After a heart attack, a global epidemic leading to chronic heart failure pathology is heart failure. In the United States, about 6 million people and 23 million worldwide suffer from this end-stage disease that involves dysfunction of the heart, a change that clinicians call cardiac remodeling. And 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.
An associate professor at the University of Alabama in the UAB Department of Medicine Division of Cardiovascular Disease, Ganesh Halade, Ph.D., is looking for 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 adequate calmed and did not receive a "get out" order.
As a result, the process of learning the details of metabolic signaling that controls the immune responses, both during the acute inflammation after injury and the resolution after that, is essential. Halade is working to discover which metabolic signatures are biomarkers for healthy physiology and which metabolic signatures are biomarkers for heart failure pathology.
Working through this process could permit the development of a prevention plan and precise, prognostic, and personalized measures to delay heart failure.
In 2017, Halade discovered that knocking out 12/15 lipoxygenase, or 12/15LOX, a lipid-modifying enzyme that competes with two other lipid-modifying enzymes. This work follows his previous discovery and leads to increased survival in a mouse model of heart failure after a heart attack.
Halade and his team detailed 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 a heart attack, while 38 percent of mice with regular 12/15LOX had mortality due to heart failure or rupture.
In essence, the researchers quantified changes in the metabolome, lipidome, and immune profiles during acute heart failure, one day after a heart attack, and during chronic heart failure, eight weeks after a heart attack.
The team discovered that the 12/15LOX-deficient mice biosynthesized the signaling molecules epoxyeicosatrienoic acids, also known as EETs or cypoxins, in left ventricle heart tissue after a heart attack to facilitate cardiac healing. The deficiency of lipoxygenase in mice also has cut down on the rate of the diabetes risk biomarkers 2-aminoadipic acid and had profound alterations of plasma metabolic signaling of hexoses, acylcarnitines, amino acids, biogenic amines, glycerophospholipids and sphingolipids during acute heart failure. These modifications are associated with improved survival and delayed heart failure.
