Biomedical subjects
Publications and source records attributed to C Napolitano.
In five children from the same family who died after unexplained cardiac arrest, Brugada syndrome syndrome was suspected based on the transient manifestation of the typical electrocardiogram pattern in one of them. A mutation in the cardiac sodium-channel confirmed the diagnosis of Brugada syndrome, which suggests that this disease may cause sudden death in children.
In patients with the long QT syndrome (LQTS), the occurrence of cardiac events (syncope or cardiac arrest) is frequently associated with acute arousal caused by exercise, swimming, emotion, or noise. However, cardiac events may also occur during sleep or with ordinary daily activities. The purpose of this study was to determine whether there are differential clinical, electrocardiographic, and genetic features among LQTS patients who experienced cardiac events with and without acute arousal. We identified 1,325 patients with cardiac events from the International LQTS Registry. Based on the precipitating conditions of the first event, 427 patients were classified as arousal, 345 as nonarousal, and the remaining 553 were unknown (not classifiable). Gene linkage was known in 78 of the 772 patients with classifiable first events. The age at first cardiac event was significantly younger in the arousal than the nonarousal group (11.7 vs. 15.5 years, respectively; p<0.001). The arousal-type patients had a higher rate of subsequent cardiac events during follow-up after the index event than the nonarousal-type patients (p = 0.02). Arousal-related cardiac events occurred in 85% of LQT1, 67% of LQT2, and 33% of LQT3 patients (p = 0.008). This study provides evidence that the genotype is an important determinant of the LQTS phenotype in terms of arousal and nonarousal-related cardiac events.
BACKGROUND: beta-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of beta-blockers in this disorder have not been evaluated. METHODS AND RESULTS: The study population comprised 869 LQTS patients treated with beta-blockers. Effectiveness of beta-blockers was analyzed during matched periods before and after starting beta-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed beta-blockers. After initiation of beta-blockers, there was a significant (P<0.001) reduction in the rate of cardiac events in probands (0.97+/-1.42 to 0.31+/-0.86 events per year) and in affected family members (0. 26+/-0.84 to 0.15+/-0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before beta-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during beta-blocker therapy compared with asymptomatic patients; 32% of these symptomatic patients will have another cardiac event within 5 years while on prescribed beta-blockers. Patients with a history of aborted cardiac arrest before starting beta-blockers (n=113) had a hazard ratio of 12.9 (95% CI, 4.7 to 35.5) for aborted cardiac arrest or death while on prescribed beta-blockers compared with asymptomatic patients; 14% of these patients will have another arrest (aborted or fatal) within 5 years on beta-blockers. CONCLUSIONS: beta-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed beta-blockers, particularly in those who were symptomatic before starting this therapy.
Acute auditory stimuli and swimming activities are frequently associated with syncope, aborted cardiac arrest, and death in the long QT syndrome (LQTS). We investigated the clinical and genetic findings associated with cardiac events precipitated by these arousal factors. The study population involved 195 patients with an index cardiac event associated with a loud noise (n = 77) or swimming activity (n = 118). Patients with events associated with loud auditory stimuli were older at their index event and were more likely to be women than patients who experienced events during swimming-related activities. Patients with an index event associated with loud noise were likely to have subsequent events related to auditory stimuli; patients with an index event associated with swimming were likely to have recurrent events related to swimming or physical activities. Family patterning of auditory and swimming and/or physical activity-related events was evident. Genotype analyses in 25 patients revealed a significant difference in the distribution of index cardiac events by genotype (p <0.001), with all 19 patients with swimming-related episodes associated with LQT1 genotype and 5 of 6 patients with auditory-related events associated with LQT2 genotype. The clinical profile and genotype findings of patients with LQTS who experience cardiac events related to acute auditory stimuli are quite different from those who experience events accompanying swimming activities.
BACKGROUND: Long-QT (LQT) syndrome is a cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. Both autosomal dominant LQT (Romano-Ward syndrome) and autosomal recessive LQT (Jervell and Lange-Nielsen syndrome, JLNS) have been reported. Heterozygous mutations in 3 potassium channel genes, KVLQT1, KCNE1 (minK), and HERG, and the cardiac sodium channel gene SCN5A cause autosomal dominant LQT. Autosomal recessive LQT, which is associated with deafness, has been found to occur with homozygous mutations in KVLQT1 and KCNE1 in JLNS families in which QTc prolongation was inherited as a dominant trait. METHODS AND RESULTS: An Amish family with clinical evidence of JLNS was analyzed for mutations by use of single-strand conformation polymorphism and DNA sequencing analyses for mutations in all known LQT genes. A novel homozygous 2-bp deletion in the S2 transmembrane segment of KVLQT1 was identified in affected members of this Amish family in which both QTc prolongation and deafness were inherited as recessive traits. This deletion represents a new JLNS-associated mutation in KVLQT1 and has deleterious effects on the KVLQT1 potassium channel, causing a frameshift and the truncation of the KVLQT1 protein. In contrast to previous reports in which LQT was inherited as a clear dominant trait, 2 parents in the JLNS family described here have normal QTc intervals (0.43 and 0.44 seconds, respectively). CONCLUSIONS: A novel homozygous KVLQT1 mutation causes JLNS in an Amish family with deafness that is inherited as an autosomal recessive trait.
BACKGROUND: It is still currently held that most patients affected by the long-QT syndrome (LQTS) show QT interval prolongation or clinical symptoms. This is reflected by the assumption in linkage studies of a penetrance of 90%. We had previously suggested that a larger-than-anticipated number of LQTS patients might be affected without showing clinical signs. We have now exploited the availability of molecular diagnosis to test this hypothesis. METHODS AND RESULTS: We identified 9 families with "sporadic" cases of LQTS, ie, families in which, besides the proband, none of the family members had clinical signs of the disease. Mutation screening by conventional single-strand conformational polymorphism and sequencing was performed on DNA of probands and family members to identify mutation carriers. Of 46 family members considered on clinical grounds to be nonaffected, 15 (33%) were found instead to be gene carriers. Penetrance was found to be 25%. In these families, conventional clinical diagnostic criteria had a sensitivity of only 38% in correctly identifying carriers of the genetic defect. CONCLUSIONS: This study demonstrates that in some families, LQTS may appear with a very low penetrance, a finding with multiple clinical implications. The family members considered to be normal and found to be silent gene carriers are unexpectedly at risk of generating affected offspring and also of developing torsade de pointes if exposed to either cardiac or noncardiac drugs that block potassium channels. It is no longer acceptable to exclude LQTS among family members of definitely affected patients on purely clinical grounds. Conversely, it now appears appropriate to perform molecular screening in all family members of genotyped patients.
The beta2 integrin CD11b plays a central role in inflammation and the systemic inflammatory response syndrome (SIRS). The CD11b molecule activates in two ways: the density of membrane-bound CD11b up-regulates and the molecule undergoes a conformational change that confers adhesiveness to counter-receptors. We studied the kinetics of CD11b activation in patients with SIRS. We found a significantly diminished CD11b activation in response to tumor necrosis factor alpha (TNF-alpha). This affected all circulating polymorphonuclear neutrophils (PMN) and was an intrinsic property of the cells and not due to antagonism by soluble TNF-alpha receptors or loss of cellular receptors for TNF-alpha. Diminished responsiveness correlated with the severity of organ failure and lasted for months in some patients but had no impact on mortality. We speculate that reduced CD11b responsiveness in SIRS contributes to the high risk of recurrent infection, but that it may also be protective against excessive PMN activation within the vascular space.
Mutations in the minK gene KCNE1 have been linked to the LQT5 variant of human long QT syndrome. MinK assembles with KvLQT1 to produce the slow delayed rectifier K+ current IKs and may assemble with HERG to modulate the rapid delayed rectifier IKr. We used electrophysiological and immunocytochemical methods to compare the cellular phenotypes of wild-type minK and four LQT5 mutants co-expressed with KvLQT1 in Xenopus oocytes and HERG in HEK293 cells. We found that three mutants, V47F, W87R and D76N, were expressed at the cell surface, while one mutant, L51H, was not. Co-expression of V47F and W87R with KvLQT1 produced IKs currents having altered gating and reduced amplitudes compared with WT-minK, co-expression with L51H produced KvLQT1 current rather than IKs and co-expression with D76N suppressed KvLQT1 current. V47F increased HERG current but to a lesser extent than WT-minK, while L51H and W87R had no effect and D76N suppressed HERG current markedly. Thus, V47F interacts with both KvLQT1 and HERG, W87R interacts functionally with KvLQT1 but not with HERG, D76N suppresses both KvLQT1 and HERG, and L51H is processed improperly and interacts with neither channel. We conclude that minK is a co-factor in the expression of both IKs and IKr and propose that clinical manifestations of LQT5 may be complicated by differing effects of minK mutations on KvLQT1 and HERG.
BACKGROUND: The congenital long-QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged ventricular repolarization and life-threatening arrhythmias. Mutations of the KVLQT1 gene, a cardiac potassium channel, generate two allelic diseases: the Romano-Ward syndrome, inherited as a dominant trait, and the Jervell and Lange-Nielsen syndrome, inherited as an autosomal recessive trait. METHODS AND RESULTS: A consanguineous family with the clinical phenotype of LQTS was screened for mutations in the KVLQT1 gene. Complementary RNAs for injection into Xenopus oocytes were prepared, and currents were recorded with the double microelectrode technique. A homozygous missense mutation, leading to an alanine-to-threonine substitution at the beginning of the pore domain of the KVLQT1 channel, was found in the proband, a 9-year-old boy with normal hearing, a prolonged QT interval, and syncopal episodes during physical exercise. The parents of the proband were heterozygous for the mutation and had a normal QT interval. The functional evaluation of the mutant channel activity showed reduction in total current, a hyperpolarizing shift in activation, and a faster activation rate consistent with a mild mutation likely to require homozygosity to manifest the phenotype. CONCLUSIONS: These findings provide the first evidence for a recessive form of the Romano-Ward long-QT syndrome and indicate that homozygous mutations on KVLQT1 do not invariably produce the Jervell and Lange-Nielsen syndrome. The implications of this observation prompt a reconsideration of the penetrance of different mutations responsible for LQTS and suggest that mild mutations in LQTS genes may be present among the general population and may predispose to drug-induced ventricular arrhythmias.
BACKGROUND: Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry. METHODS AND RESULTS: Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QTc >440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers (KVLQT1 on 11p15.5), 62 LQT2 carriers (HERG on 7q35-36), and 31 LQT3 carriers (SCN5A on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8+/-7 versus 14+/-10 years, P<0.0001) and had higher event rates by age 15 years than females (74% versus 51%, P<0.0001). Affected family members had similar findings. By Cox analysis adjusting for QTc duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 (P<0.001), and it was 1.87 (P=0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 (P<0.001) by age 15 years, and it was 3.25 (P<0.001) by age 15 to 40 years. The event rate was higher in male than female LQT1 carriers (69% versus 32%, P=0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers. CONCLUSIONS: Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation.
BACKGROUND: The emergence of psychogenic seizures after surgery for epilepsy is not well recognized. OBJECTIVES: To identify the frequency of psychogenic seizures in an 11-year surgical experience and to characterize the patients with this complication. METHODS: Ninety-six patients underwent surgery for epilepsy between 1985 and 1996. The surgical database was reviewed and all patients who experienced postoperative psychogenic seizures were identified. Patients were characterized by sex, age, psychopathologic conditions, full-scale IQ, duration of epilepsy, surgical procedure, and operative complications. Patients were compared with the surgical group as a whole for these variables. SETTING: A comprehensive epilepsy center. RESULTS: Five patients were identified: 3 men and 2 women. Mean full-scale IQ was 73 (range, 66-82). Mean age was 29.8 years (range, 22-36 years). Three patients were diagnosed as having psychosis, 1 with borderline personality disorder and 1 with generalized anxiety. Operations included 4 anterior temporal lobectomies and 1 occipital lobectomy. Two patients experienced operative complications. Compared with the surgical cohort, patients had a higher frequency of preoperative psychopathologic conditions, lower mean full-scale IQ, and a greater occurrence of operative complications. CONCLUSIONS: (1) Patients can develop new-onset psychogenic seizures after surgery for epilepsy. (2) Low full-scale IQ, serious preoperative psychopathologic conditions, and major surgical complications may be risk factors. (3) Atypical postoperative seizures should be evaluated with video electroencephalographic monitoring before concluding that they are epileptic.
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BACKGROUND: Primary operations for hyperparathyroidism performed by experienced surgeons has a success rate of about 95% without any preoperative localization. After unsuccessful cervicotomy, localization studies must be performed in order to define the surgical approach. The objective of our retrospective studies was to determine the accuracy of non invasive and invasive localization studies in patients with persistent hyperparathyroidism. METHODS: The present reoperative series involved 7 patients with persistent hyperparathyroidism. Six patients came from a series of 140 operated on at the department of Prof. J. Marescaux from 1991 to 1993 (success rate of 95.7% in cervical exploration). Patient n. 7 came from another department. RESULTS: After negative initial cervicotomy, non invasive localization procedure are undertaken, but with a high incidence of false-positive results (9% to 75%). Among available invasive techniques, it has been chosen to sample blood from large veins in the neck and mediastinum for Parathyroid Hormone (1-84 PTH) determination and to realise angiography for locating parathyroid adenomas as well as for vein mapping. Their combination permitted to localize all lesions. CONCLUSIONS: The specificity of serum concentration of 1-84 PTH determination by catheterization of cervical and mediastinal veins (100%) combined to the sensitivity of angiography (82%) allowed to obtain good result in parathyroid localization in persistent hyperparathyroidism.
BACKGROUND: The authors describe the surgical technique for right and left adrenalectomy and the per- and postoperative course of the patients. METHODS: Twenty-seven laparoscopic adrenalectomies were performed between November 1992 and February 1996: there were 18 women and 9 men ranging in age from 31 to 70 years (mean 50.8 years); the surgical procedure was a lateral decubitus transperitoneal flank approach in 26 patients, and a retroperitoneal approach in one. RESULTS: Twelve right and 15 left glands were removed. Adrenal diseases were primary aldosteronism in 20 patients, non-functional adenoma in 3 patients, 2 Cushing's syndrome, adrenal cyst in one and incidentaloma in one. Mean adrenal gland size was 2.6 cm (range 0.5 to 8 cm). Five patients (18.5%), were converted to laparotomy, for dissection problems in 4 and failure to locate the left adrenal gland in one. The mean anesthesia time was 205.7 min and the mean surgical time 141.2 min. Surgical morbidity was one adrenal vein injury sectioned close to the vena cava: the hemorrhage was controlled by laparoscopic suturing without conversion. No mortality occurred and postoperative morbidity was one minor chest infection. The mean postoperative stay in hospital was 3.7 days (range 2.8) for the non converted patients. Laparoscopic adrenal gland removal is safe and offers fast recovery and short hospital stay. Laparoscopic adrenalectomy combines the advantages of both the conventional anterior and posterior approach. CONCLUSIONS: Personal experience of laparoscopic adrenal gland removal is described: a safe adrenal vascular control and gland dissection were performed and the length of operation and postoperative course carefully presented.
BACKGROUND: The duration of the QT interval is only a gross estimate of repolarization. Besides its limited accuracy and reproducibility, it does not provide information on the morphology of the T wave; thus, morphologic alterations such as notches can be only qualitatively described but not objectively quantified. METHODS AND RESULTS: To measure the complexity of repolarization in the long-QT syndrome (LQTS) patients, we previously applied principal component analysis to body surface mapping and found it useful in distinguishing normal from abnormal repolarization patterns (sensitivity, 87%). In the present study, we applied principal component analysis to 12-lead Holter recordings. The index of complexity of repolarization that we have developed (CR24h) reflects the average 24-hour complexity of repolarization and is mathematically defined as the average ratio between the second and the first eigenvalue. We studied 36 LQTS patients and 40 control subjects. A mean of 22+/-1.3 ECG recordings at 1-hour intervals was used in each patient, and a total of 1655 recordings were analyzed. CR24h was significantly higher in LQTS than in control subjects (34+/-12% versus 13+/-3%; P<.0001). A CR24h exceeding 2 SD above the mean of the control group (>20%) was present in 32 of 36 patients (88%). The negative predictive value of CR24h in LQTS was 88%, and the combination of prolonged QT and abnormal CR24h identified all LQTS patients from normal subjects, including 4 affected symptomatic individuals with a normal QT interval duration, suggesting that CR24h provides information independent of QT duration. CONCLUSIONS: Our data suggest that principal component analysis applied to 24-hour, 12-lead Holter recording adequately quantifies the complexity of ventricular repolarization and may become a useful noninvasive diagnostic tool in LQTS.
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The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions of adrenergic activation. Recently, the genes for the LQTS inked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQT1) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQT1 potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na+ channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest that LQT3 patients are more likely to benefit from Na+ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na+ channel blocker such as mexiletine for LQT3 patients and of interventions such as K+ channel openers or increases in the extracellular concentration of potassium for LQT1 and LQT2 patients.
Main difficulties in thyroid surgery are represented by recurrent nerve anatomy and parathyroid glands. Nerve injury or accidental truncation cause definitive impairment. Risk of recurrent paralysis is 0.5 to 3% for advanced teams. Early investigation and dissection of this nerve are considered mandatory for preservation. This practice is also highly indicated due to anatomical variations, cause for accidental truncation. The most difficult case is encountered when there is nerve non recurrence, due to variations in origin and path of the nerve. Inferior laryngeal nerve non recurrence can be present on the right side, it is uncommon but possible on the left side. We have evaluated a series of 1165 cervicotomies undertaken for thyroidectomy or parathyroid gland approach. There were 9 cases of non recurrence. Literature review allowed us to study anatomical variations and nerve relationships.