Catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia
Synonyms CPVT
Specialty Cardiology
Symptoms Blackouts, sudden cardiac death
Usual onset Childhood / adolescence
Causes Genetic
Risk factors Family history
Diagnostic method Electrocardiogram (ECG), genetic testing, adrenaline provocation, exercise testing
Differential diagnosis Long QT syndrome, Brugada syndrome, Andersen-Tawil syndrome Early repolarisation syndrome
Treatment Avoidance of strenuous exercise, medication, implantable cardioverter defibrillator
Medication Beta-adrenoceptor blockers, Verapamil, Flecainide
Prognosis 13-20% life threatening arrhythmias over 7-8 years
Frequency 1:10,000

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and typically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but may experience blackouts or even sudden cardiac death.

CPVT is caused by genetic mutations affecting proteins that regulate the concentrations of calcium within cardiac muscle cells. The most commonly identified gene is RYR2, encoding a protein encoding a channel known as the ryanodine receptor, which releases calcium from the cells internal calcium store, the sarcoplasmic reticulum, during every heartbeat.

CPVT is often diagnosed on an ECG recorded during an exercise tolerance test, but may also be diagnosed with a genetic test. The condition is treated with medication including beta-adrenoceptor blockers or flecainide, and with surgical procedures including sympathetic denervation and implantation of a defibrillator.

The condition is thought to affect as many as one in ten thousand people and is estimated to cause 15% of all unexplained sudden cardiac deaths in young people. CPVT was first recognised in 1960, and the underlying genetics were described in 2001.

Signs and symptoms

Bidirectional ventricular tachycardia in a patient with CPVT during exercise testing

Although patients with CPVT may not have any symptoms, the most commonly reported symptoms in persons with CPVT are blackouts or sudden loss of consciousness, referred to as syncope.[1] These blackouts often occur during exercise or as a response to emotional stress - situations when chemical messengers known as catecholamines such as adrenaline are released within the body. In those with CPVT, catecholamine release can lead to an abnormal heart rhythm or arrhythmia known as ventricular tachycardia. [2] In CPVT, the ventricular tachycardia often takes a characteristic form known as bidirectional ventricular tachycardia.[1] This arrhythmia in some cases terminates by itself, causing a blackout from which the person then recovers. However, if the abnormal heart rhythm continues, it can degenerate into a more dangerous arrhythmia known as ventricular fibrillation causing a cardiac arrest, and if untreated, sudden death. Sudden death may be the first manifestation of the disease in some patients, which may take the form of sudden infant death syndrome or 'cot death'.[1]

There are typically very few abnormal signs on clinical examination in persons with CPVT. However, approximately 20% of those with CPVT have a slow resting heart rate known as a sinus bradycardia.[2]

Mechanism

Excitation contraction coupling

The arrhythmias that those with CPVT experience are caused by abnormalities in the way that cardiac muscle cells control their levels of calcium. [3] Calcium interacts with the protein fibres or myofibrils inside the cell that allow the cell to contract, and the concentration of calcium within each cell needs to be very tightly regulated. During each heartbeat, the concentration of calcium must rise to allow the muscle to contract, and then fall to allow the muscle to relax, a process achieved by using a store within the cell known as the sarcoplasmic reticulum.[4]

Proteins involved in cardiac calcium cycling

At the start of each heartbeat, calcium is released from the sarcoplasmic reticulum through specialised channels known as ryanodine receptors. [4] In response to an electrical signal from the cell membrane called an action potential, a small amount of calcium flowing across the cell membrane triggers ryanodine receptors to release a puff of calcium known as a calcium spark. Each spark triggers the release of further sparks from neighbouring ryanodine receptors to create an organised rise of calcium throughout the cell known as a calcium transient. At the end of each heartbeat, calcium is pumped back by a protein called SERCA, and held within the sarcoplasmic reticulum by a protein called calsequestrin.[4] Alterations to the proteins involved in this mechanism can disrupt this carefully regulated process and lead to arrhythmias.

Calcium-dependent arrhythmias

In those with CPVT, the normally tight regulation of calcium can become deranged.[3] While calcium is generally released from the sarcoplasmic reticulum response to an action potential, calcium sparks can occur spontaneously in healthy and diseased hearts. In a healthy heart, a spontaneous calcium spark is generally an isolated event and goes no further, but if ryanodine receptors or the proteins that regulate them are abnormal, these sparks can trigger releases from neighbouring ryanodine receptors which spread throughout the cell as a calcium wave.[3] These calcium waves are much more likely to occur when cardiac muscle cells are stimulated by catecholamines such as adrenaline which increase the concentration of calcium within the sarcoplasmic reticulum and sensitise the ryanodine receptors. The uncontrolled wave of calcium can be forced out through the cell membrane, causing an electrical current known as a delayed afterdepolarisation. Afterdepolarisations, if large enough, can trigger additional action potentials, premature ventricular contractions, or sustained arrhythmias.[3]

Molecular genetics

CPVT can be caused by mutations in several genes, all of which are responsible for regulating the concentrations of calcium within cardiac muscle cells. The most commonly identified genetic mutation in CPVT is a mutation in the RYR2 gene that encodes the cardiac ryanodine receptor, responsible for releasing calcium from the sarcoplasmic reticulum.[5] Mutations in this gene lead to an autosomal dominant form of CPVT. Mutations associated with CPVT have also been identified in the CASQ2 gene which encodes calsequestrin, a protein that binds calcium within the sarcoplasmic reticulum.[5] Other genes associated with CPVT include TECRL encoding Trans-2,3-enoyl-CoA reductase-like protein, CALM1 encoding Calmodulin, and TRDN encoding Triadin.[5]

Type OMIM Gene Locus Inheritance Notes
CPVT1 604772 RYR2 1q42.1-q43 AD Ryanodine receptor - releases calcium from the sarcoplasmic reticulum [5]
CPVT2 611938 CASQ2 1p13.3-p11 AR Calsequestrin - calcium buffer within the sarcoplasmic reticulum [5]
CPVT3 614021 TECRL 7p22-p14 AR Trans-2,3-enoyl-CoA reductase-like protein - interacts with RyR2 and calsequestrin [5]
CPVT4 614916 CALM1 14q32.11 AD Calmodulin - stabilises RyR2 [5]
CPVT5 615441 TRDN 6q22.31 AR Triadin - interacts with RyR2 and calsequestrin [5]

    CPVT1 (RYR2)

    Mutation of the Ryanodine receptor isoform 2 (RYR2) gene has been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT).[6] Under normal physiological conditions, RYR2 mutation has no discernable effect on calcium induced-calcium release from the sarcoplasmic reticulum (SR).[6] Ryr2 is normally activated by increased cytosolic calcium, but under stressful conditions such as increased beta adrenergic activation, RYR2 is activated by luminal calcium in association with increased SR calcium loading.[6][7][8] The increased luminal calcium activation occurs because of a phenomenon termed store-overload induced calcium release (SOICR).[9] SOICR leads to spontaneous and inappropriate action potentials, generating arrhythmias.[10][11][12] A Ryr2 mutation may increase sensitivity to luminal calcium activation, therefore increasing calcium release from the SR under store-overload conditions and thus triggered arrhythmias.[13][14]

    RYR2 mutations have been well characterized and been found to occur primarily in 4 major domains.[6] Mutations in domains III and IV of the protein (amino acid range from 3778 to 4201 and 4497 to 4959 respectively) occur in 46% of reported mutations.[6] Mutations occur less frequently in domains I and II (amino acid 77-466 and 2246-2534 respectively).[6] Causative RYR2 mutations outside these four domains are very rare, occurring in as little as 10% of reported cases.[15] Ryr2 mutations are most often single nucleotide substitutions resulting in a different amino acid substitution, however some in-frame substitutions and duplications have been documented [15][16] . It is commonly accepted that more severe mutations have not been linked to CPTV as they are more likely to underlie different cardiac pathologies.[6]

    Recent findings have characterized the pathology of RYR2 mutations and how they relate to SOICR as a matter of the intrinsic properties of the ryanodine channel. Two theories propose the underlying mechanism, domain unzipping and FKBP12.6 unbinding.[6] Firstly, domain unzipping refers to the separation of the N-terminal domain's interaction with the central domain; destabilizing the receptor.[17][18] The mutation would compromise the stability of the Ryr2's closed state and increase its sensitivity to stimuli like luminal and cytosolic calcium.[6][17][18] Domain unzipping coincides with the specific Ryr2 domain mutations associated with CPTV.[19] The second theory of FKBP12.6 is more controversial.[19] FKBP12.6 is a RYR2 binding protein that stabilizes the receptor. FKBP12.6 binding to RYR2 is regulated by RYR2 phosphorylation via PKA that results in the dissociation of FKBP12.6, rendering Ryr2 more sensitive to cytosolic calcium activation.[20] However, as mentioned above, evidence has been conflicted in determining FKBP12.6's role in CPTV.[6] So far the literature concludes that FKBP12.6 may play a role in certain CPTV mutations but not others, further research needs to clarify this protein's role.[6]

    CPVT2 (CASQ2)

    Mutations in the Calsequestrin isoform 2 (CASQ2) gene has been linked to CPVT.[21] Under normal physiological conditions, CASQ2 is the major luminal Ca2+ binding protein in the sarcoplasmic reticulum (SR)[6][21][22][23][24][25][26] ), which in the main Ca2+ storage organelle in cardiac muscle. CASQ2 is also associated with regulating SR Ca2+ release when bound to triadin, junctin and RYR2, forming a complex [22] .[21] This cytosolic to luminal Ca2+ activation process that RYR2 regulates is termed store-overload induced calcium release (SOICR). CASQ2 is responsible for initiating and terminating this process.[6] CASQ2 acts in low levels of SR Ca2+, where CASQ2 monomers inhibit RYR2 by forming the triadin-junctin-RYR2 complex, however at high levels of SR Ca2+, CASQ2 monomers form polymers and dissociate from the RYR2 channel complex, removing the inhibitory response activating the channel to spontaneously release Ca2+.[6][24] A mutation, specifically R33Q and D307H in CASQ2 tend to alter the Ca2+ binding capacity or alter the interactions between CASQ2 and RYR2 channel complex, potentially affecting the response of RYR2.[6][24]

    Mutations in the CASQ2 gene have been classified into 12 CPVT associated mutations: 4 are nonsense mutations causing shortening of proteins, and 8 are missense mutations. R33Q and D307H reduce CASQ2 protein to 5% and 45% of normal levels respectively, which reduces SR Ca2+ buffering and binding capacity.[6][22][25][26] The most severe missense mutation, D307H, converts aspartic acid (negatively charged) to a histidine within a Ca2+ chelating region. This disrupts Ca2+ binding to CASQ2, but the specific mechanism behind this mutation is still undetermined.[25][26] The missense mutation R33Q causes a substitution of glutamine for arginine, decreasing the total amount of Ca2+ stored in the SR, thus increasing the Ca2+ buffering system causing Ca2+ leak through RYR2, where the mechanism behind this mutation is proposed to interact with triadin and/or junction forming "polar zippers".[24][25]

    There are two major theories as to what is occurring when CASQ2 is deficient. It was found that decreased CASQ2 is associated with high levels of calreticulin (CRT).[22] In the absence of CASQ2 signal, CRT levels increase and provide some compensatory SR Ca2+ binding activity. CRT levels decrease significantly after birth and high levels are only present in the developing heart, leading to the theory of caused bradycardia and sinus node dysfunction which is found in CPTV patients.[22] With the absence of CASQ2, it was also found that RYR2 activity remained high in diastole since CASQ2 could not provide the inhibitory response, causing a prolonged Ca2+ leak which triggers early action potentials.[21][22][23] With reduced SR Ca2+ buffering capacity, is a faster recovery of SR free Ca2+ after each Ca2+ release, resulting in higher levels of SR free Ca2+ and SR Ca2+ loading, both increasing trigger activity and SOICR recurrence.[6][22] The exact mechanisms by which the mutations occur in the CASQ2 gene are still under investigation. Research underway is analyzing strategies to target RYR2 inhibition and approaches to increasing SR Ca2+.[22]

    Diagnosis

    CPVT may be challenging to diagnose. The structure of the heart appears normal in those affected by the condition when assessed using an echocardiogram, cardiac MRI scan or cardiac CT scan. At rest, even the electrical function of the heart appears normal when assessed using a standard 12-lead ECG.[27] However, in response to exercise or catecholamines such as adrenaline, abnormal heart rhythms such as bidirectional ventricular tachycardia or frequent polymorphic ventricular ectopic beats may be seen.[28]

    12-lead ECG

    Normal resting 12-lead ECG in a patient with CPVT

    The resting 12-lead ECG is a useful test to differentiate CPVT from other electrical diseases of the heart that can cause similar abnormal heart rhythms. Unlike conditions such as long QT syndrome and Brugada syndrome, the resting 12-lead ECG in those with CPVT is generally normal. However, approximately 20% of those affected have a slow resting heart rate or sinus bradycardia.[5]

    Exercise and other provocative testing

    Treadmill exercise stress testing

    Exercise testing, commonly performed on a treadmill or stationary bicycle, can help to diagnose CPVT. During the test, those with CPVT often experience ectopic beats, which may progress to bidirectional and then polymorphic ventricular tachycardia as the intensity of exercise increases.[29] Some of those suspected of having CPVT, such as young children, may not be able to perform an exercise tolerance test. In these cases, alternative forms of testing include adrenaline provocation testing, during which adrenaline is infused into a vein at gradually increasing doses under close supervision and ECG monitoring.[28] Additionally, long term or Holter ECG monitoring can be performed, although this form of testing is less likely to detect an arrhythmia. Invasive electrophysiological studies do not provide useful information to help diagnose CPVT or to assess the risk of life threatening arrhythmias.[27][28]

    Genetic testing

    CPVT can also be diagnosed by identifying a disease-causing mutation in a gene associated with CPVT using genetic testing.[28][27] This technique may be the only way to identify the cause of death in someone suspected of having CPVT, and in this case may be known as a molecular autopsy.[30]

    Treatment

    The treatment for CPVT aims to prevent lethal abnormal heart rhythms from occurring, and to rapidly restore a normal rhythm if they do occur. As the arrhythmias in CPVT generally occur at times when the heart is exposed to high levels of adrenaline or other similar chemical messengers (catecholamines), many treatments for CPVT aim to lower the levels of catecholamines the heart is exposed to or block their effects on the heart.

    The first line treatment for those with CVT involves lifestyle advice. This includes avoiding competitive sports,very strenuous exercise and highly stressful environments as high levels of adrenaline can occur in these settings which can provoke arrhythmias.[27]

    Medication

    Several medications can be useful for those with CPVT. The mainstays of treatment are beta blockers which block the effects of adrenaline on the heart, reducing the chance of abnormal heart rhythms developing.[27] Of all the beta blockers, Nadolol may be the most effective for treating CPVT.[5] This drug lowers the heart rate to a greater extent than other beta blockers and only needs to be taken once daily, reducing the chance of missed doses.[5] Propranolol is an alternative beta blocker as Nadolol is not available in all countries.[5]

    Flecainide is a class 1c antiarrhythmic drug that is recommended for those with CPVT who experience abnormal heart rhythms despite taking a beta blocker.[27] Flecainide reduces the risk of arrhythmias in those with CPVT, but it remains uncertain how Flecainide achieves this. Some have suggested that Flecainide directly interacts with the cardiac ryanodine receptor which is frequently abnormal in those with CPVT, while other suggest that the anti-arrhythmic effects of Flecainide rely entirely on its sodium channel blocking effects.[31]

    Verapamil is a calcium channel antagonist that, when combined with a beta blocker, may reduce the risk of arrhythmias in patients with CPVT.[32][33] Propafenone is another antiarrhythmic that may reduce the risk of arrhythmias, potentially through direct effects on the ryanodine receptor.[31]

    Sympathetic denervation

    The sympathetic nervous system

    Some persons with CPVT continue to experience life-threatening arrhythmias despite medical therapy. In this case a surgical procedure can be used to reduce the levels of adrenaline that the heart is exposed to.[27] A part of the sympathetic nervous system which supplies adrenaline to the body's organs can be intentionally damaged in an operation known as cardiac sympathetic denervation or sympathectomy.[34] While the sympathetic nervous system feeds into the heart from both sides, often only the left sided nerves are targeted during sympathectomy, although destruction of the nerves on both sides may be required.[34] By disrupting the supply of adrenaline to the heart, sympathectomy is effective at decreasing the risk of further life-threatening arrhythmias.[2]

    Implantable cardioverter-defibrillator

    Chest x-ray of a patient with an implantable defibrillator (components labelled)

    While medication and sympathectomy aim to prevent abnormal heart rhythms from occurring in the first place, an implantable defibrillator (ICD) may be used to treat arrhythmias that medication has failed to prevent and restore a normal heart rhythm.[27] These devices, usually implanted under the skin at the front of the chest below the shoulder, can continuously monitor the heart looking for abnormal heart rhythms. If a life-threatening arrhythmia is detected, the device can deliver a small electric shock to terminate the abnormal rhythm and restart the heart.[1]

    Implantable defibrillators are often recommended for those with CPVT who have experienced blackouts, ventricular arrhythmias or cardiac arrest despite taking appropriate medication.[27] These devices can be life saving, although the resulting surge of adrenaline caused by the pain of an electric shock from the device can sometimes bring on a cycle of recurrent arrhythmias and shocks known as an electrical storm.[2] Because of this, it is strongly recommended that those with an ICD implanted for CPVT should take a beta blocker to dampen down the effects of adrenaline.[2]

    Epidemiology

    CPVT is estimated to affect 1 in 10,000 people.[2] Symptoms from CPVT are typically first seen in the first or second decade of life and more than 60% of affected individuals having their first episode of syncope or cardiac arrest by age 12-20.[1] However, a small number of patients may present later in life, and genetic testing in these patients frequently fails to identify a causative gene.[2]

    Prognosis

    A significant proportion of those with CPVT will experience a life-threatening abnormal heart rhythm, with estimates of this risk ranging from 13-20% over the course of 7–8 years.[35][35] Life-threatening arrhythmias are more likely to occur if CPVT has been diagnosed in childhood, if a person with CPVT does not take beta blockers, and if arrhythmias occur on exercise testing despite taking beta blockers.[27]

    History

    In 1960, Norwegian cardiologist Dr Knut Berg published a report on 3 sisters who suffered from blackouts during exercise or emotional stress in what is now recognised as the first description of CPVT.[5] The bidirectional ventricular tachycardia associated with this condition was described by Reid in 1975.[1] The term "Catecholaminergic Polymorphic Ventricular Tachycardia" was used in the case series published by Coumel in 1978 and Leenhardt in 1995.[36] In 1999, the first genetic mutation causing CPVT to be identified was localised to chromosome 1q42-q43,[37] which was found to be a variant in the RYR2 gene in 2001.[38] Ongoing research aims to identify better treatments for CPVT, increase understanding of the mechanisms of arrhythmia, and identify other genes causing the condition.[39]

    See also

    References

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    34. 1 2 Schwartz PJ, De Ferrari GM, Pugliese L (June 2017). "Cardiac sympathetic denervation 100years later: Jonnesco would have never believed it". International Journal of Cardiology. 237: 25–28. doi:10.1016/j.ijcard.2017.03.020. PMID 28318666.
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    38. ↑ Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA (January 2001). "Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia". Circulation. 103 (2): 196–200. PMID 11208676.
    39. ↑ Behere SP, Weindling SN (2016-5). "Catecholaminergic polymorphic ventricular tachycardia: An exciting new era". Annals of Pediatric Cardiology. 9 (2): 137–46. doi:10.4103/0974-2069.180645. PMC 4867798. PMID 27212848. Check date values in: |date= (help)

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