Short QT Syndrome – Review of Diagnosis and Treatment

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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Preclinical short QT syndrome models: studying the phenotype and drug-screening

EP Europace ◽

10.1093/europace/euab214 ◽

2021 ◽

Author(s):

Xuehui Fan ◽

Guoqiang Yang ◽

Jacqueline Kowitz ◽

Firat Duru ◽

Ardan M Saguner ◽

...

Keyword(s):

Cardiac Arrest ◽

Family History ◽

Three Dimensional ◽

Induced Pluripotent Stem Cell ◽

Experimental Models ◽

Short Qt Syndrome ◽

Pathophysiological Mechanisms ◽

History Of ◽

Qt Syndrome ◽

European Society Of Cardiology

Abstract Cardiovascular diseases are the main cause of sudden cardiac death (SCD) in developed and developing countries. Inherited cardiac channelopathies are linked to 5–10% of SCDs, mainly in the young. Short QT syndrome (SQTS) is a rare inherited channelopathy, which leads to both atrial and ventricular tachyarrhythmias, syncope, and even SCD. International European Society of Cardiology guidelines include as diagnostic criteria: (i) QTc ≤ 340 ms on electrocardiogram, (ii) QTc ≤ 360 ms plus one of the follwing, an affected short QT syndrome pathogenic gene mutation, or family history of SQTS, or aborted cardiac arrest, or family history of cardiac arrest in the young. However, further evaluation of the QTc ranges seems to be required, which might be possible by assembling large short QT cohorts and considering genetic screening of the newly described pathogenic mutations. Since the mechanisms underlying the arrhythmogenesis of SQTS is unclear, optimal therapy for SQTS is still lacking. The disease is rare, unclear genotype–phenotype correlations exist in a bevy of cases and the absence of an international short QT registry limit studies on the pathophysiological mechanisms of arrhythmogenesis and therapy of SQTS. This leads to the necessity of experimental models or platforms for studying SQTS. Here, we focus on reviewing preclinical SQTS models and platforms such as animal models, heterologous expression systems, human-induced pluripotent stem cell-derived cardiomyocyte models and computer models as well as three-dimensional engineered heart tissues. We discuss their usefulness for SQTS studies to examine genotype–phenotype associations, uncover disease mechanisms and test drugs. These models might be helpful for providing novel insights into the exact pathophysiological mechanisms of this channelopathy and may offer opportunities to improve the diagnosis and treatment of patients with SQT syndrome.

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ECG patterns related to arrhythmias and sudden death: channelopathies, early repolarization, and pre-excitation

ESC CardioMed ◽

10.1093/med/9780198784906.003.0074 ◽

2018 ◽

pp. 382-389

Author(s):

Wojciech Zareba ◽

Pyotr Platonov

Keyword(s):

Sudden Death ◽

Long Qt Syndrome ◽

Ventricular Arrhythmias ◽

Prior History ◽

Long Qt ◽

Early Repolarization ◽

Genes Encoding ◽

History Of ◽

Qt Syndrome ◽

Characteristic Features

Electrocardiogram (ECG) patterns recognized in patients with sudden death without structural abnormalities in the heart have guided cardiology over the last few decades towards a better understanding of the role of cardiac ion channels in physiology and in arrhythmogenicity in rare electrical diseases. The long QT syndrome became the paradigm for evaluating the association between specific ion channel abnormalities caused by mutations in genes encoding predominantly potassium and sodium channels and phenotypic ECG expression. Specific ECG patterns observed in long QT syndrome help in diagnosis and improve prognosis in patients affected by this disorder. Short QT syndrome also is characterized by specific patterns in repolarization morphology that relate to affected potassium current or calcium handling genes. Brugada syndrome and early repolarization syndrome are considered as J-wave syndromes, having some similarities in ECG features but with distinctive patterns associated with classical forms of these disorders. Spontaneous appearance of cove-type Brugada pattern is associated with a worse prognosis. Early repolarization patterns may also indicate prognosis in subjects with a prior history of cardiac arrest or ventricular arrhythmias or a family history of cardiac arrests. Catecholaminergic polymorphic ventricular tachycardia is another channelopathy without characteristic features in standard resting ECG but with characteristic polymorphic ventricular arrhythmias during catecholaminergic challenge (exercise test, stressing situations). Pre-excitation syndromes associated with sudden cardiac death are well recognized and current understanding of these disorders leads to a better therapy.

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Ventricular tachycardia storm management in a COVID-19 patient: a case report

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytaa217 ◽

2020 ◽

Vol 4 (FI1) ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Gianfranco Mitacchione ◽

Marco Schiavone ◽

Alessio Gasperetti ◽

Giovanni B Forleo

Keyword(s):

Ventricular Tachycardia ◽

Ventricular Arrhythmias ◽

Cardiac Involvement ◽

Previous History ◽

Left Ventricular ◽

Electrical Storm ◽

Increased Risk ◽

History Of ◽

Myocardial Involvement ◽

Artery Disease

Abstract Background Coronavirus disease 2019 (COVID-19) has been associated with myocardial involvement. Among cardiovascular manifestations, cardiac arrhythmias seem to be fairly common, although no specifics are reported in the literature. An increased risk of malignant ventricular arrhythmias and electrical storm (ES) has to be considered. Case summary We describe a 68-year-old patient with a previous history of coronary artery disease and severe left ventricular systolic disfunction, who presented to our emergency department describing cough, dizziness, fever, and shortness of breath. She was diagnosed with COVID-19 pneumonia, confirmed after three nasopharyngeal swabs. Ventricular tachycardia (VT) storm with multiple implantable cardioverter defibrillator (ICD) shocks was the presenting manifestation of cardiac involvement during the COVID-19 clinical course. A substrate-based VT catheter ablation procedure was successfully accomplished using a remote navigation system. The patient recovered from COVID-19 and did not experience further ICD interventions. Discussion To date, COVID-19 pneumonia associated with a VT storm as the main manifestation of cardiac involvement has never been reported. This case highlights the role of COVID-19 in precipitating ventricular arrhythmias in patients with ischaemic cardiomyopathy who were previously stable.

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Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—short QT syndrome

10.1093/med/9780198784906.003.0150 ◽

2018 ◽

Author(s):

Erol Tülümen ◽

Martin Borggrefe

Keyword(s):

Atrial Fibrillation ◽

Genetic Basis ◽

Association Studies ◽

Single Gene ◽

Candidate Gene Approach ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Short Qt Syndrome ◽

Dispersion Of Repolarization ◽

Qt Syndrome

Short QT syndrome (SQTS) is a very rare, sporadic or autosomal dominant inherited channelopathy characterized by abnormally short QT intervals on the electrocardiogram and increased propensity to atrial and ventricular tachyarrhythmias and/or sudden cardiac death. Since its recognition as a distinct clinical entity in 2000, significant progress has been made in defining the clinical, molecular, and genetic basis of SQTS. To date, several causative gain-of-function mutations in potassium channel genes and loss-of-function mutations in calcium channel genes have been identified. The physiological consequence of these mutations is an accelerated repolarization, thus abbreviated action potentials and shortened QT interval with an increased inhomogeneity and dispersion of repolarization. Regarding other rare monogenetic arrhythmias, a genetic basis of atrial fibrillation was considered very unlikely until very recently. However, in the last decade the heritability of atrial fibrillation in the general population has been well described in several epidemiological studies. So far, more than 30 genes have been implicated in atrial fibrillation through candidate gene approach studies, and 14 loci were found to be associated with atrial fibrillation through genome-wide association studies. This genetic heterogeneity and the low prevalence of mutations in any single gene restrict the clinical utility of genetic screening in atrial fibrillation.

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Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—short QT syndrome

ESC CardioMed ◽

10.1093/med/9780198784906.003.0150_update_001 ◽

2018 ◽

pp. 676-679

Author(s):

Erol Tülümen ◽

Martin Borggrefe

Keyword(s):

Atrial Fibrillation ◽

Genetic Basis ◽

Association Studies ◽

Single Gene ◽

Epidemiological Studies ◽

Candidate Gene Approach ◽

Loss Of Function ◽

Short Qt Syndrome ◽

Qt Intervals ◽

Qt Syndrome

Short QT syndrome (SQTS) is a very rare, sporadic or autosomal dominant inherited channelopathy characterized by abnormally short QT intervals on the electrocardiogram and increased propensity to atrial and ventricular tachyarrhythmias and/or sudden cardiac death. Since its recognition as a distinct clinical entity in 2000, significant progress has been made in defining the clinical, molecular, and genetic basis of SQTS. To date, several causative gain-of-function mutations in potassium channel genes and loss-of-function mutations in calcium channel genes have been identified. The physiological consequence of these mutations is an accelerated repolarization, thus abbreviated action potentials and shortened QT interval with an increased inhomogeneity and dispersion of repolarization. Regarding other rare monogenetic arrhythmias, a genetic basis of atrial fibrillation was considered very unlikely until very recently. However, in the last decade the heritability of atrial fibrillation in the general population has been well described in several epidemiological studies. So far, more than 30 genes have been implicated in atrial fibrillation through candidate gene approach studies, and more than 25 loci were found to be associated with atrial fibrillation through genome-wide association studies. This genetic heterogeneity and the low prevalence of mutations in any single gene restrict the clinical utility of genetic screening in atrial fibrillation.

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Postnatal undernutrition in mice causes cardiac arrhythmogenesis which is exacerbated when pharmacologically stressed

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174418000156 ◽

2018 ◽

Vol 9 (4) ◽

pp. 417-424 ◽

Cited By ~ 3

Author(s):

J. R. Visker ◽

D. P. Ferguson

Keyword(s):

Body Weight ◽

Ventricular Arrhythmias ◽

Postnatal Life ◽

Cardiac Arrhythmogenesis ◽

Reduced Body ◽

Low Protein ◽

Increased Risk ◽

Electrocardiogram Ecg ◽

Cross Fostering ◽

Ventricular Depolarization

AbstractGrowth restriction caused by postnatal undernutrition increases risk for cardiovascular disease in adulthood with the potential to induce arrhythmogenesis. Thus, the purpose was to determine if undernutrition during development produced arrhythmias at rest and when stressed with dobutamine in adulthood. Mouse dams were fed (CON: 20% protein), or low-protein (LP: 8%) diet before mating. A cross-fostering model was used where pups nursed by dams fed LP diet in early [EUN; postnatal day (PN) 1–10], late (LUN; PN11–21) and whole (PUN; 1–21) phases of postnatal life. Weaned pups were switched to CON diets for the remainder of the study (PN80). At PN80, body composition (magnetic resonance imaging), and quantitative electrocardiogram (ECG) measurements were obtained under 1% isoflurane anesthesia. After baseline ECG, an IP injection (1.5 µg/g body weight) of dobutamine was administered and ECG repeated. Undernutrition significantly (P<0.05) reduced body weight in LUN (22.68±0.88 g) and PUN (19.96±0.32 g) but not in CON (25.05±0.96 g) and EUN (25.28±0.9207 g). Fat mass decreased in all groups compared with controls (CON: 8.00±1.2 g, EUN: 6.32±0.65 g, LUN: 5.11±1.1 g, PUN: 3.90±0.25 g). Lean mass was only significantly reduced in PUN (CON: 17.99±0.26 g, EUN: 17.78±0.39 g, LUN: 17.34±0.33 g, PUN: 15.85±0.28 g). Absolute heart weights were significantly less from CON, with PUN having the smallest. ECG showed LUN had occurrences of atrial fibrillation; EUN had increases of 1st degree atrioventricular block upon stimulation, and PUN had increased risk for ventricular depolarization arrhythmias. CON did not display arrhythmias. Undernutrition in early life resulted in ventricular arrhythmias under stressed conditions, but undernutrition occurring in later postnatal life there is an increased incidence of atrial arrhythmias.

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Complementarity between Arrhythmia Mechanisms Found in Silico and in Genetic Models of N588K-hERG Linked Short QT Syndrome

Journal of Integrative Cardiology Open Access ◽

10.31487/j.jicoa.2020.01.13 ◽

2020 ◽

pp. 1-4

Author(s):

Jules Hancox ◽

Chunyun Du ◽

Henggui Zhang ◽

Jules Hancox ◽

Yihong Zhang

Keyword(s):

In Silico ◽

Rabbit Model ◽

Spiral Wave ◽

Induced Pluripotent Stem Cell ◽

Short Qt Syndrome ◽

Arrhythmia Mechanisms ◽

Increased Risk ◽

Qt Syndrome ◽

Induced Pluripotent ◽

Dangerous Condition

Congenital Short QT Syndrome (SQTS) is a rare but dangerous condition involving abbreviated ventricular repolarization and an increased risk of atrial and ventricular arrhythmias. Taking the example of the first identified SQTS mutation, N588K-hERG, we consider briefly the basic science approaches used to obtain an understanding of the mechanism(s) of arrhythmogenesis in this form of the syndrome. A combination of recombinant channel electrophysiology and in silico simulations has provided insights into causality between the identified mutation, accelerated repolarization and increased susceptibility to re-entry in N588K-hERG-linked SQTS. Subsequent studies employing a transgenic rabbit model or human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) have further demonstrated mechanisms predisposing to re-entry, spiral wave activity and arrhythmia in intact tissue. The complementarity between the findings made using these different approaches gives confidence that, collectively, they have identified major arrhythmia mechanisms and their potential mitigation by Class I antiarrhythmic drugs in this form of SQTS.

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The Link Between Sex Hormones and Susceptibility to Cardiac Arrhythmias: From Molecular Basis to Clinical Implications

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.644279 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sarah Costa ◽

Ardan M. Saguner ◽

Alessio Gasperetti ◽

Deniz Akdis ◽

Corinna Brunckhorst ◽

...

Keyword(s):

Sex Hormones ◽

Cardiac Arrhythmias ◽

Molecular Basis ◽

Conduction System ◽

Cardiac Conduction ◽

Clinical Implications ◽

Cardiac Ion Channels ◽

Increased Risk ◽

Qt Syndrome ◽

Underlying Mechanisms

It is well-known that gender is an independent risk factor for some types of cardiac arrhythmias. For example, males have a greater prevalence of atrial fibrillation and the Brugada Syndrome. In contrast, females are at increased risk for the Long QT Syndrome. However, the underlying mechanisms of these gender differences have not been fully identified. Recently, there has been accumulating evidence indicating that sex hormones may have a significant impact on the cardiac rhythm. In this review, we describe in-depth the molecular interactions between sex hormones and the cardiac ion channels, as well as the clinical implications of these interactions on the cardiac conduction system, in order to understand the link between these hormones and the susceptibility to arrhythmias.

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