Role of genetic and electrolyte abnormalities in prolonged QTc interval and sudden cardiac death in end-stage renal disease patients
Mónica CollCarles Ferrer‐CostaSara PichCatarina AllegueEmilio RodrigoGema Fernández‐FresnedoP.De La BarredaJesús MatésAngel Luis Martinez De FranciscoIsrael Parra OrtegaAnna IglesiasÓscar CampuzanoEduardo SalasManuel AriasRamón Brugada
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Background Patients with end-stage renal disease have very high mortality. In individuals on hemodialysis, cardiovascular deaths account for ~50% of all deaths in this population, mostly due to arrhythmia. To determine the causes of these arrhythmic deaths is essential in order to adopt preventive strategies. The main objective of this study was to investigate whether, the presence of QTc interval alterations, from electrolyte abnormalities or presence of rare genetic variants, could have a relationship with sudden arrhythmogenic deaths in end-stage renal disease patients. Methods We recorded the pre- and post-dialysis QTc interval in 111 patients undergoing hemodialysis. In 47 of them, we analyzed 24 SCD-related genes including the most prevalent genes associated with long QT syndrome using a custom resequencing panel. Results We found a positive although not significant association between the presence of long QTc and mortality in a subset of end-stage renal disease patients. In addition, in five patients with long QTc only after dialysis (21.7%) we detected rare potentially pathogenic genetic variants. Three out of these five carriers subsequently died suddenly. Conclusions Genetic background may be determinant in the risk of sudden cardiac death in these patients. We recommend evaluating the QTc interval before and after hemodialysis, and performing a genetic analysis of individuals with long QTc after hemodialysis.Keywords:
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Background— Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. Methods and Results— Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac I Kr channel HERG (KCNH2). The mutations dramatically increase I Kr , leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to I Kr blockers. Conclusions— We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
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배경(Background) : QT interval은 심실이 전기적으로 활성화(탈분극)에서 회복(재분극)될 때까지 걸리는 시간을 의미하며, QT interval의 지연은 심실재분극이 느려졌음을 나타낸다. QT간격이 500ms 이상으로 연장되면 심실성 부정맥이 발생활 위험성이 높다. 이러한 심실성 부 정맥은 돌면사를 유발할 수 있기 때문에 QT interval에 대해 잘 살펴볼 필요가 있다. LQTS은 심장 재분극에 관여하는 ion channels의 유전자 돌연변이에 의한 선천성 LQTS와 심장 재분극에 영향을 주는 약물 복용에 의한 후천성 LQTS가 있다. 방법 (Methods) : QT interval은 유도에 따라 변동이 많아 여러 유도에서 측정한 12유도 QT 중 가장 건 간격을 QT interval로 한다. 또한 QT interval은 심박동수와 반비례로 변동하므로 심박동수 60회를 기준하여 교정한 QTc interval으로 비교하여야 한다. 사용하는 주 공식은 아래와 같이 두가지이다. - Bazet공식 QT(B)= QT 간격/√RR간격 - Fridericia 공식 QT(F) = QT 간격/3√RR간격 결과(Results) 후천성 Long QT Syndrome의 경우, 항부정맥제의 과도한 투여로 인한 QT interval의 지연은 심실빈맥의 전조격인 torsade de pointes(TdP)을 일으킬 수 있다. 이 부정맥은 정상 동율동이나 심실세동으로 진행할 수 있다. 이러한 율동은 사망의 전조 증상이기 때문에 매우 조심해야 하며, 원민 약물을 빨리 중지하고 그에 따른 치료가 필요하다. 고찰(Discussion) : Long QT Syndrome으로 실신중상이 나타난 후 치료하지 않으면 1년 이내에는 20%. 10년이내에 50%가 사망하는 위험한 질환이다. 또한 QT간격은 주위 환경이나 약물에 따라 변동이 심하다. 그러므로 LQTS 환자분만 아니라 의심환자도 정기적으로 EKG를 시행해 주는 것이 좋다.
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Prolongation of the QT interval on the electrocardiogram is clinically important due to the association with an increased risk of sudden cardiac death. A long QT interval may be genetically determined (congenital long QT syndrome) or be drug-induced long QT syndrome e.g. caused by pharmaceutical drugs and electrolyte imbalances. In this report, we describe the case a 54-year-old woman, who presented with syncope. At presentation, the QTc interval was markedly prolonged, and she was admitted for observation under telemetry. The following day the patient had experienced a near syncope during an episode of 18 s of Torsade de Pointes (TdP). At the time of TdP, the potassium level (3.4 mmol/L) was mildly reduced, and the ECG showed a QTc interval of 640 ms. In spite of correction of hypokalaemia and discontinuation of the possibly LQTS-inducing drug citalopram the QTc duration remained intermittently prolonged. A transthoracic echocardiogram and a recent coronary angiogram were normal. The patient received an implantable cardioverter-defibrillator. Subsequent genetic testing identified a heterozygous KCNE1 p.D85N (c.253G>A) variant, a known QT modifier with a population prevalence of 1.3%. We conclude that the combination of a commonly prescribed antidepressant, discrete hypokalaemia, and a common KCNE1 QT modifier may cause severe QTc prolongation and life-threatening arrhythmia.
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Long QT syndrome (LQTS) is a genetic cardiac disease, where the corrected QT (QTc) interval is prolonged. It can cause arrhythmias and lead to a sudden cardiac death. Duration of the QT interval depends on the heart rate and this dependency is treated with QT correction. However, the current QT correction methods have well known problems and limitations.
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Congenital long QT syndrome (LQTS) is caused by mutations in the cardiac Na+ or K+ channels that result in a prolonged QTc interval and increased QT dispersion. Na+ channel blockers and K+ can reverse the repolarization abnormalities in the Na+ channel variant (LQT3) and K+ channel variant (LQT1, LQT2), respectively. The phenotype of LQTS can be difficult to recognize, especially when the QTc interval is mildly prolonged. Additional noninvasive testing methods are needed to enhance the diagnosis of LQTS. This study compared the response of the QTc interval and QT dispersion to a sequential lidocaine/K+ infusion in LQTS patients with borderline QTc interval prolongation and control patients as a means of diagnosing LQTS.In this study, eight LQTS patients with borderline QTc, defined as QTc < 470 ms, and 10 healthy controls received sequential lidocaine/K+ infusion.At baseline, LQTS patients had a longer QTc (446 +/- 29 vs 416 +/- 28 ms, P < 0.05) but similar QT dispersion (43 +/- 14 vs 29 +/- 10 ms) compared to controls. After lidocaine administration, baseline QTc and QT dispersion did not change in either LQTS or controls. One LQTS patient had a 54 ms (12%) reduction in his QTc but no change in QT dispersion. Following K+ infusion, baseline QTc and QT dispersion decreased by 9% (P < 0.005) and 45% (P < 0.005), respectively in LQTS. No effect was seen in control patients, where QTc and QT dispersion shortened by 1% (5 +/- 14 ms) and 20% (6 +/- 7 ms), respectively, compared to baseline. The combined lidocaine/K+ infusion had a sensitivity, specificity, and accuracy of 88%, 100%, and 94%, respectively, in diagnosing LQTS.A simplified sequential lidocaine/K+ challenge is accurate in diagnosing LQTS among patients with borderline QTc prolongation.
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Antiepileptic rufinamide and QTc interval shortening in a patient with long QT syndrome: case report
There is limited pharmacologic therapy to reduce the QT interval in hereditary long QT syndrome (LQTS).We describe a child with Allan-Herndon-Dudley syndrome, Lennox-Gastaut epileptic syndrome (LGS), and LQTS Type 1 (LQTS1). Rufinamide was added to his antiepileptic medications to improve seizure control and was noted to be associated with a marked improvement in electrocardiogram QT interval. To the best of our knowledge, this is the first reported case of successful pharmacologic shortening of the QT interval in LQTS1.This case report highlights the potential benefits of rufinamide, a drug associated with mild QT shortening in normal individuals, to markedly reduce and normalize QT duration in a subject with LQTS1.
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Синдром удлиненного интервала QT (СУИQT) ассоциирован с потенциально фатальными желудочковыми тахиаритмиями. В то время как современные методы лечения СУИQT являются достаточно эффективными, диагностика этой патологии сегодня по-прежнему представляет серьезную проблему в связи с тем, что отсутствует стандартизованный метод оценки интервала QT (для определения интервала QT сегодня используются разные методы); определенные сложности также связаны с вариабельностью фенотипических проявлений (наличие асимптомных и латентных форм) и трудностями интерпретации генетических результатов. В настоящее время международные эксперты рекомендуют измерение интервала QT вручную с помощью касательного (тангенс) или порогового метода. Современные технологии геномного секвенирования и связанные с ними новые научные открытия приводят к тому, что алгоритмы клинической оценки и критерии патогенности генетических вариантов являются сегодня предметом непрерывного процесса реанализа и реклассификации. Так, растущее количество (теперь их более 15) генов, мутации которых ассоциированы с множеством подтипов CУИQT, способно дезориентировать клинических специалистов и вызывать сомнения молекулярных генетиков в отношении патогенности многих зарегистрированных генетических вариантов. Многоцентровые исследования последних лет продемонстрировали важные генотип-фенотипические корреляции, которые в настоящее время востребованы в клинической практике для определения тактики лечения пациентов с наиболее распространенными тремя генотипами, составляющими 85–95% всех ген-позитивных СУИQT: KCNQ1 (СУИQT тип 1), KCNH2 (СУИQT тип 2) и SCN5A (СУИQT тип 3).В представленной статье проведен анализ рекомендуемых методов измерения интервала QT, обзор новой системы генетической классификации и риск-стратификации CУИQT. Для освещения важной концепции глубокого фенотипирования, включающего каскадный скрининг членов семьи с интерпретацией результатов генетического теста и сопоставлением их с фенотипической экспрессией (сегрегационый анализ), представлены клинические наблюдения семейных форм СУИQT с генотипами KCNQ1 (СУИQT тип 1) и SCN5A (СУИQT тип 3). Эта концепцияимеет важное значение для установления точного диагноза СУИQT во избежание возможных диагностических ошибок, что в конечном итоге определяет стратегию лечения и прогноз пациентов, оптимальный выбор неинвазивных или инвазивных методов терапии. Long QT Syndrome (LQTS) is associated with potentially fatal ventricular tachyarrhythmias. While modern LQTS management is quite effective, the diagnosis of this pathology today still poses a serious problem due to the fact that there is no standardized method for estimating the QT interval (different methods are used for assessment of QT interval), variability of phenotypic manifestations (asymptomatic and latent forms) and difficulties in interpreting genetic results. Currently, international experts recommend measuring the QT interval manually using the tangent or threshold method. Modern technologies of genomic sequencing and related new scientific discoveries lead to the fact that clinical evaluation algorithms and criteria of pathogenicity of genetic variants are the subject for a continuous process of reanalysis and reclassification. Thus, the growing number (now there are more than 15) of genes, the mutations of which are associated with many LQTS types can disorient clinical specialists and raise doubts among molecular geneticists regarding the pathogenicity of many registered genetic variants. Multicenter studies of recent years have shown important genotype-phenotypic correlations that are currently in demand in clinical practice for determining the treatment tactics for patients with the most common three genotypes that comprise about 85–95% of all gene-positive LQTS: KCNQ1 (LQT 1), KCNH2 (LQT 2) and SCN5A (LQT 3).In the presented article, the analysis of the recommended methods for measuring the QT interval, the overview of new system of LQTS genetic classification and LQTS risk stratification were carried out. To highlight the important concept of deep phenotyping, including cascading screening of family members with interpretation of the results of the genetic test (segregation analysis), the clinical case reports of family LQTS with the genotypes KCNQ1 (LQT 1) and SCN5A (LQT 3) were presented. This concept is of great importance for establishing an accurate LQTS diagnosis in order to avoid possible diagnostic errors, which ultimately determines the treatment strategy and prognosis of patients, the optimal choice of non-invasive or invasive methods of therapy.
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Short QT syndrome
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