Patients with DM are at risk for atrioventricular block and left ventricular (LV) dysfunction. Non-invasive detection of diffuse myocardial fibrosis may improve disease management in this population.
Our aim was to define functional and post-contrast myocardial T1 time cardiac magnetic resonance (CMR) characteristics in myotonic muscular dystrophy (DM) patients.
Thirty-three DM patients (24 with type 1 and 9 with type 2) and 13 healthy volunteers underwent CMR for assessment of LV indices and evaluation of diffuse myocardial fibrosis by T1 mapping. The association of myocardial T1 time to ECG abnormalities and LV indices were examined among DM patients.
DM patients had lower end-diastolic volume index (68.9 vs. 60.3 ml/m2, p=0.045), cardiac index (2.7 vs. 2.33 L/min/m2, p=0.005) and shorter myocardial T1time (394.5 vs. 441.4 ms, p<0.0001), compared to control subjects. Among DM patients, there was a positive association between higher T1 time and LV mass index (2.2 ms longer per gm/m2, p=0.006), LV end-diastolic volume index (1.3 ms longer per ml/m2, p=0.026), filtered QRS duration (1.2 ms longer per unit, p=0.005) and low-amplitude (<40mcV) late-potential duration (0.9 ms longer per unit, p=0.01). Using multivariate random effects regression, each 10 ms increase in myocardial T1 time of type 1 DM patients was independently associated with 1.3 ms increase in longitudinal PR and QRS intervals during follow-up.
DM is associated with structural alterations on CMR. Post-contrast myocardial T1 time was shorter in DM patients than controls likely reflecting the presence of diffuse myocardial fibrosis.
Myotonic muscular dystrophy; MRI; T1 mapping; ventricular function
Computer simulations have predicted that the balance of various electrogenic sarcolemmal ion currents may control the amplitude and phase of beat-to-beat alternans of membrane potential (Vm). However, experimental evidence for the mechanism by which alternans of calcium transients produces alternation of Vm (Vm-ALT) is lacking.
We sought to provide experimental evidence that Ca-to-Vm coupling during alternans is determined by the balanced influence of two Ca-sensitive electrogenic sarcolemmal ionic currents, INCX and ICa.
Methods and Results
Vm-ALT and Ca-ALT were measured simultaneously from isolated guinea pig myocytes (n=41) using perforated patch and Indo-1AM fluorescence, respectively. There were three study groups: 1) Control, 2) INCX predominance created by adenoviral-induced NCX overexpression, and 3) ICa predominance created by INCX inhibition (SEA-0400) or enhanced ICa (As2O3). During alternans, 14 of 14 control myocytes demonstrated positive Ca-to-Vm coupling, consistent with INCX, but not ICa as the major electrogenic current in modulating action potential duration. Positive Ca-to-Vm coupling was maintained during INCX predominance in 8 of 8 experiments with concurrent increase in Ca-to-Vm gain (p<0.05), reaffirming the role of increased forward mode electrogenic INCX. Conversely, ICa predominance produced negative Ca-to-Vm coupling in 14 of 19 myocytes (p<0.05) and decreased Ca-to-Vm gain compared to control (p<0.05). Furthermore, computer simulation demonstrated that Ca-to-Vm coupling changes from negative to positive was due to a shift from ICa to INCX predominance with increasing pacing rate.
These data provide the first direct experimental evidence that coupling in phase and magnitude of Ca-ALT to Vm-ALT is strongly determined by relative balance of prominence of INCX versus ICa currents.
alternans; repolarization; action potentials; intracellular calcium
The clinical importance of the J-point elevation on ECG is controversial.
Study intracardiac J-point amplitude before ventricular arrhythmia.
Baseline 12-lead ECGs and far-field (FF) right ventricular (RV) intracardiac ICD electrograms (EGMs) were recorded at rest in 494 patients [mean age 60.4±13.1; 360 (72.9%) men] with structural heart disease [278 (56.3%) ischemic cardiomyopathy] who received primary [463 (93.9%) patients] or secondary prevention ICD. Ten-second intracardiac FF EGMs before the onset of arrhythmia were compared with the baseline. The J-point amplitude was measured on the baseline 12-lead surface ECG and the intracardiac FF EGM. The relative J-point amplitude was calculated as the ratio of J-point amplitude to peak-to-peak R-wave.
The paired t-test showed that the relative intracardiac J-point amplitude was significantly higher before polymorphic ventricular tachycardia (PVT)/ventricular fibrillation (VF) onset (0.28±0.08 vs. −0.19±0.39; p=0.012) than at baseline. In a mixed-effects logistic regression model, adjusted for multiple episodes per patient, each 10% increase in relative J-point amplitude increased the odds of having VT/VF by 13% [OR 1.13 (95% CI 1.07–1.19); P<0.0001] and increased the odds of having PVT/VF by 27% [OR 1.27 (95% CI 1.11–1.46); P=0.001].
The relative intracardiac J-point amplitude is augmented immediately before the onset of PVT/VF in patients with structural heart disease.
electrocardiography; implantable cardioverter-defibrillator; ventricular arrhythmia; J point elevation; intracardiac electrogram
The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable and mutations have been described in syndromatic cases.
To conduct a meta-analysis of genome-wide association studies (GWAS) to identify common genetic variants influencing ERP.
We ascertained ERP based on electrocardiograms in three large community-based cohorts from Europe and the US: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed GWAS in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached p≤1×10−5 in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages.
Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9±8.9 years, 30.3% women; ERP negative: 47.5±9.4 years, 54.2% women). After meta-analysis, eight single nucleotide polymorphisms reached p≤1×10−5: The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36–0.61; p=6.9×10−9). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25–1.69; p=8.5×10−7). In the replication step (7151 individuals), none of the eight variants replicated, and combined meta-analysis results failed to reach genome-wide significance.
In a GWAS, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.
Early repolarization; Sudden cardiac death; Arrhythmia; GWAS; Meta-analysis; Electrocardiogram
A significant proportion of implantable cardioverter-defibrillators (ICDs) have been subject to FDA advisories. The impact of device advisories on mortality or patient care is poorly understood. Although estimated risks of ICD generators under advisory are low, dependency on ICD therapies to prevent sudden death justifies assessment of long-term mortality.
To test association of FDA advisory status with long-term mortality.
The study was a retrospective, single-center review of clinical outcomes, including device malfunctions, in patients from implantation to either explant or death. Patients with ICDs first implanted at Cleveland Clinic between 8/96-5/04 who became subject to FDA advisories on ICD generators were identified. Mortality was determined using the Social Security Death Index.
In 1644 consecutive patients receiving first ICD implants, 704 (43%) became subject to an FDA advisory, of which 172 (10.5%) were Class I and 532 (32.3%) were Class II. ICDs were explanted before advisory notifications in 14.0% of Class I and 10.1% of Class II advisories. Among ICDs under advisory, 28 (4.0%) advisory related and 15 non-advisory related malfunctions were documented. Over a median follow-up of 70 months, 814 patients died. Kaplan-Meier 5-year survival was 65.6% overall, and 64.2%, 61.1%, and 69.3% in patients with no, Class I, and Class II advisories, respectively, p=0.17.
ICD advisories impacted 43% of patients. Advisory-related malfunctions affected 4% within the combined Advisory group. Based on a conservative management strategy ICDs under advisory were not associated with increased mortality over a background of significant disease-related mortality.
Implantable Cardioverter-Defibrillators; Mortality; FDA; Safety
Some studies suggest that right ventricular (RV) pacing has an adverse impact on left ventricular ejection fraction (LVEF), particularly in subjects with preexisting left ventricular (LV) dysfunction, and that direct LV pacing may be relatively protective. Interactions between pacing site and LVEF remain unclear.
The purpose of this study was to examine the relative impact of RV and LV pacing on LVEF by serial study during a period in which LV dysfunction, induced by tachypacing, was introduced and then resolved.
In each of five dogs, RV, LV, and simultaneous RV and LV (BiV) pacing modes were compared to native ventricular activation (1) prior to tachypacing (baseline), (2) weekly during a 5-week continuous tachypacing period, and (3) weekly during a 3-week post-tachypacing recovery period. At each evaluation, LVEF and LV contraction synchrony were assessed during each pacing mode.
The decrease in LVEF during the tachypacing period was more pronounced during RV pacing than during native activation or LV or BiV pacing. The magnitude of this effect correlated with a diminishment in LV contraction synchrony that was not observed during native activation or LV or BiV pacing. During the post-tachypacing period, gradual reversal of these changes toward baseline was observed.
Compared to native activation, RV pacing worsens LVEF in a manner proportional to the severity of preexisting LV dysfunction, attributable to reduced LV contraction synchrony. In comparison, both LV and BiV pacing preserve LVEF and contraction synchrony.
Contraction; Ejection fraction; Pacing; Resynchronization; Ventricle
The presence of epicardial fat can confound the quantification of scar during transpericardial electroanatomic mapping. The electrogram (EGM) characteristics of epicardial fat have not been systematically compared with infarct scar using gross and histopathologic analysis as a gold standard.
A closed-chest infarction was created in 40–50 kg pigs by occlusion of the circumflex artery for 150 minutes using an angioplasty balloon. This artery was chosen to minimize any potential overlap of epicardial fat with infarct and to spare any septal involvement. After 4–12 weeks of infarct healing, epicardial mapping was performed. EGMs in low voltage regions (<1.5mV) were analyzed and bipolar amplitude, duration, number of deflections, and the presence of late potentials were recorded. Statistical analysis was performed using unpaired t-test and chi square analysis. Gross and histopathologic examination was used to confirm areas of fat and infarct scar.
Seven porcine hearts were analyzed after high-density epicardial mapping (364±92 points) was performed 48±19 days after infarction. The mean bipolar EGM amplitude was similar in fat and scar (0.77±0.34 vs 0.75±0.38mV; P=NS). The mean EGM duration was longer in scar than fat (68.8±18.9 vs 50.1±11.6 ms; P<0.0001) and exhibited more fractionation (8.5±3.1 vs 4.7±1.8 deflections; P<0.0001). The presence of late potentials was 99% specific for scar. Further, areas of fat >4 mm in thickness registered low voltage bipolar EGMs.
Scar from healed myocardial infarction exhibits more fractionation and longer EGM duration when compared to fat. Late potentials are highly specific for locating infarct scars.
Epicardial; fat; infarction; electrogram; late potential
Ventricular fibrillation (VF) is the primary mechanism of cardiac arrest in the vast majority of sudden death patients. Whether similar modes and mechanisms of death can be generalized to denervated hearts in orthotopic heart transplantation (OHT) patients is unknown.
The purpose of this study was to determine the mode and mechanisms of death in patients who have undergone cardiac transplantation.
We analyzed the outcomes of 628 patients who underwent OHT between January 1994 and December 2004. The mode of death was classified as either sudden death (SD) or non-sudden death (NSD). The first documented rhythm taken at the time of arrest was also reviewed to determine the mechanism of cardiac arrest.
During a mean follow up of 76 months, 194 patients expired. Of these, the mode of death could be determined in 116 patients (60%). Forty-one patients (35%) died from SD and 75 patients (65%) died of NSD. The first documented rhythm of death was available in 91 patients (26 SD and 65 NSD). The terminal rhythms in patients who died suddenly were: asystole (34%), pulseless electrical activity (PEA) (20%), and VF (10%). In NSD patients, the terminal rhythms were asystole (73%), followed by VF (7%), and PEA (7%), p<0.001 compared to SD patients.
SD represented the mode of death in 35% of OHT patients. The main mechanisms underlying SD in this population were asystole and PEA, suggesting that denervation of the donor heart, among other post-transplant changes, may alter susceptibility to VF.
heart transplantation; sudden death; ventricular fibrillation
Catheter ablation of the left atrium (LA) is associated with potential collateral injury to surrounding structures, especially the esophagus and the right phrenic nerve (PN).
The purpose of this study was to evaluate the efficacy and feasibility of intrapericardial balloon placement (IPBP) for protection of collateral structures adjacent to the LA.
Electroanatomic mapping was performed in porcine hearts using a transseptal endocardial approach in eight swine weighing 40–50kg. An intrapericardial balloon was inflated in the oblique sinus, via percutaneous epicardial access, to displace the esophagus. Similarly, with the balloon positioned in the transverse sinus, IPBP was used to displace the right PN. Esophageal temperature was monitored while endocardial radiofrequency (RF) energy was delivered to the distal inferior PV.
In all cases, balloon placement was successful with no significant effects on hemodynamic function. Balloon inflation increased the distance between the esophagus and posterior LA by 12.3±4.0mm. IPBP significantly attenuated increases in luminal esophageal temperature during endocardial RF application (6.1±2.4°C vs 1.2±1.1°C, p<0.0001). High-output endocardial pacing from the RSPV ostium stimulated PN activity. Following displacement of the right PN with IPBP, PN capture was abolished in 30 of 33 sites (91%).
These findings demonstrate that in an animal model, IPBP is feasible in the setting of catheter ablation procedures and has the potential to decrease the risk of collateral damage to the esophagus and PN during LA ablation.
Catheter ablation; Esophageal injury; Phrenic nerve injury
Postural Tachycardia Syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate (HR) upon standing, and many POTS patients have low blood volume. Increasing blood volume is a promising approach to this problem.
We tested the hypothesis that desmopressin (DDAVP) will attenuate the tachycardia and improve symptom burden in patients with POTS.
In this protocol, patients with POTS (n=30) underwent acute drug trials with DDAVP 0.2 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, HR and symptoms were assessed while seated and after standing for up to 10 minutes prior to and hourly for 4 hours following study drug.
Standing HR was significantly lower following DDAVP compared to placebo (101.9 ± 14.5 vs. 109.2 ± 17.4 bpm (P<0.001)). Standing blood pressure was not affected (P=0.28). The symptom burden improved with DDAVP (from a score of 18 ± 18 to 13 ± 15 arbitrary units [au] at 2 hours) compared with placebo (from 18 ± 17 to 19 ± 16 au; P=0.010).
Oral desmopressin significantly attenuated tachycardia and improved symptoms in POTS. The safety profile of this approach would need to be examined before it can be recommended for routine treatment of these patients.
tachycardia; desmopressin; autonomic nervous system; blood volume; drugs; orthostatic intolerance
Photodynamic therapy; Targeted ablation; Arrhythmia; Nanoparticle; Methylene blue
There are limited data regarding national patterns of pharmacotherapy for atrial fibrillation (AF) among older patients. Drug exposure data are now captured for Medicare beneficiaries enrolled in prescription drug plans.
To describe pharmacotherapy for AF among Medicare beneficiaries.
Using a 5% national sample of Medicare claims data, we compared demographic characteristics, comorbidity, and treatment patterns according to Medicare Part D status among patients with prevalent AF in 2006 and 2007.
In 2006, 27,174 patients (29.3%) with prevalent AF were enrolled in Medicare Part D. In 2007, enrollment increased to 45,711 (49.1%). Most enrollees were taking rate control agents (74.0% in 2007). β-Blocker use was higher in those with concomitant AF and heart failure and increased with higher CHADS2 scores (P < .001). Antiarrhythmic use was 18.7% in 2006 and 19.1% in 2007, with amiodarone accounting for more than 50%. Class Ic drugs were used in 3.2% of patients in 2007. Warfarin use was less than 60% and declined with increasing stroke risk (P < .001).
Pharmacotherapy for AF varied according to comorbidity and underlying risk. Amiodarone was the most commonly prescribed antiarrhythmic agent. Postmarketing surveillance using Medicare Part D claims data linked to clinical data may help inform comparative safety, effectiveness, and net clinical benefit of drug therapy for AF in older patients in real-world settings.
Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Calcium Channel Blockers; Drug Therapy
Connexin43; lateralization; anisotropy
Previous studies have demonstrated that microvolt T-wave alternans (MTWA) testing is a robust predictor of ventricular tachyarrhythmias and sudden cardiac death (SCD) in at-risk patients. However, recent studies have suggested that MTWA testing is not as good a predictor of “appropriate” implantable cardioverter-defibrillator (ICD) therapy as it is a predictor of SCD in patients without ICDs.
We sought to evaluate the utility of MTWA testing for SCD risk stratification in patients without ICDs.
Patient-level data were obtained from five prospective studies of MTWA testing in patients with no history of ventricular arrhythmia or SCD. In these studies, ICDs were implanted in only a minority of patients and patients with ICDs were excluded from the analysis. We conducted a pooled analysis and examined the 2-year risk for SCD based on MTWA test result.
The pooled cohort included 2883 patients. MTWA testing was positive in 856 (30%), negative in 1627 (56%) and indeterminate in 400 (14%) patients. Among patients with LVEF ≤ 35%, annual SCD event rates were 4.0%, 0.9% and 4.6% among the MTWA positive, negative and indeterminate groups. The SCD rate was significantly lower among patients with a negative MTWA test compared to either the positive or the indeterminate groups (p<0.001 for both comparisons). In patients with LVEF > 35%, annual SCD event rates were 3.0%, 0.3% and 0.3% among the MTWA positive, negative and indeterminate groups. The SCD rate associated with a positive test was significantly higher than either the negative (p<0.001) or the indeterminate groups (p=0.003).
In patients without ICDs, MTWA testing is a powerful predictor of SCD. Among patients with LVEF ≤ 35%, a negative MTWA test is associated with a low risk for SCD. Conversely, among patients with LVEF > 35%, a positive MTWA test identifies patients at significantly heightened SCD risk. These findings may have important implications for refining primary prevention ICD treatment algorithms.
T-wave alternans; arrhythmia; sudden death; risk stratification; electrophysiology; defibrillation
Treatment of perimitral flutter (PMF) requires bidirectional mitral isthmus (MI) block, which can be difficult with radiofrequency ablation (RFA). The vein of Marshall (VOM) is located within the MI.
To test whether VOM ethanol infusion could help achieve MI block.
Perimitral conduction was studied in patients undergoing ablation of atrial fibrillation (AF). Group 1 included 50 patients with a previous AF ablation undergoing repeat ablation, 30 of which had had MI ablation. Spontaneous (8/50) or inducible PMF (21/50) was confirmed by activation mapping. Group 2 included 21 patients undergoing de novo VOM ethanol infusion. The VOM was cannulated with a quadripolar catheter for pacing and with an angioplasty balloon to deliver up to four 1mL infusions of 98% ethanol. Voltage maps were created before and after VOM ethanol. Bidirectional MI block was verified by differential pacing. RFA times required to achieve it were assessed.
In Group 1, VOM ethanol infusion acutely terminated PMF in 5/29 patients. RFA needed to achieve bidirectional MI block was 2.2±1.6 min. Presence of PMF or previous MI ablation did not affect RFA times. In Group 2, RFA needed to achieve bidirectional MI block was 2.0±1.6 min (p=NS). Five patients had bidirectional MI block achieved solely by VOM ethanol without RFA. In both groups, ablation after VOM ethanol was required in the annular aspect of the MI. There were no acute complications.
VOM ethanol infusion is useful in the treatment of PMF and assists in reliably achieving bidirectional MI block.
For late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) assessment of atrial scar to guide management and targeting of ablation in atrial fibrillation (AF), an objective, reproducible method of identifying atrial scar is required.
To describe an automated method for operator-independent quantification of LGE that correlates with colocated endocardial voltage and clinical outcomes.
LGE CMR imaging was performed at 2 centers, before and 3 months after pulmonary vein isolation for paroxysmal AF (n = 50). A left atrial (LA) surface scar map was constructed by using automated software, expressing intensity as multiples of standard deviation (SD) above blood pool mean. Twenty-one patients underwent endocardial voltage mapping at the time of pulmonary vein isolation (11 were redo procedures). Scar maps and voltage maps were spatially registered to the same magnetic resonance angiography (MRA) segmentation.
The LGE levels of 3, 4, and 5SDs above blood pool mean were associated with progressively lower bipolar voltages compared to the preceding enhancement level (0.85 ± 0.33, 0.50 ± 0.22, and 0.38 ± 0.28 mV; P = .002, P < .001, and P = .048, respectively). The proportion of atrial surface area classified as scar (ie, >3 SD above blood pool mean) on preablation scans was greater in patients with postablation AF recurrence than those without recurrence (6.6% ± 6.7% vs 3.5% ± 3.0%, P = .032). The LA volume >102 mL was associated with a significantly greater proportion of LA scar (6.4% ± 5.9% vs 3.4% ± 2.2%; P = .007).
LA scar quantified automatically by a simple objective method correlates with colocated endocardial voltage. Greater preablation scar is associated with LA dilatation and AF recurrence.
2D, 2-dimensional; AF, atrial fibrillation; CMR, cardiovascular magnetic resonance; ECG, electrocardiogram; LA, left atrial/atrium; LGE, late gadolinium enhancement; MRA, Magnetic resonance angiography; PAF, paroxysmal atrial fibrillation; RF, radiofrequency; SD, standard deviation; Atrial fibrillation; Delayed-enhancement magnetic resonance imaging; Radiofrequency ablation
Desmosomes and adherens junctions provide mechanical continuity between cardiac cells, whereas gap junctions allow for cell-cell electrical/metabolic coupling. These structures reside at the cardiac intercalated disc (ID). Also at the ID is the voltage-gated sodium channel (VGSC) complex. Functional interactions between desmosomes, gap junctions, and VGSC have been demonstrated. Separate studies show, under various conditions, reduced presence of gap junctions at the ID and redistribution of connexin43 (Cx43) to plaques oriented parallel to fiber direction (gap junction “lateralization”).
To determine the mechanisms of Cx43 lateralization, and the fate of desmosomal and sodium channel molecules in the setting of Cx43 remodeling.
Adult sheep were subjected to right ventricular pressure overload (pulmonary hypertension). Tissue was analyzed by quantitative confocal microscopy and by transmission electron microscopy. Ionic currents were measured using conventional patch clamp.
Quantitative confocal microscopy demonstrated lateralization of immunoreactive junctional molecules. Desmosomes and gap junctions in lateral membranes were demonstrable by electron microscopy. Cx43/desmosomal remodeling was accompanied by lateralization of 2 microtubule-associated proteins relevant for Cx43 trafficking: EB1 and kinesin protein Kif5b. In contrast, molecules of the VGSC failed to reorganize in plaques discernable by confocal microscopy. Patch-clamp studies demonstrated change in amplitude and kinetics of sodium current and a small reduction in electrical coupling between cells.
Cx43 lateralization is part of a complex remodeling that includes mechanical and gap junctions but may exclude components of the VGSC. We speculate that lateralization results from redirectionality of microtubule-mediated forward trafficking. Remodeling of junctional complexes may preserve electrical synchrony under conditions that disrupt ID integrity.
Connexin; Desmosomes; Sodium current; Gap junctions; EB1; Kinesin
Loss-of-function mutations in the gene KCNQ1 encoding the Kv7.1 K+ channel cause long QT syndrome type 1 (LQT1), whereas gain-of-function mutations are associated with short QT syndrome as well as familial atrial fibrillation (FAF). However, KCNQ1 mutation pleiotropy, which is capable of expressing both LQT1 and FAF, has not been demonstrated for a discrete KCNQ1 mutation. The genotype–phenotype relationship for a family with FAF suggests a possible association with the LQT1 p.Arg231Cys-KCNQ1 (R231C-Q1) mutation.
The purpose of this study was to determine whether R231C-Q1 also can be linked to FAF.
The R231C-Q1 proband with AF underwent genetic testing for possible mutations in 10 other AF-linked genes plus KCNH2 and SCN5A. Sixteen members from five other R231C-positive LQT1 families were genetically tested for 21 single nucleotide polymorphisms (SNPs) to determine if the FAF family had discriminatory SNPs associated with AF. R231C-Q1 was expressed with KCNE1 (E1) in HEK293 cells, and Q1E1 currents (IQ1E1) were analyzed using the whole-cell patch-clamp technique.
Genetic analyses revealed no additional mutations or discriminatory SNPs. Cells expressing WT-Q1 and R231C-Q1 exhibited some constitutively active IQ1E1 and smaller maximal IQ1E1 compared to cells expressing WT-Q1.
Constitutively active IQ1E1 and a smaller peak IQ1E1 are common features of FAF-associated and LQT1-associated mutations, respectively. These data suggest that the mixed functional properties of R231C-Q1 may predispose some families to LQT1 or FAF. We conclude that R231C is a pleiotropic missense mutation capable of LQT1 expression, AF expression, or both.
Atrial fibrillation; Familial atrial fibrillation; Genetics; Ion channel; KCNQ1; Long QT syndrome; Long QT syndrome type 1
Skeletal muscle sodium channel (Nav1.4) expression in border zone myocardium increases action potential upstroke velocity in depolarized isolated tissue. Because resting membrane potential in the 1 week canine infarct is reduced, we hypothesized that conduction velocity (CV) is greater in Nav1.4 dogs compared to control dogs.
To measure CV in the infarct border zone border in dogs with and without Nav1.4 expression.
Adenovirus was injected in the infarct border zone in 34 dogs. The adenovirus incorporated the Nav1.4- and a green fluorescent protein (GFP) gene (Nav1.4 group, n=16) or only GFP (n=18). After 1 week, upstroke velocity and CV were measured by sequential microelectrode recordings at 4 and 7 mM [K+] in superfused epicardial slabs. High density in vivo epicardial activation mapping was performed in a subgroup (8 Nav1.4, 6 GFP) at 3–4 locations in the border zone. Microscopy and antibody staining confirmed GFP or Nav1.4 expression.
Infarct sizes were similar between groups (30.6+/−3 % of LV mass, mean+/−SEM). Longitudinal CV was greater in Nav1.4- than in GFP- sites (58.5+/−1.8 vs 53.3+/−1.2 cm/s, 20 and 15 sites, respectively, p<0.05). Transverse CV was not different between the groups. In tissue slabs dV/dtmax was higher and CV was greater in Nav1.4 than in control at 7 mM [K+] (P<0.05). Immunohistochemical Nav1.4 staining was seen at the longitudinal ends of the myocytes.
Nav1.4 channels in myocardium surviving 1 week infarction increases longitudinal but not transverse CV, consistent with the increased dV/dtmax and with the cellular localization of Nav1.4.
conduction; arrhythmias; gene therapy; skeletal muscle; sodium channel; myocardial infarction
Gap junctions; connexins; heart development; arrhythmia
Heterozygous SCN5A mutations have been associated with varied arrhythmia phenotypes; phenotype severity may range from asymptomatic ECG changes (mild phenotype) to symptomatic arrhythmias resulting in syncope, cardiac arrest and sudden cardiac death (severe phenotype) even among family members carrying the same mutation. Risk-stratification schemes for SCN5A mutation carriers remain uncertain.
We used a family based approach to determine the role of SCN5A promoter variants and DNA methylation in predicting phenotype severity in a kindred with loss-of-function SCN5A mutation.
In a large kindred with a heterozygous SCN5A loss-of-function mutation (1936delC, Q646RfsX5; 22 mutation carriers), we sought SCN5A promoter variants. In addition, we assessed SCN5A and genome-wide DNA methylation profiles on genomic DNA derived from blood (Illumina Human Methylation27 BeadChip).
During systematic survey of 2.8kb SCN5A promoter region, we identified two SNPs in complete linkage disequilibrium (rs41310749 and rs41310239). These promoter variants were significantly associated with disease severity (mild vs. severe phenotype) (p=0.0007), as all three patients with severe phenotype carried the two-SNP variant on both mutant and wild-type alleles. Analysis did not support a role for methylation of SCN5A related genes.
These family-based genetic findings suggest that the presence of specific promoter variants increase the risk of a severe phenotype in heterozygous carriers of an SCN5A loss-of-function mutation.
Arrhythmia; Promoter; Genetic polymorphisms; Sudden cardiac death
Although QT prolongation following myocardial infarction (MI) is generally moderate, cases with marked QT prolongation leading to life-threatening torsades de pointes (TdP) have been described.
To investigate the genetic substrate of this phenomenon.
We studied 13 patients who developed TdP in the subacute phase of MI (2–11 days) and a group of 133 ethnically matched controls with uncomplicated MI. Long QT syndrome genes and the KCNH2-K897T polymorphism were screened by using denaturing high-performance liquid chromatography plus direct sequencing and a specific TaqMan assay, respectively.
Two of the 13 patients (15%) who presented with QT prolongation and TdP were found to carry long QT syndrome mutations (KCNH2-R744X and SCN5A-E446K). Nine of the remaining 11 patients (82%) carried the KCNH2-K897T polymorphism, which was present in 35% of the controls (P = .0035). Thus, patients with an acute MI carrying the KCNH2-K897T polymorphism had an 8-fold greater risk of experiencing TdP compared with controls (95% confidence interval = 2–40).
Our data suggest that the common K897T polymorphism is associated with an increased risk of TdP developing in the subacute phase of MI. Our findings support the concept that the electrical remodeling associated with this healing phase of MI may unmask a genetic substrate predisposing to a time-limited development of life-threatening arrhythmias. They also provide the first line of evidence in support of the hypothesis that a common polymorphism, previously described as a modifier of the severity of LQTS, may increase the risk of life-threatening arrhythmias in a much more prevalent cardiac disease such as myocardial infarction.
Long QT syndrome; Cardiac arrhythmia; Sudden cardiac death; Molecular genetics; Single nucleotide polymorphism
Na channel blockers are effective in suppressing delayed afterdepolarizations (DADs) in isolated Purkinje fibers. However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs.
To test the hypothesis that combined Na channel and type 2 ryanodine receptor channel blocker ((R)-propafenone) is more effective than a Na channel blocker (lidocaine) in suppressing SCaE and DADs in the intact rabbit ventricles.
We compared (R)-propafenone (3 μmol/L) with lidocaine (50 μmol/L) on SCaE and DADs by using epicardial optical mapping of intracellular calcium (Cai) and membrane voltage in Langendorff-perfused rabbit hearts. SCaE and DADs were induced by rapid pacing trains and isoproterenol (0.3 μmol/L) infusion. One arbitrary unit is equivalent to the Ca transient amplitude of paced beats.
SCaEs were observed at the cessation of rapid pacing in all hearts at baseline. (R)-Propafenone nearly completely inhibited DADs and SCaE (0.04 arbitrary units [95% confidence interval 0.02–0.06] vs 0.23 arbitrary units [95% confidence interval 0.18–0.28] at baseline; n = 6 hearts; P < .001). Lidocaine also significantly reduced the SCaE but was significantly (P < .05) less effective than (R)-propafenone. Both drugs increased the rise time of action potential upstroke and reduced conduction velocity to a similar extent, suggesting a significant inhibition of INa.
Both Na channel blockers significantly reduced tachycardia-induced SCaEs in the rabbit ventricles, but (R)-propafenone was significantly more effective than lidocaine. These data suggest that type 2 ryanodine receptor inhibition potentiates the activity of Na channel blockers against SCaE and DADs in the intact hearts.
Depolarization; Action potentials; Calcium; Antiarrhythmic agents
T-peak to T-end (TPE) interval on the electrocardiogram (ECG) is a measure of myocardial dispersion of repolarization and is associated with increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown.
We sought to identify common genetic variants that affect the TPE-interval duration in the general population.
We performed a genome-wide association study on 1 870 individuals of Finnish origin participating in the Health 2000 Study. TPE interval was measured from T-peak to T-wave end in leads II, V2 and V5 on resting ECGs 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 3 745 subjects from the Framingham Heart Study.
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 two studies was −1.7 ms (P=5.7×10−14). The common variant rs7219669 maps downstream of KCNJ2 gene, in which rare mutations cause congenital Long- and Short-QT syndromes.
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.
Electrocardiography; Repolarization; T wave; Epidemiology; Genetics; Polymorphism