Background: Mutations of the SCN5A gene are reported in 2-4% of patients with dilated cardiomyopathy (DCM). In such cases, DCM is associated with different rhythm disturbances such as the multifocal ectopic Purkinje-related premature contractions and atrial fibrillation. Arrhythmia often occurs at a young age and is the first symptom of heart disease. Case presentation: We present the case of 55-year old male with a 30-year history of heart failure (HF) in the course of familial DCM and complex ventricular tachyarrhythmias, which constituted 50-80% of the whole rhythm. The patient was qualified for heart transplantation because of the increasing symptoms of HF. We revealed the heterozygotic R222Q mutation in SCN5A by means of whole exome sequencing. After the quinidine treatment, a rapid and significant reduction of ventricular tachyarrhythmias and an improvement in the myocardial function were observed and this effect remained constant in the 2.5-year follow-up. This effect was observed even in the presence of concomitant coronary artery disease. Conclusions: Patients with familial DCM and Purkinje-related ventricular arrhythmias should be offered genetic screening. The quinidine treatment for the SCN5A R222Q mutation can be life saving for patients. Keywords: SCN5A,Na 1.5, Dilated cardiomyopathy, Multifocal ectopic Purkinje-related premature contractions Background F1520 L, and I1835T) [2, 4–6]. Most of them are Mutations of the SCN5A gene, which encodes the localised to the S3 and S4 transmembrane segments, cardiac sodium channel alpha subunit (Na 1.5) are supporting the hypothesis outlining the dysfunction reported in 2-4% of patients with dilated cardiomy- of the Na 1.5 in the pathogenesis of DCM. However, opathy (DCM) [1, 2]. Mutations in the SCN5A gene the pathological mechanism of the Na 1.5 mutation- have been reported in the congenital long QT syn- induced DCM is not completely understood. The drome and in the Brugada syndrome . A few dif- phenotype is associated with different rhythm distur- ferent mutations of voltage sensors Na 1.5 in DCM bances, such as atrial fibrillation (AF), the sick sinus were characterised (missense: T220I, R219H, R222Q, syndrome, multifocal ectopic Purkinje-related prema- R225W, E446K, R814W, D1275N, V1279I, D1595H, ture contractions (MEPPCs), progressive cardiac con- duction system disease and familial DCM. * Correspondence: email@example.com; firstname.lastname@example.org Arrhythmia (AF, multifocal premature ventricular Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of contractions - MPVCs) often occurs at a young age Cardiology, ul. Alpejska 42, 04-628 Warszawa, Poland and is the first symptom of heart disease [4–7]. Department of Medical Genetics, Medical University of Warsaw, ul. Pawinskiego 3c, 02-106 Warszawa, Poland Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zakrzewska-Koperska et al. BMC Medical Genetics (2018) 19:94 Page 2 of 7 Case presentation at the age of 27; his daughter (Fig. 1c - IV:2) died of We present the case of a 55-year old male (Fig. 1c - III: heart failure at age of 9, while waiting for a heart trans- 1) with a 30-year history of heart failure in the course of plantation, and his son (Fig. 1c - IV:1) received a heart familial DCM and MEPPCs. The patient’s family pheno- transplant at age of 23, while experiencing heart failure type was characterised in Table 1 and Fig. 1c. symptoms along with frequent complex arrhythmia since His mother (Fig. 1c - II:2) suffered from unrecognised the age of 20. In our patient, the amiodarone treatment heart disease with ‘heart palpitations’ and died suddenly was ineffective and was discontinued after amiodarone Fig. 1 Genetic characteristics of the studied family. Chromatograms and IGV views of SCN5A NM_198056.2:c.665G > A (p.R222Q) (a)and SCN5A NM_198056.2 :c.1673A > G (p.H558R) (b), variants and family pedigree (c). Pedigree: squares represent males and circles represent females. An arrowhead denotes the proband. A diagonal line marks the deceased individuals. Open symbols denote unaffected individuals Zakrzewska-Koperska et al. BMC Medical Genetics (2018) 19:94 Page 3 of 7 Table 1 Clinical characteristics of living affected family members Subject III:1 IV:1 Mutation SCN5A p.R222Q p.R222Q, p.H558R Age at onset/now (years) 25/57 7/31 Sex Male Male Symptoms Palpitations, presyncope Palpitations/SCD -successfully resuscitated NYHA functional class III IV- > 23 year old - HTx LVdD (mm)/LVEF (%) 68/20 84/10-15 Arrhythmia MPVCs/nsVT/IVR MPVCs/nsVT/VT/VF/AF Conduction disorders AVB I , RBBB No ICD Yes Yes /explantation after HTx Amiodarone Yes - > hyperthyroidism Yes - > unsuccessful Quinidine treatment Quinidine Yes No Symptoms before/after Yes/no – NYHA functional class III- > II – LVdD (mm) before/after 68/62 – LVEF (%) before/after 20/35 – Arrhythmia during 24 h before/after 65,000 MPVCs/ ~ 4000 MPVCs – SCD sudden cardiac death, HTx heart transplantation, AVB I first degree of atrio–ventricular block, RBBB right bundle branch block, IVR idioventricular rhythm, MPVCs multifocal premature ventricular contractions, LVdD left ventricle enddiastolic diameter, LVEF left ventricle ejection fraction, VT ventricular tachycardia, ns non-sustained, VF ventricular fibrillation, AF atrial fibrillation, ICD implantable cardioverter–defibrillator induced hyperthyroidism. At 46 years of age the patient episodes) as a consequence of sinus dysfunction (Fig. had a cardioverter-defibrillator (implantable cardioverter- 2b). The MPVCs comprised of > 80% of the whole-day defibrillator - ICD) implanted. At 49 years of age lead- rhythm. dependent infective endocarditis (Metyciline resistant S. Due to a lack of therapeutic options, the patient was aureus - MSSA) was diagnosed. A cardiosurgical lead enlisted for heart transplantation (HTx) in the planned extraction, tricuspid valve annoloplasty and epicardial mode. In the meantime, it was decided to perform ICD implantation was performed. At 51 years of age, whole-exome sequencing in the most severely affected the patient was diagnosed with coronary artery disease living person in the family (the patient’s son). Based on (CAD) based on the coronary angiography, which the result of the identification of the known mutation in showed permanent occlusion of the LAD distal section Na 1.5 in both affecteds (the patient and his son), we ap- with a permanent lack of perfusion in the middle and plied the known antiarrhythmic treatment that led to re- apical segments of the anterior wall and septum as moving the patient from the waiting list for HTx. In demonstrated by the SPECT Tc-99 m study. During the addition, we tried to clarify the differences in the course next few years the patient presented with NYHA class of the disease between two living affecteds in the family. II symptoms and moderate left ventricle (LV) function The clinical characteristics of the proband and his son impairment (left ventricle ejection fraction - LVEF were summarised in Table 1. 40%). At 53 years of age, an increasing number of MPVCs was found to be associated with the worsening Genetic testing of the myocardial function (LVEF 20%). His 12-lead The DNA was extracted from the peripheral blood by surface electrocardiogram (ECG) showed single sinus means of a phenol extraction. Whole-exome sequencing (or similar to sinus) beats, with different RBBB pattern (WES) was performed in the proband’s son (Fig. 1c -IV: and multiple LBBB-like pattern ventricular extrabeats 1) on HiSeq 1500 using SureSellect Kit (Agilent Tech- with variable axis (Fig. 2a). The 24-h Holter ECG re- nologies) as described previously . In WES, the mean vealed sinus bradycardia, junctional ectopies, very fre- coverage of the DNA sample was 75-fold with 98.6% of quent MPVCs (~ 65,000/24 h) with multiple different the targeted exons covered at least 10× and 94.6% cov- quite narrow morphologies, mainly RBBB- and LBBB- ered at least 20×. The SCN5A variants identified with like patterns, as well as about 3500 episodes of non- WES were followed-up in the proband’s family with sustained ventricular tachycardia (nsVT) - max. 30 Sanger sequencing using a 3500xL Genetic Analyzer beats, 170/min. and slow ventricular rhythms (4400 (Applied Biosystems, Foster City, CA, USA) according Zakrzewska-Koperska et al. BMC Medical Genetics (2018) 19:94 Page 4 of 7 Fig. 2 Electrocardiograms before (a, b)andafter(c) quinidine treatment. a representative 12-lead ECG before quinidine treatment (25 mm/sec., 10 mm/ mV), sinus beats (*) with different RBBB pattern, supraventricular and junctional beats (^) with RBBB+ LAH pattern, LBBB-like pattern ventricular extrabeats with variable saxis. b1, 2 24-h Holter ECG rhythm strip showed single sinus (*) and supraventricular (^) extrabeats and MPVCs with narrow QRS and different axis (upper panel) and nsVT (lower panel). c 12-lead ECG (25 mm/sec., 10 mm/mV) after quinidine treatment - morphology of P differed from sinus rhythm, RBBB with right axis, without ventricular arrhythmia. RBBB – right bundle branch block, LBBB - left bundle branch block, LAH – left anterior hemiblock, MPVCs - multifocal premature ventricular contractions, nsVT - non-sustained ventricular tachycardia to the manufacturer’s instructions. The results were ana- in tablets a 200 mg) was administered. After the first lysed using the Variant Reporter 1.1 Software (Applied quinidine dosage we observed a rapid antiarrhythmic ef- Biosystems). fect (Fig. 2c), which was confirmed in the 24-h ECG moni- The patient and his son (Fig. 1c, III:1, IV:1) carried a toring (reduction of MPVCs from > 80%/day, including rare heterozygous SCN5A NM_198056.2:c.665G > A (p. VT/nsVT to 3-5%/day, without VT/nsVT). The echocar- R222Q) variant in the transmembrane helical segment diographic examinations repeated over 2 years revealed S4, which is the voltage-sensor (Fig. 1a, b). In the pa- the sustained improvement of the LV contractile function tient’s son (Fig. 1c - IV:1), the SCN5A NM_198056.2:c. (LVEF 20-25%→ 30-34%). We have observed a significant 1673A > G (p.H558R) variant was furthermore found, reduction in heart failure symptoms and a significant im- inherited from the unaffected mother (Fig. 1c - III:2). provement in physical efficiency (Table 1). After 12 months of treatment, the patient presented a Quinidine treatment mild manifestation of drug-induced diarrhoea and mu- The patient was treated according to the ESC/AHA cous membrane dryness, and had to stop taking quini- guidelines for treatment of heart failure , with optimal dine. The lack of compliance resulted in an increasing dosage of ACEI (ramipril 10 mg/day), beta-blocker (biso- number of ventricular arrhythmia (MPVCs > 80% in prolol 10 mg/day), diuretic (furosemide 80 mg/day) and 24-h ECG registration). We have modified the daily spironolactone (25 mg/day) as well as oral anticoagulant quinidine dosage with positiveantiarrhythmic response. (acenocoumarol). Recently, he was also treated with After the 2 year follow-up we did not find an increasing ASA and statin (atorvastatin 20 mg/day) for CAD. Based number of MPVCs. In consequence, the number of on the published data , quinidine (Quinidine sulphate MPVCs in the 24-h ECG monitoring was stable (~ 4000/ Zakrzewska-Koperska et al. BMC Medical Genetics (2018) 19:94 Page 5 of 7 day) and the patient’s myocardial performance remained Quinidine treatment stable (LVEF-35%). The phenotype caused by the SCN5A R222Q mutation (DCM, MEPPCs) was found to be responsive to sodium Disscusion and conclusions channel blockers [10, 14]. Laurent et al. first reported SCN5A R222Q variant the association of MEPPCs and left ventricular dysfunc- SCN5A R222Q affects the positively charged arginine tion in 3 unrelated families with the SCN5A R222Q mu- which lies on the S4 segment of the DI domain (DI/S4) - tation, stressing that DCM is a secondary consequence one of the four sodium channel voltage sensors of the of the mutation. The authors found spectacular effect of primary sodium channel in the heart - Na 1.5 . This the quinidine treatment in 2 patients with the variant was previously described in at least 8 families arrhythmic phenotype within one family in whom the with DCM/arrhythmias/LQTS and segregated with dis- normalisation of the left ventricular function was noted ease among at least 38 relatives [4, 10, 12–16]. The ef- and in two affecteds from another family who had a nor- fect of the R222Q mutation on the Na 1.5 function was mal left ventricular function  . Mann et al. in turn, experimentally investigated [10, 14]. The SCN5A R222Q found a substantial reduction of MPVCs in patients with varaint leads to a gain in the function of the mutated the SCN5A R222Q mutation by known sodium channel channel, which expresses many kinetic disturbances, blocking agents, such as amiodarone or flecainide . such as an opening at more negative potentials. Mann et Our data support the spectacular results by Laurent et al.  suggest that the increasing and rate dependent al.  of the quinidine treatment in another family with automaticity of the Purkinje fibre cell is the reason for DCM and MEPPCs. The standard heart failure therapy the MPVCs. It is consistent with a previous study , in our patient and his children was ineffective. In youn- which described the mechanism of MPVCs triggered by ger generation, it led directly to HTx (son) and the death an incomplete Purkinje fibre repolarisation and their of the patient’s daugther. We observed a significant re- propagation into the ventricles. In patients with the duction of MPVCs during the quinidine treatment (re- SCN5A R222Q mutation, the entire Purkinje system is duction MPVCs > 80%/day to 3-5% /day) and a changed and can be a source of a variety of ectopic foci, significant improvement of the LV function. The earlier resulting in a phenotype called the MEPPCs syndrome. treatment with amiodarone was partially successful but DCM caused by the SCN5A R222Q mutation, seems to had to be stopped due to its toxicity. Of note, the quini- be a secondary finding to ventricular arrhythmia, of note dine treatment was effective in the patient who also had we have not observed myocardial muscle thinning in the co-existing CAD. course of the disease, like in our patient (LV wall thick- The effects of quinidine were tested on the cellular ness was 12-13 mm). model . Clinically, quinidine primarily works by However, the mechanisms of left ventricular dilation blocking the fast inward sodium current (I ) and the Na in individuals carrying the SCN5A R222Q mutation are transient outward current (I ), by repolarising the de- to 2+ not completely defined. The patient’s son, in whom we layed rectifier current I , and by inhibiting Ca and Kr performed the WES study, also carried the well-known other K currents . Quinidine usage caused the SCN5A H558R polymorphism, which was previously de- normalisation of Purkinje and ventricular cells potentials scribed in patients carrying the SCN5A R222Q variant (maximal drug dose, remaining 50% I and 30% I and Na Kr . The altered current Na activity may significantly I ). Such effect was still observed when the drug dosage to deteriorate the left ventricular function along with the was reduced (remaining 75% I and 45% I and I , Na Kr to) effects of MEPPCs or the presence of atrial fibrillation but disappeared in the case of a lower dosage of . In Mann’s study, the R222Q variant of SCN5A quinidine (remaining 85% I and 50% I and I ). Na Kr to presented a different expression related to sex, with Current guidelines inform that Class Ia antiarrhythmic more genotype-positive males (7 of 10) affected with agents are contraindicated both in heart failure and in DCM than females (1 of 7) . That fact was explained CAD. The ESC/AHA guidelines for the treatment of as a protective role associated with a higher heart rate in CHF or Ventricular Arrhythmias do not recommend women due to a reduced Purkinje cell excitability. class I drugs (quinidine, flecainid) to treat MPVCs in We observed a significant difference in the course of DCM patients [9, 19]. HF and in terms of age at the onset of symptoms be- Current guidelines also advise genetic studies in pa- tween the described patient (Fig. 1 – III:1) and his chil- tients with DCM and conduction disease . Recent dren. We only found that the SCN5A H558R data show that patients with familial DCM and accom- polymorphism, present in the proband’s son, was inher- paning MEPPCs also need individual clinical diagnostics, ited from the unaffected mother. However its presence including genetic examination toward Na 1.5 mutations. did not exacerbate the course of the disease in the study In such cases antiarrhythmic therapy containing sodium by Cheng et al. . channel blockers is supposed to be successful. Only a Zakrzewska-Koperska et al. BMC Medical Genetics (2018) 19:94 Page 6 of 7 limited number of published reports on families with the JZ-K, MF, ZB, GG, ŁS, RP, MB analysed and interpreted the molecular and the clinical data. JZ-K, MF and GT wrote the manuscript that was edited by ZB, SCN5A R222Q Na 1.5 mutation, show a promising anti- RP and MB. All authors have read and approved the final version of the arrhythmic effect of the quinidine , flecainid and manuscript submitted by ZB. amiodarone therapy . Case reports published up Ethics approval and consent to participate until now show that the reduction of MPVCs can par- All members of the family signed a written informed consent form for the tially or completely reverse LV dilation and reverse heart genetic examination and the consent for publishing all the data.The study failure symptoms; however, the influence of the treat- received the approval of the Bioethics Committee of the Institute of Cardiology 7.06.2011; Consent number: No 1276/2011. ment on the prevention of sudden cardiac death is un- known. Our study adds to the existing literature with Consent for publication information that, the quinidine treatment was effective All members of the family signed a written consent form for publishing all in the patient who also had co-existing CAD. the data. Competing interests Translation medicine The authors declare that they have no competing interests. The mutations of the SCN5A gene in the DCM patients are an important cause of life-threatening ventricular ar- Publisher’sNote rhythmias. Based on the confirmed individual specific Springer Nature remains neutral with regard to jurisdictional claims in SCN5A mutation and pharmacokinetic experimental published maps and institutional affiliations. models of antiarrhythmic drugs, we can treat patients Author details with well-matched sodium channel blockers like quini- 1 Department of Arrhythmia, Institute of Cardiology, ul. Alpejska 42, 04-628 dine in our case. Warszawa, Poland. Molecular Biology Laboratory, Department of Medical Biology, Institute of Cardiology, ul. Alpejska 42, 04-628 Warszawa, Poland. Unfortunately, genetic testing is still difficult to obtain Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of in general cardiologist practice. However, it gives per- 4 Cardiology, ul. Alpejska 42, 04-628 Warszawa, Poland. Department of Heart spective for future mutation-specific therapy dedicated Failure and Transplantology, Institute of Cardiology, ul. Alpejska 42, 04-628 Warszawa, Poland. Department of Medical Genetics, Medical University of for Purkinje cell related arrhythmia. Our case highlights Warsaw, ul. Pawinskiego 3c, 02-106 Warszawa, Poland. the value of genotype information for the treatment strategy. Received: 29 December 2017 Accepted: 1 May 2018 In conclusion, patients with familial DCM and MPVCs should be investigated for SCN5A gene mutations. The References antiarrhythmic treatment with quinidine can signifi- 1. Hershberger RE, Morales A. Dilated cardiomyopathy overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, Amemiya A, editors. cantly reduce the number of MPVCs and reverse LV GeneReviews (R). Seattle: University of Washington, Seattle; 1993. [Last dilation in a few months even in the presence of conco- Update: September 24, 2015]. mittant CAD. 2. Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL. Sodium channel mutations and susceptibility to Abbreviations heart failure and atrial fibrillation. JAMA. 2005;293(4):447–54. ACEI: Angiotensin-converting enzyme inhibitor; AF: Atrial fibrillation; 3. Zaklyazminskaya E, Dzemeshkevich S. The role of mutations in the SCN5A ASA: Acetylsalicylic acid; CAD: Coronary artery disease; DCM: Dilated gene in cardiomyopathies. Biochim Biophys Acta. 2016;1863(7 Pt B):1799–805. cardiomyopathy; ECG: Electrocardiogram; ESC/AHA: European Society of 4. McNair WP, Sinagra G, Taylor MR, Di Lenarda A, Ferguson DA, Salcedo EE, Cardiology/American Heart Association; HF: Heart failure; HTx: Heart Slavov D, Zhu X, Caldwell JH, Mestroni L, et al. SCN5A mutations associate transplantation; ICD: Implantable cardioverter-defibrillator; LAD: Left anterior with arrhythmic dilated cardiomyopathy and commonly localize to the descending coronary artery; LBBB: Left bundle branch block; LQTS: Long QT voltage-sensing mechanism. J Am Coll Cardiol. 2011;57(21):2160–8. syndrome; LV: Left ventricle; LVEF: Left ventricle ejection fraction; 5. Gosselin-Badaroudine P, Keller DI, Huang H, Pouliot V, Chatelier A, Osswald MEPPCs: Multifocal ectopic Purkinje-related premature contractions; S, Brink M, Chahine M. A proton leak current through the cardiac sodium MPVCs: Multifocal premature ventricular contractions; Na 1.5: Cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy channel alpha subunit; nsVT: Non-sustained ventricular tachycardia; phenotype. PLoS One. 2012;7(5):e38331. NYHA: New York Heart Association; RBBB: Right bundle branch block; 6. Moreau A, Gosselin-Badaroudine P, Delemotte L, Klein ML, Chahine M. VT: Ventricular tachycardia; WES: Whole-exome sequencing Gating pore currents are defects in common with two Nav1.5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy. J Gen Physiol. Funding 2015;145(2):93–106. The genetic examination was funded by the NCN grant No2011/01/B/NZ/ 7. Veerman CC, Wilde AA, Lodder EM. The cardiac sodium channel gene 03455 (R. Ploski); Zofia Bilińska’s work is supported by the ERA-CVD grant: SCN5A and its gene product NaV1.5: role in physiology and DETECTIN-HF. pathophysiology. Gene. 2015;573(2):177–87. 8. Ploski R, Pollak A, Müller S, Franaszczyk M, Michalak E, Kosinska J, Stawinski Availability of data and materials P, Spiewak M, Seggewiss H, Bilinska ZT. Does p.Q247X in TRIM63 cause All relevant data are included in the manuscript. The datasets used and/or human hypertrophic cardiomyopathy? Circ Res. 2014;114(2):e2–5. analysed during the current study are available from the corresponding 9. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, author upon request. González-Juanatey JR, Harjola VP, Jankowska EA, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task Authors’ contributions force for the diagnosis and treatment of acute and chronic heart failure of JZ-K, MB and ZB contributed to the design of the study. JZ-K, MK, TZ, MB the European Society of Cardiology (ESC) developed with the special and ZB sampled the family members and acquired the clinical data. MF, GT contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. and RP performed molecular analysis, analysed and interpreted the WES data. 2016;37(27):2129–200. Zakrzewska-Koperska et al. BMC Medical Genetics (2018) 19:94 Page 7 of 7 10. Laurent G, Saal S, Amarouch MY, Béziau DM, Marsman RF, Faivre L, Barc J, Dina C, Bertaux G, Barthez O, et al. Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy. J Am Coll Cardiol. 2012;60(2):144–56. 11. Catterall WA. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron. 2000;26(1):13–25. 12. Cheng J, Morales A, Siegfried JD, Li D, Norton N, Song J, Gonzalez-Quintana J, Makielski JC, Hershberger RE. SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del. Clin Transl Sci. 2010;3(6):287–94. 13. 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Published: Jun 5, 2018
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