Publications by authors named "Federica Dagradi"

35 Publications

Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome.

JACC Clin Electrophysiol 2020 11 26;6(12):1561-1570. Epub 2020 Aug 26.

Joe DiMaggio Children's Hospital Heart Institute, Memorial Healthcare System, Hollywood, Florida, USA.

Objectives: This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs).

Background: LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown.

Methods: A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death.

Results: A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001).

Conclusions: In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.
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http://dx.doi.org/10.1016/j.jacep.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679474PMC
November 2020

Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in Families.

Circ Genom Precis Med 2020 12 9;13(6):e002911. Epub 2020 Nov 9.

National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.).

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- is the most common mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and mutation type on BrS phenotype in BrS families with mutations.

Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles).

Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; =0.0078). Among -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; =0.0846). In -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; =0.0146). Among E1784K- positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; =0.0011).

Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a mutation and severity of loss of function.
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http://dx.doi.org/10.1161/CIRCGEN.120.002911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748043PMC
December 2020

Exercise Training-Induced Repolarization Abnormalities Masquerading as Congenital Long QT Syndrome.

Circulation 2020 Dec 19;142(25):2405-2415. Epub 2020 Oct 19.

Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin (F.D., C.S, S.C., L.C., P.J.S.).

Background: The diagnosis of long QT syndrome (LQTS) is rather straightforward. We were surprised by realizing that, despite long-standing experience, we were making occasional diagnostic errors by considering as affected subjects who, over time, resulted as not affected. These individuals were all actively practicing sports-an observation that helped in the design of our study.

Methods: We focused on subjects referred to our center by sports medicine doctors on suspicion of LQTS because of marked repolarization abnormalities on the ECG performed during the mandatory medical visit necessary in Italy to obtain the certificate of eligibility to practice sports. They all underwent our standard procedures involving both a resting and 12-lead ambulatory ECG, an exercise stress test, and genetic screening.

Results: There were 310 such consecutive subjects, all actively practicing sports with many hours of intensive weekly training. Of them, 111 had a normal ECG, different cardiac diseases, or were lost to follow-up and exited the study. Of the remaining 199, all with either clear QTc prolongation and/or typical repolarization abnormalities, 121 were diagnosed as affected based on combination of ECG abnormalities with positive genotyping (QTc, 482±35 ms). Genetic testing was negative in 78 subjects, but 45 were nonetheless diagnosed as affected by LQTS based on unequivocal ECG abnormalities (QTc, 472±33 ms). The remaining 33, entirely asymptomatic and with a negative family history, showed an unexpected and practically complete normalization of the ECG abnormalities (their QTc shortened from 492±37 to 423±25 ms [<0.001]; their Schwartz score went from 3.0 to 0.06) after detraining. They were considered not affected by congenital LQTS and are henceforth referred to as "cases." Furthermore, among them, those who resumed similarly heavy physical training showed reappearance of the repolarization abnormalities.

Conclusion: It is not uncommon to suspect LQTS among individuals actively practicing sports based on marked repolarization abnormalities. Among those who are genotype-negative, >40% normalize their ECG after detraining, but the abnormalities tend to recur with resumption of training. These individuals are not affected by congenital LQTS but could have a form of acquired LQTS. Care should be exercised to avoid diagnostic errors.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048916DOI Listing
December 2020

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 Jan 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Circulation 2020 Jul 20;142(4):324-338. Epub 2020 May 20.

Masonic Medical Research Institute, Utica, NY (R.P.).

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk.

Am J Physiol Heart Circ Physiol 2020 06 20;318(6):H1357-H1370. Epub 2020 Mar 20.

Departments of Internal Medicine (Cardiovascular) and of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan.

Synapse-associated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiac-targeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 () variants that were associated with inherited arrhythmogenic disease. The murine model of cardiac-specific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human mutation resulting in an increase in Kv4.3 current () as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease. The gene encoding SAP97 () joins a growing list of genes encoding ion channel-interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting encoded SAP97's candidacy as a minor Brugada syndrome susceptibility gene.
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http://dx.doi.org/10.1152/ajpheart.00481.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311695PMC
June 2020

Mothers with long QT syndrome are at increased risk for fetal death: findings from a multicenter international study.

Am J Obstet Gynecol 2020 03 11;222(3):263.e1-263.e11. Epub 2019 Sep 11.

IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.

Background: Most fetal deaths are unexplained. Long QT syndrome is a genetic disorder of cardiac ion channels. Affected individuals, including fetuses, are predisposed to sudden death. We sought to determine the risk of fetal death in familial long QT syndrome, in which the mother or father carries the long QT syndrome genotype. In addition, we assessed whether risk differed if the long QT syndrome genotype was inherited from the mother or father.

Objective: This was a retrospective review of pregnancies in families with the 3 most common heterozygous pathogenic long QT syndrome genotypes in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3), which occur in approximately 1 in 2000 individuals. The purpose of our study was to compare pregnancy and birth outcomes in familial long QT syndrome with the normal population and between maternal and paternal carriers of the long QT syndrome genotype. We hypothesized that fetal death before (miscarriage) and after (stillbirths) 20 weeks gestation would be increased in familial long QT syndrome compared with the normal population and that the parent of origin would not affect birth outcomes.

Study Design: Our study was a multicenter observational case series of 148 pregnancies from 103 families (80 mothers, 23 fathers) with familial long QT syndrome (60 with LQT1, 29 with LQT2, 14 with LQT3) who were recruited from 11 international centers with expertise in hereditary heart rhythm diseases, pediatric and/or adult electrophysiology, and high-risk pregnancies. Clinical databases from these sites were reviewed for long QT syndrome that occurred in men or women of childbearing age (18-40 years). Pregnancy outcomes (livebirth, stillbirth, and miscarriage), birthweights, and gestational age at delivery were compared among long QT syndrome genotypes and between maternal vs paternal long QT syndrome-affected status with the use of logistic regression analysis.

Results: Most offspring (80%; 118/148) were liveborn at term; 66% of offspring (73/110) had long QT syndrome. Newborn infants of mothers with long QT syndrome were delivered earlier and, when the data were controlled for gestational age, weighed less than newborn infants of long QT syndrome fathers. Fetal arrhythmias were observed rarely, but stillbirths (fetal death at >20 weeks gestation) were 8 times more frequent in long QT syndrome (4% vs approximately 0.5%); miscarriages (fetal death at ≤20 weeks gestation) were 2 times that of the general population (16% vs 8%). The likelihood of fetal death was significantly greater with maternal vs paternal long QT syndrome (24.4% vs 3.4%; P=.036). Only 10% of all fetal deaths underwent postmortem long QT syndrome testing; 2 of 3 cases were positive for the family long QT syndrome genotype.

Conclusion: This is the first report to demonstrate that mothers with long QT syndrome are at increased risk of fetal death and to uncover a previously unreported cause of stillbirth. Our results suggest that maternal effects of long QT syndrome channelopathy may cause placental or myometrial dysfunction that confers increased susceptibility to fetal death and growth restriction in newborn survivors, regardless of long QT syndrome status.
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http://dx.doi.org/10.1016/j.ajog.2019.09.004DOI Listing
March 2020

Prevalence of cardiac amyloidosis among adult patients referred to tertiary centres with an initial diagnosis of hypertrophic cardiomyopathy.

Int J Cardiol 2020 02 17;300:191-195. Epub 2019 Jul 17.

Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy; IRCCS, Istituto Auxologico Italiano, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy.

Background: Differential diagnosis of genetic causes of left ventricular hypertrophy (LVH) is crucial for disease-specific therapy. We aim to describe the prevalence of Cardiac Amyloidosis (CA) among patients ≥40 years with an initial diagnosis of HCM referred for second opinion to national cardiomyopathy centres.

Methods: Consecutive patients aged ≥40 years referred with a tentative HCM diagnosis in the period 2014-2017 underwent clinical evaluation and genetic testing for HCM (including trans-thyretin-TTR). Patients with at least one red flag for CA underwent blood/urine tests, abdominal fat biopsy and/or bone-scintigraphy tracing and eventually ApoAI sequencing.

Results: Out of 343 patients (age 60 ± 13 years), 251 (73%) carried a likely/pathogenic gene variant, including 12 (3.5%) in the CA-associated genes TTR (n = 11) and ApoAI (n = 1). Furthermore, 6 (2%) patients had a mutation in GLA. Among the remaining, mutation-negative patients, 26 with ≥1 CA red-flag were investigated further: 3 AL-CA and 17 wild-type-TTR-CA were identified. Ultimately, 32(9%) patients were diagnosed with CA. Prevalence of CA increased with age: 1/75 (1%) at age 40-49, 2/86 (2%) at age 50-59, 8/84 (9%) at age 60-69, 13/61 (21%) at age 70-79, 8/31 (26%) at age ≥80 (p for trend <0.01).

Conclusions: Among patients referred with and initial diagnosis of HCM, CA was the most common unrecognized mimic (9% prevalence) and increased with age (from 1% at ages 40-49 years to 26% >80 years). Age at diagnosis should be considered one of the most relevant red flags for CA in patients with HCM phenotypes; however, there is no clear age cut-off mandating scintigraphy and other second level investigations in the absence of other features suggestive of CA.
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http://dx.doi.org/10.1016/j.ijcard.2019.07.051DOI Listing
February 2020

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

Eur Heart J 2019 09;40(35):2964-2975

Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.

Aims: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.

Methods And Results: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.

Conclusion: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.
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http://dx.doi.org/10.1093/eurheartj/ehz311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748747PMC
September 2019

Mexiletine Shortens the QT Interval in Patients With Potassium Channel-Mediated Type 2 Long QT Syndrome.

Circ Arrhythm Electrophysiol 2019 05;12(5):e007280

Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.M.B., R.K.R., M.J.A.), Mayo Clinic, Rochester, MN.

Background: Long QT syndrome is a potentially lethal yet highly treatable cardiac channelopathy. Although β-blocker therapy is standard for most patients, concomitant therapy with sodium channel blockers, like mexiletine, is often utilized for patients with sodium channel-mediated type 3 long QT syndrome (LQT3). The potential role of sodium channel blockers in patients with potassium channel-mediated long QT syndrome (ie, LQT1 and LQT2) has not been investigated in detail.

Methods: We performed a retrospective chart review on 12 patients (5 females; median age at diagnosis 14.1 years (interquartile range [IQR], 7.7-23; range, 0-59, median heart rate-corrected QT interval [QTc] at diagnosis 557 ms (IQR, 529-605) with genetically established LQT2 (10) or a combination of LQT1/LQT2 (1) or LQT2/LQT3 (1), who received mexiletine. Data were collected on symptomatic status, treatments, and breakthrough cardiac events after diagnosis and initiation of treatment. Additionally, 12-lead ECGs were collected at diagnosis, before initiation of mexiletine and following mexiletine to evaluate the drug's effect on QTc.

Results: Before diagnosis, 6 patients were symptomatic and, before initiation of mexiletine, 4 patients experienced ≥1 breakthrough cardiac event on β-blocker. Median age at first mexiletine dose was 24.3 years (IQR, 14-32.4). After mexiletine, the median QTc decreased by 65±45 ms from 547 ms (IQR, 488-558) premexiletine to 470 ms (IQR, 409-529) postmexiletine ( P=0.0005) for all patients. In 8 patients (67%), the QTc decreased by ≥ 40 ms with a mean decrease in QTc of 91 ms ( P < 0.008). For the 11 patients maintained on mexiletine therapy, there have been no breakthrough cardiac events during follow-up.

Conclusions: Although commonly prescribed in patients with LQT3, mexiletine also shortens the QTc significantly in two-thirds of a small subset of patients with potassium channel-mediated LQT2. In patients with LQT2, pharmacological targeting of the physiological late sodium current may provide added therapeutic efficacy to β-blocker therapy.
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http://dx.doi.org/10.1161/CIRCEP.118.007280DOI Listing
May 2019

Partial Pericardial Agenesis Mimicking Arrhythmogenic Right Ventricular Cardiomyopathy.

Clin J Sport Med 2020 09;30(5):e159-e162

Department of Cardiovascular, Neural and Metabolic Sciences, Istituto Auxologico Italiano, IRCCS, San Luca Hospital, Milan, Italy; and.

Absence of the pericardium is a rare congenital disease in which the fibroserum membrane covering the heart is partially or totally absent. It is characterized by few echocardiography (ECG) and imaging features that can mislead the diagnosis to an inherited cardiac disease, such as arrhythmogenic right ventricular cardiomyopathy. Although it has often a benign course, this congenital defect should be identified as in some cases herniation and strangulation can be life-threatening and cause sudden cardiac death. Red flags on ECG (sinus bradycardia, variable T-wave inversion), chest x-ray (Snoopy sign, absence of tracheal deviation, and esophagus impression), and transthoracic echocardiogram (unusual windows, teardrop left ventricle, and elongated atria) should rise the suspicion of pericardium absence. The correct diagnosis, confirmed by cardiac magnetic resonance, is mandatory as the consequences on the sport activity certification, the management, and the treatment are extremely different.
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http://dx.doi.org/10.1097/JSM.0000000000000733DOI Listing
September 2020

From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2.

Eur Heart J 2019 06;40(23):1832-1836

Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Via Pier Lombardo 22, Milan, Italy.

Aims: Having shown that Lumacaftor rescued the hERG trafficking defect in the induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two LQT2 patients, we tested whether the commercial association Lumacaftor + Ivacaftor (LUM + IVA) could shorten the QTc in the same two patients.

Methods And Results: After hospital admission and 1 day of baseline recordings, half dose LUM + IVA was administered on Day 1, followed by full dose (LUM 800 mg + IVA 500 mg) for 7 days. A continuous 12-lead Holter ECG allowed a large number of blind QTc measurements. Lumacaftor + Ivacaftor shortened QTc significantly in both patients: in V6 from 551 ± 22 ms to 523 ± 35 ms in Patient 1 (Pt1) and from 472 ± 21 ms to 449 ± 20 ms in Patient 2 (Pt2); in DII from 562 ± 25 ms to 549 ± 35 ms in Pt1 and from 485 ± 32 ms to 452 ± 18 ms in Pt2. In both patients, the percentage of QTc values in the lower tertile increased strikingly: in V6 from 33% to 68% and from 33% to 76%; in DII from 33% to 50% and from 33% to 87%. In the wash-out period a rebound in QTc was observed. On treatment, both patients developed diarrhoea, Pt1 more than Pt2.

Conclusion: This represents the first attempt to validate in patients the in vitro results of a drug repurposing strategy for cardiovascular disorders. Lumacaftor + Ivacaftor shortened significantly the QTc in the two LQT2 patients with a trafficking defect, largely confirming the findings in their iPSC-CMs but with smaller quantitative changes. The findings are encouraging but immediate translation into clinical practice, without validation in more patients, would be premature.
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http://dx.doi.org/10.1093/eurheartj/ehz023DOI Listing
June 2019

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Eur Heart J 2018 08;39(31):2879-2887

L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification.

Methods And Results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE.

Conclusion: In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.
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http://dx.doi.org/10.1093/eurheartj/ehy412DOI Listing
August 2018

A wearable remote monitoring system for the identification of subjects with a prolonged QT interval or at risk for drug-induced long QT syndrome.

Int J Cardiol 2018 Sep;266:89-94

Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy. Electronic address:

Background: A correct measurement of the QT interval in the out-of-hospital setting is important whenever the long QT syndrome (LQTS) is suspected or a therapy might lead to drug-induced LQTS (diLQTS) because QT interval monitoring in the initial days of therapy could alert to dangerous QT prolongation. We explored whether automated QTc measurements (BGM) by BodyGuardian™ (BG), a wearable remote monitoring system, are sufficiently reliable compared to our own manual measurements (MM) performed on the same beats during 12‑lead Holter recordings in LQTS patients (pts) and in healthy controls.

Methods: We performed 351 measurements in 20 LQTS pts and 16 controls. MM and BGM were compared by a Bland-Altman plot (BAp). High values of BAp indicate large differences between measurements.

Results: In all 36 subjects QTc was 446 ± 41 and 445 ± 47 ms in MM and BGM, respectively. The mean ± SE BAp was -1.4 ± 1.8 ms for QTc in all subjects, 8.3 ± 2.3 and -7.2 ± 2.5 ms respectively in controls and LQTS. The disagreement between BGM and MM <15 ms in all, in controls, and in LQTS was respectively 57%, 63% and 54%. Among controls, there were only 3/132 false positive measurements (BGM QTc >470 ms when MM QTc <440 ms) in 3 different subjects. Among LQTS, there were 10/219 false negative measurements (BGM QTc <440 ms when MM QTc >470 ms) in 6 pts, but only two had multiple false negative values.

Conclusions: This wearable monitoring system reliably identifies a prolonged QT interval and probably also subjects at risk for diLQTS.
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http://dx.doi.org/10.1016/j.ijcard.2018.03.097DOI Listing
September 2018

For neonatal ECG screening there is no reason to relinquish old Bazett's correction.

Eur Heart J 2018 08;39(31):2888-2895

Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Via Pier Lombardo 22, 20135 Milan, Italy.

Aims: There is an almost endless controversy regarding the choice of the QT correction formula to be used in electrocardiograms (ECG) in neonates for screening for long QT syndrome (LQTS). We compared the performance of four commonly used formulae and a new formula derived from neonates.

Methods And Results: From a cohort of 44 596 healthy neonates prospectively studied in Italy between 2001 and 2006, 5000 ECGs including 17 with LQTS-causing mutation identified by genotyping were studied using four QT correction formulae [Bazett's (QTcB), Fridericia's (QTcF), Framingham (QTcL), and Hodges (QTcH)]. A neonate-specific exponential correction (QTcNeo) was derived using 2500 randomly selected ECGs and validated for accuracy in the remaining 2500 ECGs. Digital ECGs were recorded between the 15th and 25th day of life; QT interval was measured manually in leads II, V5, and V6. To assess the ability to provide heart rate (HR) independent QT correction, regression analysis of the QTc-HR plots for all 5000 ECGs with each correction formula was done. QTcB provided the most HR independent correction with a slope closest to zero (slope +0.086 ms/b.p.m.) followed by QTcF (slope -0.308 ms/b.p.m.), QTcL (slope -0.364 ms/b.p.m.), and QTcH (slope +0.962 ms/b.p.m.). The QTc-HR slope of QTcNeo (QT/RR0.467) was similar to QTcB. The ability to correctly identify neonates with LQTS was best with QTcB, QTcF, and QTcNeo (comparable areas under the receiver operating characteristic curves) with positive predictive value of 39-40% and sensitivity of 100%. Cut-off values were 460 ms for QTcB, 394 ms for QTcF, and 446 ms for QTcNeo.

Conclusions: The Bazett's correction provides an effective HR independent QT correction and also accurately identifies the neonates affected by LQTS. It can be used with confidence in neonates, although other methods could also be used with appropriate cut-offs.
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http://dx.doi.org/10.1093/eurheartj/ehy284DOI Listing
August 2018

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi002-A from a patient affected by the Jervell and Lange-Nielsen syndrome and carrier of two compound heterozygous mutations on the KCNQ1 gene.

Stem Cell Res 2018 05 7;29:157-161. Epub 2018 Apr 7.

Coronary Care Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy; Laboratory of Experimental Cardiology for Cell and Molecular Therapy, IRCCS Policlinico San Matteo Foundation, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Department of Medicine, University of Cape Town, Cape Town, South Africa. Electronic address:

We report the generation of human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a female patient carrier of the two compound heterozygous mutations c.568 C>T p.R190W (maternal allele), and c.1781 G>A p.R594Q (paternal allele) on the KCNQ1 gene, causing Jervell and Lange-Nielsen Syndrome (JLNS). To obtain hiPSCs, we used the classical approach of the four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC. The obtained hiPSC clones display pluripotent stem cell characteristics, and differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs).
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http://dx.doi.org/10.1016/j.scr.2018.04.002DOI Listing
May 2018

Cardiac arrest and Brugada syndrome: Is drug-induced type 1 ECG pattern always a marker of low risk?

Int J Cardiol 2018 03 16;254:142-145. Epub 2017 Nov 16.

Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy. Electronic address:

Background: Patients diagnosed as affected by Brugada syndrome (BrS) on the basis of a drug-induced type 1 ECG pattern (type1) are regarded as at low risk for cardiac arrest. We tested whether this assumption matches reality.

Methods: The study population included 26 patients from our group and 217 patients from three studies published between 2002 and 2013, all of them with aborted cardiac arrest (ACA) and in whom a previously unrecognized type1 (spontaneous or drug-induced) was discovered after the event, thus leading to the diagnosis of BrS.

Results: Among our 26 patients, a drug-induced type1 was detected in 11 (42%) and only 1/11 showed a spontaneous pattern during follow-up; of 6 patients with syncope before ACA, 4 (67%) had only a drug-induced pattern. ICD shocks rates were similar in both spontaneous and drug-induced groups (57% and 45%). Early on, year 2002, the percentage of drug-induced type1 after ACA was much lower (14%) and has progressively increased to approximately 50%.

Conclusions: If drug-induced type1 carries low arrhythmic risk, it should seldom be the only marker for BrS after an ACA. In studies on patients after an unexpected ACA, a drug-induced type1 leads to the diagnosis of BrS more often than anticipated. This contrasts with prospective studies focusing on patients already diagnosed as BrS and which consider drug-induced type1 as a marker of low risk. Contrary to current views, it is possible that not all patients with a drug-induced BrS type1 are at low risk of future events.
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http://dx.doi.org/10.1016/j.ijcard.2017.10.118DOI Listing
March 2018

The genetics underlying idiopathic ventricular fibrillation: A special role for catecholaminergic polymorphic ventricular tachycardia?

Int J Cardiol 2018 Jan 5;250:139-145. Epub 2017 Oct 5.

Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy. Electronic address:

Background: Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics.

Methods And Results: The study included 76 Finnish and Italian patients with a mean age of 31.2years at the time of the VF event, collected between the years 1996-2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF<0.005%) variants that were classified as of unknown significance (VUS).

Conclusion: The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.
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http://dx.doi.org/10.1016/j.ijcard.2017.10.016DOI Listing
January 2018

Evolution in Managing Long QT Syndrome: From Registries to Centers of Excellence.

J Am Coll Cardiol 2017 07;70(4):463-465

IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy.

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http://dx.doi.org/10.1016/j.jacc.2017.06.004DOI Listing
July 2017

Red Bull®: Red flag or red herring?

Int J Cardiol 2017 Mar;231:179-180

Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy.

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http://dx.doi.org/10.1016/j.ijcard.2016.12.181DOI Listing
March 2017

Management of survivors of cardiac arrest - the importance of genetic investigation.

Nat Rev Cardiol 2016 09 7;13(9):560-6. Epub 2016 Jul 7.

IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Centro Diagnostico e di Ricerca San Carlo, Via Pier Lombardo, Milan, 22-20135, Italy.

Management of survivors of cardiac arrest is largely based on a traditional approach. However, during the past decade, arrhythmias of genetic origin have increasingly been recognized as contributing to many more cases than previously appreciated. This realization is forcing physicians managing the survivors of cardiac arrest also to consider family members. In this Perspectives article, we examine the appropriate management approaches for survivors of cardiac arrests related to channelopathies, cardiomyopathies, or ischaemic heart disease, and for their families. Important implications for families of individuals who have experienced sudden cardiac death as part of sudden infant death syndrome or during sport activity are also discussed. Congenital long QT syndrome provides a paradigm of the logical sequence of the steps that should be performed. When a diagnosis of the cause of the cardiac arrest is certain or probable, every effort should be made to identify the genetic basis of disease, because this approach will enable the identification and early protection of similarly affected family members. Accordingly, the availability in hospitals of at least one cardiologist with cardiovascular genetics expertise would improve the management of survivors of cardiac arrest as well as of their families.
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http://dx.doi.org/10.1038/nrcardio.2016.104DOI Listing
September 2016

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome.

Heart Rhythm 2016 06 24;13(6):1274-82. Epub 2016 Feb 24.

CHU Nantes, Institut du Thorax, Nantes, France.

Background: Brugada syndrome (BrS) is an arrhythmogenic disease associated with sudden cardiac death (SCD) that seldom manifests or is recognized in childhood.

Objectives: The objectives of this study were to describe the clinical presentation of pediatric BrS to identify prognostic factors for risk stratification and to propose a data-based approach management.

Methods: We studied 106 patients younger than 19 years at diagnosis of BrS enrolled from 16 European hospitals.

Results: At diagnosis, BrS was spontaneous (n = 36, 34%) or drug-induced (n = 70, 66%). The mean age was 11.1 ± 5.7 years, and most patients were asymptomatic (family screening, (n = 67, 63%; incidental, n = 13, 12%), while 15 (14%) experienced syncope, 6(6%) aborted SCD or symptomatic ventricular tachycardia, and 5 (5%) other symptoms. During follow-up (median 54 months), 10 (9%) patients had life-threatening arrhythmias (LTA), including 3 (3%) deaths. Six (6%) experienced syncope and 4 (4%) supraventricular tachycardia. Fever triggered 27% of LTA events. An implantable cardioverter-defibrillator was implanted in 22 (21%), with major adverse events in 41%. Of the 11 (10%) patients treated with hydroquinidine, 8 remained asymptomatic. Genetic testing was performed in 75 (71%) patients, and SCN5A rare variants were identified in 58 (55%); 15 of 32 tested probands (47%) were genotype positive. Nine of 10 patients with LTA underwent genetic testing, and all were genotype positive, whereas the 17 SCN5A-negative patients remained asymptomatic. Spontaneous Brugada type 1 electrocardiographic (ECG) pattern (P = .005) and symptoms at diagnosis (P = .001) were predictors of LTA. Time to the first LTA event was shorter in patients with both symptoms at diagnosis and spontaneous Brugada type 1 ECG pattern (P = .006).

Conclusion: Spontaneous Brugada type 1 ECG pattern and symptoms at diagnosis are predictors of LTA events in the young affected by BrS. The management of BrS should become age-specific, and prevention of SCD may involve genetic testing and aggressive use of antipyretics and quinidine, with risk-specific consideration for the implantable cardioverter-defibrillator.
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http://dx.doi.org/10.1016/j.hrthm.2016.02.013DOI Listing
June 2016

The genetics underlying acquired long QT syndrome: impact for genetic screening.

Eur Heart J 2016 May 28;37(18):1456-64. Epub 2015 Dec 28.

Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan

Aims: Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors.

Methods And Results: We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7-41%] vs. 64% [95% CI 43-82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations.

Conclusion: A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members.
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http://dx.doi.org/10.1093/eurheartj/ehv695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914885PMC
May 2016

Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study.

Cardiovasc Res 2015 Jun 17;106(3):520-9. Epub 2015 Feb 17.

Inserm, UMR S1166, Faculté de Médecine Pierre et Marie Curie, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR S1166, Paris, France Institute of Cardiometabolism & Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France.

Aims: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration.

Methods And Results: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970).

Conclusion: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.
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http://dx.doi.org/10.1093/cvr/cvv042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447806PMC
June 2015

Characterization of SEMA3A-encoded semaphorin as a naturally occurring Kv4.3 protein inhibitor and its contribution to Brugada syndrome.

Circ Res 2014 Aug 24;115(4):460-9. Epub 2014 Jun 24.

From the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).

Rationale: Semaphorin 3A (SEMA3A)-encoded semaphorin is a chemorepellent that disrupts neural patterning in the nervous and cardiac systems. In addition, SEMA3A has an amino acid motif that is analogous to hanatoxin, an inhibitor of voltage-gated K(+) channels. SEMA3A-knockout mice exhibit an abnormal ECG pattern and are prone to ventricular arrhythmias and sudden cardiac death.

Objective: Our aim was to determine whether SEMA3A is a naturally occurring protein inhibitor of Kv4.3 (Ito) channels and its potential contribution to Brugada syndrome.

Methods And Results: Kv4.3, Nav1.5, Cav1.2, or Kv4.2 were coexpressed or perfused with SEMA3A in HEK293 cells, and electrophysiological properties were examined via whole-cell patch clamp technique. SEMA3A selectively altered Kv4.3 by significantly reducing peak current density without perturbing Kv4.3 cell surface protein expression. SEMA3A also reduced Ito current density in cardiomyocytes derived from human-induced pluripotent stem cells. Disruption of a putative toxin binding domain on Kv4.3 was used to assess physical interactions between SEMA3A and Kv4.3. These findings in combination with coimmunoprecipitations of SEMA3A and Kv4.3 revealed a potential direct binding interaction between these proteins. Comprehensive mutational analysis of SEMA3A was performed on 198 unrelated SCN5A genotype-negative patients with Brugada syndrome, and 2 rare SEMA3A missense mutations were identified. The SEMA3A mutations disrupted SEMA3A's ability to inhibit Kv4.3 channels, resulting in a significant gain of Kv4.3 current compared with wild-type SEMA3A.

Conclusions: This study is the first to demonstrate SEMA3A as a naturally occurring protein that selectively inhibits Kv4.3 and SEMA3A as a possible Brugada syndrome susceptibility gene through a Kv4.3 gain-of-function mechanism.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.303657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907370PMC
August 2014

A comprehensive electrocardiographic, molecular, and echocardiographic study of Brugada syndrome: validation of the 2013 diagnostic criteria.

Heart Rhythm 2014 Jul 8;11(7):1176-83. Epub 2014 Apr 8.

Laboratory of Cardiovascular Genetics and Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy. Electronic address:

Background: The debate on the diagnostic value of high intercostal spaces (ICSs) and of the number of diagnostic leads in Brugada syndrome (BrS) has been settled by a recent expert consensus statement.

Objective: To test the validity, and the underlying anatomy, of the new electrocardiographic (ECG) diagnostic criteria using echocardiographic, molecular, and clinical evidence in 1 clinical study population with BrS.

Methods: We analyzed 114 patients with BrS and with a spontaneous or drug-induced type 1 ECG pattern recorded in 1 or more right precordial leads in fourth, third, and second ICSs. The right ventricular outflow tract (RVOT) was localized by using echocardiography. All probands were screened on the SCN5A gene.

Results: The percentage of mutation carriers (MCs) and the event rate were similar regardless of the diagnostic ICS (fourth vs high ICSs: MCs 23% vs 19%; event rate 22% vs 28%) and the number of diagnostic leads (1 vs ≥2: MCs 20% vs 22%; event rate 22% vs 27%). The concordance between RVOT anatomical location and the diagnostic ICSs was 86%. The percentage of the diagnostic ECG pattern recorded was significantly increased by the exploration of the ICSs showing RVOT by echocardiography (echocardiography-guided approach vs conventional approach 100% vs 43%; P < .001).

Conclusion: The high ICSs are not inferior to the standard fourth ICS for the ECG diagnosis of BrS, and the interindividual variability depends on the anatomical location of the RVOT as assessed by using echocardiography. This approach significantly increases diagnostic sensitivity without decreasing specificity and fully supports the recently published new diagnostic criteria.
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http://dx.doi.org/10.1016/j.hrthm.2014.04.010DOI Listing
July 2014

FGF12 is a candidate Brugada syndrome locus.

Heart Rhythm 2013 Dec 4;10(12):1886-94. Epub 2013 Oct 4.

Departments of Medicine/Cardiology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.

Background: Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-FGF14) regulate cardiac Na(+) and Ca(2+) channel currents, we hypothesized that FHFs are candidate BrS loci.

Objective: The goal of this study was to test whether FGF12 is a candidate BrS locus.

Methods: We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment. We designed a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant and defined its effects on multiple ionic currents in their native milieu and on the cardiac action potential.

Results: We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2. In adult rat cardiac myocytes, Q7R-FGF12, but not wild-type FGF12, reduced Na(+) channel current density and availability without affecting Ca(2+) channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na(+) channel function.

Conclusions: These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na(+) and Ca(2+) channels are separable. Most significantly, this study establishes a new method to analyze effects of human arrhythmogenic mutations on cardiac ionic currents.
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http://dx.doi.org/10.1016/j.hrthm.2013.09.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870051PMC
December 2013

Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death.

Nat Genet 2013 Sep 21;45(9):1044-9. Epub 2013 Jul 21.

Department of Clinical and Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
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http://dx.doi.org/10.1038/ng.2712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869788PMC
September 2013

Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.

Circ Cardiovasc Genet 2013 Aug 15;6(4):354-61. Epub 2013 Jul 15.

INSERM, UMR S956, Paris, France.

Background: Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS.

Methods And Results: In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 (0.19-0.61; P<0.0002) and with shorter QTc (P<0.0001) in the combined discovery and replication cohorts.

Conclusions: We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864834PMC
August 2013

[Clinical conditions associated with abnormal QT interval: clinical implications].

G Ital Cardiol (Rome) 2013 Jan;14(1):55-65

Sezione di Cardiologia, Dipartimento di Medicina Molecolare, Università degli Studi, Pavia, Italy.

Impressive progress has been made in the last 40 years in the understanding of the role of QT interval and its genetic basis in sudden cardiac death risk. The present review will provide a first practical part on QT measurement and its correction for heart rate. Subsequently, the long QT syndrome and short QT syndrome will be described, as the two main arrhythmogenic congenital heart diseases characterized by abnormal QT length. Furthermore, we will discuss about prolonged QT in the pathogenesis of sudden infant death syndrome and the preventive role of neonatal ECG screening. The prognostic role of QT interval will be presented also in the context of myocardial infarction and hypertrophic cardiomyopathy. The last part of the review is devoted to future perspectives and latest results on modifier genes.
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http://dx.doi.org/10.1714/1207.13373DOI Listing
January 2013