UW News

November 14, 2010

Several DNA sequence variations linked to electrical signal conduction in the heart

UW Health Sciences/UW Medicine

An analysis of data from nearly 50,000 people has uncovered several DNA sequence variations associated with the electrical impulses that make the heart beat. The findings, reported today in the early online edition of Nature Genetics, pave the way for a greater understanding of how heart problems develop.

Normally, signals start from specialized muscle cells, travel across the heart and cause rhythmical muscle contractions — a system called cardiac conduction. The signals register as the pulsating wave seen on heart monitors.

Abnormalities in cardiac conduction, particularly in the ventricles of the heart, can be dangerous. Conduction abnormalities, when severe, require cardiac pacemaker implantation to ensure regular cardiac eletrical activitiy throughout the heart.

Abnormal ventricular conduction is also a risk factor for heart failure, sudden death, and death due to heart disease.

Researchers have known for some time that genetic factors contribute to electrical activity in the heart, including conduction of the electrical signal throughout the heart chambers. This study reports on several previously unsuspected regions in the genome that are associated with cardiac electrical activity.

The National Heart, Lung, and Blood Institute of the National Institutes of Health helped fund the international, multi-institutional research.

The lead and corresponding author of the report is Dr. Nona Sotoodehnia, University of Washington (UW) assistant professor of medicine, Division of Cardiology. She is a physician scientist at UW Medicine’s Harborview Medical Center in Seattle and its Cardiovascular Health Research Unit. Other corresponding authors are Dr. Stefan Kaab of Ludwig-Maximilians-University in Munich, Germany, and Dr. Dan E. Arking at Johns Hopkins University in Baltimore. More than 100 scientists from the United Kingdom, Europe and the United States contributed to the work.

Other UW researchers were part of the study team, including Dr. Kristin Marciante, research scientist; Dr. Sina Gharib, assistant professor of medicine; Dr. Josh Bis, research scientist; Dr. Ken Rice, associate professor of biostatistics, Dr. Bruce Psaty, professor of medicine and epidemiology, Dr. Susan Heckbert, professor of epidemiology, and Dr. David Siscovick, professor of medicine and epidemiology.

The data for the cardiac conduction genetics study came from a consortium of 15 European and American studies, representing nearly 50,000 individuals of European descent. Genome-wide association studies examine hundreds of thousands of genetic variants in thousands of people to try to find sequence variants and genes associated with particular diseases or conditions.

All of the subjects had an electrocardiogram (ECG) to measure their cardiac electrical activity. Ventricular conduction is measured by the length of the QRS lines on the ECG. Prolongation of the QRS duration suggests that there is conduction abnormality. The ECG is a commonly used diagnostic test for people with confirmed or suspected heart disease.

Researchers were able to identify genetic associations with cardiac ventricular conduction in 22 regions of the genome.

Some of these genetic variations were found in two sodium channel genes that sit side-by-side on the human genome. Sodium channels are molecular gated pores in living cells. These pores control the flow of sodium ions — electrically charged particles — to produce signals.

The first gene, SCN5A, is well known to be involved in cardiac conduction. The second, SCN10A, has only recently
been found in the heart. Investigators for this study localized where in the heart the SCN10A channels form. They found that they are particularly highly abundant in the conduction fibers of the mouse heart. The researchers then treated mice with a drug that selectively blocked this sodium channel and noted that cardiac conduction was delayed in these mice.

In addition to cardiac sodium channel genes, this genetic study of nearly 50,000 individuals found a number of other genes and genetic pathways involved in cardiac conduction, including calcium handling processes and transcription factors which influence cardiac development and formation. Dysfunctions in these processes before birth can lead to heart malformations in newborns.

“Better understanding of the complex biologic pathways and molecular genetics associated with cardiac conduction and QRS duration,” the researchers conclude, “may offer insight into the molecular basis underlying the pathogenesis of conduction abnormalities that can result in increased risk of sudden death, heart failure and cardiac mortality.”