Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome.

Perrault syndrome (PS) is a genetically heterogeneous disorder characterized by primary ovarian insufficiency (POI) in females and sensorineural hearing loss in males and females. In many PS subjects, causative variants have not been found in the five reported PS genes. The objective of this study was to identify the genetic cause of PS in an extended consanguineous family with six deaf individuals. Whole exome sequencing (WES) was completed on four affected members of a large family, and variants and co-segregation was confirmed by Sanger sequencing. All hearing impaired individuals, including the proband, are homozygous for a pathogenic variant of CLDN14, but this only explains the deafness. The PS proband is also homozygous for a frameshift variant (c.1453_1454delGA, p.(Glu485Lysfs*5)) in exon 7 of SGO2 encoding shugoshin 2, which is the likely cause of her concurrent ovarian insufficiency. In mouse, Sgol2a encoding shugoshin-like 2a is necessary during meiosis in both sexes to maintain the integrity of the cohesin complex that tethers sister chromatids. Human SGO2 has not previously been implicated in any disorder, but in this case of POI and perhaps others, it is a candidate for unexplained infertility.

USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22-23.

Usher syndrome (USH) is a hereditary disorder associated with sensorineural hearing impairment, progressive loss of vision attributable to retinitis pigmentosa (RP) and variable vestibular function. Three clinical types have been described with type I (USH1) being the most severe. To date, six USH1 loci have been reported. We ascertained two large Pakistani consanguineous families segregating profound hearing loss, vestibular dysfunction, and RP, the defining features of USH1. In these families, we excluded linkage of USH to the 11 known USH loci and subsequently performed a genome-wide linkage screen. We found a novel USH1 locus designated USH1H that mapped to chromosome 15q22-23 in a 4.92-cM interval. This locus overlaps the non-syndromic deafness locus DFNB48 raising the possibility that the two disorders may be caused by allelic mutations.

Haplogroup analysis supports a pathogenic role for the 7510T>C mutation of mitochondrial tRNA(Ser(UCN)) in sensorineural hearing loss.

We ascertained a large North American family, LMG309, with matrilineal transmission of non-syndromic, progressive sensorineural hearing loss (SNHL). There was no history of aminoglycoside exposure, and penetrance was complete. We sequenced the entire mitochondrial genome and identified the previously reported 7510T>C transition in the tRNA(Ser(UCN)) gene. The 7510T>C was homoplasmic in all affected members. The LMG309 mitochondrial sequence belongs to an unnamed subgroup of mitochondrial haplogroup H. We demonstrate that the previously reported Spanish family S258 carries 7510T>C on a different mitochondrial sub-haplogroup, H1. We did not detect 7510T>C among 79 Caucasian haplogroup H control samples, including 11 from sub-haplogroup H1 and one from the same sub-haplogroup as LMG309. Our results provide strong genetic evidence that 7510T>C is a pathogenic mutation that causes non-syndromic SNHL.

Life-threatening ventricular arrhythmias due to transient or correctable causes: high risk for death in follow-up.

OBJECTIVES: This study evaluated the prognosis of patients resuscitated from ventricular tachycardia (VT) or ventricular fibrillation (VF) with a transient or correctable cause suspected as the cause of the VT/VF. BACKGROUND: Patients resuscitated from VT/VF in whom a transient or correctable cause has been identified are thought to be at low risk for recurrence and often receive no primary treatment for their arrhythmias. METHODS: In the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, patients with a potentially transient or correctable cause of VT/VF were not eligible for randomization. The mortality of these patients was compared with the mortality of patients with a known high risk of recurrence of VT/VF in the AVID registry. RESULTS: Compared with patients having high risk VT/VF, those with a transient or correctable cause for their presenting VT/VF were younger and had a higher left ventricular ejection fraction. These patients were more often treated with revascularization as the primary therapy, more commonly received a beta-blocker, less often required therapy for congestive heart failure and less commonly received either an antiarrhythmic drug or an implantable cardioverter defibrillator. Nevertheless, subsequent mortality of patients with a transient or correctable cause of VT/VF was no different or perhaps even worse than that of the primary VT/VF population. CONCLUSIONS: Patients identified with a transient or correctable cause for their VT/VF remain at high risk for death. Further research is needed to define truly reversible causes of VT/VF. Meanwhile, these patients may require more aggressive evaluation, treatment and follow-up than is currently practiced.

Single catheter determination of local electrogram prematurity using simultaneous unipolar and bipolar recordings to replace the surface ECG as a timing reference.

Bipolar recordings eliminate much of the far-field signal, while minimally filtered unipolar recordings contain substantial far-field signal components. These properties may allow the onset of the unipolar recording to serve as a timing reference for the bipolar recording obtained from the same electrode catheter during mapping of focal atrial or ventricular tachycardias. Mapping and RF ablation were performed in 26 patients with focal ventricular tachycardia and 14 patients with focal atrial tachycardia. At 205 mapping sites, simultaneous recordings of (1) minimally filtered unipolar electrograms (0.5-500 Hz), (2) high pass filtered unipolar electrograms (100 Hz), and (3) filtered bipolar recordings (30-500 Hz) were analyzed. The interval between the onset of the minimally filtered unipolar electrogram and the first peak of the bipolar electrogram (UniOn-BiP) correlated closely with the timing of the local electrogram referenced to the surface ECG (r = 0.85, P < 0.001). Of 53 sites where RF ablation was performed, UniOn-BiP was shorter at successful compared to unsuccessful sites (3.8 +/- 3.5 vs 9.2 +/- 5.2 ms, P < 0.001) and was < 15 ms at all successful sites. In conclusion, the comparison of simultaneous unipolar and bipolar electrograms from a single catheter allows assessment of the prematurity of local electrograms from a focal source without the use of the P wave or QRS onset as a timing reference.

Multi atrial maco-re-entry circuits in adults with repaired congenital heart disease: entrainment mapping combined with three-dimensional electroanatomic mapping.

OBJECTIVES: We sought to characterize re-entry circuits causing intra-atrial re-entrant tachycardias (IARTs) late after the repair of congenital heart disease (CHD) and to define an approach for mapping and ablation, combining anatomy, activation sequence data and entrainment mapping. BACKGROUND: The development of IARTs after repair of CHD is difficult to manage and ablate due to complex anatomy, variable re-entry circuit locations and the frequent co-existence of multiple circuits. METHODS: Forty-seven re-entry circuits were mapped in 20 patients with recurrent IARTs refractory to medical therapy. In the first group (n = 7), ablation was guided by entrainment mapping. In the second group (n = 13), entrainment mapping was combined with a three-dimensional electroanatomic mapping system to precisely localize the scar-related boundaries of re-entry circuits and to reconstruct the activation pattern. RESULTS: Three types of right atrial macro-re-entrant circuits were identified: those related to a lateral right atriotomy scar (19 IARTs), the Eustachian isthmus (18 IARTs) or an atrial septal patch (8 IARTs). Two IARTs originated in the left atrium. Radiofrequency (RF) lesions were applied to transect critical isthmuses in the right atrium. In three patients, the combined mapping approach identified a narrow isthmuses in the lateral atrium, where the first RF lesion interrupted the circuit; the remaining circuits were interrupted by a series of RF lesions across a broader path. Overall, 38 (81%) of 47 IARTs were successfully ablated. During follow-up ranging from 3 to 46 months, 16 (80%) of 20 patients remained free of recurrence. Success was similar in the first 7 (group 1) and last 13 patients (group 2), but fluoroscopy time decreased from 60 +/- 30 to 24 +/- 9 min/procedure, probably related to the increasing experience and ability to monitor catheter position non-fluoroscopically. CONCLUSIONS: Entrainment mapping combined with three-dimensional electroanatomic mapping allows delineation of complex re-entry circuits and critical isthmuses as targets for ablation. Radiofrequency catheter ablation is a reasonable option for treatment of IARTs related to repair of CHD.

Saline-cooled versus standard radiofrequency catheter ablation for infarct-related ventricular tachycardias.

BACKGROUND: Saline cooling of the electrode during radiofrequency (RF) ablation increases lesion size in animal models. If cooled RF also increases lesion size in human infarcts, it should facilitate the termination of ventricular tachycardia (VT). METHODS AND RESULTS: In 66 patients with VT due to prior infarction, 366 ablation sites, which were classified by entrainment and isolated potentials followed by ablation during VT with either standard RF energy (247 sites) or cooled RF (119 sites), were retrospectively reviewed to compare the efficacy for terminating VT. RF energy was applied at 259 isthmus sites, 62 bystander sites, 28 inner loop sites, and 17 outer loop sites. Compared with standard RF, cooled RF terminated VT more frequently at isthmus sites where an isolated potential was present (89% versus 54%, P=0.003), isthmus sites without an isolated potential (36% versus 21%, P=0.04), and at inner loop sites (60% versus 22%, P=0.04). Termination rates were similarly low for cooled and standard RF at bystander sites (14% versus 9%, P=0.56) and outer loop sites (13% versus 11%, P=0.93). CONCLUSIONS: Greater efficacy of cooled RF for terminating VT is consistent with the production of a larger lesion in human infarctions, which should facilitate successful ablation.

The N + 1 difference: a new measure for entrainment mapping.

OBJECTIVES: The purpose of this study was to develop and test a new entrainment mapping measurement, the N + 1 difference. BACKGROUND: Entrainment mapping is useful for identifying re-entry circuit sites but is often limited by difficulty in assessing: 1) changes in QRS complexes or P-waves that indicate fusion, and 2) the postpacing interval (PPI) recorded directly from the stimulation site. METHODS: In computer simulations of re-entry circuits, the interval from a stimulus that reset tachycardia to a timing reference during the second beat after the stimulus was compared with the timing of local activation at the site during tachycardia to define an interval designated the N + 1 difference. The N + 1 difference was compared with the PPI-tachycardia cycle length (TCL) difference in simulations and at 65 sites in 10 consecutive patients with ventricular tachycardia (VT) after myocardial infarction and at 45 sites in 10 consecutive patients with atrial flutter. RESULTS: In simulations, the N + 1 difference was equal to the PPI-TCL difference. During mapping of VT and atrial flutter, the N + 1 difference correlated well with the PPI-TCL difference (r > or = 0.91, p < 0.0001), identifying re-entry circuit sites with sensitivity of > or = 86% and specificity of > or = 90%. Accuracy was similar using either the surface electrocardiogram or an intracardiac electrogram (Eg) as the timing reference. CONCLUSIONS: The N + 1 difference allows entrainment mapping to be used to identify re-entry circuit sites when it is difficult to evaluate Egs at the mapping site or fusion in the surface electrocardiogram.

Identification of left atrial origin of ectopic tachycardia during right atrial mapping: analysis of double potentials at the posteromedial right atrium.

INTRODUCTION: The high posteromedial right atrium is adjacent to the left atrium near the right superior pulmonary vein. We hypothesized that analysis of electrograms at this site could distinguish left from right atrial tachycardia. METHODS AND RESULTS: Atrial mapping was performed in 16 patients with left atrial origin ectopic tachycardia (11 patients with right superior pulmonary vein origin and 5 patients with other left atrial tachycardias). During left atrial tachycardia, earliest right atrial activation was recorded at the high posterior right atrium in 14 of 16 patients. At all of these 14 early sites, double potentials were recorded during tachycardia. The first potential was a far-field signal from left atrium as indicated by the following: (1) during sinus beats, the timing of the two potentials reversed such that the left atrial one was late; (2) ablation at the right atrial site did not decrease the amplitude of the first potential, but did decrease the amplitude of the second potential; and (3) the timing of activation at the adjacent left atrium agreed with that of the first potential. In the 11 right superior pulmonary vein tachycardias, the first potential was markedly earlier than the p wave onset, but in left atrial tachycardias with other origins it was later. In a control group of six patients with pacing to simulate right atrial tachycardia, double potentials were recorded in the posterior right atrium, but the timing of components did not reverse during sinus rhythm. CONCLUSION: For some left atrial ectopic tachycardias, particularly those originating from the right superior pulmonary vein, recognition of left versus right atrial origin can be accomplished during right atrial mapping by analysis of double potentials in the posteromedial right atrium.

A comparison of biphasic and monophasic shocks for external defibrillation. Physio-Control Biphasic Investigators.

BACKGROUND AND OBJECTIVE: The ability of a shock to defibrillate the heart depends on its waveform and energy. Past studies of biphasic truncated exponential (BTE) shocks for external defibrillation focused on low energy levels. This prospective, randomized, double-blind clinical trial compared the first-shock efficacies of 200-joule (J) BTE, 130-J BTE, and 200-J monophasic damped sine wave shocks. METHODS: Ventricular fibrillation (VF) was induced in 115 patients during evaluation of implantable cardioverter-defibrillator function and 39 patients during electrophysiologic evaluation of ventricular arrhythmias. After 19 +/- 10 seconds of VF, a randomized transthoracic shock was administered. Mean first-shock success rates of the three groups were compared using a "Tukey-like" statistical test, adjusting for multiple comparisons. Blood pressures and arterial oxygen saturations were measured before VF induction and 30, 90, and 150 seconds after successful defibrillation. RESULTS: First-shock success rates were 61/68 (90%) for 200-J monophasic, 39/39 (100%) for 200-J biphasic, and 39/47 (83%) for 130-J biphasic shocks. The 200-J biphasic shocks were simultaneously superior in first-shock efficacy to both 200-J monophasic and 130-J biphasic shocks (experimentwise error rate, alpha < 0.01). There was no significant difference between the efficacies of 200-J monophasic and 130-J biphasic shocks, nor was there any significant difference between the three groups in hemodynamic parameters after successful shocks. CONCLUSIONS: Biphasic shocks of 200 J provide better first-shock defibrillation efficacy for short-duration VF than 200-J monophasic and 130-J biphasic shocks and thus may allow earlier termination of VF in cardiac arrest patients.

Advantages and disadvantages of trial designs: a review of analysis methods for ICD studies. AVID Investigators.

General modalities of analyses that have been used for ICD studies are reviewed. Published "typical" examples are briefly described. The historical cohort method is exemplified with previously unpublished data from the Seattle Cardiac Arrest Survivor database. The AVID Study database is used to compare the results obtained from nonrandomized methodologies with randomized methodologies. Particular issues related to the use of the ICD for example, mode of death, inability to blind, selection practice, and treatment decision times make this a natural pedagogic platform.

Mapping and radiofrequency catheter ablation of the three types of sustained monomorphic ventricular tachycardia in nonischemic heart disease.

INTRODUCTION: Sustained monomorphic ventricular tachycardia (VT) associated with nonischemic cardiomyopathy (CMP) is uncommon. Optimal approaches to catheter mapping and ablation are not well characterized, but they are likely to depend on the VT mechanism. The purpose of this study was to evaluate the mechanisms of sustained monomorphic VT encountered in nonischemic CMP and to assess the feasibility, safety, and efficacy of catheter radiofrequency ablation for treatment. METHODS AND RESULTS: Twenty-six consecutive patients with nonischemic CMP referred for management of recurrent VT were studied. In 16 (62%) patients, VT was related to a region of abnormal electrograms consistent with scar and the response to pacing suggested a reentrant mechanism. In 5 (19%) patients, VT was due to bundle branch or interfascicular reentry. In 7 (27%) patients, the VT mechanism was focal automaticity, 4 of whom had evidence of tachycardia-induced CMP. After catheter ablation targeting parts of reentrant circuits, VT was not inducible in 8 (53%) of 15 patients with scar-related reentry, was modified in 5 (33%) patients, and still was inducible in 2 (13%) patients. Ablation was successful in 5 of 5 patients with bundle branch reentry and in 6 of 7 patients with a focal automaticity mechanism. Overall, catheter ablation abolished clinical recurrence of VT in 20 (77%) of 26 patients during a follow-up of 15 +/- 12 months. CONCLUSION: Three different mechanisms of VT are encountered in patients with nonischemic CMP. The mapping and ablation approach varies with the type of VT. In this selected population, the overall efficacy was 77%.

Catheter ablation for hemodynamically unstable monomorphic ventricular tachycardia.

INTRODUCTION: Hemodynamic collapse precludes extensive catheter mapping to identify focal target regions in many patients with ventricular tachycardia (VT) associated with heart disease. This study tested the feasibility of catheter ablation of poorly tolerated VTs by targeting a region identified during sinus rhythm. METHODS AND RESULTS: Ablation was attempted in five patients, ages 44 to 59 years, with left ventricular ejection fractions of 0.15 to 0.20 and poorly tolerated VT causing multiple implantable defibrillator therapies (6 to 30 episodes/month). VT was due to prior infarction in three patients and nonischemic cardiomyopathy in two. Target regions were sought that met the following criteria: (1) evidence of slow conduction from fractionated sinus rhythm electrograms and stimulus-QRS delays during pace mapping, and (2) evidence that the region contains the reentrant circuit exit from pace mapping. In 4 of 5 patients, a target region was identified and radiofrequency lesions applied. Ablation abolished all recurrences of VT in 3 of 4 patients during follow-up of 14 to 22 months. There were no complications. CONCLUSION: Ablation of poorly tolerated VT is feasible in some patients by mapping during sinus rhythm and performing ablation over a region of identifiable scar that contains abnormal conduction and a presumptive VT exit.

DDD-pacing-induced cardiomyopathy following AV node ablation for persistent atrial tachycardia.

Ventricular rate control by catheter ablation of the AV node and pacing in patients with persistent atrial tachycardia has been reported to improve left ventricular function. However, this approach requires careful selection of the pacing mode. We report a patient who underwent AV node ablation for persistent multiple atrial tachycardias, and who then had a non-mode-switching pacemaker implanted. Because of an inappropriately programmed relatively high upper rate limit, the patient developed left ventricular dysfunction after 6 years. This resolved after programming the pacemaker to VVI at 70 bpm.

Characteristics of electrograms recorded at reentry circuit sites and bystanders during ventricular tachycardia after myocardial infarction.

OBJECTIVES: The purpose of this study was to determine the relation of isolated potentials (IPs) recorded during ventricular tachycardia (VT) to reentry circuit sites identified by entrainment. BACKGROUND: Reentry circuits causing VT late after myocardial infarction are complex. Both IPs and entrainment have been useful for identifying successful ablation sites, but the relation of IPs to the location in the reentry circuit as determined by entrainment has not been completely defined. METHODS: Data from catheter mapping of 70 monomorphic VTs in 36 patients with prior myocardial infarction were retrospectively analyzed. Entrainment followed by radiofrequency current (RF) ablation was performed at 384 sites. On the basis of entrainment, sites were classified as reentry circuit exit, central-proximal, inner or outer loop sites. Sites outside the circuit were divided into remote and adjacent bystanders. RESULTS: Isolated potentials were recorded at 50% (51 of 101) of reentry circuit exit, central and proximal sites as compared with only 8% (11 of 146, p < 0.001) of inner loop and outer loop sites and only 1.8% (2 of 106) of remote bystander sites (p < 0.001). Isolated potentials were also present at 45% of adjacent bystander sites. At central and proximal sites the presence of an IP increased the incidence of tachycardia termination by RF to 47.5% from 24% (p = 0.05). At exit sites tachycardia termination occurred frequently regardless of the presence or absence of IPs (45% vs. 48%, p = NS). Isolated potentials at exit, central and proximal sites had a shorter duration at sites where ablation terminated VT than at sites without termination (20.9 +/- 9.6 ms vs. 35.7 +/- 15.3 ms, p < 0.001). CONCLUSIONS: Isolated potentials are a useful guide to sites in the central-proximal region of the reentry circuit, but often fail to identify exit sites where ablation is successful. Entrainment and analysis of electrograms provide complementary information during mapping of VT.

Ablation of ventricular tachycardia with a saline-cooled radiofrequency catheter: anatomic and histologic characteristics of the lesions in humans.

INTRODUCTION: In animal models, active cooling of the electrode during radiofrequency (RF) ablation allows creation of larger lesions, presumably by increasing the power that can be delivered without coagulum formation. These RF lesions have not been characterized in human myocardium in regions of infarction and scarring. METHODS AND RESULTS: Cooled-tip RF catheter ablation of ventricular tachycardias (VTs) was performed in two patients who had severe congestive heart failure and subsequently underwent cardiac transplantation. The first patient had four different monomorphic VTs. RF applications along the inferoseptal margin of a scarred region abolished all inducible VTs. The second patient had sarcoidosis involving the myocardium and four different inducible VTs. RF current applied at an inferobasal VT exit and at the right and left septa failed to abolish the VTs. The explanted hearts were examined at the time of cardiac transplantation 18 and 21 days later, respectively. Lesions extended to depths up to 7 mm, reaching clusters of myocardial cells deep to regions of fibrosis. Microscopically, the ablation sites contained coagulation necrosis with hemorrhage, surrounded by a rim of granulation tissue. CONCLUSION: Saline-irrigated RF catheter ablation produces relatively large lesions capable of penetrating deep into scarred myocardium.