Scientists at the Masonic Medical Research Laboratory (MMRL) in Utica, NY have uncovered a new genetic basis for abnormal rhythms of the heart responsible for sudden cardiac arrest.

The landmark discovery is reported in the current issue of Circulation, the leading Cardiology journal published by the American Heart Association (AHA). Dr. Charles Antzelevitch and a team of investigators and collaborators from Canada, Germany, France and Italy describe a new clinical entity characterized by distinctive changes in the electrocardiogram (ECG) in three families with a history of sudden cardiac death. Affected family members were all found to have mutations in the genes that encode the cardiac calcium channels. These channels permit the flow of calcium ion in and out of cells in the heart. The defective genes called CACNA1C and CACNB2b were found to generate a smaller than normal electrical current and thus to be responsible for creating an electrical imbalance that results in potentially fatal abnormal heart rhythms, known as cardiac arrhythmias.

Although the heart is a mechanical pump, each and every beat is initiated by electrical activity that originates in the upper part of the heart called the sinus node and is transmitted in a very orderly fashion through the remainder of the heart. The electrical current is due to the movement of ions such as sodium, potassium and calcium across the cell membrane. Defects in the function of the channels that permit these various ions to move in and out of the cardiac cell leads to an electrical imbalance that can disrupt the normal distribution of the electrical charge throughout the heart, resulting in abnormal rhythms. Some arrhythmias are benign, such as premature beats, and others are deadly, including ventricular tachycardia and fibrillation. The ECG, which records the electrical activity of the heart from electrodes placed on the body surface, can be used to detect these rhythm disturbances. The ECG is normally comprised of a P wave, reflecting the activation of the upper chambers of the heart (atria), a QRS wave denoting the activation of the lower chambers of the heart (ventricles) and a T wave, which is inscribed as a result of the repolarization associated with relaxation of the heart. The interval between the QRS and T waves (QT interval) normally ranges between 360 and 460 milliseconds and the ST segment of the normal ECG is isoelectric (neither elevated or depressed).

The new clinical entity is a combination of two distinct sudden death syndromes known as the Brugada and Short QT syndromes. The Brugada syndrome is characterized by an elevation of the ST segment in the ECG and the short QT syndrome distinguished by a briefer than normal QT interval (less than or equal to 360 milliseconds). These syndromes have previously been shown to be due to defects in genes that control the flow of sodium and potassium ions across the membrane of the cardiac cell. Antzelevitch, who serves as Executive Director and Director of Research of the MMRL, and his colleagues at the MMRL were the first to identify the KCNH2 gene responsible for the Short QT syndrome and together with colleagues at Baylor College of Medicine were the first to describe the SCN5A gene responsible for the Brugada syndrome. Each syndrome is capable of independently producing sudden cardiac arrest. The new clinical entity, by combining the two malfunctioning electrical features, presents a situation of double jeopardy.

Antzelevitch, the leading investigator in the new study, recently presented preliminary results of the research at the late-breaking abstract session at the annual scientific sessions of the AHA. Dr. Guido Pollevick, acting head of the Molecular Genetics program at the MMRL, presented a poster at the AHA meeting regarding additional aspects of this new clinical entity.

According to Antzelevitch "our ability to link calcium channel loss of function mutations to sudden cardiac death opens exciting new avenues for better diagnosis and treatment of inherited sudden death syndromes that affect young adults, children and infants." Scientists at the MMRL, in collaboration with colleagues in Italy, were the first to identify the genetic defect responsible for Sudden Infant Death Syndrome, linking SIDS to a malignant cardiac arrhythmia.

Dr. Jonathan Cordeiro, a research scientist involved with assessing the effects of the mutated genes on electrical function, thought that "in time many more mutations will be found to affect ion channels within the heart leading to sudden cardiac arrest." Antzelevitch agreed, indicating that "we are at the tip of the iceberg and have a great deal to learn before we can routinely use genetic screening to identify children and adults at risk for sudden cardiac arrest."

"The impressive progress that we have made in this field of medicine in recent years is encouraging and with appropriate commitment of resources, we can look forward to dramatic advances in the months and years ahead", he added

Founded in 1958 by the Grand Lodge of Free & Accepted Masons of the State of New York, the MMRL is internationally renowned medical research and educational institute dedicated to studies of the electrical activity of the heart and the mechanisms responsible for abnormal rhythms of the heart. In recent years, the MMRL has also become a central hub for genetic screening of inherited arrhythmic diseases in the United States. MMRL scientists have uncovered the mechanisms responsible for many forms of life-threatening cardiac arrhythmias as well as the mechanisms by which some drugs act to precipitate arrhythmias. In recent years, they have delineated the genetic basis for several inherited sudden cardiac death syndromes. Prominent among their most recent achievements is the identification of a novel strategy for the pharmacologic treatment of atrial fibrillation, one of the greatest unmet medical needs facing our society.