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The Genetic Background of Heart Failure and the Role of Hypertension

Researchers from Berlin, Germany have identified variations in a gene, which contributes to heart failure in the presence of hypertension.

The gene, Ephx2, encodes an enzyme (soluble epoxide hydrolase) that 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, a 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 Ephx2 gene resulting in a hyperactive soluble epoxide hydrolase, the epoxides would be degraded. This state-of-affairs would worsen the heart failure condition. The Ephx2 gene was identified by the physicians Dr. Jan Monti, Prof. Friedrich Luft (both Charité-Universitätsmedizin Berlin/Helios Klinikum Berlin-Buch), and the genome researcher Prof. Norbert Hübner (Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch), as well as by their collaborators. The results were published online in the current issue of the journal Nature Genetics (Vol. 40, No. 5, pp. 529 - 537, 2008)*. The scientists hope that their results might improve the diagnosis and therapy for heart failure.

According to the American Heart Association, more than 57,000 Americans died of heart failure in 2004. The number of Europeans is larger still. 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.

Heart failure usually develops over a longer 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. "But elevated blood pressure does not necessarily cause heart failure in all patients," Dr. Monti, physician at the Charité and Helios, explains. "Hypertension damages the heart and increases the propensity to develop heart failure. Other factors also contribute to the disease."

The spontaneously hypertensive stroke-prone (SHRSP) rat strain, which is characterized by severe hypertension, does not develop heart failure. In contrast, the spontaneously hypertensive heart failure (SHHF) rat strain regularly develops heart failure as a result of hypertension. The investigators capitalized on these observations to answer the question, "why?" When comparing both strains, the researchers observed that SHHF rats possess genetic variations that are not present in SHRSP rats. These single base pair variations are called "single nucleotide polymorphisms" (SNPs). "In SHHF rats, SNPs in the gene called Ephx2 lead to an increased production of the enzyme soluble epoxide hydrolase," Prof. Hübner explains. He is the genome researcher from the MDC who conceived the project.

The body's "self aid" drops out
"In a healthy person, the soluble epoxide hydrolase degrades the body's own substances (epoxides). Some epoxides can protect the heart from damage. When the heart is overloaded, as occurs in hypertension, we would like the epoxides to be able to fulfil their supporting tasks to the utmost. However, the genetic variation we observed in the SHHF rats prevents downregulation of the enzyme", Prof. Hübner remarks further. "Because of the variation, the soluble epoxide hydrolase is still active during overload of the heart. The epoxides that are sorely needed are degraded. Thus, the body's "self aid" drops out," he says. "Without epoxides, the heart is more prone to develop heart failure when blood pressure is high."

The soluble epoxide hydrolase was long suspected to play a role in the development of heart failure. "But a candidate gene is not a proof", notes Prof. Luft. "It took more than four years for numerous researchers working together to gather convincing evidence about the candidate gene." Clinicians and scientists now hope for the development of new diagnostic and therapeutic options. "Animal experiments with inhibitors of the soluble epoxide hydrolase are in progress," Dr. Monti comments. "However, a gene deletion in a mouse is not necessarily the same as an inhibitory drug. The way into the clinical arena is long and arduous."

*Soluble epoxide hydrolase is a susceptibility gene for heart failure in a rat model of human disease

Jan Monti1,2,9, Judith Fischer1,9, Svetlana Paskas1, Matthias Heinig1,3, Herbert Schulz1, Claudia Gösele1, Arnd Heuser1,2, Robert Fischer1,2, Cosima Schmidt1, Alexander Schirdewan2, Volkmar Gross1, Oliver Hummel1, Henrike Maatz1, Giannino Patone1, Kathrin Saar1, Martin Vingron3, Steven M Weldon4, Klaus Lindpaintner5, Bruce D Hammock6, Klaus Rohde1, Rainer Dietz1,2, Stuart A Cook7, Wolf-Hagen Schunck1, Friedrich C Luft1,8 & Norbert Hubner1

1Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. 2Department of Clinical and Molecular Cardiology, Franz-Volhard Clinic, HELIOS, Charite´ -Universitätsmedizin Berlin, Schwanebecker Chaussee 50, 13125 Berlin, Germany. 3Department of Bioinformatics, Max-Planck-Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany. 4Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368, USA. 5F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. 6Departments of Entomology and Nutrition and Cancer Research Center, University of California at Davis, One Shields Avenue, Davis, California 95616-8584, USA. 7MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. 8Department of Nephrology/Hypertension, Franz-Volhard Clinic, HELIOS, Charité -Universitätsmedizin Berlin, Schwanebecker Chaussee 50, 13125 Berlin, Germany. 9These authors contributed equally to this work.

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33

Barbara Bachtler | Max-Delbrück-Centrum
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Further reports about: Ephx2 Epoxide Genetic SHHF heart failure hydrolase hypertension soluble

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