Role of arrhythmic phenotype in prognostic stratification and management of dilated cardiomyopathy.

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.

The Role of Next-Generation Sequencing in the Management of Patients with Suspected Non-Ischemic Cardiomyopathy after Syncope or Termination of Sudden Arrhythmic Death.

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.

The evidence for the implantable loop recorder in patients with inherited arrhythmia syndromes: a review of the literature.

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.

Genetic mutations in young patients admitted to an emergency department for syncope during sport practice. / Mutaciones genéticas en los pacientes jóvenes atendidos en un servicio de urgencias por síncope durante la práctica de deporte.

BACKGROUND AND OBJECTIVES: To study the frequency of genetic mutations related to genetic heart disease among young patients admitted for syncope during sport practice. PATIENTS AND METHODS: A case series study that included patients≤45 years admitted for syncope during sport practice during 2010-2011. We collected demographic and clinical variables, genetic tests mutations and final clinical diagnosis. RESULTS: A genetic test was performed in 46 (76.7%) of 60 patients evaluated. The genetic test was positive in 12 (26%; 95% CI 15.6-40.3) patients; 10 (21.7%) had PKP2 mutation related to arrhythmogenic right ventricular dysplasia mutation, one (2.2%) KCNQ1 mutation and one (2.2%) SCN5A mutation related to channelopathies. The genetic test was positive in 11 (35.5%) cases of undetermined syncope and one (50%) case of cardiac syncope, being negative in all cases with neuromediated syncopes (P=.037). CONCLUSIONS: Gene mutations are common in young patients suffering from syncope during sports, especially in those with cardiac or undetermined aetiology.

Whole exome sequencing identified a pathogenic mutation in RYR2 in a Chinese family with unexplained sudden death.

OBJECTIVE: This study aimed to identify the pathogenic mutation in a Chinese family with unexplained sudden death (USD) or occasional syncope. MATERIALS AND METHODS: Whole exome sequencing and target capture sequencing were respectively conducted for two related patients. The genetic data was screened using the 1000 genomes project and SNP database (PubMed), and the identified mutations were assessed for predicted pathogenicity using the SIFT and Polyphen-2 algorithms. RESULTS: We identified a heterozygous mutation in the RYR2 gene at c.490C>T (p.P164S), highly conserved across all species, in three family members of USD, syncope and malignant ventricular tachycardias induced by treadmill exercise test, while another heterozygous de novo mutation in SCN5A at c.5576G>A p.R1859H was detected in one family member. Both variants were verified by Sanger sequencing. Importantly, RYR2 p.P164S is associated with the risk of sudden cardiac death, such as in catecholaminergic polymorphic ventricular tachycardia. CONCLUSIONS: A pathogenic mutation in RYR2 (p.P164S) is the likely cause of USD in a Chinese family associated with malignant ventricular arrhythmias. Whole exome and target capture sequencing can be useful for discovering the genetic causes of USD.

Fainting Fanconi syndrome clarified by proxy: a case report.

BACKGROUND: Rare diseases may elude diagnosis due to unfamiliarity of the treating physicians with the specific disorder. Yet, advances in genetics have tremendously enhanced our ability to establish specific and sometimes surprising diagnoses. CASE PRESENTATION: We report a case of renal Fanconi syndrome associated with intermittent hypoglycemic episodes, the specific cause for which remained elusive for over 30 years, despite numerous investigations, including three kidney and one liver biopsy. The most recent kidney biopsy showed dysmorphic mitochondria, suggesting a mitochondrial disorder. When her son presented with hypoglycemia in the neonatal period, he underwent routine genetic testing for hyperinsulinemic hypoglycemia, which revealed a specific mutation in HNF4A. Subsequent testing of the mother confirmed the diagnosis also in her. CONCLUSION: Modern sequencing technologies that test multiple genes simultaneously enable specific diagnoses, even if the underlying disorder was not clinically suspected. The finding of mitochondrial dysmorphology provides a potential clue for the mechanism, by which the identified mutation causes renal Fanconi syndrome.

Multigenerational Inheritance of Long QT Syndrome Type 2 in a Japanese Family.

Congenital long QT syndrome (LQTS) is an important cause of sudden cardiac death in young people without any other structural disease. Mutations in the genes encoding the cardiac ion channels or associated proteins have been shown to result in ion channel dysfunction and thereby causing LQTS. We investigated a Japanese family with LQTS for four generations, with the female family members showing severe symptoms. We performed genetic tests for LQTS-related genes and identified a heterozygous KCNH2 mutation (p.K638del). In the family, the KCNH2 mutation had a very high multigenerational inheritance, and female genotype positives showed more severe phenotypes.

Clinical Presentation and Outcomes by Sex in Arrhythmogenic Right Ventricular Cardiomyopathy: Findings from the North American ARVC Registry.

BACKGROUND: Sex differences in clinical presentation and outcomes of hereditary arrhythmias are commonly reported. We aimed to compare clinical presentation and outcomes in men and women with arrhythmogenic right ventricular cardiomyopathy (ARVC) enrolled in the North American ARVC Registry. METHODS: A total of 125 ARVC probands (55 females, mean age 38 ± 12; 70 males, mean age 41 ± 15) diagnosed, as either "affected" or "borderline" were included. Baseline clinical characteristics and time-dependent outcomes including syncope, ventricular tachycardia (VT), fast VT (>240 bpm), ventricular fibrillation (VF), and death were compared between males and females. RESULTS: The percentage of ARVC subjects diagnosed as "affected" (84% vs. 89%; P = 0.424) or "borderline" (16% vs. 11%; P = 0.424) was similar between females and males. Among the baseline characteristics, inverted T-waves in V2 trended to be more common in women (P = 0.09), whereas abnormal signal-averaged ECGs (SAECGs; P < 0.001) and inducible VT/VF (P = 0.026) were more frequent in men. During a mean follow-up of 37 ± 20 months, the probability of ICD-recorded VT/VF or death was not significantly different between men and women (P = 0.456). However, there was a trend toward lower risk of fast VT/VF or death in women compared to men (hazard ratio 0.41, 95% CI 0.151-1.113, P = 0.066). Abnormal SAECG and evidence of intramyocardial fat by cardiac MRI was associated with adverse outcomes in men (P = 0.006 and 0.02 respectively). CONCLUSION: In the North American ARVC Registry, we found similar frequency of "affected" and "borderline" subjects between men and women. Sex-related differences were observed in baseline ECG, SAECG, Holter-recorded ventricular arrhythmias, and VT inducibility. Men showed a trend toward greater risk of fast VT than women.

Pediatric Cohort With Long QT Syndrome　- KCNH2 Mutation Carriers Present Late Onset But Severe Symptoms.

BACKGROUND: In children with long QT syndrome (LQTS), risk factors for cardiac events have been reported, but age-, gender- and genotype-related differences in prognosis remain unknown in Asian countries. METHODS AND RESULTS: The study examined clinical prognosis at age between 1 and 20 years in 496 LQTS patients who were genotyped as either of LQT1-3 (male, n=206). Heterozygous mutations were observed in 3 major responsible genes:KCNQ1in271,KCNH2in 192, andSCN5Ain 33 patients. LQTS-associated events were classified into 3 categories: (1) syncope (n=133); (2) repetitive torsade de pointes (TdP, n=3); and (3) cardiopulmonary arrest (CPA, n=4). The risk of cardiac events was significantly lower in LQT1 girls than boys≤12 years (HR, 0.55), whereas LQT2 female patients ≥13 years had the higher risk of cardiac events than male patients (HR, 4.60). Patients in the repetitive TdP or CPA group included 1 LQT1 female patient, 1 LQT2 male patient, and 5 LQT2 female patients. All LQT2 patients in these groups had TdP repeatedly immediately after the antecedent event. In addition, all 5 female LQT2 patients in these groups had the event after or near puberty. CONCLUSIONS: Female LQT2 children might have repeated TdP shortly after prior events, especially after puberty. (Circ J 2016; 80: 696-702).

Syncope in genotype-negative long QT syndrome family members.

Unaffected long-QT syndrome family members (FMs) frequently experience syncope. The aims of this study were to test the hypothesis that syncope events in FMs are benign events and to compare clinical characteristics, triggers eliciting the syncope events, and long-term outcomes between FMs and those with LQT1 or LQT2 mutations from the international Long QT Syndrome Registry. A total of 679 FMs, 864 LQT1 patients, and 782 LQT2 patients were included. Seventy-eight FMs (11%) experienced cardiovascular events. Almost all cardiovascular events were nonfatal syncope; only 1 FM, with an additional mitral valve prolapse, experienced aborted cardiac arrest during exercise. The mean age at first syncope in FMs was 17 years, and female FMs experienced syncope more frequently than male FMs (14% vs 9%, p = 0.027). Syncope was more frequently triggered by exercise in LQT1 patients (43% in LQT1 patients vs 5% in FMs, p <0.001), while syncope triggered by a variety of other triggers was more frequent in FMs (54% in FMs vs 22% in LQT1 patients and 30% in LQT2 patients, p <0.001 for both). None of the FMs experienced aborted cardiac arrest or sudden cardiac death after the first syncopal episode. In conclusion, syncope is frequently present in FMs, and these syncopal events occurred more frequently in female than in male FMs, with an increased incidence in midadolescence. Triggers eliciting the syncopal events were different between FMs and patients with long-QT syndrome mutations. Hence, the type of trigger is useful in distinguishing between high- and low-risk syncope. These data indicate that FMs from families with LQTS have a benign form of syncope, most likely related to vasovagal syncope and not ventricular tachyarrhythmic syncope.

Association between non-coding polymorphisms of HOPX gene and syncope in hypertrophic cardiomyopathy.

OBJECTIVE: Homeodomain Only Protein X (HOPX) is an unusual homeodomain protein which regulates Serum Response Factor (SRF) dependent gene expression. Due to the regulatory role of HOPX on SRF activity and the regulatory role of SRF on cardiac hypertrophy, we aimed to investigate the relationship between HOPX gene variations and hypertrophic cardiomyopathy (HCM). METHODS: In this study, designed as a case-control study, we analyzed coding and flanking non-coding regions of the HOPX gene through 67 patients with HCM and 31 healty subjects. Certain regions of the gene were investigated by Single Stranded Conformation Polymorphism (SSCP) and Restriction Fragment Length Polymorphism (RFLP). Statistical analyses of genotypes and their relationship with clinical parameters were performed by chi-square, Kruskal-Wallis and the Fisher's exact test. RESULTS: In 5' Untranslated Region (UTR) and intronic region of the HOPX gene, we found a C>T substitution and an 8-bp insertion/deletion (In/Del) polymorphism, respectively. These two polymorphisms seemed to constitute an haplotype. While the frequency of homozygous genotypes of In/Del and C/T polymorphisms were found significantly lower in the patients with syncope (p=0.014 and p=0.017, respectively), frequency of their heterozygous genotypes were found significantly higher in the patients with syncope (p=0.048 and p=0.030, respectively). CONCLUSION: Though there was not found any mutation in coding sequence of HOPX gene, two non-coding polymorphisms were found related to syncope in HCM patients. While homozygous status of these polymorphisms was found to be protective against the syncope, their heterozygous status seemed to be a risk factor for syncope in HCM patients. Our results suggest that HOPX may contribute to pathogenesis or manifestation of HCM as a modifier gene.

Sensory stimulus-sensitive drop attacks and basal ganglia calcification: new findings in a patient with FOLR1 deficiency.

Loss-of-function mutations in the FOLR1 gene (MIM *136430), encoding the folate receptor alpha, impair cerebral folate transport and lead to a progressive neurometabolic disorder. We report on a 5-year-old boy with progressive ataxia, from the age of 2 years and 6 months, with myoclonic jerks, regression, and impressive myoclonic tonic spasms with drop attacks, which were partially provoked by touching his face or washing his hands. Delayed myelination and cerebellar atrophy on cranial MRI were important clues to the diagnosis of cerebral folate transport deficiency, which was confirmed by homozygosity for the known nonsense mutation p.R204X in the FOLR1 gene. Computed tomography taken after head injury revealed bilateral calcifications in the basal ganglia as a novel finding in a patient with FOLR1 mutation.

"Drop attacks" as first clinical symptoms in a child carrying MTTK m.8344A>G mutation.

UNLABELLED: We describe a child with dyslexia and difficulty in school who, at the age of 13 years, began to suffer from several head injuries resulting from falls of uncertain cause. Two years later, the patient developed symptoms of a severe mitochondrial disorder (involving bulbar-pyramidal paralysis, ophthalmoplegia, and hyperlactatemia) that coincided with VPA administration. Brain MR imaging revealed rapidly developing Leigh syndrome (LS), and muscle biopsy showed ragged blue fibres (RBF). A diminished expression of the E1α subunit of pyruvate dehydrogenase was found in muscle homogenate (signal 28.7% of normal). The accurate diagnosis of mitochondrially inherited LS (MILS) and the identification of an almost homoplasmic m.8344G>A mutation in the MTTK gene was delayed due to an initial incorrect diagnosis of epilepsy, misdiagnosis of neuroinfection, and failure to note LS on the first brain MRI. Periods of exacerbation or improvement were observed in association with the administration of certain drugs or procedures (VPA administration or intensive rehabilitation associated with worsening; ketogenic diet associated with remission). However, the random association of these factors with natural disease fluctuations cannot be excluded. CONCLUSIONS: 1) To improve the early detection of mitochondrial disorder, we recommend screening for mtDNA (and nDNA) mutations in all patients with LS present on brain MRI. 2) Brain MRI protocols should include diffusion-weighted and T2-weighted imaging, and LS-like changes should be analysed by a neuroradiologist experienced in the field. 3) Additional controlled studies are urgently needed to assess the causal relationship between management strategies and the natural history of the disease. Until the association between VPA and disease exacerbation can be ruled out, VPA should be avoided in patients with these symptoms unless the mitochondrial disorder has been excluded.

Digenic inheritance novel mutations in SCN5a and SNTA1 increase late I(Na) contributing to LQT syndrome.

SCN5A and SNTA1 are reported susceptible genes for long QT syndrome (LQTS). This study was designed to elucidate a plausible pathogenic arrhythmia mechanism for the combined novel mutations R800L-SCN5A and A261V-SNTA1 on cardiac sodium channels. A Caucasian family with syncope and marginally prolonged QT interval was screened for LQTS-susceptibility genes and found to harbor the R800L mutation in SCN5A and A261V mutation in SNTA1, and those with both mutations had the strongest clinical phenotype. The mutations were engineered into the most common splice variant of human SCN5A and SNTA1 cDNA, respectively, and sodium current (INa) was characterized in human embryonic kidney 293 cells cotransfected with neuronal nitric oxide synthase (nNOS) and the cardiac isoform of the plasma membrane Ca-ATPase (PMCA4b). Peak INa densities were unchanged for wild-type (WT) and for mutant channels containing R800L-SCN5A, A261V-SNTA1, or R800L-SCN5A plus A261V-SNTA1. However, late INa for either single mutant was moderately increased two- to threefold compared with WT. The combined mutations of R800L-SCN5A plus A261V-SNTA1 significantly enhanced the INa late/peak ratio by 5.6-fold compared with WT. The time constants of current decay of combined mutant channel were markedly increased. The gain-of-function effect could be blocked by the N(G)-monomethyl-l-arginine, a nNOS inhibitor. We conclude that novel mutations in SCN5A and SNTA1 jointly exert a nNOS-dependent gain-of-function on SCN5A channels, which may consequently prolong the action potential duration and lead to LQTS phenotype.

Microvolt T-wave alternans in short QT syndrome.

BACKGROUND: T-wave alternans (TWA) is an accepted marker of risk for malignant ventricular arrhythmias, for which prognosis value has been established in different populations. Short QT syndrome (SQTS) is a very rare primary electrical disease carrying the risk of ventricular fibrillation. TWA in SQTS has not been evaluated yet. METHODS: Thirteen patients with SQTS (QT = 308 ± 16 ms, QTc = 329 ± 10 ms, heart rate = 69 ± 8 beats/min) underwent microvolt TWA measurement using spectral analysis. TWA testing was performed using Heartwave II (Cambridge Heart™, Inc., Bedford, MA, USA) during bicycle exercice and classified as negative, positive, or indeterminate according to the published standards for clinical interpretation. RESULTS: Twelve patients were male (mean age 23 ± 5 years). Five were asymptomatic, three presented with aborted sudden cardiac death, and five with unexplained syncope. Six patients belonged to two unrelated families, while familial cases of SQTS were present for two other patients. A familial history of sudden death (SD) was present for seven patients. Ventricular fibrillation was inducible in three patients. Four patients were implanted with an implantable cardioverter-defibrillator and one presented with polymorphic ventricular tachycardia during follow-up. TWA was negative in each but one patient (indeterminate). Maximal negative heart rate was 118 ± 12 beats/min. Patients with previous SD displayed significant shorter QT and higher resting heart rate compared to the remaining cases. CONCLUSIONS: TWA testing is negative in 12 of 13 SQTS patients, even in the symptomatic or inducible ones. Measurement of TWA using conventional protocol and criteria for risk stratification in SQTS seems therefore useless.

The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands.

AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic disorder with a highly malignant clinical course. Exercise-stress test is the first-line approach to diagnose suspected individuals. We sought to elucidate the value of exercise-stress test for predicting mutations and future cardiac events in CPVT-family relatives. METHODS AND RESULTS: The present study included 67 asymptomatic relatives (24 ± 15 years) of 17 genetically positive CPVT probands, who underwent exercise-stress test without any medication and genetic testing. Exercise-stress test, which was considered positive with the induction of ventricular tachycardia or premature ventricular contractions consisting of bigeminy or couplets, was positive in 17 relatives (25%). Genetic analysis disclosed mutations in 16 of these 17 relatives (94%) and in 16 of the 50 relatives (32%) with negative exercise-stress test; the sensitivity and specificity for a positive genotype were 50 and 97%, respectively (P< 0.001). Among 32 mutation carriers, cardiac events occurred in 7 of the 16 relatives with positive and 2 of the 16 relatives with negative exercise-stress test during the follow-up period of 9.6 ± 3.8 years, and four with positive and two with negative stress test were not on regular beta-blocker treatment at these events. In the 16 relatives with positive stress test, those on beta-blocker treatment demonstrated a trend of lower cardiac event rate (Log-rank P= 0.054). CONCLUSION: In asymptomatic relatives of CPVT probands, exercise-stress test can be used as a simple diagnostic tool. Nevertheless, because of the low sensitivity for predicting mutations and future cardiac events in those with negative stress test, genetic analysis should be performed to improve patient management.

Muscle glycogen storage disease 0 presenting recurrent syncope with weakness and myalgia.

Muscle glycogen storage disease 0 (GSD0) is caused by glycogen depletion in skeletal and cardiac muscles due to deficiency of glycogen synthase 1 (GYS1), which is encoded by the GYS1 gene. Only two families with this disease have been identified. We report a new muscle GSD0 patient, a Japanese girl, who had been suffering from recurrent attacks of exertional syncope accompanied by muscle weakness and pain since age 5 years until she died of cardiac arrest at age 12. Muscle biopsy at age 11 years showed glycogen depletion in all muscle fibers. Her loss of consciousness was gradual and lasted for hours, suggesting that the syncope may not be simply caused by cardiac event but probably also contributed by metabolic distress.