Source of abnormal electrical impulses in hypertrophied hearts revealed

Cardiac disorders such as valve problems or high blood pressure make the heart work harder to pump blood. This increased work can lead to enlargement (thickening) of the heart, or cardiac hypertrophy — a potentially life-threatening problem.

This MRI shows ventricular hypertrophy.
This MRI shows ventricular hypertrophy.

But when heart problems cause the heart to enlarge, it doesn’t grow more muscle cells. Instead each individual cell grows bigger.

Researchers at Washington University School of Medicine in St. Louis have shown that this cellular enlargement causes marked decreases in the density of potassium selective ion channels, important cell surface structures needed to generate cardiac rhythms. These changes lead to abnormal heart rhythms.

“We found that when the cells in the hypertrophic heart grow larger they don’t proportionately increase the number of potassium ion channels on their surface, so the density of these channels decreases,” says senior author Jeanne M. Nerbonne, Ph.D., the Alumni Endowed Professor of Molecular Biology in the Department of Developmental Biology. “You can visualize this by thinking of a balloon covered with a fixed number of spots. When the balloon expands, the spots get further apart.”

The heart is an electromechanical pump, and normal contraction of the heart depends on normal electrical activity, reflecting the coordinated activation (opening) and inactivation (closing) of ion channels in the surface membrane of heart muscle cells. Ion channels are proteins that control the passage of electrically charged ions and are important for nerve communication, muscle contraction, hormone secretion, cell division and immune function, to name just a few.

Channels selective for sodium, potassium or calcium ions allow the flow of these ions into or out of cells. The currents that flow through the heart with each beat depend on the orchestrated opening and closing of these ion channels, and subtle alterations in channel density can affect the heart’s performance.

Studying potassium ion channels in mice with surgically induced cardiac hypertrophy, Nerbonne and colleagues demonstrated that enlargement of heart cells and the resulting reductions in potassium ion channel densities is responsible for changing the electrical properties of the heart. Their findings were reported in the June issue of Circulation Research.

Nerbonne says that it has been assumed that the production of potassium ion and other channels was decreased in hypertrophic heart muscle cells. This recent work has shown that the number of potassium ion channels produced is in fact the same, but they are less densely packed on the cell surface. Apparently, although heart cells turn up the production of many proteins and other materials that they need to grow bigger, they don’t also turn up production of these particular ion channels.

“These results may be key to understanding the difference between pathological and physiological hypertrophy,” Nerbonne says. “It is well recognized that trained athletes have enlarged hearts, but this physiological hypertrophy, unlike pathological hypertrophy, is not associated with arrhythmias or poor prognosis, suggesting that in the athletic heart, more ion channels are produced to compensate for the increase in cell size. If correct, then therapeutic strategies to reduce the morbidity and mortality associated with pathological cardiac hypertrophy could be aimed at increasing the ability of heart cells to produce more potassium ion channels.”

With Colin G. Nichols, Ph.D., the Carl Cori Professor of Cell Biology and Physiology, Nerbonne is co-director of the Center for the Investigation of Membrane Excitability Disorders (CIMED), one of the Interdisciplinary Research Centers of BioMed 21, the University’s initiative dedicated to rapidly translating laboratory discoveries into new approaches for patient diagnosis and treatment. CIMED focuses on gaining a better understanding of ion channel functioning and regulation to aid in the development of new treatments for diseases as wide ranging as cystic fibrosis, epilepsy, migraine, abnormal heart rhythms and type 2 diabetes.

Marionneau C, Brunet S, Flagg TP, Pilgram TK, Demolombe S, Nerbonne JM. Distinct cellular and molecular mechanisms underlie functional remodeling of repolarizing K currents with left ventricular hypertrophy. Circulation Research 2008 Jun 6;102(11):1406-15.

Funding from the National Heart, Lung, and Blood Institute, the Heartland Affiliate of the American Heart Association and Agence Nationale de la Recherche supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare