When reading the following information, it is important to remember that there are no guranteed answers for most clinical situations. The final judgement regarding care of a particular patient must be made by the health care provider and the patient in light of all relevant circumstances.
The heart is a muscular organ that pumps blood, which provides the body with oxygen and nutrients, through the blood vessels of the circulatory system. The heart is situated in the center of the chest, between the lungs, and is enclosed in a sac called the pericardium. The heart's muscular wall is made up of three layers: the epicardium, myocardium, and endocardium.
In humans, the heart is divided into four chambers: the upper left and upper right atria and the lower left and lower right ventricles. The upper and lower parts of the heart are connected by atrioventricular valves; the tricuspid valve connects the right atrium and the right ventricle and the mitral valve connects the left atrium and the left ventricle. Two additional valves are situated at the "exit" of the ventricles. The pulmonary valve, located at the base of the pulmonary artery is in the right ventricle and the aortic valve is located as the base of the aorta in the left ventricle.
When all systems are working properly, the heart circulates oxygen and nutrient-rich blood through the body to the cells. The "used" blood (blood that is depleted of oxygen and nutrients) returns to the heart via the superior and inferior venae cavae which delivers it to the right atrium. The blood is then pumped to the right ventricle and onto the lungs to be oxygenated. From the lungs, the blood returns to the heart via the left atrium and then goes to the left ventricle. It is then pumped out of the aorta to be recirculated. Because of the extra force needed to pump the blood throughout the body, the muscle of the left ventricle is thicker than the right.
To pump the blood, the heart uses an electrical conduction system composed of nodes and conducting fibers. The sinoatrial node, or SA node, which is a group of pacemaking cells in the myocardium of the right atrium, produces an electrical impulse that travels through the heart in specific pathways causing it to contract. These signals start at the right and left atrium and then move to the right and left ventricles. It is these electrical signals that are recorded by an electrocardiogram (ECG).
On this page, we discuss a general overview of some of the genetic heart diseases (GHDs) that are seen the most in Mayo Clinic’s Genetic Heart Rhythm Clinic, their symptoms, risk factors, and treatments. Then we break down each disease and go into each one in more depth. Knowing the basics of your GHD can ease some of your worries related to this diagnosis.
Sudden death predisposing genetic heart diseases (GHDs), also known as inherited heart rhythm (channelopathies) and inherited heart muscle (cardiomyopathies) diseases are a group of diseases that include a wide variety of relatively rare heart disorders. The term “genetic” indicates that the disease may be familial, meaning one or both of your parents may have passed on the condition through their genes. There’s a chance that this genetic condition has existed in your family for generations. This is why, after you or your family member was diagnosed, it was strongly encouraged that other family members underwent screening. Alternatively, it is possible that the GHD started in you through what is known as a de novo or spontaneous germline mutation that started in you after conception. If this is the case, although you did not inherit it from one of your parents, it is now possible to pass the variant on to your children.
Although we are the Genetic Heart Rhythm Clinic, we actually specialize in two broad types of GHDs: channelopathies (heart rhythm diseases) and cardiomyopathies (heart muscle diseases).
Diseases like long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT) are examples of the cardiac channelopathies. Channelopathies effect the electrical system of the heart. There are two types of cardiac channelopathies: congenital and acquired. Congenital means you were born with a genetic mutation, either inherited from one or both parents or one that arose de novo after conception. Acquired channelopathies can be caused by certain medications, electrolyte abnormalities, and other medical conditions.
The electrical system transmits signals that cause your heart to contract, allowing blood to be pumped through your body. Genetic heart rhythm diseases occur when the electrical system malfunctions, causing irregular, fast, or slow heart rhythms.
Cardiomyopathies, on the other hand, are diseases that affect the heart muscle itself such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).
In HCM for example, the heart muscle thickens (hypertrophies) creating issues with how blood is pumped through your heart and making the thickened heart muscle more “twitchy” for an abnormal heart rhythm. Arrythmogenic right ventricular cardiomyopathy (ARVC) is the most common subtype of arrhythmogenic cardiomyopathy (ACM) where scar tissue builds up in the right ventricle which can lead to heart rhythm issues.
A lot of times, these GHDs can go undetected due to mild or nonexistent symptoms. Unfortunately, this means that sometimes a family only becomes aware of the disease due to a sudden cardiac death. However, great improvements have been made to detect heart rhythm abnormalities in non-symptomatic patients before tragedy strikes. Nevertheless, there are symptoms and warning signs that could suggest the presence of one of these GHDs. Common characteristics vary between diseases, but there are several symptoms that can present themselves in almost all GHDs.
The two words used to describe how a disease presents itself are genotype and phenotype. Genotype refers to the genetics of an individual and phenotype is the observable characteristics of the disease in an individual. Patients can be genotype-positive and phenotype-negative, genotype-negative and phenotype-positive, or genotype-positive and phenotype-positive.
Patients that are genotype-negative and phenotype-positive have characteristics of a particular disease, such as a prolonged QT or a hypertrophied heart muscle, but no known pathogenic variant has been found in their code (patients who have variants of uncertain significance (VUS) are considered genotype-negative). Continuous research is being done to find new genetic mutations and on VUSs to determine whether or not their presence indicates a patient has a specific condition.
Patients that are genotype-positive and phenotype-negative have a known pathogenic variant in their genetic code, but show no signs or symptoms of the disease. There is no telling if, when, or what symptom or symptoms might emerge in a patient. This uncertainty can be hard for some patients. Thankfully, genetic cardiologists and genetic counselors are trained to determine the different possibilities based on factors such as how a disease is inherited and the mutation itself.
Specific risk factors of GHDs vary between each disease and even between each disease sub-type (for example, LQT1 vs. LQT3). These are specified below under each individual disease. Your risk depends on your family history, race, age, gender and more. It is important to be evaluated by a genetic cardiologist to assess your personal risk. However, there are several overarching factors that may put someone at higher risk of an inherited heart rhythm disease.
If you or someone you know has a history like this, it is important to be evaluated promptly.
To diagnose any GHD, your doctor will go through a number of things. A physical exam will be performed and your current symptoms, past medical and family history, and current and past medications will be reviewed. There are several tests that your doctor will likely order to confirm the presence or absence of a GHD.
The overall goal of treatment is to control your heart and keep it beating in a normal rhythm. However, the secondary goal is to be prepared and able to prevent sudden death in the event your heart goes into an abnormal rhythm. Your doctor will assess your risk factors and inform you on your options. Treatments for these GHDs can range from simple preventive measures and lifestyle changes to medications, devices, and/or surgery depending on your specific risk factors and disease. Often times, treatment is a combination of these. It is important that you and your doctor work together to decide which treatment options are best for you.
Keep in mind that all of these treatments have their own benefits and risks. Your doctor will discuss these with you in detail to make sure you understand your treatment of choice. If a surgery is necessary, you will also be able to meet your surgeon before the procedure to discuss what will take place and you'll get an opportunity to ask any questions you may have.
Congenital long QT syndrome (LQTS) comprises a distinct group of cardiac channelopathies characterized by delayed repolarization, QT prolongation and increased risk of syncope, seizures and sudden cardiac death in the setting a structurally normal heart.
The name long QT syndrome (LQTS) comes from the waves and intervals of an electrocardiogram (ECG) that show the signature of LQTS, namely prolongation of the QT interval. An ECG measures the electrical conduction of your heart. To the right, you can see an ECG tracing that is labeled with the waves (Q, R, S and T) and intervals (RR and QT). The QT interval is measured in milliseconds (ms). A normal heart rate-corrected QT interval (known as the QTc) is characterized as 440 ms in prepubescent children, 450 ms in post-pubescent men, and 460 ms in post pubescent females. For screening programs, the > 99th percentile QTc values are used which are 1) 460 ms before puberty, 2) 470 ms in postpubertal males, and 3) 480 ms in postpubertal females. 500 ms is an indicator of increased risk for a potentially dangerous heart rhythm to occur.
A long QT interval is caused by delayed repolarization. This means that it takes longer for the heart to recharge than it should. You can see this in the images to the left. Repolarization begins right after the S wave (the dip in the QT interval) and goes to the end of the T wave. The top image shows a normal QT interval and repolarization time and the bottom image shows a longer repolarization time thus lengthening the QT interval. Problems might occur if the heart beats again (from a premature ventricular beat) before it is done repolarizing (recharging). If this happens, it can "trip up" the electrical conduction system and trigger arrhythmias. In some cases, these rapid, chaotic heartbeats may cause a sudden faint or seizure. If the heart in unable to restore its normal rhythm, LQTS can cause sudden death.
At least 1 in 2,000 people are affected by congenital long QT syndrome.
Specifics of Acquired Long QT Syndrome
In contrast to genetic mediated LQTS, there are several factors that can cause a prolonged QT interval. Drug-induced QT prolongation is a result of certain medications such as antiarrhythmics, antibiotics, analgesics and antidepressants. A full, updated list of medications that prolong the QT interval can be found at www.crediblemeds.org.
Besides medications, there are other health factors that can influence the QT interval. Hypokalaemia (low potassium levels) and hypomagnesaemia (low magnesium levels) are two specific types of electrolyte imbalances that can also cause acquired long QT syndromes.
It is important to note that these factors are additive, meaning that the more QT-aggravating factors present will translate into increasing your risk of having a QT-triggered symptom such as syncope (fainting). Sometimes, a person will have genetic risk allele or polymorphism that makes their heart more sensitive to acquired long QT syndrome. By itself, these more common genetic variants generally will not cause long QT syndrome, but its presence plus a QT prolonging medication or conditions such as anorexia nervosa that can cause malnutrition and lower the potassium levels of your blood can increase the chances of having a symptomatic episode.
Specific Genetic Subtypes of Congenital Long QT Syndrome
Congenital long QT syndrome, also known as inherited long QT syndrome, is a result of a genetic abnormality in your genetic code. This abnormality is most often received from one or both of your parents from the genes they passed on to you. It is possible, however, that in rare cases, a mutation in the genes can spontaneously develop without either parent having the genetic mutation. This is called a de novo mutation.
There are currently mutations in seventeen genes that are known to cause congenital LQTS. LQT1-LQT3 make up roughly 80% of all congenital LQTS. Up to 15%-20% of patients with clinically diagnosed LQTS remain genetically elusive, meaning their genetic tests were negative or only revealed Variance of Uncertain Significance (VUS). Again, these are known as phenotype positive, genotype negative patients. On the other hand, 20-25% of patients with a LQTS positive gene have a normal QTc, known as phenotype negative, genotype positive patients. Ongoing research is being conducted in these patients.
The clinical symptoms of LQTS fall under two categories: arrhythmic events and electrocardiographic (ECG) aspects. Arrhythmic events include symptomatic or asymptomatic sustained or nonsustained spontaneous ventricular tachycardia (SVT/NSVT), or unexplained syncope/resuscitated cardiac arrest. Electrocardiographic aspects present on electrocardiograms (ECG) as a prolongation of the QT interval and/or morphologic alterations. For roughly 5 percent of people with a LQTS gene mutation, the first symptom is sudden death.
Arrhythmic events occur when there are runs of torsades de pointes (TdP) ventricular tachycardia (VT). These runs, depending on the length, can result in syncope and seizures. If the heart is unable to resume its normal rhythm, VT can deteriorate to ventricular fibrillation (VF) and result in cardiac arrest and sudden death. A lot of the time, arrhythmic event triggers are gene specific. For example, LQT1 mainly presents as an arrhythmic event during physical and emotion stress, LQT2 occurs at rest or with sudden noises, and LQT3 often occurs at rest or during sleep.
Electrocardiographic aspects of LQTS are important and numerous, some of which also tend to be gene-specific. An ECG can be used to diagnose long QT syndrome, but it cannot be used to rule it out. 20-25% of patients with a positive LQTS genetic test have a normal QTc range.
Diagnostics for LQTS are mostly standard cardiac tests that are used for GHDs, including an electrocardiogram (ECG), Holter monitor and stress test. Because the contribution of a positive genetic test is so high, genetic testing is the standard of care for any patient in whom the diagnosis of LQTS is being considered.
Based on clinical and genetic clues, a physician is able to determine a personalized risk stratification to determine the correct therapeutic recommendations. There are many considerations that go into a full risk stratification including age, gender, previous symptoms, genetics and family history.
Treatment depends on the risk stratification determined by a physician. Treatments can include prevention measures, pharmacological treatments (beta-blockers and possibly mexiletine), a procedure called left cardiac sympathetic denervation (LCSD) and/or placement of an implantable cardioverter-defibrillator (ICD).
For any patient with long QT syndrome (LQTS), the top 5 overarching preventative measures should always be observed:
Brugada syndrome (BrS) is a potentially life-threatening GHD. Like LQTS, BrS causes irregular heartbeats in the ventricles (lower chambers) of the heart. The ventricles then become uncoordinated, causing ventricular arrhythmias. These abnormal rhythms can lead to syncope, seizures and/or sudden death. BrS is most often recognized in an ECG. Although 23 BrS-susceptibility genes have been published, only one gene, SCN5A, has been deemed as a definitive evidence BrS gene. Overall, only 25% of patients with a definite diagnosis of BrS will have a positive SCN5A genetic teste.
Many people with BrS do not have any symptoms. If symptoms do arise, they often occur during rest or sleep, and rarely with exercise. These exhibit as ventricular fibrillation (VF) or aborted sudden cardiac death (SCD), syncope, nocturnal agonal respiration, palpitations and chest discomfort.
Diagnosing BrS can be a little more difficult than it is for long QT syndrome. For example, genetic testing is not as effective as in LQTS because the likelihood of getting a positive test result is less and even when positive, the genetic test result does not guide/influence the treatment program like it does in LQTS. An electrocardiogram, stress test and Holter monitor are the most common tests used to diagnosis Brugada syndrome. If a Brugada ECG pattern is not detected in a standard ECG, it can sometimes be captured by moving some of the leads. Three ECGs are then taken in a row, each time moving the leads to a specific place. This three serial ECG is known as the Brugada high-lead ECG.
The prevalence of Brugada syndrome is much higher in Asian and Southeast Asian countries, especially Thailand, Philippines and Japan. It is also 8-10 more prevalent in males than females. Brugada syndrome generally manifests at a later age (40 years old or greater) than long QT syndrome.
Treatment depends on the risk stratification determined by a physician. The only proven effective therapeutic strategy for the prevention of sudden cardiac death (SCD) in symptomatic Brugada patients is an implantable cardioverter-defibrillator (ICD). Other treatments include prevention measures, pharmacological treatments, and/or radiofrequency catheter ablation.
For any patient with Brugada syndrome, the top 5 overarching preventative measures should always be observed:
CPVT is a rare arrhythmogenic disorder triggered by exercise or stress. The heart's pumping chambers go into an uncontrolled, dangerously fast and chaotic rhythm. This can lead to syncope, seizures and even sudden cardiac death. However, with a proper diagnosis and treatment, sudden death from CPVT can be prevented.
It's prevalence is not well known due to a normal resting ECG and unremarkable cardiac imaging in CPVT patients, but it is estimated that CPVT affects roughly one in 10,000 people. Typically, it is diagnosed in people under the age of 40 and affects both genders equally.
CPVT usually manifests in the first or second decade of life and is usually prompted by physical activity or emotional stress. The symptoms mimic the arrhythmic events of long QT syndrome, LQT1 in particular, including exercise/activity-triggered syncope, seizures, and sudden cardiac death.
Another important characteristic of CPVT is a family history of exercise-related syncope, seizure or sudden death which is reported in 30% of patients. In contrast to LQTS, CPVT is associated typically with a completely normal resting ECG.
Because electrocardiograms and echocardiograms are ineffective at diagnosing CPVT, physicians often rely on Holter monitoring, exercise stress tests and/or implantable loop recorders to establish a diagnosis. Sometimes, a catecholamine infusion test is required. Epinephrine (adrenaline) or isoproterenol is given through an IV in your arm or hand and your heart is monitored for its reaction. Genetic testing is a very important diagnostic test of a patient suspected to have CPVT. Mutations in just one gene, RYR2, explain nearly two-thirds of all cases of CPVT.
Athletes, swimmers especially, are at a higher risk of having a CPVT-related episode. It is generally diagnosed prior to the age of 40 and women generally present with symptoms at an earlier age than men do.
Treatment depends on the risk stratification determined by a physician. Treatments can include prevention measures, pharmacological treatments, left cardiac sympathetic denervation (LCSD) surgery, a catheter ablation, and/or placement of an implantable cardioverter-defibrillator (ICD). Usually, treatment is a combination of these depending on the presentation of the patient's disease. In contrast to symptomatic BrS where an ICD by itself is considered first line therapy, symptomatic patients with CPVT should never receive an ICD as monotherapy. In fact, evidence is emerging to conclude that the ICD should be one of the last therapies used in CPVT.
Hypertrophic cardiomyopathy (HCM) is a genetic heart condition where the heart muscle is thickened (hypertrophied) in the absence of precipitating factors like hypertension. Generally, HCM involves the left ventricle, making it much harder for your heart to pump blood effectively. HCM affects roughly 1 in 500 people, making it one of the most prevalent GHDs. HCM commonly presents between the second and fourth decades of life, but it is seen in all ages.
HCM is highly variable in disease presentation, spanning from asymptomatic disease to heart failure, although many are asymptomatic through most or all of their lives. There are many anatomical sub-types of HCM. The four most common sub-types include sigmoid septum, reverse septal curvature, apical, and neutral contour variant. In addition, patients are further divided as to whether they have non-obstructive HCM, obstructive HCM with resting left ventricular outflow tract obstruction, or labile HCM where there is no obstruction at rest but dynamic obstruction emerges with various maneuvers.
The most common symptoms of HCM involve exertional dyspnea (shortness of breath during exertion), chest pain, syncope (fainting) and pre-syncope. Again, these symptoms vary extremely from patient to patient. Some have very mild symptoms while some cannot walk twenty feet without having to stop for breath.
Unlike channelopathies, the most important test used in diagnosing HCM is an echocardiogram. This test allows your doctor to visualize the heart and see whether or not the heart muscle is abnormally thick. If it is hypertrophied, they can also see what other problems HCM is causing, such as improper blood flow. Other tests involved can be an electrocardiogram (ECG), stress test and a Holter monitor. If HCM has been identified, your doctor will usually order a cardiac MRI which uses magnetic fields and radio waves to create images of your heart and to measure the amount of fibrosis in the heart muscle.
Hypertrophic Cardiomyopathy is one of the most common causes of sudden cardiac arrest in young people, especially athletes. A family history of HCM increases your risk of developing the disease.
The goal of HCM treatment is to relieve symptoms and prevent sudden cardiac death. There are several treatment options depending on the severity of the disease. If the symptoms are relatively minor, medications can be useful for primary treatment. For more severe forms of HCM, septal reduction therapies such as a surgical myectomy or an alcohol septal ablation may be recommended. A myectomy is an open-heart procedure where a cardiac surgeon removes part of the thickened muscle. An alochol septal ablation is less invasive. However, in our program, surgical myectomy is the preferred septal reduction therapy in an otherwise young, healthy person without other medical issues.
Arrhythmogenic (causing an arrhythmia) cardiomyopathies (disorder of the heart muscle) are a specific type of cardiomyopathy that disrupts the electrical signals of the heart and causes abnormal heart rhythms. There are several types of ACM. The most common, arrhythmogenic right ventricular cardiomyopathy (ARVC) is discussed below. Other types include arrhythmogenic left ventricular cardiomyopathy (ALVC) and arrhythmogenic biventricular cardiomyopathy (ABiVC). Although the various ACMs have their own distinct and unique features, the information covered below is generally typical of all of them.
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a specific type of genetic, progressive ACM that affects the right ventricle of the heart. It is caused by at least eight different genes, most involved in the function of desmosomes which are structures that attach heart cells to one another. ARVC impairs how these desmosomes function and without them, the cells of the heart muscle begin to die. Over time, the heart muscle of the right ventricle is replaced by fat and fibrosis (scar tissue). Gradually, this can disrupt the electrical signals of the heart and can cause abnormal heart rhythms (arrhythmias).
ARVC is estimated to affect roughly one in 5,000 people. Generally, it is diagnosed in adulthood, but children and teenagers can be diagnosed with this disorder as well.
Due to the abnormal heart rhythms caused by ARVC, common symptoms include palpitations, light-headedness, and syncope. Gradually, and over time, ARVC can cause heart failure and, in rare cases, sudden cardiac death.
Diagnosing ARVC can often be difficult. Finding a cardiologist that is familiar with the disease is very important. Generally, a standard 12-lead ECG, a signal-average ECG (more detailed ECG), a 24-hour Holter monitor, a treadmill or bike stress test, and echocardiogram, a cardiac MRI and genetic testing. Your cardiologist will also likely take a detailed personal and family history to try to determine if and how the disease presents itself in you and your family.
Unfortunately, unlike the lack of evidence regarding risk of exercise for other GHDs, there is clear evidence that a high diose of endurance training sports can serve as a disease accelerator for patients with ARVC. For many, exercise can be a cause of arrhythmias. In addition, it is believed that exercise puts an extra strain on the already weak desmosomes that hold the heart muscle cells together. Therefore, it is currently recommended that patients with ARVC should not do any vigorous exercise.
It is important to avoid stimulants of any kind, such as nicotine, caffeine and certain pharmacological stimulants such as Sudafed that contains pseudoephedrine. Patients prone to arrhythmias are advised to limit their alcohol intake as this is also known to provoke arrhythmias.
Although ARVC and pregnancy hasn't been fully studied, women diagnosed with this disorder often have uncomplicated pregnancies. Working with your cardiologist while trying to get pregnant, during pregnancy and postpartum is essential as some medications might effect ababy's development. Your cardiologist might temporarily change your medications during these periods. Discussing medication and delivery options with your OB-GYN and cardiologist is very important. Precautionary measures and heart monitoring during labor should be utilized. If your genetic cause of ARVC is known, you can also have your baby genetically tested for ARVC after birth to determine if your baby will need to be followed periodically or could be dismissed immediately.
Like most other GHDs, treatment depends on the risk stratification determined by a physician. Treatments can include observation only, prevention measures, pharmacological treatments, a catheter ablation to target and elminiate the premature ventricular beats that are triggering the arrhythmias, and/or placement of an implantable cardioverter-defibrillator (ICD). In extreme cases, a heart transplant is required when the heart is too weak to function and the abnormal, life threatening rhythms can no longer be controlled by medications or other treatments.