Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is a genetic, progressive heart condition in which the muscle of the right ventricle is replaced by fat and fibrosis, which causes abnormal heart rhythms. Arrhythmogenic means causing an arrhythmia. The right ventricle is the chamber of the heart that is affected and dysplasia means there is an abnormality of the structure. ARVD/C is a specific type of cardiomyopathy (a disorder of the cardiac muscle) and as a result, the condition is also referred to as ARVC for short.

ARVD/C is estimated to affect one in 5,000 people. The disease can affect both men and women. Although it is a relatively uncommon cause of sudden cardiac death, it accounts for up to one fifth of sudden cardiac death in people under 35 years of age.

An arrhythmia occurs when the heart beats at an abnormal rhythm. The heart may beat too fast, too slow, or have an irregular rhythm. Severe arrhythmias may cause heart failure, fainting, or sudden death.

The symptoms of ARVD/C are usually a result of an arrhythmia. Many people do not know they have an arrhythmia. There are many different symptoms of an arrhythmia and healthy people without ARVD/C can have these symptoms. When you feel your heart speed up or slow down or feel it pounding or skipping beats, it is called palpitations. Palpitations are a normal response to fright or exertion but can, in other circumstances, be abnormal. If the change in rhythm makes it difficult for the heart to pump blood, other symptoms can occur such as lightheadedness and fainting (also called syncope). Arrhythmias can also impair the flow of blood to the heart muscle and cause chest pain, which is also called angina. An arrhythmia can also cause sudden death if the heart cannot pump enough blood to its own muscle and to the lungs and body. Fortunately, sudden death is not a common complication, but the risk must be considered when deciding on the treatment.

Sometimes people with ARVD/C develop symptoms of heart failure. Heart failure means that the heart muscle is not pumping blood through the body effectively. Symptoms include swelling of the legs, feet, and abdomen; feelings of shortness of breath while lying down and while exercising, and feelings of extreme fatigue.

In addition to these common symptoms of arrhythmias and heart failure other symptoms individuals with ARVD/C have reported include nausea, dizziness, heart fluttering, heart racing, etc.

It is often difficult to diagnose ARVD/C and there is no single test which can alone definitively make or exclude the diagnosis. However, the results of a careful medical history, physical exam by a nurse or doctor and a number of cardiac tests can be used to make a diagnosis. The cardiac tests include:

• Electrocardiogram (ECG)
• A signal averaged ECG (SAECG)
• An exercise stress test
• An echocardiogram
• Cardiac MRI
• 24-hour Holter monitor

It is extremely important that the cardiac MRI be performed at in institution familiar in doing cardiac MRI's to evaluate for ARVD/C, as these studies are difficult to interpret accurately. In addition to these standard tests, an electrophysiology study (EP study), right ventriculogram, and biopsy may be recommended to completely evaluate for ARVD/C. Other tests that provide information about the heart structure and function include a CT scan and MUGA scan. An autopsy can show ARVD/C if the heart is carefully examined.

There is a set of criteria that are based on the finding of certain major and minor findings on cardiac tests and on the family history.

Treatment focuses on controlling the arrhythmias and in managing any signs or symptoms of heart failure. Most people with ARVD/C take medications such as beta blockers or antiarrhythmic agents which can help lessen the frequency and severity of arrhythmias. A common treatment for ARVD/C is the implantation of an implantable cardioverter defibrillator (ICD). This device monitors the heart's rhythm and delivers an electrical shock to the heart to return it to the normal rhythm if necessary. Sometimes an electrophysiology study (EP study) can determine which areas of the heart are causing the abnormal rhythm, and these areas can be eliminated (ablated). However, because ARVD/C is a progressive disease, the arrhythmias are not permanently cured by this procedure.

Individuals with signs or symptoms of heart failure are treated with medications. These medications include ACE inhibitors which make it easier for the heart to pump blood and diuretics which reduce symptoms of heart failure. Although there is not yet a proven benefit to ACE inhibitors in ARVD/C patients without heart failure symptoms, many doctors are now treating patients prophylactically to help delay the progression of ARVD/C.

The most extreme treatment of ARVD/C is to have a heart transplant. This is rarely necessary. It is used only when the heart is very weak or when arrhythmias cannot be controlled and no other treatment is successful. For more information on heart transplants at Johns Hopkins Medicine, please visit the Johns Hopkins Heart Transplant Program.

Once ARVD/C has been diagnosed, the majority of patients undergo implantation of an implantable cardioverter defibrillator (ICD). In general, this will require that you see your doctor for an ICD check-up every 3-6 months. In addition, the status and progression of your ARVD/C should be monitored with yearly echocardiograms and electrocardiograms. Some institutions may also be able to perform a cardiac MRI depending on the type of ICD that you have. Your doctor may also request additional testing, such as a CT scan or stress test every couple of years. A close working relationship with your doctor is necessary to monitor the effectiveness of your medications in controlling your arrhythmias.

Catheter ablation is a treatment option for some patients when medications are not as effective in controlling the arrhythmias or if there appears to be a dominant focus of arrhythmia. You should discuss with your doctor if catheter ablation is an appropriate treatment strategy for you and where the procedure should be performed, as not all physicians are experienced in the different techniques used for patients with ARVD/C.

The majority of patients who stop exercising early on in the course of their ARVD/C do quite well. Once the arrhythmias are controlled with medication and an ICD is in place, very few individuals die from ARVD/C. However, now that the ICD is the recommended treatment offering protection from sudden cardiac death, individuals with ARVD/C are living longer. This means there may be more individuals with heart failure requiring a heart transplant in the future.

ARVD/C is a genetic, heritable condition where an affected person has a chance of passing on a specific gene change to his or her children. There is also some evidence that ARVD/C could result from an infection of the heart muscle.

ARVD/C is often caused by mutations in the desmosomal proteins. The desmosome is the mechanical bridge that links one heart cell to the next. The major components of the desmosome are

• Plakophilin-2 (PKP2)
• Desmoglein-2 (DSG2)
• Desmocollin-2 (DSC2)
• Desmoplakin (DSP)
• Plakoglobin (JUP)

Patients with ARVD/C are commonly found to have genetic abnormalities in the genes that encode for these desmosomal proteins. When there is a mutation in these genes the mechanical bonds that hold heart cells together are defective. Over time, the heart cells can pull apart, starting a process of scar and fat replacement. This can be increased with a high level of exercise, which explains why it appears to be common among young athletes.

ARVD/C is still being studied. It is possible that there are other causes, such as viral infections. There is a great deal of research on the mechanisms and we expect to learn more in the next five to ten years.

In general, someone who inherits a gene change or mutation for ARVD/C has inherited a genetic predisposition to developing ARVD/C. A single gene change is usually not sufficient for the development of ARVD/C. We think that for most individuals, additional factors such as other genes, athletic lifestyle, exposure to certain viruses, etc. are needed for an individual to actually develop signs and symptoms of ARVD/C. This is an area of very active research and we have a lot to learn about all the factors that can cause ARVD/C.

There is a lot of evidence that ARVD/C is genetic and as a result, there are some recommendations for other family members. After the diagnosis is made in one person, all of his or her first-degree relatives should be screened. First-degree relatives are:

• Siblings
• Parents
• Children of someone diagnosed with ARVD/C

If another person in the family is then found to be affected, then all of their first-degree relatives of that person need to be screened. This is called stepwise screening. To further explain this, take an example of Joe who is diagnosed with ARVD/C. Joe's first-degree relatives (his siblings, parents and children) are all screened in step 1. Joe's father, Ed is also affected. Now in step 2, Ed's first-degree relatives need to be screened. This process is repeated until all at-risk relatives have been screened. If a more distant relative has symptoms of an arrhythmia, we would recommend that person be screened as well.

While ARVD/C is most commonly diagnosed in adults in their 20s and 30s, both children and older people have been diagnosed. Children who have an affected parent should see a pediatric cardiologist to discuss appropriate cardiac testing. Similarly, older relatives, though they may not appear to have any symptoms, should still be tested because they may have mild symptoms of ARVD/C.

Unfortunately, no single cardiac test can diagnose ARVD/C. First degree relatives should be carefully evaluated in order to determine if they are affected or unaffected. The tests listed below are helpful in determining the presence or absence of disease and subsequent treatment strategies.

Suggested tests:

• Standard 12 lead ECG
• Signal averaged ECG with 40mHz filter
• Holter monitor for 24 hours
• Echocardiogram
• Exercise stress test
• Cardiac MRI

It may be necessary to have more cardiac testing if some of the above tests are abnormal. The additional testing may be needed to clarify indeterminate results of the previous tests. Genetic testing may also play a role when a familial mutation is known.

First-degree family members of an individual diagnosed with ARVD/C should be evaluated every 2-5 years with an ECG, signal averaged ECG, exercise stress test, 24-hour Holter monitor, echocardiogram, and/or cardiac MRI. The recommended time period for repeat screening will vary among family members depending on results of previous testing, age, reported symptoms, family history, and genetic test results.

Yes, but it is rare. Young children rarely have symptoms and are rarely affected. Several of these tests are not routinely performed on children or may require sedation in order to be performed. Thus, cardiac testing young children should be discussed with your cardiologist and pediatrician who may refer your child to a pediatric cardiologist. Testing recommendations will vary depending on the child's symptoms and family history.

Yes, adolescents and teens can and do develop ARVD/C. Teens should have the same tests as adult relatives:

Suggested tests:

• Standard 12 lead ECG
• Signal averaged ECG with 40mHz filter
• Holter monitor for 24 hours
• Echocardiogram
• Exercise stress test
• Cardiac MRI

When you agree to participate in any study, you should take the time to read the consent form carefully. Ask questions if you don't understand something. Many genetic research studies do not release results, mainly because the laboratory that the genetic research is being performed in is not a Clinical Laboratory Improvement Amendment (CLIA) certified lab. The role of the CLIA program is to ensure quality laboratory testing. Research labs are not required to adhere to any special regulations. In the majority of cases when you donate a blood sample for research, a unique number, not your name, is written on the sample tube. There is always the chance for a sample mix-up, mislabeling, or inactive reagents resulting in an inaccurate result.

If you meet the diagnostic criteria for ARVD/C, you may have provided a blood sample as part of the Clinical and Genetic Investigations of ARVD/C study at Johns Hopkins. We have been screening blood samples from individuals meeting the diagnostic criteria for gene changes thought to be associated with ARVD/C. Although the Johns Hopkins Institutional Review Board does not permit us to release research results, we will notify you if a result becomes available and will assist you in obtaining clinical confirmation testing through a CLIA certified laboratory. There is a fee associated with this confirmation testing. This confirmation testing is important as samples may become mixed up or mislabeled since they are labeled with a research number only and not your name. Genetic results should not be used to determine management until they are confirmed in a CLIA certified laboratory.

Not every patient with ARVD/C needs to have an ICD. Each person's medical case is different, so it is best to discuss this with your doctor. ICDs are not a cure although they have been shown to effectively treat episodes of ventricular tachycardia and ventricular fibrillation in ARVD/C patients.

The exact relationship between ARVD/C and exercise is not clear. For many patients with ARVD/C, exercise can be an immediate cause of arrhythmia. There seems to be an increased incidence of ARVD/C in young very athletic people, particularly men. There are also numerous reports of sudden cardiac death from ARVD/C that occur during physical exertion. In addition, the gene changes recently found in many people with ARVD/C are in genes that hold heart muscle cells together. We think that exercise, therefore, puts an extra strain on these already weak heart muscle connections. Therefore, it's possible that an athletic lifestyle for someone who has inherited a genetic predisposition for ARVD/C may be sufficient for that individual to develop ARVD/C. Therefore, we recommend that patients with ARVD/C should not do vigorous exercise. It is best to discuss with your doctor about what types of exercise are appropriate for you.

Although there is very limited information on pregnancy in individuals with ARVD/C, Women with ARVD/C can have uncomplicated pregnancies, even when on medications or with an ICD. There are some medications that can harm the baby as it develops, and your doctor may recommend that you switch medications on a temporary basis. Pregnancy does put extra strain on the heart, and thus, if you are planning a pregnancy or become pregnant, you should see your cardiologist and obstetrician as early as possible. You should discuss with your doctor about medication options during delivery, delivery options, and monitoring of your heart during labor.

Patients who are prone to arrhythmias, caused by ARVD/C or other conditions, are generally advised to avoid stimulants of all kinds. Stimulants include nicotine and caffeine as well as pharmacological stimulants such as Sudafed (pseudoephedrine), which is commonly used in cold and flu medications. Patients prone to arrhythmias are advised to limit their intake of alcohol, a depressant, which is also proven to cause arrhythmias.

If you take medications to suppress your arrhythmias, such as Atenolol or another beta blocker, and your arrhythmia is under control, then moderate exposure to stimulants should not be problematic. This means go ahead and take the cold medicine for a week or two, or have an occasional bar of chocolate, just don't take either in huge amounts for a long time. Arrhythmias can be provoked for many different reasons when you are ill, including fever, electrolyte imbalance and decreased absorption of the anti-arrhythmia medication. People who are predisposed to arrhythmias may have more arrhythmias when they are ill, but it is difficult, if not impossible, to be sure of the exact cause. Thus, our advice is to use cold medications only as needed, but read the labels and ask your pharmacist about the stimulant content, so you know what you are taking. Always consult your physician before taking new medications.

Patients with ARVD/C can get arrhythmias without an increase in stimulants or exposure to alcohol. These arrhythmias can happen at any time, because the heart has an abnormal ability to conduct electrical impulses. Although it is human nature to try to find a cause and effect relationship, there will not be an identifiable cause for all arrhythmias. Understanding this is true and that one cannot control for all the variables that cause or effect an arrhythmia, may help patients in coping with the unpredictable nature of their symptoms.