Generation and characterization of twelve human induced pluripotent stem cell (iPSC) lines from four familial long QT syndrome type 1 (LQT1) patients carrying KCNQ1 c.1201dupC mutation.

In this study, we describe the generation and characterization of induced pluripotent stem cell (iPSC) lines from familial long QT syndrome type 1 (LQT1) patients carrying the KCNQ1 c.1201dupC (p.Arg401fs) frame shift mutation by using non-integrational Sendai reprogramming method. The patient-specific iPSC lines harboring the c.1201dupC mutation on KCNQ1 gene expressed pluripotency markers and had the capacity to differentiate into three germ layers.

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi004-A from a carrier of the KCNQ1-R594Q mutation.

We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a male carrier of the heterozygous mutation c.1781 G > A p.R594Q on the KCNQ1 gene. hiPSCs, generated using four retroviruses each encoding for OCT4, SOX2, KLF4 and cMYC, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi005-A from a patient carrying the KCNQ1-R190W mutation.

We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a woman carrier of the heterozygous mutation c.568C > T p.R190W on the KCNQ1 gene. hiPSCs, obtained using four retroviruses enconding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).

Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome.

KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal-hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano-Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants.

Complex aberrant splicing in the induced pluripotent stem cell-derived cardiomyocytes from a patient with long QT syndrome carrying KCNQ1-A344Aspl mutation.

BACKGROUND: Long QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1, which encodes the α subunit of the slow delayed rectifier potassium current channel. We previously reported that a synonymous mutation, c.1032G>A, p.A344Aspl, in KCNQ1 is most commonly identified in genotyped patients with LQT1 in Japan and the aberrant splicing was analyzed in the lymphocytes isolated from patients' blood samples. However, the mechanisms underlying the observed processes in human cardiomyocytes remain unclear. OBJECTIVE: The purpose of this study was to establish and analyze patient-specific human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model carrying KCNQ1-A344Aspl. METHODS: We generated hiPSCs from the peripheral blood mononuclear cells obtained from a patient with LQT1 carrying KCNQ1-A344Aspl. Using the differentiated cardiomyocytes, we analyzed splicing variants and performed electrophysiology studies. RESULTS: We identified 7 aberrant RNA variants in A344Aspl hiPSC-CMs, which were more complex compared with those in peripheral lymphocytes. Multielectrode array analysis revealed that 1 µM isoproterenol significantly prolonged the duration of the corrected field potential in A344Aspl hiPSC-CMs as compared with that in control hiPSC-CMs. In addition, 100 nM E-4031, which inhibits the rapid component of the delayed rectifier potassium current, was shown to induce early afterdepolarization-like waveforms in A344Aspl hiPSC-CMs. Action potential durations (APDs) did not significantly differ between the hiPSC-CM groups. After administering 500 nM isoproterenol, APDs of A344Aspl hiPSC-CMs were significantly longer than those of the controls. (R)-N-(4-(4-Methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide and phenylboronic acid, slow delayed rectifier potassium current activators, ameliorated the APDs of hiPSC-CMs. CONCLUSION: We identified complex aberrant messenger RNA variants in the A344Aspl hiPSC-CM model and successfully recapitulated the clinical phenotypes of the patient with concealed LQT1. This model allows the investigation of the underlying mechanisms and development of novel therapies.

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi003-A from a patient affected by an autosomal recessive form of Long QT Syndrome type 1.

We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 51years old female patient homozygous for the mutation c.535 G>A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1), not associated with deafness. The hiPSCs, generated using four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC, are pluripotent and can differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs).

Studying KCNQ1 Mutation and Drug Response in Type 1 Long QT Syndrome Using Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs) are becoming a valuable model for studying inherited cardiac arrhythmias. Type 1 long-QT syndrome is associated with the genetic variants of KCNQ1 gene that encodes Kv7.1, the α-subunit of the voltage-gated potassium channel QKT subfamily member 1 that channels the slow component of the outwardly rectifying K+ channel current in cardiac myocytes. Patient- or disease-specific hiPSC-CM model could facilitate the characterization of the genotype-phenotype relationships and testing of individualized drug responses.Here, we describe the methods in the generation of hiPSC-CMs, molecular and electrophysiological characterizations of their cellular phenotypes associated with KCNQ1/Kv7.1 defects, and evaluation of the effects of K+ channel-specific drugs.

Microscopic mechanisms for long QT syndrome type 1 revealed by single-channel analysis of I(Ks) with S3 domain mutations in KCNQ1.

BACKGROUND: The slowly activating delayed rectifier current IKs participates in cardiac repolarization, particularly at high heart rates, and mutations in this K(+) channel complex underlie long QT syndrome (LQTS) types 1 and 5. OBJECTIVE: The purpose of this study was to determine biophysical mechanisms of LQT1 through single-channel kinetic analysis of IKs carrying LQT1 mutations in the S3 transmembrane region of the pore-forming subunit KCNQ1. METHODS: We analyzed cell-attached recordings from mammalian cells in which a single active KCNQ1 (wild type or mutant) and KCNE1 complex could be detected. RESULTS: The S3 mutants of KCNQ1 studied (D202H, I204F, V205M, and S209F), with the exception of S209F, all led to a reduction in channel activity through distinct kinetic mechanisms. D202H, I204F, and V205M showed decreased open probability (Po) compared with wild type (0.07, 0.04, and 0.12 vs 0.2); increased first latency from 1.66 to >2 seconds at +60 mV (I204F, V205M); variable-to-severe reductions in open dwell times (≥50% in V205M); stabilization of closed states (D202H); and an inability of channels to reach full conductance levels (V205M, I204F). S209F is a kinetic gain-of-function mutation with a high Po (0.40) and long open-state dwell times. CONCLUSION: S3 mutations in KCNQ1 cause diverse kinetic defects in I(Ks), affecting opening and closing properties, and can account for LQT1 phenotypes.

Cuidados de enfermería a personas en edad pediátrica con síndrome de QT largo congénito / Nursing care for people in childhood with congenital long QT syndrome", "_i": "

El síndrome de QT largo es una anomalía del sistema eléctrico del corazón caracterizado por prolongación del intervalo QT en el electrocardiograma debido a la alteración en la función de los canales iónicos; ocasiona múltiples mutaciones en los canales de sodio y potasio. Por lo tanto, tiende a desarrollar fibrilación ventricular y Torsade de Pointes poniendo en riesgo la integridad y la vida. El objetivo de la presente revisión bibliográfica es describir el síndrome de QT largo de tipo congénito y subrayar la importancia de ejecutar un plan de cuidados, orientado a la persona en edad pediátrica, de manera que se eviten complicaciones y reincidencias hospitalarias para mejorar su calidad de vida. La valoración de los signos y síntomas por parte del personal de enfermería y todo el equipo de salud, así como la interpretación de los diversos métodos diagnósticos, son fundamentales para brindar una atención de calidad. Aun cuando las manifestaciones son inespecíficas, el diagnóstico eficaz de la enfermedad permite iniciar el manejo apropiado y disminuir la mortalidad infantil.

The long QT syndrome is an anomaly of the electrical system of the heart characterized by prolongation of the QT interval on the electrocardiogram due to an alteration in the function of sodium and potassium ion channels causing multiple mutations in these. Therefore, it tends to develop ventricular fibrillation and helical tachyarrhythmia (Torsades de Pointes), putting at risk the integrity and the life of the child. The objective of this review is to describe congenital long QT syndrome and underline the importance to develop a care plan aimed at the pediatric person in order to avoid complications and hospital recurrence in order to improve their quality of life. Evaluation of signs and symptoms by staff nurses and all health team, as well as the interpretation of the various diagnostic methods, are essential to provide quality care, timely and accurate. Even though the manifestations are no specific, the effective diagnosis of this disease allows starting a proper handling and reducing infant mortality

LQTS in Northern BC: homozygosity for KCNQ1 V205M presents with a more severe cardiac phenotype but with minimal impact on auditory function.

Long QT syndrome (LQTS), a rare congenital cardiac condition associated with life-threatening ventricular arrhythmias is characterized by a prolonged QT interval on electrocardiograph corrected for heart rate [corrected QT (QTc)]. LQTS has been historically categorized into the autosomal dominant Romano-Ward syndrome (RWS) and the autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS). JLNS is associated with prelingual sensorineural deafness. Both types of LQTS can be caused by mutations in channel genes (e.g. KCNQ1) responsible for potassium homeostasis in cardiac myocytes and cochlea. Autosomal dominant mutations often cause the RWS phenotype and homozygous or compound heterozygous mutations contribute to JLNS. Two First Nations communities in northern British Columbia are affected disproportionately with LQTS largely due to the V205M mutation in KCNQ1, however, the pathology and phenotypic expression for those V205M homozygous has been unknown. Here, we show that four V205M homozygous individuals have a significantly higher 'peak' QTc, and a more severe cardiac phenotype compared with 41 V205M heterozygous carriers and 57 first to third degree relatives without mutations. Given the lack of prelingual deafness the homozygous V205M LQTS patients present with a phenotype more typical of RWS than JLNS.

In silico cardiac risk assessment in patients with long QT syndrome: type 1: clinical predictability of cardiac models.

OBJECTIVES: The study was designed to assess the ability of computer-simulated electrocardiography parameters to predict clinical outcomes and to risk-stratify patients with long QT syndrome type 1 (LQT1). BACKGROUND: Although attempts have been made to correlate mutation-specific ion channel dysfunction with patient phenotype in long QT syndrome, these have been largely unsuccessful. Systems-level computational models can be used to predict consequences of complex changes in channel function to the overall heart rhythm. METHODS: A total of 633 LQT1-genotyped subjects with 34 mutations from multinational long QT syndrome registries were studied. Cellular electrophysiology function was determined for the mutations and introduced in a 1-dimensional transmural electrocardiography computer model. The mutation effect on transmural repolarization was determined for each mutation and related to the risk for cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) among patients. RESULTS: Multivariate analysis showed that mutation-specific transmural repolarization prolongation (TRP) was associated with an increased risk for cardiac events (35% per 10-ms increment [p < 0.0001]; ≥upper quartile hazard ratio: 2.80 [p < 0.0001]) and life-threatening events (aborted cardiac arrest/sudden cardiac death: 27% per 10-ms increment [p = 0.03]; ≥upper quartile hazard ratio: 2.24 [p = 0.002]) independently of patients' individual QT interval corrected for heart rate (QTc). Subgroup analysis showed that among patients with mild to moderate QTc duration (<500 ms), the risk associated with TRP was maintained (36% per 10 ms [p < 0.0001]), whereas the patient's individual QTc was not associated with a significant risk increase after adjustment for TRP. CONCLUSIONS: These findings suggest that simulated repolarization can be used to predict clinical outcomes and to improve risk stratification in patients with LQT1, with a more pronounced effect among patients with a lower-range QTc, in whom a patient's individual QTc may provide less incremental prognostic information.

Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

BACKGROUND: Hundreds of nonsynonymous single nucleotide variants (nsSNVs) have been identified in the 2 most common long-QT syndrome-susceptibility genes (KCNQ1 and KCNH2). Unfortunately, an ≈3% BACKGROUND: and KCNH2 nsSNVs amongst healthy individuals complicates the ability to distinguish rare pathogenic mutations from similarly rare yet presumably innocuous variants. METHODS AND RESULTS: In this study, 4 tools [(1) conservation across species, (2) Grantham values, (3) sorting intolerant from tolerant, and (4) polymorphism phenotyping] were used to predict pathogenic or benign status for nsSNVs identified across 388 clinically definite long-QT syndrome cases and 1344 ostensibly healthy controls. From these data, estimated predictive values were determined for each tool independently, in concert with previously published protein topology-derived estimated predictive values, and synergistically when ≥3 tools were in agreement. Overall, all 4 tools displayed a statistically significant ability to distinguish between case-derived and control-derived nsSNVs in KCNQ1, whereas each tool, except Grantham values, displayed a similar ability to differentiate KCNH2 nsSNVs. Collectively, when at least 3 of the 4 tools agreed on the pathogenic status of C-terminal nsSNVs located outside the KCNH2/Kv11.1 cyclic nucleotide-binding domain, the topology-specific estimated predictive value improved from 56% to 91%. CONCLUSIONS: Although in silico prediction tools should not be used to predict independently the pathogenicity of a novel, rare nSNV, our results support the potential clinical use of the synergistic utility of these tools to enhance the classification of nsSNVs, particularly for Kv11.1's difficult to interpret C-terminal region.

Proteomic analyses of transgenic LQT1 and LQT2 rabbit hearts elucidate an increase in expression and activity of energy producing enzymes.

Various biochemical and genomic mechanisms are considered to be a hallmark of metabolic remodeling in the stressed heart, including the hypertrophied and failing heart. In this study, we used quantitative proteomic 2-D Fluorescence Difference In-Gel Electrophoresis (2-D DIGE) in conjunction with mass spectrometry to demonstrate differential protein expression in the hearts of transgenic rabbit models of Long QT Syndrome 1 (LQT1) and Long QT Syndrome 2 (LQT2) as compared to littermate controls (LMC). The results of our proteomic analysis revealed upregulation of key metabolic enzymes involved in all pathways associated with ATP generation, including creatine kinase in both LQT1 and LQT2 rabbit hearts. Additionally, the expression of lamin-A protein was increased in both LQT1 and LQT2 rabbit hearts as was the expression of mitochondrial aldehyde dehydrogenase and desmoplakin in LQT1 and LQT 2 rabbit hearts, respectively. Results of the proteomic analysis also demonstrated down regulation in the expression of protein disulfide-isomerase A3 precuorsor and dynamin-like 120 kDa protein (mitochondrial) in LQT1, and of alpha-actinin 2 in LQT2 rabbit hearts. Up regulation of the expression of the enzymes associated with ATP generation was substantiated by the results of selective enzyme assays in LQT1 and LQT2 hearts, as compared to LMC, which revealed increases in the activities of glycogen phosphorylase (+50%, +65%, respectively), lactate dehydrogenase (+25%, +25%) pyruvate dehydrogenase (+31%, +22%), and succinate dehydrogenase (+32%, +60%). The activity of cytochrome c-oxidase, a marker for the mitochondrial function was also found to be significantly elevated (+80%) in LQT1 rabbit hearts as compared with LMC. Western blot analysis in LQT1 and LQT2 hearts compared to LMC revealed an increase in the expression of very-long chain-specific acyl-CoA dehydrogenase (+35%, +33%), a rate-limiting enzymes in ß-oxidation of fatty acids. Collectively, our results demonstrate similar increases in the expression and activities of key ATP-generating enzymes in LQT1 and LQT2 rabbit hearts, suggesting an increased demand, and in turn, increased energy supply across the entire metabolic pathway by virtue of the upregulation of enzymes involved in energy generation.

Disease characterization using LQTS-specific induced pluripotent stem cells.

AIMS: Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs). METHODS AND RESULTS: We reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells. CONCLUSIONS: This study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.

Bupivacaine destabilizes action potential duration in cellular and computational models of long QT syndrome 1.

BACKGROUND: The effects of the local anesthetic bupivacaine on cardiac action potentials (APs) are mainly attributed to inhibition of cardiac Na(+) channels. The relevance of its ability to also induce high-affinity blockade of human ether-à-gogo-related gene (hERG) channels is unclear. We investigated whether this interaction may functionally become more significant in cellular and computational models of long (L)QT syndromes. METHODS: Left ventricular cardiomyocytes were isolated from adult guinea pig hearts, and bupivacaine-induced effects on APs were investigated using the patch-clamp technique. LQT-like states were pharmacologically induced by either blocking I(Ks) (LQT1-like, 10 µmol/L chromanol 293B), or I(Kr) (LQT2-like, 10 µmol/L E4031). Computational analysis of bupivacaine's effects was based on the Luo-Rudy dynamic model. RESULTS: Bupivacaine induced dose-dependent AP shortening in control myocytes. However, in the presence of 1 to 30 µmol/L bupivacaine, a high variability in AP duration with AP prolongations of up to 40% was observed. This destabilizing effect on AP duration was significantly increased in LQT1-like but not in LQT2-like myocytes. Similarly, the incidence of AP prolongations in the presence of 3 µmol/L bupivacaine was significantly increased from 6% in control myocytes to 24% in LQT1-like but not in LQT2-like myocytes. Computational modeling supported the concept that this bupivacaine-induced AP instability and the AP prolongations in the control and LQT1-like myocytes were caused by inhibition of hERG channels. CONCLUSIONS: This study provides evidence that bupivacaine induces inhibition of hERG channels, which is functionally silent under normal conditions but will become more relevant in LQT1-like states in which repolarization relies to a larger degree on hERG channels. Interactions with ion channels other than cardiac Na(+) channels may, therefore, determine the net cardiac effects of bupivacaine when the normal balance of ionic currents is altered.

Low incidence of sudden cardiac death in a Swedish Y111C type 1 long-QT syndrome population.

BACKGROUND: A 10% cumulative incidence and a 0.3% per year incidence rate of sudden cardiac death in patients younger than 40 years and without therapy have been reported in type 1 long-QT syndrome. The Y111C-KCNQ1 mutation causes a severe phenotype in vitro, suggesting a high-risk mutation. This study investigated the phenotype among Y111C-KCNQ1 mutation carriers in the Swedish population with a focus on life-threatening cardiac events. METHODS AND RESULTS: We identified 80 mutation carriers in 15 index families, segregating the Y111C-KCNQ1 mutation during a national inventory of mutations causing the long-QT syndrome. Twenty-four mutation carriers <40 years experienced syncope (30%). One mutation carrier had an aborted cardiac arrest (1.25%). No case of sudden cardiac death was reported during a mean nonmedicated follow-up of 25+/-20 years. This corresponds to a low incidence rate of life-threatening cardiac events (0.05%/year versus 0.3%/year, P=0.025). In 8 Y111C families connected by a common ancestor, the natural history of the mutation was assessed by investigating the survival over the age of 40 years for 107 nonmedicated ascertained mutation carriers (n=24) and family members (n=83) born between 1873 and 1968. In total, 4 deaths in individuals younger than 40 years were noted: 1 case of noncardiac death and 3 infant deaths between 1873 and 1915. CONCLUSIONS: The dominant-negative Y111C-KCNQ1 mutation, associated with a severe phenotype in vitro, presents with a low incidence of life-threatening cardiac events in a Swedish population. This finding of discrepancy emphasizes the importance of clinical observations in the risk stratification of long-QT syndrome.

Una forma atípica de síndrome de QT largo: heraldos de muerte súbita cardíaca / Atypical form of long QT syndrome: cardiac sudden death signs

El estudio presenta dos casos clínicos con hallazgos relacionados con formas atípicas de síndrome de QT largo. En años recientes los síndromes de QT están sometidos a continua revisión. El balance autonómico, la dispersión de la repolarización y lo heterogéneo de sus bases genéticas explican las diversas presentaciones clínicas. Dos hermanos (varón y hembra) fueron estudiados; ambos presentaron taquicardia ventricular en condiciones de aumento del tono adrenergico (miedo y ejercicio) y su madre murió súbitamente antes de cumplir 50 años. Se estudiaron con electrocardiograma, vectocardiograma, electrocardiograma de alta frecuencia, electrocardiograma de esfuerzo, ecocardiograma y adicionalmente en el varón angiografía coronaria. El electrocardiograma de reposo mostró trastornos no específicos de repolarización. En una ocasión tuvo taquicardia ventricular con morfología de bloqueo de rama derecha. La prueba de esfuerzo mostró una falta de acortamiento del QT al aumentar la frecuencia cardíaca. El ecocardiograma, electrocardiograma de alta frecuencia y la angiografía coronaria fueron normales. Ella teniendo un electrocardiograma de reposo normal desarrolló una taquicardia ventricular con morfología de bloqueo de rama izquierda durante la prueba de esfuerzo. Los pacientes con una historia familiar de muerte súbita, anormalidades no específicas de la repolarización, falta de acortamiento del QT al aumentar la frecuencia cardíaca (hipodinamia del QT) son sospechosos de desarrollar taquicardias ventriculares en condiciones de aumento del tono adrenérgico y por lo consiguiente en ellos deben tomarse medidas preventivas

The study presents two cases with features related to atypical forms of long QT syndrome. The QT syndrome has been reviewed recently, the presence of autonomic imbalance, the dispersion of repolarization, the heterogeneity of its genetic basis in explaining its clinical presentations have call the atention of the investigators. Two siblings patients (male and female) were studied; both presented ventricular tachycardia under conditions of augmented adrenergic tone (fear and exercise) and their mother died suddenly before age fifty. Electrocardiogram, vectocardiogram, signal average electrocardiogram, bidimensional echo were performed in both, additionally he was studied with coronary angiography. The resting electrocardiogram in him showed non-specific repolarization anormalities, ventricular tachycardia with right bundle branch configuration in one occasion. Lack of proper shortening of the QT interval during de stress test. Signal average electrocardiogram, bi-dimensional echo and coronary angiography were normal. She had a normal electrocardiogram and echocardiogram but developed a ventricular tachycardia with left bundle branch configuration during the early stages of an stress test. Patients with a positive family history of sudden death, non-specific repolarization anormalities, lack of shortening of the QT interval with increasing heart rate (hypodinamic QT) are suspicious of developing ventricular tachycardia under conditions of augmented adrenergic tone. Preventive measures should be taken in patients with this conditions