Fondazione Salvatore Maugeri

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

BACKGROUND: Experimental evidence suggests that autonomic markers such as heart-rate variability and baroreflex sensitivity (BRS) may contribute to postinfarction risk stratification. There are clinical data to support this concept for heart-rate variability. The main objective of the ATRAMI study was to provide prospective data on the additional and independent prognostic value for cardiac mortality of heart-rate variability and BRS in patients after myocardial infarction in whom left-ventricular ejection fraction (LVEF) and ventricular arrhythmias were known. METHODS: This multicentre international prospective study enrolled 1284 patients with a recent (<28 days) myocardial infarction. 24 h Holter recording was done to quantify heart-rate variability (measured as standard deviation of normal to normal RR intervals [SDNN]) and ventricular arrhythmias. BRS was calculated from measurement of the rate-pressure response to intravenous phenylephrine. FINDINGS: During 21 (SD 8) months of follow-up, the primary endpoint, cardiac mortality, included 44 cardiac deaths and five non-fatal cardiac arrests. Low values of either heart-rate variability (SDNN <70 ms) or BRS (<3.0 ms per mm Hg) carried a significant multivariate risk of cardiac mortality (3.2 [95% CI 1.42-7.36] and 2.8 [1.24-6.16], respectively). The association of low SDNN and BRS further increased risk; the 2-year mortality was 17% when both were below the cut-offs and 2% (p<0.0001) when both were well preserved (SDNN >105 ms, BRS >6.1 ms per mm Hg). The association of low SDNN or BRS with LVEF below 35% carried a relative risk of 6.7 (3.1-14.6) or 8.7 (4.3-17.6), respectively, compared with patients with LVEF above 35% and less compromised SDNN (> or = 70 ms) and BRS (> or = 3 ms per mm Hg). INTERPRETATION: ATRAMI provides clinical evidence that after myocardial infarction the analysis of vagal reflexes has significant prognostic value independently of LVEF and of ventricular arrhythmias and that it significantly adds to the prognostic value of heart-rate variability.

The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient's guardian or carer. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

AIMS: Large randomized trials have shown that beta-blockers reduce mortality and hospital admissions in patients with heart failure. The effects of beta-blockers in elderly patients with a broad range of left ventricular ejection fraction are uncertain. The SENIORS study was performed to assess effects of the beta-blocker, nebivolol, in patients >/=70 years, regardless of ejection fraction. METHODS AND RESULTS: We randomly assigned 2128 patients aged >/=70 years with a history of heart failure (hospital admission for heart failure within the previous year or known ejection fraction </=35%), 1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg once daily), and 1061 to placebo. The primary outcome was a composite of all cause mortality or cardiovascular hospital admission (time to first event). Analysis was by intention to treat. Mean duration of follow-up was 21 months. Mean age was 76 years (SD 4.7), 37% were female, mean ejection fraction was 36% (with 35% having ejection fraction >35%), and 68% had a prior history of coronary heart disease. The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg. The primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo [hazard ratio (HR) 0.86, 95% CI 0.74-0.99; P=0.039]. There was no significant influence of age, gender, or ejection fraction on the effect of nebivolol on the primary outcome. Death (all causes) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on placebo (HR 0.88, 95% CI 0.71-1.08; P=0.21). CONCLUSION: Nebivolol, a beta-blocker with vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

BACKGROUND: Mutations in potassium-channel genes KCNQ1 (LQT1 locus) and KCNH2 (LQT2 locus) and the sodium-channel gene SCN5A (LQT3 locus) are the most common causes of the long-QT syndrome. We stratified risk according to the genotype, in conjunction with other clinical variables such as sex and the length of the QT interval. METHODS: We evaluated 647 patients (386 with a mutation at the LQT1 locus, 206 with a mutation at the LQT2 locus, and 55 with a mutation at the LQT3 locus) from 193 consecutively genotyped families with the long-QT syndrome. The cumulative probability of a first cardiac event, defined as the occurrence of syncope, cardiac arrest, or sudden death before the age of 40 years and before the initiation of therapy, was determined according to genotype, sex, and the QT interval corrected for heart rate (QTc). Within each genotype we also assessed risk in the four categories derived from the combination of sex and QTc (<500 msec or > or =500 msec). RESULTS: The incidence of a first cardiac event before the age of 40 years and before the initiation of therapy was lower among patients with a mutation at the LQT1 locus (30 percent) than among those with a mutation at the LQT2 locus (46 percent) or those with a mutation at the LQT3 locus (42 percent) (P<0.001 by Fisher's exact test). Multivariate analysis showed that the genetic locus and the QTc, but not sex, were independent predictors of risk. The QTc was an independent predictor of risk among patients with a mutation at the LQT1 locus and those with a mutation at the LQT2 locus but not among those with a mutation at the LQT3 locus, whereas sex was an independent predictor of events only among those with a mutation at the LQT3 locus. CONCLUSIONS: The locus of the causative mutation affects the clinical course of the long-QT syndrome and modulates the effects of the QTc and sex on clinical manifestations. We propose an approach to risk stratification based on these variables.

We performed a multicenter survey using a semistructured interview in 1,072 consecutive patients with Parkinson's disease (PD) enrolled during 12 months in 55 Italian centers to assess the prevalence of nonmotor symptoms (NMSs), their association with cognitive impairment, and the impact on patients' quality of life (QoL). We found that 98.6% of patients with PD reported the presence of NMSs. The most common were as follows: fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency and nocturia (35%), drooling of saliva and difficulties in maintaining concentration (31%). The mean number of NMS per patient was 7.8 (range, 0-32). NMS in the psychiatric domain were the most frequent (67%). Frequency of NMS increased along with the disease duration and severity. Patients with cognitive impairment reported more frequently apathy, attention/memory deficit, and psychiatric symptoms. Apathy was the symptom associated with worse PDQ-39 score but also presence of fatigue, attention/memory, and psychiatric symptoms had a negative impact on QoL. These findings further support a key role for NMS in the clinical frame of PD and the need to address them specifically in clinical trials using dedicated scales.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia is a genetic arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. The electrocardiographic pattern of this ventricular tachycardia closely resembles the arrhythmias associated with calcium overload and the delayed afterdepolarizations observed during digitalis toxicity. We speculated that a genetically determined abnormality of intracellular calcium handling might be the substrate of the disease; therefore, we considered the human cardiac ryanodine receptor gene (hRyR2) a likely candidate for this genetically transmitted arrhythmic disorder. METHODS AND RESULTS: Twelve patients presenting with typical catecholaminergic polymorphic ventricular tachycardia in the absence of structural heart abnormalities were identified. DNA was extracted from peripheral blood lymphocytes, and single-strand conformation polymorphism analysis was performed on polymerase chain reaction-amplified exons of the hRyR2 gene. Four single nucleotide substitutions leading to missense mutations were identified in 4 probands affected by the disease. Genetic analysis of the asymptomatic parents revealed that 3 probands carried de novo mutations. In 1 case, the identical twin of the proband died suddenly after having suffered syncopal episodes. The fourth mutation was identified in the proband, in 4 clinically affected family members, and in none of 3 nonaffected family members in a kindred with 2 sudden deaths that occurred at 16 and 14 years, respectively, in the sisters of the proband. CONCLUSIONS: We demonstrated that, in agreement with our hypothesis, hRyR2 is a gene responsible for catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

The 1996 American Heart Association consensus panel recommendations stated that pre-participation cardiovascular screening for young competitive athletes is justifiable and compelling on ethical, legal, and medical grounds. The present article represents the consensus statement of the Study Group on Sports Cardiology of the Working Group on Cardiac Rehabilitation and Exercise Physiology and the Working Group on Myocardial and Pericardial diseases of the European Society of Cardiology, which comprises cardiovascular specialists and other physicians from different European countries with extensive clinical experience with young competitive athletes, as well as with pathological substrates of sudden death. The document takes note of the 25-year Italian experience on systematic pre-participation screening of competitive athletes and focuses on relevant issues, mostly regarding the relative risk, causes, and prevalence of sudden death in athletes; the efficacy, feasibility, and cost-effectiveness of population-based pre-participation cardiovascular screening; the key role of 12-lead ECG for identification of cardiovascular diseases such as cardiomyopathies and channelopathies at risk of sudden death during sports; and the potential of preventing fatal events. The main purpose of the consensus document is to reinforce the principle of the need for pre-participation medical clearance of all young athletes involved in organized sports programmes, on the basis of (i) the proven efficacy of systematic screening by 12-lead ECG (in addition to history and physical examination) to identify hypertrophic cardiomyopathy-the leading cause of sports-related sudden death-and to prevent athletic field fatalities; (ii) the potential screening ability in detecting other lethal cardiovascular diseases presenting with ECG abnormalities. The consensus document recommends the implementation of a common European screening protocol essentially based on 12-lead ECG.

OBJECTIVE: To improve, with the aid of psychometric analysis, the Balance Evaluation Systems Test (BESTest), a tool designed to analyse several postural control systems that may contribute to poor functional balance in adults. METHODS: Performance of the BESTest was examined in a convenience sample of 115 consecutive adult patients with diverse neurological diagnoses and disease severity, referred to rehabilitation for balance disorders. Factor (both explorative and confirmatory) and Rasch analysis were used to process the data in order to produce a new, reduced and coherent balance measurement tool. RESULTS: Factor analysis selected 24 out of the 36 original BESTest items likely to represent the unidimensional construct of "dynamic balance". Rasch analysis was then used to: (i) improve the rating categories, and (ii) delete 10 items (misfitting or showing local dependency). The model consisting of the remaining 14 tasks was verified with confirmatory factor analysis to meet the stringent requirements of modern measurement. CONCLUSION: The new 14-item scale (dubbed mini-BESTest) focuses on dynamic balance, can be conducted in 10-15 min, and contains items belonging evenly to 4 of the 6 sections from the original BESTest. Further studies are needed to confirm the usefulness of the mini-BESTest in clinical settings.

BACKGROUND: Treatment of patients with Brugada syndrome is complicated by the incomplete information on the natural history of the disease related to the small number of cases reported. Furthermore, the value of programmed electrical stimulation (PES) for risk stratification is highly debated. The objective of this study was to search for novel parameters to identify patients at risk of sudden death. METHODS AND RESULTS: Clinical data were collected for 200 patients (152 men, 48 women; age, 41+/-18 years) and stored in a dedicated database. Genetic analysis was performed, and mutations on the SCN5A gene were identified in 28 of 130 probands and in 56 of 121 family members. The life-table method of Kaplan-Meier used to define the cardiac arrest-free interval in patients undergoing PES failed to demonstrate an association between PES inducibility and spontaneous occurrence of ventricular fibrillation. Multivariate Cox regression analysis showed that after adjusting for sex, family history of sudden death, and SCN5A mutations, the combined presence of a spontaneous ST-segment elevation in leads V1 through V3 and the history of syncope identifies subjects at risk of cardiac arrest (HR, 6.4; 95% CI, 1.9 to 21; P<0.002). CONCLUSIONS: The information on the natural history of patients obtained in this study allowed elaboration of a risk-stratification scheme to quantify the risk for sudden cardiac death and to target the use of the implantable cardioverter-defibrillator.

BACKGROUND: The predictive value of heart rate variability (HRV) in chronic heart failure (CHF) has never been tested in a comprehensive multivariate model using short-term laboratory recordings designed to avoid the confounding effects of respiration and behavioral factors. METHODS AND RESULTS: A multivariate survival model for the identification of sudden (presumably arrhythmic) death was developed with data from 202 consecutive patients referred between 1991 and 1995 with moderate to severe CHF (age 52+/-9 years, left ventricular ejection fraction 24+/-7%, New York Heart Association class 2.3+/-0.7; the derivation sample). Time- and frequency-domain HRV parameters obtained from an 8' recording of ECG at baseline and during controlled breathing (12 to 15 breaths/min) were challenged against clinical and functional parameters. This model was then validated in 242 consecutive patients referred between 1996 and 2001 (validation sample). In the derivation sample, sudden death was independently predicted by a model that included low-frequency power (LFP) of HRV during controlled breathing < or =13 ms2 and left ventricular end-diastolic diameter > or =77 mm (relative risk [RR] 3.7, 95% CI 1.5 to 9.3, and RR 2.6, 95% CI 1.0 to 6.3, respectively). The derivation model was also a significant predictor in the validation sample (P=0.04). In the validation sample, LFP < or =11 ms2 during controlled breathing and > or =83 ventricular premature contractions per hour on Holter monitoring were both independent predictors of sudden death (RR 3.0, 95% CI 1.2 to 7.6, and RR 3.7, 95% CI 1.5 to 9.0, respectively). CONCLUSIONS: Reduced short-term LFP during controlled breathing is a powerful predictor of sudden death in patients with CHF that is independent of many other variables. These results refine the identification of patients who may benefit from prophylactic implantation of a cardiac defibrillator.

STUDY DESIGN: Prospective, single-group observational design. OBJECTIVES: To determine the minimal clinically important difference (MCID) for the Disabilities of the Arm, Shoulder and Hand (DASH) outcome measure and its shortened version (QuickDASH) in patients with upper-limb musculoskeletal disorders, using a triangulation of distribution- and anchor-based approaches. BACKGROUND: Meaningful threshold change values of outcome tools are crucial for the clinical decision-making process. METHODS: The DASH and QuickDASH were administered to 255 patients (mean ± SD age, 49 ± 15 years; 156 women) before and after a physical therapy program. The external anchor administered after the program was a 7-point global rating of change scale. RESULTS: The test-retest reliability of the DASH and QuickDASH was high (intraclass correlation coefficient model 2,1 = 0.93 and 0.91, respectively; n = 30). The minimum detectable change at the 90% confidence level was 10.81 points for the DASH and 12.85 points for the QuickDASH. After triangulation of these results with those of the mean-change approach and receiver-operating-characteristic-curve analysis, the following MCID values were selected: 10.83 points for the DASH (sensitivity, 82%; specificity, 74%) and 15.91 points for the QuickDASH (sensitivity, 79%; specificity, 75%). After treatment, the MCID threshold was reached/surpassed by 61% of subjects using the DASH and 57% using the QuickDASH. CONCLUSION: The MCID values from this study for the DASH (10.83 points) and the QuickDASH (15.91 points) could represent the lower boundary for a range of MCID values (reasonably useful for different populations and contextual characteristics). The upper boundary may be represented by the 15 points for the DASH and 20 points for the QuickDASH proposed by the DASH website.

This international consensus statement provides the state of genetic testing for the channelopathies and cardiomyopathies. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the use and role of genetic testing for these potentially heritable cardiac conditions. This document focuses primarily on the state of genetic testing for the 13 distinct entities detailed and the relative diagnostic, prognostic, and therapeutic impact of the genetic test result for each entity. It does not focus on the therapeutic management of the various channelopathies and cardiomyopathies. Treatment/ management issues are only discussed for those diseases (i.e., LQTS, HCM, DCM + CCD, RCM) in which the genetic test result could potentially influence treatment considerations.

BACKGROUND: The need for reintubation after extubation and discontinuation of mechanical ventilation is not uncommon and is associated with increased mortality. Noninvasive positive-pressure ventilation has been suggested as a promising therapy for patients with respiratory failure after extubation, but a single-center, randomized trial recently found no benefit. We conducted a multicenter, randomized trial to evaluate the effect of noninvasive positive-pressure ventilation on mortality in this clinical setting. METHODS: Patients in 37 centers in eight countries who were electively extubated after at least 48 hours of mechanical ventilation and who had respiratory failure within the subsequent 48 hours were randomly assigned to either noninvasive positive-pressure ventilation by face mask or standard medical therapy. RESULTS: A total of 221 patients with similar baseline characteristics had been randomly assigned to either noninvasive ventilation (114 patients) or standard medical therapy (107 patients) when the trial was stopped early, after an interim analysis. There was no difference between the noninvasive-ventilation group and the standard-therapy group in the need for reintubation (rate of reintubation, 48 percent in both groups; relative risk in the noninvasive-ventilation group, 0.99; 95 percent confidence interval, 0.76 to 1.30). The rate of death in the intensive care unit was higher in the noninvasive-ventilation group than in the standard-therapy group (25 percent vs. 14 percent; relative risk, 1.78; 95 percent confidence interval, 1.03 to 3.20; P=0.048), and the median time from respiratory failure to reintubation was longer in the noninvasive-ventilation group (12 hours vs. 2 hours 30 minutes, P=0.02). CONCLUSIONS: Noninvasive positive-pressure ventilation does not prevent the need for reintubation or reduce mortality in unselected patients who have respiratory failure after extubation.

BACKGROUND: Revision of the guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy, published in 2005, has become appropriate owing to publication of more relevant articles. Most of the new studies focused on small fiber neuropathy (SFN), a subtype of neuropathy for which the diagnosis was first developed through skin biopsy examination. This revision focuses on the use of this technique to diagnose SFN. METHODS: Task force members searched the Medline database from 2005, the year of the publication of the first EFNS guideline, to June 30th, 2009. All pertinent articles were rated according to the EFNS and PNS guidance. After a consensus meeting, the task force members created a manuscript that was subsequently revised by two experts (JML and JVS) in the field of peripheral neuropathy and clinical neurophysiology, who were not previously involved in the use of skin biopsy. RESULTS AND CONCLUSIONS: Distal leg skin biopsy with quantification of the linear density of intraepidermal nerve fibers (IENF), using generally agreed upon counting rules, is a reliable and efficient technique to assess the diagnosis of SFN (Recommendation Level A). Normative reference values are available for bright-field immunohistochemistry (Recommendation Level A) but not yet for confocal immunofluorescence or the blister technique. The morphometric analysis of IENF density, either performed with bright-field or immunofluorescence microscopy, should always refer to normative values matched for age (Recommendation Level A). Newly established laboratories should undergo adequate training in a well-established skin biopsy laboratory and provide their own stratified for age and gender normative values, intra- and interobserver reliability, and interlaboratory agreement. Quality control of the procedure at all levels is mandatory (Good Practice Point). Procedures to quantify subepidermal nerve fibers and autonomic innervated structures, including erector pili muscles, and skin vessels, are under development but need to be confirmed by further studies. Sweat gland innervation can be examined using an unbiased stereologic technique recently proposed (Recommendation Level B). A reduced IENF density is associated with the risk of developing neuropathic pain (Recommendation Level B), but it does not correlate with its intensity. Serial skin biopsies might be useful for detecting early changes of IENF density, which predict the progression of neuropathy, and to assess degeneration and regeneration of IENF (Recommendation Level C). However, further studies are warranted to confirm its potential usefulness as an outcome measure in clinical practice and research. Skin biopsy has not so far been useful for identifying the etiology of SFN. Finally, we emphasize that 3-mm skin biopsy at the ankle is a safe procedure based on the experience of 10 laboratories reporting absence of serious side effects in approximately 35,000 biopsies and a mere 0.19% incidence of non-serious side effects in about 15 years of practice (Good Practice Point).

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.

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.