, several groups have demonstrated the potential significance of this signaling molecule as a treatment target for heart failure triggered by heart attack and ischemia-reperfusion injury.

People can survive without a spleen, a fist-sized abdominal organ that helps fight infection. But its removal (due to abdominal trauma, or certain medical conditions) has been linked to an increased risk of death from ischemic heart disease.

The USF Health study captured time-dependent movement of S1P from the spleen through circulating blood plasma to the heart. The work was the first to quantify interactions between S1P and S1P receptor 1 (S1PR1) during the progression from acute to chronic heart failure, Dr. Halade said.

The researchers defined S1P/S1PR1 signaling in both mice and humans with heart failure after a heart attack. The otherwise young, healthy “risk-free” mice had no variable cardiovascular risk factors such as obesity, diabetes, hypertension, and aging commonly seen in a clinical setting. The researchers correlated the physiological data from the cardiac-repair mouse model experiments with what they observed in pathologically failing human hearts.

Among their key findings:

• Cardiac-specific S1P and S1PR1 levels were reduced in patients with ischemic heart failure.
• In the risk-free mice, physiological cardiac repair was facilitated by activation of S1P in the heart and the spleen. S1P/S1PR1 signaling increased in both organs from acute through chronic heart failure, helping to promote cardiac repair after heart attack.
• Increased plasma S1P indicates cardiac repair in the acute phase of heart failure.
• Selective activation of the S1P receptor in macrophages (immune cells that that help clear inflammation and guide tissue repair) suppressed biomarkers of inflammation and accelerated biomarkers of cardiac healing in mouse cells.

“This study provides another example that the spleen should not be underestimated, because it contributes to the foundation of our immune health as well as the root cause of inflammatory diseases, including cardiovascular disease,” Dr. Halade said.

The research was supported by grants from the National Institutes of Health and the U.S. Department of Veterans Affairs.  The University of South Florida team worked with collaborators at the University of Alabama at Birmingham and Hokkaido University, Japan.

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.

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]

“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]

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

Mice deficient in a receptor needed to safely clear unresolved cardiac inflammation may help in discovering therapies for heart failure with preserved ejection fraction

TAMPA, Fla (June 22, 2020) — A receptor that plays an essential role in safely clearing chronic unresolved cardiac inflammation may offer new targets for treating an increasing type of heart failure associated with age-related obesity, suggests a preclinical study led by researchers at the University of South Florida Health (USF Health) Heart Institute, Morsani College of Medicine.

Heart failure with preserved ejection fraction, or HFpEF, is one of two types of heart failure – both characterized by shortness of breath, exercise intolerance, fatigue and fluid retention. Unlike the second type of heart failure, known as heart failure with reduced ejection fraction, HFpEF currently has no FDA-approved drugs to improve the weakened heart’s pumping function.

Ganesh Halade, PhD, USF Health associate professor of cardiovascular sciences, was senior author of the The FASEB Journal paper on age-related obesity and heart failure with preserved ejection fraction.

More than half of all patients with clinical heart failure have HFpEF, a growing public health problem because of the aging population and growing incidence of obesity. In HFpEF, the heart contracts normally and seems to pump out a normal proportion of blood; however, the heart muscle can thicken and weaken causing the ventricle to withhold an abnormally small volume of blood. So, while the heart’s output as measured by ejection fraction may appear within the normal range, it is insufficient to meet the body’s demands.

In a study published June 16 in The FASEB Journal, the USF Health-led team identified a mouse model that thoroughly mimics HFpEF syndrome in humans. These obesity-prone mice lack the inflammation clearing (resolution) receptor, ALX/FPR2 or ALX for short — a deficiency previously shown to drive cardiac and kidney inflammation in aging mice.

Using this unique model, the researchers defined how the ALX resolution receptor promotes the activity of specialized proresolving mediators (SPMs), fatty-acid derived signaling molecules. These SPM molecules support the body’s innate immune response to help clear out chronic inflammation and advance cardiac repair following an acute heart attack. Conversely, the researchers noted that sustained, unresolved inflammation after heart attack can aggravate abnormalities in endothelial cells lining the heart and kidneys. These abnormalities prompt endothelial dysfunction that changes blood vessel integrity — a primary sign of both age-related obesity and HFpEF.

Dr. Halade (center) with his research team, postdoctoral fellow Bochra Tourki, PhD, (left) and research associate Vasundhara Kain, PhD, (right), in their USF Health Heart Institute laboratory.

“Remarkably, the deficiency of a single receptor triggers obesity in mice at an early age and this, in turn, gives rise to many molecular and cellular processes ultimately leading to heart failure with preserved ejection fraction,” said senior author Ganesh Halade, PhD, associate professor of cardiovascular sciences at the USF Health Heart Institute.

The FASEB study’s three key findings were:

• The obesity-prone ALX-deficient mice had increased food intake and impaired energy metabolism compared to normal mice (with a working ALX receptor) of the same ages. The obesity-driven metabolic dysfunction led to heart structural remodeling, defective cardiac electrical activity and weakened heart muscle.
• Deletion of the ALX receptor increased ion channel gene expression and disrupted multiple ion channels, which supported electrocardiogram evidence of heart rhythm disturbances in the mice.
• Obesity-prone, ALX-deficient mice develop heart muscle damage characteristic of HFpEF with steady inflammation in the heart and kidneys. This suboptimal inflammation is directed remotely by immune cells (leukocytes) in the spleen and advanced by dysfunctional (leaky) cardio-renal endothelial tissue in older ALX-deficient obese mice.

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Overall, the research describes the importance of the resolution receptor essential for SPM action, particularly resolvins that suppress the inflammatory response to acute injury without compromising a healthy immune response. In fact, a specific resolvin (D1) is a key that unlocks the ALX resolution receptor to enable pharmacological action and, eventually, safe clearance of inflammation, Dr. Halade said.

The study offers insight into potential targeted treatments for HFpEF that would harness the benefits of naturally-produced SPMs. Omega 3-rich diets and/or SPM supplements to preserve the receptor’s normal function may help prevent this type of heart failure, Dr. Halade said, while SPMs or other molecules specifically designed to reactivate a dysfunctional receptor might help treat existing HFpEF.

This latest research builds upon previous work by Dr. Halade’s laboratory – all focused on discovering the best ways to prevent, delay or treat the unresolved inflammation influencing heart failure. The team’s goal is to contribute to individualized therapies that may account for possible sex, racial/ethnic or age-related physiological differences.

Absence of the inflammation resolution receptor ALX triggers heart muscle endothelial dysfunction: Immunofluorescent microscopic image (below) shows a decrease in expression of CD31 (endothelial cells stained red)  in a 4-month old, obesity-prone mouse deficient in the ALX receptor, compared to same-age normal mouse with a functioning receptor (above).  Images courtesy of Halade laboratory; appeared first in The FASEB Journal, Jun 16, 2020, doi: 10.1096/fj.202000495RR

Approximately, 6.5 million Americans have heart failure, which contributes to one in every eight deaths, according the Centers for Disease Control and Prevention.

The USF Health researchers collaborated with Charles N. Serhan, PhD, DSc, Harvard Medical School; Saame Raza Shaikh, PhD, University of North Carolina at Chapel Hill; and Xavier Leroy, Domain Therapeutics, France. The team science study was supported in part by grants from the NIH’s  National Heart, Blood and Lung Institute.

– Photos by Allison Long, USF Health Communications and Marketing

USF Health-UAB study indicates that lipid mediators may offer new targets for more personalized heart failure diagnosis and treatment

The new study profiled bioactive lipids in blood samples collected from hospitalized black and white patients soon after a severe heart attack.

TAMPA, Fla (May 4, 2020) — Black men and women have higher incidences than whites of developing advanced heart failure following a heart attack. Despite racial disparities in heart attacks (a leading contributor to heart failure), and rehospitalizations and deaths caused by heart disease, the underlying physiology accounting for worse cardiovascular outcomes among blacks is poorly understood.

A new study published May 4 in ESC Heart Failure profiles bioactive lipids in blood samples from hospitalized black and white patients soon after a severe heart attack. The preliminary research was conducted by a team at the University of South Florida Health (USF Health) Morsani College of Medicine and the University of Alabama at Birmingham. The researchers wanted to delineate potential differences in the immune-responsive processes needed to safely clear (resolve) acute inflammation after heart attack-induced tissue injury, with the aim of finding more individualized therapies for heart failure.

“Metabolic and leukocyte-responsive signaling control the acute inflammation needed for timely cardiac repair after a heart attack. But inflammation that is not cleared and remains long-term plays a key role in the pathology leading to heart failure,” said lead author Ganesh Halade, PhD, associate professor of cardiovascular sciences at the Morsani College of Medicine and a member of the USF Health Heart Institute.

“Understanding race and sex-based differences in inflammation and its resolution will help us develop more personalized diagnoses and treatments to delay or prevent heart failure.”

A mouse model study published by Dr. Halade last month discovered that heart repair occurs faster in female mice than males after a heart attack, which improves survival and delays cardiac failure.

In this human study, the researchers collected blood plasma from 53 patients, grouped by race and sex, within 24 to 48 hours after a heart attack. Baseline acute injury caused by the heart attack was similar in all the patients, and so were their ages and body mass indexes. No significant sex-or race-specific differences were detected in total cholesterol, HDL, LDL or triglyceride levels – all indicators (biomarkers) currently used by clinicians to help predict risk and manage cardiovascular disease. Measures of various subtypes of leukocytes (cells that regulate immune fitness) were similar across all patients.

Lead author Ganesh Halade, PhD, associate professor of cardiovascular sciences, USF Health Morsani College of Medicine

Looking for distinct bioactive lipid “signatures,” or inflammatory biomarkers, that might predict poorer cardiovascular outcomes after heart attack, the researchers measured three major polyunsaturated fatty acids: arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). These omega fatty acids circulate in blood and depend upon what people eat. Also analyzed were dozens of specific proresolving mediator (SPM) indicators and a few other signaling molecules that form when these fatty acids metabolize in response to immune activation.

Overall, black patients showed higher concentrations of the three activated fatty acids after a heart attack than white patients, the researchers found. The comparative analyses of SPMs showed that resolvin E1, a potent proresolving mediator of inflammation derived from the fatty acid EPA, was significantly lower in black men and women than in whites. An earlier major clinical trial linked EPA with reduced ischemic events such as heart attack and stroke in patients with high risk for, or existing, cardiac disease, and another showed that high levels of EPA significantly decreased the risk of heart failure.

The researchers conclude that bioactive lipids are key for diagnosis and treatment of cardiac repair after heart attack to delay heart failure.

Randomized controlled clinical trials will be needed to definitively determine whether distinct SPM signatures can be used to predict, diagnose, treat or prevent heart failure following a heart attack, Dr. Halade said. “If we can stratify risk among larger patient groups to determine who is deficient in SPMs critical for cardiac repair, we may be able to restore those targeted SPMs to improve outcomes.”

The study was supported by grants from the National Institutes of Health.

Heart failure affects about 6.5 million adults nationwide and leads to one in 8 deaths each year, according to the Centers for Disease Control and Prevention. The condition usually develops as the heart gradually loses its ability to pump enough blood through the body.

A University of South Florida-led study of mouse cardiac healing may lead to more precise, sex-specific therapies for heart failure, a leading cause of death

TAMPA, Fla. (April 17, 2020) –  The short-term acute inflammatory response triggered to mend injured cardiac tissue following a heart attack can lead to weakening of the heart’s pumping function if the inflammation remains active over the long-term. Heart failure associated with this unresolved chronic cardiac inflammation has become a leading cause of death in the U.S. and worldwide, yet little is known about the differences in cardiac repair and safe clearance of inflammation between men and women.

Ganesh Halade, PhD, an associate professor of cardiovascular sciences at the University of South Florida Health (USF Health) Morsani College of Medicine and Heart Institute, looks for ways to delay or prevent heart failure — including targeted therapies that may account for potential physiological sex differences.

Ganesh Halade, PhD

Dr. Halade’s team delves into the details of metabolic and leukocyte responsive signaling that facilitate cardiac repair during acute inflammation after injury (like a heart attack) and the resolution thereafter. In particular, he studies how unresolved inflammation driven by a deficiency in fatty acid-derived signaling molecules influences heart failure. Known as specialized proresolving mediators (SPMs), these molecules are naturally made by the body (endogenous).

Now, a new study led by Dr. Halade has investigated the molecular and cellular processes underlying cardiac repair in male and female mice after a severe heart attack. The USF Health study, conducted with collaborator Charles N Serhan, PhD, DSc, at Harvard Medical School, reports that females showed improved heart failure survival characterized by differences in cardiac functional recovery and structure, more reparative immune cells and higher levels of epoxyeicosatrienoic acids (EETs), signaling molecules with anti-inflammatory effects.

The findings were published April 16 in the Journal of the American Heart Association.

“We discovered heart repair happens faster in the female mice than the males after heart attack, that improves survival and delays cardiac failure,” said Dr. Halade, the paper’s senior author.

His ongoing translational work may have applications for the development of sex-specific and other more precise heart failure therapies with fewer side effects due to endogenous nature of bioactive signaling molecules. Currently, men and women receive the same standard first-line medications (angiotensin converting enzyme/receptor inhibitors, diuretics, and beta-blockers) to manage mild-to-severe forms of heart failure.

For this study appearing in JAHA, the researchers used “risk-free” young, healthy mice to control for variable cardiovascular risk factors — such as obesity, insulin resistance, diabetes, hypertension and aging, — common in a clinical setting. They compared the risk-free male and female mice who underwent a procedure to induce severe heart attack with those that did not.

To frame the study, it helps to know that physiological inflammation after tissue injury has two steps — an acute response, where white blood cells rush to the heart to remove dead cardiac tissue, and a resolving phase, where inflammation is cleared with the help of macrophages that arrive to repair the damage, and form stable scar. Both responses are governed by ‘get in’ and ‘get out’ signals to leukocytes (a type of immune cell) infiltrating at the site of the heart muscle injured by the heart attack.

Among the key USF Health research findings:

• Following a heart attack, leukocyte infiltration to clear diseased cardiac muscle cells is coordinated by the production of SPMs that resolve inflammation and promote timely cardiac repair.
• Female mice showed better recovery of the heart’s capacity to pump blood compared to males. “Improvement in heart functional recovery is believed to be enabling the female mice to ‘bounce back’ and survive at a significantly higher rate than male mice after myocardial infarction (heart attack),” the authors wrote.
• Less post-MI scarring and adverse structural remodeling of heart muscle in female mice helps explain their improved recovery of cardiac function and survival in acute and chronic heart failure.
• While both male and female mice equally produced SPMs in response to massive heart attacks, the females generated higher levels of a particular lipid signaling molecule known as epoxyeicosatrienoic acid (EET) to facilitate healing after a heart attack.

“The beauty of these SPM and EET molecules is that they are endogenously biosynthesized and can be useful for clearing harmful inflammation in asthma and other diseases, not just heart failure,” Dr. Halade said.

The USF Health researchers plan to study these bioactive lipid signaling molecules after heart attack in men and women, and consider human-related variable factors absent in mice, such as race.

The study was supported by grants from the NIH’s National Institute of Heart Lung and Blood Institute (Dr. Halade) and the National Institute of General Medical Sciences (Dr. Serhan).