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Long QT syndrome
Long QT in sport review PMID 30416732

LQT genetics review PMID 29661707

ESC channelopathy guidelines PMID 26320108.

The sensorineural hearing loss in JLNS is present from birth and can be diagnosed using audiometry or physiological tests of hearing. ref 20301607 The cardiac features of JLNS can be diagnosed by measuring the QT interval corrected for heart rate (QTc) on a 12-lead electrocardiogram (ECG). The QTc is less than 450 ms in 95% of normal males, and less than 460 ms in 95% of normal females. In those with Jervell and Lange-Nielsen syndrome the QTc is typically greater than 500 ms. ref 20301579. Other factors beyond the QT interval should be taken into account when making a diagnosis, some of which have been incorporated into scoring systems such as the Schwartz score. These factors include a history of characteristic abnormal heart rhythms (Torsades de Pointes), unexplained blackouts (syncope), and a family history of confirmed LQT syndrome. Genetic testing to identify variants in the KCNQ1 or KCNE1 genes can also be used.

Causes
Several subtypes of Romano-Ward syndrome have been described based on the underlying genetic variant. These subtypes differ in clinical presentation and their response to treatment. There is robust evidence that the genetic variants associated with the three most common subtypes (LQT1, LQT2 and LQT3) are truly causative of the syndrome. However, there is uncertainty as to whether some of the other rarer subtypes are truly disease-causing by themselves or instead make individuals more susceptible to QT prolongation in response to other factors such as medication or low blood potassium levels (hypokalaemia).

LQT1
LQT1 is the most common subtype of Romano-Ward syndrome, responsible for 30 to 35% of all cases. The gene responsible, KCNQ1, has been isolated to chromosome 11p15.5 and encodes the alpha subunit of the KvLQT1 potassium channel. This subunit interacts with other proteins (in particular, the minK beta subunit) to create the channel, which carries the delayed potassium rectifier current IKs responsible for the repolarisation phase of the cardiac action potential.

Variants in KCNQ1 cause the LQT1 subtype of Romano-Ward syndrome when a single copy of the variant is inherited (heterozygous, autosomal dominant inheritance). When two copies of the variant are inherited (homozygous, autosomal recessive inheritance) the more severe Jervell and Lange-Nielsen syndrome is found, associated with more marked QT prolongation, congenital sensorineural deafness, and a greater risk of arrhythmias.

LQT1 is associated with a high risk of faints but lower risk of sudden death than LQT2.

LQT1 may also affect glucose regulation. After ingesting glucose, those with LQT1 produce more insulin than would be expected, which is followed by a period of insulin resistance. When the resistance diminishes, abnormally low blood glucose levels (hypoglycaemia) are sometimes seen.

LQT2
The LQT2 subtype is the second-most common form of Romano-Ward syndrome, responsible for 25 to 30% of all cases. This form of Romano-Ward syndrome is caused by variants in the KCNH2 gene on chromosome 7. KCNH2 (also known as hERG) encodes the potassium channel which carries the rapid inward rectifier current IKr. This current contributes to the terminal repolarisation phase of the cardiac action potential, and therefore the length of the QT interval.

LQT3
The LQT3 subtype of Romano-Ward syndrome is caused by variants in the SCN5A gene located on chromosome 3p21-24. SCN5A encodes the alpha subunit of the cardiac sodium channel, NaV1.5, responsible for the sodium current INa which depolarises cardiac cells at the start of the action potential. Cardiac sodium channels normally inactivate rapidly, but the mutations involved in LQT3 slow their inactivation leading to a small sustained 'late' sodium current. This continued inward current prolongs the action potential and thereby the QT interval.

A large number of mutations have been characterized as leading to or predisposing to LQT3. Calcium has been suggested as a regulator of SCN5A protein, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Furthermore, mutations in SCN5A can cause Brugada syndrome, cardiac conduction disease, and dilated cardiomyopathy. In rare situations, some affected individuals can have combinations of these diseases.

Other subtypes
LQT5 is caused by variants in the the KCNE1 gene. This gene is responsible for the potassium channel beta subunit MinK which, in conjunction with the alpha subunit encoded by KCNQ1, is responsible for the potassium current IKs, and variants associated with prolonged QT intervals decrease this current. The same variants in KCNE1 can cause the the more severe Jervell and Lange-Nielsen syndrome when two copies are inherited (homozygous inheritance) and the milder LQT5 subtype of Romano-Ward syndrome when a single copy of the variant is inherited (heterozygous inheritance).

The LQT6 subtype is caused by variants in the KCNE2 gene. This gene is responsible for the potassium channel beta subunit MiRP1 which generates the potassium current IKr, and variant that decrease this current have been associated with prolongation of the QT interval. However, subsequent evidence such as the relatively common finding of variants in the gene in those without long QT syndrome, and the general need for a second stressor such as hypokalaemia to be present to reveal the QT prolongation, has suggested that this gene instead represents a modifier to susceptibility to QT prolongation. Some therefore dispute whether variants in the gene are sufficient to cause Romano-Ward syndrome by themselves.

LQT9 is caused by variants in the membrane structural protein, caveolin -3. Caveolins form specific membrane domains called caveolae in which voltage-gated sodium channels sit. Similar to LQT3, these caveolin variants increase the late sustained sodium current, which impairs cellular repolarization.

LQT10 is an extremely rare subtype, caused by variants in the SCN4B gene. The product of this gene is an auxillary beta-subunit (NaVβ4) forming cardiac sodium channels, variants in which increase the late sustained sodium current. LQT13 is caused by variants in GIRK4, a protein involved in the parasympathetic modulation of the heart. Clinically, the patients are characterized by only modest QT prolongation, but an increased propensity for atrial arrhythmias. LQT14, LQT15 and LQT16 are caused by variants in the genes responsible for calmodulin (CALM1, CALM2, and CALM3 respectively). Calmodulin interacts with several ion channels and its roles include modulation of the L-type calcium current in response to calcium concentrations, and trafficking the proteins produced by KCNQ1 and thereby influencing potassium currents. The precise mechanisms by which means these genetic variants prolong the QT interval remain uncertain.

LQTS mechanism
The various forms of long QT syndrome, both congenital and acquired, lead to a tendency to abnormal heart rhythms through their effects on the electrical signals used to coordinate individual heart cells. The common theme linking the various causes is a prolongation of the cardiac action potentia l - the characteristic pattern of voltage changes across the cell membrane that occur with each heart beat. Heart cells when relaxed normally have fewer positively charged ions on the inner side of their cell membrane than on the outer side, referred to as the membrane being polarised. When heart cells contract, positively charged ions such as sodium and calcium enter the cell, equalising or reversing this polarity, at which point the cell is said to be depolarised. After a contraction has taken place, the cell restores it's polarity (or repolarises) by allowing positively charged ions such as potassium to leave the cell, restoring the membrane to its relaxed, polarised state. In long QT syndrome it takes longer for this repolarisation to occur, shown in individual cells as a longer action potential and marked on the surface ECG as a long QT interval.

The prolonged action potentials can lead to arrhythmias through several potential mechanisms. The characteristic arrhythmia seen in long QT syndrome, Torsades de Pointes, starts when additional action potentials occur after an initial triggering beat in the form of afterdepolarisations. Early afterdepolarisations, occurring before the cell has fully repolarised, are particularly likely to be seen when action potentials are prolonged, and arise due to reactivation of calcium and sodium channels that would normally switch off until the next heartbeat is due. Ref Wit 2017 PMID 29920724 Under the right conditions, reactivation of these currents, facilitated by the sodium-calcium exchanger, can cause further depolarisation of the cell. Ref Wit 2017 PMID 29920724  The early afterdepolarisations triggering arrhythmias in long QT syndrome tend to arise from the Purkinje fibres of the cardiac conduction system. Ref Sherif 2019 PMID 31114687 Early afterdepolarisations may occur as single events, but may occur repeatedly leading to multiple rapid activations of the cell. Ref Wit 2017 PMID 29920724

Some research suggests that delayed afterdepolarisations, occurring after repolarisation has completed, may also play a role in long QT syndrome. Ref Sherif 2019 PMID 31114687  This form of afterdepolarisation originates from the spontaneous release of calcium from the intracellular calcium store known as the sarcoplasmic reticulum, forcing calcium out of cell through the sodium calcium exchanger in exchange for sodium, generating a net inward current. Ref Wit 2017 PMID 29920724

While there is strong evidence that the trigger for Torsades de Pointes comes from afterdepolarisations, it is less certain what sustains this arrhythmia. Some lines of evidence suggest that repeated afterdepolarisations from many sources contribute to the continuing arrhythmia. Ref Sherif 2019 PMID 31114687 However, some suggest that the arrhythmia sustains through a mechanism known as re-entry. According to this model, the action potential prolongation occurs to a variable extent in different layers of the heart muscle with longer action potentials in some layers than others. Ref Sherif 2019 PMID 31114687 In response to a triggering impulse, the waves of depolarisation will spread through regions with shorter action potentials but block in regions with longer action potentials. This allows the depolarising wavefront to bend around areas of block, potentially forming a complete loop and self-perpetuating. The twisting pattern on the ECG can be explained by movement of the core of the re-entrant circuit in the form of a meandering spiral wave. Ref Sherif 2019 PMID 31114687

LQTS in pregnancy
Influence of Pregnancy in Patients With Congenital Long QT Syndrome. Review. PMID: 27054604



Treatment
PMID 24383070 - ATS review

ESC channelopathy guidelines PMID 26320108.

Mechanism
Andersen-Tawil syndrome increases the risk of abnormal heart rhythms by disturbing the electrical signals that are used to coordinate individual heart cells. The genetic variant disturbs an ion channel responsible for the flow of potassium, reducing the /K1 current. This prolongs of the cardiac action potentia l - the characteristic pattern of voltage changes across the cell membrane that occur with each heart beat, and depolarises the resting membrane potential of cardiac and skeletal muscle cells. Ref Nguyen 2013.

Cardiac and skeletal muscle cells, when relaxed, have fewer positively charged ions on the inner side of their cell membrane than on the outer side, referred to as their membranes being polarised. The main ion current responsible for maintaining this polarity is /K1, and a decrease in this current leads to less polarity at rest, or a depolarised resting membrane potential. When these cells contract, positively charged ions such as sodium and calcium enter the cell through ion channels, depolarising or reversing this polarity. After a contraction has taken place, the cell restores its polarity (or repolarises) by allowing positively charged ions such as potassium to leave the cell, restoring the membrane to its relaxed, polarised state. The genetic variant found in those with Andersen-Tawil decreases the flow of potassium, slowing the rate of repolarisation which can be seen in individual cardiac muscle cells as a longer action potential and on the surface ECG as a prolonged QT interval.

The prolonged action potentials can lead to arrhythmias through several potential mechanisms. The frequent ventricular ectopy and bidirectional VT typical of Andersen-Tawil syndrome are initiated by a triggering beat in the form of an afterdepolarisation. Early afterdepolarisations, occurring before the cell has fully repolarised, arise due to reactivation of calcium and sodium channels that would normally be inactivated until the next heartbeat is due. Ref Wit 2017 PMID 29920724 Under the right conditions, reactivation of these currents can cause further depolarisation of the cell, facilitated by the sodium-calcium exchanger Ref Wit 2017 PMID 29920724 Early afterdepolarisations may occur as single events, but may occur repeatedly leading to multiple rapid activations of the cell. Ref Wit 2017 PMID 29920724 Delayed afterdepolarisations, occurring after repolarisation has completed, arise from the spontaneous release of calcium from the intracellular calcium store known as the sarcoplasmic reticulum. This calcium release then leaves the cell through the sodium calcium exchanger in exchange for sodium, generating a net inward current and depolarising the cell membrane. Ref Wit 2017 PMID 29920724 If this transient inward current is large enough, a premature action potential is triggered.

The muscle weakness seen in those with Andersen-Tawil syndrome arises from the depolarisation of the resting membrane potential caused by a decrease in /K1. Ref Nguyen. The depolarised resting membrane potential means that sodium channels which are responsible for initiating action potentials are unable to fully recover from inactivation, leading to a less excitable membrane and less forceful muscle contraction. Ref Nguyen.

The mechanisms underlying the skeletal abnormalities seen in Andersen-Tawil syndrome have not been fully explained. Possibilities include impaired function of osteoclasts, cells which regulate bone growth, or disruption of the bone morphogenetic protein signalling cascade. Ref Nguyen.

Myotonic dystrophy
https://www.myotonic.org/mdf-releases-updated-anesthesia-guidelines

Update info regarding anaesthesia and regarding cardiac involvement in the condition

AVNRT treatment
Treatments for AVNRT aim to terminate episodes of tachycardia, and to prevent further episodes from occurring in the future. These treatments include physical manoeuvres, medication, and invasive procedures such as ablation.

Arrhythmia termination
An episode of supraventricular tachycardia due to AVNRT can be terminated by any action that transiently blocks the AV node. Some of those with AVNRT may be able to stop their attack by using physical manoeuvres that increase the activity of the vagus nerve on the heart, specifically on the atrioventricular node. These manoeuvres include carotid sinus massage (pressure on the carotid sinus in the neck) and the Valsalva manoeuvre (increasing the pressure in the chest by attempting to exhale against a closed airway by bearing down or holding one's breath). Medications that slow or briefly halt electrical conduction through the AV node of the heart can terminate AVNRT, including adenosine, beta blockers, or non-dihydropyridine calcium channel blockers (such as verapamil or diltiazem). Both adenosine and beta blockers may cause tightening of the airways, and are therefore used with caution in people who are known to have asthma. Less commonly used drugs for this purpose include antiarrhythmic drugs such as flecainide or amiodarone.

If the fast heart rate is poorly tolerated (e.g. the development of heart failure symptoms, low blood pressure or coma) then AVNRT can be terminated electrically using a cardioversion. In this procedure, after administering a strong sedative or general anaesthetic, an electric shock is applied to the heart to restore a normal rhythm.

Arrhythmia prevention
While preventative treatment may be very helpful at stopping the unpleasant symptoms associated with AVNRT, as this arrhythmia is a benign condition, preventative treatment is not essential. Some of those who choose not to have further treatment will eventually become asymptomatic. Those who wish to have further treatment can choose to take long term antiarrhythmic medication. The first line drugs are calcium channel antagonists and beta blockers, with second line agents including flecainide, amiodarone, and occasionally digoxin. These drugs are moderately effective at preventing further episodes but need to be taken long term.

Alternatively, an invasive procedure called an electrophysiology (EP) study can be used to confirm the diagnosis and potentially offer a cure. This procedure involves introducing wires or catheters into the heart through a vein in the leg. The tip of one of these catheters can be used to heat or freeze the slow pathway of the AV node, destroying its ability to conduct electrical impulses, and preventing AVNRT. The risks and benefits are weighed up before this is performed. Catheter ablation of the slow pathway, if successfully carried out, can potentially cure AVNRT with success rates of >95%, balanced against a small risk of complications including damaging the AV node and subsequently requiring a pacemaker.

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