Johns Hopkins Pathology

Long QT Syndrome and Short QT Syndrome are both genetic abnormalities resulting in a problem with the electrical conducting system of the heart. The heart has a finely balanced system of exciting the heart ventricles to contract and pump blood. The electrical system of the heart can be visualized by performing an electrocardiogram (EKG). A picture of an EKG is to the right. In long QT syndrome, there is an extension of time between the Q wave and the T wave. This results in delayed repolarization of the heart. In short QT syndrome, the T wave arrives early, shortening the time of repolarization. Unfortunately, this greatly increases the risk of sudden cardiac death as a result of an arrhyhmia called ventricular fibrillation.

A number of different genes have been found which can cause both Long and Short QT syndromes. These genes code for ion channels. Ion channels control the flow of electrical current in the heart. Individuals diagnosed with either of these diseases generally are given an implantable cardioverter-defibrillator (ICD) to prevent arrhythmogenic events.

Wolf-Parkinson-White (WPW) is a rare disease in which the electrical conducting system of the heart is abnormal. A normal heart has two "pacemakers" that keep the heart beating synchronously. They are called the sinoatrial (SA) node and the atrioventricular (AV) node. They are usually connected to each other by a single conducting pathway. There are two pathways out of the AV node, which pass through the bundle of His and are called Purkinje fibers. In WPW, there is an accessory pathway, known as the bundle of Kent, that bypasses all or part of the typical AV node conduction system. This can cause the heart to get "confused" as it can recieve different signals on when to beat. This results in a preactivation contraction and can cause tachyarrhythmias (accelerated heartbeats) and a typical appearance on the EKG of a delta wave. In some individuals this can result in sudden cardiac death. Some individuals who have been diagnosed with WPW will actually improve and lose the accessory excitation pathway.

There are a number of different treatments for WPW, which depends on the type of reentrant pathway. Some individuals can stop arrhythmias by coughing, bearing down, or massaging the neck. Some individuals need to undergo radiofrequency ablation, in which the abnormal pathway is destroyed.

Arrhythmogenic Right Ventricular Cardiomyopathy / Dysplasia (ARVC/ ARVD) is a rare genetic disease associated with defects of parts of the heart muscle (myocardium), with a prevalence of between 1/10,000 and 1/1,000 in the United States. Approximately 90% of individuals with ARVC/D will have abnormalities present in their EKG, and additional tests include echocardiography, cardiac MRI, and right ventricular angiography. Individuals often first present with an abnormal heart beat or SCD, typically in their teens and early adulthood. ARVC/D is a progressive disease, and treatment can involve a combination of dietary recommendations, pharmacological intervention, surgery, and if at particularly high risk for SCD, an implantable cardioverter-defibrillator (ICD). Approximately 10% of SCD events are likely due to ARVC/D, with a higher rate among athletes, with equal prevalence among men and women. ARVC/D heart pathology is defined by an infiltration of the walls by fat cells and fibrosis and a loss of normal heart cells. The loss of heart cells makes it possible to transilluminate the heart as seen in this image.

Up to 12 regions of the genome have been identified that play a role in ARVC/D risk, and specific genes in 8 of these regions have been identified. Genetic testing is available, and approximately 50% of cases will have an identifiable mutation in one of the known genes, which can then be used to screen additonal family members to identify those at risk, and those not at risk for ARVC/D. Johns Hopkins has a specialty clinic designed to evaluate families with ARVC/D.

Brugada Syndrome is a genetic disease resulting in a characteristic abnormal EKG pattern and increased risk of SCD. Arrhythmic events generally occur in early to mid adulthood (22-45 yrs of age), are more likely at night, and men are more likely to be affected. Current treatment relies upon the implantable cardioverter-defibrillator (ICD), which can detect and correct an abnormal and potentially lethal heart rhythm.

There has been a great deal of progress in recent years identifying the genetic causes of Brugada Syndrome, with as many as 8 specific genes identified. Genetic screening is available for families with a history of Brugada Syndrome, and can help identify individuals who are at risk for SCD, and those who are not at risk.

Hypertrophic cardiomyopathy (HCM) is a disease that is caused by genetic mutations. It is found in roughly 1/500 individuals. The main finding in this disease is a thickened septum which separates the left and right ventricles. In this disease the contractile elements of the heart, known as myofibrils, lose their proper parallel orientation. Instead they become disorganized into a pattern known as disarray as seen in the microscopic image. This causes the heart to beat ineffectively resulting in the thickening of the walls. This thickening causes a number of structural problems that can limit flow through the heart. It can also lead to arrhthymias and sudden cardiac death. As exercise can increase heart size, individuals with HCM are discouraged from intense activity. Over 10 separate genes have been found to cause HCM. Most of these genes make proteins that contract the heart cells.

A prior history of a heart attack (myocardial infarction) is a significant risk factor for SCD, increasing risk 4-5 times above someone who has not had a heart attack. This is often due to the damaged heart containing regions of dead tissue that cannot properly conduct the electrical current, resulting in mis-timing and localization of the electrical signal, which can result in a fatal arrhythmia. For individuals with severly compromised heart function, an implantable cardioverter-defibrillator (ICD) may be warranted to prevent SCD, but even in these high-risk individuals, most implanted ICDs are not needed (the individual never experiences a lethal abnormal heart rhythm). Thus, there is a great deal of research focused on identifying risk factors that will further distinguish between those who will benefit from an ICD, and those who will not require one.

While extremely rare (1/50,000 to 1/300,000 over a 10 to 20 year period), sudden cardiac death does occur in the setting of athletic activity, often in young, apparently healthy individuals. In some cases, the prolonged physical training can lead to alterations of the heart, increasing risk of SCD, whereas in others, extreme physical activity can exacerbate an underlying physical condition (for example, HCM and ARVC/D). For those under 35 years of age, the cause of SCD is often related to unappreciated structural heart disease or inherited arrhythmias, whereas for those over 35 years of age, coronary artery disease is often the predominant cause.

Dilated cardiomyopathy (DCM) is a heart condition in which the ventricles, primarily the left ventricle, become enlarged and thin-walled. They can become so large they are unable to effectively pump blood. This typically leads to heart failure. However, it also predisposes a small subset of individuals to an increased risk of SCD. There are many causes of DCM. These include genetic diseases, complications of substance abuse (alcohol and cocaine), and secondary changes after an infection of the heart (ie, viral myocarditis).

A potential treatment for individuals with DCM would be the use of an implantable cardioverter-defibrillator (ICD). It has been very difficult to predict who will or will not benefit from ICD use because such a small number of individuals with DCM will die from SCD. This is another area where research is critical to find markers to help predict who would or would not benefit from ICD use.