This is an exciting time to be involved in and to invest in medical research, because the discoveries that lay ahead promise to change the face of medicine as we know it. Recent advances in basic research have translated into clinical breakthroughs that have heralded exciting new ways to prevent, diagnose, treat and cure disease.

For over four decades our Laboratory has remained at the cutting edge of medical discovery in the field of cardiac arrhythmias and sudden death. To maintain its leadership role, our Laboratory embraced a new discipline several years ago. The addition of a Molecular Biology program served to complement at the molecular level the pioneering electrophysiological research conducted over the past decade. Much of this effort was devoted to delineation of the molecular characteristics of the new cardiac cell type discovered at the MMRL and to defining the role of these cells in the development of life-threatening abnormal rhythms of the heart.

Using these techniques, our scientists were also able to unravel the basis for a number of inherited diseases including the short QT, long QT and Brugada syndromes. The experimental models developed provided valuable insights into sudden death of young adults and children. Studies in which genetic mutations linked to these diseases were expressed in cultured cell lines provided the first definitive data linking Sudden Infant Death Syndrome (SIDS) to the long QT syndrome, a syndrome that can be readily diagnosed from the ECG and is amenable to treatment. The broad implication of this and more recent studies is that with proper monitoring these babies could be identified and their lives saved.

Our ability to link specific diseases to defective genes has opened up new vistas in our understanding of human disease and in our approach to the development of the much needed therapies and cures. With this in mind, our institute has decided to take another bold step forward by establishing a Molecular Genetics Program. This program will make our Laboratory one of a handful of world centers capable of determining the genetic basis of cardiac arrhythmias responsible for sudden cardiac death in young adults, children and infants. The new program will facilitate a more patient-focused approach to research aimed at the identification of genes causing malignant arrhythmias. It will complement our other two programs and work in concert with them to optimize and accelerate scientific discovery at the MMRL.

INTRODUCTION TO GENETICS

All of our genetic information is stored in the deoxyribonucleic acid (DNA) molecule. DNA is contained within almost all of our cells in a compartment called the nucleus.

Each DNA molecule is made of two individual strands paired together. The double-stranded molecule then twists like a coiled ribbon into a shape called a double helix. A piece of DNA millions of base pairs long in conjunction with some proteins is a chromosome.

Humans inherit 23 chromosomes from each of their parents for a total of 46 chromosomes. There are 44 chromosomes, known as autosomes, that are identical in men and women. The remaining two chromosomes are called sex chromosomes, that are designated X and Y. Women inherit two X chromosomes, whereas men inherit one X chromosome from their mother and one Y chromosome from their father. Although some strands of DNA contain segments that account for only 2% of the entire DNA molecule, they are in charge of making the protein molecules that form the building blocks of the human body.

These DNA segments are called genes, the basic physical and functional units of heredity. The manner in which we inherit our chromosomes provides each of us with two copies of every gene that is contained on the autosomes. Each chromosome contains thousands of genes, each being several thousand bases long. The sequence of bases in each gene contains instructions for making a single protein. Each protein serves a particular function in the body. For example, enzymes help us digest food, structural elements give our cells shape, and signaling molecules help the cells communicate with each other. The human genome is estimated to contain 30,000 to 40,000 genes. Depending on the combination of the genes we inherit, we end up with some traits that resemble our mother and others that resemble our father. Unfortunately, we not only inherit the looks but also some abnormal genes that may cause disease.

DNA MUTATIONS

Each gene is made up of a series of bases and those bases provide instructions for making a single protein. Any change in the sequence of bases affects the normal protein instruction which then causes a mutation. Just like changing a letter in a sentence can change the sentence's meaning, a mutation can change the instruction contained in the gene. Some mutations have little or no effect on the protein, while others cause the protein not to function at all.

Our risk for almost any medical condition is a function of both our genes and our environment. While we can not change our genes, we can apply our knowledge of our family medical history to predict our risk of disease. This knowledge allows us to focus on the things we can change such as diet, lifestyle, screening, and treatment to ensure a long, healthy life.

Many diseases occur as a result of mutations in certain genes. However, inheriting a gene with a mutation from only one parent does not mean that you are at risk for the disease. Everyone has two copies of most genes - one copy from each parent. Sometimes it only takes one damaged copy of a gene to cause disease while other times it takes two. In fact, there are many different ways to inherit diseases and other traits.

Everyone acquires some changes to their DNA during the course of their lives. These changes occur in a number of ways. Sometimes there are simple copying errors that are introduced when DNA replicates itself. (Every time a cell divides, its entire DNA is duplicated so that the each of the two resulting cells has a full set of DNA.) Other changes are introduced as a result of DNA damage through environmental agents including sunlight, cigarette smoke, and radiation. Our cells have built in mechanisms that catch and repair most of the changes that occur during DNA replication or from environmental damage. As we age our DNA repair does not work as effectively and accumulate changes occur in our DNA.

Some of these changes occur in cells of the body such as in skin cells as a result of sun exposure. Fortunately these types of changes are not passed on to our children. However, other types of errors can occur in the DNA of cells that produce the eggs and sperm. These errors are called germ line mutations and can be passed from parent to child. If a child inherits a germ line mutation from their parents, every cell in their body will have this error in their DNA. Germ line mutations are what cause diseases to run in families, and are responsible for hereditary diseases.

THE HEART

The heart works as a pump that pushes blood to the organs, tissues, and cells of the body. Blood delivers oxygen and nutrients to every cell and removes the waste products made by those cells. Blood is carried from the heart to the rest of the body through a complex network of arteries, arterioles, and capillaries. Blood is returned to the heart through venules and veins.

The heart weighs between 7 and 15 ounces and is a little larger than the size of your fist. By the end of a long life, a person's heart may have beaten (expanded and contracted) more than 3.5 billion times. In fact, the average heart beats 100,000 times, pumping about 2,400 gallons of blood each day.

The heart is composed of four chambers. The upper two chambers are called the left and right atria, and the lower two chambers are called the left and right ventricles. A wall of muscle called the septum separates the left and right atria and the left and right ventricles. The left ventricle is the largest and strongest chamber. Its half-inch thick chamber walls have enough force to push blood into the body.

ELECTRICAL ACTIVITY IN THE HEART

The heart has its own electrical system, like a battery. This special electrical conduction system tells it to beat (contract) in a regular, coordinated and effective way. The electrical impulse starts in the right atrium. The impulse spreads throughout the atria, causing them to contract. Next, the impulse moves to the ventricles. As the impulse travels down the Purkinje fibers, the ventricles contract. The cycle then repeats itself. The heart rate changes depending on physical demands, stress, or hormonal factors.

ARRHYTHMIA

The regular cycle of atrial contractions, followed by ventricular contractions, pumps blood effectively from the heart to the rest of the body. Problems may occur anywhere within the electrical system and interfere with effective pumping of blood. The heart may beat too fast (tachycardia) or too slow (bradycardia). These abnormal rhythms are known as arrhythmias. An arrhythmia broadly defined is any irregular heart beat that is brought about by the electrical instability or impairment of the electrical pathways in the heart.

An arrhythmia may arise in either the upper (atria) or the lower (ventricles) chambers of the heart. During an arrhythmia, patients may notice different sensations; ranging from feeling nothing to a pounding or fluttering sensation. They may also feel a heaviness in the chest or shortness of breath. However, when the arrhythmia is so severe that the heart is not able to pump blood efficiently the patient may experience a fainting spell or die due to lack of oxygen. This can happen when the heart beats either too slow or too fast.

Arrhythmias and sudden death represent an important public health problem in all developed countries. It is estimated that there are 3 million people suffering from atrial fibrillation (AF), an arrhythmia in which the upper chambers of the heart beat at a very fast irregular rate. The AF accounts for over one third of all strokes and is a major cause of mortality and morbidity in the elderly. When the ventricles beat erratically, oxygenated blood cannot reach the brain and s person may faint or die. Over 1.5 million Americans experience a heart attack every year with one third dying soon after as a direct result of cardiac arrhythmia.

GENETICS AND ARRHTYHMIAS

Sudden cardiac death (SCD) is a widespread health problem with several known inherited causes. Inherited SCD generally occurs in healthy individuals who do not have other conventional cardiac risk factors. Mutations in the genes in charge of creating the electrical activity of the heart have been found to be responsible for most arrhythmias, among them Short QT Syndrome, Long QT Syndrome, Brugada Syndrome, Familial Bundle Branch Block, Sudden Infant Death Syndrome and Sudden Unexpected Death Syndrome.

CURRENT RESEARCH PROJECTS

SUDDEN INFANT DEATH SYNDROME

Nothing is more devastating for a parent than the death of a child. Sudden Infant Death Syndrome (SIDS) is one of the leading causes of death among infants one month through one year of age in the United States. SIDS claims 3,000 lives each year in the US. SIDS is a diagnosis of exclusion; a multitude of unknown causes that are cataloged under the umbrella of sudden death of infants. Some interventions have proven useful in preventing SIDS, like placing the baby to sleep face up, or on a hard mattress. But not all deaths are prevented with these techniques. Recent studies in which the MMRL has participated point to inherited arrhythmias as one of the causes of SIDS. Among the genetic causes of SIDS are the Long QT syndrome and Brugada syndrome. Both diseases are caused by mutations in the genes that control the electrical activity of the heart.

Long QT Syndrome (LQTS) is an inherited electrical defect of the heart that can cause a very fast heart rhythm (arrhythmia) which leads to fainting and sometimes sudden cardiac death. LQTS affects 1 in every 7,000 people and causes between 3,000 - 4,000 deaths per year in children and young adults. It is often misdiagnosed as seizures or the 'common faint'. Death is preventable in almost all cases if the patient is diagnosed in time and properly treated.

The usual symptom is sudden fainting (syncope) during exercise or emotional excitement such as anger, fear or startle, but can also occur during sleep or arousal from sleep. There is usually no typical seizure activity, and there is an absence of 'feeling faint' or dizziness prior to the fainting. Symptoms of the Long QT Syndrome most often begin in pre-teen to teenage years, but may be present in individuals at a few days old to middle age. In one third of cases there are no symptoms shown prior to sudden cardiac death, the young person would have appeared perfectly fit and healthy.

Six genes have been linked to this syndrome so far, indicating that there is a strong genetic background responsible for the disease. Several cases of SIDS have been liked to this syndrome as well. This is a major focus of our research.

BRUGADA SYNDROME

In 1986 a two-year old boy from Poland experienced cardiac arrest. It was the third time in his short life, and fortunately each time he had his father at his side to resuscitate him. It was not luck, just the father's guilt and worry that something might happen to him and that he would not be there to take care of the problem. The boy's sister had died one year earlier from a cardiac arrest while the father was out of the house. She was just two. The father, tremendously worried, decided to take his son, across the Berlin wall into West Europe and seek the advice of Drs. Pedro and Josep Brugada in Holland. Interestingly, the electrocardiograms of the two children were similar, suggesting that they could have inherited the same disease. The boy enjoyed a completely normal life until his unexpected death while dancing at age 18.

These first two patients started research into this unknown cause of cardiac arrest in many research centers worldwide. Since the identification of Brugada syndrome in 1986, hundreds of cases have been identified all over the world. This devastating disease, kills 30% of the individuals affected every two years. After the first research publication in 1992, colleagues around the world renamed the disease as Brugada syndrome in honor to the two cardiologists, Drs. Pedro and Josep Brugada who identified it.

Sudden Unexpected Death Syndrome (SUDS) usually happens at night and only affects males. The incidence of this form of sudden death has been estimated between 26 and 38 per 100,000 people per year. In countries like Thailand, it is the most common cause of death in individuals younger than 50, second only to car accidents.

The only treatment for the Brugada syndrome is the implantation of an Implantable Cardiac Defibrillator at this point in time.

ATRIAL FIBRILLATION

Atrial fibrillation, the most common form of sustained cardiac arrhythmia. It affects over 3 million people in the United States. The most dreaded complication of atrial fibrillation is cerebral stroke. Stroke is the third most common cause of death in the western world with atrial fibrillation accounting for 1/3 of all strokes in individuals over the age of 65.Present therapy consists of controlling the heart rate and preventing stroke with the use of blood thinners. However, it is ineffective in eliminating atrial fibrillation

Some forms of atrial fibrillation are inherited. In these cases, the patients carries the genetic abnormality from birth and the arrhythmias may manifests itself in the first years of life.

Molecular Genetics and the Future of Medicine

As researchers discover the role genes play in disease, there will be more genetic tests available to help doctors make diagnoses and pinpoint the cause of the disease. For example, heart disease can be caused either by a mutation in certain genes, or by environmental factors such as diet or exercise to name a few.

Physicians can easily diagnose a person with heart disease once they present symptoms. However, physicians can not easily identify the cause of the heart disease is in each person. Thus, most patients receive the same treatment regardless of underlying cause of the disease.

In the future, a panel of genetic tests for heart disease might reveal the specific genetic factors that are involved in a given person. People with a specific mutation may be able to receive treatment that is directed to that mutation, thereby treating the cause of the disease, rather than just the symptoms.

The ultimate goal of the MMRL's Molecular Genetics Program is to identify the factors that are responsible for these diseases. This knowledge will facilitate the development of gene-specific therapies and cures for arrhythmias and identify individuals at risk for sudden cardiac deaths.