Nav: Home

How the enzyme lipoxygenase drives heart failure after heart attacks

May 31, 2019

BIRMINGHAM, Ala. - Heart failure after a heart attack is a global epidemic leading to chronic heart failure pathology. About 6 million people in the United States and 23 million worldwide suffer from this end-stage disease that involves dysfunction of the heart, a change that clinicians call cardiac remodeling. Despite medical advances, 2 to 17 percent of patients die within one year after a heart attack due to failure to resolve inflammation. More than 50 percent die within five years.

Ganesh Halade, Ph.D., is seeking ways to delay or reverse this heart failure, which comes from non-resolved chronic inflammation. Over-activated leukocytes from the spleen that rushed into the heart muscle to remove dead tissue and start repairs are not adequately calmed and do not receive a "get out" signal.

So, learning the details of metabolic signaling that controls the immune responses -- both during the acute inflammation after injury and the resolution thereafter -- is important. Halade, a University of Alabama at Birmingham associate professor in the UAB Department of Medicine Division of Cardiovascular Disease, is working to discover which metabolic signatures are biomarkers for healthy physiology and which metabolic signatures are biomarkers for heart failure pathology.

This could permit the development of a prevention plan and precise, prognostic and personalized measures to delay heart failure.

This work follows his 2017 discovery that knocking out 12/15 lipoxygenase, or 12/15LOX, a lipid-modifying enzyme that competes with two other lipid-modifying enzymes, leads to increased survival in a mouse model of heart failure after a heart attack.

In a study now published online ahead of print in the journal Metabolism: Clinical and Experimental, Halade and colleagues detail the profound lipidomic and metabolic signatures and the modified leukocyte profiling that delay heart failure progression and provide improved survival in 12/15LOX-deficient mice. Only 6 percent of the 12/15LOX-deficient mice died in the progression of chronic heart failure, 56 days after heart attack, while 38 percent of mice with normal 12/15LOX had mortality due to heart failure or rupture.

Specifically, the researchers quantified changes in the metabolome, lipidome and immune profiles during acute heart failure, one day after heart attack, and during chronic heart failure, eight weeks after heart attack.

They found that the 12/15LOX-deficient mice biosynthesized the signaling molecules epoxyeicosatrienoic acids -- also known as EETs or cypoxins -- in left ventricle heart tissue after heart attack to facilitate cardiac healing. The lipoxygenase-deficient mice also had reduced amounts of the diabetes risk biomarker 2-aminoadipic acid and had profound alterations of plasma metabolic signaling of hexoses, amino acids, biogenic amines, acylcarnitines, glycerophospholipids and sphingolipids during acute heart failure. These changes are accompanied by delayed heart failure and improved survival.

"Future studies are warranted to define the molecular network of the lipidome and metabolome in acute and chronic heart failure patients," Halade said, though he notes this needs to be preceded by work with other animal models. "Collectively, our studies have discovered a novel link of LOX signaling between lipidomic and metabolic signatures in acute and chronic heart failure syndrome."

Co-authors with Halade in the study, "Lipoxygenase drives lipidomic and metabolic reprogramming in ischemic heart failure," are Vasundhara Kain, Bochra Tourki and Jeevan Kumar Jadapalli, Division of Cardiovascular Disease, UAB Department of Medicine.

Support came from National Institutes of Health grants AT006704 and HL132989, a UAB Pittman Scholar award, and the American Heart Association postdoctoral fellowship POST31000008.
-end-


University of Alabama at Birmingham

Related Heart Failure Articles:

Type 2 diabetes may affect heart structure and increase complications and death among heart failure patients of Asian ethnicity
The combination of heart failure and Type 2 diabetes can lead to structural changes in the heart, poorer quality of life and increased risk of death, according to a multi-country study in Asia.
Preventive drug therapy may increase right-sided heart failure risk in patients who receive heart devices
Patients treated preemptively with drugs to reduce the risk of right-sided heart failure after heart device implantation may experience the opposite effect and develop heart failure and post-operative bleeding more often than patients not receiving the drugs.
How the enzyme lipoxygenase drives heart failure after heart attacks
Heart failure after a heart attack is a global epidemic leading to heart failure pathology.
Novel heart pump shows superior outcomes in advanced heart failure
Severely ill patients with advanced heart failure who received a novel heart pump -- the HeartMate 3 left ventricular assist device (LVAD) -- suffered significantly fewer strokes, pump-related blood clots and bleeding episodes after two years, compared with similar patients who received an older, more established pump, according to research presented at the American College of Cardiology's 68th Annual Scientific Session.
NSAID impairs immune response in heart failure, worsens heart and kidney damage
Non-steroidal anti-inflammatory drugs, or NSAIDs, are widely known as pain-killers and can relieve pain and inflammation.
Heart cell defect identified as possible cause of heart failure in pregnancy
A new Tel Aviv University study reveals that one of the possible primary causes of heart failure in pregnant women is a functional heart cell defect.
In heart failure, a stronger heart could spell worse symptoms
Patients with stronger-pumping hearts have as many physical and cognitive impairments as those with weaker hearts, suggesting the need for better treatment.
Patients with common heart failure more likely to have lethal heart rhythms
New Smidt Heart Institute Research shows that patients with Heart Failure with Preserved Ejection Fraction (HFpEF) are more likely to have lethal heart rhythms.
Why does diabetes cause heart failure?
A Loyola University Chicago Stritch School of Medicine study reveals how, on a cellular level, diabetes can cause heart failure.
Oxygen therapy for patients suffering from a heart attack does not prevent heart failure
Oxygen therapy does not prevent the development of heart failure.
More Heart Failure News and Heart Failure Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Risk
Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#540 Specialize? Or Generalize?
Ever been called a "jack of all trades, master of none"? The world loves to elevate specialists, people who drill deep into a single topic. Those people are great. But there's a place for generalists too, argues David Epstein. Jacks of all trades are often more successful than specialists. And he's got science to back it up. We talk with Epstein about his latest book, "Range: Why Generalists Triumph in a Specialized World".
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.