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Many algorithms have been developed to ensure the safety and accuracy of cardiac implantable electric devices (CIED). A specific algorithm designed to prevent pacemaker induced tachycardia (PMT) after a premature ventricular complex (PVC response) is available in all Abbott (former St. Jude Medical) CIED. However, a few case reports suggest that this algorithm may be proarrhythmic when programmed to Atrial Pace (A-Pace on PVC).We analyzed the data of all (n = 333) Abbot implantable cardioverter defibrillator (ICD) and cardiac resynchronization defibrillator (CRT-D) devices followed remote using the Merlin.net Patient Care Network in our institute in 2020. Status of the PVC response algorithm A-Pace on PVC or Off was collected, and all atrial mode switch (AMS) episodes longer than 30 s were thoroughly evaluated. Data on clinical characteristics of the patients was collect from the electronic patient records.A total of 173 patients had A-Pace on PVC and twenty-five of them (14%) had at least one atrial high rate episode (AHRE)30 s (AHRE) triggered by the action of this algorithm. The median PVC count was higher in patients who had algorithm triggered AHRE than in those with no algorithm-triggered AHRE (1.7% [IQR 0-3.2] vs. 0% [IQR 0-1.1], p .0001). The major clinical characteristics were comparable in the two groups.The A-Pace on PVC setting was frequently used in our patients. Our study shows that a considerable number of patients had at least one AHRE triggered by the algorithm. The use of this algorithm should be carefully reconsidered.

Funding Information: Funding Sources: Dr Koponen was supported by a research grant from the Aarne Koskelo Foundation. Publisher Copyright: © 2022 Heart Rhythm Society Background: Long QT syndrome (LQTS) is an inherited arrhythmia disorder characterized by ventricular repolarization abnormalities and a risk of sudden cardiac death. The electrophysiological components generating the high risk of arrhythmias in LQTS are prolonged repolarization, increased dispersion of repolarization, and early afterdepolarizations, which are clinically estimated as QT interval, T-wave peak to T-wave end (TPE) interval, and T2/T1-wave amplitude ratio, respectively. In experimental LQTS type 2 (LQT2) models, β-blockers decrease dispersion of repolarization and prevent early afterdepolarizations. In clinical studies in patients with LQT2, β-blockers are more effective against exercise-induced than arousal-induced cardiac events. Objectives: The aim of the study was to investigate the effects of β-blocker therapy on repolarization properties in LQT2. Methods: QT and TPE intervals and maximal T2/T1-wave amplitude ratios recorded by 24-hour electrocardiograms before and during β-blocker therapy were evaluated in 25 patients with LQT2. Results: β-Blocker therapy decreased the maximal T2/T1-wave amplitude ratio from 2.9 ± 1.1 to 1.8 ± 0.7 (P < .001), but did not change the pause-induced T2/T1-wave amplitude ratio. Under medication, abrupt maximal TPE intervals were shorter at heart rates of ≥75 beats/min and maximal QT intervals were shorter at a heart rate of 100 beats/min. Conclusion: β-Blockers stabilize ventricular repolarization in LQT2 by reducing electrocardiographic early afterdepolarizations and by reducing abrupt prolongation of electrocardiographic dispersion of repolarization and ventricular repolarization duration at elevated heart rates. The effect of β-blockers on pause-induced electrocardiographic early afterdepolarizations is weak. The findings provide electrocardiographic explanation for the protective effects of β-blockers against exercise-induced cardiac events in LQT2.

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmic disease associated with a risk of syncope and sudden cardiac death (SCD). Aims We aimed at identifying RYR2 P2328S founder mutation carriers and describing the clinical course associated with the mutation. Methods The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry, and from the present genealogical study. Kaplan-Meier graphs, log-rank test and Cox regression model were used to evaluate the clinical course. Results Genealogical study revealed a common ancestor couple living in the late 17th century. A total of 1837 living descendants were tested for RYR2 P2328S mutation unveiling 62 mutation carriers aged mean 39±23 years old. No arrhythmic deaths were documented among genotyped subjects, but 11 SCDs were detected in non-genotyped family members since 1970. Three genotyped patients (5%) suffered an aborted cardiac arrest (ACA), and 15 (25%) had a syncope triggered by exercise or stress. Rate of cardiac events was higher among patients who in exercise stress test showed a maximum rate of premature ventricular contractions >30/min (68% vs 17%, p Conclusions Previously undiagnosed CPVT patients may be identified by well-conducted genealogical studies. The RYR2 P2328S mutation causes a potentially severe phenotype, but its expression is variable, thus calling for additional studies on modifying factors.

Background The cardiac sodium channel Nav1.5, encoded by the gene SCN5A, is associated with a wide spectrum of hereditary arrhythmias. The gain-of-function mutation p.I141V in SCN5A was identified in a large multigenerational family with exercise-induced polymorphic ventricular arrhythmias. The purpose of this study was to evaluate the molecular and clinical effects of flecainide administration on patients with this syndrome. Methods Eleven p.I141V carriers who exhibited frequent multiformic premature ventricular complexes (PVCs) during exercise were subjected to exercise stress tests, both before and after intravenous infusion of 2 mg/kg flecainide. The in vitro effects of flecainide were evaluated using the patch-clamp technique with HEK293 cells expressing the Nav1.5 channel. Results The flecainide treatment significantly reduced the frequency of PVCs during and after exercise. Next, the sensitivity of the p.I141V mutant channel to flecainide was compared to that of the wild type channel. Perfusion of flecainide inhibited the peak and window currents in both groups. Conclusion The clinical investigations of the affected patients, as well as the molecular and pharmacological characterization of the SCN5A p.I141V mutation, provide new evidence supporting the association of this mutation with exercise-induced polymorphic ventricular arrhythmias. These data also demonstrate that flecainide may serve as an effective treatment for the defect in Nav1.5 that leads to an increased sodium window current.

Background Long QT syndrome (LQTS) is an inherited cardiac disorder predisposing to sudden cardiac death (SCD). We studied factors affecting the clinical course of genetically confirmed patients, in particular those not receiving β-blocker treatment. In addition, an attempt was made to associate risk of events to specific types of KCNQ1 and KCNH2 mutations. Methods A follow-up study covering a mean of 18.6 ± 6.1 years was conducted in 867 genetically confirmed LQT1 and LQT2 patients and 654 non-carrier relatives aged 18–40 years. Cox regression models were used to evaluate the contribution of clinical and genetic risk factors to cardiac events. Results In mutation carriers, risk factors for cardiac events before initiation of β-blocker included LQT2 genotype (hazard ratio [HR] = 2.1, p = 0.002), female gender (HR = 3.2, p G and other KCNQ1 mutation carriers after adjusting for gender, QTc duration, and cardiac events before age 18. KCNH2 c.453delC, L552S and R176W mutations associated with lower risk (HR = 0.11–0.23, p

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Background T-peak to T-end (TPE) interval on the electrocardiogram is a measure of myocardial dispersion of repolarization and is associated with an increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown. Objective To identify common genetic variants that affect the duration of the TPE interval in the general population. Methods We performed a genome-wide association study on 1870 individuals of Finnish origin participating in the Health 2000 Study. The TPE interval was measured from T-peak to T-wave end in leads II, V 2 , and V 5 on resting electrocardiograms, and the mean of these TPE intervals was adjusted for age, sex, and Cornell voltage-duration product. We sought replication for a genome-wide significant result in the 3745 subjects from the Framingham Heart Study. Results We identified a locus on 17q24 that was associated with the TPE interval. The minor allele of the common variant rs7219669 was associated with a 1.8-ms shortening of the TPE interval ( P = 1.1 × 10 −10 ). The association was replicated in the Framingham Heart Study (−1.5 ms; P = 1.3 × 10 −4 ). The overall effect estimate of rs7219669 in the 2 studies was −1.7 ms ( P = 5.7 × 10 −14 ). The common variant rs7219669 maps downstream of the KCNJ2 gene, in which rare mutations cause congenital long and short QT syndromes. Conclusion The common variant rs7219669 is associated with the TPE interval and is thus a candidate to modify repolarization-related arrhythmia susceptibility in individuals carrying the major allele of this polymorphism.

Epinephrine Infusion in Diagnosis of CPVT. Introduction: A test involving intravenous infusion of epinephrine has been proposed as a method alternative to exercise stress test in diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). We aimed at estimating the predictive value of intravenous epinephrine administration in CPVT patients with frequent exercise-induced ventricular ectopy. Methods and Results: We recruited 81 subjects, including 25 CPVT-linked ryanodine receptor 2 (RYR2) mutation carriers, 11 genetically undefined CPVT patients, and 45 unaffected family members. All subjects underwent a maximal exercise stress test and an intravenous epinephrine infusion test. Exercise stress test was positive in 25 (31%) patients including 14 of 25 (56%) established RYR2-mutation carriers and all 11 (100%) genetically undefined CPVT patients. Epinephrine infusion induced arrhythmias in 3 (12%) RYR2-mutation carriers, 4 (36%) genetically undefined CPVT patients, and 1 (2%) unaffected family member. A total of 18 exercise stress test positive patients did not respond to intravenous epinephrine administration, whereas only 1 epinephrine test responder had a normal exercise stress test. Thus, if exercise stress test is used as a standard, the sensitivity of the epinephrine infusion test is 28% and specificity is 98%. Conclusions: Intravenous epinephrine infusion has low sensitivity and may not be considered as an alternative method for a maximal exercise stress test in diagnosis of CPVT. (J Cardiovasc Electrophysiol, Vol. 23, pp. 194-199, February 2012)

Background Single-nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels and nitric oxide synthase-1 adaptor protein (NOS1AP) are associated with electrocardiographic (ECG) QT-interval duration, but the association of these SNPs with new, prognostically important ECG measures of ventricular repolarization is unknown. Objective The purpose of this study was to examine the relationship of SNPs to ECG T-wave peak to T-wave end (TPE) interval and T-wave morphology parameters. Methods We studied 5,890 adults attending the Health 2000 Study, a Finnish epidemiologic survey. TPE interval and four T-wave morphology parameters were measured from digital 12-lead ECGs and related to the seven SNPs showing a phenotypic effect on QT-interval duration in the Health 2000 Study population. Results In multivariable analyses, the KCNH2 K897T minor allele was associated with a 1.2-ms TPE-interval shortening (P = .00005) and the KCNH2 intronic rs3807375 minor allele was associated with a 0.8-ms TPE-interval prolongation (P = .001), whereas the KCNE1 D85N variant had no TPE-interval effect (P = .20). NOS1AP minor alleles (rs2880058, rs4657139, rs10918594, rs10494366) were associated with a shorter TPE interval (effects from 0.5 to 0.8 ms, P from .032 to .002), which resulted from their stronger effects on QTpeak than QTend interval. None of the SNPs showed a consistent association with T-wave morphology parameters. Conclusion KCNH2 K897T and rs3807375 as well as the four studied NOS1AP variants have modest effects on ECG TPE interval but are not related to T-wave morphology measures. The previously observed prognostic value of T-wave morphology parameters likely is not based on these SNPs.

Objectives. QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30–40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample. Methods. We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. Results. The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QTNc interval (P = 3.6 × 10−11) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QTNc interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P = 4.7 × 10−5], KCNH2 K897T [−2.6 ms (SE 0.5) or −0.14 SD, P = 2.1 × 10−7] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P = 3.2 × 10−24] under additive models. Conclusions. We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.

Long QT syndrome (LQTS) is an inherited arrhythmia disorder with an estimated prevalence of 0.01%-0.05%. In Finland, four founder mutations constitute up to 70% of the known genetic spectrum of LQTS. In the present survey, we sought to estimate the actual prevalence of the founder mutations and to determine their effect sizes in the general Finnish population.We genotyped 6334 subjects agedor =30 years from a population cohort (Health 2000 study) for the four Finnish founder mutations using Sequenom MALDI-TOF mass spectrometry. The electrocardiogram (ECG) parameters were measured from digital 12-lead ECGs, and QT intervals were adjusted for age, sex, and heart rate using linear regression. A total of 27 individuals carried one of the founder mutations resulting in their collective prevalence estimate of 0.4% (95% CI 0.3%-0.6%). The KCNQ1 G589D mutation (n=8) was associated with a 50 ms (SE 7.0) prolongation of the adjusted QT interval (P=9.0x10(-13)). The KCNH2 R176W variant (n=16) resulted in a 22 ms (SE 4.7) longer adjusted QT interval (P=2.1x10(-6)).In Finland 1 individual out of 250 carries a LQTS founder mutation, which is the highest documented prevalence of LQTS mutations that lead to a marked QT prolongation.

Alkylresorcinols (AR) could be good biomarkers of consumption of fiber-rich cereal products. The aim of this study was to examine the relationship between plasma ARs or urinary AR metabolites and cereal fiber intake in women consuming their habitual diet. Twenty-five postmenopausal and 31 premenopausal women were recruited. The subjects included also vegetarians (n = 20) to obtain a broad range of cereal intake. Dietary intake, plasma ARs, and urinary AR metabolites [3,5-dihydroxybenzoic acid and 3-(3,5-dihydroxyphenyl)-1-propanoic acid] were measured. Pearson's and Partial correlation tests were done between dietary fiber intake and plasma ARs or urinary AR metabolites. Cereal fiber intake correlated significantly with plasma AR C17:0 (r = 0.387), AR C19:0 (r = 0.350), AR C21:0 (r = 0.428), AR C23:0 (r = 0.409), AR C25:0 (r = 0.283), and total AR (r = 0.406) and with urinary AR metabolites DHBA (r = 0.359) and DHPPA (r = 0.402) even after adjustment for body mass index and age, which could be confounding variables. This is the first study to show a significant correlation between plasma ARs or urinary AR metabolites and cereal fiber intake during consumption of a habitual diet. These results indicate that assay of plasma ARs or urinary AR metabolites may be used as biomarkers in epidemiologic studies in free-living populations to evaluate the role of cereal fiber intake in various diseases. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2244–8)

Background— Inherited long-QT syndrome (LQTS) is associated with risk of sudden death. We assessed the clinical course and the fulfillment of current treatment strategies in molecularly defined pediatric LQTS type 1 and (LQT1) and type 2 (LQT2) patients. Methods and Results— Follow-up data covering a mean of 12 years were collected for 316 genotyped LQT1 and LQT2 patients aged 0 to 18 years. No arrhythmic deaths occurred during the follow-up. Finnish KCNQ1 and KCNH2 founder mutations were associated with fewer cardiac events than other KCNQ1 and KCNH2 mutations (hazard ratio [HR], 0.33; P =0.03 and HR, 0.16; P =0.01, respectively). QTc interval ≥500 ms increased the risk of cardiac events compared with QTc P =0.001). Treatment with β-blocker medication was associated with reduced risk of first cardiac event (HR, 0.23; P =0.001). Noncompliant LQT2 patients were more often symptomatic than compliant LQT2 patients (18% and 0%, respectively; P =0.03). Treatment with implantable cardioverter defibrillator was rare (3%) and resulted in reinterventions in 44% of cases. Conclusions— Severe cardiac events are uncommon in molecularly defined and appropriately treated pediatric LQTS mutation carriers. β-Blocker medication reduces the risk of cardiac events and is generally well tolerated in this age group of LQTS patients.

The cardiac sodium channel Nav1.5, encoded by the gene SCN5A, is associated with several hereditary arrhythmias. The gain-of-function mutation p.I141V in SCN5A was identified in a large family with exercise-induced polymorphic ventricular arrhythmias. The aim of this study was to evaluate the clinical and molecular effect of flecanide therapy on patients with this syndrome. First, the functional alterations caused by the p.I141V mutation were confirmed to lead to an increase in the sodium window current. Next, eleven p.I141V carriers who exhibited frequent multiformic premature ventricular complexes (PVCs) during exercise were subjected to exercise stress tests, both before and after intravenous infusion of 2 mg/kg flecainide. This treatment significantly reduced the frequency of PVCs during and after exercise. The in vitro effects of flecainide were evaluated using the patch-clamp technique. The sensitivity of the p.I141V mutant channel to flecainide was compared to that of the wild type channel. Perfusion of flecainide inhibited the peak and window currents in both groups. Altogether, these data demonstrates that flecainide may serve as an effective treatment for the defect in Nav1.5 that leads to an increased sodium window current. The author hereby declares no conflict of interest

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive myocardial disorder caused by mutations of desmosomal cell adhesion proteins. The prevalence of these variants in the general population is unknown. Objective This study examined the spectrum and population prevalence of desmosomal mutations predisposing to ARVC in Finland. Methods We screened 29 Finnish ARVC probands for mutations in the DSP, DSG2, and DSC2 genes. All Finnish-type ARVC-associated mutations, including those 3 previously identified in PKP2 in the same patient group, were analyzed in the population-based Health 2000 cohort of 6,334 individuals and tested for association with electrocardiographic variables. Results We detected 2 novel mutations: DSG2 3059_3062delAGAG and DSP T1373A. DSG2 3059_3062delAGAG was present in a family with 5 mutation carriers. The endomyocardial samples of the DSG2 deletion carrier showed reduced immunoreactive signal for desmoglein-2, plakophilin-2, plakoglobin, and desmoplakin. DSP T1373A was found in 1 proband with typical right ventricular disease and exercise-related ventricular tachycardia. In the population sample, the collective prevalence of all 5 mutations identified in the 29 ARVC patients (PKP2 Q62K, Q59L, N613K, DSG2 3059_3062delAGAG, and DSP T1373A) was 31 of 6,334 individuals, or 0.5%. The apparent founder mutation PKP2 Q59L is present in 0.3% of Finns and was previously shown to have an approximately 20% disease penetrance. Conclusion One of 200 Finns carries a desmosomal mutation that may predispose to ARVC and its clinical sequelae. ARVC-associated mutations may thus be more prevalent in the population than expected based on the published ARVC prevalence data.

Cardiac sodium channel is a complex which includes the poreforming alpha subunit and regulatory proteins that allow sodium influx during the depolarization phase of the ventricular action potential. The alpha subunit, Nav1.5, is encoded by SCN5A . Mutations in this gene are responsible for a wide spectrum of hereditary arrhythmias such as cardiac conduction disease and atrial fibrillation. A mutation in SCN5A , leading to a p.I141V substitution, was identified in a large multigenerational family with an arrhythmia syndrome resembling catecholaminergic polymorphic ventricular tachycardia through whole-exome sequencing. The purpose of this study was to identify the molecular mechanisms linking the p.I141V mutation to this arrhythmia. To evaluate the incidence of this substitution on Nav1.5 function, whole-cell patch-clamp experiments were performed on HEK293 cells transfected with the human alpha and beta subunits. The presence of the p.I141V mutation shifted the voltage-dependence of steady state activation towards more negative potentials. Thus, we studied the effect of this mutation on the sodium window current. Compared to the WT, the p.I141V window current exhibited a larger peak and this peak was shifted towards more negative potentials. To investigate the functional consequences of the cardiac hyperexcitability due to the p.I141V mutation, we incorporated biophysical properties of the mutant into atrial, Purkinje and ventricular cell models. The computational analyses imply that the biophysical changes caused by the p.I141V mutation accelerates the spontaneous rate in the Purkinje cell model, and reduce the excitation threshold leading to an increase of the excitability of the cardiac cells. In conclusion, the present study demonstrates that mutations in SCN5A also may result in exercise-induced polymorphic ventricular premature complexes and tachycardia resembling CPVT.

Background Catecholaminergic polymorphic ventricular tachycardia caused by mutations in the RyR2 gene manifests as severe arrhythmias, and may provide a candidate for sudden cardiac deaths. Methods We screened 19 victims of SCD for mutations in the RyR2 gene by direct sequencing, and analyzed DNAs from available family members and from 300 controls. Medico-legal investigations were conducted by experienced pathologists. We performed resting ECG, cardiac ultrasonography, exercise stress test, epinephrine test and 24-hour ambulatory ECG recording to related mutation carriers ( n =17). The single channel recordings of the mutant RyR2s were conducted in planar lipid bilayers, and the open probabilities were determined by sequential addition of CaCl 2 to the cis -side. Results We identified two novel RyR2 missense mutations (G2145R and R3570W) in three victims of SCD. The surviving carriers of these mutations exhibited only minor, if any structural abnormalities, and two carriers of R3570W showed ventricular arrhythmias predominantly at rest. Single channel recordings revealed a gain-of-function defect in native unphosphorylated R3570W and a similar but milder defect in native G2145R. Conclusions RyR2 mutations manifesting as a gain-of-function defect in vitro may be detectable in some cases of SCD. Not all RyR2 mutations lead to a uniform, highly penetrant CPVT phenotype.

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias. Methods and Results We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L) and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes. Conclusion We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.

Background— Over the past 15 years, a myriad of mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been linked to a long list of inherited atrial and ventricular arrhythmias. The purpose of this study was to identify the genetic and functional determinants underlying exercise-induced polymorphic ventricular arrhythmia present in a large multigenerational family. Methods and Results— A large 4-generation family presenting with exercise-induced polymorphic ventricular arrhythmia, which was followed for 10 years, was clinically characterized. A novel SCN5A mutation was identified via whole exome sequencing and further functionally evaluated by patch-clamp studies using human embryonic kidney 293 cells. Of 37 living family members, a total of 13 individuals demonstrated ≥50 multiformic premature ventricular complexes or ventricular tachycardia upon exercise stress tests when sinus rate exceeded 99±17 beats per minute. Sudden cardiac arrest occurred in 1 individual during follow-up. Exome sequencing identified a novel missense mutation (p.I141V) in a highly conserved region of the SCN5A gene, encoding the Na v 1.5 sodium channel protein that cosegregated with the arrhythmia phenotype. The mutation p.I141V shifted the activation curve toward more negative potentials and increased the window current, whereas action potential simulations suggested that it lowered the excitability threshold of cardiac cells. Conclusions— Gain-of-function of Na v 1.5 may cause familial forms of exercise-induced polymorphic ventricular arrhythmias.