Enzyme Variant Identified as a Susceptibility Factor for Heart Failure

Bruce D. Hammock, Ph.D.
Departments of Entomology and Nutrition and Cancer Research Center
University of California at Davis
NIEHS Grant R37ES002710

Researchers from Germany and the U.S. have identified variations in a gene that contributes to heart failure in people with hypertension. Ephx2, codes for the enzyme soluble epoxide hydrolase, which normally degrades specific epoxides. In this case, the epoxides can be cardioprotective in the setting of heart failure but not necessarily relevant for healthy individuals. In persons with heart failure, low Ephx2 activity would not break down the epoxides and as a result, the heart could be protected from further damage. However, in persons with both heart failure and an altered gene resulting in a hyperactive soluble epoxide hydrolase, the epoxides would be degraded and put the person at increased risk for heart failure conditions.

The Centers for Disease Control and Prevention list heart disease as the leading cause of death in the U.S. Heart failure is the third most common cause of death in Western countries, after coronary heart disease and stroke. Heart failure commonly results from coronary disease and hypertension. It usually develops over a long period of time and is therefore commonly seen in older individuals. When the heart is no longer able to pump enough blood to meet the body’s requirements, the heart muscle enlarges in an effort to compensate. However, often the heart does not overcome the increased burden and becomes weakened further, especially in cases of pre-existing hypertension.

Using two strains of laboratory rats, one susceptible to hypertension and stroke and the other susceptible to hypertension and heart failure, the researchers observed that the heart failure rats possessed a single nucleotide polymorphism in the Ephx2 gene that is not present in the stroke prone rats. They conclude the demonstrated role of Ephx2 in the initial stages of heart disease in laboratory animals and humans, suggests "a potential avenue for developing new heart failure treatments."

Citation:Monti J, Fischer J, Paskas S, Heinig M, Schulz H, Gösele C, Heuser A, Fischer R, Schmidt C, Schirdewan A, Gross V, Hummel O, Maatz H, Patone G, Saar K, Vingron M, Weldon SM, Lindpaintner K, Hammock BD, Rohde K, Dietz R, Cook SA, Schunck WH, Luft FC, Hubner N. Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. Nat Genet. 2008 May;40(5):529-37.