In the pacemaking cells of the heart (e.g., the sinoatrial node), the pacemaker potential (also called the pacemaker current) is the slow, positive increase in voltage across the cell's membrane, that occurs between the end of one action potential and the beginning of the next. It is responsible for the self-generated rhythmic firing (automaticity) of pacemaker cells.
The cardiac pacemaker is the heart's natural rhythm generator. It employs pacemaker cells that generate electrical impulses, known as cardiac action potentials. These potentials cause the cardiac muscle to contract, and the rate of which these muscles contract determines the heart rate.
As with any other cells, pacemaker cells have an electrical charge on their membranes. This electrical charge is called the membrane potential. After the firing of an action potential, the pacemaking cell's membrane repolarizes (decreases in voltage) to its resting potential of -60 mV. From here, the membrane gradually depolarizes (increases in voltage) to the threshold potential of -40 mV, [1] upon which the cell would go on to fire the next action potential. The rate of depolarization is the slope: the faster voltage increases, the steeper the slopes are in graphs. The slope determines the time taken to reach the threshold potential, and thus the timing of the next action potential. [2]
In a healthy sinoatrial node (SAN, a complex tissue within the right atrium containing pacemaker cells that normally determine the intrinsic firing rate for the entire heart [3] [4] ), the pacemaker potential is the main determinant of the heart rate. Because the pacemaker potential represents the non-contracting time between heart beats (diastole), it is also called the diastolic depolarization . The amount of net inward current required to move the cell membrane potential during the pacemaker phase is extremely small, in the order of few pAs, but this net flux arises from time to time changing contribution of several currents that flow with different voltage and time dependence. Evidence in support of the active presence of K+, Ca2+, Na+ channels and Na+/K+ exchanger during the pacemaker phase have been variously reported in the literature, but several indications point to the “funny”(If) current as one of the most important. [5] (see funny current). There is now substantial evidence that also sarcoplasmic reticulum (SR) Ca2+-transients participate to the generation of the diastolic depolarization via a process involving the Na–Ca exchanger.
The rhythmic activity of some neurons like the pre-Bötzinger complex is modulated by neurotransmitters and neuropeptides, and such modulatory connectivity gives to the neurons the necessary plasticity to generating distinctive, state-dependent rhythmic patterns that depend on pacemaker potentials. [6]
The heart has several pacemakers, each which fires at its own intrinsic rate:
The potentials will normally travel in order
SA node → Atrioventricular node → Purkinje fibres
Normally, all the foci will end up firing at the SA node rate, not their intrinsic rate in a phenomenon known as overdrive-suppression. Thus, in the normal, healthy heart, only the SA node intrinsic rate is observable.
However, in pathological conditions, the intrinsic rate becomes apparent. Consider a heart attack which damages the region of the heart between the SA node and the AV node.
SA node → |block| AV node → Purkinje fibres
The other foci will not see the SA node firing; however, they will see the atrial foci. The heart will now beat at the intrinsic rate of the AV node.
The firing of the pacemaker cells is induced electrically by reaching the threshold potential of the cell membrane. The threshold potential is the potential an excitable cell membrane, such as a myocyte, must reach in order to induce an action potential. [7] This depolarization is caused by very small net inward currents of calcium ions across the cell membrane, which gives rise to the action potential. [8] [9]
Bio-pacemakers are the outcome of a rapidly emerging field of research into a replacement for the electronic pacemaker. The bio-pacemaker turns quiescent myocardial cells (e.g. atrial cells) into pacemaker cells. This is achieved by making the cells express a gene which creates a pacemaker current. [10]
Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathologic processes, it is commonly a physiologic response to cardiovascular conditioning or due to asymptomatic type 1 atrioventricular block.
An action potential occurs when the membrane potential of a specific cell rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of excitable cells, which include animal cells like neurons and muscle cells, as well as some plant cells. Certain endocrine cells such as pancreatic beta cells, and certain cells of the anterior pituitary gland are also excitable cells.
The cardiac pacemaker is the heart's natural rhythm generator. It employs pacemaker cells that produce electrical impulses, known as cardiac action potentials, which control the rate of contraction of the cardiac muscle, that is, the heart rate. In most humans, these cells are concentrated in the sinoatrial (SA) node, the primary pacemaker, which regulates the heart’s sinus rhythm.
Systole is the part of the cardiac cycle during which some chambers of the heart contract after refilling with blood. Its contrasting phase is diastole, the relaxed phase of the cardiac cycle when the chambers of the heart are refilling with blood.
Refractoriness is the fundamental property of any object of autowave nature not responding to stimuli, if the object stays in the specific refractory state. In common sense, refractory period is the characteristic recovery time, a period that is associated with the motion of the image point on the left branch of the isocline .
The Purkinje fibers, named for Jan Evangelista Purkyně, are located in the inner ventricular walls of the heart, just beneath the endocardium in a space called the subendocardium. The Purkinje fibers are specialized conducting fibers composed of electrically excitable cells. They are larger than cardiomyocytes with fewer myofibrils and many mitochondria. They conduct cardiac action potentials more quickly and efficiently than any of the other cells in the heart's electrical conduction system. Purkinje fibers allow the heart's conduction system to create synchronized contractions of its ventricles, and are essential for maintaining a consistent heart rhythm.
The sinoatrial node is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximately 15 mm long, 3 mm wide, and 1 mm thick, located directly below and to the side of the superior vena cava.
The cardiac conduction system transmits the signals generated by the sinoatrial node – the heart's pacemaker, to cause the heart muscle to contract, and pump blood through the body's circulatory system. The pacemaking signal travels through the right atrium to the atrioventricular node, along the bundle of His, and through the bundle branches to Purkinje fibers in the walls of the ventricles. The Purkinje fibers transmit the signals more rapidly to stimulate contraction of the ventricles.
Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generation capability. In healthy hearts, these cells form the cardiac pacemaker and are found in the sinoatrial node in the right atrium. They produce roughly 60–100 action potentials every minute. The action potential passes along the cell membrane causing the cell to contract, therefore the activity of the sinoatrial node results in a resting heart rate of roughly 60–100 beats per minute. All cardiac muscle cells are electrically linked to one another, by intercalated discs which allow the action potential to pass from one cell to the next. This means that all atrial cells can contract together, and then all ventricular cells.
A pacemaker action potential is the kind of action potential that provides a reference rhythm for the network. The pacemaker potential is the slow depolarization because of sodium influx, and once threshold has been reached the continued depolarization due to calcium influx. Repolarization follows, which is due to the efflux of potassium, which allows for the membrane potential to return to its negative voltage. Additionally, the longer the action potential duration the slower the heart rate will be. This means that it takes longer for the threshold to be reached because of the slow influx of sodium and the calcium and potassium channels opening at a later time. This contrasts with pacemaker potential or current which drives rhythmic modulation of firing rate.
Azimilide is a class ΙΙΙ antiarrhythmic drug. The agents from this heterogeneous group have an effect on the repolarization, they prolong the duration of the action potential and the refractory period. Also they slow down the spontaneous discharge frequency of automatic pacemakers by depressing the slope of diastolic depolarization. They shift the threshold towards zero or hyperpolarize the membrane potential. Although each agent has its own properties and will have thus a different function.
Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.
The pacemaker current is an electric current in the heart that flows through the HCN channel or pacemaker channel. Such channels are important parts of the electrical conduction system of the heart and form a component of the natural pacemaker.
The myogenic mechanism is how arteries and arterioles react to an increase or decrease of blood pressure to keep the blood flow constant within the blood vessel. Myogenic response refers to a contraction initiated by the myocyte itself instead of an outside occurrence or stimulus such as nerve innervation. Most often observed in smaller resistance arteries, this 'basal' myogenic tone may be useful in the regulation of organ blood flow and peripheral resistance, as it positions a vessel in a preconstricted state that allows other factors to induce additional constriction or dilation to increase or decrease blood flow.
A sinoatrial block is a disorder in the normal rhythm of the heart, known as a heart block, that is initiated in the sinoatrial node. The initial action impulse in a heart is usually formed in the sinoatrial node and carried through the atria, down the internodal atrial pathways to the atrioventricular node (AV) node. In normal conduction, the impulse would travel across the bundle of His, down the bundle branches, and into the Purkinje fibers. This would depolarize the ventricles and cause them to contract.
Afterdepolarizations are abnormal depolarizations of cardiac myocytes that interrupt phase 2, phase 3, or phase 4 of the cardiac action potential in the electrical conduction system of the heart. Afterdepolarizations may lead to cardiac arrhythmias. Afterdepolarization is commonly a consequence of myocardial infarction, cardiac hypertrophy, or heart failure. It may also result from congenital mutations associated with calcium channels and sequestration.
In mammals, cardiac electrical activity originates from specialized myocytes of the sinoatrial node (SAN) which generate spontaneous and rhythmic action potentials (AP). The unique functional aspect of this type of myocyte is the absence of a stable resting potential during diastole. Electrical discharge from this cardiomyocyte may be characterized by a slow smooth transition from the Maximum Diastolic Potential to the threshold for the initiation of a new AP event. The voltage region encompassed by this transition is commonly known as pacemaker phase, or slow diastolic depolarization or phase 4.
Cardiac physiology or heart function is the study of healthy, unimpaired function of the heart: involving blood flow; myocardium structure; the electrical conduction system of the heart; the cardiac cycle and cardiac output and how these interact and depend on one another.
BRL-32872 is an experimental drug candidate that provides a novel approach to the treatment of cardiac arrhythmia. Being a derivative of verapamil, it possesses the ability to inhibit Ca+2 membrane channels. Specific modifications in hydrogen bonding activity, nitrogen lone pair availability, and molecular flexibility allow BRL-32872 to inhibit K+ channels as well. As such, BRL-32872 is classified as both a class III (K+ blocking) and class IV (Ca+2 blocking) antiarrhythmic agent.
Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.
[Depolarization] starts when the membrane potential reaches -40 mV, the threshold potential for pacemaker cells. [...This] results in an upstroke in membrane potential from -40 mV to +10mV. [... Repolarization involves a] rapid decrease of membrane potential from +10 mV to -60 mV.
[When the pacemaker potential] reaches threshold (approximately –40mV in nodal cells) it triggers an action potential, which sparks off the next heart beat. The slope of the pacemaker potential determines the time taken to reach the threshold value, so the slope governs heart rate; the steeper the slope the sooner threshold is reached and the shorter the time between beats. Since the pacemaker slope is steeper in SA node cells than elsewhere in the electrical system, the SA node has the fastest intrinsic firing rate and initiates each heart beat.