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Christian Wolpert - One of the best experts on this subject based on the ideXlab platform.
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Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile and Outcome.
Journal of the American Heart Association, 2018Co-Authors: Ibrahim El-battrawy, Rainer Schimpf, Christian Wolpert, Boris Rudic, Johanna Besler, Volker Liebe, Erol Tülümen, Siegfried Lang, Xiaobo Zhou, Ibrahim AkinAbstract:Background Short QT Syndrome (SQTS) is a rare inheritable disease associated with sudden cardiac death. Data on long‐term outcomes of families with SQTS are limited. Methods and Results Seventeen p...
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PQ segment depression in patients with Short QT Syndrome: a novel marker for diagnosing Short QT Syndrome?
Heart rhythm, 2014Co-Authors: Erol Tülümen, Chiara Scrocco, Carla Giustetto, Christian Wolpert, Olli Anttonen, Philippe Maury, Pascal Sbragia, Vincent Probst, Jean-jacques Blanc, Boris RudicAbstract:Background Patients with Short QT Syndrome (SQTS) have an increased risk for atrial tachyarrhythmias, ventricular tachyarrhythmias, and/or sudden cardiac death. PQ segment depression (PQD) is related to atrial fibrillation and carries a poor prognosis in the setting of acute inferior myocardial infarction and is a well-defined electrocardiographic (ECG) marker of acute pericarditis. Objective To evaluate the prevalence of PQD in SQTS and to analyze the association with atrial arrhythmias. Methods Digitalized 12-lead ECGs of SQTS patients were evaluated for PQD in all leads and for QT intervals in leads II and V 5 . PQD was defined as ≥0.05 mV (0.5 mm) depression from the isoelectric line. Results A total of 760 leads from 64 SQTS patients (mean age 36 ± 18 years; 48 [75%] men) were analyzed. PQD was seen in 265 (35%) leads from 52 (81%) patients and was more frequent in leads II, V 3 , aVF, V 4 , and I (n = 43 [67%], n=30 [47%], n=27 [42%], n=25 [39%], and n=25 [39%], respectively). Nine of 64 (14%) patients presented with atrial tachyarrhythmias, and all of them had PQD. Conclusion Fifty-two of 64 (81%) patients with SQTS reveal PQD. As PQD is rarely observed in healthy individuals, this ECG stigma may constitute a novel marker for SQTS in addition to a Short QT interval.
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Long-Term Follow-Up of a Pediatric Cohort with Short QT Syndrome
Heart Rhythm, 2012Co-Authors: Juan Villafañe, Christian Wolpert, Olli Anttonen, Philippe Maury, Ming-lon Young, J. Kannankeril, Michael H. Gollob, Joseph Atallah, Brett Faulknier, Roman GebauerAbstract:Background Short QT Syndrome (SQTS) is a primary electrical disease associated with atrial fibrillation and sudden cardiac death (SCD). The long-term prognosis in young patients has not been reported. The aim of this study was to define the clinical characteristics and long-term outcome of pediatric patients with SQTS. Methods This is an international case series involving 15 centers. Patients were analyzed for Gollob score, ECG characteristics, genetics, clinical events, and efficacy of medical/ICD therapy. To assess the prognostic value of Gollob scoring we devised a modified Gollob score that excludes clinical events from the original scorecard. Results Twenty-five patients KCNH2 (2), KCNJ2 (2), and KCNQ1 (1). Symptomatic patients had a higher median modified Gollob score compared with asymptomatic patients (5.0 ± 1.0 vs 4.0 ± 1.0, P = .044). Those with a score Conclusions SQTS is associated with a high risk of aborted SCD and arrhythmias among the pediatric population. Asymptomatic patients with a modified Gollob score
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Arrhythmogenic hereditary Syndromes: Brugada Syndrome, long QT Syndrome, Short QT Syndrome and CPVT.
Minerva cardioangiologica, 2010Co-Authors: Rainer Schimpf, Christian Wolpert, Christian Veltmann, Borggrefe MAbstract:In approximately 10-20% of all sudden deaths no structural cardiac abnormalities can be identified. Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada Syndrome, long QT Syndrome (LQTS), Short QT Syndrome and catecholaminergic polymorphic ventricular tachyarrhythmias. Each of these cardiac channelopathies is charaterized by unique genetic and clinical features. The resting ECG and the ECG under exercise are pivotal for the diagnosis of ion channel diseases. Molecular genetic screening can reveal underlying mutations in a variable degree among the cardiac ion channel diseases in up to 70% (LQTS) and may identify individuals with incomplete penetration of the disease. In patients with primary electrical diseases specific clinical triggers for arrhythmic events such as syncope or sudden cardiac death have been identified including exercise, strenuous activity, auditory stimuli or increased vagal tone. The significance of programmed ventricular stimulation is at present unclear concerning risk stratification in patients with Brugada Syndrome and Short QT Syndrome and of no significance in long QT Syndrome and catecholaminergic polymorphic ventricular tachycardias. The success of medical therapy remains modest for prevention of sudden cardiac death and may necessitate the insertion of an implantable cardioverter. However, side effects with inappropriate therapies in this patient group with often young and active individuals have to be encountered. More insights into the arrhythmogenesis is critical for future development of effective medical treatment strategies.
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Short QT Syndrome in a Pediatric Patient
Pediatric cardiology, 2009Co-Authors: Juan Villafañe, Christian Wolpert, Olli Anttonen, Philippe Maury, Ming-lon Young, Robert J. Hamilton, J. Kannankeril, Peter S. FischbachAbstract:Short QT Syndrome (SQTS) is a recently described genetic Syndrome characterized by abnormally brisk ventricular repolarization. Similar to long QT Syndrome, SQTS might result in ventricular arrhythmias, syncope, and sudden death. The clinical diagnosis of SQTS is supported by the finding of an abnormally Short QT interval on the resting electrocardiogram in combination with a suggestive clinical or family history. To date, few pediatric cases have been reported and the ideal therapy is unknown. We report a teenage boy who suffered a witnessed ventricular fibrillation arrest and was subsequently diagnosed with SQTS. Additional data from nine other pediatric patients diagnosed with SQTS are presented.
Preben Bjerregaard - One of the best experts on this subject based on the ideXlab platform.
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Diagnosis and management of Short QT Syndrome.
Heart rhythm, 2018Co-Authors: Preben BjerregaardAbstract:Establishing a definition of Short QT Syndrome (SQTS), including symptomatology and QT-interval duration, is still a work in progress. However, it is clear , that SQTS is a rare, life-threatening, inherited heart disease presenting as sudden cardiac death (SCD) or aborted SCD in 34% and a family history of SCD in 15%. Genetic testing is important in diagnosing the disease, but to date a causative mutation is found in KCNH2-V141M mutation, and recently a mutation in the cardiac Cl/HCO 3 exchanger AE3 was found to cause SQTS. Issues related to measuring and correcting the QT interval for heart rate has made it difficult to rely entirely on QT duration for the diagnosis of SQTS. In order to establish the diagnosis on firmer grounds, symptoms, family history, and genetic testing need to be considered. Although the benefit of insertion of an implantable cardioverter–defibrillator as secondary prophylaxis against SCD in a patient with SQTS is well documented, the benefit as primary prophylaxis is controversial and not proven by solid data. In 2 recent similar studies involving 115 patients with approximately 5 years of follow-up, insertion of an implantable cardioverter–defibrillator in 40 patients saved the lives of 12, 11 who had presented with cardiac arrest and 1 with syncope. No appropriate shocks were delivered in any patients who did not have a history of either syncope or cardiac arrest. Currently quinidine is the only drug that has undergone any clinical testing.
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Proposed diagnostic criteria for Short QT Syndrome are badly founded.
Journal of the American College of Cardiology, 2011Co-Authors: Preben BjerregaardAbstract:I would like to commend Gollob et al. ([1][1]) for their attempt to generate criteria on how to diagnose Short-QT Syndrome (SQTS), but I would also like to point out some of the Shortfalls and errors in their report. In Table 1 of their report, at least 1 patient appears to have been included twice
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Targeted therapy for Short QT Syndrome.
Expert opinion on therapeutic targets, 2006Co-Authors: Preben Bjerregaard, Arshad Jahangir, Ihor GussakAbstract:Identified in 2000, Short QT Syndrome is an electrical disease of the heart characterised as a channelopathy. At first considered extremely rare, families with this disease have been found in Brazil, Finland, Germany, Spain, the Netherlands, France, Turkey, Italy and the US. The focus of the paper is to present a current review of Short QT Syndrome, as well as providing an overview upon the potential molecular target-based strategies for management of this very deadly disease. Abnormalities in three different potassium channels have been recognised as the cause of the disease and targets for therapy will be discussed for each potassium channel individually. In addition to pharmacological strategies, gene therapy with transfer of genes coding for specific ion channel subunits or regulatory proteins are discussed.
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Short QT Syndrome
Annals of Noninvasive Electrocardiology, 2005Co-Authors: Preben Bjerregaard, Ihor GussakAbstract:Short QT Syndrome (SQTS) is an inheritable primary electrical disease of the heart, discovered in 1999. It is characterized by an abnormally Short QT interval (<300 ms) and a propensity to atrial fibrillation and sudden cardiac death (SCD). Like in the case of long QT Syndrome there is more than one genetic mutation that can lead to a Short QT interval in the ECG and so far two have been identified. Shortening of the effective refractory period combined with increased dispersion of repolarization is the likely substrate for reentry and life threatening tachyarrhythmias. Only 22 people have been classified as having SQTS: 15 from the actual measurement of a Short QT interval in their ECG and 7 by history, all having died from SCD. It is very likely that several cases, especially among children, have been overlooked, since the Shortness of the QT interval only becomes apparent at heart rates <80 beats/min. The best form of treatment is still not known, but prevention of atrial fibrillation has been accomplished by propafenone, and an implantable cardioverter defibrillator is recommended for prevention of SCD.
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Short QT Syndrome and atrial fibrillation caused by mutation in KCNH2.
Journal of cardiovascular electrophysiology, 2005Co-Authors: Kui Hong, Preben Bjerregaard, Ihor Gussak, Ramon BrugadaAbstract:Short QT Syndrome and Atrial Fibrillation. Background: The Short QT Syndrome is a newly described clinical entity characterized by the presence of a Short QT interval associated with cardiac tachyarrhythmias including sudden cardiac death at a young age in otherwise healthy individuals. A genetic basis has been identified linking the disease to mutations in KCNH2 in the familial forms and a mutation in KCNQ1 in a sporadic form of the disease. Methods and Results: We identified a family with Short QT Syndrome with a high incidence of paroxysmal atrial fibrillation in their members and no known history of sudden cardiac death. QT interval ranged from 225 to 240 ms within normal heart rate ranges in the affected individuals. Programmed electrical stimulation (PES) was performed in all affected members, which revealed a remarkably Short atrial and ventricular refractory period, and inducibility of atrial and ventricular fibrillation. Treatment with propafenone has maintained the individuals free of atrial fibrillation to date. Genetic analysis identified a missense mutation (C to G substitution at nucleotide 1764) which resulted in the amino acid change (N588K) in KCNH2. This mutation had been previously described in two other families with a high incidence of sudden cardiac death. Conclusions: Our study confirms that N588K is a hotspot for familial form of the Short QT Syndrome. The disease is clinically heterogeneous, as indicated by the fact that, in the three families with the same mutation, there is a wide range of symptoms, varying from atrial to ventricular fibrillation and sudden death. While the implantation of a defibrillator appears warranted due to the inducibility at PES, the clinical follow-up provides indication that the class Ic agent propafenone could be effective to prevent episodes of paroxysmal atrial fibrillation.
Rainer Schimpf - One of the best experts on this subject based on the ideXlab platform.
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Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile and Outcome.
Journal of the American Heart Association, 2018Co-Authors: Ibrahim El-battrawy, Rainer Schimpf, Christian Wolpert, Boris Rudic, Johanna Besler, Volker Liebe, Erol Tülümen, Siegfried Lang, Xiaobo Zhou, Ibrahim AkinAbstract:Background Short QT Syndrome (SQTS) is a rare inheritable disease associated with sudden cardiac death. Data on long‐term outcomes of families with SQTS are limited. Methods and Results Seventeen p...
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Abstract 18021: Combining Human Induced Pluripotent Stem Cell Derived Cardiac Sheets, CRISPR-Based Genome Editing, and Optical Mapping of Rotors to Study the Short QT Syndrome
Circulation, 2017Co-Authors: Rami Shinnawi, Rainer Schimpf, Martin Borggrefe, Naim Shaheen, Assad Shiti, Irit Huber, Gil Arbel, Amira Gepstein, Anke J. Tijsen, Lior GepsteinAbstract:Introduction: The congenital Short QT Syndrome (SQTS) is a familial arrhythmogenic Syndrome caused by abnormal ion channel function leading to action-potential duration (APD) Shortening, life-threa...
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Usefulness of exercise test in the diagnosis of Short QT Syndrome.
Europace : European pacing arrhythmias and cardiac electrophysiology : journal of the working groups on cardiac pacing arrhythmias and cardiac cellula, 2015Co-Authors: Carla Giustetto, Chiara Scrocco, Rainer Schimpf, Olli Anttonen, Philippe Maury, Andrea Mazzanti, Marco Levetto, Paola Dalmasso, Natascia Cerrato, Elena GribaudoAbstract:Aims Short QT Syndrome (SQTS) is a rare arrhythmogenic inherited heart disease. Diagnosis can be challenging in subjects with slightly Shortened QT interval at electrocardiogram. In this study we compared the QT interval behaviour during exercise in a cohort of SQTS patients with a control group, to evaluate the usefulness of exercise test in the diagnosis of SQTS. Methods and results Twenty-one SQTS patients and 20 matched control subjects underwent an exercise test. QT interval was measured at different heart rates (HRs), at rest and during effort. The relation between QT interval and HR was evaluated by linear regression analysis according to the formula: QT = β ×HR + α, where β is the slope of the linear relation, and α is the intercept. Rest and peak exercise HRs were not different in the two groups. Short QT Syndrome patients showed lower QT intervals as compared with controls both at rest (276 ± 27 ms vs. 364 ± 25 ms, P < 0.0001) and at peak exercise (228 ± 27 ms vs. 245 ± 26 ms, P = 0.05), with a mean variation from rest to peak effort of 48 ± 14 ms vs. 120 ± 20 ms ( P < 0.0001). Regression analysis of QT/HR relationship revealed a less steep slope for SQTS patients compared with the control group, never exceeding the value of −0.90 ms/beat/min (mean value −0.53 ± 0.15 ms/beat/min vs. −1.29 ± 0.30 ms/beat/min, P < 0.0001). Conclusion Short QT Syndrome patients show a reduced adaptation of the QT interval to HR. Exercise test can be a useful tool in the diagnosis of SQTS.
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Short QT Syndrome - Review of Diagnosis and Treatment.
Arrhythmia & electrophysiology review, 2014Co-Authors: Boris Rudic, Rainer Schimpf, Martin BorggrefeAbstract:Short QT Syndrome (SQTS) is an inherited cardiac channelopathy characterised by an abnormally Short QT interval and increased risk for atrial and ventricular arrhythmias. Diagnosis is based on the evaluation of symptoms (syncope or cardiac arrest), family history and electrocardiogram (ECG) findings. Mutations of cardiac ion channels responsible for the repolarisation orchestrate electrical heterogeneity during the action potential and provide substrate for triggering and maintaining of tachyarrhythmias. Due to the malignant natural history of SQTS, implantable cardioverter defibrillator (ICD) is the first-line therapy in affected patients. This review summarises current data and addresses the genetic basis and clinical features of SQTS.
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Arrhythmogenic hereditary Syndromes: Brugada Syndrome, long QT Syndrome, Short QT Syndrome and CPVT.
Minerva cardioangiologica, 2010Co-Authors: Rainer Schimpf, Christian Wolpert, Christian Veltmann, Borggrefe MAbstract:In approximately 10-20% of all sudden deaths no structural cardiac abnormalities can be identified. Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada Syndrome, long QT Syndrome (LQTS), Short QT Syndrome and catecholaminergic polymorphic ventricular tachyarrhythmias. Each of these cardiac channelopathies is charaterized by unique genetic and clinical features. The resting ECG and the ECG under exercise are pivotal for the diagnosis of ion channel diseases. Molecular genetic screening can reveal underlying mutations in a variable degree among the cardiac ion channel diseases in up to 70% (LQTS) and may identify individuals with incomplete penetration of the disease. In patients with primary electrical diseases specific clinical triggers for arrhythmic events such as syncope or sudden cardiac death have been identified including exercise, strenuous activity, auditory stimuli or increased vagal tone. The significance of programmed ventricular stimulation is at present unclear concerning risk stratification in patients with Brugada Syndrome and Short QT Syndrome and of no significance in long QT Syndrome and catecholaminergic polymorphic ventricular tachycardias. The success of medical therapy remains modest for prevention of sudden cardiac death and may necessitate the insertion of an implantable cardioverter. However, side effects with inappropriate therapies in this patient group with often young and active individuals have to be encountered. More insights into the arrhythmogenesis is critical for future development of effective medical treatment strategies.
Fiorenzo Gaita - One of the best experts on this subject based on the ideXlab platform.
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The Short QT Syndrome
Cardiac Repolarization, 2020Co-Authors: Chiara Scrocco, Fiorenzo Gaita, Carla GiustettoAbstract:The Short QT Syndrome (SQTS) is a rare inherited ion channel disease associated with life-threatening arrhythmias and familiar sudden death (SD) in the absence of cardiac structural abnormalities. The diagnosis is based on the detection of constantly Short QTc values at ECG (≤ 340 ms) and the presence of previous aborted CA (aCA) or syncope, a family history of SD or SQTS, or a positive genotype supporting the diagnosis in borderline cases. Mutations causing hyperfunction of genes encoding for potassium channels, but also reduced function of the calcium channel involved in the cardiac repolarization, have been associated with the disease (SQTS1–6), although the yield of the genetic test is scarce (less than 25%) and precise data on genotype- phenotype correlation are lacking due to the extreme rarity of the condition. Males are diagnosed more often than females, representing more than 75% of cases. The mean age at observation is below 25 years. SD or aCA is the first symptom in one-third of subjects, occurring mostly in the first year of life and between 20 and 40 years, both at rest and during exercise, without gender differences. A previous cardiac arrest is the only recognized risk factor for events at follow-up. An implantable cardiac defibrillator is the therapy of choice in high-risk patients but is burdened by high rates of complications, including inappropriate shocks. Prophylactic therapy with hydroquinidine proved to be effective in prolonging the QT interval and prevent the occurrence of arrhythmias in previously symptomatic and asymptomatic subjects.
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The Short QT Syndrome
Cardiac Repolarization, 2020Co-Authors: Chiara Scrocco, Fiorenzo Gaita, Carla GiustettoAbstract:The Short QT Syndrome (SQTS) is a rare inherited ion channel disease associated with life-threatening arrhythmias and familiar sudden death (SD) in the absence of cardiac structural abnormalities. The diagnosis is based on the detection of constantly Short QTc values at ECG (≤ 340 ms) and the presence of previous aborted CA (aCA) or syncope, a family history of SD or SQTS, or a positive genotype supporting the diagnosis in borderline cases. Mutations causing hyperfunction of genes encoding for potassium channels, but also reduced function of the calcium channel involved in the cardiac repolarization, have been associated with the disease (SQTS1–6), although the yield of the genetic test is scarce (less than 25%) and precise data on genotype- phenotype correlation are lacking due to the extreme rarity of the condition. Males are diagnosed more often than females, representing more than 75% of cases. The mean age at observation is below 25 years. SD or aCA is the first symptom in one-third of subjects, occurring mostly in the first year of life and between 20 and 40 years, both at rest and during exercise, without gender differences. A previous cardiac arrest is the only recognized risk factor for events at follow-up. An implantable cardiac defibrillator is the therapy of choice in high-risk patients but is burdened by high rates of complications, including inappropriate shocks. Prophylactic therapy with hydroquinidine proved to be effective in prolonging the QT interval and prevent the occurrence of arrhythmias in previously symptomatic and asymptomatic subjects.
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Shortening of the Short Refractory Periods in Short QT Syndrome.
Journal of the American Heart Association, 2017Co-Authors: Anne Rollin, Chiara Scrocco, Carla Giustetto, Pierre Mondoly, Christelle Cardin, Estelle Gandjbakhch, Carole Fourcade, Benjamin Monteil, Carole Maupain, Fiorenzo GaitaAbstract:Background Diagnosis of Short QT Syndrome (SQTS) remains difficult in case of borderline QT values as often found in normal populations. Whether some Shortening of refractory periods (RP) may help in differentiating SQTS from normal subjects is unknown. Methods and Results Atrial and right ventricular RP at the apex and right ventricular outflow tract as determined during standard electrophysiological study were compared between 16 SQTS patients (QTc 324±24 ms) and 15 controls with similar clinical characteristics (QTc 417±32 ms). Atrial RP were significantly Shorter in SQTS compared with controls at 600‐ and 500‐ms basic cycle lengths. Baseline ventricular RP were significantly Shorter in SQTS patients than in controls, both at the apex and right ventricular outflow tract and for any cycle length. Differences remained significant for RP of any subsequent extrastimulus at any cycle length and any pacing site. A cut‐off value of baseline RP Conclusions Patients with SQTS have Shorter ventricular RP than controls, both at baseline during various cycle lengths and after premature extrastimuli. A cut‐off value of 200 ms at the right ventricular outflow tract during 600‐ and 500‐ms basic cycle length may help in detecting true SQTS from normal subjects with borderline QT values.
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new echocardiographic insights in Short QT Syndrome more than a channelopathy
Heart Rhythm, 2015Co-Authors: Simone Frea, Chiara Scrocco, Carla Giustetto, Michele Capriolo, Cristina Fornengo, Sara Benedetto, Francesca Bianchi, Stefano Pidello, Mara Morello, Fiorenzo GaitaAbstract:Background Short QT Syndrome (SQTS) is a congenital ion channel disease characterized by an increased risk of sudden cardiac death. Little is known about the possibility that accelerated repolarization alters mechanical function in SQTS. Objectives The study investigated the presence of left ventricular dysfunction and mechanical dispersion, assessed by tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE), and their correlation with QT interval duration and genetics. Methods Fifteen SQTS patients (7 with HERG and 3 with KCNQ1 mutation) were studied. Electrocardiographic and echocardiographic parameters were compared with age- and sex-matched healthy controls. Results When compared to the control group, SQTS patients showed reduced left ventricular contraction (global longitudinal strain: −16.0% ± 3.4% vs −22.6% ± 1.7%, P P P = .04). Mechanical dispersion assessed by TDI ( P P Conclusion This study showed that in SQTS systolic function may also be affected. SQTS patients presented a significant dispersion of myocardial contraction. TDI and STE could become part of the evaluation of this rare disease.
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Short QT Syndrome
Cardiogenetics, 2011Co-Authors: Carla Giustetto, Chiara Scrocco, Charles Antzelevitch, Daniela Giachino, Fiorenzo GaitaAbstract:The Short QT Syndrome (SQTS) is a recently described genetic arrhythmogenic disorder, characterized by abnormally Short QT intervals on surface electrocardiogram (ECG) and a high incidence of sudden death (SD) during life, including the first months of life. The inheritance of SQTS is autosomal dominant, with genetic heterogeneity. Gain-of-function mutations in 3 genes encoding potassium channels have been associated to the disease: KCNH2 encoding IKr (SQT1), KCNQ1 encoding IKs (SQT2), and KCNJ2 encoding IK1 (SQT3). Loss-of-function mutations in 3 genes encoding the cardiac L-type calcium channel, CACNA1C, CACNB2b and CACNA2D1 may underlie a mixed phenotype of Brugada pattern ECG (or non-specific repolarization changes in case of CACNA2D1) and Shorter than normal QT intervals. Clinical presentation is often severe, as cardiac arrest represents the first clinical presentation in most subjects. Moreover, often a noticeable family history of cardiac SD is present. Atrial fibrillation may be observed, also in young individuals. At electrophysiological study, Short atrial and ventricular refractory periods are found, and atrial and ventricular fibrillation are easily induced by programmed electrical stimulation. The outcome of patients with SQTS becomes relatively safe when they are identified and treated. Currently, the suggested therapeutic strategy is an implantable cardioverter- defibrillator (ICD) in patients with personal history of aborted SD or syncope. In asymptomatic adult patients from highly symptomatic families and in newborn children pharmacological treatment with hydroquinidine, which has been shown to prolong the QT interval and reduce the inducibility of ventricular arrhythmias, may be proposed
Henggui Zhang - One of the best experts on this subject based on the ideXlab platform.
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Learning from studying very rare cardiac conditions: the example of Short QT Syndrome
Journal of Congenital Cardiology, 2019Co-Authors: Jules C. Hancox, Henggui Zhang, Dominic G Whittaker, Alan G. StuartAbstract:Background Some congenital heart conditions are very rare. In a climate of limited resources, a viewpoint could be advanced that identifying diagnostic criteria for such conditions and, through empiricism, effective treatments should suffice and that extensive mechanistic research is unnecessary. Taking the rare but dangerous Short QT Syndrome (SQTS) as an example, this article makes the case for the imperative to study such rare conditions, highlighting that this yields substantial and sometimes unanticipated benefits. Genetic forms of SQTS are rare, but the condition may be under-diagnosed and carries a risk of sudden death. Genotyping of SQTS patients has led to identification of clear ion channel/transporter culprits in
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modelling the effects of propafenone on human atrial patho electrophysiology associated with herg linked Short QT Syndrome
Computing in Cardiology Conference, 2018Co-Authors: Dominic G Whittaker, Jules C. Hancox, Henggui ZhangAbstract:The N588K mutation to the human Ether-a-go-go-Related Gene (hERG) underlies Short QT Syndrome variant 1 (SQT1), which is associated with atrial fibrillation (AF). However, mechanisms and management of AF in the context of SQT1 remain poorly understood. In this study, multi-scale computational modelling was used to investigate pharmacotherapeutic effects of the class Ic drug propafenone for SQT1-mediated human atrial patho-electrophysiology. A Markov chain formulation of rapid delayed rectifier potassium current, I Kr , describing wild type (WT) and N588K mutant currents was incorporated into a recent model of the human atrial action potential (AP), which was integrated into multi-scale tissue models. Effects of multi-channel block by propafenone were simulated on single- and multi-cellular electrophysiology models. At the single cell level, propafenone prolonged the AP duration under SQT1 (heterozygous N588K) conditions in a dose-dependent manner. In tissue, propafenone prolonged the effective refractory period and excitation wavelength, whilst reducing the conduction velocity. In 2D sheet simulations, propafenone demonstrated efficacy in pharmacological conversion of re-entry. Our findings suggest that propafenone shows efficacy in reversing AF associated with hERG-linked Short QT Syndrome.
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CinC - Modelling the Effects of Propafenone on Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome
2018 Computing in Cardiology Conference (CinC), 2018Co-Authors: Dominic G Whittaker, Jules C. Hancox, Henggui ZhangAbstract:The N588K mutation to the human Ether-a-go-go-Related Gene (hERG) underlies Short QT Syndrome variant 1 (SQT1), which is associated with atrial fibrillation (AF). However, mechanisms and management of AF in the context of SQT1 remain poorly understood. In this study, multi-scale computational modelling was used to investigate pharmacotherapeutic effects of the class Ic drug propafenone for SQT1-mediated human atrial patho-electrophysiology. A Markov chain formulation of rapid delayed rectifier potassium current, I Kr , describing wild type (WT) and N588K mutant currents was incorporated into a recent model of the human atrial action potential (AP), which was integrated into multi-scale tissue models. Effects of multi-channel block by propafenone were simulated on single- and multi-cellular electrophysiology models. At the single cell level, propafenone prolonged the AP duration under SQT1 (heterozygous N588K) conditions in a dose-dependent manner. In tissue, propafenone prolonged the effective refractory period and excitation wavelength, whilst reducing the conduction velocity. In 2D sheet simulations, propafenone demonstrated efficacy in pharmacological conversion of re-entry. Our findings suggest that propafenone shows efficacy in reversing AF associated with hERG-linked Short QT Syndrome.
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Emerging therapeutic targets in the Short QT Syndrome.
Expert opinion on therapeutic targets, 2018Co-Authors: Jules C. Hancox, Dominic G Whittaker, A Graham Stuart, Henggui ZhangAbstract:Introduction: Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the Syndrome. Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K+ channel inhibitors. A combination of K+ current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K+ channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.
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Modelling the effects of chloroquine on KCNJ2-linked Short QT Syndrome.
Oncotarget, 2017Co-Authors: Cunjin Luo, Kuanquan Wang, Henggui ZhangAbstract:// Cunjin Luo 1 , Kuanquan Wang 1 and Henggui Zhang 1, 2, 3, 4 1 School of Computer Science and Technology, Harbin Institute of Technology (HIT), Harbin, China 2 School of Physics and Astronomy, The University of Manchester, Manchester, United Kingdom 3 Space Institute of Southern China, Shenzhen, China 4 Key Laboratory of Medical Electrophysiology, Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease/Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China Correspondence to: Cunjin Luo, email: cunjin.luo@yahoo.co.uk Kuanquan Wang, email: wangkq@hit.edu.cn Henggui Zhang, email: H.Zhang-3@manchester.ac.uk Keywords: arrhythmia; Short QT Syndrome (SQTS); inward rectifier; chloroquine (CQ); computer modelling Received: June 24, 2017 Accepted: October 28, 2017 Published: November 18, 2017 ABSTRACT A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of Short QT Syndrome (SQT3), which is associated with increased susceptibility to arrhythmias and sudden death. Anti-malarial drug chloroquine was reported as an effective inhibitor of Kir2.1 channels. Using biophysically-detailed human ventricle computer models, this study assessed the effects of chloroquine on SQT3. The ten Tusscher et al . model of human ventricular cell action potential was modified to recapitulate functional changes in the inward rectifier K + current ( I K1 ) due to heterozygous and homozygous forms of the D172N mutation. Mutant formulations were incorporated into multi-scale models. The blocking effects of chloroquine on ionic currents were modelled using IC 50 and Hill coefficient values from literatures. Effects of chloroquine on action potential duration (APD), effective refractory period (ERP) and pseudo-ECGs were quantified. It was shown that chloroquine caused a dose-dependent reduction in I K1 , prolonged APD, and decreased the maximum voltage heterogeneity. Chloroquine prolonged QT interval and declined the T-wave amplitude. Although chloroquine reduced tissue’s temporal vulnerability, it increased the minimum substrate size necessary for sustaining re-entry. The actions of chloroquine decreased arrhythmia risk, due to the reduced tissue vulnerability, prolonged ERP and wavelength of re-entrant excitation waves, which in combination prevented and terminated re-entry in the tissue models. In conclusion, the results of this study provide new evidence that the anti-arrhythmic effects of chloroquine on SQT3 and, by extension, to the possibility that chloroquine may be a potential therapeutic agent for SQT3 treatment.