Catecholaminergic polymorphic ventricular tachycardia
|Catecholaminergic polymorphic ventricular tachycardia|
|Classification and external resources|
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rhythm disorder of the ventricles of the heart that occurs in genetically predisposed individuals. Synonyms: Familial Polymorphic Ventricular Tachycardia (FPVT), Catecholamine-Induced Polymorphic Ventricular Tachycardia. Thought to affect as many as one in ten thousand people, it is estimated to cause 15% of all unexplained sudden cardiac deaths in young people.
First recognized in 1975, this condition is due to mutations in genes encoding a calcium channel or proteins related to this channel. All mutated proteins participate in the regulation of calcium ion flow in and out of the sarcoplasmatic reticulum of cardiac cells. Therefore reduced electrical stability of cardiomyocytes may cause the heart to enter a life-threatening state of ventricular arrhythmia as response to the natural release of catecholamines from nerve endings on the heart muscle and from the adrenal glands into the circulation. This rhythm disturbance prevents the heart from pumping blood appropriately. Ventricular tachycardia may self-terminate or degenerate into ventricular fibrillation, causing sudden death unless immediate cardiopulmonary resuscitation is applied.
Signs and symptoms
The most common symptom is dizziness or syncope which often occurs during exercise or as a response to emotional stress.
Age at onset
CPVT typically start manifesting during the first or second decade of life. The majority of events occur during childhood with more than 60% of affected individuals having their first episode of syncope or cardiac arrest by age 20.
Symptoms are typically precipitated ("triggered") by exercise-induced ventricular arrhythmias during periods of physical activity or acute emotional stress.
Affected patients demonstrate no structural problems of the heart upon echocardiographic, CT or MRI imaging.
CPVT diagnosis is based on reproducing irregularly shaped ventricular arrhythmias during ECG exercise stress testing, syncope occurring during physical activity and acute emotion, and a history of exercise or emotion-related palpitations and dizziness with an absence of structural cardiac abnormalities.
Because its symptoms are usually only triggered when the body is subjected to intense emotional or physical stress, the condition is often not detected by the traditional methods of electrophysiologic examination such as a resting electrocardiogram.
CPVT can be caused by mutations in either one of at least five genes, four of which are currently known. Mutations in two genes cause CPVT inherited by an autosomal dominant (AD) inheritance pattern while the other ones follow autosomal recessive (AR) inheritance
- The Ryanodine receptor (RYR2) is involved in intracardiac Ca2+ handling; Ca2+ overload triggers abnormal cardiac activity.
- Calsequestrin (CASQ2) is a calcium buffering protein of the sarcoplasmic reticulum.
Mutation of the Ryanodine receptor isoform 2 (RYR2) gene has been linked to catecholaminergic polymorphic ventricular tachycardia (CPTV). Under normal physiological conditions, RYR2 mutation has no discernable effect on calcium induced-calcium release from the sarcoplasmic reticulum (SR). 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. The increased luminal calcium activation occurs because of a phenomenon termed store-overload induced calcium release (SOICR). SOICR leads to spontaneous and inappropriate action potentials, generating arrhythmias. 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.
RYR2 mutations have been well characterized and been found to occur primarily in 4 major domains. 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. Mutations occur less frequently in domains I and II (amino acid 77-466 and 2246-2534 respectively). Causative RYR2 mutations outside these four domains are very rare, occurring in as little as 10% of reported cases. 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  . It is commonly accepted that more severe mutations have not been linked to CPTV as they are more likely to underlie different cardiac pathologies.
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. Firstly, domain unzipping refers to the separation of the N-terminal domain's interaction with the central domain; destabilizing the receptor. The mutation would compromise the stability of the Ryr2's closed state and increase its sensitivity to stimuli like luminal and cytosolic calcium. Domain unzipping coincides with the specific Ryr2 domain mutations associated with CPTV  . The second theory of FKBP12.6 is more controversial  . 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  . However, as mentioned above, evidence has been conflicted in determining FKBP12.6's role in CPTV. 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.
Mutations in the Calsequestrin isoform 2 (CASQ2) gene has been linked to CPVT. Under normal physiological conditions, CASQ2 is the major luminal Ca2+ binding protein in the sarcoplasmic reticulum (SR)  ), 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  . 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. 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+. 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.
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. 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. 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".
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). 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. 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. 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  . 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+.
In recent reports, left cardiac sympathetic denervation and bilateral thoracoscopic sympathectomy have shown promising results in individuals whose symptoms cannot be controlled by beta blockers.[clarification needed]
- Napolitano, Carlo; Silvia G. Priori (May 2007). "Diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia" (PDF). Heart Rhythm 4 (5): 675–8. doi:10.1016/j.hrthm.2006.12.048. PMID 17467641. Retrieved 2008-12-17.[dead link]
- Iyer, Vivek; Antonis A. Armoundas (2006). "Proc. IEEE Eng Med Biol Soc". Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference (Cardiovascular Research Center, Massachusetts General Hospital: IEEE). Suppl: 6761–4. doi:10.1109/IEMBS.2006.260941. PMID 17959506.
- Liu, N; Ruan Y; Priori SG (July–August 2008). "Catecholaminergic polymorphic ventricular tachycardia". Progress in Cardiovascular Diseases 51 (1): 23–30. doi:10.1016/j.pcad.2007.10.005. PMID 18634915.
- Wilde, Arthur; Zahurul A. Bhuiyan; Lia Crotti; Mario Facchini; Gaetano M. De Ferrari; Thomas Paul; Chiara Ferrandi; Dave R. Koolbergen; Attilio Odero; Peter J. Schwartz (2008-05-08). "Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia". New England Journal of Medicine 358 (19): 2024–9. doi:10.1056/NEJMoa0708006. PMID 18463378. Retrieved 2008-12-17.
- "Interview with Michael J. Ackerman, M.D., Ph.D." (PDF). Hannah Wernke Memorial Foundation. Retrieved 2009-02-09.[dead link]
- Wehrens XH, Marks AR (November 2004). "Sudden unexplained death caused by cardiac ryanodine receptor (RyR2) mutations". Mayo Clin. Proc. 79 (11): 1367–71. doi:10.4065/79.11.1367. PMID 15544013.[dead link]
- Priori, S. G.; Chen W. S. (2011). "Inherited dysfunction of Sarcoplasmic Reticulum Ca2+ Handling and Arrythmogenesis". Circ Res 108: 871–883. doi:10.1161/circresaha.110.226845.
- Lakatta, EG (1992). ". Functional implications of spontaneous sarcoplasmic reticulum Ca2+ release in the heart". Cardiovasc Res 26: 193–214. doi:10.1093/cvr/26.3.193.
- Lakatta, E. G.; Guarnieri T. (1993). "Spontaneous myocardial calcium oscillations: are they linked to ventricular fibrillation?". Journal of Cardiovascular Electrophysiology 4 (473-489).
- Laver, DR (2007). "Ca2+ stores regulate ryanodine receptor Ca2+ release channels via luminal and cytosolic Ca2+ sites". Biophys J 92: 3541–3555. doi:10.1529/biophysj.106.099028.
- Bers, DM (2002). "Calcium and cardiac rhythms: physiological and pathophysiological". Circ Res 90: 14–17.
- Pogwizd, SM; Bers DM (2004). "Cellular basis of triggered arrhythmias in heart failure". Trends Cardiovasc. Med. 14: 61–66. doi:10.1016/j.tcm.2003.12.002.
- Schlotthauer, K; Bers DM (2000). "Sarcoplasmic reticulum Ca2+ release causes myocyte depolarization. Underlying mechanism and threshold for triggered action potentials". Circ Res 87 (774-778).
- Jiang, D; Wang R; Xiao B; Kong H; Hunt DJ; Choi P; Zhang L; Chen SR (2005). "Enhanced store overload-induced Ca2+ release and channel sensitivity to luminal Ca2+ activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death". Circ Res 97: 1173–1181. doi:10.1161/01.res.0000192146.85173.4b.
- Jiang, D; Xiao B; Yang D; Wang R; Choi P; Zhang L; Cheng H; Chen SR (2004). "RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR)". Proc.Natl.Acad Sci 101: 13062–13067. doi:10.1073/pnas.0402388101.
- Medeiros-Domingo, A; Bhuiyan ZA; Tester DJ; Hofman N; Bikker H; van Tintelen JP; Mannens MM; Wilde AA; Ackerman MJ (2009). "The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis". J Am Coll Cardiol 54: 2065–2074. doi:10.1016/j.jacc.2009.08.022.
- Tester, DJ; , Kopplin LJ, Will ML, Ackerman MJ (2005). "Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing". Heart Rhythm 2 (1099-1105).
- Ikemoto, N; Yamamoto T (2000). "Postulated role of inter-domain interaction within the ryanodine receptor in Ca2+ channel regulation". Trends Cardiovasc Med 10: 310–316. doi:10.1016/s1050-1738(01)00067-6.
- Tateishi, H; Yano M, Mochizuki M, Suetomi T, Ono M, Xu X, Uchinoumi H, Okuda S, Oda T, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M (2009). "Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts". Cardiovasc Res 81: 536–545. doi:10.1093/cvr/cvn303.
- Wehrens, XH; Lehnart SE, Huang F, Vest JA, Reiken SR, Mohler PJ, Sun J, Guatimosim S, Song LS, Rosemblit N, D'Armiento JM, Napolitano C, Memmi M, Priori SG, Lederer WJ, Marks AR (2003). "FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death". Cell 113: 829–840. doi:10.1016/s0092-8674(03)00434-3.
- Marx, SO; Reiken S; Hisamatsu Y; Jayaraman T; Burkhoff D; Rosemblit N; Marks AR (2000). "PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts". Cell 101: 365–376. doi:10.1016/s0092-8674(00)80847-8.
- Faggioni, Michela; Kryshtal, Dmytro O.; Knollman, Bjorn C. (2012). "Calsequestrin Mutations and Catecholaminergic Polymorphic Ventricular Tachycardia". Pediatr Cardiol 33 (6): 959–967. doi:10.1007/s00246-012-0256-1.
- Priori, S.G; Chen, W. S. R (2011). "Inherited dysfunction of Sarcoplasmic Reticulum Ca2+ Handling and Arrythmogenesis". Circ Res 108: 871–883. doi:10.1161/circresaha.110.226845.
- Song, Lei; Alcalai, Ronny., Arad, Michael et al. (2007). "Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia". The Journal of Clinical Investigation 117: 1814–1823. doi:10.1172/jci31080.
- Priori, Silvia G; Lui, Nian (2008). "Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin". Cardiovascular Research 77: 293–301. doi:10.1093/cvr/cvm004.
- Terentyev, Dmitry; Nori, Alessandra., Santoro, Massimo et al. (2006). "Abnormal Interactions of Calsequestrin With the Ryanodine Receptor Calcium Release Channel Complex Linked to Exercise-Induced Sudden Cardiac Death". Circ Res 98: 1151–1158. doi:10.1161/01.res.0000220647.93982.08.
- Viatchenko-Karpinski, Serge; Terentyev, Dmitry., Gyorke, Inna et al. (2004). "Abnormal Calcium Signaling and Sudden Cardiac Death Associated With Mutation of Calsequestrin". Circ Res 94: 471–477. doi:10.1161/01.res.0000115944.10681.eb.
- Lahat, H; Pras, E; Olender, T et al. (2001). "A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel". Am J Hum Genet 69: 1378–1384. doi:10.1086/324565.
- Sumitomo, Naokata; Harada K, Nagashima M, Yasuda T, Nakamura Y, Aragaki Y, Saito A, Kurosaki K, Jouo K, Koujiro M, Konishi S, Matsuoka S, Oono T, Hayakawa S, Miura M, Ushinohama H, Shibata T, Niimura I (January 2003). "Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics / optimal therapeutic strategies to prevent sudden death". Heart 89 (1): 66–70. doi:10.1136/heart.89.1.66. PMC 1767500. PMID 12482795.
- Watanabe, Hiroshi; Nagesh Chopra; Derek Laver; Hyun Seok Hwang; Sean S. Davies; Daniel E. Roach; Henry J. Duff; Dan M. Roden; Arthur A. M. Wilde; Björn C. Knollmann (2009-04-01). "Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans". Nature Medicine 15 (4): 380–383. doi:10.1038/nm.1942. PMC 2904954. PMID 19330009. Retrieved 2009-05-04.
- Hughes, Sue (2008-05-07). "Denervation successfully treats catecholaminergic polymorphic ventricular tachycardia". HeartWire (WebMD). Retrieved 2008-12-17.
- Scott, P. A.; A. J. Sandilands; G. E. Morris; J. M. Morgan (October 2008). "Successful treatment of catecholaminergic polymorphic ventricular tachycardia with bilateral thoracoscopic sympathectomy". Heart Rhythm 5 (10): 1461–1463. doi:10.1016/j.hrthm.2008.07.007. PMID 18760972.
- Receptor defects cause inherited disorder CPVT
- Denervation successfully treats catecholaminergic polymorphic ventricular tachycardia
- Screening relatives of sudden-death victims provides likely cause of death and potentially saves lives
- Nakajima T, Kaneko Y, Taniguchi Y et al. (March 1997). "The mechanism of catecholaminergic polymorphic ventricular tachycardia may be triggered activity due to delayed afterdepolarization". Eur Heart J. 18 (3): 530–1. doi:10.1093/oxfordjournals.eurheartj.a015281. PMID 9076398.
- Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Information sheet - Auckland District Health Board's Cardiac Inherited Disease Registry
- Clinical Data's PGxHealth Division Launches CPVT Cardiac Channelopathy Test - Business Wire
- SADS UK - What is CPVT
- Arrhythmogenesis in CPVT: Lessons Learned from a CPVT Mouse Model
- Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Information Sheet
- GeneReviews article
- The Hannah Wernke Memorial Foundation