Citations

Mutations in 11 genes that encode ion channels or their associated proteins cause inherited long QT syndrome (LQTS) and account for ≈75–80% of cases (LQT1–11). Direct sequencing of SNTA1 , the gene encoding α1-syntrophin, was performed in a cohort of LQTS patients that were negative for mutations in the 11 known LQTS-susceptibility genes. A missense mutation (A390V-SNTA1) was found in a patient with recurrent syncope and markedly prolonged QT interval (QTc, 530 ms). SNTA1 links neuronal nitric oxide synthase (nNOS) to the nNOS inhibitor plasma membrane Ca-ATPase subtype 4b (PMCA4b); SNTA1 also is known to associate with the cardiac sodium channel SCN5A. By using a GST-fusion protein of the C terminus of SCN5A, we showed that WT-SNTA1 interacted with SCN5A, nNOS, and PMCA4b. In contrast, A390V-SNTA1 selectively disrupted association of PMCA4b with this complex and increased direct nitrosylation of SCN5A. A390V-SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared with WT-SNTA1, and the increase was partially inhibited by NOS blockers. Expression of A390V-SNTA1 in cardiac myocytes also increased late sodium current. We conclude that the A390V mutation disrupted binding with PMCA4b, released inhibition of nNOS, caused S -nitrosylation of SCN5A, and was associated with increased late sodium current, which is the characteristic biophysical dysfunction for sodium-channel-mediated LQTS (LQT3). These results establish an SNTA1-based nNOS complex attached to SCN5A as a key regulator of sodium current and suggest that SNTA1 be considered a rare LQTS-susceptibility gene.

AbstractLeukemia-cell expression of ZAP-70, CD38, or unmutated immunoglobulin heavy chain variable region genes (U-IGHV) each is associated with aggressive disease in patients with chronic lymphocytic leukemia (CLL). To assess the relative strength of each marker, we defined thresholds for designating a case as positive for CD38 or ZAP-70 in a test cohort of 307 patients and used these data-defined criteria to stratify patients in an independent cohort of 705 patients. Multivariable analysis revealed that ZAP-70 was the strongest risk factor. Knowledge of the IGHV mutation status or CD38 did not improve our ability to predict the time to first treatment except for ZAP-70–negative cases, which could be segregated into 2 groups of intermediate-risk or low-risk disease based on whether they expressed unmutated or mutated IGHV. ZAP-70 maintained its high relative prognostic value for the subset of patients with early-stage, asymptomatic disease, including patients evaluated within 1 year of diagnosis. Although it is premature to recommend therapy based on these risk factors, patients with ZAP-70–positive CLL cells should be monitored closely for disease progression as they have a median time from diagnosis to requiring initial therapy by standard criteria of approximately 3 years.

Background— Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-α 1 (SNTA1) is known to interact with the cardiac sodium channel (hNa v 1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNa v 1.5 by secondarily disturbing sodium channel function. Methods and Results— Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc≥480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G- SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa v 1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation ( V h ) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1. Conclusion— SNTA1 is a new susceptibility gene for LQTS. A257G- SNTA1 can cause gain-of-function of Na v 1.5 similar to the LQT3.

Background: Studies have failed to show a survival difference between intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT). Comparative cost analyses are limited and fail to control for differences in patient disease severity and comorbid conditions. The authors retrospectively estimated clinical and economic outcomes associated with CRRT and IHD among critically ill patients experiencing acute renal failure (ARF) in 2 tertiary care hospitals in Rochester, Minnesota, between January 1, 2000, and December 12, 2001. Methods: 161 critically ill patients requiring dialysis for ARF were analyzed. Patient demo-graphics, comorbid conditions, ARF etiology, mode of renal replacement therapy (RRT), renal recovery, and survival were abstracted from medical chart. APACHE II scores at dialysis initiation were calculated. Administrative data tracked length of stay (LOS) and direct medical costs from initiation of RRT to death or intensive care unit (ICU) and hospital discharge. Multivariate modeling was used to adjust outcomes for baseline differences. Results: 84 (52%) of the patients received CRRT and 77 (48%) received IHD. CRRT-treated patients were younger (58 vs 65 years), less likely male (58% vs 77%), had higher APACHE II scores (32 vs 27) with a higher incidence of sepsis (46% vs 30%) and respiratory disease (56% vs 39%), and were less likely to have chronic renal insufficiency (32% vs 49%). With adjustment for differences in baseline patient characteristics, the RRT method did not affect the likelihood of renal recovery, in-hospital survival, or survival during follow-up. Mean adjusted ICU LOS was 9.5 days shorter for IHD-treated than CRRT-treated patients ( P < .001), and the adjusted mean difference in hospital and total costs associated with ICU stay was $56 564 and $60 827, in favor of IHD ( P < .001). Mean adjusted total costs through hospital discharge were $93 611 and $140 733 among IHD-treated and CRRT-treated patients, respectively ( P < .001). Conclusions: This observational study suggests that costs may significantly differ by mode of RRT despite similar severity-adjusted patient outcomes. Future prospective comparisons of renal replacement modalities will need to include both clinical and economic outcomes.

Background— Previous studies that assessed the risk of life-threatening cardiac events in patients with congenital long-QT syndrome (LQTS) have focused mainly on the first 4 decades of life, whereas the clinical course of this inherited cardiac disorder in the older population has not been studied. Methods and Results— The risk of aborted cardiac arrest or death from age 41 though 75 years was assessed in 2759 subjects from the International LQTS Registry, categorized into electrocardiographically affected (corrected QT interval [QTc] ≥470 ms), borderline (QTc 440 to 469 ms), and unaffected (QTc <440 ms) subgroups. The affected versus unaffected adjusted hazard ratio for aborted cardiac arrest or death was 2.65 ( P <0.001) in the age range of 41 to 60 years and 1.23 ( P =0.31) in the age range of 61 to 75 years. The clinical course of study subjects displayed gender differences: Affected LQTS women experienced a significantly higher cumulative event rate (26%) than borderline (16%) and unaffected (12%) women ( P =0.001), whereas event rates were similar among the 3 respective subgroups of men (29%, 26%, and 27%; P =0.16). Recent syncope (<2 years in the past) was the predominant risk factor in affected subjects (hazard ratio 9.92, P <0.001), and the LQT3 genotype was identified as the most powerful predictor of outcome in a subset of 871 study subjects who were genetically tested for a known LQTS mutation (hazard ratio 4.76, P =0.02). Conclusions— LQTS subjects maintain a high risk for life-threatening cardiac events after age 40 years. The phenotypic expression of affected subjects is influenced by age-specific factors related to gender, clinical history, and the LQTS genotype.

Background— The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified. Methods and Results— Cox proportional-hazards regression modeling was used to identify risk factors for aborted cardiac arrest or sudden cardiac death in 3015 LQTS children from the International LQTS Registry who were followed up from 1 through 12 years of age. The cumulative probability of the combined end point was significantly higher in boys (5%) than in girls (1%; P <0.001). Risk factors for cardiac arrest or sudden cardiac death during childhood included corrected QT interval [QTc] duration >500 ms (hazard ratio [HR]; 2.72; 95% confidence interval [CI], 1.50 to 4.92; P =0.001) and prior syncope (recent syncope [<2 years]: HR, 6.16; 95% CI 3.41 to 11.15; P <0.001; remote syncope [≥2 years]: HR, 2.67; 95% CI, 1.22 to 5.85; P =0.01) in boys, whereas prior syncope was the only significant risk factor among girls (recent syncope: HR, 27.82; 95% CI, 9.72 to 79.60; P <0.001; remote syncope: HR, 12.04; 95% CI, 3.79 to 38.26; P <0.001). β-Blocker therapy was associated with a significant 53% reduction in the risk of cardiac arrest or sudden cardiac death ( P =0.01). Conclusions— LQTS boys experience a significantly higher rate of fatal or near-fatal cardiac events than girls during childhood. A QTc duration >500 ms and a history of prior syncope identify risk in boys, whereas prior syncope is the only significant risk factor among girls. β-Blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.

Abstract Background: Guidelines for treatment of acute coronary syndrome (ACS) recommend observing a rise or fall in cardiac troponin (cTn) concentrations for assessing acute injury. It is unknown whether a rising pattern presages a more adverse long-term prognosis than elevations that do not change. The present study assessed whether a rising pattern of cardiac biomarkers was more prognostic than simple elevations. Methods: We measured N-terminal pro-brain natriuretic peptide (NT-proBNP) (Roche), cTnT (Roche) and cTnI (Beckman Coulter) in 212 ACS patients. These biomarkers were measured in coincident EDTA and heparin plasma samples available from at least 2 different time points, an early first specimen obtained a median of 2 hours after onset of symptoms, interquartile range (IQR) 2–4 hours, and a later second specimen obtained at 9 hours, IQR 9–9 hours. The cTn concentration in the second specimen was used to classify myocardial necrosis (cTnI &gt;0.04 ug/L; cTnT &gt;0.01 ug/L). Outcomes [death, myocardial infarction (MI), heart failure (HF)] were obtained &gt;8 years after the initial presentation. For patients with myocardial necrosis and a cTn concentration ratio (second/first measured concentrations) ≥1.00, the concentration ratios and the absolute concentrations in the second specimen were used to assess prognosis after 4 years. Results: In myocardial necrosis, the relative change (cTn2/cTn1) was greater for cTnI than for cTnT (P &lt;0.01), whereas the relative change in NT-proBNP was the same regardless of which troponin was used to classify necrosis (P = 0.71). The concentration ratio for cTnI, cTnT, and NT-proBNP was not useful for risk stratification (i.e., death/MI/HF; P ≥0.15). Conclusions: A rise in cardiac troponin or NT-proBNP concentration in ACS patients presenting early after onset of pain is not helpful for long-term prognosis.

AbstractWe examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.

Object The authors reviewed the long-term outcome of focal resection in a large group of patients who had intractable partial nonlesional epilepsy, including mesial temporal lobe sclerosis (MTS), and who were treated consecutively at a single institution. The goal of this study was to evaluate the long-term efficacy of epilepsy surgery and the preoperative factors associated with seizure outcome. Methods This retrospective analysis included 399 consecutive patients who underwent epilepsy surgery at Mayo Clinic in Rochester, Minnesota, between 1988 and 1996. The mean age of the patients at surgery was 32 ± 12 years (range 3–69 years), and the mean age at seizure onset was 12 ± 11 years (range 0–55 years). There were 214 female (54%) and 185 male (46%) patients. The mean duration of epilepsy was 20 ±12 years (range 1–56 years). The preceding values are given as the mean ± standard deviation. Of the 399 patients, 237 (59%) had a history of complex partial seizures, 119 (30%) had generalized seizures, 26 (6%) had simple partial seizures, and 17 (4%) had experienced a combination of these. Preoperative evaluation included a routine and video-electroencephalography recordings, magnetic resonance imaging of the head according to the seizure protocol, neuropsychological testing, and a sodium amobarbital study. Patients with an undefined epileptogenic focus and discordant preoperative studies underwent an intracranial study. The mean duration of follow up was 6.2 ± 4.5 years (range 0.6–15.7 years). Seizure outcome was categorized based on the modified Engel classification. Time-to-event analysis was performed using Kaplan–Meier curves and Cox regression models to evaluate the risk factors associated with outcomes. Among these patients, 372 (93%) underwent temporal and 27 (7%) had extratemporal resection of their epileptogenic focus. Histopathological examination of the resected specimens revealed MTS in 113 patients (28%), gliosis in 237 (59%), and normal findings in 49 (12%). Based on the Kaplan–Meier analysis, the probability of an Engel Class I outcome (seizure free, auras, or seizures related only to medication withdrawal) for the overall patient group was 81% (95% confidence interval [CI] 77–85%) at 6 months, 78% (CI 74–82%) at 1 year, 76% (CI 72–80%) at 2 years, 74% (CI 69–78%) at 5 years, and 72% (CI 67–77%) at 10 years postoperatively. The rate of Class I outcomes remained 72% for 73 patients with more than 10 years of follow up. If a patient was in Class I at 1 year postoperatively, the probability of seizure remission at 10 years postoperatively was 92% (95% CI 89–96%); almost all seizures occurred during the 1st year after surgery. Factors predictive of poor outcome from surgery were normal pathological findings in resected tissue (p = 0.038), male sex (p = 0.035), previous surgery (p < 0.001), and an extratemporal origin of seizures (p < 0.001). Conclusions The response to epilepsy surgery during the 1st follow-up year is a reliable indicator of the long-term Engel Class I postoperative outcome. This finding may have important implications for patient counseling and postoperative discontinuation of anticonvulsant medications.