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Why The Heart Stops Pumping: Researchers Identify Cellular-Molecular Defect In Heart Failure

Date:
May 1, 1997
Source:
University of Maryland at Baltimore
Summary:
University of Maryland researchers have found a silent defect in the heart's pumping mechanism, produced by high blood pressure and seen in heart failure.

Untreated high blood pressure underlies much cardiovascular disease, including enlargement of the heart, heart failure, arrhythmias and stroke. It is a leading cause of death in the United States. When high blood pressure persists untreated, it enlarges the cells of the heart and produces a silent defect in the heart's pumping mechanism, according to a team of researchers headed by W. Jonathan Lederer, M.D., Ph.D. at the University of Maryland School of Medicine and Medical Biotechnology Center.

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They report their findings in the May 2 issue of the journal Science.


Although the enlargement of the heart cells may appear as a beneficial adaptation of the heart in its task of pumping blood, the silent defect remains hidden like the enemy army within the Trojan horse. The Maryland researchers found that the defect within each enlarged heart cell of the animal with high blood pressure - which they traced to the same cellular and molecular changes - is identical to the defect seen later in heart failure.


A professor of physiology at the University of Maryland School of Medicine and senior author of the Science paper, Lederer is head of the Department of Molecular Biology at the University of Maryland Medical Biotechnology Center in Baltimore.


He likens the defect to a Trojan horse because it appears to be masked initially by increased activity of the sympathetic nervous system which is able to improve heart function; the defect, therefore, is not readily noticed, Lederer explains. However as the sensitivity of the heart to continuous activity of the nervous system declines with time, the defect is unmasked and contributes to the developing heart failure.


Under normal conditions, the heart beats in response to a complex electrical-chemical process called excitation-contraction (EC) coupling. During EC coupling, an electrical signal sweeps through the heart to trigger the contraction that pumps blood throughout the body. This wave of electrical activation spreads through the heart, permitting a minute amount of calcium to enter each heart cell through some 100,000 calcium channels that cover the surface of the cells. These calcium channels are the targets for widely-used "calcium channel-blocker" medications.


Normally, the calcium that enters through each calcium channel is like a muffled starting gun, which must be amplified before it can be heard calling the cell to action. Luckily, there are close to a million amplifier modules throughout the cell, conveniently located close to the calcium channels. They amplify the weak signal from the calcium channels to produce a much larger rise in calcium, which in turn causes the heart cells to contract.


Studying the EC coupling of heart cells of rats with high blood pressure displaying either simple cellular enlargement or contractile failure, Lederer and his research team found a surprising defect. Although each of the elements in the calcium amplification system worked properly, the signals produced by the calcium channels were nonetheless inadequately amplified and thus remained muffled in both cell types. This defect reduces the contraction in each heart cell and therefore leads to "cellular" heart failure.


They studied the cells' calcium release process using a special confocal microscope to visualize the amplified signal triggered by the calcium channels. These are seen as "calcium sparks." The discovery of "Ca2+ sparks" by Lederer and his co-workers four years ago has revolutionized the investigation of cardiac, skeletal and smooth muscle function and is an essential element in the present work. All of the other features of heart cell function were measured optically or electrically.


"Our data suggest that hypertension-induced cardiac hypertrophy (enlargement of the heart) reduces the ability of calcium channels to activate calcium release from intracellular stores, even though all elements of the system are normal," said Lederer. "It appears that defect is one of communication between calcium channels and the intracellular organelles. The activity of the sympathetic nervous system is able to improve the communication without fixing the defect during cardiac hypertrophy before heart failure develops. But in heart failure the defect has its full negative effect because the heart cells respond poorly to activity of the sympathetic nervous system."


"Because of our improved understanding of the molecular defects that develop in heart failure, it may be possible to develop novel drugs, molecular therapies or treatment programs to treat this devastating disease. Furthermore, our findings, which link high blood pressure to the development of the "stealth defect" found within the heart cells before failure develops, provide an additional reason for all hypertensive patients to seek immediate effective treatment. While late treatment may fix the high blood pressure, it may not be able to reverse this defect and the consequent heart failure."


Lederer and colleagues at the University of Maryland School of Medicine and Medical Biotechnology Center collaborated with scientists from the University of Wisconsin Medical Center, the National Institute of Aging, St. George's Hospital Medical School in London, England, and Ohio State University. Their work was supported by the National Institutes of Health, the Maryland Heart Association, the BHF and Wellcome Trust, the Spanish Ministry of Education and Science, and a Minority Scientist Development Award from the American Heart Association.


Story Source:

The above story is based on materials provided by University of Maryland at Baltimore. Note: Materials may be edited for content and length.


Cite This Page:

University of Maryland at Baltimore. "Why The Heart Stops Pumping: Researchers Identify Cellular-Molecular Defect In Heart Failure." ScienceDaily. ScienceDaily, 1 May 1997. <www.sciencedaily.com/releases/1997/05/970501091119.htm>.
University of Maryland at Baltimore. (1997, May 1). Why The Heart Stops Pumping: Researchers Identify Cellular-Molecular Defect In Heart Failure. ScienceDaily. Retrieved December 20, 2014 from www.sciencedaily.com/releases/1997/05/970501091119.htm
University of Maryland at Baltimore. "Why The Heart Stops Pumping: Researchers Identify Cellular-Molecular Defect In Heart Failure." ScienceDaily. www.sciencedaily.com/releases/1997/05/970501091119.htm (accessed December 20, 2014).

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