Sick sinus syndrome (also known as sinus node dysfunction) is a group of related heart conditions that can affect how the heart beats. "Sick sinus" refers to the sino-atrial (SA) node, which is an area of specialized cells in the heart that functions as a natural pacemaker. The SA node generates electrical impulses that start each heartbeat. These signals travel from the SA node to the rest of the heart, signaling the heart (cardiac) muscle to contract and pump blood. In people with sick sinus syndrome, the SA node does not function normally. In some cases, it does not produce the right signals to trigger a regular heartbeat. In others, abnormalities disrupt the electrical impulses and prevent them from reaching the rest of the heart.

Sick sinus syndrome tends to cause the heartbeat to be too slow (bradycardia), although occasionally the heartbeat is too fast (tachycardia). In some cases, the heartbeat rapidly switches from being too fast to being too slow, a condition known as tachycardia-bradycardia syndrome. Symptoms related to abnormal heartbeats can include dizziness, light-headedness, fainting (syncope), a sensation of fluttering or pounding in the chest (palpitations), and confusion or memory problems. During exercise, many affected individuals experience chest pain, difficulty breathing, or excessive tiredness (fatigue). Once symptoms of sick sinus syndrome appear, they usually worsen with time. However, some people with the condition never experience any related health problems.

Sick sinus syndrome occurs most commonly in older adults, although it can be diagnosed in people of any age. The condition increases the risk of several life-threatening problems involving the heart and blood vessels. These include a heart rhythm abnormality called atrial fibrillation, heart failure, cardiac arrest, and stroke.

Sick sinus syndrome can result from genetic or environmental factors. In many cases, the cause of the condition is unknown.

Genetic changes are an uncommon cause of sick sinus syndrome. Mutations in two genes, SCN5A and HCN4, have been found to cause the condition in a small number of families. These genes provide instructions for making proteins called ion channels that transport positively charged atoms (ions) into cardiac cells, including cells that make up the SA node. The flow of these ions is essential for creating the electrical impulses that start each heartbeat and coordinate contraction of the cardiac muscle. Mutations in these genes reduce the flow of ions, which alters the SA node's ability to create and spread electrical signals. These changes lead to abnormal heartbeats and the other symptoms of sick sinus syndrome.

A particular variation in another gene, MYH6, appears to increase the risk of developing sick sinus syndrome. The protein produced from the MYH6 gene forms part of a larger protein called myosin, which generates the mechanical force needed for cardiac muscle to contract. Researchers believe that the MYH6 gene variation changes the structure of myosin, which can affect cardiac muscle contraction and increase the likelihood of developing an abnormal heartbeat.

More commonly, sick sinus syndrome is caused by other factors that alter the structure or function of the SA node. These include a variety of heart conditions, other disorders such as muscular dystrophy, abnormal inflammation, or a shortage of oxygen (hypoxia). Certain medications, such as drugs given to treat abnormal heart rhythms or high blood pressure, can also disrupt SA node function. One of the most common causes of sick sinus syndrome in children is trauma to the SA node, such as damage that occurs during heart surgery.

In older adults, sick sinus syndrome is often associated with age-related changes in the heart. Over time, the SA node may harden and develop scar-like damage (fibrosis) that prevents it from working properly.

Normal Function

The HCN4 gene provides instructions for making a channel that transports positively charged atoms (ions) into heart muscle cells. This channel is located primarily in the sino-atrial (SA) node, which is an area of specialized cells in the heart that functions as a natural pacemaker. The HCN4 channel allows potassium and sodium ions to flow into cells of the SA node. This ion flow is often called the "pacemaker current" because it generates electrical impulses that start each heartbeat and is involved in maintaining a regular heart rhythm.

Health Conditions Related to Genetic Changes

Sick sinus syndrome

At least five mutations in the HCN4 gene have been identified in people with sick sinus syndrome, a heart condition that affects the function of the SA node. Most of these mutations change single protein building blocks (amino acids) in the HCN4 channel. In some cases, fewer of the altered channels reach the cell membrane, where they are needed to transport ions. In other cases, the channel is in the right place but has an abnormal structure that changes how ions flow through it. All of the mutations reduce the overall flow of ions into cells of the SA node, preventing it from creating the electrical signals that control the heartbeat. These changes increase the risk of an abnormally slow heartbeat (bradycardia), which can cause dizziness, light-headedness, fainting (syncope), and related symptoms. HCN4 gene mutations have also been found in people who have a slow heartbeat without any other symptoms (asymptomatic bradycardia).

Brugada syndrome

MedlinePlus Genetics provides information about Brugada syndrome

Left ventricular noncompaction

MedlinePlus Genetics provides information about Left ventricular noncompaction

Other Names for This Gene

• HCN4_HUMAN
• hyperpolarization activated cyclic nucleotide-gated cation channel 4
• hyperpolarization activated cyclic nucleotide-gated potassium channel 4
• potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
• SSS2

Genomic Location

Normal Function

The SCN5A gene belongs to a family of genes that provide instructions for making sodium channels. These channels open and close at specific times to control the flow of positively charged sodium atoms (sodium ions) into cells. The sodium channels containing proteins produced from the SCN5A gene are abundant in heart (cardiac) muscle cells and play key roles in these cells' ability to generate and transmit electrical signals. These channels play a major role in signaling the start of each heartbeat, coordinating the contractions of the upper and lower chambers of the heart, and maintaining a normal heart rhythm.

Health Conditions Related to Genetic Changes

Brugada syndrome

More than 400 mutations in the SCN5A gene have been identified in people with Brugada syndrome, which is a heart condition characterized by an irregular heart rhythm (arrhythmia). SCN5A gene mutations also cause sudden unexpected nocturnal death syndrome (SUNDS), which was originally described in Southeast Asian populations. Researchers have since determined that SUNDS and Brugada syndrome are the same disorder.

Some SCN5A gene mutations associated with Brugada syndrome change single protein building blocks (amino acids) in the SCN5A protein. These mutations alter the structure of ion channels made with the SCN5A protein and disrupt the flow of sodium ions into cardiac muscle cells. Other mutations prevent the SCN5A gene from producing any functional ion channels, which also reduces the inward flow of sodium ions. A disruption in ion transport changes the way the heart beats, leading to the arrhythmia often found in Brugada syndrome and SUNDS.

Progressive familial heart block

A few mutations in the SCN5A gene have been found to cause progressive familial heart block. This condition alters the normal beating of the heart and can lead to fainting (syncope) or sudden cardiac arrest and death. The SCN5A gene mutations change single amino acids in the SCN5A protein. Channels made with this altered protein allow little or no sodium to enter the cell. Cardiac cells with these altered channels have difficulty producing and transmitting electrical signals that coordinate normal heartbeats. Interruption of this signaling is known as heart block. The impaired cardiac cells die, leading to a buildup of scar tissue (fibrosis) over time that worsens the heart block.

Romano-Ward syndrome

At least 238 mutations in the SCN5A gene are known to cause Romano-Ward syndrome, which is the most common form of an arrhythmia called long QT syndrome. Mutations in this gene account for five to 10 percent of cases of Romano-Ward syndrome. In individuals with this condition the cardiac muscle takes longer than usual to recharge between beats.

The SCN5A gene mutations that cause Romano-Ward syndrome include changes in single amino acids and deletions or insertions of a small number of amino acids in the SCN5A protein. Channels made with these altered SCN5A proteins stay open longer than usual, which allows sodium ions to continue flowing into cardiac muscle cells abnormally. This delay in channel closure alters the transmission of electrical signals in the heart, increasing the risk of an irregular heartbeat that can cause syncope or sudden death.

Sick sinus syndrome

At least 16 mutations in the SCN5A gene have been found to cause another heart condition called sick sinus syndrome. This condition affects the function of the sino-atrial (SA) node, which is an area of specialized cells in the heart that functions as a natural pacemaker. The SCN5A gene mutations that cause sick sinus syndrome lead to the production of nonfunctional sodium channels or abnormal channels that cannot transport ions properly. The flow of these ions is essential for creating the electrical impulses that start each heartbeat and spread these signals to other areas of the heart. Mutations reduce the flow of sodium ions, which alters the SA node's ability to create and spread electrical signals. These changes increase the risk of abnormally fast or slow heartbeats, which can cause dizziness, light-headedness, syncope, and related symptoms.

Familial atrial fibrillation

MedlinePlus Genetics provides information about Familial atrial fibrillation

Familial dilated cardiomyopathy

MedlinePlus Genetics provides information about Familial dilated cardiomyopathy

Left ventricular noncompaction

MedlinePlus Genetics provides information about Left ventricular noncompaction

Other disorders

Variations in the SCN5A gene are associated with several other heart conditions. These include potentially life-threatening forms of arrhythmia called atrial fibrillation and ventricular fibrillation. The genetic variations associated with these conditions alter the flow of sodium ions through the channel, which can lead to abnormal heart rhythms and affect the heart's ability to pump blood.

SCN5A gene mutations have also been identified in some cases of sudden infant death syndrome (SIDS). SIDS is a major cause of death in babies younger than 1 year. It is characterized by sudden and unexplained death, usually during sleep. Researchers are working to determine how changes in the SCN5A gene could contribute to SIDS. Other genetic and environmental factors, many of which have not been identified, also play a part in determining the risk of this disorder.

Certain drugs, including medications used to treat arrhythmias, infections, seizures, and psychotic disorders, can lead to an abnormal heart rhythm in some people. This drug-induced heart condition, which is known as acquired long QT syndrome, increases the risk of cardiac arrest and sudden death. A small percentage of cases of acquired long QT syndrome occur in people who have an underlying change in the SCN5A gene.

Other Names for This Gene

• HH1
• LQT3
• Nav1.5
• SCN5A_HUMAN
• Sodium channel protein, cardiac muscle alpha-subunit
• sodium channel, voltage gated, type V alpha subunit
• sodium channel, voltage-gated, type V, alpha (long QT syndrome 3)
• sodium channel, voltage-gated, type V, alpha subunit
• SSS1

Genomic Location

Most cases of sick sinus syndrome are not inherited. They are described as sporadic, which means they occur in people with no history of the disorder in their family.

When sick sinus syndrome results from mutations in the HCN4 gene, it has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means that one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

When sick sinus syndrome is caused by mutations in the SCN5A gene, it is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Sick sinus syndrome accounts for 1 in 600 patients with heart disease who are over age 65. The incidence of this condition increases with age.