RESUMEN
AIMS: Dilated cardiomyopathy (DCM) with arrhythmic phenotype combines phenotypical aspects of DCM and predisposition to ventricular arrhythmias, typical of arrhythmogenic cardiomyopathy. The definition of DCM with arrhythmic phenotype is not universally accepted, leading to uncertainty in the identification of high-risk patients. This study aimed to assess the prognostic impact of arrhythmic phenotype in risk stratification and the correlation of arrhythmic markers with high-risk arrhythmogenic gene variants in DCM patients. METHODS AND RESULTS: In this multicentre study, DCM patients with available genetic testing were analysed. The following arrhythmic markers, present at baseline or within 1 year of enrolment, were tested: unexplained syncope, rapid non-sustained ventricular tachycardia (NSVT), ≥1000 premature ventricular contractions/24 h or ≥50 ventricular couplets/24 h. LMNA, FLNC, RBM20, and desmosomal pathogenic or likely pathogenic gene variants were considered high-risk arrhythmogenic genes. The study endpoint was a composite of sudden cardiac death and major ventricular arrhythmias (SCD/MVA). We studied 742 DCM patients (45 ± 14 years, 34% female, 410 [55%] with left ventricular ejection fraction [LVEF] <35%). During a median follow-up of 6 years (interquartile range 1.6-12.1), unexplained syncope and NSVT were the only arrhythmic markers associated with SCD/MVA, and the combination of the two markers carried a significant additive risk of SCD/MVA, incremental to LVEF and New York Heart Association class. The probability of identifying an arrhythmogenic genotype rose from 8% to 30% if both early syncope and NSVT were present. CONCLUSION: In DCM patients, the combination of early detected NSVT and unexplained syncope increases the risk of life-threatening arrhythmic outcomes and can aid the identification of carriers of malignant arrhythmogenic genotypes.
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Cardiomiopatía Dilatada , Muerte Súbita Cardíaca , Fenotipo , Humanos , Femenino , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/fisiopatología , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/complicaciones , Masculino , Persona de Mediana Edad , Pronóstico , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Adulto , Medición de Riesgo/métodos , Síncope/genética , Síncope/etiología , Síncope/fisiopatología , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/diagnóstico , Volumen Sistólico/fisiología , Taquicardia Ventricular/genética , Taquicardia Ventricular/fisiopatología , Taquicardia Ventricular/diagnóstico , Pruebas Genéticas/métodosRESUMEN
Cardiac arrhythmias and sudden death are frequent in patients with non-ischemic cardiomyopathy and can precede heart failure or additional symptoms where malignant cardiac arrhythmias are mostly the consequence of advanced cardiomyopathy and heart failure. Finding these subgroups and making an early diagnosis could be lifesaving. In our retrospective study, we are presenting arrhythmic types of frequent cardiomyopathies where an arrhythmogenic substrate is less well defined, as in ischemic or structural heart disease. In the period of 2 years, next-generation sequencing (NGS) tests along with standard clinical tests were performed in 208 patients (67 women and 141 men; mean age, 51.2 ± 19.4 years) without ischemic or an overt structural heart disease after syncope or aborted sudden cardiac death. Genetic variants were detected in 34.4% of the study population, with a significant proportion of pathogenic variants (P) (14.4%) and variants of unknown significance (VUS) (20%). Regardless of genotype, all patients were stratified according to clinical guidelines for aggressive treatment of sudden cardiac death with an implantable cardioverter defibrillator (ICD). The P variant identified by NGS serves for an accurate diagnosis and, thus, better prevention and specific treatment of patients and their relatives. Results in our study suggest that targeted sequencing of genes associated with cardiovascular disease is an important addendum for final diagnosis, allowing the identification of a molecular genetic cause in a vast proportion of patients for a definitive diagnosis and a more specific way of treatment. VUS in this target population poses a high risk and should be considered possibly pathogenic in reanalysis.
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Cardiopatías , Insuficiencia Cardíaca , Masculino , Animales , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Síncope/diagnóstico , Síncope/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Muerte Súbita Cardíaca/etiología , Anuros , Arritmias Cardíacas/genética , Arritmias Cardíacas/terapiaRESUMEN
BACKGROUND: Sex-specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life-threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel-mediated LQTS. METHODS AND RESULTS: The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and ß-blocker therapy. Anderson-Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow-up. The genotype-phenotype risk prediction model identified low-, intermediate-, and high-risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low-risk group, high-risk male subjects experienced a pronounced 5.2-fold increased risk of recurrent CEs (P<0.001), whereas intermediate-risk patients had a 2.1-fold (P=0.004) increased risk . At age 20 years, the low-, intermediate-, and high-risk adolescent male patients had on average 0.3, 0.6, and 1.4 CEs per person, respectively. Corresponding 10-year adjusted probabilities for a first LTE were 2%, 6%, and 8%. CONCLUSIONS: Personalized genotype-phenotype risk estimates can be used to guide sex-specific management in male adolescents with potassium channel-mediated LQTS.
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Síndrome de QT Prolongado , Canales de Potasio , Humanos , Masculino , Adolescente , Femenino , Adulto Joven , Adulto , Niño , Canales de Potasio/genética , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/congénito , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Síncope/genética , Síncope/epidemiología , Genotipo , Factores de Riesgo , Medición de Riesgo , ElectrocardiografíaRESUMEN
BACKGROUND: Although structural heart disease is frequently present among patients who experience sudden cardiac death (SCD), inherited arrhythmia syndromes can also play an important role in the occurrence of SCD. CPVT2, which is the second-most prevalent form of CPVT, arises from an abnormality in the CASQ2 gene. OBJECTIVE: We represent a novel CASQ2 variant that causes CPVT2 and conduct a comprehensive review on this topic. METHODS: The proband underwent Whole-exome sequencing (WES) in order to ascertain the etiology of CPVT. Subsequently, the process of segregating the available family members was carried out through the utilization of PCR and Sanger Sequencing. We searched the google scholar and PubMed/Medline for studies reporting CASQ2 variants, published up to May 10,2023. We used the following mesh term "Calsequestrin" and using free-text method with terms including "CASQ2","CASQ2 variants", and "CASQ2 mutation". RESULTS: The CASQ2 gene was found to contain an autosomal recessive nonsense variant c.268_269insTA:p.Gly90ValfsTer4, which was identified by WES. This variant was determined to be the most probable cause of CPVT in the pedigree under investigation. CONCLUSION: CASQ2 variants play an important role in pathogenesis of CPVT2. Notabely, based on results of our study and other findings in the literature the variant in this gene may cause an neurological signs in the patients with CPVT2. Further studies are needed for more details about the role of this gene in CPVT evaluation, diagnosis, and gene therapy.
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Calsecuestrina , Taquicardia Ventricular , Niño , Femenino , Humanos , Masculino , Calsecuestrina/genética , Electrocardiografía , Secuenciación del Exoma , Corazón/fisiopatología , Linaje , Síncope/genética , Taquicardia Ventricular/genética , Codón sin Sentido/genética , MutaciónRESUMEN
OBJECTIVE: To analyze the clinical and genetic characteristics of a patient with long QT syndrome type 14 (long QT syndrome-14, LQT14, OMIM # 616247) caused by a de novo CALM1 mutation. METHODS: The clinical data of the patient were collected, next-generation sequencing technology was used to determine the exome gene sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing. RESULTS: A 5-year and 9-month-old girl was admitted to the hospital due to a syncopal episode. During the attack, the main symptoms were loss of consciousness, cyanosis of the face and lips, and weakness of limbs. The child had multiple seizures in the past, all of which occurred after emotional excitement and activity. She was diagnosed with epilepsy for more than 3 years, but the effect of antiepileptic treatment was not satisfactory. The electrocardiogram was normal in the past. A month ago, convulsions occurred again after exercise, and the electrocardiogram showed QTc 496 ms. The treadmill test showed a significant prolongation of QTc after exercise, and the genetic results suggested a new heterozygous variant of CALM1, c.395A>G; p. (Asp132Gly). Consequently, she was diagnosed with LQT14 and treated with propranolol. During a follow-up of 15 months, there were no seizures or syncope. CONCLUSIONS: This patient had multiple episodes of convulsions or syncope after emotional stimulation or activity, with intermittent prolongation of the QTc on routine ECG, marked prolongation of the QTc after exercise, and T-wave alternans, which differed from the LQT14 phenotype caused by the previous CALM1 mutation.
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Síndrome de QT Prolongado , Niño , Femenino , Humanos , Lactante , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/tratamiento farmacológico , Síncope/genética , Síncope/diagnóstico , Electrocardiografía/efectos adversos , Mutación , ConvulsionesRESUMEN
The autosomal recessive (AR) form of Long QT Syndrome (LQTS) is described both associated with deafness known as Jervell and Lange-Nielsen (JLN) syndrome, and without deafness (WD). The aim of the study is to report the characteristics of AR LQTS patients and the efficacy of the therapy. Data of all children with AR LQTS referred to the Bambino Gesù Children's Hospital IRCCS from September 2012 to September 2021were included. Three (30%) patients had compound heterozygosity and 7 (70%) had homozygous variants of the KCNQ1 gene, the latter showing deafness. Four patients (40%) presented aborted sudden cardiac death (aSCD): three with previous episodes of syncope (75%), the other without previous symptoms (16.6% of asymptomatic patients). An episode of aSCD occurred in 2/3 (66.7%) of WD and heterozygous patients, while in 2/7 (28%) JLN and homozygous patients and in 2/2 patients with QTC > 600 ms. All patients were treated with Nadolol. In 5 Mexiletine was added, shortening QTc and obtaining the disappearance of the T-wave alternance (TWA) in 3/3. Episodes of aSCD seem to be more frequent in LQTS patients with compound heterozygous variants and WD than in those with JLN and homozygous variants. Episodes of aSCD also appear more frequent in children with syncope or with QTc value > 600 ms, even on beta-blocker therapy, than in patients without syncope or with Qtc < 600 ms. However, our descriptive results should be confirmed by larger studies. Moreover, Mexiletine addition reduced QTc value and eliminated TWA.
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Sordera , Paro Cardíaco , Síndrome de Jervell-Lange Nielsen , Síndrome de QT Prolongado , Niño , Humanos , Canal de Potasio KCNQ1/genética , Mexiletine/uso terapéutico , Síndrome de QT Prolongado/tratamiento farmacológico , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Síndrome de Jervell-Lange Nielsen/tratamiento farmacológico , Síndrome de Jervell-Lange Nielsen/genética , Síndrome de Jervell-Lange Nielsen/diagnóstico , Síncope/genéticaRESUMEN
The purpose of the study is to explore the use of Calgary scoring (CS) and Modified Calgary scoring (MCS) in the differentiation of genetic generalized epilepsy and syncope in children. The study involved 117 patients aged < 18 years who presented to our hospital's pediatric neurology outpatient clinic with TLOC between June 2020 and June 2022. In addition to CS and MCS scoring, all patients were subjected to statistical analysis based on their age, sex, number of episodes and distribution during the day, duration of syncope, and family history. Seventy-one patients with syncope and 46 with epilepsy were included in the study. At a CS value > - 1, sensitivity was 86.9% and specificity 63.4%, while at an MCS value > - 1, sensitivity was 76.1% and specificity 71.8%. CS had less specificity and sensitivity in predicting epilepsy when focal epilepsies were excluded. Abnormal behavior noted by bystanders, including witnessed unresponsive, unusual posturing, or limb jerking? (Q5) emerged as the most important question for the detection of epilepsy. Compared with other syncope findings, loss of consciousness during prolonged sitting or standing (Q9) emerged as the most important for the detection of syncope.
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Epilepsias Parciales , Epilepsia Generalizada , Epilepsia , Humanos , Niño , Animales , Diagnóstico Diferencial , Síncope/diagnóstico , Síncope/genética , Epilepsia/diagnóstico , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Epilepsias Parciales/diagnóstico , AnurosRESUMEN
Congenital long QT syndrome (LQTS) is one type of inherited fatal cardiac arrhythmia that may lead to sudden cardiac death (SCD). Mutations in more than 16 genes have been reported to be associated with LQTS, whereas the genetic causes of about 20% of cases remain unknown. In the present study, we investigated a four-generation pedigree with familial history of syncope and SCD. The proband was a 33-year-old young woman who experienced 3 episodes of syncope when walking at night. The electrocardiogram revealed a markedly epinephrine-provoked prolonged QT interval (QT = 468 ms, QTc = 651 ms) but no obvious arrhythmia in the resting state. Three family members have died of suspected SCD. Whole-exome sequencing and bioinformatic analysis based on pedigree revealed that a novel missense mutation KCNA10 (c.1397Gï¼A/Arg466Gln) was the potential genetic lesion. Sanger sequencing was performed to confirm the whole-exome sequencing results. This mutation resulted in the KV1.8 channel amino acid residue 466 changing from arginine to glutamine, and the electrophysiological experiments verified it as a loss-of-function mutation of KV1.8, which reduced the K+ currents of KV1.8 and might result in the prolonged QT interval. These findings suggested that KCNA10 (c.1397Gï¼A) mutation was possibly pathogenic in this enrolled LQTS family, and may provide a new potential genetic target for diagnosis and counseling of stress-related LQTS families as well as the postmortem diagnosis of SCD.
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Síndrome de QT Prolongado , Adulto , Femenino , Humanos , Arritmias Cardíacas , Muerte Súbita Cardíaca/etiología , Epinefrina , Secuenciación del Exoma , Síndrome de QT Prolongado/complicaciones , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismo , Mutación , Síncope/complicaciones , Síncope/genéticaRESUMEN
AIMS: Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications. METHODS AND RESULTS: This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders. CONCLUSION: The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope.
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Enfermedades Cardiovasculares , Diabetes Mellitus , Humanos , Estudio de Asociación del Genoma Completo/métodos , Síncope/genética , Enfermedades Cardiovasculares/genética , Sistema Nervioso Autónomo , Análisis de la Aleatorización MendelianaRESUMEN
BACKGROUND: Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated to sudden cardiac death. Overall, variants have been identified in eighteen genes encoding for ion channel subunits and seven genes for regulatory proteins. Recently, a missense variant in DLG1 has been found within a BrS phenotype-positive patient. DLG1 encodes for synapse associated protein 97 (SAP97), a protein characterized by the presence of multiple domains for protein-protein interactions including PDZ domains. In cardiomyocytes, SAP97 interacts with Nav1.5, a PDZ binding motif of SCN5A and others potassium channel subunits. AIM OF THE STUDY: To characterize the phenotype of an Italian family with BrS syndrome carrying a DLG1 variant. METHODS: Clinical and genetic investigations were performed. Genetic testing was performed with whole-exome sequencing (WES) using the Illumina platform. According to the standard protocol, a variant found by WES was confirmed in all members of the family by bi-directional capillary Sanger resequencing. The effect of the variant was investigated by using in silico prediction of pathogenicity. RESULTS: The index case was a 74-year-old man with spontaneous type 1 BrS ECG pattern that experienced syncope and underwent ICD implantation. WES of the index case, performed assuming a dominant mode of inheritance, identified a heterozygous variant, c.1556G>A (p.R519H), in the exon 15 of the DLG1 gene. In the pedigree investigation, 6 out of 12 family members had the variant. Carriers of the gene variant all had BrS ECG type 1 drug induced and showed heterogeneous cardiac phenotypes with two patients experiencing syncope during exercise and fever, respectively. The amino acid residue #519 lies near a PDZ domain and in silico analysis suggested a causal role for the variant. Modelling of the resulting protein structure predicted that the variant disrupts an H-bond and a likelihood of being pathogenic. As a consequence, it is likely that a conformational change affects protein functionality and the modulating role on ion channels. CONCLUSIONS: A DLG1 gene variant identified was associated with BrS. The variant could modify the formation of multichannel protein complexes, affecting ion channels to specific compartments in cardiomyocytes.
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Síndrome de Brugada , Humanos , Síndrome de Brugada/genética , Pruebas Genéticas , Fenotipo , Miocitos Cardíacos , Síncope/complicaciones , Síncope/genética , Homólogo 1 de la Proteína Discs Large/genéticaRESUMEN
Risk stratification of patients with inherited arrhythmia syndromes (IASs) can be challenging. Recent guidelines acknowledge a place for considering the implantable loop recorder (ILR) to outrule malignant arrhythmia as a cause of syncope in certain inherited arrhythmia patients who are at low risk of sudden cardiac death. In this comprehensive literature review, we evaluate the available evidence for the use of the ILR in the IASs and in relatives of victims of sudden arrhythmic death syndrome.
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Arritmias Cardíacas , Síncope , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/terapia , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Electrocardiografía Ambulatoria/efectos adversos , Humanos , Prótesis e Implantes/efectos adversos , Síncope/etiología , Síncope/genética , SíndromeAsunto(s)
Displasia Ventricular Derecha Arritmogénica/complicaciones , ADN/genética , Enfermedades del Cabello/complicaciones , Queratodermia Palmoplantar/complicaciones , Mutación , Enfermedades Raras , Eliminación de Secuencia/genética , Síncope/etiología , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/genética , Secuencia de Bases , Análisis Mutacional de ADN , Ecocardiografía , Femenino , Enfermedades del Cabello/diagnóstico , Enfermedades del Cabello/genética , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Homocigoto , Humanos , Queratodermia Palmoplantar/diagnóstico , Queratodermia Palmoplantar/genética , Imagen por Resonancia Cinemagnética/métodos , Linaje , Síncope/genética , Adulto Joven , gamma Catenina/genética , gamma Catenina/metabolismoRESUMEN
Importance: Reflex syncope is the major cause of transient loss of consciousness, which affects one-third of the population, but effective treatment for individuals with severe syncope is lacking. Better understanding of reflex syncope predisposition may offer new therapeutic solutions. Objectives: To determine the familial risk of syncope in first-, second-, and third-degree relatives of affected individuals and to explore the role of genes and family environment in reflex syncope. Design, Setting, and Participants: In this national population-based family cohort study, the Swedish multigeneration register was linked to 3 Swedish nationwide registers: hospital discharge, outpatient care, and primary care registers for the period from 1997 to 2015. Sibling pairs born to Swedish parents between 1948 and 2005 were included. Linkage was also made to half-siblings and cousins. Data analysis was performed from June to October 2020. Exposures: Register-based syncope diagnosis among relatives: pairs of twins, siblings, half-siblings, and cousins. Main Outcomes and Measures: Odds ratios for syncope were calculated for relatives (twins, siblings, half-siblings, and cousins) of individuals who had syncope compared with relatives of individuals without syncope for reference. Sensitivity analysis excluding families with definite nonreflex syncope diagnosis was performed. Results: Among the study population of 2â¯694â¯442 participants, 1â¯381â¯453 (51.3%) were male, and the median (interquartile range) age was 32 (22-43) years. The study population consisted of 24â¯020 twins, 1â¯546â¯108 siblings, 264â¯244 half-siblings, and 1â¯044â¯546 cousins. In total, 61â¯861 (2.30%) unique individuals were diagnosed with syncope. Sixty-two percent (38â¯226) of the syncope-positive individuals were female. The odds ratio (OR) for syncope was 2.39 (95% CI, 1.61-3.53) for twins, 1.81 (95% CI, 1.71-1.91) for siblings, 1.28 (95% CI, 1.20-1.37) for half-siblings, and 1.13 (95% CI, 1.10-1.17) for cousins of individuals with syncope. The OR was highest among male twins at 5.03 (95% CI, 2.57-9.85). The proportion of syncope-positive individuals was consistently higher in women vs men, regardless of degree of relationship (twins: 346 [2.88%] vs 193 [1.61%]; siblings: 22â¯111 [2.92%] vs 13â¯419 [1.70%], half-siblings: 4148 [3.44%] vs 2425 [1.93%], cousins: 14â¯498 [2.87%] vs 9246 [1.72%]). Exclusion of nonreflex syncope diagnoses did not change syncope risk in affected families. Conclusions and Relevance: In this Swedish national population-based study, the risk of syncope among relatives of affected individuals was associated with the relationship degree and was strongest in twins and siblings, which suggests that there are genetic components of reflex syncope. Women were more likely to experience syncope independently of family relationship. A better understanding of genetic predisposition to reflex syncope may offer new therapeutic options in severely affected individuals.
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Relaciones Familiares , Sistema de Registros , Medición de Riesgo/métodos , Síncope/epidemiología , Adulto , Femenino , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Masculino , Estudios Retrospectivos , Factores de Riesgo , Suecia/epidemiología , Síncope/etiología , Síncope/genética , Adulto JovenRESUMEN
While a KCND3 V392I mutation uniquely displays a mixed electrophysiological phenotype of Kv4.3, only limited clinical information on the mutation carriers is available. We report two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), in whom we identified the KCND3 V392I mutation. We propose a link between the KCND3 mutation with a mixed electrophysiological phenotype and cardiocerebral phenotypes, which may be defined as a novel cardiocerebral channelopathy.
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Fibrilación Atrial/genética , Canalopatías/genética , Epilepsias Parciales/genética , Discapacidad Intelectual/genética , Canales de Potasio Shal/genética , Adolescente , Muerte Súbita Cardíaca , Electrocardiografía , Electroencefalografía , Femenino , Humanos , Persona de Mediana Edad , Madres , Mutación , Linaje , Hermanos , Síncope/genética , Adulto JovenRESUMEN
PURPOSE: To determine the lifetime cumulative incidence of syncope, potential ethnic differences and factors associated with syncope using the Malaysian elders longitudinal research (MELoR) study first wave dataset. METHODS: The MELoR study recruited community-dwelling adults aged 55 years and over, selected through stratified random sampling from three parliamentary constituencies. The baseline data collected during the first wave was obtained through face-to-face interviews in participants' homes using computer-assisted questionnaires. During their baseline assessments, participants were asked whether they had ever experienced a blackout in their lifetime and if they had experienced a blackout in the preceding 12 months. RESULTS: Information on blackouts and ethnicity were available for 1530 participants. The weight-adjusted lifetime cumulative incidence of syncope for the overall population aged 55 years and above was 27.7%. The estimated lifetime cumulative incidence according to ethnic groups was 34.6% for Malays, 27.8% for Indians and 23.7% for Chinese. The estimated 12-month incidence of syncope was 6.1% overall, equating to 11.7% for Malays, 8.7 % for Indians and 2.3% for Chinese. Both Malay [odds ratio (OR) 1.46; 95% confidence interval (CI) 1.10-1.95 and OR 3.62, 95% CI 1.96-6.68] and Indian (OR 1.34; 95% CI 1.01-1.80 and OR 3.31, 1.78-6.15) ethnicities were independently associated with lifetime and 12-month cumulative incidence of syncope, respectively, together with falls, dizziness and myocardial infarction. CONCLUSION: Ethnic differences exist for lifetime cumulative incidence of syncope in community-dwelling individuals aged 55 years and over in an urban area in Southeast Asia. Future studies should now seek to determine potential genetic, cultural and lifestyle differences which may predispose to syncope.
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Investigación Biomédica/tendencias , Etnicidad , Síncope/diagnóstico , Síncope/etnología , Anciano , Investigación Biomédica/métodos , Estudios Transversales , Etnicidad/genética , Femenino , Humanos , Incidencia , Estilo de Vida/etnología , Estudios Longitudinales , Malasia/etnología , Masculino , Persona de Mediana Edad , Síncope/genéticaRESUMEN
We present a 10-year-old boy with syncope who was found to have long-QT syndrome and severe Pulmonary Hypertension (PH) both in the absence of a secondary cause; to our knowledge, this is the first report with this unusual coexistence. His genetic tests were positive for hereditary hemorrhagic telangiectasia and Long QT Syndrome (LQTS) without any family history of PH or LQTS. We demonstrated that digital subtraction pulmonary angiography was more useful compared to CT angiogram to demonstrate pulmonary vascular changes which correlated with a noresponse to acute vasoreactivity testing during right heart catheterization. He has been stable for the last 2 years on Ambrisentan, Sildenafil, and Nadolol without recurrence of symptoms.
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Hipertensión Pulmonar , Síndrome de QT Prolongado , Síncope , Telangiectasia Hemorrágica Hereditaria , Angiografía , Niño , Ecocardiografía , Electrocardiografía , Pruebas Genéticas , Humanos , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/genética , Síndrome de QT Prolongado/diagnóstico por imagen , Síndrome de QT Prolongado/tratamiento farmacológico , Síndrome de QT Prolongado/genética , Masculino , Nadolol/uso terapéutico , Fenilpropionatos/uso terapéutico , Piridazinas/uso terapéutico , Citrato de Sildenafil/uso terapéutico , Síncope/diagnóstico por imagen , Síncope/tratamiento farmacológico , Síncope/genética , Telangiectasia Hemorrágica Hereditaria/diagnóstico por imagen , Telangiectasia Hemorrágica Hereditaria/tratamiento farmacológico , Telangiectasia Hemorrágica Hereditaria/genética , Tomografía Computarizada por Rayos XRESUMEN
AIMS: Syncope is a common condition associated with frequent hospitalization or visits to the emergency department. Family aggregation and twin studies have shown that syncope has a heritable component. We investigated whether common genetic variants predispose to syncope and collapse. METHODS AND RESULTS: We used genome-wide association data on syncope on 408 961 individuals with European ancestry from the UK Biobank study. In a replication study, we used the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86 189), to investigate the risk of incident syncope stratified by genotype carrier status. We report on a genome-wide significant locus located on chromosome 2q32.1 [odds ratio = 1.13, 95% confidence interval (CI) 1.10-1.17, P = 5.8 × 10-15], with lead single nucleotide polymorphism rs12465214 in proximity to the gene zinc finger protein 804a (ZNF804A). This association was also shown in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (1.30, 95% CI 1.15-1.46, P = 1.68 × 10-5) of incident syncope. Quantitative polymerase chain reaction analysis showed ZNF804A to be expressed most abundantly in brain tissue. CONCLUSION: We identified a genome-wide significant locus (rs12465214) associated with syncope and collapse. The association was replicated in an independent cohort. This is the first genome-wide association study to associate a locus with syncope and collapse.
Asunto(s)
Cromosomas Humanos Par 2 , Factores de Transcripción de Tipo Kruppel/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Síncope/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Línea Celular , Bases de Datos Factuales , Dinamarca/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Herencia , Humanos , Incidencia , Recién Nacido , Masculino , Persona de Mediana Edad , Fenotipo , Medición de Riesgo , Factores de Riesgo , Síncope/diagnóstico , Síncope/epidemiología , Síncope/fisiopatología , Reino Unido/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Migraine is associated with syncope. We investigated risk factors for syncope and burden of syncope in migraine patients. METHODS: Participants were recruited from a headache clinic. All participants provided information on lifestyle, co-morbidity, syncope, headache and suicide, and completed the MIDAS and HADS questionnaires. Genetic data were available for a subset of participants. Risk of syncope in relation to participant's characteristics and migraine susceptibility loci, and risks of psychological disorders associated with syncope, were calculated using logistic regression. RESULTS: Underweight, regular tea intake, diabetes mellitus, and migraine with aura were associated with increased syncope risks, with adjusted ORs of 1.76 (95% CI 1.03-3.03), 1.84 (95% CI 1.22-2.79), 4.70 (95% CI 1.58-13.95), and 1.78 (95% CI 1.03-3.10), respectively. Preliminary results showed that rs11172113 in LRP1 was associated with syncope risks. Comorbid syncope in migraine patients was associated with increased risks of depression (OR 1.95, 95% CI 1.18-3.22) and suicide attempt (OR 2.85, 95% CI 1.48-5.48). CONCLUSION: Our study showed the potential roles of vascular risk factors in the association between migraine and syncope. Modifiable risk factors for syncope in patients with migraine include body mass index and tea intake. The debilitating psychological impact of co-morbid syncope in migraine patients warrants clinical attention of treating physicians.
Asunto(s)
Trastornos Migrañosos/epidemiología , Trastornos Migrañosos/genética , Encuestas y Cuestionarios , Síncope/epidemiología , Síncope/genética , Adulto , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/genética , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/diagnóstico , Factores de Riesgo , Síncope/diagnóstico , Té/efectos adversos , Delgadez/diagnóstico , Delgadez/epidemiología , Delgadez/genéticaAsunto(s)
Ablación por Catéter/efectos adversos , Desmina/genética , Bloqueo Cardíaco/genética , Distrofia Muscular de Cinturas/genética , Síncope/genética , Síndrome de Wolff-Parkinson-White/cirugía , Adulto , Biopsia , Estimulación Cardíaca Artificial , Progresión de la Enfermedad , Ecocardiografía Doppler , Electrocardiografía , Femenino , Predisposición Genética a la Enfermedad , Bloqueo Cardíaco/diagnóstico , Bloqueo Cardíaco/terapia , Humanos , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/terapia , Mutación , Fenotipo , Recurrencia , Síncope/diagnóstico , Síncope/terapia , Resultado del Tratamiento , Síndrome de Wolff-Parkinson-White/diagnóstico , Síndrome de Wolff-Parkinson-White/fisiopatologíaRESUMEN
BACKGROUND: Long-QT (LQT) syndrome mutation carriers have higher risk of cardiac events than unaffected family members even in the absence of QTc prolongation. Changes in T-wave morphology may reflect penetrance of LQT syndrome mutations. We aimed to assess whether T-wave morphology may improve risk stratification of LQT2 mutation carriers with normal QTc interval. METHODS: LQT2 mutation carriers with QTc <460 ms in men and <470 ms in women (n=154) were compared with unaffected family members (n=1007). Baseline ECGs recorded at age ≥18 years underwent blinded assessment. Flat, notched, or negative T waves in leads II or V5 were considered abnormal. Cox regression analysis was performed to assess the association between T-wave morphology, the presence of mutations in the pore region of KCNH2, and the risk of cardiac events defined as syncope, aborted cardiac arrest, defibrillator therapy, or sudden cardiac death. Sex-specific associations were estimated using interactions terms. RESULTS: LQT2 female carriers with abnormal T-wave morphology had significantly higher risk of cardiac events compared with LQT2 female carriers with normal T waves (hazard ratio, 3.31; 95% confidence interval, 1.68-6.52; P=0.001), whereas this association was not significant in men. LQT2 men with pore location of mutations have significantly higher risk of cardiac events than those with nonpore mutations (hazard ratio, 6.01; 95% confidence interval, 1.50-24.08; P=0.011), whereas no such association was found in women. CONCLUSIONS: The risk of cardiac events in LQT2 carriers with normal QTc is associated with abnormal T-wave morphology in women and pore location of mutation in men. The findings further indicate sex-specific differences in phenotype and genotype relationship in LQT2 patients.