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''Sébastien Krul, MD''
''Sébastien Krul, MD''
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=Introduction=
=Introduction=
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Bradycardias are defined as symptomatic heart rhythm disorders resulting in a inappropriately low heart rhythm or loss of conduction during during physiologic conditions. Generally this results in a cut-off value of <60 beats per minute, however variation of heart rate exists. For instance, during sleep and in athletes the heart rate can be as low as 40 beats per minute.  
Bradycardias are symptomatic heart rhythm disorders resulting from an inappropriately low heart rhythm due to inappropriate slow impulse formation or conduction delay of the cardiac impulse in the myocardium or conduction system during physiologic conditions. These two problems can lead to a slow heart rate, a bradycardia. Generally the definition of bradycardia is a heart rate of <60 beats per minute. However, a normal variation of heart rate exists<cite>Spodick</cite>. For instance, during sleep and in athletes the heart rate can be as low as 40 beats per minute.<cite>Talan</cite>


Bradycardia can be caused by a variety of intrinsic and extrinsic causes. The most common intrinsic cause is ageing, but ischaemic heart disease, infiltrative diseases or surgery can result in conduction disorders. Medication that modifies the excitability of the heart is the most frequent extrinsic cause, however electrolyte and metabolic disorders may influence the heart rate directly or indirect. To understand the pathophysiologic basis of most conduction disorders or disorders of impulse formation it is important to have knowledge about the physiology of cardiac conduction and mechanisms of arrhythmia as detailed in the general cardiac arrhythmia section [Link].
Bradycardia can be caused by a variety of intrinsic and extrinsic causes. The most common intrinsic cause is ageing, but ischemic heart disease, infiltrative diseases or surgery can also result in conduction disorders.<cite>Ferrer, Mangrum, ESC</cite> Medication that modifies the excitability of the heart is the most frequent extrinsic cause. However, electrolyte and metabolic disorders may influence the heart rate directly or indirect.
 
Complaints from bradycardia result from an insufficient capacity of the heart to supply the body with blood. Complaints of palpitations, syncope or heart failure may result from bradyarrhythmias, but often vague symptoms like dizziness, exercise intolerance or fatigue may be more prominent<cite>Mova</cite>. A causal relation between complaints and the bradycardia should be established and reversible causes should be identified (for instance use of certain drugs).  


The heart being a mechanical pump, complaints from bradycardia result from an insufficient capacity of the pump to supply the rest of the body with blood. Complaints of palpitations, syncope or heart failure may result from conduction disorders. However often vague symptoms for instance like dizziness, exercise intolerance or fatigue may be caused by bradycardia. A causal relation between complaints and the bradycardia should be established and reversible causes should be identified (medication).


=Disorders of Conduction and Impulse Formation=
=Disorders of Conduction and Impulse Formation=
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===Sinus Bradycardia===
===Sinus Bradycardia===
Sinus bradycardia is a slow sinus rhythm of <60 beats per minute. Sinus bradycardia can be physiological, as is athletes or during sleep. Commonly sinus bradycardia is caused by medication, ischemia or neuro-mediated bradycardia, such as in a vasovagal reaction. Furthermore metabolic diseases can cause bradycardia, e.g. hypothermia or hypothyroidism.
Sinus bradycardia is a slow sinus rhythm of <60 beats per minute<cite>Spodick</cite>. Sinus bradycardia can be physiological, as in athletes or during sleep<cite>Ector2</cite>. Commonly sinus bradycardia is caused by medication, ischemia or neuro-mediated bradycardia, such as in a vasovagal reaction<cite>ESC</cite>. Furthermore metabolic diseases can cause bradycardia, e.g. hypothermia or hypothyroidism.
 
[[File:Sinusnode.svg|thumb|500px|Sinus node dysfunction.]]
[[File:Sinusnode.svg|thumb|500px|Sinus node dysfunction.]]


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Like AV-nodal conduction disorders (see below) multiple subtypes can be distinguished:
Like AV-nodal conduction disorders (see below) multiple subtypes can be distinguished:
* <b>Second degree Type I:</b> (Wenkebach) SA exit block: the P-P interval progressively shortens prior to the pause
* Second degree Type I (Wenkebach) SA exit block: the P-P interval progressively shortens prior to the pause
* <b>Second degree Type II SA exit block:</b> the pause equals approximately 2-4 times the preceding PP interval
* Second degree Type II SA exit block: the pause equals approximately 2-4 times the preceding PP interval
* <b>Third degree SA exit block:</b> absence of P waves (can only be diagnosed with an sinus node electrode, during electrophysiological evaluation)  
* Third degree SA exit block: absence of P waves, but still impulse formation at the level of the sinus node (can only be diagnosed with an sinus node electrode, during electrophysiological evaluation)  


===Sinus Arrest===
===Sinus Arrest===
If the sinus node has a problem with impulse formation it is defined as a sinus arrest. There can be the appearance of a irregular rhythm, however sinus P-waves are clearly present. In comparison with the sinus node exit block, there is no relation with a previous P-P interval. Often an ectopic pacemaker takes over lower in the conduction system, but the new rate varies slightly from the old one.
If the sinus node has a problem with impulse formation it is defined as a sinus arrest. There can be the appearance of an irregular rhythm, however sinus P-waves are clearly present, between intervals of no rhythm or an escape rhythm. In comparison with the sinus node exit block, there is no relation with a previous P-P interval. Often an ectopic pacemaker takes over lower in the conduction system, but the new rate varies slightly from the old one.  


===Asystole===
===Asystole===
Asystole is the lack of cardiac activity eventually leading to immediate death.
Asystole is the lack of cardiac activity eventually leading to immediate death.  


===Sick Sinus Syndrome===
===Sick Sinus Syndrome===
Sick sinus syndrome is a denoter of diseases of inappropriate sinus node responses. These encompass for instance:
Sick sinus syndrome is a denoter of diseases of inappropriate sinus node responses <cite>Ferrer</cite>. These encompass for instance:
* An inappropriate response after tachycardia due to overdrive suppression (which can result in long pauses)
* An inappropriate response after tachycardia due to overdrive suppression (which can result in long pauses)
* An inadequate response to exercise.  
* An inadequate response to exercise.  
* Bradycardia-tachycardia syndrome; where alternating bradycardia and tachycardia arise.
* Bradycardia-tachycardia syndrome; where alternating bradycardia and tachycardia arise.


==AV-Block==
==AV-Block==
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===First Degree AV Block===
===First Degree AV Block===
Technically an AV-delay and not a AV block, 1st degree AV block is defined as a prolonged interval between atrial and ventricular activation (>200ms). This delay results from disease in the AV-node or His-Purkinje system. An AV block is not the cause of bradycardia, because every atrial impulse results in conduction to the ventricles.
Technically an AV-delay and not an AV block, 1st degree AV block is defined as a prolonged interval between atrial and ventricular activation (>200ms). This delay results from disease in the AV-node or His-Purkinje system. An AV block is not the cause of bradycardia, because every atrial impulse results in conduction to the ventricles.  


===Second Degree AV Block===
===Second Degree AV Block===
The second degree AV block can be divided in two separate entities depending on the clinical characteristics of the conduction disorder. If conduction to the ventricle is conducted in a 2:1 fashion; that is if after every second P-wave there is no conduction to the ventricle, it is not possible to distinguish between the two types and a severe kind of conduction block should be assumed. If two sequential P-wave are not followed by a QRS-complex the term malignant block is used, as this could lead to or be an indication of a total block.
The second degree AV block can be divided in two separate entities depending on the clinical characteristics of the conduction disorder. If conduction to the ventricle is conducted in a 2:1 fashion; that is if after every second P-wave there is no conduction to the ventricle, it is not possible to distinguish between the two types and a severe kind of conduction block should be assumed. If two sequential P-wave are not followed by a QRS-complex the term malignant block is used, as this could lead to or be an indication of a total block.
* <b>Mobitz I (Wenkebach)</b>: The Mobitz type I block is characterized by a progressively increased P-Q interval until atrial activation is blocked in the AV-node. Thereafter conduction is restored and this cycle repeats itself. A common finding in the Mobitz I block is that the first prolongation of the PR interval is associated with the largest increase in interval. After this first prolongation of the interval, the interval gradually increases. Usually Mobitz type II block is located at the atrioventricular node and rarely deteriorates to a more severe conduction block.
* <b>Mobitz I (Wenkebach)</b>: The Mobitz type I block is characterized by a progressively increased P-Q interval until atrial activation is blocked in the AV-node. Thereafter conduction is restored and this cycle repeats itself. A common finding in the Mobitz I block is that the first prolongation of the PR interval is associated with the largest increase in interval. After this first prolongation of the interval, the interval gradually increases. Usually Mobitz type II block is located at the atrioventricular node and rarely deteriorates to a more severe conduction block.<cite>Simons, Strasberg</cite>
* <b>Mobitz II:</b> When atrial activation is blocked, without progressively increasing P-Q interval a Mobitz Type II AV block is present. This sudden failure of AV conduction is an omen of severe conduction disease in usually infra-Hision part of the atrioventricular conduction system.  
* <b>Mobitz II:</b> When atrial activation is blocked, without progressively increasing P-Q interval a Mobitz Type II AV block is present. This sudden failure of AV conduction is an omen of severe conduction disease in usually infra-Hision part of the atrioventricular conduction system.<cite>Simons, Zipes, Donoso</cite>


===Third Degree AV Block===
===Third Degree AV Block===
Third degree AV block is complete block of conduction between atria en ventricle. Atrial and ventricular rhythms are complete dissociated.
Third degree AV block is complete block of conduction between atria en ventricle. Atrial and ventricular rhythms are complete dissociated.<cite>Levine</cite>
 
==Paroxysmal AV block==
Paroxysmal atrioventricular block (PAVB), is characterized by a sudden and unexpected block of the atrial impulse. Due to the delayed emerge of an escape rhythm, these patients often present with syncope. However, if a escape rhythm is established patients may present themselves without symptoms. Two different variations of the PAVB are commonly distinguished;
 
<b>1. Pause-dependent PAVB</b><br/>
The PD-PAVB occurs after the onset of a pause. This pause can be compensatory after a premature beat, overdrive suppression of sinus rhythm or other disorders of impulse formation. There are several hypothesis to explain this phenomenon, amongst them phase 4 depolarization (see Phase 4 abberation).
 
<b>2. Tachycardia-dependent PAVB</b><br/>
The TD-PAVB occurs more frequently in patients due to the increased rate of the atria. TD-PAVB is associated with 2nd degree Mobitz block and Adam-Stokes Syndrome. However, some occurrences of TD-PAVB occur without a noticeable increase in atrial rate, due to minor electrophysiological changes due to changes in autonomic tone or coronary perfusion. The mechanism responsibly for the occurrence of TD-PAVB is probably repetitive concealed conduction.<cite>Elsherrif</cite>
 


==Ventricular Conduction Block==
==Ventricular Conduction Block==
Ventricular conduction blocks predominantly prolong the QRS-complex, but are rarely the result of bradycardias. However, the occurrence of ventricular block on the surface ECG inform the clinician about the health of the underlying conduction system and might occur simultaneously with other types of conduction disorders. 


===Right bundel branch block (RBBB)===
===Right bundel branch block (RBBB)===
The right bundle branch is composed of one fascicle. Right bundle branch block is a unifascicular block of the right bundle and can be found in healthy people and is represented by a broad QRS complex (>120ms). However a new RBBB in a patient with a history of normal ventricular conduction warrens further cardiological investigation. The last activity is to the right and results in a RSR’ pattern in V1 where R’ > R. This results from the delayed activation of the right ventricle. In V6 a slurred S wave can be seen at the end of the QRS complex.
The right bundle branch is composed of one fascicle. Right bundle branch block is a unifascicular block of the right bundle and can be found in healthy people and is represented by a broad QRS complex (>120ms). However, a new RBBB in a patient with a history of normal ventricular conduction warrens further cardiological investigation. The last activity is to the right and results in a RSR’ pattern in V1 where R’ > R. This results from the delayed activation of the right ventricle. In V6 a slurred S wave can be seen at the end of the QRS complex<cite>ESC, ECGpedia, Robles, Wellens</Cite>


===Left anterior fascicular block (LAFB)===
===Left anterior fascicular block (LAFB)===
The left bundle branch is composed of two fascicles. One of the fascicle has an anterior location and activates the interventricular septum and the anterior of the ventricle. Clinically this is represented by a left axis deviation and an absent or very small S and normal q in lead I and a S>R in lead II and III. QRS duration should be <120ms.
The left bundle branch is composed of two fascicles. One of the fascicle has an anterior location and activates the interventricular septum and the anterior of the ventricle. Clinically a LAFB is represented by a left axis deviation and an absent or very small S and normal q in lead I and a S>R in lead II and III. QRS duration should be <120ms<cite>ESC, ECGpedia, Robles, Wellens</Cite>.


===Left posterior fascicular block (LPFB)===
===Left posterior fascicular block (LPFB)===
The second fascicle of the left bundle branch is the posterior fascicle. This fascicle has a posterior location and activates the posterior and lateral part of the ventricle. This fascicular block results in a right axis deviation and is represented by a deep S in I and small q in III with a QRS duration of <120ms.
The second fascicle of the left bundle branch is the posterior fascicle. This fascicle has a posterior location and activates the posterior and lateral part of the ventricle. A left posterior fascicular block results in a right axis deviation and is represented by a deep S in I and small q in III with a QRS duration of <120ms<cite>ESC, ECGpedia, Robles,Wellens</Cite>.


===Left bundel branch block (LBBB)===
===Left bundel branch block (LBBB)===
If the two fascicles of the left bundle branch show conduction block there is a left bundle branch block, this bifascicular block is uncommon in healthy patients and further cardiologic investigations need to be performed to screen for underlying disease. Left bundle branch block causes the left ventricle to activate later then the right ventricle. This results in typical ECG characteristics, most importantly a broad QRS of >120ms. In V1 a broad monomorphic S wave can be seen (sometimes with a small r wave) representing slow left ventricular activation. In the lead V6 a broad monomorphic R wave is seen with no Q waves.
If the two fascicles of the left bundle branch show conduction block there is a left bundle branch block. This bifascicular block is uncommon in healthy patients and further cardiologic investigations need to be performed to screen for underlying disease. Left bundle branch block causes the left ventricle to activate later then the right ventricle. This results in typical ECG characteristics, most importantly a broad QRS of >120ms. In V1 a broad monomorphic S wave can be seen (sometimes with a small r wave) representing slow left ventricular activation. In the lead V6 a broad monomorphic R wave is seen with no Q waves<cite>ESC, ECGpedia, Robles, Wellens</Cite>.  
[Afbeelding samenvatting alle Ventriculaire geleidingsstoornissen]


[[File:Intraventricular Conduction.svg|thumb|600px|Traces of right bundle branch block and the different types of left bundle branch conduction disorders.]]
[[File:Intraventricular Conduction.svg|thumb|600px|Traces of right bundle branch block and the different types of left bundle branch conduction disorders.]]


==Functional conduction disorders: Aberrant Conduction==
==Functional conduction disorders: Aberrant Conduction==
In certain conditions a conduction disorder can arise on the ECG. This functional conduction disorder is called aberrant conduction and can mimic any form of interventricular conduction disorder. In most cases a right bundle branch block pattern can be seen on the surface ECG because the right bundle has a longer refractory period. There are a few mechanisms which can cause aberrant conduction.
In certain physiological conditions a ventricular conduction disorder can arise on the ECG. This functional conduction disorder is called aberrant conduction and can mimic any form of interventricular conduction disorder. In most cases a right bundle branch block pattern can be seen on the surface ECG because the right bundle has a longer refractory period. There are a few mechanisms which can cause aberrant conduction<cite>Robles, Wellens</Cite>.
===Phase 3 aberration===
===Phase 3 aberration===
Phase 3 aberration is a situation that occurs when the bundle branches receive a new impulse, before they are repolarized. The bundles are still in their refractory period. This is also called Ashman phenomenon. As a result of the refractionary state of the bundle, conduction can not proceed along the refractory bundle and a conduction block is visible on the surface ECG. Thus for instance short coupled atrial activity can procedure phase 3 abberant conduction.
Phase 3 aberration is a situation that occurs when the bundle branches receive a new impulse, before they are repolarized. The bundles are still in their refractory period. This is also called Ashman phenomenon. As a result of the refractionary state of the bundle, conduction can not proceed along the refractory bundle and a conduction block is visible on the surface ECG. Thus for instance short coupled atrial activity can procedure phase 3 aberrant conduction<cite>Robles, Wellens</Cite>.
===Phase 4 abberation or deceleration dependant===
===Phase 4 abberation or deceleration dependant===
During a prolonged interval the Purkinje fibers can depolarize spontaneously. This depolarisation results in the conduction slowing and can even produce a conduction block. This is usually a pathological response, resulting from an increased activity in the Purkinje fibers, but can be normal at very low heart rates. Phase 4 aberration thus only occurs after prolonged pause.
During a prolonged interval between cardiac activity, the Purkinje fibers can depolarize spontaneously. This depolarisation results in the conduction slowing and can even produce a conduction block. This is usually a pathological response, resulting from an increased activity in the Purkinje fibers, but can be normal at very low heart rates. Phase 4 aberration thus only occurs after prolonged pause <cite>Robles, Wellens</Cite>.  
===Acceleration dependant===
===Acceleration dependant===
This kind of aberrant conduction resembles phase 3 aberrant conduction; however appearance of the conduction disorders is the result of a small increase in rhythm. The conduction disorder is a result of an abnormal response of tissue that has diminished excitability.
This kind of aberrant conduction resembles phase 3 aberrant conduction; however appearance of the conduction disorders is the result of a small increase in rhythm. The ventricular conduction disorder is a result of an abnormal response of tissue that has diminished excitability and fails to excite the corresponding bundle<cite>Robles, Wellens</Cite>.
 
=Diagnosis=
=Diagnosis=
In the diagnosis of bradyarrhythmias the identification of reversible causes is important to prevent unnecessary treatment. After a detailed history and physical examination there are additional investigations which can give information about the location of the nature of the bradyarrhythmia. While not all investigations are necessary, a thorough work-up has to be performed to prevent serious clinical events or pacemaker implantation. Espaccially the differentiation between bradyarrhtyhmias and vasovagal syncope can be difficult, but is very important for the management of symptoms.
In the diagnosis of bradyarrhythmias the identification of reversible causes is important to prevent unnecessary treatment. After a detailed history and physical examination there are additional investigations which can give information about the location of the nature of the bradyarrhythmia.<cite>Mangrum</cite>. While not all investigations are necessary, a thorough work-up has to be performed to prevent serious clinical events or pacemaker implantation. Especially the differentiation between bradyarrhtyhmias and vasovagal syncope can be difficult, but is very important for the management of symptoms <cite>Mova</cite>.
===Symptoms===
===Signs & Symptoms===
A patient with a bradyarrhythmia can be complete asymptomatic. However patients with bradycardia may present with a diversity of signs and symptoms. A complete cardiac standstill can result in syncope (pause >6 sec) or near syncope. More often symptoms are nonspecific and chronic and are a result of the chronotopic incompetence and reduced cardiac output. Symptoms like for example, dizziness, light-headedness or confusional states, episodes of fatigue or muscular weakness, exercise intolerance, heart failure or palpitations can be described by the patient.
A patient with a bradyarrhythmia can be completely asymptomatic. Otherwise, patients with bradycardia may present with a diversity of signs and symptoms. A pause in ventricular contraction > 6 seconds often resuls in syncope or near syncope <cite>Mova</cite>. More often symptoms are nonspecific and chronic and are a result of the chronotopic incompetence and reduced cardiac output. Symptoms like dizziness, light-headedness or confusional states, episodes of fatigue or muscular weakness, exercise intolerance, heart failure or palpitations can be experienced by the patient.<cite>ESC</cite>
===Investigations===
===Investigations===
There are a number of additional investigations which can uncover the cause of bradyarrhythmias.
There are a number of additional investigations which can uncover the cause of bradyarrhythmias.
* <b>ECG:</b> A surface ECG can demonstrate the conduction disorder and relate complaints to electrocardiographic findings. A Valsalva manoeuvre or carotid sinus massage whilst performing an ECG can give information about function of the autonomous nervous system and its possible role in the occurrence of the bradyarrrhythmia.
* <b>ECG:</b> A surface ECG can demonstrate the conduction disorder and relate complaints to electrocardiographic findings. A Valsalva manoeuvre or carotid sinus massage whilst performing an ECG can give information about function of the autonomous nervous system and its possible role in the occurrence of the bradyarrrhythmia.
* <b>X-ECG:</b> An exercise test can give information about the chronotropic competence of the cardiac conduction system.
* <b>X-ECG:</b> An exercise test can give information about the chronotropic competence of the cardiac conduction system <cite>Wiens</cite>.
* <b>Long-term ECG recording:</b> Holter recording can identify causes of paroxysmal or intermittent bradyarrhythmias. Importantly a correlation with symptoms can be made and pathological causes of bradyarrhythmias or long pause (>3sec) during the night can be identified. If 24h or 48h Holter recordings cannot identify the cause of symptoms longer duration of monitoring may be required.  Transient event recorders can record up to 30seconds of ECG when a patient activates the device. This device can be especially useful when non-invasive monitoring is required due to the low occurrence of the bradyarrhythmia. For longer monitoring an implantable loop recorder can be used. This small device can be implanted and observe rhythm over an extensive period.  
* <b>Long-term ECG recording:</b> Holter recording can identify causes of paroxysmal or intermittent bradyarrhythmias. Importantly a correlation with symptoms can be made and pathological causes of bradyarrhythmias or long pause (>3sec) during the night can be identified. If 24h or 48h Holter recordings cannot identify the cause of symptoms longer duration of monitoring may be required<cite>Lichstein</cite>.  Transient event recorders can record up to 30seconds of ECG when a patient activates the device. This device can be especially useful when non-invasive monitoring is required due to the low occurrence of the bradyarrhythmia<cite>Kinley</cite>. For longer monitoring an implantable loop recorder can be used. This small device can be implanted and observe rhythm over an extensive period <cite>Krahn</cite>.
* <b>Electrophysiological testing:</b> If non-invasive testing does not discover the bradyarrhythmia underlying the symptoms and electrophysiologic study may be undertaken to assess sinus nodal function and atrioventricular conduction. The measurement of conduction intervals and reaction to standard electrophysiological pacing protocols can elucidate the cause of bradyarrhtyhmia.
* <b>Electrophysiological testing:</b> If non-invasive testing does not discover the arrhythmia underlying the symptoms, an electrophysiologic study may be undertaken to assess sinus nodal function and atrioventricular conduction. The measurement of conduction intervals and reaction to standard electrophysiological pacing protocols can elucidate the cause of bradyarrhtyhmia.


=Treatment=
=Treatment=
Fortunately the human heart has a couple of backup mechanisms that can sustain a heart rate in case of severe bradycardia. These escape mechanisms can occur in every part of the heart (i.e. atrium, AV, node, ventricle). In general, the rate of the escape mechanism is faster when the escape rhythm is located higher in the conduction system. If no reversible cause for the bradyarrhythmia can be found and the bradyarrhythmia persist, further therapy is required if the patients remains symptomatic.
Fortunately the human heart has a couple of backup mechanisms that can sustain a heart rate in case of severe bradycardia. These escape mechanisms can occur in every part of the heart (i.e. atrium, AV, node, ventricle). In general, the rate of the escape mechanism is faster when the escape rhythm is located higher in the conduction system, for instance an escape rhythm of the atrium has a higher frequency than an escape rhythm from the ventricles. If no reversible cause for the bradyarrhythmia can be found and the bradyarrhythmia persist, further therapy is required if the patients remains symptomatic.
===Drug Therapy===
===Drug Therapy===
There are no options for chronic drug therapy in bradyarrhthmias. In the acute setting atropine or isoprenaline may be used to increase heart rate or AV-nodal conduction. Patients with severe bradyarrhythmias (Type 2 AV nodal Mobitz II block, Type 3 AV nodal block, sinus arrest >3 seconds) should be considered for permanent or temporary pacing therapy.
There are no options for chronic drug therapy in bradyarrhthmias. In the acute setting atropine or isoprenaline may be used to increase heart rate or AV-nodal conduction <cite>Hoffman</cite>. Patients with severe bradyarrhythmias (Type 2 AV nodal Mobitz II block, Type 3 AV nodal block, sinus arrest >3 seconds) should be considered for permanent or temporary pacing therapy.
===Temporary pacing===
===Temporary pacing===
Temporary pacing can be used to bridge the time to pacemaker implantation or until the bradyarrhythmia is resolved. Transvenous pacing is the most accepted method and can be used to pace the right atrium or the right ventricle after insertion of a temporary pacemaker wire through venous access. Pacing through the oesophagus can only capture the atrium, due to the anatomical position of the heart in relation with the oesophagus. Transcutanous pacing is a painful and emergency option in which muscle and heart are stimulated with large electrodes. Finally epicardal pacing is usually performed after cardiac surgery and requires surgical implantation of the electrodes.
Temporary pacing can be used to bridge the time to pacemaker implantation or until the bradyarrhythmia is resolved. Transvenous pacing is the most accepted method and can be used to pace the right atrium or the right ventricle after insertion of a temporary pacemaker wire through venous access. Pacing through the oesophagus can only capture the atrium, due to the anatomical position of the heart in relation with the oesophagus. Transcutanous pacing is a painful and emergency option in which muscle and heart are stimulated with large electrodes. Finally epicardal pacing is usually performed after cardiac surgery and requires surgical implantation of the electrodes on the epicardium.
===Device Therapy===
===Device Therapy===
Implantable pacemakers activate cardiac myocardium with electrical stimulation, leading to muscle contraction. Due to the nature of a pacemaker, the activation is different from the physiological conduction system, there are electrical and mechanical consequences. It is therefore important to adjust pacemaker setting to the individual patient. The type of pacemakers and their settings are extensively covered in the device chapter of cardiac arrhythmias. The indications for pacemaker implantation in patients with bradyarrhythmias are mentioned below.
Implantable pacemakers activate cardiac myocardium with electrical stimulation, leading to muscle contraction. Due to the nature of a pacemaker, the activation is different from the physiological conduction system, there are electrical and mechanical consequences. It is therefore important to adjust pacemaker setting to the individual patient. The type of pacemakers and their settings are extensively covered in the device chapter of cardiac arrhythmias. The indications for pacemaker implantation in patients with bradyarrhythmias are mentioned below.
* <b>Sinus node disease:</b> Pacemaker implantation should be considered in patients with sinus node disease which manifests as symptomatic bradycardia in which the symptom-rhythm correlation must have been 1) spontaneously occurring or 2) drug-induced where alternative drug therapy is lacking. Furthermore other eligible candidates for permanent pacing are patients with syncope with sinus node disease, either spontaneously occurring or induced at electrophysiological study and sinus node disease manifests as symptomatic chronotropic incompetence which is 1) spontaneously occurring or 2) drug-induced where alternative drug therapy. Patients with sinus node disease without symptoms including use of bradycardia-provoking drugs, ECG findings of sinus node dysfunction with symptoms not due directly or indirectly to bradycardia or symptomatic sinus node dysfunction where symptoms can reliably be attributed to non-essential medication do not have an indication for permanent pacemaker therapy.
* <b>Sinus node disease:</b>  
* <b>Atrioventricular Block:</b> The following patients with AV conduction block have an indication for pacemaker therapy; 1) chronic symptomatic third or second degree (Mobitz I or II) atrioventricular block 2) neuromuscular diseases (e.g. myotonic muscular dystrophy etc.) with third-degree or second-degree atrioventricular Block or 3) third or second degree (Mobitz I or II) atrioventricular block after catheter ablation of the atrioventricular junction or after valve surgery when the block is not expected to resolve. Patients with asymptomatic first degree atrioventricular block, asymptomatic second degree Mobitz I with supra-Hisian conduction block or atrioventricular block expected to resolve do not require a pacemaker implantation.
Pacemaker implantation should be strongly considered in patients with sinus node disease which manifests as symptomatic bradycardia in which the symptom-rhythm correlation must have been 1) spontaneously occurring or 2) drug-induced where alternative drug therapy is lacking.<cite>Kay, Epstein</cite> Other reasonable eligible candidates for permanent pacing are patients with syncope with sinus node disease, spontaneously occurring or induced at electrophysiological study or patients with symptoms clearly associated to bradycardia but without documentation of this bradycardia.
* <b>Intraventricular conduction Block:</b> Patient which show a intermittent third-degree atrioventricular block, second-degree Mobitz II atrioventricular block. alternating bundle branch block or findings on electrophysiological study of markedly prolonged His-Ventrical interval (≥100ms) or pacing-induced infra-His block in patients with symptoms have an indication for pacemaker therapy. Patients with a bundle branch block without atrioventricular block or symptoms and bundle branch block with first-degree atrioventricular block without symptoms should not have a pacemaker implanted.
Patients with sinus node disease without symptoms including use of bradycardia-provoking drugs, patients with symptoms of sinus node dysfunction occurring in the absence of the bradycardia or patients with symptomatic sinus node dysfunction where symptoms can reliably be attributed to non-essential medication do not have an indication for permanent pacemaker therapy.<cite>Epstein</cite>
* <b>Atrioventricular Block:</b> The following patients with AV conduction block have an strong indication for pacemaker therapy; 1) chronic symptomatic third or second degree (Mobitz I or II) atrioventricular block including induced third or second degree atrioventricular block by required medication<cite>Kastor, Dreifus, Epstein</cite> 2) asymptomatic patients with third or second degree (Mobitz I or II) atrioventricular block and documented asystole greater than 3.0 seconds in SR or 5.0 seconds in AF, an escape rhythm less than 40 bpm (or >40 bpm with left ventricular dysfunction) or infranodal escape rhythm <cite>Epstein, Ecktor, Shaw</cite>3) neuromuscular diseases (e.g. myotonic muscular dystrophy, Kearns–Sayre syndrome, etc.) with third-degree or second-degree atrioventricular Block<cite>Stevenson, James</cite> or 4) third or second degree (Mobitz I or II) atrioventricular block after catheter ablation of the atrioventricular junction or after valve surgery when the block is not expected to resolve<cite>Langberg, Kim, Glikson, Epstein</cite> and 5) patient with third or second degree AV block during exercise with no myocardial ischemia<cite>Chokski, Epstein</cite>. Patients with asymptomatic first degree atrioventricular block, asymptomatic second degree Mobitz I with supra-Hisian conduction block or atrioventricular block expected to resolve do not require a pacemaker implantation.<cite>Mymin, Strasberg, Epstein</cite>
* <b>Intraventricular conduction Block:</b> Patient which show a intermittent third-degree atrioventricular block, advanced second-degree or Mobitz II atrioventricular block have an strong indication for pacemaker therapy<cite>Dhingra, McAnulty1, McAnulty2, Friedberg, Epstein</cite>. Patients with a bundle branch block without atrioventricular block or symptoms and bundle branch block with first-degree atrioventricular block without symptoms should not have a pacemaker implanted.<cite>McAnulty, Epstein</cite>


=References=
=References=
<biblio>
<biblio>
# Vardas pmid=17726042
# Epstein pmid=23255456
# Ferrer pmid=5695590
# Talan pmid=7083929
# Mangrum pmid=10706901
# Strasberg pmid 7471363
# Donoso pmid 14118480
# Zipes pmid 378457
# Levine pmid=13356435
# Kay pmid=6461235
# Kastor pmid=1089890
# Dreifus pmid=6826942
# Ector pmid=6191291
# Langberg pmid 2598419
# Kim pmid=11230857
# Glikson pmid=9388104
# Shaw pmid=4005079
# Choksk pmid=2360528
# Mymin pmid=3762641
# Stevenson pmid=2299071
# James pmid=14451031
# Friedberg pmid=14206803
# Dhingra pmid=4817704
# McAnulty1 pmid=7088050
# McAnulty2 pmid=619828
# Spodick pmid=1529897
# Ector2 pmid=6147639
# Mova pmid=19713422
# Simons pmid=9894656
# Wiens pmid=6741841
# Lichstein pmid=6176956
# Kinley pmid=7503472
# Krahn pmid=15125724
# Hoffman pmid=3536438
# ESC isbn=9780199566990
# ESC isbn=9780199566990
# Braunwald isbn=1437703984
# ECGpedia http://en.ecgpedia.org
# ECGpedia.org
# Robles isbn=9789031313983
# Wellens isbn=9781416002598
# Elsherrif PMCID: PMC2877697

Latest revision as of 07:10, 7 January 2014

Sébastien Krul, MD

Introduction

Abbreviations
  • AV: Atrio Ventricular
  • bpm: beats per minute
  • LBBB: Left Bundle Branch Block
  • LAFB: Left Anterior Fascicular Block
  • LPFB: Left Posterior Fascicular Block
  • RBBB: Right Bundle Branch Block

Bradycardias are symptomatic heart rhythm disorders resulting from an inappropriately low heart rhythm due to inappropriate slow impulse formation or conduction delay of the cardiac impulse in the myocardium or conduction system during physiologic conditions. These two problems can lead to a slow heart rate, a bradycardia. Generally the definition of bradycardia is a heart rate of <60 beats per minute. However, a normal variation of heart rate exists[1]. For instance, during sleep and in athletes the heart rate can be as low as 40 beats per minute.[2]

Bradycardia can be caused by a variety of intrinsic and extrinsic causes. The most common intrinsic cause is ageing, but ischemic heart disease, infiltrative diseases or surgery can also result in conduction disorders.[3, 4, 5] Medication that modifies the excitability of the heart is the most frequent extrinsic cause. However, electrolyte and metabolic disorders may influence the heart rate directly or indirect.

Complaints from bradycardia result from an insufficient capacity of the heart to supply the body with blood. Complaints of palpitations, syncope or heart failure may result from bradyarrhythmias, but often vague symptoms like dizziness, exercise intolerance or fatigue may be more prominent[6]. A causal relation between complaints and the bradycardia should be established and reversible causes should be identified (for instance use of certain drugs).


Disorders of Conduction and Impulse Formation

Sinus Node Dysfunction

Sinus Bradycardia

Sinus bradycardia is a slow sinus rhythm of <60 beats per minute[1]. Sinus bradycardia can be physiological, as in athletes or during sleep[7]. Commonly sinus bradycardia is caused by medication, ischemia or neuro-mediated bradycardia, such as in a vasovagal reaction[5]. Furthermore metabolic diseases can cause bradycardia, e.g. hypothermia or hypothyroidism.

Sinus node dysfunction.

Sinus Node Exit Block

In the case of sinus node exit block, an impulse generated from the sinus node is blocked at one of the exit sides of the sinus node. However impulse formation is not affected, therefore the interval between subsequent beats should be similar to n=x times the P-P interval. On the surface electrocardiogram this is expressed as a pause.

Like AV-nodal conduction disorders (see below) multiple subtypes can be distinguished:

  • Second degree Type I (Wenkebach) SA exit block: the P-P interval progressively shortens prior to the pause
  • Second degree Type II SA exit block: the pause equals approximately 2-4 times the preceding PP interval
  • Third degree SA exit block: absence of P waves, but still impulse formation at the level of the sinus node (can only be diagnosed with an sinus node electrode, during electrophysiological evaluation)

Sinus Arrest

If the sinus node has a problem with impulse formation it is defined as a sinus arrest. There can be the appearance of an irregular rhythm, however sinus P-waves are clearly present, between intervals of no rhythm or an escape rhythm. In comparison with the sinus node exit block, there is no relation with a previous P-P interval. Often an ectopic pacemaker takes over lower in the conduction system, but the new rate varies slightly from the old one.

Asystole

Asystole is the lack of cardiac activity eventually leading to immediate death.

Sick Sinus Syndrome

Sick sinus syndrome is a denoter of diseases of inappropriate sinus node responses [3]. These encompass for instance:

  • An inappropriate response after tachycardia due to overdrive suppression (which can result in long pauses)
  • An inadequate response to exercise.
  • Bradycardia-tachycardia syndrome; where alternating bradycardia and tachycardia arise.

AV-Block

The three different types of AV nodal block.

First Degree AV Block

Technically an AV-delay and not an AV block, 1st degree AV block is defined as a prolonged interval between atrial and ventricular activation (>200ms). This delay results from disease in the AV-node or His-Purkinje system. An AV block is not the cause of bradycardia, because every atrial impulse results in conduction to the ventricles.

Second Degree AV Block

The second degree AV block can be divided in two separate entities depending on the clinical characteristics of the conduction disorder. If conduction to the ventricle is conducted in a 2:1 fashion; that is if after every second P-wave there is no conduction to the ventricle, it is not possible to distinguish between the two types and a severe kind of conduction block should be assumed. If two sequential P-wave are not followed by a QRS-complex the term malignant block is used, as this could lead to or be an indication of a total block.

  • Mobitz I (Wenkebach): The Mobitz type I block is characterized by a progressively increased P-Q interval until atrial activation is blocked in the AV-node. Thereafter conduction is restored and this cycle repeats itself. A common finding in the Mobitz I block is that the first prolongation of the PR interval is associated with the largest increase in interval. After this first prolongation of the interval, the interval gradually increases. Usually Mobitz type II block is located at the atrioventricular node and rarely deteriorates to a more severe conduction block.[8, 9]
  • Mobitz II: When atrial activation is blocked, without progressively increasing P-Q interval a Mobitz Type II AV block is present. This sudden failure of AV conduction is an omen of severe conduction disease in usually infra-Hision part of the atrioventricular conduction system.[8, 10, 11]

Third Degree AV Block

Third degree AV block is complete block of conduction between atria en ventricle. Atrial and ventricular rhythms are complete dissociated.[12]

Paroxysmal AV block

Paroxysmal atrioventricular block (PAVB), is characterized by a sudden and unexpected block of the atrial impulse. Due to the delayed emerge of an escape rhythm, these patients often present with syncope. However, if a escape rhythm is established patients may present themselves without symptoms. Two different variations of the PAVB are commonly distinguished;

1. Pause-dependent PAVB
The PD-PAVB occurs after the onset of a pause. This pause can be compensatory after a premature beat, overdrive suppression of sinus rhythm or other disorders of impulse formation. There are several hypothesis to explain this phenomenon, amongst them phase 4 depolarization (see Phase 4 abberation).

2. Tachycardia-dependent PAVB
The TD-PAVB occurs more frequently in patients due to the increased rate of the atria. TD-PAVB is associated with 2nd degree Mobitz block and Adam-Stokes Syndrome. However, some occurrences of TD-PAVB occur without a noticeable increase in atrial rate, due to minor electrophysiological changes due to changes in autonomic tone or coronary perfusion. The mechanism responsibly for the occurrence of TD-PAVB is probably repetitive concealed conduction.[13]


Ventricular Conduction Block

Ventricular conduction blocks predominantly prolong the QRS-complex, but are rarely the result of bradycardias. However, the occurrence of ventricular block on the surface ECG inform the clinician about the health of the underlying conduction system and might occur simultaneously with other types of conduction disorders.

Right bundel branch block (RBBB)

The right bundle branch is composed of one fascicle. Right bundle branch block is a unifascicular block of the right bundle and can be found in healthy people and is represented by a broad QRS complex (>120ms). However, a new RBBB in a patient with a history of normal ventricular conduction warrens further cardiological investigation. The last activity is to the right and results in a RSR’ pattern in V1 where R’ > R. This results from the delayed activation of the right ventricle. In V6 a slurred S wave can be seen at the end of the QRS complex[5, 14, 15, 16]

Left anterior fascicular block (LAFB)

The left bundle branch is composed of two fascicles. One of the fascicle has an anterior location and activates the interventricular septum and the anterior of the ventricle. Clinically a LAFB is represented by a left axis deviation and an absent or very small S and normal q in lead I and a S>R in lead II and III. QRS duration should be <120ms[5, 14, 15, 16].

Left posterior fascicular block (LPFB)

The second fascicle of the left bundle branch is the posterior fascicle. This fascicle has a posterior location and activates the posterior and lateral part of the ventricle. A left posterior fascicular block results in a right axis deviation and is represented by a deep S in I and small q in III with a QRS duration of <120ms[5, 14, 15, 16].

Left bundel branch block (LBBB)

If the two fascicles of the left bundle branch show conduction block there is a left bundle branch block. This bifascicular block is uncommon in healthy patients and further cardiologic investigations need to be performed to screen for underlying disease. Left bundle branch block causes the left ventricle to activate later then the right ventricle. This results in typical ECG characteristics, most importantly a broad QRS of >120ms. In V1 a broad monomorphic S wave can be seen (sometimes with a small r wave) representing slow left ventricular activation. In the lead V6 a broad monomorphic R wave is seen with no Q waves[5, 14, 15, 16]. [Afbeelding samenvatting alle Ventriculaire geleidingsstoornissen]

Traces of right bundle branch block and the different types of left bundle branch conduction disorders.

Functional conduction disorders: Aberrant Conduction

In certain physiological conditions a ventricular conduction disorder can arise on the ECG. This functional conduction disorder is called aberrant conduction and can mimic any form of interventricular conduction disorder. In most cases a right bundle branch block pattern can be seen on the surface ECG because the right bundle has a longer refractory period. There are a few mechanisms which can cause aberrant conduction[15, 16].

Phase 3 aberration

Phase 3 aberration is a situation that occurs when the bundle branches receive a new impulse, before they are repolarized. The bundles are still in their refractory period. This is also called Ashman phenomenon. As a result of the refractionary state of the bundle, conduction can not proceed along the refractory bundle and a conduction block is visible on the surface ECG. Thus for instance short coupled atrial activity can procedure phase 3 aberrant conduction[15, 16].

Phase 4 abberation or deceleration dependant

During a prolonged interval between cardiac activity, the Purkinje fibers can depolarize spontaneously. This depolarisation results in the conduction slowing and can even produce a conduction block. This is usually a pathological response, resulting from an increased activity in the Purkinje fibers, but can be normal at very low heart rates. Phase 4 aberration thus only occurs after prolonged pause [15, 16].

Acceleration dependant

This kind of aberrant conduction resembles phase 3 aberrant conduction; however appearance of the conduction disorders is the result of a small increase in rhythm. The ventricular conduction disorder is a result of an abnormal response of tissue that has diminished excitability and fails to excite the corresponding bundle[15, 16].

Diagnosis

In the diagnosis of bradyarrhythmias the identification of reversible causes is important to prevent unnecessary treatment. After a detailed history and physical examination there are additional investigations which can give information about the location of the nature of the bradyarrhythmia.[4]. While not all investigations are necessary, a thorough work-up has to be performed to prevent serious clinical events or pacemaker implantation. Especially the differentiation between bradyarrhtyhmias and vasovagal syncope can be difficult, but is very important for the management of symptoms [6].

Signs & Symptoms

A patient with a bradyarrhythmia can be completely asymptomatic. Otherwise, patients with bradycardia may present with a diversity of signs and symptoms. A pause in ventricular contraction > 6 seconds often resuls in syncope or near syncope [6]. More often symptoms are nonspecific and chronic and are a result of the chronotopic incompetence and reduced cardiac output. Symptoms like dizziness, light-headedness or confusional states, episodes of fatigue or muscular weakness, exercise intolerance, heart failure or palpitations can be experienced by the patient.[5]

Investigations

There are a number of additional investigations which can uncover the cause of bradyarrhythmias.

  • ECG: A surface ECG can demonstrate the conduction disorder and relate complaints to electrocardiographic findings. A Valsalva manoeuvre or carotid sinus massage whilst performing an ECG can give information about function of the autonomous nervous system and its possible role in the occurrence of the bradyarrrhythmia.
  • X-ECG: An exercise test can give information about the chronotropic competence of the cardiac conduction system [17].
  • Long-term ECG recording: Holter recording can identify causes of paroxysmal or intermittent bradyarrhythmias. Importantly a correlation with symptoms can be made and pathological causes of bradyarrhythmias or long pause (>3sec) during the night can be identified. If 24h or 48h Holter recordings cannot identify the cause of symptoms longer duration of monitoring may be required[18]. Transient event recorders can record up to 30seconds of ECG when a patient activates the device. This device can be especially useful when non-invasive monitoring is required due to the low occurrence of the bradyarrhythmia[19]. For longer monitoring an implantable loop recorder can be used. This small device can be implanted and observe rhythm over an extensive period [20].
  • Electrophysiological testing: If non-invasive testing does not discover the arrhythmia underlying the symptoms, an electrophysiologic study may be undertaken to assess sinus nodal function and atrioventricular conduction. The measurement of conduction intervals and reaction to standard electrophysiological pacing protocols can elucidate the cause of bradyarrhtyhmia.

Treatment

Fortunately the human heart has a couple of backup mechanisms that can sustain a heart rate in case of severe bradycardia. These escape mechanisms can occur in every part of the heart (i.e. atrium, AV, node, ventricle). In general, the rate of the escape mechanism is faster when the escape rhythm is located higher in the conduction system, for instance an escape rhythm of the atrium has a higher frequency than an escape rhythm from the ventricles. If no reversible cause for the bradyarrhythmia can be found and the bradyarrhythmia persist, further therapy is required if the patients remains symptomatic.

Drug Therapy

There are no options for chronic drug therapy in bradyarrhthmias. In the acute setting atropine or isoprenaline may be used to increase heart rate or AV-nodal conduction [21]. Patients with severe bradyarrhythmias (Type 2 AV nodal Mobitz II block, Type 3 AV nodal block, sinus arrest >3 seconds) should be considered for permanent or temporary pacing therapy.

Temporary pacing

Temporary pacing can be used to bridge the time to pacemaker implantation or until the bradyarrhythmia is resolved. Transvenous pacing is the most accepted method and can be used to pace the right atrium or the right ventricle after insertion of a temporary pacemaker wire through venous access. Pacing through the oesophagus can only capture the atrium, due to the anatomical position of the heart in relation with the oesophagus. Transcutanous pacing is a painful and emergency option in which muscle and heart are stimulated with large electrodes. Finally epicardal pacing is usually performed after cardiac surgery and requires surgical implantation of the electrodes on the epicardium.

Device Therapy

Implantable pacemakers activate cardiac myocardium with electrical stimulation, leading to muscle contraction. Due to the nature of a pacemaker, the activation is different from the physiological conduction system, there are electrical and mechanical consequences. It is therefore important to adjust pacemaker setting to the individual patient. The type of pacemakers and their settings are extensively covered in the device chapter of cardiac arrhythmias. The indications for pacemaker implantation in patients with bradyarrhythmias are mentioned below.

  • Sinus node disease:

Pacemaker implantation should be strongly considered in patients with sinus node disease which manifests as symptomatic bradycardia in which the symptom-rhythm correlation must have been 1) spontaneously occurring or 2) drug-induced where alternative drug therapy is lacking.[22, 23] Other reasonable eligible candidates for permanent pacing are patients with syncope with sinus node disease, spontaneously occurring or induced at electrophysiological study or patients with symptoms clearly associated to bradycardia but without documentation of this bradycardia. Patients with sinus node disease without symptoms including use of bradycardia-provoking drugs, patients with symptoms of sinus node dysfunction occurring in the absence of the bradycardia or patients with symptomatic sinus node dysfunction where symptoms can reliably be attributed to non-essential medication do not have an indication for permanent pacemaker therapy.[23]

  • Atrioventricular Block: The following patients with AV conduction block have an strong indication for pacemaker therapy; 1) chronic symptomatic third or second degree (Mobitz I or II) atrioventricular block including induced third or second degree atrioventricular block by required medication[23, 24, 25] 2) asymptomatic patients with third or second degree (Mobitz I or II) atrioventricular block and documented asystole greater than 3.0 seconds in SR or 5.0 seconds in AF, an escape rhythm less than 40 bpm (or >40 bpm with left ventricular dysfunction) or infranodal escape rhythm [23, 26, 27]3) neuromuscular diseases (e.g. myotonic muscular dystrophy, Kearns–Sayre syndrome, etc.) with third-degree or second-degree atrioventricular Block[28, 29] or 4) third or second degree (Mobitz I or II) atrioventricular block after catheter ablation of the atrioventricular junction or after valve surgery when the block is not expected to resolve[23, 30, 31, 32] and 5) patient with third or second degree AV block during exercise with no myocardial ischemia[23, 33]. Patients with asymptomatic first degree atrioventricular block, asymptomatic second degree Mobitz I with supra-Hisian conduction block or atrioventricular block expected to resolve do not require a pacemaker implantation.[9, 23, 34]
  • Intraventricular conduction Block: Patient which show a intermittent third-degree atrioventricular block, advanced second-degree or Mobitz II atrioventricular block have an strong indication for pacemaker therapy[23, 35, 36, 37, 38]. Patients with a bundle branch block without atrioventricular block or symptoms and bundle branch block with first-degree atrioventricular block without symptoms should not have a pacemaker implanted.[23, 39]

References

<biblio>

  1. Epstein pmid=23255456
  2. Ferrer pmid=5695590
  3. Talan pmid=7083929
  4. Mangrum pmid=10706901
  5. Strasberg pmid 7471363
  6. Donoso pmid 14118480
  7. Zipes pmid 378457
  8. Levine pmid=13356435
  9. Kay pmid=6461235
  10. Kastor pmid=1089890
  11. Dreifus pmid=6826942
  12. Ector pmid=6191291
  13. Langberg pmid 2598419
  14. Kim pmid=11230857
  15. Glikson pmid=9388104
  16. Shaw pmid=4005079
  17. Choksk pmid=2360528
  18. Mymin pmid=3762641
  19. Stevenson pmid=2299071
  20. James pmid=14451031
  21. Friedberg pmid=14206803
  22. Dhingra pmid=4817704
  23. McAnulty1 pmid=7088050
  24. McAnulty2 pmid=619828
  25. Spodick pmid=1529897
  26. Ector2 pmid=6147639
  27. Mova pmid=19713422
  28. Simons pmid=9894656
  29. Wiens pmid=6741841
  30. Lichstein pmid=6176956
  31. Kinley pmid=7503472
  32. Krahn pmid=15125724
  33. Hoffman pmid=3536438
  34. ESC isbn=9780199566990
  35. ECGpedia http://en.ecgpedia.org
  36. Robles isbn=9789031313983
  37. Wellens isbn=9781416002598
  38. Elsherrif PMCID: PMC2877697