Precordial mapping of R, S and Q waves in healthy children and in those with heart defects and cardiomyopathies

Precordial maps of R, S and Q waves were performed in 43 children with congenital and acquired cardiac defects, with cardiomyopathies and also in 55 healthy children. Two subgroups with the left and right ventricular hypertrophies were separated basing on a standard electrocardiogram. Multilead electrocardiogram (M60--ecg) was recorded from 60 points of a chest wall. Obtained data indicate that a multilead electrocardiogram is useful for ventricular hypertrophy estimation in cardiac defects and cardiomyopathies. Of analyzed R, S and Q waves R wave is essentially important. Different localization and extent of a region of large R wave amplitudes was observed in children with cardiac defects and cardiomyopathies in comparison with healthy persons. Accessory precordial points for R wave registration (besides standard ones) with statistically significant larger R wave amplitude than in healthy children are: A9, A10, B9, B10 for left ventricular hypertrophy assessment and A1, A5, B2, C3, C4, C5, D3, D5, E3, E4, E5, F4 for right ventricular hypertrophy estimation.     

The S wave in acute anterior Q-wave myocardial infarction: a study with serial multilead precordial maps and standard ECGs

To investigate the relationship of S waves with R waves and/or Q waves in the ECGs of patients with acute myocardial infarction, 20 patients with anterior Q-wave infarcts had serial 49-lead precordial maps and simultaneously recorded standard ECGs on admission and at 13 predetermined time intervals, extending to their discharge from the hospital. The sums of S waves (sigma S) from ECG leads of both precordial maps and standard ECGs showing ST-segment elevation on admission were correlated with the corresponding sums of R waves (sigma R) and/or Q waves (sigma Q). Correlation of sigma S by the precordial maps and the sigma S by the standard ECG was good (r = 0.88). However, correlation of sigma S with sigma R and sigma Q by both the precordial maps and standard ECG were poor (r values ranged between -0.02 and -0.32). Fair correlations were found between sigma S + sigma Q and the corresponding sigma R by both ECG systems (r = 0.36, precordial map and r = 0.40, standard ECG). The present study demonstrates (1) that precordial (consequently partial) ECG mapping systems have no advantage over standard precordial ECG, and (2) that quantitative data from S waves correlate weakly with similar information from corresponding R waves or Q waves, but fairly with the latter two combined, as recorded by the two ECG systems employed.     

In vitro coexpression and pharmacological rescue of mutant gonadotropin-releasing hormone receptors causing hypogonadotropic hypogonadism in humans expressing compound heterozygous alleles

We analyzed the function of mutant GnRH receptor (GnRHR) pairs associated with compound heterozygous patients showing complete or partial forms of hypogonadotropic hypogonadism. We did this to examine potential interactions between misfolded mutants that may influence net receptor function and response to pharmacological rescue. Nine pairs of GnRHR mutants and an unreported combination (L314X((stop))/R262Q) were studied. Coexpression of each pair of mutants in COS-7 cells resulted in an active predominant effect (Q106R/L266R, A171T/Q106R, T32I/C200Y, and R262Q/A129D mutant GnRHR pairs), an additive effect (R262Q/Q106R, N10K/Q106R, and R262Q/Y284C human GnRHR pairs), or a dominant-negative effect (L314X((stop))/Q106R, Q106R+S217R/R262Q, and L314X((stop))/R262Q GnRHRs). For all combinations, addition of the pharmacoperone IN3 increased both agonist binding and effector coupling. The IN3 response was unpredictable because responses could be either similar, higher, or lower, compared with that exhibited by the less affected mutant. The clinical phenotype in patients expressing complex heterozygous alleles appears to be dictated by both the contribution from each mutant and a dominant-negative effect similar to that reported for mutants and wild-type receptor. Depending on the genotype, partial or full restoration of receptor function in response to pharmacological chaperones may be achievable goals in patients bearing inactivating mutations in the GnRHR gene.     

The natural course of electrocardiographic stages of acute inferior myocardial infarction in regard to R/Q ratio group classification

Forty-three patients with their first acute inferior wall myocardial infarction (IWMI) were divided into three groups according to the R/Q ratio in standard lead II. This was done to correlate these groups with the characteristic course of electrocardiographic stages. The R/Q ratio was measured on the ninth day of follow-up study, and the electrocardiographic stages were followed from the onset of the IWMI up until the ninth day. Patients with R/Q greater than 2 (group I) had a more rapid progression through the electrocardiographic stages, along with a better clinical course than patients with a lower R/Q ratio. Patients in group III, with R/Q less than 1, had a slower electrocardiographic stage progression, which correlates well with a more complicated clinical course. Group II was an intermediate group in both the electrocardiographic and clinical course. Rapid stage evolution in the first 12 hours of the IWMI was followed by a more rapid progression through stages during the rest of the follow-up period. It is suggested that the R/Q ratio in lead II can be used as a marker of the severity of IWMI, since it correlates well with the course of electrocardiographic stages. The greater the R/Q ratio, the more rapid the progression of electrocardiographic stages, and the better the clinical course. This may be an additional simple and inexpensive electrocardiographic tool for following the natural course of IWMI.     

山东省部分19岁以下正常人群VCG上的Q/R,S/R,Rx,Ry,Rz值的监测

目的对19岁以下不同年龄和性别正常人群在VCG上的Q/R,S/R值及最大R振幅在X,Y,Z轴上的投影进行研究,探讨不同年龄和性别有关这些项目均值的变化规律.方法在城市1个月至19岁正常人群中,选择经检查无心脏病者1 950名健康人群进行了VCG描记,在VCG上测量与分析Q/R,S/R比值及最大R振幅在X,Y,Z轴上的投影. 结果 Q/R值在性别上区别不明显,但在年龄上稍有所不同,男女的S/R 值在8岁前无性别上的明显区别,8岁后各年龄组男性高于女性;Rx值男性在10岁前,女性在8岁前随年龄增长而增高.男性在10岁～14岁,女性在8岁～14岁随年龄的增长而降低,男女在14岁后稳定在一定范围;在1岁内男女的Ry较小外,其余年龄组在性别和年龄上无明显的区别;Rz值各年龄组的男性均高于女性,男女各年龄组均随年龄的增长而降低. 结论该组人群的VCG各项指标在年龄和性别有所差异,因而应用这些项目监测心脏大小时,应考虑年龄和性别的差异.     

Isolation, sequence, and developmental profile of a brain-specific polypeptide, PEP-19.

By comparing the HPLC profiles of cerebellar extracts from adult and neonatal rats, a developmentally regulated polypeptide, termed PEP-19, was identified. The concentration of PEP-19 rose from 0.1 nmol/g of cerebellum at birth to 2 nmol/g at 20 days postpartum. The polypeptide could also be detected at lower levels in olfactory bulbs of adult rats but was absent in cerebral cortex, brain stem, and all non-neural tissues examined. HPLC-purified PEP-19 contained 61 amino acids and had a molecular size of 7.6 kDa. The native polypeptide is blocked at its amino terminus but was sequenced following proteolytic and chemical fragmentation. The primary amino acid sequence was determined to be: X (S-E) R Q S A G A T N G K D K T S G D N D G Q K K V Q E E F D I D M D A P E T E R A A V A I Q S Q F R K F Q K K K A G S Q S. PEP-19 has a unique sequence, but shares some homology with several calcium binding proteins including the beta chain of S100 and intestinal calcium binding protein. This polypeptide is the primary translation product of cerebellar poly(A)+ mRNA.     

Isolation of alligator gar (Lepisosteus spatula) glucagon, oxyntomodulin, and glucagon-like peptide: amino acid sequences of oxyntomodulin and glucagon-like peptide

Oxyntomodulin, glucagon, and a glucagon-like peptide (GLP) have been isolated from the endocrine pancreas of the alligator gar (Lepisosteus spatula), a ganoid fish. The three peptides were isolated by gel filtration and HPLC and were identified by size, composition, and glucagon-like immunoreactivity. The amino acid sequences of the oxyntomodulin and GLP were determined. The oxyntomodulin contains 36 amino acid residues and its sequence is H S Q G T F T N D Y S K Y L D T R R A Q D F V Q W L M S T K R S G G I T. The composition of the glucagon is identical to the N-terminal 29 residues of the gar oxyntomodulin. The single form of GLP found contains 34 amino acid residues in the following sequence: H A D G T Y T S D V S S Y L Q D Q A A K K F V T W L K Q G Q D R R E. These findings suggest that all three peptides are derived from a common precursor.     

Functional effects of a KCNQ1 mutation associated with the long QT syndrome

OBJECTIVE: Long QT syndrome (LQTS) is an inherited disorder of ventricular repolarization caused by mutations in cardiac ion channel genes, including KCNQ1. In this study the electrophysiological properties of a LQTS-associated mutation in KCNQ1 (Q357R) were characterized. This mutation is located near the C-terminus of S6, a region that is important for the gate structure. METHODS AND RESULTS: Co-assembly of KCNE1 with the mutant Q357R elicited a current displaying slower activation compared to the wild-type KCNQ1/KCNE1 channels. The voltage dependence of activation of Q357R was shifted to more positive potentials. Moreover, a strong reduction in current density was observed that was partially attributed to the altered voltage dependence and kinetics of activation. The reduced current amplitude was also caused by intracellular retention of Q357R/KCNE1 channels as was shown by confocal microscopy. It indicated that the Q357R mutation disturbed protein expression by a trafficking or assembly problem of the Q357R/KCNE1 complex. To mimic the patient status KCNQ1, Q357R and KCNE1 were co-expressed, which revealed a dominant negative effect on current density and activation kinetics. CONCLUSION: The effects of the Q357R mutation on the activation of the channel together with a reduced expression at the membrane would lead to a reduction in I(Ks) and thus in "repolarization reserve" under physiological circumstances. As such it explains the long QT syndrome observed in these patients.     

Duchenne electrocardiogram in myotonia dystrophica

The term “myopathic pattern” is applied to the electrocardiographic finding of R/S in lead V1 of more than 1.5 in association with deep Q and prominent R waves in leads V4-V6.¹ Such findings are characteristic of Duchenne's pseudohypertrophic muscular dystrophy and reportedly do not occur in other types of muscular dystrophy or myopathy.^2,3The purpose of this paper is to describe a case of myotonia dystrophica with the Duchenne electrocardiographic pattern.     

Loss of electrically active myocardium during anterior infarction in man

A method has been developed of praecordial mapping of changes in R/S ratio and the appearance of Q waves in acute myocardial infarction. Observation of the serial changes in R and Q waves in 40 patients with uncomplicated anterior infarction shows that the loss of electrically active myocardium occurs within 6 hours of the onset of chest pain. Complications, such as recurrent chest pain, associated with extension of myocardial necrosis can be identified and assessed. The total praecordial changes in R/S ratio and Q wave amplitude correlate with the total MB fraction of creatine kinase activity released into the plasma in 20 patients after uncomplicated anterior infarction. This technique for identifying those factors that may modify the progressive loss of active myocardium in the early phase of acute infarction of the heart is noninvasive and repeatable.     

Loss of electrically active myocardium during anterior infarction in man.

A method has been developed of praecordial mapping of changes in R/S ratio and the appearance of Q waves in acute myocardial infarction. Observation of the serial changes in R and Q waves in 40 patients with uncomplicated anterior infarction shows that the loss of electrically active myocardium occurs within 6 hours of the onset of chest pain. Complications, such as recurrent chest pain, associated with extension of myocardial necrosis can be identified and assessed. The total praecordial changes in R/S ratio and Q wave amplitude correlate with the total MB fraction of creatine kinase activity released into the plasma in 20 patients after uncomplicated anterior infarction. This technique for identifying those factors that may modify the progressive loss of active myocardium in the early phase of acute infarction of the heart is noninvasive and repeatable.     

Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden).

With the aim of establishing whether the HR2 haplotype in factor V affects the risk of venous thromboembolism, a retrospective multicenter cohort study was performed in 810 family members identified through 174 probands who suffered from at least 1 episode of deep vein thrombosis and/or pulmonary embolism and had an inherited defect associated with thrombophilia (antithrombin, protein C, or protein S deficiency; factor V R506Q or prothrombin G20210A). Fifty-eight percent (468/810) of the family members had an inherited defect and 10% (47/468) were symptomatic. The HR2 haplotype was found in association with factor V R506Q more frequently in family members with venous thromboembolism (18%) than in those without (8%). Double heterozygosity for factor V R506Q and HR2 conferred a 3- to 4-fold increase in the relative risk of venous thromboembolism compared with factor V R506Q alone. The median age at first event was lower when the 2 defects were associated (46 v 52 years). No increase in risk of venous thromboembolism could be demonstrated when the HR2 haplotype was associated with inherited thrombophilic defects other than factor V R506Q. Because both factor V R506Q and the HR2 haplotype are very frequent, the effect of their coinheritance on the risk of venous thromboembolism might represent a clinically relevant issue, and screening for HR2 in carriers of factor V R506Q should be considered.     

Hot-spot mutants of p53 core domain evince characteristic local structural changes.

Most of the oncogenic mutations in the tumor suppressor p53 map to its DNA-binding (core) domain. It is thus a potential target in cancer therapy for rescue by drugs. To begin to understand how mutation inactivates p53 and hence to provide a structural basis for drug design, we have compared structures of wild-type and mutant p53 core domains in solution by NMR spectroscopy. Structural changes introduced by five hot-spot mutations (V143A, G245S, R248Q, R249S, and R273H) were monitored by chemical-shift changes. Only localized changes are observed for G245S, R248Q, R249S, and R273H, suggesting that the overall tertiary folds of these mutant proteins are similar to that of wild type. Structural changes in R273H are found mainly in the loop-sheet-helix motif and the loop L3 of the core domain. Mutations in L3 (G245S, R248Q, and R249S) introduce structural changes in the loop L2 and L3 as well as terminal residues of strands 4, 9, and 10. It is noteworthy that R248Q, which is often regarded as a contact mutant that affects only interactions with DNA, introduces structural changes as extensive as the other loop L3 mutations (G245S and R249S). These changes suggest that R248Q is also a structural mutant that perturbs the structure of loop L2-L3 regions of the p53 core domain. In contrast to other mutants, replacement of the core residue valine 143 to alanine causes chemical-shift changes in almost all residues in the beta-sandwich and the DNA-binding surface. Long-range effects of V143A mutation may affect the specificity of DNA binding.     

Genetic and clinical features of patients with Gaucher disease in Hungary

The aim of this study was to identify mutations in the gene encoding for lysosomal beta-glucocerebrosidase (GBA; gene symbol, GBA) in Hungarian patients with Gaucher disease (GD), and to study genotype-phenotype relationships. Genotypes and allele variations in 27 patients with type I GD of 25 unrelated families were studied. Of the 54 mutant alleles, we detected 38 frequent (N370S, 22/54; RecNciI, 8/54; L444P, 8/54) and 9 rare (N188S, R257Q, R285C, G377S, R120W, T323I, 84GG, 1263-1317del and 1263-1317del/RecTL) mutations. In addition, we identified two novel mutations. The N370S/RecNciI genotype found in 8 patients and the N370S/L444P genotype found in 5 patients were the most frequent genotypes in this cohort. In 22 patients the mutations occurred in heterozygosity with the N370S sequence variant, and one patient was homozygous for the L444P mutation. These data suggest that N370S, RecNciI, and L444P are the most prevalent mutations in Hungarian patients with GD. This mutation profile is characteristic for a Caucasian (non-Jewish) population. The c.260G>A and c.999G>A missense mutations are described here for the first time in GD patients contributing to the panel of reported GBA mutations.     

既往有偿献血HIV-1感染者中合并感染的HCV对telaprevir和boceprevir天然耐药分析

目的分析既往有偿献血人群HIV-1感染者中合并感染的HCV对telaprevir和boceprevir的天然耐药,为HCV的耐药监测及临床抗病毒治疗提供基础数据。方法收集既往有偿献血人群HIV阳性患者的血浆样本,检测其HCV抗体,应用巢式PCR扩增HCV NS3/4A区,对测序结果进行耐药分析,计算耐药率,评价耐药毒株的流行趋势。结果从150份符合要求的样本里共获得70份(46.67%)HCV NS3/4A基因序列。检测出耐药相关突变4例(5.71%),其中对boceprevir耐药2例(2.86%),耐药位点为R117H和A156V;对telaprevir耐药2例(2.86%),耐药位点为R117H和A156V;对telaprevir可能耐药2例(2.86%),耐药位点为T54S。尚未发现V36A/M/L/C、Q41H/R、F43C/S、T54A、V55A、Q80R、R109K、S138C、R155G/I/K/M/T/Q/S、A156S/T、D168A/E/G/H、V170A/T/I、N174G/S、L175M等已报道的耐药位点。其他突变中,氨基酸替换率超过90%的变异位点有I35V、A40T、R62K、I64L、V71I、S66G、S91A和T42S;在系统进化树中,耐药序列呈点状散在分布,未发现聚集性。结论既往有偿献血HIV-1感染者中合并感染的HCV对telaprevir和boceprevir存在天然耐药,耐药相关突变率分别为5.71%和2.86%。其他氨基酸位点出现突变率较高,但是未发现与耐药相关。各耐药菌株之间未发现传播关联性。     

Corroboration of Dahl S Q276L alpha1Na,K-ATPase protein sequence: impact on affinities for ligands and on E1 conformation

OBJECTIVE: Multifactorial analyses support the hypothesis that alpha1Na,K-ATPase is a hypertension susceptibility gene in Dahl S rats. However, two studies report non-detection of the A1079T transversion underlying the Q276L substitution in Dahl S alpha1Na,K-ATPase questioning the validity of ATP1A1 as a hypertension susceptibility gene. To resolve this discordance, we investigated the issue at the protein level. DESIGN AND METHODS: We employed protein blot analysis using Q276L- and Q276-specific; antipeptide-specific antibodies; tested differential chymotrypsin cleavage efficiency, measured differential Na and K affinities of alpha1Na,K-ATPases in Dahl S and Dahl R renal membranes and determined amino acid sequences of purified Dahl S alpha1Na,K-ATPase chymotryptic-digest peptides. RESULTS: We detected Q276L variant protein in Dahl S rats; and Q276 wild-type variant in Dahl R, spontaneously hypertensive (SHR), Lewis and Wistar-Kyoto (WKY) rat kidney membranes. Q276L variant exhibits less chymotrypsin cleavage efficiency than the Q276 wild-type variant, consistent with the substitution of hydrophobic L for hydrophilic Q. Kinetic studies of kidney membranes detect increased Na affinity and decreased K affinity in renal Dahl S alpha1Na,K-ATPase compared with Dahl R. Protein sequencing of high pressure liquid chromatography (HPLC)-purified chymotrypsin digested 77 kDa peptide confirms Q276L substitution in the Dahl S alpha1Na,K-ATPase. CONCLUSIONS: Data demonstrate the existence and functional significance of the Q276L variant in Dahl S rats.     

Induction of experimental allergic encephalomyelitis in Lewis rats with purified synthetic peptides: delineation of antigenic determinants for encephalitogenicity, in vitro activation of cellular transfer, and proliferation of lymphocytes.

Four highly purified synthetic peptides encompassing segments of the 68-86 region [for the numbering system used, see Eylar, E.H., Brostoff, S., Hashim, G., Caccam, J. & Burnett, P. (1971) J. Biol. Chem. 246, 5770-5784] of myelin basic protein (MBP), a region known to induce experimental allergic encephalomyelitis (EAE) in Lewis rats, were used to define and compare structure-function relationships between the primary structure of the 68-86 sequence and the three following biological activities: induction of EAE in Lewis rats, stimulation of T lymphocytes in vitro as measured by augmented cellular transfer of EAE to syngeneic recipients, and lymphocyte proliferation, as measured by [3]thymidine incorporation. Guinea pig (GP) MBP was approximately 60 or 1500 times more active than the GP68-84 (Y G S L P Q K S Q R S Q D E N; single-letter amino acid abbreviations) or the modified bovine (MB) 68-84 (Y G S L P Q K A Q R P Q D E N) peptides for induction of EAE, respectively. Furthermore, lymphocytes primed with either GPMBP, GP68-84, or MB68-84 crossreacted in vitro with either GPMBP, GP68-84, or MB68-84 for activation of lymphocyte transfer activity. In contrast, lymphocytes primed with either GP68-84 or MB68-84 exhibited antigen-specific proliferation in vitro exclusively in response to either GP or MB sequences, respectively. Neither GP75-84 (S Q R S Q D E N) nor GP75-86 (S Q R S Q D E N P V) induced EAE, activated lymphocytes for EAE transfer, or stimulated lymphocyte proliferation under conditions and doses tested. We conclude that (i) structurally distinct determinants, reflecting existence of functionally independent classes of antigen receptors, specify encephalitogenic and proliferative responses of primed lymphocytes and (ii) determinants for EAE induction, cellular transfer of EAE, and lymphocyte proliferation include amino acid residues in the 68-74 (Y G S L P Q K) sequence of GPMBP.     

Analysis of the β-Glucocerebrosidase Gene in Czech and Slovak Gaucher Patients: Mutation Profile and Description of Six Novel Mutant Alleles

ABSTRACT: The aim of this study was to characterize the spectrum of β-glucocerebrosidase gene mutations in Czech and Slovak Gaucher patients and to study genotype/phenotype associations. We have analyzed fifty-eight chromosomes from twenty-six type 1, two type 2, and one type 3 β-glucocerebrosidase deficient subjects by direct sequencing of PCR products. Fifty-eight mutant alleles were identified.Seventy-eight percent of mutant alleles carried common mutations (N370S 28/58, L444P 11/58, recNciI 5/58, and IVS2(+1)A 1/58), the remaining twenty-two percent carried rare and private mutations (1263del55, 1326insT, S196P, rec(g4889–6506), 203delC, G202E, F216Y, R257X, R120W, R359Q, S107L, L444P + V460V, and D409H + T369M). Six of these alleles have not been previously described (rec(g4889–6506), 1326insT, S196P, G202E, D409H + T369M, and L444P + V460V). The most common genotypes were N370S/L444P (8/29), N370S/recNciI (5/29), and N370S/N370S (2/29).The spectrum of the mutations is characteristic for a Caucasian (non-Jewish) population, with N370S, L444P and recNciI being the most prevalent mutations. The absence of the mutation 84insG that is frequently associated with severe bone disease may have contributed to the low incidence of severe bone disease in Czech and Slovak Gaucher subjects.     

肥厚型心肌病体表心电图特征

目的 探讨肥厚型心肌病（HCM）患者体表心电图（ECG）特征。 方法 选取2015年5月~2017年4月期间住院治疗的HCM患者60例，同时选取本院同期查体的正常人60例，作为对照组，要求两组人员性别、年龄、体质量指数匹配。分析ECG各导联QRS波时限和R波、S波振幅，异常q波情况，QTC时限，R/S比值， ST段下移与抬高，T波低平、倒置，P波时限等指标。 结果 ①HCM组的V2、V3导联QRS波时限；Ⅱ、V4导联异常Q波比例；QTC时限；P波时限；左心室肥厚ECG诊断公式SV1+RV5/V6及（SV3+RaVL）×QRS波时限均显著高于正常对照组。②HCM组的I、aVR、aVL、aVF导联QRS波时限；aVR导联Q波所占比例； I、Ⅱ、Ⅲ、aVL、aVF、V3、V4、V5、V6导联QRS波主波与T波方向一致性； V4、V5、V6导联R/S比值均显著低于正常对照组。 结论 ECG诊断HCM首先要满足左心室肥厚的诊断标准，再结合上述ECG导联的特异性参数进行综合判断。     

Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants

BACKGROUND: Eight common (>0.5%) polymorphisms of SCN5A have been described in the US population. Every human also continuously generates two wild-type (WT) splice variants, one with a glutamine residue at position 1077 (Q1077) and one lacking this glutamine (Q1077del). One polymorphism (H558R) has been studied in both splice variants, five polymorphisms (R34C, R481W, S524Y, P1090L,V1951L) have not been previously studied, and two polymorphisms (S1103Y and R1193Q) have been studied in only one of the two splice variants. OBJECTIVES: The purpose of this study was to examine the electrophysiologic molecular phenotype of the eight common polymorphisms in the two human splice variants of SCN5A. METHODS: Currents from 16 channels (all polymorphisms in both splice variants) were determined by voltage clamp and compared with WT after expression in HEK-293 cells. RESULTS: Six of eight polymorphisms showed a distinct phenotype that depended upon the background splice variant used for expression. Only R34C and V1951L showed no functional differences. S524Y showed a dramatic reduction in current density in the Q1077 background similar to that previously described for H558R. Four other polymorphisms (R481W, P1090L, S1103Y, R1193Q) showed shifts in activation, inactivation, or recovery that depended upon the splice variants. Shifts of a similar magnitude have been reported for arrhythmia syndrome mutations and are thought to be pathogenic. CONCLUSION: The majority of common human SCN5A polymorphisms have a distinct molecular phenotype that depends upon the splice variant background. These findings have implications for the interpretation of previous studies of arrhythmia mutations. The significance of these findings for clinical arrhythmia remains to be elucidated.