Early biochemical indicators of the obliterative bronchiolitis syndrome in lung transplantation

The diagnosis of the obliterative bronchiolitis syndrome in lung transplantation is presently best established by evaluation of postoperative lung function tests. Unfortunately the decline in lung function occurs only when obliteration has progressed significantly and is therefore not an early predictive indicator. To distinguish patients at increased risk for the development of obliterative bronchiolitis, we regularly assessed the chemiluminescence response of polymorphonuclear leukocytes, opsonic capacity, and plasma elastase/beta-N-acetylglucosaminidase in 52 outpatients (25 women and 27 men; mean age 45 +/- 12 years) who underwent transplantation between January 1991 and January 1992. Recent onset bronchiolitis within the described observation period occurred in 16 patients (group obliterative bronchiolitis). A matched cohort of 16 patients was formed according to type of procedure, age and follow-up (control) from the remaining 36 patients. Data obtained from a period 6 months before clinical onset of the syndrome showed a significant drop of the opsonic capacity (group obliterative bronchiolitis = 87% +/- 7%; control = 100% +/- 9%; p < 0.023) and rise of the N-acetyl-D-glucosaminidase (group obliterative bronchiolitis = 7.5 +/- 2 U/L; control = 5.8 +/- 1.8 U/L; p < 0.04). No correlation was found between the number of infectious events or rejection episodes and the incidence of obliterative bronchiolitis. According to these results, it can be concluded that a decrease in the plasma opsonic capacity and a rise in beta-N-acetylglucosaminidase may be early markers before clinical onset of obliterative bronchiolitis. The nonspecific immune system may therefore play an important role in the development of obliterative bronchiolitis.

University of Wisconsin versus St. Thomas' Hospital solution for human donor heart preservation

Prolongation of the safe period of ischemia of the heart is an efficient way to overcome donor organ shortage, as demonstrated in renal and hepatic transplantation. We present the results of a prospective, randomized study comparing preservation with University of Wisconsin solution (UWS) versus St. Thomas' Hospital solution (STS) in clinical heart transplantation. A total of 39 patients were enrolled in the study (n = 20 for UWS and n = 19 for STS). Hemodynamic, electron microscopic, and biochemical evaluation did not reveal any significant differences in postoperative myocardial performance. Only the number of intraoperative defibrillations (0.82 for UWS versus 1.7 for STS) and the rhythm stability after reperfusion (13/20 UWS hearts versus 6/19 STS hearts in sinus rhythm) were significantly different. Heart preservation with UWS and STS appears to be of comparable efficacy at mean ischemic times of less than 4 hours.

Long-term outcome of ablative therapy of postoperative supraventricular tachycardias in patients with univentricular heart: a European multicenter study

BACKGROUND: Catheter ablation has evolved as a possible curative treatment modality for supraventricular tachycardias (SVT) in patients with univentricular heart. However, the long-term outcome of ablation procedures is unknown. We evaluated the procedural and long-term outcome of ablative therapy of late postoperative SVT in patients with univentricular heart. METHODS AND RESULTS: Patients with univentricular heart (n=19, 11 male; age, 29+/-9 years) referred for ablation of SVT were studied. Ablation was guided by 3D electroanatomic mapping in all but 2 procedures. A total of 41 SVT were diagnosed as intra-atrial reentrant tachycardia (n=30; cycle length, 310+/-68 ms), typical atrial flutter (n=4; cycle length, 288+/-42 ms), focal atrial tachycardia (n=6; cycle length, 400+/-60 ms), and atrial fibrillation (n=1). Ablation was successful in 73% of intra-atrial reentrant tachycardia, 75% of atrial flutter, and all focal atrial tachycardia and focal atrial fibrillation. During the follow-up period of 53+/-34 months, 2 patients were lost to follow-up, 3 died of heart failure, 2 underwent heart transplantation, and 1 underwent conduit replacement. Of the remaining group, 8 had sinus rhythm and 3 had SVT. CONCLUSIONS: Focal and reentrant mechanisms underlie postoperative SVT in patients with univentricular heart. Successive SVT developing over time may be caused by different mechanisms. Ablative therapy is potentially curative, with a procedural success rate of 78%. In patients who had multiple ablation procedures, the SVT originated from different atrial sites, suggesting that these new SVT were caused by progressive atrial disease. Despite recurrent SVT, sinus rhythm at the end of the follow-up period was achieved in 72%.

Ventricular tachycardia in a Brugada syndrome patient caused by a novel deletion in SCN5A

The aim of the present study was to identify the molecular mechanism behind ventricular tachycardia in a patient with Brugada syndrome. Arrhythmias in patients with Brugada syndrome often occur during sleep. However, a 28-year-old man with no previously documented arrhythmia or syncope who experienced shortness of breath and chest pain during agitation is described. An electrocardiogram revealed monomorphic ventricular tachycardia; after he was converted to nodal rhythm, he spontaneously went into sinus rhythm, and showed classic Brugada changes with coved ST elevation in leads V(1) to V(2). Mutation analysis of SCN5A revealed a novel mutation, 3480 deletion T frame shift mutation, resulting in premature truncation of the protein. Heterologous expression of this truncated protein in human embryonic kidney 293 cells showed a markedly reduced protein expression level. By performing whole-cell patch clamp experiments using human embryonic kidney 293 cells transfected with the mutated SCN5A, no current could be recorded. Hence, the results suggest that the patient suffered from haploinsufficiency of Na(v)1.5, and that this mutation was the cause of his Brugada syndrome.

[The patent nasopalatine duct. A rare anomaly and diagnostic pitfall]

The patent nasopalatine duct is a rare anomaly in the anterior maxilla. During the early fetal period, a bilateral and epithelium-lined duct is formed within the primary palatal process as an oro-nasal communication. However, the duct obliterates and degenerates before birth. A persisting patent or through-and-through nasoplatine duct is therefore considered a developmental anomaly. A patent nasopalatine duct normally presents as one (or two) tiny openings lateral or posterior to the incisive papilla. In such a case, the ducts can be partially or completely probed with gutta-percha points with subsequent radiographic imaging. The patients report strange sensations such as squeaking noise, palatal drainage, nasal regurgitation, or airway communication between nasal and oral cavities; however, patients rarely complain about pain. About 40 cases have been documented in the literature. We describe two patients who have been referred to our department for evaluation of "sinus tracts" in the anterior palate. Since a patent nasopalatine duct can become a diagnostic pitfall, a thorough inspection of the mucosa around the incisive papilla is essential to avoid unnecessary endodontic or surgical interventions in the area of the central maxillary incisors.

Prosthetically driven, computer-guided implant planning for the edentulous maxilla: a model study

OBJECTIVES: To analyze computer-assisted diagnostics and virtual implant planning and to evaluate the indication for template-guided flapless surgery and immediate loading in the rehabilitation of the edentulous maxilla. MATERIALS AND METHODS: Forty patients with an edentulous maxilla were selected for this study. The three-dimensional analysis and virtual implant planning was performed with the NobelGuide software program (Nobel Biocare, Göteborg, Sweden). Prior to the computer tomography aesthetics and functional aspects were checked clinically. Either a well-fitting denture or an optimized prosthetic setup was used and then converted to a radiographic template. This allowed for a computer-guided analysis of the jaw together with the prosthesis. Accordingly, the best implant position was determined in relation to the bone structure and prospective tooth position. For all jaws, the hypothetical indication for (1) four implants with a bar overdenture and (2) six implants with a simple fixed prosthesis were planned. The planning of the optimized implant position was then analyzed as follows: the number of implants was calculated that could be placed in sufficient quantity of bone. Additional surgical procedures (guided bone regeneration, sinus floor elevation) that would be necessary due the reduced bone quality and quantity were identified. The indication of template-guided, flapless surgery or an immediate loaded protocol was evaluated. RESULTS: Model (a) - bar overdentures: for 28 patients (70%), all four implants could be placed in sufficient bone (total 112 implants). Thus, a full, flapless procedure could be suggested. For six patients (15%), sufficient bone was not available for any of their planned implants. The remaining six patients had exhibited a combination of sufficient or insufficient bone. Model (b) - simple fixed prosthesis: for 12 patients (30%), all six implants could be placed in sufficient bone (total 72 implants). Thus, a full, flapless procedure could be suggested. For seven patients (17%), sufficient bone was not available for any of their planned implants. The remaining 21 patients had exhibited a combination of sufficient or insufficient bone. DISCUSSION: In the maxilla, advanced atrophy is often observed, and implant placement becomes difficult or impossible. Thus, flapless surgery or an immediate loading protocol can be performed just in a selected number of patients. Nevertheless, the use of a computer program for prosthetically driven implant planning is highly efficient and safe. The three-dimensional view of the maxilla allows the determination of the best implant position, the optimization of the implant axis, and the definition of the best surgical and prosthetic solution for the patient. Thus, a protocol that combines a computer-guided technique with conventional surgical procedures becomes a promising option, which needs to be further evaluated and improved.

Nervous system dysfunction in Henoch-Schonlein syndrome: systematic review of the literature

OBJECTIVE: CNS or peripheral nervous system dysfunction sometimes occurs in Henoch-Schönlein patients. METHODS: We review all Henoch-Schönlein cases published after 1969 with CNS dysfunction without severe hypertension and neuroimaging studies (n = 35), cranial or peripheral neuropathy (n = 15), both CNS and peripheral nervous system dysfunction without severe hypertension (n = 2) or nervous system dysfunction with severe hypertension (n = 2). Forty-four of the 54 patients were <20 years of age. RESULTS: In patients with CNS dysfunction without or with severe hypertension the following presentations were observed in decreasing order of frequency: altered level of consciousness, convulsions, focal neurological deficits, visual abnormalities and verbal disability. Imaging studies disclosed the following lesions: vascular lesions almost always involving two or more vessels, intracerebral haemorrhage, posterior subcortical oedema, diffuse brain oedema and thrombosis of the superior sagittal sinus. Following lesions were noted in the subjects with cranial or peripheral neuropathy without severe hypertension: peroneal neuropathy, peripheral facial palsy, Guillain-Barré syndrome, brachial plexopathy, posterior tibial nerve neuropathy, femoral neuropathy, ulnar neuropathy and mononeuritis multiplex. Persisting signs of either CNS (n = 9) or peripheral (n = 1) nervous system dysfunction were sometimes reported. CONCLUSIONS: In Henoch-Schönlein syndrome, signs of nervous system dysfunction are uncommon but clinically relevant. This review helps clinicians managing Henoch-Schönlein syndrome with nervous system dysfunction.

Effects of Novel Growth Hormone Secretagogues on Growth Hormone Secretion in Farm Animals

The requirement for growth hormone (GH) secretion by the anterior pituitary gland in beef calves is demonstrated by a complete lack of long bone-growth and muscle accretion after hypophysectomy (surgical removal of the pituitary gland). When the connecting link (hypophyseal stalk) to the basal region (hypothalamus) of the brain is surgically severed, long bone growth and body weight gain are greatly limited compared with sham-operated controls. This limited growth results from obliteration of episodic GH secretion and reduced basal blood concentration of the hormone compared with sham-operated controls. Thus, the hypophyseal stalk-transected (HST) calf provides an appropriate model to determine mechanisms by which hypothalamic neuropeptides from the brain regulate GH secretion, and thereby growth in the young calf. Neuropeptides have been isolated and characterized in bovine hypothalamus that stimulate GH secretion (GH-releasing hormone [GHRH]) or factor [GHRF] and inhibit GH secretion (GH release-inhibiting hormone [GHRIH] or somatostatin [SRIH]). A dose of .067 micrograms of GHRF per kilogram of body weight injected intravenously in HST calves abruptly increased plasma GH concentration to 55 nanograms per milliliter from the control period mean of 5 nanograms per milliliter. HST calves then were infused intravenously with .033 and .067 microgram somatostatin per kilogram of body weight, during which a pulse injection of .067 microgram of GHRF was administered. GH increase was limited to 9 and 5 micrograms per kilogram body weight during the .033- and .067 microgram SRIH infusions after GHRF; no GH rebound was observed after the SRIH was discontinued. GHRF from humans contains 40 to 44 amino acids. Rat hypothalamic GHRF analogs containing 29 to 32 amino acids elicited dose-dependent GH peak release in these HST calves. In 1977, Bowers and Monomy isolated novel GH releasing peptides consisting of only six amino acids; they caused GH release by isolated pituitary cells in culture and acute GH release when administered intravenously. We recently have utilized a novel nonpeptidyl GH secretagogue of low molecular weight in the pig to determine its mechanisms of action within the central nervous system.

Anatomical characteristics and dimensions of edentulous sites in the posterior maxillae of patients referred for implant therapy

The purpose of this study was to analyze the width and height of edentulous sites in the posterior maxilla using cone beam computed tomography (CBCT) images from patients referred for implant therapy. A total of 122 CBCT scans were included in the analysis, resulting in a sample size of 252 edentulous sites. The orofacial crest width was measured in coronal slices, perpendicular to the alveolar ridge. The bone height was analyzed in the respective sagittal slices. Additionally, the following secondary outcome parameters were evaluated: the morphology of the sinus floor, the presence of septa in the maxillary sinus, and the thickness of the sinus membrane. The mean crest width for all analyzed sites was 8.28 mm, and the mean bone height was 7.22 mm. The percentage of patients with a crest width of less than 6 mm was 27% in premolar sites and 7.8% in molar sites. The bone height decreased from premolar to molar areas, with a high percentage of first and second molar sites exhibiting a bone height of less than 5 mm (54.12% and 44.64%, respectively). Regarding the morphology of the sinus floor, 53% of the edentulous sites exhibited a flat configuration. A septum was present in 67 edentulous sites (26.59%). Analysis of the sinus membrane revealed 88 sites (34.9%) with increased mucosal thickness (> 2 mm). For the crest width, the location of the edentulous site and the morphology of the sinus floor were both statistically significant variables. For the crest width and mean bone height, the location of the edentulous site and the morphology of the sinus floor were both statistically significant variables. The study confirmed that a high percentage of edentulous sites in the posterior maxilla do require sinus floor elevation to allow the placement of dental implants. Therefore, a detailed three-dimensional radiograph using CBCT is indicated in most patients for proper treatment planning.

Dimensions of the Ascending Aorta in Conotruncal Heart Defects

Dilatation of the ascending aorta is an important sequel in conotruncal anomalies, such as tetralogy of Fallot (TOF) or d-transposition of the great arteries (TGA). We measured dimensions and their progression at different levels of the ascending aorta in 80 patients. In TOF patients, mean z-score for aortic annulus was 1.65 (range -3.16-6.47), for sinus 1.93 (range -2.28-5.39), for st-junction 4.15 (range 0.0-8.18), and for ascending aorta 3.51 (range -1.23-6.36). Over time, annulus z-scores increased in the univariate analysis [0.07/year, 95 % confidence interval (CI) 0.01-0.14; p = 0.02], and this was unique to male patients (0.08/year, 95 % CI 0.00-0.15; p = 0.05). z-scores of the ascending aorta decreased (-0.1/year, 95 % CI -0.18 to -0.02; p = 0.02), and this was confined to patients without aortic regurgitation (AR; -0.09/year, 95 % CI -0.18 to -0.01; p = 0.04). In TGA, mean z-score for the aortic annulus was 2.13 (range -3.71-8.39), for sinus 1.77 (range -3.04-6.69), for st-junction 1.01 (range -5.44-6.71), and for ascending aorta 0.82 (range -4.91-6.46). In bivariate analysis, annulus z-scores decreased in females (-0.14/year, 95 % CI -0.25 to -0.03; p = 0.01) and in patients without AR (-0.07/year, 95 % CI -0.14-0.0; p = 0.03). z-scores of the ascending aorta increased significantly in males (0.08/year, 95 % CI 0.0 to 0.16; p = 0.05) and in patients with AR (0.12/year, 95 % CI 0.03-0.21; p = 0.01). In conclusion, TOF and TGA z-scores of the ascending aorta differ significantly from those of the normal population. Progression of z-scores over time is influenced by diagnosis, sex, and presence of AR.

Electrophysiologic characterization of local abnormal ventricular activities in postinfarction ventricular tachycardia with respect to their anatomic location.

BACKGROUND Local abnormal ventricular activities (LAVA) in patients with scar-related ventricular tachycardia (VT) may appear at any time during or after the far-field electrogram. Although they may be separated from the far-field signal by an isoelectric line and extend beyond the end of surface QRS, they may also appear fused or buried within the QRS. OBJECTIVE The purpose of this study was to characterize LAVA in postinfarction VT patients with respect to their anatomic locations. METHODS Thirty-one patients with postinfarction VT underwent mapping/ablation during sinus rhythm with a three-dimensional electroanatomic mapping system. From a total of 18,270 electrograms reviewed in all study subjects, 1104 LAVA (endocardium 839, epicardium 265) were identified and analyzed. RESULTS The interval from onset of QRS complex to ventricular electrogram (EGM onset) on the endocardium was significantly shorter than the epicardium (P < .001). EGM onset was shortest in the septal endocardium and longest in the inferior and lateral epicardium. There was a significant positive correlation between EGM onset and LAVA lateness as estimated by the interval from surface QRS onset to LAVA (r = 0.52, P < .001). LAVA were more frequently detected after the QRS complex in the epicardium (241/265 [91%]) than in the endocardium (551/839 [66%], P < .001). Only 43% of endocardial septal LAVA were detected after the QRS complex. CONCLUSION Lateness of LAVA is affected to a large extent by their locations. The chance of detecting late LAVA increases when electrogram onset is later. Substrate-based approach targeting delayed signals relative to the QRS complex may miss critical the arrhythmogenic substrate, particularly in the septum and other early-to-activate regions.

Validation of novel 3-dimensional electrocardiographic mapping of atrial tachycardias by invasive mapping and ablation: a multicenter study

OBJECTIVES This study prospectively evaluated the role of a novel 3-dimensional, noninvasive, beat-by-beat mapping system, Electrocardiographic Mapping (ECM), in facilitating the diagnosis of atrial tachycardias (AT). BACKGROUND Conventional 12-lead electrocardiogram, a widely used noninvasive tool in clinical arrhythmia practice, has diagnostic limitations. METHODS Various AT (de novo and post-atrial fibrillation ablation) were mapped using ECM followed by standard-of-care electrophysiological mapping and ablation in 52 patients. The ECM consisted of recording body surface electrograms from a 252-electrode-vest placed on the torso combined with computed tomography-scan-based biatrial anatomy (CardioInsight Inc., Cleveland, Ohio). We evaluated the feasibility of this system in defining the mechanism of AT-macro-re-entrant (perimitral, cavotricuspid isthmus-dependent, and roof-dependent circuits) versus centrifugal (focal-source) activation-and the location of arrhythmia in centrifugal AT. The accuracy of the noninvasive diagnosis and detection of ablation targets was evaluated vis-à-vis subsequent invasive mapping and successful ablation. RESULTS Comparison between ECM and electrophysiological diagnosis could be accomplished in 48 patients (48 AT) but was not possible in 4 patients where the AT mechanism changed to another AT (n = 1), atrial fibrillation (n = 1), or sinus rhythm (n = 2) during the electrophysiological procedure. ECM correctly diagnosed AT mechanisms in 44 of 48 (92%) AT: macro-re-entry in 23 of 27; and focal-onset with centrifugal activation in 21 of 21. The region of interest for focal AT perfectly matched in 21 of 21 (100%) AT. The 2:1 ventricular conduction and low-amplitude P waves challenged the diagnosis of 4 of 27 macro-re-entrant (perimitral) AT that can be overcome by injecting atrioventricular node blockers and signal averaging, respectively. CONCLUSIONS This prospective multicenter series shows a high success rate of ECM in accurately diagnosing the mechanism of AT and the location of focal arrhythmia. Intraprocedural use of the system and its application to atrial fibrillation mapping is under way.

Regional myocardial wall thinning at multidetector computed tomography correlates to arrhythmogenic substrate in postinfarction ventricular tachycardia: assessment of structural and electrical substrate

BACKGROUND A majority of patients undergoing ablation of ventricular tachycardia have implanted devices precluding substrate imaging with delayed-enhancement MRI. Contrast-enhanced multidetector computed tomography (MDCT) can depict myocardial wall thickness with submillimetric resolution. We evaluated the relationship between regional myocardial wall thinning (WT) imaged by MDCT and arrhythmogenic substrate in postinfarction ventricular tachycardia. METHODS AND RESULTS We studied 13 consecutive postinfarction patients undergoing MDCT before ablation. MDCT data were integrated with high-density 3-dimensional electroanatomic maps acquired during sinus rhythm (endocardium, 509±291 points/map; epicardium, 716±323 points/map). Low-voltage areas (<1.5 mV) and local abnormal ventricular activities (LAVA) during sinus rhythm were assessed with regard to the WT. A significant correlation was found between the areas of WT <5 mm and endocardial low voltage (correlation-R=0.82; P=0.001), but no such correlation was found in the epicardium. The WT <5 mm area was smaller than the endocardial low-voltage area (54 cm(2) [Q1-Q3, 46-92] versus 71 cm(2) [Q1-Q3, 59-124]; P=0.001). Among a total of 13 060 electrograms reviewed in the whole study population, 538 LAVA were detected and analyzed. LAVA were located within the WT <5 mm (469/538 [87%]) or at its border (100% within 23 mm). Very late LAVA (>100 ms after QRS complex) were almost exclusively detected within the thinnest area (93% in the WT<3 mm). CONCLUSIONS Regional myocardial WT correlates to low-voltage regions and distribution of LAVA critical for the generation and maintenance of postinfarction ventricular tachycardia. The integration of MDCT WT with 3-dimensional electroanatomic maps can help focus mapping and ablation on the culprit regions, even when MRI is precluded by the presence of implanted devices.

Integration of merged delayed-enhanced magnetic resonance imaging and multidetector computed tomography for the guidance of ventricular tachycardia ablation: a pilot study

BACKGROUND Delayed enhancement (DE) MRI can assess the fibrotic substrate of scar-related VT. MDCT has the advantage of inframillimetric spatial resolution and better 3D reconstructions. We sought to evaluate the feasibility and usefulness of integrating merged MDCT/MRI data in 3D-mapping systems for structure-function assessment and multimodal guidance of VT mapping and ablation. METHODS Nine patients, including 3 ischemic cardiomyopathy (ICM), 3 nonischemic cardiomyopathy (NICM), 2 myocarditis, and 1 redo procedure for idiopathic VT, underwent MRI and MDCT before VT ablation. Merged MRI/MDCT data were integrated in 3D-mapping systems and registered to high-density endocardial and epicardial maps. Low-voltage areas (<1.5 mV) and local abnormal ventricular activities (LAVA) during sinus rhythm were correlated to DE at MRI, and wall-thinning (WT) at MDCT. RESULTS Endocardium and epicardium were mapped with 391 ± 388 and 1098 ± 734 points per map, respectively. Registration of MDCT allowed visualization of coronary arteries during epicardial mapping/ablation. In the idiopathic patient, integration of MRI data identified previously ablated regions. In ICM patients, both DE at MRI and WT at MDCT matched areas of low voltage (overlap 94 ± 6% and 79 ± 5%, respectively). In NICM patients, wall-thinning areas matched areas of low voltage (overlap 63 ± 21%). In patients with myocarditis, subepicardial DE matched areas of epicardial low voltage (overlap 92 ± 12%). A total number of 266 LAVA sites were found in 7/9 patients. All LAVA sites were associated to structural substrate at imaging (90% inside, 100% within 18 mm). CONCLUSION The integration of merged MDCT and DEMRI data is feasible and allows combining substrate assessment with high-spatial resolution to better define structure-function relationship in scar-related VT.

Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A.

BACKGROUND Functional characterization of mutations involving the SCN5A-encoded cardiac sodium channel has established the pathogenic mechanisms for type 3 long QT syndrome and type 1 Brugada syndrome and has provided key insights into the physiological importance of essential structure-function domains. OBJECTIVE This study sought to present the clinical and biophysical phenotypes discerned from compound heterozygosity mutations in SCN5A on different alleles in a toddler diagnosed with QT prolongation and fever-induced ventricular arrhythmias. METHODS A 22-month-old boy presented emergently with fever and refractory ventricular tachycardia. Despite restoration of sinus rhythm, the infant sustained profound neurological injury and died. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open-reading frame/splice mutational analysis of the 12 known long QT syndrome susceptibility genes was performed. RESULTS The infant had 2 SCN5A mutations: a maternally inherited N-terminal frame shift/deletion (R34fs/60) and a paternally inherited missense mutation, R1195H. The mutations were engineered by site-directed mutagenesis and heterologously expressed transiently in HEK293 cells. As expected, the frame-shifted and prematurely truncated peptide, SCN5A-R34fs/60, showed no current. SCN5A-R1195H had normal peak and late current but abnormal voltage-dependent gating parameters. Surprisingly, co-expression of SCN5A-R34fs/60 with SCN5A-R1195H elicited a significant increase in late sodium current, whereas co-expression of SCN5A-WT with SCN5A-R34fs/60 did not. CONCLUSIONS A severe clinical phenotype characterized by fever-induced monomorphic ventricular tachycardia and QT interval prolongation emerged in a toddler with compound heterozygosity involving SCN5A: R34fs/60, and R1195H. Unexpectedly, the 94-amino-acid fusion peptide derived from the R34fs/60 mutation accentuated the late sodium current of R1195H-containing Na(V)1.5 channels in vitro.